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2021-11-26T16:04:19.973Z | 2021-11-05T00:00:00.000Z | 244655631 | s2ag/train | Complete Remission with Devimistat (CPI-613) in Refractory Burkitt Lymphoma
Introduction: Patients (pts) with primary refractory or relapsed high-grade lymphoma (HGL) including Burkitt lymphoma (BL) and high-grade B-cell lymphoma with rearrangements of MYC and BCL2 and/or BCL6 (double-hit lymphoma, DHL) have a dismal prognosis with patients almost never achieving a meaningful remission to second line therapy. No standard second line therapeutic approach exists, particularly for BL. The characteristic hallmark of these diseases is a dysregulated MYC oncogene with both downstream effects on proliferation and a high metabolic fluxes which use tricarboxylic acid (TCA) cycle intermediates as biosynthetic precursors. CPI-613 (devimistat) is a non-redox active analogue of lipoic acid, a required cofactor for two key mitochondrial enzymes of the TCA cycle, pyruvate dehydrogenase and alpha ketoglutarate dehydrogenase. Disruption of mitochondrial function by CPI-613 results in a shutdown of ATP and biosynthetic-intermediate production, leading to cancer cell death by apoptosis or necrosis. In the initial phase I trial (n=26) one patient with multiply refractory BL had a partial remission sustained for over one year and then consolidated by surgical resection. She remains alive 7 years later. As of July 2021, 20 clinical studies for various cancers have been conducted (ongoing/completed) with devimistat with over 700 patients having received study drug. We initiated a phase II trial to further explore efficacy in HGL. Devimistat has FDA orphan status for BL and 4 other cancers.
Methods: NCT03793140 is a multicenter study aiming to enroll 17 patients on each of two cohorts, BL and DHL, with a Simon's 2-stage design for each cohort, requiring one response among the first 9 treated patients to expand to 17. Patients must have had at least one prior line of therapy or are refusing standard of care and must be more than 3 months after a prior stem cell transplant. Active central nervous system (CNS) parenchymal disease is excluded, but prior leptomeningeal disease is allowed if the CSF is negative for more than 4 weeks at enrollment and maintenance intrathecal therapy is ongoing. Devimistat is given by central line over 2 hours daily x 5 days for two 14-day cycles and then as maintenance x5 days every 21 days. Pts were evaluable for response if they received at least 4 infusions over 5 days of the first cycle.
Results: 9 pts were enrolled in the DHL/THL arm. Mediannumber of prior therapies were 3 (range, 1-6). No responses were seen, with only 1 patient achieving stable disease as best response, resulting in cohort closure. Thus far, 8 BL pts were enrolled. Median number of prior therapies was 3 (range, 2-4). Two patients were inevaluable for response. 1/6 patients had stable disease through cycle 7 and one had a complete response (CR). This CR patient (HIV+) with 4 prior therapies entered the study with only a biopsy proven thigh mass. He was not a transplant candidate for social reasons. He had a near complete metabolic remission after 4 cycles of devimistat and a CR after cycle 7. (Table and Figure) As of July 2021, he is in cycle 11, having had a 4-week treatment delay of cycle 5 due to CoVID 19 infection. ECOG improved from 3 to 0. Adverse events (AE): As of July30, 2021, no patient experienced a serious adverse event related to study drug. Four patients had grade 3 events at least possibly related: 2 neutropenia, 1 thrombocytopenia and 1 elevated bilirubin. 1 patient had a dose reduction for grade 2 alanine aminotransferase increase.
Conclusions: Although our results are preliminary, the complete remission in this patient is promising in a disease where no viable treatment options exist in the relapsed, refractory BL. Enrollment to the BL cohort is ongoing.
Figure 1 Figure 1.
Nikolaenko: Pfizer: Research Funding; Rafael Pharmaceuticals: Research Funding. Pardee: Celgene/BMS: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees; CBM Biopharma: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Research Funding; Rafael Pharmaceuticals: Research Funding. Abramson: Genentech: Consultancy; Kymera: Consultancy; Karyopharm: Consultancy; AbbVie: Consultancy; Seagen Inc.: Research Funding; Allogene Therapeutics: Consultancy; Astra-Zeneca: Consultancy; Incyte Corporation: Consultancy; BeiGene: Consultancy; Bluebird Bio: Consultancy; Genmab: Consultancy; EMD Serono: Consultancy; Bristol-Myers Squibb Company: Consultancy, Research Funding; C4 Therapeutics: Consultancy; Morphosys: Consultancy; Kite Pharma: Consultancy; Novartis: Consultancy. Horwitz: Vividion Therapeutics: Consultancy; Shoreline Biosciences, Inc.: Consultancy; Tubulis: Consultancy; Verastem: Research Funding; ONO Pharmaceuticals: Consultancy; Myeloid Therapeutics: Consultancy; SecuraBio: Consultancy, Research Funding; Trillium Therapeutics: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Millennium /Takeda: Consultancy, Research Funding; Kura Oncology: Consultancy; Janssen: Consultancy; Kyowa Hakko Kirin: Consultancy, Research Funding; Forty Seven, Inc.: Research Funding; Daiichi Sankyo: Research Funding; C4 Therapeutics: Consultancy; Celgene: Research Funding; Aileron: Research Funding; Affimed: Research Funding; Acrotech Biopharma: Consultancy; ADC Therapeutics: Consultancy, Research Funding. Matasar: GlaxoSmithKline: Honoraria, Research Funding; Teva: Consultancy; Janssen: Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Genentech, Inc.: Consultancy, Honoraria, Research Funding; Merck Sharp & Dohme: Current holder of individual stocks in a privately-held company; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; IGM Biosciences: Research Funding; Merck: Consultancy; Juno Therapeutics: Consultancy; TG Therapeutics: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria, Research Funding; Memorial Sloan Kettering Cancer Center: Current Employment; Pharmacyclics: Honoraria, Research Funding; Daiichi Sankyo: Consultancy; ImmunoVaccine Technologies: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Rocket Medical: Consultancy, Research Funding. Noy: Rafael Parhma: Research Funding; Morphosys: Consultancy; Targeted Oncology: Consultancy; Medscape: Consultancy; Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy, Honoraria; Epizyme: Consultancy.
CPI-613 (devimistat) is a non-redox active analogue of lipoic acid, a required cofactor for two key mitochondrial enzymes of the TCA cycle, pyruvate dehydrogenase and alpha ketoglutarate dehydrogenase. Disruption of mitochondrial function by CPI-613 results in a shutdown of ATP and biosynthetic-intermediate production, leading to cancer cell death by apoptosis or necrosis
| v2 |
2021-11-25T16:24:48.162Z | 2021-11-05T00:00:00.000Z | 244543411 | s2ag/train | Phase I/II Study of MAK683 in Patients with Advanced Malignancies, Including Diffuse Large B-Cell Lymphoma
Introduction:
Polycomb repressive complex 2 (PRC2) regulates transcription via trimethylation of histone H3 at lysine 27 (H3K27me3). Enhancer of zeste homolog 2 (EZH2) in conjunction with embryonic ectoderm development (EED) is a catalytic subunit of PRC2 and functions as a histone methyltransferase for H3K27. H3K27me3 appears to be a unifying component in many malignancies, inducing transcriptional repression. EED is a core component of PRC2 that modifies the epigenetic status of target genes, including cell cycle control genes. Dysregulation of this pathway leads to tumorigenesis in several diseases. MAK683 is a specific oral inhibitor that impairs EED binding to H3K27me3. This is a Phase I/II study of MAK683 in adult patients with advanced malignancies for whom no effective standard treatment is available. Here, we present data from a subset of patients with diffuse large B-cell lymphoma (DLBCL).
Methods:
Patients with DLBCL received escalating doses of MAK683 in fasted conditions. Patients were administered MAK683 10, 20, 40, 80, 120, 240, 300, 500, and 800 mg once daily (QD) or 60, 80, 120, 150, and 300 mg twice daily (BID) orally in 28-day cycles until unacceptable or dose-limiting toxicities (DLTs) had developed, disease progression, or death. The primary objective was to characterize safety and tolerability and determine the maximum tolerated dose and/or recommended Phase II dose (RP2D).
Results:
As of March 5, 2021, 31 patients with an Eastern Cooperative Oncology Group Performance Status of 0-2 were treated. Median age was 70 years (range: 33-84) and patients were heavily pre-treated, with a median of 4 (range: 1-16) prior lines of therapy. Overall, 30 patients (97%) discontinued treatment due to progressive disease (26 patients, 84%), adverse events (3 patients, 10%), and physician's decision (1 patient, 3%). In total, 21 (68%) patients experienced ≥1 treatment-related adverse event (TRAE) of any grade, and the most common (≥20%) TRAEs were thrombocytopenia (29%) and anemia (23%). Grade 3/4 TRAEs were reported in 14 (45%) patients, with ≥15% of patients reporting thrombocytopenia (19%), neutropenia, and decreased neutrophil count (16% each). DLTs were reported in 7 patients, all of which were hematological and therefore may be related to the underlying disease in this subset of patients. Patients in both the QD dosing group (120 mg, 240 mg, and 800 mg; n=1 each) and BID dosing group (60 mg, n=1; 80 mg, n=2; 150 mg, n=1) reported DLTs. There were no treatment-related deaths in this study. Overall response rate was 16% (95% CI: 5─34) and the disease control rate was 29% (95% CI: 14─48). Two patients (6%) achieved a complete response (CR) and 3 patients (10%) achieved a partial response. Four patients (13%) reported stable disease. Pharmacokinetic data showed rapid absorption of MAK683 across all dosing regimens tested and drug exposure increased with dose.
Conclusions:
MAK683 was generally well tolerated and there were preliminary signs of activity in patients with treatment-resistant DLBCL. The use of MAK683 as a novel strategy for the inhibition of EED may have potential in relapsed/refractory DLBCL.
Ribrag: PharmaMar: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Astex Pharmaceuticals: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees; MSD Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Epizyme: Honoraria, Research Funding; Argen-X: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Nanostring: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Infinity Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; GSK: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees. Michot: GSK: Honoraria; MSD: Consultancy, Honoraria; Celgene: Honoraria; Innate Pharma: Research Funding; Incyte: Research Funding; H3 biomedecine: Research Funding; GSK: Consultancy, Honoraria, Research Funding; Genentech: Research Funding; Gamamabs: Research Funding; Forma: Research Funding; Exelixis: Research Funding; Eos: Research Funding; Eisai: Research Funding; Debiopharm: Research Funding; Daiichi Sankyo,: Research Funding; Clovis: Research Funding; Chugai: Research Funding; Boeringer Ingelheim: Research Funding; Celgene: Research Funding; Blueprint: Research Funding; Beigene: Research Funding; Bayer: Research Funding; Argen-x: Research Funding; Amgen: Research Funding; Agios: Research Funding; Aduro: Research Funding; Abbvie: Research Funding; ASTEX: Research Funding, Speakers Bureau; Astra Zeneca: Honoraria, Research Funding; Roche: Honoraria; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding. Igleias: Merck Serono, MSD, BMS, Lilly, Roche, Bayer, Sanofi: Consultancy. Tan: Novartis, Bayer, Boehringer Ingelheim, MSD, Astra Zeneca, Eli-Lilly, Loxo: Consultancy; Astra Zeneca, Pfizer, Novartis: Research Funding; Merck, Pfizer, Novartis, Takeda, Bayer, Boehringer Ingelheim, Roche: Honoraria. Ma: Novartis, Merck, Y-Biologies, Taiho, Daiichi: Honoraria, Speakers Bureau; Novartis, Inglheim: Research Funding. Wainberg: Plexxikon, BMS, EMD Serono: Research Funding; Roche, Novartis, BMS, Merck, Pfizer, Lilly, Bayer, Astra Zeneca, Daiichi, Astellas, Amgen: Consultancy. Fan: Novartis Institutes for Biomedical Research: Current Employment. Suenaga: Novartis Pharma K.K.: Current Employment. Cheng: Novartis: Current Employment. Lai: Novartis: Current equity holder in publicly-traded company; Novartis Institutes for Biomedical Research: Current Employment. Yokota: AstraZeneca, Chugai Pharma, MSD, Syneos Health, Lilly, Incyte, Novartis, GlaxoSmithKline, Ascent: Research Funding; Abbott Japan, Ono Pharmaceutical, Chugai Pharma, Bristol-Myers Squibb, Merck Biopharma, MSD, Rakuten Medical, Eisai: Honoraria; Merck Biopharma, MSD, Rakuten Medical: Membership on an entity's Board of Directors or advisory committees.
| v2 |
2019-04-03T13:09:21.353Z | 2018-11-21T00:00:00.000Z | 92208951 | s2ag/train | Genomics of Limited-Stage Diffuse Large B-Cell Lymphoma Developing Late Relapse: Analysis of Gene Alterations in Paired Primary and Late Relapsed Tumors By Target Sequencing
Introduction:
In limited-stage diffuse large B-cell lymphoma (DLBCL), a continued risk of relapse has been reported (Stephens et al. J Clin Oncol 2016). Another report highlighted that initial limited-stage DLBCL, a favorable International Prognostic Index and extranodal involvement seemed to be risk factors for late relapse (LR; Larouche et al. J Clin Oncol 2010). However, even if a subgroup of patients (pts) with LR shows distinct clinical characteristics, the underlying biology is largely unknown.
Methods:
Nineteen consecutive pts who developed LR were identified among 337 pts with de novo DLBCL of Ann Arbor stage I/II who were treated with CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone), with/without rituximab, between 1997 and 2012. LR was defined as the first relapse of B-cell lymphoma (BCL; including indolent BCL) occurring more than 5 years after a primary diagnosis. The 19 pts underwent clinical, pathological (cell of origin according to the Hans algorithm) and genetic analyses.
Genomic DNA (gDNA) was extracted from formalin-fixed, paraffin-embedded sections of tumor specimens at primary diagnosis and relapse, and from bone marrow (BM) specimens without tumor invasion as controls. Genomic DNA samples from paired primary and relapsed tumors were analyzed using BIOMED-2 multiplex PCR for immunoglobulin heavy chain (IGH) rearrangements (Invivoscribe Technologies, San Diego, CA, USA) to determine whether the paired tumors shared the same clonal IGH rearrangements.
Target sequencing of 2709 regions across 69 lymphoma-related genes was performed on gDNA samples. Mutational calls were made in comparisons with individual control BM gDNA samples according to the criteria outlined in Table 1. All functional mutations detected in paired tumors per pt were compared, and shared and non-shared mutations were identified.
Results:
Baseline characteristics of the 19 pts were as follows: median age of 60 years (range, 32-77); 13 (68%) had stage I disease, and 11 (58%) had extranodal disease. At primary diagnosis, 14 of 19 pts (74%) had a non-germinal center B-cell-like (non-GCB) type DLBCL. As an initial treatment, CHOP therapy (median 4 cycles; range, 3-8), with (n=17) or without (n=2) radiation therapy, was performed in all 19 pts. Seven pts were treated with CHOP and rituximab.
The median duration from initial diagnosis to LR was 8 years (range, 5-18). At LR, the median age was 71 years (range, 45-84). One pt relapsed as a composite of DLBCL and indolent BCL, and two pts relapsed as indolent BCL.
Seven of the 19 pts were excluded from gene analysis because their paired gDNAs were of poor quality. The results of target sequencing combined with clinicopathological information and the results of IGH-PCR analysis are described in Table 2.
Shared mutations between individual pairs of primary and relapsed tumors were detected in nine of the 12 pts analyzed. The most frequent shared mutation was a CD79B missense mutation of a single base substitution in positions 196 (n=5) or 199 (n=2). The second most frequent mutation was a MYD88 (L265P) missense mutation (n=5). Co-mutation of CD79B and MYD88 was found in four pts, who were considered to have a MCD (MyD88,CD79b) type DLBCL (Schmitz et al. N Engl J Med 2018). All eight pts with a CD79B and/or MYD88 mutation had a non-GCB type DLBCL. The same clonal IGH rearrangements between paired tumors were found in six of the eight pts. Seven of the eight pts presented with primarily extranodal disease originating from the testis (n=3), nasal/paranasal cavity (n=2) or gingiva (n=2).
One pt (#9 in Table 2) with a GCB type DLBCL had shared mutations in MLL2, CREBBP, MEF2B and PIM1. However, different clonal IGH rearrangements were detected between paired tumors, implying these mutations may be the basis for lymphomagenesis; an on-going IGH rearrangement may occur.
In the other three pts (#10-12), shared mutations were not detected. Mutations in TP53 were not detected in any pts. We did not identify any specific mutations considered to be associated with LR.
Conclusions:
Common characteristics shared in a subgroup of pts with limited-stage DLBCL who developed LR were as follows: non-GCB type, CD79B and/or MYD88 mutations, and extranodal disease at primary manifestation. The mechanisms of LR from the viewpoint of gene alterations were considered heterogeneous.
Maruyama: Asahi Kasei Pharma: Honoraria; Takeda: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria; Dai-ichi-Sankyo: Honoraria; Dai-Nippon-Sumitomo: Honoraria; MSD: Honoraria, Research Funding; Chugai Pharma: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Fujifilm: Honoraria, Research Funding; Zenyaku Kogyo: Honoraria, Research Funding; AstraZeneca: Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Kyowa Hakko Kirin: Honoraria, Research Funding; GlaxoSmithKline: Research Funding; Abbvie: Research Funding; Astellas Pharma: Research Funding; Amgen Astellas BioPharma: Research Funding; Otsuka: Research Funding; Novartis: Research Funding; Nippon Boehringer Ingelheim: Research Funding; Pfizer: Research Funding; Solasia Pharma: Research Funding; Celgene: Honoraria, Research Funding; Biomedis International: Honoraria, Research Funding; Mundipharma International: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Izutsu:Amgen: Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Kyowa Hakko Kirin: Honoraria; Bayer: Consultancy, Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; MSD: Honoraria; HUYA Bioscience International: Research Funding; Celgene: Consultancy, Research Funding; Celltrion: Research Funding; Zenyaku: Research Funding; Sanofi: Research Funding; Gilead Sciences: Honoraria; Eisai: Honoraria, Research Funding; Novartis: Honoraria; Ono: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Nihon Medi-Physics: Honoraria; Symbio: Research Funding; Solasia: Research Funding; Mundhi: Honoraria; Otsuka: Honoraria; Bristol- Myers Squibb: Honoraria; Janssen: Honoraria, Research Funding; Astellas: Honoraria, Research Funding; Meiji Seika: Honoraria; Shionogi: Honoraria; Asahi Kasei: Honoraria. Tobinai:Takeda: Honoraria, Research Funding; SERVIER: Research Funding; Abbvie: Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding; HUYA Bioscience International: Consultancy, Honoraria; Zenyaku Kogyo: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Research Funding; Chugai Pharma: Honoraria, Research Funding; Kyowa Hakko Kirin: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Eisai: Honoraria, Research Funding. Kobayashi:Pfizer: Research Funding; Ohtuka: Research Funding; Astellas: Research Funding.
| v2 |
2020-12-14T20:14:16.273Z | 2020-11-05T00:00:00.000Z | 228856241 | s2ag/train | Overcoming NOTCH1-Driven Chemoresistance in T-Cell Acute Lymphoblastic Leukemia Via Metabolic Intervention with Oxphos Inhibitor
The inferior cure rate of T-cell acute lymphoblastic leukemia (T-ALL) is associated with inherent drug resistance. The activating NOTCH1 gene mutations have been reported to cause chemoresistance at the stem cell level1. Direct NOTCH1 inhibition has failed in clinical trials due to a narrow therapeutic window but targeting key oncogenic and metabolic pathways downstream of mutated NOTCH1 may offer novel approaches. We previously reported that rapid transformation of thymocytes at the DN3 differentiation stage into preleukemic stem cells (pre-LSC) requires elevated Notch1 in addition to the presence of Scl/Lmo11. Notably, we showed that cellular metabolism of NOTCH1-mutated T-ALLs depends on Oxidative Phosphorylation (OxPhos) and that OxPhos inhibition using the complex I inhibitor IACS-010759 (OxPhos-i) is efficacious in NOTCH1-mutated T-ALL patient derived xenografts (PDXs)2.
Here, we investigated the link between NOTCH1-mutated chemoresistance and OxPhos in pre-leukemic and leukemic cells, utilizing comprehensive molecular and functional assays.
We hypothesized that chemotherapy aided by OxPhos-i overcomes chemoresistance, depletes LSCs and combats T-ALL.
First, we analyzed the role of OxPhos in downstream Notch1 targets at the pre- and leukemic stage considering four stages of thymocyte differentiation (D1-D4), in a mouse model of human T-ALL1. Gene set enrichment analysis (GSEA) implicated increased expression of Notch1 target genes starting at DN1, and OxPhos target genes were the highest-ranked gene set at DN3.
Next, activation of Notch1 by its ligand DL4 and inhibition of OxPhos reduced viability of pre-LSCs, indicating that ligand-dependent activation of Notch1 signaling upregulates the OxPhos pathway and sensitizes pre-LSCs to OxPhos-i. To clarify the role of Notch1 signaling, we examined the effect of IACS-010759 on pre-leukemic thymocytes harboring LMO1, SCL-LMO1, NOTCH1, LMO1-NOTCH1 and SCL-LMO1-NOTCH1 with and without DL4 stimulation. We found that in the absence of DL4, only thymocytes harboring the Notch1 oncogene responded to OxPhos-i, whereas all DL4-stimulated thymocytes responded regardless of Notch1 status (Fig. 1a). In addition, at the leukemic stage, we found elevation of the OxPhos pathway driven by oncogenic Notch1 when we compared transcriptomes of SCL-LMO1 induced T-ALL in the presence or absence of the NOTCH1 oncogene.
In line with the murine T-ALL NOTCH1 model, we performed transcriptome analysis of two independent T-ALL patient cohorts prior to chemotherapy, COG TARGET ALL (n=263) and AALL1231 (n=75), comparing transcriptomes of NOTCH1-mutated vs NOTCH1-wt T-ALLs. We found co-segregation of NOTCH1 mutations with significant upregulation of OxPhos and TCA cycle genes and downregulation of apoptosis signaling. Aiming to reverse the NOTCH1-controlled anti-apoptotic program and chemoresistance, we next tested the combination of Vincristine, Dexamethasone and L-Asparaginase (VXL) with IACS-010759. When compared to vehicle, OxPhos-i or VXL alone, only the VXL-OxPhos-i treatment caused an energetic crisis indicated by decreased OCR and ECAR (Seahorse), which translated to a profound reduction of viability (CTG, flow cytometry) in T-ALL cell lines (n=9) and primary T-ALL samples (n=5). Additionally, the IACS-VXL combination in vivo resulted in pan-metabolic blockade, which caused metabolic shut-down and triggered early induction of apoptosis in leukemic cells in peripheral blood, spleen and bone marrow (Fig. 1b). Single cell Proteomic analysis (CyTOF) of spleen showed reduced expression of cell proliferation marker -ki67, c-myc, ERK and p38 proteins, and reduction in number of leukemic cells. Finally, this combination therapy resulted in reduced leukemia burden and extension of overall survival across all three aggressive NOTCH1-mutated T-ALL PDX models (p<0.0001) (Fig.1 c, d). In summary, we demonstrated that targeting OxPhos with IACS-010759 in combination with chemotherapy facilitates eradication of chemoresistant NOTCH1-driven T-ALL through direct targeting of the key metabolic regulators of OxPhos conferred by mutant NOTCH1 in T-ALL. Clinical trials rewiring metabolism by incorporation of OxPhos-i to standard-of-care therapy in patients with NOTCH1-mutated T-ALL are warranted to improve patients' outcomes.
Jabbour: Pfizer: Other: Advisory role, Research Funding; Genentech: Other: Advisory role, Research Funding; BMS: Other: Advisory role, Research Funding; Takeda: Other: Advisory role, Research Funding; Amgen: Other: Advisory role, Research Funding; Adaptive Biotechnologies: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding. Teachey:Sobi: Consultancy; Amgen: Consultancy; Janssen: Consultancy; La Roche: Consultancy. Rezvani:Takeda: Other: Licensing agreement; GemoAb: Membership on an entity's Board of Directors or advisory committees; Adicet Bio: Membership on an entity's Board of Directors or advisory committees; Virogen: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Other: Educational grant; Affimed: Other: Educational grant; Formula Pharma: Membership on an entity's Board of Directors or advisory committees. Andreeff:Daiichi-Sankyo; Jazz Pharmaceuticals; Celgene; Amgen; AstraZeneca; 6 Dimensions Capital: Consultancy; Daiichi-Sankyo; Breast Cancer Research Foundation; CPRIT; NIH/NCI; Amgen; AstraZeneca: Research Funding; Centre for Drug Research & Development; Cancer UK; NCI-CTEP; German Research Council; Leukemia Lymphoma Foundation (LLS); NCI-RDCRN (Rare Disease Clin Network); CLL Founcdation; BioLineRx; SentiBio; Aptose Biosciences, Inc: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding. Lorenzi:Precision Pathways: Consultancy. Konopleva:Calithera: Research Funding; Kisoji: Consultancy; AbbVie: Consultancy, Research Funding; Sanofi: Research Funding; Genentech: Consultancy, Research Funding; F. Hoffmann La-Roche: Consultancy, Research Funding; Cellectis: Research Funding; Rafael Pharmaceutical: Research Funding; Eli Lilly: Research Funding; Reata Pharmaceutical Inc.;: Patents & Royalties: patents and royalties with patent US 7,795,305 B2 on CDDO-compounds and combination therapies, licensed to Reata Pharmaceutical; Agios: Research Funding; AstraZeneca: Research Funding; Ablynx: Research Funding; Forty-Seven: Consultancy, Research Funding; Amgen: Consultancy; Stemline Therapeutics: Consultancy, Research Funding; Ascentage: Research Funding.
| v2 |
2016-03-01T03:19:46.873Z | 2010-01-01T00:00:00.000Z | 14951921 | s2ag/train | Next Generation High-Efficiency Low-cost Thin Film Photovoltaics
Our goal is to develop novel growth approaches for producing low cost solar cells that have efficiency comparable to those made from high-cost, single-crystalline materials. Our efforts to date focus on using ion beam assisted deposition (IBAD) to control the grain boundary alignment in polycrystalline silicon thin films. The boundaries between highly aligned grains have smaller defect densities, which lead to higher carrier mobilities and lifetimes. Our approach can be extended to other thin film PV systems. In this initial period, we have produced highly aligned Si films by using a biaxially textured template layer of CaF2. We have chosen CaF2 as a candidate material due to its close lattice match with silicon and its suitability as an ion beam assisted deposition (IBAD) material. We show that the IBAD produces biaxially textured CaF2 at a thickness of ~10 nm and, with the addition of an epitaxial CaF2 layer, has an in-plane texture of ~15°. Deposition of a subsequent layer of Si aligns on the template layer with an in-plane texture of 10.8°. The additional improvement of in-plane texture is similar to the behavior observed in more fully characterized IBAD materials systems. A germanium buffer layer is used to assist in the epitaxial deposition of Si on CaF2 template layers and single crystal substrates. These experiments confirm that an IBAD template can be used to biaxially orient polycrystalline Si. Anticipating improved control of the texture with the IBAD process, we also investigated the ultimate limit of seeded orientation of silicon by growing silicon on CaF2 that is epitaxially grown on single crystal yttria-stabilized zirconia (YSZ) with an extremely high degree of orientation. This approach yielded Si films with in-plane orientation of about 0.7°, showing that the heteroepitaxial growth of Si on highly oriented seeds will produce a very high degree of texture. Introduction The
solar
cell
market
is
currently
dominated
by
crystalline
silicon
modules
due to
their
high
efficiency
and
reliability.
The
cost
of
electricity
produced
by
crystalline silicon
panels
however
is
still
significantly
higher
than
the
cost
of
today’s
grid
power ($0.27/kW.hr
vs.
$0.06/kW.hr).
As
a
result,
in
order
to
increase
the
deployment
of solar
power,
there
is
a
need
for
new
technologies
to
both
decrease
the
cost
and increase
the
efficiency
of
photovoltaics
(PVs).
Thin-‐film
solar
cells
offer
the opportunity
to
dramatically
lower
the
price
of
solar
energy
by
using
small
amounts of
materials
and
low-‐cost
manufacturing
technologies.
Ultimately,
the
efficiency
of inorganic
thin
film
solar
cells
is
fundamentally
limited
by
the
fact
that
the
active layers
are
polycrystalline
and
therefore
by
definition
contain
defects.
In
particular, recombination
of
photogenerated
carriers
at
grain-‐boundaries
is
extremely detrimental
to
the
efficiency
of
thin
film
solar
cells.[1]
Thus,
a
technology
that drastically
reduces
the
density
of
minority
carrier
recombination
sites
at
the
grain-‐ boundaries
of
inorganic
thin
films
would
clearly
be
a
step-‐out
innovation
as
it
would allow
thin
film
PVs
to
approach
the
performance
of
single
crystal
devices
at
a fraction
of
the
cost.
Such
devices
constitute
the
next
generation
thin
film
PVs. Here
we
propose
to
develop
ion-beam
based
processing
strategies
that
reduce grain
boundary
misalignment
in
polycrystalline
inorganic
thin
films.
Reducing
the relative
misalignment
of
neighboring
grains
will
lead
to
lower
recombination
rates
at grain-boundaries.
We
will
thus
create
polycrystalline
solar
cells
with
power
conversion efficiencies
approaching
those
of
their
single
crystal
counterparts.
In
this
exploratory proposal
we
concentrate
on
Si
PVs
because
they
constitute
a
well-known
and controlled
system
and
because
of
their
relevance
in
the
marketplace.
The
process
we will
develop
however
is
quite
general
and
could
be
applied
to
many
other polycrystalline
thin
films
systems,
such
as
CuInGaSe2
(CIGS)
or
Cu2ZnSnS4
(CZTS). Solar cell efficiency is a strong function of minority carrier lifetime, since photogenerated carriers that recombine before reaching the p-n junction do not contribute to photocurrent. Grain boundaries in polycrystalline silicon films provide electron traps that act as recombination centers that reduce minority carrier lifetimes [1]. This recombination is a function of the grain boundary structure. In particular, the high dislocation density of high angle grain boundaries result in higher recombination rate than low angle grain boundaries. Dimitriadis et al. showed that the effective carrier lifetime increases as the dislocation density decreases [2], and in an elegant experiment using electron beam induced current contrast ratios in polycrystalline silicon films, Seifert et al. showed that recombination is a strong function of grain boundary defect density [3]. Grain boundaries can be described as having both out-of-plane and in-plane misorientation known as tilt and twist, respectively. Both types of misorientation result in defect densities that lead to recombination. The degree of tilt and twist in a thin film grain boundary population reflects the crystallographic texture of the film. Biaxial texture, which has a preferred crystallographic direction for both out-of-plane and inplane directions, can decrease both twist and tilt misorientation between grains. One way to develop biaxial texture is application of an ion beam during the initial stages of nucleation of a thin film. This ion beam assisted deposition (IBAD) process uses a low energy (< 1keV), inert (Ar) ion beam to develop in-plane texture in a growing thin film during concurrent physical vapor deposition of the desired source material. The ion beam is aligned along a particular crystallographic direction at an oblique angle relative to the desired out-of-plane growth direction. The ion beam sputters away unfavorably oriented crystallites and allows favorably oriented crystallites to survive and grow. If the correct channeling angle is selected then bi-axial texture can be developed. | v2 |
2018-12-12T04:08:12.803Z | 1983-07-01T00:00:00.000Z | 55269351 | s2ag/train | Habitat Differences Between Basin and Wyoming Big Sagebrush in Contiguous Populations
Basin and Wyoming big sagebrush plants growing in contiguous populations were studied to identify potential habitat differences in plant water and soil relationships. At 3 study sites, basin big sagebrush plants were growing in and adjacent to a drainage, while Wyoming big sagebrush plants occupied areas adjacent to the basin big sagebrush populations. Soiland leaf-water potentials and leaf-transpiration resistances were measured from May to October 1980 to identify differences between basin and Wyoming big sagebrush plant-water relationships. Soil identification and plant tissue analyses were conducted to help characterize edaphic differences between the subspecies. The results of these studies showed that basin big sagebrush plants grew in a more mesic and fertile habitat than did Wyoming big sagebrush plants. Understanding the environmental differences of these two big sagebrush subspecies is important in effectively managing basin and Wyoming big sagebrush ranges. The woody sagebrushes (subgenus tridentatae (Rhdb.) E.D. McArthur of Artemisia L.) occur naturally only in western North America, ranging from southern Canada to northern Mexico (Beetle 1960, McArthur et al. I98 I). The most common, important, and widely distributed species is big sagebrush (Artemisia tridentata Nutt.). Big sagebrush plants are common on about 58,655,OOO hectares from the arid lands of the Great Basin to the moist, cool areas of mountain ranges (Beetle 1960, Hall and Clements 1923, McArthur 1979, Winward 1970). Considering the wide distribution of big sagebrush, it is not surprising to find genotypic variation among A. tridentata populations (Caldwell 1979). Presently, the big sagebrush complex consists of 3 subspecies with 2 forms (Beetle 1960, Beetle and Young Authors are range ecologist, Bio-Resources, Inc., P.O. Box 3447, Logan, Utah 8432 1 and vice-president for research, Native Plants, Inc. 360 Wakara Way, Salt Lake City, Utah 84101. Authors acknowledge the assistance of Chris Call and Marianne Barker in collecting field data. The work was supported by the Department of Energy, Utah Agricultural Experiment Station, and Ecology Center, Utah State University, Logan, 84322. Manuscript received November IO. 198 I. 1965, McArthur 1979, Winward 1980). According to range scientists the big sagebrush subspecies and forms are habitat specific (McArthur and Plummer 1978, McArthur et al. 1979, Morris et al. 1976, West et al. 1978, Winward 1980, Winward and Tisdale 1977). General habitat differences between basin (A, tridentata ssp. tridentata) and Wyoming big sagebrush (A. tridentata spp. wyomingensis) have been reported in the literature. Basin big sagebrush usually grows in deep, seasonally dry, well-drained, fertile soils on plains, valleys, and foothills between elevations 610-2,140m (McArthur and Plummer 1978, McArthur et al. 1979, Morris et al. 1976, Winward 1980, Winward and Tisdale 1977). In contrast, Wyoming big sagebrush grows in dry, shallow, rocky soils on foothills and valleys between elevations of 1,520-2,150 m (McArthur and Plummber 1978, McArthur et al. 1979, Morris et al. 1976, Winward and Tisdale 1977). Furthermore, Beetle and Young (1965) reported that whenever basin and Wyoming big sagebrush are found close together, the latter subspecies always occupies the drier, poorer, more shallow soils. West et al. (1978), in a biogeographical sagebrush study in Nevada, found that Wyoming big sagebrush occupied soils warmer and drier than did basin big sagebrush. For the present study, 3 sites were selected where basin and Wyoming big sagebrush grew in contiguous populations. At each site, basin big sagebrush plants grew within and next to a drainage while Wyoming big sagebrush plants occupied adjacent sites. Big sagebrush plant height decreased with distance from the drainages (Barker 1981). Plant height near the drainages averaged about 2.5 m and decreased with distances along an apparent moisture gradient to less than 1.0 m (Fig. 1). In considering the difference in plant stature, a logical question arises. Is basin big sagebrush larger than Wyoming big sagebrush in these contiguous populations because of habitat or genetic differences? The research reported herein discusses habitat variation in water and soil relationships between the two subspecies that would partially account for the differences in plant stature. The genetic influence on plant stature is reported in Barker (1981) and JOURNAL OF RANGE MANAGEMENT 36(4). July 1963 Barker et al. (1983). Description of Study Sites The Sage Creek study site (N 41° 46’ 36” W I I lo IO’ I I”) is located about 4.8 km west of Sage Creek Junction on Highway 30 in Rich County in northeastern Utah. Average annual precipitation varies from 25 to 30 cm. The frost-free period ranges between 55 to 65 days(Personalcommunication, Soil Conservation Service Personnel, Logan, Utah). Elevation is 1,950 m. Slope associated with both the small and the large plants varies from 3 to 4%. The exposure is northerly. Other important plants in the area include low rabbitbrush (Chrysorhamnus viscidiflorus), western yarrow (Achika milkfolium), gray horsebrush (Tetradymio canescens), canby bluegrass (Po~oa cnnbyi), letterman needle grass (Stipa lettermonii), and slender wheatgrass (Agropvron tmchvcaulum~. The Greasewood Wash studysite(N4lO 55’64”W 108’ 52’30”) is located about 10.2 km north of the Jim Bridge1 Coal Minealong Sweetwater County Road 4-17 in southwestern Wyoming. Average annual precipitation varies from I2 to 22 cm. The frost-free period ranges from 80 to 1 IO days (Personal communication, Soil Conservation Service Personnel, Rock Springs, Wyo.). The elevation is 2,063 m. The slope of the site varies from 2 to 5% with a western exposure. Other important plants in the area include bud sage (Artemisia spinescens), gardner saltbush (Atriplexgardneri). low rabbithrush (Chrysothamnus visiciflorus), thickspike wheatgrass (Agropyron dasystachyum), pacific aster (Aster chilensis), and Great Basin wildrye (Elymus cinereus). The Maeserstudy site (N 400 34’ I I”W400 35’)islocated inthe Uinta Basin, Il.2 km north of Maeser, Utah along Taylor Mountain Road. Average annual precipitation is 25 to 30 cm. The frost-free period ranges between I10 to I40 days (Personal communication, Soil Conservation Service Personnel, Vernal, Utah). Slope of the area is 3 to 4% with a southern exposure. Elevation is 2,296 m. Other important plants at the study site include shadscale (Atriplex confertifolia), greasewood (Sarcobatus vermiculatus), and rubber rabbithrush (Chrysorhomnus nauseosus). | v2 |
2018-01-06T20:04:45.274Z | 2006-01-01T00:00:00.000Z | 44208321 | s2ag/train | APhase IBiological and Pharmacologic Study of the Heparanase Inhibitor PI-88 in Patients with Advanced SolidTumors
Purpose: PI-88 is a mixture of highly sulfated oligosaccharides that inhibits heparanase, an extracellular matrix endoglycosidase, and the binding of angiogenic growth factors to heparan sulfate. This agent showed potent inhibition of placental blood vessel angiogenesis as well as growth inhibition inmultiple xenograft models, thus forming the basis for this study. Experimental Design: This study evaluated the toxicity and pharmacokinetics of PI-88 (80-315 mg) when administered s.c. daily for 4 consecutive days bimonthly (part 1) or weekly (part 2). Results: Forty-two patients [median age, 53 years (range, 19-78 years); median performance status, 1] with a range of advanced solid tumors received a total of 232 courses. The maximum tolerated dose was 250 mg/d. Dose-limiting toxicity consisted of thrombocytopenia and pulmonary embolism. Other toxicity was generally mild and included prolongation of the activated partial thromboplastin time and injection site echymosis.The pharmacokineticswere linear with dose. Intrapatient variability was low and interpatient variability was moderate. Both AUC and Cmax correlated with the percent increase in activated partial thromboplastin time, showing that this pharmacodynamic end point can be used as a surrogate for drug exposure. No association between PI-88 administration and vascular endothelial growth factor or basic fibroblast growth factor levels was observed. One patient with melanoma had a partial response, which wasmaintained for >50 months, and 9 patients had stable disease forz6 months. Conclusion: The recommended dose of PI-88 administered for 4 consecutive days bimonthly or weekly is 250 mg/d. PI-88 was generally well tolerated. Evidence of efficacy in melanoma supports further evaluation of PI-88 in phase II trials. Inhibition of angiogenesis has recently been shown to be an important therapeutic strategy for cancer patients (1). Numerous targets of cancer-induced angiogenesis exist, including enzymes involved in the breakdown of the extracellular matrix, such as matrix metalloproteinases and heparanase. Preclinical evidence suggests that heparanase is important to metastasis and angiogenesis and may therefore be an important therapeutic target (2–4). Elevated heparanase expression is associated with locoregional lymph node metastases or distant metastases in multiple solid tumors, including bladder, breast, esophagus, oral cavity, pancreas, stomach, and thyroid papillary carcinoma, and is associated with shorter survival in patients with pancreatic cancer (5–13). PI-88 is a mixture of highly sulfated oligosaccharides derived from the yeast Pichia (Hanensula) holstii NRRL Y-2448 (14, 15). It was selected for development because it is a potent inhibitor of heparanase. PI-88 has shown antiangiogenic activity in vitro and in vivo , which is attributable to three distinct mechanisms: (a) inhibition of heparanase, an endoglycosidase that releases vascular endothelial growth factor (VEGF) and active complexes of fibroblast growth factor by cleaving heparan sulfate proteoglycans in blood vessel basement membranes and the extracellular matrix; (b) direct inhibition of heparan sulfate binding to the growth factors VEGF and fibroblast growth factor; and (c) stimulation of the release of tissue factor pathway inhibitor, an endogenous antiangiogenic protein (16–18). Previously, PI-88 was tested in healthy volunteers by s.c. injection and in cancer patients by prolonged continuous infusion. First, a phase I trial was conducted in cancer patients evaluating PI-88 administered by prolonged i.v. infusion at doses between 0.57 and 2.28 mg/kg/d. Dose-limiting grade 3 thrombocytopenia occurred in two of six patients treated with 2.28 mg/kg/d as a 14-day infusion. Both patients developed anti-heparin platelet factor 4 (PF4) complex antibodies, suggesting that the thrombocytopenia was immune mediated. Only 2 of 14 patients developed prolongation of the activated Cancer Therapy: Clinical Authors’Affiliations: University of Colorado Cancer Center, Aurora, Colorado; Progen Industries Ltd., Darra, Queensland, Australia; Centre for Studies in Drug Disposition, School of Medicine, University of Queensland, Brisbane, Queensland, Australia; and McMaster University, Hamilton, Ontario, Canada Received11/7/05; revised 3/22/06; accepted 5/30/06. Grant support: Progen Industries Ltd. The costs of publication of this article were defrayed in part by the payment of page charges.This article must therefore be hereby marked advertisement in accordance with18 U.S.C. Section1734 solely to indicate this fact. Requests for reprints: S. Gail Eckhardt, University of Colorado Cancer Center, 12801East 17th Avenue, Campus Box 8117, Aurora, CO 80010. Phone: 303-7243850; Fax: 303-724-3892; E-mail: [email protected]. F2006 American Association for Cancer Research. doi:10.1158/1078-0432.CCR-05-2423 www.aacrjournals.org Clin Cancer Res 2006;12(18) September15, 2006 5471 Research. on January 6, 2018. © 2006 American Association for Cancer clincancerres.aacrjournals.org Downloaded from partial thromboplastin time (APTT), a pharmacodynamic marker of PI-88 (19). Thus, because of the development of dose-limiting toxicity (DLT) in the absence of appreciable pharmacodynamic effects, an alternative dosing strategy was evaluated using a s.c. formulation. Next, a phase IA study evaluated s.c. administration of PI-88 in healthy volunteers. Doses of up to 160 mg were well tolerated. Mild injection site echymosis was noted as well as dose-dependent prolongation of the APTT. The maximum increase in APTT occurred 1 to 2 hours after dosing, and the levels returned to baseline within 14 hours after dosing. Mean F SD bioavailability was 96 F 22% (20). These results supported the evaluation of PI-88 by s.c. administration along with premedication with dexamethasone to potentially ameliorate immune-mediated thrombocytopenia. A fixed dose was evaluated because at the time there were no data available to support dosing by weight or body surface area. Based on evidence showing the role of heparanase in angiogenesis and metastasis, encouraging preclinical data, and the favorable safety and pharmacokinetic profiles of PI-88 in healthy volunteers, the present phase I dose escalation study was undertaken in patients with advanced solid tumors. The objectives of this study were to (a) characterize the toxicities of PI-88 when administered s.c. daily for 4 consecutive days bimonthly or weekly, (b) determine the maximum tolerated dose (MTD) and recommended dose for subsequent phase II trials, (c) characterize the pharmacokinetic profile of PI-88 administered s.c. in this population, (d) seek preliminary evidence of antitumor activity in patients with advanced solid tumors, and (e) assess the effects of PI-88 on soluble biomarkers, including VEGF and basic fibroblast growth factor (bFGF). | v2 |
2019-11-22T00:52:14.144Z | 2019-11-13T00:00:00.000Z | 209243581 | s2ag/train | Northstar-2: Updated Safety and Efficacy Analysis of Lentiglobin Gene Therapy in Patients with Transfusion-Dependent β-Thalassemia and Non-β0/β0 Genotypes
Background
Transfusion-dependent β-thalassemia (TDT) is treated with regular, lifelong red blood cell (RBC) transfusions and despite iron-chelating therapy, carries a risk of serious organ damage from iron overload and other complications. Transplantation with autologous CD34+ cells encoding a βA-T87Q-globin gene (LentiGlobin for β-thalassemia) is being evaluated in patients with TDT. Interim results are presented here from the ongoing, international, single-arm, phase 3 Northstar-2 study (HGB-207; NCT02906202) of LentiGlobin gene therapy in pediatric, adolescent, and adult patients with TDT (defined by receiving ≥100 mL/kg/yr of RBCs or ≥8 RBC transfusions/yr) and non-β0/β0 genotypes.
Methods
Patients undergo hematopoietic stem cell (HSC) mobilization with G-CSF and plerixafor. Following apheresis, CD34+ cells are transduced with BB305 lentiviral vector and infused into patients after pharmacokinetic-adjusted, single-agent busulfan myeloablation. The primary efficacy endpoint is transfusion independence (TI; weighted average hemoglobin [Hb] ≥9 g/dL without RBC transfusions for ≥12 months). HSC engraftment, βA-T87Q-globin expression, Hb levels, detection of replication competent lentivirus (RCL), and adverse events (AE) are also assessed. Patients are followed for 2 years and offered participation in a long-term follow-up study. Summary statistics are presented as median (min - max).
Results
Twenty patients were treated in Northstar-2 as of 13 December 2018 and have been followed for a median of 8.1 (0.5 - 22.2) months. At enrollment, median age was 16 (8 - 34) years; 5 patients were <12 years of age. Median drug product cell dose was 8.0 (5.0 - 19.9) x106 cells/kg and vector copy number was 3.2 (1.9 - 5.6) copies/diploid genome. Time to neutrophil and platelet engraftment in the 18/20 and 15/20 evaluable patients was 22.5 (13 - 32) and 45 (20 - 84) days, respectively.
Non-hematologic grade ≥3 AEs in ≥3 patients after LentiGlobin infusion included stomatitis (n=12), febrile neutropenia (n=6), pyrexia (n=4), epistaxis (n=3), and veno-occlusive liver disease (n=3). One serious AE of grade 3 thrombocytopenia was considered possibly related to LentiGlobin. No patient died, had graft failure, or had detection of RCL. No insertional oncogenesis has been observed.
Gene therapy-derived HbAT87Q stabilized approximately 6 months after infusion. In adolescent and adult patients treated with LentiGlobin, median HbAT87Q at Months 6, 12 and 18 was 9.5 (n=11), 9.2 (n=8), and 9.5 (n=3) g/dL, respectively. The median total Hb without transfusions at Months 6, 12, and 18 were 11.9 (n=11), 12.4 (n=8), 12.3 (n=2) g/dL, respectively. At Month 6, 91% (10/11) of patients had total Hb of >11 g/dL without transfusions.
Five adolescent and adult patients were evaluable for the primary endpoint of transfusion independence, 4 (80%) of whom achieved TI. The median weighted average Hb during TI was 12.4 (11.5 - 12.6) g/dL which compared favorably to pre-transfusion nadir Hb levels before enrollment (median 9.1 g/dL [7.5 - 10.0 g/dL]). At time of analysis, the median duration of TI was 13.6 (12.0 - 18.2) months. One patient who did not achieve TI stopped transfusions for 11.4 months but resumed transfusions due to recurrent anemia. This patient had a 71.4% reduction in RBC transfusion volume from Month 6 to Month 18 compared to baseline.
Marrow cellularity and myeloid:erythroid (M:E) ratios were evaluated in 8 adolescent and adult patients with ≥12 months follow-up to assess the effect of LentiGlobin treatment on dyserythropoiesis. Seven of 8 patients had improved marrow M:E ratios at Month 12 (0.63 - 1.90) compared with baseline (0.14 - 0.48). In patients who stopped transfusions, soluble transferrin receptor levels were reduced by a median of 72% (58% - 78%) at Month 12 (n=6). Updated outcomes in adolescents and adults and outcomes in pediatric patients will be reported.
Summary
In this update of the Northstar-2 study of LentiGlobin gene therapy in patients with TDT and non-β0/β0 genotypes, transfusion independence was observed in 4/5 evaluable adolescent and adults and 10/11 treated patients had total Hb of >11 g/dL without transfusion support 6 months after LentiGlobin infusion. HbAT87Q stabilized approximately 6 months after treatment and patients who stopped RBC transfusions had improved erythropoiesis. A safety profile consistent with busulfan conditioning was observed after LentiGlobin gene therapy.
Thompson: bluebird bio, Inc.: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Baxalta: Research Funding. Walters:TruCode: Consultancy; AllCells, Inc: Consultancy; Editas Medicine: Consultancy. Kwiatkowski:bluebird bio, Inc.: Consultancy, Research Funding; Terumo: Research Funding; Celgene: Consultancy; Agios: Consultancy; Imara: Consultancy; Apopharma: Research Funding; Novartis: Research Funding. Porter:Protagonism: Honoraria; Celgene: Consultancy, Honoraria; Bluebird bio: Consultancy, Honoraria; Agios: Consultancy, Honoraria; La Jolla: Honoraria; Vifor: Honoraria; Silence therapeutics: Honoraria. Thrasher:Rocket Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orchard Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Generation Bio: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; 4BIOCapital: Membership on an entity's Board of Directors or advisory committees. Thuret:BlueBird bio: Other: investigators for clinical trials, participation on scientific/medical advisory board; Celgene: Other: investigators for clinical trials, participation on scientific/medical advisory board; Novartis: Other: investigators for clinical trials, participation on scientific/medical advisory board; Apopharma: Consultancy. Elliot:bluebird bio, Inc.: Employment, Equity Ownership. Tao:bluebird bio, Inc.: Employment, Equity Ownership. Colvin:bluebird bio, Inc.: Employment, Equity Ownership. Locatelli:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy; Miltenyi: Honoraria.
| v2 |
2020-09-19T14:37:54.676Z | 2020-01-01T00:00:00.000Z | 221804611 | s2ag/train | Kinetic isotope effects of 12CH3D + OH and 13CH3D + OH from 278 to 313K
Methane is the second most important long-lived greenhouse gas and plays a central role in the chemistry of the Earth's atmosphere. Nonetheless there are significant uncertainties in its source budget. Analysis of the isotopic composition of atmospheric methane, including the doubly substituted species 13CH3D, offers new insight into the methane budget as the sources and sinks have distinct isotopic signatures. The most important sink of atmospheric methane is oxidation by OH in the troposphere, which accounts for around 84% of all methane removal. Here we present experimentally derived methane+OH kinetic isotope effects and their temperature dependence over the range of 278 to 313K for CH3D and 13CH3D; the latter is reported here for the first time. We find kCH4/kCH3D Combining double low line 1.31 ± 0.01 and kCH4/k13CH3D Combining double low line 1.34 ± 0.03 at room temperature, implying that the methane+OH kinetic isotope effect is multiplicative such that (kCH4/k13CH4)(kCH4/ kCH3D) Combining double low line kCH4/k13CH3D, within the experimental uncertainty, given the literature value of kCH4/k13CH4 Combining double low line 1.0039 ± 0.0002. In addition, the kinetic isotope effects were characterized using transition state theory with tunneling corrections. Good agreement between the experimental, quantum chemical, and available literature values was obtained. Based on the results we conclude that the OH reaction (the main sink of methane) at steady state can produce an atmospheric clumped isotope signal (δ(13CH3D) Combining double low line ln([CH4][13CH3D]/[13CH4][CH3D])) of 0.02 ± 0.02. This implies that the bulk tropospheric δ(13CH3D) reflects the source signal with relatively small adjustment due to the sink signal (i.e., mainly OH oxidation). Disciplines Medicine and Health Sciences | Social and Behavioral Sciences Publication Details Joelsson, L. M. T., Schmidt, J. A., Nilsson, E. J. K., Blunier, T., Griffith, D. W. T., Ono, S. & Johnson, M. S. (2016). Kinetic isotope effects of CH3D + OH and CH3D + OH from 278 to 313K. Atmospheric Chemistry and Physics, 16 (7), 4439-4449. Authors L M. T Joelsson, J A. Schmidt, E J. K Nilsson, T Blunier, David W. T Griffith, S Ono, and Matthew S. Johnson This journal article is available at Research Online: https://ro.uow.edu.au/smhpapers/3979 Atmos. Chem. Phys., 16, 4439–4449, 2016 www.atmos-chem-phys.net/16/4439/2016/ doi:10.5194/acp-16-4439-2016 © Author(s) 2016. CC Attribution 3.0 License. Kinetic isotope effects of CH3D + OH and CH3D + OH from 278 to 313 K L. M. T. Joelsson, J. A. Schmidt, E. J. K. Nilsson, T. Blunier, D. W. T. Griffith, S. Ono, and M. S. Johnson Department of Chemistry, University of Copenhagen, Copenhagen, Denmark Division of Combustion Physics, Department of Physics, Lund University, Lund, Sweden Centre for Ice and Climate (CIC), Niels Bohr Institute, University of Copenhagen, Copenhagen, Denmark University of Wollongong, Department of Chemistry, Wollongong, Australia Department of Earth, Atmospheric and Planetary Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA Correspondence to: M. S. Johnson ([email protected]) Received: 16 September 2015 – Published in Atmos. Chem. Phys. Discuss.: 15 October 2015 Revised: 2 March 2016 – Accepted: 16 March 2016 – Published: 11 April 2016 Abstract. Methane is the second most important long-lived greenhouse gas and plays a central role in the chemistry of the Earth’s atmosphere. Nonetheless there are significant uncertainties in its source budget. Analysis of the isotopic composition of atmospheric methane, including the doubly substituted species CH3D, offers new insight into the methane budget as the sources and sinks have distinct isotopic signatures. The most important sink of atmospheric methane is oxidation by OH in the troposphere, which accounts for around 84 % of all methane removal. Here we present experimentally derived methane+OH kinetic isotope effects and their temperature dependence over the range of 278 to 313 K for CH3D and CH3D; the latter is reported here for the first time. We find kCH4/kCH3D = 1.31±0.01 and kCH4/k13CH3D = 1.34±0.03 at room temperature, implying that the methane+OH kinetic isotope effect is multiplicative such that (kCH4/k13CH4)(kCH4/kCH3D)= kCH4/k13CH3D, within the experimental uncertainty, given the literature value of kCH4/k13CH4 = 1.0039± 0.0002. In addition, the kinetic isotope effects were characterized using transition state theory with tunneling corrections. Good agreement between the experimental, quantum chemical, and available literature values was obtained. Based on the results we conclude that the OH reaction (the main sink of methane) at steady state can produce an atmospheric clumped isotope signal (1(CH3D)= ln([CH4][ CH3D]/[ CH4][CH3D])) of 0.02± 0.02. This implies that the bulk tropospheric 1(CH3D) reflects the source signal with relatively small adjustment due to the sink signal (i.e., mainly OH oxidation). Methane is the second most important long-lived greenhouse gas and plays a central role in the chemistry of the Earth’s atmosphere. Nonetheless there are significant uncertainties in its source budget. Analysis of the isotopic composition of atmospheric methane, including the doubly substituted species CH3D, offers new insight into the methane budget as the sources and sinks have distinct isotopic signatures. The most important sink of atmospheric methane is oxidation by OH in the troposphere, which accounts for around 84 % of all methane removal. Here we present experimentally derived methane+OH kinetic isotope effects and their temperature dependence over the range of 278 to 313 K for CH3D and CH3D; the latter is reported here for the first time. We find kCH4/kCH3D = 1.31±0.01 and kCH4/k13CH3D = 1.34±0.03 at room temperature, implying that the methane+OH kinetic isotope effect is multiplicative such that (kCH4/k13CH4)(kCH4/kCH3D)= kCH4/k13CH3D, within the experimental uncertainty, given the literature value of kCH4/k13CH4 = 1.0039± 0.0002. In addition, the kinetic isotope effects were characterized using transition state theory with tunneling corrections. Good agreement between the experimental, quantum chemical, and available literature values was obtained. Based on the results we conclude that the OH reaction (the main sink of methane) at steady state can produce an atmospheric clumped isotope signal (1(CH3D)= ln([CH4][ CH3D]/[ CH4][CH3D])) of 0.02± 0.02. This implies that the bulk tropospheric 1(CH3D) reflects the source signal with relatively small adjustment due to the sink signal (i.e., mainly OH oxidation). | v2 |
2019-03-13T13:31:14.279Z | 2014-05-01T00:00:00.000Z | 76126921 | s2ag/train | Differentiation of Human-Induced Pluripotent Stem Cells (iPSCs) on Laminin-functionalized PEG Hydrogels under Nucleus Pulposus-Like Culture Conditions
Introduction Cell delivery to the pathological intervertebral disc (IVD) has significant therapeutic potential for enhancing IVD regeneration1-4; however, few viable sources of cells have been identified. Induced pluripotent stem cells (iPSCs) are an attractive cell source since they are derived from the patient's somatic cells,5 thereby providing an autologous source of cells for IVD regeneration. We have previously demonstrated that mouse and human iPSCs can differentiate into nucleus pulposus (NP)-like cells in vitro when cultured in a laminin-rich (Matrigel) system.6 To provide for a more controlled microenvironment, we have developed an injectable, laminin-111 functionalized poly (ethylene glycol) (PEG-LM111) hydrogel for IVD cell-mediated regeneration.6 The stiffness and laminin density of this PEG-LM111 hydrogel was previously optimized to promote or maintain the expression of immature NP-specific markers for primary NP cells in vitro.7 The goal of this study is to evaluate if human iPSCs can be promoted to similarly express markers specific to the immature NP cell when cultured upon this PEG-LM111 hydrogel, toward the goal of promoting generation of native NP-like tissue from stem cells in vitro. Materials and Methods Cell Generation iPSCs were generated from human embryonic dermal fibroblasts through transient inducible overexpression of transcription factors (OCT4, SOX2, KLF4, and MYC) by a lentiviral-based gene delivery system (a polycystronic vector with the reverse tetracycline transactivator (M2rtTA) and doxycycline). Selected iPSC colonies were maintained in culture upon a primary mouse embryo fibroblasts (PMEF) feeder layer. As we reported previously, iPSC colonies expressed a subset of human pluripotent cell markers (i.e., OCT4, SOX2, SSEA-4, TRA1-60, TRA1-81, and alkaline phosphatase), NP-associated integrins (α3, α6, and β1 subunit), NP-specific molecular markers (CD24 and Brachyury), as well as MSC markers (CD29 and CD90).9 Cell Differentiation “Soft” PEG-LM111 (2% PEG-diacrylate prepared with chemically coupled 1 mg/mL laminin-111/PEG; ∼ 200 Pa) hydrogels were UV-crosslinked in Transwell inserts. Undifferentiated iPSCs were seeded (106 cells/insert) on PEG-LM111 substrates in in each Transwell and cultured in notochordal cell conditioned medium (NCCM) from porcine NP tissue (DMEM based, 1% ITS10) under 2% hypoxia condition;11 undifferentiated iPSCs cultured under equivalent conditions but with NP differentiation medium (DMEM/F12, ITS, NEAA9) was used as a control. Immunohistochemistry Differentiated cells were harvested for cryosectioning at 10 or 21 days of culture. Cell morphology and proteoglycan synthesis was assessed by histological staining (H&E and Safranin O). Expression of NP markers was evaluated by immunostaining for matrix proteins (type II collagen [COL II], laminin 10 [LM511]), laminin related receptors (CD239, integrin subunits α6, β4), a subset of NP-specific markers (cytokeratin 8 [KRT8], N-cadherin, CD24), and some non-NP-markers (type I collagen, E-cadherin). Results On the “soft” laminin-presenting substrate, differentiated cells expressed collagen II but not collagen I at both 10 and 21 days, which is characteristic of the NP cell phenotype (Figs. A and B). NCCM promoted expression of NP-specific markers (LM511, CD239, cytokeratin 5/8, Fig. B) in the differentiated cells when cultured on “soft” PEG-LM111 gels, as compared with NP differentiation medium (Fig. A). Differentiated cells also stained positively for CD24 (Fig.), proteoglycans (by Safranin O) and N-cadherin under both culture medium conditions (data not shown). It is noteworthy that other laminin receptors (integrin subunits α6, β4) and E-cadherin were not detected in the differentiated iPSCs under either culture medium conditions (data not shown). Fig. Immunostaining for NP markers(Col II, LM511, CD239, CD24, KRT8) in differentiated iPSCs cultured for 21 days in a PEG-LM111 hydrogel system under (A) NP differentiation medium (NPDM) and (B) notochordal cell conditioned medium (NCCM) from porcine NP tissue (bar = 50 µm). Conclusion Human iPSCs have the potential to differentiate toward an NP-like phenotype when cultured on laminin presenting hydrogels and culture conditions similar to native NP tissue environment. It suggests the possibility that they may be used as a novel cell source for cellular therapy in the IVD. Ongoing studies are focusing on selection of NP progenitor cells with notochordal lineage potential from nonvirally transformed human iPSCs. Acknowledgments Supported by NIH R01AR057410, R01EB002263, R01AR047442, AOSpine Foundation. Disclosure of Interest None declared References Nishimura K, Mochida J. Percutaneous reinsertion of the nucleus pulposus. An experimental study. Spine 1998;23(14):1531-1538, discussion 1539 Okuma M, Mochida J, Nishimura K, Sakabe K, Seiki K. Reinsertion of stimulated nucleus pulposus cells retards intervertebral disc degeneration: an in vitro and in vivo experimental study. J Orthop Res 2OR10.02;18(6):988–997 Meisel HJ, Ganey T, Hutton WC, Libera J, Minkus Y, Alasevic O. Clinical experience in cell-based therapeutics: intervention and outcome. Eur Spine J 2006;15(Suppl 3):S397-S405 Sakai D. Stem cell regeneration of the intervertebral disk. Orthop Clin North Am 2011;42(4):555-562, viii-ix Yamanaka S. A fresh look at iPS cells. Cell 2009;137(1):13–17 Chen J, Lee EJ, Jing L, Christoforou N, Leong KW, Setton LA. Differentiation of mouse induced pluripotent stem cells (iPSCs) into nucleus pulposus-like cells in vitro. PLoS ONE 2013;8(9):e75548 Francisco AT, Mancino RJ, Bowles RD, et al. Injectable laminin-functionalized hydrogel for nucleus pulposus regeneration. Biomaterials 2013;34(30):7381–7388 Francisco AT, Hwang PY, Jeong CG, Jing L, Chen J, Setton LA. Photocrosslinkable laminin-functionalized polyethylene glycol hydrogel for intervertebral disc regeneration. Acta Biomater 2014;10(3):1102–1111 Jing L, Christoforou N, Leong KW, Setton LA, Chen J. Differentiation potential of human induced pluripotent stem cells (iPSCs) to nucleus pulposus-like cells in vitro. Global Spine J 2012;2(Suppl 1):S36 Purmessur D, Schek RM, Abbott RD, Ballif BA, Godburn KE, Iatridis JC. Notochordal conditioned media from tissue increases proteoglycan accumulation and promotes a healthy nucleus pulposus phenotype in human mesenchymal stem cells. Arthritis Res Ther 2011;13(3):R81 Risbud MV, Albert TJ, Guttapalli A, et al. Differentiation of mesenchymal stem cells towards a nucleus pulposus-like phenotype in vitro: implications for cell-based transplantation therapy. Spine 2004;29(23):2627–2632 | v2 |
2019-01-14T13:12:51.758Z | 2000-04-01T00:00:00.000Z | 107309601 | s2ag/train | Concept and Applications of Carrier Pocket Engineering to Design Useful Thermoelectric Materials Using Superlattice Structures
Inthisthesis,ageneraloptimizationapproachtomaximizethevaluesofthethermoelectricfigureofmeritZ3DTisproposedusillgsemiconductingsuperlatticesystems. Thisoptimizationprocess,denotedbythe`°CarrierPocketEngineeringconcept"in thetext,takesthefollowingfourstagesofactualinvestigation:(1)theoreticalpredictionsforthematerialscombinationstobeusedandforthedetailedstructureof thesuperlatticesinordertoachievethemaximumvalueofZ3D7「forthewholesuperlattice,usingthesimplestpossiblemodels;(II)experimentalproof--ofLprinciplestudy ofthetheoreticalpredictionsmadein(1)andgivefeedbacktothetheoreticalconceptanditsexplicitimplementation;(III)improvementofthetheoreticalmodelsto understandtheexperimentalresultsobtainedin(II)andtomakeimprovedtheoreticalpredictions;and(IV)applicationoftheknowledgeacquiredforthemechanisms responsibleforenhancingZ3D7「duringtheinvestigationofonematerialssystem,to anothermaterialssystemthatmayprovideevenlargervaluesofZ3DTafterincorpo. ratingthenewlyacquiredknowledgeforenhancingZ3DT. Todemonstratetheaboveoptimizationprocess,aseriesoftheoreticalandexperimentalinvestigationswerecarriedoutusingthefollowingmaterialssystems: (1)(111)orientedPbTe/Pb1_xEuxTemultiple-quantum-wellsuperlatticestoclarify thedetailedmechanismsresponsibleforthepreviouslyobservedenhancementinthe thermoelectricpowerSinthissystem;(2)GaAs/AIAsshort-periodsuperlatticesto proposethenewconceptofCarrierPocketEngineering,whereunconventionalX-and L-pointvalleys,thatdonotcontributetothethermoelectrictransportinthebulk form,canbemadetocontributetothethermoelectrictransportinthesuperlattice form,enhancingthevaluesofZ3DTsignificantlyrelativetothoseforthecorrespondingbulkmaterials;(3)Si/Geshort-periodsuperlatticestoproposeayetnewconcept oflatticestrainengineeringtofurtherincreasethevaluesofZ3DTinthissuperlattice system,andtoprovideanexperimentalproofLof-principlestudyoftheCarrierPocket Engineeringconceptusingthismaterialssystem. Besidestheabovemainstreamofthisthesis,thepropertiesof(111)oriented 3 bstract this th sis , a general opti ization appr ach to maximize the values of the thermolectr c figure of merit Z30T is proposed u ing semiconducting superlattice systems. his optimi zation process, d not d by the "Canier Pocket Engineering concept" in t t t, t kes t f llowing fo ur stages f tual investigat ion: (I) theoretical preictions for tho materials combinations to be used and fo r the detailed structure of t e superlattic s in ord r to achieve the maximum value of Z30T for the whole superl t t ice, using the simplest possible models; (II) experimental proof~of~principle study f t theor t al pr dictions made in (I) and give feedback to the theoretical conpt and its explicit imple enta tion; (III) improvement of the theoretical models to nderstand the experime tal results obtained in (II) and to make improved theoretal predictions; and (IV) application of the k owledge acquired for the mechanisms responsible for enhanci g Z30T during the invest igation of one materials system, to noth r materials syst m that may provide even larger values of Z30T after incorporat ing the n wly acquired knowledge for enhancing Z3DT. o demonstrate the above ptimiz tion process, a series of theoretical and exerimental inv st igations were c rried out using the following materials systems : (1) (Ill ) oriented b e/Pb1_xEux Te multiple-quantu ell superlattices to clarify t detailed mechanism resp nsibl f r the p eviously observed enhancement in the h rm ectric power i this syst ; (2) GaAs/ IAs short-period sllperla ti t r pose the new c ncept of Ca.rrier Pocket Engi eeri g, where unconventional X and -point va.lleys, tha do not contribute to the thermoelectric transport in the bulk , can be made to c ntribute to the thermoelectric transport in the superlattice , enha cing the value of Z30T signif cantly relative to th se for the corresponding; l materi ls; (3) Si/Ge t-period superJattices to propose a yet new concept f la tice strai e gineering to further increase the value of Z3DT in this superlattice st , and to provid an experimental proof-or-principle study of the Carrier Pocket ngineering concept using this mat ri a.ls system. e des above main stream of his thesis, the p op rties of (111) oriented PbTe/TealldPbSeo .g8Teo.02/PbTe"qualltum-dot"superlattices,(001)orientedshortperiodsuperlatticesofPbTe/Pb1_xEuxTe,aIld(111)orieIltedBi/Pb1_xEuxTesuperlatticesarealsodiscussedaspossiblecandidatesforthefuturehighZTmaterials. 4 e/ Te an PbSeO 98 Teo.02/PbTe "quantum-dot" superlattices, (001 ) oriented shortiod lattices of PbTe/Pb,_xEux Te, and (Ill) oriented Bi/ Pb'_xEux I e superare also di cussed as poss ble candidates for the futm€ high ZT materials . Acknowledgments ThisthesisisasummaryofmyworkcarriedoutatMIT(MassachusettsInstitutionof Technology)underthesupervisionofProfessorMildredS.Dresselhaus(MIT)during theperiodbetweenJanuary1997andMarch2000. First,IwouldliketothankProfessorMildredS.Dresselhausforintroducingmeto theworldoflow-dimensionalthermoelectricityaswellasforheracademicguidance, colltilluousellcouragemellt,trustandpatiencethroughoutmythesisworkthatwas carriedoutintheDresselhausgroup(MGM).IamalsoobligedtoDr.GeneDresselhausandMs.LauraDoughtyinMGM,respectively,forvariousacademicsupport andforherprofessionaladministrativesupportthatwereprovidedtomeduringmy stavinMGM. り Mr.TheodoreC.HarmanofMITLincolnLaboratoryandProfessorHenryEhrenreichofHarvardUniversityhavebeentwoofthemostrespectedscientiststome, respectively,inexperimentandintheory.Theirphysicalinsightsintotheresearch problemswerepreciseandconcrete,andtaughtmehowtolookattheproblemsfrom variousdifferentangles.IwouldalsoliketothankTedforsharinghisprecious,highqualitysuperlatticesampleswithusfortheexperimentalinvestigationscarriedout inthisthesis. ProfessorDavidA.BroidoofBostonCollegeandDr.ThomasL.Reineckeof NavalResearchLaboratoryhaveprovidedanadditionalsourcefortheoreticalinsights throughoutthethesiswork.Iwouldalsoliketothankthemforteachingmehowtodo thecomputercalculationthatisnecessarytosolvetheBoltzmanntransportequation numerically,andIwouldliketothankProfessorBroidoforkindlyansweringallthe questionsIaskedduringmycomputersimulationwork. IwouldliketothankProfessorVenkateshNarayanamllrtiandProfessorFransA. SpaepenofHarvardUniversityforbeingonmythesiscommitteeatHarvard,andfor monitoringmythesisworkatMITonaregularbasis. IwouldliketothankallourcollaboratorsundertheDOD/ONRMURIprogramon"QuantumStructuresforThermoelectricApplications".Especially,Profes一 5 cknow ledgments hi t is is a mary of my work carried out at MIT (Mas achusetts Instituti n of ogy) t e supervi ion r es or i dred . r selhaus (M duri t e period b tween .January 1997 and March 2000. irst , I wou ld like to thank Professor IV[ildred S. Dresselhaus f r introducing me to e world of low-dimensiona thermoelectricity as well as for h r academic guidance, ntinuo s encourag ment , trust and patience through ut my thesis work that was rried o t i the Dre sel group (MGM) . I am also obliged to Dr. Gene Dreslh us nd Ms. Laura Doughty in MGM. respec tively, [or various academic supporl nd for her professional administrative support that were provided to me during my tay in MGM. Ivlr. Theodore C. Harman of NIIT Lincoln Laboratory a d Professor Henry Ehrenreic of Harvard Uni versity have been two of the most respected scientists to me, ectively, in xp rimen and in t heory T heir physical insights into the research r blems were precise and concrete, and tanght me how to look at the problems from ri us different angles. I would also lik t t ank Ted for sharing his precious, highal ity superlattice sample with us for he experime tal investigat ions carried out. this thesis. rofe sor David A. roido of Boston Colleg and Dr. T homas L. Reinecke of l\aval Research Laborato y have prov ded an addi ional source for theoreticaJ insights roughout t e thesis rk. I would also like to thank t em f r teaching me how to do e computer c lculation that is necessary to solve the Boltzmann transport equation Lllnerically. and I would li e to thank Professor Broido for kindly answering all the estions I asked during my computer simulation work. would like to thank Pmfessor Vellk teslt Narayanamurti and Pmfessor Frans A. paepen of Harvard University for be ng on my thesis committee at Harvard, and for onitoring my thesis w rk at MIT on a regular basis. I would like to thank all our collaborators under the DOD/ ONR MURI proram o "Quantum Stru tures for Thermoelectric Applications" . EspeciaUy, Pl'OfessorGangChen,ProfessorKangL.WaIlg,Dr.JianliIlLiuandMr.TheodorianBorcaTasciucofUCLA(UniversityofCaliforniaatLosAngeles)fornumerousscielltific discussions,andProfessorWangandJianlinforgrowingthehighestqualitySi/Ge superlatticesamplesintheworldfortheexperimentalproofLof-principlestudycarried outinthisthesis. IamalsoindebtedtoProfessorGuntherBauerandDr.GuntherSpringholzof theJohannesKeplerUniversit翫,Linz,Austria,forgrowillgthePbTe/Pb1_xEuxTe multiple-quantum-wellsamplesforthesupplementalstudycarriedoutinthisthesis andforgivingusscientificinputs. IwouldliketothankallthemembersinMGM:Dr.XiangzhongSunforsharing hisexpertiseinphysicsandcomputersciencewithme,Mr.StephenB.Croninfor providingmewithvarioustechnicalandscientifichelp,andallotherMGMmembers includingDr.ManyaliboJ.Matthews,Dr.DmitryGekhtman,Dr.ZhiboZhang, Ms.SandraBrown,Dr.MarcosPimenta,Dr.AlessandraMarucci,Mr.HaoXin, Dr.PaolaCorio,Mr.YumingLin,Ms.MarcieR.Black,Mr.OdedRabin,Dr.Ado Jorio,andothers,forvariousscientificdiscussions,theirfriendship,andcreatingan excellentresearchatmosphereinMGM. Finally,Iwouldliketothankmyparents,TatsuhikoandMasayo,andmysister, Tamaki,fortheirwarmlove,continuoushelp,andallkindofencouragementthey providedtomeduringmystayintheUnitedStates. 6 s r Gang Chen, Professor Kang L. Wang, Dr. ,Jianlin Liu and lv1r. T heodorian Borcas iuc f UCLA (University of Californi at Los Angeles) for numerous scient ific scus ions, and P ofes or W and J ianlin for growing t e highest quality SilGe s perlattice samples in the world f r the ex e | v2 |
2020-11-05T09:06:01.985Z | 2020-11-05T00:00:00.000Z | 228907801 | s2ag/train | Pembrolizumab with R-CHOP in Previously Untreated Diffuse Large B-Cell Lymphoma: Long Term Follow up and Analysis of the Mechanism of Pdl-1 Tumor Expression
Background: Rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone (RCHOP) remains standard therapy for previously untreated diffuse large B-cell lymphoma (DLBCL). We previously reported that adding pembrolizumab to RCHOP (PR-CHOP), shows no significant additive toxicity and a promising 2-year progression free survival of 83% (Smith B J Haem 2019), with no progression events among 19 pts with known PDL-1+ tumors. In that analysis, we noted 83% of patients had tumor PDL-1 expression by IHC using a centralized standard assay, including 18/23 (78%) and 13/23 (56%) demonstrating positivity in ≥5% and ≥30% of lymphoma cells respectively. Herein we report long-term clinical follow up, as well as results of high-resolution molecular karyotyping using chromosome genomic array testing (CGAT), to assess whether 9p24.1 abnormalities explained the extent of PDL1 tumor expression.
Methods: Pts age 18 years or older with previously untreated DLBCL, transformed lymphoma and grade 3 B follicular lymphoma eligible for 6-cycle, curative-intent RCHOP were eligible. Steroids within 7 days of treatment, active autoimmune disease, or history of pneumonitis were excluded. This phase I study combined pembrolizumab (200 mg IV q 3 weeks x 6) to RCHOP x 6, with supportive care per standard practice. There was no maintenance or consolidation therapy. Baseline PDL1 expression was analyzed centrally (Merck/Qualtek). CGAT was performed from DNA extracted from formalin-fixed, paraffin-embedded tissue sections using the OncoScan platform (ThermoFisher). H&E slides of adjacent sections of the tissue used for CGAT were evaluated by a pathologist to ensure a minimum of 30% tumor content. Patients were followed for relapse and survival.
Results: Among 30 treated pts with a median follow up of 32 months, there have been no additional DLBCL relapses or deaths since the published report. There has been one relapse of follicular lymphoma in a patient with initial composite lymphoma , who is now in remission 1 year after autologous stem cell transplantation. 3-year estimated PFS is 83% and OS is 86%. On univariate analysis, only tumor bulk 7.5 cm or greater (p=.02) and absence tumor PDL-1 expression by IHC (p=.001) predicted inferior PFS. Tumor bulk, (p=.03), IPI 3 or higher (p=.01), and absence of tumor PDL-1 expression (p=.001) predicted worse overall survival. PFS and OS were unaffected by cell of origin by IHC, double expresser status, or diagnosis to treatment interval greater than median (29 days).
Regarding safety, there were late cases of paraneoplastic pemphigus and rheumatoid arthritis 5 and 8 months from last dose of pembrolizumab, respectively. Both of these were managed successfully with immunosuppression.
Chromosome genomic array testing CGAT) was performed to assess copy number aberrations (CNAs) and copy neutral loss of heterozygosity (cnLOH), particularly for the presence of gains or amplifications involving locus 9p24.1, containing the CD274 (PDL1) gene. Of 15 tested pretreatment baseline diagnostic tissue specimens, 14 provided informative result with 12 abnormal and 2 normal. Notably, no gain or amplification in 9p24.1 were seen; there was one case of deletion and 1 with cnLOH. The percent genome altered among abnormal cases ranged from 2% to 37% (median 12%). Complex karyotype, defined as genomic aberrations involving at least 3 chromosome arms (or % genome altered greater than 5% by CGAT), was seen in 10/14 pts (71%). This 14-sample data set included 6/14 pts with >30% PDL1 tumor expression (and 10 with 5% or greater PDL1-tumor expression).
Conclusions: No additional safety signals have been observed, and PFS/OS remain favorable for the combination of pembrolizumab + RCHOP in this single arm trial with the best results in PDL-1+ disease. Despite frequent tumor PDL1-expression at baseline, no gains or implications of 9p24.1 were observed suggesting alternative mechanisms for overexpression of PDL-1. Further study this regimen and others testing combinations of immune checkpoint inhibition with first-line DLBCL therapy are warranted, to better ascertain the potential superiority of this strategy in this setting.
Smith: Portola: Research Funding; Incyte: Research Funding; Ignyta: Research Funding; Genentech: Research Funding; AstraZeneca: Research Funding; Acerta Pharma BV: Research Funding; Karyopharm: Consultancy; Beigene: Consultancy; Seattle Genetics: Research Funding; AstraZeneca: Consultancy; Millenium/Takeda: Consultancy; Pharmacyclics: Research Funding; Merck: Research Funding; De Novo Biopharma: Research Funding; Bayer: Research Funding; Ayala: Research Funding; Bristol Meyers Squibb: Research Funding. Fromm:Merck: Research Funding. Till:Mustang: Patents & Royalties, Research Funding. Shadman:Mustang Bio, Celgene, Pharmacyclics, Gilead, Genentech, Abbvie, TG therapeutics, Beigene, Astra Zeneca, Sunesis, Beigene: Research Funding; Abbvie, Genentech, Astra Zeneca, Sound Biologics , Pharmacyclics, Verastem, ADC therapeutics, Beigene, Cellectar, BMS, Morphosys and Atara Biotherapeutics: Consultancy. Lynch:Bayer: Research Funding; Rhizen Pharmaceuticals: Research Funding; Incyte: Research Funding; TG Therapeutics: Research Funding; Takeda: Research Funding; Juno Therpeutics: Research Funding; MorphoSys: Consultancy; Genentech: Research Funding; Cyteir: Research Funding. Cowan:Janssen: Consultancy, Research Funding; Bristol Myers Squibb: Research Funding; Sanofi: Consultancy; Cellectar: Consultancy; Abbvie: Research Funding. Ujjani:Gilead/Kite: Consultancy, Research Funding; Atara: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; MorphoSys: Consultancy; Verastem Oncology: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding. Shustov:Seattle Genetics: Research Funding. Cassaday:Vanda Pharmaceuticals: Research Funding; Seattle Genetics: Current Employment, Current equity holder in publicly-traded company; Merck: Research Funding; Pfizer: Honoraria, Research Funding; Amgen: Consultancy, Research Funding; Kite/Gilead: Consultancy, Research Funding. Gopal:Seattle Genetics; Janssen; Takeda; IgM Bio; IMab Bio; BMS; Astra Zeneca; Merck; Gilead: Research Funding; Seattle Genetics; Janssen; IMab Bio; TG Therapeutics; Astra Zeneca; Merck; Gilead; ADC Therapeutics; Nurix; TG therapeutics, Cellectar; Actinium: Consultancy; IgM bio, BMS, merck: Research Funding; imab bio, takeda,astrazeneca,gilead: Research Funding.
| v2 |
2014-10-01T00:00:00.000Z | 2004-09-24T00:00:00.000Z | 8722251 | s2ag/train | Thermodynamics and Introductory Statistical Mechanics
PREFACE. 1 INTRODUCTORY REMARKS. 1.1 Scope and Objectives. 1.2 Level of Course. 1.3 Course Outline. 1.4 Books. PART I: THERMODYNAMICS. 2 BASIC CONCEPTS AND DEFINITIONS. 2.1 Systems and Surroundings. 2.2 State Variables and Thermodynamic Properties. 2.3 Intensive and Extensive Variables. 2.4 Homogeneous and Heterogeneous Systems, Phases. 2.5 Work. 2.6 Reversible and Quasi-Static Processes. 2.6.1 Quasi-Static Process. 2.6.2 Reversible Process. 2.7 Adiabatic and Diathermal Walls. 2.8 Thermal Contact and Thermal Equilibrium. 3 THE LAWS OF THERMODYNAMICS I. 3.1 The Zeroth Law-Temperature. 3.2 The First Law-Traditional Approach. 3.3 Mathematical Interlude I: Exact and Inexact Differentials. 3.4 The First Law-Axiomatic Approach. 3.5 Some Applications of the First Law. 3.5.1 Heat Capacity. 3.5.2 Heat and Internal Energy. 3.5.3 Heat and Enthalpy. 3.6 Mathematical Interlude II: Partial Derivatives. 3.6.1 Relations Between Partials of Dependent Variables. 3.6.2 Relations Between Partials with Different Subscripts. 3.7 Other Applications of the First Law. 3.7.1 CP -- CV. 3.7.2 Isothermal Change, Ideal Gas. 3.7.3 Adiabatic Change, Ideal Gas. 3.7.4 The Joule and the Joule-Thomson Coefficients. 4 THE LAWS OF THERMODYNAMICS II. 4.1 The Second Law-Traditional Approach. 4.2 Engine Efficiency: Absolute Temperature. 4.2.1 Ideal Gas. 4.2.2 Coupled Cycles. 4.3 Generalization: Arbitrary Cycle. 4.4 The Clausius Inequality. 4.5 The Second Law-Axiomatic Approach (Carathe-odory). 4.6 Mathematical Interlude III: Pfaffian Differential Forms. 4.7 Pfaffian Expressions in Two Variables. 4.8 Pfaffian Expressions in More Than Two Dimensions. 4.9 Carathe-odory's Theorem. 4.10 Entropy-Axiomatic Approach. 4.11 Entropy Changes for Nonisolated Systems. 4.12 Summary. 4.13 Some Applications of the Second Law. 4.13.1 Reversible Processes (PV Work Only). 4.13.2 Irreversible Processes. 5 USEFUL FUNCTIONS: THE FREE ENERGY FUNCTIONS. 5.1 Mathematical Interlude IV: Legendre Transformations. 5.1.1 Application of the Legendre Transformation. 5.2 Maxwell Relations. 5.3 The Gibbs-Helmholtz Equations. 5.4 Relation of DELTAA and DELTAG to Work: Criteria for Spontaneity. 5.4.1 Expansion and Other Types of Work. 5.4.2 Comments. 5.5 Generalization to Open Systems and Systems of Variable Composition. 5.5.1 Single Component System. 5.5.2 Multicomponent Systems. 5.6 The Chemical Potential. 5.7 Mathematical Interlude V: Euler's Theorem. 5.8 Thermodynamic Potentials. 6 THE THIRD LAW OF THERMODYNAMICS. 6.1 Statements of the Third Law. 6.2 Additional Comments and Conclusions. 7 GENERAL CONDITIONS FOR EQUILIBRIUM AND STABILITY. 7.1 Virtual Variations. 7.2 Thermodynamic Potentials-Inequalities. 7.3 Equilibrium Condition From Energy. 7.3.1 Boundary Fully Heat Conducting, Deformable, Permeable (Normal System). 7.3.2 Special Cases: Boundary Semi-Heat Conducting, Semi-Deformable, or Semi-Permeable. 7.4 Equilibrium Conditions From Other Potentials. 7.5 General Conditions for Stability. 7.6 Stability Conditions From E. 7.7 Stability Conditions From Cross Terms. 7.8 Stability Conditions From Other Potentials. 7.9 Derivatives of Thermodynamic Potentials With Respect to Intensive Variables. 8 APPLICATION OF THERMODYNAMICS TO GASES, LIQUIDS, AND SOLIDS. 8.1 Gases. 8.2 Enthalpy, Entropy, Chemical Potential, Fugacity. 8.2.1 Enthalpy. 8.2.2 Entropy. 8.2.3 Chemical Potential. 8.2.4 Fugacity. 8.3 Standard States of Gases. 8.4 Mixtures of Gases. 8.4.1 Partial Fugacity. 8.4.2 Free Energy, Entropy, Enthalpy, and Volume of Mixing of Gases. 8.5 Thermodynamics of Condensed Systems. 8.5.1 The Chemical Potential. 8.5.2 Entropy. 8.5.3 Enthalpy. 9 PHASE AND CHEMICAL EQUILIBRIA. 9.1 The Phase Rule. 9.2 The Clapeyron Equation. 9.3 The Clausius-Clapeyron Equation. 9.4 The Generalized Clapeyron Equation. 9.5 Chemical Equilibrium. 9.6 The Equilibrium Constant. 10 SOLUTIONS-NONELECTROLYTES. 10.1 Activities and Standard State Conventions. 10.1.1 Gases. 10.1.2 Pure Liquids and Solids. 10.1.3 Mixtures. 10.1.3.1 Liquid-Liquid Solutions-Convention I (Con I). 10.1.3.2 Solid-Liquid Solutions-Convention II (Con II). 10.2 Ideal and Ideally Dilute Solutions Raoult's and Henry's Laws. 10.2.1 Ideal Solutions. 10.2.2 Ideally Dilute Solutions. 10.3 Thermodynamic Functions of Mixing. 10.3.1 For Ideal Solutions. 10.3.2 For Nonideal Solutions. 10.4 Colligative Properties. 10.4.1 Lowering of Solvent Vapor Pressure. 10.4.2 Freezing Point Depression. 10.4.3 Boiling Point Elevation. 10.4.4 Osmotic Pressure. 11 PROCESSES INVOLVING WORK OTHER THAN PRESSURE-VOLUME WORK. 11.1 P-V Work and One Other Type of Work. 11.2 P-V, sigmaA, and fL Work. 12 PHASE TRANSITIONS AND CRITICAL PHENOMENA. 12.1 Stable, Metastable, and Unstable Isotherms. 12.2 The Critical Region. PART II: INTRODUCTORY STATISTICAL MECHANICS. 13 PRINCIPLES OF STATISTICAL MECHANICS. 13.1 Introduction. 13.2 Preliminary Discussion-Simple Problem. 13.3 Time and Ensemble Averages. 13.4 Number of Microstates, OMEGAD, Distributions DI. 13.5 Mathematical Interlude VI: Combinatory Analysis. 13.6 Fundamental Problem in Statistical Mechanics. 13.7 Maxwell-Boltzmann, Fermi-Dirac, Bose-Einstein Statistics "Corrected" Maxwell-Boltzmann Statistics. 13.7.1 Maxwell-Boltzmann Statistics. 13.7.2 Fermi-Dirac Statistics. 13.7.3 Bose-Einstein Statistics 13.7.4 "Corrected" Maxwell-Boltzmann Statistics. 13.8 Systems of Distinguishable (Localized) and Indistinguishable (Nonlocalized) Particles. 13.9 Maximizing OMEGAD 13.10 Probability of a Quantum State: The Partition Function. 13.10.1 Maxwell-Boltzmann Statistics. 13.10.2 Corrected Maxwell-Boltzmann Statistics. 14 THERMODYNAMIC CONNECTION. 14.1 Energy, Heat, and Work. 14.2 Entropy. 14.2.1 Entropy of Nonlocalized Systems (Gases). 14.2.2 Entropy of Localized Systems (Crystalline Solids). 14.3 Identification of beta with 1/kT. 14.4 Pressure. 14.5 The Functions E, H, S, A, G, and mu. 15 MOLECULAR PARTITION FUNCTION. 15.1 Translational Partition Function. 15.2 Vibrational Partition Function: Diatomics. 15.3 Rotational Partition Function: Diatomics. 15.4 Electronic Partition Function. 15.5 Nuclear Spin States. 15.6 The "Zero" of Energy. 16 STATISTICAL MECHANICAL APPLICATIONS. 16.1 Population Ratios. 16.2 Thermodynamic Functions of Gases. 16.3 Equilibrium Constants. 16.4 Systems of Localized Particles: The Einstein Solid. 16.4.1 Energy. 16.4.2 Heat Capacity. 16.4.3 Entropy. 16.5 Summary. ANNOTATED BIBLIOGRAPHY. APPENDIX I: HOMEWORK PROBLEM SETS. Problem Set I. Problem Set II. Problem Set III. Problem Set IV. Problem Set V. Problem Set VI. Problem Set VII. Problem Set VIII. Problem Set IX. Problem Set X. APPENDIX II: SOLUTIONS TO PROBLEMS. Solution to Set I. Solution to Set II. Solution to Set III. Solution to Set IV. Solution to Set V. Solution to Set VI. Solution to Set VII. Solution to Set VIII. Solution to Set IX. Solution to Set X. INDEX. | v2 |
2021-11-25T16:19:14.211Z | 2021-11-05T00:00:00.000Z | 244560301 | s2ag/train | Incidence of Pleural Effusion with Dasatinib and the Effect of Switching Therapy to Bosutinib in Patients with Chronic Phase CML
Introduction:
Dasatinib is a second generation tyrosine kinase inhibitor (TKI) which is approved for treatment of chronic myeloid leukemia (CML). Pleural effusion (PE) is a unique toxicity associated with dasatinib use. The risk of development of PE with dasatinib was reported to be 6-9% per year in DASISION and 5-15% per year in CA180-034. At a 5 and 7 year follow up 28% and 33% of patients developed PE in DASISION and CA180-034, respectively (Cortes et. al. J Clin Onc 2016 and Shah et. al. Am J Hematol 2016). PE led to discontinuation of dasatinib in only 6% and 7% patients in DASISION and CA180-034, respectively. Alternative TKIs are required in these cases with the goal to avoid recurrence of PE. Recently, switching to bosutinib after development of a PE while on dasatinib has been shown to be associated with a 30% risk of developing a recurrent PE, higher than the reported rate in front line trials (Tribelli et. al. Ann Hematol 2019).
Objective:
The aim of this study was to identify the incidence of pleural effusions in a cohort of patients treated with dasatinib for chronic phase (CP)-CML, and the safety of switching therapy to bosutinib.
Methods:
A retrospective chart review of all patients who had received dasatinib for treatment of CP-CML between 1992 and 2020 at Moffitt Cancer Center was performed. Patient data including baseline characteristics, date of diagnosis, line of treatment, date of initiation and termination of treatment, reason for discontinuation and dose were collected. PE was graded according to the CTCAE v5.0 (common terminology criteria for adverse events). A descriptive analysis of the data collected is reported.
Results:
A total of 390 patients, 184 males and 206 females, were treated with dasatinib during their course of treatment for CP-CML. The median age of diagnosis of CML was 50 years. 79% of patients were Caucasian. Dasatinib was used as front line therapy in 150 (38.4%) patients, second line in 177 (45.3%) patients and third line or above in 63 (16.1%) patients. A total of 69 patients (17.6%) developed any grade of PE, with 33 (48%) patients considered to have CTCAE grade 2 PE, 34 (49%) patients grade 3, and only 1 patient developed grade 4 PE. The dose of dasatinib for the patients that developed PE was 140 mg (6%), 100 mg (71%), 70 mg BID (4.3%), 70 mg (3%), 20 mg (3%) and unknown (13%). Therapy was changed to another TKI without a dose modification in 43% patients, the dose was reduced in 46% patients and we do not have information about dose available for the other 11% patients. Recurrence of PE was observed in 34 (49%) patients. PE directed treatment included a combination of furosemide (49%), steroids (20%) and thoracentesis (49%). The median time from initiation of dasatinib to development of PE was 31 months. Only 12 patients (17.3%) continued dasatinib after development of PE, while the other 57 patients discontinued the drug. Median duration of therapy on dasatinib was 39 months in patients that developed PE. Therapy was switched to bosutinib in 13 patients out of whom 6 (46%) re-developed PE. The median time to re-accumulation of PE after switching to bosutinib was 9 months. While only 14.2% patients developed re-accumulation of pleural fluid in patients switched to imatinib, none of the patients switched to nilotinib re-developed PE.
Conclusion:
A change in TKI to bosutinib was associated with a 46% risk of recurrence of pleural effusion in patients who develop pleural effusion on dasatinib for the treatment of CP-CML. The incidence of recurrent PE was markedly lower in patient switched to imatinib or nilotinib. Further prospective studies are needed to determine the safety of bosutinib in this setting.
Nodzon: Takeda: Consultancy. Komrokji: BMSCelgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; PharmaEssentia: Membership on an entity's Board of Directors or advisory committees; Geron: Consultancy; Jazz: Consultancy, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy; Acceleron: Consultancy; Taiho Oncology: Membership on an entity's Board of Directors or advisory committees. Sallman: Kite: Membership on an entity's Board of Directors or advisory committees; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Syndax: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Aprea: Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Magenta: Consultancy; Incyte: Speakers Bureau; Takeda: Consultancy; Intellia: Membership on an entity's Board of Directors or advisory committees. Padron: Stemline: Honoraria; Blueprint: Honoraria; Incyte: Research Funding; Kura: Research Funding; BMS: Research Funding; Taiho: Honoraria. Kuykendall: Prelude: Research Funding; PharmaEssentia: Honoraria; Novartis: Honoraria, Speakers Bureau; Incyte: Consultancy; CTI Biopharma: Honoraria; Celgene/BMS: Honoraria, Speakers Bureau; BluePrint Medicines: Honoraria, Speakers Bureau; Abbvie: Honoraria; Protagonist: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Lancet: Jazz: Consultancy; Astellas: Consultancy; BerGenBio: Consultancy; Agios: Consultancy; ElevateBio Management: Consultancy; Daiichi Sankyo: Consultancy; Celgene/BMS: Consultancy; Millenium Pharma/Takeda: Consultancy; AbbVie: Consultancy. Pinilla Ibarz: Sellas: Other: ), patents/royalties/other intellectual property; MEI, Sunesis: Research Funding; AbbVie, Janssen, AstraZeneca, Takeda: Speakers Bureau; AbbVie, Janssen, AstraZeneca, Novartis, TG Therapeutics, Takeda: Consultancy, Other: Advisory. Sweet: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; AROG: Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees.
| v2 |
2021-11-25T16:13:50.486Z | 2021-11-05T00:00:00.000Z | 244548281 | s2ag/train | A Phase 2 Study of Bezuclastinib (CGT9486), an Oral, Selective, and Potent KIT D816V Inhibitor, in Adult Patients with Advanced Systemic Mastocytosis (AdvSM)
Systemic mastocytosis (SM) is characterized by excessive accumulation of mast cells in bone marrow and other extracutaneous tissues encompassing a spectrum of variants ranging from non-advanced to advanced disease (Shomali et al, 2018). Advanced systemic mastocytosis (AdvSM) is an aggressive and life-threatening form of SM with an overall survival from <6 months to ~3-4 years depending on subtype (Gotlib et al, 2018; NCCN Systemic Mastocytosis, Version 2.2019; Pardanani, 2019; Rossignol et al, 2019; Shomali et al, 2018). The three distinct subtypes of AdvSM include aggressive systemic mastocytosis (ASM), SM with an associated hematologic neoplasm (SM-AHN), and mast cell leukemia (MCL) (NCCN Systemic Mastocytosis, Version 2, 2019; Pardanani, 2019; Shomali et al, 2018).
The molecular pathogenesis of SM is driven by mutations in the KIT gene leading to ligand-independent proliferation of mast cells, with 95% of patients carrying the D816V mutation in exon 17 (Garcia-Montero et al, 2006; Jara-Acevedo et al, 2015; Vaes et al, 2017). Bezuclastinib, an oral, highly selective tyrosine kinase inhibitor with potent activity against KIT D816V has shown preliminary clinical activity and a tolerable safety profile in a Ph 1/2 study of patients with advanced solid tumors including gastrointestinal stromal tumor (GIST). In that study, a reduction in KIT exon 17 mutational burden was observed in subjects treated with bezuclastinib. This reduction was temporally associated with a reduction in tumor burden supporting bezuclastinib as an active therapy in KIT-driven diseases (Wagner et al, 2018).
Other agents targeting the KIT D816V mutations have shown activity in the treatment of AdvSM; however, toxicities such as cognitive impairment, intracranial hemorrhage, and edema may limit dosing and appropriateness of these therapies. Besides targeting KIT D816V, bezuclastinib was designed to avoid other closely related kinases with known liabilities, such as PDGFRα, PDGFRβ, wild-type KIT, VEGFR2 (KDR), and CSF1R (FMS). Additionally, minimal brain penetration has been observed with bezuclastinib, and no CNS toxicities have been identified in preclinical studies.
This is a multi-center, Phase 2, open-label, 2-part clinical study to evaluate the safety, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of bezuclastinib in subjects with AdvSM. This study will enroll subjects who meet WHO diagnostic criteria for AdvSM, have measurable SM-related organ damage according to modified IWG-MRT-ECNM consensus eligibility and response criteria, and have a baseline serum tryptase of ≥20 ng/mL. The diagnosis of AdvSM and evidence of measurable disease will be confirmed by an Eligibility Committee prior to enrollment.
This study will enroll approximately 140 patients. Part 1 will consist of a dose optimization period to determine the optimal dose of bezuclastinib for subjects with AdvSM. Subjects will be randomized into one of four dose cohorts (50, 100, or 200 mg twice daily, or 400 mg once daily) in a 1:1:1:1 manner. A planned interim analysis to assess safety, efficacy, and biomarker endpoints will occur when approximately half the planned number of Part 1 patients have been evaluated through at least 2 cycles of treatment. After all subjects in Part 1 complete at least two cycles, the optimal dose will be selected. Part 2 will enroll subjects at the selected dose level to determine efficacy of bezuclastinib and to further characterize safety, PK, and PD. The primary assessment of efficacy is overall response rate, defined as the percentage of subjects classified as confirmed responders (CR, CR with incomplete hematologic recovery [CRh], partial response [PR], and clinical improvement [CI]) according to modified IWG-MRT-ECNM response criteria as assessed by a Central Response Review Committee (CRRC).
Data from this study will support continued development of bezuclastinib in SM including Non-Advanced SM.
This study opened in June 2021.
Gotlib: BMS: Research Funding; Kartos: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; PharmaEssentia: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cogent Biosciences: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Chair for the Eligibility and Central Response Review Committee, Research Funding; Allakos: Consultancy; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Deciphera: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Blueprint Medicines: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. George: Celgene: Consultancy; Blueprint Medicines: Consultancy; Bristol Meyers Squibb: Consultancy; Incyte Corporation: Consultancy. Deininger: Sangamo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Part of a Study Management Committee, Research Funding; Novartis: Consultancy, Research Funding; Incyte: Consultancy, Honoraria, Research Funding; SPARC, DisperSol, Leukemia & Lymphoma Society: Research Funding; Fusion Pharma, Medscape, DisperSol: Consultancy; Blueprint Medicines Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Part of a Study Management Committee, Research Funding. Tashi: PharmaEssentia: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board. Pullarkat: Amgen, Dova, and Novartis: Consultancy, Honoraria; AbbVie, Amgen, Genentech, Jazz Pharmaceuticals, Novartis, Pfizer, and Servier: Membership on an entity's Board of Directors or advisory committees. Bose: Celgene Corporation: Honoraria, Research Funding; Astellas: Research Funding; NS Pharma: Research Funding; Novartis: Honoraria; Promedior: Research Funding; BMS: Honoraria, Research Funding; CTI BioPharma: Honoraria, Research Funding; Sierra Oncology: Honoraria; Incyte Corporation: Honoraria, Research Funding; Blueprint Medicines: Honoraria, Research Funding; Pfizer: Research Funding; Kartos Therapeutics: Honoraria, Research Funding; Constellation Pharmaceuticals: Research Funding. Payumo: Cogent Biosciences, Inc: Current Employment. Pilla: Cogent Biosciences: Current Employment. Jolin: Cogent Biosciences: Current Employment. DeAngelo: Abbvie: Research Funding; Takeda: Consultancy; Servier: Consultancy; Pfizer: Consultancy; Novartis: Consultancy, Research Funding; Jazz: Consultancy; Incyte: Consultancy; Forty-Seven: Consultancy; Autolus: Consultancy; Amgen: Consultancy; Agios: Consultancy; Blueprint: Research Funding; Glycomimetrics: Research Funding.
Study is for investigational agent
| v2 |
2018-05-11T01:28:26.911Z | 2018-01-01T00:00:00.000Z | 24463241 | s2ag/train | Interventions for improving adherence to iron chelation therapy in people with sickle cell disease or thalassaemia.
BACKGROUND
Regularly transfused people with sickle cell disease (SCD) and people with thalassaemia (who are transfusion-dependent or non-transfusion-dependent) are at risk of iron overload. Iron overload can lead to iron toxicity in vulnerable organs such as the heart, liver and endocrine glands; which can be prevented and treated with iron chelating agents. The intensive demands and uncomfortable side effects of therapy can have a negative impact on daily activities and well-being, which may affect adherence.
OBJECTIVES
To identify and assess the effectiveness of interventions (psychological and psychosocial, educational, medication interventions, or multi-component interventions) to improve adherence to iron chelation therapy in people with SCD or thalassaemia.
SEARCH METHODS
We searched CENTRAL (the Cochrane Library), MEDLINE, Embase, CINAHL, PsycINFO, Psychology and Behavioral Sciences Collection, Web of Science Science & Social Sciences Conference Proceedings Indexes and ongoing trial databases (01 February 2017). We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register (12 December 2017).
SELECTION CRITERIA
For trials comparing medications or medication changes, only randomised controlled trials (RCTs) were eligible for inclusion.For studies including psychological and psychosocial interventions, educational Interventions, or multi-component interventions, non-RCTs, controlled before-after studies, and interrupted time series studies with adherence as a primary outcome were also eligible for inclusion.
DATA COLLECTION AND ANALYSIS
Three authors independently assessed trial eligibility, risk of bias and extracted data. The quality of the evidence was assessed using GRADE.
MAIN RESULTS
We included 16 RCTs (1525 participants) published between 1997 and 2017. Most participants had β-thalassaemia major; 195 had SCD and 88 had β-thalassaemia intermedia. Mean age ranged from 11 to 41 years. One trial was of medication management and 15 RCTs were of medication interventions. Medications assessed were subcutaneous deferoxamine, and two oral-chelating agents, deferiprone and deferasirox.We rated the quality of evidence as low to very low across all outcomes identified in this review.Three trials measured quality of life (QoL) with validated instruments, but provided no analysable data and reported no difference in QoL.Deferiprone versus deferoxamineWe are uncertain whether deferiprone increases adherence to iron chelation therapy (four trials, very low-quality evidence). Results could not be combined due to considerable heterogeneity (participants' age and different medication regimens). Medication adherence was high (deferiprone (85% to 94.9%); deferoxamine (71.6% to 93%)).We are uncertain whether deferiprone increases the risk of agranulocytosis, risk ratio (RR) 7.88 (99% confidence interval (CI) 0.18 to 352.39); or has any effect on all-cause mortality, RR 0.44 (95% CI 0.12 to 1.63) (one trial; 88 participants; very low-quality evidence).Deferasirox versus deferoxamineWe are uncertain whether deferasirox increases adherence to iron chelation therapy, mean difference (MD) -1.40 (95% CI -3.66 to 0.86) (one trial; 197 participants; very-low quality evidence). Medication adherence was high (deferasirox (99%); deferoxamine (100%)). We are uncertain whether deferasirox decreases the risk of thalassaemia-related serious adverse events (SAEs), RR 0.95 (95% CI 0.41 to 2.17); or all-cause mortality, RR 0.96 (95% CI 0.06 to 15.06) (two trials; 240 participants; very low-quality evidence).We are uncertain whether deferasirox decreases the risk of SCD-related pain crises, RR 1.05 (95% CI 0.68 to 1.62); or other SCD-related SAEs, RR 1.08 (95% CI 0.77 to 1.51) (one trial; 195 participants; very low-quality evidence).Deferasirox film-coated tablet (FCT) versus deferasirox dispersible tablet (DT)Deferasirox FCT may make little or no difference to adherence, RR 1.10 (95% CI 0.99 to 1.22) (one trial; 173 participants; low-quality evidence). Medication adherence was high (FCT (92.9%); DT (85.3%)).We are uncertain if deferasirox FCT increases the incidence of SAEs, RR 1.22 (95% CI 0.62 to 2.37); or all-cause mortality, RR 2.97 (95% CI 0.12 to 71.81) (one trial; 173 participants; very low-quality evidence).Deferiprone and deferoxamine combined versus deferiprone alone We are uncertain if deferiprone and deferoxamine combined increases adherence to iron chelation therapy (very low-quality evidence). Medication adherence was high (deferiprone 92.7% (range 37% to 100%) to 93.6% (range 56% to 100%); deferoxamine 70.6% (range 25% to 100%).Combination therapy may make little or no difference to the risk of SAEs, RR 0.15 (95% CI 0.01 to 2.81) (one trial; 213 participants; low-quality evidence).We are uncertain if combination therapy decreases all-cause mortality, RR 0.77 (95% CI 0.18 to 3.35) (two trials; 237 participants; very low-quality evidence).Deferiprone and deferoxamine combined versus deferoxamine aloneDeferiprone and deferoxamine combined may have little or no effect on adherence to iron chelation therapy (four trials; 216 participants; low-quality evidence). Medication adherence was high (deferoxamine 91.4% to 96.1%; deferiprone: 82.4%)Deferiprone and deferoxamine combined, may have little or no difference in SAEs or mortality (low-quality evidence). No SAEs occurred in three trials and were not reported in one trial. No deaths occurred in two trials and were not reported in two trials.Deferiprone and deferoxamine combined versus deferiprone and deferasirox combinedDeferiprone and deferasirox combined may improve adherence to iron chelation therapy, RR 0.84 (95% CI 0.72 to 0.99) (one trial; 96 participants; low-quality evidence). Medication adherence was high (deferiprone and deferoxamine: 80%; deferiprone and deferasirox: 95%).We are uncertain if deferiprone and deferasirox decreases the incidence of SAEs, RR 1.00 (95% CI 0.06 to 15.53) (one trial; 96 participants; very low-quality evidence).There were no deaths in the trial (low-quality evidence).Medication management versus standard careWe are uncertain if medication management improves health-related QoL (one trial; 48 participants; very low-quality evidence). Adherence was only measured in one arm of the trial.
AUTHORS' CONCLUSIONS
The medication comparisons included in this review had higher than average adherence rates not accounted for by differences in medication administration or side effects.Participants may have been selected based on higher adherence to trial medications at baseline. Also, within the clinical trial context, there is increased attention and involvement of clinicians, thus high adherence rates may be an artefact of trial participation.Real-world, pragmatic trials in community and clinic settings are needed that examine both confirmed or unconfirmed adherence strategies that may increase adherence to iron chelation therapy.Due to lack of evidence this review cannot comment on intervention strategies for different age groups. | v2 |
2016-03-14T22:51:50.573Z | 2004-01-01T00:00:00.000Z | 5533861 | s2ag/train | A Step Towards A Computing Grid For The LHC Experiments : ATLAS Data Challenge 1 The ATLAS DC 1 Task Force * )
The ATLAS Collaboration at CERN is preparing for the data taking and analysis at the LHC that will start in 2007. Therefore, a series of Data Challenges was started in 2002 whose goals are the validation of the Computing Model, of the complete software suite, of the data model, and to ensure the correctness of the technical choices to be made for the final offline computing environment. A major feature of the first Data Challenge (DC1) was the preparation and the deployment of the software required for the production of large event samples as a worldwide distributed activity. It should be noted that it was not an option to “run the complete production at CERN” even if we had wanted to; the resources were not available at CERN to carry out the production on a reasonable time-scale. The great challenge of organising and then carrying out this large-scale production at a significant number of sites around the world had therefore to be faced. However, the benefits of this are manifold: apart from realising the required computing resources, this exercise created worldwide momentum for ATLAS computing as a whole. This report describes in detail the main steps carried out in DC1 and what has been learned from them as a step towards a computing Grid for the LHC experiments. (To be submitted to Nucl. Instr. Meth.) *) See next pages for the list of authors 1 The ATLAS DC1 Task Force R. Sturrock University of Melbourne, AUSTRALIA R. Bischof, B. Epp, V. M. Ghete, D. Kuhn Institute for Experimental Physics, University of Innsbruck, AUSTRIA A.G. Mello Universidade Federal do Rio de Janeiro, COPPE/EE/IF, Rio de Janeiro, BRAZIL B. Caron Centre for Subatomic Research, University of Alberta and TRIUMF, Vancouver, CANADA M.C. Vetterli Department of Physics, Simon Fraser University, Burnaby, CANADA G. Karapetian Laboratoire de Physique Nucleaire, Université de Montréal, CANADA K. Martens Department of Physics, University of Toronto, CANADA A. Agarwal, P. Poffenberger, R.A. McPherson, R.J. Sobie Department of Physics and Astronomy, University of Victoria, CANADA S. Armstrong, N. Benekos, V. Boisvert, M. Boonekamp, S. Brandt, P. Casado, M. Elsing, F. Gianotti, L. Goossens, M. Grote, J.B. Hansen, K. Mair, A. Nairz, C. Padilla, A. Poppleton, G. Poulard, E. Richter-Was, S. Rosati, T. Schoerner-Sadenius, T. Wengler CERN G.F. Xu Institute of High Energy Physics, Chinese Academy of Sciences, CHINA J.L. Ping Nanjing University, CHINA J. Chudoba, J. Kosina, M. Lokajicek, J. Svec Institute of Physics, Academy of Sciences of the Czech Republic, Praha , CZECH REPUBLIC P. Tas Charles University in Prague, Faculty of Mathematics and Physics, IPNP, Praha, CZECH REPUBLIC J. R. Hansen, E. Lytken, J. L. Nielsen, A. Wäänänen Niels Bohr Institutet for Astronomi, Fysik og Geofysik, Copenhagen, DENMARK S. Tapprogge Helsinki Institute of Physics, Helsinki, FINLAND D. Calvet Université Blaise Pascal de Clermont-Ferrand, FRANCE S. Albrand, J. Collot, J. Fulachier, F. Ledroit-Guillon, F. Ohlsson-Malek, S. Viret, M. Wielers LPSC, CNRS-IN2P3, Université Joseph Fourier, Grenoble, FRANCE a Now at the Institute of Particle Physics of Canada b Now at CEA-Saclay c Now at Crakow d Now at Hamburg e At TRIUMF until 01/02/03 2 K. Bernardet, S. Corréard, A. Rozanov, J-B. de Vivie de Regie CPPM, CNRS-IN2P3, Université de la Méditérannée, Marseille, FRANCE C. Arnault, C. Bourdarios, J. Hrivnac, M.Lechowski, G. Parrour, A. Perus, D. Rousseau, A. Schaffer, G. Unal LAL-Orsay, CNRS-IN2P3, Université Paris XI, Orsay, FRANCE F. Derue LPNHEP, CNRS-IN2P3, Université Paris 6/7, Jussieu, Paris, FRANCE L. Chevalier, S. Hassani, J-F. Laporte, R. Nicolaidou, D. Pomarède, M. Virchaux CEA/DAPNIA, Saclay, FRANCE N. Nesvadba Rheinische Friedrich-Wilhelms Universität, Bonn, GERMANY Sergei Baranov Universität Freiburg, GERMANY A. Putzer Kirchhoff -Institut für Physik, Universität Heidelberg, GERMANY A. Khonich Universität Mannheim, GERMANY G. Duckeck , P. Schieferdecker LMU München, GERMANY A. Kiryunin, J. Schieck MPI für Physik, München, GERMANY Th. Lagouri Nuclear Physics Laboratory, Aristotle University of Thessaloniki, GREECE E. Duchovni, L. Levinson, D. Schrager, Weizmann Institute of Science, ISRAEL G. Negri CNAF, Bologna, ITALY H. Bilokon, L. Spogli LNF, Frascati, ITALY D. Barberis, F. Parodi Università di Genova e INFN, ITALY G. Cataldi, E. Gorini, M. Primavera, S. Spagnolo Università di Lecce e INFN, ITALY D. Cavalli, M. Heldmann, T. Lari, L. Perini, D. Rebatto, S. Resconi, F. Tartarelli, L. Vaccarossa Università di Milano e INFN, ITALY M. Biglietti, G. Carlino, F. Conventi, A. Doria, L. Merola, Università di Napoli “Federico II” e INFN, ITALY G. Polesello, V. Vercesi Sezione INFN di Pavia, ITALY f At Milano before Dec. 2002 g Now at Freiburg 3 A. De Salvo, A. Di Mattia, L. Luminari, A. Nisati, M. Reale, M. Testa Università di Roma “La Sapienza” e INFN , ITALY A. Farilla , M. Verducci Università di Roma Tre e INFN, ITALY M. Cobal, L.Santi Università di Udine e INFN, ITALY Y. Hasegawa Shinshu University, JAPAN M. Ishino, T. Mashimo, H. Matsumoto, H. Sakamoto, J. Tanaka, I. Ueda International Center for Elementary Particle Physics(ICEPP), the University of Tokyo, JAPAN S.Bentvelsen, A.Fornaini, G.Gorfine, D.Groep, J.Templon NIKHEF, NETHERLANDS J. Koster, Parallab / UNIFOB, University of Bergen, NORWAY A. Konstantinov ,T. Myklebust, F. Ould-Saada University of Oslo, Department of Physics, NORWAY T. Bold, A. Kaczmarska, P. Malecki, T. Szymocha, M. Turala The Henryk Niewodniczanski Institute of Nuclear Physics, Krakow, POLAND Y. Kulchitsky, G. Khoreauli, N. Gromova, V. Tsulaia Joint Institute for Nuclear Research, Dubna, RUSSIA A. Minaenko, R. Rudenko, E. Slabospitskaya, A. Solodkov Institute of High Energy Physics, Protvino, RUSSIA I. Gavrilenko P.N. Lebedev Institute of Physics (FIAN), Moscow, RUSSIA N. Nikitine, S. Sivoklokov, K. Toms Skobeltsyn Institute of Nuclear Physics, Moscow State University, RUSSIA A. Zalite, I. Zalite St.Petersburg Nuclear Physics Institute, RUSSIA B.Kersevan University of Ljubljana and Iozef Stefan Institut, Ljubljana, SLOVENIA M. Bosman Institut de Física d'Altes Energies (IFAE), Barcelona, SPAIN S. Gonzalez, J. Sanchez, J. Salt Instituto de Fisica Corpuscular (IFIC, Centro Mixto CSIC-UVEG), Valencia, SPAIN N. Andersson , L. Nixon NSC, Linköping University, SWEDEN h Also at IMSAR, Vilnius University i Also at Faculty of Physics and Nuclear Techniques, UST-AGH Krakow, POLAND k Supported by a grant under contract CERN-INTAS-0052-4297 | v2 |
2019-04-11T13:14:24.103Z | 1998-01-15T00:00:00.000Z | 197403351 | s2ag/train | Residential Broadband Networks: XDSL, HFC and Fixed Wireless Access
1. Introduction. Problems at the Local Loop. Bandwidth Requirements Beyond Voice. Problems Beyond the Local Loop. Growth in Voice, Data and Video Use. The Increased Need for More Capacity. Circuit and Packet Switching. Approaches to Solving the Problems. Present Residential Local Loop Configuration. Full Service Terminal. An Overview of the Local Loop. LATAs. The Outside Plant. Subscriber Loop Systems. POTS Design Goals. Digital Loop Carrier (DLC) Systems. Basic Subscriber System Arrangement. Digital Subscriber Line (DSL). Coding/Modulation and Wiring Schemes. High-bit-rate Digital Subscriber Line (HDSL). ADSL/VADSL. Access Technologies (Wiring Plans). FTTC, FTTH: FITL. Hybrid Fiber Coax (HFC). Switched Digital Video (SDV). SONET in Residential Broadband. ATM in Residential Broadband. Wireless Topology for Residential Broadband. Summary. 2. Coding and Modulation. High-Data-Rate Digital Subscriber Line (HDSL) Modulation. Multilevel Coding. Symbol Rates and Bit Rates. Carrierless Amplitude Modulation (CAP). Analysis of CAP Performance. The ATM Forum CAP Specification. Discrete Multi-tone (DMT) Modulation. CAP/QAM versus DMT. Asymmetrical Digital Subscriber Line (ADSL). ADSL Architecture. RADSL and VDSL. ITU-T V Series Modems. Crosstalk. Summary. 3.GR-303: Current RBB Architecture. GR-303 Architecture. IDLC Architecture. Types of Services. Remote Digital Terminal (RDT). Integrated Network Access. The GR-303 Layered Model. GR-303 Framing Conventions. Call Processing Options. GR-303 and the Signaling bits. LAPD in GR-303 Operations. Example of LAPD Operations. GR-303 Requirements for LAPD. The Basic Rate Interface (BRI) Topologies. The Service Access Point Identifiers (SAPI). Other LAPD Operations. SAPI/TEI Addressing Conventions. GR-303 Layer 3 Operation. Assignment Initiations. Timeslot Clearing. Loop Start Circuits. Establishment by Customer (Loop Start Circuits). Clearing (Loop Start Circuits). Ground Start Circuits. Establishment by Customer (Ground Start Circuits). Call Clearing (Loop Reverse Battery Circuits). 911 Calls (Loop Reverse Battery Circuits). Reverting Call Establishment (Multiparty Option). ISDN Basic Access Circuits. GR-303 Messages. Functions of the Messages. Information Elements (Parameters) in the Message. Summary. 4.Fiber in the Loop and the Synchronous Optical Network (SONET). Active Network Interface Device (ANID). Coaxial Spectrum Allocation. The ANID Interfaces and layers. Physical Layer to Coaxial and Twisted Pair Plant at NIU (1). Data Link Layer at the NIU (2). Physical Layer on the Customer Side NIU (3). Physical Layer on the Customer Side (SIU) (4). Data Link Layer at the SIU (5). Session Layer at the SIU (6). Physical Layer Interface between SIU and Customer Plant (7). Other FITL Services. SONET in Residential Broadband. Structural Diversity in the Access Network. Line Protection and Path Protection. Restoration Alternatives. Summary of Options for Protecting the Distribution Network. 1+1 and 1:1 Linear Configurations. 1:N Linear Configuration. Regenerator. Two- or Four-Fiber Ring/Add-Drop Multiplexer. SONET Payloads. SONET Configuration. SONET Signal Hierarchy. SONET Transmission and Relationship to Asynchronous Payloads. The Envelope (Frame). Pointer Operations. Vt/VC Groups. Wave Division Multiplexing (WDM). Bandwidth Management. Summary. 5.ATM Networks in Two-Way Access Systems. features of atm. The ATM Cell. Switching. Examples of Protocol Placement in the B-ISDN Layers. The ATM ADAPTATION Layer (AAL). Service Classes. ATM Forum RBB. ATM RBB Reference Architecture. ATM Digital Terminal (ADT). ATM Interface Unit (AIU). ATM over HFC. Physical Interface for the Home ATM Network. ATM over ADSL. ATM Connection-Oriented Options on Residential Broadband. Relationship of the ATM Forum and IEEE 802.14 Specifications. Summary. 6.Internet and LAN Considerations. Problems with the Internet Service Providers (ISPs). Problems with the Telephone Service Providers. Some Solutions. Modem Termination Options. The 56 kbits Modem. Using the local loop for lan access. Summary. 7.New Generation Protocols for RBB HFC. The IEEE 802.14 Specification. The Adaptive DigiTal Access Protocol (ADAPt+). ADAPt+ Functional Groups. The PHY Layer. Symbol Rates, Bit Rates, and Byte Rates for ADAPt+. Bandwidth Capacity. Upstream and Downstream Synchronization. Upstream and Downstream Byte Rates. Downstream and Upstream PDU Structure. Downstream PDU Structure. Framing. Fast Control Field (FCF). ATR1 and ATR2 PDUs and Sdus. Forward Error Correction (FEC). Upstream PDU Structure. Upstream PHY Layer Requirements. The Contention Protocol. Bandwidth Requests and Allocations. Summary of the ADAPt+ Operations. Summary. 8.Fixed Wireless Access. Topology of Fixed Wireless Access (FWA). Fixed Wireless versus Fixed Wire Access. Wireless Local Loop (WLL) Options. Local Multipoint Multichannel Distribution Service (LMDS) and Multipoint Multichannel Distribution Service (MMDS). CDMA and TDMA. TDMA Concepts. CDMA Concepts. CDMA: Pros and Cons. DECT: An Alternative for FWA. DECT Architecture. DECT's Future in RBB? Current Issues With Spectrum Allocation. Cost-Sharing Formula. Effect of the Spectrum Allocation Plan in RBB. U.S. Market Forecast. Summary. Appendix A.Signaling Basics. Common Terms and Operations. Access and Supervisory Signaling. Signaling Arrangement (Loop start). Ground start signaling. Wink Start Signaling. Multifrequency Codes. DTMF Pairs. Example of Trunk-side Access Arrangement. OperAtor Service Signaling (SO). Appendix B.Media. Importance of Communications Media. Local Loops. Twisted-Pair Cable. Shielded and Unshielded Cable. Electronics Industries Association (EIA) Cable Categories. Coaxial Cable. Optical Fiber. Radio Frequency Bands. A Microwave System. Satellite Communications. Geosynchronous Satellites. Cellular Radio. Upcoming Wireless Networks. Appendix C.V.34. Features of V.34. Symbol Rates and Carrier Frequencies. The V.34 Use of V.24 Interchange Circuits. V8 and V.34 Signals and Their use. V.36 Phases. Phase 1: Network Interaction. Phase 2. Phase 3. Phase 4. Appendix D.Channel Performance and Measurements. Decibel Losses and Power Ratio. Decibels and Signal-to-Noise Ratios. dB Losses in Relation to Power Losses in Electrical Circuits. The Carrier Interference Ratio (Co-Channel Interference). Decibel 1 milliwatt. Example. Nyquist Model. Noise and Shannon's Law. Appendix E.TR-57, TR-507, TR-08. aspects of tr-57. aspects of TR-507. aspects of TR-08. Appendix F.GR-303 Requirements for ADSL, HFC, ATM, and Wireless-loop Distribution. GR-303-ILF Requirements. ADSL/IDLC Functional Reference Architecture. GR-303 ADSL/IDLC Requirements (Not all-inclusive). GR-303 HFC Requirements. GR-303-Wireless-Loop Distribution System (WLDS) Requirements. GR-303 Wireless-Loop Distribution System (WLDS). Summary. Additional References and Acknowledgments. Index. | v2 |
2019-12-12T08:03:29.810Z | 2019-11-13T00:00:00.000Z | 209233581 | s2ag/train | Nonmyeloablative Allogeneic Transplantation (NMAT) Confers an Overall Survival Benefit with Similar Non-Relapse Mortality When Compared to Autologous Stem Transplantation (ASCT) for Patients (pts) with Relapsed Follicular Lymphoma (FL)
Purpose: The roles of allogeneic vs autologous SCT for pts with relapsed FL are under debate. Past studies suggested that allogeneic SCT has a lower relapse rate due to a graft-versus-lymphoma effect, but the risks of graft-versus-host disease (GVHD) and early death negated any survival benefit over ASCT. NMAT allows the performance of transplants with a lower toxicity. Efforts to answer address the debate were attempted through a prospective Blood and Marrow Transplant Clinical Trials Network randomized trial; however it was closed early due to a low accrual. In this report, we compared the outcomes of NMAT vs. ASCT in pts with relapsed FL at a single center.
Methods: Pts with relapsed FL received an NMAT if they had an 8/8 HLA-matched adult donor. Pts who had no suitable donors or were not able to have an NMAT due to Medicare/Medicaid reimbursement guidelines received instead an ASCT if they had chemo-sensitive disease (PR or CR) and no bone marrow involvement by disease. Organ eligibility criteria were comparable between the two transplant groups. Conditioning for NMAT consisted of fludarabine (30 mg/m2 daily x3), cyclophosphamide (750 mg/m2 daily x3) (or bendamustine 130 mg/m2 daily x3), rituximab (375 m2 day -13, then 1000 mg/m2 days -6,+1 and +8) +/- Yttrium-90 ibritumomab tiuxetan (0.4 mCi/kg) (Blood 2012 ;119:6373; Blood 2014;124:2306). Tacrolimus and mini-methotrexate were used for GVHD prophylaxis. In addition, thymoglobulin of 1 mg/kg was given on days -2 and -1 in patients receiving a matched-unrelated donor (MUD) transplant. Pts with ASCT underwent chemo-mobilization of stem cells with rituximab for in-vivo purging; rituximab was also given on days+1 and +8 with BEAM conditioning (Clin Cancer Res 2018; 24:2304-11). This study was IRB-approved at our center.
Results: The study included 98 NMAT and 96 ASCT pts treated between 2000-2017. Median age was 53 and 56 yrs, respectively and 24 (24%) and 32 (33%) pts were older than 60 yrs (P=0.21). Male gender was 50% vs 48%, respectively. Eleven NMAT pts (11%) and 18 ASCT (19%) pts had an HCT-CI of > 4 (P=0.16). The time from diagnosis to transplant was 38 months in both groups. Rituximab-chemo induction was received in 54 (55%), and 66 (69%) pts at diagnosis, respectively (P=0.056). Seventy-one NMAT (72%) and 61 ASCT (64%) pts relapsed within 2 yrs of their induction chemotherapy (P=0.22). Most pts (94% and 100%) received transplant from peripheral blood. Significant differences between treatment groups were observed for disease status, prior number of chemotherapies, and year of SCT. More pts receiving NMAT had refractory disease compared with the ASCT group (P=0.018). In addition, a higher percentage of NMAT pts had bulky disease (P=0.016), had a transplant > 1st relapse (P=0.001), received > 3 prior chemotherapies (P=0.003), and had a transplant between 2000-2005 rather than later years (P=0.033) compared with the ASCT pts. NMAT transplant characteristics included MUDs in 28 (29%) patients, 42 (43%) ABO-mismatched and CMV was reactive in 80% of pts and/or donors. With a median follow-up for NMAT pts of 98 months (range, 3-208 months) and 94 months (range, 1-207 months) for ASCT pts, overall survival was significantly better for NMAT patients compared to ASCT patients (62% vs 46%; P=0.048) (Figure 1). Similarly, progression-free-survival was better for NMAT pts compared to ASCT pts (52% vs 31%; P <0.001) (Figure 2). The cumulative incidence (CI) of relapse was 15% vs 48%, respectively (P<0.0001).The significant differences were also seen in propensity score matched analysis where the two groups were matched on age, bulk, disease status, number of prior therapies, induction chemotherapy and year of transplant. The OS and PFS benefits of NMAT were also observed for pts >60 yrs of age. The CI of grade II-IV and III-IV acute GVHD in the NMAT group was 22% and 9%, respectively. The CI of chronic extensive GVHD was 38%. The 8-year CI of secondary MDS/AML in the ASCT group was 12%, which progressively increased to 21% at end of assessment. Non-relapse mortality was similar between the two groups (Figure 3).
Conclusions: This is the first study to show that NMAT confers a superior survival in pts with relapsed/FL compared with ASCT. Our conclusions are supported by long-term follow-up. A collaborative effort is needed to allow Medicare/Medicaid pts with high-risk relapsed FL to benefit from NMAT.
Nastoupil: Spectrum: Honoraria; TG Therapeutics: Honoraria, Research Funding; Novartis: Honoraria; Janssen: Honoraria, Research Funding; Gilead: Honoraria; Bayer: Honoraria; Celgene: Honoraria, Research Funding; Genentech, Inc.: Honoraria, Research Funding. Jabbour:Pfizer: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Cyclacel LTD: Research Funding; Amgen: Consultancy, Research Funding. Bashir:Amgen: Membership on an entity's Board of Directors or advisory committees; Imbrium: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; StemLine: Research Funding; Acrotech: Research Funding; Celgene: Research Funding. Ciurea:Miltenyi: Research Funding; Spectrum: Membership on an entity's Board of Directors or advisory committees; MolMed: Membership on an entity's Board of Directors or advisory committees; Kiadis Pharma: Membership on an entity's Board of Directors or advisory committees, Other: stock holder. Molldrem:M. D. Anderson & Astellas Pharma: Other: Royalties. Oran:Astex pharmaceuticals: Research Funding; AROG pharmaceuticals: Research Funding. Popat:Bayer: Research Funding; Incyte: Research Funding; Jazz: Consultancy. Qazilbash:Bioclinica: Consultancy; Amgen: Other: Advisory Board; Autolous: Consultancy; Speaker: Other: Speaker.
| v2 |
2019-04-12T13:54:28.111Z | 2015-04-01T00:00:00.000Z | 109037391 | s2ag/train | Survey of LDL-c Diameter and sdLDL-c Serum Levels in Relation with Hypertriglyceridemic waist Circumference Phenotype in Middle Aged Women
Background and Objectives: Obesity is a major risk factor of cardiovascular diseases. Visceral adipose tissue (VAT) plays an important role in complications obesity. Although the measurement of waist circumference is a useful index for evaluating obesity and its complications, always increasing of waist circumference is not associated with VAT accumulation. HTGW (Hypertriglyceridemic waist circumference) phenotype is a useful marker for visceral adipose tissue accumulation. The purpose of this study is comparison of sdLDL-c serum level and LDL-c particle size as risk factors for cardiovascular diseases in middle aged woman with HTGW phenotype and without it. Materials and Methods: For this purpose, 90 volunteer women between 40 and 60 years old based on the four common definitions of HTGW phenotype, were divided into two groups with and without this phenotype. It was used precipitation method for measurement of serum levels of sdLDL-c. LDL-c particle size also was measured by the gradient gel electrophoresis technique. Results: Although in all of definitions, LDL-c particle size significantly was smaller in group with this HTGW phenotype, sdLDL-c serum level was statistical significant different in both definitions of HTGW-L and HTGW-H. Conclusion: According to significant difference in diameter of LDL-c particles and sdLDL-c concentrations grouped based on the definitions HTGW-L and HTGW-H as well as the role of sdLDL-c particles in cardiovascular diseases, therefore mentioned definitions are useful inexpensive screening tools to identify individuals at risk for cardiovascular diseases. References 1- Despres J-P. Cardiovascular disease under the influence of excess visceral fat. Critical Pathways In Cardiology. 2007 6: 51-9. 2- Sarrafzadegan N, Kopaei SA. The Association between hypertriglyceridemic waist phenotype, menopause, and cardiovascular risk factors. Arch Iran Med. 2012 16: 161-6. 3- Janssen I, Katzmarzyk PT, Ross R. Waist circumference and not body mass index explains obesity-related health risk. Am J Clin Nutr. 2004 84: 379: (3)79. 4- Lemieux I, Poirier P, Bergeron J, et al. Hypertriglyceridemic waist: a useful screening phenotype in preventive cardiology? Can J Cardiol. 2007 23: 23B-31B. 5- Rexrode KM, Carey VJ, Hennekens CH, et al. Abdominal adiposity and coronary heart disease in women. JAMA. 1998 280: 1843-8. 6- Hamdi O, Porramatikul S, Al-Ozairi E. Metabolic obesity: the paradox between visceral and subcutaneous fat. Curr Diabetes Rev. 2006 2: 367-73. 7- Frayn KN. Visceral fat and insulin resistance causative or correlative? Br J of Nutr. 2000 83: S71-S7. 8- Cornier M-A, Dabelea D, Hernandez TL, et al. The metabolic syndrome. Endocr Rev. 2008 29: 777-822. 9- Leroith D. Pathophysiology of the metabolic syndrome: implications for the cardiometabolic risks associated with type 2 diabetes. Am J Med Sci. 2012 343: 13-6. 10- Therond P. Catabolism of lipoproteins and metabolic syndrome. Curr Opin Clin Nutr Metab Care. 2009 12: 366-71. 11- Superko HR, Gadesam RR. Is it LDL particle size or number that correlates with risk for cardiovascular disease? Curr Atheroscler rep. 2008 10: 377-85. 12- Rizzo M, Berneis K. Low-density lipoprotein size and cardiovascular risk assessment. QJM. 200699:1-14. 13- Gazi IF, Milionis HJ, Filippatos TD, et al. Hypertriglyceridaemic waist phenotype criteria and prevalent metabolic triad in women. Diabetes Metab Res Rev. 2008 24: 223-30. 14- Jellife DB .The assessment of the nutritional status of the Community. Monogr Set World Health. 1966: 53: 3-271. 15- Hirano T, Ito Y, Koba S,et al. Clinical significance of small dense low-density lipoprotein cholesterol levels determined by the simple precipitation method. Arterioscler, Thrombosis, Vasc biol. 2004 24: 558-63. 16- Matthews D, Hosker J, Rudenski A, Naylor B, Treacher D, Turner R. Homeostasis model assessment: insulin resistance and β-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985 28: 412-9. 17- Esteghamati A, Ashraf H, Esteghamati A-R, et al. Optimal threshold of homeostasis model assessment for insulin resistance in an Iranian population: the implication of metabolic syndrome to detect insulin resistance. Diabetes Res Clin Pract. 2009 84: 279-87. 18- Rainwater DL, Moore P, Shelledy W, Dyer TD, Slifer SH. Characterization of a composite gradient gel for the electrophoretic separation of lipoproteins. J Lipid Res. 1997 38: 1261-6. 19- Ghassab RK, Gohari LH, Firoozray M, Yegane MN. Determination of low density lipoprotein particle size by polyacrylamide gradient gel electrophoresis in patients with coronary artery stenosis. Lab Medicine. 2010 41: 164-6. 20- Gazi IF, Filippatos TD, Tsimihodimos V, et al. The hypertriglyceridemic waist phenotype is a predictor of elevated levels of small, dense LDL cholesterol. Lipids. 2006 41: 647-54. 21- Bos G, Dekker JM, Heine RJ. Non-HDL cholesterol contributes to the "Hypertriglyceridemic Waist" as a cardiovascular risk factor. The Hoorn study. Diabetes care. 2004 27: 283-4. 22- Nikolic D, Katsiki N, Montalto G, Isenovic ER, Mikhailidis DP, Rizzo M. Lipoprotein subfractions in metabolic syndrome and obesity: clinical significance and therapeutic approaches. Nutrients. 2013 5: 928-48. 23- Group UPDS. UK prospective diabetes study 27: plasma lipids and lipoproteins at diagnosis of NIDDM by age and sex. Diabetes care. 1997 20: 1683-7. 24- Hosseini Gohari L, Karimzadeh Ghassab R, Firoozray M, Zavarehee A, Basiri HA. The association between small dense low density lipoprotein, apolipoprotein B, apolipoprotein B/apolipoprotein A1 ratio and coronary artery stenosis. Med J I.R.Iran. 2009 23: 8-13. | v2 |
2019-11-22T01:07:43.735Z | 2019-11-13T00:00:00.000Z | 209225271 | s2ag/train | Waldenström Macroglobulinemia with Excess Plasma Cells: Is It a Distinct Entity?
Introduction: Waldenström macroglobulinemia (WM) is characterized by circulating monoclonal IgM and bone marrow infiltration with lymphoplasmacytic lymphoma (LPL) cells. Presently, there is limited data to guide prognosis or treatment options of WM based on the proportion of lymphocytes or plasma cells in the LPL population on the pathology. In this study, we aim to look at differing clinical features and outcomes of patients with WM based on the plasma cell (PC) percentage in the diagnostic bone marrow biopsy.
Methods Patients with WM seen at Mayo Clinic, Rochester, MN between January 2001 and December 2017, with a bone marrow biopsy and a corresponding serum free light chain (FLC) examination at diagnosis of WM were included. The percentage of lymphocytes and PCs in the marrow biopsy was determined based on morphology ± immunohistochemistry. On immunohistochemistry, CD138 and/or MUM-1 positivity was used to quantify PCs, whereas CD20 and/or PAX5 were used to quantify lymphocytes. Patients with ≥10% PC component in the lymphoplasmacytic (LPL) cells on bone marrow biopsy were considered to have WM with excess plasma cells (WMEPC), while those with <10% PCs were considered to have lymphocytic WM (LWM). Continuous variables were compared using Wilcoxon test and categorical variables were compared using Chi square test or Fisher's exact test. Time-to-next therapy (TTNT) was defined as the period from initiation of first line therapy to start of second line therapy or death due to any cause before second line therapy. Time-to-event analyses were conducted using Kaplan Meier method.
Results: Of 228 evaluable patients, 147 (64%) had ≥ 10% PCs in the initial marrow biopsy. The median follow-up was 3.4 years (95% CI: 2.3-4.3 years) for LWM and 4.3 years (95% CI: 3.4-4.8 years) for WMEPC (p=0.33). The baseline characteristics of WMEPC versus LWM are depicted in Table 1. Patients with WMEPC had lower bone marrow involvement by LPL (30%) compared to LWM (60%; p<0.001) at diagnosis, but the rate of symptomatic hyperviscosity was higher in WMEPC during the disease course (Table 1). The TTNT was shorter for WMEPC [2.6 years (95% CI: 1.8-4.5 years)] compared to LWM [4.5 years (95% CI 3.2-8.2)], although it did not reach statistical significance (p=0.09, Figure 1). There was a trend towards shorter OS for WMEPC [Not reached (95% CI 7.2- NR)] compared to LWM [10.7 years (95% CI 7.3 -12.1 years); p=0.28], Figure 2. Of the 228 patients, 79% (n=182) had data available for systemic therapy. The rate of PR or better with frontline therapy was higher in rates in LWM compared to WMEPC (61 % vs 42% p=0.02, Table 1). Among WMEPC cohort, patients receiving either a proteasome inhibitor (PI)-based or an immunomodulatory (IMiD)-based combination as frontline therapy (n=16) had higher rates of partial response or better (68%) compared to non-PI/non-IMiD based therapy (n=114), p=0.04.
Conclusion: WM with excess plasma cells at diagnosis is associated with a trend towards shorter TTNT and OS compared to WM with <10% plasma cells in the lymphoplasmacytic population at diagnosis. Our preliminary data shows higher rates of partial response or better with the use of PI/IMiD based therapy, but the small cohort size limits the strength of this finding which needs to be validated externally.
Ansell: Bristol-Myers Squibb: Research Funding; Trillium: Research Funding; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; LAM Therapeutics: Research Funding; Mayo Clinic Rochester: Employment; Regeneron: Research Funding; Trillium: Research Funding; Bristol-Myers Squibb: Research Funding; Affimed: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Bristol-Myers Squibb: Research Funding; Affimed: Research Funding; LAM Therapeutics: Research Funding; Trillium: Research Funding; Mayo Clinic Rochester: Employment; Seattle Genetics: Research Funding; Mayo Clinic Rochester: Employment; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Mayo Clinic Rochester: Employment; Trillium: Research Funding; LAM Therapeutics: Research Funding; Affimed: Research Funding; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; Regeneron: Research Funding; Mayo Clinic Rochester: Employment; Trillium: Research Funding; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; LAM Therapeutics: Research Funding; LAM Therapeutics: Research Funding; Regeneron: Research Funding; Mayo Clinic Rochester: Employment; Affimed: Research Funding; Mayo Clinic Rochester: Employment; Trillium: Research Funding; Regeneron: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding; Affimed: Research Funding; Seattle Genetics: Research Funding; Mayo Clinic Rochester: Employment; Trillium: Research Funding; Trillium: Research Funding; Bristol-Myers Squibb: Research Funding; Trillium: Research Funding; LAM Therapeutics: Research Funding; LAM Therapeutics: Research Funding; Regeneron: Research Funding; Regeneron: Research Funding; Affimed: Research Funding; Seattle Genetics: Research Funding; LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Affimed: Research Funding; Mayo Clinic Rochester: Employment; LAM Therapeutics: Research Funding; Affimed: Research Funding. Gertz:Spectrum: Honoraria, Research Funding; Janssen: Honoraria; Celgene: Honoraria; Prothena: Honoraria; Alnylam: Honoraria; Ionis: Honoraria. Dingli:alexion: Consultancy; Janssen: Consultancy; Millenium: Consultancy; Rigel: Consultancy; Karyopharm: Research Funding. Nowakowski:Selvita: Membership on an entity's Board of Directors or advisory committees; NanoString: Research Funding; MorphoSys: Consultancy, Research Funding; Genentech, Inc.: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Curis: Research Funding; Bayer: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Dispenzieri:Alnylam: Research Funding; Celgene: Research Funding; Takeda: Research Funding; Pfizer: Research Funding; Janssen: Consultancy; Intellia: Consultancy; Akcea: Consultancy. Lacy:Celgene: Research Funding. Kumar:Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Research Funding. Kapoor:Janssen: Research Funding; Cellectar: Consultancy; Glaxo Smith Kline: Research Funding; Amgen: Research Funding; Takeda: Honoraria, Research Funding; Sanofi: Consultancy, Research Funding; Celgene: Honoraria.
| v2 |
2020-02-20T09:12:36.045Z | 2019-11-13T00:00:00.000Z | 214309301 | s2ag/train | Dose-Intensification in Early Unfavorable Hodgkin Lymphoma: Long-Term Follow up of the German Hodgkin Study Group (GHSG) HD14 Trial
Background:
In early unfavorable Hodgkin Lymphoma (HL), long-term tumor control with 4xABVD and 30Gy involved field radiotherapy (IFRT) is approximately 80%. To improve these results, the GHSG HD14 trial compared an intensified chemotherapy regimen consisting of 2xBEACOPPescalated plus 2xABVD (2+2) to 4xABVD. All patients received 30Gy IFRT. Due to a progression-free survival (PFS) difference of 6.2% at five years in favor of the intensified treatment, 2+2 plus 30Gy RT is the current GHSG standard and is a treatment option in the NCCN guidelines for early unfavorable HL. However, there was no overall survival (OS) difference between 2+2 and 4xABVD at the final analysis of HD14 and the potential long-term toxicity of 2+2 is debated. We therefore performed a long-term follow up analysis of HD14.
Patients and Methods:
Between January 2003 and July 2008, 1,550 patients with early unfavorable HL ≤60 years were randomized and treated with 4xABVD or 2+2, followed by 30Gy IFRT in all patients. Randomization was discontinued after the third planned interim analysis showed a significant advantage of 2+2 in terms of the primary endpoint freedom from treatment failure (FFTF, difference 7.2% at 5 years). Accrual to the 2+2 arm continued from July 2008 to December 2009 and 339 additional qualified patients were treated with 2+2 plus 30Gy IFRT. These patients were not reported in the initial report and are added to all analyses of this long-term follow-up. Time-to-event end points were compared between groups using the Kaplan-Meier method as well as univariate and multivariate Cox regression models.
Results:
After a median observation time of 97 months, 10.2% (79 of 777) and 3.4% (38 of 1112) of patients treated with 4xABVD and 2+2, respectively, had progression or relapse. The 10-year PFS was 85.6% for 4xABVD (95%-CI 82.9% to 88.4%) and 91.2% for 2+2 (95%-CI 89.0% to 93.4%) accounting for a significant PFS difference of 5.6% (95%-CI 2.1% to 9.1%) in favor of 2+2 (Figure 1). Two or more relapses were experienced by 21 of 777 (2.7%) and 10 of 1112 (0.9%) patients who had received 4xABVD or 2+2 as first-line treatment, respectively. However, there was still no OS difference between the two groups (OS 94.1% [95%-CI 92.3% to 96%] and 94% [95%-CI 92.3% to 95.8%] for 4xABVD and 2+2, respectively; difference at 10 years -0.1% [95%-CI -2.6% to 2.4%], median observation time for OS 104 months). In a multivariate regression analysis adjusting for age, B-symptoms, infra-diaphragmatic disease, and the 4 GHSG risk factors (elevated ESR, involvement of ≥3 lymph node areas, extranodal disease, and large mediastinal tumor) as predictive factors for PFS, age ≥50 (HR 2.260, 95%-CI 1.543 to 3.309), presence of infra-diaphragmatic disease (HR 1.766, 95%-CI 1.055 to 2.955), or of a large mediastinal tumor (HR 1.811, 95%-CI 1.226 to 2.675) and treatment with 4xABVD (HR 1.929, 95%-CI 1.423 to 2.614) were significant predictors of PFS. Slightly more patients in the 4xABVD group died from toxicity of salvage therapy as compared to 2+2 patients (1% [8 of 777] versus 0.6% [7 of 1112]) whereas there were relatively more deaths due to study therapy in the 2+2 group as compared to 4xABVD patients (0.6% [7 of 1112] versus 0.1% [1 of 777]), leading to a similar OS in both groups. There were no apparent differences in other causes of death including HL (5 of 777 [0.6%] versus 9 of 1112 [0.8%]) and second neoplasms (12 of 777 [1.5%] versus 16 of 1112 [1.4%]) between 4xABVD and 2+2, respectively. A total of 95 second malignancies corresponding to 10-year cumulative second malignancy incidences of 4.7% and 6.4% were reported for 4xABVD and 2+2, respectively, without a difference between the two groups (p=0.86). Standardized incidence ratios (SIR) showed elevation compared to the general German population and no significant difference between 4xABVD (2.3 [95%-CI 1.6 to 3.2]) and 2+2 (2.6 [95%-CI 2.0 to 3.4]).
Conclusions:
This long-term analysis confirms the superior tumor control of 2+2 as compared to 4xABVD in patients ≤60 with early unfavorable HL. However, this does not translate into an OS difference. At longer follow-up, there is no difference regarding second primary malignancies between the groups. In comparison to 4xABVD, the 2+2 regimen spares a significant number of patients from the burden of cancer recurrence and additional treatment without increased long-term toxicity. Therefore, 2+2 remains the GHSG standard for patients with early unfavorable HL ≤60.
Greil: Novartis: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; GSK: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Ratiopharm: Research Funding; Roche: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Eisai: Honoraria; Boehringer Ingelheim: Honoraria; Pfizer: Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding; MSD: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Amgen: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Daiichi Sankyo: Consultancy, Honoraria; Sandoz: Honoraria; Janssen-Cilag: Honoraria; Genentech: Honoraria, Research Funding; Sanofi Aventis: Honoraria; Celgene: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Merck: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding. Topp:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Regeneron Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Zijlstra:Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria. Borchmann:Novartis: Honoraria, Research Funding. von Tresckow:Takeda: Consultancy, Honoraria, Other: Travel and congress funding, Research Funding; Novartis: Consultancy, Honoraria, Other: Travel and congress funding, Research Funding; Pfizer: Honoraria; Amgen: Honoraria; Roche: Honoraria; MSD: Consultancy, Honoraria, Other: Travel and congress funding, Research Funding.
| v2 |
2021-11-25T16:19:14.283Z | 2021-11-05T00:00:00.000Z | 244548111 | s2ag/train | Central Memory T-Cell Differentiation Correlates with Depth of Response in Relapsed/Refractory Multiple Myeloma Patients Receiving Elotuzumab in Combination with Carfilzomib, Lenalidomide and Dexamethasone (Elo-KRd)
Introduction: The addition of elotuzumab (Elo), an anti SLAMF7 immunostimulatory antibody, to carfilzomib, lenalidomide and dexamethasone (KRd) can lead to synergistic anti-myeloma immune effects. Pre-clinical data showed that both Elo and KRd promote innate NK cell response and adaptive cytotoxic T cell response. Here we report longitudinal NK and T cell profiling data in relation to clinical response and MRD status in the context of an Elo-KRd Phase II study (NCT03361306).
Methods: Patients with relapsed refractory multiple myeloma (RRMM) after first-line therapy who enrolled in this phase II study received treatment with 4 cycles of Elo-KRd induction followed by Elo-Rd maintenance. Peripheral blood (PB) specimens were collected pre-induction (n=15), after induction (n=14), and every other month during maintenance (n=10). Bone marrow (BM) aspirates were collected pre- and post-induction and at the time of CR confirmation. Minimal residual disease (MRD) was assessed by next-generation flow cytometry (MRD NGF, 10 -5 sensitivity) post-induction for patients achieving very good partial response or better (≥VGPR). PB and BM NK, CD4 and CD8 T cell subset distribution, activation and anergy status were assessed by flow cytometry. Longitudinal Elo-KRd immune modulatory effect was modelled by polynomial regression analyses. Wilcoxon signed rank tests were used for timepoints comparisons. Mann-Whitney U tests were used for response groups comparisons between. Population frequency data, among mononuclear cells, are presented as mean±SD unless otherwise noted.
Results: We first investigated Elo-KRd immune modulatory activity during induction treatment. Immature / mature NK cell distribution in PB remained unaltered pre- and post-induction (iNK: 8.9±6.4 vs 8.6±3.5, p=0.808; mNK: 14.9±6.8 vs 13.1±6.1, p=0.463). No significant change in PB NK activation markers KIR2DS4, KIR3DL1, NKG2A, NKG2D or NKp46 was observed throughout Elo-KRd induction. A lack of NK cell maturation was also observed in the BM despite a rise of iNK NKG2D expression (iNK NKG2D+: 22.5±7.7 vs 30.1±8.8, p=0.0.039). The number of both PB effector T helper (CD4+ Th) and cytotoxic T cell (CD8+ CTL) significantly decreased post-induction (PB ThEff: 28.5±16.4 vs 14.4±10.6, p<0.001; PB CTLEff: 58.6±19.7 vs 39.0±13.9, p=0.005), whereas CTL central memory cell counts increased (PB CTLCM 11.7±11.2 vs, 15.9±11.4 p=0.058). A similar effector to central memory T cell conversion was observed in BM and was more pronounced among CTL (BM CTLEff/CM ratio: 21.6±54.8 vs 2.1±1.6, p= 0.002). Overall response rate on study was 80%, with 53.5% (8/15) achieving ≥VGPR. MRD negativity rate (at 10-5 sensitivity) post-induction was 20% (3/15). The subset of patients who achieved ≥VGPR had higher rates of Th and CTL CM cell differentiation at baseline [≥VGPR vs <VGPR; PB ThEff/CM ratio: median 1.0 (range 0.1 - 1.5) vs 3.1 (0.8 - 212.1); p=0.018; PB CTLEff/CM ratio: median 4.1 (range 0.7 - 16.3) vs 13.2 (4.3 - 10607.1); p=0.056]. Among the MRD negative group, one patient remained in sustained CR at 38 months follow up and retained a high Th/CTL CM conversion rate throughout. At the time of relapse, PB (n=6) and BM (n=2) specimens were collected. While no significant alterations in PB NK cell maturation or activation were observed, circulating CTL Eff / CM distribution reverted to baseline levels (baseline vs relapse; PB CTLEff/CM ratio: 743.6±2755.1 vs 282.7±672.0; p=0.156). BM CTL cell effector / central memory distribution also tends to return to pre-induction levels.
Conclusions: Unlike preclinical data where Elo has shown to enhance NK cell activity, longitudinal immune profiling analysis in patients with RRMM treated with Elo-KRd revealed limited activation of NK cell and no effect on NK cell maturation. Instead, we noted several changes within T cell compartment, notably activation and subsequent loss of Th and CTL effector cells, along with gain of central memory phenotype. This observation was most apparent for patients achieving ≥VGPR who exhibited significant higher rate of Effector to CM T cell conversion. On relapse, CM CTL cell frequency in both PB and BM compartments decreased to baseline level. Taken together, our results suggest that higher CM conversion rate, typically associated with sustained antigen stimulation, was associated with response to study treatment.
Foureau: Cytognos: Honoraria; TeneoBio, Celgene: Research Funding. Bhutani: Amgen, BMS, Takeda: Speakers Bureau; Sanofi: Consultancy; Janssen, MedImmune, Takeda, Celgene, BMS, Cerecor, Celularity: Research Funding. Atrash: GSK: Research Funding; AMGEN: Research Funding; Jansen: Research Funding, Speakers Bureau. Paul: Regeneron: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals Inc: Membership on an entity's Board of Directors or advisory committees; Amgen Inc.: Speakers Bureau; Bristol Myers Squibb: Divested equity in a private or publicly-traded company in the past 24 months. Symanowski: Eli Lilly: Consultancy, Other: DSMB Member; Immatics: Consultancy, Other: DSMB Member; Carsgen: Consultancy. Voorhees: Bristol-Myers Squibb Company.: Other: Data Safety & Monitoring; AbbVie Inc, Bristol-Myers Squibb Company; Consulting Agreement: GlaxoSmithKline, Novartis, Oncopeptides: Other: Advisory Committee. Usmani: EdoPharma: Consultancy; Janssen: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy, Research Funding, Speakers Bureau; Array BioPharma: Consultancy, Research Funding; Abbvie: Consultancy; GSK: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding, Speakers Bureau; Sanofi: Consultancy, Research Funding, Speakers Bureau; Seattle Genetics: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Janssen Oncology: Consultancy, Research Funding; Takeda: Consultancy, Research Funding, Speakers Bureau; SkylineDX: Consultancy, Research Funding; Bristol-Myers Squibb: Research Funding.
| v2 |
2018-04-03T01:15:07.784Z | 2016-11-01T00:00:00.000Z | 3451221 | s2ag/train | Acceptability of Oral Preexposure Prophylaxis Among Men Who Have Sex With Men in Philadelphia.
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Xia Q, Wiewel EW, Torian LV. Comparison of single-visit and multiple-visit measures of retention in care for HIV monitoring and evaluation. J Acquir Immune Defic Syndr. 2016;71:e59–e62. 15. Xia Q, Wiewel EW, Braunstein SL, et al. Comparison of indicators measuring the proportion of human immunodeficiency virus-infected persons with a suppressed viral load. Ann Epidemiol. 2015;25:226–230. 16. Branson BM, Handsfield HH, Lampe MA, et al. Revised recommendations for HIV testing of adults, adolescents, and pregnant women in health-care settings. MMWR Recomm Rep. 2006;55:1–17. 17. State of New York Laws Chapter 308 (2010). HIV Testing and Counseling, Amendment to New York State Public Health Law Article 21, Amendment of Part 63 of Title 10, Codes, Rules and Regulations of the State of New York (HIV/AIDS Testing, Reporting and Confidentiality of HIV-related Information). Available at: http://www.health.ny.gov/ diseases/aids/providers/testing/. Accessed June 3, 2016. 18. 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Achievement and maintenance of viral suppression in persons newly diagnosed with HIV, New York City, 2006–2009: using population surveillance data to measure the treatment part of “test and treat.” J Acquir Immune Defic Syndr. 2013;63:379–386. 27. Torian LV, Xia Q, Wiewel EW. Retention in care and viral suppression among persons living with HIV/AIDS in New York City, 2006–2010. Am J Public Health. 2014;104: e24–e29. 28. Wiewel EW, Braunstein SL, Xia Q, et al. Monitoring outcomes for newly diagnosed and prevalent HIV cases using a care continuum created with New York City surveillance data. J Acquir Immune Defic Syndr. 2015;68:217–226. 29. Hanna DB, Felsen UR, Ginsberg MS, et al. Increased antiretroviral therapy use and virologic suppression in The Bronx in the context of multiple HIV prevention strategies. AIDS Res Hum Retroviruses. 2016. doi: 10.1089/aid. 2015.0345. 30. Xia Q, Braunstein SL, Wiewel EW, et al. Persistent racial disparities in HIV infection in the USA: HIV prevalence matters. J Racial Ethn Health Disparities. 2016. doi: 10.1007/s40615-015-0205-9. 31. Irvine MK, Chamberlin SA, Robbins RS, et al. Improvements in HIV care engagement and viral load suppression following enrollment in a comprehensive HIV care coordination program. Clin Infect Dis. 2015;60: 298–310. 32. Xia Q, Ning Z, Torian LV. A run-in period is needed in randomized controlled trials of directly observed antiretroviral therapy for HIV infection. J Acquir Immune Defic Syndr. 2015;68:e20–e23. 33. Swendeman D, Ramanathan N, Baetscher L, et al. Smartphone self-monitoring to support self-management among people living with HIV: perceived benefits and theory of change from a mixed-methods randomized pilot study. J Acquir Immune Defic Syndr. 2015; 69(suppl 1):S80–S91. | v2 |
2022-06-02T07:44:43.049Z | 2010-01-01T00:00:00.000Z | 249239471 | s2ag/train | Changes in the Plasma and Urine ƒ¿ Human Atrial Natriuretic Peptide (ƒ¿hANP) Concentration in Patients with Thyroid Disorders
In order to assess the possible involvement of thyroid hormone in a human atrial natriuretic peptide (ƒ¿hANP), we investigated the plasma and urine ANP concentration in patients with primary hyperthyroidism and hypothyroidism. Plasma and urine were extracted through Sep-Pak Ci8 cartridges and the urine ANP concentration was corrected by urine creatinine (cre. mg/dl) and expressed as fmol/mg•cre.. The plasma ANP concentration in patients with untreated hyperthyroidism (32.3•}7.0 fmol/ml; n=22) was higher than in normal subjects (p <0.01 vs control; 6.2•}0.7 fmol/ml). After restoration to euthyroidism, the plasma ANP concentration (patients with treated hyperthyroidism) fell to normal (8.9•}1.9 fmol/ml). The plasma ANP concentration in patients with untreated hypothyroidism (14.1•}3.0 fmol/ml; n=7) was higher than normal, but in two of them there was mild renal dysfunction and an incomplete right blundle branch block in the electrocardiogram. It was possible that these factors contributed to the observed increase in plasma ANP. However, a significant positive correlation was found between plasma ANP and free thyroxine (n=40, r = 0.449; p<0.01) and free triiodothyronine (n=40, r=0.546; p <0.01). The urine ANP concentration in patients with untreated hyperthyroidism was markedly higher than in normal subjects (p<0.01), but in untreared hypothyroidism not significantly different from normal. It is well-known that thyroid hormone, which has positive inotropic and chronotropic actions, influences the cardiovascular system. The heart rate, stroke volume and cardiac output are increased in hyperthyroidism, and inversely all of the parameters are reduced in hypothyroidism (Buccino et al., 1967; Amidi et al., 1968; Grossman et al., 1971; Sefidper et al., 1971). It was reported that a rapid and potent natriuretic response to intravenous injection Received September 30, 1987 Correspondence to YOSHINOBU SUZUKI, M. D., Dept. of Endocrinology, Internal Medicine, School of Medicine Dokkyo University, Mibu, Tochigi 321-02, Japan 908 SUZUKI et al. Endocrinol. Jopon. December 1988 of atrial myocardial extracts occurs in rats (De Bold et al., 1981) and later the complete amino acid sequence of atrial natriuretic peptide (ANP) was determined (Kangawa et al., 1984). ANP has potent natriuretic, diuretic and vasorelaxant actions and is closely related with the circulating blood volume (Lang et al., 1985; Anderson et al., 1986 b), and the plasma ANP concentration is increased in various conditions which caused blood or extracellular fluid to increase, i.e. congestive heart failure (Burnett et al., 1986; Tikkanen et al., 1985), chronic renal failure (Anderson et al., 1986 a; Rascher et al., 1985; Suzuki et al., 1987) and pregnancy (Cusson et al., 1985). In this study, we used a radioimmunoassay for ahANP constituted with labeled αhANP and rabbit anti-αANP antiserum obtained from a commercial source, and investigated the plasma and urine ANP concentrations in patients with thyroid disorders to see whether any significant changes could be found in these conditions. Materials and Methods Subjects Twenty-two patients with untreated hyperthyroidism (18 women and 4 men, mean age 32.6•}1.3 yrs., range 13-67 yrs.), ten patients with treated hyperthyroidism (8 women and 2 men, mean age 26.5•}3.8 yrs., range 11-47 yrs.), seven patients with untreated primary hypothyroidism (5 women and 2 men, mean age 45.9•}9.3 yrs., range 11-79 yrs.), four with treated hypothyroidism (4 women, 30-43 yrs., mean age 38.3•} 4.0 yrs.) and fifty-one normal subjects (26 women and 25 men, mean age 32.8•}1.3 yrs., range 1660 yrs.) were studied. None of the normal subjects showed evidence of any disease and none had taken drugs. The diagnosis of thyroid disorders was based on the clinical assessment and confirmed by radioimmunoassay of serum total thyroxine (TT4), total triiodothyronine (TT3), free thyroxine (fT4), free triiodothyronine (fT3) and TSH. TT4, TT3 and TSH were measured with kits purchased from Dainabot RI Lab. Tokyo Japan. FT4 and fT3 were measured with kits purchased from Travenol Co. Ltd. and Amersham International plc., respectively. The patients with hyperand hypothyroidism were treated with an antithyroid drug (propylthiouracil or methimazole) or levo-thyroxine Na. The mean duration of treatment was 161.6•}57.1 days and 2.4•}0.8 yrs, respectively. Preparation of Samples Blood samples (usally 10ml) were collected in plastic tubes containing aprotinine (400 KIU/ ml) and EDTA (1mg/ml) from subjects in a resting, supine position, and urine samples were obtained from morning partial urine. The patients were allowed to take sodium and water freely. The plasma was immediately separated by centrifugation (750 xg) for 20 min at 4•Ž. ANP was extracted from plasma or urine with Sep-Pak C18 cartridges (Waters Associates Milford MA, recovery 71.8•}0.6%) according to the method described in our previous report (Suzuki et al., 1987). Radioimmunoassay Procedure The immunoreactive ANP (IR-ANP) in plasma and urine was determined with (3-[125I] iodotyrosol 28) ƒ¿hANP (Amersham International plc.) as tracer and rabbit anti-ƒ¿ ANP antiserum (Cat No. RAS8798 and Lot No.009325, Peninsula Lab. Inc.). Details of the assay are given elsewhere (Suzuki et al., 1987). The coefficients of variation in the intraand interassay with the same reagents for 7 and 5 replicates of the median concentration of ANP were 10.9 and 10.6%, respectively. Reverse phase high performance liquid chromatography (HPLC) IR-ANP was characterised by reverse phase HPLC. HPLC was performed on a ƒÊ Bondashere 5 ƒÊ C18-100A column (3.9•~150 mm, Waters Japan, Co.) under stepwise isocratic elution at 10, 35 and 40% acetonitrile (ACN)/water containing 0.1% trifluoroacetic anhydride (TFA). The HPLC system included a pump (LC-6A, Shimazu Corporation Kyoto, Japan), column oven (CTO-6A, Shimazu Corp. Kyoto, Japan) and injector (7125, Rhepdyne Cotaro, California, USA). Plasma and urine extracts obtained from hyperthyroid patients were applied to the column at a flow rate of 1 ml/min and 2 ml fractions were collected. These fractions were evaporated to dryness. The dry residue was reconstitutde Vol.35, No.6 ANP & THYROID DYSFUNCTION 909 in 200ƒÊl of assay buffer and assayed. Calculation Statistical analysis was performed by Student's t-test and linear regression analysis. Results were expressed as the mean•}SEM of molar equivalents of synthetic ahANP. The plasma IR-ANP concentration was expressed as femtomolars per ml. The urine IR-ANP concentration was corrected for urine creatinine (mg/dl, cre.) and expressed as femtomolars per mg•E creatinine (fmol/mg•cre.). | v2 |
2018-04-03T05:12:36.954Z | 2010-07-22T00:00:00.000Z | 206441831 | s2ag/train | Translating Current Dietary Guidelines Into a Culturally Tailored Nutrition Education Program for Korean American Immigrants With Type 2 Diabetes
Purpose The purpose of this article is to describe the process of translating evidence-based dietary guidelines into a tailored nutrition education program for Korean American immigrants (KAI) with type 2 diabetes mellitus (DM). Methods Community-based participatory research (CBPR) is a research process involving researchers and communities to build a collaborative partnership. The study was conducted at a community-based organization. In a total of 79 KAI (intervention, n = 40; control, n = 39) with uncontrolled type 2 DM (A1C ≥7.5%), 44.3% were female and the mean age was 56. 5 ± 7.9 years. A culturally tailored nutrition education was developed by identifying community needs and evaluating research evidence. The efficacy and acceptability of the program was assessed. Results In translating dietary guidelines into a culturally relevant nutrition education, culturally tailored dietary recommendations and education instruments were used. While dietary guidelines from the American Diabetes Association (ADA) were used to frame nutrition recommendations, additional content was adopted from the Korean Diabetes Association (KDA) guidelines. Culturally relevant intervention materials, such as Korean food models and an individually tailored serving table, were utilized to solidify nutritional concepts as well as to facilitate meal planning. Evaluation of the education revealed significantly increased DM-specific nutrition knowledge in the intervention group. The participants’ satisfaction with the education was 9.7 on a 0 to10-point scale. Conclusion The systematic translation approach was useful for producing a culturally tailored nutrition education program for KAI. The program was effective in improving the participants’ DM-specific nutrition knowledge and yielded a high level of satisfaction. Future research is warranted to determine the effect of a culturally tailored nutrition education on other clinical outcomes. References 1. Schafer RG, Bohannon B, Franz M, et al. Translation of the diabetes nutrition recommendations for health care institutions: technical review. J Am Diet Assoc. 1997;97:43-51. 2. Narayan KM, Gregg EW, Engelgau MM, et al. Translation research for chronic disease: the case of diabetes. Diabetes Care. 2000;23:1794-1798. 3. Rubin RR, Peyrot M, Saudek CD. Differential effect of diabetes education on self-regulation and life-style behaviors. Diabetes Care. 1991;14:335-338. 4. Haffner SM, Hazuda HP, Mitchell BD, Patterson JK, Stern MP. Increased incidence of type II diabetes mellitus in Mexican Americans. Diabetes Care. 1991;14:102-108. 5. Vijan S, Stuart NS, Fitzgerald JT, et al. Barriers to following dietary recommendation in Type 2 diabetes. Diabet Med. 2005;22:32-38. 6. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulponylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352:837-853. 7. Wylie-Rosett J. In: Proceedings from the American Diabetes Association Annual Scientific Sessions ; June 6, 1989. 8. Samanta A, Campbell JE, Spaulding DL, et al. Eating habits in Asian diabetics. Diabet Med . 1986;3:283. 9. Park SY, Paik HY, Skinner JD, Spindler AA, Park HR. Nutrient intake of Korean Americans, Korean, and American adolescents. J Am Diet Assoc. 2004;104:242-245. 10. Lee SK, Sobal J, Frongillo EA Jr. Acculturation and dietary practices among Korean Americans. J Am Diet Assoc. 1999;99:1084-1089. 11. Brown SA, Hanis CL. A community-based, culturally sensitive education and group-support intervention for Mexican Americans with NIDDM: a pilot study of efficacy. Diabetes Educ. 1995;21:203-210. 12. Kim MT, Han HR, Song H, Lee JE, Kim J, Kim KB. A community-based culturally tailored behavioral intervention for Korean Americans with diabetes. Diabetes Educ. 2009;35:986-994. 13. Fitzgerald JT, Funnell MM, Hess GE, et al. The reliability and validity of a brief diabetes knowledge test. Diabetes Care. 1998;21: 706-710. 14. Han HR, Kim KB, Kim MT. Evaluation of the training of Korean community health workers for chronic disease management. Health Edu Res. 2007;9:137-146. 15. Franz MJ, Bantle JP, Beebe CA, et al. Evidence-based nutrition principles and recommendations for the treatment and prevention of diabetes and related complications. Diabetes Care. 2002;25:148-198. 16. Korean Diabetes Association Web site. http://www.diabetes .or.kr. Accessed September 28, 2009. 17. Szczepura A. Access to health care for ethnic minority populations. Postgrad Med J. 2005;81:141-147. 18. Resnicow K, Baranowski T, Ahluwalia JS, et al. Cultural sensitivity in public health: defined and demystified. Ethn Dis. 1999;9:10-21. 19. Cooper LA, Hill MN, Powe NR. Designing and evaluating interventions to eliminate racial and ethnic disparities in health care. J Gen Intern Med. 2002;17:477-486. 20. Hawthorne K. Asian diabetics attending a British hospital clinic: a pilot study to evaluate their case. Br J Gen Pract. 1990;40: 243-247. 21. Lee JA, Yeo G, Gallagher-Thompson D. Cardiovascular disease risk factors and attitudes towards prevention among Korean American elders. J Cross Cult Gerontol. 1993;8:17-33. 22. Brown JB, Harris SB, Webster-Bogaert S, Wetmore S, Faulds C, Stewart M. The role of patient, physician, and systematic factors in the management of type 2 diabetes mellitus. Fam Pract. 2002;19:344-349. 23. Nicolucci A, Cavaliere D, Scorpiglione N, et al. A comprehensive assessment of the avoidability of long-term complications of diabetes: a case-control study. Diabetes Care. 1996;19:927-933. 24. Lonner TD. The group as a basic asset to ethnic minority patients with diabetes. Diabetes Educ. 2000;26:645-655. 25. Fisher TL, Burnet DL, Huang ES, Chin MH, Cagney KA. Cultural leverage: interventions utilizing culture to narrow racial disparities in health care. Med Care Res and Rev. 2007;64:243S-282S. 26. Fiscella K, Franks P, Doescher MP, Saver BG. Disparities in health care by race, ethnicity, and language among the insured. Medical Care. 2002;40:52-59. | v2 |
2017-04-16T14:22:27.655Z | 2008-01-01T00:00:00.000Z | 15078071 | s2ag/train | APhase 1 Study of Mapatumumab ( Fully HumanMonoclonal Antibody toTRAIL-R 1 ) in Patients with Advanced Solid Malignancies Se ¤
Purpose:Mapatumumab (TRM-1, HGS-ETR1) is a fully human agonistic monoclonal antibody that targets and activates tumor necrosis factor ^ related apoptosis-inducing ligand (TRAIL) receptor 1 (death receptor 4). Mapatumumab functions like the natural receptor ligand,TRAIL, a tumor necrosis factor superfamily member that is an important mediator of apoptosis in cancer cell lines. Promising preclinical activity with mapatumumab has been observed. Experimental Design:This phase I, open-label, dose-escalation study assessed the tolerability and toxicity profile of z2 doses of mapatumumab administered i.v. in patients with advanced solid tumors. Patients received mapatumumab every 28 days until progression or dose-limiting toxicity. Results: There were escalation levels from 0.01to 20.0 mg/kg. Forty-one patients, 27 female, with a median age of 55 years (range, 23-81) were entered into the study and received 143 courses. The most common diagnoses were colorectal (10 patients) and ovarian cancer (9 patients). Patients received a median of two cycles (range, 1-33). Mapatumumab was well tolerated. Adverse events considered at least possibly related to mapatumumab that occurred most frequently included fatigue (36.2%), hypotension (34.1%), nausea (29.3%), and pyrexia (12.2%).The majority of adverse events were grade1or 2.The maximum tolerated dose was not reached. Linear pharmacokinetics was observed for doses up to 0.3 mg/kg and for the 20 mg/kg level, whereas exposure at 3 and 10 mg/kg increased less than proportionally. No objective responses were observed, but12 patients had stable disease for1.9 to 29.4 months. Conclusions:Mapatumumab is well tolerated and further evaluation of thisTRAIL-R1targeting agent is warranted. The evolution of a cancer cell is dependent on six essential alterations including self-sufficiency in growth signals, insensitivity to growth-inhibitory signals, limitless replicative potential, sustained angiogenesis, tissue invasion, and evasion of apoptosis (1). Similar to the cell division cycle, the pathways that lead to apoptosis are complex and consist of a fine homeostatic balance between cell death blockers and inducers (2). Because apoptosis is a physiologic death culminating in fragmentation of cells cleared by phagocytosis, inflammatory reaction or tissue scarring usually does not occur (2). Defects in apoptosis can prolong cellular lifespan and contribute to neoplastic cell expansion and can create a permissive environment for genetic instability that can contribute significantly to carcinogenesis. Apoptosis is triggered by two major pathways: the death receptor–induced extrinsic pathway and the mitochondrial–mediated intrinsic pathway, the latter is more typically activated by conventional chemotherapy (3). Both of these pathways lead to caspase activation and cleavage of cellular substrates. The extrinsic pathway activates procaspase-8. Once activated, this initiator caspase can activate effector caspases, such as caspase-3, caspase-6, and caspase-7, which in turn cleave a variety of substrates to give rise to DNA degradation and characteristic morphologic changes (4). Recombinant members of the tumor necrosis factor family, including Fas ligand, tumor necrosis factor, and tumor necrosis factor–related apoptosisinducing ligand (TRAIL) can induce apoptosis in preclinical models (5). TRAIL was identified in 1995 and is a type II membrane protein that can be cleaved from the cell surface to form a soluble ligand capable of inducing apoptosis in a wide variety of cancer cell lines (6). TRAIL can bind to five Cancer Therapy: Clinical Authors’ Affiliations: Juravinski Cancer Centre, Hamilton, Ontario, Canada; Princess Margaret Hospital, Toronto, Ontario, Canada; and Human Genome Sciences, Rockville, Maryland Received 6/7/07; revised12/12/07; accepted1/16/08. The costs of publication of this article were defrayed in part by the payment of page charges.This article must therefore be hereby marked advertisement in accordance with18 U.S.C. Section1734 solely to indicate this fact. Note: This study was presented previously in part at the 2005 Annual American Society of Clinical Oncology Meeting, Orlando, Florida; 2004 National Cancer Institute-AACR-European Organization for Research on Treatment of Cancer Meeting in Geneva, Switzerland; 2004 American Society of Clinical Oncology Meeting in New Orleans, Louisiana; and 2005 National Cancer Institute-AACREuropean Organization for Research onTreatment of Cancer Meeting in Brussels, Belgium. Requests for reprints: Se¤ bastien J. Hotte, Juravinski Cancer Centre at Hamilton Health Sciences, 699 Concession Street, Hamilton, Ontario, Canada L8V 5C2. Phone: 905-387-9495, ext. 64602; Fax: 905-575-6326; E-mail: sebastien. [email protected]. F2008 American Association for Cancer Research. doi:10.1158/1078-0432.CCR-07-1416 www.aacrjournals.org Clin Cancer Res 2008;14(11) June1, 2008 3450 Research. on April 16, 2017. © 2008 American Association for Cancer clincancerres.aacrjournals.org Downloaded from different receptors, including four membrane-bound and one soluble receptor (7, 8). Two of these membrane receptors, TRAIL-R1 (death receptor 4) and TRAIL-R2 (death receptor 5) have a cytoplasmic death domain through which TRAIL can transmit its apoptotic signal by binding as a homotrimer. Interestingly, the apoptotic activity of TRAIL appears selective for cancer cell lines with minimal activity against normal cell types (6, 9–12). Because of its purported role in inducing apoptosis in cancer cells while sparing normal cells, several TRAIL receptor agonists have recently entered the clinic (5, 13). Mapatumumab (TRM1, HGS-ETR1) is a fully human monoclonal antibody that is agonistic to TRAIL-R1 with very high specificity and affinity (14). Mapatumumab was able to induce apoptosis in multiple tumor cell lines representing various tumor types. Treatment with various concentrations of mapatumumab resulted in a dose-dependent reduction of cell viability preceded by activation of caspase-3 and/or caspase-7 in most cell lines. Mapatumumab was also shown to enhance chemotherapeutic agent activity in vitro and reduced the growth of human tumors in xenograft models, including preestablished colon, lung, and kidney xenograft models. Although TRAIL-R1 cell surface expression was required for the cytotoxic activity of mapatumumab in preclinical models, TRAIL-R1 expression did not predict the level of sensitivity. Preclinically, mapatumumab was also found to have a desirable toxicity profile. Specifically, it did not readily bind normal tissues by flow cytometry or in a tissuebinding assay. Of three cell types that showed binding, only hepatocytes had any decreased viability to 80% to 90% of control cell values in response to mapatumumab. Based on these promising preclinical observations, the current phase I study attempted to evaluate the safety and tolerability, immunogenicity, and pharmacokinetic profile in patients with advanced solid tumors. | v2 |
2018-04-03T05:36:31.418Z | 2017-01-25T00:00:00.000Z | 205210561 | s2ag/train | Oral anti-diabetic pharmacological therapies for the treatment of women with gestational diabetes.
BACKGROUND
Gestational diabetes mellitus (GDM) is a major public health issue with rates increasing globally. Gestational diabetes, glucose intolerance first recognised during pregnancy, usually resolves after birth and is associated with short- and long-term complications for the mother and her infant. Treatment options can include oral anti-diabetic pharmacological therapies.
OBJECTIVES
To evaluate the effects of oral anti-diabetic pharmacological therapies for treating women with GDM.
SEARCH METHODS
We searched Cochrane Pregnancy and Childbirth's Trials Register (14 May 2016), ClinicalTrials.gov, WHO ICTRP (14 May 2016) and reference lists of retrieved studies.
SELECTION CRITERIA
We included published and unpublished randomised controlled trials assessing the effects of oral anti-diabetic pharmacological therapies for treating pregnant women with GDM. We included studies comparing oral anti-diabetic pharmacological therapies with 1) placebo/standard care, 2) another oral anti-diabetic pharmacological therapy, 3) combined oral anti-diabetic pharmacological therapies. Trials using insulin as the comparator were excluded as they are the subject of a separate Cochrane systematic review.Women with pre-existing type 1 or type 2 diabetes were excluded.
DATA COLLECTION AND ANALYSIS
Two review authors independently assessed trials for inclusion and trial quality. Two review authors independently extracted data and data were checked for accuracy.
MAIN RESULTS
We included 11 studies (19 publications) (1487 women and their babies). Eight studies had data that could be included in meta-analyses. Studies were conducted in Brazil, India, Israel, UK, South Africa and USA. The studies varied in diagnostic criteria and treatment targets for glycaemic control for GDM. The overall risk of bias was 'unclear' due to inadequate reporting of methodology. Using GRADE the quality of the evidence ranged from moderate to very low quality. Evidence was downgraded for risk of bias (reporting bias, lack of blinding), inconsistency, indirectness, imprecision and for oral anti-diabetic therapy versus placebo for generalisability. Oral anti-diabetic pharmacological therapies versus placebo/standard careThere was no evidence of a difference between glibenclamide and placebo groups for hypertensive disorders of pregnancy (risk ratio (RR) 1.24, 95% confidence interval (CI) 0.81 to 1.90; one study, 375 women, very low-quality evidence), birth by caesarean section (RR 1.03, 95% CI 0.79 to 1.34; one study, 375 women, very low-quality evidence), perineal trauma (RR 0.98, 95% CI 0.06 to 15.62; one study, 375 women, very low-quality evidence) or induction of labour (RR 1.18, 95% CI 0.79 to 1.76; one study, 375 women; very low-quality evidence). No data were reported for development of type 2 diabetes or other pre-specified GRADE maternal outcomes (return to pre-pregnancy weight, postnatal depression). For the infant, there was no evidence of a difference in the risk of being born large-for-gestational age (LGA) between infants whose mothers had been treated with glibenclamide and those in the placebo group (RR 0.89, 95% CI 0.51 to 1.58; one study, 375, low-quality evidence). No data were reported for other infant primary or GRADE outcomes (perinatal mortality, death or serious morbidity composite, neurosensory disability in later childhood, neonatal hypoglycaemia, adiposity, diabetes). Metformin versus glibenclamideThere was no evidence of a difference between metformin- and glibenclamide-treated groups for the risk of hypertensive disorders of pregnancy (RR 0.70, 95% CI 0.38 to 1.30; three studies, 508 women, moderate-quality evidence), birth by caesarean section (average RR 1.20, 95% CI 1.20; 95% CI 0.83 to 1.72, four studies, 554 women, I2 = 61%, Tau2 = 0.07 low-quality evidence), induction of labour (0.81, 95% CI 0.61 to 1.07; one study, 159 women; low-quality evidence) or perineal trauma (RR 1.67, 95% CI 0.22 to 12.52; two studies, 158 women; low-quality evidence). No data were reported for development of type 2 diabetes or other pre-specified GRADE maternal outcomes (return to pre-pregnancy weight, postnatal depression). For the infant there was no evidence of a difference between the metformin- and glibenclamide-exposed groups for the risk of being born LGA (average RR 0.67, 95% CI 0.24 to 1.83; two studies, 246 infants, I2 = 54%, Tau2 = 0.30 low-quality evidence). Metformin was associated with a decrease in a death or serious morbidity composite (RR 0.54, 95% CI 0.31 to 0.94; one study, 159 infants, low-quality evidence). There was no clear difference between groups for neonatal hypoglycaemia (RR 0.86, 95% CI 0.42 to 1.77; four studies, 554 infants, low-quality evidence) or perinatal mortality (RR 0.92, 95% CI 0.06 to 14.55, two studies, 359 infants). No data were reported for neurosensory disability in later childhood or for adiposity or diabetes. Glibenclamide versus acarboseThere was no evidence of a difference between glibenclamide and acarbose from one study (43 women) for any of their maternal or infant primary outcomes (caesarean section, RR 0.95, 95% CI 0.53 to 1.70; low-quality evidence; perinatal mortality - no events; low-quality evidence; LGA , RR 2.38, 95% CI 0.54 to 10.46; low-quality evidence). There was no evidence of a difference between glibenclamide and acarbose for neonatal hypoglycaemia (RR 6.33, 95% CI 0.87 to 46.32; low-quality evidence). There were no data reported for other pre-specified GRADE or primary maternal outcomes (hypertensive disorders of pregnancy, development of type 2 diabetes, perineal trauma, return to pre-pregnancy weight, postnatal depression, induction of labour) or neonatal outcomes (death or serious morbidity composite, adiposity or diabetes).
AUTHORS' CONCLUSIONS
There were insufficient data comparing oral anti-diabetic pharmacological therapies with placebo/standard care (lifestyle advice) to inform clinical practice. There was insufficient high-quality evidence to be able to draw any meaningful conclusions as to the benefits of one oral anti-diabetic pharmacological therapy over another due to limited reporting of data for the primary and secondary outcomes in this review. Short- and long-term clinical outcomes for this review were inadequately reported or not reported. Current choice of oral anti-diabetic pharmacological therapy appears to be based on clinical preference, availability and national clinical practice guidelines.The benefits and potential harms of one oral anti-diabetic pharmacological therapy compared with another, or compared with placebo/standard care remains unclear and requires further research. Future trials should attempt to report on the core outcomes suggested in this review, in particular long-term outcomes for the woman and the infant that have been poorly reported to date, women's experiences and cost benefit. | v2 |
2018-12-07T02:22:38.449Z | 2007-03-09T00:00:00.000Z | 106442971 | s2ag/train | Maintaining Mission Critical Systems in a 24/7 Environment
Chapter 1 An Overview of Reliability and Resiliency in Today s Mission Critical Environment. 1.1 Introduction. 1.2 Risk Assessment. 1.3 Capital Cost versus Operation Cost. 1.4 Critical Environment Workflow and Change Management. 1.5 Testing and Commissioning. 1.6 Documentation and Human Factor. 1.7 Education and Training. 1.8 Operation and Maintenance. 1.9 Employee Certification. 1.10 Standard and Benchmarking. 1.11 Conclusion. 1.12 Risk Analysis and Improvement. Chapter 2 Energy Security and its Effect on Business Resiliency. 2.1 Introduction. 2.2 Risks Related to Information Security. 2.3 How Risks are Addressed. 2.4 Use of Distributed Generation. 2.5 Documentation and Its Relation to Information Security. 2.6 Smart Grid. 2.7 Conclusion. 2.8 Risk Analysis and Improvement. Chapter 3 Mission Critical Engineering with an Overview of Green Technologies. 3.1 Introduction. 3.2 Companies Expectations Risk Tolerance and Reliability. 3.3 Identifying the Appropriate Redundancy in a Mission Critical Facility. 3.4 Improving Reliability, Maintainability, and Proactive Preventative Maintenance. 3.5 The Mission Critical Facilities Manager and the Importance of the Boardroom. 3.6 Quantifying Reliability and Availability. 3.7 Design Considerations for the Mission Critical Data Center. 3.8 The Evolution of Mission Critical Facility Design. 3.9 Human Factors and the Commissioning Process. 3.10 Short Circuit and Coordination Studies. 3.11 Introduction to Direct Current in the Data Center. 3.12 Containerized Systems Overview. 3.13 Conclusion. Chapter 4 Mission Critical Electrical System Maintenance and Safety. 4.1 Introduction. 4.2 The History of the Maintenance Supervisor and the Evolution of the Mission Critical Facilities Engineer. 4.3 Internal Building Deficiencies and Analysis. 4.4 Evaluating Your System. 4.5 Choosing a Maintenance Approach. 4.6 Safe Electrical Maintenance. 4.7 Maintenance of Typical Electrical Distribution Equipment. 4.8 Being Proactive In Evaluating the Test Reports. 4.9 Conclusion. Chapter 5 Standby Generators: Operations and Maintenance. 5.1 Introduction. 5.2 The Necessity for Standby Power. 5.3 Emergency, Legally Required, and Optional Systems. 5.4 Standby Systems That Are Legally Required. 5.5 Optional Standby Systems. 5.6 Understanding Your Power Requirements. 5.7 Management Commitment and Training. 5.8 Standby Generator Systems Maintenance Procedures. 5.9 Documentation Plan. 5.10 Emergency Procedures. 5.11 Cold Start and Load Acceptance. 5.12 Non-Linear Load Problems. 5.13 Conclusion. Chapter 6 Fuel Systems Design and Maintenance. 6.1 Introduction. 6.2 Brief Discussion on Diesel Engines. 6.3 Bulk Storage Tank Selection. 6.4 Codes and Standards. 6.5 Recommended Practices for All Tanks. 6.6 Fuel Distribution System Configuration. 6.7 Day Tank Control System. 6.8 Diesel Fuel and A Fuel Quality Assurance Program. 6.9 Conclusion. Chapter 7 Power Transfer Switch Technology, Applications, and Maintenance. 7.1 Introduction. 7.2 Transfer Witch Technology and Applications. 7.3 Types of Power Transfer Switches. 7.4 Control Devices. 7.5 Design Features. 7.6 Additional Characteristics and Ratings of ATS. 7.7 Installation and Commissioning, Maintenance, and Safety. 7.8 General Recommendations. 7.9 Conclusion. Chapter 8 The Static Transfer Switch. 8.1 Introduction. 8.2 Overview. 8.3 Typical Static Switch One Line. 8.4 STS Technology and Application. 8.5 Testing. 8.6 Conclusion. Chapter 9 The Fundamentals of Power Quality. 9.1 Introduction. 9.2 Electricity Basics. 9.3 Transmission of Power. 9.4 Understanding Power Problems. 9.5 Tolerances of Computer Equipment. 9.6 Power Monitoring. 9.7 The Deregulation Wildcard. 9.8 Conclusion. Chapter 10 UPS Systems: Applications and Maintenance with an Overview of Green Technologies. 10.1 Introduction. 10.2 Purpose of UPS Systems. 10.3 General Description of UPS Systems. 10.4 Components of a Static UPS System. 10.5 Line Interactive UPS System. 10.6 Offline (Standby). 10.7 The Evolution of Static UPS Technology. 10.8 Rotary System. 10.9 Redundancy, Configurations, and Topology. 10.10 Energy Storage Devices. 10.11 UPS Maintenance and Testing. 10.12 Static UPS and Maintenance. 10.13 UPS Management. 10.14 Conclusion. Chapter 11 Data Center Cooling Systems. 11.1 Introduction. 11.2 Background Information. 11.3 Cooling Within Datacom Rooms. 11.4 Cooling Systems. 11.5 Components Outside the Datacom Room. 11.6 Components Inside Datacom Rooms. 11.7 Conclusion. Chapter 12 Data Center Cooling Efficiency and Advanced Technology. 12.1 Introduction. 12.2 Heat Transfer inside Data Centers. 12.3 Cooling and other Airflow Topics. 12.4 Design Approaches for Data Center Cooling. 12.5 Additional Considerations. 12.6 Hardware and Associated Efficiencies. 12.7 Best Practices. 12.8 Efficiency Problem Solving. 12.9 Conclusion. 12.10 Conversions, Formulas, Guidelines. Chapter 13 Raised Access Floors. 13.1 Introduction. 13.2 Design Considerations. 13.3 Safety Concerns. 13.4 Panel Cutting. 13.5 Access Floor Maintenance. 13.6 Troubleshooting. 13.7 Additional Design Considerations. 13.8 Conclusion. Chapter 14 Fire Protection in Mission Critical Infrastructures. 14.1 Introduction. 14.2 Philosophy. 14.3 Alarm and Notification. 14.4 Early Detections. 14.5 Fire Suppression. 14.6 System Designs. 14.7 Fire Detection. 14.8 Fire Suppression Systems. References. APPENDICES. Appendix A Policies and Regulations. A.1 Introduction. A.2 Industry Policies and Regulations. A.2.1 USA Patriot Act. A.2.2 Sarbanes-Oxley Act (SOX). A.2.3 Comprehensive Environmental Response, Compensation, and Liability act of 1980 (Superfund Act). A.2.4 Executive Order 13423: Strengthening Federal Environmental, Energy and Transportation Management. A.2.5 ISO27000 Information Security Management Systems (ISMS). A.2.6 The National Strategy for the Physical Protection of Critical Infrastructure and Key Assets. A.2.7 2009 National Infrastructure Protection Plan. A.2.8 North American Electric Reliability Corporation (NERC). A.2.9 U.S. Security and Exchange Commission. A.2.10 Sound Practices to Strengthen in the Resilience of the U.S. Financial System. A.2.11 C4I Command, Control, Communications, Computers and Intelligence. A.2.12 Basel II Accord. A.2.13 National Institute of Standards and Technology (NIST). A.2.14 Business Continuity Management Agencies and Regulating Organizations. A.2.15 FFIEC Federal Financial Institution Examination Council. A.2.16 National Fire Prevention Association 1600 Standard on Disaster/Emergency Management and Business Continuity Programs. A.2.17 Private Sector Preparedness Act. A.3 Data Protection. A.4 Encryption. A.5 Protecting Critical Data through Security and Vaulting. A.6 Conclusion. Appendix B Mission Critical Questions. Appendix C Airflow Management (A Systems Approach). C.1 Introduction. C.2 Control is the Key. C.3 Obtaining Control. C.4 Air Management Technologies. C.5 Conclusion. | v2 |
2018-04-03T02:32:45.248Z | 2016-02-04T00:00:00.000Z | 205200941 | s2ag/train | The role of iron in the management of chemotherapy-induced anemia in cancer patients receiving erythropoiesis-stimulating agents.
BACKGROUND
Erythropoiesis-stimulating agents (ESAs) are commonly used to treat chemotherapy-induced anemia (CIA). However, about half of patients do not benefit.
OBJECTIVES
To evaluate the benefits and harms related to the use of iron as a supplement to ESA and iron alone compared with ESA alone in the management of CIA.
SEARCH METHODS
We searched for relevant trials from the Cochrane Central Register of Controlled Trials (CENTRAL) (issue 1 January 2016), MEDLINE (1950 to February 2016), and www.clinicaltrials.gov without using any language limits.
SELECTION CRITERIA
All randomized controlled trials (RCTs) comparing 'iron plus ESA' or 'iron alone' versus 'ESA alone' in people with CIA were eligible for inclusion.
DATA COLLECTION AND ANALYSIS
We used standard methodological procedures expected by Cochrane.
MAIN RESULTS
We included eight RCTs (12 comparisons) comparing ESA plus iron versus ESA alone enrolling 2087 participants. We did not find any trial comparing iron alone versus ESAs alone in people with CIA. None of the included RCTs reported overall survival. There was a beneficial effect of iron supplementation to ESAs compared with ESAs alone on hematopoietic response (risk ratio (RR) 1.17, 95% confidence interval (CI) 1.09 to 1.26; P < 0.0001; 1712 participants; 11 comparisons; high-quality evidence). Assuming a baseline risk of 35% to 80% for hematopoietic response without iron supplementation, between seven and 16 patients should be treated to achieve hematopoietic response in one patient. In subgroup analyses, RCTs that used intravenous (IV) iron favored ESAs and iron (RR 1.20 (95% CI 1.10 to 1.31); P < 0.00001; 1321 participants; eight comparisons), whereas we found no evidence for a difference in hematopoietic response in RCTs using oral iron (RR 1.04 (95% CI 0.87 to 1.24); P = 0.68; 391 participants; three comparisons). There was no evidence for a difference between the subgroups of IV and oral iron (P = 0.16). There was no evidence for a difference between the subgroups of types of iron (P = 0.31) and types of ESAs (P = 0.16) for hematopoietic response.The iron supplementation to ESAs might be beneficial as fewer participants treated with iron supplementation required red blood cell (RBC) transfusions compared to the number of participants treated with ESAs alone (RR 0.74 (95% CI 0.60 to 0.92); P = 0.007; 1719 participants; 11 comparisons; moderate-quality evidence). Assuming a baseline risk of 7% to 40% for RBC transfusion without iron supplementation, between 10 and 57 patients should be treated to avoid RBC transfusion in one patient.We found no evidence for a difference in the median time to hematopoietic response with addition of iron to ESAs (hazard ratio (HR) 0.93 (95% CI 0.67 to 1.28); P = 0.65; 1042 participants; seven comparisons; low-quality evidence). In subgroup analyses, RCTs in which dextran (HR 0.95 (95% CI 0.36 to 2.52); P = 0.92; 340 participants; three comparisons), sucrose iron (HR 1.15 (95% CI 0.60 to 2.21); P = 0.67; 102 participants; one comparison) and sulfate iron (HR 1.24 (95% CI 0.99 to 1.56); P = 0.06; 55 participants; one comparison) were used showed no evidence for difference between iron supplementation versus ESAs alone compared with RCTs in which gluconate (HR 0.78 (95% CI 0.65 to 0.94); P = 0.01; 464 participants; two comparisons) was used for median time to hematopoietic response (P = 0.02). There was no evidence for a difference between the subgroups of route of iron administration (P = 0.13) and types of ESAs (P = 0.46) for median time to hematopoietic response.Our results indicated that there could be improvement in the hemoglobin (Hb) levels with addition of iron to ESAs (mean difference (MD) 0.48 (95% CI 0.10 to 0.86); P = 0.01; 827 participants; seven comparisons; low-quality evidence). In RCTs in which IV iron was used there was evidence for a difference (MD 0.84 (95% CI 0.21 to 1.46); P = 0.009; 436 participants; four comparisons) compared with oral iron (MD 0.07 (95% CI -0.19 to 0.34); P = 0.59; 391 participants; three comparisons) for mean change in Hb level (P = 0.03). RCTs in which dextran (MD 1.55 (95% CI 0.62 to 2.47); P = 0.001; 102 participants; two comparisons) was used showed evidence for a difference with iron supplementation versus ESAs alone compared with RCTs in which gluconate (MD 0.54 (95% CI -0.15 to 1.22); P = 0.12; 334 participants; two comparisons) and sulfate iron (MD 0.07 (95% CI -0.19 to 0.34); P = 0.59; 391 participants; three comparisons) were used for mean change in Hb level (P = 0.007). RCTs in which epoetin was used showed evidence for a difference with iron supplementation versus ESAs alone (MD 0.77 (95% CI 0.25 to 1.29); P = 0.004; 337 participants; five comparisons) compared with darbepoetin use (MD 0.10 (95% CI -0.13 to 0.33); P = 0.38; 490 participants; two comparisons) for mean change in Hb level (P = 0.02).We found no evidence for a difference in quality of life with addition of iron to ESAs (standardized mean difference 0.01 (95% CI -0.10 to 0.12); P = 0.88; 1124 participants; three RCTs; high-quality evidence).We found no evidence for a difference in risk of grade III-IV thromboembolic events (RR 0.95 (95% CI 0.54 to 1.65); P = 0.85; 783 participants; three RCTs; moderate-quality evidence). The incidence of treatment-related mortality (TRM) was 0% (997 participants; four comparisons; high-quality evidence).Other common adverse events included vomiting, asthenia, and leukopenia, and were similar in both arms.Overall the risk of bias across outcomes was high to low. Since the included RCTs had shorter follow-up duration (up to 20 weeks), the long-term effects of iron supplementation are unknown. Our main reasons for downgrading the quality of evidence were inconsistency across the included studies and imprecision of results.
AUTHORS' CONCLUSIONS
Our systematic review shows that addition of iron to ESAs offers superior hematopoietic response, reduces the risk of RBC transfusions, and improves Hb levels, and appears to be well tolerated. None of the included RCTs reported overall survival. We found no evidence for a difference in quality of life with iron supplementation. | v2 |
2020-10-28T19:12:49.541Z | 2020-10-08T00:00:00.000Z | 242947171 | s2ag/train | Mars dust properties by means of TGO/NOMAD UVIS and LNO channels nadir data analysis
<p>Abstract<br />Here we analyse nadir data from both the UVIS and LNO channels of the NOMAD spectrometer [1], onboard ExoMars/TGO, to obtain information about Martian dust densities and grains sizes. The combined dataset is analyzed with the MITRA radiative transfer tool [2,3,4]. The method is validated on a NOMAD orbit registered during the 2018 global dust storm to assess its most critical issues and is currently being extended to the whole available spatially and temporally coincident UVIS and LNO nadir data.<br />Introduction<br />The investigation of the presence and distribution of trace gases on Mars is fundamental to understand the atmosphere past evolution and provides insights on the research of biotic activities. Recent studies focused on the 2018 global-scale dust event as observed from the TGO instruments demonstrate that Martian dust can affect the abundance and distribution of atmospheric trace gases [5,6,15], making it a driver for their evolution. Suspended dust on Mars drives the planet’s thermal structure and climate [7], heating the lower atmosphere through absorption in the VIS-NIR spectral range [8] and efficiently radiating heat to space through IR emission [9,10,8,11]. These heating and cooling mechanisms affect the water-ice clouds formation, strengthen the mean meridional circulation and can drive deep localized convection, leading to variations and redistributions of water vapour abundances [6,15]. For the above reasons, the understanding of dust properties is mandatory in order to correctly investigate the vertical distribution of Martian trace gases.<br />Observations<br />The NOMAD spectrometer operates with three channels in the ultraviolet/visible spectral range (UVIS channel) and in the infrared (LNO and SO channels) in nadir, limb and solar occultation geometries. Although the instrument has been mainly conceived to study the trace gases in the atmosphere of the red planet, it can also provide valuable information regarding the properties of Martian dust. In this regard, in this work we use the UVIS and LNO channels nadir data to construct a dataset of spatially and temporally coincident data to study the microphysical properties of Martian dust. <br />Method<br />The UVIS spectral range alone (0.20–0.65 μm) does not allow to disentangle with high precision the information related to the dust density from that of dust grains sizes. The use of both the ultraviolet/visible and infrared ranges together is mandatory in order to obtain these properties. Indeed, we show that while the order of magnitude of the dust optical depth can be inferred from the UVIS data alone, dust grains sizes can be retrieved only by studying how the observed spectra bend between visual and near infrared wavelengths. For the purpose of the analysis presented here we use only LNO orders covering the wavelength range 2.20-2.65 μm, which is approximately free from gaseous absorption and, hence, it is suitable to investigate dust properties. We use the MITRA radiative transfer model and inversion algorithm to retrieve dust densities and grain sizes. We take the temperature-pressure profiles from the Mars Climate Database (MCD, [12]) and  use the dust optical constants from [13]. The procedure followed to derive the surface albedo spectra, needed in the forward model, is based on the SAS method [14] applied to the OMEGA dataset.  For this reason, we use UVIS data only down to 0.4 μm to avoid extrapolating the information of the surface albedo at wavelengths shorter than OMEGA lower spectral limit. This method is tested and validated on a NOMAD observation acquired on the 8th of June 2018 during a global dust storm and is now being extended to all spatially and temporally coincident observations of UVIS and LNO channels. If no coincident LNO observations are available for a certain UVIS orbit, we apply the MITRA tool to the UVIS spectral range alone to obtain the dust integrated optical depth.<br />Summary<br />The presented method allows to study the properties of Martian dust obtaining information on grains densities and sizes whenever temporally and spatially coincident UVIS and LNO observations are available. When this is not possible, the analysis is performed on the UVIS data alone to obtain the dust integrated optical depth. Through the application of this method to the whole NOMAD dataset we aim to produce a set of dust properties associated to each observation with a precision that is only achievable by exploiting the combined UVIS and LNO spectral ranges.<br />Acknowledgements<br />ExoMars is a space mission of the European Space Agency (ESA) and Roscosmos. The NOMAD experiment is led by the Royal Belgian Institute for Space Aeronomy (IASB-BIRA), assisted by Co-PI teams from Spain (IAA-CSIC), Italy (INAF-IAPS), and the United Kingdom (Open University). This project acknowledges funding by the Belgian Science Policy Office (BELSPO), with the financial and contractual coordination by the ESA Prodex Office (PEA 4000103401, 4000121493), by Spanish Ministry of Science and Innovation (MCIU) and by European funds under grants PGC2018-101836-B-I00 and ESP2017-87143-R (MINECO/FEDER), as well as by UK Space Agency through grants ST/R005761/1, ST/P001262/1, ST/R001405/1 and ST/R001405/1 and Italian Space Agency through grant 2018-2-HH.0. This work was supported by the Belgian Fonds de la Recherche Scientifique – FNRS under grant number 30442502 (ET_HOME). The IAA/CSIC team acknowledges financial support from the State Agency for Research of the Spanish MCIU through the ‘Center of Excellence Severo Ochoa’ award for the Instituto de Astrofísica de Andalucía (SEV-2017-0709). US investigators were supported by the National Aeronautics and Space Administration. Canadian investigators were supported by the Canadian Space Agency.<br />References:[1]Neefs, E., et al, 2015. Appl. Opt. 54, 28, 8494-8520.[2]Oliva, F., et al, 2016. Icarus 278, 215-237.[3]Sindoni, G., et al, 2013. EPSC2013.[4]Oliva, F., et al, 2018. Icarus 300, 1-11.[5]Daerden, F., et al, 2019. Icarus 326, 197-224.[6]Vandaele, A.C., et al, 2019. Nature 568, 521-525.[7]Kahre, M.A., et al, 2008. Icarus 195, 576-597.[8]Korablev, O. ,et al, 2005. Adv. Space Res. 35, 21–30.[9]Gierasch, P.G., Goody, R.M., 1972. J. Atmos. Sci. 29, 400–402.[10]Pollack, J.,et al, 1979. J. Geophys. Res. 84, 2929–2945.[11]Määttänen, A., et al, 2009. Icarus 201, 504-516.[12]Millour, E., et al, 2015. EPSC2015.[13]Wolff, M.J., et al, 2009. J. Geophys. Res., 114, E9.[14]Geminale, A., et al, 2015. Icarus 253, 51-65.[15]Aoki, S., et al. 2019. J. Geophys. Res.: Planets,124, 3482-3497.</p> | v2 |
2019-03-18T14:06:46.297Z | 2018-11-29T00:00:00.000Z | 81302671 | s2ag/train | A Phase II Lysa Study of Obinutuzumab Combined with Lenalidomide for Advanced Untretated Follicular B-Cell Lymphoma in Need of Systemic Therapy
BACKGROUND: Obinutuzumab is a type II anti-CD20 monoclonal antibody that induces antibody-dependent cellular cytotoxicity, antibody-dependent cell-mediated phagocytosis, and direct cell death better than rituximab. Given promising results with lenalidomide and rituximab (R2), we assessed the safety and efficacy of lenalidomide combined with obinutuzumab (GALEN)in a large phase Ib/II study in separate patient populations (NCT01582776). In relapsed/refractory follicular B-cell lymphoma (FL), we found the GALEN regimen might be even more efficient than R2 while retaining a similarly manageable safety profile. Here, we report the results for the phase II part assessing efficacy and safety of GALEN in advanced untreated FL patients (pts) in need of systemic therapy.
METHODS: Eligible pts had grade 1-3a FL and required systemic therapy per GELF criteria. Induction treatment consisted of lenalidomide (LEN) 20 mg on day (d) 1-21 of a 28-d cycle for the first cycle and on d2-22 of a 28-d cycle from cycles 2 to 6. Obinutuzumab (GA) 1000 mg was given IV on d8, 15, and 22 of cycle 1 and d1 of cycles 2 to 6. Responding pts then received maintenance with LEN at 10 mg on d2-22 every 28d for 12 cycles and GA 1000 mg every 8 wk for 12 cycles until progression or unacceptable toxicity. The primary study endpoint was complete response (CR)/CR unconfirmed (CRu) rate by investigator assessment at the end of induction according to 1999 IWG criteria. Secondary endpoints included overall response rate (ORR) and CR according to IWG 2007, progression-free survival (PFS), duration of response (DOR), overall survival (OS) and safety.
RESULTS: 100 pts with WHO FL gr 1-2 (91%) and 3a (9%) according to local pathology reports were enrolled between October 2015 and February 2017. Median age was 60.5 years (range, 32-89), 43% had FLIPI score ≥3, 89% stage III/IV, and 31% bulky disease (>7 cm). All 100 pts were evaluable for safety and efficacy. At a median follow-up of 2.1 years, 96 pts (96%) completed induction, 41 completed maintenance, 36 were ongoing in maintenance, and 23 prematurely discontinued treatment due to disease progression (n=12, including 2 during induction), toxicity (n=6, including 2 during induction), concurrent illness (n=3), consent withdrawal (n=1), or other cause (n=1). At the end of induction, 61 pts had regression by more than 75% of sum of the product of the greatest diameters (SPD) of target lesions and 83/97 (85.6%) with PET assessment were PET negative (Juweid criteria) including 79/93 (84.9%) with a 5PS (Deauville scale) score of 1-3. Sixteen pts with SPD regression >75% and 25 pts with negative PET were conservatively downgraded to PR due to missing bone marrow evaluation, leading to 47% CR/CRu rate and 59% CR rate at the end of induction per IWG1999 and 2007 criteria, respectively. Response rates at the end of induction, PFS, DOR and OS are summarized in the Table and Figure.
Most common AEs (>10% of pts) during induction (% all gr/% gr 3/4) were neutropenia (43/42), asthenia (35/2), constipation (32/0), infusion-related reactions (23/3), diarrhea (21/2), rash (21/2), cough (18/0), nausea (13/0), pruritus (12/1), weight decrease (12/0), bronchitis (11/0), muscle spasms (11/1), and pyrexia (11/0). Febrile neutropenia occurred in 2% of pts. Eight second primary malignancies were reported in 8 pts, including 2 deemed unrelated since they were misdiagnosed at baseline. Three (3%) pts had died, 1 each due to lymphoma, toxicity of additional treatment, and intestinal adenocarcinoma.
CONCLUSION: The immunomodulatory GALEN regimen is highly effective with no unexpected toxicity in advanced, untreated FL pts in need of systemic therapy and has the potential to challenge immunochemotherapy in this setting.
Morschhauser: BMS: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy; Janssen: Other: Scientific Lectures. Salles:Celgene: Honoraria, Research Funding; AbbVie: Honoraria; Acerta: Honoraria; Janssen: Honoraria; Gilead: Honoraria; Amgen: Honoraria; Epizyme: Honoraria; Merck: Honoraria; Morphosys: Honoraria; Takeda: Honoraria; Servier: Honoraria; Pfizer: Honoraria; Roche: Honoraria, Research Funding; Novartis: Consultancy, Honoraria. Feugier:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Cartron:Celgene: Consultancy, Honoraria; Janssen: Honoraria; Roche: Consultancy, Honoraria; Sanofi: Honoraria; Gilead Sciences: Honoraria. Maerevoet:abbvie: Membership on an entity's Board of Directors or advisory committees, Other: travel grant; roche: Other: travel grant; takeda: Membership on an entity's Board of Directors or advisory committees, Other: travel grant; Karyopharm: Membership on an entity's Board of Directors or advisory committees. Tilly:Roche: Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria. Haioun:Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Sciences: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; Roche: Consultancy, Honoraria. Houot:BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Janssen: Honoraria; Novartis: Honoraria.
| v2 |
2019-03-17T13:06:55.684Z | 2017-08-21T00:00:00.000Z | 79821901 | s2ag/train | 28 Do not attempt resuscitation: university of aberdeen student perspectives
Introduction Do Not Attempt Resuscitation Orders(DNAR) and their contemporary counterparts are cornerstones of End of Life care and as such, of importance within medical education. Previous research indicates the need for a better understanding of patient and physicians perceptions of DNAR topics. Aims and methods The objective of the study was to explore medical students(MS) and non-medical students perspectives on DNAR discussions(DNARD), and explore any differences. This was a cross-sectional questionnaire study. MS and Education students(ES) were asked how they felt regarding DNARD taking place in 5 scenarios, a number of questions regarding previous experience, knowledge of DNARD, future preferences, and basic demographics. Results The number of valid respondents was 601 (375[MS],226[ES]) representing a response rate of over 70%. There were statistically significant differences between MS and ES in the presented clinical scenarios and future preferences. Ranking of clinical scenarios, highest agreement to lowest, for DNARD to take place were: before surgery, when critically ill, at a GP appointment, on admission to hospital, at an outpatient appointment. Statistically significant demographic differences were also found: 93% of MS having heard of DNAR previously as compared to 59% of ES. Both groups held the view that a DNARD would be beneficial for them in the future but that they should have the final decision regarding DNAR. Conclusion MS and ES were found to hold differing views regarding DNARD in scenario preferences and personal future preferences. However, the majority of both groups felt that DNARD would be beneficial to them in the future. References . Mary Catherine Beach, R Sean Morrison. The Effect of Do-Not-Resuscitate Orders on Physician Decision-Making. Ethics, public policy, and medical economics2002;50:2057–206. . Cathy Charles, Tim Whelan, Amiram Gafni. What do we mean by partnership in making decisions about treatment?BMJ1999;319:780. . James Downar, Tracy Luk, Robert W Sibbald, Tatiana Santini, Joseph Mikhael, Hershl Berman, Laura. Why Do Patients Agree to a “Do Not Resuscitate” or “Full Code” Order? Perspectives of Medical Inpatients. Journal of internal medicine2011;26(6):582–587. . Thomas H. Gallagher, Steven Z. Pantilat, Bernard Lo & Maxine A. Papadakis (1999) Teaching Medical Students to Discuss Advance Directives: A Standardised Patient Curriculum, Teaching and Learning in Medicine, 11:3, 142–147, DOI: 10.1207/S15328015TL110304 . Paul Garrud. (2011). Who applies and who gets admitted to UK graduate entry medicine? - an analysis of UK admission statistics. BMC Medical Education. 11:71. . General Medical Council. (2013). Chapter1: The changing shape of the profession and medical education. In: The state of medical education and practice in the UK report: 2013. General Medical Council. 32. . GMC, 2010. End of life treatment and care: Good practice in decision-making. Specifically paragraphs 11, 132 and 134. Can be accessed at: http://www.gmcuk.org/guidance/ethical_guidance/end_of_life_care.asp . Todd E. Gorman, MD, FRCP(C), Ste'phane P. Ahern, MD, FRCP(C), Jeffrey Wiseman, MD, FRCP(C), MA, and Yoanna Skrobik, MD, FRCP(C). (2005). Residents’ End-of-Life Decision Making with Adult Hospitalised Patients: A Review of the Literature. Academic Medicine. 80 (7), 622–633. . Gorton, A.J., Jayanthi, N.V.G., Lepping, P., Scriven, M.W., 2008. Patients’ attitudes towards “do not attempt resuscitation” status. J Med Ethics. Vol 34; 624–626. . W. Hafferty, Joseph F. O’Donnell (2015). The Hidden Curriculum in Health Professional Education. United States of America: Dartmouth College Press. 5. . Karen Hancock, Josephine M Clayton, Sharon M Parker, Sharon Wal der, Phyllis N Butow, Sue Carrick, David Currow, Davina Ghersi, Paul Glare, Rebecca Hagerty, Martin HN Tattersall . (2007). Truth-telling in discussing prognosis in advanced life-limiting illnesses: a systematic review. Palliative Medicine. 21 , 507–517. . Jan C. Hofmann, Neil S. Wenger, Roger B. Davis, Joan Teno, Alfred F. Connors, Norman Desbiens, Joanne Lynn, Russell S. Phillips. (1997). Patient Preferences for Communication with Physicians about End-of-Life Decisions . Annals of Internal Medicine. 1 July 1997. . NHS Scotland. (2016). NHSScotland. Available: http://www.gov.scot/Topics/Health/About/NHS-Scotland. Last accessed 25th Nov 2016. . NRS: National Records of Scotland. (2013). Religion, Scotland, 2001 and 2011.Available: http://www.scotlandscensus.gov.uk/documents/censusresults/release2a/rel2asbtable7.pdf. Last accessed 25th Nov 2016 . ONS: Office for National Statistics. (2011). Full story: What does the Census tell us about religion in 2011?. Available: http://www.ons.gov.uk/peoplepopulationandcommunity/culturalidentity/religion/articles/fullstorywhatdoesthecensustellusaboutreligionin2011/2013-05-16. Last accessed 25th Nov 2016. . Stephen R. Porter and Michael E. Whitcomb. (2005). NON-RESPONSE IN STUDENT SURVEYS: The Role of Demographics, Engagement and Personality. Research in Higher Education. 46 (2). . Amy Sanderson, David Zurakowski, Joanne Wolfe. (2013). Clinician Perspectives Regarding the Do-Not-Resuscitate Order. JAMA paediatrics. 167 (10), 954–958. . Scottish Government, 2010. Do Not Attempt Cardiopulmonary Resuscitation (DNACPR): Integrated Adult Policy. Reviewed 2015. Can be accessed at: http://www.gov.scot/Topics/Health/Quality-sImprovement-Performance/peolc/DNACPR . Clive Seale. (2010). The role of doctors’ religious faith and ethnicity in taking ethically controversial decisions during end-of-life care. Journal of Medical Ethics. doi:10.1136/jme.2010.036194. . C O Sham, Y W Cheng, K W Ho, P H Lai, L W Lo, H L Wan, C Y Wong, Y N Yeung, S H Yuen, A Y C Wong. (2007). Do-not-resuscitate decision: the attitudes of medical and non medical students. Clinical Ethics . 33 (5), 261–265. . UKMCRG: UK Medical Careers Research Group (2001). 1999 cohort of UK Medical Graduates: Report of First Survey. Oxford: Institute of Health Sciences, University of Oxford. 14. . Jacqueline K. Yuen, M. Carrington Reid, and Michael D. Fetters. (2011). Hospital Do-Not-Resuscitate Orders: Why They Have Failed and How to Fix Them. Journal of General Internal Medicine. 26 (7), 791–797. . Rocksheng Zhong, Joshua Knobe, PhD, Neal Feigenson, JD, and Mark R. Mercurio, MD, MA. (2011). Age and Disability Biases in Paediatric Resuscitation Among Future Physicians. Clinical Paediatrics., 1–4. | v2 |
2019-08-01T04:47:20.115Z | 2019-01-01T00:00:00.000Z | 150413771 | s2ag/train | PERSONEL DIMENSIONING AND ITS INTERFERENCE IN THE QUALITY
Objective: to analyze the nursing staff dimensioning the quality of care. Method: this is a bibliographical study, an integrative review, of articles published in the period 2007 to 2017, in the MEDLINE, LILACS and BDENF databases. The articles were read and the summaries of the results of the articles in figures. Results: 103 publications were identified in the initial search. Eleven articles were selected from the analysis of the title, the researched topic and the eligibility criteria, and three contents remained in the reading of the contents, two of which were qualitative and one quantitative approach. It should be highlighted that the descriptors most used by the authors of the articles were Nursing care, personnel dimensioning, quality of health care, being the field of research of these studies the dimensioning of Nursing staff. Conclusion: it can be considered that the personnel dimension is an important step, which directs the assistance of the Nursing team, so that it recognizes the need to devise strategies to identify the profile of patients attended and the need for professionals to assist them. Descritores: Nursing Care; Personnel Downsizing; Quality of Health Care; Human Resources; Nurse Practitioners; Competence Professional. RESUMO Objetivo: analisar o dimensionamento de pessoal de Enfermagem frente à qualidade da assistência. Método: trata-se de um estudo bibliográfico, tipo revisão integrativa, de artigos publicados no período de 2007 a 2017, nas bases de dados MEDLINE, LILACS e BDENF. Apresentaram-se as sínteses dos resultados dos artigos em figuras. Resultados: identificaram-se, na busca inicial, 103 publicações. Selecionaram-se 11 artigos a partir da análise do título, da temática pesquisada e dos critérios de elegibilidade e, na leitura na íntegra dos conteúdos, restaram três, sendo dois de abordagem metodológica qualitativa e uma de abordagem quantitativa. Destaca-se que os descritores mais utilizados pelos autores dos artigos foram cuidados de Enfermagem, dimensionamento de pessoal, qualidade da assistência à saúde, sendo o campo de pesquisa desses estudos o dimensionamento de pessoal de Enfermagem. Conclusão: pode-se considerar que o dimensionamento de pessoal é uma etapa importante, que direciona a assistência da equipe de Enfermagem, de modo que ela reconheça a necessidade de planejar estratégias para identificar o perfil dos pacientes atendidos e a necessidade de profissionais para assisti-los. Descritores: Cuidados de Enfermagem; Dimensionamento Pessoal; Qualidade da Assistência à Saúde; Recursos Humanos; Profissionais de Enfermagem; Competência Profissional. RESUMEN Objetivo: analizar el dimensionamiento de personal de enfermería frente a la calidad de la asistencia. Método: se trata de un estudio bibliográfico, tipo revisión integrativa, de artículos publicados en el período de 2007 a 2017, en las bases de datos MEDLINE, LILACS y BDENF. Se presentaron las síntesis de los resultados de los artículos en figuras. Resultados: se identificaron, en la búsqueda inicial, 103 publicaciones. Se seleccionaron 11 artículos a partir del análisis del título, de la temática investigada y de los criterios de elegibilidad y, en la lectura íntegra de los contenidos, quedaron tres, siendo dos de abordaje metodológico cualitativo y uno de abordaje cuantitativo. Se destaca que los descriptores más utilizados por los autores de los artículos fueron cuidados de Enfermería, dimensionamiento de personal, calidad de la asistencia a la salud, siendo el campo de investigación de esos estudios el dimensionamiento de personal de Enfermería. Conclusión: se puede considerar que el dimensionamiento de personal es una etapa importante, que dirige la asistencia del equipo de Enfermería, de modo que ella reconozca la necesidad de planificar estrategias para identificar el perfil de los pacientes atendidos y la necesidad de profesionales para asistirlos. Descritores: Atencíon de Enfermería; Reduccíon de Personal; Calidad de la Atencíon de Salud; Recursos Humanos; Enfermeras Practicantes; Competencia Profissional. Nursing students, Centro Universitário Tabosa de Almeida ASCES-UNITA. Caruaru (PE). Email: [email protected] ORCID iD: https://orcid.org/0000-0001-8500-0883; Email: [email protected] ORCID iD: https://orcid.org/0000-0003-0383-7888; Email: [email protected] ORCID iD: https://orcid.org/0000-0001-8682-1018; Email: [email protected] ORCID iD: https://orcid.org/0000-0002-6883-2028; Email: [email protected] ORCID iD: https://orcid.org/0000-0002-9778-3659; Email: [email protected] ORCID iD: https://orcid.org/0000-0002-5626-3438; Masters student, University of Pernambuco/UPE. Caruaru (PE), Brazil. E-mail: [email protected] ORCID iD: https://orcid.org/0000-0003-1754-7275; Master, Federal University of Pernambuco / UPE. Caruaru (PE). Email: [email protected] ORCID iD: https://orcid.org/0000-0002-9278-9234 INTEGRATIVE REVIEW ARTICLE Silva LC da, Oliveira DAL, Santos ABR et al. Personel dimensioning and its interference in... English/Portuguese J Nurs UFPE online., Recife, 13(2):491-8, Feb., 2019 492 ISSN: 1981-8963 https://doi.org/10.5205/1981-8963-v13i02a236551p491-498-2019 Through the changes in the world political context, the diffusion of new technologies and the socialization of the media has been contributed, so that the population becomes more and more aware of their rights and, therefore, more demanding in relation to quality of the services placed at their disposal, making quality a criterion that is increasingly present in hospitals, through a commitment to meeting customer needs, seeking to increase the level of user satisfaction, by offering an effective assistance and safe, with the technical quality of care processes under appropriate structural and ethical conditions. It is known that, within this context, the Nursing services face challenges in order to meet the clients' demands, in order to achieve the excellence of care quality in the hospital context. The Federal Nursing Council (COFEN) has decreed guidelines that represent minimum technical standards, through COFEN Resolution Num. 189/1996, repealing COFEN Resolution Num. 293/2004 on topics related to the increase number of hours of nursing care per level of complexity and per bed, establishing that it is the responsibility of the nurse to quantify and qualitative definition of the pannel of Nursing professionals needed to meet the need for care. It is detailed in COFEN Resolution No. 543/2017, on the other hand, specifies that the size of the nursing profession is determined by the context of the unit and by the identification of the workload, where, for the identification of the variables, it is necessary to in order to measure the time used for the provision of skilled nursing care. | v2 |
2021-11-26T16:14:53.326Z | 2021-11-05T00:00:00.000Z | 244643331 | s2ag/train | Prevalence and Overall Survival of Low Count Monoclonal B-Cell Lymphocytosis (LC-MBL): A Screening Study of 8,297 Individuals from the Mayo Clinic Biobank
Monoclonal B-cell lymphocytosis (MBL) is one of the most common pre-malignant conditions and is characterized by a circulating population of clonal B-cells with an absolute clonal B-cell count < 5x10 9/L and no evidence of lymphadenopathy, organomegaly, or cytopenias. MBL can be classified by the immunophenotype: CLL-like MBL (CD5+, CD20dim), atypical MBL (CD5+, CD20+), or non-CLL-like MBL (CD5-, CD20+), as well as by the size of the clone (low-count or high-count) with low-count MBL (LC-MBL) defined as clonal B-cell <0.5x10 9/L or percent clonal B-cell count <85% out of total B-cell count. The prevalence of MBL varies depending on detection methods and population tested. In a Spanish screening study of 608 individuals, they identified 73 MBLs (12%) with CLL-like MBL; moreover, these authors also evaluated overall survival (OS) compared to 290 individuals without MBL and found a significantly shorter OS among these predominantly LC-MBLs. Here, we evaluate the prevalence and OS of LC-MBL in a large screening cohort of 8,297 individuals.
Study participants from the Mayo Clinic Biobank, a large-scale biorepository of adult patients, who had no prior history of hematologic malignancy, provided blood samples between 7/2009 to 4/2021. Stored peripheral blood mononuclear cells were screened for MBL with an eight-color flow cytometry assay capable of detecting clonal B-cell event to the 0.005% level. We classified each MBL by immunophenotype as CLL-like MBL, atypical MBL, and non-CLL-like MBL. Individuals with more than one immunophenotype were classified into one immunophenotype based on the following hierarchy: CLL-like MBL, then atypical MBL, then non-CLL like MBL. Based on previously published evidence, individuals were also classified by clonal counts using the percent clonal B-cell count <85% out of the total B-cell count to define LC-MBL. Individuals were followed from sample date to the earliest of death, loss to follow-up, or 5/31/2021. OS for LC-MBL and controls (individuals who screened negative for MBL) was assessed by Kaplan-Meier method. Age- and sex-adjusted OS was analyzed using inverse weights methods. Cox regression was used to calculate hazard ratios (HR) and 95% confidence intervals (CIs), adjusted for age and sex.
We screened 8,297 individuals 40 years or older (median age 67 years, 39% male) and identified 1,326 (16%) with LC-MBL and 6,651 (80%) controls. Those individuals detected with high-count MBL (N=90, 1%) or individuals who had insufficient cells for flow cytometry interpretation (N=230, 3%) were excluded from subsequent analyses. The prevalence of LC-MBL was higher in males (21%) than females (14%; p<0.01) and significantly increased with age (p<0.01) ranging from 3% among those 40-49 years, 10% among those 50-59 years, 15% among those 60-69 years, 23% among those 70-79 years, and 29% for those 80+ years. Sixty-one individuals had clones with more than one type of immunophenotype. Based on our hierarchy, CLL-like MBL was the most common (N=1,155), followed by non-CLL-like (N=168) and atypical MBL (N=67). The median follow-up time in our cohort was 26 months (range 0-142), and 432 individuals had subsequently died. The 5-year and 10-year OS adjusted for age and sex among LC-MBLs was 95% and 87%, respectively; control estimates were 95% and 84%, respectively. We did not observe a significant difference in OS between those individuals with LC-MBL versus controls (HR=0.98, CI=0.77-1.24, P=0.84, Fig 1a), nor when we stratified individuals by age <65 (P=0.77) or age >= 65 (P=0.68). Among females, OS was longer among LC-MBL compared to controls (HR=0.61, CI=0.38-0.97, P=0.04); but no evidence of a difference in OS among males was observed (HR=1.22, CI=0.92-1.62, P=0.17). When we evaluated OS by MBL immunophenotype, we observed no statistically significant difference (Fig 1b, log rank P=0.44). When we stratified the MBLs by immunophenotype versus controls, we also did not observe a difference: CLL-like (HR=0.91, CI=0.71-1.18, P=0.5), atypical (HR=1.73, CI=0.92-3.27, P=0.09), non-CLL like (HR=0.98, CI=0.58-1.66, P=0.95).
In the largest MBL screening cohort to date, LC-MBL was a common condition among adults 40 years or older reaching a prevalence as high as 29% among individuals 80 years of age or older. OS among those with and without LC-MBL was similar, regardless of immunophenotype and age. The longer survival in females with MBL versus controls requires further evaluation.
Figure 1 Figure 1.
Parikh: Pharmacyclics, AstraZeneca, Genentech, Gilead, GlaxoSmithKline, Verastem Oncology, and AbbVie: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics, MorphoSys, Janssen, AstraZeneca, TG Therapeutics, Bristol Myers Squibb, Merck, AbbVie, and Ascentage Pharma: Research Funding. Kay: Juno Therapeutics: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Meyer Squib: Membership on an entity's Board of Directors or advisory committees, Research Funding; Targeted Oncology: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Research Funding; Sunesis: Research Funding; Dava Oncology: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Behring: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta Pharma: Research Funding; MEI Pharma: Research Funding; Tolero Pharmaceuticals: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; CytomX Therapeutics: Membership on an entity's Board of Directors or advisory committees; Oncotracker: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios Pharm: Membership on an entity's Board of Directors or advisory committees; Morpho-sys: Membership on an entity's Board of Directors or advisory committees; Rigel: Membership on an entity's Board of Directors or advisory committees. Shanafelt: Genentech, Pharmacyclics: Research Funding.
| v2 |
2019-08-23T02:03:45.332Z | 2018-11-29T00:00:00.000Z | 201179321 | s2ag/train | Patient Co-Morbidity Profile Should Drive PI3K Inhibitor Selection for Relapsed Follicular Lymphoma
Background: Idelalisib (Zydelig®, IDELA), an oral agent, and copanlisib (Aliqopa®, COPA), an intravenous agent, are the only B-cell receptor pathway targeting agents approved for treatment of follicular lymphoma (FL). Both agents target PI3Kδ while COPA also targets PI3Kα. These drugs received accelerated approvals, and overall response rates in their respective phase 2 trials were comparable. Safety profiles may be impacted by distinct kinase inhibitory profiles, delivery method, and dosing. Given similar response rates with these agents, the administration schedule and safety profile become important considerations. A challenge is the appropriate regimen choice to maximize anti-tumor benefit while limiting treatment-emergent adverse events (TEAEs) or exacerbation of pre-existing co-morbidities.
Objective: To compare the safety profiles of IDELA and COPA to determine which drug may be more suitable for select patient populations.
Methods: We selected key AEs for analysis based on the "Highlights of Prescribing Information" in each drug's United States package insert (USPI) to assess the incidence of TEAEs in patients receiving COPA or IDELA. Using the Safety Analysis Set for patients with iNHL treated with IDELA (N=163, median duration of treatment [mDoT] 27 weeks) and TEAEs reported for patients with FL and other hematological malignancies treated with COPA (Aliqopa® USPI [N=168, mDoT 22 weeks], Dreyling et al., J. Clin. Oncol. 2017; 35:3898 [N=142, mDoT 22 weeks], and Dreyling et al., Blood. 2017; 130:2777 [N=142, mDoT 26 weeks]), we ascertained the most common TEAEs, compared the incidence of specific TEAEs (estimate difference in proportions, Fisher's exact test), and assessed the effect of pre-existing conditions on IDELA- and COPA-mediated AEs.
Results: All grade (aGr) and grade 3/4 (Gr3/4) diarrhea and transaminitis were significantly more common in IDELA-treated patients, and aGr and Gr3/4 hyperglycemia (blood glucose >160 mg/dL and >250 mg/dL, respectively) and hypertension (systolic blood pressure [SBP] >120 mmHg; diastolic blood pressure [DBP] > 80 mmHg and SBP > 160 mmHg; DBP > 100 mmHg, respectively) were significantly more common in COPA-treated patients (Figs. 1 and 2). The incidences of aGr and Gr3/4 infection, neutropenia, and pneumonitis were similar in IDELA- and COPA-treated patients. IDELA-treated patients with pre-existing diabetes mellitus or hyperglycemia experienced more Gr3/4 hyperglycemia than IDELA-treated patients without either diagnosis (7.1% vs. 0%, p=0.0286), but at rates lower than in COPA-treated patients (10.7% vs. 53.6%, p<0.0001 for aGr and 7.1% vs. 39.3%, p=0.0005 for Gr3/4 hyperglycemia). In contrast, pre-existing hypertension had no impact on the frequency of aGr and Gr3/4 hypertension among IDELA-treated patients; IDELA-treated patients with pre-existing hypertension also experienced lower rates of aGr and Gr3/4 hypertension compared to COPA-treated patients (3.2% vs. 35.1% for aGr; 1.6% vs. 27.4% for Gr3/4; both p<0.0001). Similarly, a history of or predisposition to diarrhea did not increase the rate of diarrhea in IDELA-treated patients, but Gr3/4 diarrhea was more frequent in IDELA-treated patients with no history of diarrhea than in COPA-treated patients (13.2% vs. 4.8%, p=0.0094). Finally, pre-existing ALT/AST elevations also did not increase the risk for treatment-emergent ALT/AST elevations in IDELA-treated patients, but IDELA-treated patients without pre-existing ALT/AST elevations demonstrated higher rates of aGr and Gr3/4 ALT/AST elevation than COPA-treated patients (39% vs. 1.4% for Gr3/4 ALT; 31.7% vs. 1.4% for Gr3/4 AST; both p<0.0001).
Conclusion: Pre-existing co-morbidities and the nature of emergent therapy-associated side effects (including type, severity, and duration [transient vs. chronic]) may impact PI3K inhibitor choice for the treatment of relapsed FL. Findings in this analysis suggest that for patients with pre-existing diabetes mellitus or hypertension, IDELA may be a more appropriate option. For patients at increased risk for diarrhea-related complications, COPA may be a more appropriate option. IDELA-treated patients should be followed closely for diarrhea and should be monitored routinely for hepatotoxicity regardless of hepatic status at treatment initiation. Patients treated with either compound should be followed closely for infection, neutropenia, and pneumonitis.
Ye: Gilead Sciences, Inc.: Employment, Equity Ownership. Xing:Gilead Sciences: Employment. Roudet:Gilead Sciences, Inc.: Employment. Ruzicka:Gilead Sciences, Inc.: Employment. Dreyling:Bayer: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Mundipharma: Consultancy, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria; Acerta: Consultancy; Sandoz: Consultancy. Zinzani:Janssen: Honoraria, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astra Zeneca: Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; SERVIER: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Honoraria, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees. Gopal:Teva: Research Funding; Asana: Consultancy; Incyte: Consultancy; Merck: Research Funding; Aptevo: Consultancy; Janssen: Consultancy, Research Funding; Spectrum: Research Funding; Takeda: Research Funding; BMS: Research Funding; Pfizer: Research Funding; Seattle Genetics: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Brim: Consultancy.
| v2 |
2021-09-28T15:30:28.898Z | 2021-07-22T00:00:00.000Z | 242322311 | s2ag/train | Calibration of the NOMAD-LNO channel onboard ExoMars 2016 Trace Gas Orbiter using solar spectra
<p><strong>Calibration of the NOMAD-LNO channel onboard ExoMars 2016 Trace Gas Orbiter using solar spectra</strong></p>
<p><strong>Cruz Mermy </strong>(1), F. Schmidt (1), I. R. Thomas (2), F. Daerden (2), B. Ristic (2), M. R. Patel (3,4), J.-J. Lopez-Moreno (5), G. Bellucci (6), A. C. Vandaele (2) and the NOMAD Team</p>
<p><strong>Introduction</strong></p>
<p>The LNO channel is a compact high-resolution echelle grating spectrometer with an acousto-optic tunable filter (AOTF) working in the infrared domain from 2.3 μ m to 3.8 μ m (4250-2630 cm -1 ) with a resolving power ( λ / Δ λ ) of around 10000, specially designed for nadir observation. With such high resolving power combined with the near-circular orbit of TGO that allow completion of 12 orbits in one sol, promoting a global coverage of the planet, the NOMAD-LNO instrument fits in with the science objective of the ExoMars program [Vandaele2015, Vandaele2018] and is perfectly suited to study the martian surface and atmosphere. The main objective here is to propose an original calibration procedure, adaptable for the full dataset of NOMAD-LNO. This calibration is complementary to the one proposed by [I.R.Thomas2021] in the sense that we will not assume the temporal stability of the instrument here. Our approach is thus able to test the temporal stability of the instrument in front of degradation by energetic particles. This approach will be based on an empirical continuum removal to take into account the departure between actual blaze function and theoretical one.</p>
<p><strong>Dataset</strong></p>
<p>The NOMAD-LNO fullscans is a solar observation made for calibration purposes. The instrument, normally in nadir position, is pointing toward the sun. The choice of using solar fullscans was made for two reasons: first, there are not enough miniscans to cover all diffraction orders with a significant amount of data while fullscans always cover the whole spectral range which allows testing the time dependence of the calibration. Second, it is important to estimate the instrumental sensitivity over the whole diffraction order range. As of June 2020, six solar calibrations have been performed. Typical fullscan observation is shown in figure 1 the x-axis is the spectel number, the y-axis is the diffraction order (i.e. the AOTF frequency) and the z-axis shows the sensitivity of the detector (in ADU for Analog to Digital Units).</p>
<p><img src="data:image/png;base64, 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| v2 |
2019-04-21T13:05:23.000Z | 2012-10-31T00:00:00.000Z | 124470551 | s2ag/train | Simulations And Observations Of Radiation In the Electron Cyclotron Frequency Range On the C-2 Device
n Several different antennas have recently been fielded on Tri Alpha Energy’s C-2 [1] experimental system to measure radiation emission in the range of 1-60 GHz, where the fundamental electron cyclotron frequency is approximately 2.5 GHz at the edge of the field-reversed configuration (FRC). Initial power measurements are correlated with changes in plasma parameters, and have magnitudes consistent with known electron temperatures and densities. Genray simulations of rays launched above the edge electron cyclotron frequency indicate that externally launched waves couple to the plasma in the OXB scheme and may damp inside the separatrix. Genray Use For The C-2 Device n The ray tracing code Genray [2] has been modified to accept profiles based on Cartesian coordinates n Simple 1D rigid-rotor equilibria have been used to estimate ray propagation in the range of frequencies near the electron cyclotron frequency n External waves are coupled to Bernstein modes via an BXO or OXB scheme n Initial ray trajectories and frequencies were scanned to assess transmission and propagation characteristics n Optimal coupling[3] between Bernstein modes and external waves is predicted to occur at a particular angle (N// ) with respect to the external magnetic field , which allows the left hand cutoff frequency to be equal to the plasma frequency at the X-O conversion point n Initial angle settings that produce the smallest discontinuities in Genray calculations coincide with the estimates for the optimal N// Initial Measurements Of Microwaves Correlate With Plasma Changes On C-2 n Antennas have been mounted on a 12” window looking near the Xpoint of the FRC (Log Periodic, Gain ~10dB) n Frequencies covered are .9 – 11 GHz in two separate bands n Radiated power is consistent with a low density and temperature plasma, but is highly modulated by the FRC n Future plans include moving the antennas toward the midplane to look for ECE from the FRC itself Summary And Future Plans n Genray simulations using reasonable equilibrium profiles for plasma density, temperature, and magnetic field suggest that microwaves in the 3-6 GHz range (1-2 X the edge cyclotron frequency) originating inside the plasma separatrix will couple to externally observable radiation via an OXB scheme n Initial measurements of radiated power correlate with plasma conditions. Antenna location will be moved in the future to a port with a better view of the FRC to further assess radiation characteristics Analytic Profiles Are Matched To C-2 Measurements Separatrix Radius .425 m Peak Density 5e19 m-3 Electron Temperature ~150 eV External B Field 1.0 kG Characteristic Frequency Profiles Illustrate Accessible Harmonic Locations n As the wave frequency is raised for a given set of plasma parameters, the location of the cyclotron resonance shifts outwards n For the given analytic equilibria, regions inside the separatrix may be accessible only for frequencies between the first and second harmonic at the edge Angle Scan At Second Harmonic Shows Coupling Between EBWs And External O-Modes n Increased angle (from radial direction) changes the axial distance traveled, but has little effect on the damping location or plasma dielectric once the wave has converted to the Bernstein mode n All the action is in the wave coupling region where an external Omode (E Bz) is coupled to a slow X-mode (E Bz) at the left hand cutoff (LHC), which converts to the EBW at the upper hybrid resonance (UH) n A closer look at the coupling region reveals the Genray root finding algorithm at work, which may not always be physical Numerical Settings Influence Ray Trajectories n Current Genray settings may not be ideal for tracking the mode conversion region. Reflections do not always occur where expected n Discontinuities in ray refraction and location are due to searches for roots to the plasma dispersion function near wave cutoff locations Ray Tracing Maps EC Harmonics To Ideal Viewing Angles n Radial location shifts outwards for increasing cyclotron harmonic n Transmission percentage in the OX region is up to 100% for all scanned harmonics (F2 F8) n External angle of emitted radiation becomes more parallel to the radial direction as frequency is increased [1] M. W. Binderbauer et al, Phys.Rev.Lett. 105, 045003 (2010). [2] A. P. Smirnov and R.W. Harvey, Bull. Am. Phys. Soc. 40, p. 1837, abstract 8p35, 1995). [3] J. Preinhaelter and V. Kopecky, J. Plas. Phys. 10, 1 (1973) | v2 |
2018-04-03T03:19:13.331Z | 2014-02-28T00:00:00.000Z | 1817721 | s2ag/train | Peginterferon plus ribavirin versus interferon plus ribavirin for chronic hepatitis C.
BACKGROUND
Pegylated interferon (peginterferon) plus ribavirin is the recommended treatment for patients with chronic hepatitis C, but systematic assessment of the effect of this treatment compared with interferon plus ribavirin is needed.
OBJECTIVES
To systematically evaluate the benefits and harms of peginterferon plus ribavirin versus interferon plus ribavirin for patients with chronic hepatitis C.
SEARCH METHODS
We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Science Citation Index-Expanded, and LILACS. We also searched conference abstracts, journals, and grey literature. The last searches were conducted in September 2013.
SELECTION CRITERIA
We included randomised clinical trials comparing peginterferon plus ribavirin versus interferon plus ribavirin with or without co-intervention(s) (e.g., other antiviral drugs) for chronic hepatitis C. Quasi-randomised and observational studies retrieved through the searches for randomised clinical trials were also considered for reports of harms. Our primary outcomes were liver-related morbidity, all-cause mortality, serious adverse events, adverse events leading to treatment discontinuation, other adverse events, and quality of life. Our secondary outcome was sustained virological response in serum, that is, undetectable hepatitis C virus RNA in serum by sensitive tests six months after the end of treatment.
DATA COLLECTION AND ANALYSIS
Two review authors independently used a standardised data collection form. We meta-analysed data with both fixed-effect and random-effects models. For each outcome, we calculated the odds ratio (OR) (for liver-related morbidity or all-cause mortality) or the risk ratio (RR) along with 95% confidence interval (CI) based on intention-to-treat analysis. We used domains of the trials to assess the risk of systematic errors (bias) and trial sequential analyses to assess the risk of random errors (play of chance).For each outcome, we calculated the RR with 95% CI based on intention-to-treat analysis. Effects of interventions on outcomes were assessed according to GRADE.
MAIN RESULTS
We included 27 randomised trials with 5938 participants. All trials had high risk of bias. We considered that the risk of bias did not impact on the quality of evidence for liver-related mortality and adverse event outcomes, but it did for virological response. All trials compared peginterferon alpha-2a or peginterferon alpha-2b plus ribavirin versus interferon plus ribavirin for participants with chronic hepatitis C. Three trials administered co-interventions (amantadine hydrochloride 200 mg daily to both intervention groups), and 24 trials were conducted without co-interventions. The effect observed between the two intervention groups regarding liver-related morbidity plus all-cause mortality (5/907 (0.55%) versus 4/882 (0.45%) was imprecise: OR 1.14 ( 95% CI 0.38 to 3.42; five trials; low quality of evidence), as was the risk of adverse events leading to treatment discontinuation (332/2692 (12.3%) versus 409/2176 (18.8%); RR 0.86, 95% CI 0.68 to 1.09; 15 trials; low quality of evidence) or regarding adverse events leading to treatment discontinuation (332/2692 (12.3%) versus 409/2176 (18.8%); RR 0.86, 95% CI 0.66 to 1.12; 17 trials; low quality of evidence). However, peginterferon plus ribavirin versus interferon plus ribavirin significantly increased the risk of neutropenia (332/2202 (15.1%) versus 117/1653 (7.1%); RR 2.15, 95% CI 1.76 to 2.61; 13 trials), thrombocytopenia (65/1113 (5.8%) versus 23/1082 (2.1%); RR 2.63, 95% CI 1.68 to 4.11; 10 trials), arthralgia (517/1740 (29.7%) versus 282/1194 (23.6%); RR 1.19, 95% CI 1.05 to 1.35; four trials), injection site reaction (627/1168 (53.7%) versus 186/649 (28.7%); RR 1.71, 95% CI 1.50 to 1.93; four trials), and nausea (606/1784 (34.0%) versus 354/1239 (28.6%); RR 1.13, 95% CI 1.01 to 1.26; four trials). The most frequent adverse event was fatigue, which occurred in 57% of participants (2024/3608). No significant difference was noted between peginterferon plus ribavirin versus interferon plus ribavirin in terms of fatigue (1177/2062 (57.1%) versus 847/1546 (54.8%); RR 1.01, 95% CI 0.96 to 1.07; 12 trials). No significant differences were reported between the two treatment groups regarding anaemia, headache, rigours, myalgia, pyrexia, weight loss, asthenia, depression, insomnia, irritability, alopecia, pruritus, skin rash, thyroid malfunction, decreased appetite, or diarrhoea. We were unable to identify any data on quality of life. Peginterferon plus ribavirin versus interferon plus ribavirin seemed to significantly increase the number of participants achieving sustained virological response (1673/3300 participants (50.7%) versus 1081/2804 patients (36.7%); RR 1.39, 95% CI 1.25 to 1.56; I2 = 64%; 27 trials; very low quality of evidence). However, the risk of bias in the 13/27 (48.1%) trials reporting on this outcome was high and was considered only 'lower' in the remainder. Because the conventional meta-analysis did not reach its required information size (n = 14,486 participants), we used trial sequential analysis to control for risks of random errors. Again, in this analysis, the estimated effect was statistically significant in favour of peginterferon. Subgroup analyses according to risk of bias, viral genotype, baseline viral load, past treatment history, and type of intervention yielded similarly significant results favouring peginterferon over interferon on the outcome of sustained virological response.
AUTHORS' CONCLUSIONS
Peginterferon plus ribavirin versus interferon plus ribavirin seems to significantly increase the proportion of patients with sustained virological response, as well as the risk of certain adverse events. However, we have insufficient evidence to recommend or reject peginterferon plus ribavirin for liver-related morbidity plus all-cause mortality compared with interferon plus ribavirin. The clinical consequences of achieved sustained virological response are unknown, as sustained virological response is still an unvalidated surrogate outcome. We found no evidence of the potential benefits on quality of life in patients with achieved sustained virological response. Further high-quality research is likely to have an important impact on our confidence in the estimate of patient-relevant outcomes and is likely to change our estimates.There is very low quality evidence that peginterferon plus ribavirin increases the proportion of patients with sustained virological response in comparison with interferon plus ribavirin. There is evidence that it also increases the risk of certain adverse events. | v2 |
2019-11-22T00:49:00.134Z | 2019-11-13T00:00:00.000Z | 209262211 | s2ag/train | Phase II Trial of SGI-110 (Guadecitabine) in Philadelphia Negative Myeloproliferative Neoplasms
Introduction:
Philadelphia negative myeloproliferative neoplasms (Ph- MPN) are hematopoietic stem cell malignancies associated with poor median survival of 12.4 months. They are often excluded from clinical trials because there are no accepted standards for treatment or assessment of disease response. SGI-110 (guadecitabine) is a second-generation DNA hypomethylating agent (HMA) that is currently in clinical trials for the treatment of myelodysplastic syndrome and acute myeloid leukemia. Guadecitabine was designed to resist degradation by protein aminases and prolong the exposure of tumor cells to the active metabolite decitabine. The purpose of this study was to test the efficacy and safety of SGI-110 in Philadelphia chromosome negative MPNs (Ph- MPN) and to also test the clinical applicability of the International IWG MDS/MPN response criteria in a prospective trial1.
Methods:
This is an interim analysis of an open label single-arm, single-institution study to evaluate the efficacy and safety of SGI-110 in Philadelphia chromosome negative (Ph-) myeloproliferative Neoplasms as classified by WHO, including chronic neutrophilic leukemia (CNL), atypical chronic myeloid leukemia (aCML), chronic myelomonocytic leukemia (CMML), myelodysplastic/myeloproliferative neoplasm unclassifiable, accelerated phase myelofibrosis and MPN unclassifiable (defined as peripheral and or bone marrow blasts of 10-19%). PV, ET and primary/secondary myelofibrosis were excluded. Patients were required to complete at least 3 cycles of guadecitabine to be considered evaluable for efficacy. Safety analyses were done on all patients who received any treatment with guadecitabine. Guadecitabine was administered subcutaneously at a dose of 60mg/m2 on days 1-5 repeated every 28 days. The IWG MDS/MPN response classification was used to assess treatment response.
Results:
Baseline characteristics of the study participants are presented in Table 1. Among the 20 treated patients, 2 (10.0%) were treated with previous HMAs, 3 had progressive disease, 1 transferred care, 7 were not yet evaluable for response, and 1 died after receiving only 2 cycles of treatment. Of the 13 evaluable, protocol specific response was seen in 8 (61.5%) patients: 2 (15.4%) achieved complete remission (CR), 3 (23.1%) with optimal marrow response (OMR), 3 (23.1%) with hematological response/clinical benefit (CB). Stable disease was seen in 4 patients (30.8%). Of the 7 patients that were inevaluable: 3 had progressive disease before completing 3 cycles, 2 received <3 cycles of therapy, 1 discontinued treatment due to personal choice, and 1 patient died from infection after receiving 2 cycles of treatment.
The median overall survival (OS) for all evaluable patients was 27.4 months with 25.8 months for responders. Median OS for patients who achieved CR was 27.4 months and 25.0 months for OMR. For patients with CB, mean survival was 21.0 months. There was 1 patient with stable disease with prolonged survival (21 cycles), which elevated the mean survival to 26.0 months for the SD category. The median number of cycles to achieve a response was 3. The median times to first and best response were 3.6 and 3.8 months, respectively. The combination of ASXL1 and EZH2 mutations was associated with rapid progression.
The most common AEs and SAEs related to guadecitabine are listed in Tables 2 and 3 respectively.
Conclusion: SGI-110 was safe and well tolerated in patients with Ph negative MPN, with encouraging efficacy in this difficult-to-treat patient population. Further investigation of this agent in MDS/MPN overlap syndromes is warranted, and the present trial is ongoing.
1. Savona MR, Malcovati L, Komrokji R, et al. An international consortium proposal of uniform response criteria for myelodysplastic/myeloproliferative neoplasms (MDS/MPN) in adults. Blood. Mar 19 2015;125(12):1857-1865.
Desai: Cellerant: Consultancy; Astex: Research Funding; Astellas: Honoraria; Sanofi: Consultancy; Celgene: Consultancy. Lee:Helsinn: Consultancy; Jazz Pharmaceuticals, Inc: Consultancy; Roche Molecular Systems: Consultancy; AstraZeneca Pharmaceuticals: Consultancy; Karyopharm Therapeutics: Consultancy; Ai Therapeutics: Research Funding. Ritchie:Celgene, Incyte, Novartis, Pfizer: Consultancy; Ariad, Celgene, Incyte, Novartis: Speakers Bureau; AStella, Bristol-Myers Squibb, Novartis, NS Pharma, Pfizer: Research Funding; Celgene, Novartis: Other: travel support; Jazz Pharmaceuticals: Research Funding; Celgene: Other: Advisory board; Pfizer: Other: Advisory board, travel support; agios: Other: Advisory board; Tolero: Other: Advisory board; Genentech: Other: Advisory board. Roboz:Trovagene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astex: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Eisai: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees; Otsuka: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Actinium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amphivena: Consultancy, Membership on an entity's Board of Directors or advisory committees; Argenx: Consultancy, Membership on an entity's Board of Directors or advisory committees.
| v2 |
2018-04-03T05:39:26.451Z | 2004-03-01T00:00:00.000Z | 43726931 | s2ag/train | Antibiotic Resistance and Distribution of Tetracycline Resistance Genes in Escherichia coli O157:H7 Isolates from Humans and Bovines
Escherichia coli O157:H7 is rare yet widely distributed within bovine populations, where it is a benign commensal of the gastrointestinal tract (3). Most E. coli O157:H7-related human illness has been the result of contamination of meat, other foodstuffs, and/or drinking water with bovine wastes containing this organism (Division of Bacterial and Mycotic Diseases, Centers for Disease Control and Prevention, Escherichia coli O157:H7 [http://www.cdc.gov/ncidod/dbmd/diseaseinfo/escherichiacoli_g.htm]). In humans, E. coli O157:H7 may cause no symptoms, mild to severe diarrhea, hemorrhagic colitis, or hemolytic-uremic syndrome (11; http://www.cdc.gov/ncidod/dbmd/diseaseinfo/escherichiacoli_g.htm). As previously reported, an increase in antibiotic resistance has been noted within E. coli O157:H7 populations over the last 20 years (3, 4, 10).
Testing of susceptibility to 12 different antibiotics and antibiotic combinations was performed on 901 randomly selected E. coli O157:H7 isolates collected between 1997 and 2000 from our collection. This included 663 bovine isolates from feedlots in the midwestern United States and 238 human isolates, which represented both outbreaks and sporadic cases, from public health departments of Washington, Oregon, Nevada, Wisconsin, Georgia, and Illinois. Isolates were verified as E. coli O157:H7 by being plated on sorbitol MacConkey agar (Becton Dickinson, Sparks, Md.), followed by a latex agglutination test (Oxoid, Basingstoke, Hampshire, United Kingdom). Disk diffusion assays were done using the National Committee for Laboratory Standards protocol and the control E. coli strain ATCC 25922 (7). The following antibiotic disks were used: ampicillin (10 μg), ampicillin-sulbactam (10 and 10 μg, respectively), ceftriaxone (30 μg), nalidixic acid (30 μg), ciprofloxacin (5 μg), kanamycin (30 μg), gentamicin (10 μg), amikacin (30 μg), streptomycin (10 μg), tetracycline (30 μg), and trimethoprim-sulfamethoxazole (1.25 and 23.75 μg, respectively). Antibiotic disks were supplied by Becton Dickinson Microbiology Systems (Franklin Lakes, N.J.).
Forty-four (6.6%) bovine isolates and 29 (12.2%) human isolates were resistant to one or more antibiotics. Tetracycline resistance (Tcr) was the most common resistance found, with 43 of 44 (98%) resistant bovine isolates and 15 of 29 (52%) resistant human isolates being tetracycline resistant. Streptomycin resistance was found in 29 (66%) resistant bovine isolates and 13 (45%) resistant human isolates. Ampicillin was the third most common resistance phenotype with four (9%) of the resistant bovine isolates and eight (27%) of the resistant human isolates being ampicillin resistant. Thirty (68%) of the resistant bovine isolates and 15 (52%) of the resistant human isolates were multidrug resistant, defined as resistance to two or more different classes of antibiotics such as tetracycline and ampicillin. These results are similar to those of Kim et al. (4), who reported 13 of 176 (7.4%) isolates collected between 1989 and 1991 to be resistant to streptomycin, sulfisoxazole, and tetracycline. Schroeder et al. (10) also found similar results with 5% of 85 human isolates being ampicillin resistant and 11% of 93 cow isolates being tetracycline resistant among isolates collected between 1985 and 2002. In contrast, Galland et al. (3) found 10 (38.5%) isolates resistant to tetracycline and 2 (7.7%) resistant to ampicillin from 26 cattle isolates of E. coli O157:H7. However, this group tested very few isolates, which may account for the differences found. The level of antibiotic resistance within E. coli O157:H7 from humans and bovines between 1997 and 2000 was lower than that traditionally found with other E. coli isolates; however the level of resistance appears stable compared to those found in other studies of resistance within O157:H7 (3, 4, 10).
Previously the tet(A), tet(B), tet(C), tet(D), tet(E), and tet(G) genes have been identified in tetracycline-resistant E. coli strains (1, 2, 3, 4, 5, 6, 9). However, little is known about distribution among E. coli O157:H7 isolates from either humans or animals. Whole-bacterium dot blots were used to screen for the presence of the six genes as previously described (6, 8). The oligonucleotide sequence for each probe and the number of isolates carrying each gene are listed in Table Table11.
TABLE 1.
Primers used for DNA-DNA hybridization of tetracycline resistance determinants and distribution of tetracycline genes by host
Sixty percent of the Tcr strains carried the tet(B) gene, which was the most prevalent tet gene found (Table (Table1).1). In a previous study, of non-O157 E. coli strains, tet(B) was also the dominant gene and found in 80% of Tcr E. coli isolates (1). The tet(A) gene was found in four (10%) of the Tcr bovine isolates and three (20%) of the Tcr human isolates. The tet(C) gene was found in three (7%) of the Tcr bovine isolates and no human isolates. The tet(G) gene was found in one (2%) Tcr bovine isolate and three (20%) Tcr human isolates. The tet(D) and tet(E) genes were not found in any of the isolates. One Tcr bovine isolates and four Tcr human isolates carried two different tetracycline resistance genes, and one Tcr bovine isolate carried three different tet genes. Thirteen (31%) Tcr bovine isolates and three (20%) Tcr human isolates did not hybridize with any of the known genes examined. In preliminary analysis, none of the 16 isolates hybridized with the recently identified tet(Y) gene (9), suggesting that these strains either may carry one of the other known tet genes not previously identified in E. coli or may have a novel gene. To distinguish between these hypotheses, the other known efflux tet genes, the only type currently identified in E. coli, will need to be screened. The finding that 31% of the Tcr bovine isolates carried unidentified tetracycline resistance genes, in this study, is very similar to a recent report that 40% of the Tcr isolates from Chilean salmon farms (6) carried unidentified tetracycline resistance genes. The data from these two studies suggest that Tcr gram-negative bacteria taken from nonhuman animals and/or the environment carry a more diverse group of tetracycline resistance genes than are usually found when characterizing Tcr gram-negative bacteria from humans. | v2 |
2019-08-20T06:04:21.478Z | 2006-07-15T00:00:00.000Z | 220555871 | s2ag/train | DIARRHEA FOLLOWING RENAL TRANSPLANTATION: INFLUENCES OF IMMUNOSUPPRESSION AND IMPLICATIONS FOR SURVIVAL.
1222 Poster Board #-Session: P17-I DIARRHEA FOLLOWING RENAL TRANSPLANTATION: INFLUENCES OF IMMUNOSUPPRESSION AND IMPLICATIONS FOR SURVIVAL. Paolo Salvalaggio, Brett Pinsky, Steven K Takemoto, Thomas E Burroughs, Krista Lentine, Mark A Schnitzler, Suphamai Bunnapradist. Saint Louis University; Cedars-Sinai. It has been shown that the combination of gastrointestinal (GI) complications and mycophenolate mofetil (MMF) discontinuation following renal transplant is associated with increased risk of graft failure. We aimed to assess risk factors for diarrhea a common GI complication associated with immunosuppression and consequences for graft survival. Methods: Patient records for all adults who received a renal transplant with Medicare as primary payer between 1995 and 2002 were obtained from the United States Renal Data System (USRDS). Patients were followed until the earlier of the last date of Medicare eligibility, graft failure, death or three-years post-transplant. Diagnoses of diarrhea were drawn from ICD-9-CM codes contained in Medicare billing data supplied by the USRDS. Associations were estimated using single-level interaction time-varying Cox proportional hazards analysis. Violations of proportional hazards and colinearity assumptions were tested and corrected when observed. Results: 42,257 renal transplant recipients were examined. The most common etiology of diarrhea was unspecified noninfectious with an incidence of 18.4% by 3-years post-transplant. Three-year incidence of other etiologies included: Ulcerative Colitis 2.8%, specified infectious 2.1%, unspecified infectious 1.7%, other specified noninfectious 0.4%. Most patients with a diarrhea diagnosis never received a specified diarrhea diagnosis. Immunosuppressive risk factors for unspecified noninfectious diarrhea included tacrolimus compared to cyclosporine (HR: 1.40, P<0.0001), MMF compared to azathioprine (HR: 1.15, P=0.0007) and non calcineurin inhibitor compared to cyclosporine (HR: 1.11, P=0.03). Tacrolimus was found to be a risk factor for unspecified infectious and specified infectious diarrhea as well (HR: 1.66, P<0.0001; HR:1.23, P=0.04 respectively). Numerous adverse associations were noted for diarrhea etiologies. Most prominently, unspecified noninfectious diarrhea was associated with subsequent graft failure (HR: 1.93, P<0.0001), death censored graft failure (HR:1.57, P<0.0001), and death (HR1.54, P<0.0001). Conclusions: Diarrhea is commonly diagnosed following renal transplantation. Unspecified noninfectious is of particular concern as it was diagnosed in nearly 20% of the patients in this study, doubled the risk of graft failure, and increased by more than 50% the risk of death censored graft failure and death. Abstract# 1223 Poster Board #-Session: P18-I 1223 Poster Board #-Session: P18-I PHARMACOKINETICS OF MYCOPHENOLATE SODIUM AND COMPARISON WITH THE MOFETIL FORMULATION IN KIDNEY TRANSPLANT RECIPIENTS. Simona Merlini, Sara Baldelli, Norberto Perico, Eliana Gotti, Giuseppe Remuzzi, Dario Cattaneo. Department of Medicine and Transplantation, Mario Negri Institute for Pharmacological Research, Bergamo, Italy. The introduction of mycophenolate mofetil (MMF) has improved longterm graft survival after organ transplantation. However the use of this agent may be limited by gastrointestinal and hematological side-effects. To overcome these problems, an enteric-coated formulation of mycophenolate sodium (EC-MPS) has been recently developed. The two formulations have shown to be bioequivalent in the short term, however, data in stable kidney transplant recipients are lacking. To address this issue, we have performed full pharmacokinetic studies in 20 kidney transplant recipients given EC-MPS (n=10) or MMF (n=10) in combination with cyclosporine as a part of their immunosuppressive regimens and compared the profiles of mycophenolic acid (MPA) derived from the two formulations at months 6 and 12 post-transplantation. At month 6 post-surgery, despite no differences in mean MPA Cmax and AUC0-12 between the two formulations, aberrant and extremely variable pharmacokinetic curves with multiple peaks of MPA were found in all patients given EC-MPS, whereas those on MMF had regular MPA kinetic profiles, characterized by a sharp peak within 2 hours and a second flat peak at 6-12 h post MMF dosing, corresponding to the enterohepatic recycling. Moreover, patients on ECMPS presented MPA Tmax ranging from 0 to 480 minutes and higher doseadjusted MPA trough levels compared to patients given MMF (5.9+5.01 vs 1.3+0.8 mg/L/MPA eq, p<0.01). These results were confirmed also at month 12 post-surgery. At variance with MMF, The extremely variable kinetic of MPA in patient on EC-MPS precluded the development of limited sampling strategies to estimate daily drug exposure. Given the emerging clinical benefit of MPA monitoring in transplant setting, therapeutic drug monitoring problems with the enteric coating of EC-MPS should be taken into account. Abstract# 1224 Poster Board #-Session: P19-I 1224 Poster Board #-Session: P19-I CHANGES IN BODY COMPOSITION OVER 24 MONTHS FOLLOWING KIDNEY TRANSPLANTATION: THE EFFECT OF STEROID WITHDRAWAL FROM THE IMMUNOSUPPRESSIVE REGIMEN. Wael El Haggan, Bruno Hurault de Ligny, Jean-Pierre Sabatier, Thierry Lobbedez, Jean-Philippe Ryckelynck. Nephrology and Renal Transplantation, Caen University Hospital, Caen, France. Malnutrition is common in patients with terminal renal failure. After kidney transplantation (KTx), there is usual increase in body weight, in which steroids could play a potential role. Yet, this weight gain seems to be predominantly due to an increase in body fat mass. However, few studies have described the outcome of body composition after KTx, particularly in a longitudinal follow-up. In this prospective study, we assessed body composition changes and the effect of steroid withdrawal from the standard immunosuppressive regimen on weight gain and body composition during the two years post KTx. Thirty-eight consecutive cadaveric kidney transplant recipients (M/F: 26/ 12, mean age: 49+/-14 y, mean BMI: 23,7+/-4,1) were followed-up during 24 months after KTx. Total and segmental body composition were measured by dual energy X-ray absorptiometry (DEXA) at the time of KTx (M0) and 3, 6, 12, 24 months later (M3, M6, M12, M24). In 28 patients (group A), prednisone was stopped by month 6, whereas, in 10 patients (group B), prednisone (10 mg/d) was continued throughout the study. All patients received cyclosporine and MMF and had adequate renal function during the study period. The two groups did not differ in age, baseline body mass index, serum creatinine at M24; moreover, both groups were followed by the same dietitian. Changes in weight, total fat mass, total lean mass (expressed as % change of the initial value) were as follows: | v2 |
2019-11-22T00:52:07.435Z | 2019-11-13T00:00:00.000Z | 209291381 | s2ag/train | Preliminary Results of Ibrutinib Followed By Ofatumumab Consolidation in Previously Untreated Patients with Chronic Lymphocytic Leukemia (CLL): GELLC7 Trials from the Spanish Group of CLL (GELLC)
Introduction. Despite the high proportion of prolonged remissions obtained with ibrutinib in patients with CLL, complete responses (CR) are rarely observed. For the purpose of increasing the deepness of response, ibrutinib has been tested in combination with other drugs that exert a different mechanism of action. Thus, monoclonal antibodies (mAbs) have been concomitantly combined with ibrutinib in untreated or R/R CLLs. Nonetheless, several data derived from both in vitro and clinical studies do not support a synergistic effect of the concomitant administration of ibrutinib with anti-CD20 mAbs. Herein, we present the preliminary results of a multi-center, non-randomized phase 2 study aimed to determine the efficacy and safety of the sequential treatment of CLL patients with ibrutinib followed, in those not attaining CR, by a consolidation phase with ofatumumab (GELLC-7, EudraCT number 2016-004937-26).
Patients and methods. Patients aged ≥18 years, physically fit (CIRS score < 6) with treatment-naïve CLL were enrolled in this study. Patients received an induction phase consisting of 12 cycles (28-day) of ibrutinib in monotherapy at 420 mg once daily. Patients attaining a CR after this induction phase were kept on ibrutinib until progression. In contrast, patients not obtaining a CR also continued on ibrutinib but received a consolidation treatment with 7 doses of ofatumumab (300 mg D1 and 1000mg D8 of C13, 1000 mg D1 of C14-C18). The primary endpoint of the study was the CR rate assessed after 20 cycles of treatment (2 months after completing ofatumumab consolidation).
Results. 84 patients with a median age 69 years (range 38-84 yrs), 71% male, were included in this study. At inclusion, 83.3% had Binet stage B/C, 61% unmutated IGHV status, and 19% high risk genetic aberrations (7.6% 17p deletion and/or TP53mut, and 11.4% 11q deletion). At the interim data cut-off (June 2019), 7 patients had discontinued the study (progression to Richter transformation, n=1; patient withdrawal, n=3; adverse events [AE], n=3, including one G5 AE), 5 of them during the first 12 cycles of treatment. Sixty-seven patients received the induction phase with 12 cycles of ibrutinib, whereas 22 patients completed 20 cycles of treatment and were evaluable for the primary endpoint of the study. After 12 cycles of ibrutinib, 3 patients (4.5%) were in CR, 54 patients (80.5%) in PR, 6 patients (9%) in PR with lymphocytosis, and 4 patients (6%) in SD. In 20 patients receiving the consolidation with ofatumumab an improvement in response was observed, with 8/20 patients (40%) attaining a CR (7 patients converted PR to CR, and one patient SD to CR), whereas the remaining 12 patients were classified as PR. Two patients that were already in CR at cycle 12 maintained the CR under ibrutinib monotherapy. MRD was undetectable in blood (<10-4 by flow cytometry) only in one of the 22 patients. With a median follow-up of 15 months (2 - 20.2 months), the estimated 12-months PFS and OS was 98%.
Grade ≥3 adverse events (AEs) were experienced by 26 patients (31%), whilst 22 serious AEs were observed in 16 patients (19%) (14 infections, 1 febrile neutropenia, 3 dyspnoea, 1 anemia, 1 edema/pleural effusion, 1 renal insufficiency, 1 squamous carcinoma). The most common G3/4 AEs were hematological toxicity (neutropenia [7.1%], anemia [4.5%], thrombocytopenia [2.4%]) and infections (8.5%). The Gr 5 AE consisted of a severe peripheral edema and pleural effusion leading to death. The great majority of SAEs (67%) and G3/4 AEs (66%) were observed during the first 12 cycles of treatment with ibrutinib monotherapy.
Conclusions. The preliminary analysis of the GELLC7 trial showed that the addition of consolidation with ofatumumab after 12 cycles of prior treatment with ibrutinib was well tolerated and elicited a deeper response. These results support the potential role of a sequential therapeutic strategy in CLL, where the addition of a consolidation with mAbs in patients with low tumor burden might improve the quality of the response. Finally, more mature results will be further presented at the meeting.
Abrisqueta: Roche: Consultancy, Honoraria, Other: Travel, Accommodations, expenses, Speakers Bureau; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, expenses, Speakers Bureau; Celgene: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Other: Travel, Accommodations, expenses, Speakers Bureau. González-Barca:Kiowa: Consultancy; Celgene: Consultancy; Takeda: Honoraria; AbbVie: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celtrion: Consultancy. Terol:Roche: Consultancy; Janssen: Consultancy, Research Funding; Abbvie: Consultancy; Astra Zeneca: Consultancy; Gilead: Research Funding. Baltasar Tello:GILEAD: Honoraria; JANSSEN: Consultancy, Honoraria; ABBVIE: Honoraria; ROCHE: Honoraria. de la Serna:Roche, AbbVie, Gilead, Janssen, Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche, AbbVie, Janssen, Gilead: Speakers Bureau. Ramirez Payer:GILEAD SCIENCES: Research Funding. Cordoba:Janssen: Consultancy, Honoraria, Speakers Bureau; Servier: Consultancy, Honoraria, Speakers Bureau; Kyowa-Kirin: Consultancy, Honoraria, Speakers Bureau; Gilead: Consultancy, Research Funding, Speakers Bureau; Roche: Honoraria, Speakers Bureau; FUNDACION JIMENEZ DIAZ UNIVERSITY HOSPITAL: Employment; Celgene: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy. Bosch:AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AstraZeneca: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd/Genentech, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Kyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.
Ibrutinib followed by Ofatumumab Consolidation
| v2 |
2021-07-27T00:04:48.764Z | 2021-06-01T00:00:00.000Z | 236336061 | s2ag/train | POS1208 EPIDEMIOLOGY AND OUTCOMES OF PATIENTS WITH RHEUMATIC DISEASES AND SARS-CoV-2 INFECTION: DATA FROM THE ARGENTINEAN SAR-COVID REGISTRY
In the last time, many papers about SARS-CoV-2 have been published in the world. However, data from latinamerican patients is still scarce. In order to assess the impact of SARS-CoV-2 infection in patients with rheumatic diseases in our country and contribute to the global knowledge about the effect of immunosuppressive therapies in this group, the Argentine Society of Rheumatology has developed the National Registry of Patients with Rheumatic Diseases and COVID-19 (SAR-COVID).The aim of this study was to evaluate clinical characteristics and outcomes of SARS-CoV-2 infection in patients with rheumatic diseases, treated or not with immunomodulators and/or immunosuppressants.SAR-COVID is a national, multicenter, prospective and observational registry, in which patients, ≥18 years of age, with a diagnosis of a rheumatic disease who had SARS-CoV-2 infection (PCR or positive serology) are consecutively included between August 13, 2020 and January 17, 2021. Sociodemographic data, comorbidities, underlying rheumatic disease and treatment, clinical characteristics, complications, laboratory and treatment of the SARS-CoV-2 infection were recorded. Hospitalization, mechanical ventilation requirements and death were assessed to evaluate COVID-19 outcome. Statistical analysis: Descriptive analysis. Chi2 or Fischer test and T test or Mann-Whitney U test or ANOVA, as appropriate. Multiple logistic regression.A total of 525 patients were included, 80.4% were female, with a median age of 52 years (IQR 40-62). Comorbidities were reported in half of them (53.3%). The most frequent rheumatological diseases were rheumatoid arthritis (40.4%) and systemic lupus erythematosus (14.9%). At the time of the infection, most of them were in remission or in minimal/low disease activity (68.2%) and 72.9% were receiving immunosuppressive or immunomodulatory treatment.Symptoms were present in 96% of the patients, the most frequent being fever (56.2%), cough (46.7%) and headache (39.2%). During infection, 35.1% received some pharmacological treatment, dexamethasone (20%) the most frequently used. One third (35.1%) of the patients were hospitalized, 11.6% were admitted to the ICU, 10.1% needed mechanical ventilation and 6.9% died due to COVID-19. Complications were reported in 12.4%, being acute respiratory distress syndrome the most prevalent (8.8%).Patients over 65 years of age were more frequently hospitalized, admitted to the ICU, needed mechanical ventilation and died due to COVID-19 (50% vs 31.4%, 22% vs 9%, 16.3% vs 5.2%, 14% vs 5%, respectively; p<0.001 in all cases). Similar results were seen in patients with vasculitis (57.7% vs 33.9%, 46.2 vs 9.8%, 34.6% vs 6 %; 30.8% vs 5.6%, respectively; p< 0.001 in all cases) and those with moderate/high disease activity (55.7% vs 26.5%, 21.3 vs 7.8%, 17.2% vs 4.2 %; 17.2% vs 4.2 %, respectively; p< 0.001 in all cases). Patients with APS were more frequently admitted to the ICU (29.4% vs 11%, p= 0.037). The presence of comorbidities was associated with higher hospitalization (46% vs 22.6%, p<0.001), admission to the ICU (17.2% vs 5.9%, p<0.001) and mechanical ventilation (10.2% vs 4.6%, p= 0.028). Immunosuppressive treatment was not associated with worse outcomes.In this cohort of patients with a wide distribution of rheumatic diseases, we have found clinical characteristics similar to those reported by other international cohorts. Compared with national data, the mortality reported in these patients is higher. However, it should be noted that these are early data collected during isolation and that there may be an underreporting of asymptomatic patients or with mild symptoms who do not attend the rheumatologist.Older patients, those with comorbidities, with vasculitis and with higher disease activity showed poor COVID-19 outcomes.Carolina Ayelen Isnardi Speakers bureau: Janssen, BMS, Grant/research support from: Unrestricted grants: Pfizer, Abbvie, Elea Phoenix. None of them have access to patient data., Rosana Quintana Grant/research support from: Unrestricted grants: Pfizer, Abbvie, Elea Phoenix. None of them have access to patient data., Karen Roberts Grant/research support from: Unrestricted grants: Pfizer, Abbvie, Elea Phoenix. None of them have access to patient data., Vanessa Viviana Castro Coello Grant/research support from: Unrestricted grants: Pfizer, Abbvie, Elea Phoenix. None of them have access to patient data., Alvaro Andres Reyes Grant/research support from: Unrestricted grants: Pfizer, Abbvie, Elea Phoenix. None of them have access to patient data., Yohana Tissera Grant/research support from: Unrestricted grants: Pfizer, Abbvie, Elea Phoenix. None of them have access to patient data., Micaela Cosatti Grant/research support from: Unrestricted grants: Pfizer, Abbvie, Elea Phoenix. None of them have access to patient data., Romina Rojas Tessel Grant/research support from: Unrestricted grants: Pfizer, Abbvie, Elea Phoenix. None of them have access to patient data., Julia Scafati Grant/research support from: Unrestricted grants: Pfizer, Abbvie, Elea Phoenix. None of them have access to patient data., Tatiana Barbich Grant/research support from: Unrestricted grants: Pfizer, Abbvie, Elea Phoenix. None of them have access to patient data., María Soledad Gálvez Elkin Grant/research support from: Unrestricted grants: Pfizer, Abbvie, Elea Phoenix. None of them have access to patient data., Gustavo Fabian Rodriguez Gil Grant/research support from: Unrestricted grants: Pfizer, Abbvie, Elea Phoenix. None of them have access to patient data., Sebastian Moyano Grant/research support from: Unrestricted grants: Pfizer, Abbvie, Elea Phoenix. None of them have access to patient data., Marina Laura Werner Grant/research support from: Unrestricted grants: Pfizer, Abbvie, Elea Phoenix. None of them have access to patient data., Jonathan Rebak Grant/research support from: Unrestricted grants: Pfizer, Abbvie, Elea Phoenix. None of them have access to patient data., Julieta Morbiducci Grant/research support from: Unrestricted grants: Pfizer, Abbvie, Elea Phoenix. None of them have access to patient data., Victoria Martire Grant/research support from: Unrestricted grants: Pfizer, Abbvie, Elea Phoenix. None of them have access to patient data., María Sol Castaño Grant/research support from: Unrestricted grants: Pfizer, Abbvie, Elea Phoenix. None of them have access to patient data., Carolina Dieguez Grant/research support from: Unrestricted grants: Pfizer, Abbvie, Elea Phoenix. None of them have access to patient data., Gisela Constanza Subils Grant/research support from: Unrestricted grants: Pfizer, Abbvie, Elea Phoenix. None of them have access to patient data., Guillermo Pons-Estel Grant/research support from: Unrestricted grants: Pfizer, Abbvie, Elea Phoenix. None of them have access to patient data. | v2 |
2019-03-18T14:04:51.801Z | 2018-11-29T00:00:00.000Z | 81539211 | s2ag/train | Impact of Modified Dose Schedule of Bortezomib, Melphalan, and Prednisone (VMP) for Previously Untreated, Transplant-Ineligible Patients with Multiple Myeloma (MM): A Matching-Adjusted Indirect Comparison
Introduction: For transplant-ineligible patients (pts) with newly diagnosed MM, the efficacy of VMP was established in the phase 3 VISTA trial. To reduce toxicity of VMP, twice-weekly bortezomib (V) was limited to the first cycle or completely replaced with once-weekly V in subsequent VMP-based trials (GIMEMA MM-03-05, GEM2005MAS65, and ALCYONE), and recent guidelines have recommended a less-intensive VMP schedule (Moreau P, et al. Ann Oncol 2017. 28[suppl_4]:iv52-iv61). In the absence of clinical trials directly comparing the VISTA VMP dosage regimen with modified VMP regimens, a matching adjusted indirect comparison (MAIC) provides a means to compare absolute treatment effects across diverse populations while minimizing the risk of bias associated with a naive indirect comparison. The objective of the present analysis is to compare the efficacy and safety of a modified dosing schedule of V in VMP-based regimens vs the dosing schedule established in VISTA for transplant-ineligible MM.
Methods: Primary analysis was a comparison of the VMP schedule of VISTA vs modified VMP schedules pooled from the ALCYONE (once-weekly V during Cycles 2-9) and GIMEMA MM-03-05 trials; only the once-weekly V schedule (Cycles 1-9) from GIMEMA MM-03-05 (GIMEMA-QW) was included in this analysis. GEM2005MAS65 was excluded from the primary analysis because there was no control arm without maintenance (all patients received V-based maintenance after VMP). The supplemental analysis was a comparison of VISTA vs pooled modified VMP schedules from all 3 trials.
Individual pt-level data (IPD) were obtained from the sponsor for the VISTA and ALCYONE trials, and a published validated method was used to reconstruct IPD for both progression-free survival (PFS) and overall survival (OS) of the GIMEMA-QW and GEM2005MAS65 trials (Guyot P, et al. BMC Med Res Methodol 2012.12:9).
For each analysis, two comparisons were performed, a naive comparison and MAIC. The naive comparison made no adjustments. MAIC comparison weighted individual pts in the VISTA VMP treatment arm to match the baseline characteristics to those in the pooled VMP-modified treatment arms. Available effect modifiers and prognostic factors included age, gender, International Staging System, β2-microglobulin, albumin, serum creatinine, creatinine clearance, and cytogenetic risk. For each pt in the VISTA VMP arm, a weight was attached based on propensity scores. These weights were then used to calculate weighted outcomes.
Results: A total of 344 pts received VMP in the VISTA trial and 356, 191, and 130 pts received modified VMP in the ALCYONE, GIMEMA-QW, and GEM2005MAS65 trials, respectively. Baseline demographics and clinical characteristics are provided in Table 1.
The primary analysis of VISTA vs pooled data from GIMEMA-QW and ALCYONE revealed that there were no significant differences in median PFS between VISTA (20.7 months) vs GIMEMA-QW and ALCYONE (19.6 months) in the naive comparison (HR: 0.96; 95% CI, 0.77-1.20; P = 0.74) and 23.1 vs 19.6 months in the MAIC (HR: 0.99; 95% CI, 0.76-1.30; P = 0.96; Figure 1A).
Similarly, there were no significant differences between the observed overall response rates for the VISTA schedule and the modified VMP dosing schedule for both the naive (75% vs 76%; P = 0.63) and MAIC (77% vs 76%; P = 1.00) comparisons.
For OS, survival data from ALCYONE have not yet matured, thus the median OS values for the pooled GIMEMA-QW and ALCYONE data were not reached. Median OS in VISTA was 56.4 months for the naive comparison and 58.1 months for MAIC (naive HR: 0.92; 95% CI, 0.70-1.21; P = 0.54; MAIC HR: 0.94; 95% CI, 0.68-1.28; P = 0.68; Figure 1B).
For safety, incidences of peripheral neuropathy were significantly reduced with the modified VMP dosing schedule compared with the VISTA schedule for both the naive (all-grade: 32% vs 47%; P <0.0001; Gr. 3/4: 4% vs 13%; P <0.0001) and MAIC (all-grade: 32% vs 48%; P <0.0001; Gr. 3/4: 4% vs 11%; P = 0.001) comparisons.
The supplemental analysis showed consistent results to the primary analysis for both efficacy and safety outcomes.
Conclusions: As naive, indirect comparisons are prone to bias due to patient heterogeneity between studies, a MAIC can provide useful insights for clinicians and reimbursement decision-makers on the relative efficacy and safety of different treatments. Our MAIC analysis demonstrates similar efficacy of modified VMP with VISTA VMP and a potential reduction in rates of peripheral neuropathy.
San-Miguel: Sanofi: Honoraria; Novartis: Honoraria; BMS: Honoraria; Amgen: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Roche: Honoraria. Mateos:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees. Goldschmidt:Amgen: Consultancy, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Adaptive Biotechnology: Consultancy; Janssen: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Chugai: Honoraria, Research Funding; Mundipharma: Research Funding; Novartis: Honoraria, Research Funding; ArtTempi: Honoraria. Sonneveld:Amgen: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Karyopharm: Honoraria, Research Funding. Dimopoulos:Takeda: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Amgen: Honoraria; Bristol-Myers Squibb: Honoraria. Heeg:Ingress-health Nederland BV: Employment, Equity Ownership, Research Funding. Hashim:Ingress Health: Employment. Deraedt:Janssen Research & Development, LLC: Employment. Hu:Janssen Research & Development, LLC: Employment. Lam:Janssen Global Services, LLC: Employment. He:Janssen global services: Employment.
| v2 |
2020-11-05T09:05:37.810Z | 2020-11-05T00:00:00.000Z | 228842671 | s2ag/train | Differential Impact of Prognostically Significant Gene Mutations in Acute Myeloid Leukemia (AML) Patients (Pts) Older Than 70 Years (y) Treated with Cytarabine-Based Induction Therapy
Introduction: AML is a heterogeneous disease of mainly older pts, with a median age of 68 y at diagnosis. Previous studies have shown that age is one of the most important prognosticators for overall survival (OS) of AML pts. In addition, several cytogenetic and molecular markers have been used for risk stratification of AML pts and to guide therapeutic decisions. However, the role of these established molecular marker (e.g. FLT3-ITD and NPM1 mutations) in pts aged ≥70 y is not fully understood.
Aims: The goal of this study was to analyze the prognostic role of FLT3-ITD and other molecular markers in AML pts ≥70 y. We also compared this cohort with pts 60-69 y, who received a similar treatment, to identify potential differences between these age groups.
Methods: We analyzed 269 de novo AML pts ≥70 y and 250 pts 60-69 y. All pts were treated on frontline Cancer and Leukemia Group B/Alliance for Clinical Trials in Oncology protocols that were based on standard intensity cytarabine/anthracycline induction followed by consolidation with varied chemotherapy regimens. None of the pts received an allogeneic stem cell transplant in first complete remission (CR). In pretreatment bone marrow or blood samples, the mutational status of 80 cancer- and leukemia-associated genes (Eisfeld et al., Leukemia 2017;31:2211) were determined using a targeted next-generation sequencing panel. All variants that occurred with variant allele fractions of <0.1 were defined as not mutated. CEBPA mutations were determined using Sanger sequencing, and the presence of FLT3-ITD using fragment analysis (cut-off >.05). The pts' pretreatment karyotypes were determined locally and reviewed centrally.
Results: There were no significant differences in frequencies of any clinical or specific cytogenetic markers between AML pts ≥70 y and pts 60-69 y. Pts 60-69 y presented more often with Favorable-risk disease based on the European LeukemiaNet classification (Döhner et al. Blood 2017;129:424; 30% vs 23%, P<.001), whereas pts ≥70 y were more often classified as Adverse-risk (45% vs 51%, P<.001). Concerning recurrent gene mutations, we found that pts ≥70 y less frequently harbored mutations in NPM1 (28% vs 44%; P<.001) and PTPN11 (4% vs 8%; P=.03), and more frequently mutations in RUNX1 (21% vs 10%; P<.001) than pts 60-69 y. In line with previous studies, outcome for both groups of older pts was generally poor. Pts 60-69 y had a higher CR rate (50% vs 37%, P=.003) and longer overall survival (OS; median: 0.7 y vs 0.4 y, P=.003) compared with pts ≥70 y. There was no significant difference in disease-free survival (DFS) between the age groups. Next, we analyzed the prognostic role of FLT3-ITD (present in 26% of pts ≥70 y and 23% of pts 60-69 y) and found that its presence had a prognostic impact on DFS (P<.001) and OS (P=.003) only in pts 60-69 y but not in pts ≥70 y in univariate analyses (Figure 1) and in the final multivariable analyses (MVA, Table 1). In these pts, FLT3-ITD was found to be associated with worse outcome independent from the FLT3-ITD allelic ratio or the presence of additional NPM1 mutations. Similarly, to FLT3-ITD, DNMT3A mutations associated with shorter OS only in pts 60-69 y in MVA. In the final MVA for both pts 60-69 y and those ≥70 y, NPM1 mutations were the only prognostic marker associated with better outcome for all clinical endpoints tested (i.e., CR rates, DFS and OS) (Table 1), while complex karyotype (i.e., the presence of ≥3 chromosome aberrations) was a poor prognostic factor both in pts 60-69 y (DFS, OS) and those ≥70 y (CR rates, OS). In contrast, in MVA of pts ≥70 y, mutations in U2AF1 associated with lower CR attainment (P=.03), and TP53 mutations with shorter DFS (P=.01).
Conclusions: Although pts aged ≥70 y had similar pretreatment clinical and cytogenetic features as pts 60-69 y, we showed that distinct differences can be found regarding prognosticators. Interestingly, we found that presence of a FLT3-ITD had no impact on outcome of pts ≥70 y, regardless of allelic ratio or presence of an additional NPM1 mutation. Only NPM1 mutations and complex karyotype had a prognostic impact on both age groups.
Support: U10CA180821, U10CA180882 U24CA196171; https://acknowledgments.alliancefound.org; Clinicaltrials.gov Identifiers: NCT00048958 (CALGB-8461), NCT00899223 (CALGB 9665), and NCT00900224 (CALGB 20202)
Walker: Vigeo Therapeutics: Consultancy; Karyopharm: Current Employment, Current equity holder in publicly-traded company. Blachly:AbbVie, AstraZeneca, KITE Pharma: Consultancy. Wang:Bristol Meyers Squibb (Celgene): Consultancy; Astellas: Consultancy; Jazz Pharmaceuticals: Consultancy; Macrogenics: Consultancy; PTC Therapeutics: Consultancy; Abbvie: Consultancy; Stemline: Speakers Bureau; Pfizer: Speakers Bureau; Genentech: Consultancy. Kolitz:Pfizer: Membership on an entity's Board of Directors or advisory committees; Magellan: Membership on an entity's Board of Directors or advisory committees. Powell:Rafael Pharmaceuticals: Consultancy, Other: Advisor, Research Funding; Pfizer: Research Funding; Jazz Pharmaceuticals: Consultancy, Other: Advisor, Research Funding; Novartis: Research Funding; Genentech: Research Funding. Stone:Gemoab: Consultancy; Syros: Consultancy; Arog: Consultancy, Research Funding; Celgene: Consultancy, Other; Macrogenics: Consultancy; Agios: Consultancy, Research Funding; Janssen: Consultancy; Aztra-Zeneca: Consultancy; Biolinerx: Consultancy; Trovagene: Consultancy; Daiichi-Sankyo: Consultancy; Argenix: Other; Actinium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Other: DSMB; Abbvie: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Astellas: Consultancy; Syntrix: Other: DSMB; Jazz: Consultancy; Stemline: Consultancy; Pfizer: Consultancy; Syndax: Consultancy, Research Funding. Byrd:Novartis: Research Funding; Acerta Pharma: Research Funding; Syndax: Research Funding; Pharmacyclics LLC, an AbbVie Company, Janssen, Novartis, Gilead, TG Therapeutics: Other; Vincera: Research Funding; Kartos Therapeutics: Research Funding; Trillium: Research Funding; Pharmacyclics LLC, an AbbVie Company, Gilead, TG Therapeutics, BeiGene: Research Funding; Pharmacyclics LLC, an AbbVie Company, Gilead, TG Therapeutics, Novartis, Janssen: Speakers Bureau; Leukemia and Lymphoma Society: Other; Janssen: Consultancy. Eisfeld:Vigeo Therapeutics: Consultancy; Karyopharm: Current Employment, Current equity holder in publicly-traded company.
| v2 |
2018-04-03T05:49:24.602Z | 2016-03-22T00:00:00.000Z | 44587361 | s2ag/train | Dietary supplements for dysmenorrhoea.
BACKGROUND
Dysmenorrhoea refers to painful menstrual cramps and is a common gynaecological complaint. Conventional treatments include non-steroidal anti-inflammatory drugs (NSAIDs) and oral contraceptive pills (OCPs), which both reduce myometrial activity (contractions of the uterus). A suggested alternative approach is dietary supplements. We used the term 'dietary supplement' to include herbs or other botanical, vitamins, minerals, enzymes, and amino acids. We excluded traditional Chinese medicines.
OBJECTIVES
To determine the efficacy and safety of dietary supplements for treating dysmenorrhoea.
SEARCH METHODS
We searched sources including the Cochrane Gynaecology and Fertility Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, AMED, PsycINFO (all from inception to 23 March 2015), trial registries, and the reference lists of relevant articles.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) of dietary supplements for moderate or severe primary or secondary dysmenorrhoea. We excluded studies of women with an intrauterine device. Eligible comparators were other dietary supplements, placebo, no treatment, or conventional analgesia.
DATA COLLECTION AND ANALYSIS
Two review authors independently performed study selection, performed data extraction and assessed the risk of bias in the included trials. The primary outcomes were pain intensity and adverse effects. We used a fixed-effect model to calculate odds ratios (ORs) for dichotomous data, and mean differences (MDs) or standardised mean differences (SMDs) for continuous data, with 95% confidence intervals (CIs). We presented data that were unsuitable for analysis either descriptively or in additional tables. We assessed the quality of the evidence using Grading of Recommendations Assessment, Development and Evaluation (GRADE) methods.
MAIN RESULTS
We included 27 RCTs (3101 women). Most included studies were conducted amongst cohorts of students with primary dysmenorrhoea in their late teens or early twenties. Twenty-two studies were conducted in Iran and the rest were performed in other middle-income countries. Only one study addressed secondary dysmenorrhoea. Interventions included 12 different herbal medicines (German chamomile (Matricaria chamomilla, M recutita, Chamomilla recutita), cinnamon (Cinnamomum zeylanicum, C. verum), Damask rose (Rosa damascena), dill (Anethum graveolens), fennel (Foeniculum vulgare), fenugreek (Trigonella foenum-graecum), ginger (Zingiber officinale), guava (Psidium guajava), rhubarb (Rheum emodi), uzara (Xysmalobium undulatum), valerian (Valeriana officinalis), and zataria (Zataria multiflora)) and five non-herbal supplements (fish oil, melatonin, vitamins B1 and E, and zinc sulphate) in a variety of formulations and doses. Comparators included other supplements, placebo, no treatment, and NSAIDs.We judged all the evidence to be of low or very low quality. The main limitations were imprecision due to very small sample sizes, failure to report study methods, and inconsistency. For most comparisons there was only one included study, and very few studies reported adverse effects. Effectiveness of supplements for primary dysmenorrhoea We have presented pain scores (all on a visual analogue scale (VAS) 0 to 10 point scale) or rates of pain relief, or both, at the first post-treatment follow-up. Supplements versus placebo or no treatmentThere was no evidence of effectiveness for vitamin E (MD 0.00 points, 95% CI -0.34 to 0.34; two RCTs, 135 women).There was no consistent evidence of effectiveness for dill (MD -1.15 points, 95% CI -2.22 to -0.08, one RCT, 46 women), guava (MD 0.59, 95% CI -0.13 to 1.31; one RCT, 151 women); one RCT, 73 women), or fennel (MD -0.34 points, 95% CI -0.74 to 0.06; one RCT, 43 women).There was very limited evidence of effectiveness for fenugreek (MD -1.71 points, 95% CI -2.35 to -1.07; one RCT, 101 women), fish oil (MD 1.11 points, 95% CI 0.45 to 1.77; one RCT, 120 women), fish oil plus vitamin B1 (MD -1.21 points, 95% CI -1.79 to -0.63; one RCT, 120 women), ginger (MD -1.55 points, 95% CI -2.43 to -0.68; three RCTs, 266 women; OR 5.44, 95% CI 1.80 to 16.46; one RCT, 69 women), valerian (MD -0.76 points, 95% CI -1.44 to -0.08; one RCT, 100 women), vitamin B1 alone (MD -2.70 points, 95% CI -3.32 to -2.08; one RCT, 120 women), zataria (OR 6.66, 95% CI 2.66 to 16.72; one RCT, 99 women), and zinc sulphate (MD -0.95 points, 95% CI -1.54 to -0.36; one RCT, 99 women).Data on chamomile and cinnamon versus placebo were unsuitable for analysis. Supplements versus NSAIDSThere was no evidence of any difference between NSAIDs and dill (MD 0.13 points, 95% CI -1.01 to 1.27; one RCT, 47 women), fennel (MD -0.70 points, 95% CI -1.81 to 0.41; one RCT, 59 women), guava (MD 1.19, 95% CI 0.42 to 1.96; one RCT, 155 women), rhubarb (MD -0.20 points, 95% CI -0.44 to 0.04; one RCT, 45 women), or valerian (MD points 0.62 , 95% CI 0.03 to 1.21; one RCT, 99 women),There was no consistent evidence of a difference between Damask rose and NSAIDs (MD -0.15 points, 95% CI -0.55 to 0.25; one RCT, 92 women).There was very limited evidence that chamomile was more effective than NSAIDs (MD -1.42 points, 95% CI -1.69 to -1.15; one RCT, 160 women). Supplements versus other supplementsThere was no evidence of a difference in effectiveness between ginger and zinc sulphate (MD 0.02 points, 95% CI -0.58 to 0.62; one RCT, 101 women). Vitamin B1 may be more effective than fish oil (MD -1.59 points, 95% CI -2.25 to -0.93; one RCT, 120 women). Effectiveness of supplements for secondary dysmenorrhoea There was no strong evidence of benefit for melatonin compared to placebo for dysmenorrhoea secondary to endometriosis (data were unsuitable for analysis). Safety of supplements Only four of the 27 included studies reported adverse effects in both treatment groups. There was no evidence of a difference between the groups but data were too scanty to reach any conclusions about safety.
AUTHORS' CONCLUSIONS
There is no high quality evidence to support the effectiveness of any dietary supplement for dysmenorrhoea, and evidence of safety is lacking. However for several supplements there was some low quality evidence of effectiveness and more research is justified. | v2 |
2019-04-12T13:52:17.938Z | 1982-12-01T00:00:00.000Z | 202871601 | s2ag/train | Monitoring for Health Hazards at Work
List of Illustrations. List of Instruction Sheets. Preface. Acknowledgements. Units and Abbreviations. Part 1 Introduction. Chapter 1 Occupational Hygiene and Risk Assessment. 1.1 Introduction. 1.2 Hazard and risk. 1.3 Risk assessment. 1.4 The stages of a risk assessment. 1.5 Who should carry out risk assessment. Chapter 2 Identifying Hazards. 2.1 Introduction. 2.2 Identifying hazards. 2.3 Example of hazard identification. 2.4 Conclusions arising from a hazard assessment. Chapter 3 Exposure, Exposure Routes and Biological Monitoring. 3.1 Introduction. 3.2 Measuring exposure. 3.3 Biological monitoring. 3.4 Exposure assessment: what the legislation requires. 3.5 Conclusions. Chapter 4 The Exposure Context. 4.1 Context for measurement. 4.2 Sources of hazardous substances. 4.3 Dispersion through the workroom. 4.4 Receptor. 4.5 Jobs and tasks. Chapter 5 Why Measure? 5.1 Introduction. 5.2 Reasons for undertaking monitoring. Chapter 6 How to Carry Out a Survey. 6.1 Introduction. 6.2 Planning the survey. 6.3 Workplace monitoring. 6.4 Monitoring strategies. 6.5 Quality assurance and quality control. 6.6 Survey checklists. Chapter 7 Analysis of Measurement Results. 7.1 Introduction. 7.2 Dealing with variability in measurement results. 7.3 Summary statistics and data presentation. Chapter 8 Hygiene Reports and Records. 8.1 Measurement records. 8.2 Survey reports. Part 2 Inhalation Exposure. Chapter 9 Dust and Fibrous Aerosols. 9.1 Introduction. 9.2 Airborne dust. 9.3 Fibres. 9.4 Measurement of airborne dust levels. 9.5 Measurement of flow rate. 9.6 Pumps. 9.7 Direct-reading aerosol monitors. 9.8 Calibration of a rotameter or electronic flow calibrator by using the soap-bubble method. 9.9 The measurement of inhalable airborne dust. 9.10 The measurement of airborne respirable dust by using a cyclone sampler. 9.11 The sampling and counting of airborne asbestos fibres. 9.12 The choice of filter and filter holder to suit a specific dust, fume or mist. 9.13 To trace the behaviour of a dust cloud by using a Tyndall beam. Chapter 10 Gases and Vapours. 10.1 Introduction. 10.2 Collection devices. 10.3 Containers. 10.4 Direct-reading instruments. 10.5 To measure personal exposure to solvent vapours using an adsorbent tube. 10.6 Sampling for gases by using a bubbler. 10.7 Tomeasure the short-term airborne concentration of a gas by using a colorimetric detector tube. 10.8 To measure a vapour concentration using a diffusive sampler. Chapter 11 Bioaerosols. 11.1 Introduction. 11.2 Classification of microorganisms. 11.3 Viruses. 11.4 Bacteria. 11.5 Moulds and yeasts. 11.6 Allergens. 11.7 Principles of containment. 11.8 Handling microorganisms. 11.9 Monitoring bioaerosols. 11.10 Measurement of endotoxins and allergens. 11.11 Interpretation of sample results. Part 3 Dermal and Ingestion Exposure. Chapter 12 Dermal and Ingestion Exposure Measurement. 12.1 Introduction. 12.2 Occupations where dermal exposure is important. 12.3 Local and systemic effects. 12.4 How do we know if dermal exposure is an issue? 12.5 What do we measure? 12.6 Methods for dermal exposure measurement. 12.7 Sampling strategy. 12.8 Liquids and solids. 12.9 Biomonitoring and modelling of dermal exposure. 12.10 From exposure to uptake. 12.11 Controlling dermal exposure. 12.12 Inadvertent ingestion exposure. Part 4 Physical Agents. Chapter 13 Noise. 13.1 Introduction. 13.2 Pressure and magnitude of pressure variation. 13.3 Frequency. 13.4 Duration. 13.5 Occupational exposure limits. 13.6 Equipment available. 13.7 Sound level meters and personal noise dosimeters. 13.8 Personal noise dosimeters. 13.9 Calibration. 13.10 To measure workplace noise using a SLM. 13.11 To measure workplace noise using a PND. 13.12 To measure the spectrum of a continuous noise by octave band analysis. 13.13 To determine the degree of noise exposure and the actions to take. Chapter 14 Vibration. 14.1 Introduction. 14.2 Vibration. 14.3 Occupational exposure limits. 14.4 Risk assessment. 14.5 Measurements and measurement equipment. 14.6 To measure hand arm vibration. 14.7 Control of vibration. Chapter 15 Heat and Cold. 15.1 Introduction. 15.2 Heat stress. 15.3 Measurement equipment. 15.4 Personal monitoring. 15.5 Measurement of the thermal environment. 15.6 Predicted Heat Strain Index. 15.7 Risk assessment strategy. 15.8 Cold. 15.9 To calculate the wind chill factor. Chapter 16 Lighting. 16.1 Introduction. 16.2 Lighting Standards. 16.3 Equipment available. 16.4 Calibration. 16.5 To measure lighting. 16.6 Control. Chapter 17 Ionising Radiation. 17.1 Introduction. 17.2 Ionising radiation. 17.3 Background radiation. 17.4 Basic concepts and quantities. 17.5 Types of radiation. 17.6 Energy. 17.7 Activity. 17.8 Radiation dose units. 17.9 Dose limits. 17.10 Derived limits. 17.11 Procedures to minimise occupational dose. 17.12 Personal dosimetry and medical surveillance. Chapter 18 Non-Ionising Radiation. 18.1 Introduction. 18.2 Ultraviolet radiation. 18.3 Infrared radiation. 18.4 Microwaves and radiowaves. 18.5 Lasers. Part 5 Assessing the Effectiveness of Control. Chapter 19 Introduction to Control. 19.1 Introduction. 19.2 Specific control measures. 19.3 The effectiveness of control measures. Chapter 20 Ventilation. 20.1 Introduction. 20.2 Air pressure. 20.3 Measurement equipment. 20.4 Ventilation measurement records. 20.5 Measurement of air flow in ducts. 20.6 Measurement of pressure in ventilation systems. 20.7 To measure the face velocity on a booth or hood. 20.8 To measure the face velocity on a fume cupboard. 20.9 To measure the performance of a suction inlet. Chapter 21 Personal Protective Equipment. 21.1 Introduction. 21.2 Components of an effective PPE programme. 21.3 Face-fit testing using a particle counter. Part 6 Risk Assessment and Risk Communication. Chapter 22 Risk Assessment. 22.1 Introduction. 22.2 Identify all hazardous substances or agents. 22.3 Identify the likely levels of exposure. 22.4 Identify all persons likely to be exposed. 22.5 Assess whether the exposures are likely to cause harm. 22.6 Consider elimination or substitution. 22.7 Define additional control measures necessary to reduce the harm to acceptable levels. Chapter 23 Risk Communication. 23.1 Introduction. 23.2 Risk perception. 23.3 Trust. 23.4 Communication. 23.5 An example of quantitative risk assessment to aid risk communication. Equipment Suppliers. Chemical Analytical Services. Index. | v2 |
2019-04-17T15:50:49.034Z | 2008-09-01T00:00:00.000Z | 117382201 | s2ag/train | Newly Recognized QSO/Galaxy Pairs at Small Impact Parameters for Low Redshift Galaxies
A search for emission lines in foreground galaxies, in QSO spectra (zgal 5 x 10-17 ergs cm-2 s-1 • Confirmed additional, expected galactic emissions at the same redshift as H to weed out false positives: H, H, [O III], [O II], [N II], [S II] • Emission line search produced 21 examples of QSOs overlapped by foreground low redshift galaxies (QSO/Galaxy pairs). Figure 2: Composite SDSS image of QJ1042+0748 (the blue object just above center). The QSO is at z=2.665. Emission lines (Figure 1) from the spectrum of the overlaying galaxy are at z=0.03321. Figure 1: The SDSS spectrum of QJ1042+0748, a z=2.665 QSO with a superimposed spectrum of a (narrow-line) galaxy from an object that falls in the SDSS fiber. PHOTOMETRY • IDL and IDP3 software used to de-blend the overlapped QSO/Galaxy pairs • Color magnitudes for each galaxy obtained by subtracting an adjusted PSF to remove the paired QSO • Color magnitudes for each QSO obtained by measuring the magnitudes of the fitted PSF MEASURED PROPERTIES QSO g and i-band magnitudes Galaxy u and r-band magnitudes QSO (g-i) [observer-frame color excess] QSO E(B-V)g-i [absorber-frame color excess; extinction measure] Star Formation Rate H/H Flux Ratio QSO/Galaxy centroid offset [impact parameter] Galactic length, width, and orientation QSOALS Expectations • Each QSO/Galaxy pair spectrum was searched for expected absorption features due to the foreground galaxy. • Ca II and Na I lines were identified and measured for equivalent widths and errors using IRAF. • Table 3 shows the relevant absorption features for best pairs. | v2 |
2020-12-14T20:14:19.865Z | 2020-11-05T00:00:00.000Z | 228909081 | s2ag/train | TAK-573, an Anti-CD38/Attenuated Ifnα Fusion Protein, Has Clinical Activity and Modulates the Ifnα Receptor (IFNAR) Pathway in Patients with Relapsed/Refractory Multiple Myeloma
Background:
TAK-573 is a first-in-class, humanized, anti-CD38, IgG4 monoclonal antibody genetically fused to 2 attenuated interferon alpha-2b (IFNα2b) molecules. The specificity for CD38 and reduced binding affinity of the attenuated IFNα molecules significantly reduces the potential for off-target toxicity. TAK-573 binds to a site on CD38 that is distinct from the binding sites of currently available therapeutic antibodies, and therefore does not compete for binding with daratumumab or isatuximab. Non-clinical studies have shown that TAK-573 has robust anti-tumor activity, including complete responses, in MM xenograft models.
Patients and Methods:
The first in human phase I trial (NCT03215030) enrolled patients (pts) with relapsed or refractory multiple myeloma (RRMM) after at least 3 previous lines of treatment. Pts received TAK-573 as a 1 to 4-hour IV infusion in 11 dose levels from 0.001 to 3 mg/kg. The initial schedule was weekly for 8 doses, then every 2 weeks for 8 doses, and then monthly. Subsequent cohorts are also exploring dosing once every 2 (Q2), every 3 (Q3) or every 4 weeks (Q4).
Peripheral blood (PB) and bone marrow (BM) aspirates were collected before and after TAK-573 dosing. CD38 receptor occupancy (RO) and receptor density (RD) were determined using 9-color flow cytometry. Serum samples were analyzed using the Immuno-Oncology panel of Olink's proximity extension assay platform to measure changes in cytokine and chemokine levels. Whole transcriptome sequencing of bulk RNA was performed to determine the type I interferon (IFN) gene signature induction. Mass cytometry-based immunophenotyping was utilized to characterize changes in immune cell prevalence and activation status of cryopreserved cells from both the PB and BM.
Results:
As of June 2020, 59 patients had been treated on all schedules. The median number of prior lines of therapy was 7 (range: 3-20); 93% had received at least 1 daratumumab-containing regimen, and 14% had received previous CAR-T cell therapy. Thrombocytopenia was the most frequent TEAE (83%) and was Grade ≥3 in 28 (47%) pts. Prolonged thrombocytopenia was a dose limiting toxicity (DLT) in 7 pts, but was not associated with clinical bleeding, and 9 pts required platelet transfusions. Neutropenia was reported as a TEAE in 54% of pts (Grade ≥3 in 49% pts), and was a DLT in 4 patients, including one pt who had febrile neutropenia. The maximum tolerated dose for the initial schedule was 0.1 mg/kg, and evaluation of other schedules is ongoing. Myeloma responses have been observed starting at doses of 0.1 mg/kg on the initial schedule, 0.4 mg/kg q2 weeks, and 1.5 mg/kg q4 weeks (as shown in Table 1).
Single administration of TAK-573 resulted in a dose dependent increase in CD38 RO of PB-derived immune cells, with saturation of CD38 RO 4 hours after the end of infusion (EOI) at doses ≥ 0.2 mg/kg. The duration of saturation was dose dependent, with doses ≥ 0.75 mg/kg TAK-573 saturating CD38 RO through 24 hours. CD38 RO in BM samples showed similar results, with added variability due to the timing of sample collection and individual patients' tumor burden. At all dose levels, TAK-573 administration resulted in increases in the type I IFN gene signature 24 hours after the dose. As CD38 is an IFN-stimulated gene, TAK-573 treatment resulted in CD38 RD increases, most notably on NK cells but also on other CD38 positive cells, including MM cells within the BM. BM MM cells also showed decreases in complement-inhibitory proteins CD55 and CD59 after TAK-573 treatment. Circulating levels of IFN-associated chemokines (IFNγ, CXCL10, MCP-1 and IL-15) also increased, with maximal induction 4 hours after EOI. CD69 expression, a marker of early activation, increased on BM CD8+ T cells in 7 of 9 patients analyzed; the CD8+ T-cells for 3 of those 7 patients also showed increases in IFNγ positivity, indicating that TAK-573 treatment can increase the cytolytic potential of CD8+ T-cells in the BM of a subset of patients.
Conclusion:
TAK-573 is a clinically and pharmacologically active molecule that mediates IFNAR pathway modulation and leads to myeloma responses. Additional biomarker data is being collected to further refine the MOA, which will inform the recommended phase 2 dose, optimal schedule of administration, and rational development of TAK-573.
Vogl: Active Biotech: Consultancy, Research Funding; Takeda: Consultancy; Karyopharm: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Oncopeptides: Consultancy; MorphoSys: Consultancy. Kaufman:Takeda: Consultancy, Honoraria; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Sanofi/Genyzme: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Tecnopharma: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; AbbVie: Consultancy. Holstein:GSK: Consultancy; Celgene: Consultancy; Sorrento: Consultancy; Sanofi: Consultancy; Oncopeptides: Consultancy, Research Funding; Takeda: Consultancy; Adaptive Biotechnologies: Consultancy; Genentech: Consultancy. Nadeem:Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Suryanarayan:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment. Collins:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment. Parot:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment. Chaudhry:Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees.
TAK-573 is a first-in-class, humanized, anti-CD38, IgG4 monoclonal antibody genetically fused to 2 attenuated interferon alpha-2b (IFNα2b) molecules
| v2 |
2021-11-26T16:14:53.433Z | 2021-11-05T00:00:00.000Z | 244645431 | s2ag/train | NIMBLE: A Phase I/II Study of AZD0466 Monotherapy or in Combination in Patients with Advanced Hematological Malignancies
Introduction: While BCL2 inhibition benefits many patients with acute myeloid leukemia (AML), resistance often occurs due to upregulation of other anti-apoptotic proteins such as MCL and BCLxL. Dual BCL2/xL inhibition with AZD4320 has potential for broader activity than BCL2-specific inhibition with venetoclax (Balachander et al, Clinical Cancer Research 2020). AZD0466 is a drug-dendrimer conjugate in which AZD4320 is covalently conjugated to a pegylated poly-L-lysine dendrimer and where, following IV infusion, AZD4320 is gradually released by hydrolysis. The dendrimer construct allows for efficient delivery of the highly potent but poorly soluble active drug, and this release profile was designed to mitigate potential maximum concentration (Cmax)-dependent BCLxL mediated effects (Patterson et al, Nature Communications Biology 2021). AZD0466 has shown antitumor activity in a range of preclinical models of hematological malignancy, including cell-line derived and patient-derived xenograft models of acute myeloid leukemia (AML), B-cell acute lymphoblastic leukemia (B-ALL), and T-cell acute lymphoblastic leukemia (T-ALL - Kannan et al AACR 2020 Abstract 3075). AZD0466 has previously been administered to 9 patients with advanced solid malignancies at doses declared tolerable through 200 mg in the first-time-in-human study (NCT04214093), and a physiologically based PK model validated across nonclinical species was used to predict human doses and exposures expected to drive tumor regression in hematologic malignancy. These studies provide rationale for testing AZD0466 in refractory AML and ALL patients in this phase I/II dose escalation and monotherapy expansion and drug-drug interaction study (NCT04865419).
Study Design and Methods: NIMBLE (drug deNdrIMer targeting BCL2/xL in acute LEukemias) is a modular, non-randomized phase I/II dose escalation and expansion study. Module 1 will evaluate safety, tolerability, pharmacokinetics, and preliminary efficacy of AZD0466 as monotherapy in patients with relapsed/refractory AML or ALL. Patients are eligible if ≥ 18 years of age with any subtypes of relapsed/refractory AML or ALL without active CNS involvement and after at least one prior line of therapy. Treatment with hydroxyurea during screening and cycle 1 is permitted to control white blood cell count. Patients with extramedullary disease are also eligible. Primary endpoints are safety and tolerability of AZD0466 in patients with acute leukemia. In dose escalation, patients will be treated in each dose level according to an mTPI-2 design. Secondary endpoints are to determine pharmacokinetic parameters for total and released AZD4320. Exploratory endpoints include association of pharmacodynamic effects including changes to peripheral blasts and cleaved caspase activation, and initial evaluation of efficacy in relation to baseline leukemia characteristics. Planned dose expansion cohorts are AML patients with a prior history of MPN with ≤ 2 prior lines of therapy, AML patients with TP53 mutation treated with ≤ 3 prior lines of therapy, other AML treated with ≤ 3 prior lines (including venetoclax), and B- or T-ALL treated with ≤ 3 prior lines. Module 2 is a drug-drug interaction (DDI) study that will investigate the safety and establish the sensitivity of AZD0466 to voriconazole, a strong inhibitor of CYP3A4. There are no additional inclusion or exclusion criteria specific to Module 2. Further modules will be added via protocol amendment to investigate AZD0466 in combination with other antileukemia treatments, and may be triggered at the planned interim analyses during expansion.
AZD0466 will be administered with a dose ramp-up in cycle 1 from a starting dose on day 1, with subsequent titration to an intermediate dose on day 4, and target dose on day 8, with weekly 1-hour IV administration thereafter at the target dose. The duration of cycle 1 is 35 days, and subsequent cycles are 28 days in which AZD0466 will be administered once weekly. Patients will continue until treatment failure, unacceptable toxicity, or withdrawal of consent.
This study is actively enrolling patients at sites in the USA, and will be opening at multiple sites in Australia, Europe and South Korea. An update of preliminary safety and pharmacokinetics will be presented.
Figure 1 Figure 1.
Konopleva: AstraZeneca: Other: grant support, Research Funding; Sanofi: Other: grant support, Research Funding; AbbVie: Consultancy, Honoraria, Other: Grant Support, Research Funding; Genentech: Consultancy, Honoraria, Other: grant support, Research Funding; Eli Lilly: Patents & Royalties: intellectual property rights, Research Funding; Stemline Therapeutics: Research Funding; Forty Seven: Other: grant support, Research Funding; KisoJi: Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Other: grant support; Ascentage: Other: grant support, Research Funding; Ablynx: Other: grant support, Research Funding; Calithera: Other: grant support, Research Funding; Reata Pharmaceuticals: Current holder of stock options in a privately-held company, Patents & Royalties: intellectual property rights; Agios: Other: grant support, Research Funding; Rafael Pharmaceuticals: Other: grant support, Research Funding; Cellectis: Other: grant support; Novartis: Other: research funding pending, Patents & Royalties: intellectual property rights. Jain: Fate Therapeutics: Research Funding; Cellectis: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Adaptive Biotechnologies: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Incyte: Research Funding; AbbVie: Honoraria, Research Funding; ADC Therapeutics: Honoraria, Research Funding; Precision Biosciences: Honoraria, Research Funding; Servier: Honoraria, Research Funding; Pfizer: Research Funding; Aprea Therapeutics: Research Funding; Pharmacyclics: Research Funding; Janssen: Honoraria; Beigene: Honoraria; TG Therapeutics: Honoraria. Andersen: AstraZeneca: Current Employment, Current equity holder in publicly-traded company. Couto Francisco: AstraZeneca: Current Employment, Other: may own stock or stock options. Elgeioushi: AstraZeneca: Current Employment, Other: may own stock or stock options. Hobson: AstraZeneca: Current Employment, Other: may own stock or stock options. Scott: AstraZeneca: Current Employment, Other: may own stock or stock options. Stone: AstraZeneca: Current Employment, Other: may own stock or stock options. Sharma: AstraZeneca: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Morentin Gutierrez: AstraZeneca: Current Employment, Other: may own stock or stock options. Tibes: AstraZeneca: Current Employment, Other: may own stock or stock options. Davies: AstraZeneca: Current Employment, Other: may own stock or stock options. Winkler: AstraZeneca: Current Employment, Other: may own stock or stock options. Fabbri: AstraZeneca: Current Employment, Other: may own stock or stock options. Zumla Cader: AstraZeneca: Current Employment, Other: may own stock or stock options. McNeer: AstraZeneca: Current Employment, Other: may own stock or stock options.
| v2 |
2020-10-29T10:19:54.762Z | 2006-01-01T00:00:00.000Z | 225101751 | s2ag/train | Analysis of intact phosphoinositides in biological samples
It is now apparent that each of the known, naturally occurring polyphosphoinositides, the phosphatidylinositol monophosphates (PtdIns3P, PtdIns4P, PtdIns5P), phosphatidylinositol bisphosphates [PtdIns(3,4)P2, PtdIns(3,5)P2, PtdIns(4,5)P2], and phosphatidylinositol trisphosphate [PtdIns(3,4,5)P3], have distinct roles in regulating many cellular events, including intracellular signaling, migration, and vesicular trafficking. Traditional identification techniques require [P]inorganic phosphate or [H]inositol radiolabeling, acidified lipid extraction, deacylation, and ion-exchange head group separation, which are time-consuming and not suitable for samples in which radiolabeling is impractical, thus greatly restricting the study of these lipids in many physiologically relevant systems. Thus, we have developed a novel, high-efficiency, buffered citrate extraction methodology to minimize acid-induced phosphoinositide degradation, together with a high-sensitivity liquid chromatography-mass spectrometry (LC-MS) protocol using an acetonitrile-chloroform-methanol-water-ethylamine gradient with a microbore silica column that enables the identification and quantification of all phosphoinositides in a sample. The liquid chromatograph is sufficient to resolve PtdInsP3 and PtdInsP2 regioisomers; however, the PtdInsP regioisomers require a combination of LC and diagnostic fragmentation to MS. Data are presented using this approach for the analysis of phosphoinositides in human platelet and yeast samples.—Pettitt, T. R., S. K. Dove, A. Lubben, S. D. J. Calaminus, and M. J. O. Wakelam. Analysis of intact phosphoinositides in biological samples. J. Lipid Res. 2006. 47: 1588–1596. Supplementary key words lipidomics . mass spectrometry . liquid chromatography-mass spectrometry . platelets . yeast As our understanding of lipids as highly dynamic structures with both structural and signaling roles matures, one group stands out. These are the phosphoinositides, which regulate a host of cellular events, such as membrane trafficking, secretion, adhesion, migration, cell survival, and replication (1–4). Many of these outcomes are regulated by interactions between phosphoinositides and effector proteins bearing specific phosphoinositide binding domains (e.g., ENTH, FYVE, PH, PX) (5). Within this lipid family, the best known are phosphatidylinositol (PtdIns), the parent of the higher phosphorylated forms, which itself has no known signaling role, phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2], and phosphatidylinositol 3,4,5-trisphosphate [PtdIns(3,4,5)P3]. PtdIns(4,5)P2 is the precursor to diacylglycerol and inositol 1,4,5-trisphosphate in receptor signaling and also directly regulates cytoskeletal reorganizations and the activities of enzymes such as phospholipase D. PtdIns(3,4,5)P3 regulates cell movement, apoptosis, metabolism, and proliferation via the activation of phosphoinositide dependent kinase 1, protein kinase B, and other PH and PX domain proteins. However, it is now also apparent that other PtdInsP2 regioisomers, such as phosphatidylinositol 3,4-bisphosphate [PtdIns(3,4)P2] and phosphatidylinositol 3,5-bisphosphate [PtdIns(3,5)P2], together with the phosphatidylinositol monophosphate regioisomers phosphatidylinositol 3phosphate (PtdIns3P), phosphatidylinositol 4-phosphate (PtdIns4P), and phosphatidylinositol 5-phosphate (PtdIns5P), have their own specific functions. PtdIns3P and PtdIns4P regulate membrane trafficking, whereas PtdIns5P has been reported to bind to the PHD domain in the candidate tumor suppressor nuclear protein ING2 (6). PtdIns(3,4)P2 binds PH and PX domains in many proteins, whereas PtdIns(3,5)P2 can bind to ENTH and a subset of WD40 domains involved in autophagy and stress responses (7). Mutations in the signaling pathways involving generation, removal, or responses to these lipids have been detected in many cancers and other diseases, further emphasizing the critical functions of the phosphoinositides (8–11). To fully understand the role of these phosphoinositides, we need the ability to follow their individual changes. As it becomes clear that the different regioisomers have Manuscript received 2 February 2006. Published, JLR Papers in Press, April 21, 2006. DOI 10.1194/jlr.D600004-JLR200 Abbreviations: LC-MS, liquid chromatography-mass spectrometry; PtdIns, phosphatidylinositol; PtdInsP, phosphatidylinositol monophosphate; PtdInsP2, phosphatidylinositol bisphosphate; PtdInsP3, phosphatidylinositol 3,4,5-trisphosphate. To whom correspondence should be addressed. e-mail: [email protected] Copyright D 2006 by the American Society for Biochemistry and Molecular Biology, Inc. This article is available online at http://www.jlr.org 1588 Journal of Lipid Research Volume 47, 2006 by gest, on July 0, 2015 w w w .j.org D ow nladed fom different signaling functions, exact isomeric identification is essential. At present, this is very difficult, requiring equilibrium [H]inositol or [P]inorganic phosphate radiolabeling of cells before extraction. Equilibrium radiolabeling is not possible for many primary cells, as they cannot be stably maintained in culture for a sufficient length of time. After radiolabeling, the lipids are extracted and deacylated to remove fatty acids, and the glycerophosphoinositol head groups are resolved by ion-exchange chromatography. Because most of these structures are normally only found in trace amounts [e.g., PtdIns(3,4,5)P3 in resting cells is present at only z0.1% of its precursor PtdIns(4,5)P2, although it can increase up to 100-fold after stimulation], the multiple manipulation steps required often result in substantial losses, making these techniques inappropriate for many studies in which starting material is limited. Deacylation also loses all structural information relating to the acyl part of the molecule, which may prove important in the same way that the mammalian signaling forms of diacylglycerol have polyunsaturated acyl compositions and signaling phosphatidic acid normally has monounsaturated and diunsaturated acyl compositions (12). Indeed, recent work suggests that the PtdIns(3,4,5)P3 acyl structures formed may be stimulus-dependent (13). Thus, there is an urgent need to develop novel, sensitive methods to detect and resolve intact phosphoinositides. A few reports of tandem mass spectrometry identification of PtdInsP, PtdInsP2, and PtdInsP3 have been published (13–16); however, these methods were unable to resolve the regioisomers. Furthermore, these approaches suffer from the ion suppression effects inherent to direct infusion of unfractionated, complex lipid mixtures, which can lead to a significant loss of sensitivity. This is particularly the case for minor components such as the polyphosphoinositides. Here, we report the development of liquid chromatography-mass spectrometry (LC-MS) procedures that enable the complete identification, at high sensitivity, of all of the phosphoinositides in a complex total lipid extract, without prior fractionation, and apply the techniques to analyze physiologically relevant biological samples. MATERIALS AND METHODS | v2 |
2021-11-26T16:52:55.300Z | 2021-11-05T00:00:00.000Z | 244639691 | s2ag/train | TP53 Aberrations and Outcomes in MBL and Untreated CLL
Introduction: TP53 aberrations, including mutations and deletion of 17p (del17p), are important adverse prognostic markers in chronic lymphocytic leukemia (CLL). Prevalence of TP53 aberrations ranges from 7-11% in untreated CLL and increases with disease progression and treatment. Among CLL patients with TP53 aberrations, co-occurrence of TP53 mutations with del(17p) is common. CLL patients with TP53 mutations or del(17p) have significantly worse outcomes when compared to wild-type patients. Previous studies, focusing on CLL patients at time of treatment, are mixed as to whether a single or more than one TP53 aberration impacts outcomes. TP53 is less well studied in monoclonal B-cell lymphocytosis (MBL), an asymptomatic pre-malignant state of CLL. Del(17p) occurs in 3-4% of MBL individuals, and a study of 54 MBL individuals reported a 2% mutation frequency in TP53. Here we estimated prevalence and evaluated the impact of TP53 aberrations in a large cohort MBL or untreated CLL individuals.
Methods : Patients with CLL or MBL diagnosed between 2000 and 2019 from the Mayo Clinic CLL Resource with pre-treatment peripheral blood mononuclear cells (PBMC) collected within two years of diagnosis were considered. DNA was extracted from PBMCs with purity >80% or with sorted CD5+/CD19+ clonal cells. The entire coding regions of 59 CLL driver genes were paired end sequenced. Median coverage depth was >1000x per nucleotide, allowing for detection of mutations with variant allelic fraction (VAF) as low as 1%. Somatic mutations were called using MuTect2 in tumor-only mode, and high impact mutations (frameshift, nonsense, and splicing variants) and missense mutations in CLL hot spots were selected.
Somatic mutations and FISH del(17p) were used to define TP53 state for each patient: 1) wild-type [no TP53 mutations and normal del(17p)], 2) single-hit [one TP53 mutation or del(17p)], or 3) multi-hit [multiple TP53 mutations or TP53 mutation and del(17p)].
Time to first treatment (TTFT) and overall survival (OS) were analyzed by TP53 state. TTFT and OS were defined as time from sample collection to first treatment or death, respectively, or last follow-up date. Median TTFT and OS was estimated by the Kaplan-Meier method. We used Cox regression to estimate hazard ratios (HRs) and 95% confidence intervals for TTFT and OS associations. The models were adjusted for known adverse prognostic factors including clinical diagnosis (CLL or MBL), age at diagnosis, Rai stage, b2 microglobulin, and IGHV mutation status.
Results: Individuals with CLL (N=597) or MBL (N=285) were analyzed for prevalence of TP53 mutations and del(17p). We found 58 CLL patients (9.7%) and 15 MBL individuals (5.3%) had TP53 mutations. The median VAF in CLL was 30.9% (<10% VAF, n=21) and in MBL was 13.5% (<10% VAF, n=7). Del(17p) was present in 37 patients with CLL (6.2%) and 7 individuals with MBL (2.7%). In total, 86 CLL/MBL patients had a TP53 mutation and/or del(17p): 56.8% (48 patients) were single-hit and 44.2% (38 patients) were multi-hit (Fig. 1a).
Patients with any TP53 aberration had shorter TTFT than wild-type patients (median 2.3 vs 9.4 years). Among patients with TP53 aberrations, median TTFT was shorter in multi-hit patients (20 events, 1.8 years) compared to single-hit patients (24 events, 3.2 years) (Fig. 1b). In Cox regression, single-hit (HR = 1.7 [1.1-2.6]) and multi-hit (HR = 1.8 [1.1-2.9]) patients had shorter TTFT compared to wild-type patients after adjusting for covariates (Fig. 1c).
Multi-hit patients also had shorter OS compared to wild-type patients, while OS in single-hit patients did not significantly differ from wild-type patients (Fig. 1d). Median OS was 5.5 years in multi-hit patients (22 deaths) compared to 15.1 years in wild-type patients (196 deaths) and 14.3 years in single-hit patients (15 deaths). In the OS model adjusted for covariates, multi-hit patients had a significant increased risk (HR = 2.6 [1.6-4.1]), but single-hit patients did not (HR = 1.4 [0.8-2.5]) compared with wild-type patients (Fig. 1e). OS HRs remained stable after censoring at time of treatment. Both TTFT and OS HRs were consistent when mutations with VAF < 10% were excluded.
Conclusions: This study suggests single versus multi-hit TP53 aberrations may be important for prognostic outcomes in untreated CLL and MBL patients. Prognostic metrics may need to consider single versus multi-hit TP53 aberrations and include TP53 mutations with low VAF.
Figure 1 Figure 1.
Cerhan: Regeneron Genetics Center: Other: Research Collaboration; Celgene/BMS: Other: Connect Lymphoma Scientific Steering Committee, Research Funding; NanoString: Research Funding; Genentech: Research Funding. Parikh: Pharmacyclics, MorphoSys, Janssen, AstraZeneca, TG Therapeutics, Bristol Myers Squibb, Merck, AbbVie, and Ascentage Pharma: Research Funding; Pharmacyclics, AstraZeneca, Genentech, Gilead, GlaxoSmithKline, Verastem Oncology, and AbbVie: Membership on an entity's Board of Directors or advisory committees. Kay: MEI Pharma: Research Funding; Bristol Meyer Squib: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Dava Oncology: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Juno Therapeutics: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tolero Pharmaceuticals: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Agios Pharm: Membership on an entity's Board of Directors or advisory committees; Targeted Oncology: Membership on an entity's Board of Directors or advisory committees; CytomX Therapeutics: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Behring: Membership on an entity's Board of Directors or advisory committees; Sunesis: Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta Pharma: Research Funding; Oncotracker: Membership on an entity's Board of Directors or advisory committees; Morpho-sys: Membership on an entity's Board of Directors or advisory committees; Rigel: Membership on an entity's Board of Directors or advisory committees.
| v2 |
2021-11-25T16:10:00.666Z | 2021-11-05T00:00:00.000Z | 244567631 | s2ag/train | Mitapivat Improves Ineffective Erythropoiesis and Reduces Iron Overload in Patients with Pyruvate Kinase Deficiency
Background: Pyruvate kinase (PK) deficiency is a rare hereditary disease resulting in chronic hemolytic anemia, which is associated with serious complications, including iron overload, regardless of transfusion status. Ineffective erythropoiesis is linked to iron overload in patients (pts) with hemolytic anemias. Mitapivat is a first-in-class, oral, allosteric activator of the red blood cell PK enzyme (PKR) that has demonstrated improvement in hemoglobin (Hb), hemolysis, and transfusion burden in pts with PK deficiency. This analysis assessed the effect of mitapivat on markers of erythropoiesis and iron overload in pts with PK deficiency enrolled in 2 phase 3 studies, ACTIVATE (NCT03548220) and ACTIVATE-T (NCT03559699), and the long-term extension (LTE) study (NCT03853798).
Methods: In ACTIVATE (double-blind, placebo-controlled study), 80 pts (age ≥ 18 years [yrs]) with a confirmed diagnosis of PK deficiency who were not regularly transfused (≤ 4 transfusion episodes in the prior yr; none in the prior 3 months) were randomized to receive mitapivat or placebo. In ACTIVATE-T (open-label, single-arm study), 27 pts (age ≥ 18 yrs) with a confirmed diagnosis of PK deficiency who were regularly transfused (≥ 6 transfusion episodes in the prior yr) were treated with mitapivat. Pts who completed either trial (24 weeks [wks] [ACTIVATE], 40 wks [ACTIVATE-T]) were eligible to continue in the LTE. Erythropoiesis markers included erythropoietin (EPO), erythroferrone, reticulocytes, and soluble transferrin receptor (sTfR). Markers of iron overload included hepcidin, iron, transferrin saturation (TSAT), ferritin, and liver iron concentration (LIC) by magnetic resonance imaging (MRI). In the LTE all pts received mitapivat. Pts from ACTIVATE were categorized into either the mitapivat-to-mitapivat arm (M/M) or the placebo-to-mitapivat arm (P/M). The ACTIVATE-T/LTE analysis includes pts who achieved transfusion-free status in ACTIVATE-T. The ACTIVATE/LTE analysis assessed change in markers from baseline (BL) over time in both study arms.
Results: Eighty pts were included in the ACTIVATE/LTE analysis (M/M = 40; P/M = 40). Pts in both arms had abnormal BL erythropoiesis markers consistent with underlying ineffective erythropoiesis, and BL abnormal markers of iron overload. In the M/M arm, mean (SD) EPO, erythroferrone, reticulocytes, and sTfR decreased from BL to Wk 24 of mitapivat treatment by -32.9 IU/L (62.47), -9834.9 ng/L (13081.15), -202.0 10 9/L (246.97), and -56.0 nmol/L (82.57), respectively, while they remained stable or increased in the P/M arm on placebo (Figure). Twenty-four wks after starting mitapivat in the LTE (Wk 48 post BL), pts in the P/M arm had comparable beneficial decreases in mean (SD) EPO, erythroferrone, reticulocytes, and sTfR of -11.6 IU/L (30.74), -9246.1 ng/L (8314.17), -283.7 10 9/L (374.27), and -38.7 nmol/L (48.37), respectively. Improvements in hepcidin, iron, TSAT, and LIC were also observed with mitapivat treatment; ferritin remained stable (Table). Mean (SD) hepcidin increased in the M/M arm at Wk 24 and in the P/M arm 24 wks after starting mitapivat (Wk 48 post BL). At Wk 24, mean (SD) iron and TSAT, and median (Q1, Q3) LIC decreased in the M/M arm, while they increased on placebo. In the P/M arm, iron, TSAT, and LIC decreased 24 wks after starting mitapivat (Wk 48 post BL). Transfusion-free responders from ACTIVATE-T (n = 6) also experienced improvements in markers of erythropoiesis and iron overload in the LTE.
Conclusions: In addition to improving Hb, hemolysis, and transfusion burden, data from ACTIVATE, ACTIVATE-T, and the LTE study indicate that activation of PKR with mitapivat improves markers of ineffective erythropoiesis and iron homeostasis in PK deficiency, thereby decreasing iron overload in these pts. Mitapivat has the potential to become the first approved therapy in PK deficiency with beneficial effect on iron overload.
Figure 1 Figure 1.
Van Beers: Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; RR Mechatronics: Research Funding; Pfizer: Research Funding. Al-Samkari: Amgen: Research Funding; Argenx: Consultancy; Rigel: Consultancy; Novartis: Consultancy; Dova/Sobi: Consultancy, Research Funding; Agios: Consultancy, Research Funding; Moderna: Consultancy. Grace: Agios: Research Funding; Dova: Membership on an entity's Board of Directors or advisory committees, Research Funding; Principia: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding. Barcellini: Bioverativ: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Alexion Pharmaceuticals: Honoraria; Novartis: Honoraria; Agios: Honoraria, Research Funding. Glenthoej: Bluebird Bio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Calgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Alexion: Research Funding; Novo Nordisk: Honoraria. Judge: Agios Pharmaceuticals: Current Employment, Current holder of stock options in a privately-held company. Kosinski: Agios Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Xu: Agios Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Beynon: Agios Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. McGee: Agios Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Porter: La Jolla Pharmaceuticals: Honoraria; Protagonism: Honoraria; Agios: Consultancy, Honoraria; bluebird bio, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene (BMS): Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Vifor: Honoraria, Membership on an entity's Board of Directors or advisory committees; Silence Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kuo: Celgene: Consultancy; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria; Alexion: Consultancy, Honoraria; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Research Funding; Bluebird Bio: Consultancy; Apellis: Consultancy.
| v2 |
2019-07-26T12:37:16.104Z | 2019-06-01T00:00:00.000Z | 198802841 | s2ag/train | SYNTHESIS AND MECHANICAL CHARACTERIZATION OF HYBRID NANOCOMPOSITES REINFORCED EPOXY COMPOSITES
Today’s scientists and engineers are finding a wide variety of ways to deliberately make materials at the nano scale to take advantage of their enhanced properties such as higher strength, lighter weight, good wear property, greater chemical reactivity than their counterparts. Traditionally, composites were reinforced with micron-sized inclusions/reinforcements. Recently, processing techniques have been developed to allow the size of inclusions to go down to nano-scale, nano-sized inclusions are defined as those that have at least one dimension in the range 1100 nm. The size range for nanoparticles may be more accurately defined as the size range from 1 nm to the largest nanometer dimension, Polymer composites are well known for offering engineers high strength-to weight ratios and flexibility in material design. The physical properties of a composite can be custom fitted to fulfill different practical necessities of an application, including firmness and quality, warm and electrical transport and wear protection from name a couple. Often, composites are designed to fulfill several functions simultaneously. In the present work epoxy based hybrid nano composites are fabricated (using nano materials such as Multi walled carbon nano tube and Nano diamond) with different weight fractions of reinforcement. The mechanical properties of these composites are investigated and found possess increase in hardness and wear properties with increased weight fraction compared to the base matrix fabricated with same process. Index Terms Hybrid nanocomposites,MWCNT, nanodiamond powder, Epoxy resin. [1] INTRODUCTION Polymer nanocomposites represents a new class of materials alternative to environmental filled polymers, in which nanosized inorganic fillers (having at least one dimension in the nano range) are dispersed in polymer matrix offering tremendous improvement in performance properties of the polymer, nanoscale material have been the subject of research interest in recent years because of their unique properties as compared to the bulk counterparts and their potential application in a wide variety of areas. Experiments were carried out to find out the properties. Nanocomposites A Nanocomposite is a multiphase strong material where one of the stages has one, a few elements of under 100 nanometers (nm), or structures having nano-scale rehash separates between the various stages that make up the material. In the broadest sense this definition can incorporate permeable media, colloids, gels and copolymers, yet is all the more typically interpreted as meaning the strong mix of a mass lattice and nano-dimensional phase(s) varying in properties because of dissimilarities in structure and science. The mechanical, electrical, warm, optical, electrochemical, synergist properties of the nanocomposite will vary notably from that of the part materials. Hybrid nanocomposites A Nanocomposite is a multiphase strong material where one of the stages has one, a few elements of under 100 nanometers (nm), or structures having nano-scale rehash separates between the various stages that make up the material. In the broadest sense this definition can incorporate permeable media, colloids, gels and copolymers, yet is all the more typically interpreted as meaning the strong mix of a mass lattice and nano-dimensional phase(s) varying in properties because of dissimilarities in structure and science. The mechanical, electrical, warm, optical, electrochemical, synergist properties of the nanocomposite will vary notably from that of the part materials. Materials used 1.Nanodiamond powder 2.Multi walled carbon nanotubes (MWCNT) © 2019 IJRAR June 2019, Volume 6, Issue 2 www.ijrar.org (E-ISSN 2348-1269, PISSN 2349-5138) IJRAR1AMP012 International Journal of Research and Analytical Reviews (IJRAR)www.ijrar.org 81 [2] Research Methodology Figure 1 Research methodology diagram Sonication Sonication is the act of applying sound usually ultra sound energy agitate particles I a sample , for various purposes. In the laboratory, it is applied using an ultra-sonic bath or an ultrasonic probe, colloquially known as sonicator. Figure 2 Sonication Process Fabrication 1. Using the above described nanomaterials we have synthesized the below mentioned hybrid nanocomposites. 2. MWCNT+ND Powder, epoxy resin and hardner are to be taken in the appropriate weight standards (composition),with respect to mould which we use it, (Fro different percentage of MWCNT+ND such as 0.25%, 0.50%, 0.75%, 1.00%, 1.25%, 1.50%, 1.75%, 2.00%, 2.25%, 2.50%). 3. Epoxy to hardner should be in the 10:1 ration in terms of volume and epoxy to MWCNT+ND should be in 100:1 ratio in terms of volume. 4. MWCNT+ND is mixed with ethanol and sonicated for 15 minutes in a beaker. The sonication helps to disperse the nano particles uniformly and reduce the lumps thus countering the Van der walls forces setup. This procedure helps us in getting the fine grained MWCNT+ND. 5. Heat the above mixture (MWCNT+ND & ethanol ) to evaporate the ethanol by electric heater in the same beaker. 6. NoteCare must be taken not to overheat MWCNT+ND above 75°C 7. Add the epoxy resin to MWCNT+ND with appropriate weight &sonicate the mixture for 30 minutes. The sonication is carried out in a water bath thereby lowering the undesired heat which polymerises the epoxy fluid .the sonication helps to disperse the nano particles uniformly throughout the epoxy polymer matrix. 8. Add the hardner to above mixture (MWCNT+ND & epoxy resin) 10:1 and stir it for 5 minutes with a stirrer. © 2019 IJRAR June 2019, Volume 6, Issue 2 www.ijrar.org (E-ISSN 2348-1269, PISSN 2349-5138) IJRAR1AMP012 International Journal of Research and Analytical Reviews (IJRAR)www.ijrar.org 82 Tabulation Rockwell Hardness Test The specimen was prepared according to the ASTM standard ASTM785. 6 mm Fig 4 Hardness test specimen Sl No Weight Fractions Total Mass In gms Epoxy In gms Hardner In gms MWCNT In gms Nanodiamond powder In gms 01 Pure Epoxy 30.4832 27.4348 3.04832 02 0.25% 30.4832 27.3662 3.0407 0.038104 0.038104 03 0.50% 30.4832 27.2977 3.0330 0.076208 0.076208 04 0.75% 30.4832 27.2291 3.0254 0114312 0114312 05 1.00% 30.4832 27.1605 3.0178 0.152416 0.152416 06 1.25% 30.4832 27.0919 3.0102 0.195020 0.195020 07 1.50% 30.4832 27.0234 3.0026 0.22856 0.22856 08 1.75% 30.4832 26.9547 2.9949 0.266728 0.266728 09 2.00% 30.4832 26.8861 2.9873 0.304832 0.304832 10 2.25% 30.4832 26.8175 2.9779 0.342936 0.342936 11 2.50% 30.4832 26.7490 2.97212 0.381040 0.381040 270.5766 30.0640 2.095656 2.095656 | v2 |
2021-11-26T16:39:03.547Z | 2021-11-05T00:00:00.000Z | 244659021 | s2ag/train | Ocular Toxicity of Commercially Available Belantamab Mafodotin in Patients with Advanced Multiple Myeloma
INTRODUCTION: Belantamab mafodotin (BLMF) is a first-in-class, antibody-drug conjugate targeting B-cell maturation antigen on myeloma cells. BLMF was approved for use in patients (pts) with advanced multiple myeloma (MM). Due to the risk of ocular toxicity, it is made available through a restricted program under a Risk Evaluation and Mitigation Strategy. It is speculated that monomethyl auristatin F (MMAF), the cytotoxic payload of BLMF may be internalised by the corneal epithelium via an off-target mechanism, leading to epithelial changes. In the pivotal DREAMM-2 trial, only 1% of pts permanently discontinued treatment due to keratopathy. Data regarding BLMF-induced ocular toxicity following its commercial availability since August 2020, are sparse, and in this context, we evaluated our clinical experience with BLMF to determine the impact of its ocular toxicity on outcomes when utilized outside of stringent clinical trial settings.
METHODS: We reviewed records of pts with advanced MM who were evaluated at Mayo Clinic between 09/01/2020-07/01/2021 and initiated on BLMF monotherapy following a baseline ophthalmic examination that was also performed prior to each dose, and as needed for worsening ocular symptoms. Data pertaining to ocular symptoms, best corrected visual acuity (BCVA) and corneal examinations were collected and analyzed with respect to patient outcomes. Adverse events were graded using the National Cancer Institute Common Toxicity Criteria for Adverse Events v5.0.
RESULTS: Thirty-four pts, with median age of 67 (range:49-90) years who received BLMF at the approved 2.5 mg/kg dose as their first infusion and completed at least one cycle were included. All patients were instructed to use preservative-free lubricant eye drops at least 4 times a day, starting with the initial infusion and continuing until the end of therapy, and avoid contact lenses. The median number of prior lines of therapy was 8 (range: 2-15). The median time to BLMF initiation from the diagnosis of MM was 7.5 (range: 1.3-19.7) years.
The median follow-up from initiation of BLMF was 7 [95% confidence interval (CI): 5.7-8.6] months, and the median number of BLMF doses administered was 2 (range: 1-6). Twenty-seven (79%) pts experienced ocular toxicity, comprising keratopathy [n=25 (74%)] and/or decreased visual acuity [n=21 (62%)]. Table 1 outlines the keratopathy-related details. Thirteen pts (38%) developed symptomatic xerophthalmia.
A clinically significant decrease in BCVA of equal or worse than 20/40 in the better-seeing eye was observed in 12 (35%) pts at a median of 1.7 (95%CI: 1.4-2.2) months of commencing BLMF. In 7 (58%) pts, it improved to better than 20/40 within a median of 3 (range: 0.7-4) months from the time of documentation of impaired BCVA following withholding treatment (n=5), with or without subsequent dose reduction or its permanent discontinuation (n=2).
Treatment was permanently discontinued in 5 (15%) pts after a median of 3 doses due to grade ≥2 keratopathy. It was withheld in 9 (26%) due to grade ≥2 keratopathy. Four (12%) pts required dose reduction due to keratopathy (Table 1). Of 14 pts in whom BLMF was held or permanently discontinued due to keratopathy, 10 (77%) had disease progression within a median of 1 month (range 0.4-2.5) following BLMF interruption.
Among 11 pts (32%) responded to BLMF, 45% developed grade 2 or higher keratopathy after the first dose compared to 13% of pts who were refractory to BLMF (n=23). The median duration of response was 4 (95%CI: 0.7-NR) months. Among responders, 2 pts (18%) had to permanently discontinue BLMF due to keratopathy, with subsequent progression from partial remission at 1.4 and 4.6 months following its discontinuation. Additionally, 73% of responders required dose withholding due to keratopathy and of those, 50% had evidence of disease progression within a median of 1.2 month (range: 0.7-1.7) following BLMF interruption.
DISCUSSION & CONCLUSIONS : Despite efficacy in pts with advanced MM, in routine practice, ocular toxicity of BLMF is a major challenge and a deterrent to its continuous use. While frequent ocular toxicity-related interruptions were observed at expected rates, permanent treatment discontinuation due to keratopathy was observed in a higher proportion of pts than that encountered in the DREAMM-2 trial. Larger prospective studies are warranted to accurately discern the effects of ocular toxicities on outcomes of pts treated with BLMF.
Figure 1 Figure 1.
Patel: Emmecell: Consultancy; GlaxoSmithKline: Consultancy; Senju Pharmaceuticals: Consultancy; Santen, Inc.: Consultancy. Kumar: Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Research Funding; Roche-Genentech: Consultancy, Research Funding; Carsgen: Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Amgen: Consultancy, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tenebio: Research Funding; Beigene: Consultancy; Oncopeptides: Consultancy; Antengene: Consultancy, Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bluebird Bio: Consultancy; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding. Ailawadhi: AbbVie: Consultancy; Xencor: Research Funding; Medimmune: Research Funding; Genentech: Consultancy; Ascentage: Research Funding; Takeda: Consultancy; Sanofi: Consultancy; Amgen: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Cellectar: Research Funding; BMS: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; GSK: Consultancy, Research Funding; Karyopharm: Consultancy; Beigene: Consultancy. Bergsagel: Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Patents & Royalties: human CRBN mouse; Genetech: Consultancy, Honoraria; Oncopeptides: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Gertz: Ionis Pharmaceuticals: Other: Advisory Board; Akcea Therapeutics, Alnylam Pharmaceuticals Inc, Prothena: Consultancy; Akcea Therapeutics, Ambry Genetics, Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Karyopharm Therapeutics, Pfizer Inc (to Institution), Sanofi Genzyme: Honoraria; Aurora Biopharma: Other: Stock option; AbbVie Inc, Celgene Corporation: Other: Data Safetly & Monitoring. Kapoor: Karyopharm: Consultancy; AbbVie: Research Funding; Sanofi: Research Funding; Takeda: Research Funding; Cellectar: Consultancy; BeiGene: Consultancy; Pharmacyclics: Consultancy; Sanofi: Consultancy; Amgen: Research Funding; Ichnos Sciences: Research Funding; Regeneron Pharmaceuticals: Research Funding; Glaxo SmithKline: Research Funding; Karyopharm: Research Funding.
| v2 |
2016-04-15T09:12:14.267Z | 2007-04-01T00:00:00.000Z | 60431661 | s2ag/train | Multimedia Signal Processing: Theory and Applications in Speech, Music and Communications
Preface. Acknowledgement. Symbols. Abbreviations. Part I Basic Digital Signal Processing. 1 Introduction. 1.1 Signals and Information. 1.2 Signal Processing Methods. 1.3 Applications of Digital Signal Processing. 1.4 Summary. 2 Fourier Analysis and Synthesis. 2.1 Introduction. 2.2 Fourier Series: Representation of Periodic Signals. 2.3 Fourier Transform: Representation of Nonperiodic Signals. 2.4 Discrete Fourier Transform. 2.5 Short-Time Fourier Transform. 2.6 Fast Fourier Transform (FFT). 2.7 2-D Discrete Fourier Transform (2-D DFT). 2.8 Discrete Cosine Transform (DCT). 2.9 Some Applications of the Fourier Transform. 2.10 Summary. 3 z-Transform. 3.1 Introduction. 3.2 Derivation of the z-Transform. 3.3 The z-Plane and the Unit Circle. 3.4 Properties of z-Transform. 3.5 z-Transfer Function, Poles (Resonance) and Zeros (Anti-resonance). 3.6 z-Transform of Analysis of Exponential Transient Signals. 3.7 Inverse z-Transform. 3.8 Summary. 4 Digital Filters. 4.1 Introduction. 4.2 Linear Time-Invariant Digital Filters. 4.3 Recursive and Non-Recursive Filters. 4.4 Filtering Operation: Sum of Vector Products, A Comparison of Convolution and Correlation. 4.5 Filter Structures: Direct, Cascade and Parallel Forms. 4.6 Linear Phase FIR Filters. 4.7 Design of Digital FIR Filter-banks. 4.8 Quadrature Mirror Sub-band Filters. 4.9 Design of Infinite Impulse Response (IIR) Filters by Pole-zero Placements. 4.10 Issues in the Design and Implementation of a Digital Filter. 4.11 Summary. 5 Sampling and Quantisation. 5.1 Introduction. 5.2 Sampling a Continuous-Time Signal. 5.3 Quantisation. 5.4 Sampling Rate Conversion: Interpolation and Decimation. 5.5 Summary. Part II Model-Based Signal Processing. 6 Information Theory and Probability Models. 6.1 Introduction: Probability and Information Models. 6.2 Random Processes. 6.3 Probability Models of Random Signals. 6.4 Information Models. 6.5 Stationary and Non-Stationary Random Processes. 6.6 Statistics (Expected Values) of a Random Process. 6.7 Some Useful Practical Classes of Random Processes. 6.8 Transformation of a Random Process. 6.9 Search Engines: Citation Ranking. 6.10 Summary. 7 Bayesian Inference. 7.1 Bayesian Estimation Theory: Basic Definitions. 7.2 Bayesian Estimation. 7.3 Expectation Maximisation Method. 7.4 Cramer-Rao Bound on the Minimum Estimator Variance. 7.5 Design of Gaussian Mixture Models (GMM). 7.6 Bayesian Classification. 7.7 Modelling the Space of a Random Process. 7.8 Summary. 8 Least Square Error, Wiener-Kolmogorov Filters. 8.1 Least Square Error Estimation: Wiener-Kolmogorov Filter. 8.2 Block-Data Formulation of the Wiener Filter. 8.3 Interpretation of Wiener Filter as Projection in Vector Space. 8.4 Analysis of the Least Mean Square Error Signal. 8.5 Formulation of Wiener Filters in the Frequency Domain. 8.6 Some Applications of Wiener Filters. 8.7 Implementation of Wiener Filters. 8.8 Summary. 9 Adaptive Filters: Kalman, RLS, LMS. 9.1 Introduction. 9.2 State-Space Kalman Filters. 9.3 Sample Adaptive Filters. 9.4 Recursive Least Square (RLS) Adaptive Filters. 9.5 The Steepest-Descent Method. 9.6 LMS Filter. 9.7 Summary. 10 Linear Prediction Models. 10.1 Linear Prediction Coding. 10.2 Forward, Backward and Lattice Predictors. 10.3 Short-Term and Long-Term Predictors. 10.4 MAP Estimation of Predictor Coefficients. 10.5 Formant-Tracking LP Models. 10.6 Sub-Band Linear Prediction Model. 10.7 Signal Restoration Using Linear Prediction Models. 10.8 Summary. 11 Hidden Markov Models. 11.1 Statistical Models for Non-Stationary Processes. 11.2 Hidden Markov Models. 11.3 Training Hidden Markov Models. 11.4 Decoding Signals Using Hidden Markov Models. 11.5 HMM in DNA and Protein Sequences. 11.6 HMMs for Modelling Speech and Noise. 11.7 Summary. 12 Eigenvector Analysis, Principal Component Analysis and Independent Component Analysis. 12.1 Introduction - Linear Systems and Eigenanalysis. 12.2 Eigenvectors and Eigenvalues. 12.3 Principal Component Analysis (PCA). 12.4 Independent Component Analysis. 12.5 Summary. Part III Applications of Digital Signal Processing to Speech, Music and Telecommunications. 13 Music Signal Processing and Auditory Perception. 13.1 Introduction. 13.2 Musical Notes, Intervals and Scales. 13.3 Musical Instruments. 13.4 Review of Basic Physics of Sounds. 13.5 Music Signal Features and Models. 13.6 Anatomy of the Ear and the Hearing Process. 13.7 Psychoacoustics of Hearing. 13.8 Music Coding (Compression). 13.9 High Quality Audio Coding: MPEG Audio Layer-3 (MP3). 13.10 Stereo Music Coding. 13.11 Summary. 14 Speech Processing. 14.1 Speech Communication. 14.2 Acoustic Theory of Speech: The Source-filter Model. 14.3 Speech Models and Features. 14.4 Linear Prediction Models of Speech. 14.5 Harmonic Plus Noise Model of Speech. 14.6 Fundamental Frequency (Pitch) Information. 14.7 Speech Coding. 14.8 Speech Recognition. 14.9 Summary. 15 Speech Enhancement. 15.1 Introduction. 15.2 Single-Input Speech Enhancement Methods. 15.3 Speech Bandwidth Extension - Spectral Extrapolation. 15.4 Interpolation of Lost Speech Segments - Packet Loss Concealment. 15.5 Multi-Input Speech Enhancement Methods. 15.6 Speech Distortion Measurements. 15.7 Summary. 16 Echo Cancellation. 16.1 Introduction: Acoustic and Hybrid Echo. 16.2 Telephone Line Hybrid Echo. 16.3 Hybrid (Telephone Line) Echo Suppression. 16.4 Adaptive Echo Cancellation. 16.5 Acoustic Echo. 16.6 Sub-Band Acoustic Echo Cancellation. 16.7 Echo Cancellation with Linear Prediction Pre-whitening. 16.8 Multi-Input Multi-Output Echo Cancellation. 16.9 Summary. 17 Channel Equalisation and Blind Deconvolution. 17.1 Introduction. 17.2 Blind Equalisation Using Channel Input Power Spectrum. 17.3 Equalisation Based on Linear Prediction Models. 17.4 Bayesian Blind Deconvolution and Equalisation. 17.5 Blind Equalisation for Digital Communication Channels. 17.6 Equalisation Based on Higher-Order Statistics. 17.7 Summary. 18 Signal Processing in Mobile Communication. 18.1 Introduction to Cellular Communication. 18.2 Communication Signal Processing in Mobile Systems. 18.3 Capacity, Noise, and Spectral Efficiency. 18.4 Multi-path and Fading in Mobile Communication. 18.5 Smart Antennas - Space-Time Signal Processing. 18.6 Summary. Index. | v2 |
2019-06-30T03:50:26.638Z | 2012-01-01T00:00:00.000Z | 195821751 | s2ag/train | Effect of Mineral Filler and Additives Materials on the Adhesion Properties between Asphalt and Aggregate
Numerous attempts to study adhesion properties between the coarse aggregate and asphalt and then study effect of additives materials and filler aggregate (fine) by using three types of pure asphalts (according to penetration grade 40/50, 60/70 and 85/100), which obtained from Durah refinery. Low density Polyethylene as additive material in three percent (0%, 2% and 4%) is used too, and limestone filler in two percent (0 % and 4%) are made. The surface tension stress theory between asphalt, aggregate and water is applied at assuming the aggregate which used are hydrophilic type (explain this type as glass plane plate). From the results are obtained, the asphalt viscosity improved by using additives materials (increasing surface tension force between asphalt and aggregate (adhesion forces) greater than using mineral filler materials, then increase ability of mixture asphalt to resist stripping. Keyword: Adhesion Properties, Aggregate, Additives Materials, Filler Materials. ةصلاخلا : يل لياديع تلاوباحه ثلذب ةاسار داواولا زيذباج ةاسارد ناذ ياهو ثلفاسلااو ياسلالا مباكزلا تباتيتا يياب قاصلاحلا اواو صئباصخ ( ا( تب درياج خلارابو لرويالا ىفصه يه ثلفساا مايلاحسبب كلذو )ةئلبولا داوولا ( نعبٌلا مبكزلا و ةفبضولا 04 / 04 و 04 / 04 و 50 / 044 ( ا( ا ً خلارابو ةفباضه لدباوك ةافبرفلا لااوالا ييالذا لوالوتلا مايلاحساو ) 4 و % 2 و % 0 لرواٌلا مايلاحاساو )% ( باو( ييحتا ٌبو ةائلبه لدبوك ةئفطولا 4 و % 0 ىالعو باولاو مباكزلاو ثلفاسلاا يياب حطا لا ياسلا تادباداا ةادزرً قايتطجو ) % ةدوحا ه ةاياباس ةا طزب مباكزلا رايروج ةايًبفها زاف ثلفاسلاا ةا وشل ىباب ا لاً داحتلا باديلا راصوج احلا تئباحٌلا للااخ ياه . اواو لدبادس ( مباكزلاو ثلفاسلاا يياب حطا لا ياسلا لواو لدبادس لباحلببو ةفبضولا لدبولا ةت ً لدبدشبو تبفبضولا مايلاحسبب ثٌ حج لا ةايلببو لدبادس لبحلببو ةئلبولا داوولا مايلاحسا يه زركا لروصب )بودٌيب قصلاحلا يياب كاففحلا و لباصفًلاا ةاهوبزول ةيحلفاسلاا ةاطللا .بدجبًوفه Introduction : The durability of asphalt paving mixtures is mainly affected by securing and maintaining the adhesion between the asphalt and the aggregates in the presences of water. The loss of adhesion in the mixture (stripping) induces instability and promotes failure conditions in the asphalts pavement. This condition can be observed in asphalt layers using hydrophilic aggregates. Petersen et. al.(1994); in some locations only hydrophilic aggregates are available. A certain modification to ensure a durable adhesion must be made. Such modifications are usually made in two ways: 1) Modification of the adhesion properties of the asphalt by tensioactive adhesions. 2) Modification of the surface properties of the aggregates by a treatment with a cement-water solution or a hydrated lime-water solution. Of the two, the first modification is more useful in asphalt paving technology. However, high quality additives are quite expensive for the mass production of asphalt mixtures. A solution to this problem can be obtained by considering the influence of natural mixture ingredients, such as filler, on the adhesion between the aggregate and the asphalt in the presence of water. This paper describes a mechanism for creating adhesion between the aggregate and the asphalt , using certain types of fillers. Quantitative methods are used for evaluating the adhesion and for investigating the influence of the filler arch. 2008 Journal of Kerbala University , Vol. 6 No.1 Scientific .M 202 Adhesion Phenomenon in Aggregate – Asphalt Systems. The adhesion in the interface between aggregate and asphalt can be defined as the property of the asphalt to adhere to the aggregate surface, and to maintain this condition in the presence of water. The adhesion phenomenon and water effects are complex. Many theories have been expressed regarding the water –resistance of asphalt –coated aggregates. Rice (1977); classifies the theory of adhesion into three concepts. 1) The Chemical Reaction Concept. When aggregates are wetted by the asphalt, selective adsorption occurs the interface, followed by a chemical reaction between the adsorbed material and the constituents of the solid phase. Under this condition the acidic components of the bituminous material chemical react with the basic aggregate mineral to form water-insoluble compounds. 2) The Mechanical Concept. The surface texture of the aggregate surface is the main factor, which affects mechanical adhesion factors such as the size of individual crystal faces, aggregate porosity, adsorption, and surface coating. 3) The Surface Energy Concept. Petersen (1994) ; adhesion results from the interfacial energy relationship at aggregate-bitumen water-air-interface. In This regard, the mechanisms of spreading, wetting, and stripping may be mentioned. Generally when a liquid and a solid are brought to gather, the liquid may a) Neither spread on nor wet the solid surface. b) Spread on the surface without wetting, c) Spread on and wet the surface Among these three theories, the interfacial energy concept is the most widely accepted. It provides a physical basis for a quantitative expression and evaluation of the adhesion and the effect of water. This expression can be obtained by the equilibrium state of the interfacial forces at the mutual contact point of the aggregate, asphalt and water. Figure (1) describes the Interfacial forces acting at the mutual contact point (M) of a asphalt drop touching an aggregate surface in the presence of water. The equilibrium conditions of M are expressed as follows: * wa Cos bw ab ......................................................................................(1) Figure (1): Interfacial Forces acting at the Mutual Contact Point of a Bitumen Drop. Ishai, 1977 The adhesion potential can be expressed, using the angle of adhesion (θ) as follows: bw ab Cos wa .....................................................................................(2) where: σwa = Interfacial tension between water and aggregate. σab = Interfacial tension between aggregate and binder. σbw = Interfacial tension between binder and water. θ = Angle of adhesion. When Cos θ > 0 (It is the spreading stage as shown in Figure (1-a). Bitumen Water Aggregat e M σwa σbw | v2 |
2018-12-05T06:12:34.549Z | 2006-01-01T00:00:00.000Z | 119022211 | s2ag/train | New and confirmed cepheid variables found in the NSVS and ASAS-3 databases
A search for variable stars in the NSVS and ASAS-3 databases resulted in the discovery or confirmation of seven pulsating variables of the CW or DCEP types. Methodology The public data release from the Northern Sky Variability Survey (NSVS; Wozniak et al., 2004) was search for variable stars using the SQL interface available from the Skydot website (http://skydot.lanl.gov/nsvs/nsvs.php). Stars were selected on the basis of a number of statistical criteria as explained in Otero et al. (2004). The stars needed to have at least 80 data points, and a significantly larger standard deviation compared to the average value for their magnitude and the skewness calculated from a star's magnitudes had to be smaller than 1 (making it easier to find stars that spend more time at minimum than at maximum). Standard flagged data and data with the APINCOMPL mask set (Wozniak et al., 2004) were not taken into account during these calculations. Also data for stars in the New Catalogue of Suspected Variable Stars (NSV) (Kukarkin and Kholopov, 1982) and its supplement (NSVS) (Kazarovetz et al., 1998) were checked against the ASAS-3 database (Pojmanski, 2002) to confirm their suspected variability. The cepheid nature of two of the stars in this paper (NSV 3571 and NSV 9046) was discovered that way. Periods were found with AVE (Barberá, 1996) and then refined using Microsoft Excel. Elements were determined from the folded ligthcurves using all the available data combined as a single dataset. The time span of the observations varies depending on the star, but NSVS observations were taken in 1999 and 2000 while ASAS-3 data span from the year 2000 to the present. The accuracy of the elements given depends on the quality and quantity of the observations. The formula given in Lenz and Breger (2005) was adopted as a first step to determine the errors for the periods found but the resulting values were far too optimistic. The original photometric errors were underestimated by a factor of two or three in the original publications as became evident in the folded lightcurves. The total scatter in magnitudes was used instead of the magnitude uncertainty: (sqrt(6/N)*scatter on mag/semi-amplitude/pi/T)*P^2 where N = number of data points; T = time span of the observations and P = period. The new error values for all the stars were empirically checked against the phase plots and were more realistic. This seems to be a useful way to derive errors for datasets containing individual data points from different nights and not from a single night lightcurve. Epochs were also determined from the phase plots and are uncertain for stars with flat maxima. The aim of this paper is to present and classify these stars. Further study will help improve these provisional elements. Results Table 1 gives positions and cross-identifications for all the variables. The first column gives the star’s number in this paper. The following columns give the ASAS or NSVS identifier; the GSC number; a GCVS name if available and the star's position according to the NOMAD catalogue (Zacharias et al., 2005). OPEN EUROPEAN JOURNAL ON VARIABLE STARS December 2006 http://var.astro.cz/oejv ISSN 1801-5964 2 Table 1 – Positions and cross-identifications for the seven cepheids studied Star Name # ASAS/NSVS ID GSC ID GCVS ID NOMAD position (J2000.0) 1 NSVS 71579 GSC 4621-0688 New 04 56 53.16 +85 28 23.4 2 NSVS 6848896 GSC 2388-0772 New 05 03 29.65 +31 09 41.7 3 ASAS 072315-2943.3 GSC 6549-2823 NSV 3571 07 23 15.15 -29 43 20.8 4 NSVS 103348 GSC 4547-1890 New 09 24 14.77 +81 13 28.5 5 ASAS 173122-1743.7 NSV 9046 17 31 21.88 -17 43 39.5 6 ASAS 192007+1247.7 GSC 1050-0361 New 19 20 06.95 +12 47 43.0 7 NSVS 141961 GSC 4613-1113 New 23 05 59.02 +81 10 42.4 Table 2 lists the elements and data for the seven cepheids found. The first column gives the star’s number in this paper. The other columns give the brightness range of the variable; the passband of the observations (V for ASAS-V magnitudes and R1 for ROTSE1 magnitudes); the variability type; the period; the epoch of maximum light derived from the complete dataset; the number of observations used for the analysis; the time span of the observations and the J-K color from the 2MASS catalogue. Table 2 – Elements and data for the seven cepheids studied Magnitude range # Max Min Filt Type Period (days) Epoch (HJD) Number Obs. Time span (days) + years of obs. J-K 1 12.7 13.3 R1 CWA 20.95(9) 2451353.8(4) 81 138 (1999) 0.80 2 11.60 12.10 R1 CWA 16.98(3) 2451444.3(9) 237 233 (1999-2000) 0.91 3 12.5 13.25 V DCEP 3.3363(2) 2452496.49(4) 248 2023 (2000-2006) 0.48 4 14.05 14.9 R1 CWB 1.8118(3) 2451449.82(3) 637 359 (1999-2000) 0.44 5 13.35 14.6 V CWB 1.17156(2) 2452463.615(9) 169 2323 (1999-2005) 0.54 6 10.21 10.60 V CW 8.6274(6) 2452915.6(6) 231 1848 (1999-2004) 0.85 7 12.45 12.7 R1 CWA 45.35(15) 2451379(1) 682 341 (1999-2000) 0.77 Notes and other cross-identifications for individual stars: #1 – 2MASS J04565325+8528232 #2 – 1RXS J050328.9+310955 = UCAC2 42717226 = 2MASS J05032964+3109416 #3 – AN 845.1936 = HV 08082 = 2MASS J07231515-2943208 = UCAC2 19338235 #4 – NSVS 844618 = NSVS 760484 = NSVS 722462 = 2MASS J09241476+8113284 #5 – NSVS 16594505 = HV 03958 = 2MASS J17312188-1743394 = UCAC2 25125897 #6 – BD+12 3884 = MSX6C G047.5638-00.4203 = NSVS 11164699 = 2MASS J19200694+1247429 = UCAC2 36348612. Classified as DCEP-FU in the ASAS catalogue with a period of 8.627245 d. #7 – NSVS 1422651 = 2MASS J23055895+8110421 OPEN EUROPEAN JOURNAL ON VARIABLE STARS December 2006 http://var.astro.cz/oejv ISSN 1801-5964 3 Figures 1 to 7 show the lightcurves of all the cepheids studied in this paper. GSC 4621-0688 12.4 12.6 12.8 13.0 13.2 13.4 13.6 -0.5 -0.25 0 0.25 0.5 0.75 1 Phase R O T S E 1 NSVS GSC 2388-0772 11.4 | v2 |
2018-04-03T02:31:29.442Z | 2000-12-01T00:00:00.000Z | 21482271 | s2ag/train | Publication Rights for Sequence Data Producers
Lee Rowen and colleagues highlight in their Policy Forum (15 Sept., p. [1881][1]) their concerns with the publication of articles containing information derived from publicly available sequence data that have not yet been published in peer-reviewed primary papers. They refer to two review articles ([1][2], [2][3]) on the murine major histocompatibility complex (MHC) that were published before any primary papers from the data producers. In both cases, great care was taken to ensure that the source of primary sequence data was acknowledged in accordance with the guidelines set out by the hosting databases, the labs that produced the primary sequence were credited, and the European Molecular Biology Laboratory/GenBank accession numbers were quoted. It should be noted that Rowen's lab was one of those involved in the primary sequencing efforts, and the decision to publish was taken after a period of consultation with all those involved, including an offer of coauthorship. Although rejected, this latter offer is in line with the “agreeable options” for etiquette-led protocols on use of third-party database entries or annotations.
At present, there is no worldwide policy governing the use of sequence data publicly available on genome databases. A major factor that was taken into consideration in the cases referred to above was the length of time that the primary sequence had been available in the public domain. We recognize that the value of work done by labs that contribute to publicly available genome data goes far beyond their skill in identifying and sequencing genes, and that they deserve priority in bringing the wider impact of these analyses to the primary literature. For the two MHC review papers referred to here, however, most of the primary sequences were deposited in the databases before the end of 1998. Sufficient time had therefore elapsed for the sequence producers to prepare, submit, and publish primary papers.
We welcome the guidelines suggested by Rowen and colleagues in their Policy Forum. However, as they themselves admit, there will be instances where data producers do not publish their analyses within a reasonable time frame and that disputes will occur. They suggest that the research community develop a policy with guidelines about the kinds of analyses for which data producers can claim priority. Additionally, we would argue for a “statute of limitations” on such priority that would define a “reasonable time frame” in which sequence producers can publish their analyses of primary data. After this set time frame—say, a year after public release of the sequence—third parties would have the right to use the data freely.
1. [↵][4]1. R.J. N. Allcock 2. et al.
, Immunol. Today 21, 328 (2000).
[OpenUrl][5][CrossRef][6][PubMed][7][Web of Science][8]
2. [↵][9]1. C. Y. Yu 2. et al.
, Immunol. Today 21, 320 (2000).
[OpenUrl][10][CrossRef][11][PubMed][12][Web of Science][13]
# Response {#article-title-2}
In our Policy Forum, we argued that the producers of freely available sequence data should have the right to define the scope of the primary paper they intend to write once the data-gathering effort is completed. Our discussion was prompted by the publication of the two review articles to which Bell, the editor of Immunology Today , refers. Although she is correct in stating that the data had been released for a considerable period of time, Bell does not address a key point of dissension, namely that the sequencing projects that were reviewed in the articles were not finished. In the case of Yu et al .'s review, it consisted of a comprehensive analysis of half of the human and mouse MHC class III region, an analysis that relied heavily on the annotation we provided with the data entries. The review was written while we were still sequencing the other half of the region. In the case of the review by Allcock et al ., it included a comprehensive map and gene table for the mouse MHC region, with a clear indication that the sequence of the class I region was not finished. The authors of this review preempted and ignored the publication plans of three laboratories that are collaborating on the completion of the mouse MHC locus.
There are three important issues at stake. First, we do not believe that reviews should be written on unpublished data and analyses that have not gone through the peer-review process. Preparation for publication and peer review give the data producers a chance to correct inadvertent errors in the publicly released data. Second, we do not sanction the preempting of obvious primary publications by third parties when permission to do so has been neither sought nor granted. We argue instead that publicly released data and analyses should be given respect analogous to that given to personal communications. Finally, projects such as the mouse MHC locus research are of sufficient complexity that the time frame for mapping, sequencing, and analyzing the data can be long, especially if funding resources are limited. With an immediate data release policy, some of the data will be available well before completion of the entire project. Thus, imposition of a time frame is only fair to data producers if the clock begins to tick when the data-gathering phase is done.
In sum, we endorse the policy of open data release, and we encourage third parties to make use of the data to further research. However, we maintain that the right to publish a peer-reviewed, well-defined landmark or comprehensive analysis of the primary data should be reserved for the data producers. Precedents set now will define the norms and standard practices for the future. Thus, we urge journal editors to exercise fair and reasonable judgment vis-a-vis third-party publications.
[1]: /lookup/doi/10.1126/science.289.5486.1881
[2]: #ref-1
[3]: #ref-2
[4]: #xref-ref-1-1 "View reference 1 in text"
[5]: {openurl}?query=rft.jtitle%253DImmunology%2Btoday%26rft.stitle%253DImmunol%2BToday%26rft.aulast%253DAllcock%26rft.auinit1%253DR.%2BJ.%26rft.volume%253D21%26rft.issue%253D7%26rft.spage%253D328%26rft.epage%253D332%26rft.atitle%253DThe%2Bmouse%2Bas%2Ba%2Bmodel%2Bfor%2Bthe%2Beffects%2Bof%2BMHC%2Bgenes%2Bon%2Bhuman%2Bdisease.%26rft_id%253Dinfo%253Adoi%252F10.1016%252FS0167-5699%252800%252901654-6%26rft_id%253Dinfo%253Apmid%252F10871872%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx
[6]: /lookup/external-ref?access_num=10.1016/S0167-5699(00)01654-6&link_type=DOI
[7]: /lookup/external-ref?access_num=10871872&link_type=MED&atom=%2Fsci%2F290%2F5497%2F1696.2.atom
[8]: /lookup/external-ref?access_num=000088024700006&link_type=ISI
[9]: #xref-ref-2-1 "View reference 2 in text"
[10]: {openurl}?query=rft.jtitle%253DImmunology%2Btoday%26rft.stitle%253DImmunol%2BToday%26rft.aulast%253DYung%2BYu%26rft.auinit1%253DC.%26rft.volume%253D21%26rft.issue%253D7%26rft.spage%253D320%26rft.epage%253D328%26rft.atitle%253DThe%2Bhuman%2Band%2Bmouse%2BMHC%2Bclass%2BIII%2Bregion%253A%2Ba%2Bparade%2Bof%2B21%2Bgenes%2Bat%2Bthe%2Bcentromeric%2Bsegment.%26rft_id%253Dinfo%253Adoi%252F10.1016%252FS0167-5699%252800%252901664-9%26rft_id%253Dinfo%253Apmid%252F10871871%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx
[11]: /lookup/external-ref?access_num=10.1016/S0167-5699(00)01664-9&link_type=DOI
[12]: /lookup/external-ref?access_num=10871871&link_type=MED&atom=%2Fsci%2F290%2F5497%2F1696.2.atom
[13]: /lookup/external-ref?access_num=000088024700005&link_type=ISI | v2 |
2014-10-01T00:00:00.000Z | 2011-01-01T00:00:00.000Z | 18523331 | s2ag/train | Integrating corporate innovation communities: the role of structure and culture
A fundamental weakness of current research on corporate innovation communities is that knowledge about how to alter them for innovation endeavors remains vague. To help facilitate this gap, we analyze the influence of organizational contexts on innovation activities and outcomes from a contingency theory perspective. From the analysis of multiple in-depth case studies, four types of organizational integration as triggers for distinct sets of innovation activities as well as enablers for divergent sets of innovation outcomes have been identified. Based on our findings a taxonomy of organizational integration of corporate innovation communities is developed. INFORMATIK 2011 Informatik schafft Communities 41. Jahrestagung der Gesellschaft für Informatik , 4.-7.10.2011, Berlin www.informatik2011.de erschienen im Tagungsband der INFORMATIK 2011 Lecture Notes in Informatics, Band P192 ISBN 978-3-88579-286-4 weitere Artikel online: http://informatik2011.de/519.html 1. Setting the Stage Organizations increasingly rely on corporate innovation communities as a means to unleash the innovative potential of their employees. These communities are typically (but not necessarily) characterized by mutual collaboration in online setting to search, select and develop innovations. They are mostly supported by social software and bound to organizational contexts in which they are integrated [AR08][BH02]. However, organizational integration as a pre-condition for innovation to occur [AR08] often remains limited due to missing understanding on its effects on innovation activities and outcomes. Thus, the present article illuminates the question ‘how does organizational integration influence corporate innovation communities?’. To help facilitate this endeavor we apply contingency theory [Ga73] [BS94] [LL67]. It builds on the premise that organizational contexts frame individuals’ activities and outcomes [Gl84] [BS94] [LL67]. Specifically, several scholars emphasize the crucial role of supporting cultural and structural contingencies for innovation activities and outcomes to occur [BS94][LL67][BK04]. Hence, contingency theory offers an instrument to determine the antecedents of organizational contexts on corporate innovation communities. 2. Theoretical Perspectives Contingency theory underlines that contingency, i.e. structural conditions of a given organization [BS94][LL67], explain antecedents determining particular activities and outcomes of employees [Gl84][BS94][LL67]. Whereas contingencies may relate to the nature of tasks or teams [Gl84], this study focuses on two contingencies frequently highlighted to enhance innovation activities and outcomes in general: organizational culture and structure [BK04] [BS94][LL67]. Conclusively, individuals’ innovation-related activities depend on contingencies in which they are integrated. Community researchers stress the importance of organizational integration, such as cultural and structural integration, for corporate communities to flourish [Ko05][Br01][KB01]. First, cultural integration comprises sets of norms, values, beliefs, attitudes and procedures [De84] that value activities of organizational communities [KB01]. Specifically, innovation activities are fostered by cultures that embrace proactivity, creativity and risk taking while relying on open and informal interactions [An01][CF92][GS01][GW90][Sm98]. Second, structural integration includes amalgamation of administrative procedures – e.g., goal system integration, provision of resources, integration of performance appraisal systems etc. [Br01][VW07][LC03][GZ99]. For instance, several empirical studies show that financial resources have to be provided to ensure efficiency of community activities [Br01] [LC03] [VW07]. 1 For a more nuanced discussion with a clear management focus, see also Bansemir, B., Neyer, A-K., Möslein, K. M.: Anchoring Corporate Innovation Communities in Organizations: A taxonomy. International Journal of Knowledge-Based Organizations, (in print). INFORMATIK 2011 Informatik schafft Communities 41. Jahrestagung der Gesellschaft für Informatik , 4.-7.10.2011, Berlin www.informatik2011.de erschienen im Tagungsband der INFORMATIK 2011 Lecture Notes in Informatics, Band P192 ISBN 978-3-88579-286-4 weitere Artikel online: http://informatik2011.de/519.html Although it is well-known that adequate sets of contingencies support community viability at large via cultural and structural integration, insights concerning the influence of these contingencies on innovation activities and outcomes remain rather limited and often speculative. 3. Research Approach To answer our research question, multiple case study method was applied [Ei89][Yi03] including twelve in-depth case studies from varying industry sectors. All of the participating firms in knowledge intensive industries typically applied a wide range of innovation methods and possessed versatile practical experiences about innovation supportive contexts. In sum, 45 in-depth interviews were conducted, using a semistructured interview guideline. Each interview lasted from 45 to 120 minutes, averaging 90 minutes. Usually, at least two interviews per case were conducted and recorded. Besides interviews, data were enriched by extensive documentary analysis. Data analysis followed Mayring’ [Ma02] five step research procedure, including determination, explication and revision of categories, summative check and interpretation. Accordingly, transcripts, notes from meetings and extensive documentary were analyzed following these typical content analysis procedures [Ma02][MH94][RB00]. To achieve high levels of credibility and to reduce potential post hoc response bias, interviewees were explicitly asked to explain their statements in terms of stories and individual experiences [Go92]. Interviews following a semi-structured guideline lasted from 45 to 120 minutes, averaging 90 minutes. All interviewees held an academic degree (around 30 % PhDs). Usually, at least two interviews per case were conducted. Altogether, 46 interviews were conduct. Further information about organizational affiliation, professions of interviewees etc. refer to table 1. Case Employees Professions of interviewees Interviews Business 50.000100.000 Innovation & strategic managers 9 Employment agency 15.00030.000 Innovation, strategic, project & human resource managers 8 Service provider 5.00015.000 Executive officer, innovation, project, strategic & human resource managers 8 Accounting / Auditing > 100.000 Innovation & strategic managers 2 Communication service > 100.000 Innovation managers 2 Airline 50.000100.000 Innovation & project managers, engineers 5 Automotive manufacturer 50.000100.000 Innovation managers 2 Semiconductor 5.00015.000 Project & innovation managers, mechanical engineer 3 High-tech manufacturer < 5.000 Strategic manager & consultant 2 Innovation Consulting < 5.000 Strategic manager 1 IT solutions INFORMATIK 2011 Informatik schafft Communities 41. Jahrestagung der Gesellschaft für Informatik , 4.-7.10.2011, Berlin www.informatik2011.de erschienen im Tagungsband der INFORMATIK 2011 Lecture Notes in Informatics, Band P192 ISBN 978-3-88579-286-4 weitere Artikel online: http://informatik2011.de/519.html < 5.000 Strategic manager & software engineer 2 IT services < 5.000 Marketing manager & consultant 2 Innovation solutions Table 1: Case study companies. | v2 |
2021-11-26T16:04:20.096Z | 2021-11-05T00:00:00.000Z | 244644451 | s2ag/train | The Omission of High-Dose Cytarabine during Consolidation Therapy of Ph-Positive ALL Patients Treated with Nilotinib and Low-Intensity Chemotherapy Results in an Increased Risk of Relapses Despite Non-Inferior Levels of Late BCR-ABL1 MRD Response. First Results of the Randomized Graaph-2014 Study
On behalf of the GRAALL group.
Introduction. Tyrosine kinase inhibitors (TKIs) have dramatically improved the outcome of patients diagnosed with Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL). In a previous randomized trial (GRAAPH-2005; Chalandon Y., Blood 2015), our group demonstrated that anthracycline and cyclophosphamide could be safely omitted during the first Hyper-CVAD chemotherapy cycle when combined to imatinib. In the present GRAAPH-2014 trial, we investigated whether the use of nilotinib, a 2 nd generation TKI, would allow further decreasing chemotherapy intensity through the omission of high-dose cytarabine (HD-AraC) during consolidation cycles 2 and 4.
Methods. From March 2016, patients aged 18-60 years old were randomized frontline to receive 4 cycles (1=3, 2=4) of chemotherapy combined with continuous nilotinib 400 mg bid. Cycle 1 and 3 were similar in both arms, identical to the less-intensive first cycle of the previous GRAAPH-2005 trial with weekly vincristine and dexamethasone and nilotinib instead of imatinib. Cycle 2 and 4 differed between control arm A (MTX 1 g/sqm over 24h, HD-AraC 3 g/sqm/12h for 2 days) and experimental arm B (MTX 1 g/sqm over 24h only). Marrow minimal residual disease (MRD) was assessed by both BCR-ABL1 and IG-TCR qPCR after each cycle (MRD1-4). Patients in complete remission (CR) after cycle 4 were eligible to receive allogeneic stem cell transplant (alloSCT). Non allografted patients had the option to receive autologous SCT (autoSCT) if a major molecular response (MMolR) (MRD4 BCR-ABL1 <0.1%) was achieved. AlloSCT and autoSCT were followed by a 2-year imatinib maintenance. The randomization was stratified on age (≤40y, >40y) and BCR-ABL1 breakpoint region (M/m-bcr). MMolR rate at MRD4 was the primary endpoint of this non-inferiority study, with a margin set at 0.15. In February 2019, the study DSMB decided to stop the randomizations after an unplanned analysis demonstrating a significant excess of relapse in arm B (without HD-AraC). An intention-to-treat analysis is provided. All patients gave informed consent. The study is registered at EudraCT under the number: 2014-002146-44.
Results. A total of 156 patients were randomized (77 in arm A, and 79 in arm B). Median age was 47.1 years old (range 18.1-59.9). One-hundred and ten patients had the m-bcr (70.5%) and 46 (29.5%) the M-bcr. An IKZF1 intragenic deletion was found in 87/153 (56.9%). Median follow-up was 2.8 years (95%CI 2.6-3.1). All evaluable patients reached CR after a maximum of two cycles. Three patients died during cycle 1 (2 in arm A, 1 in arm B), and 2 during cycle 2 (1 per arm). Most patients received the 4 scheduled cycles (n=143, 91,7%). AlloSCT was performed in 91 patients (58.3%), whereas 41 patients received an autoSCT (26.3%) with no difference in allo/autoSCT rates between arms. A non-inferiority in late MRD response (MRD4) between the two arms was observed (primary endpoint). MMolR was reached in 55/75 (73.3%) and 61/78 (78.2%) of CR patients in arm A and B, respectively, with an estimated 95% CI of difference of -11% to +16% (-9.2% to +20.8% in the ITT analysis treating missing data as failures). At 3 years, overall survival (OS) was 86.0% in arm A versus 74.2% in arm B (p=.08, Figure A). Progression-free survival (PFS) was 79.6% in arm A versus 57.2% in arm B (p=.008, Figure B). Thirty-one patients experienced hematological relapse (8 in arm A and 23 in arm B). Twenty-height out of 31 relapsed patients were tested for the acquisition of BCR-ABL1 mutations, 20/28 (71%) had at least one mutation and 10/28 (36%) had a T315I mutation. At 3 years, the cumulative incidence of relapse (CIR) was 21.3%, significantly higher in arm B than in arm A (30.8% vs 10.6%, p=.007). When analyzing the CIR considering alloSCT as a competing event for relapse, a significant higher CIR was still observed in arm B as compared to arm A (Figure C).
Conclusion. Four cycles of the combined administration of nilotinib and chemotherapy is very efficient for bridging younger adults with Ph-positive ALL to SCT. However, omitting HD-AraC is associated with a higher relapse incidence despite non-inferior levels of BCR-ABL1 MRD4.
Figure 1 Figure 1.
Rousselot: Incyte, Pfizer: Consultancy, Research Funding. Chalandon: Incyte, BMS, Pfizer, Abbie, MSD, Roche, Novartis, Gilead, Amgen, Jazz, Astra Zenec: Other: Travel EXpenses, Accomodation; Incyte: Speakers Bureau; Incyte, BMS, Pfizer, Abbie, MSD, Roche, Novartis, Amgen: Other: Advisory Board. Huguet: Novartis: Other: Advisor; Jazz Pharmaceuticals: Other: Advisor; Celgene: Other: Advisor; BMS: Other: Advisor; Amgen: Other: Advisor; Pfizer: Other: Advisor. Vincent: Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Vey: Amgen: Honoraria; BMS: Honoraria; BIOKINESIS: Consultancy, Research Funding; NOVARTIS: Consultancy, Honoraria, Research Funding; SERVIER: Consultancy; JAZZ PHARMACEUTICALS: Honoraria; JANSSEN: Consultancy. Raffoux: PFIZER: Consultancy; CELGENE/BMS: Consultancy; ASTELLAS: Consultancy; ABBVIE: Consultancy. Boissel: Amgen: Consultancy, Honoraria, Research Funding; CELGENE: Honoraria; Servier: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Incyte: Honoraria; SANOFI: Honoraria; PFIZER: Consultancy, Honoraria; JAZZ Pharma: Honoraria, Research Funding. Dombret: Amgen: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Novartis: Research Funding; Pfizer: Honoraria, Research Funding; Servier: Research Funding; Abbvie: Honoraria; BMS-Celgene: Honoraria; Daiichi Sankyo: Honoraria.
Nilotinib as a therapy for PH-positive acute lymphoblastic leukemia
| v2 |
2019-04-03T13:08:29.870Z | 2018-11-29T00:00:00.000Z | 91783251 | s2ag/train | Lymphoma Virome Dynamics Revealed By Cell-Free DNA Sequencing
Background : Infectious disease plays a central role in malignancy, with up to one in six cancers having a microbial association (Parkin Int. J. Cancer 2006). Lymphomas in particular are associated with multiple viral pathogens, including Epstein Barr virus (EBV), Kaposi Sarcoma herpesvirus (KSHV), and HIV. Sequencing of cell-free DNA (cfDNA) is an emerging technique in the diagnosis and surveillance of cancer. While studies to date have focused primarily on tumor-associated somatic variants, cfDNA may also provide insight into the infectious and immune state of cancer patients. We examined cfDNA from lymphoma patients of multiple histologic subtypes to characterize viral detection and dynamics.
Methods: Plasma from 360 pre-treatment patients with various lymphoma histologies was analyzed along with that of 69 healthy adults. Multiple samples per patient were included when available. All samples underwent deep sequencing with error correction by CAPP-Seq (Newman Nat Biotech 2016). Reads were filtered for homology to the human genome and endogenous retroviruses, mapped to NCBI consensus genomes for human-hosted viral species, and filtered by breadth of genomic coverage. Viral read count was normalized by total sequencing depth to determine viral read fraction (VRF). EBV fragment size was assessed via single-read BLAST alignment length considering reads with expect value < 1E-5. Integration sites were assessed with the VirusClip package (Ho Oncotarget 2015).
Results: Patients with most lymphoma histologic subtypes had viral loads not significantly different from those of healthy adults. However, post-transplant lymphoproliferative disorder (PTLD) patients receiving immunosuppression for solid organ transplants had significantly increased total viremia (Fig 1A) and EBV levels (Fig 1B) when compared to healthy adults and non-transplant DLBCL patients. EBER+ classical Hodgkin lymphoma (cHL) displayed no difference in total viremia but had significantly elevated EBV. In an EBV-positive PTLD patient, cfDNA viral levels tracked both clinical viral qPCR and circulating tumor DNA (ctDNA) levels in serial samples leading to diagnosis (Fig 1C).
Elevated EBV levels were also present in a subset of non-transplant DLBCL. In a cohort of DLBCL patients treated with frontline R-CHOP-like chemotherapy (n=152), individuals with pre-treatment EBV frequency greater than VRF 1E-7 had significantly higher risk of disease progression at three years (HR 1.8, CI 1.0-3.4, p=0.013) (Fig 1D).
Immunosuppression in transplant patients is associated with the expansion of the endogenous anellovirus family (De Vlaminck Cell 2013). Accordingly, anellovirus was detected significantly more often in PTLD patients (91% of samples) compared to DLBCL NOS (2.8%) and controls (1.4%) (Fig 1E, p < 0.0001). As the standard-of-care R-CHOP regimen for DLBCL has activity against both B- and T- lymphocytes, we hypothesized that an immunosuppressive effect might be observed. In non-transplant DLBCL patients receiving R-CHOP (n=31), we detected anellovirus in 6% of samples at the time of first chemotherapy infusion, 16% immediately before cycle 2, but in no samples from post-treatment patients in complete response (Fig 1F).
Viral integration into the host genome is associated with malignant transformation. We profiled a cohort of EBER+ cHL (n=8) and found circulating EBV/human chimeric reads suggesting integration in all cases. Viral fragment size distribution also distinguishes integrated DNA from shorter free episomes and may increase cancer screening performance (Lam PNAS 2018). We profiled EBV fragment sizes in cHL and PTLD patients grouped by EBER positivity. Plasma from EBER+ cHL and PTLD patients was significantly enriched in longer fragments (Fig 1G), suggesting nucleosomal protection of EBV integrated within tumor genomes but not their benign episomal counterparts.
Conclusions: Viral infection in lymphoma has diagnostic and prognostic significance: elevated circulating EBV levels are associated with active PTLD (Kanakry Blood 2016) and poor outcomes in advanced HL (Kanakry Blood 2013) and DLBCL (Tisi Leuk & Lymph 2015). Our work demonstrates the utility of cfDNA sequencing for simultaneous characterization of malignancy, infection, and immunosuppression. The integration of viral dynamics into cfDNA analysis may assist in risk stratification and treatment monitoring in lymphoma patients.
Dührsen: Amgen: Research Funding; Celgene: Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Roche: Honoraria, Research Funding; Gilead: Consultancy, Honoraria; Janssen: Honoraria. Hüttmann:Celgene: Other: Travel expenses; Roche: Other: Travel expenses. Meignan:F. Hoffman-La Roche Ltd: Honoraria. Casasnovas:Janssen: Consultancy; Takeda: Honoraria; Janssen: Honoraria; MSD: Honoraria; Merck: Honoraria; Gilead Sciences: Honoraria; Celgene: Honoraria; Roche: Consultancy; Roche: Research Funding; takeda: Consultancy; Gilead Sciences: Consultancy; Roche: Honoraria; Gilead Sciences: Research Funding; merck: Consultancy; MSD: Consultancy. Westin:Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Apotex: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees; Celgen: Membership on an entity's Board of Directors or advisory committees. Gaidano:Amgen: Consultancy, Honoraria; Morphosys: Honoraria; Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Roche: Consultancy, Honoraria. Advani:Bayer: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Agensys: Research Funding; Infinity: Research Funding; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Merck: Research Funding; Janssen: Research Funding; Cell Medica: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Kyowa: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millenium: Research Funding; Celgene: Research Funding; Kura: Research Funding; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Regeneron: Research Funding; Autolus: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Gilead/Kite: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Forty Seven Inc.: Research Funding; Celgene: Research Funding.
| v2 |
2018-12-18T23:48:15.811Z | 2015-01-01T00:00:00.000Z | 56344651 | s2ag/train | Defining Modernities. Interpretations of Cultural Modernity in the Southern African Middle Stone Age
patterns/objects, use of pigments, symbolism “Symbolic material culture that [...] integrates socially shared symbolic meaning” (d'Errico and Henshilwood 2011:50) (d'Errico, et al. 2005; d'Errico, et al. 2012; d'Errico, et al. 2013; Henshilwood and d'Errico 2011b; Henshilwood, et al. 2009; Mackay and Welz 2008; Texier, et al. 2010; Texier, et al. 2013; Vanhaeren, et al. 2013; Watts 2010) Advanced behaviour or complex cognition, seen in production of tools and technological standardizations Behaviour that “involve[s] language (in itself symbolic), abstract thought, and capacity for novel, sustained multilevel operations” (Wadley 2011:98). (Conard, et al. 2012; Högberg and Larsson 2011; Pelegrin 2009; Wadley 2011; Will, et al. 2014; Wurz 1999, 2008, 2011) Social organization and exchange Intra-social organization demanding language and structure, and extra-social exchange demanding shared group mentalities. (Deacon 2001; Knight 2010; Parkington, et al. 2013; Porraz, et al. 2013; Texier, et al. 2010) Defining Modernities 2 Lithic raw material acquisition, treatment and deposition Non-locally acquired raw materials, heat treatment for adapted lithic production, and deposition of tools. (Albert and Marean 2012; Avery, et al. 2008; Coulson, et al. 2011; Nash, et al. 2013) Bone tools Worked bone and antler tools. (Backwell, et al. 2008; Henshilwood, et al. 2001) Advanced hunting techniques (Traps, bow and arrow) (Indirect) Evidence of hunting techniques demanding foresight and an ability to keep objects “out of sight, but not out of mind”. (Wadley 2010, 2011) Processes of technological change, adaptation Technological differences demonstrating stylistic standardization in archaeological phases outside clear technocomplexes such as Stillbay and Howiesons Poort. (Conard, et al. 2012; Högberg and Larsson 2011; Will, et al. 2014; Wurz 2008) Food procurement Archaeological evidence demonstrating an ability to procure food from a variety of sources, e.g. marine foraging (Albert and Marean 2012; Avery, et al. 2008; Jerardino and Marean 2010; Klein, et al. 2004; Marean 2010; Marean, et al. 2010; Wurz 2011) The type of behaviour mentioned above was believed to not emerge any earlier than 40 kya, during the Upper Palaeolithic in Europe. From this point on in time there is a rapid emergence of new technology and figurative and pictorial art in the archaeological record, such as cave paintings located in France (e.g. Chauvet, et al. 1996), figurines from present day Germany (e.g. Nelson 2008), and advanced forms of technology such as bone tools (Mellars 1989; White 1982:169). This change in the archaeological record was connected to a change in human behaviour towards cultural modernity, recognized as the Upper Palaeolithic Revolution (Bar-Yosef 2002; Klein 2009:684-720). Cultural modernity is one of many terms aimed to describe fully human cognitive abilities (see Table 2). These cognitive abilities are recognised in the archaeological record in Defining Modernities 3 a variety of ways (see table 1). Cultural modernity refers to a point in time when humans cognitively evolved to present day’s mental levels (Conard 2010:2671). Lyn Wadley (2001:201) further defines cultural modernity specifically as the ability to store information outside the human brain. Table 2: A variety of terms applied to describe cultural modernity Terms applied to describe cultural modernity Examples of references Symbolically mediated behaviour (d'Errico and Henshilwood 2011; Henshilwood, et al. 2009; Wurz 1999) Symbolic behaviour (d'Errico, et al. 2005; Henshilwood, et al. 2001; Wurz 1999) Modern (human) behaviour (d'Errico, et al. 2012:942; Henshilwood, et al. 2001; Henshilwood, et al. 2009; Henshilwood and Marean 2003; Jerardino and Marean 2010; Texier, et al. 2010; Thompson and Henshilwood 2014; Wurz 2008) Behavioural modernity (Conard 2008; Deacon 2008:148; Henshilwood, et al. 2001; Texier, et al. 2010; Vanhaeren, et al. 2013:500) Symbolic material culture (d'Errico, et al. 2012:942) Modern humans (Deacon 1992, 2001; Klein 1995, 2013; McCall 2006) Human behaviour (Mackay and Welz 2008) Modern Cognition (Wynn and Coolidge 2009, 2011) Complex Cognition (Wadley 2011) Towards the end of the 1990’s the Upper Palaeolithic Revolution was challenged by several articles (Bar-Yosef 2002; Deacon 2001; Henshilwood, et al. 2001; Henshilwood, et al. 2002; Wadley 2001; Wurz 1999), some more significant than others (McBrearty and Brooks 2000). The Upper Palaeolithic Revolution was here argued to exist on the basis of a negligence of evidence for cultural modernity from the southern African MSA, as well as a variety of other geographical areas and datings. The connection between development of cultural traits and anatomical evolution had earlier been questioned (Mellars 1989), and it seemed now that the southern African MSA contained several types of artefacts demonstrating cultural modernity, generally dated to sometime between 70 140 kya (e.g. Henshilwood, et al. 2001; Wurz 1999, 2002). This pushed the dating of such behaviour at least 30 000 years back in time. Southern Africa quickly became the leading geographical area of research on the emergence of cultural modernity in the MSA, seen in the number of South African projects in table 3, as well as the argued centre of the development of these traits (e.g. Deacon 2001; Henshilwood, et al. 2001; Henshilwood, et al. 2002; Wadley 2001). D ef in in g M o d er n it ie s 4 T a b le 3 : A s el ec ti o n o f a rc h a eo lo g ic a l si te s, d em o n st ra ti n g t h e ra n g e o f th e cu rr en t d is p u te o ve r cu lt u ra l m o d er n it y in t h e so u th er n A fr ic a n M S A . A rc h a eo lo g ic a l P ro je ct D a ti n g s o f fi n d s co n n ec te d to | v2 |
2020-11-05T09:10:13.256Z | 2020-11-05T00:00:00.000Z | 228814071 | s2ag/train | Identification of a Novel Role for PD-1 Signaling in Promotion Tumor Proliferation in B-Cell Lymphoma
Introduction: PD-1 inhibits the cytotoxic T-cell functions via the interaction with its ligands (PDL1 and PDL2). Recently, our group showed a selective response (~40%) with PD-1 blocking antibody pembrolizumab in patients with Richter transformation (RT), particularly after prior exposure to ibrutinib (Wei Ding et al, Blood, 2017). Additionally, PD-1 showed an increased expression in tumor B-cells of patients with RT (Rong He et al, AJSP, 2018). Here we investigated the functional implications of the PD-1 signaling axis in lymphoma B-cell pathobiology.
Methods: 26 CLL-involved lymph node (LN) and 20 RT-involved LN samples were tested for PD-1 expression by immunohistochemistry (mouse clone NAT105, Abcam). Then, we checked PD-1 expression in 10 lymphoma cell lines and 1 CLL cell line (MEC-1) by both, flow cytometry and Western blot (WB) analysis. Over-expression of PD-1 using pLEX-lentiviral system (Thermo Scientific) was evaluated for in vitro cell cycle regulation and in vivo tumor growth. Overexpression of PD-1 was further examined on the regulation of cell signaling pathways using human phospho kinase array kit (R&D) and WB analysis. Gene expression signatures in CLL and RT patients were also identified by Illumina-based RNA sequencing using Formalin-Fixed Paraffin-embedded (FFPE)-nodal tissue obtained by clinical biopsy (Tempus Labs; Chicago, IL).
Results: The expression of PD-1 was significantly increased in RT-LN compared to CLL-LN (mean ± SEM in RT vs. CLL, 30.6% ± 4.7% vs. 11.5% ± 2.8%, p < 0.001) [Fig 1A]. PD-1 expression was highest in patients with RT where the last prior CLL therapy was ibrutinib. To test the role of PD-1 in lymphoma B-cells, its expression was assessed in lymphoma and CLL cell lines. The expression of PD-1 was found to be variable, but at very low-levels in lymphoma lines OCI-LY7 and OCI-LY19 (data not shown). Constitutive lentiviral (pLEX-PD-1)-mediated overexpression of PD-1 in OCI-LY7 and OCI-LY19 cells led to increased cell growth (1.4 and 1.9 fold compared to original lines on day 4, respectively, Fig 1BI-II), which was further confirmed by cell cycle analysis which showed an increase in S phase by 20.4% and 24.53% in OCI-LY7 and OCI-LY19 cells (Fig 1B III), respectively. When the luciferase + PD-1 expressing OCI-LY7 cells were injected intravenously (1X106 cells) into NSG mice, increased tumor growth was observed at 22 days of follow up by bioluminescence imaging (p<0.01, Fig 1C). Using phospho-kinase array, an overall decrease of phosphorylation was detected on multiple sites of p53 (S392, S15, S46) and CHK2 (T68) (data not shown). This finding was further confirmed by WB analyses (Fig1DI). In addition, decreased of total p53 and increased phosphorylation on both SHP-1 and SHP-2 were found in PD-1 overexpressing OCI-LY19 and OCI-LY17 cell lines (Fig 1DI). Immunoprecipitation experiments with anti-PD1 antibody showed that PD-1 was in the same complex with SHP-1 and SHP-2 in OCI-LY7 cells but only with SHP-2 in OCI-LY19 cells (Fig 1DII). In parallel, mRNA sequencing was performed on 11 nodal tissues from either RT (n=8) or progressive CLL (n=3) after they developed clinical progression. The expression of PD-1 (PDCD1) was positively correlated with the expression of SHP-1 (PTPN6, r=0.56) and Cyclin E1 (CCNE1, r=0.62), implicating a direct role of PD-1 in regulating cellular proliferation and the induction in phosphatase expression in RT and CLL.
Conclusion: Our data support the notion that PD-1 overexpression in lymphoma cells modifies cell proliferation in vitro and in vivo and regulates the function of phosphatase SHP and p53- pathways. These findings also indicate that aggressive lymphoma or CLL leukemic cells have the ability to hijack the PD-1 pathway and may result in downregulation of the p53 mediated DNA repair. This novel information provide for new strategies to further evaluate the interaction of checkpoint signals with DNA repair pathway, and possibly provide novel targets for Richter's transformation.
Ding: alexion: Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees; Abbvie: Research Funding; Astra Zeneca: Research Funding; Octapharma: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; DTRM: Research Funding; MEI Pharma: Membership on an entity's Board of Directors or advisory committees. Sakemura:Humanigen: Patents & Royalties. Parikh:Janssen: Honoraria, Research Funding; Merck: Research Funding; Pharmacyclics: Honoraria, Research Funding; Ascentage Pharma: Research Funding; GlaxoSmithKline: Honoraria; MorphoSys: Research Funding; AstraZeneca: Honoraria, Research Funding; Verastem Oncology: Honoraria; Genentech: Honoraria; AbbVie: Honoraria, Research Funding; TG Therapeutics: Research Funding. Wang:Novartis: Research Funding; Incyte: Research Funding; Innocare: Research Funding. Liu:Eisal: Research Funding; Genentech: Research Funding; GRAIL: Research Funding; Menarini Silicon Biosystems: Research Funding; Merck: Research Funding; Seattle Genetics: Research Funding; Tesaro: Research Funding. Braggio:DASA: Consultancy; Bayer: Other: Stock Owner; Acerta Pharma: Research Funding. Ansell:Seattle Genetics: Research Funding; Takeda: Research Funding; AI Therapeutics: Research Funding; ADC Therapeutics: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Regeneron: Research Funding; Bristol Myers Squibb: Research Funding. Kenderian:Sunesis: Research Funding; Tolero: Research Funding; Torque: Consultancy; BMS: Research Funding; Gilead: Research Funding; Kite: Research Funding; Humanigen: Consultancy, Patents & Royalties, Research Funding; Mettaforge: Patents & Royalties; Novartis: Patents & Royalties, Research Funding; MorphoSys: Research Funding; Lentigen: Research Funding; Juno: Research Funding. Kay:Acerta Pharma: Research Funding; Oncotracker: Membership on an entity's Board of Directors or advisory committees; Juno Theraputics: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Research Funding; MEI Pharma: Research Funding; Sunesis: Research Funding; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; Agios Pharma: Membership on an entity's Board of Directors or advisory committees; Cytomx: Membership on an entity's Board of Directors or advisory committees; Morpho-sys: Membership on an entity's Board of Directors or advisory committees; Dava Oncology: Membership on an entity's Board of Directors or advisory committees; Tolero Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Meyer Squib: Membership on an entity's Board of Directors or advisory committees, Research Funding; Rigel: Membership on an entity's Board of Directors or advisory committees.
| v2 |
2021-11-25T16:21:12.930Z | 2021-11-05T00:00:00.000Z | 244571951 | s2ag/train | Treatment-Free Remission (TFR) after Two Different Durations of Nilotinib Consolidation in Patients with Chronic Myeloid Leukemia (CML) Previously Treated with Imatinib: Enestpath Study Results
Background
TFR following cessation of tyrosine kinase inhibitor (TKI) therapy is increasingly regarded as a feasible objective for many patients (pts) with CML in chronic phase (CML-CP) who achieve a sustained deep molecular response (DMR). In Evaluating Nilotinib Efficacy and Safety in clinical Trials (ENEST)-complete molecular response (ENESTcmr), pts unable to achieve DMR on imatinib (IM) were able to reach deeper levels of MR by switching to nilotinib (NIL) 400 mg twice daily (BID) vs continuing IM (Hughes et al. 2017). Recent long-term analysis from ENESTop illustrated the durability and safety of TFR for pts who achieved sustained DMR only after switching from IM to NIL 400 mg (Hughes et al. 2021). European LeukemiaNet guidelines allow discontinuation of TKI therapy following >2 years of DMR (MR 4.0 or better) (Hochhaus et al. 2020). However, the optimal duration of NIL consolidation (CONS) to increase the chances for successful TFR is not yet known.
Objectives
The ENESTPath study was designed to evaluate the impact of 12 or 24 months (mos) of NIL 300 mg BID CONS, on the TFR rate in pts who had not achieved sustained DMR with IM.
Methods
ENESTPath (NCT01743989) is a prospective, randomized, open-label, two-arm phase 3 study that enrolled pts with CML-CP who achieved a complete cytogenetic response (CCyR), but not MR 4.0, after ≥24 mos of IM. After enrollment, pts received NIL 300 mg BID for 12 mos each of induction (IND) and CONS. Pts with sustained DMR for at least the last 12 mos (≥MR 4.0; BCR-ABL1IS ≤0.01% in 4 of the 5 preceding quarterly assessments and ≥MR 4.0 in the last assessment) were randomized (1:1) either to enter the TFR phase (Arm 1) or to continue NIL for an additional 12 mos CONS, before entering TFR (Arm 2) if eligibility criteria were still met, resulting in a 36- or 24- mos TFR phase, respectively (Figure 1). The primary endpoint was the number of pts who remained in TFR (≥MR 4.0) without molecular relapse 12 mos after entering TFR. Molecular relapse was defined as loss of major molecular response (loss of MMR, BCR-ABL1IS >0.1%) or the confirmed loss of MR 4.0 (3 tests <MR 4.0 assessed at 3 consecutive visits).
Results
Overall, 620 pts were enrolled. In the full analysis set (FAS, N=619), 238 pts were randomized after 24 mos of NIL, 381 patients were not randomized and followed for survival, and one pt was excluded from FAS due to major protocol deviation. Baseline characteristics were well balanced between Arm 1 (N=120) and Arm 2 (N=118): 49.5 and 49.0 years median age; 60.0% and 58.5% male; 56.11 vs 57.97 mos median time since initial diagnosis; 54.08 vs 57.99 mos median prior exposure to IM, respectively. The number of pts in the FAS entering TFR was 119 in Arm 1 and 104 in Arm 2. There was no significant difference in the primary endpoint of MR 4.0 rate at 12 mos of TFR between arms (Arm 1, 31.9% [95% CI: 23.7 - 41.1]; Arm 2, 37.5% [95% CI: 28.2 - 47.5]; P=0.383) (Table 1). Median time to treatment-free survival event (TFS; defined as loss of MMR, confirmed loss of MR 4.0, re-start of NIL for any reason, progression to accelerated phase/blast crisis, or death from any cause) was 4.1 (95% CI: 3.7 - 5.5) mos in Arm 1 and 4.2 (95% CI: 3.7 - 19.7) in Arm 2 (Figure 2). Among the 129 pts who relapsed during TFR and were re-treated with NIL, the majority regained MMR and MR 4.0 by 3 mos (Table 2). In the 619 pts who received NIL during IND/CONS, the raw cumulative rate of MR 4.0 and MR 4.5 was 64.3% and 36.8% by 12 mos and 72.4% and 48.0% by 24 mos, respectively. The proportion of pts who achieved MR 4.0 and MR 4.5 was 48.0% and 25.0% at 12 mos, and 44.1% and 24.9% at 24 mos, respectively. During IND/CONS before randomization, 87.7% (543/619) pts experienced an adverse event (AE), 18.1% (112/619) serious AEs (SAEs), 9.7% (60/619) cardiovascular AEs, and 12.1% (75/619) discontinued study treatment due to AEs. In the TFR phase, 63.2% (141/223) pts experienced AEs, and 6.7% (15/223) pts SAEs (Table 3); and three patients had SAEs suspected to be related to study drug (all in Arm 1): one cerebrovascular accident, one peripheral artery stenosis, and one Grade 3/4 myocardial infarction.
Conclusions
ENESTPath results suggest there is no significant incremental benefit in terms of TFR success from an additional year of NIL CONS for pts with CML-CP who achieved sustained DMR after 2 years on NIL following a switch from IM. The efficacy of NIL at a dose of 300 mg BID in achieving MR in pts unable to reach sustained DMR with first-line IM for ≥24 mos was confirmed. No new safety signals were observed.
Figure 1 Figure 1.
Rea: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Sportoletti: AstraZeneca: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Mayer: Principia: Research Funding. Illes: Novartis, Janssen, Pfizer, Roche: Other: Travel, Accommodations, Expenses; Takeda, Seattle Genetics: Research Funding; Janssen, Celgene, Novartis, Pfizer, Takeda, Roche: Consultancy. Kiani: Novartis Pharma GmbH: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Charbonnier: Pfizer: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Marinakis: Novartis: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria. Stenke: Incyte: Membership on an entity's Board of Directors or advisory committees. Shah: Cognizant technology Solutions: Current Employment. Supekar: Novartis Farma: Current Employment. Di Caprio: Novartis Pharma: Current Employment. Baccarani: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees.
| v2 |
2018-01-24T17:25:33.048Z | 2017-02-01T00:00:00.000Z | 204994161 | s2ag/train | P701 Late-onset Crohn's disease is associated with high risk of intestinal perforation and low risk of perianal fistula as compared with early-onset Crohn's disease: the CONNECT cohort.
s of the 12th Congress of ECCO – European Crohn’s and Colitis Organisation S439 lapsed between HBI assessments, and baseline disease severity category. Results: A total of 1469 IBD patients met eligibility criteria and 916 (62%) of these had received CCC. Of the 1469 patients, 1046 (71%) were in HBI remission at the second assessment, 682 (74%) in the CCC group and 364 (66%) in the group not receiving CCC. In the multivariable regression analysis, there was a 12% increased likelihood of achieving HBI remission in the CCC group relative to the group without CCC (RR=1.12, 95% confidence interval: 1.04, 1.20; p-value =0.002). Conclusions: IBD patients receiving tailored services through the ADL PSP in the form of care coach calls have an increased likelihood of achieving HBI remission within 6 to 18 months. These results may help refine interventions aiming at improving clinical outcomes in IBD patients. P700 Epidemiology of genital lymphoedema as the initial presentation of paediatric Crohn’s disease F. Jagger*1, A. Dall2, P. Henderson2, D. Wilson1 1University of Edinburgh, Child Life and Health, Edinburgh, United Kingdom; 2Royal Hospital For Sick Children, Department of Pediatric Gastroenterology, Edinburgh, United Kingdom Background: Genital lymphoedema is caused by inflammation and granuloma formation in the lymphatic system and is recognised as a presentation of cutaneous metastatic Crohn’s disease (CD). It can precede luminal presentation by months to years, particularly in younger patients; many children with cutaneous CD have genital involvement. Despite several case reports, there is a scarcity of epidemiological studies demonstrating the incidence of genital lymphoedema in a paediatric population with Crohn’s disease. We aimed to identify the incidence of genital lymphoedema as the initial presentation of paediatric CD within a population-based cohort. Methods: Using a prospective regional database demographics and phenotypic data of all incident and prevalent paediatric inflammatory bowel disease (PIBD) patients in South-East Scotland between 01.08.97 and 31.12.11 were reviewed. Case notes of all CD patients were reviewed and those with genital involvement identified. Using all CD as the denominator, the incidence of genital lymphoedema as the initial presentation of CD in all patients (incident and prevalent) in this cohort was calculated. Results: A total of 204 incident and prevalent cases of CD diagnosed less than 17 years of age were recorded in SES during the study period. 5 patients (2.5%) were identified as having genital involvement prior to, or at the time of, CD diagnosis. These patients were aged 4–15 years at presentation (median 9 years); 3 were male. One patient was diagnosed with CD despite normal endoscopic examination after developing perianal abscesses and fissures one year after histologically proven granulomatous genital oedema. Of the other 4 patients, only one presented with concomitant gastrointestinal and genital disease. The other patients were diagnosed with CD on endoscopy 8 months, 1 year and 3 years after initial presentation with genital oedema. 4 patients with genital oedema had concurrent perianal disease and one had oral disease. Conclusions: To our knowledge, this is the first paediatric population-based study of genital lymphoedema as an initial presentation of CD. In this cohort, 2.5% of paediatric CD within a regional PIBD cohort at diagnosis had prior or concurrent genital lymphoedema due to CD. This significant proportion highlights the importance of considering CD as one of the many differential diagnoses of genital oedema, particularly in the presence of perianal disease or other gastrointestinal symptoms. P701 Late-onset Crohn’s disease is associated with high risk of intestinal perforation and low risk of perianal fistula as compared with early-onset Crohn’s disease: the CONNECT cohort H.M. Kim*1, H.-S. Kim1, J.S. Kim2, Y.S. Kim3, J.H. Cheon4, B.D. Ye5, Y.H. Kim6, D.S. Han7 1Yonsei University Wonju College of Medicine, Division of Gastroenterology and Hepatology, Wonju, South Korea; 2Seoul National Uinversity College of Medicine, Internal Medicine and Liver Research Institute, Seoul, South Korea; 3Inje University College of Medicine, Internal Medicine, Seoul, South Korea; 4Yonsei University College of Medicine, Internal Medicine and Institute of Gastroenterology, Seoul, South Korea; 5University of Ulsan College of Medicine, Asan Medical Center, Gastroenterology and Inflammatory Bowel Disease Center, Seoul, South Korea; 6Sungkyunkwan University School of Medicine, Department of Internal Medicine, Seoul, South Korea; 7Hanyang University Guri Hospital, Department of Internal Medicine, Guri, South Korea Background: The late-onset Crohn’s disease has several different clinical characteristics from the early-onset Crohn’s disease. This study was aimed to compare abdominal and perianal complications between early-onset and late-onset Crohn’s disease. Methods: The Crohn’s Disease Clinical Network and Cohort (CONNECT) retrospective cohort was used in this study. Between 1982 and 2010, patients with confirmed Crohn’s disease were enrolled. The early-onset Crohn’s disease was defined as age at the diagnosis ≥20 and 30< (549 patients), and the late-onset as ≥40 and <70 (185 patients). The multivariable logistic regression analyses were performed with adjustment of sex, smoking, location (L), and behavior (B) or Crohn’s disease. Results: The patients with late-onset Crohn’s disease underwent higher rate of abdominal surgery and lower rate of perianal surgery than those with the early-onset Crohn’s disease (33.0% vs. 25.0% and 3.8% vs. 22.6%, p<0.0001). The patients with late-onset Crohn’s disease had lower rate of perianal fistula than those with the early-onset Crohn’s disease (14.8% vs. 41.7%, p<0.0001). In the multivariable analysis, the patients with late-onset Crohn’s disease had odds ratio of 3.090 (n=312, 95% confidence interval [CI]: 1.228–7.772, p=0.017) for intestinal perforation, and odds ratio of 0.122 (n=313, 95% CI: 0.053–0.285, p<0.0001) for perianal fistula. Table 1. Association between late-onset Crohn’s disease and complications Dependent variable Number Odds ratio (95% CI)* p value Intestinal perforation 312 3.090 (1.228–7.772) 0.017 Intrabdominal abscess 313 0.703 (0.261–1.890) 0.485 Intestinal stricture 311 0.956 (0.464–1.968) 0.903 Perianal fistula 313 0.122 (0.053–0.285) < 0.0001 Conclusions: The late-onset Crohn’s disease is associated with high risk of abdominal surgery and intestinal perforation, but low risk of perianal fistula as compared with the early-onset Crohn’s disease. This work was supported by the Research Program funded by the Korea Centers for Disease Control and Prevention. (2013-E63004– 01) | v2 |
2021-04-24T06:17:57.822Z | 2021-04-20T00:00:00.000Z | 233370391 | s2ag/train | [Epidemiological characteristics and outcome analysis of 266 patients with inhalation injuries combined with total burn area less than 30% total body surface area].
Objective: To explore the epidemiological characteristics and treatment outcomes of patients with inhalation injuries combined with total burn area less than 30% total body surface area (TBSA). Methods: A retrospective observational study was performed on medical records of 266 patients with inhalation injuries combined with total burn area less than 30%TBSA who were admitted to the First Affiliated Hospital of Naval Medical University from January 2008 to December 2016 and met the inclusion criteria. The following statistical data of the patients were collected, including gender, age, injury site, injurious factors of inhalation injury, degree of inhalation injury, combined total burn area, tracheotomy, time of tracheotomy, mechanical ventilation, whether stayed in intensive care unit (ICU) or not, microbial culture results of bronchoalveolar lavage fluid, length of hospital stay, length of ICU stay, mechanical ventilation days, and respiratory tract infections. Single factor and multivariate linear regression analysis were used to screen out the risk factors impacting the length of hospital stay, length of ICU stay, and mechanical ventilation days of patients. Single factor and multivariate logistic regression analysis were used to screen out the risk factors impacting respiratory tract infections of patients. Results: The 266 patients included 190 males and 76 females, with the majority age of above or equal to 21 years and below 65 years (217 patients). The major injury site was confined space. The major factor causing inhalation injury was hot air. Mild and moderate inhalation injuries were more common in patients. The combined total burn area was 9.00% (3.25%, 18.00%) TBSA. In 111 patients who had tracheotomy, most of them received the procedures before being admitted to the First Affiliated Hospital of Naval Medical University. The length of hospital stay of patients was 27 (10, 55) days. The length of ICU stay of 160 patients who were hospitalized in ICU was 15.5 (6.0, 40.0) days. The mechanical ventilation days of 109 patients who were conducted with mechanical ventilation were 6.0 (1.3, 11.5) days. A total of 119 patients were diagnosed with respiratory tract infections, with 548 strains including 35 types of pathogens isolated, mainly Gram-negative bacteria. Single factor linear regression analysis showed that age, injurious factors of inhalation injury, combined total burn area, degree of inhalation injury (moderate and severe), tracheotomy, mechanical ventilation, and respiratory tract infections were the factors impacting the length of hospital stay of patients (β=-0.198, -0.224, 0.021, 0.127, 0.164, -0.298, 0.357, 0.447, 95% confidence interval (CI)=-0.397--0.001, -0.395--0.053, 0.015-0.028, 0.009-0.263, 0.008-0.319, -0.419--0.176, 0.242-0.471, 0.340-0.555, P<0.1). Multivariate linear regression analysis showed that with mechanical ventilation and respiratory tract infections were the independent risk factors impacting the length of hospital stay of patients (β=0.146, 0.383, 95% CI=0.022-0.271, 0.261-0.506, P<0.05 or P<0.01). Single factor linear regression analysis showed that injurious factors of inhalation injury, combined total burn area, degree of inhalation injury (moderate and severe), tracheotomy (no tracheotomy and prophylactic tracheotomy), mechanical ventilation, and respiratory tract infections were the factors impacting the length of ICU stay of patients (β=0.225, 0.008, 0.237, 0.203, -0.408, -0.334, 0.309, 0.523, 95% CI=0.053-0.502, 0.006-0.010, -0.018-0.457, -0.022-0.428, -0.575--0.241, -0.687--0.018, 0.132-0.486, 0.369-0.678, P<0.1). Multivariate linear regression analysis showed that with respiratory tract infections was the independent risk factor impacting the length of ICU stay of patients (β=0.440, 95% CI=0.278-0.601, P<0.01). Single factor linear regression analysis showed that injury site, injurious factors of inhalation injury (smoke and chemical gas), combined total burn area, degree of inhalation injury (moderate and severe), tracheotomy (no tracheotomy and prophylactic tracheotomy), and respiratory tract infections were the factors impacting mechanical ventilation days of patients (β=-0.300, 0.545, 0.163, 0.005, 0.487, 0.799, -0.791, -0.736, 0.300, 95% CI=-0.565--0.034, 0.145-0.946, 0.051-1.188, 0.001-0.009, 0.127-0.847, 0.436-1.162, -1.075--0.508, -1.243--0.229, 0.005-0.605, P<0.1). Multivariate linear regression analysis showed that smoke inhalation, severe inhalation injury, and respiratory tract infections were the independent risk factors impacting mechanical ventilation days of patients (β=0.210, 0.495, 0.263, 95% CI=0.138-0.560, 0.143-0.848, 0.007-0.519, P<0.05 or P<0.01). Single factor logistic regression analysis showed that age, injury site, combined total burn area (10%-19%TBSA and 20%-29%TBSA), degree of inhalation injury (moderate and severe), tracheotomy (prophylactic tracheotomy and no tracheotomy), and mechanical ventilation were the factors impacting respiratory tract infections of patients (odds ratio=1.079, 0.815, 1.400, 1.331, 1.803, 1.958, 0.990, 0.320, 3.094, 95% CI=0.840-1.362, 0.641-1.044, 1.122-1.526, 1.028-1.661, 1.344-2.405, 1.460-2.612, 0.744-1.320, 0.241-0.424, 2.331-4.090, P<0.1). Multivariate logistic regression analysis showed that with mechanical ventilation was the independent risk factor impacting respiratory tract infections of patients (odds ratio=4.300, 95% CI=2.152-8.624, P<0.01). Conclusions: The patients with inhalation injuries combined with total burn area less than 30%TBSA are mainly young and middle-aged males. Smoke inhalation, degree of inhalation injury, with mechanical ventilation and respiratory tract infections are the factors that affect the outcomes of patients with inhalation injuries combined with total burn area less than 30%TBSA. Additionally, prophylactic tracheotomy shows its potential value in reducing respiratory tract infections in patients with moderate or severe inhalation injuries. | v2 |
2021-02-23T06:16:27.100Z | 2021-02-22T00:00:00.000Z | 231987831 | s2ag/train | Xpert Ultra versus Xpert MTB/RIF for pulmonary tuberculosis and rifampicin resistance in adults with presumptive pulmonary tuberculosis.
BACKGROUND
Xpert MTB/RIF and Xpert MTB/RIF Ultra (Xpert Ultra) are World Health Organization (WHO)-recommended rapid tests that simultaneously detect tuberculosis and rifampicin resistance in people with signs and symptoms of tuberculosis. This review builds on our recent extensive Cochrane Review of Xpert MTB/RIF accuracy.
OBJECTIVES
To compare the diagnostic accuracy of Xpert Ultra and Xpert MTB/RIF for the detection of pulmonary tuberculosis and detection of rifampicin resistance in adults with presumptive pulmonary tuberculosis. For pulmonary tuberculosis and rifampicin resistance, we also investigated potential sources of heterogeneity. We also summarized the frequency of Xpert Ultra trace-positive results, and estimated the accuracy of Xpert Ultra after repeat testing in those with trace-positive results.
SEARCH METHODS
We searched the Cochrane Infectious Diseases Group Specialized Register, MEDLINE, Embase, Science Citation Index, Web of Science, LILACS, Scopus, the WHO ICTRP, the ISRCTN registry, and ProQuest to 28 January 2020 with no language restriction.
SELECTION CRITERIA
We included diagnostic accuracy studies using respiratory specimens in adults with presumptive pulmonary tuberculosis that directly compared the index tests. For pulmonary tuberculosis detection, the reference standards were culture and a composite reference standard. For rifampicin resistance, the reference standards were culture-based drug susceptibility testing and line probe assays.
DATA COLLECTION AND ANALYSIS
Two review authors independently extracted data using a standardized form, including data by smear and HIV status. We assessed risk of bias using QUADAS-2 and QUADAS-C. We performed meta-analyses comparing pooled sensitivities and specificities, separately for pulmonary tuberculosis detection and rifampicin resistance detection, and separately by reference standard. Most analyses used a bivariate random-effects model. For tuberculosis detection, we estimated accuracy in studies in participants who were not selected based on prior microscopy testing or history of tuberculosis. We performed subgroup analyses by smear status, HIV status, and history of tuberculosis. We summarized Xpert Ultra trace results.
MAIN RESULTS
We identified nine studies (3500 participants): seven had unselected participants (2834 participants). All compared Xpert Ultra and Xpert MTB/RIF for pulmonary tuberculosis detection; seven studies used a paired comparative accuracy design, and two studies used a randomized design. Five studies compared Xpert Ultra and Xpert MTB/RIF for rifampicin resistance detection; four studies used a paired design, and one study used a randomized design. Of the nine included studies, seven (78%) were mainly or exclusively in high tuberculosis burden countries. For pulmonary tuberculosis detection, most studies had low risk of bias in all domains. Pulmonary tuberculosis detection Xpert Ultra pooled sensitivity and specificity (95% credible interval) against culture were 90.9% (86.2 to 94.7) and 95.6% (93.0 to 97.4) (7 studies, 2834 participants; high-certainty evidence) versus Xpert MTB/RIF pooled sensitivity and specificity of 84.7% (78.6 to 89.9) and 98.4% (97.0 to 99.3) (7 studies, 2835 participants; high-certainty evidence). The difference in the accuracy of Xpert Ultra minus Xpert MTB/RIF was estimated at 6.3% (0.1 to 12.8) for sensitivity and -2.7% (-5.7 to -0.5) for specificity. If the point estimates for Xpert Ultra and Xpert MTB/RIF are applied to a hypothetical cohort of 1000 patients, where 10% of those presenting with symptoms have pulmonary tuberculosis, Xpert Ultra will miss 9 cases, and Xpert MTB/RIF will miss 15 cases. The number of people wrongly diagnosed with pulmonary tuberculosis would be 40 with Xpert Ultra and 14 with Xpert MTB/RIF. In smear-negative, culture-positive participants, pooled sensitivity was 77.5% (67.6 to 85.6) for Xpert Ultra versus 60.6% (48.4 to 71.7) for Xpert MTB/RIF; pooled specificity was 95.8% (92.9 to 97.7) for Xpert Ultra versus 98.8% (97.7 to 99.5) for Xpert MTB/RIF (6 studies). In people living with HIV, pooled sensitivity was 87.6% (75.4 to 94.1) for Xpert Ultra versus 74.9% (58.7 to 86.2) for Xpert MTB/RIF; pooled specificity was 92.8% (82.3 to 97.0) for Xpert Ultra versus 99.7% (98.6 to 100.0) for Xpert MTB/RIF (3 studies). In participants with a history of tuberculosis, pooled sensitivity was 84.2% (72.5 to 91.7) for Xpert Ultra versus 81.8% (68.7 to 90.0) for Xpert MTB/RIF; pooled specificity was 88.2% (70.5 to 96.6) for Xpert Ultra versus 97.4% (91.7 to 99.5) for Xpert MTB/RIF (4 studies). The proportion of Ultra trace-positive results ranged from 3.0% to 30.4%. Data were insufficient to estimate the accuracy of Xpert Ultra repeat testing in individuals with initial trace-positive results. Rifampicin resistance detection Pooled sensitivity and specificity were 94.9% (88.9 to 97.9) and 99.1% (97.7 to 99.8) (5 studies, 921 participants; high-certainty evidence) for Xpert Ultra versus 95.3% (90.0 to 98.1) and 98.8% (97.2 to 99.6) (5 studies, 930 participants; high-certainty evidence) for Xpert MTB/RIF. The difference in the accuracy of Xpert Ultra minus Xpert MTB/RIF was estimated at -0.3% (-6.9 to 5.7) for sensitivity and 0.3% (-1.2 to 2.0) for specificity. If the point estimates for Xpert Ultra and Xpert MTB/RIF are applied to a hypothetical cohort of 1000 patients, where 10% of those presenting with symptoms have rifampicin resistance, Xpert Ultra will miss 5 cases, and Xpert MTB/RIF will miss 5 cases. The number of people wrongly diagnosed with rifampicin resistance would be 8 with Xpert Ultra and 11 with Xpert MTB/RIF. We identified a higher number of rifampicin resistance indeterminate results with Xpert Ultra, pooled proportion 7.6% (2.4 to 21.0) compared to Xpert MTB/RIF pooled proportion 0.8% (0.2 to 2.4). The estimated difference in the pooled proportion of indeterminate rifampicin resistance results for Xpert Ultra versus Xpert MTB/RIF was 6.7% (1.4 to 20.1).
AUTHORS' CONCLUSIONS
Xpert Ultra has higher sensitivity and lower specificity than Xpert MTB/RIF for pulmonary tuberculosis, especially in smear-negative participants and people living with HIV. Xpert Ultra specificity was lower than that of Xpert MTB/RIF in participants with a history of tuberculosis. The sensitivity and specificity trade-off would be expected to vary by setting. For detection of rifampicin resistance, Xpert Ultra and Xpert MTB/RIF had similar sensitivity and specificity. Ultra trace-positive results were common. Xpert Ultra and Xpert MTB/RIF provide accurate results and can allow rapid initiation of treatment for rifampicin-resistant and multidrug-resistant tuberculosis. | v2 |
2021-11-25T16:16:12.441Z | 2021-11-05T00:00:00.000Z | 244534061 | s2ag/train | Prognostic Factors for Early (<2 years) and Late (>5 years) Relapse in Multiple Myeloma- Pivotal Role of Cytogenetic Changes
Background
Multiple myeloma (MM) is an incurable disease, and its prognosis is largely influenced by clinicopathological features, response to therapy, and relapse characteristics. Despite novel agents and the attempts to individualize treatment strategies based on baseline risk stratification, significant variations in progression-free survivals (PFS) and overall survivals (OS) are observed between patients. We examined the outcomes of MM patients stratified according to timing of first relapse into early (<2 years) and late (>5 years).
Methods
We retrospectively assessed 1441 MM patients seen at Mayo Clinic between 2003 and 2018. Patients were 18 years or older and had at least one disease relapse that required an additional line of treatment. The study cohort was divided into three groups based on time of first relapse: early relapse (<2 years from diagnosis), relapse between 2 to 5 years from diagnosis, and late relapse (>5 years from diagnosis). The independent predictors of early/late relapse were identified using a forward stepwise multivariate logistic regression. Odds ratios in multivariate models were adjusted for age and sex.
Results
Early relapse has been recognized in 758 patients (52.6%), relapse between 2-5 years in 561 patients (38.9%), late relapse in 122 patients (8.5%). Six patients had a PFS >10 years. In comparison to patients with late relapse, patients with early relapse were older (median 63 vs 61 years, p=0.04), more frequently ISS stage III (40% vs 20%, p<0.001) had higher bone marrow plasma cell infiltration (median 60% vs 40%, p<0.001), and were more likely to have high-risk (HR) FISH (defined as translocation t[4;14], t[14;16], t[14;20], deletion 17p or p53 mutation; 28% vs 11%, p<0.001). At diagnosis, early relapse group more often presented with anemia (35% vs 21%, p=0.004), hypercalcemia (15% vs 5%, p<0.001), renal insufficiency (19% vs 5%, p<0.001) and higher serum beta-2-microglobulin (median 4.4 vs 3.4 mg/l, p<0.001).
In terms of first line treatment, novel agents use was higher in early relapse group in comparison to late relapse group (82% vs 72%, p=0.007). Early relapse patients more often received PI-based therapy (30% vs 10%, p<0.001) or PI+IMID-based therapy (22% vs 12%, p=0.01), whereas late relapse patients received more often IMID-based therapy (63% vs 37%, p<0.001). No differences in the maintenance therapy were observed. Early relapse patients were less frequently treated with upfront autologous stem cell transplantation (ASCT, 35% vs 60%, p<0.001). Progression on active treatment/maintenance was observed more often in the early relapse group (55% vs 18%, p<0.001).
On multivariable logistic regression model early relapse (vs all remaining patients) was predicted by HR cytogenetic features (odds ratio [OR] 3.06, 95% confidence interval [CI] 1.71-5.46, p<0.001), non-IgG isotype disease (OR 2.17, 95% CI 1.33-3.54, p=0.02), a non-ASCT pathway (OR 2.78, 95% CI 1.71-4.52, p<0.01), and by achieving less than a very good partial remission (VGPR; OR 3.23, 95% CI 1.96-5.35, p<0.01).
The only factor associated with decreased chances of late relapse (vs all remaining patients) on multivariate logistic regression model was the presence of HR FISH features (OR 0.18, 95% CI 0.04-0.82, p=0.03).
Median PFS from first relapse for the whole population was 13.9 months (95% CI 12.9-15.1), median OS from first relapse - 44.6 months (95% CI 41.7-183.0). Early relapse group exhibited worse median PFS and OS from first relapse (median PFS 9.1 months; median OS 26.6 months) than patients who relapsed 2-5 years after diagnosis (median PFS 18.5 months; OS 71.9 months), or late relapse group (median PFS 31.6 months; median OS 87.8 months; p<0.001) (Figure 1).
Conclusions
Early relapse (<2 years) is an indicator for shorter duration of response to subsequent treatments, and worse OS. Treatment with upfront ASCT and achieving VGPR or better after first line therapy lower the risk of early relapse. The only parameter that is predictive for both early and late relapse is HR FISH features. Although factors that predict worse survival in MM are well defined, further studies are needed to identify predictors of a more indolent disease course so that future therapeutic approaches can be tailored to each individual.
Figure 1 Figure 1.
Kapoor: AbbVie: Research Funding; Glaxo SmithKline: Research Funding; Takeda: Research Funding; Karyopharm: Research Funding; Sanofi: Research Funding; Karyopharm: Consultancy; Cellectar: Consultancy; BeiGene: Consultancy; Pharmacyclics: Consultancy; Sanofi: Consultancy; Amgen: Research Funding; Ichnos Sciences: Research Funding; Regeneron Pharmaceuticals: Research Funding. Dispenzieri: Sorrento Therapeutics: Consultancy; Oncopeptides: Consultancy; Pfizer: Research Funding; Alnylam: Research Funding; Takeda: Research Funding; Janssen: Consultancy, Research Funding. Gertz: Akcea Therapeutics, Alnylam Pharmaceuticals Inc, Prothena: Consultancy; Ionis Pharmaceuticals: Other: Advisory Board; AbbVie Inc, Celgene Corporation: Other: Data Safetly & Monitoring; Aurora Biopharma: Other: Stock option; Akcea Therapeutics, Ambry Genetics, Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Karyopharm Therapeutics, Pfizer Inc (to Institution), Sanofi Genzyme: Honoraria. Dingli: Alexion: Consultancy; Janssen: Consultancy; Novartis: Research Funding; GSK: Consultancy; Sanofi: Consultancy; Apellis: Consultancy. Kumar: Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Tenebio: Research Funding; Roche-Genentech: Consultancy, Research Funding; Beigene: Consultancy; Oncopeptides: Consultancy; Amgen: Consultancy, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Antengene: Consultancy, Honoraria; Carsgen: Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bluebird Bio: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding.
| v2 |
2021-11-26T16:40:00.756Z | 2021-11-05T00:00:00.000Z | 244647911 | s2ag/train | Oral Administration of Mavorixafor, a CXCR4 Antagonist, Increases Peripheral White Blood Cell Counts across Different Disease States
Introduction: Peripheral leukocyte deficiency is a common feature of multiple diseases and may render affected individuals susceptible to infections, both common and opportunistic. The CXCR4 chemokine receptor regulates the trafficking of leukocytes among the bone marrow, blood, and lymphatic system (Al Ustwani O, et al. Br J Haematol. 2014;164:15-23). Mavorixafor is an orally available investigational, small-molecule, selective antagonist of the CXCR4 receptor with potential to restore physiological trafficking and maturation of white blood cells (WBCs). Mavorixafor was previously shown to increase totals and subsets of WBCs in healthy volunteers and in a phase 2 clinical trial in adults with WHIM (Warts, Hypogammaglobulinemia, Infections, Myelokathexis) syndrome (Stone N, et al. Antimicrob Agents Chemother. 2007;51(7):2351-2358; Dale D, et al. Blood. 2020;136(26):2994-3003). Here, we report the effect of daily oral administration of mavorixafor on peripheral WBC counts and subsets in patients with clear cell renal cell carcinoma (ccRCC), WHIM syndrome, and Waldenström's macroglobulinemia (WM).
Methods: Percentage changes in total peripheral WBC count, absolute neutrophil count (ANC), absolute lymphocyte count (ALC), and absolute monocyte count (AMC) from pretreatment levels were evaluated in the following settings: a phase 1/2 trial evaluating mavorixafor (200 mg twice daily or 400 mg once daily [QD]) in combination with axitinib (5 mg twice daily) in patients with advanced ccRCC who received ≥1 prior therapy; a phase 1b trial evaluating mavorixafor (400 mg QD) in combination with nivolumab (240 mg QD) in patients with metastatic ccRCC unresponsive to prior nivolumab monotherapy; a long-term extension of the aforementioned phase 2 trial evaluating mavorixafor 300 or 400 mg QD in patients with WHIM syndrome with pathogenic CXCR4 gain-of-function mutation and ANC ≤400/μL and/or ALC ≤650/μL; and an ongoing phase 1b trial evaluating mavorixafor (200 mg QD for 4 weeks, increased to 400 mg and 600 mg QD thereafter) in combination with ibrutinib (420 mg QD) in patients with WM with MYD88 and CXCR4 mutations.
Results: In the study evaluating combination mavorixafor (400 mg QD) and axitinib in ccRCC, total WBC count, ANC, ALC, and AMC increased to 153%, 158%, 143%, and 182% of baseline after 4 weeks (n=49), and with increases sustained at 159%, 171%, 139% and 166% of baseline after 6 months' treatment (n=20). In the study evaluating mavorixafor in combination with nivolumab in ccRCC, total WBC count, ANC, ALC, and AMC increased to 146%, 143%, 141%, and 179% of baseline after 4 weeks (n=9), and with increases sustained at 147%, 136%, 152%, and 191% of baseline after 6 months (n=2). In an interim analysis of the phase 1b trial in WM, compared to screening values, total WBC count, ANC, ALC, and AMC increased to 192%, 170%, 219%, and 186% of baseline after 4 weeks (n=8), and with increases sustained at 163%, 192%, 106%, 172% of baseline after 6 months' (n=5) treatment. In the WHIM syndrome phase 2 extension, total WBC count, ANC, ALC, and AMC increased to 339%, 652%, 239%, and 486% of baseline after 6 months' (n=5) treatment, with annualized infection rate decreasing from 5.6 (SD ± 3.13) events at baseline to 2.2 (SD ± 0.93) events after 40 months. Mavorixafor was generally well tolerated, with manageable safety profile across all indications either alone or in combination with other drugs.
Conclusions: Mavorixafor alone or in combination with other therapies is the first oral treatment to either acutely or chronically increase total peripheral WBCs 1.5- to 3-fold and WBC subsets across all disease populations examined, in both the presence (WHIM syndrome and WM) and absence (ccRCC and healthy volunteers) of CXCR4 gain-of-function mutation. Increases in WBC subsets occurred rapidly and were sustained during chronic treatment, with a larger treatment effect in patients with pre-existing cytopenia (WHIM syndrome) compared to patients without cytopenia at baseline (ccRCC and WM). Co-occurring reduction in infection burden was observed in the phase 2 trial in WHIM syndrome. Assessment of the beneficial effects of mavorixafor on total and WBC subsets is ongoing in a phase 3 trial of WHIM syndrome and a phase 1 trial of severe chronic neutropenia (SCN) that will assess the potential to correct cytopenias by elevating total WBC counts.
Dale: X4 Pharmaceuticals: Consultancy, Honoraria, Research Funding. Treon: AbbVie: Consultancy, Research Funding; Dana Farber Cancer Institute: Current Employment; Self: Patents & Royalties: Holder of multiple patents related to testing and treatment of MYD88 and CXCR4 mutated B-cell malignancies; BMS: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; X4: Research Funding. McDermott: Johnson and Johnson: Consultancy, Honoraria; Genentech: Research Funding; Eisia Inc.: Consultancy, Honoraria; Werewolf Therapeutics: Consultancy, Honoraria; Calithera Biosciences: Consultancy, Honoraria; X4 Pharmaceuticals: Research Funding; Iovance: Consultancy, Honoraria; EMD Serono: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Exelixis: Research Funding; Alkermes, Inc.: Consultancy, Honoraria, Research Funding; Eli Lilly and Company: Consultancy, Honoraria. Cadavid: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Luo: X4 Pharmaceuticals: Consultancy. Garg: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Tang: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Jiang: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Chen: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Taveras: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Bhandari: X4 Pharmaceuticals: Current Employment.
| v2 |
2020-01-02T21:18:48.674Z | 2019-12-20T00:00:00.000Z | 211536961 | s2ag/train | Biologics for chronic rhinosinusitis.
BACKGROUND
This living systematic review is one of several Cochrane Reviews evaluating the medical management of patients with chronic rhinosinusitis. Chronic rhinosinusitis is common. It is characterised by inflammation of the nasal and sinus linings, nasal blockage, rhinorrhoea, facial pressure/pain and loss of sense of smell. It occurs with or without nasal polyps. 'Biologics' are medicinal products produced by a biological process. Monoclonal antibodies are one type, already evaluated in related inflammatory conditions (e.g. asthma and atopic dermatitis).
OBJECTIVES
To assess the effects of biologics for the treatment of chronic rhinosinusitis.
SEARCH METHODS
The Cochrane ENT Information Specialist searched the Cochrane ENT Register; CENTRAL (2019, Issue 9); Ovid MEDLINE; Ovid Embase; Web of Science; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished trials. The date of the search was 16 September 2019.
SELECTION CRITERIA
Randomised controlled trials (RCTs) with at least three months follow-up comparing biologics (currently, monoclonal antibodies) against placebo/no treatment in patients with chronic rhinosinusitis.
DATA COLLECTION AND ANALYSIS
We used standard Cochrane methodological procedures. Our primary outcomes were disease-specific health-related quality of life (HRQL), disease severity and serious adverse events (SAEs). The secondary outcomes were avoidance of surgery, extent of disease (measured by endoscopic or computerised tomography (CT) score), generic HRQL and adverse events (nasopharyngitis, including sore throat). We used GRADE to assess the certainty of the evidence for each outcome.
MAIN RESULTS
We included eight RCTs. Of 986 adult participants, 984 had severe chronic rhinosinusitis with nasal polyps; 43% to 100% of participants also had asthma. Three biologics, with different targets, were evaluated: dupilumab, mepolizumab and omalizumab. All the studies were sponsored or supported by industry. Anti-IL-4Rα mAb (dupilumab) versusplacebo/no treatment (all receiving intranasal steroids) Three studies (784 participants) evaluated dupilumab. Disease-specific HRQL was measured with the SNOT-22 (score 0 to 110; minimal clinically important difference (MCID) 8.9 points). At 24 weeks, the SNOT-22 score was 19.61 points lower (better) in participants receiving dupilumab (mean difference (MD) -19.61, 95% confidence interval (CI) -22.54 to -16.69; 3 studies; 784 participants; high certainty). Symptom severity measured on a 0- to 10-point visual analogue scale (VAS) was 3.00 lower in those receiving dupilumab (95% CI -3.47 to -2.53; 3 studies; 784 participants; moderate certainty). The risk of serious adverse events may be lower in the dupilumab group (risk ratio (RR) 0.45, 95% CI 0.28 to 0.75; 3 studies; 782 participants; low certainty). The number of participants requiring nasal polyp surgery (actual or planned) during the treatment period is probably lower in those receiving dupilumab (RR 0.17, 95% CI 0.05 to 0.52; 2 studies; 725 participants; moderate certainty). Change in the extent of disease using the Lund Mackay computerised tomography (CT) score (0 to 24, higher = worse) was -7.00 (95% CI -9.61 to -4.39; 3 studies; 784 participants; high certainty), a large effect favouring the dupilumab group. The EQ-5D visual analogue scale (0 to 100, higher = better; MCID 8 points) was used to measure change in generic quality of life. The mean difference favouring dupilumab was 8.59 (95% CI 5.31 to 11.86; 2 studies; 706 participants; moderate certainty). There may be little or no difference in the risk of nasopharyngitis (RR 0.95, 95% CI 0.72 to 1.25; 3 studies; 783 participants; low certainty). Anti-IL-5 mAb (mepolizumab) versusplacebo/no treatment (all receiving intranasal steroids) Two studies (137 participants) evaluated mepolizumab. Disease-specific HRQL measured with the SNOT-22 at 25 weeks was 13.26 points lower (better) in participants receiving mepolizumab (95% CI -22.08 to -4.44; 1 study; 105 participants; low certainty; MCID 8.9). It is very uncertain whether there is a difference in s ymptom severity: on a 0- to 10-point VAS symptom severity was -2.03 lower in those receiving mepolizumab (95% CI -3.65 to -0.41; 1 study; 72 participants; very low certainty). It is very uncertain if there is difference in the risk of serious adverse events (RR 1.57, 95% CI 0.07 to 35.46; 2 studies; 135 participants, very low certainty). It is very uncertain whether or not the overall risk that patients still need surgery at trial end is lower in the mepolizumab group (RR 0.78, 95% CI 0.64 to 0.94; 2 studies; 135 participants; very low certainty). It is very uncertain whether mepolizumab reduces the extent of disease as measured by endoscopic nasal polyps score (scale range 0 to 8). The mean difference was 1.23 points lower in the mepolizumab group (MD -1.23, 95% -1.79 to -0.68; 2 studies; 137 participants; very low certainty). The difference in generic quality of life (EQ-5D) was 5.68 (95% CI -1.18 to 12.54; 1 study; 105 participants; low certainty), favouring the mepolizumab group. This difference is smaller than the MCID of 8 points. There may be little or no difference in the risk of nasopharyngitis (RR 0.73, 95% 0.36 to 1.47; 2 studies; 135 participants; low certainty). Anti-IgE mAb (omalizumab) versus placebo/no treatment (all receiving intranasal steroids) Three very small studies (65 participants) evaluated omalizumab. We are very uncertain about the effect of omalizumab on disease-specific HRQL, severe adverse events, extent of disease (CT scan scores), generic HRQL and adverse effects.
AUTHORS' CONCLUSIONS
In adults with severe chronic rhinosinusitis and nasal polyps, using regular topical nasal steroids, dupilumab improves disease-specific HRQL compared to placebo, and reduces the extent of the disease as measured on a CT scan. It probably also improves symptoms and generic HRQL and there is no evidence of an increased risk of serious adverse events. It may reduce the need for further surgery. There may be little or no difference in the risk of nasopharyngitis. In similar patients, mepolizumab may improve both disease-specific and generic HRQL. It is uncertain whether it reduces the need for surgery or improves nasal polyp scores. There may be little or no difference in the risk of nasopharyngitis. It is uncertain if there is a difference in symptom severity and the risk of serious adverse events. We are uncertain about the effects of omalizumab. | v2 |
2018-04-03T00:40:34.317Z | 2005-07-15T00:00:00.000Z | 26288361 | s2ag/train | Chronic Versus Acute Diseases
In their Editorial “Global chronic diseases” (21 Jan., p. 317), D. Yach et al. quote a World Bank analysis that states that more gains in life expectancy would accrue from the control of cardiovascular diseases (CVD) than from targets related to child and maternal mortality ([1][1]), and they question the Millennium Development Goals (MDG), which target infectious diseases and maternal/child health. We think it is unfortunate to base suggestions for global funding changes on what was essentially a regional report.
Although we share the view of the authors that obesity-related diseases and smoking are rapidly becoming pandemic, we strongly believe that infectious diseases still remain a major economic burden for low- and middle-income countries. Annually, malaria kills about 3 million, 3 million die from HIV/AIDS, and tuberculosis (TB) claims another 2 million lives. The total costs of malaria as a proportion of household income have been estimated to be between 4.9 and 18% for infected households in endemic countries, and this burden can be considerably higher for poorer households, reaching up to 32% ([2][2]). Economic growth has been estimated to be 1.3% lower in malaria-endemic countries ([2][2]).
Although the monetary value of economic losses due to TB is difficult to assess, estimates for India, where there are 2 million new cases and 500,000 deaths annually, indicate that the total cost of TB could reach as high as 40% of annual per capita household income ([3][3]).
It is projected that by 2010, there will be 25 to 50 million AIDS orphans, most of them in Africa and Asia. A World Bank document ([4][4]) reports that in the typical developing country, cost per adult death ranges from 8 to 400% of annual income per capita (average = 150% annual income/capita). The number of AIDS orphans stands at over 10 million, and destitute children may turn to violence and prostitution and drop out of school.
Effective prevention and treatment programs as envisioned under the MDG will go a long way to save lives, reduce poverty, and help economies to develop. We fear that the statements made by the authors could generate a climate of confusion, diverting allocation of resources from much-needed health interventions. We cannot afford to focus on chronic noncommunicable diseases at the expense of preventable killer infectious diseases.
1. [↵][5]World Bank, “Millennium Development Goals for Health in Europe and Central Asia: Relevance and Policy Implications” (World Bank, Washington, DC, 2004.
2. [↵][6]1. S. Russell
, “The economic burden of illness for households: A review of cost of illness and coping strategy studies focusing on malaria, tuberculosis and HIV/AIDS,” Disease Control Priorities Project (DCPP) Working Paper 15 (Bethesda, MD, DCPP 2003).
3. [↵][7]1. R. Rajeswari 2. et al.
, Int. J. Tuberc. Lung Dis. 3, 869 (1999).
[OpenUrl][8][PubMed][9][Web of Science][10]
4. [↵][11]1. M. P. Over 2. et al.
, Impact of Adult Death on Household expenditures in Jagera, Tanzania (Policy Research Working Paper, World Bank, Washington DC, 2001).
# Response {#article-title-2}
The need for effective investment in global health is urgent. Senok and Botta balance our call for attention to noncommunicable diseases by arguing persuasively for continued investment in infectious disease control. Such investments will have their major impact among the poorest billion people.
But we cannot wait until these problems are solved before addressing concurrent chronic disease risks like tobacco, increasingly unhealthy diets, and increasing physical inactivity, which are prevalent in much of the developing world. In low- and middle-income countries that are home to over 4 billion people, tobacco use (already causing nearly 5 million deaths a year) ([1][12]) and diabetes rates are soaring ([2][13]). Waiting would accelerate both a health and an economic tragedy.
Heart attack and stroke, thought to be quintessential western diseases of affluence, are fast becoming major threats in developing countries. They now cause four times as many deaths in mothers in most developing countries as childbirth and HIV/AIDS combined ([3][14]). Worldwide, HIV/AIDS causes 3 million deaths a year; stroke and heart attacks cause 17 million (11 million deaths in developing countries) ([3][14]).
Yet heart disease, diabetes, and cancers receive only trivial interest from international agencies committed to improving global health. Heart disease and stroke are pushing families into poverty in developing countries as breadwinners and mothers die young. These breadwinners are also the most productive members of the workforce, and their efforts determine future prosperity and investment.
Billions of dollars have been committed to the Global Fund for AIDS, Malaria and TB, and the Global Alliances for Vaccine and Immunization (GAVI) and for Improved Nutrition (GAIN). But although it is true that chronic diseases are more prevalent among countries that are above desperate poverty, virtually no funds have been raised to reduce chronic diseases or their risks. Less than 5% of the World Health Organization budget, less than 3% World Bank loans for health, and few international donors support chronic disease research, policy development, or actions.
Is the case for investment in global health either/or? We think not.
An investment approach to global health that includes diseases on the basis of need rather than whim or fashion has much to commend it.
1. [↵][15] World Health Report 2002–Reducing Risks, Promoting Healthy Life (World Health Organization, Geneva, 2002.
2. [↵][16]Diabetes Atlas (International Diabetes Federation, Brussels, ed. 2, 2003).
3. [↵][17] World Health Report 2003–Shaping the Future (World Health Organization, Geneva, 2003), chap. 6.
[1]: #ref-1
[2]: #ref-2
[3]: #ref-3
[4]: #ref-4
[5]: #xref-ref-1-1 "View reference 1 in text"
[6]: #xref-ref-2-1 "View reference 2 in text"
[7]: #xref-ref-3-1 "View reference 3 in text"
[8]: {openurl}?query=rft.jtitle%253DThe%2Binternational%2Bjournal%2Bof%2Btuberculosis%2Band%2Blung%2Bdisease%2B%253A%2B%2Bthe%2Bofficial%2Bjournal%2Bof%2Bthe%2BInternational%2BUnion%2Bagainst%2BTuberculosis%2Band%2BLung%2BDisease%26rft.stitle%253DInt%2BJ%2BTuberc%2BLung%2BDis%26rft.aulast%253DRajeswari%26rft.auinit1%253DR.%26rft.volume%253D3%26rft.issue%253D10%26rft.spage%253D869%26rft.epage%253D877%26rft.atitle%253DSocio-economic%2Bimpact%2Bof%2Btuberculosis%2Bon%2Bpatients%2Band%2Bfamily%2Bin%2BIndia.%26rft_id%253Dinfo%253Apmid%252F10524583%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx
[9]: /lookup/external-ref?access_num=10524583&link_type=MED&atom=%2Fsci%2F309%2F5733%2F380.2.atom
[10]: /lookup/external-ref?access_num=000082812800005&link_type=ISI
[11]: #xref-ref-4-1 "View reference 4 in text"
[12]: #ref-5
[13]: #ref-6
[14]: #ref-7
[15]: #xref-ref-5-1 "View reference 1 in text"
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[17]: #xref-ref-7-1 "View reference 3 in text" | v2 |
2020-10-28T19:11:58.301Z | 2020-08-04T00:00:00.000Z | 229535531 | s2ag/train | Radiation and ablation coupling applied to the study of the Lost City bolide.
<p><strong>Introduction</strong></p>
<p>Meteor phenomena involve a series of complex aspects, from multiphase physics of the meteoroid (melting and evaporation) to non-equilibrium effects within the flow.</p>
<p>The current meteor physics equations (single-body theory), rely on a zero-dimensional method and lack a precise treatment of the particle interaction with the atmosphere from the fluid dynamics point of view.</p>
<p>Moreover, the study of the material response (melting and possible material removal) is often neglected.</p>
<p>Another approach involves detailed computational simulations of the phenomena. Although these simulations are computationally expensive, they provide physical features of the flow that the single body theory cannot.</p>
<p>The complexity of these detailed simulations significantly increases when one tries to couple all physical aspects, where Golub et al. [1], Johnston and Stern [2], Johnston et al. [3], Shuvalov and Artemieva [4], Svettsov et al. [5] show some examples.</p>
<p>This abstract aims to simulate Lost City entry with a quasi-1D approach employing high-fidelity models by coupling a material solver with a flow solver, where the latter includes radiative features.</p>
<p>Finally, we compare the mass loss from the numerical simulations with the dynamic mass derived from the observations of Ceplecha and ReVelle [6].</p>
<p> </p>
<p><strong>Methodology</strong></p>
<p>We describe the coupling procedure to study Lost City ablation, which involves three solvers.</p>
<p>Stagnation-line solver: It solves the discretized Navier-Stokes equations employing the Finite-Volume method. It includes an evaporation boundary condition based on the Hertz-Knudsen model. The open-source library Mutation++ [7] provides the necessary thermodynamic, transport, and kinetic closure to the Navier-Stokes equations.</p>
<p>Radiation solver: It solves the Radiative Transport Equation (RTE) using the tangent slab method allowing the computation of radiative fluxes, radiative powers, and the mass production rate due to photochemistry. Chemical and energy source terms due to radiation are included in the Navier-Stokes equations (stagnation-line solver) by following the work of Soucasse et al. [8] and Dias et al. [9].</p>
<p>Material solver: It solves the material phase-change and the removal of the liquid layer by shear forces. The solver takes as boundary conditions from the stagnation-line solver the heat flux, aerodynamic forces, and evaporation rate.  The reader is referred to Dias et al. [10] for a complete description of the material solver.</p>
<p>Finally, we use an implicit approach to couple the material and flow solver [11, 12].</p>
<p> </p>
<p><strong>Results & Conclusion</strong></p>
<p>We simulate a trajectory between 60 km and 53 km – with an interval of 1 km from a point to another – with a constant velocity of 14.15 km/s [6].</p>
<p>A fair comparison has been obtained at the first trajectory points between the numerical results and the dynamic mass derived from observations.</p>
<p>Bellow 57 km, the numerical results underestimate the ablation.</p>
<p>The removal of mass due to shear forces is the primary source of ablation above 54 km, whereas the evaporation rate becomes dominant at 53 km. The evaporation rate increases at lower altitudes due to a surface temperature rise owed to the rise of the radiative heat flux at the surface.</p>
<p>The average shear forces, which causes molten layer removal, increase along the trajectory due to an increase of the free-stream pressure. Despite the rise of the aerodynamic forces, the melting mass removal tends to an asymptotic value. This effect is owed to a decrease of the molten thickness caused by a more substantial evaporation rate.</p>
<p>Regarding the in-dept material, one observes a large temperature gradient close to the surface while the core remains cold.</p>
<p>This large temperature gradient at the surface is a combination of the low material thermal diffusivity and the large mass removal.</p>
<p> </p>
<p>Due to the coupling between the flow and material, we have observed a much lower evaporation rate than in the results shown in Dias et al. [9]. </p>
<p>These results support the importance of material/flow coupling for this type of bolide. Moreover, the liquid layer removal is the dominant source of ablation for most of the trajectory. Additional processes might be missing from our analysis, such as the mass removal due to the inertial forces that might explain the small discrepancy between our results and the observations.</p>
<p> </p>
<p><strong>References</strong></p>
<p><strong> </strong></p>
<p>[1] A. P. Golub, I. B. Kosarev, I. V. Nemchinov, and V. V. Shuvalov. Emission and Ablation of a Large Meteoroid in the Course of Its Motion through the Earth’s Atmosphere. Solar System Research, 30:183, 1996.</p>
<p>[2] C. O. Johnston and E. C. Stern. A model for thermal radiation from the Tunguska airburst. Icarus, 327:48–59, Jul 2019.</p>
<p>[3] C. O. Johnston, E. C. Stern, and L. F. Wheeler. Radiative heating of large meteoroids during atmospheric entry. Icarus, 309:25 – 44, 2018.</p>
<p>[4] V. Shuvalov and N. Artemieva. Numerical modeling of Tunguska like impacts. Planetary and Space Science, 50(2):181 – 192, 2002.</p>
<p>[5] V. V. Svettsov, V. V. Shuvalov, and O. P. Popova. Radiation from a superbolide. Solar System Research, 52(3):195–205, May 2018.</p>
<p>[6] Z. Ceplecha and D. O. ReVelle. Fragmentation model of meteoroid motion, mass loss, and radiation in the atmosphere. Meteoritics & Planetary Science, 40(1):35–54, 2005.</p>
<p>[7] J. B. Scoggins, V. Leroy, G. Bellas-Chatzigeorgis, B. Dias and T. E. Magin, Mutation++:</p>
<p>MUlticomponent Thermodynamic And Transport properties for IONized gases in C++, arXiv:2002.01783v1 [physics.comp-ph] (submitted to SoftwareX), 2020.</p>
<p>[8] L. Soucasse, J. Scoggins, P. Rivière, T. Magin, and A. Soufiani. Flow radiation coupling for atmospheric entries using a hybrid statistical narrow-band model. Journal of Quantitative Spectroscopy and Radiative Transfer, 180:55–69, 2016.</p>
<p>[9] B. Dias, J.B. Scoggins, T. E. Magin, Luminosity calculation of meteoroid entry based on detailed flow simulations in the continuum regime, Astronomy & Astrophysics 635, A184 (2020).</p>
<p>[10] B. Dias, A. Turchi, E. Stern, and T. E. Magin, A model for meteoroid ablation including melting and vaporization, Icarus, 345(2020) 113710.</p>
<p>[11] P. Schrooyen, A. Turchi, K. Hillewaert, P. Chatelain, and T. E. Magin. Two-way coupled simulations of stagnation-point ablation with transient material response. International Journal of Thermal Sciences, 134:639 –652, 2018.</p>
<p>[12] B. Dias, F. Bariselli, A. Turchi, A. Frezzotti, P. Chatelain, and T. E. Magin, Development of a melting model for meteors, AIP Conference Proceedings 1786(1) 160004.</p> | v2 |
2019-11-22T01:00:53.275Z | 2019-11-13T00:00:00.000Z | 209227901 | s2ag/train | Gene Expression and Cytokine Analyses Identify Markers of Progression from CLL-like Monoclonal B-Cell Lymphocytosis to Chronic Lymphocytic Leukemia
INTRODUCTION: Chronic lymphocytic leukemia (CLL)-like monoclonal B cell lymphocytosis (MBL) is considered a precursor of CLL. It is found in 5-10% of elderly healthy individuals and shows a progression rate to CLL requiring therapy of 1.1% per year. A balance between microenvironmental factors and intrinsic properties of the emerging B cell clone may be decisive for the transition from MBL to CLL, although biomarkers of progression remain unknown. The objective is to describe biological markers (B cell gene expression profiles and serum cytokine levels) that predict progression from MBL to CLL.
METHODS: Gene expression profiles of clonal B cells from 14 MBL subjects (median age: 76 years, clonal B cells: 0.5-4.3 x109/L) were evaluated. With a median follow-up from analysis of 59 months (range: 10-77), 3 cases (21.4%) had progressed to CLL Binet stage A at last follow-up (clonal lymphocytosis >5x109/L, range: 6.2-7.9). Clonal B cells (CD19+CD5+) were isolated from peripheral blood by immunomagnetic methods (Miltenyi Biotec). Extracted RNA (RIN>7) was hybridized to GeneChip Human Gene 2.0 ST arrays (Affymetrix). Gene expression profiles were compared between MBL cases that progressed to CLL (P-MBL, n=3) and non-progressive MBL cases (NP-MBL, n=11). Differential gene expression was evaluated employing linear models for microarrays in R, and genes with P<0.05 and Fold Change >1.5 or <-1.5 were considered differentially expressed. To obtain insight into the functional significance of the differential genetic signatures, the Ingenuity Pathway Analysis tool (IPA, QIAGEN) was employed. On the other hand, serum levels of IL1β, IL2, IL4, IL5, IL6, IL8, IL10, IL12, IL15, IL17, IFNα, IFNγ, TNFα, GM-CSF, CCL3, CCL4, CCL19, CXCL9, CXCL10 and CXCL11 were quantified using the U-PLEX Platform (Meso Scale Discovery) and Human CXCL9/MIG Quantikine ELISA Kit (R&D Systems) in 41 MBL subjects (median age: 67 years, clonal B cells: 0.5-4.8 x109/L). With a median follow-up from analysis of 47 months (range: 0-117), 5 of them (12.2%) had progressed to CLL Binet stage A at last follow-up (clonal lymphocytosis >5x109/L, range: 6.4-17.3). Clonal B cells and cytokine levels were compared between P-MBL (n=5) and NP-MBL (N=36). For cytokine levels, the optimal cut-off values to stratify MBL cases according to their progression risk were assessed using the maxstat R package, whereas for clonal B cells a cut-off value of 3.9 x109/L was considered according to the results obtained by Kostopoulos et al (Blood Cancer J, 2017). The effect of different covariates on progression-free survival was evaluated using log-rank test. Cox proportional hazards regression models were performed to assess their independent prognostic value. P<0.05 was considered significant.
RESULTS: A total of 455 genes were differentially expressed (250 upregulated and 205 downregulated in P-MBL). IPA predicted an inhibition of apoptosis as well as proteins with tumor suppressor activity (SMARCA4) in P-MBL, besides enhanced bioenergetic processes (transmembrane potential of mitochondria) and anti-inflammatory features (activation of IL13 pathway and decreased chemotaxis of phagocytes and granulocytes) (Table 1). P-MBL displayed increased clonal B cells (4.2 vs. 1.7 x109/L, P=0.003) and levels of IL10 (1.15 vs. 0.9 pg/mL, P=0.087) as well as diminished levels of IL6 (2.04 vs. 3.75 pg/mL, P=0.041). MBL cases with ≥3.9 x109/L clonal B cells, ≥1.08 pg/mL of IL10 and ≤2.04 pg/mL of IL6 had an increased risk of progression to CLL (P<0.001, P=0.006 and P=0.034, respectively) (Figure 1, Table 2). Multivariate analysis for clonal B cells and levels of IL10 maintained significance for both factors (HR=12.8, P=0.013 and HR=10.2, P=0.047, respectively) (Table 2).
CONCLUSIONS: 1. P-MBL cases showed an inhibition of the apoptotic pathway and an activation of bioenergetic processes, which may account for the increased clonal B cells observed in this group. 2. P-MBL exhibited enhanced anti-inflammatory features, including augmented levels of the anti-inflammatory cytokine IL10. 3. Increased clonal B cells and IL10 levels predicted a higher risk of progression to CLL, suggesting that an augmented proliferative rate of clonal B cells together with a supporting tumor microenvironment are required for progression from MBL to CLL.
ACKNOWLEDGEMENTS. PI11/01621, PI15/00437, 2017/SGR437, Fundació La Caixa, Fundación Española de Hematología y Hemoterapia (FEHH).
Gimeno: JANSSEN: Consultancy, Speakers Bureau; Abbvie: Speakers Bureau. Rai:Cellectis: Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; Pharmacyctics: Membership on an entity's Board of Directors or advisory committees. Abrisqueta:Roche: Consultancy, Honoraria, Other: Travel, Accommodations, expenses, Speakers Bureau; Abbvie: Consultancy, Honoraria, Other: Travel, Accommodations, expenses, Speakers Bureau; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, expenses, Speakers Bureau; Celgene: Consultancy, Honoraria. Bosch:AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Kyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; F. Hoffmann-La Roche Ltd/Genentech, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria, Research Funding; Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AstraZeneca: Honoraria, Research Funding; Takeda: Honoraria, Research Funding.
| v2 |
2019-11-17T08:13:24.375Z | 2019-08-17T00:00:00.000Z | 202068161 | s2ag/train | Alterations in human reaction time upon Consumption of taurine-caffeine based energy Drink. a gender based study.
Bckground: Energy drinks contains several potentially psychoactive ingredients including taurine, glucoronolactone, and caffeine that increases the human performances, reaction time and mood with relative differences to visual and auditory stimuli between both the genders. Objective: we aim to evaluate and compare the effects of energy drink on reaction time of male and female subjects upon visual cue, auditory cue and tactile cue. Methods: The study was conducted on 50 healthy individuals of age group 18-25, residing in Karachi, Pakistan. Ruler Catching Method was used to calculate the reaction time on auditory visual and tactile cues and formula t = √ d ⁄ 490 was applied to calculate the reaction time in cm/sec2. Results: It was analysed that the mean reaction time for all visual, auditory and tactile cues decreased significantly after the consumption of the energy drink. However, visual response after consumption of energy drink was quicker in males whereas, auditory and tactile responses were faster in females. Conclusion: Consumption of energy drinks surely influence the visual, auditory and tactile responses positively in both the genders but on the other hand also poses vulnerable impact on human health. Correspondence to: Faizan Mirza Department of Physiology, University of Karachi Email : [email protected] Date of submission: January 21, 2019 Date of revision: March 28, 2019 Date of acceptance: April 5, 2019 References: 1. Meier, B., Energy Drinks Promise Edge, but Experts Say Proof Is Scant. Energy, 2013. 2. Loeb, H., Do the Ingredients in Energy Drinks Work?. . 2009. https://www.menshealth.com/nutrition/a1953653 1/energy-drink-ingredients/ 3. Mintel, Energy Drinks Market Research July 2006. http://reports.mintel.com/display/121102/. 4. Forbes, S.C., et al., Effect of Red Bull energy drink on repeated Wingate cycle performance and bench-press muscle endurance. International journal of sport nutrition and exercise metabolism, 2007. 17(5): p. 433-444. 5. Alford, C., H. Cox, and R. Wescott, The effects of red bull energy drink on human performance and mood. Amino acids, 2001. 21(2): p. 139-150. 6. Van den Eynde, F., et al., The effects of energy drinks on cognitive performance. Tijdschrift voor psychiatrie, 2008. 50(5): p. 273-281. 7. Shelton, J. and G.P. Kumar, Comparison between auditory and visual simple reaction times. Neurosci Med, 2010. 1(1): p. 30-32. 8. Pain, M.T. and A. Hibbs, Sprint starts and the minimum auditory reaction time. Journal of sports sciences, 2007. 25(1): p. 79-86. 9. Ishak, W.W., et al., Energy drinks: psychological effects and impact on well-being and quality of life—a literature review. Innovations in clinical neuroscience, 2012. 9(1): p. 25. 10. Glade, M.J., Caffeine—not just a stimulant. Nutrition, 2010. 26(10): p. 932-938. 11. Rao, A., H. Hu, and A.C. Nobre, The effects of combined caffeine and glucose drinks on attention in the human brain. Nutritional neuroscience, 2005. 8(3): p. 141-153. 12. Smith, A., D. Sutherland, and G. Christopher, Effects of repeated doses of caffeine on mood and performance of alert and fatigued volunteers. Journal of Psychopharmacology, 2005. 19(6): p. 620-626. 13. Christopher, G., D. Sutherland, and A. Smith, Effects of caffeine in non‐withdrawn volunteers. Human Psychopharmacology: Clinical and Experimental, 2005. 20(1): p. 47-53. 14. Spierer, D.K., R.A. Petersen, K. Duffy, B.M. Corcoran and T. Rawls-Martin Gender influence on response time to sensory stimuli. J. Strength Condition., 2010: p. Res., 24: 957-964 DOI: 10.1519/JSC.0b013e3181c7c536 15. Allen, J.S., H. Damasio, T.J. Grabowski, J. Bruss and W.Zhang. , Sexual dimorphism and asymmetries in the gray-white composition of the human cerebrum. . Neuroimage, 2003. 18: p. 8 8 0 8 9 4 . DOI:10.1016/S1053-8119(03)00034-X 16. Jausovec, N.a.K.J., Gender related differences in visual and auditory processing of verbal and figural tasks. . Brain, 2009. Res., 1300: 135-145.DOI: 10.1016/j.brainres.2009.08.0934. 17. Steinmetz H, S.J., Schlaug G, Huang Y and Jancke L Corpus callosum and brain volume in women and men. Neuroreport 1995. 6: p. 1002–1004. 18. Owen DS, B.D., The impact of raising blood glucose on reaction times. . Neuropsychobiology, 1994. 30: p. 106-113. 19. GL., W., An hypothesis on the role of glucose on the mechanism of action of cognitive enhancers. Psychopharmacology, 1989. 99: p. 431-438. 20. Inglis F M, D.J., Fibiger HC. , Enhanced Acetylcholine release in hippocampus and cortex during the anticipation and consumption of a palatable meal. Neuroscience 1994. 62: p. 1049-1056. 21. Pasman WJ, v.B.M., Jeukendrup AE, de Haan A., The effect of different dosages of caffeine on endurance performance time. . Int J Sports Med, 1995. 16: p. 225-230. 22. Berglund B, H.P., Effects of caffeine ingestion on exercise performance at low and high altitudes in cross-country skiers. . Int J Sports Med, 1982. 3: p. 234-236. 23. Higgins JP, T.T., Higgins CL. , Energy beverages: content and safety. InMayo clinic proceedings Elsevier, 2010 Nov 1. 85(11): p. 1033-1041. V O L . 1 4 ( 2 ) A P R I L J U N E 2 0 1 9 an external measurement parameter [8]. However, there are relative differences between the reaction time to visual and auditory stimuli between both the genders [7]. Thereby, we aim to evaluate and compare the effects of energy drink on reaction time of male and female subjects upon visual cue, auditory cue and tactile cue. Materials and Methods The study was conducted on 50 subjects (25 males and 25 females) of 18-25 age group. They were all the residents of Karachi, Pakistan, and were not suffering from any pathological condition at the time of sampling. Ruler Catching Method was used to calculate the reaction time on auditory visual and tactile cues and following formula was applied to calculate the reaction time in cm/sec2. t = √ d ⁄ 490 Where, T= time for the reaction D= Distance | v2 |
2021-11-25T16:07:14.550Z | 2021-11-05T00:00:00.000Z | 244551161 | s2ag/train | Isatuximab in Combination with Chemotherapy in Pediatric Patients with Relapsed/Refractory Acute Lymphoblastic Leukemia or Acute Myeloid Leukemia (ISAKIDS): Interim Analysis
Introduction: Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer, representing ~25% of cancer diagnoses in children. Approximately 20% of childhood leukemias are of myeloid origin with the majority being acute. Isatuximab (Isa) is a monoclonal antibody that binds to a specific epitope of CD38 and exerts anti-multiple myeloma (MM) effects through several modes of action. Isa is approved for use in MM in adults. CD38 expression is high in some acute leukemia subsets in pediatric patients, making CD38 a potential target for acute leukemia treatment in children.
Methods: ISAKIDS (NCT03860844) is a Phase 2, single-arm, multicenter, open-label study evaluating the antitumor activity, safety, and pharmacokinetics (PK) of Isa in combination with standard salvage chemotherapies in children with relapsed or refractory (R/R) leukemia in first or second relapse; including both T-ALL and B-ALL and acute myeloid leukemia (AML), conducted in 3 separate cohorts. Children from 2 years (yrs) to <18 yrs of age were eligible for inclusion. In all cohorts, participants received 20 mg/kg Isa as a single agent on Day 1 and then weekly for 5 weeks in the ALL groups or weekly for 3 weeks in the AML groups. Combination chemotherapy was added on Day 8 (modified UKALL R3 and fludarabine, cytarabine, G-CSF induction for ALL and AML patients (pts), respectively) unless it was judged necessary to start chemotherapy earlier than Day 8. The primary endpoint was complete response (CR) rate, defined as the proportion of pts with CR or CR with incomplete peripheral recovery (CRi). Secondary endpoints included duration of response, event-free survival, overall survival, and overall response rate. CD38 receptor density was assessed at baseline and CD38 occupancy was assessed at Day 15. Descriptive statistics were carried out on the evaluable population. Confidence intervals were computed using the Clopper-Pearson method. For this first interim analysis, PK parameters for Isa were assessed in the first 20 pts to confirm Isa dose and schedule in very young pts. Safety analyses included treatment-emergent adverse events (TEAEs) of all grades.
Results: 24 pts were enrolled (10, B-ALL; 7, T-ALL; 7, AML) and treated. Baseline characteristics were comparable between cohorts; median age (range) B-ALL 6.5 (3-14) yrs; T-ALL 10.0 (7-16) yrs; AML 7.0 (2-17) yrs. Males (4/10 B-ALL; 6/7 T-ALL; 3/7 AML). Evaluable Lansky scores of 90 - 100 (9/10 B-ALL; 3/4 T-ALL; 4/6 AML). Mean (standard deviation) time from initial diagnosis to first dose of investigational medicinal product (IMP) was 2.6 (1.0) yrs, 1.2 (0.6) yrs, and 1.0 (0.3) yrs for the B-ALL, T-ALL, and AML groups, respectively. Number of prior regimens, median (range) was 6 (1-≥8), 3 (1-≥8), 4 (1-≥8) for the B-ALL, T-ALL, and AML groups, respectively, corresponding to inclusion of pts with very advanced disease. Three pts presented with hyperleukocytosis >20 x 10 9/L. Among 23 pts assessed for CD38 expression, all except 2 (1 B-ALL and 1 AML) were CD38 positive. There were 17 evaluable pts with valid response data collected up to the cutoff date (May 11, 2021). Of the evaluable participants, CR+CRi were observed for: 3/7 (42.9%) in the B-ALL cohort, 2/6 (33.3%) in the T-ALL cohort, and 2/4 (50.0%) in the AML cohort (Table). Safety data showed that Grade ≥3 TEAEs occurred in 17 pts (Table). Infusion reactions (majority Grade 1 or 2) occurred in 9/24 pts (2/10 B-ALL; 4/7 T-ALL; 3/7 AML). Three pts had Grade 5 TEAEs (deaths: 1 B-ALL and 2 AML). One subject in the AML cohort had cytokine-release syndrome (CRS) related to IMP with progressive disease as a confounding factor. The other 2 deaths were not treatment related. One subject in the AML cohort had cellulitis Grade 5 and 1 subject in the B-ALL cohort had septic shock Grade 5 as cause of death. Preliminary PK analysis on 18 pts (>2 yrs) showed that Isa PK parameters including exposure PK parameters in children with ALL or AML are consistent with those observed in adult ALL pts. PK modeling approaches predict a slightly lower exposure (<20%) in pts <2 yrs old (4-12 kg) compared with exposure achieved in adults (51-100 kg) at the same dose.
Conclusions: In a poor prognostic relapsed population, 7/17 (41.2%) pts achieved CR+CRi. Safety profile and exposure is consistent with the available data for adults. Enrollment will be opened for pts <2 yrs of age with R/R ALL or AML.
Figure 1 Figure 1.
Baruchel: Kite/Gilead: Other: Investigator; Novartis, Servier, Celgene, Jazz, Janssen, Sanofi, Amgen,Astra-Zeneca: Membership on an entity's Board of Directors or advisory committees, Other: Satellite symposium; Shire Servier: Research Funding. Abrahamsson: wedish Children´s Cancer Foundation. Research grants and 50% senior research position for clinical research on pediatric leukemia: Research Funding. Nysom: Bayer, Y-mAbs, EUSA Pharma: Consultancy, Honoraria. Rizzari: Sobi: Other: personal fees; Jazz Pharmaceuticals: Other: Personal fees; Amgen: Other: Personal fees; Medac: Other: Grants and personal fees; Shire: Other: Grants and personal fees. Cesaro: Sobi: Membership on an entity's Board of Directors or advisory committees; Gilead: Speakers Bureau. Duarte: Amgen: Consultancy, Other: Advisory Board; Novartis: Consultancy; Jazz Pharma: Research Funding. Kang: Amgen Korea: Membership on an entity's Board of Directors or advisory committees, Research Funding; Cartexell: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Korea: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kattamis: Agios Pharmaceuticals: Consultancy; IONIS: Consultancy; VIFOR: Consultancy; CRISPR/Vertex: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria, Research Funding; Chiesi: Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Amgen: Consultancy. Tøndel: Sanofi: Research Funding. Ivanina: Sanofi: Current Employment. Brillac: Sanofi: Current Employment. Wang: Sanofi: Current Employment. Oprea: Sanofi: Current Employment, Other: may have stock options . Abbadessa: Sanofi: Current Employment. Zwaan: Sanofi: Consultancy.
| v2 |
2019-03-30T13:12:28.690Z | 2013-01-01T00:00:00.000Z | 86073941 | s2ag/train | RESEARCH ARTICLE QUALITATIVE AND QUANTITATIVE STUDY OF EPIPELIC ALGAE AND RELATED ENIVERNOMENTAL PARAMETERS IN AL -HILLA RIVER, IRAQ
The present investigation involves the study of qualitative, quantitative study of epipelic algae and some environmental parameters of Al-Hilla River for the period from April 2009 -March 2010. Six sites have been chosen along the studied river. The study i ncluded measuring some physical and chemical properties of water and sediments, and quality and quantity of epipelic algae as well as the measuring of chlorophyll a and phaeophytin pigments monthly. Results shown the following ranges: (7-40.5 oC), (10-36.5 oC), (11-35.5 oC) for air, water and sediment temperature respectively. Values of pH showed a narrow range, TDS ranged (219-1280 mg/L), TSS ranged (12-75 mg/L), (600-895 s/cm) and (0.384 -0.572) for EC , S. While (0.15 -0.45) m/Sec, (4.8-11) mg/l, (0.6-4.6) mg/l for water flow, DO and BOD5. Light alkalinity, very hardness values were recorded, while the concentrations of calcium were higher than magnesium. The concentration of nutrients ranged (N.D - 9), (N.D.-82), (N.D-39-7) mg/l for nitrite, nitrate, an d phosphate respectively. Silicates values varied between (0.35-39.5) g/l. The sediment texture tended to be silty -clay and high values of TOC in sediments were recorded. Diatoms were the most dominant species among the identified algae followed by chlorophyceae, cyanophyceae and Euglenophyceae. A total of 58 genus with (116) species were recorded in site1, (55) genus, (121) species in site2, and (54) genus with (120) species in site3, (56) genus with (121) species in site4, and (55) genus, (112) species i n the fifth place and (56) genus with (112) species in site 6. The most common taxa were Cyclotella, Scendesmus, Oscillatoria, Melosira, Synedra, Cocconeis and Nitzschia.High total number of epipelic algae observed in March 2010 in site 3, while the lowes t number was recorded in August 2009 at site 4. Chlorophyll1 and Phaeophytin ranged (0.2-16.6) g dm -2 and (N.D-9.05) g dm -2 respectively. Closely values of Shannon index were recorded in all sites and Chandler scores was used in this study. ABSTRACT The present investigation involves the study of qualitative, quantitative study of epipelic algae and some environmental parameters of Al-Hilla River for the period from April 2009 -March 2010. Six sites have been chosen along the studied river. The study i ncluded measuring some physical and chemical properties of water and sediments, and quality and quantity of epipelic algae as well as the measuring of chlorophyll a and phaeophytin pigments monthly. Results shown the following ranges: (7-40.5 oC), (10-36.5 oC), (11-35.5 oC) for air, water and sediment temperature respectively. Values of pH showed a narrow range, TDS ranged (219-1280 mg/L), TSS ranged (12-75 mg/L), (600-895 s/cm) and (0.384 -0.572) for EC , S. While (0.15 -0.45) m/Sec, (4.8-11) mg/l, (0.6-4.6) mg/l for water flow, DO and BOD5. Light alkalinity, very hardness values were recorded, while the concentrations of calcium were higher than magnesium. The concentration of nutrients ranged (N.D - 9), (N.D.-82), (N.D-39-7) mg/l for nitrite, nitrate, an d phosphate respectively. Silicates values varied between (0.35-39.5) g/l. The sediment texture tended to be silty -clay and high values of TOC in sediments were recorded. Diatoms were the most dominant species among the identified algae followed by chlorophyceae, cyanophyceae and Euglenophyceae. A total of 58 genus with (116) species were recorded in site1, (55) genus, (121) species in site2, and (54) genus with (120) species in site3, (56) genus with (121) species in site4, and (55) genus, (112) species i n the fifth place and (56) genus with (112) species in site 6. The most common taxa were Cyclotella, Scendesmus, Oscillatoria, Melosira, Synedra, Cocconeis and Nitzschia.High total number of epipelic algae observed in March 2010 in site 3, while the lowes t number was recorded in August 2009 at site 4. Chlorophyll1 and Phaeophytin ranged (0.2-16.6) g dm -2 and (N.D-9.05) g dm -2 respectively. Closely values of Shannon index were recorded in all sites and Chandler scores was used in this study. ABSTRACT The present investigation involves the study of qualitative, quantitative study of epipelic algae and some environmental parameters of Al-Hilla River for the period from April 2009 -March 2010. Six sites have been chosen along the studied river. The study i ncluded measuring some physical and chemical properties of water and sediments, and quality and quantity of epipelic algae as well as the measuring of chlorophyll a and phaeophytin pigments monthly. Results shown the following ranges: (7-40.5 oC), (10-36.5 oC), (11-35.5 oC) for air, water and sediment temperature respectively. Values of pH showed a narrow range, TDS ranged (219-1280 mg/L), TSS ranged (12-75 mg/L), (600-895 s/cm) and (0.384 -0.572) for EC , S. While (0.15 -0.45) m/Sec, (4.8-11) mg/l, (0.6-4.6) mg/l for water flow, DO and BOD5. Light alkalinity, very hardness values were recorded, while the concentrations of calcium were higher than magnesium. The concentration of nutrients ranged (N.D - 9), (N.D.-82), (N.D-39-7) mg/l for nitrite, nitrate, an d phosphate respectively. Silicates values varied between (0.35-39.5) g/l. The sediment texture tended to be silty -clay and high values of TOC in sediments were recorded. Diatoms were the most dominant species among the identified algae followed by chlorophyceae, cyanophyceae and Euglenophyceae. A total of 58 genus with (116) species were recorded in site1, (55) genus, (121) species in site2, and (54) genus with (120) species in site3, (56) genus with (121) species in site4, and (55) genus, (112) species i n the fifth place and (56) genus with (112) species in site 6. The most common taxa were Cyclotella, Scendesmus, Oscillatoria, Melosira, Synedra, Cocconeis and Nitzschia.High total number of epipelic algae observed in March 2010 in site 3, while the lowes t number was recorded in August 2009 at site 4. Chlorophyll1 and Phaeophytin ranged (0.2-16.6) g dm -2 and (N.D-9.05) g dm -2 respectively. Closely values of Shannon index were recorded in all sites and Chandler scores was used in this study. | v2 |
2016-02-02T08:36:57.578Z | 2015-01-01T00:00:00.000Z | 68733331 | s2ag/train | Oxidative Status and Hypertension: An Examination of the Prospective Association Between Urinary F2-isoprostanes and Hypertension
Background:
Hypertension
is
a
pathological
increase
in
blood
pressure
that
affects
nearly
30%
of
the
U.S.
population
and
is
a
primary
modifiable
risk
factor
for
cardiovascular
disease.
Despite
advancements
in
prevention
and
treatment,
hypertension
is
still
one
of
the
most
common
conditions
around
the
world,
and
for
a
majority
of
cases
the
causal
mechanisms
remain
to
be
fully
elucidated.
A
growing
body
of
literature
suggests
that
oxidative
stress
status
may
play
an
etiological
role
in
many
chronic
conditions,
including
hypertension.
Specifically,
a
systemic
overabundance
of
reactive
oxygen
species
may
give
rise
to
endothelial
dysfunction,
increased
sodium
and
H2O
retention,
and
alterations
in
sympathetic
outflow,
leading
to
an
increase
in
blood
pressure.
Purpose:
The
main
objective
of
this
study
is
to
investigate
the
prospective
association
between
F2‐isoprostanes,
a
validated
biomarker
of
oxidative
status,
and
development
of
hypertension
in
a
large,
multi‐centered,
multi‐ethnic
cohort
of
adults
aged
40‐69
at
baseline.
Methods:
This
is
a
secondary
data
analysis
that
utilized
previously
collected
data
from
the
Insulin
Resistance
Atherosclerosis
Study.
844
participants
were
included
in
the
analysis.
Briefly,
four
urinary
F2‐isoprostane
isomers
(F2‐IsoP1,
F2‐IsoP2,
F2‐IsoP3,
and
F2‐IsoP4)
were
quantified
using
liquid
chromatography/
tandem
mass
spectrometry
and
adjusted
for
urinary
creatinine
levels.
Hypertension
was
assessed
at
baseline
and
follow‐up
visits
and
defined
as
systolic
blood
pressure
>
140
mm
Hg
and/or
diastolic
blood
pressure
>
90
mm
Hg
and/or
currently
taking
antihypertensive
medications.
Crude
associations
between
study
population
characteristics
and
hypertensive
status
were
analyzed
with
the
chi‐square
and
Wilcoxon‐rank
sum
tests.
Crude
associations
between
study
population
characteristics
and
F2‐isoprostane
levels
were
analyzed
with
Wilcoxon‐rank
sum,
Kruskal‐Wallis,
and
Spearman’s
rank
correlation
measures.
Finally,
the
adjusted
prospective
associations
between
hypertensive
status
and
F2‐isoprostane
concentrations
were
modeled
using
logistic
regression.
Results:
Of
the
844
participants
who
were
included
in
the
study,
258
(31%)
were
classified
as
hypertensive
at
baseline.
Among
the
586
participants
who
were
normotensive
at
baseline,
123
(21%)
developed
hypertension
over
the
five‐year
study
period.
Importantly,
none
of
four
F2‐isoprostane
isomers
predicted
a
significant
increase
in
the
odds
of
developing
hypertension,
as
indicated
by
their
odds
ratio
95%
confidence
intervals;
F2‐IsoP1:
(0.85,
1.31),
F2‐IsoP2:
(0.62,
1.13),
F2‐IsoP3:
(0.80,
1.27),
and
F2‐IsoP4:
(0.84,
1.29).
Conclusion:
Previous
studies
have
investigated
the
association
between
oxidative
status
and
hypertension
prevalence,
however
the
cross
sectional
nature
of
the
study
designs
have
made
it
difficult
to
establish
temporality
between
exposure
and
outcome.
To
our
knowledge,
this
is
the
first
study
to
model
the
odds
of
developing
hypertension
as
a
function
of
F2‐isoprostane
levels.
The
results
of
this
study
suggest
that
oxidative
status
is
not
involved
in
the
development
of
hypertension. | v2 |
2020-02-20T09:09:21.669Z | 2019-11-13T00:00:00.000Z | 213844081 | s2ag/train | Mgta-456, an Aryl Hydrocarbon Receptor (AHR) Antagonist Based Expansion of CD34+ Hematopoietic Stem Cells (HSC), Permits Selection of Better HLA Matched Cord Blood Units (CBUs) and Promotes Faster Neutrophil Recovery and Uniform Engraftment with Potentially Less Acute Graft-Vs-Host Disease (GVHD)
Background. HSC dose and HLA match are independent risk factors that impact non-relapse mortality in children and adults undergoing umbilical cord blood (UCB) transplant for acute leukemia (Eapen et al. Blood 2014 123:133-140). Low number of CD34+ HSCs results in prolonged periods of cytopenia and higher risk of graft failure. To reduce these risks, a minimum cell dose threshold, e.g. 3.0 x 107 total nucleated cells (TNC)/kilogram (kg), has generally been required in CBU selection. While beneficial in terms of hematopoietic recovery, this cell dose threshold markedly limits the number of available cord blood units (CBUs) particularly for larger adolescent and adult recipients, thus reducing the probability of identifying a 7-8/8 HLA-matched graft. In addition, a second UCB unit is often required for adults as a single unit may not meet the cell dose threshold. MGTA-456 is an expanded CD34+ HSC product utilizing an AHR antagonist in the presence of SCF, Flt-3L, IL-6 and TPO. In previous studies with fresh MGTA-456, 36 patients with hematologic malignancies demonstrated rapid neutrophil recovery and sustained engraftment in all patients. The aims of this study (NCT03674411) were to evaluate the safety and efficacy of cryopreserved MGTA-456 as well as the effectiveness of lowering the minimum cell dose threshold of the selected CBU from 3.0 x 107 to 1.0 x 107 TNC/kg to improve donor-recipient HLA match.
Patients and Methods: Ten patients with high-risk hematologic malignancy were enrolled with 9 transplanted to date. Conditioning consisted of cyclophosphamide 120 mg/kg, fludarabine 75 mg/m2 and total body irradiation 1320 cGy (total doses) with cyclosporine and mycophenolate mofetil as immunoprophylaxis. G-CSF was initiated on the day after infusion and continued until the neutrophil count exceeded 2500/uL for 3 consecutive days.
Results: Cryopreserved MGTA-456 contained a median of 1.9 x 109 CD34+ cells (range, 1.1-6.2) after expansion culture (a 491-fold expansion of CD34+ cells [range, 219-672]). As shown in Table 1, neutrophil recovery occurred in 100% of patients (with one pending after recent transplant) at a median of 15 days (range, 0-31), similar to recipients of fresh MGTA-456 in a prior study (median 14 days, range 7-32) and significantly faster than in recipients of unmodified UCB (median 25 days). Platelet recovery (>20,000/uL for 7 days without transfusion) was also comparable in recipients of cryopreserved and fresh MGTA-456 (median 42 [range 27-53] vs 45 days [range 28-54], respectively), and again faster relative to recipients of unmodified CBUs (median 64 days). In line with preclinical experiments in NSG murine recipients that demonstrates all engrafting cells are retained in the CD34+CD90+ subpopulation, CD34+CD90+ content strongly correlated with speed of neutrophil recovery in recipients of MGTA-456 (cryopreserved and fresh) as shown in Figure 1. As expected, lowering the cell dose requirement from 3.0 x 107 to 1.0 x 107 TNC/kg for UCB unit selection prior to expansion culture improved HLA match and/or eliminated the need for double UCB transplant in 5 of 6 adults (Table 1). As a result, all but one patient received an 8/8 (n=5) and 7/8 (n=4) HLA matched UCB graft, potentially contributing to the low incidence of acute GVHD with only one patient of the 7 out >42 days having grade 2 acute GVHD. This low rate of GVHD compares favorably to that observed in the prior study of fresh MGTA-456. With a follow-up of 19-187 days (median 89), all patients are alive.
Conclusion: Transplantation of cryopreserved MGTA-456 resulted in complete engraftment and rapid recovery with speed of neutrophil recovery correlating with the CD34+CD90+ cell dose. Based on the marked expansion that is now possible, units with fewer cells can now be considered, increasing the probability of finding a better HLA matched unit, particularly for adults. Availability of MGTA-456 could reduce the barriers associated with cell dose and poor HLA match previously limiting the successful use of UCB in transplantation.
Stefanski: Novartis: Consultancy, Speakers Bureau. Brunstein:Magenta: Research Funding; Gamida: Research Funding; Astex: Research Funding. McKenna:Icahn School of Medicine, New York, New York: Consultancy; CIBMTR BMT CTN (NIH): Other: Medical Monitor; National Eye Institute (NIH): Other: DSMB (2); Magenta Therapeutics: Research Funding; Gamida: Research Funding; NMDP: Other: Donor and Patient Safety Monitoring Advisory Group; Fate Therapeutics: Research Funding; Intima: Patents & Royalties: Royalities, Research Funding. Miller:Dr. Reddys Laboratory: Membership on an entity's Board of Directors or advisory committees; Moderna: Membership on an entity's Board of Directors or advisory committees; Fate Therapeutics, Inc: Consultancy, Research Funding; GT BioPharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; CytoSen: Membership on an entity's Board of Directors or advisory committees; OnKImmune: Membership on an entity's Board of Directors or advisory committees. Blazar:KidsFirst Fund: Research Funding; Childrens' Cancer Research Fund: Research Funding; Abbvie Inc: Research Funding; Leukemia and Lymphoma Society: Research Funding; Kamon Pharmaceuticals, Inc: Membership on an entity's Board of Directors or advisory committees; Magenta Therapeutics and BlueRock Therapeuetics: Membership on an entity's Board of Directors or advisory committees; Five Prime Therapeutics Inc: Co-Founder, Membership on an entity's Board of Directors or advisory committees; Regeneron Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Alpine Immune Sciences, Inc.: Research Funding; RXi Pharmaceuticals: Research Funding; Fate Therapeutics, Inc.: Research Funding; Tmunity: Other: Co-Founder; BlueRock Therapeutics: Membership on an entity's Board of Directors or advisory committees. Boitano:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Cooke:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Raffel:Magenta Therapeutics: Employment, Equity Ownership. Davis:Magenta Therapeutics: Employment, Equity Ownership. Wagner:Rocket Pharmaceuticals: Consultancy; Magenta: Consultancy, Research Funding; BlueRock: Research Funding; Gadeta: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding.
| v2 |
2022-12-18T16:08:00.013Z | 2022-10-01T00:00:00.000Z | 254817191 | s2ag/train | 2022-RA-1322-ESGO A feasibility study of endometrial cavity cytological sampling for precision treatment in endometrial cancer
2022-RA-1322-ESGO Table 1 Patient cohort characteristics Conclusion DNA isolation from endometrial cytology samples was successful in 91% of samples and isolation of CTNNB1 mutations showed an appropriate level of specificity, but optimisation of sensitivity is needed for clinical use implementation. 2022-RA-1323-ESGO ENDOMETRIAL CANCER AGGRESSIVENESS MAY BE ASSOCIATED WITH EXPOSURE TO PHTHALATES Jure Knez, Jure Zganec, Petra Kotnik, Maša Knez, Monika Sobočan. Department for Gynaecological Oncology, University Medical Centre Maribor, Maribor, Slovenia; Faculty of Medicine, Maribor, Slovenia 10.1136/ijgc-2022-ESGO.308 Introduction/Background Phthalates are endocrine-disrupting chemicals (EDCs) widely used in consumer products. They can competitively bind to oestrogen and androgen receptors and impact signalling. In-vitro studies have shown certain phthalates to cause considerable inflammatory reaction. Analysis of EC cell lines exposure indicates butyl-benzyl phthalate (BBP) to influence transcription and miRNA expression. Certain phthalates, such as dibutyl phthalate (DBP) have also been directly associated with increased EC risk. Common small phthalate esters (diethyl phthalate (DEP) and DBP were evaluated in this study to examine the association of exposure to phthalates with EC risk profiles. Methodology A prospective, single-centre, cohort study including all women diagnosed with EC between December 2020 and February 2022. Patients were asked to provide a urine sample, peripheral venous blood sample as well as complete a lifestyle questionnaire before management. Gas chromatography-mass spectrometry (GC-MS) was used to detect phthalates. All results were adjusted for urinary dilution by measuring urinary creatinine levels. Results Thirty-nine women with a median age 60 (range 35– 86) were included in this study. 29 women (74%) were diagnosed at FIGO I or II stage of the disease, while others were diagnosed at advanced stage. Women were stratified based on Abstracts A144 Int J Gynecol Cancer 2022;32(Suppl 2):A1–A504 on D ecem er 6, 2022 by gest. P rocted by coright. http/ijgc.bm jcom / nt J G ynecol C acer: frst pulished as 10.11ijgc-2022-E S G O .08 on 20 O cber 222. D ow nladed fom clinical features into risk-profiles according to the ESGOESTRO-ESP guidelines. DEP was detectable in 24 (75%) of urine samples, DBP was detectable in 31 (97%) samples. Median levels of DEP in urine were 22.8 mg/L (range 4 – 54 mg/L) and 74.9 mg/L (range 23 – 166 mg/L) for DBP. Clinical risk assessment was significantly correlated with DEP r=9.475; p<.050, but not with DBP expression levels r=5.573; p>.233. Conclusion Exposure to higher concentrations of DEP may be associated with increased biological aggressiveness of EC. If these findings are confirmed in other EC populations, this could influence counselling and management of women with EC. 2022-RA-1335-ESGO THE IMPACT OF COMBINATION OF SYSTEMIC INFLAMMATORY AND MOLECULAR MARKERS ON SURVIVAL OF APPARENT EARLY-STAGE ENDOMETRIAL CANCER Nicolò Bizzarri, Ilaria Capasso, Emanuele Perrone, Alessandro Baroni, Ettore Di Stefano, Lucia Tortorella, Serena Cappuccio, Camilla Nero, Gian Franco Zannoni, Giovanni Scambia, Francesco Fanfani. UOC Ginecologia Oncologica, Dipartimento per la Salute della Donna e del Bambino e della Salute Pubblica, Fondazione Policlinico Universitario A. Gemelli, IRCCS, Rome, Italy; Gynecopathology and Breast Pathology Unit, Dipartimento per la Salute della Donna e del Bambino e della Salute Pubblica, Fondazione Policlinico Universitario A. Gemelli, IRCCS, Rome, Italy 10.1136/ijgc-2022-ESGO.309 Introduction/Background The primary endpoint of the present study was to assess the role of systemic inflammatory and molecular markers on DFS in patients with apparent earlystage endometrial cancer. Methodology Retrospective, single-center, observational study. Patients with apparent endometrial cancer undergoing primary surgery between 06/2013–06/2019 were included. Data on systemic inflammatory markers were calculated on complete blood count performed at time of anesthetic assessment (1– 30-days before surgery). Information about molecular markers P53, MLH1, MSH2, MSH6, PMS2, ER, PR and MMR stability was retrieved by immunohistochemistry (IHC) analysis of tumor tissue on uterus histology. Analyzed inflammatory markers included neutrophil-lymphocyte ratio (NLR), plateletlymphocyte ratio (PLR), eosinophil-lymphocyte ratio (ELR), monocyte-lymphocyte ratio (MLR), systemic immune inflammation index (SII), (eosinophil x neutrophil)/lymphocyte (ENL) and fibrinogen-albumin ratio (FAR). The ROC curve was used to determine the optimal cut-off value of different baseline inflammatory biomarkers for the DFS analysis. Results Characteristics of 495 included patients are showed in table 1. Univariate analysis showed that following inflammatory markers values were significantly associated with worse DFS: NLR 3.5 (HR:2.424;95%CI:1.512–3.886;p<0.001), SII 1050 (HR:2.738;95%CI:1.665–4.502;p<0.001), PLR 250 (HR:2.747;95%CI:1.453–5.194;p=0.002), FAR 10 (HR: 1.841;95%CI:1.138–2.978;p=0.013), MLR 0.3 (HR:2.288; 95%CI:1.409–3.716;p<0.001). When stratifying according to molecular risk-groups from ESGO-ESTRO-ESP-2021 guidelines, we found that in MMRd patients, patients with SII<1050 had better 3-year DFS than patients with SII 1050 (91.0% versus 60.0%;p=0.002). Similarly, we found that in MMRd patients and p53 mutated patients, patients with PLR<250 had better 3-year DFS than those with PLR 250 (90.1% versus 62.5%, p=0.020 and 74.9% versus 33.3%,p=0.045, respectively).Multivariable analysis including molecular and systemic inflammatory markers showed that PLR 250 was independently associated with increased risk of recurrence. Abstract 2022-RA-1335-ESGO Table 12022-RA-1335-ESGO Table 1 Conclusion SII and PLR were the systemic inflammatory markers with major impact on recurrence risk. SII and PLR might help in further stratifying risk of recurrence when adopting the molecular risk-groups from ESGO-ESTRO-ESP2021 guidelines. PLR 250 surpassed ER, PR and p53 in conferring risk of recurrence. 2022-RA-1344-ESGO ENDOMETRIAL CANCER PATIENTS WITH AN OVEREXPRESSION OF THE ORPHAN NUCLEAR RECEPTOR NR2F6 SHOW AN IMPROVED SURVIVAL Louisa Proppe, Tobias Jagomast, Julika Ribbat-Idel, Sophie Beume, Georgios Gitas, Franziska Hemptenmacher, Achim Rody, Sven Perner, Lars Christian Hanker. Gynecology and Obstretrics, UKSH, Campus Luebeck, Luebeck, Germany; Department of Pathology, UKSH. Campus Luebeck, Luebeck, Germany; Department of Pathology, UKSH, Campus Luebeck, Luebeck, Germany 10.1136/ijgc-2022-ESGO.310 Introduction/Background NR2F6 (nuclear receptor subfamily 2 group F member 6, also called Ear-2) is known to be an orphan nuclear receptor being an intracellular immune checkpoint in effector T cells. It might play an essential role for tumor development and growth. Therefore, the prognostic impact of NR2F6 in endometrial cancer is evaluated in this study. Abstracts Int J Gynecol Cancer 2022;32(Suppl 2):A1–A504 A145 on D ecem er 6, 2022 by gest. P rocted by coright. http/ijgc.bm jcom / nt J G ynecol C acer: frst pulished as 10.11ijgc-2022-E S G O .08 on 20 O cber 222. D ow nladed fom | v2 |
2019-03-18T14:06:41.418Z | 2018-11-29T00:00:00.000Z | 80957501 | s2ag/train | Efficacy of Mogamulizumab By Prior Systemic Therapy in Patients with Previously Treated Cutaneous T-Cell Lymphoma: Post Hoc Analysis from the Phase 3 Mavoric Study
Aims: Patients with the cutaneous T-cell lymphoma subtypes mycosis fungoides (MF) and Sézary syndrome (SS) often require multiple lines and types of systemic therapy. The phase 3 MAVORIC study (NCT01728805) showed that mogamulizumab (MOGA), a monoclonal antibody directed against C-C chemokine receptor 4 (CCR4), is superior to vorinostat (VORI) in median progression-free survival (PFS; 7.7 vs 3.1 months, P<0.0001) and confirmed overall response rate (ORR [complete response plus partial response]; 28% vs 4.8%, P<0.0001) in patients with MF/SS with a median of three prior systemic therapies (range: 1-18). Preclinical studies have suggested that histone deacetylase inhibitors (HDACi) may downregulate CCR4 expression in neoplastic T-cells. Further, romidepsin (an HDACi) has also been shown to suppress NK cell function, which could negatively influence the antibody activity of MOGA. As a result, this post hoc analysis of the MAVORIC study examined the effect of prior systemic therapies, including romidepsin, on response to MOGA.
Methods: Patients with MF/SS who had failed ≥1 systemic therapy were randomized to MOGA 1.0 mg/kg intravenously or VORI 400 mg orally daily until disease progression or unacceptable toxicity. Confirmed ORR was based on a global composite response score in each of four disease compartments (skin, blood, lymph nodes, and viscera), achieved at two consecutive visits. PFS, ORR, and the interaction with time from treatment were assessed based on immune activity of last prior regimens, and analyzed using Cox proportional hazards and logistic regression models, respectively.
Results: In total, 372 patients (median age: 64 years) were randomized (MOGA, n=186; VORI, n=186). Baseline characteristics, including number and type of prior systemic therapies, were similar between cohorts. The most common last prior systemic therapies in patients randomized to MOGA were oral bexarotene (n=46; 25%), chemotherapy (n=44; 24%), methotrexate (n=20; 11%), interferon alpha (n=17; 9%), extracorporeal photophoresis (ECP; n=16; 9%), and romidepsin (n=16; 9%). Confirmed ORRs in MOGA-treated patients after 1, 3, or ≥6 prior therapies were 25%, 35%, and 30%, respectively. Patients who crossed over to MOGA from VORI, due to progression or intolerance, had an ORR of 30%. ORR and duration of response to MOGA did not vary by last prior systemic therapy (Table). Logistic regression analyses demonstrated that neither the impact of immune activity of the last prior therapy (immune stimulatory or immunosuppressive regimens) nor the time from prior treatment had an effect on PFS or ORR observed in response to MOGA (P>0.05)
Conclusions: This post hoc analysis of the MAVORIC study shows no difference in MOGA response by the number of prior systemic therapies, type, or immune activity of last prior therapy.
Zinzani: MSD: Honoraria, Speakers Bureau; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SERVIER: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Speakers Bureau. Horwitz:Spectrum: Research Funding; Innate Pharma: Consultancy; Forty Seven: Consultancy, Research Funding; Trillium: Consultancy; Infinity/Verastem: Consultancy, Research Funding; Kyowa-Hakka-Kirin: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Portola: Consultancy; Celgene: Consultancy, Research Funding; Mundipharma: Consultancy; Aileron Therapeutics: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Corvus: Consultancy. Kim:Medivir: Membership on an entity's Board of Directors or advisory committees; Portola: Research Funding; miRagen: Research Funding; Neumedicine: Consultancy, Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Kyowa-Kirin-Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tetralogic: Research Funding; Galderma: Research Funding; Innate Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Horizon Pharma: Consultancy, Research Funding; Soligenix: Research Funding; Merck: Research Funding; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Forty Seven Inc: Research Funding. Moskowitz:ADC Therapeutics: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Bristol Myers-Squibb: Consultancy, Research Funding; Merck: Research Funding; Incyte: Research Funding; Takeda: Honoraria. Porcu:Innate Pharma: Consultancy. Scarisbrick:National Health System, UK: Employment; Kyowa: Consultancy; Takeda: Consultancy; Helsinn: Consultancy; Actellion: Consultancy; Mallinkcrodt: Consultancy; 4SC: Consultancy; Innate Pharma: Consultancy. Leoni:Kyowa Kirin: Employment. Dwyer:Kyowa Kirin: Employment. Sun:Kyowa Kirin: Employment. Nikonova:Kyowa Kirin: Employment. Bagot:Takeda: Membership on an entity's Board of Directors or advisory committees; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees; Innate Pharma: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Actelion: Membership on an entity's Board of Directors or advisory committees.
| v2 |
2021-11-25T16:13:50.899Z | 2021-11-05T00:00:00.000Z | 244540121 | s2ag/train | Highly Selective Irreversible ITK Inhibitor Cpi-818 Reduces Acute Graft-Versus Host Disease
Background
Acute graft-versus-host disease (aGVHD) remains a major limitation of allogeneic hematopoietic cell transplantation (allo-HCT) despite prophylactic immunosuppression. Not all patients who develop aGVHD respond to currently available treatment and thus there is a pressing need for novel prophylactic and therapeutic strategies.
Interleukin-2-Inducible T-Cell Kinase (ITK) is a Tec-family, non-receptor tyrosine kinase expressed in T-cells, homologous with Bruton's tyrosine kinase (BTK) in B cells and is involved in proximal T-cell receptor (TCR) signaling, activating Phospholipase Cγ1 (PLCγ1) and initiating a signaling cascade that includes the NFAT, NF-κB, and MAPK pathways tuning T-cell activation, proliferation, and differentiation. Targeting ITK (ITK-/- in T cell graft and short-term exposure of donor graft to ITK inhibitor) has been shown to be associated with less GVHD in preclinical studies (Mammadli et al 2020, Kondo et al 2021).
CPI-818 is a highly selective irreversible ITK inhibitor that covalently binds to cysteine 442 of ITK and abolishes kinase activity. In vitro assays demonstrate that CPI-818 inhibits phosphorylation of the ITK substrate PLC γ1 (Y783) and downstream signaling molecules ERK and S6, and blocks IL-2 secretion. CPI-818 reduced clinical and histological disease severity in a Th1-driven T cell adoptive transfer model of colitis (not published). CPI-818 is currently being evaluated in a Phase 1/1b study in patients with relapsed/refractory T-cell lymphoma (NCT03952078), and thus far appears well tolerated.
Methods and Results
We used 2 well established preclinical aGVHD models (MHC-disparate B6 → BALB/c and minor MHC-mismatched B6 → 129) to explore the effects of ITK inhibition by CPI-818. Recipient mice were treated with CPI-818-formulated (300 mg/kg/day) or control diet from day -7 to day 90 relative to allo-HCT. We found significantly improved survival (MHC-disparate: p<0.0001, n=20/group, 2 independent experiments, Figure A; minor mismatch: p=0.019, n=20/group, 2 independent experiments), in mice treated with CPI-818 compared with control. In the MHC-disparate model we observed reduced serum concentrations of IL-5 and IL-17a on day 7 after allo-HCT (IL-5: 6.9 vs 22.1 pg/mL, p=0.048; IL-17a: 2.7 vs 9.2 pg/mL, p=0.037, 10 mice/group, Figure B). When we analyzed T cells in the spleen, 3 days post transplant, we saw reduced proliferation of both CD4 and 8 T cells as measured by CFSE dilution (CD4: 73.0 vs 85.1%, p=0.002, CD8: 53.5 vs 65.1%, p=0.002, n=10/group, Figure C), accompanied by a reduction in CD4 T cell expression of CD25 (MFI CD25, 2034.5 vs 2693.5, p=0.037, 10 mice/group, Figure D). By day 7, we observed reduced T cell activation in the small and large intestine (p<0.02, n=10/group, Figure D). Conversely, CPI-818 treated mice had increased serum concentrations of anti-inflammatory IL-10 (Day 7, 10.1 vs 3.1 pg/mL, p=0.012, n=10/group, Figure B) and increased proportions of FoxP3+ T reg in mesenteric lymph nodes (6.2 vs 3.1%, p=0.002, n=10/group, Figure E) and both small and large intestines (small intestine: p=0.01, n=10/group; large intestine: p=0.004, Figure E) on day 7 after allo-HCT. In vitro, 1uM CPI-818 reduced proliferation of T cells exposed to LPS-activated allogeneic DCs compared with vehicle control (CD4: 73.0 vs 81.4%, p=0.008; CD8: 90.1 vs 93.9%, p=0.012; data from 3 independent experiments). This was also seen when T cells were stimulated with CD3/CD28 beads (CD4: 66.2 vs 81.3%, p=0.03; CD8: 67.3 vs 90.6, p=0.03; data from 2 independent experiments) and was not caused by reduced viability of T cells due to drug exposure.
Conclusion
These data in two clinically relevant GVHD models demonstrate that ITK inhibition has potential as a novel targeted approach to prevent aGVHD through a) the suppression of T cell activation and proliferation, b) decreased concentrations of pro-inflammatory cytokines and increased concentration of anti-inflammatory cytokines. CPI-818 is the most potent and selective ITK inhibitor reported to date and these data highlight its promise as a novel agent for the prevention of aGVHD.
Figure 1 Figure 1.
Smith: Janssen: Consultancy, Honoraria. Perales: Celgene: Honoraria; Kite/Gilead: Honoraria, Other; MorphoSys: Honoraria; Merck: Honoraria; Incyte: Honoraria, Other; Cidara: Honoraria; Bristol-Myers Squibb: Honoraria; Omeros: Honoraria; Novartis: Honoraria, Other; Medigene: Honoraria; Karyopharm: Honoraria; Nektar Therapeutics: Honoraria, Other; Equilium: Honoraria; Takeda: Honoraria; Sellas Life Sciences: Honoraria; NexImmune: Honoraria; Miltenyi Biotec: Honoraria, Other; Servier: Honoraria. Buggy: Corvus Pharmaceuticals Inc: Consultancy, Current holder of individual stocks in a privately-held company. Janc: Corvus Pharmaceuticals Inc: Current Employment, Current holder of individual stocks in a privately-held company. van den Brink: Forty-Seven, Inc.: Honoraria; WindMILTherapeutics: Honoraria; Kite Pharmaceuticals: Other; Da Volterra: Other: has consulted, received honorarium from or participated in advisory boards; Notch Therapeutics: Honoraria; Pluto Therapeutics: Current holder of stock options in a privately-held company, Other: has consulted, received honorarium from or participated in advisory boards ; GlaskoSmithKline: Other: has consulted, received honorarium from or participated in advisory boards; Synthekine (Spouse): Other: has consulted, received honorarium from or participated in advisory boards; Priothera: Research Funding; Wolters Kluwer: Patents & Royalties; Pharmacyclics: Other; Rheos: Honoraria; Nektar Therapeutics: Honoraria; Ceramedix: Other: has consulted, received honorarium from or participated in advisory boards ; Novartis (Spouse): Other: has consulted, received honorarium from or participated in advisory boards; Lygenesis: Other: has consulted, received honorarium from or participated in advisory boards ; Frazier Healthcare Partners: Honoraria; DKMS (nonprofit): Other; Juno Therapeutics: Other; MagentaTherapeutics: Honoraria; Merck & Co, Inc: Honoraria; Amgen: Honoraria; Therakos: Honoraria; Jazz Pharmaceuticals: Honoraria; Seres: Other: Honorarium, Intellectual Property Rights, Research Fundingand Stock Options.
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2021-05-05T20:59:35.614Z | 2006-01-01T00:00:00.000Z | 233767121 | s2ag/train | Nodular Thyroid Disease in Children and Adolescents : A High Incidence of Carcinoma
363 Thyroid Carcinoma 371 Gastroesophageal Refiux (GER) and Cystic Fibrosis during Infancy: Don’t Blame GER for Everything 373 Sleep Apnea and Upper Airway Obstruction 379 Surgical Treatment of Pediatric Cardiac Arrhythmia 382 Simultaneous Administration of MMR, DTP, and OPV 383 Cervical Cancer and Sexually Transmitted Diseases 383 Monitoring of pH in Gastroesophageal Reflux 384 Hypoalbuminemia at Time of Diagnosis of Cystic Fibrosis as a Marker for Seventy of Respiratory Course 385 Cumulative Index Cover: Two Young Girls at the Piano, by Pierre August RENOIR (© 1989 The Metropolitan Museum of Art; Robert Lehman Collection, 1975. (1975.1 .201)). Two Young Girls at the Piano is one of at least five Versions of the same scene by Renoir, including a lovely pastel recently sold at auction. Renoir was 51 years of age at the time he did this work in 1892, and at the height of his popularity. This lovely presentation evokes a former era when adolescents, at least those in favored economic status, spent their leisure learning skills such as playing the piano and singing. One of the major tasks of adolescence is to develop one’s identity and sense of competence.Whether it is the charming skills so beautifully depicted in this painting or others, the task of pediatricians is to assist young people in developing skills of which they can be proud. The printing and production of Pediatrics in Review is made possible, cre in part, by an educational grant from RD S S Ross Laboratories. Answer Key: 1 .C; 2.A; 3.C; 4.C; 5. ‘ 7 B; 8.C; 9.C; lOG; 11 .B. Vol 12, No. 12, June 1991 Pediatrics in Review EDITOR Robert J. Haggerty New York Hospital-Cornell Medical Center New York, NY Editoriai Office: The William T. Grant Foundation 515 Madison Aye, 6th Floor, New York, NY 10022-5403 ASSOCIATE EDITOR Lawrence F. Nazanan Panorama Pediatric Group Rochester, NY ABSTRACTS EDITOR Steven B. Shelov, Bronx, NYS EDITOR Steven B. Shelov, Bronx, NY MANAGING EDITOR Jo A. Largent, Elk Grove Wllage, IL EDITORIAL CONSULTANT Victor C. Vaughan III, Stanford, CA EDITORIAL BOARD Morvis A. Angulo, Mineola, NY Ralph Cash, betroit, MI Daniel D. Chapman, Mn Arbor, Ml Even Chamey, Worcester, MA Russell W. Chesney, Memphis, TN Catherine DeAngelis, Baltimore, MD Peggy Ferry, Tucson, AZ Alan L. Goldbloom, Toronto, ON Richard B. Goldbloom, Halifax, Nova Scotia John L. Green, Rochester, NY Robert L. Johnson, Newark, NJ Alan M. Lake, Glen Arm, MD Frederick H. Lovejoy, Jr., Boston, MA John T. McBride, Rochester, NY Marie C. McCormick, Boston, MA Vincent J. Menna, Doylestown, PA Kurt Metzel, Kansas City, MO Lawrence C. Pakula, Timonium, MD Phillip A. Pizzo, Bethesda, MD Ronald L. Poland, Hershey, PA James E. Rasmussen, Mn Arbor, Ml Robert Rennebohm, Columbus, OH William 0. Robertson, Seattle, WA James S. Seidel, Torrance, CA Richard Sills, Newark, NJ Laurie Smith, Washington, DC William B. Strong, Augusta, GA Vernon T. Tolo, Los Angeles, CA Robert J. Touloukian, New Haven, CT W. Allan Walker, Boston, MA Terry Yamauchi, Little Rock, AR Moritz M. Ziegler, Cincinnati, OH EDITORIAL ASSISTANT Elizabeth A. Nelson PUBLISHER American Academy of Pediatrics Errol A. Alden, Director, Department of Education Nancy Wachter, Copy Editor PEDIATRICS IN REVIEW (ISSN 0191-9601) is owned and controlled by the American Academy of PedIatrics. ft is published six times a year (January through June, 1991) by the American Academy of Pediatrics. 141 Northwest Point Blvd. P0 Box 927. Elk Grove Village, IL 60009-0927. Subscription price per year Candidate Fellow of the AAP $50; AAP Fellow $75; Allied Health or Residents $50; Nonmember or Institution $100. Current single Issues $8. Second-class postage paid at ARUNGTON HEIGHTS, 1WNOIS 60009 and at additional mailing offices. o American Academy of PedIatrics, 1991. All Rights Reserved. Printed in U.S.A. No part may be duplicated or reproduced without permission of the American Academy of Pediatrics. POSTMASTER: Send address changes to PEDIATRICS IN REViEW, American Academy of PedIatrics, 141 Northwest Point Blvd. P0 Box 927. Elk Grove Village. IL 60009-0927. EDUCATIONAL OBJECTIVE 158. The pediatrician should have the appropriate ability to diagnose and manage carcinoma of the thyroid. (Recent Advances, 90/91) ENDOCRINOLOGY pediatrics in review #{149} vol.12 no.12 june 1991 PIR 363 51 . Lancet. 1989;1 :51 1-51 2. Editorial. 52. Stabler B, Siegel PT, Clopper AR, Holmes CS, Stoppani CE, Compton PG. Risk for academic underachievement and behavior problems in short children. Pediatr Res. 1990;27:87A 53. Siegel P,Bedway M, Koepke T,Hobart C, Postellon D. Assessment of attentional deficits among underachieving growth hormone deficient children. Pediatr Res. 1990;27:18A 54. Cuttler L, Michon A, Aeinecke M, Stocking C. Attitudinal and behavioral concomitants of short stature. Pediatr Res. 1990;27:4A 55. Aotnem D, Cohen D, Hintz AL, et al. Psychological sequelae of relative treatment failure for children receiving human growth hormone replacement. J Am Acad Child Adolesc Psychiatry. 1979;1 8:505-520 56. Aobin AA. Reshaping the psyche: the concurrent improvement in appearance and mental state after rhinoplasty. Br J Psychiatry. 1988;1 52:539-543 Self-Evaluation Quiz 1. Of the following children who have short stature, which one presents the least convincing evidence that he or she will respond to growth hormone (GH) therapy? A. Alice is 7 years old and has Turner syndrome; she responds normally to a GH stimulation test. B. Paul is 9 years old and has chronic renal failure; he responds normally to a GH stimulation test. C. Edward is 8 years old and apparently healthy except for short stature; he has a GH levelof 14 ng/mL in a fasting specimen. Bone age is 8 years. D. Barbara is 15 years old and has recently had a craniopharyngioma successfully removed; her bone age is 11 years. 2. Which of the following is the least appropriate contribution to a decision to undertake a 12-month trial of GH therapy in a child who has short stature? A. Assurance of some psychologic benefit. B. A growth velocity less than 25% of normal during the past year. C. Predicted height under 157 cm (62 in) in a boy. D. Predicted height under 152 cm (60 in) in | v2 |
2018-12-02T19:39:54.850Z | 1973-06-01T00:00:00.000Z | 54156451 | s2ag/train | On Uses and Misuses of Computer Programs in Statistics.
Distributions and linear regressions are discussed. The section dealing with the former topic emphasizes the usefulness of computer programs in statistics, demonstrating their ability to handle tedious and time-consuming tasks. The normal curve is stressed since the assumption of a normal distribution is common. An example of 200 data points is presented which illustrates a computer program's ability to do descriptive statistics for data not grouped, data which is distributed into any number of classes of equal width and testing if the 200 points are normally distributed. The section of linear regression emphasizes how computer programs can lead to erroneous results. In the area linear regression there are in current use "canned programs" which display the t-values corresponding to the coefficients of the least square estimate, but do not take autocorrelation into account. In the presence of autocorrelation it is incorrect to use these t-values. An example is presented in which autocorrelation is present but can be removed by a suitable transformation of variables. (Author) ON USES AND MISUSES OF COMPUTER PROGRAMS IN STATISTICS Dr. Herman Munick* College of Business St. John's University Jamaica, New York 11432 (212) 969-8000 John Allison 940 East 27th Street Brooklyn, New York 11210 (212) 252-7056 This paper is divided into two sections, DISTRIBUTIONS, and LINEAR REGRESSION. The first section DISTRIBUTIONS emphasizes the usefulness of ccmputer programs in statistics. Some very tedious and time-consuming tasks are made considerably easier and clarified by use of these computer programs. In particular, the normal curve is emphasized since in many areas of statistics the assumption "a population is normally distributed" appears time and time again. An example of 200 data points is presented illustrating the computer program's ability to do descriptive statistics for data not grouped, data which is grouped into any number of classes of equal width, and testing if the 200 points are normally distributed. A graph of the data also appears in the output. The second section LINEAR REGRESSION emphasizes Low computer programs can lead to erroneous results. In the area of linear regression there are in current use "canned programs" which display the t-values corresponding to the coefficients of the least square estimate, but do not take autocorrelation into acccunt. In the presence of autocorrelation it is incorrect to use these t-values. An example of this is presented where autocorrelation is present but can be removed by a suitable transformation cf variables. Distributions The following are the salient features of a program written to obtain the following: 1. Descriptive statistics for data which is nct-grouped. 2. Indicators that a set of points are normally distributed (necessary but not sufficient conditions) . 3. Grouping original data into any number of classes of egual width, with descriptive statistics. 4. A graph of the grouped data (frequency plotted against mid-point of CLASS). 5. CHI-SQUARE test for goodness of fit of normal curve. U S DEPARTMENT OF HEALTH. EDUCATION & WELFARE NATIONAL INSTITUTE OF EDUCATION THIS DOCUMENT HAS BEEN REPRO DUCED EXACTLY AS RECEIVED FROM THE PERSON OR ORGANIZATION ORIGIN ATING IT POINTS OF VIEW OR OPINIONS STATED DO NOT NECESSARILY REPRE SENT OFFICIAL NATIONAL INSTITUTE OF EDUCATION POSITION OR POLICY FILMED FROM BEST AVAILABLE COPY Example The following is a display of an input and output cf the program for data points as indicated: 9900 DATA 4.7,4.62,4.48,4.45,4.2,4.14,4.1,4.08,4,4.39 9901 DATA 4.44,4.35,4.29,4.28,4.13,4.33,4.37,4.43,4.59,4.1 9902 DATA 4.49,4.34,4.33,4.24,4.2,4.17,4.28,3.76,4.16,4.5 9903 DATA 4,4.07,4.22,4.53,4.55,4.44,4.02,4.2,4.13,4.16 9904 DATA 4.2,4.13,4.12,4.19,4.18,3.98,3.96,4.17,4.2,3.99 9905 DATA 4.16,4.44,4.33,4.59,4.54,4.16,4.21,4.42,4.33,4.34 9906 DATA 4.13,4.31,4.22,4.33,4.12,4.46,4.27,4.21,4.2,4.05 9907 DATA 4.26,4.15,4.08,4.12,4.1,4.15,4.07,4.25,4.3,4.29 9908 DATA 4.45,4.37,4.2,4.31,4.09,4.23,4.2,4.19,4,4.39 9909 DATA 4.38,4.48,4.42,4.38,4.11,4.13,3.63,4.23,4.23 9910 DATA 4.17,4.25,4.18,4.19,3.99,4.07,3.76,4.12,4,4.09 9911 DATA 3.34,4.13,3.37,4.21,4.19,4.28,4.02,4.02,4.24,4.07 9912 DATA 4.35,4.27,4.05,4.14,4.16,4.13,4.19,4.05,3.91,3.89 9913 DATA 4,4.03,4.07,3.98,4.2,4.1,4.13,4.07,4.28,4.06 9914 DATA 4.45,4.24,4.08,4.09,3.95,3.95,3.87,4.13,4.09,3.97,3.95 9915 DATA 3.93,4.25,4.23,3.99,3.95,4,3.95,4.08,4.13,4.13 9916 DATA 4.36,4.36,4.06,4.2,4.17,3.88,3.99,3.98,4.1,3.88 9917 DATA 4.02,4.18,4.35,4.08,4.06,3.92,3.9,4.16,4.14,4.06 9918 DATA 4.25,4.41,4.07,4.08,4.04,4.1,4.21,3.87,3.9,3.93 9919 DATA 4.15,4.08,4.25,4.07,4.01,4.25,4.03,4.27,4.07,4.17 9998 DATA -1 9999 END CHOOSE WHAT INFORMATICN YOU NEED A) NOT-GROUPED DATA B) GROUPED DATA C) BOTH D) NONE OF THE ABOVE ANSWER A,B,C, OE D ?C HOW MANY CLASSES At." THERE? ?9 WHAT IS THE MINIMUM NUMBER OF THE FIRST CLASS? ?3.67 WHAT IS THE MAXIMUM NUMBER OF THE LAST CLASS? ?4.75 STATISTICS FOR 'NOT GROUPED' EATA THERE WERE 200 OBSERVATIONS MADE THE AVERAGE IS 4.1714 THE VARIANCE IS 3.09021E-02 THE STANDARD DEVIATION IS .17579 THE MAXIMUM VALUE IS 4.7 THE MINIMUM VALUE IS 3.68 THE RANGE OF THE OBSERVATIONS IS 1.02 THE MEASURE OF SYMMETRY IS .260124 THE MEASURE OF PEAKEDNESS IS 3.10359 THE FIRST DEVIATION BAND BETWEEN 3.99561 AND 4.34719 CONTAINS 68% OF THE OBSERVATIONS THE SECOND DEVIATION BAND BETWEEN 3.81982 AND 4.52298 CONTAINS 95% OF THE OBSERVATIONS THE THIRD DEVIATION BAND BETWEEN 3.64403 AND 4.69877 CONTAINS 99.5% OF THE OBSERVATIONS STATISTICS FOR ,GF2UPED1 DATA FROM CLASS BOUNCARIES TO MIDPOINT FREQUENCY 3.67 3.79 3.73 3 3.79 3.91 3.85 9 3.91 4.03 3.97 28 4.03 4.15 4.09 54 4.15 4.27 4.21 51 4.27 4.39 4.33 31 4.39 4.51 4.45 17 4.51 4.63 4.57 6 4.63 4.75 4.69 1 | v2 |
2021-11-25T16:16:12.369Z | 2021-11-05T00:00:00.000Z | 244534201 | s2ag/train | Myeloablative Fractionated Busulfan Conditioning Regimen with Sorafenib in Patients with AML: Results of Phase I Clinical Trial
Background: Myeloablative conditioning can be given safely to older patients by administering busulfan over a longer period (fractionated busulfan regimen) than the standard four-day regimen. (Popat, et al Lancet Haematology 2018). This longer conditioning regimen duration allows the addition of oral targeted agents like sorafenib, which may be synergistic with conditioning chemotherapy and thus further improve disease control. Therefore, we added sorafenib to fludarabine and fractionated busulfan regimen (f-bu) in a phase 1 dose-finding trial studying 4 different doses of sorafenib with f-bu (NCT03247088). Here we report the results of this trial.
Methods: Between 3/2018 and 6/2021, 24 patients with AML aged 18 to 70 years with adequate organ function and 8/8-HLA matched related or unrelated donors were enrolled prospectively. The dose of sorafenib was varied among the four values 200, 400, 600, and 800 mg administered from day -24 to -5. Dose-limiting toxicity (DLT) was defined as grade 3 or higher regimen-related non-hematologic, non-infectious, non-GVHD toxicity occurring between day -24 and day 3. The Bayesian Model Averaging Continual Reassessment Method (BMA-CRM) with target DLT probability 0.30 was used to choose doses for successive cohorts of 3 patients. The first cohort was treated at the lowest sorafenib dose 200, with all successive cohorts' doses chosen adaptively by the BMA-CRM. The doses and schedules of busulfan and fludarabine were fixed, with f-Bu dose targeting an area under the concentration vs time curve (AUC) of 20,000 ± 12% μmol.min given over 3 weeks. The first two doses of busulfan (80 mg/m2 IV each) were administered on days -20 and -13 on an outpatient basis. The last four Bu doses were calculated to give a total course AUC of 20,000 ± 12% μmol.min and were given as inpatient following each dose of Flu 40 mg/m2 on days -6 through -3. GVHD prophylaxis was post-transplant cyclophosphamide (PTCy) 50mg/kg on days 3 and 4 and tacrolimus. Recipients of unrelated donor grafts also received MMF. All patients were eligible to receive post-transplant maintenance sorafenib after engraftment.
Results: The median age was 52 years (range, 30-70). Disease status was CR in 16 (66.6%) patients, CRi in 5 (20.8%), and advanced in 3 (12.5%). Adverse risk karyotype was present in 10 (41.7%) patients. MRD was present in 13 (54.2%). 9 (38%) had mutated flt3. The donor was unrelated in 14 (58%), and peripheral blood stem cells were the graft source in 21(87.5%). Due to the absence of DLTs, the BMA-CRM assigned 200mg, 400mg, 600mg, and 800mg of sorafenib, respectively, to the first 4 cohorts, and the next 4 cohorts were given 800mg. Only 2 dose-limiting skin toxicities were seen, one in cohort 3 with 600mg of sorafenib and the second in cohort 6 with 800mg of sorafenib. 800mg was the final recommended phase 2 dose.
The median follow-up in 20 surviving patients was 7.6 months and 1-year progression free survival was 89% (95% CI 75-100%). Other outcomes are summarized in Table 1.
Conclusion: Sorafenib can be safely added to the fractionated busulfan regimen. Early data on efficacy appear promising, with an 89% PFS at 1 year of follow up.
Figure 1 Figure 1.
Popat: Bayer: Research Funding; Abbvie: Research Funding; Novartis: Research Funding; Incyte: Research Funding. Hosing: Nkarta Therapeutics: Membership on an entity's Board of Directors or advisory committees. Rezvani: Bayer: Other: Scientific Advisory Board ; AvengeBio: Other: Scientific Advisory Board ; Navan Technologies: Other: Scientific Advisory Board; GSK: Other: Scientific Advisory Board ; Virogin: Other: Scientific Advisory Board ; Affimed: Other: License agreement and research agreement; education grant, Patents & Royalties, Research Funding; Pharmacyclics: Other: Educational grant, Research Funding; Caribou: Other: Scientific Advisory Board; GemoAb: Other: Scientific Advisory Board ; Takeda: Other: License agreement and research agreement, Patents & Royalties. Qazilbash: Bristol-Myers Squibb: Other: Advisory Board; Biolline: Research Funding; Amgen: Research Funding; Oncopeptides: Other: Advisory Board; NexImmune: Research Funding; Angiocrine: Research Funding; Janssen: Research Funding. Daver: Daiichi Sankyo: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; Glycomimetics: Research Funding; Abbvie: Consultancy, Research Funding; Hanmi: Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; FATE Therapeutics: Research Funding; Sevier: Consultancy, Research Funding; Novimmune: Research Funding; Trovagene: Consultancy, Research Funding; Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy, Other: Data Monitoring Committee member; Dava Oncology (Arog): Consultancy; Celgene: Consultancy; Syndax: Consultancy; Shattuck Labs: Consultancy; Agios: Consultancy; Kite Pharmaceuticals: Consultancy; SOBI: Consultancy; STAR Therapeutics: Consultancy; Karyopharm: Research Funding; Newave: Research Funding. Ravandi: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; AstraZeneca: Honoraria; Novartis: Honoraria; Xencor: Honoraria, Research Funding; Taiho: Honoraria, Research Funding; Astex: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Prelude: Research Funding; Syros Pharmaceuticals: Consultancy, Honoraria, Research Funding. Shpall: Magenta: Consultancy; Bayer HealthCare Pharmaceuticals: Honoraria; Magenta: Honoraria; Adaptimmune: Consultancy; Novartis: Consultancy; Navan: Consultancy; Novartis: Honoraria; Takeda: Patents & Royalties; Affimed: Patents & Royalties; Axio: Consultancy. Mehta: CSLBehring: Research Funding; Kadmon: Research Funding; Syndax: Research Funding; Incyte: Research Funding.
| v2 |
2019-11-22T00:57:14.681Z | 2019-11-13T00:00:00.000Z | 209254621 | s2ag/train | A Phase 1b/2 Study of TAK-981, a First-in-Class Sumoylation Inhibitor, in Combination with Rituximab in Patients with Relapsed/Refractory (r/r) CD20-Positive Non-Hodgkin Lymphoma (NHL)
Background
TAK-981 is a first-in-class, small molecule inhibitor of SUMOylation, a reversible post-translational modification that regulates protein function by covalent attachment of small ubiquitin-like modifier (SUMO) proteins to a protein substrate. SUMOylation has a key role in restraining Type I interferon (IFN) responses (Decque, Nature Immunology 2016; Seeler, Nat Rev Cancer 2017). In-vivo preclinical studies have demonstrated that inhibition of SUMOylation by TAK-981 promotes innate and adaptive antitumor immune responses dependent on induction of Type I IFN signaling. This includes modulating the activity of innate effector cells. In macrophages, TAK-981 induced polarization towards the M1 phenotype, upregulated Fcγ receptors, and enhanced phagocytosis and antibody-dependent cellular phagocytosis (ADCP) in an ex-vivo assay. In natural killer (NK) cells, TAK-981 promoted upregulation of the activation marker CD69 and the degranulation marker CD107, increased the number of IFNγ+ NK cells in tumors, and enhanced cytotoxicity and antibody-dependent cellular cytotoxicity (ADCC) in an ex-vivo assay. This enhancement of ADCP and ADCC supports the combination of TAK-981 with IgG1 therapeutic monoclonal antibodies.
In-vivo studies have demonstrated synergistic antitumor activity with TAK-981 combined with rituximab in severe combined immunodeficient mice (lacking lymphocytes but retaining a functional innate immune system) bearing human diffuse large B-cell lymphoma xenografts. Specifically, in OCI-Ly-10 and TMD8 tumor models, the combination reproducibly resulted in complete regression (CR) of all treated tumors at doses at which no CRs were achieved with either single agent. In the PHTX-166L patient-derived xenograft model, tumor growth delay and 1 CR were achieved at doses that showed only very modest tumor growth delay with single agents.
Methods
This is an open-label, multicenter, non-randomized, phase 1b/2 study investigating the safety and efficacy of TAK-981 in combination with rituximab in adult patients with CD20-positive r/r NHL. The study comprises Phase 1b (dose escalation) and Phase 2 (2 treatment arms: indolent [iNHL] and aggressive [aNHL] NHL).
Eligible patients must have CD20-positive r/r NHL (excluding mantle cell lymphoma in Phase 2) and have failed ≥2 prior lines of therapy; one prior line of therapy must have included a CD20-directed antibody.
TAK-981 will be administered intravenously (IV) on Days 1 and 8 in 21-day cycles. The starting dose will be informed by the ongoing first-in-human TAK-981-1002 Phase 1 trial (NCT03648372). Rituximab will be administered IV weekly at 375 mg/m2 x 3 doses followed by 375 mg/m2 on Day 1 of subsequent 21-day cycles. Treatment will continue until disease progression or unacceptable toxicity.
Phase 1b will enroll ~34 patients to identify the maximum tolerated dose and/or pharmacologically active dose of the combination. Dose escalation will be guided by an adaptive Bayesian logistic regression model that implements escalation with overdose control.
Phase 2 will enroll ~56 patients in 2 parallel arms (iNHL/aNHL). Efficacy of the combination will be assessed by the investigator per Lugano 2014 response criteria. The primary endpoint for Phase 2 is overall response rate (ORR). The design is based on Simon's 2-stage design, in which the null hypothesis for each arm (true ORR is 20%) will be tested against a one-sided alternative. In the first stage, 12 patients will be accrued in each arm. If there are ≤2 responses in the 12 patients in either arm, the arm(s) will be stopped. Otherwise, 13 additional patients will be accrued per arm. The null hypothesis will be rejected for an arm if ≥8 responses are observed in the 25 patients on that arm. This design yields a type I error rate of 0.1 and 80% power when the true ORR is 40%.
Tumor biopsies will be collected to determine SUMO pathway inhibition by immunohistochemistry and the induction of innate and/or adaptive immune response by measuring levels of IFN-regulated gene transcripts and the activation state of tumor-infiltrating lymphocytes and myeloid cells, including NK cells and macrophages. Innate and/or adaptive immune response and IFN signalling activation will also be assessed in peripheral blood by immunoprofiling, gene expression analysis, and measurement of cytokine and/or chemokine secretion.
Enrollment is planned to open in October 2019.
Assouline: Pfizer: Consultancy, Honoraria, Speakers Bureau; Abbvie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria. Mehta:Seattle Genetics: Research Funding, Speakers Bureau; Astex: Research Funding; TG Therapeutics: Research Funding; Incyte: Research Funding; Spectrum: Consultancy, Speakers Bureau; Imbrium therapeutics: Consultancy; Roche-Genentech: Research Funding; miRagen: Research Funding; Kyowa-Kirin: Consultancy, Speakers Bureau; Astra-Zeneca: Speakers Bureau; Sanofi: Consultancy; Affimed: Research Funding; Forty Seven Inc: Research Funding; Juno/Celgene: Research Funding; Kite/Gilead: Research Funding, Speakers Bureau; Takeda: Research Funding; Rhizen: Research Funding; ADC therapeutics: Research Funding; Pharmacyclics: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau. Caimi:Fate Therapeutics: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADC Therapeutics: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Speakers Bureau; Kite Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Wang:Millennium Pharmaceuticals, Inc., Cambridge, MA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Patel:Millennium Pharmaceuticals, Inc., Cambridge, MA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Kim:Millennium Pharmaceuticals, Inc., Cambridge, MA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Huszar:Millennium Pharmaceuticals, Inc., Cambridge, MA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment, Other: Shareholder. Berger:Millennium Pharmaceuticals, Inc., Cambridge, MA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Friedlander:Millennium Pharmaceuticals, Inc., Cambridge, MA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Gomez-Pinillos:Millennium Pharmaceuticals, Inc., Cambridge, MA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Proscurshim:Millennium Pharmaceuticals, Inc., Cambridge, MA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment.
TAK-981 is a first-in-class, small molecule inhibitor of SUMOylation, a reversible post-translational modification that regulates protein function by covalent attachment of small ubiquitin-like modifier (SUMO) proteins to a protein substrate.
| v2 |
2019-04-10T13:11:58.744Z | 2011-07-01T00:00:00.000Z | 105848451 | s2ag/train | Plasticisation of Polyvinyl Chloride Using Bis-Adducts of Methylene Dioxolanes with Ethane Dithiol
Numerical modelling was used to study the temperature field in a diamond-containing composite material with an organic matrix. The main polymers used in the manufacture of diamond-based abrasive cutting tools are phenolic resins. An analysis was made of the influence of the thermophysical properties of the binder, and also of the coatings on the diamond grains, on the temperature field in the composite. The results of modelling of a non-stationary temperature field in the diamond tool composite are presented. 10 refs. (Article translated from Plast.Massy, No.5, 2010, p.34-38) Title: STUDY OF THE AERODYNAMICS OF A REGULAR LINER MADE OF POLYMER MESH FABRIC Page Range: p.T/31-T/33 Author(s): Trusov M S; Pushnov A S; Bulatov S N; Vitkovskaia R F; Shishov V I File size: 111K Download the pdf (subscribers only) Buy the pdf (non-subscribers) Journal: International Polymer Science and Technology Issue Year: ipsat Volume: 38 Issue No: No.7 Abstract The aerodynamics of a liner made from a Lavsan PETP woven fabric mesh were studied. The liner was made of vertical strips of polymer mesh with horizontal corrugations. Pressure head loss and air flow rate were monitored. The potential use of the liner for evaporation cooling processes, e.g. in water recycling systems at factories and in mass exchange processes in chemical engineering, was examined. An important advantage of the proposed liner is the two-way flow of liquid and gas, together with the high phase contact area and the low cost and ease of both manufacture and installation. 7 refs. (Article translated from Plast.Massy, No.5, 2010, p.39-41) Title: BIODEGRADABLE POLYMER COMPOSITES BASED ON AGRO-INDUSTRIAL COMPLEX WASTE Page Range: p.T/35-T/38 Author(s): Kirsh I A; Chutkina E P File size: 101K Download the pdf (subscribers only) Buy the pdf (non-subscribers) Journal: International Polymer Science and Technology Issue Year: ipsat Volume: 38 Issue No: No.7 Abstract The production of filled biodegradable polymer composites based on agro-industrial complex (AIC) and packaging waste was studied with the aim of producing raw material and articles from it. PE film waste was used with AIC waste in the form of cacao husks, beet pulp, husks of buckwheat, rice, millet and sunflowers, and potato and maize pulp. Particular attention was paid to study of the physical/mechanical properties of filled biodegradable polymer composites. Mathematical modelling and tests on physical/mechanical properties suggested that beet pulp, cacao husks and rice husks were the most effective of these fillers for production of biodegradable polymer composites. Processes of biodegradation of polymer composites filled with AIC wastes were also examined. A mixed modifier based on a sorbent and bentonite was developed for production of biodegradable polymeric materials based on PE waste filled with 30-40% AIC waste. 2 refs. (Article translated from Plast.Massy, No.5, 2010, p.45-48) Title: DEPENDENCE OF THE MOLECULAR TOPOLOGICAL STRUCTURE OF POLYTETRAFLUOROETHYLENE ON THE TECHNOLOGICAL ASPECTS OF INDUSTRIAL SYNTHESIS. I. THERMOMECHANICAL SPECTROSCOPY Page Range: p.T/39-T/43 Page 3 of 5 3/18/2012 http://www.polymerjournals.com/default.asp?Page=111&JournalType=ipsat&JournalIssue=ipsat38-7&JIP= Author(s): Ol'khov Y A; Allayarov S R; Kochetkova G V; Dixon D A File size: 99K Download the pdf (subscribers only) Buy the pdf (non-subscribers) Journal: International Polymer Science and Technology Issue Year: ipsat Volume: 38 Issue No: No.7 Abstract In order to obtain a solutionless complex diagnosis based on thermomechanical analysis, experimental approaches were developed for investigation of the molecular topological structure of PTFEs synthesised by different methods. Data on the thermomechanical curve of PTFE, TGA and DTA curves of PTFE, and temperature dependence of the weight loss of PTFE are presented and discussed. 27 refs. (Article translated from Plast.Massy, No.7, 2010, p.4-7) Title: BEHAVIOUR OF SEGMENTED POLYETHER URETHANE UREA IN A HUMID ATMOSPHERE AFTER MECHANICAL LOADING Page Range: p.T/45-T/49 Author(s): Tereshatov V V; Gladkova O A; Strel'nikov V N; Makarova M A; Volkova E R File size: 84K Download the pdf (subscribers only) Buy the pdf (non-subscribers) Journal: International Polymer Science and Technology Issue Year: ipsat Volume: 38 Issue No: No.7 Abstract The laws governing the mechanical behaviour of plasticised polyether-urethane-ureas over a wide range of air relative humidity were studied. It was shown that, in the presence of a plasticiser which lowered the solubility of the rigid blocks in the flexible phase of the polymer, there was an increase in the stability of the mechanical characteristics of the polymers on exposure to a humid atmosphere. 10 refs. (Article translated from Plast.Massy, No.7, 2010, p.8-11) Title: SYNTHESIS AND PROPERTIES OF POLYETHER SULPHONE KETONE TEREPHTHALOYL DI(POXYBENZOATES) Page Range: p.T/51-T/55 Author(s): Khasbulatova Z S; Shustov G B; Mikitaev A K File size: 111K Download the pdf (subscribers only) Buy the pdf (non-subscribers) Journal: International Polymer Science and Technology Issue Year: ipsat Volume: 38 Issue No: No.7 Abstract A method was proposed for synthesising polyether sulphone ketones containing fragments of terephthaloyl-di(p-oxybenzoic)acid by polycondensation reaction. The structure of the polymers obtained was confirmed by elemental analysis and IR spectroscopy. Their properties were studied, including yield, reduced viscosity, Tg and weight loss, and the results are presented and discussed. The copolymers were shown to possess a combination of valuable physicochemical properties for use in various sectors of industry. 10 refs. (Article translated from Plast.Massy, No.7, 2010, p.11-15) Page 4 of 5 3/18/2012 http://www.polymerjournals.com/default.asp?Page=111&JournalType=ipsat&JournalIssue=ipsat38-7&JIP= Title: INTERACTION OF POLYVINYLPYRROLIDONE WITH CHLOROACETAMIDE IN AN ALCOHOLIC MEDIUM Page Range: p.T/57-T/60 Author(s): Artykova Z B; Goryachaya A V; Tashmukhamedov R I; Gritskova I A; Shtil'man M I File size: 90K Download the pdf (subscribers only) Buy the pdf (non-subscribers) Journal: International Polymer Science and Technology Issue Year: ipsat Volume: 38 Issue No: No.7 Abstract An examination was made of the conditions under which poly-N-vinylpyrrolidone reacted with chloroacetamide in an alcoholic medium to form an epoxy-containing polymer. It was shown that the polymer could be obtained in high yield (about 80%) with the required content of epoxy groups (about 11 mol %) and possessing good solubility in water, with a molec.wt. of 9 x 10^3. The polymer yield was higher when the reaction was carried out in 1-butanol than when using ethanol as the solvent. Potential applications in medical and biological fields are considered. 3 refs. (Article translated from Plast.Massy, No.7, 2010, p.15-19) | v2 |
2018-12-28T21:53:37.798Z | 1929-11-30T00:00:00.000Z | 91951261 | s2ag/train | On Organic Compounds of Arsenic. Part IV. : Reaction between the Grignard Reagent and Arsenic Trisulphide
The actions of arsenic trisulphide onphenylmagnesium bromide, a-naphthylmagnesium bromide and p-tolylmagnesium bromide were studied. An interesting fact observed is that arsenic trisulphide acts upon p-tolylmaguesium bromide in two different ways according to the mode of the preparation. When arsenic trisulphide precipitated by hydrogen sulphide in an acid solution and subsequently dried at oo° was used, tri-p-tolylarsine sulphide and di-p-tolylarsine sulphide were produced with a small quantity of tri-p-tolylarsine, while arsenic trisulphide precipitated by hydrogen sulphide and subsequently treated with carbon dioxide to drive off the excess of hydrogen sulphide, washed with carbon bisulphide and then dried at too°, gave tri-p-tolylarsine and di-p-tolylarsine sulphide but not tri-p-to]ylarsine sulphide. Di-a-naphihylarsine sulphide was obtained in the form of colourless crystals, m. p. 185-186°. It was also prepared from di-a-naphthylarsine oxide or di-x-naphthylchloroarsine by the action of hydrogen sulphide, and was transformed to di-a-naphthylarsinic acid by treating it with chlorine. 2[(C1 H7)2As]2S+7 C13=-4(C0H7)2AsC13-1S2 C12, (CI 0117)2AsC13 + 2 Hp = (C101:17)2As02H+3HC1. The formation of sulphur monochloride in this reaction was easily recognized by its characteristic smell. Triphenylarsine sulphide mercurichloride, (C6115)3AsS.HgC12, m. p. 239-241°, tripdolylarsine sulphide mercurichloride, (C7 H7) 3A0S . HgC12, m. p. 227-229°, were prepared and their properties were recorded. From the study of the action of arsenic trisulphide on the Grignard reagent the interesting fact was found that the mode of its preparation has a great influence upon the reaction. Finely powdered arsenic trisulphide and phenylmagnesium bromide reacted energetically and gave triphenylarsine sulphide and triphenylarsine when the reaction product was treated with water and dilute acetic acid. Diphenylarsine sulphide, which is rather 58 Kaoru Matsumiya and Minoru Na kaz: difficult to crystallize, was identified by transforming it into diphenylarsinic acid. The reaction between p-tolylmagnesium bromide and arsenic trisulphide smoothly set in and produced tri-p-tolylarsine sulphide with an oily product, which could easily be oxidized into di-p-tolylarsinic acid. By the reaction between a-naphthylmagnesium bromide and arsenic trisulphide, di-a.-naphthylarsine sulphide was only produced: From the above experiments, it will be noticed that arsenic trisulphide reacts upon the Grignard reagent just in a way analogous to the action of the trioxide' and produces the secondary and tertiary arsine compounds, but not the primary thus As,S3 4RMgBr (R,As),S 2MgS 2MgBr2 , (1) (R2As)2S 2RMgBr = 2R3As MgS Mg-Br2 . (ii) In the case of a-naphthylmagnesium bromide, the reaction conies to a stop at the stage of equation (i), probably because a-naphthylmagnesium bromide does not react on di-a-naphthylarsine sulphide so as to change the latter into the tertiary compound. To confirm whether the reaction (ii) actually takes place, diphenylarsine sulphide prepared by treating the corresponding arsine oxide with hydrogen sulphide, was treated with phenylmagnesium bromide. As was expected, triphenylarsine was obtained as the only reaction product, triphenylarsine sulphide not being produced. The formation of diarylarsinic acid by oxidation of diarylarsine sulphide was confirmed by experiment as was described in the experimental part of this memoir. The reaction may be represented by the following equationS. 2 [ (C101-17) 2As]2S + 7 C12 =4 (CioEI7)2AsC13 S2C12 , (C,,,F17)2AsC13 2H20 = (C1cH7)2AsO2H 3HC1. As to the formation of triphenylarsine sulphide and tri-p-tolyl.arsine sulphide a doubt naturally arises that they may be the products of reactions of triarylarsines upon sulphur which may have existed as an impurity in the arsenic trisulphide, for those tertiary arsines are generally very active towards sulphur and combine with it without difficulty'. To make this ambiguous point clear several experiments were performed arsenic trisulphide prepared in four diffrent ways being used. I. The precipitates formed in a warm hydrochloric acid solution by hydrogen sulphide were well washed with hot water containing a small quantity of hydrogen sulphide and dried in a desiccator and then at i oo° in an air bath. I K. Matsumiya and M. Nakai, These Memoirs , 8, 307 (1925). 2 La Coste and Michxlis, Lieb. Ann., 201, 244 (1880) ; Miclr lis, Lieb. Ann,, 321, 204 (1902). On Organic Conzpounds of Arsenic. Parte IV. 59 II. After the precipitates were dried as above, they were washedin a Soxlet tube with carbon bisulphide and then dried at 1 od. III. The precipitates together with the mother liquor were treated with carbon dioxide gas so as to expel hydrogen sulphide completely. Then they were well washed with warm water containing a small quantity of hydrogen sulphide, dried in a desiccator and finally heated at i oo° in an air bath. IV. The precipitates prepared in the manner described in III were washed with carbon bisulphide in a Soxlet tube and dried in an air bath at z oo°. All these arsenic trisulphides readily acted upon p-tolylmagnesium bromide, but the reaction products differed in each case. Sulphide (I) The main product was tri-p-tolylarsine sulphide, together with a small quantity of tri-p-tolylarsine and di-p-tolylarsine sulphide. Sulphide (II) Tri-p-tolylarsine was chiefly produced. A small quantity of tri-p-tolylarsine sulphide and di-p-tolylarsine sulphide was also produced. Sulphide (III) and (IV) Tri-p-tolylarsine and di-p-tolylarsine sulphide were formed, but no tri-p-tolylarsine sulphide. According to the investigation of 0. Puller,' arsenic trisulphide prepared by method (I) contains about 2 Vo more sulphur than the theory demands, and the above experiment shows that the more free sulphur is washed away the less tri-p-tolylarsine sulphide is formed. These facts seem at first sight to show that the formation of tri-p-tolylarsine sulphide is due to the action of sulphur. Nevertheless, the quantity of tri-p-tolylarsine sulphide produced was rather great to be regarded as having been formed by the action of sulphur contained as an impurity. No such different reactions with arsenic trisulphide could be observed in the case of phenylmagnesium bromide, triphenylarsinesulphide being found almost in the same quantity in every case. Accordingly the presence of sulphur as an imprity was seen to have no influence upon the resulting product. | v2 |
2018-04-03T05:43:40.915Z | 2005-09-09T00:00:00.000Z | 44346681 | s2ag/train | Firearms, Violence, and Self-Protection
The association that J. B. Bingenheimer et al. have found between exposure to firearm violence and subsequent perpetration of violence (“Firearm violence exposure and serious violent behavior,” Reports, 27 May, p. [1323][1]) may well reflect a causal effect of prior victimization, but I believe they have misread what is being caused. They classified a subject as a “perpetrator of serious violence” if she or he reported being theatened or attacked by another or had “been in” a gang fight, but also if the subject had “carried a hidden weapon.” Their dependent or outcome variable is problematic partly because it makes no distinction between defensive, even lawful, violence and offensive violence. More importantly, this variable probably reflects just one type of behavior, carrying weapons for self-protection, which should not be described as violent behavior.
The authors report that 12.6% of their sample of (roughly high school age) youth were classified as perpetrators of serious violence, but do not say what share of these were so classified solely because the person had carried weapons for self-protection. But there is strong reason to believe that this share is over half and could approach 100%. A survey of Chicago high school students conducted by the U.S. Centers for Disease Control and Prevention [([1][2]), p. 26] in the same year as the present study, 2001, revealed that 21.2% had carried weapons (6.3% had carried guns) in the previous 30 days. Thus, one would expect that at least 21% of the present study's sample would report defensive weapon carrying alone, easily enough to account for all of the 12.6% classified as “violent perpetrators.”
If most of the variation in the outcome variable is really variation in defensive weapon carrying, it means that all the authors have really discovered, or rediscovered, is the rather banal fact that people who have reasons to believe they are likely to be victimized in the future are more likely to carry guns for defensive purposes ([2][3]).
1. [↵][4] Centers for Disease Control and Prevention, “Youth risk behavior surveillance—United States, 2001,” Morbid. Mortal. Weekly 51 , 1 (28 June 2002).
2. [↵][5] 1. G. Kleck, 2. M. Gertz
, J. Res. Crime Delinquency 35((no. 2)), 193 (1998).
[OpenUrl][6][Abstract/FREE Full Text][7]
# Response {#article-title-2}
We appreciate Kleck's thoughtful letter. It is true that carrying a concealed weapon was the most commonly reported of the behaviors that make up our measure of violent behavior. Nearly 10% of adolescents in our sample reported carrying a concealed weapon in the year prior to their Assessment 3 interview, compared with 4% who reported participating in a gang fight, 2% who reported attacking someone with a weapon, 1% who reported shooting at someone, and less than 1% who reported shooting someone.
Contrary to Kleck's conjecture, however, we believe that it is reasonable to include carrying a concealed weapon in our index of serious violent behavior. Weapon carrying is a logical prerequisite to several explicitly violent acts and is indicative of a certain degree of willingness or intent to engage in violence. Moreover, carrying a hidden weapon is strongly associated with all of the other behaviors included in our measure. Compared with those who denied carrying a hidden weapon, subjects who reported doing so were over 23 times as likely to report attacking someone with a weapon, some 27 times as likely to report shooting at someone, and nearly 10 times as likely to report being in a gang fight. Although almost 70% of those who reported carrying a concealed weapon also reported another violent behavior, less than 3% of those who denied carrying a concealed weapon reported other forms of violence.
Furthermore, the relationships we found between exposure to firearm violence and our index of violent behavior are also evident when each behavior is analyzed as a separate outcome. We reported in our paper that subjects who reported exposure to firearm violence at Assessment 2 were over three times as likely to report some form of violent behavior at Assessment 3 [odds ratio (OR) = 3.71, χ2 = 41.99, P < 0.001]. Breaking this down by behavior, exposed subjects were more likely than unexposed subjects to report carrying a concealed weapon (OR = 3.47, χ2 = 31.36, P < 0.001), being in a gang fight (OR = 3.74, χ2 = 16.73, P < 0.001), attacking someone with a weapon (OR = 9.77, χ2 = 21.62, P < 0.001), or shooting at someone (OR = 11.40, χ2 = 13.18, P < 0.001). Within the analytic propensity strata, those who were exposed to firearm violence were approximately twice as likely to report some form of violent behavior (OR = 2.43, χ2 = 11.76, P = 0.001) and were also more likely to report carrying a concealed weapon (OR = 2.34, χ2 = 9.00, P = 0.003), shooting at someone (OR = 2.78, χ2 = 1.62, P = 0.204), being in a gang fight (OR = 3.27, χ2 = 7.95, P = 0.005), and attacking someone with a weapon (OR = 8.10, χ2 = 9.06, P = 0.003). These unadjusted and propensity-stratified analyses show that our original results apply not only to weapon carrying but also to other forms of violent behavior.
As Kleck suggests, some of the violent behaviors reported by participants in our study may have been motivated in part by self-defense. Yet motivations can be complex, and people often delude themselves and others about the reasons for their actions. Ours is a study of behavior, and our data on adolescents living in Chicago in the late 1990s strongly support the conclusion that exposure to firearm violence increases the likelihood of violent behavior.
[1]: /lookup/doi/10.1126/science.1110096
[2]: #ref-1
[3]: #ref-2
[4]: #xref-ref-1-1 "View reference 1 in text"
[5]: #xref-ref-2-1 "View reference 2 in text"
[6]: {openurl}?query=rft.jtitle%253DJournal%2Bof%2BResearch%2Bin%2BCrime%2Band%2BDelinquency%26rft.stitle%253DJournal%2Bof%2BResearch%2Bin%2BCrime%2Band%2BDelinquency%26rft.issn%253D0022-4278%26rft.aulast%253DKLECK%26rft.auinit1%253DG.%26rft.volume%253D35%26rft.issue%253D2%26rft.spage%253D193%26rft.epage%253D224%26rft.atitle%253DCarrying%2BGuns%2Bfor%2BProtection%253A%2BResults%2Bfrom%2Bthe%2BNational%2BSelf-Defense%2BSurvey%26rft_id%253Dinfo%253Adoi%252F10.1177%252F0022427898035002004%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx
[7]: /lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6NToic3BqcmMiO3M6NToicmVzaWQiO3M6ODoiMzUvMi8xOTMiO3M6NDoiYXRvbSI7czoyMzoiL3NjaS8zMDkvNTc0MS8xNjc1LmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ== | v2 |
2020-02-20T09:11:58.228Z | 2019-11-13T00:00:00.000Z | 213080721 | s2ag/train | Efficacy and Tolerability of Ixazomib, Daratumumab and Low Dose Dexamethasone (Ixa Dara dex) in Unfit and Frail Newly Diagnosed Multiple Myeloma (NDMM) Patients; Results of the Interim Efficacy Analysis of the Phase II HOVON 143 Study
Introduction
Elderly non-transplant eligible newly diagnosed multiple myeloma (nte-NDMM) patients also benefit from novel therapies, however, overall survival (OS) is inferior in unfit and frail compared to fit patients as defined by the International Myeloma Working Group (IMWG) frailty index. This is caused by a high discontinuation rate due to toxicity. Therefore, a less toxic effective treatment for unfit and frail patients is needed. In view of the favorable safety profile of ixazomib (Ixa) and daratumumab (Dara), we investigated the efficacy and feasibility of treatment with Ixa and Dara plus low dose dexamethasone (Ixa-Dara-dex) in unfit and frail patients. This trial was registered at www.trialregister.nlwww.trialregister.nl as NTR6297.
Methods
In this prospective multicenter phase II trial, treatment consisted of nine 28 day-induction cycles consisting of Ixa 4 mg (days 1, 8, 15), Dara 16 mg/kg (cycle 1-2: days 1, 8, 15, 22; cycle 3-6: days 1, 15; cycle 7-9: day 1) and dex (in combination with Dara; cycle 1-2: 20 mg; subsequent cycles 10 mg) followed by maintenance therapy with Ixa (days 1, 8, 15, 29, 36, 43) and Dara (day 1) of 8-week cycles, until progression for a maximum of 2 years. A pre-specified efficacy analysis was planned for the first eligible 23 unfit and 23 frail patients separately at the time the data of the first 9 cycles induction therapy was available.
Inclusion criteria were unfit or frail NDMM patients according to the IMWG frailty index. Main exclusion criteria were severe cardiac dysfunction, chronic obstructive pulmonary disease with an FEV1 <50% of expected and a creatinine clearance of <20 ml/minute.
We here report the overall response rate (ORR) on induction treatment, progression free survival (PFS) and OS, treatment discontinuation and toxicity of the first 23/65 eligible unfit and 23/65 frail patients during induction therapy. In addition, we present the mortality rate for all patients who were included in the study (65 unfit, 67 frail), with data cut-off June 18, 2019.
Results
The demographics of the first 23 unfit and 23 frail patients are described in Table 1. Median follow-up of these first 23 unfit and 23 frail patients is 12.7 months (range 9.1-18.3) and 13.4 months (range 9.2-17.7), respectively.
ORR during induction was 87% in unfit (48% partial response [PR] and 39% very good partial response [VGPR]) and 78% in frail (48% PR, 26% VGPR, 4% stringent complete response). Nine months PFS rates were 78% (95% Confidence Interval [CI] 55-90) and 61% (95% CI 38-77), respectively. Nine months OS rates were 100% and 83% (95% CI 60-93), respectively.
Sixteen/23 (70%) unfit and 14/23 (61%) frail patients completed induction treatment with Ixa-Dara-dex. Reasons for treatment discontinuation were progressive disease (PD, n=5), toxicity (n=1) and incompliance (n=1) in unfit and intercurrent death (n=3, all within 3 cycles), PD (n=2), incompliance (n=2) and other reasons (n=2) in frail. The median and inter-quartile range of relative dose intensity (RDI) for respectively unfit and frail were 0.96 and 0.91 for Ixa, 0.98 and 0.96 for Dara and 1.0 and 0.99 for dex.
Toxicity is described in Table 2. Hematological toxicity was limited, being mainly neutropenia (in unfit both 4% grade 3 and 4; in frail 4% grade 3 and 13% grade 4) and thrombocytopenia occurring only in frail (17% grade 3, 4% grade 4). Non-hematological toxicity was manageable, with grade 3 infections occurring in 9% of both unfit and frail patients. In both arms, there were no infusion related reactions and only 4% grade 3 neuropathy was reported.
Additionally, we investigated the mortality rate of all included 65 unfit and 67 frail patients, with a limited follow-up of 7.1 months (range 1-18.3) and 8.8 months (range 0.4-17.7), respectively. The mortality rate was only 2% in unfit (1/65 due to PD). Thirteen/67 (19%) of frail patients died, which was caused by infections (n=6; 3 pneumonia, 1 influenza B, 1 erysipelas), sudden death (n=2), organ dysfunction (n=2), incompliance (n=1) and PD (n=2). Early death rate (≤3 months of registration) was 0% in unfit and 8/67 (12%) in frail.
Conclusion
Ixa-Dara-dex is an effective therapeutic regimen in unfit patients with limited toxicity, not giving rise to (early) mortality. Additionally, in the majority of frail patients this regimen is active and feasible. However, better identification and support of those patients is warranted, as we observed early mortality due to vulnerability and infections.
Van De Donk: Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; AMGEN: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees. Sonneveld:SkylineDx: Research Funding; Takeda: Honoraria, Research Funding; Karyopharm: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; BMS: Honoraria; Amgen: Honoraria, Research Funding. Levin:Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Educational grant ; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Educational Grant; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Educational Grant; Abbvie: Membership on an entity's Board of Directors or advisory committees, Other: Educational Grant; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Educational grant . Zweegman:Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding.
| v2 |
2019-11-22T01:11:30.555Z | 2019-11-13T00:00:00.000Z | 209226922 | s2ag/train | A Comparison of Two-Year Outcomes in ZUMA-1 (Axicabtagene Ciloleucel) and SCHOLAR-1 in Patients with Refractory Large B Cell Lymphoma
Background: In the SCHOLAR-1 study, the largest published retrospective analysis of outcomes in patients with refractory large B-cell lymphoma (LBCL), the objective response rate (ORR) was 26% and complete response (CR) rate was 7% with available salvage therapies in the pre-chimeric antigen receptor (CAR) T cell therapy era (Crump et al. Blood. 2017). These results served as a benchmark for assessing novel therapies. ZUMA-1 (NCT02348216) is the pivotal, multicenter, single-arm Phase 1/2 study evaluating axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 CAR T cell therapy, in patients with refractory LBCL that supported the approval of axi-cel in the United States and Europe. At a median follow-up of 27.1 months, the ORR in ZUMA-1 was 83% and the CR rate was 58% (Locke et al. Lancet Oncol. 2019). Here, we describe comparative analyses of outcomes in ZUMA-1 and SCHOLAR-1 after adjusting for potential imbalances in refractory status between the 2 studies.
Methods: Patients in both studies had refractory LBCL defined as stable disease of ≤ 6 months with ≥ 4 cycles of frontline or ≥ 2 cycles of later-line therapy, progressive disease as best response, or relapse ≤ 12 months post autologous stem cell transplant (SCT). To address potential imbalances between studies in refractory status which could affect response and survival outcomes, standardized analyses were performed which equally weighted the proportions of patients by refractory categorization (primary refractory, refractory to ≥ second-line therapy, or relapse after SCT) and presence of post-refractory SCT in each study. Stratified Cochran-Mantel-Haenszel (CMH) tests and Cox models were used to compare the odds ratio for response and hazard ratio (HR) for survival between ZUMA-1 and SCHOLAR-1. P values were descriptive and were not adjusted for multiplicity.
Results: Axi-cel was administered to 101 patients in the pivotal Phase 2 portion of ZUMA-1. In the SCHOLAR-1 analysis, 508 patients were evaluable for response and 497 were evaluable for survival. The median follow-up in ZUMA-1 was 2.3 years, and the median follow-up from the overall SCHOLAR-1 study ranged from 7.6 to 14.8 years across different cohorts. In general, ZUMA-1 patients were more heavily pretreated with more patients receiving ≥ 3 lines of therapy as compared with SCHOLAR-1 (69% vs 23%). ZUMA-1 also had more patients who were refractory to second- or later-line therapy compared with SCHOLAR-1 (76% vs 62%). Fewer patients in ZUMA-1, however, were classified as primary refractory vs those in SCHOLAR-1 (26% vs 45%), and a similar proportion of patients between studies relapsed within 1 year of SCT (21% vs 18%). After standardization, the ORR and CR rate in ZUMA-1 vs SCHOLAR-1 were 72% and 54% vs 22% and 7%, respectively. The odds ratios for ORR and CR rate were 7.2-fold and 11.5-fold higher, respectively in ZUMA-1 vs SCHOLAR-1 (CMH test; P < .0001 for both ORR and CR rate). The 2-year survival rate after standardization was 50% (95% CI, 40% - 59%) in ZUMA-1 and 12% (95% CI, 9% - 15%) in SCHOLAR-1, which translated to a 73% reduction in the risk of death in ZUMA-1 relative to SCHOLAR-1 (HR, 0.27; P < .0001).
Conclusions: This standardized analysis of the ZUMA-1 and SCHOLAR-1 studies indicates that treatment with axi-cel in this selected population results in 11.5-fold higher odds of CR and a 73% reduction in the risk of death compared with standard salvage regimens in an unselected population. Although limited by retrospective evaluation and cross-study comparisons, these results support the previous literature indicating that axi-cel is a highly effective treatment option for patients with refractory LBCL.
Neelapu: Pfizer: Consultancy; BMS: Research Funding; Cellectis: Research Funding; Precision Biosciences: Consultancy; Allogene: Consultancy; Acerta: Research Funding; Cell Medica: Consultancy; Celgene: Consultancy, Research Funding; Karus: Research Funding; Novartis: Consultancy; Poseida: Research Funding; Unum Therapeutics: Consultancy, Research Funding; Incyte: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Merck: Consultancy, Research Funding. Locke:Novartis: Other: Scientific Advisor; Kite: Other: Scientific Advisor; Cellular BioMedicine Group Inc.: Consultancy. Bartlett:Genentech, Inc.: Research Funding; Gilead: Research Funding; Autolus: Research Funding; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Forty Seven: Research Funding; Affimed: Research Funding; Immune Design: Research Funding; Incyte: Research Funding; Janssen: Research Funding; Kite Pharma: Research Funding; Merck: Research Funding; Millennium: Research Funding; Pfizer: Research Funding; Pharmacyclics: Research Funding. Reagan:Kite, A Gilead Company: Consultancy; Curis: Consultancy; Seattle Genetics: Research Funding. Miklos:Celgene-Juno: Consultancy; Novartis: Consultancy; Adaptive Biotechnologies: Consultancy, Research Funding; Janssen: Consultancy; Miltenyi: Consultancy, Research Funding; AlloGene: Consultancy; Kite, A Gilead Company: Consultancy, Research Funding; Pharmacyclics: Consultancy, Patents & Royalties, Research Funding; Becton Dickinson: Consultancy; Precision Bioscience: Consultancy. Jacobson:Pfizer: Research Funding; Celgene: Consultancy, Other: travel support; Humanigen: Consultancy, Other: travel support; Precision Biosciences: Consultancy, Other: travel support; Bayer: Consultancy, Other: travel support; Novartis: Consultancy, Honoraria, Other: travel support; Kite, a Gilead Company: Consultancy, Honoraria, Other: travel support. Oluwole:Pfizer: Consultancy; Spectrum: Consultancy; Gilead Sciences: Consultancy; Bayer: Consultancy. Siddiqi:BeiGene: Research Funding; Celgene: Research Funding; TG Therapeutics: Research Funding; Kite, A Gilead Company: Research Funding; Seattle Genetics: Speakers Bureau; Janssen: Speakers Bureau; Juno Therapeutics: Consultancy, Other: travel support, Research Funding; PCYC: Consultancy, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Research Funding, Speakers Bureau. Crump:Kite/Gilead: Consultancy; F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Servier: Consultancy. Kuruvilla:Seattle Genetics: Honoraria; Roche: Honoraria; Novartis: Honoraria; Merck: Honoraria; Karyopharm: Honoraria; Janssen: Honoraria; Gilead: Honoraria; Celgene: Honoraria; BMS: Honoraria; Astra Zeneca: Honoraria; Amgen: Honoraria; Seattle Genetics: Consultancy; Roche: Consultancy; Merck: Consultancy; Karyopharm: Consultancy; Gilead: Consultancy; Abbvie: Consultancy; BMS: Consultancy; Janssen: Research Funding; Roche: Research Funding. Van Den Neste:Gilead: Other: travel support. Farooq:Celgene: Honoraria; Kite Pharma: Research Funding. Navale:Kite, A Gilead Company: Employment, Equity Ownership; Gilead: Equity Ownership; Allogene: Equity Ownership; Cellectis: Equity Ownership; Bluebird Bio: Equity Ownership; Amgen: Equity Ownership; Organesis: Equity Ownership; Jounce: Equity Ownership; Editas: Equity Ownership; Intellia: Equity Ownership. DePuy:Kite, A Gilead Company: Consultancy, Other: travel support. Kim:Kite, A Gilead Company: Employment.
| v2 |
2022-08-13T15:19:39.108Z | 2022-05-23T00:00:00.000Z | 251528102 | s2ag/train | POS0239 RISK OF VENOUS THROMBOEMBOLIC EVENTS IN PATIENTS WITH RHEUMATOID ARTHRITIS AGED ≥50 YEARS WITH ≥1 CARDIOVASCULAR RISK FACTOR: RESULTS FROM A PHASE 3b/4 RANDOMISED STUDY OF TOFACITINIB VS TUMOUR NECROSIS FACTOR INHIBITORS
ORAL Surveillance (NCT02092467) was a randomised, open-label, non-inferiority, Phase 3b/4 study assessing the relative risk of major adverse cardiovascular (CV) events (MACE) and malignancies with tofacitinib vs TNF inhibitors (TNFi) in patients (pts) with moderate to severe rheumatoid arthritis despite methotrexate (MTX) and a high risk of MACE (aged ≥50 yrs; ≥1 additional CV risk factor).To assess risk of venous thromboembolic events (VTE; including deep vein thrombosis [DVT] and pulmonary embolism [PE]) in ORAL Surveillance.Pts on stable MTX received tofacitinib 5 or 10 mg twice daily (BID) or a TNFi (etanercept 50 mg weekly or adalimumab 40 mg once every 2 weeks). Incidence rates (IRs; pts with first events/100 pt-yrs [PY]) and 95% CIs were calculated for adjudicated VTE, DVT and PE (overall by 6-month interval and for pts with/without history of VTE). For overall VTE, DVT and PE, numbers needed to harm (NNH; tofacitinib 5 or 10 mg BID vs TNFi) were calculated post hoc. Multivariate Cox models were used post hoc to identify overall independent baseline (BL) risk factors for PE. Censoring time was a 28-day on-treatment period (minimum of last contact date or last study treatment dose date +28 days).Analysis included 1455, 1456 and 1451 pts receiving tofacitinib 5 mg BID, 10 mg BID and TNFi, respectively. Generally, across 6-month intervals to >54 months, VTE, DVT and PE IRs were numerically higher with both tofacitinib doses vs TNFi, and with tofacitinib 10 vs 5 mg BID; IRs were consistent across time (data not shown). Across treatments, VTE, DVT and PE IRs were higher in pts with vs without history of VTE; however, only a small number of pts per treatment had history of VTE (Figure 1). NNH for tofacitinib 5 and 10 mg BID, respectively, vs TNFi were 763 and 198 PY for VTE, 1347 and 589 PY for DVT, and 870 and 229 PY for PE, or, over 5 yrs, 153 and 40 pts for VTE, 269 and 118 pts for DVT, and 174 and 46 pts for PE. Identified BL risk factors for PE across treatments included history of VTE, antidepressant use, body mass index ≥30 kg/m2, corticosteroid use, male sex, age ≥65 yrs, oral contraceptives/hormone-replacement therapy (HRT) use, and history of hypertension (Table 1).Table 1.Multivariate Cox analyses to identify overall independent BL risk factors for PE across treatmentsHR (95% CI)p valueBL covariateHistory of VTE7.06 (2.46, 20.25)0.0003Antidepressant usea2.94 (1.44, 6.02)0.0032Body mass index ≥30 kg/m22.97 (1.40, 6.32)0.0047Corticosteroid useb3.01 (1.40, 6.46)0.0047Proton pump inhibitor use0.32 (0.15, 0.71)0.0052Male sexc2.18 (1.06, 4.48)0.0340Age ≥65 yrs2.00 (1.03, 3.88)0.0401Oral contraceptives/HRT use3.56 (1.05, 12.10)0.0422History of hypertension2.57 (0.98, 6.76)0.0554aBL antidepressant use was an indicator of an underlying condition of depression, and subgroup analysis did not identify the difference in HRs for depression across treatmentsbProxy for elevated BL disease activity; HRs for BL corticosteroid use were similar between all tofacitinib doses combined and TNFi; includes any BL corticosteroid usecImpact of sex on PE risk considered inconclusiveMultivariate Cox model using backward selection included treatment effects (not subject to model selection) and overall potential independent risk factors (those affecting PE IRs equally across treatments; subject to model selection) identified from a prior set of Cox regression analyses (which included treatment and a single candidate risk factor in each model fitting, cycling through a predetermined set of risk factors); cut-off for risk factor to stay in multivariate model was p<0.10; nominal p value and HR (95% CI) based on this modelHR, hazard ratioGenerally, in ORAL Surveillance, VTE, DVT and PE IRs were numerically higher for tofacitinib (10 > 5 mg BID) vs TNFi across 6-month intervals, and for pts with vs without history of VTE. Multivariate Cox models identified BL risk factors for PE that may help support future treatment decisions.Study sponsored by Pfizer Inc. Medical writing support was provided by Emma Mitchell, CMC Connect, and funded by Pfizer Inc.Christina Charles-Schoeman Consultant of: AbbVie, Gilead Sciences, Pfizer Inc and Regeneron-Sanofi, Grant/research support from: AbbVie, Bristol-Myers Squibb and Pfizer Inc, Roy M. Fleischmann Consultant of: AbbVie, Amgen, Bristol-Myers Squibb, Eli Lilly, Galvani, Gilead Sciences, GSK, Janssen, Novartis, Pfizer Inc, Sanofi-Aventis and UCB, Grant/research support from: AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Flexion, Galapagos, Galvani, Genentech, Gilead Sciences, GSK, Horizon, Janssen, Novartis, Noven, Pfizer Inc, Samumed, Sanofi Aventis, SciSelecta, Teva Pharmaceuticals, UCB, Viela and Vorso, Eduardo Mysler Speakers bureau: AbbVie, Bristol-Myers Squibb, Eli Lilly, Janssen, Pfizer Inc, Roche and Sanofi, Grant/research support from: Eli Lilly, Pfizer Inc and Roche, Maria Greenwald Grant/research support from: AbbVie, Eli Lilly, Galapagos, Gilead Sciences, Novartis and Pfizer Inc, Cunshan Wang Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, All-shine Chen Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Carol A. Connell Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, John Woolcott Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Sujatha Menon Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Yan Chen Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Kristen Lee Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Zoltán Szekanecz Speakers bureau: AbbVie, Eli Lilly, Novartis, Pfizer Inc, Roche and Sanofi, Paid instructor for: AbbVie, Eli Lilly, Gedeon Richter, Novartis, Pfizer Inc and Roche, Consultant of: AbbVie, Eli Lilly, Novartis, Pfizer Inc, Roche and Sanofi, Grant/research support from: Pfizer Inc | v2 |
2021-11-26T16:52:54.766Z | 2021-11-05T00:00:00.000Z | 244655152 | s2ag/train | Blockade of Tigit on AML-Derived M2 Macrophages Results in Reprograming into the M1 Phenotype and Enhances CD47-Mediated Phagocytosis
Background: Bidirectional interactions between the tumor microenvironment (TME) and AML cells lead to disease progression through induction of angiogenesis, migration, cancer stemness and local immunosuppression. Leukemia-associated macrophages (LAM) constitute an important cell population within the TME, but little is known about the phenotype, function, and plasticity of these cells. In the present study we provide an extensive characterization of the macrophage population in patients with AML.
Methods: The phenotype and expression of co-regulatory receptors was assessed on different bone marrow-derived CD68 +CD14 + LAM populations, in comparison to corresponding CD3 + T-cells and CD117 +CD34 + AML cells (n=35), as well as peripheral blood monocytes from healthy donors (HD, n=16) using multi-parameter flow cytometry. The expression of surface markers and the distribution of LAM subpopulations was correlated with clinical parameters. The effect of a blocking anti-TIGIT antibody on the in vitro plasticity on primary LAMs and monocyte-derived macrophages from healthy donors was investigated. Furthermore, we analyzed if the treatment with blocking anti-TIGIT and anti-CD47 antibodies could increase the anti-leukemic phagocytosis of AML cell lines and in vitro polarized monocyte-derived M2 macrophages.
Results: Phenotypic analysis of M1 and M2 macrophages in AML and HD revealed that the predominant macrophage population in patients with AML is made up of immunosuppressive alternatively activated M2 LAMs defined by expression of CD163 and CD86 (M1 AML vs. HD p<0.01 and M2 AML vs. HD p=0.02). These M2 LAMs contained significantly higher frequencies of cells expressing the immune checkpoint receptors TIGIT and TIM-3 than M1 LAMs (TIGIT + M2 vs. M1 p<0.01 and TIM-3 + M2 vs. M1 p<0.01, respectively). Regarding co-expression of multiple co-inhibitory receptors, the frequency of macrophages co-expressing TIM-3 or LAG-3 with TIGIT was higher in samples from AML patients in comparison to HDs (p=0.01 and p<0.01, respectively). This difference was caused by the significant up-regulation of TIM-3 and LAG-3 on TIGIT + M2 LAMs in comparison to their corresponding M1 LAMs (p<0.01and p<0.01, respectively).
Importantly, in vitro blockade of TIGIT in primary LAMs of AML patients or differentiated PB-derived M2 macrophages of HDs resulted in a change in polarization from the M2 towards the M1 phenotype after 24 hours (AML: anti-TIGIT vs. IgG2a p<0.01, n=7 and HD: anti-TIGIT vs. IgG2a p=0.02, n=3).
Moreover, the additional blockade of TIGIT on PB-derived M2 macrophages augmented the anti-CD47-mediated phagocytosis of the AML cell lines MOLM-13 and MV4-11 after 4 hours (MOLM-13: anti-CD47 vs. IgG1a 31% vs. 10.9%, p=0.04; anti-CD47 vs. combined anti-CD47 + anti-TIGIT 31% vs. 46.4%, p<0.01 and combined anti-CD47 + anti-TIGIT vs. IgG1a + IgG2a 46.4% vs. 13.6%, p<0.01, n=3 and for MV4-11: anti-CD47 vs. IgG1a 14.4% vs. 7.345%, p=0.03; anti-CD47 vs. combined anti-CD47 + anti-TIGIT 14.4% vs. 28.6%, p=0.03 and combined anti-CD47 + anti-TIGIT vs. IgG1a + IgG2a 28.6% vs. 12.85%, p=0.04, n=2).
Next, we correlated the phenotypic data with clinical parameters. AML patients of the intermediate risk group according to ELN criteria exhibited a significantly higher frequency of M2 LAMs co-expressing TIGIT and LAG-3 than those in the favorable group (p=0.04 and p=0.01). Moreover, the frequency of TIM-3 + M2 LAMs was significantly increased in patients with adverse and intermediate risk in comparison to those with a favorable risk (p=0.01, p=0.0053). Furthermore, TIGIT + M2 LAMs were significantly more frequent in patients with the FLT3 ITD mutation in comparison with the wilde type (p=0.03).
Conclusions: Our findings suggest that the proven clinical effect of monoclonal antibodies against TIGIT and TIM-3 in cancer may be due in part to their action on macrophages and depend on macrophage polarization. Our study identifies TIGIT + M2 LAMs co-expressing TIM-3 and LAG-3 as a promising effector population in AML. Further experiments should be conducted to investigate macrophage-mediated cytotoxicity in AML.
Brauneck: Daiichi Sankyo: Consultancy, Honoraria, Other: meeting attendance; Servier: Consultancy, Honoraria, Other: meeting attendance; Jazz Pharmaceuticals: Other: meeting attendance; Novartis: Other: meeting attendance. Bokemeyer: BMS: Honoraria, Other: Travel accomodation, Research Funding; Sanofi: Consultancy, Honoraria, Other: Travel accomodation; Merck Serono: Consultancy, Other: Travel accomodation ; Bayer Schering Pharma: Consultancy; GSO: Consultancy; AOK Health insurance: Consultancy; Abbvie: Research Funding; ADC Therapeutics: Research Funding; Agile Therapeutics: Research Funding; Alexion Pharmaceuticals: Research Funding; Amgen: Research Funding; Apellis Pharmaceuticals: Research Funding; Astellas: Research Funding; BerGenBio: Research Funding; Blueprint Medicine: Research Funding; Boehringer Ingelheim: Research Funding; Celgene: Research Funding; Daiichi Sankyo: Research Funding; Eisai: Research Funding; Gilead Sciences: Research Funding; Gylcotope GmbH: Research Funding; GlaxoSmithKline: Research Funding; Inside: Research Funding; IO Biotech: Research Funding; Isofol Medical: Research Funding; Janssen-Cilag: Research Funding; Karyopharm Therapeutics: Research Funding; Lilly: Research Funding; Millenium: Research Funding; MSD: Research Funding; Merck KGaA: Honoraria; Bayer: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Merck Sharp Dohme: Consultancy, Honoraria; AstraZeneca: Honoraria, Research Funding; Lilly/ImClone: Consultancy; Nektar: Research Funding; Rafael Pharmaceuticals: Research Funding; Springworks Therapeutics: Research Funding; Taiho Pharmaceutical: Research Funding; Pfizer: Other. Fiedler: Celgene: Consultancy; Servier: Consultancy, Other: support for meeting attendance; Abbvie: Consultancy, Honoraria; Morphosys: Consultancy; Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Other: support for meeting attendance; Jazz Pharmaceuticals: Consultancy, Other: support for meeting attendance; Stemline: Consultancy; Novartis: Consultancy; ARIAD/Incyte: Consultancy; Amgen: Consultancy, Other: support for meeting attendance, Patents & Royalties, Research Funding.
| v2 |
2019-11-22T00:44:32.524Z | 2019-11-13T00:00:00.000Z | 209273772 | s2ag/train | A Phase 2, Open-Label, Multicenter Study Evaluating the Safety and Efficacy of Axicabtagene Ciloleucel in Combination with Either Rituximab or Lenalidomide in Patients with Refractory Large B-Cell Lymphoma (ZUMA-14)
Background: Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy approved for the treatment of adult patients who have relapsed/refractory large B cell lymphoma (LBCL) and have had ≥ 2 prior systemic therapies. In ZUMA-1, the registrational study of axi-cel in patients with refractory LBCL, the objective response rate was 83% (complete response rate, 58%), with ongoing responses in 39% after a median follow-up of 27.1 months (Locke FL, et al. Lancet Oncol. 2019). Despite the success of axi-cel, approximately 60% of patients have no response or relapse after treatment, indicating that additional strategies are needed for patients with relapsed/refractory LBCL. Preclinical murine studies have shown that rituximab augmented the tumor-suppressing effects of anti-CD19 CAR T cells, and the combination led to higher rates of tumor reduction (Mihara K, et al. Br J Haematol. 2010; Rufener GA, et al. Cancer Immunol Res. 2016). The IMiD® immunomodulatory agent lenalidomide has shown activity in patients with relapsed/refractory diffuse large B cell lymphoma and has also been shown to enhance the antitumor functions of anti-CD19 and anti-CD20 CAR T cells in mice (Otahal P, et al. Oncoimmunology. 2016). In ZUMA-14, the aim is to investigate the efficacy and safety of axi-cel in combination with rituximab or lenalidomide in adult patients with refractory LBCL.
Methods: This Phase 2 study (NCT04002401) has a planned enrollment of approximately 60 patients aged ≥ 18 years with refractory LBCL, defined as a response of either progressive disease or stable disease to previous chemotherapy or progressive disease or relapse ≤ 12 months after an autologous stem cell transplant. Patients with prior IMiD® treatment, including lenalidomide, prior CAR T cell therapy, and/or prior CD19-targeted therapy are excluded. After leukapheresis, patients will be assigned 1:1 to receive axi-cel with either rituximab (Cohort 1) or lenalidomide (Cohort 2). Patients will receive lymphodepleting chemotherapy of fludarabine (30 mg/m2) and cyclophosphamide (500 mg/m2) on days -5 to -3 before axi-cel infusion (2 × 106 cells/kg) on Day 0. Cohort 1 will receive rituximab (375 mg/m2) every 28 days starting on Day -5 for a total of 6 doses. Cohort 2 will receive lenalidomide (10 mg) daily starting 7 days after leukapheresis through Day 3 and for 5 additional cycles (20 mg, first 21 days of each 28-day cycle) beginning after axi-cel infusion starting on Day 21. Patients may not receive any therapy other than conditioning therapy and rituximab or lenalidomide, as specified by cohort, between leukapheresis and axi-cel infusion. The primary endpoint is investigator-assessed complete response rate per the Lugano classification (Cheson BD, et al. J Clin Oncol. 2014). Key secondary endpoints include safety, objective response rate, duration of response, progression-free survival, overall survival, and pharmacokinetics (levels of blood CAR T cells over time). Exploratory endpoints for both cohorts include pharmacodynamic assessment of cytokine profiles and the rate of CD19-negative relapses. An additional exploratory endpoint for Cohort 2 is to investigate immunomodulation of the tumor microenvironment, including the number and activation of T cells and natural killer cells. Enrollment is expected to start in September 2019.
Neelapu: Cell Medica: Consultancy; Pfizer: Consultancy; BMS: Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Novartis: Consultancy; Precision Biosciences: Consultancy; Acerta: Research Funding; Karus: Research Funding; Incyte: Consultancy; Merck: Consultancy, Research Funding; Unum Therapeutics: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Cellectis: Research Funding; Allogene: Consultancy; Poseida: Research Funding. Kharfan-Dabaja:Daiichi Sankyo: Consultancy; Pharmacyclics: Consultancy. Oluwole:Pfizer: Consultancy; Spectrum: Consultancy; Gilead Sciences: Consultancy; Bayer: Consultancy. Krish:Celgene: Consultancy, Research Funding, Speakers Bureau; Genetech: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Takeda: Research Funding; Curis: Research Funding; MEI Pharma: Research Funding; Bristol Meyers Squibb: Research Funding; Xencor: Research Funding; Roche: Research Funding; AstraZeneca: Consultancy, Research Funding, Speakers Bureau; Sunesis: Consultancy, Research Funding. Reshef:BMS: Consultancy; Shire: Research Funding; Incyte: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Atara: Consultancy, Research Funding; Magenta: Consultancy; Pfizer: Consultancy; Pharmacyclics: Consultancy, Research Funding; Celgene: Research Funding. Riedell:Bayer: Honoraria, Speakers Bureau; Kite/Gilead: Honoraria, Research Funding, Speakers Bureau; Verastem: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding. Stiff:Amgen: Research Funding; Gamida-Cell: Research Funding; Incyte: Research Funding; Cellectar: Research Funding; Unum: Research Funding; Gilead/Kite Pharma: Consultancy, Honoraria, Research Funding. Goyal:Kite, a Gilead Company: Employment. Kawashima:Kite, a Gilead Company: Employment, Equity Ownership. Milletti:Roche: Employment, Equity Ownership, Other: Travel Expenses, Patents & Royalties; Gilead: Employment, Equity Ownership, Other: Travel Expenses, Patents & Royalties; Kite, a Gilead Company: Employment. Oliva:Kite, a Gilead Company: Employment. Sun:Kite, A Gilead Company: Employment. Munoz:Pharmacyclics /Janssen: Consultancy, Research Funding, Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Merck: Consultancy; Kyowa: Consultancy, Honoraria, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene/Juno: Consultancy, Research Funding; Genentech: Consultancy, Research Funding, Speakers Bureau; Kite/Gilead: Consultancy, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy; Alexion: Consultancy; Pfizer: Consultancy; Fosunkite: Speakers Bureau; AstraZeneca: Speakers Bureau; Portola: Research Funding; Incyte: Research Funding.
ZUMA-14 is a clinical trial evaluating the investigational combination of axicabtagene ciloleucel with either rituximab or lenalidomide in refractory large B cell lymphoma
| v2 |
2019-01-02T06:52:47.330Z | 2008-01-01T00:00:00.000Z | 145046942 | s2ag/train | ANALYSIS OF THE ACTION OF A PSEUDODIFFERENTIAL OPERATOR OVER ( CQlx ) T * x By
Let M be a real analytic manifold, QcM an open set, X a complexification of M, P a pseudodifferential operator on X. Using the action of P over holomorphic functions on suitable domains of X, by [B-S], and the theory of representation of microfunctions at the boundary (Cqix)t*mx, by [S-Z], [Z], we show that P defines in a natural manner a sheaf morphism of (Cq\x)t*mxLet us note that the hypotheses on dQ are here weaker than in [K 2] where dQ is supposed to be analytic. We also easily prove that P is an isomorphism of (Cqix)t*mx out of T%Xr\char (P) (both by composition rule and by non-characteristic deformation). We shall apply the method of this paper in our forthcoming work on regularity at the boundary for solutions of P(cf. [D'A-Z]). 0. Preliminaries. Let M be a C"'-manifold, X a complexification of M. We denote by T*M, T*X the cotangent bundles to M, X, and by T%X the conormal bundle to M in I; in particular we denote by T*X the zero section of T*X. We set t*X=T*X\T%X. For subsets S, V(zX one denotes by C{S, V) the normal cone to S along V and by N(S) the normal cone to S in X; these are objects of TX (cf. [K-S]). We will denote by BM (resp. CM\x) the sheaf of hyperfunctions on M (resp. of microfunctions). Let Q be an open subset of M and let Cq]X be the complex of sheaves defined in [S] (cf. also [K 1]). In this paper we shall assume that: (1) Q is O-convex. (2) H\CQ[x)=(COiX)T*x. Received May 14, 1989. Revised March 22, 1990. 176 Andrea D'Agnolo and Giuseppe Zampieri (One can prove that if Q has a C2-boundary then (1) and (2) are satisfied.) Let y be an open subset of QXMTMX with convex conic fibers; a domain UdX is said to be an Q-tuboid with profiley iff C(X\U, Q)ny1=0 for some open set JiCiTX with convex conic fiberssuch that y{Ho(N{Q)), p(Ti)^THere TMX <£―MXxTX <― TM are the canonical maps. If one chooses coordinates x<bM, z=xJrV―IjgI then U is an i2-tuboid with profiley iff for every y'<$=Lythere exists e=sr such that UZ){(x, y)^QxMy'; \y\<sdist(x, 8Q)Al\. (Here we identify TMX~X in local coordinates.) For example if Q={Xi>0} and y=QX{yn>0}, the set U={(x, y)^X; x^Q, ynxx>y'*\ is an J2-tuboid with profiley. We now recall how sections of (Cqix)t*mx can be represented as boundary values of holomorphic functions (cf. [S-Z], [Z]). Take f(Eiz*rroa((CQix)T*MxXS), S a ball in a local chart M=Rn, n: T%X -≫M the projection, ycQ XMTMX open with convex conic fibers over S and with 7t{y)=Sr\Q. Then one can write / as the boundary value b(F), F(=OX{U), U being both an i2-tuboid with profiley and a domain of holomorphy. At this subject we refer the reader to [Z]. Note here that the results of [S-Z], [Z] concerning the representation of the stalks {7t^ryaa{{CQ]X)T^x))x, x^it{y), easily extend to global sections over vectors spaces. For f^rQ{BM)i, xEidQ, one denotes by SSa(f) the support of / identified to a section of (Cqix)t*mx in n~\x). On account of the above characterization one proves that given (*, V^I^eT^X one has (x, V^I^SSflC/) iff /= ^ib(Fj) with Fj holomorphic in Ujf Uj i2-tuboid whose profile y} verifies V―\fj One also gets the following decomposition of microsupport. Let /e/flCSjfXS) and decompose ±-1(S)nSSi3(/)cU,r*% ((r*a)* closed proper convex ^x^Tc{yi)=Sr\Q). Then one can write f=2b(Fi), Fj^Ox(Uj), Uj £?-tuboid(of holomorphy) with profiley,. Let P^ex,t* be a pseudodifferentialoperator of order m defined in a neighborhood of a point t*^t%X. Fix a system of coordinates near t*: x=(xi, ・・・,xn) <=M=Rn, z=x + s/^ly^X=Cn, (z;Q^T*X=CnxCn, £=£+ V=It],(x ',V^ij) ELT%X^Rnx->/~-LRn, t*=(x\ V~-Lt}),^=(0, ・・・,0, 1). One can write the symbol of P as Analysis of the action of a pseudodifferential operator JlPtiz, 0, P^QT*x(UxW) 177 UxW open subsetof T*X, Wu{Z: |C*Î £olCI, i=h , w-1}, f/3i, Pz homogeneous in C of degree /, ~ sup t&J, iCilS&olSnl' \Z\l\P-i(z,Q\£Ml0+H\ In [B-S] Bony and Schapira have shown that, under these conditions, if one fixes a complex hyperplane Z= {z: <z, r]}=xn+V―Is} it is possible to define an "action" for P over holomorphic functions on suitable domains. Definition 0.1. Let k>0. An open convex subset U of Cn is said to be k-I-plat if: Mz^U, VfeJ such that \zn―zn\~^k\zt―zt\, i=l, ・・■, n―1 we have Z<^Ur\2. We refer the reader to [B-S] for the definition of the operator P2 over holomorphic functions defined in domains k0―I―plat with diameter fSl/M0. 1. Definition of the action. Let P(E<SX(V) be a pseudodifferential operator on an open set Vat%X. Our aim is to define an action for P over sections of {Cq\X)t*mxMore precisely, if a is the map a: 7t-\rQ{BM)) ―> (CqiX)t£x , we will show how P operates on a(7:~\ra(^M)))\v. To this end we will proceed in several steps. First we will make the operator act on cohomology classes of holomorphic functions defined on 42-tuboids with prescribed profile. Since each germ of a{iz~1{rQ{^M)))is represented as boundary value of a holomorphic function defined on a domain as above we can interpret the previous action as an action over {fiL(jc-\r(&&H)))\x.-/=ii,->, for every (x, V^ly^V. Finally we will show how P operates on a{K'\rQ{SM)))\v glueing up the actions over each fiber. Let (x, V^I^eF with x<b8Q. We fix a system of local coordinates so that ^=(0, ・・・, 0, 1), Q={x ; p(x)>0} (where p(x)=x1―<p(x2, ・・・, xn) for a convex function <p),and the symbol of P is defined on a set UxV as in the previous section. Let S={x ; \x―x\<r}, | v2 |
2021-05-10T00:04:33.925Z | 2021-01-27T00:00:00.000Z | 234004512 | s2ag/train | SAKK 16/14: Durvalumab in Addition to Neoadjuvant Chemotherapy in Patients With Stage IIIA(N2) Non-Small Cell Lung Cancer — A Multicentre Single-Arm Phase II Trial
Background: For patients with resectable stage IIIA(N2) non-small cell lung cancer (NSCLC) neoadjuvant chemotherapy with three cycles of cisplatin and docetaxel followed by surgery has been shown to yield a 1-year event-free survival (EFS) rate of 48% and is an accepted standard of care. Neoadjuvant PD-(L)1 inhibitors can result in high response rates in resectable NSCLC.
Methods: Neoadjuvant treatment consisted of three cycles of cisplatin 100 mg/m 2 and docetaxel 85 mg/m 2 q3w followed by two cycles of durvalumab 750 mg q2w. Adjuvant durvalumab was continued for 1 year after surgery. The primary endpoint was 1-year EFS. The hypothesis for statistical considerations was an improvement of 1-year EFS from 48% to 65%. This trial is registered with ClinicialTrials.gov, NCT02572843.
Findings: Sixty-eight patients were enrolled, 67 were included in the full analysis set. Radiographic response rate was 43·3% (95%CI: 31·2-56·0) after neoadjuvant chemotherapy (complete remission (CR): 2·9%, partial remission (PR): 40·3%, stable disease (SD): 44·8%) and 58·1% (95%CI: 44·8-70·5) after additional neoadjuvant immunotherapy (CR: 6·5%, PR: 51·6%, SD: 25·8%). Fifty-five patients were resected, of which 34 (61·8%) achieved a major pathological response (MPR; ≤10% viable tumour cells), and 10 (18·2%) amongst them a complete pathological response. Postoperative nodal down-staging (ypN0-1) was observed in 37 patients (67·3%). Fifty-one (92·7%) patients had an R0 resection. There was no significant effect of pre-treatment PD-L1 expression on MPR or nodal down-staging. In the entire study population, the 1-year EFS rate was 73·4% (90%CI: 62·7-81·5). Median EFS and overall survival were not reached after 28 months of median follow-up. Fifty-nine (88·1%) patients had an adverse event (AE) grade ≥3 including two fatal AEs that were not assessed to be treatment-related.
Interpretation: This is thus far the largest report on perioperative PD-(L)1 inhibition in patients with resectable stage IIIA(N2) NSCLC. The addition of perioperative durvalumab to neoadjuvant chemotherapy is safe and exceeds historical data of chemotherapy alone with a high MPR and an encouraging 1-year EFS rate of 73·4%.
Trial Registration: This trial is registered with ClinicialTrials.gov, NCT02572843.
Funding Statement: The study was supported by research agreements with the following institutions: Swiss State Secretary for Education, Research and Innovation (SERI), Swiss Cancer Research Foundation (SCS) and Swiss Cancer League (SCL). Research funding for translational research projects was granted by Gateway for Cancer Research and Rising Tide Foundation. AstraZeneca provided drug and financial support.
Declaration of Interests: SIR: Honoraria for advisory boards and consulting (all paid to the institution) from Astra-Zeneca, BMS, Boehringer-Ingelheim, Eisai, Eli Lilly, Merck Serono, MSD, Novartis, Pfizer, Roche, Takeda. Research funding from AbbVie, Astra-Zeneca, BMS, Boehringer-Ingelheim, Merck. Support for travel and accommodations from Amgen, AstraZeneca, BMS, Boehringer-Ingelheim, MSD, Roche, Takeda. Member of the Federal Drug Commission of the Federal Office of Public Health.
AZ: Honoraria for advisory boards and consulting (all paid to the institution) from Bristol-Myers Squibb, Merck Sharp & Dohme, Hoffmann–La Roche, NBE Therapeutics, Secarna, ACM Pharma and Hookipa. Non-commercial research agreements with Hoffmann–La Roche, NBE Therapeutics, Secarna, ACM Pharma, Hookipa, and BeyondSpring.
EIE: None
SSP: Honoraria for advisory boards and consulting from Astra-Zeneca, BMS, Boehringer-Ingelheim, MSD, Novartis, Pfizer and Roche.
DB: None
AB: None
MF: Research grants from Bristol-Myers-Squibb and Astra Zeneca (paid to the institution). Honoraria for advisory boards from Bristol-Myers Squibb, AstraZeneca, Takeda, Roche, Boehringer-Ingelheim and MSD.
MJ: Research grants from Bristol-Myers Squibb, Roche and Merck.
DL: None
HG: None
LAM: Honoraria for advisory boards from AstraZeneca, Bristol-Myers-Squibb, Takeda, Roche and MSD. Support for travel and accommodations from AstraZeneca and Roche.
CB: Honoraria for advisory boards from AstraZeneca, Pfizer, Roche, Takeda, Janssen-Cilag and Boehringer-Ingelheim. Support for travel and accommodations from AstraZeneca and Takeda.
WW: Honoraria for advisory boards and consulting from Astra Zeneca
SP: Personal fees from Abbvie, grants and personal fees from Amgen, grants and personal fees from AstraZeneca, personal fees from Bayer, personal fees from Biocartis, grants and personal fees from Boehringer-Ingelheim, grants and personal fees from Bristol-Myers Squibb, grants and personal fees from Clovis, personal fees from Daiichi Sankyo, personal fees from Debiopharm, personal fees from Eli Lilly, grants and personal fees from F. Hoffman - La Roche, personal fees from Foundations Medicine, grants and personal fees from Illumina, personal fees from Janssen, grants and personal fees from Novartis, personal fees from Pharma Mar, grants and personal fees from Pfizer, personal fees from Regeneron, personal fees from Sanofi, personal fees from Seattle Genetics, personal fees from Takeda, grants and personal fees from Merck Sharp and Dohme, personal fees from Merck Serono, personal fees from Merrimack.
MM: Honoraria for advisory boards from AstraZeneca, Bristol-Myers-Squibb, MSD, Roche and Takeda. Research grant (to the institution) from AstraZeneca.
RC: Honoraria for advisory boards (all paid to the institution) from AstraZeneca, Astellas, MSD, Bristol-Myers-Squibb, Janssen-Cilag, Roche, Pfizer, Merck Serono, Ipsen and Bayer.
AFO: None
WDJ: None
CW: None
NM: None
PF: Honoraria for advisory from Pfizer, Roche, Takeda, Boehringer-Ingelheim and BristolMyers Squibb.
MB: None
PB: None
GG: None
CR: None
MG: Honoraria for advisory boards and consulting (all paid to the institution) from Astra-Zeneca.
MP: Honoraria for advisory boards from AbbVie, AstraZeneca, Boehringer-Ingelheim, BristolMyers-Squibb, Eisai, MSD, Novartis, Pfizer, Roche, Takeda and Merck. Speakers fee from Janssen-Cilag. Support for travel and accommodations from AstraZeneca, BoehringerIngelheim, Bristol-Myers-Squibb and Vifor.
Ethics Approval Statement: The trial was done in accordance with the principles of the Declaration of Helsinki. The protocol was approved by the ethics committee of each participating site. Written informed consent was obtained from all patients. | v2 |
2021-11-25T16:19:14.544Z | 2021-11-05T00:00:00.000Z | 244535662 | s2ag/train | Chronic Lymphocytic Leukemia (CLL) Clonal Growth Rate Is Slower Following Venetoclax-Rituximab (VenR): Results from a Minimal Residual Disease (MRD) Model from the Randomized Phase 3 Murano Trial
Introduction: At a median follow-up of 5 years (cutoff of May 8, 2020), the MURANO trial (NCT02005471) demonstrated deeper responses, including superior rates of undetectable (u)MRD and progression-free survival, in patients (pts) with relapsed/refractory (R/R) CLL treated with fixed-duration VenR vs bendamustine-rituximab (BR). With longitudinal MRD assessments in peripheral blood (PB), we now report kinetics of MRD growth after end of treatment (EOT), and the clinical and molecular factors associated with MRD growth rates.
Methods: Pts were randomized to VenR (venetoclax 400mg daily for 2 years + standard-dose rituximab for the first 6 months) or BR (6 months). PB MRD samples were collected every 3-6 months and analyzed centrally by allele-specific oligonucleotide-polymerase chain reaction and/or flow cytometry; uMRD threshold was <10 −4. Mutations were identified using whole-exome sequencing on available DNA specimens from CD19-enriched baseline samples.
For longitudinal analysis of MRD growth dynamics, a population-based logistic growth model with a nonlinear mixed effects approach was developed as previously described (Al-Sawaf et al. EHA 2021). Pts who completed treatment (Tx) without progressive disease (PD) and who had ≥2 measurable time points post-EOT were included; data below the lower limit of quantification in those pts was handled by a likelihood-based method (Bergstrand & Karlsson, AAPS J 2009). Prognostic markers and patient demographics were screened as covariates for impact on key model parameters, based on statistical and graphical assessments. Variables with >20% missing data or with low representation (<10% in any category) were excluded from the analysis. Statistical inference on MRD doubling time was derived for the stratified subgroups; all p-values are descriptive.
Results: Overall, 284 pts completed the study Tx without PD. Pts with no MRD data (n=23), pts with MRD data only on-Tx (n=6) or only after PD/next-line of Tx (n=2), or pts with <2 measurable MRD values (n=42) were excluded, leaving a total of 211 pts (91 VenR-treated and 120 BR-treated) included in the analysis. With a faster time to PD for the BR arm, median duration of MRD data collection post-EOT was 395 days for BR-treated pts and 735 days for VenR-treated pts.
The median MRD level at EOT was significantly lower after VenR (1.88 x 10 −5) than BR (7.06 x 10 −4; p=5.1 x 10 −8, Figure 1A). In the VenR arm, no statistically significant difference in median MRD level at EOT was seen in pts with mutated or unmutated immunoglobulin heavy chain variable gene (IGHV), or pts with or without TP53 mutation (Table 1). However, in the BR arm, pts with TP53 mutation had significantly higher median MRD levels at EOT than those with TP53 wild-type (Table 1).
Overall, median MRD doubling time post-EOT was significantly longer for pts treated with VenR (93 days; n=91) than BR (53 days; n=120; p=1.2 x 10 −7, Figure 1B). Based on covariate screening of 27 prognostic markers and patient demographics, age (< or ≥65 years), VenR Tx, IGHV status, TP53 mutation status, and disease burden at study initiation (low/medium risk of tumor lysis syndrome vs high risk) showed significant impact on MRD growth rate (Table 1). The median MRD doubling time was 53 days in pts aged <65 years (n=92) and 66 days in pts aged ≥65 years (n=119; p=0.013); similar differences were seen in both Tx arms (Table 1). After adjusting the other three covariates in the model, the effect of VenR Tx on MRD growth rate remained statistically significant (0.51-fold of that for the BR arm, 95% confidence interval, 0.41-0.64).
Conclusion: Using a robust, population-based model of MRD growth dynamics, we demonstrate that post-EOT MRD growth was slower in pts with R/R CLL treated with VenR compared with BR. Together with similar observations in the frontline setting of venetoclax-obinutuzumab Tx, these results suggest that, compared with chemoimmunotherapy, fixed-duration venetoclax plus anti-CD20 therapy may contribute to prolonged CLL disease control by slowing the growth of the residual disease clones. It also implies that clonal growth may be influenced by biological and Tx-related parameters. The underlying mechanisms need to be further explored.
Figure 1 Figure 1.
Kater: Abbvie: Honoraria, Other: Ad Board, Research Funding; BMS, Roche/Genentech: Other: Ad Board, , Research Funding; Janssen, AstraZeneca: Other: Ad Board, steering committee, Research Funding; Genmab, LAVA: Other: Ad Board, Steering Committee. Lu: Genentech, Inc.: Current Employment; F. Hoffmann-La Roche Ltd: Current holder of individual stocks in a privately-held company. Langerak: Erasmus MS, University Medical Center: Current Employment; F. Hoffmann-La Roche Ltd/Genentech, Inc.: Research Funding; Gilead: Research Funding; Janssen: Speakers Bureau. Mellink: Cytogenetic Field: Consultancy; Genome Diagnostics Laboratory, AUMC: Current Employment; Financial support related to microarray analysis of Murano samples: Research Funding. Chyla: AbbVie: Current Employment, Current equity holder in publicly-traded company. Wu: Genentech, Inc.: Current Employment; Roche/GNE: Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Boyer: Roche: Current Employment. Lefebure: F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company; Roche: Current Employment. Jiang: F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company; Genentech, Inc./F.Hoffmann-La Roche Ltd: Current Employment. Seymour: Sunesis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Mei Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Morphosys: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees.
| v2 |
2016-05-17T00:53:02.412Z | 2016-04-01T00:00:00.000Z | 7903572 | s2ag/train | Morbillivirus and Pilot Whale Deaths, Canary Islands, Spain, 2015
To the Editor: Four strains of cetacean morbillivirus (CeMV; family Paramyxoviridae, genus Morbillivirus) have been detected in the global cetacean population: porpoise morbillivirus (1), dolphin morbillivirus (2), pilot whale morbillivirus (PWMV) (3), and Longman’s beaked whale morbillivirus (4). In addition, 2 novel CeMV sequences or strains isolated from the Indo-Pacific bottlenose dolphin (Tursiops aduncus) and the Guiana dolphin (Sotalia guianensis) have been recently reported in the Southern Hemisphere (5,6).
Pilot whales are known to be susceptible to 2 strains of CeMV, PWMV, and dolphin morbillivirus (3,7,8). Only 2 deaths of whales have been reported to be caused by PWMV: 1 long-finned pilot whale (Globicephala melas) (3) and 1 short-finned pilot whale (G. macrorhynchus) (8). We report deaths of 3 short-finned pilot whales caused by PWMV in the northeastern Atlantic Ocean along the coast of the Canary Islands, Spain.
During mid-January–May 2015, a total of 3 whales (animals 1, 2, and 3) were found dead along the coasts of the Canary Islands (Table). Complete standardized necropsy was performed for all whales. Tissue samples from animals 1 and 2 were fixed in 10% neutral-buffered formalin for histologic and immunohistochemical analyses (Technical Appendix Figure). Immunohistochemical analysis was performed (brain, intestine, lymph nodes, lung, kidney, adrenal gland, uterus, ovary, testis, and spleen) by using a monoclonal antibody against the nucleoprotein of canine distemper virus (CDV-NP; VMRD, Inc., Pullman, WA, USA) (7). Samples of lung, pulmonary lymph nodes, larynx, laryngeal tonsil, intestine, spleen, and brain were frozen (−80°C) for virologic analysis.
Table
Characteristics for 3 short-finned pilot whales stranded along the Canary Islands, Spain, 2015*
Grossly, the most remarkable findings in animal 1 were severe suppurative rhinitis, with clogged nasal passages by the accumulation of large quantity of purulent material, otitis media, sacculitis, and laryngitis. Severe diffuse epithelial hyperplasia and hyperkeratosis was observed along the upper respiratory tract and keratinized stomach. Animal 2 had severe proliferative dermatitis and cheilitis, and severe, suppurative, laryngeal tonsillitis. Animal 3 had advanced autolysis, which precluded pathologic analysis.
Histologically, moderate, multifocal, bronchointerstitial pneumonia, severe suppurative tonsillitis and systemic lymphoid depletion were identified in animals 1 and 2. Severe nonsuppurative meningoencephalitis with neuronal and glial cell degeneration and necrosis, microgliosis and syncytial cells were observed in animal 2.
Immunohistochemical analysis showed morbillivirus antigen in the bronchiolar epithelium, type 2 pneumocytes, and alveolar multinucleate cells. Syncytia from lymph nodes, laryngeal tonsil, spleen, and intestine also showed positive immunolabeling for morbillivirus. Epithelial tropism caused by the virus was suggested by identification of viral antigen in epithelia of the lung, larynx, keratinized stomach, intestine, kidney, urinary bladder, epididymis, and endometrial glands. In addition, intense immunolabeling was detected in neurons (soma, dendrites, axon hillock, and axons) and glial cells, primarily throughout the cerebral gray matter of animal 2.
Molecular detection of CeMV was performed by a using a 1-step reverse transcription PCR for a 426-bp conserved region of the phosphoprotein gene (7). All tested samples from animals 1 and 2 and a laryngeal tonsil sample from animal 3 showed positive PCR results. Because co-infections with herpesvirus and morbillivirus were observed during morbillivirus epizootics in seals in 1988 and dolphins in 2006–2007, we also tested the same tissue for herpesvirus by conventional nested PCR (9). Herpesvirus DNA was detected in all samples from animal 1 except lung, although no specific lesions compatible with this infectious agent were observed.
A pool containing all morbillivirus-positive PCR amplicons for animals 1 and 2 (GenBank accession nos. {"type":"entrez-nucleotide","attrs":{"text":"KT006289","term_id":"961377517"}}KT006289 and {"type":"entrez-nucleotide","attrs":{"text":"KT006290","term_id":"961377519"}}KT006290), a PCR amplicon for the brain sample from animal 2 (GenBank accession no. {"type":"entrez-nucleotide","attrs":{"text":"KT006291","term_id":"961377521"}}KT006291), and a PCR amplicon for the larynx from animal 3 were sequenced. A BLAST search (http://www.ncbi.nlm.nih.gov/blast/Blast.cgi) showed that amplified samples were nearly identical to reference PWMV sequences (GenBank accession nos. {"type":"entrez-nucleotide","attrs":{"text":"AF200817","term_id":"7329127"}}AF200817 [3] and {"type":"entrez-nucleotide","attrs":{"text":"FJ842381","term_id":"239775410"}}FJ842381 [8]). The sequence obtained from animal 3 was too short and degenerated to be accurately classified as CeMV, although it showed high homology with PWMV and porpoise morbillivirus.
It has been proposed that pilot whales might be enzootically infected with CeMV (10). These whales might be responsible for maintaining and transmitting CeMV over long distances or to other odontocetes. No die-offs have been observed in these species. However, an outbreak of a lethal morbillivirus infection in long-finned pilot whales caused by a dolphin morbillivirus strain occurred in the Mediterranean Sea during the end of October 2006–April 2007 (7).
Results of this study support the previous hypothesis that pilot whales have a species-adapted morbillivirus but indicate that lethal infections are not as rare as previously believed (3). The tropism of the virus in these cases, the high number of multinucleated syncytial cells, and the severity of the lesions resemble the acute systemic symptoms observed in dolphins infected with morbillivirus (2). Thus, pilot whales in the northeastern Atlantic Ocean could be at risk for infection, especially in one of the main pilot whale–watching regions between La Gomera and Southern Tenerife Islands in the Canary Islands, which has >700,000 visitors each year.
Technical Appendix. Microscopic images of tissue samples from 2 short-finned pilot whales (Globicephala macrorhynchus) from the eastern Atlantic Ocean stranded along the Canary Islands, Spain, 2015.
Click here to view.(380K, pdf) | v2 |
2019-05-03T13:10:12.100Z | 2003-06-01T00:00:00.000Z | 143239212 | s2ag/train | Oikos/Anthropos: Rationality, Technology, Infrastructure
Volume en los albores del PaleoJilico superior. Munibe (Antropologia Arkcologial5 2 • BRACE, C. L. 1964. The fate of the classic Neanderthals: A consideration of hominid catastrophism. CURRENT ANTHROPOL' Q(;y 5:3-·B· D'EHHJCO, FHANCESCO, IOAO ZILHAo, MICHELE IU LIEN, DOMINIQUE BAfflER, AND JACQUES rELE- G It IN. 1998. Neandenal acculturation in Western Europe? A critical review of the evidence and its interpretation. CURRENT ANTHROrOLOGY 39:51-544. KUHN, STEVEN, MARY C. STINER, DAVID S. REESE, AND E R K SIN GOLEC;. 200T. Ornaments of the earliest Up Number June 2003 I 42 I per Paleolithic: New insights from the Levant. Proceedings of the National Academy of Sciences, U.S.A. 98:7641-46. LArLAcE, GEORGES. 19660. Les niveaux castelperronien, pro toaurignacit:n Ct aurignaciens de 101 grottc Gatzarria a Suhare, en Pays Basque. Quartor 17:117-4°. - - . 1966b. Recherches sur l'origine et l'evolution des com plexes leplO/ilhiques. Melanges d'Archcologie et d'Histoire de l'tcole Franpise de Rome supp\. 4. MELLAltS, PAUL, MARCEL OTTE, AND LAWRENCE G. STRAUS 1999. The eanderthal problem continued CURRENT AJ';THRorOLOGV 40:34-1-64. MONTES, HAMON, AND IUAN SANGUINO 1001. La cueva de £1 Pen do: Acwaciones arqueol6gicas [994-2000. Santander: GO!llerno de Cantabria. S .... E -'Z DE BURUAGA, ANDONl. 1991. El Pa/eolilicosuperior de /a cueva de Galzarria (ZubelOa. Pais Vasco). Veleia lAne lOS series maior! 6. STHAUS, LAWRENCE G. 1986. Late W(lrm adaptive systems ill Camabrian Spain: The case of eastern ASlurias. Journal of Amhropo10gical Archaeology 5:330-68. - - . 1991. Iberia before lhe Iberians. Albuquerque: University of New Mexico Press. VITA-FINZI, C., AND E. HIGGS. 1970. Prehistoriccconomy in the Mount Carmel area of Palestine: Site catchment analy· sis. Proceedings of (he PrehistOric Society 36:1-37. ZJLH,\O, IOAO, AND FRANCESCO D'ERRICO. 1999. The chronology and taphonomy of the earliest Aurignacian and its implications for the understanding of Neanderthal extinction. loumal of World Prehiscory 13: 1-68. as a Social Institution, administered through the Social Science Research Council? The workshop was organized around an emerging interdisciplinary approach to sci ence, administration, politics, and economic organiza tion as areas in which the forms and values of oikas and amhropos-human communities and human be ings-are studied in the human sciences. The partici pants represented areas of vital interdisciplinary inquiry that have in recent years brought anthropologists to gether with scholars in geography, sociology, and social studies of science. These areas include studies of the biosciences and biomedicine, urban studies, economic sociology, social studies of finance, development studies, and the social·scientific study of modernity. The work shop's premise was that these approaches had something in common methodologically, conceptually, and theo retically and that a more explicit conversation about these commonalities would be productive. The papers used fine-grained studies of the sciences, state bureaucracy or administration, and modern eco nomic organization to pose questions about human be ings and human communities more commonly raised In political theory or philosophy. The panicipants J shared We thank Andrew Lakoff and Paul Rabinow for input in for mulating the workshop's organizing Ihemes. We also thank Jennifer Collier, Ben Orlove, George Marcus, Nikolas Rose, Marilyn Strath ern, and Caitlin Zaloom for comments on this report. 3. Geoffrey Bowker, Department of Communication, University of CaliforOla, San Diego, Time, Money, and Biodiversity ; Teresa Caldeira, Department of Anthropology, Universlty of California, Irvine, State and Urban Space in Modern Brazil: From Total Plan ning to Democratic Interventions (co-written with James HoI stonl; Lawrence Cohen, Department of Anthropology, UniverSity of California, Berkeley, The Ethics of the Exception: Some Prelim inary Frames ; Stcphen Collier, The Harriman Institute, Columbia University, Budgets and Bio-Politics in Post-Soviet Russia ; Eliz abeth Dunn, Department of Geography, University of Colorado, Boulder, Standards and Person-making in East Central Europe ; Sarah Franklin, Department of Sociology, Lancaster University, Stem Cells R Us: Emergent Forms of Life and the Global Biolog Ical ; Susan Greenhalgh, Department of Anthropology, IrVine, Governing by Numbers: Globalization and Population Gover n:lnce in China ; Andrew Lakoff, Department of Sociology, Uni versity of California, San Diego, The Private Life of Numbers: Audit Firms and the Government of Expcrtise in Post-Welfare Ar gentina ; George Marcus, Department of Anthropology, Rice Uni versity, Cultures of Expertise and the Management of Globaliza tion: Toward the Rc-functioning of Ethnography (co-written with Douglas Holmes]; Bill Mamer, Department of Anthropology, Uni versity of California, Irvine, Anthropological and Accounting Knowledge in Islamic Banking and Finance: Rethinking Critical Accounts ; Vinh-Kim Nguyen, Faculty of Medicine, lmmune De ficiency Treatment Centre, Montreal General Hospital, Antiret rovirals, Biomedical Globalism, and Therapeutic Economy ; Kris aids, Department of Geography, University of Wisconsin, Madison, Cultures on the Brink: Re-enginccring the Soul of Capitalism-on a Global Scale (with Nigel Thriftl; Aihwa Ong, Department of Anthropology, University of California, Berkeley, Baroque Econ omy ; Paul Rabinow, Department of Anthropology, University of CaliforIlla, Berkeley, Midst Anthropology's Problems ; Tobias Rees, Department of Anthropology, University of California, Berke ley, From the Social to the Bio-Social: Life and Science Today ; Nikolas Rose, Department of Sociology, London School of Econom ics, Biological Citizenship lwlth Carlos Novas!; Jeffrey Sallaz, Department of Sociology, University of California, Berkeley Gam bling wah Development: The 8mh of Casino Industries in South Oikos/Anthropos: Rationalityl Technology, Infrastructure STEPHEN J. COLLIER AND AIHWA ONG The Harriman Instltuce, 420 W. 1 18th St. New York, NY JO027, USA. (SC2093@co!umbiaedu)./ Department of Anthropology, University 0/ Cali/omia, Belkele)', Calif 94720, U.S.A 29 x 02 The workshop OikosIAnrhropos: Rationality, Technol ogy, Infnlstructure was convened on April 26 and 27, 2002, at New York University's Global Education Office I in Prague, the Czech Republic, with generous sup pan from the Sloan Foundation's Program on the Corporation ',9 1003 by The Wenner-Gren Foundation for Anthropological Re search. All rights reserved 0011-3104/1003/4403-0007SI.00 We are particularly grateful to Doug Guthrie of SSRC and Jjri Pehe, Director of YU's Prague office, for their suPPOrt. | v2 |
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