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2019-08-18T20:01:11.334Z | 2011-10-01T00:00:00.000Z | 202650910 | s2ag/train | Title Page / Table of Contents
s HORMONE RESEARCH IN PÆDIATRICS Basel • Freiburg • Paris • London • New York • New Delhi • Bangkok • Beijing • Tokyo • Kuala Lumpur • Singapore • Sydney HRP_2011_076_S02_tivo.indd I 01.07.2011 11:02:11 This publication was sponsored by Eli Lilly and Company Ferring Pharmaceuticals Ipsen Merck Serono S.A. Novo Nordisk A/S Pfizer Endocrine Care Sandoz International GmbH S. Karger Medical and Scientifi c Publishers Basel • Freiburg • Paris • London New York • Bangalore • Bangkok Shanghai • Singapore • Tokyo • Sydney Disclaimer Th e statements, options and data contained in this publication are solely those of the individual authors and contributors and not of the publisher and the editor(s). Th e appearance of advertisements in the journal is not a warranty, endorsement, or approval of the products or services advertised or of their eff ectiveness, quality or safety. Th e publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements. Drug Dosage Th e authors and the publisher have exerted every eff ort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant fl ow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any change in indications and dosage and for added warnings and precautions. Th is is particularly important when the recommended agent is a new and/or infrequently employed drug. All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specifi ed fee to the Copyright Clearance Center (see ‘General Information’). © Copyright 2011 by S. Karger AG, P.O. Box, CH–4009 Basel (Switzerland) ISBN 978–3–8055–9835–4 e–ISBN 978–3–8055–9836–1 Electronic production of the abstract book by pharma service – a business unit of documediaS GmbH Günther-Wagner-Allee 13, D–30177 Hannover (Germany) www.pharmaservice.de Printed by Lindendruck Verlagsgesellschaft mbH Fössestrasse 97A, D–30453 Hannover (Germany) www.lindendruck.de Fax +41 61 306 12 34 E-Mail [email protected] www.karger.com HRP_2011_076_S02_tivo.indd II 01.07.2011 11:02:29 Page Abstract No. Date Plenary Lectures 1 PL1 Strengths and Limitations of Evidence-based Medicine 1-2 Sunday, September 25 1 PL2 Frontiers in Diabetes 3-4 Monday, September 26 PL3 ESPE Award Session & Activities 1 no abstracts Monday, September 26 2 PL4 ESPE Award Session & Activities 2 5-6 Tuesday, September 27 2 PL5 New Paradigms in Molecular Medicine 7 Tuesday, September 27 2 PL6 Food for Thought before Going Home 8-9 Wednesday, September 28 Symposia 4 S1 Evidence-based Medicine in Growth Assessment In memory of Professor James Tanner 10-12 Sunday, September 25 4 S2 Early Life Origins of Health and Disease 13-15 Sunday, September 25 5 S3 New Insights in Phosphate Metabolism 16-18 Sunday, September 25 5 S4 Principles of Evidence-based Medicine 19-21 Monday, September 26 6 S5 Long Term Safety of Drugs 22-24 Monday, September 26 7 S6 Unexpected Ef fects of Hormones on the Brain 25-27 Monday, September 26 7 S7 Evidence-based Medicine in Childhood and Adolescent Diabetes ISPAD/ESPE 28-30 Tuesday, September 27 8 S8 The Cortisol-Cortisone Shuttle in Health and Disease 31-33 Tuesday, September 27 8 S9 Impact of Chronic Conditions on Growth 34-36 Tuesday, September 27 9 S10 Evidence-based Medicine in Thyroid Diseases 37-39 Wednesday, September 28 9 S11 New Insights in the Pathogenesis of PCOS APPES/ESPE 40-42 Wednesday, September 28 10 S12 Update on Growth Hormone Long Term Safety 43-46 Wednesday, September 28 New Perspectives 12 NP1 New Perspectives in Brain Imaging 47-48 Monday, September 26 12 NP2 New Perspectives in Molecular Analysis 49-50 Tuesday, September 27 ESPE Working Groups 13 WG1 ESPE Bone and Growth Plate Working Group 51-58 Sunday, September 25 15 WG2 ESPE Disorder of Sex Development Working Group 59-66 Sunday, September 25 17 WG3 ESPE Obesity Working Group: Long and Short-term Consequences of Childhood Obesity 67-69 Sunday, September 25 17 WG4 ESPE Paediatric and Adolescent Gynaecology Working Group: Amenorrhea in Adolescence 70-75 Sunday, September 25 19 WG5 ESPE Turner Syndrome Working Group: Ovarian Failure in Turner Syndrome 76-80 Sunday, September 25 Free Communications 20 FC1 Adipose Tissue and Obesity 81-86 Monday, September 26 22 FC2 Adrenal 87-92 Monday, September 26 23 FC3 Pituitary 93-98 Monday, September 26 26 FC4 Bone and Mineral Metabolism 99-104 Tuesday, September 27 28 FC5 Growth Hormone 105-110 Tuesday, September 27 30 FC6 Sexual Development 111-116 Tuesday, September 27 32 FC7 Cell Growth and Endocrine Oncology 117-122 Tuesday, September 27 34 FC8 Diabetes and the Beta Cell 123-128 Tuesday, September 27 36 FC9 Reproductive System 129-134 Tuesday, September 27 38 FC10 The X Chromosome 135-140 Tuesday, September 27 40 FC11 Diabetes Complications 141-146 Wednesday, September 28 42 FC12 Growth/Acid Labile Subunit 147-152 Wednesday, September 28 44 FC13 Puberty 153-158 Wednesday, September 28 46 FC14 Thyroid 159-164 Wednesday, September 28 Poster Presentations 49 P1-d1 Adrenal and HPA Axis 1 165-176 Sunday, September 25 53 P1-d2 Adrenal and HPA Axis 2 177-186 Monday, September 26 56 P1-d3 Autoimmune Endocrine Disease/Endocrine Oncology 1 187-192 Tuesday, September 27 58 P1-d1 Bone, Growth Plate and Mineral Metabolism 1 193-201 Sunday, September 25 61 P1-d3 Bone, Growth Plate and Mineral Metabolism 2 202-210 Tuesday, September 27 | v2 |
2019-03-19T13:07:13.819Z | 1987-01-01T00:00:00.000Z | 82402150 | s2ag/train | Molecular genetics of plant-microbe interactions : proceedings of the Third International Symposium on the Molecular Genetics of Plant-Microbe Associations, Montréal, Québec, Canada, July 27-31, 1986
Section I: Molecular Genetics of Agrobacterium and Plant Transformation.- "Ecology of Agrobacterium: plasmids and biovars".- "The Agrobacterium rhizogenes root-inducing system".- "Effect of the presence of the plasmid pSA and of auxin on the attachment of Agrobacterium tumefaciens to plant host cells".- "Dual regulation of virulence genes of Agrobacterium plasmid pTiC58".- "Overdrive, a T-DNA transmission enhancer on the A. tumefaciens tumor-inducing plasmid".- "Physical structure and genetics of the T-DNA in plants transformed by Agrobacterium tumefaciens".- "Mammalian metallothionein functions in plants".- "Tumorigenesis and root nodulation by Agrobacterium tumefaciens carrying Rhizobium symplasmids".- Supplementary articles (see Section VI).- Section II: Molecular Genetics of Phytopathogenic Bacteria and Fungi.- "Cutinase and pectinase in host-pathogen and plant-bacterial interaction".- "Siderophore biosynthesis, uptake and effect on potato growth of rhizosphere strains".- "A gene cluster in Xanthomonas campestris PV Campestris required for pathogenicity controls the excretion of enzymes".- "Direct analysis of the invasiveness of Xanthomonas campestris mutants generated by Tn4431, a transposon containing a promoterless luciferase cassette for monitoring gene expression".- "Analysis of the spontaneous mutation to avirulence by Pseudomonas solanacearum".- "Characterization of pathogenicity genes of Erwinia carotovora".- "Characterization of a novel esterase produced by plant pathogenic Streptomyces".- Supplementary articles (see Section VI).- Section III: Molecular Genetics of the Host = (Symbiosis/Pathogenicity).- "Induced symbiosis mutants of Pisum sativum".- "Plant host genetics of nodulation initiation in soybean".- "A mutant of pea (Pisum sativum) possibly disturbed in the production of a compound required for the induction of nitrogenase activity in bacteroids".- "Non-modulation mutants of soybean".- "Early nodulins in root nodule development".- "Peribacteroid membrane nodulins of soybean".- "Isolation of nodule specific c-DNA clones from Medicago sativa".- "Analysis of nodule-specific gene expression in ineffective alfalfa root nodules and callus cultures derived from ineffective root nodules".- "Nodule specific genes in Phaseolus vulgaris".- "Investigation of plant genes expressed during symbiotic nitrogen fixation".- "Rhizobium induced plant proteins in target root epidermal cells of Vigna unguiculata".- "Four soybean nodulin genes evolved from a common ancestor".- "Coordinated expression of nodule-specific and root genes in yellow lupin".- "Plant gene expression during effect and ineffective nodule development of the tropical stem-nodulated legume Sesbania rostrata".- "Expression of two enzymes involved in ureide formation in soybean regulated by oxygen".- "Probing cell wall structure in the soybean root nodule".- "Monoclonal antibodies to components of Rhizobium-induced pea nodules".- "Localization of the glutamine synthetase polypeptides in Phaseolus root nodules".- "Changes in protein and mRNA accumulation in potato tubers treated with an elicitor".- Section IV: Molecular Genetics of Rhizobium.- "Organization of the Rhizobium phaseoli genome".- "Rifampin resistance and nodulating competitiveness in Rhizobium meliloti".- "A method for isolating competition defective mutants in Rhizobium".- "Genetic determinants of nodulation in pR1e 1001a: nodD".- "Symbiotic mutants of Rhizobium meliloti which produce non-succinylated exopolysaccharide".- "Rhizobium mutants defective in lipopolysaccharide and infection".- "Analysis of three Rhizobium phaseoli genes, psi, psr and pss, which affect exopolysaccharide synthesis and symbiotic nitrogen fixation and/or nodulation".- "Involvement of pSym nodulation genes in production of surface and extracellular components of Rhizobium trifolii which interact with white clover root hairs".- "Rhizobium exopolysaccharides are essential for the formation of nitrogen fixing nodules in the Rhizobium-legume symbiosis".- "Coinoculation with symbiotically defective mutants of Rhizobium meliloti".- "Surface properties of Rhizobium meliloti associated with symbiosis".- "Degradative enzymes in Rhizobium meliloti".- "Identification of host specificity DNA regions determining the broad host range nodulation of Rhizobium strain NGR234".- "Nif, Fix and Nod gene clusters in Bradyrhizobium japonicum, and nifA-mediated control of symbiotic nitrogen fixation".- "Molecular genetics of nodulation of soybean by Bradyrhizobium japonicum".- "Characterization of genes essential for symbiotic nitrogen fixation from Bradyrhizobium japonicum strain I110".- "Nodulation genes of the stem nodulating Sesbania rostrata symbiont, strain ORS571".- "Nod-linked host specific gene for soybean (Peking) nodulation in Rhizobium fredii USDA193".- "Genomic organization of nodulation genes in Rhizobium phaseoli".- "Common and host specific nodulation genes in Rhizobium meliloti and their conservation in other Rhizobia".- "Host specific nodulation: effects of multiple nodD genes of Rhizobium meliloti".- "Nodulation genes of Rhizobium leguminosarum".- "Interactions between Rhizobium mililoti and Rhizobium trifolii nodulation genes: what is the basis for dominance by R. mililoti?".- "Multiple host-specificity loci in the broad host-range Rhizobium NGR234".- "Conserved nodulation genes are obligatory for non-legume nodulation".- "Characterization of symbiotic genes and regulation of their expression in Rhizobium leguminosarum pre".- "Regulation of the promoters in the nodulation region of the symbiosis plasmid pRL1J1 of Rhizobium leguminosarum".- "Narigenin induces the nodABC promoter of Rhizobium leguminosarum as well as Tsr factor production".- "An ntrC homologue in B. japonicum".- "Glutamine synthetases of Rhizobium leguminosarum".- "Molecular analysis of a Fix cluster from Rhizobium meliloti".- "Regulation of the nitrogen fixation (Nif) genes in Rhizobium meliloti".- "The unusual symbiosis between the nitrogen fixing bacterium ORS571 and its host Sesbania rostrata: regulation of nitrogen fixation and assimilation genes in the free living versus symbiotic state".- "Analysis of Azorhizobium sesbaniae ORS571 N2 fixation genes".- "Identification, characterisation and sequence analysis of the Rhizobium leguminosarum nifA gene".- "Analysis of hup DNA and Hup host range of Rhizobium leguminosarum BIO".- "Bioluminescence in root nodules of soybean controlled by nitrogenase promoters".- "In vivo cloning of genes from Bradyrhizobium japonicum".- "Genes for the catabolism and synthesis of a nodule-specific, opine-like compound are closely linked and on the Sym plasmid of Rhizobium meliloti".- "Molecular biology of genes involved in carbon metabolism in Rhizobium meliloti and Bradyrhizobium japonicum".- "Azorhizobium sesbaniae ORS571 conducts synergistic N2 fixation and nicotinic acid oxidation".- "At least three loci encode the leaf-curl phenotype in Rhizobium strain IC3342".- Section V: Molecular Genetics of the Other Diazotrophic Organisms.- "Use of heterologous hybridization in phylogenetic studies of symbiotic Anabaena strains".- "Chromobacterium lividum NCTC 10590 is a nitrogen-fixing Agrobacterium radiobacter".- "Studies on the diazotrophic nature of Agrobacterium".- "Developments in the genetic analysis of Azospirillum".- Section VI: Supplementary Articles for Sections I and II.- "Role of Vir genes in the excision of T-DNA from the ti-plasmid".- "Cloning vectors for Coryneform bacteria".- "Cloning of Serratia liquefaciens chitinase gene(s)".- Author Index. | v2 |
2019-11-22T00:50:09.442Z | 2019-11-13T00:00:00.000Z | 209286010 | s2ag/train | Synergistic Targeting of BTK and E-Selectin/CXCR4 in the Microenvironment of Mantle Cell Lymphomas
Mantle cell lymphoma (MCL) is a rare subtype of aggressive B-cell non-Hodgkin lymphoma that remains incurable with standard therapy. Overexpression of B-cell receptor signaling through Bruton tyrosine kinase (BTK) is a hallmark of MCL (Pal Singh et al., 2018). Inactivation of BTK signaling with the small molecule inhibitor ibrutinib is currently the most broadly used treatment of B cell lymphoma. However, it induces only low rates of apoptosis in vitro at clinically achievable concentrations. Frequently, primary and acquired resistance is observed (Chiron et al., 2014; Wang et al., 2013). One of the molecular mechanisms of acquired resistance is the development of BTKC481S mutations (Martin et al., 2016). In addition, the tumor microenvironment (TME), in which mesenchymal stroma cells (MSC) and vascular endothelial cells (ECs) are specialized components, has increasingly been recognized as a central determinant of drug resistance, subclonal evolution and late progression/transformation of B-cell lymphomas (Balsas et al., 2017; Weis and Cheresh, 2011).
Although the pro-tumoral ecosystem that supports MCL is still poorly understood, it has been reported that MCL cells express high levels of functional CXCR4 and CXCR5 chemokine receptors and VLA-4 adhesion molecules (Kurtova et al., 2009) . Lymphoma cells also display high levels of CD44, one of E-selectin ligands, in co-culture with ECs (Cao et al., 2014). These findings strongly suggest the association of acquired BTK mutations and the TME with resistance to BTK-targeted therapy in MCL. Therefore, we hypothesize that disrupting the crosstalk of MCL cells and TME by blocking CXCR4/CXCL12 or E-selectin/CD44 might benefit BTK-targeted therapy against MCL.
In this study, we investigated the anti-lymphoma effect of a novel small-molecule multi-kinase inhibitor CG-806 which exerts promising enzymatic inhibitory activity against the C481S mutation and wild type BTK at extremely low doses (IC50s were 2.52 and 5 nM, respectively). CG-806 demonstrated impressive anti-lymphoma effects in MCL cell lines Z138, MINO, Jeko-1 and JVM2 (IC50s of 2.7, 3.87, 3.79 and 8.27 nM, respectively), all of which were much less sensitive to ibrutinib (IC50s ≈ 10,000 nM). Mechanistically, CG-806 not only suppressed BTK activation, but also its downstream signaling targets phospho-Stat3,-AKT,-ERK and -Src, as well as NF-κB and c-Myc, and surprisingly upregulated p53 in MCL cells but exerted no suppression of phospho-FLT3 and aurora kinase at tested doses in MCL cells, two of the other potential CG-806 targets. Interestingly, CG-806 triggered profound apoptosis in Z138 and MINO cells as evidenced by increased cleavage of caspase-3 and PARP and expression of annexin V (EC50s 4.91 and 6.35 nM, respectively), but showed resistance in Jeko-1 and JVM2 cells (EC50s 7,800 and 3260 nM, respectively), which was accompanied with marked upregulation of autophagy, implicating autophagy as a novel resistance mechanism to BTK inhibition. Interestedly, our previous studies demonstrated that TME components MSC/hypoxia mediated autophagy upregulation which was associated with resistance in AML cells (Zhang et al., 2018), and, on the other hand, upregulation of autophagy was also observed in FLT3 wild type AML cells after CG-806 treatment, which resulted in resistance to CG-806-triggered apoptosis induction (Zhang et al., unpublished). Nevertheless, suppression of autophagy with the ULK1 inhibitor SBI-0206965 (Egan et al., 2015) or a putative autophagy inhibitor Chloroquine (CQ) (Mauthe et al., 2018) partially enhanced CG-806-induced apoptosis in the resistant Jeko-1 cells, confirming a role for autophagy in resistance to BTK inhibitors in MCL.
Furthermore, CXCR4 and E-selectin ligand levels were upregulated by exposing MCL cells in either ibrutinib or CG-806, and co-culture of MCL cells Z138 with MSC or HUVEC cells partially protected MCL cells from CG-806-triggered apoptosis. Of note, blockade of CXCR4 or E-selectin with their antagonist plerixafor or GMI-1271, respectively, re-sensitized to CG-806-induced apoptosis in MCL cells, suggesting potential benefit of disrupting the crosstalk of TME and lymphoma cells in MCL therapy. Taken together, our findings may provide the basis for a new therapeutic strategy co-targeting TME, autophagy and BTK with the goal of overcoming the resistance to BTK-targeted therapy in MCL.
Zhang: Aptose Biosciences, Inc: Employment. Fogler:GlycoMimetics Inc: Employment, Equity Ownership. Rice:Aptose Biosciences, Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Magnani:GlycoMimetics Inc: Employment, Equity Ownership. Borthakur:BMS: Research Funding; Tetralogic Pharmaceuticals: Research Funding; AstraZeneca: Research Funding; Eisai: Research Funding; Xbiotech USA: Research Funding; Argenx: Membership on an entity's Board of Directors or advisory committees; AbbVie: Research Funding; Cyclacel: Research Funding; Janssen: Research Funding; NKarta: Consultancy; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; PTC Therapeutics: Consultancy; Cantargia AB: Research Funding; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Eli Lilly and Co.: Research Funding; Strategia Therapeutics: Research Funding; Bayer Healthcare AG: Research Funding; Oncoceutics: Research Funding; Novartis: Research Funding; Arvinas: Research Funding; Merck: Research Funding; Oncoceutics, Inc.: Research Funding; Agensys: Research Funding; GSK: Research Funding; Incyte: Research Funding; Polaris: Research Funding; BioTheryX: Membership on an entity's Board of Directors or advisory committees. Andreeff:CLL Foundation: Membership on an entity's Board of Directors or advisory committees; BiolineRx: Membership on an entity's Board of Directors or advisory committees; Eutropics: Equity Ownership; Aptose: Equity Ownership; Reata: Equity Ownership; 6 Dimensions Capital: Consultancy; AstaZeneca: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Daiichi Sankyo, Inc.: Consultancy, Patents & Royalties: Patents licensed, royalty bearing, Research Funding; Jazz Pharmaceuticals: Consultancy; Center for Drug Research & Development: Membership on an entity's Board of Directors or advisory committees; NIH/NCI: Research Funding; CPRIT: Research Funding; Breast Cancer Research Foundation: Research Funding; Oncolyze: Equity Ownership; NCI-RDCRN (Rare Disease Cliln Network): Membership on an entity's Board of Directors or advisory committees; Leukemia Lymphoma Society: Membership on an entity's Board of Directors or advisory committees; German Research Council: Membership on an entity's Board of Directors or advisory committees; NCI-CTEP: Membership on an entity's Board of Directors or advisory committees; Cancer UK: Membership on an entity's Board of Directors or advisory committees; Oncoceutics: Equity Ownership; Senti Bio: Equity Ownership, Membership on an entity's Board of Directors or advisory committees.
| v2 |
2021-07-07T06:16:39.963Z | 2021-06-30T00:00:00.000Z | 235746660 | s2ag/train | Epidemiology and future prediction of Korean liver, pancreatic and biliary cancer.
Lecture
Supported by a national policy on cancer prevention and screening in Korea, the incidence of all types of cancers peaked in 2011 and turned into a declining trend. The overall cancer mortality rate has also steadily decreased since 2002 due to advances in diagnostic and treatment modalities. In 2018, liver, pancreas, gallbladder and biliary tract cancer were the 6th (6.5% of all cancers), 8th (3.1%), and 9th (2.9%) most common cancers in Korea [1]. Although the incidence of hepatocellular carcinoma is decreasing due to vaccination and effective treatment for viral hepatitis, incidences of pancreatic and biliary tract cancer are rapidly increasing. Moreover, liver and pancreatic cancer ranked the 2nd and 5th most common causes of death in 2019 [2]. However, due to relatively small number of patients, liver, pancreatic and biliary tract cancer have not been given a priority in national health policy, despite being fatal. Moreover, there are no studies related to future predictions regarding long-term changes in incidence and mortality. Therefore, the purpose of this study was to predict epidemiologic features of liver, pancreatic, and biliary tract cancer to build evidence that could provide insight into health policy and budget allocation, including cancer prevention, diagnosis and treatment strategies.
Incidence and mortality rate of liver, pancreas, and biliary tract cancer in Korea from 1999 to 2017
Summary statistics of liver cancer (C22) was retrieved from annual report of cancer statistics published by Korea Central Cancer Registry [1]. For pancreatic and biliary tract cancer, incidence data was retrieved from Korea Central Cancer Registry, National Cancer Center. Individuals with corresponding International Statistical Classification of Diseases and Related Health Problems (ICD)-10 codes and international classification of diseases for oncology (ICD-O) morphology codes were categorized as follows; gallbladder cancer (C23), intrahepatic bile duct cancer (C22.1, excluding M8162/3), extrahepatic bile duct cancer (C24.0 and M8162/3), ampulla of Vater cancer (C24.1), and pancreatic cancer (C25). Individuals with a morphology code "M8162/3" were reclassified as extrahepatic bile duct cancer because changes in topographic classification of Klatskin tumor overestimated cases of intrahepatic bile duct cancer [3]. However, mortality data retrieved from Statistics Korea from 2002 to 2018 did not have an identifier to reclassify the bile duct cancer accordingly. Therefore, mortality rate analysis and future epidemiology prediction utilized the sum of intra- and extrahepatic bile duct cancer as a single category for consistent analysis. From 2009 to 2018, annual percentage change (APC) of age-standardized incidence rate (ASIR, per 100,000 population) of liver cancer was -4.1% (24.0 to 16.7) [1]. From 1999 to 2017 trends in ASIR of each cancer were as follows; 2.9 to 2.6 (gallbladder [GB], APC -1.03%, p < 0.0001), 2.0 to 2.7 (intrahepatic bile duct [IBD], APC 2.30%, p = 0.0033), 2.9 to 3.2 (extrahepatic bile duct [EBD], APC 0.93%, p = 0.0009), 0.9 to 0.9 (ampulla of Vater [AoV], APC -0.37%, p = 0.1992), and 5.6 to 7.1 (pancreas, APC 1.46%, p < 0.0001). Especially, APC of pancreatic cancer ASIR in females was significantly higher than in males (2.30% vs. 0.61%, p < 0.0001). Male to female ASR ratio decreased in GB (1.08 to 1.00), IBD (2.55 to 2.18), EBD (2.28 to 1.94), and pancreatic cancer (1.95 to 1.45). Age-standardized mortality rate (ASMR) of each cancer was as follows; 18.7 to 8.0 (liver), 2.4 to 1.6 (GB), 5.5 to 4.6 (IBD and EBD), 0.4 to 0.4 (AoV) and 5.5 to 5.6 (pancreas).
Predicting future epidemiology of liver, pancreatic, and biliary tract cancer in Korea until 2040
Incidence and mortality rate was predicted using an age-period-cohort model (λ(age, period) = g{fA (age) + fP (period) + fC (cohort)}; λ, incidence [mortality] rate as a function of age and calendar period; g, 'link' function; fA, function of age; fP, function of period [year of incidence or mortality]; fC, function of cohort [year of birth, i.e., cohort=period-age]) [4]. Due to inconsistent coding practice in the causes of death statistics, ICD-10 codes used for prediction on future incidence and mortality were categorized as follows; Liver cancer (C22.0, C22.9), GB cancer (C23), IBD and EBD cancer (C22.1, C24.0, C24.8, C24.9), AoV cancer (C24.1), and pancreatic cancer (C25). To adjust future demographic structure, estimated population by Statistics Korea was applied to calculate ASIRs and ASMRs. Predicted annual cases of newly diagnosed cancer from 2021 to 2040 increased in all types of cancers as follows; 12,169 to 13,089 (liver), 2,857 to 4,038 (GB), 6,600 to 7,964 (IBD and EBD), 935 to 1,376 (AoV), 8,578 to 16,170 (pancreas). Predicted ASIR increased only in pancreatic cancer (7.5 to 8.2), while other cancers had declining trends; 12.0 to 8.5 (liver), 2.3 to 1.7 (GB), 5.4 to 3.2 (IBD and EBD), and 0.8 to 0.6 (AoV). Predicted annual deaths from 2021 to 2040 decreased in liver cancer (7,119 to 6,037), while other cancers had increasing trends as follows; 1,822 to 2,391 (GB), 5,598 to 7,928 (IBD and EBD), 408 to 536 (AoV), and 6,598 to 11,023 (pancreas). Predicted ASMR decreased in all types of cancers; 6.5 to 3.2 (liver), 1.4 to 0.9 (GB), 4.3 to 2.9 (IBD and EBD), 0.3 to 0.2 (AoV), and 5.4 to 4.7 (pancreas).
Conclusion
Pancreatic cancer revealed an increasing trend in ASIR, and the projected cases in 2040 are expected to outnumber those of liver cancer where ASIR is rapidly declining. ASIRs of GB, IBD and EBD, and AoV cancer had declining trends. Predicted ASMRs tended to decrease in all types of cancers, and ASMR of pancreatic cancer surpasses that of liver cancer from 2026. Epidemiologic analysis and prediction should be conducted on an ongoing bases by researchers, including clinicians. Based on the accumulated results, we look forward to the establishment and implementation of a better national cancer policy in the future. | v2 |
2022-06-10T02:09:24.536Z | 2014-01-01T00:00:00.000Z | 249519660 | s2ag/train | Abstract 1 – Insights Into Pancreatic Cancer Metabolism
1 – Insights Into Pancreatic Cancer Metabolism NABEEL BARDEESY,MASSACHUSETTS GENERAL HOSPITAL, BOSTON, MASSACHUSETTS, USA Cancercellsdependonwidespreadchanges incellmetabolismtomaintain rapidgrowth.Themetabolic requirementsofpancreatic cancers may be particularly stringent because of their fibrotic and poorly vascularized tumor microenvironment and resulting hypoxia and limited nutrient availability. Accordingly, these tumors exhibit multiple alterations in nutrient acquisition and utilization that are required for malignant growth, including activation of autophagy, a process by which organelles and protein aggregates are recycled by engulfment in modified membranes and degraded in lysosomes. In this presentation, we discuss the mechanisms leading to autophagy activation and the output from this process that maintains energy homeostasis in pancreatic cancer.We also discuss howmutations in pancreatic cancer driver genes rewire tumor cell metabolism as part of their oncogenic program. The identification of these metabolic dependencies in pancreatic cancer suggests novel therapeutic strategies. Abstract 2 – TheHistoneDeacetylase SIRT6: Linking Epigenetics to CancerMetabolism RAUL MOSTOSLAVSKY,MASSACHUSETTS GENERAL HOSPITAL, BOSTON, MASSACHUSETTS, USA2 – TheHistoneDeacetylase SIRT6: Linking Epigenetics to CancerMetabolism RAUL MOSTOSLAVSKY,MASSACHUSETTS GENERAL HOSPITAL, BOSTON, MASSACHUSETTS, USA Efficient glucose metabolism is critical for maintaining cellular viability. Under normal nutrient and oxygen conditions, glucose is converted to pyruvate, entering the mitochondria for oxidative phosphorylation and ATP production. Under hypoxia or nutrient stress,metabolismis switchedtoglycolysis, increasing lactateproductionandreducingmitochondrial respiration—aswitchknown to play an important role in cancer cells, as defined by OttoWarburg decades ago. Little is known about whether chromatin plays a role in carbohydrate flux. Recently,wediscovered that themammalian histone deacetylase sirtuin 6 (SIRT6) is a chromatin factor that influences glucose metabolism and DNA repair. At the cellular level, SIRT6 inactivation leads to increased cellular glucose uptake, higher lactate production, and decreased mitochondrial activity. Our results indicate that SIRT6 directly regulates expression of several key glycolytic and ribosomal genes. SIRT6 corepresses hypoxia-inducible factor-1a, acting as a histone H3 lysine 9andH3 lysine 56deacetylase to inhibit expressionof their target genes and functioningas a tumor suppressor to inhibit the Warburg effect. Strikingly, our new studies indicate that SIRT6, in contrast to other histone deacetylases (HDACs), appears to regulate transcriptional elongation, a novel function for HDACs. Our work identified SIRT6 as a critical chromatin deacetylase at a nodal point between epigenetics and metabolism, functioning as an important tumor suppressor. Abstract 3 – Improving the Treatment of Prostate Cancer JOHANN DE BONO, INSTITUTE OF CANCER RESEARCH, THE ROYAL MARSDEN, SUTTON, UNITED KINGDOM3 – Improving the Treatment of Prostate Cancer JOHANN DE BONO, INSTITUTE OF CANCER RESEARCH, THE ROYAL MARSDEN, SUTTON, UNITED KINGDOM This presentation will focus on the improved understanding of castration-resistant prostate cancer and the delivery of precision medicine for this disease. Recent developments with abiraterone, enzalutamide, cabazitaxel, and radium-223 will be discussed. Dataonnovelagents includingAKT,p110b,andpoly(ADP-ribose)polymerase inhibitorsandcabozantinibwill alsobediscussed.The study of exome and transcriptome data in early clinical trials for advanced prostate cancer to drive the pharmacological audit trail will also be presented. TheOncologist 2014;19(Supplement 1):S1–S6 www.TheOncologist.com ©AlphaMed Press 2014 Abstract 4 – Curative Potential of Cell Transfer Immunotherapy for Cancer4 – Curative Potential of Cell Transfer Immunotherapy for Cancer STEVEN A. ROSENBERG, NATIONAL CANCER INSTITUTE, BETHESDA, MARYLAND, USA Adoptive cell transfer (ACT) immunotherapy for patients with metastatic melanoma using autologous tumor-infiltrating lymphocytes (TILs) mediated a 56% objective response rate, including 20% of patients with durable complete regression ongoing from6.7 to 10.3 years. Administration of autologous TILs to nine patients with human papillomavirus-inducedmetastatic cervical cancer mediated objective responses in three patients, including two complete regressions that are ongoing beyond a year. The ideal targets for ACT are the uniquemutations that occur in cancers (Table 1). Using deep exomic sequencing, a technique has been developed to identify any cancer mutation—presented on any of the patient’s major histocompatibility complex molecules—that gives rise to reactive T cells.We recently reported the successful application of this approach to treat a patient with ametastatic bile duct cancer. Because virtually all cancers containmutations, this approach is nowbeing vigorously studied to expand the current reach of cancer immunotherapy to common epithelial cancers. Genes encoding conventional a-b T-cell receptors or chimeric antigen receptors (CARs) can be efficiently transduced into autologous lymphocytes, although choosing suitable targets expressed on the cancer is critical to avoid toxicities to essential normal tissues. ACT using CARs to target the CD19 molecule present on normal B cells and on the great majority of B-cell lymphomas and leukemiaswas first reportedtosuccessfully treatapatientwith refractory lymphoma in2010; thatpatient remainsprogression free at 5 years. Durable complete and partial responses have been seen in patients with chemotherapy-refractory indolent and aggressive large B-cell lymphomas. Of 9 patients heavily pretreated with large cell lymphomas receiving ACT, 4 patients have had complete regressions (2 ongoing from 9 to 22 months), and 2 additional patients have had partial response. Cancer-testis antigens such as NY-ESO-1 and MAGE-A3 are expressed during fetal development and in 10%–80% of cancers frommultiple tissuesbutoftenarenotexpressed inadult normal tissues.ACT targetingNY-ESO-1 resulted ina67%response rate in 15 treated patients with refractory synovial cell sarcoma and a 53% response rate in 19 patientswithmelanoma including durable complete regressions. Shared mutations that are unique to an individual cancer type also represent excellent targets for cell transfer immunotherapy, andweare conducting a trial usinga CAR targeting the EGFRvIIImutation, expressed in∼40%ofpatients with high-grade glioblastoma. Table 1. Surgery Branch, National Cancer Institute program for the application of cell transfer therapy to awide variety of human cancers Receptor Type Cancers Status Mutations TCR All cancers Accruing MART-1 TCR Melanoma Closed gp100 TCR Melanoma Closed NY-ESO-1 TCR Epithelial and sarcomas Accruing CEA TCR Colorectal Closed CD19 CAR Lymphomas Accruing VEGFR2 CAR All cancers Accruing 2G-1 TCR Kidney Accruing IL-12 Cytokine Adjuvant for all receptors Accruing MAGE-A3 TCR Epithelial Accruing EGFRvIII CAR Glioblastoma Accruing SSX-2 TCR Epithelial In development Mesothelin CAR Pancreas and mesothelioma Accruing CSP4 (HMWAg) CAR Melanoma, TN breast, Pancreas In development HPV-16 and -17 TCR Cervix, anal, oropharyngeal In development Abbreviations: CAR, chimeric antigen receptor; HPV, human papillomavirus; TCR, T-cell receptor; TN breast, triple-negative breast. ©AlphaMed Press 2014 The Oncologist S2 | v2 |
2020-11-05T09:06:01.233Z | 2020-11-05T00:00:00.000Z | 228878150 | s2ag/train | Symptom Burden and Quality of Life in High-Risk Essential Thrombocythemia and Polycythemia Vera Patients Receiving Hydroxyurea or Pegylated Interferon Alfa-2a: Results of Myeloproliferative Neoplasms Research Consortium (MPN-RC) 111 and 112 Trials
Introduction
Essential thrombocythemia (ET) and polycythemia vera (PV) patients suffer from various symptoms that worsen quality of life (QOL), yet serial data on symptom changes resulting from therapy are sparse in the literature. Patient questionnaires from 2 large multicenter trials (MPN-RC 111, 112) were used to assess change in symptom burden and QOL over 12 months and impact of baseline symptom burden on subsequent change in ET / PV patients on hydroxyurea (HU) or pegylated interferon alfa-2a (PEG).
Methods
Trials
MPN-RC 111 was a single-arm, open-label, phase II trial evaluating response to PEG in high-risk ET / PV patients with HU resistance/intolerance or splanchnic vein thrombosis (SVT; NCT01259817). MPN-RC 112 was a randomized, open-label, phase III trial comparing response to PEG versus HU in cytoreductive therapy naïve high-risk ET / PV patients diagnosed < 5 years ago (NCT01258856).
Measures
Patients reported disease-related symptoms via the validated Myeloproliferative Neoplasms Symptom Assessment Form (MPN-SAF), QOL via the European Organisation for the Research and Treatment of Cancer Core QOL Questionnaire (EORTC QLQ-C30), and (if applicable) PEG-related symptoms (flu-like symptoms, injection site irritation, blurry vision, vision change, flushing) at baseline, 3, 6, 9, and 12 months.
Analysis
Mixed models assessed mean changes from baseline in the MPN-SAF Total Symptom Score (TSS), MPN-SAF items, QOL, and PEG-related symptoms in MPN-RC 111, 112 PEG, and 112 HU patients. Mixed models also assessed the impact of baseline symptom burden (high [TSS ≥ 20] versus low) on subsequent change in PEG (MPN-RC 111 and 112) and HU patients.
Results
Patients
Of the 135 enrolled MPN-RC 111 patients, 20 with SVT and 1 with no questionnaires were excluded. Of the remaining 114, 64 (56%) / 50 (44%) had ET / PV. Patients were 51% / 48% female. Median age was 65 / 64 years, and median time since diagnosis was 38 / 55 months. 31% / 22% had prior thrombosis, and 19% / 56% had splenomegaly.
Of the 168 enrolled MPN-RC 112 patients (82 PEG, 86 HU), 2 with no questionnaires were excluded. Of the remaining 166, 79 (48%) / 87 (52%) had ET / PV. Patients were 50% / 33% female. Median age was 60 / 62 years, and median time since diagnosis was 3 / 3 months. 25% / 29% had prior thrombosis, and 11% / 37% had splenomegaly.
Symptoms
Questionnaire completion rates ranged from 90 - 99%, 87 - 100%, and 75 - 96% for on-treatment MPN-RC 111, 112 PEG, and 112 HU patients. At baseline, TSS (0 [absent] - 100 [worst imaginable]) and QOL (0 [very poor] - 100 [excellent]) means (SDs) were 19.5 (18.4) and 71.6 (20.1) for MPN-RC 111, 17.0 (13.6) and 67.9 (24.3) for MPN-RC 112 PEG, and 14.6 (11.4) and 73.8 (18.8) for MPN-RC 112 HU patients. On average, MPN-RC 111 patients had significant improvement of TSS, fatigue, abdominal pain, abdominal discomfort, dizziness, numbness, night sweats, and fever; MPN-RC 112 PEG patients had significant worsening of fever; and MPN-RC 112 HU patients had significant worsening of inactivity (no mean changes indicating improvement were observed). PEG patients had significant worsening of PEG-related symptoms.
The greatest improvements occurred in the 46 (40%), 27 (33%), and 23 (28%) MPN-RC 111, 112 PEG, and 112 HU patients with high baseline symptom burden. On average, PEG patients with high baseline symptom burden had significant improvement of TSS, fatigue, early satiety, abdominal pain, abdominal discomfort, inactivity, headache, concentration, dizziness, numbness, insomnia, cough, night sweats, itching, bone pain, fever, weight loss, and QOL, while those with low baseline symptom burden had significant worsening of TSS, early satiety, headache, itching, and bone pain. On average, HU patients with high baseline symptom burden had significant improvement of TSS, early satiety, abdominal discomfort, headache, dizziness, numbness, insomnia, itching, and weight loss, while those with low baseline symptom burden had significant worsening of TSS, early satiety, abdominal discomfort, inactivity, concentration, and sexual desire/function (Figures 1 and 2).
Conclusions
Although no statistical comparisons were made across trials, overall improvements were seen in MPN-RC 111 but not 112. Patients with high baseline symptom burden experienced the greatest improvements in symptom burden and QOL during treatment with PEG or HU, which may explain the improvements seen in the more advanced patients in MPN-RC 111 compared to 112.
Mascarenhas: Celgene, Prelude, Galecto, Promedior, Geron, Constellation, and Incyte: Consultancy; Incyte, Kartos, Roche, Promedior, Merck, Merus, Arog, CTI Biopharma, Janssen, and PharmaEssentia: Other: Research funding (institution). Yacoub:Dynavax: Current equity holder in publicly-traded company; Ardelyx: Current equity holder in publicly-traded company; Cara Therapeutics: Current equity holder in publicly-traded company; Hylapharm: Current equity holder in private company; Incyte: Speakers Bureau; Agios: Honoraria, Speakers Bureau; Novartis: Speakers Bureau; Roche: Other: Support of parent study and funding of editorial support. Hoffman:Protagonist: Consultancy; Forbius: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Dompe: Research Funding. Silver:PharmaEssentia: Speakers Bureau. Mesa:Bristol Myers Squibb: Research Funding; Incyte: Research Funding; AbbVie: Research Funding; Samus Therapeutics: Research Funding; Genentech: Research Funding; CTI BioPharma: Research Funding; Promedior: Research Funding; Sierra Oncology: Consultancy; LaJolla Pharmaceutical Company: Consultancy; Novartis: Consultancy.
| v2 |
2017-10-27T08:41:57.735Z | 2001-01-01T00:00:00.000Z | 44850270 | s2ag/train | Mossbauer , EPR , and ENDOR Studies of the Hydroxylase and Reductase Components of Methane Monooxygenase from Methylosinus trichosporium OB 3 b
Soluble methane monooxygenase (MMO) isolated from Methylosinus trichosporium OB3b consists of three components: hydroxylase, reductase, and component B. The active-site diiron cluster of the hydroxylase has been studied with Mossbauer, ENDOR, and EPR spectroscopies. Mossbauer spectra of the oxidized cluster show that the two high-spin irons are antiferromagnetically coupled in accord with our preliminary study (Fox et al. J . Biol. Chem. 1988, 263, 10553-10556). Mossbauer studies also reveal the presence of two cluster conformations at pH 9. The excited-state S = 2 multiplet of the exchange-coupled cluster (Fe3+.Fe3+) gives rise to an integer-spin EPR signal near g = 8; this is the first quantitative study of such a signal from any system. Analysis of the temperature dependence of the g = 8 signal yields J = 15 f 5 cm-I for the exchange-coupling constant (Hex = JSleS2). This value is more than 1 order of magnitude smaller than those reported for the oxo-bridged clusters of hemerythrin and Escherichia coli ribonucleotide reductase (Hex = JSI.S2, J = 270 and 220 cm-I, respectively), suggesting that the bridging ligand of the hydroxylase cluster is not an unsubstituted oxygen atom. Mossbauer spectra of the hydroxylase in applied fields of up to 8 T reveal a paramagnetic admixture of a low-lying excited state into the ground singlet. Both the spectral shape and intensity are well represented by assuming that the spin expectation values for the cluster sites increase linearly with magnetic field. However, the origin of this effect is not fully explicable in the framework of the standard spin Hamiltonian including zero-field splittings and antisymmetric exchange. EPR studies of the uncomplexed mixed valence (Fe3+.Fe2+) hydroxylase show that it is composed of two slightly different cluster forms in an approximate 4: 1 ratio. The zero-field splitting (ZFS) of the ferrous site of the mixed valence hydroxylase is sensitive to complexation with products or inhibitors, while complexation by the component B perturbs the exchange coupling. The binding of the inhibitor dimethyl sulfoxide results in the smallest distribution of ZFS parameters and thus is investigated here in a correlated study using each of the three spectroscopic techniques. The data were analyzed with a spin Hamiltonian that includes exchange coupling ( J = 60 cm-l) and mixing of multiplets by zero-field splittings. The analysis shows that the orbital ground state of the ferrous site has predominantly d, symmetry; the z-axis of this orbital points along the z-direction of the cluster g-tensor. Mossbauer and 57Fe-ENDOR spectra indicate that the A-tensor of the ferric site is anisotropic; the 57Fe-ENDOR signals are the first reported for diiron-oxo clusters. Analysis of the Miissbauer spectra of the uncomplexed, reduced (Fe2+.Fe2+) hydroxylase cluster recorded in strong applied fields (up to 6.0 T) unambiguously shows that the two iron sites are inequivalent. Spectra of the oxidized cluster are also best fit by assuming that the irons of the cluster reside in inequivalent environments. Considered in light of the overall two-fold symmetry of hydroxylase revealed by ongoing structural studies, the present findings show that the hydroxylase contains two, probably identical, active-site diiron clusters whose individual iron atoms are structurally distinct. Mossbauer and EPR spectra of the [2Fe-2SI2+J+ cluster of the M M O reductase component are also reported and analyzed. Soluble methane monooxygenase (MMO, EC 1.14.13.25) consists of three protein components: a 40-kDa reductase containing both FAD and a [2Fe2S] cluster; a 16-kDa protein termed component B containing no metals or organic cofactors; and a 245-kDa hydroxylase (quaternary structure (afly)2) containing up to 4 mol of iron.] Soluble M M O catalyzes the 02-dependent oxidation of methane to methanoL2 In addition, a wide variety of other hydrocarbons are adventitiously ~ x i d i z e d . ~ Efficient reconstitution of NADH-linked catalytic turnover * Authors to whom correspondence should be directed. + Carnegie Mellon University. f University of Minnesota. (1) (a) Fox, B. G.; Froland, W. A.; Dege, J. E.; Lipscomb, J . D. J. Biol. Chem. 1989,264, 10023-10033. (b) Froland, W. F.; Andersson, K. K.; Lee, S.-K.; Liu, Y.; Lipscomb, J . D. In Applications of Enzyme Biotechnology; Kelly, J. W., Baldwin, T. O., Eds.; Plenum Press: New York, 1991; pp 39-53. (c) Fox, B. G.; Lipscomb, J. D. In Biological Oxidation Systems; Reddy, C . C . , Hamilton, G. A,, Madyastha, K. M., Eds.; Academic Press: New York, 1990; Vol. 1, pp 367-388. (2) Dalton, H. Adu. Appl. Microbiol. 1980, 26, 71-87. 0002-7863/93/1515-3688$04.00/0 requires all three protein component^.^ However, in the absence of the other components, the hydroxylase is able to catalyze hydroxylation reactions either upon chemical reduction and e x p o ~ u r e l ~ ~ ~ ~ to 0 2 or upon a d d i t i ~ n ~ ~ , ~ of H202, demonstrating that the complete active site required for oxygenase catalysis resides on the hydroxylase alone. All EPR and Mijssbauer studiesconducted to date are consistent with the presence of a spin-coupled diiron cluster in the hydroxylase active site.] Iron quantitation in combination with theobservation (3) (a) Rataj, M. J.; Knauth, J. E.; Donnelly, M. I. J. Biol. Chem. 1991, 266,18684-18690. (b) Fox, B.G.;Borneman, J.G.; Wackett,L.P.;Lipscomb, J. D. Biochemistry 1990, 29, 641945427. (c) Ruzicka, F.; Huang, D.-S.; Donnelly, M. I.; Frey, P. A. Biochemistry 1990, 29, 1696-1700. (d) Green, J.; Dalton, H. J. Biol. Chem. 1989, 246, 17698-17703. (4) (a) Fox, B. G.; Liu, Y.; Dege, J. E.; Lipscomb, J. D. J . Biol. Chem. 1991, 266, 540-550. (b) Froland, W. A.; Andersson, K. K.; Lee, S.-K.; Liu, Y.; Lipscomb, J. D. J . Biol. Chem. 1992, 267, 17588-17597. (c) Green, J.; Dalton, H. J. Biol. Chem. 1985, 260, 15795-15801, (5) Andersson, K. K.; Froland, W. A.; Lee, S.-K.; Lipscomb, J. D. New J. Chem. 1991, 15, 411-415. | v2 |
2020-09-26T13:05:53.361Z | 2020-09-20T00:00:00.000Z | 221913700 | s2ag/train | [Research value of 50 MHz high-frequency ultrasound on sonography of normal facial skin in adult].
Objective: To observe the differences in normal facial skin thickness and echo density by different ages and sites of healthy adults of the same sex using 50 MHz high-frequency ultrasound. Methods: From January to June 2019, 200 healthy adult volunteers with normal facial skin who were from Sichuan, Yunnan, Guizhou, and Chongqing and met the inclusion criteria were recruited by the Affiliated Hospital of Southwest Medical University with simple random sampling method, and then were included in this cross-sectional investigation study. Then 50 MHz high-frequency ultrasound was used to obtain skin ultrasonogram of volunteers' forehead, canthus, eyelid, and cheek. According to the ages, 100 female volunteers were divided into 20-29 years old (30 females), 30-39 years old (25 females), 40-49 years old (20 females), and 50-70 years old (25 females) groups; 100 male volunteers were divided into 20-29 years old (30 males), 30-39 years old (25 males), 40-49 years old (20 males), and 50-70 years old (25 males) groups. The thickness of full-skin, the upper dermal echo density, and the lower dermal echo density of the female and male volunteers'forehead, canthus, eyelid, and cheek were recorded respectively. Data were statistically analyzed with one-way analysis of variance, analysis of variance for repeated measurement, least significant difference test, and Bonferroni correction. Results: (1) The thickness of full-thickness skin in forehead, canthus, eyelid, and cheek of female and male volunteers in 20-29 years old group were (1.86±0.26), (1.36±0.11), (1.24±0.25), and (1.90±0.21) mm, (2.45±0.37), (1.64±0.19), (1.44±0.16), and (2.53±0.26) mm, respectively, in 30-39 years old group were (1.98±0.24), (1.43±0.13), (1.15±0.15), and (2.12±0.13) mm, (2.34±0.27), (1.63±0.27), (1.50±0.38), and (2.43±0.40) mm, respectively, in 40-49 years old group were (1.90±0.21), (1.43±0.18), (1.24±0.27), and (1.98±0.12) mm, (2.14±0.24), (1.54±0.25), (1.28±0.14), and (2.39±0.36) mm, respectively, in 50-70 years old group were (1.64±0.25), (1.36±0.19), (1.16±0.12), and (1.89±0.29) mm, (2.28±0.27), (1.73±0.25), (1.58±0.18), and (2.38±0.32) mm, respectively. There were no statistically significant differences between female volunteers in the 4 groups and male volunteers in the 4 groups in thickness of full-thickness skin in canthus, eyelid, and cheek (F=0.677, 0.666, 0.136, 0.697, 0.294, 0.888, P>0.05). The thickness of full-thickness skin in forehead and cheek of the female volunteers in the 4 groups and male volunteers in the 4 groups was similar (P>0.05), and was significantly higher than that of canthus and eyelid (P<0.05). The thickness of full-thickness skin in canthus and eyelid of female volunteers in 20-29 years old, 40-49 years old, and 50-70 years old group was similar (P>0.05), while thickness of full-thickness skin in canthus and eyelid of male volunteers in the 4 groups was similar (P>0.05). (2) The upper dermal echo density of forehead, canthus, eyelid, and cheek of female volunteers in 50-70 years old group was significantly lower than that in 20-29 years old and 30-39 years old groups (P<0.05). The upper dermal echo density of forehead, canthus, eyelid, and cheek of male volunteers in 50-70 years old group was significantly lower than that in 20-29 years old group (P<0.05). The upper dermal echo density of forehead, canthus, eyelid, and cheek of female and male volunteers in 20-29 years old and 30-39 years old groups was similar (P>0.05). The upper dermal echo density of forehead and cheek of female volunteers in 20-29 years old, 40-49 years old, and 50-70 years old groups was significantly lower than that of canthus and eyelid (P<0.05). The echo density of upper dermis of cheek of male volunteers in the 4 groups was significantly lower than that of canthus and eyelid (P<0.05). The upper dermal echo density of canthus and eyelid of female volunteers in the 4 groups and male volunteers in the 4 groups was similar (P>0.05), the upper dermal echo density of forehead and cheek was similar (P>0.05). (3) The lower dermal echo density of forehead, canthus, eyelid, and cheek of female volunteers in 50-70 years old group was significantly higher than that in 20-29 years old and 30-39 years old groups (P<0.05). The lower dermal echo density of forehead, canthus, eyelid, and cheek of male volunteers in 50-70 years old group was significantly higher than that in 20-29 years old group (P<0.05). The echo density of the lower dermis of forehead, eyelid, and cheek of female and male volunteers in 20-29 years old, 30-39 years old, and 40-49 years old groups was similar (P>0.05). The lower dermal echo density of forehead and cheek of female volunteers in the 4 groups was significantly lower than that of canthus and eyelid (P<0.05). The lower dermal echo density of forehead and cheek of male volunteers in 30-39 years old, 40-49 years old, and 50-70 years old groups was significantly lower than that of canthus and eyelid (P<0.05). The lower dermal echo density between canthus and eyelid and between forehead and check of female volunteers in the 4 groups and male volunteers in the 4 groups was similar (P>0.05). Conclusions: The 50 MHz high-frequency ultrasonography shows that the thickness of full-thickness skin of canthus, eyelid, and cheek is similar in all age groups of female and male adult volunteers with normal facial skin. In the same age group, the thickness of full-thickness skin of forehead and cheek of male and female volunteers is significantly higher than that of canthus and eyelid. The upper dermal echo density of forehead, canthus, eyelid, and cheek of female and male volunteers shows a decreasing trend with age, while the lower dermal echo density shows an increasing trend with age. In addition, the echo density of upper and lower dermis of canthus and eyelid was significantly higher than that of cheek in all the four age groups. | v2 |
2019-12-14T06:52:40.945Z | 2013-01-01T00:00:00.000Z | 209350290 | s2ag/train | INTERNAL STRUCTURE , STRATIGRAPHIC RANGE AND PHYLOGENETIC RELATIONSHIPS OF CERTAIN AMERICAN EOCENE FORAMINIFERA
The inte rnal s tructure of toootypes of Cnmt' rlna cutenula. (Cushman and Ja rvis) a nd E oconuloides Imr\'ulus (Cushman) and of s peci me ns of Eoconuloidc8 well s i Cole a nd Bermudez and lIelicosteg ina l)oiygYralis (Barke r ) Is discu ssed a nd illustrated and notes are given on thei r stratigraph ic ranges. In t he int!'oduclory r emarks a postulate by H ofke r (196 8) concerning the phyloge netic J'c la tionship of the genua LepidocYCUnR and related genera is rejected . LellidocycUna ecuR(lorens is H ofker Is without <Iucatlon a synonym of H elicolepidinR Sll iralis Tobler. The phylogenetic relationships proposed by B arker and Grimsdale (19 36) for the lepidocycline and helicolepid lne lineages are maintained a.nd re-emphasized. INTRODUCTION This article is an attempt to clarify certa in misconceptions concerning the internal structure and stratigraphic range of several species of American Eocene Foraminifera. Such data are essenti al to an understanding of the phylogenetic relationships which have been postulated. Barker and Grimsdale (1936, p. 244) proposed a phylogenetic scheme in which the subgenus Polylepidina of the genus Lepidocyclina was derived from the Helicostegilla lineage. Helieostegilla had as its ancestor A mpllistegina lopeztrigoi D. K. Palmer [= Eocolluloides par\"IIlus (Cushman) of this article]. The proposal of Barker and Grimsdale has been accepted generally, as their postulate seemed to sati fy both the stratigraphic appearance of the genera and the progressive development of the internal lructures by which these genera are interrelated (Cole, 1960a, p. 62). Recentl y, Hofker ( 1968, p. 24, 27) stated that Lepidocyclilla (Polylepidilla) antil/ea Cushman, the earliest known species of Lepidocyclilla, could not have been derived from Helicostegilla, as L. alltil/ea does not possess siphonate apertures. Hofker (1968, p. 22) also wrote: "Lepidoeyclilla is known from the upper Eocene in the species L . alltillea (see Cole, 1960a, p. 62); so I believe that Lepidocyclina ecuadorell sis . somewhat older than L. antil/ea and may have been the ancestor of it. .. " In my 1960a article I stated ( p. 60): "Several of these specimens [Lepidocyelina alltil/ea] . . . have the trochoid spire and apertures which supposedly characterize Eulinderilla," a synonym of Lepido• The deDartment of Geological Sciences of Cornell Uni ,oeraity supported this research in part and contributed to the cost of publication. eyclina (Polylepidilla) . In 1963 (Cole, p. 20, pI. 7, figs. 5, 6) I published illustrations which show the siphonate apertures of Lepidocyclina (Polylepidina ) alltillea Cushman. Moreover, in my 1960a article ( p. 62) cited by Hofker ( 1968, p. 22) I wrote: "During the upper middle Eocene the first subgenus, Polylepidina, of the genus Lepidocyclina was derived ... " The middle Eocene age of L epidocyclilla (Poiylepidina) alltillea has long been established in surface outcrop (Cole, 1956, Table 4; 1958a, p. 190; Grimsdale, 1959, p. 17) and in well s (Cole, 1938, p. 48 ; 1944, p. 34; Gravell and Hanna, 1938, p. 1007). The specimens which Hofker ( 1968, p. 22) identified as Lepidocyclina eeuadorensis are strikingly similar to specimens from northwest Peru which L. Rutten (1928, p. 945) named Lepidocyclina vicllayalensis. M. G . Rutten ( 1935, p. 544) transferred this species to the genus A ctinosiphon. Cole ( 1960a, p. 60) stated " . . . Lepidocyclina vichayalensis Rutten (1928, p. 945) was based on specimens of Helicolepidina nortolli Vaughan." Later, Cole (1962, p. 147 ) concluded that H . lIortolli was a synonym of H elicolepidilla spiralis Tobler. The specimens illustrated by Hofker (1968, pI. II , fig. 3; pI. 14, fig. 2) as Lepidocyclina eCl/adorellsis should be compared with topotypes of H elicolepidina nortolli (Cole, 1962, pI. 24, figs. 1-3). All of these specimens have Type IIIb embryonic apparatuses (Cole, 1962, p. 146), which is characteristic of upper Eocene specimens (Cole, 1962. p. 147 ) of Helicolepidina spiralis. One specimen (Hofker, 1968, pI. 14, fi g. 2) shows the row of spiral chambers (about two rows below the second embryonic chamber and continuing across the illustration to the right ) best, but the spiral chambers also appear in figure I , plate 14 (Hofker, 1968) to the right of the embryonic chambers. The embryonic apparatus, the possession of a sequence of spiral chambers beyond the embryonic apparatus, and the shape and alignment of the equatorial chambers in Lepidocyclilla eCl/adorensis are characteri stic of Helicolepidina, not Lepidocyclina. In unit 4 assigned by Cushman and Stainforth (1951, p. 34) to a reefal facies of upper middle Eocene age, Hofker (1968, pI. 8, fi g. 4) found specimens which he correctly identified as H elicolepidilia spiralis in association with abundant specimens 78 COLE-ST UDIE S ON AMERICAN EOCENE FOHAMINIFERA which he referred incorrectly to the genus L epidocyclina (his LepidocyC/illa ecuadorellsis = Helicolepidina spira/is). Other specimens in unit 4 were identified as H elicolepidilla paucispira, a species placed by Cole (1960a, p. 59) in the synonymy of H elicostegina polygyralis (Barker). Hofker (1968, p. 21) in one place correctly observed that unit 4 is upper Eocene. However, he modified this statement by writing: " ... Van der Vlerk (see later) believes that unit 4 is from the uppermost part of the Middle Eocene." Unfortunately, Hofker and Van der Vlerk identified L epidocyC/illa ecuadorensis (= He/icolepidina spira/is) incorrectly. Therefore, the statistics (Vlerk, ill Hofker, 1968, p. 27, 28) upon which Van der Vlerk based the middle Eocene age of unit 4 are meaningless, as his statistical method is based on an analysis of the embryonic chambers of LepidocyC/ina, whereas the measurements given were made on | v2 |
2019-02-01T14:08:45.874Z | 2018-11-29T00:00:00.000Z | 59593140 | s2ag/train | Efficacy and Toxicity of JCAR014 in Combination with Durvalumab for the Treatment of Patients with Relapsed/Refractory Aggressive B-Cell Non-Hodgkin Lymphoma
Introduction
Autologous T cells engineered to express a CD19-specific chimeric antigen receptor (CAR) have shown high overall response rates (ORR) in otherwise treatment-refractory CD19+ B-cell non-Hodgkin lymphoma (NHL); however, not all patients (pts) achieve complete remission (CR). PD-L1 expression on tumor cells and/or other tissues could impair the function of PD-1+ CAR-T cells and the efficacy of CD19 CAR-T cell immunotherapy. PD-1 pathway blockade may enhance the function and antitumor activity of CD19 CAR-T cells. Here we report preliminary data from a phase 1 dose-finding study (NCT02706405) of the safety and feasibility of combination therapy with JCAR014 CD19-specific 4-1BB-costimulated CAR-T cells and escalating doses of durvalumab, an anti-PD-L1 monoclonal antibody, in adults with relapsed/refractory aggressive B-cell NHL.
Methods
Pts are treated in one of two groups. All pts receive lymphodepletion chemotherapy with cyclophosphamide and fludarabine followed by infusion of JCAR014. Pts in group 1 receive the first infusion of durvalumab (225 mg, 750 mg, or 1500 mg) 21-28 days after treatment with JCAR014. Pts in group 2 receive the first dose of durvalumab (7.5 mg, 22.5 mg, 75 mg, 225 mg, 750 mg, or 1500 mg) 1 day prior to JCAR014 infusion. Up to 10 doses of durvalumab are administered after JCAR014 at the highest identified safe dose at 4-week intervals until toxicity or disease progression. We evaluated the safety, tolerability, and efficacy of the combination therapy and the pharmacokinetic profile of JCAR014 after infusion. Adverse events were graded using the Common Terminology Criteria for Adverse Events (CTCAE) v4.03, with the exception of cytokine release syndrome (CRS), which was graded according to consensus criteria (Lee, Blood 2014). Positron emission tomography/computed tomography was performed approximately 1, 2, 4, 6, 9, and 12 months after JCAR014 infusion and the best anti-tumor response was reported according to the Lugano criteria (Cheson, JCO 2014).
Results
Patient characteristics are shown in Table 1. Fifteen pts have been treated, including 6 in group 1 who received post-JCAR014 durvalumab doses of 225 mg (n = 3) and 750 mg (n = 3), and 9 in group 2 who received pre-JCAR014 durvalumab doses of 7.5 mg (n = 1), 22.5 mg (n = 1), 75 mg (n = 3), or 225 mg (n = 4). Durvalumab dose escalation is ongoing. JCAR014 manufacturing was successful for all pts. All pts received 2 x 106 JCAR014 CAR-T cells/kg, except the first 2 pts treated on the study who received 7 x 105 CAR-T cells/kg. Of the 13 pts who received JCAR014 at 2 x 106 CAR-T cells/kg, 5 pts (38%) developed CRS (2 grade 1, 2 grade 2, and 1 grade 4) and one (8%) developed grade 1 neurotoxicity. CRS and/or neurotoxicity occurred within 4 weeks of JCAR014 infusion, and were not observed when durvalumab was administered after JCAR014. With the exception of B cell aplasia, no autoimmune adverse events were observed.
Twelve of 13 pts who received 2 x 106 CAR-T cells/kg were evaluable for response. One patient, who had grade 4 CRS and biopsy evidence of extensive CAR-T cell infiltration into persistent sites of disease, elected to receive hospice care and died on day 32 after JCAR014 infusion without full response evaluation. The overall response rate was 50% (5 CR, 42%; 1 PR, 8%). Of the 5 pts who achieved CR, 3 were in CR at the first restaging after JCAR014 and 2 subsequently converted to CR after the first post-JCAR014 durvalumab infusion. Only one patient who achieved CR has relapsed (median follow-up 10.6 months, range 3.7-11.8). Continued stable disease or evidence of regression was seen in 4 of 6 (67%) initially non-responding pts who continued durvalumab therapy (median 5 doses, range 1-6).
CAR-T cell counts expanded in the peripheral blood within 14 days of JCAR014 infusion in all pts. Higher peak and day 28 CAR-T cell copy numbers in blood by qPCR were observed in responding pts. CAR-T cells were detected for a median of 5.1 months (range, 1.7 to 9.1 months) in responding pts. In vivo re-accumulation of CAR-T cells after the first post-JCAR014 durvalumab dose was observed in the blood of two patients in group 2.
Conclusion
The combination of JCAR014 with durvalumab for the treatment of adult pts with aggressive B-cell NHL appears safe; however, dose escalation is ongoing. Complete responses were observed both at initial restaging after JCAR014 infusion, and also subsequently in pts continuing durvalumab therapy after initially failing to achieve CR.
Hirayama: DAVA Oncology: Honoraria. Hay:DAVA Oncology: Honoraria. Till:Mustang Bio: Patents & Royalties, Research Funding. Kiem:Homology Medicine: Consultancy; Magenta: Consultancy; Rocket Pharmaceuticals: Consultancy. Shadman:Verastem: Consultancy; Beigene: Research Funding; Mustang Biopharma: Research Funding; Gilead Sciences: Research Funding; TG Therapeutics: Research Funding; AbbVie: Consultancy; Genentech: Research Funding; Pharmacyclics: Research Funding; Celgene: Research Funding; Qilu Puget Sound Biotherapeutics: Consultancy; Genentech: Consultancy; AstraZeneca: Consultancy; Acerta Pharma: Research Funding. Cassaday:Jazz Pharmaceuticals: Consultancy; Amgen: Consultancy, Research Funding; Merck: Research Funding; Seattle Genetics: Other: Spouse Employment, Research Funding; Pfizer: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy; Kite Pharma: Research Funding; Incyte: Research Funding. Acharya:Juno Therapeutics: Research Funding; Teva: Honoraria. Riddell:Cell Medica: Membership on an entity's Board of Directors or advisory committees; Juno Therapeutics: Equity Ownership, Patents & Royalties, Research Funding; Adaptive Biotechnologies: Consultancy; NOHLA: Consultancy. Maloney:Roche/Genentech: Honoraria; Juno Therapeutics: Research Funding; Janssen Scientific Affairs: Honoraria; GlaxoSmithKline: Research Funding; Seattle Genetics: Honoraria. Turtle:Precision Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy; Bluebird Bio: Consultancy; Gilead: Consultancy; Nektar Therapeutics: Consultancy, Research Funding; Eureka Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Juno Therapeutics / Celgene: Consultancy, Patents & Royalties, Research Funding; Caribou Biosciences: Consultancy; Aptevo: Consultancy.
| v2 |
2019-04-17T15:47:44.701Z | 2004-02-25T00:00:00.000Z | 118213920 | s2ag/train | Integrable Hamiltonian Systems: Geometry, Topology, Classification
BASIC NOTIONS Linear Symplectic Geometry Symplectic and Poisson Manifolds The Darboux Theorem Liouville Integrable Hamiltonian Systems. The Liouville Theorem Non-Resonant and Resonant Systems Rotation Number The Momentum Mapping of an Integrable System and Its Bifurcation Diagram Non-Degenerate Critical Points of the Momentum Mapping Main Types of Equivalence of Dynamical Systems THE TOPOLOGY OF FOLIATIONS ON TWO-DIMENSIONAL SURFACES Generated by Morse Functions Simple Morse Functions Reeb Graph of a Morse Function Notion of an Atom Simple Atoms Simple Molecules Complicated Atoms Classification of Atoms Symmetry Groups of Oriented Atoms and the Universal Covering Tree Notion of a Molecule Approximation of Complicated Molecules by Simple Ones Classification of Morse-Smale Flows on Two-Dimensional Surfaces by Means of Atoms and Molecules ROUGH LIOUVILLE EQUIVALENCE OF INTEGRABLE SYSTEMS WITH TWO DEGREES OF FREEDOM Classification of Non-degenerate Critical Submanifolds on Isoenergy 3-Surfaces The Topological Structure of a Neighborhood of a Singular Leaf Topologically Stable Hamiltonian Systems Example of a Topologically Unstable Integrable System 2-Atoms and 3-Atoms Classification of 3-Atoms 3-Atoms as Bifurcations of Liouville Tori The Molecule of an Integrable System Complexity of Integrable Systems LIOUVILLE EQUIVALENCE OF INTEGRABLE SYSTEMS WITH TWO DEGREES OF FREEDOM Admissible Coordinate Systems on the Boundary of a 3-Atom Gluing Matrices and Superfluous Frames Invariants (Numerical Marks) r, e, and n The Marked Molecule is a Complete Invariant of Liouville Equivalence The Influence of the Orientation Realization Theorem Simple Examples of Molecules Hamiltonian Systems with Critical Klein Bottles Topological Obstructions to Integrability of Hamiltonian Systems with Two Degrees of Freedom ORBITAL CLASSIFICATION OF INTEGRABLE SYSTEMS WITH TWO DEGREES OF FREEDOM Rotation Function and Rotation Vector Reduction of the Three-Dimensional Orbital Classification to the Two-Dimensional Classification up to Conjugacy General Concept of Constructing Orbital Invariants of Integrable Hamiltonian Systems CLASSIFICATION OF HAMILTONIAN FLOWS ON TWO-DIMENSIONAL SURFACES UP TO TOPOLOGICAL CONJUGACY Invariants of a Hamiltonian System on a 2-Atom Classification of Hamiltonian Flows with One Degree of Freedom up to Topological Conjugacy Classification of Hamiltonian Flows on 2-Atoms with Involution up to Topological Conjugacy The Pasting-Cutting Operation Description of the Sets of Admissible delta-Invariants and Z-Invariants SMOOTH CONJUGACY OF HAMILTONIAN FLOWS ON TWO-DIMENSIONAL SURFACES Constructing Smooth Invariants on 2-Atoms Theorem of Classification of Hamiltonian Flows on Atoms up to Smooth Conjugacy ORBITAL CLASSIFICATION OF INTEGRABLE HAMILTONIAN SYSTEMS WITH TWO DEGREES OF FREEDOM. THE SECOND STEP Superfluous t-Frame of a Molecule (Topological Case). The Main Lemma on t-Frames The Group of Transformations of Transversal Sections. Pasting-Cutting Operation The Action of GP on the Set of Superfluous t-Frames Three General Principles for Constructing Invariants Admissible Superfluous t-Frames and a Realization Theorem Construction of Orbital Invariants in the Topological Case. A t-Molecule Theorem on the Topological Orbital Classification of Integrable Systems with Two Degrees of Freedom A Particular Case: Simple Integrable Systems Smooth Orbital Classification LIOUVILLE CLASSIFICATION OF INTEGRABLE SYSTEMS WITH NEIGHBORHOODS OF SINGULAR POINTS l-Type of a Four-Dimensional Singularity The Loop Molecule of a Four-Dimensional Singularity Center-Center Case Center-Saddle Case Saddle-Saddle Case Almost Direct Product Representation of a Four-Dimensional Singularity Proof of the Classification Theorems Focus-Focus Case Almost Direct Product Representation for Multidimensional Non-degenerate Singularities of Liouville Foliations METHODS OF CALCULATION OF TOPOLOGICAL INVARIANTS OF INTEGRABLE HAMILTONIAN SYSTEMS General Scheme for Topological Analysis of the Liouville Foliation Methods for Computing Marks The Loop Molecule Method List of Typical Loop Molecules The Structure of the Liouville Foliation for Typical Degenerate Singularities Typical Loop Molecules Corresponding to Degenerate One-Dimensional Orbits Computation of r- and e-Marks by Means of Rotation Functions Computation of the n-Mark by Means of Rotation Functions Relationship Between the Marks of the Molecule and the Topology of Q3 INTEGRABLE GEODESIC FLOWS ON TWO-DIMENSIONAL SURFACES 409 Statement of the Problem Topological Obstructions to Integrability of Geodesic Flows on Two-Dimensional Surfaces Two Examples of Integrable Geodesic Flows Riemannian Metrics Whose Geodesic Flows are Integrable by Means of Linear or Quadratic Integrals. Local Theory Linearly and Quadratically Integrable Geodesic Flows on Closed Surfaces LIOUVILLE CLASSIFICATION OF INTEGRABLE GEODESIC FLOWS ON TWO-DIMENSIONAL SURFACES The Torus The Klein Bottle The Sphere The Projective Plane ORBITAL CLASSIFICATION OF INTEGRABLE GEODESIC FLOWS ON TWO-DIMENSIONAL SURFACES Case of the Torus Case of the Sphere Examples of Integrable Geodesic Flows on the Sphere Non-triviality of Orbital Equivalence Classes and Metrics with Closed Geodesics THE TOPOLOGY OF LIOUVILLE FOLIATIONS IN CLASSICAL INTEGRABLE CASES IN RIGID BODY DYNAMICS Integrable Cases in Rigid Body Dynamics Topological Type of Isoenergy 3-Surfaces Liouville Classification of Systems in the Euler Case Liouville Classification of Systems in the Lagrange Case Liouville Classification of Systems in the Kovalevskaya Case Liouville Classification of Systems in the Goryachev-Chaplygin-Sretenskii Case Liouville Classification of Systems in the Zhukovskii Case Rough Liouville Classification of Systems in the Clebsch Case Rough Liouville Classification of Systems in the Steklov Case Rough Liouville Classification of Integrable Four-Dimensional Rigid Body Systems The Complete List of Molecules Appearing in Integrable Cases of Rigid Body Dynamics MAUPERTUIS PRINCIPLE AND GEODESIC EQUIVALENCE General Maupertuis Principle Maupertuis Principle in Rigid Body Dynamics Classical Cases of Integrability in Rigid Body Dynamics and Related Integrable Geodesic Flows on the Sphere Conjecture on Geodesic Flows with Integrals of High Degree Dini Theorem and the Geodesic Equivalence of Riemannian Metrics Generalized Dini-Maupertuis Principle Orbital Equivalence of the Neumann Problem and the Jacobi Problem Explicit Forms of Some Remarkable Hamiltonians and Their Integrals in Separating Variables EULER CASE IN RIGID BODY DYNAMICS AND JACOBI PROBLEM ABOUT GEODESICS ON THE ELLIPSOID. ORBITAL ISOMORPHISM Introduction Jacobi Problem and Euler Case Liouville Foliations Rotation Functions The Main Theorem Smooth Invariants Topological Non-Conjugacy of the Jacobi Problem and the Euler Case REFERENCES SUBJECT INDEX | v2 |
2022-11-22T06:17:25.335Z | 2022-11-21T00:00:00.000Z | 253733050 | s2ag/train | Prothrombin complex concentrate in cardiac surgery for the treatment of coagulopathic bleeding.
BACKGROUND
Coagulopathy following cardiac surgery is associated with considerable blood product transfusion and high morbidity and mortality. The treatment of coagulopathy following cardiac surgery is challenging, with the replacement of clotting factors being based on transfusion of fresh frozen plasma (FFP). Prothrombin complex concentrate (PCCs) is an alternative method to replace clotting factors and warrants evaluation. PCCs are also an alternative method to treat refractory ongoing bleeding post-cardiac surgery compared to recombinant factor VIIa (rFVIIa) and also warrants evaluation. OBJECTIVES: Assess the benefits and harms of PCCs in people undergoing cardiac surgery who have coagulopathic non-surgical bleeding.
SEARCH METHODS
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, MEDLINE, Embase and Conference Proceedings Citation Index-Science (CPCI-S) on the Web of Science on 20 April 2021. We searched Clinicaltrials.gov (www.
CLINICALTRIALS
gov), and the World Health Organisation (WHO) International Clinical Trials Registry Platform (ICTRP; apps.who.int/trialsearch/), for ongoing or unpublished trials. We checked the reference lists for additional references. We did not limit the searches by language or publication status.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) and non-randomised trials (NRSs). DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: Eighteen studies were included (4993 participants). Two were RCTs (151 participants) and 16 were NRSs. Both RCTs had low risk of bias (RoB) in almost all domains. Of the 16 NRSs, 14 were retrospective cohort analyses with one prospective study and one case report. The nine studies used in quantitative analysis were judged to have critical RoB, three serious and three moderate. 1. PCC versus standard treatment Evidence from RCTs showed PCCs are likely to reduce the number of units transfused compared to standard care (MD -0.89, 95% CI -1.78 to 0.00; participants = 151; studies = 2; moderate-quality evidence). Evidence from NRSs agreed with this, showing that PCCs may reduce the mean number of units transfused compared to standard care but the evidence is uncertain (MD -1.87 units, 95% CI -2.53 to -1.20; participants = 551; studies = 2; very low-quality evidence). There was no evidence from RCTs showing a difference in the incidence of red blood cell (RBC) transfusion compared to standard care (OR 0.53, 95% CI 0.20 to 1.40; participants = 101; studies = 1; low-quality evidence). Evidence from NRSs disagreed with this, showing that PCCs may reduce the mean number of units transfused compared to standard care but the evidence is uncertain (OR 0.54, 95% CI 0.30 to 0.98; participants = 1046; studies = 4; low-quality evidence). There was no evidence from RCTs showing a difference in the number of thrombotic events with PCC compared to standard care (OR 0.68 95% CI 0.20 to 2.31; participants = 152; studies = 2; moderate-quality evidence). This is supported by NRSs, showing that PCCs may have no effect on the number of thrombotic events compared to standard care but the evidence is very uncertain (OR 1.32, 95% CI 0.87 to 1.99; participants = 1359; studies = 7; very low-quality evidence). There was no evidence from RCTs showing a difference in mortality with PCC compared to standard care (OR 0.53, 95% CI 0.12 to 2.35; participants = 149; studies = 2; moderate-quality evidence). This is supported by evidence from NRSs, showing that PCCs may have little to no effect on mortality compared to standard care but the evidence is very uncertain (OR 1.02, 95% CI 0.69 to 1.51; participants = 1334; studies = 6; very low-quality evidence). Evidence from RCTs indicated that there was little to no difference in postoperative bleeding (MD -107.05 mLs, 95% CI -278.92 to 64.83; participants = 151, studies = 2; low-quality evidence). PCCs may have little to no effect on intensive care length of stay (RCT evidence: MD -0.35 hours, 95% CI -19.26 to 18.57; participants = 151; studies = 2; moderate-quality evidence) (NRS evidence: MD -18.00, 95% CI -43.14 to 7.14; participants = 225; studies = 1; very low-quality evidence) or incidence of renal replacement therapy (RCT evidence: OR 0.72, 95% CI 0.14 to 3.59; participants = 50; studies = 1; low-quality evidence) (NRS evidence: OR 1.46, 95% CI 0.71 to 2.98; participants = 684; studies = 2; very low-quality evidence). No studies reported on additional adverse outcomes. 2. PCC versus rFVIIa For this comparison, all evidence was provided from NRSs. PCC likely results in a large reduction of RBCs transfused intra-operatively in comparison to rFVIIa (MD-4.98 units, 95% CI -6.37 to -3.59; participants = 256; studies = 2; moderate-quality evidence). PCC may have little to no effect on the incidence of RBC units transfused comparative to rFVIIa; evidence is very uncertain (OR 0.16, 95% CI 0.02 to 1.56; participants = 150; studies = 1; very low-quality evidence). PCC may have little to no effect on the number of thrombotic events comparative to rFVIIa; evidence is very uncertain (OR 0.51, 95% CI 0.23 to 1.16; participants = 407; studies = 4; very low-quality evidence). PCC may have little to no effect on the incidence of mortality (OR 1.07, 95% CI 0.38 to 3.03; participants = 278; studies = 3; very low-quality evidence) or intensive care length of stay comparative to rFVIIa (MD -40 hours, 95% CI -110.41 to 30.41; participants = 106; studies = 1; very low-quality evidence); evidence is very uncertain . PCC may reduce bleeding (MD -674.34 mLs, 95% CI -906.04 to -442.64; participants = 150; studies = 1; very low-quality evidence) and incidence of renal replacement therapy (OR 0.29, 95% CI 0.12 to 0.71; participants = 106; studies = 1; very low-quality evidence) comparative to rFVIIa; evidence is very uncertain. No studies reported on other adverse events. AUTHORS' CONCLUSIONS: PCCs could potentially be used as an alternative to standard therapy for coagulopathic bleeding post-cardiac surgery compared to FFP as shown by moderate-quality evidence and it may be an alternative to rFVIIa in refractory non-surgical bleeding but this is based on moderate to very low quality of evidence. | v2 |
2019-11-22T00:55:54.994Z | 2019-11-13T00:00:00.000Z | 209226800 | s2ag/train | Dual Inhibition of MDM2 and XPO1 Synergizes to Induce Apoptosis in Acute Myeloid Leukemia Progenitor Cells with Wild-Type TP53 through Nuclear Accumulation of p53 and Suppression of c-Myc
Background. MDM2 is frequently overexpressed in acute myeloid leukemias (AML) and suppresses p53-mediated apoptosis while p53 mutations are relatively rare in AML. MDM2 inhibitors as a monotherapy have shown limited efficacy in clinical trials in AML (~25% response rate) (Andreeff, Clin Cancer Res 2015). XPO1 transports around 300 proteins, including p53 and other tumor suppressors, from the nucleus to the cytoplasm. Overexpression of XPO1 is associated with unfavorable outcomes in AML (Kojima, Blood 2013). p53 activation or XPO1 inhibition have been reported to decrease c-Myc protein levels through diverse mechanisms (Porter Mol Cell 2017 and Tabe PLoSOne 2015).
Objective: We investigated anti-leukemia effect of dual MDM2 and XPO1 inhibition, with the intent to maximize the pro-apoptotic functions of p53, using the MDM2 inhibitor milademetan (Daiichi-Sankyo), and selinexor, a recently FDA-approved XPO1 inhibitor or its analog eltanexor (Karyopharm).
Results: Treatment with milademetan and selinexor (1:1 molar ratio) induced synergistic apoptosis in AML cell lines with wild-type p53 (ED50, 89.3 ± 18.6 nM, combination index (CI), 0.60 ± 0.08). Activity in p53 mutant AML required 40-fold higher ED50 (3572 ± 1986 nM), reflected in an antagonistic CI of 6.94 ± 3.06. Knockdown of wild-type p53 by shRNA in OCI-AML3 (OCI-AML3 shp53) cells or presence of TP53 mutation (p.R248W) in MOLM-13 cells eliminated the synergistic effects, suggesting that normal p53 function is a major determinant of sensitivity to combined treatment.
Next, we treated primary AML samples with milademetan and selinexor or eltanexor and observed that effects were mutation-agnostic (e.g. RAS and FLT3) except for TP53. Combined treatment significantly reduced AUC determined by absolute live cell numbers compared to each drug alone, and induced synergistic apoptosis in primary AML samples with wild-type p53 (ED50 values, 27.2 - 937.4 nM, CI, 0.51 ± 0.07), with similar efficacies in complex and non-complex karyotype AMLs (279.6 ± 94.7 vs 256.6 ± 56.4 nM, P = 0.84). In contrast, combined treatment showed antagonistic effects in primary AML samples with loss-of-function TP53 mutations (CI > 1.0). Immature CD34+CD38- AML cells were more susceptible to combined treatment than CD34- AML cells (apoptosis induction, 76.2 ± 6.7% vs 47.5 ± 6.8%, P = 0.0002)
Mechanistically, combined inhibition increased p53 protein levels and accumulated p53 but not MDM2 protein in the nucleus compared to each drug alone. Combined treatment induced more TP53 target genes (MDM2, CDKN1A, BBC3, FAS and Bax) in OCI-AML3 cells with control shRNA compared with OCI-AML3 shp53 cells. Combinatorial inhibition showed much enhanced reduction of c-Myc mRNA and protein levels in OCI-AML3 shC cells compared with OCI-AML3 shp53 cells (82% vs 32%). In confirmation, combined inhibition reduced c-Myc protein levels profoundly in wild-type p53 primary AMLs (ANOVA P < 0.0001). In contrast, c-Myc reduction was not observed in primary AMLs with p53-inactivating mutations. Intriguingly, OCI-AML3 cells overexpressing c-Myc by lentiviral transduction showed greater sensitivity to XPO1 inhibitors and the combination compared to empty-vector controls, and baseline levels of c-Myc protein also negatively correlated with ED50 for combined treatment in primary AML samples (Spearman R = -0.5357, P = 0.0422).
Conclusion: These preclinical data suggest that dual inhibition of MDM2 and XPO1 induces synergistic apoptosis through accumulation of nuclear p53 and suppression of c-Myc in wild-type p53 AMLs. A clinical trial testing this concept in AML is under development.
Ishizawa: Daiichi Sankyo: Patents & Royalties: Joint submission with Daiichi Sankyo for a PTC patent titled "Predictive Gene Signature in Acute Myeloid Leukemia for Therapy with the MDM2 Inhibitor DS-3032b," United States, 62/245667, 10/23/2015, Filed. Daver:Novartis: Consultancy, Research Funding; Agios: Consultancy; Jazz: Consultancy; Hanmi Pharm Co., Ltd.: Research Funding; Pfizer: Consultancy, Research Funding; Astellas: Consultancy; Immunogen: Consultancy, Research Funding; Forty-Seven: Consultancy; Abbvie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Servier: Research Funding; Incyte: Consultancy, Research Funding; NOHLA: Research Funding; Glycomimetics: Research Funding; BMS: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Celgene: Consultancy; Otsuka: Consultancy. Lesegretain:Daiichi-Sankyo Inc.: Employment, Equity Ownership. Shacham:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Andreeff:NIH/NCI: Research Funding; Center for Drug Research & Development: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Amgen: Consultancy; AstaZeneca: Consultancy; 6 Dimensions Capital: Consultancy; Reata: Equity Ownership; Aptose: Equity Ownership; Eutropics: Equity Ownership; Senti Bio: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Oncoceutics: Equity Ownership; Oncolyze: Equity Ownership; Breast Cancer Research Foundation: Research Funding; CPRIT: Research Funding; NCI-RDCRN (Rare Disease Cliln Network): Membership on an entity's Board of Directors or advisory committees; CLL Foundation: Membership on an entity's Board of Directors or advisory committees; BiolineRx: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo, Inc.: Consultancy, Patents & Royalties: Patents licensed, royalty bearing, Research Funding; Leukemia Lymphoma Society: Membership on an entity's Board of Directors or advisory committees; Cancer UK: Membership on an entity's Board of Directors or advisory committees; NCI-CTEP: Membership on an entity's Board of Directors or advisory committees; German Research Council: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy.
| v2 |
2017-10-17T16:34:39.636Z | 2017-03-01T00:00:00.000Z | 38885030 | s2ag/train | Processed Food-An Experiment That Failed.
Opinion Viewpoint buy previously unaffordable luxuries for her grandson including toi- letries, fresh produce, winter blankets, and a nightlight. Like Beatrice, single women making less than $10 000 yearly headed many of the families we served. The good news for these women and their children was 2-fold. First, these types of families are the EITC’s target population and, as such, received thousands of dollars in tax credit. Second, for those who filed in prior years, StreetCred saved them money previously lost to the for-profit tax- filing industry by providing free services in the comfort of a trusted setting: their pediatrician’s office. These women expressed both gratitude and practical impact as they reported their ability to not only more fully meet their children’s basic needs, but also take a first step toward financial stability by paying off loans, which are stories consistent with national data on the ways taxpayers use EITC monies. 7 Moreover, StreetCred empowered families with EITC edu- cation. Some clients expressed enthusiasm about working more hours in the coming year to qualify for a larger EITC on their next tax return. Other single mothers learned that they, not their ex- -earned-income-tax-credit. Published January 15, 2016. Accessed July 7, 2016. ARTICLE INFORMATION Published Online: January 17, 2017. doi:10.1001/jamapediatrics.2016.3868 Conflict of Interest Disclosures: None reported. Additional Contributions: We thank Barry Zuckerman, MD (Boston University School of Medicine); Paul Wise, MD, MPH (Stanford University); and James Perrin, MD (Harvard Medical School), for editing assistance and manuscript review. They did not receive compensation for their contributions. REFERENCES 1. Center on Budget and Policy Priorities. Policy basics: the earned income tax credit. http://www .cbpp.org/research/federal-tax/policy-basics-the VIEWPOINT Robert H. Lustig, MD, MSL Department of Pediatrics, University of California, San Francisco; and Philip R. Lee Institute for Health Policy Studies, University of California, San Francisco. Corresponding Author: Robert H. Lustig, MD, MSL, Division of Pediatric Endocrinology, University of California, San Francisco, 550 16th St, PO Box 0434, San Francisco, CA 94143 ([email protected]). husbands, should claim the children as tax-return dependents be- cause they served as primary caretakers. StreetCred is another example of how the US health care sys- tem can be a gateway to the public benefits, community resources, and financial stability supporting low-income parents, like Bea- trice, in one of the most important jobs in the United States: raising healthy children. The trust and regular contact between families and their children’s medical professionals present a special opportunity to screen for and address the social determinants of health. Street- Cred aims to make accessing programs, such as the EITC, cheaper, faster, and easier to understand. The program’s short-term goals are 2-fold: (1) expand free tax-preparation services to other clinics and hospitals serving low-income families with children and (2) expand its services portfolio with additional asset-building tools so families might truly break the cycle of poverty. Innovative programs extend- ing beyond the traditional boundaries of pediatric health services remain an important approach to promoting the health and devel- opment of our patients growing up poor. 5. Council on Community Pediatrics. Poverty and child health in the United States. Pediatrics. 2016; 137(4):e20160339. 2. Marr C, Huang C-C, Sherman A, Debot B. EITC and child tax credit promote work, reduce poverty, and support children’s development, research finds. Center on Budget and Policy Priorities website. http://www.cbpp.org/research/federal-tax /eitc-and-child-tax-credit-promote-work-reduce -poverty-and-support-childrens. Published October 1, 2015. Accessed July 7, 2016. 6. Holzer HJ, Shanzenbach DW, Duncan GJ, Ludwig J; National Poverty Center. National Poverty Center Working Paper Series, 07-04: The economic costs of poverty in the United States: subsequent effects of children growing up poor. http://www.npc.umich .edu/publications/u/working_paper07-04.pdf. Published January 2007. Accessed July 7, 2016. 3. US Internal Revenue Service. About EITC. http://www.eitc.irs.gov/EITC-Central/abouteitc. Accessed April 1, 2015. 7. Goodman-Bacon A, McGranahan L. How do EITC recipients spend their refunds? Econ Perspect. 4. Weinstein P, Patten B. The Price of Paying Taxes II: How Paid Tax Preparer Fees are Diminishing the Earned Income Tax Credit (EITC). Washington, DC: The Progressive Policy Institute; 2016. Processed Food—An Experiment That Failed Those of us who have participated in science know that 9 of every 10 experiments are failures. Now imagine that the last 50 years has been a grand clinical research experi- ment, with the American population as unwitting partici- pants,conductedby10principalinvestigators—Coca-Cola, Pepsico, Kraft, Unilever, General Mills, Nestle, Mars, Kellogg, Proctor & Gamble, and Johnson & Johnson. In 1965, these corporations posed the hypothesis that pro- cessed food is better than real food. To determine if the ex- perimentwasasuccessorafailure,wehavetoexaminethe outcomevariables.Inthiscase,thereare4:foodconsump- tion, health/disease, environment, and cash flow, divided into companies, consumers, and society. Processed food is defined by 7 food engineering crite- ria; it is mass produced, is consistent batch to batch, is con- sistentcountrytocountry,usesspecializedingredientsfrom specialized companies, consists of prefrozen macronutri- ents, stays emulsified, and has long shelf life or freezer life. 1 Furthermore, 11 nutritional properties distinguish pro- cessed food. 2 (1) Too little fiber. When fiber (soluble and insoluble) is consumed within food, it forms a gelatinous barrier along the intestinal wall. This delays the intestine’s ability to absorb nutrients, instead feeding the gut micro- biome. Attenuation of the glucose rise results in insulin re- duction. Attenuation of fructose absorption reduces liver fataccumulation.(2)and(3)Toofewω-3andtoomanyω-6 fatty acids. ω-3s are precursors to docahexaenoic and ei- cosapentanoicacids(anti-inflammatory).Conversely,ω-6s are precursors of arachidonic acid (proinflammatory). Our ratio of ω-6 to ω-3 fatty acids should be approximately 1:1. Currently, our ratio is about 25:1, favoring a proinflamma- tory state, which can drive oxidative stress and cell dam- age. (4) Too few micronutrients. Antioxidants, such as vi- tamins C and E, quench oxygen radicals in peroxisomes to preventcellulardamage,whileothers,suchascarotenoids and α-lipoic acid, prevent lipid peroxidation. (5) Too many JAMA Pediatrics March 2017 Volume 171, Number 3 (Reprinted) Copyright 2017 American Medical Association. All rights reserved. Downloaded From: http://jamanetwork.com/pdfaccess.ashx?url=/data/journals/peds/936064/ by a UCSF LIBRARY User on 04/05/2017 jamapediatrics.com | v2 |
2019-12-12T08:03:39.592Z | 2019-11-13T00:00:00.000Z | 209261540 | s2ag/train | Preliminary Results from a Phase 1 First-in-Human Study of AMG 673, a Novel Half-Life Extended (HLE) Anti-CD33/CD3 BiTE® (Bispecific T-Cell Engager) in Patients with Relapsed/Refractory (R/R) Acute Myeloid Leukemia (AML)
Background: AMG 673 is a novel half-life extended (HLE) BiTE® (bispecific T-cell engager) construct that binds both CD33 and CD3 and is genetically fused to the N-terminus of a single-chain IgG Fc region, thereby potentially increasing the half-life of the molecule. AMG 673 redirects T cells toward CD33+ cells, with the induced proximity leading to T-cell‒mediated cytotoxicity against acute myeloid leukemia (AML) blasts. Anti-AML activity of other CD33/CD3 bispecific T-cell engager molecules has been previously reported (Blood, 2018, 132, 25; Blood, 2018, 132, 1455). The objectives of this ongoing study are to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of AMG 673 in adult patients aged ≥18 years with relapsed/refractory (R/R) AML.
Methods: This is an ongoing first-in-human, open-label, phase 1, sequential dose escalation study (NCT03224819). AMG 673 was administered as two, short, and intermittent intravenous (IV) infusions during a 14-day cycle in adult patients with R/R AML. Patients received treatment cycles of AMG 673 until disease progression or unacceptable toxicities. T-cell activation, cytokine, and AMG 673 levels in patients' blood were evaluated by validated assays. Results were summarized descriptively by the dosing cohorts and potential associations between PK, PD, safety, and preliminary efficacy were evaluated.
Results: As of June 14, 2019, 30 patients had enrolled in 10 cohorts and were treated with AMG 673 (dose range, 0.05-72 μg IV per dose). The median age was 67.5 (range: 25.0-84.0) years; 20/30 (67%) patients had received ≥4 prior anti-AML treatments, baseline myelosuppression at study entry was common (grade ≥3 neutropenia 21/30 [70%], thrombocytopenia 25/30 [83%], leukopenia 14/30 [47%]), and 7/30 (23%) patients had undergone hematopoietic stem cell transplant (HSCT) before enrolling in the study.
Patients received a median of 1.5 (range: 1.0-6.0) cycles of AMG 673; 27/30 (90%) patients discontinued treatment due to disease progression (n=21), patient request (n=2), protocol-specified criteria (n=2), or adverse events (AEs; n=2). A total of 3 patients were still receiving AMG 673 at the time of data analysis. The most common treatment-related AE was cytokine release syndrome (CRS) reported in 15/30 (50%) patients (grade 1, n=6; grade 2, n=5; grade 3, n=4; no grade 4 CRS). Treatment-related serious AEs were reported in 11/30 (37%) patients, and 15/30 (50%) patients experienced treatment-related AEs of grade ≥3, with the most common being abnormal hepatic enzymes (n=5, 17%), CRS (n=4, 13%), leukopenia (n=4, 13%), thrombocytopenia (n=2, 7%), and febrile neutropenia (n=2, 7%). Two deaths, unrelated to AMG 673, were reported on days 19 and 28 after the last dose.
Assessment of bone marrow in treated patients showed a decrease in blasts in 12/27 (44%) evaluable patients, of which 6 experienced ≥50% reduction in blasts compared with baseline (Figure 1). One patient achieved complete remission with incomplete hematologic recovery (CRi) with 85% reduction in bone marrow blasts at a dose of 36 µg.
Dose-related increases in Cmax and AUC were observed following AMG 673 infusions. Preliminary half-life estimates for AMG 673 were longer than those observed for canonical CD33-specific BiTE® molecule with short half-lives. Upregulation of T-cell activation markers CD25 and CD69 on T-cell subsets and cytokine release post-infusion were observed at higher doses. Preliminary associations between AMG 673 exposures, T-cell activation, safety, and clinical response have been evaluated.
Conclusions: Preliminary data of AMG 673 dosed up to 72 µg provide early evidence of the molecule's acceptable safety profile, drug tolerability, and anti-leukemic activity. An association was observed between PK/PD relationships that were consistent with the biological activity of AMG 673. These preliminary results support further dose escalation of the AMG 673 HLE BiTE® molecule in patients with R/R AML.
Subklewe: AMGEN: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Morphosys: Research Funding; Janssen: Consultancy; Celgene: Consultancy, Honoraria; Miltenyi: Research Funding; Oxford Biotherapeutics: Research Funding; Pfizer: Consultancy, Honoraria. Stein:Celgene: Speakers Bureau; Stemline: Speakers Bureau; Amgen: Consultancy, Speakers Bureau. Walter:Amgen: Consultancy; Amphivena Therapeutics: Consultancy, Equity Ownership; Aptevo Therapeutics: Consultancy, Research Funding; Argenx BVBA: Consultancy; Astellas: Consultancy; BioLineRx: Consultancy; BiVictriX: Consultancy; Seattle Genetics: Research Funding; Boehringer Ingelheim: Consultancy; Boston Biomedical: Consultancy; Covagen: Consultancy; Daiichi Sankyo: Consultancy; Agios: Consultancy; Race Oncology: Consultancy; Jazz Pharmaceuticals: Consultancy; Kite Pharma: Consultancy; Pfizer: Consultancy, Research Funding; New Link Genetics: Consultancy. Wei:Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: 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; Macrogenics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Honoraria, Research Funding; Janssen: Honoraria; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: AHW is a former employee of the Walter and Eliza Hall Institute and receives a fraction of its royalty stream related to venetoclax, Research Funding, Speakers Bureau. Ritchie:Amgen: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy; BMS: Research Funding; Takeda: Research Funding; Beigene: Research Funding; Imago: Research Funding; Novartis: Honoraria; Sanofi: Honoraria. Vachhani:AbbVie: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Agios: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Astellas: Speakers Bureau. Dai:Amgen: Employment, Equity Ownership. Hindoyan:Amgen Inc.: Employment, Other: stock ownership. Agarwal:Amgen: Employment, Equity Ownership; AbbVie: Equity Ownership. Anderson:Amgen Inc.: Employment, Equity Ownership. Khaldoyanidi:Amgen: Employment, Equity Ownership; BMS: Equity Ownership. Ravandi:Macrogenix: Consultancy, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Xencor: Consultancy, Research Funding; Menarini Ricerche: Research Funding; Selvita: Research Funding; Cyclacel LTD: Research Funding.
| v2 |
2018-04-03T02:32:06.852Z | 2017-01-04T00:00:00.000Z | 205178210 | s2ag/train | Planned early birth versus expectant management (waiting) for prelabour rupture of membranes at term (37 weeks or more).
BACKGROUND
Prelabour rupture of membranes (PROM) at term is managed expectantly or by planned early birth. It is not clear if waiting for birth to occur spontaneously is better than intervening, e.g. by inducing labour.
OBJECTIVES
The objective of this review is to assess the effects of planned early birth (immediate intervention or intervention within 24 hours) when compared with expectant management (no planned intervention within 24 hours) for women with term PROM on maternal, fetal and neonatal outcomes.
SEARCH METHODS
We searched Cochrane Pregnancy and Childbirth's Trials Register (9 September 2016) and reference lists of retrieved studies.
SELECTION CRITERIA
Randomised or quasi-randomised controlled trials of planned early birth compared with expectant management (either in hospital or at home) in women with PROM at 37 weeks' gestation or later.
DATA COLLECTION AND ANALYSIS
Two review authors independently assessed trials for inclusion, extracted the data, and assessed risk of bias of the included studies. Data were checked for accuracy.
MAIN RESULTS
Twenty-three trials involving 8615 women and their babies were included in the update of this review. Ten trials assessed intravenous oxytocin; 12 trials assessed prostaglandins (six trials in the form of vaginal prostaglandin E2 and six as oral, sublingual or vaginal misoprostol); and one trial each assessed Caulophyllum and acupuncture. Overall, three trials were judged to be at low risk of bias, while the other 20 were at unclear or high risk of bias.Primary outcomes: women who had planned early birth were at a reduced risk of maternal infectious morbidity (chorioamnionitis and/or endometritis) than women who had expectant management following term prelabour rupture of membranes (average risk ratio (RR) 0.49; 95% confidence interval (CI) 0.33 to 0.72; eight trials, 6864 women; Tau² = 0.19; I² = 72%; low-quality evidence), and their neonates were less likely to have definite or probable early-onset neonatal sepsis (RR 0.73; 95% CI 0.58 to 0.92; 16 trials, 7314 infants;low-quality evidence). No clear differences between the planned early birth and expectant management groups were seen for the risk of caesarean section (average RR 0.84; 95% CI 0.69 to 1.04; 23 trials, 8576 women; Tau² = 0.10; I² = 55%; low-quality evidence); serious maternal morbidity or mortality (no events; three trials; 425 women; very low-quality evidence); definite early-onset neonatal sepsis (RR 0.57; 95% CI 0.24 to 1.33; six trials, 1303 infants; very low-quality evidence); or perinatal mortality (RR 0.47; 95% CI 0.13 to 1.66; eight trials, 6392 infants; moderate-quality evidence).
SECONDARY OUTCOMES
women who had a planned early birth were at a reduced risk of chorioamnionitis (average RR 0.55; 95% CI 0.37 to 0.82; eight trials, 6874 women; Tau² = 0.19; I² = 73%), and postpartum septicaemia (RR 0.26; 95% CI 0.07 to 0.96; three trials, 263 women), and their neonates were less likely to receive antibiotics (average RR 0.61; 95% CI 0.44 to 0.84; 10 trials, 6427 infants; Tau² = 0.06; I² = 32%). Women in the planned early birth group were more likely to have their labour induced (average RR 3.41; 95% CI 2.87 to 4.06; 12 trials, 6945 women; Tau² = 0.05; I² = 71%), had a shorter time from rupture of membranes to birth (mean difference (MD) -10.10 hours; 95% CI -12.15 to -8.06; nine trials, 1484 women; Tau² = 5.81; I² = 60%), and their neonates had lower birthweights (MD -79.25 g; 95% CI -124.96 to -33.55; five trials, 1043 infants). Women who had a planned early birth had a shorter length of hospitalisation (MD -0.79 days; 95% CI -1.20 to -0.38; two trials, 748 women; Tau² = 0.05; I² = 59%), and their neonates were less likely to be admitted to the neonatal special or intensive care unit (RR 0.75; 95% CI 0.66 to 0.85; eight trials, 6179 infants), and had a shorter duration of hospital (-11.00 hours; 95% CI -21.96 to -0.04; one trial, 182 infants) or special or intensive care unit stay (RR 0.72; 95% CI 0.61 to 0.85; four trials, 5691 infants). Women in the planned early birth group had more positive experiences compared with women in the expectant management group.No clear differences between groups were observed for endometritis; postpartum pyrexia; postpartum antibiotic usage; caesarean for fetal distress; operative vaginal birth; uterine rupture; epidural analgesia; postpartum haemorrhage; adverse effects; cord prolapse; stillbirth; neonatal mortality; pneumonia; Apgar score less than seven at five minutes; use of mechanical ventilation; or abnormality on cerebral ultrasound (no events).None of the trials reported on breastfeeding; postnatal depression; gestational age at birth; meningitis; respiratory distress syndrome; necrotising enterocolitis; neonatal encephalopathy; or disability at childhood follow-up.In subgroup analyses, there were no clear patterns of differential effects for method of induction, parity, use of maternal antibiotic prophylaxis, or digital vaginal examination. Results of the sensitivity analyses based on trial quality were consistent with those of the main analysis, except for definite or probable early-onset neonatal sepsis where no clear difference was observed.
AUTHORS' CONCLUSIONS
There is low quality evidence to suggest that planned early birth (with induction methods such as oxytocin or prostaglandins) reduces the risk of maternal infectious morbidity compared with expectant management for PROM at 37 weeks' gestation or later, without an apparent increased risk of caesarean section. Evidence was mainly downgraded due to the majority of studies contributing data having some serious design limitations, and for most outcomes estimates were imprecise.Although the 23 included trials in this review involved a large number of women and babies, the quality of the trials and evidence was not high overall, and there was limited reporting for a number of important outcomes. Thus further evidence assessing the benefits or harms of planned early birth compared with expectant management, considering maternal, fetal, neonatal and longer-term childhood outcomes, and the use of health services, would be valuable. Any future trials should be adequately designed and powered to evaluate the effects on short- and long-term outcomes. Standardisation of outcomes and their definitions, including for the assessment of maternal and neonatal infection, would be beneficial. | v2 |
2021-09-28T15:28:24.926Z | 2021-06-28T00:00:00.000Z | 239667800 | s2ag/train | Future instruments and sustainable outposts for deep space, Moon and Mars: Highlights and lessons from geologists supporting Apollo astronauts
<p>A fundamental goal of international human and robotic space exploration is to establish human outposts and bases on the Moon and Mars.  We seek to provide a <em>planetary science</em> perspective on lessons learned from the Apollo Lunar Exploration Program.</p>
<p><strong>1) Why?:</strong> What is the legacy, the long-term impact of our efforts? Apollo revealed the Earth as a planet, showed the inextricable links of the Earth-Moon system, and made the Solar System our neighborhood. We now ask: What are our origins and where are we heading?: We seek to understand the origin and evolution of the Moon, the Moon’s links to the earliest Earth history, and its lessons for exploration and understanding of Mars. These perspectives impel us to learn the lessons of off-Earth, long-term, long-distance resupply and self-sustaining presence, in order to prepare for the exploration of Mars.</p>
<p><strong>2) Where?:</strong> The combination of Transformative Lunar Science (TLS) questions [1] and exploration operational requirements compel us to explore the South Polar Region (SPR) of the Moon. The <em>scientific goals </em>are clear: 1) What is the origin, nature and abundance of polar volatile deposits and what do they tell us about internal/external sources and volatile history? [2-3] 2) What is the nature/composition/age of the South Pole-Aitken basin, and how does this inform us about lunar interior/chronology/bombardment history, and early Solar System dynamics? [4-5] The <em>scientific objectives </em>are: 1) explore, document/sample volatile deposits in permanently shadowed and stratigraphically related regions. 2) explore/document/sample/date SPA ejecta/pre-SPA crustal materials.  <em>E</em><em>xploration operational goals/objectives</em> are clear: 1) Define regions that optimize realization of scientific goals/objectives. 2) Define regions of continuous/near-continuous solar illumination to provide power to survive lunar night, establish long-term presence. 3) Explore SPR to establish the nature/abundance/mode of occurrence/“grade” of candidate volatile deposits. 4) Characterize surface physical properties/trafficability in order to optimize scientific/operational activities. 5) Prepare for dedicated human/robotic exploration missions to other parts of the Moon and Mars. 6) Test nascent technologies required for sustained human Moon/Mars presence (habitation/energy storage/radiation protection/ISRU).</p>
<p><strong>3) How?:</strong> Necessary is the development of a conceptual/operational framework built on a firm foundation of existing knowledge and data, and inclusion/optimization of new ideas/technologies. This permits us to continue the exploration to the next logical stages following the remarkably successful Apollo Lunar Exploration Program and multiple followon orbital/surface robotic missions. What are foundation pillars? a) Science and Engineering Synergism (SES): Apollo was successful because of the shoulder-to-shoulder engineer-scientist work culture that developed, and enabled longer-duration stay times and EVAs, significant mobility, additional equipment and experiments, and significantly greater sample return. SES requires concentrated/dedicated effort, but the rewards are clear, essential and <em>synergistic</em>.  SES maps out into operations at all levels of mission planning and execution. b) Human-Robotic Partnerships: Exploration is not a technique contest, but a partnership. The US sent 21 robotic missions prior to Apollo 11. The key to continual success lies in developing an architecture that complements and optimizes robotic and human capabilities.  c) Exploration Guidelines: Define human and robotic strengths and weaknesses, and optimize exploration plans. Longer-term stays mean both increased interactions with Earth and exploration independence of the Astronauts. Avoid “creeping determinism” [6], and encourage the Apollo T<sup>3</sup> approach (Train ‘em/Trust ‘em/Turn ‘em loose). Science and operational goals and objectives require exploration of broad areas: build in extensive Apollo LRV-like mobility. New remote-sensing technologies will enable more in situ characterization, sample analysis and selection but Earth laboratory technology advances will always outpace in situ analysis. Build in significant sample return mass from the beginning. d) Exploration Architectures: Individual missions are viewed as integrated elements in an operational strategy/architecture that is designed to accomplish the overarching goals. Candidate elements: I) <em>Precursor</em> (What do we need to know before we send humans?). II) <em>Context</em> (What are robotic mission requirements for final landing site selection/regional context for results?). III) <em>Infrastructure/Operations</em> (What specific robotic capabilities are required to optimize human scientific exploration performance?). IV) <em>Interpolation</em> (How do we use robotic missions to interpolate between human traverses?). V) <em>Extrapolation</em> (How do we use robotic missions to extrapolate beyond the human exploration radius?). VI) <em>Progeny </em>(What targeted robotic successor missions might be sent to the region to follow up on discoveries during exploration and from post-campaign analysis?). The NASA Commercial Lunar Payload Services (CLPS) Program complements the Artemis Program in this manner. e) Flexibility and Adaptability: <em>Science is the exploration of the unknown.</em></p>
<p><strong>Site Selection/Traverse Planning Guidelines</strong><strong>:</strong> Landing site selection always involves a balance of mission goals and objectives, and landing/operation safety/success. Science and Engineering Synergism (SES) is the key to this success as demonstrated during Apollo, and should be implemented throughout the exploration architecture. The same principles apply to traverse planning. SES ensures that science/engineering data needed for key decisions will be available and optimizes decisions. SES also optimizes the long-term goal of lunar base siting: for example, Mons Malapert, an inviting target for base siting due to favorable illumination/power, is difficult to traverse with Lunokhod and Apollo LRV-type vehicles [7].</p>
<p><strong>Surface Operations</strong><strong>:</strong> New instrumentation and technologies will significantly enhance exploration planning and accomplishment of goals. A multispectral laser reflectometer on the surface can confirm the presence of water ice and its location and distribution on scales relevant to human operations (cm to m), and be used to direct sampling and ISRU efforts undertaken by Artemis astronauts, a capability [9] highly complementary to orbital approaches. The parallel operations of robotic rovers, CLPS payload deliveries, and human activities will require continuous engineering and science operations/analysis centers on Earth. Lessons from the ISS should be incorporated, while also recognizing the human exploration capabilities of the Astronauts on the Moon [6]. </p>
<p><strong>References: </strong>1. Pieters et al. (2018)*; 2. Zuber et al (2012) Nature 486, 378;<strong> </strong>3. Li et al. (2019) PNAS 115, 8907;<strong> </strong>4. Moriarty & Pieters (2018) JGR 123, 729;<strong> </strong>5. Ivanov et al. (2018) PSS 162, 190;<strong> </strong>6. Krikalev et al. (2010) Acta Astro. 66, 70;<strong> </strong>7. Mazarico et al., 2020, LSSW;<strong> </strong>8. Baslievsky et al. (2019) SSR 53, 383; 9. Cremons et al. (2020) LSSW. *http://www.planetary.brown.edu/pdfs/5480.pdf</p> | v2 |
2021-11-25T16:22:19.411Z | 2021-11-05T00:00:00.000Z | 244546430 | s2ag/train | Evidence of NF-ΚB Pathway Activation in Patients with Advanced, High Molecular Risk Myelofibrosis
Introduction: Patients with myelofibrosis who discontinue treatment with the JAK1/2 inhibitor ruxolitinib have a poor prognosis that is often associated with advanced phases of disease and severe cytopenias. While these patients are more likely to have high molecular risk genomic markers, biological drivers of disease in this advanced population are not well characterized. PAC203, a Phase 2 dose-finding study in patients with symptomatic myelofibrosis who were intolerant of or resistant to ruxolitinib, represents an opportune cohort for analyzing the association between high molecular risk (HMR) mutations and disease phenotype. Patients had advanced disease at study entry, with profound cytopenias and high mutational burden [O'Sullivan J et al. Blood (2019) 134 (Sup_1):4214.]. Here, we analyzed the interaction between high-risk mutations and cytokine profiles of patients treated in PAC203.
Methods: Cytokine and mutation data were available in 108 (of total 164 recruited; 161 treated) patients. Using the Myriad RBM platform, a microsphere-based immuno-multiplexing technology, 47 cytokines were assessed. Mutation profiles were determined using an ISO accredited Illumina TruSeq Custom Amplicon Panel, composed of mutational-hotspots/exons from 32 genes (~36,000 bp, 287 amplicons). CALR mutation screening was carried out independently. Accepted coverage was achievement of a depth of ≥100 reads per base in ≥95% of targeted bases. The initial analysis assessed possible relationships between individual plasma cytokine levels and specific somatic gene mutation and clinical demographic data. An unsupervised approach was then used applying hierarchical agglomerative clustering to identify related sets of cytokines. Associations between cluster scores, based on the median overall cytokine concentration within each cluster for each patient, and clinical and genomic data was assessed.
Results: The median baseline platelet count was 64 x10 9/L (38% with platelets <50 x10 9/L) and baseline Hb <10g/dL in 68% of patients. The median age was 68 (37-87) years. The mutation profile of this cohort was previously described, with JAK2 V617F mutations (78%) the most prevalent driver mutation, followed by CALR mutations (13%), MPL mutations (7%), and patients were "triple-negative" in 2% of cases. Non-MPN driver mutations (NDM) were present in 76%, most commonly mutated-ASXL1 and -TET2 (27% and 24% respectively). Overall, 41% of patients had a high molecular risk mutation (HMR; IDH1/2, SRSF2, ASXL1, SRSF2, U2AF1Q157), splicing factor (SF) gene mutations were detected in 32% of patients and RAS pathway mutations (KRAS/NRAS) were found at a higher frequency than previously in MF cohorts (18%).
Analysis of cytokine data using unsupervised learning identified 6 clusters (Figure 1). Among these, elevations in clusters 2 (p=0.009) and 4 (p=0.006) were associated with presence of HMR mutations. Higher cluster 2 scores were also associated with driver mutation variant allele frequencies≥50%, p=0.007. Notably, the pro-inflammatory cytokines in cluster 2 linked to HMR mutations (HMR+) represented a transcriptional cluster regulated by the NF-κB pathway. The presence of a HMR mutation was associated with higher IL-8 levels (40.5pg/ml) as compared with absence (24.5pg/ml), p<0.0001. Elevated tumour necrosis factor-alpha (TNF- α) and IL-18 levels were also associated with HMR mutations; TNF-α 61pg/ml in HMR+ vs. 48.5pg/ml for HMR-. Although RAS-pathway mutations were not associated with a specifc cluster scores, these patients did have higher levels of the NF-kB-associated cytokine IL12P40 (1.1ng/ml) as compared with RAS-pathway wild-type patients (0.6ng/ml), p=0.001. There was no association between cytokine cluster scores and recent exposure to RUX at trial entry.
Conclusions: In this high-risk cohort of previously RUX-treated MF patients enriched for HMR and RAS-pathway mutations, we report for the first time a relationship between HMR somatic gene mutations and an NF-κB directed pro-inflammatory cytokine signature, implicating the activation of a distinct biological signaling pathway operative in this molecularly-defined cohort.
Figure 1 Figure 1.
Gerds: CTI BioPharma: Research Funding; AbbVie: Consultancy; Sierra Oncology: Consultancy; PharmaEssentia Corporation: Consultancy; Constellation: Consultancy; Celgene/Bristol Myers Squibb: Consultancy; Novartis: Consultancy. Harrison: Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Geron: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte Corporation: Speakers Bureau; Gilead Sciences: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Constellation Pharmaceuticals: Research Funding; Promedior: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AOP Orphan Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Keros: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Galacteo: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sierra Oncology: Honoraria; Shire: 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, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Oh: Abbvie: Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines: Membership on an entity's Board of Directors or advisory committees; Celgene Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Constellation: Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees; Disc Medicine: Membership on an entity's Board of Directors or advisory committees; Geron: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Kartos Therapeutics: Membership on an entity's Board of Directors or advisory committees; PharamaEssentia: Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Membership on an entity's Board of Directors or advisory committees. Buckley: CTI Biopharm: Current Employment. List: CTI Biosciences: Consultancy; Halia Therapeutics: Consultancy, Current holder of individual stocks in a privately-held company; Precision BioSciences: Current Employment, Current equity holder in publicly-traded company; Aileron Therapeutics: Consultancy. Mead: Celgene/BMS: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Speakers Bureau.
| v2 |
2019-03-17T13:04:43.363Z | 2016-12-02T00:00:00.000Z | 79739610 | s2ag/train | Pharmacodynamic Profile of a Recombinant ADAMTS13 (BAX930) in Hereditary Thrombotic Thrombocytopenic Purpura (Upshaw-Schulman Syndrome (USS))
Introduction The plasma metalloprotease, ADAMTS13, regulates the size of VWF multimers by cleaving VWF at Tyr1605-Met1606 in the A2 domain. A recombinant ADAMTS13 (rADAMTS13, BAX930), manufactured using a plasma-free method, may provide an important alternative replacement therapy for patients with ADAMTS13 deficiencies, such as hereditary thrombotic thrombocytopenic purpura (hTTP). In contrast to plasma infusions, which are currently the standard treatment of hTTP, rADAMTS13 can be infused at lower volumes and contains no additives of human or animal origin. The safety, tolerability, pharmacokinetic (PK) and pharmacodynamic (PD) profiles of rADAMTS13 have been evaluated in a first-in-human phase 1 prospective, open-label, multicenter, dose escalation trial in patients with hTTP (plasma ADAMTS13 activity Methods Subjects were assigned to one of three dose cohorts, receiving a single dose of rADAMTS13 at 5, 20 or 40 U/kg BW. PK parameters were assessed for ADAMTS13 activity (using FRETS-VWF73 and the commercially available Technozym assay) and ADAMTS13 antigen (ADAMTS13:Ag) at standardized time points (pre-infusion; 15, 30, 60 minutes and at regular intervals up to 12 days post-infusion). PD effects including the time course of VWF:RCo and VWF:Ag levels and VWF structural analysis were also performed. Results Fifteen patients with hTTP were treated with single injections of rADAMTS13 at doses of 5 U/kg (3 subjects), 20 U/kg (3 subjects), and 40 U/kg (9 subjects, 2 of whom were adolescents [ rADAMTS13 was well tolerated; there were no related serious or non-serious AEs. No binding or inhibitory anti-ADAMTS13 antibodies related to rADAMTS13 infusion were detected. Four possibly related AEs (nausea, flatulence, decreased VWF:RCo and VWF:Ag) were observed and all resolved without treatment. PK parameters were estimated based on data from the 7 adult subjects in the 40 U/kg dose cohort. The incremental recovery (IR; mean ± SD) was 0.023 ± 0.004 (U/mL x kg/U); T1/2 (mean ± SD) was 60.5 ± 13.5 hours; and AUC(0-inf) (mean ± SD) was 54.5±14.9 hours x U/mL (ADAMTS13 activity via FRETS). ADAMTS13 activity measurements by FRETS and chromogenic assays were comparable. Cmax values obtained from the 3 dosing cohorts demonstrated a dose response consistent with dose proportionality, with means of 0.08, 0.42 and 0.96 U/mL for the 5, 20, and 40 U/kg dose groups, respectively. The estimated clearances for the two adolescent subjects were 64.9 and 54.5 mL/h, respectively, which were within the range observed with adult subjects (n=7; range: 44.4 - 115 mL/h).[1] There was a dose-dependent increase in ADAMTS13-mediated VWF cleavage products observed over time, in line with the dose-dependent increases of ADAMTS13:Ag and activity markers. Specifically, ultra-large VWF multimers, a typical biomarker in hTTP subjects, were detected in the samples collected prior to dosing and decreased in the first 24 hours post-dose at the higher doses of 20 U/kg or 40 U/kg rADAMTS13. In parallel, the intermediate size VWF multimer fraction increased. ADAMTS13-mediated VWF cleavage products were detectable in all subjects up to 3 hours, 24 hours, and 48 hours after injection of 5 U/kg, 20 U/kg, and 40 U/kg, respectively. In all dosing groups, changes in VWF were accompanied by an increase in the platelet count and a decrease of LDH during the first 96 hours after rADAMTS13 injection. Taken together, these findings provide evidence of in vivo ADAMTS13 activity following rADAMTS13 administration. Conclusion In this first-in-man, phase 1 study, rADAMTS13 was safe and well tolerated, demonstrated a PK profile comparable to that estimated from plasma infusion studies, and showed evidence of PD activity in vivo, including effects on VWF multimers, platelet count, and serum LDH. [1] There were differences in sampling schedules between adults (extensive sampling) and adolescents (sparse sampling). Disclosures Scully:Baxalta, now part of Shire: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alexion: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Ablynx: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Octapharma: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding, Speakers Bureau. Knoebl:Baxalta, now part of Shire: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau. Rice:Selexys: Other: Participation in multi-center research trial; Ablynx: Other: Participation in multi-center research trial; Apellis/Synergy: Other: Data Safety Monitoring Committee member; Alexion: Membership on an entity9s Board of Directors or advisory committees, Other: Participation in registry studies; Novartis Pharma: Speakers Bureau; Incyte: Other: Participation in multi-center research trial. Windyga:Sanofi: Consultancy, Equity Ownership, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Patents & Royalties, Research Funding, Speakers Bureau; Octapharma: Consultancy, Equity Ownership, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Patents & Royalties, Research Funding, Speakers Bureau; Alexion: Other: Speaker9s honorarium; Baxalta, now part of Shire: Consultancy, Equity Ownership, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Other: Investigator Clinical Studies, Patents & Royalties, Research Funding, Speakers Bureau; Aspen: Consultancy, Equity Ownership, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Patents & Royalties, Research Funding, Speakers Bureau; Nordisk: Consultancy, Equity Ownership, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Patents & Royalties, Research Funding, Speakers Bureau; Biogen: Consultancy, Equity Ownership, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Patents & Royalties, Research Funding, Speakers Bureau; CSL Behring: Consultancy, Equity Ownership, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Patents & Royalties, Research Funding, Speakers Bureau. Schneppenheim:Baxalta, now part of Shire: Membership on an entity9s Board of Directors or advisory committees. Kremer Hovinga:NovoNordisk: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Bayer: Membership on an entity9s Board of Directors or advisory committees, Research Funding; CSL-Behring: Membership on an entity9s Board of Directors or advisory committees, Research Funding. Maggiore:Quintiles: Employment. Doralt:Baxalta, now part of Shire: Employment. Martell:Baxalta, now part of Shire: Employment. Ewenstein:Shire: Employment, Equity Ownership. | v2 |
2019-11-22T01:08:49.625Z | 2019-11-13T00:00:00.000Z | 209267460 | s2ag/train | POLARGO: A Randomized Phase III Study Evaluating Polatuzumab Vedotin Plus Rituximab, Gemcitabine, and Oxaliplatin in Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma Who Had Received One or More Previous Therapies
Introduction: The antibody-drug conjugate polatuzumab vedotin (pola) targets CD79b on B-cell malignancies. Pola in combination with bendamustine and rituximab (BR) improved complete response (CR) rate and overall survival (OS) in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL), compared with BR alone (CR rate: 40% vs 18%, respectively, p=0.026; median OS: 12.4 vs 4.7 months, respectively, p=0.0023; Sehn et al. ASH 2018). Based on these results, pola + BR was recently approved by the FDA for patients with R/R DLBCL after at least two prior therapies.
NCCN guidelines (2019) suggest multiple second-line and subsequent treatment options for patients with R/R DLBCL; in practice, a wide range of options are used (Herrera et al. Hematol Oncol 2019). One recommended option is rituximab plus gemcitabine and oxaliplatin (R-GemOx; Mounier et al. Haematol 2013; Cazelles et al. Hematol Oncol 2019). Platinum-based chemotherapies such as oxaliplatin are a preferred salvage approach for patients with R/R DLBCL (Tilly et al. Ann Oncol 2015). The safety of pola combined with platinum-based therapies in R/R DLBCL has not yet been assessed, and both pola and platinum-based therapies are associated with neuropathy. In the POLARGO study, we will assess the safety and efficacy of pola in combination with R-GemOx, compared with R-GemOx alone, in patients with R/R DLBCL.
Methods: POLARGO (MO40598) is a multicenter, open-label, Phase III study, comprising two stages: 1) a safety run-in stage evaluating pola + R-GemOx in 10 patients and 2) a randomized controlled trial (RCT) stage comparing pola + R-GemOx with R-GemOx alone in an expected 206 patients. In the RCT stage, patients will be recruited from 80─90 sites globally.
Patients must have histologically confirmed R/R DLBCL, confirmed availability of archival or freshly collected tumor tissue (RCT stage), and ECOG performance status of 0-2. Relapse is defined as disease that recurs following a response lasting ≥ 6 months from completion of the last line of therapy. Refractory is defined as disease that progressed during previous therapy or stable disease for up to 6 months from completion of the last line of therapy. Patients will be excluded if they have had allogeneic stem-cell transplantation (SCT) and/or have planned autologous/allogeneic SCT. Patients with baseline peripheral neuropathy greater than grade 1 (as assessed by National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 [NCI CTCAE v5.0]) will be excluded.
The primary endpoint of the safety run-in stage is the safety and tolerability of pola (1.8mg/kg) + R-GemOx (R, 375mg/m2; Gem, 1000mg/m2; Ox, 100mg/m2) administered in 21-day cycles, as assessed by the incidence, nature, and severity of adverse events (AEs; NCI CTCAE v5.0), with a focus on peripheral neuropathy.
If pola + R-GemOx is tolerable in the safety run-in stage, new patients will be enrolled in the RCT stage. At randomization, patients will be stratified by number of previous lines of systemic therapy for DLBCL, outcome of last systemic therapy (relapsed vs refractory), and age (≤70 years vs >70 years). Patients will be randomized (1:1) to receive up to eight 21-day cycles of either pola + R-GemOx or R-GemOx alone.
The primary endpoint of the RCT stage is OS, defined as the time from randomization to death from any cause. The secondary efficacy endpoints are: best overall response, progression-free survival, duration of objective response, event-free survival, CR rate and objective response rate (according to Lugano 2014 criteria), as determined by the investigator and an independent review committee. Safety will be assessed by recording the incidence, nature, and severity of AEs (NCI CTCAE v5.0), with a focus on peripheral neuropathy. Dose interruptions, reductions, and intensity will be used to determine tolerability. The impact of treatment on health-related quality of life will be assessed. PET-CT and CT scans will be obtained at screening, during, and after the treatment period; 28 days after the last dose of study drug; and then every two (PET-CT), and six (CT) months during follow-up for up to 2 years.
McMillan: Sandoz: Honoraria; Novartis: Honoraria; Celgene: Honoraria, Speakers Bureau; Gilead: Honoraria; Pfizer: Honoraria, Research Funding; MSD: Honoraria; F. Hoffmann-La Roche Ltd: Honoraria, Speakers Bureau; BMS: Honoraria. Matasar:Bayer: Other: Travel, accommodation, expenses; Janssen: Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Honoraria, Research Funding; Daiichi Sankyo: Consultancy; Seattle Genetics: Consultancy, Honoraria, Other: Travel, accomodation, expenses, Research Funding; Rocket Medical: Consultancy, Research Funding; Genentech, Inc.: Consultancy, Honoraria, Other: Travel, accommodation, expenses , Research Funding; Bayer: Consultancy, Honoraria, Other; Roche: Consultancy, Honoraria, Other: Travel, accommodation, expenses , Research Funding; Merck: Consultancy, Equity Ownership; Juno Therapeutics: Consultancy; Teva: Consultancy. Sancho:Sandoz: Consultancy; F. Hoffmann-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria; Celltrion: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squib: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Other: Advisory board; Novartis: Honoraria; Kern Pharma: Honoraria, 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. Viardot:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Kite/Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees. Hernandez:F. Hoffmann-La Roche Ltd: Employment. Perretti:F. Hoffmann-La Roche Ltd: Employment. Haioun:Servier: Honoraria; Miltenyi: Honoraria; Takeda: Honoraria; F. Hoffmann-La Roche Ltd: Honoraria; Gilead: Honoraria; Amgen: Honoraria; Celgene: Honoraria; Novartis: Honoraria; Janssen: Honoraria.
Polatuzumab vedotin (POLIVY, Genentech, Inc.) is a CD79b-directed antibody-drug conjugate. It was approved by the FDA in June 2019 in combination with bendamustine and rituximab for the treatment of adults with relapsed/refractory diffuse large B-cell lymphoma after at least two prior therapies.
| v2 |
2018-04-03T00:10:44.311Z | 2008-06-27T00:00:00.000Z | 9465120 | s2ag/train | Carbonyl propargylation from the alcohol or aldehyde oxidation level employing 1,3-enynes as surrogates to preformed allenylmetal reagents: a ruthenium-catalyzed C-C bond-forming transfer hydrogenation.
Over the past half century, numerous protocols for carbonyl propargylation using allenylmetal reagents have been developed.[1] Allenic Grignard reagents were used by Prevost et al.[2a] in carbonyl additions to furnish mixtures of β-acetylenic and α-allenic carbinols, which led to them to coin the term “propargylic transposition.”[2a,b] Subsequent studies by Chodkiewicz and co-workers[2c] demonstrated relative stereocontrol in such additions. Shortly thereafter, Lequam and Guillerm[2d] reported that isolable allenic stannanes provide products of carbonyl propargylation upon exposure to chloral. Later, Mukaiyama and Harada[2e] demonstrated that stannanes generated in situ from propargyl iodides and stannous chloride reacted with aldehydes to provide mixtures of β-acetylenic and α-allenic carbinols. Related propargylations employing allenylboron reagents were first reported by Favre and Gaudemar,[2f] and propargylations employing allenylsilicon reagents were first reported by Danheiser and Carini.[2g] Asymmetric variants followed (Scheme 1). Allenylboron reagents chirally modified at the boron center engage in asymmetric propargylation, as was first reported by Yamamoto and co-workers[2h] and Corey et al.[2i] Allenylstannanes chirally modified at the tin center also induce asymmetric carbonyl propargylation, as was first reported by Minowa and Mukaiyama.[2j] Axially chiral allenylstannanes, allenylsilanes, and allenylboron reagents propargylate aldehydes enantiospecifically, as was first described by Marshall et al.,[2k,l] and Hayashi and coworkers,[2m] respectively. Finally, asymmetric aldehyde propargylation using allenylmetal reagents may be catalyzed by chiral Lewis acids or chiral Lewis bases, as was first reported by Keck et al.,[2n] and Denmark and Wynn,[2o] respectively.
Scheme 1
Chirally modified allenylmetal reagents for carbonyl propargylation. Tf =trifluoromethanesulfonyl, Ts =para-toluenesulfonyl.
Here, we report a new approach to carbonyl propargylation based on ruthenium-catalyzed C–C bond-forming transfer hydrogenation.[3–5] Specifically, upon exposure of 1,3-enynes 1a–1g to alcohols 2a–2o in the presence of [RuHCl(CO)(PPh3)3]/dppf (dppf =1,1′-bis(diphenylphosphino)ferrocene), hydrogen shuffling between reactants occurs to generate nucleophile–electrophile pairs that regioselectively combine to furnish products of carbonyl propargylation.[6] Under related transfer hydrogenation conditions and employing isopropanol as the terminal reductant, 1,3-enynes couple to aldehydes to furnish identical products of carbonyl propargylation. The observed regiochemistry is unique with respect to related enyne–carbonyl reductive coupling reactions that are catalyzed by rhodium[5,7] and nickel complexes, [8,9,10] which favor coupling at the acetylenic terminus of the enyne. Significantly, this protocol enables carbonyl propargylation from the alcohol or aldehyde oxidation level in the absence of preformed allenylmetal reagents (Scheme 2).
Scheme 2
Divergent regioselectivity observed in metal-catalyzed enyne–carbonyl coupling.
In connection with our efforts to exploit catalytic hydrogenation in C–C coupling reactions beyond hydroformylation,[5] we recently demonstrated that C–C bond formation may be achieved under the conditions of iridium- and ruthenium-catalyzed transfer hydrogenation.[11] These processes enable direct carbonyl allylation from the alcohol or aldehyde oxidation level by using commercially available allenes or dienes as allyl donors. Seeking to develop corresponding carbonyl propargylations, diverse iridium and ruthenium complexes were assayed for their ability to catalyze the coupling of enyne 1a and alcohol 2a. Gratifyingly, both [{Ir(cod)Cl}2]/biphep (biphep =diphenylphosphine, cod =cycloocta-l,5-diene) and [RuHCl(CO)(PPh3)3]/dppf catalyze the desired coupling. The ruthenium-based catalyst was most effective and, under optimized conditions, enyne 1a coupled to benzylic, allylic, and aliphatic alcohols 2a–2o to form homopropargyl alcohols 3a–3o in good to excellent yields (Table 1). To probe the scope of the enyne coupling partner, enynes 1b–1g were coupled to benzyl alcohol 2b under standard reaction conditions. Good to excellent yields of propargylation products 3p–3u were observed (Table 2). Substitution at the olefinic terminus of the enyne was found to diminish conversion to product. Finally, carbonyl allylation can also be achieved from the aldehyde oxidation level by employing isopropanol as the terminal reductant. Under standard reaction conditions, aldehydes 4a–4c couple to enyne 1a to provide the products of carbonyl propargylation 3a–3c, respectively, in good to excellent yield. Thus, carbonyl propargylation may be achieved from either the alcohol or aldehyde oxidation level (Table 3). The coupling products 3a–3u are remarkably resistant to over-oxidation to form the corresponding β,γ-acetylenic ketones. However, such over-oxidation is observed if cationic ruthenium complexes are employed as catalysts. This result suggests that, for the neutral ruthenium complexes employed in this study, the alkyne moiety of the coupling product blocks a coordination site required for β hydride elimination of the carbinol C–H bond. Other aspects of the catalytic mechanism, including determination of the structural and interactive features of the ruthenium complex that influence relative and absolute stereocontrol, are currently under investigation.
Table 1
Carbonyl propargylation from the alcohol oxidation level by ruthenium-catalyzed transfer hydrogenation.a
Table 2
Coupling of enynes 1b–1g to benzyl alcohol 2b by ruthenium-catalyzed transfer hydrogenation.a
Table 3
Carbonyl propargylation from the aldehyde oxidation level by ruthenium-catalyzed transfer hydrogenation.a
A general catalytic mechanism is likely to involve the following steps:[11] a) alcohol dehydrogenation to generate a ruthenium hydride is followed by b) enyne hydrometalation to generate an allenyl metal–aldehyde/nucleophile–electrophile pair, which undergoes c) carbonyl addition with propargylic transposition. Consistent with this interpretation, the coupling of enyne 1a to [D]-2b under standard reaction conditions provides [D]-3b, in which deuterium is incorporated at the benzylic position (>95%), the allylic methyl group (56%), and the allylic methine position (24%), thus suggesting reversible olefin-hydrometalation [Eq. (1)].
(1)
Our collective studies on hydrogenative and transfer hydrogenative C–C coupling define a departure from the use of preformed organometallic reagents in carbonyl addition chemistry.[5,11] For such transfer hydrogenative coupling reactions, hydrogen embedded within isopropanol or an alcohol substrate is redistributed among reactants to generate nucleophile–electrophile pairs, thus enabling carbonyl addition from the aldehyde or alcohol oxidation level. In this way, carbonyl additions that transcend the boundaries of oxidation level are devised. In the present study, we have demonstrated that 1,3-enynes serve as allenylmetal equivalents under the conditions of transfer hydrogenative coupling, thus also enabling carbonyl propargylation from the alcohol or aldehyde oxidation level. These studies contribute to a growing body of catalytic methods for the direct functionalization of carbinol C–H bonds.[11,12] Future studies will focus on the development of related alcohol–unsaturate C–C coupling processes. | v2 |
2022-06-09T06:12:50.542Z | 2007-01-01T00:00:00.000Z | 249467640 | s2ag/train | IP REGULATION OF INDUCIBLE NITRIC OXIDE SYNTHASE AND CATIONIC AMINO ACID TRANSPORT BY p38a AND p38p MAP KINASES IN RAT CULTURED AORTIC SMOOTH MUSCLE CELLS
Previous studies suggest that induction of nitric oxide synthase (iNOS) and cationic amino acid transport (CAT) may be regulated by the p38 mitogen activated protein kinase (MAPK) pathway in cultured rat aortic smooth muscle cells (RASMC) (Baydoun et al., 1999). This conclusion was based on the fact that both processes could be inhibited by SB203580, a potent inhibitor of the p38 MAPK. There is, however, growing concern over the selectivity of this compound since it also inhibits other parallel signalling pathways including the c-Jun N-terminal kinases (JNK; Clerk and Sugden, 1998). We have therefore extended our original studies by examining the effects of SB203580-sensitive isoforms of p38 on the induction of both iNOS and CATs by transfecting wild-type p38a or p380 MAPKs into RASMCs. Briefly, RASMC rats were plated out in 24-well plates and allowed to grow to -40-60% confluency before transfection with either p38a or p38j constructs in a pcDNA vector. Transfections were carried out using an integrin-binding polycationic peptide in the presence of lipofectin. Cells wer? activated for 24h with LPS (100 gg mLV1) and IFN-y (50 U mL') 3h, 6h, 12h and in the supernatant In spontaneously hypertensive rat (SHR), the endothelium-dependent relaxation to acetylcholine (ACh) of the aorta due to the of a concomitant endothelium-dependent Vanhoutte, The present study was designed to determine whether or not a diffusible substance (or substances) is involved in these endothelium-dependent contractions. Capsaicin activates a non-specific cation channel, the VR1 (vanilloid) receptor that has been cloned from rat dorsal root ganglia. Recent studies suggest that VRl-immunoreactivity occurs on neuronal fibres of the human colon (Yiangou et al., 2001) and intrinsic neurones of the rat and porcine intestine. The present confocal immunohistochemical study was performed to probe the neurochemical identity and possible functional significance of VRl in the myenteric plexus of the guinea-pig ileum and colon. Sensory neural dysfunction is common in patients with peripheral neuropathy, a major complication of diabetes mellitus 2001). A key measure of sensory neurone function is stimulus-evoked neuropeptide release. We investigated the effect of cannabinoids on capsaicin-evoked release of calcitonin gene-related peptide (CGRP) from rat paw skin in vitro, which is mediated by the vanilloid VR1 receptor (Kilo et al, 1997), comparing non-diabetic and diabetic animals. The study employed the synthetic CB,/CB2 receptor agonist CP55940, the endocannabinoid anandamide, which activates both CB, and VR1 receptors and the CB, receptor selective antagonist SR141716A (Pertwee, 2001). Capsaicin-sensitive sensory nerves are widely distributed in the cardiovascular system (Maggi & Meli, 1988). In the mesenteric arterial bed calcitonin gene-related peptide (CGRP) is released upon activation of sensory nerves producing vasodilatation (Kawasaki et al., 1988). Preliminary investigations using synthetic cannabinoids in the mesenteric bed indicate the presence of a functional cannabinoid receptor that attenuates sensory neurotransmission (Duncan et a!, 2001). Noladin ether (NE), reported to be an endogenous cannabinoid, binds weakly to CB, and CB2 receptors but exerts cannabimimetic effects in vWvo (Hanus et al, 2001). The aim of the present study was to determine if this endocannabinoid mimics the actions of synthetic cannabinoids previously shown in the rat mesenteric arterial bed. Our data demonstrate a novel inhibition of electrically evoked CGRP release by (S)-AMPA superfusion, which is reversed by the CB, antagonist (SRI). AMPA inhibition may be due to the release of endogenous cannabinoids from second order neurones, acting retrogradely to inhibit the electrically evoked CGRP release. Central N/OFQ to N/OFQ ([Nphe']) this we have confirmed the ability of to block N/OFQ-induced food intake, to investigate the involvement of N/OFQ in the mediation of physiological feeding behaviour. hypothesized if the on dark-phase Arc (activity-regulated cytoskeleton associated protein) is an effector immediate early gene whose mRNA is selectively localised in neuronal dendrites. Its expression has been shown to be induced by neuronal stimulation and by agonist stimulation of 5-HT2A receptors (Pei et al., 2000). Regulation of the 5-HT2A receptor is atypical in that both agonists and antagonists induce a decrease in receptor density. Mianserin is a tetracyclic antidepressant, which has shown these properties when administered both in vitro (Newton and Elliott, 1997) and in vivo (Blackshear and Sanders-Bush, 1982). The aim of the present study was to identify the functional consequences of this down-regulation induced by mianserin, as indicated by Arc mRNA expression stimulated by 1-(2,5-dimethoxy-4- iodophenyl)-2-aminopropane (DOI), a selective 5-HT2MC agonist. Peptidergic neurones accumulate amines via an unusual uptake process designated Transport-P. Our work so far has identified two types of compounds which act as ligands for Transport-P: Group A compounds, exemplified by prazosin, are accumulated in a cooperative manner. Group B compounds, which include phenylethylamines, are accumulated non-cooperatively by the same uptake process. We studied the structural properties of this group by examining a large series of compounds for their ability to inhibit competitively the uptake of prazosin (1 uM) in immortalised gonadotrophin-releasing hormone neurones (GTl-l GnRH cells) as previously described in detail (Al-Damluji & Kopin, 1998). All the compounds were soluble in warm DMSO at 0.1 M. The results were as follows: L-3,4-dihydroxyphenylalanine (L-DOPA) is still the mainstay of pharmacological treatment of Parkinson's disease. Apart from its ability to readily generate dopamine (DA), however, L-DOPA may also increase noradrenaline (NA) synthesis or release. Release of NA by L-DOPA was determined: a) in isolated, electrically field- stimulated (EFS) vasa deferentia treated with yohimbine and desipramine (3 and I gM respectively); b) by microdialysis technique in rat frontal cortex. Striatal dopamine loss in Parkinson's disease produces excess glutamate release from subthalamic efferents leading to over-activity of basal ganglia output nuclei such as the substantia nigra pars reticulata (SNr). Activation of GABAB receptors on subthalamonigral terminals may counteract this and so help to restore normal motor fimction. The aims of this study were to examine (i) whether GABAB receptor activation either locally (SNr) or distally (3rd ventricle; 3V) alleviates akinesia in a rodent model of PD and (ii) whether GABAB receptor activation reduces glutamate release in the SNr. (SNr) (ALUs; 90 min of anti-akinetic efficacy, different 1-way ANOVA. of pre-treatment the CGP 46381 g), intranigral (800 ng) using a t-test. | v2 |
2021-11-25T16:07:39.731Z | 2021-11-05T00:00:00.000Z | 244539100 | s2ag/train | Completed Induction Phase Analysis of Magnify: Phase 3b Study of Lenalidomide + Rituximab (R 2) Followed By Maintenance in Relapsed/Refractory Indolent Non-Hodgkin Lymphoma
Background: Patients with relapsed indolent NHL (iNHL) have limited standard treatment options. Lenalidomide combined with rituximab (R 2) has shown complimentary clinical activity and is a tolerable regimen in both untreated and relapsed or refractory (R/R) patients with iNHL (RELEVANCE : N Engl J Med 2018;379:934 and AUGMENT: J Clin Oncol. 2019;37:1188).
Methods: MAGNIFY is a multicenter, phase 3b trial in patients with R/R follicular lymphoma (FL) grades 1-3b, transformed FL (tFL), marginal zone lymphoma (MZL), or mantle cell lymphoma (MCL; NCT01996865) exploring optimal lenalidomide duration. In the induction phase, lenalidomide 20 mg PO on days 1-21 of a 28-day cycle + rituximab IV at 375 mg/m 2/week cycle 1 and then every 8 weeks starting with cycle 3 (R 2) are administered for 12 cycles. Patients with stable disease, partial response, or complete response/complete response unconfirmed (CR/CRu) were randomized 1:1 to R 2 vs rituximab maintenance for 18 months. Data presented here are the complete analysis from the induction phase in efficacy-evaluable patients with FL grades 1-3a or MZL (FL grade 3b, tFL, and MCL not included). The focus of this interim analysis was overall response rate (ORR) by 1999 IWG criteria in the induction intention-to-treat population.
Results: As of March 5, 2021, 394 patients (318 [81%] FL gr1-3a; 76 [19%] MZL) were enrolled. The median follow-up was 40.6 mo (range, 0.6-79.6). Median age was 66 y (range, 35-91), 328 (83%) had stage III/IV disease, with a median of 2 prior therapies (94% prior rituximab-containing). ORR was 71% (n = 279) with 42% (n = 164) CR/CRu (Table). All patients have completed R 2 induction (n = 232, 59%) or discontinued study treatment (n = 162, 41%). 141 patients (36%) prematurely discontinued both lenalidomide and rituximab, primarily due to adverse events (AEs) (n = 54, 14%) or progressive disease (n = 42, 11%). The majority of patients who have completed induction have been randomized and entered maintenance (n = 217). Median duration of response in the induction period was not reached (95% CI, 43.9 mo-NR), and median progression-free survival in the induction safety population (n = 393) was 50.5 mo (95% CI, 39.5-NR). Efficacy results are reported in the table by histology subgroups (FL vs MZL), and rituximab-refractory, double-refractory, and early relapse statuses. Most common all-grade AEs were 47% fatigue, 43% neutropenia, 37% diarrhea, 30% nausea, and 30% constipation. Grade 3/4 AEs occurring in ≥ 5% of patients included 37% neutropenia (10 patients [3%] had febrile neutropenia), 8% leukopenia, 6% thrombocytopenia, 5% anemia, and 5% fatigue.
Conclusions: These data represent complete analysis of all patients in the induction phase of MAGNIFY which continue to support that R 2 is active with a tolerable safety profile in patients with R/R FL grade 1-3a and MZL, including rituximab-refractory, double-refractory, and early relapse patients.
Figure 1 Figure 1.
Lansigan: Celgene/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees. Andorsky: Abbvie: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding; Epizyme: Research Funding. Coleman: immunomedics: 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; Abbvie: Research Funding; Bristol Myers: Research Funding; Celgene: Research Funding; Genentech: Research Funding; Gilead: Research Funding; BeiGene: Research Funding; Innocare: Research Funding; Merck: Research Funding; Pfizer: Research Funding; Roche: Research Funding. Yacoub: Dynavex: Current equity holder in publicly-traded company; Cara: Current equity holder in publicly-traded company; Ardelyx: Current equity holder in publicly-traded company; Agios: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ACCELERON PHARMA: Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau; Seattle Genetics: Honoraria, Speakers Bureau; Hylapharm: Current equity holder in publicly-traded company. Melear: TG Therapeutics: Speakers Bureau; Astrazeneca: Speakers Bureau; Janssen: Speakers Bureau. Fanning: Sanofi: Speakers Bureau; Genmab: Membership on an entity's Board of Directors or advisory committees; TG Pharma: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Membership on an entity's Board of Directors or advisory committees; Takeda: Speakers Bureau; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; BMS: Speakers Bureau. Kolibaba: TG Therapeutics: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Atara Biotechm: Consultancy; McKesson Specialty Health: Consultancy; Sunitomo Dainippon Pharma: Consultancy; Tolero Pharma: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Nowakowski: Incyte: Consultancy; Kymera Therapeutics: Consultancy; TG Therapeutics: Consultancy; Blueprint Medicines: Consultancy; Nanostrings: Research Funding; Curis: Consultancy; Selvita: Consultancy; Zai Labolatory: Consultancy; Daiichi Sankyo: Consultancy; Bantham Pharmaceutical: Consultancy; Karyopharm Therapeutics: Consultancy; Ryvu Therapeutics: Consultancy; Genentech: Consultancy, Research Funding; Kyte Pharma: Consultancy; Roche: Consultancy, Research Funding; Celgene/Bristol Myers Squibb: Consultancy, Research Funding; MorphoSys: Consultancy. Gharibo: BMS: Current Employment, 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. Ahn: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company; ADC therapeutics: Current equity holder in publicly-traded company. Li: BMS: Current Employment, 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, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding. Sharman: BeiGene: Consultancy; TG Therapeutics: Consultancy; Lilly: Consultancy; Centessa: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics LLC, an AbbVie Company: Consultancy; AstraZeneca: Consultancy; BMS: Consultancy; AbbVie: Consultancy.
| v2 |
2017-04-16T06:24:50.682Z | 2008-01-01T00:00:00.000Z | 8636450 | s2ag/train | Inhibition of MammalianTarget of Rapamycin by Rapamycin Causes the Regression of Carcinogen-Induced SkinTumor Lesions
Purpose: The activation of Akt/mammalian target of rapamycin (mTOR) pathway represents a frequent event in squamous cell carcinoma (SCC) progression, thus raising the possibility ofusing specific mTOR inhibitors for the treatment of SCC patients. In this regard, blockade of mTORwith rapamycin prevents the growth of human head and neck SCC cells when xenotransplanted into immunodeficient mice. However, therapeutic responses in xenograft tumors are not always predictive of clinical anticancer activity. Experimental Design: As genetically defined and chemically induced animal cancer models often reflect better the complexity of the clinical setting, we used here a two-step chemical carcinogenesis model to explore the effectiveness of rapamycin for the treatment of skin SCC. Results: Rapamycin exerted a remarkable anticancer activity in this chemically induced cancer model, decreasing the tumor burden of mice harboring early and advanced tumor lesions, and even recurrent skin SCCs. Immunohistochemical studies on tumorbiopsies and clustering analysis revealed that rapamycin causes the rapid decrease in the phosphorylation status of mTOR targets followed by the apoptotic death of cancer cells and the reduction in the growth and metabolic activity of the surviving ones, concomitant with a decrease in the population of cancer cells expressing mutant p53. This approach enabled investigating the relationship among molecular changes caused by mTOR inhibition, thus helping identify relevant biomarkers for monitoring the effectiveness of mTOR inhibition in the clinical setting. Conclusions:Together, these findings provide a strong rationale for the early evaluationof mTOR inhibitors as a molecular targeted approach to treat SCC. Cancer arises in multistep process resulting from the sequential accumulation of genetic defects and the clonal expansion of selective cell populations (1). For example, in the case of human head and neck squamous carcinomas (HNSCC), tumor progression often involves the sequential genetic or epigenetic inactivation of multiple tumor suppressor genes, such as p16 (9p21), APC (5q21-22), and p53 (17p13; ref. 2), concomitant with changes in the activation state of signaling pathways that promote the aberrant growth of the cancerous cells. The latter frequently result from the overexpression and/or activity of cell surface receptors, including epidermal growth factor receptors, hepatocyte growth factor receptors (c-Met), and receptors for numerous cytokines, chemokines, and inflammatory mediators (3–5). These receptors share the ability to promote the activation of several intracellular signaling pathways, including the Ras-mitogen-activated protein kinase kinase-extracellular signal-regulated kinase biochemical route and the phosphatidylinositol 3-kinase-Akt-mammalian target of rapamycin (mTOR) pathway, which in turn promote cell proliferation and survival (6). This emerging knowledge on the nature of the signaling networks driving the unrestricted growth of cancerous cells has now enabled the development of novel therapies targeting key signaling molecules whose dysregulation contribute to tumor progression in each cancer type. In particular, the widespread activation of the phosphatidylinositol 3-kinase/Akt/mTOR pathway in HNSCC progression has raised the possibility of using specific mTOR inhibitors and their derivatives for the treatment of HNSCC patients (7, 8). In this regard, blockade of mTOR with rapamycin exerts a potent antitumoral effect and even prevents minimal residual disease in several human HNSCC xenograft models (9–11). However, effectiveness in human xenograft tumors is not always predictive of a clinical anticancer activity (12, 13). Genetically defined and chemically induced animal cancer models are often more difficult to treat than xenotransplanted human tumors in immunocompromised mice but reflect better the more complex and challenging situation of the clinical setting (12–14). Thus, in this study, we took advantage of the well-established two-step chemical carcinogenesis model, in which squamous carcinogenesis (SCC) is initiated by the topical application of a tobacco-related chemical carcinogen Cancer Therapy: Preclinical Authors’Affiliation: Oral and Pharyngeal Cancer Branch, National Institute of Craniofacial and Dental Research, NIH, Bethesda, Maryland Received 3/17/08; revised 8/18/08; accepted 8/19/08. 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: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). Requests for reprints: J. Silvio Gutkind, Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, NIH, 30 Convent Drive, Building 30, Room 212, Bethesda, MD 20892-4330. Phone: 301-496-6259; Fax: 301-402-0823; E-mail: [email protected]. F2008 American Association for Cancer Research. doi:10.1158/1078-0432.CCR-08-0703 www.aacrjournals.org Clin Cancer Res 2008;14(24) December15, 2008 8094 Research. on April 15, 2017. © 2008 American Association for Cancer clincancerres.aacrjournals.org Downloaded from [7,12-dimethylbenz(a)anthracene (DMBA)] to the skin followed by the prolonged treatment with phorbol esters [12-O-tetradecanoylphorbol-13-acetate (TPA); ref. 15], to explore the effectiveness of rapamycin for the treatment of skin SCC lesions. We show here that rapamycin exerts a potent anticancer activity in this chemically induced cancer model, as chronic administration of rapamycin decreases the tumor burden of mice harboring early and advanced primary tumor lesions and even recurrent SCC. Indeed, the inhibition of mTOR with rapamycin results in the regression of carcinogeninduced skin SCC, thus providing a strong rationale for the early clinical evaluation of rapamycin and its derivatives in SCC patients. Materials andMethods Reagents. DMBA was purchased from Sigma and phorbol ester TPA was from Alexis Biochemicals. Rapamycin was provided by the Developmental Therapeutics Program (National Cancer Institute). Antibodies. Polyclonal rabbit antibodies against phospho-Akt (pAkt; S473), phospho-S6 (pS6), eIF4E, and cyclin D1 were purchased from Cell Signaling. Rat monoclonal anti-mouse CD31 (BD Pharmingen), polyclonal rabbit anti-mouse CD3 (Dako), rat monoclonal antiF4/80 (Serotec), rabbit polyclonal anti-p53 (Novocastra), rabbit polyclonal anti-glucose transporter 1 (Chemicon), polyclonal rabbit anti-vascular endothelial growth factor (Santa Cruz Biotechnology), and mouse monoclonal anti-proliferating cell nuclear antigen (PCNA; Zymed) were used when indicated. Animals. All animal studies were carried out according to NIHapproved protocols, in compliance with the Guide for the Care and Use of Laboratory Animals. Six-week-old female FVB/N mice were obtained from Taconic Farm, Inc., housed in appropriate sterile filter-capped cages, and fed and watered ad libitum . All handling, tumor induction, and treatment procedures were conducted in a laminar flow biosafety | v2 |
2016-10-31T15:45:48.767Z | 2007-01-01T00:00:00.000Z | 107169730 | s2ag/train | Evaluating Court Processes for Determining Indigency
* We appreciate the assistance we received in visioning, collecting, and assessing the information used in this evaluation. We are especially grateful for the help and guidance we received from the Project Oversight Committee, beginning with their ideas for what needed to be evaluated and concluding with comments and corrections to earlier drafts. The Oversight Committee members included: Steven Burns (Lancaster County District Court Judge), Kerry Eagan (Lancaster County Chief Administrative Officer), James Foster (Committee Chair and Lancaster County Court Judge), Peggy Gentles (Lancaster County Court Judicial Administrator), Dennis Keefe (Lancaster County Public Defender), Gary Lacey (Lancaster County Attorney), Catherine Reech (Lancaster County Court Screener), Toni Thorson (Lancaster County Juvenile Court Judge), Mike Thurber (Lancaster County Corrections Director), and Janice Walker (Nebraska State Court Deputy Administrator). We would also like to acknowledge the following for their assistance: Kimberly Applequist (University of Nebraska Public Policy Center), Pamela Casey (National Center for State Courts), Ian Christensen (University of Nebraska Public Policy Center), Carly Duvall (University of Nebraska Public Policy Center), Jenn Elliott (University of Nebraska Public Policy Center), Carol Flango (National Center for State Courts), Roger Hanson (Independent Law and Society Researcher, Williamsburg, VA), Patrick J. DornKennedy (University of Nebraska Public Policy Center), Katie Novak (University of Nebraska Public Policy Center), David Rottman (National Center for State Courts), Nancy Shank (University of Nebraska Public Policy Center), and Ann Skove (National Center for State Courts). 1. 372 U.S. 335 (1963). 2. E.g., Argersinger v. Hamlin, 407 U.S. 25 (1972); Scott v. Illinois, 440 U.S. 367 (1979); Glover v. United States, 531 U.S. 198 (2001); Alabama v. Shelton, 535 U.S. 654 (2002). 3. E.g., Alexander v. State, 527 S.W. 2d 927 (Ark. 1975); Carey v. Zayre of Beverly, Inc., 324 N. E. 2d 619 (Mass. 1975); Brown v. Multnomah County Dist. Court, 570 P. 2d 52 (Or. 1977); State v. Ponce, 611 P. 2d 407 (Wash. 1980); State v. Jones, 404 So. 2d 1192 (La. 1981); State v. Novak, 318 N.W. 2d 364 (Wis. 1982); Canaday v. State, 687 P.2d 897 (Wyo. 1984); State v. Buchholz, 462 N. E. 2d 1222 (Ohio 1984); State v. Orr, 375 N.W. 2d 171 (N.D. 1985); Commonwealth v. Thomas, 507 A.2d 57 (PA 1986); State v. Lynch, 796 P. 2d 1150 (Okla. 1990); Hlad v. State, 585 So. 2d 928 (Fla. 1991); In re Advisory Opinion to the Governor, 666 A. 2d 813 (R.I. 1995); Peeler v. Hughes & Luce, 909 S. W. 2d 494 (Tex, 1995); People v. Monge, 941 P.2d 1121 (Cal. 1997); Russell v. Armitage, 697 A.2d 630 (Vt. 1997); State v. Woodruff, 951 P. 2d 605 (N.M. 1997); El Pueblo de Puerto Rico v. Amparo Concepcion, 98 TSPR 93 (PR 1998); State v. Stott, 586 N.W. 2d 436 (Neb. 1998); Johnson v. State, 735 A. 2d 1003 (MD.1999); Ex parte Lareed Shelton, 851 So. 2d 96 (Ala. 2000); In re Welfare of G.L.H., 614 N.W. 2d 718 (Minn. 2000); Barnes v. State, 570 S.E. 2d 277 (Ga. 2002); City of Urbana v. Andrew N.B., 813 N.E. 2d 132 (Ill. 2004); People v. Russell, 684 N. W. 2d 745 (Mich. 2004); Lucero v. Kennard, 125 P.3d 917 (Utah, 2005). 4. Robert L. Spangenberg & Marea L. Beeman, Indigent Defense Systems in the United States, 58 LAW & CONTEMP. PROBS. 31 (1995)[hereinafter Spangenberg & Beeman, Indigent Defense Systems]; Spangenberg Group, Indigent Defense Services in the State of Nevada: Findings and Recommendations (Dec. 13, 2000) (available at http://www.spangenberggroup.com/reports/report_ 121301.pdf); Spangenberg Group, Determination of Eligibility for Public Defense (2002) [hereinafter Spangenberg Group, Determination of Eligibility] (available at http://www.abanet.org/ legalservices/downloads/sclaid/indigentdefense/determinationofeligibility.pdf#search=%22Determination%20of%20Eligibility%20f or%20Public%20Defense%22). 5. Spangenberg Group, Determination of Eligibility, supra note 4. The Sixth Amendment to the Constitution guarantees all people accused of a crime the right to legal counsel. In the landmark 1963 decision Gideon v. Wainright,1 the United States Supreme Court affirmed the right of indigent defendants to have counsel provided. But Gideon did not end the Supreme Court’s discussion of the circumstances in which the state is required to provide defendants with an attorney when they claim not to have the means to pay for one.2 Nor did it end the states’ examination of the requirement of any legal assistance paid for by taxpayers.3 Moreover, it is not mandated by constitutional law, congressional statute, or U.S. Supreme Court interpretation how states will fund these programs (will it be a state or local, e.g., county, responsibility?) or the procedures by which a defendant will be deemed indigent. States and counties have developed a range of programs designed to provide counsel to indigent defendants (the most well known is the public defender model; other examples are the appointment from a roster of practicing attorneys and contracts with willing practitioners). States and counties have also developed a range of procedures to assess whether a defendant is unable to afford an attorney without assistance.4 A 2002 report by the Spangenberg Group documents the variability across states with regard to various aspects of indigency determinations, including how presumptions of indigency are determined (i.e., what factors are taken into consideration, such as the defendant’s income in relation to federal poverty guidelines, assets, complexity of the case, resources of relatives and friends, whether the defendant can afford to pay bail, etc.), whether or not formal guidelines are in place, who makes the determination (the public defender’s office or the court), whether the court utilizes a financial questionnaire or affidavit, whether the client’s claim is investigated, and so on.5 The specific purpose of this article is to report on an evaluEvaluating Court Processes for Determining Indigency | v2 |
2020-11-05T09:10:20.987Z | 2020-11-05T00:00:00.000Z | 228822530 | s2ag/train | Ibrutinib Induces Durable Remissions in Treatment-Naïve CLL Patients with 17p Deletion/TP53 Mutations: Five Year Follow-up from a Phase 2 Study
Introduction: Bruton's tyrosine kinase (BTK) inhibitors and the BCL-2 antagonist venetoclax have significantly improved the outcome of CLL patients, including patients with high risk CLL who had dismal outcome with chemo-immunotherapies. Nonetheless, CLL patients with 17p deletion and/or TP53 mutations may continue to have an increased risk for treatment failure with BTK inhibitors or venetoclax when compared to CLL patients with lower-risk disease. For example, the median progression free survival (PFS) of ibrutinib-treated relapsed and refractory CLL patients in the PCYC-1102 study was 52 months for the entire population, but only 26 months for those with 17p deletion. In a phase-2 study of ibrutinib in CLL patients with 17p deletion/TP53 mutations (NCT01500733) it was noted that the 5-year PFS was 19% for relapsed and refractory patients, but 74% in treatment-naïve CLL patients, indicating that remission duration is substantially longer in patients with 17p deletion/TP53 mutation when ibrutinib is used in the frontline disease setting. Here, we reviewed the long-term outcome of treatment -naïve CLL patients with 17p deletion and/or TP53 mutation receiving ibrutinib, alone or in combination with rituximab on an investigator-initiated Phase-2 trial (NCT02007044).
Patients: 27 treatment-naïve CLL patients with 17p deletion and/or TP53 mutation received ibrutinib, alone (n=15) or in combination with rituximab (n=12). Responses were evaluated according to the 2008 iwCLL criteria, with the exception that lymphocytosis was not the sole criterion for disease progression. PFS was defined as the time from start of treatment to progression, death or last follow-up.
Results: The median age was 62 years, 67% were male, 78% had unmutated IGHV, and 33% advanced stage disease (Rai stage III-IV). After a median follow-up of 61 months, median progression free and overall survival were not reached, and the estimated 5-year progression free and overall survival were 66% and 85%, respectively (Figure). This is markedly better than the published 5-year PFS of 15.3% in 17p deleted CLL patients after fludarabine, cyclophosphamide and rituximab (FCR). Most common reason for treatment discontinuation was disease progression, which occurred in 6 patients (22%), with a median time to progression of 39 months (range, 10 - 53 months). Objective responses were noted in all except one patient (overall response rate 96%), with complete remissions in 10 patients (37%), and partial remissions in 16 patients (59%). Median levels of CLL bone marrow infiltration declined from 76% at baseline, to 26% after 12 months, and 14% after 24 months of therapy. Remission duration was not different in patients achieving complete or partial remissions, suggesting that deep remissions are not a prerequisite for durable remissions. Venetoclax-based therapy, which generally induces deeper remissions, does not seem to induce more durable remissions (2-year PFS 74% with venetoclax plus obinutuzumab in treatment-naïve CLL with 17p deletion and/or TP53 mutation), although cross-trial comparisons are problematic, especially given that venetoclax was administered as a fixed-duration regimen. Future research will determine if combination therapy results in a further survival improvement.
Conclusions: Our data demonstrate that frontline therapy with ibrutinib results in long-term remissions in high-risk CLL patients with 17p deletion and/or TP53 mutations, despite the lack of deep remissions, with an estimated 5-year PFS of 66%.
Jain: Aprea Therapeutics: Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Precision Bioscienes: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; BeiGene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Fate Therapeutics: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Servier: 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; Cellectis: Research Funding; Incyte: Research Funding; ADC Therapeutics: Research Funding. Kadia:Ascentage: Research Funding; Astra Zeneca: Research Funding; Celgene: Research Funding; Pulmotec: Research Funding; BMS: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Novartis: Honoraria; Cyclacel: Research Funding; Incyte: Research Funding; Cellenkos: Research Funding; Astellas: Research Funding; Amgen: Research Funding; JAZZ: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding. Andreeff: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; Daiichi-Sankyo; Jazz Pharmaceuticals; Celgene; Amgen; AstraZeneca; 6 Dimensions Capital: Consultancy; Amgen: Research Funding; Daiichi-Sankyo; Breast Cancer Research Foundation; CPRIT; NIH/NCI; Amgen; AstraZeneca: Research Funding. Thompson:AbbVie: Research Funding; Adaptive Biotechnologies: Consultancy, Research Funding; Pharmacyclics: Research Funding; Genentech: Consultancy; Janssen-Cilag: Honoraria. Kantarjian:Janssen: Honoraria; Oxford Biomedical: Honoraria; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive biotechnologies: Honoraria; Aptitute Health: Honoraria; Ascentage: Research Funding; BioAscend: Honoraria; Delta Fly: Honoraria; BMS: Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Immunogen: Research Funding; Jazz: Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Sanofi: Research Funding; Amgen: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding. O'Brien:Eisai: Consultancy; Amgen: Consultancy; Regeneron: Research Funding; KITE: Research Funding; GlaxoSmithKline: Consultancy; Vida Ventures: Consultancy; Janssen Oncology: Consultancy; Vaniam Group LL: Consultancy; Gilead: Consultancy; Sunesis: Research Funding; Pfizer: Research Funding; Alexion: Consultancy; Acerta: Research Funding; Pharmacyclics: Research Funding; Verastem: Consultancy; AbbVie: Consultancy; Aptose Biosciences: Consultancy; Celgene: Consultancy; TG Therapeutics: Research Funding; Juno Therapeutics: Consultancy; Astellas: Consultancy. Burger:Gilead Sciences: Consultancy, Research Funding; AstraZeneca: Consultancy; Janssen Pharmaceuticals: Consultancy, Speakers Bureau; Pharmacyclics, an AbbVie company: Consultancy, Research Funding, Speakers Bureau; Beigene: Research Funding, Speakers Bureau; TG Therapeutics: Research Funding, Speakers Bureau.
| v2 |
2019-03-18T14:06:38.717Z | 2018-11-21T00:00:00.000Z | 81732120 | s2ag/train | Long-Term Carfilzomib for High-Risk Patients with Newly Diagnosed Multiple Myeloma: A Pooled Analysis of Two Phase 1/2 Studies
INTRODUCTION: High-risk cytogenetic abnormalities, such as del(17p), t(4;14), and/or t(14;16), are associated to an unfavorable prognosis. Several trials investigating current approved regimens have shown that high-risk multiple myeloma (MM) patients have shorter progression-free survival (PFS) and overall survival (OS) as compared to standard-risk patients. Carfilzomib, a second generation proteasome inhibitor, demonstrated to be able to improve the survival of high-risk MM patients in the relapse setting. Here we present a pooled analysis of two phase 1/2 studies to investigate the role of carfilzomib in high-risk, newly diagnosed (ND) MM patients.
METHODS: Transplant ineligible patients with NDMM enrolled in the IST-CAR 561 and IST-CAR 506 studies were pooled together and analyzed. All patients received 9 28-day induction cycles of carfilzomib, either 70 mg/m2 once weekly (IST-CAR 561) or 36 mg/m2 twice weekly (IST-CAR 506), combined with weekly cyclophosphamide (300 mg/m2) and dexamethasone (40 mg) (CCyd). After the induction phase, patients proceeded to maintenance with single-agent carfilzomib until progressive disease or intolerable toxicity. The primary objective was to compare response to treatment, PFS, PFS-2 and OS in standard versus high-risk FISH, defined by the presence of del(17p), t(4;14), and/or t(14;16). A 15% cut-off point was used for detection of translocation [t(4;14) and t(14;16)] and 10% for detection of del(17p).
RESULTS: 121 NDMM patients were enrolled in the IST-CAR 561 (n=63) and in the IST-CAR 506 (n=58) study. Cytogenetic data were available in 94 patients: 37 (31%) had high-risk chromosomal abnormalities by FISH, including 10% of patients with t(4;14), 3% with t(14;16) and 18% with del(17p), while 57 patients (47%) were classified as standard-risk.
After the induction phase, no difference in terms of overall response rate (ORR; 86% vs. 92%; p=0.52) and at least near complete response (39% vs. 41%; p=1) was observed between standard and high-risk patients.
After a median follow-up of 39 months, median PFS from enrollment was NR in standard-risk patients and 27.8 months in high-risk ones (HR: 0.76; p=0.38) (Figure 1); at 3 years, 52% and 43% of patients, respectively, were alive and free from progression. The PFS benefit for the comparison between standard and high-risk patients was more pronounced in patients who received once weekly carfilzomib at 70 mg/m2, (median: NR vs. 39.6 months; HR: 0.78, p=0.63) as compared to those treated with twice weekly carfilzomib at 36 mg/m2 (median: NR vs. 24.2 months; HR: 0.52, p=0.12).
Median PFS-2 from enrollment was NR in standard-risk patients and 44.1 months in high-risk ones (HR: 0.66; p=0.26), without significant differences in the once weekly (median, NR vs. 39.6; p=0.27) and the twice weekly group (median; NR vs. 44.1; p=0.63).
Median OS from enrollment was NR in standard-risk patients and 47.5 months in high-risk ones (HR:0.71; p=0.36) (Figure 1). In patients who received once weekly carfilzomib, median OS was NR and 47.5 months (HR:0.66, p=0.48) in standard and high-risk patients, respectively, while median OS in the twice weekly group was NR in standard-risk patients and 44.1 months (HR:0.73; p=0.55) in high-risk ones.
CONCLUSION: In transplant ineligible patients with NDMM, carfilzomib combined with cyclophosphamide and dexamethasone as initial treatment mitigated the poor prognosis of high-risk FISH in terms of PFS, PFS-2 and OS. The median PFS of high-risk patients treated with CCyd compares favorably with those reported with current standard of care. As compared to twice weekly carfilzomib at 36 mg/m2, once weekly carfilzomib, at the dose of 70 mg/m2, confirmed to be effective in high-risk patients. These data support the use of carfilzomib for the treatment of high-risk NDMM patients.
Figure 1. Figure 1.
Larocca: Janssen-Cilag: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria; Amgen: Honoraria. Petrucci:Amgen: Honoraria, Other: Advisory Board; Takeda: Honoraria, Other: Advisory Board; Bristol-Myers Squibb: Honoraria, Other: Advisory Board; Janssen-Cilag: Honoraria, Other: Advisory Board; Celgene: Honoraria, Other: Advisory Board. Gaidano:AbbVie: Other: Advisory Board; Janssen: Other: Advisory Board, Speakers Bureau. Musto:Amgen: Honoraria; BMS: Honoraria; Takeda: Honoraria; Janssen: Honoraria; Celgene: Honoraria. Offidani:Janssen: Honoraria, Other: Advisory Board; Takeda: Honoraria, Other: Advisory Board; Amgen: Honoraria, Other: Advisory Board; Bristol-Myers Squibb: Honoraria, Other: Advisory Board; Celgene: Honoraria, Other: Advisory Board. Cavo:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: 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, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Caravita di Toritto:Bristol-Myers Squibb: Honoraria, Other: Travel and Accomodation EMN; Amgen: Other: Advisory Board; Johnson & Johnson: Other: Advisory Board, Travel and Accomodation EHA; Celgene: Other: Advisory Board, Travel and Accomodation ASH, Research Funding; Takeda: Other: Advisory Board. Montefusco:Janssen: Other: Advisory Board; Amgen: Other: Advisory Board; Celgene: Other: Advisory Board. Palumbo:Takeda: Employment. Boccadoro:Bristol-Myers Squibb: Honoraria, Research Funding; AbbVie: Honoraria; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Mundipharma: Research Funding. Bringhen:Celgene: Honoraria; Amgen: Honoraria, Other: Advisory Board; Janssen: Honoraria, Other: Advisory Board; Takeda: Consultancy; Bristol-Myers Squibb: Honoraria.
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2019-04-29T13:17:45.844Z | 2012-01-01T00:00:00.000Z | 136078540 | s2ag/train | Study the Effect of Ambient Oxygen Pressure on Structural and Optical Properties of Pure SnO2Thin films Prepared by Pulsed Laser Deposition
Polycrystalline pure SnO2 thin films were deposited on glass substrates at fixed substrate temperature (400C°) by (Nd-YAG )pulsed laser deposition (PLD) with pulse energy(5000 mJ), pulse width(10ns) at a different ambient oxygen pressure (10 -1 ,10 -2 ,10 -3 ) torr. The effect of ambient oxygen pressure on the structural and optical properties of SnO2 thin films was studied. (XRD) X-ray diffraction and AFM (atomic force microscopy) methods were used to examine the structure and morphology of the films in this work. From (XRD) X-ray diffraction of the SnO2 films, it was found that the deposited films showed some differences compared with the oxygen pressure and the intensities of the peaks of the crystalline phases decreased with the increase of oxygen. From AFM images, the distinct variations in the morphology of the thin films were also observed, from the transmittance of SnO2 it was found that the optical transmission of SnO2 films at high oxygen pressure is low than for low ambient oxygen pressure. :ةصلاخلا طادها ساشدس ةدعسد ذدٍا ةديعاعص تايدظسا ًدما ىبيدهشج هدج يدقٍلا شرذدصقلا ذيسكوا يٌاث تاسىمبلا دذعحو قيقشلا ءاشغلا 022 ةرضميه يعبٍلا كار نىيىرذٍلا سضيمب بيهشحلا ةطهاىب ةقاطب 0222 سضديملا ةعبٌ ضشاو, لىع يمو 12 ةديٌاث ىٌادٌ ذدٍا ًي دسكولال ةد محخو غىطغدظ 10 -2 ,10 -3 , 10 -1 ةديبيكشحلا اىدخلا ًدما ًي دسكوىا ػغدظ شيثادج ةدهاسد ثدىج .قدبئص.همو) ةيدششى ةرشدصبلاو ةعد وا دىديس لاىعحده ب ةيدششوا ةدي اششىبىغو بديكشج ادو هدج كدىعلا ازدم يد شرذدصقلا ذيدسكوا يٌادث ةيٍيدسلا (XRD) ةدرسزلا يىدقلا شده وو (AFM) ي ذدعو شرذدصقلا ذيدسكوا يٌادث ةيدششى ةيٍيدسلا ةعد ىا دىديس غادىٌا ًدو . تا لاحخوا طعب تشهظ ةبهشىلا ةيششوا ًي سكوىا ػغظ شيغحب تاذ و . ًي دسكوىا دادرضب كدقج ةرسىمبلا ساىغلأل هىقلا شرذدصقلا ذيدسكوا يٌادث ةدررا ٌ ًدو . ةدقيقشلا ةيدششوا ةدي اششىبىغ يد ضيىحو تا لاحخ اٍظسى ةرسزلا يىقلا شه و سىص ًو ا ػغدظ ةدلاس يد ادىو كدقا يلادعلا ًي دسكوىا ػغدظ ذدٍا شرذدصقلا ذيدسكوا يٌاث ءاشغل ةرشصبلا ةررا ٍلا ىٌا اٌذعو ًي دسكوى .ةميمقلا 1-Introduction: Pulsed laser deposition (PLD) is a thin film deposition method which uses short and intensive laser pulses to evaporate target material. The ablated particles escape from the target and condense on the substrate. The deposition process occurs in a vacuum chamber to minimize the scattering of the particles[1,4]. Earlier a seemingly esoteric technique of Pulsed Laser Deposition (PLD) has emerged as a potential methodology for growing nanostructures of various materials including semiconductors[1]. Since it is a cold-wall processing, which excites only the beam focused areas on the target enabling a clean ambient, it is highly suited for the growth of nanostructures with high chemical purity and controlled Stoichiometry. The other characteristics of PLD such as its ability to create high-energy source particles, permitting high quality film growth at low substrate temperatures [2], simple and inexpensive experimental setup, possible operation in high ambient gas pressure, and sequential multi-target and multiof kerbala university , vol. 10 no.3 scientific . 2012 Journal 011 component materials' congruent evaporation make it particularly suited for the growth of oxide thin films and nanostructures. Tin oxide ( 2 SnO ) is an n-type semiconductor with band gap of eV Eg 00 . 4 62 . 3 at room temperature [3]. The ( 2 SnO ) research for its applications has been mainly focused on this films. Up to date, ( 2 SnO ) thin films have been achieved by a variety of deposition techniques such as chemical vapor deposition (CVD) [5,6], sol-gel processing [7,8],reactive sputtering [9] and pulsed laser deposition (PLD) [10,11]. Among these fabrication techniques, PLD has attached much attention. It is well known that ambient oxygen pressure is one of the key experimental parameters in the process of PLD. In this paper,( 2 SnO ) thin films were prepared by PLD and the influence of ambient oxygen pressure (10 -1 ,10 -2 ,10 -3 ) torr on structural and optical properties of 2 SnO thin films were reported. 2-Experimental procedures: SnO2 thin films were prepared by pulsed laser deposition system with a titanium target of 99.99% purity on microscope glass slides as substrates. The target was pressed less than 5 ton to form a target with 2.5 cm diameter and 0.4 cm thickness. Microscope glass slides were used as the substrates for thin films. Prior to deposition, the glass slides were sequentially cleaned in an ultrasonic bath with ethanol. Finally they were rinsed with distilled water and dried. The substrate is placed in front of the target with its surface parallel to that of the target the substrate deposited at temperature 400 o C with Oxygen pressure (10 -1 ,10 -2 ,10 -3 ) torr. The pulsed laser deposition is carried out inside a vacuum chamber generally at three different oxygen pressures. Nd-YAG laser (Huafei Tangda Technelogy-Diamond-288 pattern EPLS) second harmonic generation with laser wavelength (1064/532)nm, pulse energy (100-1000)mJ, pulse width (10ns). The focused Nd-YAG SHG Q-switching laser beam coming through a window is incident on the target surface making an angle of 45° with it, given in Fig (1) below. 1. Nd:YAG Laser Head. 6. Flexible tube KF16 2. O2 cylinder gas 7. Quartz Chamber. 3. Stainless steel Flange. 8. Substrate holder 4. N2 cylinder gas. 9. Vacuum system 5. Nd:YAG laser Power supply 10.Variac devices Figure (1): Pulsed laser deposition (PLD) system 1 | v2 |
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