text:
bims-myxlip Biomed News
on Myxoid liposarcoma
Issue of 2020‒12‒27
thirty-four papers selected by
Laura Mannarino
Mario Negri Institute
lncRNA involvement in cancer stem cell function and epithelial-mesenchymal transitions.
A rapid and cost-effective gene expression assay for the diagnosis of well-differentiated and dedifferentiated liposarcomas.
Small molecule DNA-PK inhibitors as potential cancer therapy: a patent review (2010-present).
Accelerated subcutaneous abdominal stem cell adipogenesis predicts insulin sensitivity in normal-weight women with polycystic ovary syndrome.
Efficacy of hyperthermic isolated limb perfusion in the treatment of locally recurrent high-grade soft tissue sarcoma of the extremities.
Multi-omics data integration considerations and study design for biological systems and disease.
The pivotal role of MicroRNAs in glucose metabolism in cancer.
Characteristics of the Tumor Microenvironment That Influence Immune Cell Functions: Hypoxia, Oxidative Stress, Metabolic Alterations.
ChREBP-Mediated Regulation of Lipid Metabolism: Involvement of the Gut Microbiota, Liver, and Adipose Tissue.
Safety and efficacy of pazopanib as a second-line treatment and beyond for soft tissue sarcomas: A real-life tertiary-center experience in the MENA region.
Talabostat Alleviates Obesity and Associated Metabolic Dysfunction via Suppression of Macrophage-Driven Adipose Inflammation.
Tuft and Cancer Stem Cell Marker DCLK1: A New Target to Enhance Anti-Tumor Immunity in the Tumor Microenvironment.
Inducible beige adipocytes improve impaired glucose metabolism in interscapular BAT-removal mice.
DNA damaging agents and DNA repair: From carcinogenesis to cancer therapy.
Should metastatic lymph nodes be considered at the same clinical stage as distant metastasis in soft tissue sarcomas?
The nicotinamide phosphoribosyltransferase antagonist FK866 inhibits growth of prostate tumour spheroids and increases doxorubicin retention without changes in drug transporter and cancer stem cell protein expression.
Tackle Epithelial-Mesenchymal Transition With Epigenetic Drugs in Cancer.
Relationships between DNA repair and RTK-mediated signaling pathways.
High-Throughput Affinity Measurements of Transcription Factor and DNA Mutations Reveal Affinity and Specificity Determinants.
Novel piperazine-chalcone hybrids and related pyrazoline analogues targeting VEGFR-2 kinase; design, synthesis, molecular docking studies, and anticancer evaluation.
Exosomes from microRNA-126 overexpressing mesenchymal stem cells promote angiogenesis by targeting the PIK3R2-mediated PI3K/Akt signalling pathway.
Lurbinectedin: A New Treatment Option for Relapsed/Refractory Small-Cell Lung Cancer.
Marine-derived drugs: Recent advances in cancer therapy and immune signaling.
Targeting Akt-associated microRNAs for cancer therapeutics.
RORα regulates hepatic lipolysis by inducing transcriptional expression of PNPLA3 in mice.
Dynamics of transcriptional and post-transcriptional regulation.
Cell-free DNA and RNA - measurement and applications in clinical diagnostics with focus on metabolic disorders.
MicroRNAs involved in the EGFR pathway in glioblastoma.
LncRNA SOX21-AS1 Promotes the Growth and Invasiveness of Osteosarcoma Cells Through miR-7-5p/IRS2 Regulatory Network.
Variable interplay of UV-induced DNA damage and repair at transcription factor binding sites.
An Enhancer-Based Analysis Revealed a New Function of Androgen Receptor in Tumor Cell Immune Evasion.
Topological network measures for drug repositioning.
Addition of TLR9 agonist immunotherapy to radiation improves systemic antitumor activity.
To mock or not: a comprehensive comparison of mock IP and DNA input for ChIP-seq.
Semin Cancer Biol. 2020 Dec 17. pii: S1044-579X(20)30272-8. [Epub ahead of print]
McCabe EM, Rasmussen TP.
Epithelial to mesenchymal transition (EMT) is a cellular process in which cells composing epithelial tissue lose requirements for physical contact with neighboring cells and acquire mesenchymal characteristics consisting of increased migratory and invasive behaviors. EMT is a fundamental process that is required for initial and later events during embryogenesis. Cancer stem cells (CSCs) possess multipotency sufficient for their differentiation into bulk tumor cells and also have the capacity to undergo EMT. When CSCs initiate EMT programs the resulting cancerous mesenchymal cells become invasive and this migratory behavior also poises them for metastatic activity. Long noncoding RNAs (lncRNAs) are functional RNA molecules that do not encode proteins, yet regulate the expression of protein-coding genes through recruitment or sequestration of gene-regulatory proteins and microRNAs. lncRNA exhibit tissue-specific patterns of gene expression during development and specific sets of lncRNAs are also involved in various cancer types. This review considers the interplay between lncRNAs and the biogenesis of CSCs. We also review function of lncRNAs in EMT in CSCs. In addition, we discuss the utility of lncRNAs as biomarkers of cancer progression, and their potential use as therapeutic targets for treatment of cancer.
Keywords: cancer stem cell; epithelial-mesenchymal transition (EMT); lncRNA
DOI: https://doi.org/10.1016/j.semcancer.2020.12.012
J Mol Diagn. 2020 Dec 17. pii: S1525-1578(20)30586-9. [Epub ahead of print]
Wang XQ, Wang XQ, Ye Way Hsu AT, Goytain A, Tin Ng TL, Nielsen TO.
Histology does not reliably distinguish benign lipomas from atypical lipomatous tumor / well differentiated liposarcoma, nor dedifferentiated liposarcoma from other pleomorphic sarcomas, entities with different prognosis and management. Molecular confirmation of pathognomonic 12q13-15 amplifications leading to overexpression of MDM2 is a diagnostic gold standard. Currently the most commonly used assay for this purpose is Fluorescent In-Situ Hybridization (FISH), but this is labor-intensive. We assessed if newer NanoString-based technology could allow for more rapid and cost-efficient diagnosis of liposarcomas on standard formalin-fixed tissues through gene expression. Leveraging large-scale transcriptome data from The Cancer Genome Atlas, we identified 20 genes, most derived from the 12q13-15 amplicon, that distinguish dedifferentiated liposarcoma from other sarcomas and can be measured within a single NanoString assay. Using 21 cases of histologically-ambiguous low grade adipocytic tumors with available MDM2 amplification status, we built a machine learning based analytical pipeline that assigns a given sample as negative or positive for liposarcoma based on quantitative gene expression. We validated the assay's effectiveness on an independent set of 100 sarcoma samples (including 40 incident prospective cases), where histology was considered insufficient for clinical diagnosis. The NanoString assay had a 93% technical success rate, and an accuracy of 97.8% versus an MDM2 amplification FISH gold standard. Turnaround time at our institution with NanoString was considerably faster and less expensive than FISH.
DOI: https://doi.org/10.1016/j.jmoldx.2020.11.011
Expert Opin Ther Pat. 2020 Dec 21.
Hu S, Hui Z, Lirussi F, Garrido C, Ye XY, Xie T.
INTRODUCTION: DNA-dependent protein kinase (DNA-PK) plays a crucial role in the repair of DSBs via non-homologous end joining (NHEJ). Several DNA-PK inhibitors are being investigated for potential anticancer treatment in clinical trials.AREA COVERED: This review aims to give an overview of patents published since 2010 aiming to analyze the patent space and structure features of scaffolds used in those patents. It also discusses the recent clinical developments and provides perspectives on future challenges and directions of developing DNA-PK inhibitor drugs for cancer treatment.
EXPERT OPINION: As a key component of the DNA damage response (DDR) pathway, DNA-PK appears to be a viable drug target for anticancer therapy. The clinical investigation of a DNA-PK inhibitor employs both a monotherapy and a combination strategy. In the combination strategy, a DNA-PK inhibitor is typically combined with a DSB inducer, radiation, a chemotherapy agent, or a PARP inhibitor etc. Patent analyses suggest that diverse structures comprising different scaffolds from mono- heteroaryl to bicyclic heteroaryl to tricyclic heteroaryl are capable to achieve good DNA-PK inhibitory activity and good DNA-PK selectivity over other closely related enzymes. Several DNA-PK inhibitors are currently being evaluated in clinics, with the hope to get approval in the near future.
Keywords: DNA damage response (DDR); DNA double strand breaks (DSBs); DNA-PK; cancer therapy; inhibitor; patent review
DOI: https://doi.org/10.1080/13543776.2021.1866540
Fertil Steril. 2020 Dec 16. pii: S0015-0282(20)32511-5. [Epub ahead of print]
Dumesic DA, Tulberg A, Leung KL, Fisch SC, Grogan TR, Abbott DH, Naik R, Chazenbalk GD.
OBJECTIVE: To examine whether subcutaneous (SC) abdominal adipose stem cell differentiation into adipocytes in vitro predicts insulin sensitivity (Si) in vivo in normal-weight women with polycystic ovary syndrome (PCOS) and controls.DESIGN: Prospective cohort study.
SETTING: Academic medical center.
PATIENT(S): Eight normal-weight women with PCOS and 8 age- and body mass index-matched controls.
INTERVENTION(S): Women underwent circulating hormone/metabolic determinations, intravenous glucose tolerance testing, total-body dual-energy x-ray absorptiometry, and SC abdominal fat biopsy.
MAIN OUTCOME MEASURE(S): PPARγ and CEBPa gene expression and lipid content of adipocytes matured in vitro were compared between women with PCOS and control women, and correlated with patient characteristics, systemic Si, and adipose insulin resistance (adipose-IR).
RESULT(S): Serum androgen levels, adipose-IR, and percentage of android fat were greater in women with PCOS than control women. Stem cell PPARγ and CEBPa gene expression increased maximally by day 12 without a female-type effect. In control cells, gene expression positively correlated with fasting serum insulin levels (both genes) and adipose-IR (CEBPa) and negatively correlated with Si (CEBPa). Conversely, CEBPa gene expression in PCOS cells negatively correlated with adipose-IR and serum free testosterone, whereas total lipid accumulation in these cells positively corelated with Si.
CONCLUSION: In normal-weight women with PCOS, accelerated SC abdominal adipose stem cell differentiation into adipocytes in vitro favors Si in vivo, suggesting a role for hyperandrogenism in the evolution of metabolic thrift to enhance fat storage through increased cellular glucose uptake.
Keywords: Adipose; adipocyte; hyperandrogenism; polycystic ovary syndrome; stem cell
DOI: https://doi.org/10.1016/j.fertnstert.2020.10.003
World J Surg Oncol. 2020 Dec 21. 18(1): 332
Farzaliyev F, Touma A, Taeger G, Steinau HU, Hardes J, Streitbürger A, Podleska LE.
BACKGROUND: This novel study compared the use of tumor necrosis factor (TNF)-alpha and melphalan-based isolated limb perfusion (TM-ILP) to the standard treatment of locally recurrent soft tissue extremity sarcoma. The aim was to assess whether TM-ILP positively influences the recurrence-free survival of locally recurrent high-grade soft tissue sarcoma (STS) of the extremities.METHODS: We retrospectively analyzed our clinical database for patients with STS. Variables were analyzed using chi-square test or Mann-Whitney rank-sum test. Furthermore, Kaplan-Meier survival plots were calculated and a proportional hazard regression model was developed.
RESULTS: Out of 448 patients with extraabdominal STS treated between August 2012 and December 2015, 52 cases involving 47 patients had locally recurrent STS. Twenty-eight of these patients were treated with TM-ILP prior to surgical resection (TM-ILP-group), and 24 were treated with standard therapy (without TM-ILP). The 3-year recurrence-free survival for the TM-ILP-group was estimated at 75% (95% confidence interval (CI), 71.5-78.5). Local recurrence-free survival in the standard group was significantly lower (LRFS: 43.4%, 95% CI 38.7-48.1, p = 0.026). Multivariable analysis revealed resection with negative margins, lower number of previous recurrences, and TM-ILP as positive predictors for recurrence-free survival.
CONCLUSIONS: TM-ILP and consecutive resection of residual tumor with negative resection margins significantly improves local recurrence-free survival for patients with a first local recurrence of high-grade STS in the extremities.
Mol Omics. 2020 Dec 21.
Graw S, Chappell K, Washam CL, Gies A, Bird J, Robeson MS, Byrum SD.
With the advancement of next-generation sequencing and mass spectrometry, there is a growing need for the ability to merge biological features in order to study a system as a whole. Features such as the transcriptome, methylome, proteome, histone post-translational modifications and the microbiome all influence the host response to various diseases and cancers. Each of these platforms have technological limitations due to sample preparation steps, amount of material needed for sequencing, and sequencing depth requirements. These features provide a snapshot of one level of regulation in a system. The obvious next step is to integrate this information and learn how genes, proteins, and/or epigenetic factors influence the phenotype of a disease in context of the system. In recent years, there has been a push for the development of data integration methods. Each method specifically integrates a subset of omics data using approaches such as conceptual integration, statistical integration, model-based integration, networks, and pathway data integration. In this review, we discuss considerations of the study design for each data feature, the limitations in gene and protein abundance and their rate of expression, the current data integration methods, and microbiome influences on gene and protein expression. The considerations discussed in this review should be regarded when developing new algorithms for integrating multi-omics data.
DOI: https://doi.org/10.1039/d0mo00041h
Pathol Res Pract. 2020 Dec 04. pii: S0344-0338(20)32169-5. [Epub ahead of print]217 153314
Taefehshokr S, Taefehshokr N, Hemmat N, Hajazimian S, Isazadeh A, Dadebighlu P, Baradaran B.
Cancer cells are able to undergo aerobic glycolysis and metabolize glucose to lactate instead of oxidative phosphorylation, which is known as Warburg effect. Accumulating evidence has revealed that microRNAs regulate cancer cell metabolism, which manifest a higher rate of glucose metabolism. Various signaling pathways along with glycolytic enzymes are responsible for the emergence of glycolytic dependence. MicroRNAs are a class of non-coding RNAs that are not translated into proteins but regulate target gene expression or in other words function pre-translationally and post-transcriptionally. MicroRNAs have been shown to be involved in various biological processes, including glucose metabolism via targeting major transcription factors, enzymes, oncogenes or tumor suppressors alongside the oncogenic signaling pathways. In this review, we describe the regulatory role of microRNAs of cancer cell glucose metabolism, including in the glucose uptake, glycolysis, tricarboxylic acid cycle and several signaling pathways and further suggest that microRNA-based therapeutics can be used to inhibit the process of glucose metabolism reprogramming in cancer cells and thus suppressing cancer progression.
Keywords: Cancer; Glucose; Metabolism; MicroRNA
DOI: https://doi.org/10.1016/j.prp.2020.153314
Cancers (Basel). 2020 Dec 17. pii: E3802. [Epub ahead of print]12(12):
Augustin RC, Delgoffe GM, Najjar YG.
Immunotherapy (IMT) is now a core component of cancer treatment, however, many patients do not respond to these novel therapies. Investigating the resistance mechanisms behind this differential response is now a critical area of research. Immune-based therapies, particularly immune checkpoint inhibitors (ICI), rely on a robust infiltration of T-cells into the tumor microenvironment (TME) for an effective response. While early efforts relied on quantifying tumor infiltrating lymphocytes (TIL) in the TME, characterizing the functional quality and degree of TIL exhaustion correlates more strongly with ICI response. Even with sufficient TME infiltration, immune cells face a harsh metabolic environment that can significantly impair effector function. These tumor-mediated metabolic perturbations include hypoxia, oxidative stress, and metabolites of cellular energetics. Primarily through HIF-1-dependent processes, hypoxia invokes an immunosuppressive phenotype via altered molecular markers, immune cell trafficking, and angiogenesis. Additionally, oxidative stress can promote lipid peroxidation, ER stress, and Treg dysfunction, all associated with immune dysregulation. Finally, the metabolic byproducts of lipids, amino acids, glucose, and cellular energetics are associated with immunosuppression and ICI resistance. This review will explore these biochemical pathways linked to immune cell dysfunction in the TME and highlight potential adjunctive therapies to be used alongside current IMT.
Keywords: cellular energetics; immunometabolism; immunotherapy
DOI: https://doi.org/10.3390/cancers12123802
Front Endocrinol (Lausanne). 2020 ;11 587189
Iizuka K, Takao K, Yabe D.
Carbohydrate response element-binding protein (ChREBP) plays an important role in the development of type 2 diabetes, dyslipidemia, and non-alcoholic fatty liver disease, as well as tumorigenesis. ChREBP is highly expressed in lipogenic organs, such as liver, intestine, and adipose tissue, in which it regulates the production of acetyl CoA from glucose by inducing Pklr and Acyl expression. It has recently been demonstrated that ChREBP plays a role in the conversion of gut microbiota-derived acetate to acetyl CoA by activating its target gene, Acss2, in the liver. ChREBP regulates fatty acid synthesis, elongation, and desaturation by inducing Acc1 and Fasn, elongation of long-chain fatty acids family member 6 (encoded by Elovl6), and Scd1 expression, respectively. ChREBP also regulates the formation of very low-density lipoprotein by inducing the expression of Mtp. Furthermore, it plays a crucial role in peripheral lipid metabolism by inducing Fgf21 expression, as well as that of Angptl3 and Angptl8, which are known to reduce peripheral lipoprotein lipase activity. In addition, ChREBP is involved in the production of palmitic-acid-5-hydroxystearic-acid, which increases insulin sensitivity in adipose tissue. Curiously, ChREBP is indirectly involved in fatty acid β-oxidation and subsequent ketogenesis. Thus, ChREBP regulates whole-body lipid metabolism by controlling the transcription of lipogenic enzymes and liver-derived cytokines.
Keywords: carbohydrate response element-binding protein (Chrebp); fatty acid synthesis; gut microbiota; ketogenesis; lipoprotein metabolism; β-oxidation
DOI: https://doi.org/10.3389/fendo.2020.587189
Cancer Treat Res Commun. 2020 Dec 11. pii: S2468-2942(20)30110-6. [Epub ahead of print]26 100275
Halim NA, Sayed RE, Alameh IA, Khoury J, Nakib CE, Zerdan MB, Charafeddine M, Farhat F, Karak FE, Assi HI.
INTRODUCTION: Sarcomas are uncommon malignancies. No advances have been recently achieved despite multiple efforts. Pazopanib is a safe and effective tyrosine kinase inhibitor used in managing soft tissue sarcomas (STS) after chemotherapy failure. However, its use is limited in developing countries and no efficacy data exist from our region. We aimed to study the efficacy of pazopanib in our population, characterized by response rates of patients with chemotherapy-refractory advanced STS receiving pazopanib. Secondary endpoints included progression-free survival (PFS), overall survival (OS) and toxicity profile.MATERIALS AND METHODS: 15 patients (age≥18 year) diagnosed with advanced STS, refractory to first-line chemotherapy, receiving pazopanib as ≥second-line therapy in one tertiary center in Lebanon were included between January 1st, 2014 and October 31st, 2018. Patient and disease characteristics, disease evaluation, as well as tolerance to treatment, were extracted from charts retrospectively. Statistical analysis was done using SPSS version 24.
RESULTS: The mean age was 48.6 [19-66] years. Eleven patients (73.3%) received pazopanib in second-line, whereas four patients (26.7%) received it in third-line. Thirteen patients (86.7%) progressed, and two patients (13.3%) had stable disease. The median PFS was three months [1-19] and the mean OS was 25.4 months [17.2-33.6]. Five patients required dose-reductions due to poor tolerance.
CONCLUSION: Conclusions cannot be drawn due to small patient numbers. However, given the 3-month PFS, 13% of patients maintaining stable disease, and tolerable safety profile, it is reasonable to incorporate pazopanib in STS treatment. More focused studies with larger patient populations need to be done in Lebanon.
Keywords: Adverse events; Outcomes; Pazopanib; Safety; Soft tissue sarcoma
DOI: https://doi.org/10.1016/j.ctarc.2020.100275
Obesity (Silver Spring). 2020 Dec 20.
Wu Y, Shi T, Wang J, He R.
OBJECTIVE: Adipose tissue macrophages (ATMs) play critical roles in obesity-associated inflammation that contributes to metabolic dysfunction. Talabostat (TB) exerts some therapeutic effects on tumors and obesity. However, it remains unknown whether the metabolic benefits of TB on obesity is dependent on ATM-mediated adipose inflammation.METHODS: Male C57BL/6J mice were fed a normal chow diet (NCD) or a high-fat diet for 12 weeks, and mice were orally administered TB daily at a low dose (0.5 mg/kg).
RESULTS: Administration of TB to mice fed a high-fat diet significantly improved adiposity and obesity-associated metabolic dysfunction, including glucose intolerance and insulin resistance, hyperlipidemia and hepatic steatosis, which were accompanied by increased whole-body energy expenditure. RNA sequencing analysis revealed extensive alterations in the transcriptome profiles associated with lipid metabolism and immune responses in adipose tissue of obese mice. Notably, TB treatment led to a significant reduction in ATM accumulation and a shift of the activation state of ATMs from the proinflammatory M1-like to the anti-inflammatory M2-like phenotype. Moreover, depletion of ATMs significantly abolished the TB-induced metabolic benefits.
CONCLUSIONS: Our study demonstrates that TB at a low dose could increase energy expenditure and control ATM-mediated adipose inflammation in obese mice, thereby alleviating obesity and its associated metabolic dysfunction.
DOI: https://doi.org/10.1002/oby.23058
Cao Z, Weygant N, Chandrakesan P, Houchen CW, Peng J, Qu D.
Microtubule-associated doublecortin-like kinase 1 (DCLK1) is an accepted marker of tuft cells (TCs) and several kinds of cancer stem cells (CSCs), and emerging evidence suggests that DCLK1-positive TCs participate in the initiation and formation of inflammation-associated cancer. DCLK1-expressing CSCs regulate multiple biological processes in cancer, promote resistance to therapy, and are associated with metastasis. In solid tumor cancers, tumor epithelia, immune cells, cancer-associated fibroblasts, endothelial cells and blood vessels, extracellular matrix, and hypoxia all support a CSC phenotype characterized by drug resistance, recurrence, and metastasis. Recently, studies have shown that DCLK1-positive CSCs are associated with epithelial-mesenchymal transition, angiogenesis, and immune checkpoint. Emerging data concerning targeting DCLK1 with small molecular inhibitors, monoclonal antibodies, and chimeric antigen receptor T-cells shows promising effects on inhibiting tumor growth and regulating the tumor immune microenvironment. Overall, DCLK1 is reaching maturity as an anti-cancer target and therapies directed against it may have potential against CSCs directly, in remodeling the tumor microenvironment, and as immunotherapies.
Keywords: DCLK1; cancer stem cells; immunotherapies; microenvironment; tuft cells
Biochim Biophys Acta Mol Cell Biol Lipids. 2020 Dec 17. pii: S1388-1981(20)30263-8. [Epub ahead of print] 158871
Jia XW, Fang DL, Shi XY, Lu T, Yang C, Gao Y.
Inducible beige adipocytes are emerging as an interesting issue in obesity and metabolism research. There is a neglected possibility that brown adipocytes are equally activated when external stimuli induce the formation of beige adipocytes. Thus, the question is whether beige adipocytes have the same functions as brown adipocytes when brown adipose tissue (BAT) is lacking. This question has not been well studied. Therefore we determine the beneficial effects of beige adipocytes upon cold challenge or CL316243 treatments in animal models of interscapular BAT (iBAT) ablation by surgical denervation. We found that denervated iBAT were activated by cold exposure and CL316243 treatments. The data show that beige adipocytes partly contribute to the improvement of impaired glucose metabolism resulting from denervated iBAT. Thus, we further used iBAT-removal animal models to abolish iBAT functions completely. We found that beige adipocytes upon cold exposure or CL316243 treatments improved impaired glucose metabolism and enhanced glucose uptake in iBAT-removal mice. The insulin signaling was activated in iBAT-removal mice upon cold exposure. Both the activation of insulin signaling and up-regulation of glucose transporter expression were observed in iBAT-removal mice with CL316243 treatments. The data show that inducible beige adipocytes may have different mechanisms to improve impaired glucose metabolism. Inducible beige adipocytes can also enhance energy expenditure and lipolytic activity of white adipose tissues when iBAT is lacking. We provide direct evidences for the beneficial effect of inducible beige adipocytes in glucose metabolism and energy expenditure in the absence of iBAT in vivo.
Keywords: energy expenditure; glucose tolerance; glucose transporter genes; removal; surgical denervation
DOI: https://doi.org/10.1016/j.bbalip.2020.158871
Cancer Genet. 2020 Dec 09. pii: S2210-7762(20)30291-X. [Epub ahead of print]252-253 6-24
de Almeida LC, Calil FA, Machado-Neto JA, Costa-Lotufo LV.
Cancer genome instability arises from diverse defects in DNA-repair machinery, which make cancer cells more susceptible to DNA targeting agents. The interrelation between DNA repair deficiency and the increased effect of DNA targeting agents highlights the double-strand break (DSB) repair, which comprises the homologous recombination (HR) and non-homologous end joining (NHEJ) pathways. The DNA targeting agents are classified into two major groups: non-covalent DNA binding agents and covalent DNA-reactive agents. Although these agents have well-known limitations, such as resistance and secondary carcinogenesis risk, they are extremely important in today's real-life cancer therapy in combination with targeted therapy and immunotherapy. Indeed, DNA targeting drugs are promising therapeutics with a precise application through the background of cancer-specific DNA repair failure. In the current review, the mechanisms of action of diversified DNA-targeting agents, as well as the modulation of DNA repair pathways to increase the DNA-damaging drugs efficacy are presented. Finally, DNA-targeting-based therapies are discussed considering risks, resistance and its uses in the medicine precision era.
Keywords: Cancer; Carcinogenesis; Chemotherapy; DNA damage; DNA repair
DOI: https://doi.org/10.1016/j.cancergen.2020.12.002
Garcia-Ortega DY, Alvarez-Cano A, Clara-Altamirano MA, Martín-Tellez KS, Caro-Sánchez CHS, Ruvalcaba-Gonzalez CC, Martinez-Said H, Cuellar-Hubbe M, Luna-Ortiz K.
INTRODUCTION: Lymph node metastasis (LNM) in soft tissue sarcomas (STS) are uncommon, occurring in only 3% - 5% of all sarcomas, and are classified as Stage IV, along with distant metastasis (DM). This paper compares the prognosis of patients with lymphatic and DM, in extremity STS (eSTS).METHODS: A retrospective study was carried out in a high-volume sarcoma center; 853 patients with eSTS sarcomas were identified and classified from January 1, 1997 to December 31, 2017. Cases with pathological confirmation of LNM were included. Five-year survival rates were analyzed using the Kaplan-Meier method and the Cox proportional hazards model.
RESULTS: LNM was present in 46 of the cases (5.4%), with an overall survival of 21 months (95% confidence interval [CI], 16.7 - 25.2), compared to 18 months (95% confidence interval [CI], 14.2 - 21.7) in those with only DM. Median recurrence-free survival was 21 months (95% confidence interval [CI], 19.7 - 22.4), vs. 20 months (95% confidence interval [CI], 16.2- 23.7), respectively. LNM only and DM only had also a similar OS of 21 months (95% CI 16.7-25.2) vs 18 months (95% CI 14.2-21.7. N1M1 cases had the worse median OS with 15 months (95% confidence interval [CI], 10.9-19.7) CONCLUSIONS: Overall survival and recurrence free survival in patients with lymph node disease and metastatic disease are similar. However prognosis is worse in N1M1. Use of systemic treatment in patients with LNM is not as common as in metastatic cases, this difference in treatment and the fact that prognosis is similar suggests that both biological behavior and effect of treatment have been underestimated. A subclassification of clinical stage IV might be the next step.
Keywords: Disease-free survival; Metastatic lymph nodes; Overall survival; Soft tissue sarcoma
Clin Exp Pharmacol Physiol. 2020 Dec 21.
Sauer H, Kampmann H, Kosravi F, Sharifpanah F, Wartenberg M.
Nicotinamide phosphoribosyltransferase (NAMPT) is a rate-limiting enzyme for nicotinamide adenine dinucleotide (NAD) synthesis and is involved in cancer cell proliferation through regulation of energy production pathways. Therefore, NAMPT inhibitors are promising drugs for cancer therapy by limiting energy supply of tumours. Herein, we demonstrated that the NAMPT inhibitor FK866 ((E)-N-(4-(1-Benzoylpiperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide) dose-dependently inhibited growth and cell motility of DU-145 prostate tumour spheroids and decreased the intracellular ATP concentration. The apoptosis marker cleaved caspase-3 remained unchanged, but the autophagy marker microtubule-associated protein 1A/1B-light chain 3 (LC3) was upregulated. Growth inhibition was reversed upon co-administration of NAD to the cell culture medium. FK866 decreased calcein as well as pheophorbide A efflux from tumour spheroids and increased doxorubicin toxicity, indicating interference with function of drug efflux transporters. DU-145 multicellular tumour spheroids expressed the stem cell associated markers CD133, CD44, Oct4, Nanog, Sox2, and drug transporters ABCB1, ABCG2, and ABCC1 which are associated with stem cell properties in cancer cells. The ABCB1 inhibitor zosuquidar, the ABCG2 inhibitor Ko143, and the ABCC1 inhibitor MK571 increased calcein retention. Neither protein expression of stem cell markers, nor drug transporters was significantly changed upon FK866 treatment. In conclusion, our data suggest that FK866 inhibits prostate cancer cell proliferation by interference with the energy metabolism, and function of drug efflux transporters.
Keywords: ABCB1; ABCC1; ABCG2; autophagy; cancer stem cells; multidrug resistance; nicotinamide phosphoribosyltransferase; prostate tumour spheroid
DOI: https://doi.org/10.1111/1440-1681.13452
Front Pharmacol. 2020 ;11 596239
Dong B, Qiu Z, Wu Y.
Epithelial-mesenchymal Transition (EMT) is a de-differentiation process in which epithelial cells lose their epithelial properties to acquire mesenchymal features. EMT is essential for embryogenesis and wound healing but is aberrantly activated in pathological conditions like fibrosis and cancer. Tumor-associated EMT contributes to cancer cell initiation, invasion, metastasis, drug resistance and recurrence. This dynamic and reversible event is governed by EMT-transcription factors (EMT-TFs) with epigenetic complexes. In this review, we discuss recent advances regarding the mechanisms that modulate EMT in the context of epigenetic regulation, with emphasis on epigenetic drugs, such as DNA demethylating reagents, inhibitors of histone modifiers and non-coding RNA medication. Therapeutic contributions that improve epigenetic regulation of EMT will translate the clinical manifestation as treating cancer progression more efficiently.
Keywords: cell migration; epigenetic modification; epithelial-mesenchymal transition; inhibitor; metastasis
DOI: https://doi.org/10.3389/fphar.2020.596239
Biochim Biophys Acta Rev Cancer. 2020 Dec 17. pii: S0304-419X(20)30214-6. [Epub ahead of print] 188495
Chabot T, Cheraud Y, Fleury F.
Receptor Tyrosine Kinases (RTK) are an important family involved in numerous signaling pathways essential for proliferation, cell survival, transcription or cell-cycle regulation. Their role and involvement in cancer cell survival have been widely described in the literature, and are generally associated with overexpression and/or excessive activity in the cancer pathology. Because of these characteristics, RTKs are relevant targets in the fight against cancer. In the last decade, increasingly numerous works describe the role of RTK signaling in the modulation of DNA repair, thus providing evidence of the relationship between RTKs and the protein actors in the repair pathways. In this review, we propose a summary of RTKs described as potential modulators of double-stranded DNA repair pathways in order to put forward new lines of research aimed at the implementation of new therapeutic strategies targeting both DNA repair pathways and RTK-mediated signaling pathways.
Keywords: Cancer; DNA repair; Inhibition; Receptor tyrosine kinase
DOI: https://doi.org/10.1016/j.bbcan.2020.188495
Cell Syst. 2020 Dec 14. pii: S2405-4712(20)30463-4. [Epub ahead of print]
Aditham AK, Markin CJ, Mokhtari DA, DelRosso N, Fordyce PM.
Transcription factors (TFs) bind regulatory DNA to control gene expression, and mutations to either TFs or DNA can alter binding affinities to rewire regulatory networks and drive phenotypic variation. While studies have profiled energetic effects of DNA mutations extensively, we lack similar information for TF variants. Here, we present STAMMP (simultaneous transcription factor affinity measurements via microfluidic protein arrays), a high-throughput microfluidic platform enabling quantitative characterization of hundreds of TF variants simultaneously. Measured affinities for ∼210 mutants of a model yeast TF (Pho4) interacting with 9 oligonucleotides (>1,800 Kds) reveal that many combinations of mutations to poorly conserved TF residues and nucleotides flanking the core binding site alter but preserve physiological binding, providing a mechanism by which combinations of mutations in cis and trans could modulate TF binding to tune occupancies during evolution. Moreover, biochemical double-mutant cycles across the TF-DNA interface reveal molecular mechanisms driving recognition, linking sequence to function. A record of this paper's Transparent Peer Review process is included in the Supplemental Information.
Keywords: DNA specificity; bHLH; basic helix-loop-helix; binding affinity; conformational selection; double-mutant cycle; microfluidics; protein-DNA binding; scanning mutagenesis; transcription factor; transcriptional regulation
DOI: https://doi.org/10.1016/j.cels.2020.11.012
J Enzyme Inhib Med Chem. 2021 Dec;36(1): 307-318
Ahmed MF, Santali EY, El-Haggar R.
New piperazine-chalcone hybrids and related pyrazoline derivatives have been designed and synthesised as potential vascular endothelial growth factor receptor-2 (VEGFR-2) inhibitors. The National Cancer Institute (NCI) has selected six compounds to evaluate their antiproliferative activity in vitro against 60 human cancer cells lines. Preliminary screening of the examined compounds indicated promising anticancer activity against number of cell lines. The enzyme inhibitory activity against VEGFR-2 was evaluated and IC50 of the tested compounds ranged from 0.57 µM to 1.48 µM. The most potent derivatives Vd and Ve were subjected to further investigations. A cell cycle analysis showed that both compounds mainly arrest HCT-116 cell cycle in the G2/M phase. Annexin V-FITC apoptosis assay showed that Vd and Ve induced an approximately 18.7-fold and 21.2-fold total increase in apoptosis compared to the control. Additionally, molecular docking study was performed against VEGFR (PDB ID: 4ASD) using MOE 2015.10 software and Sorafenib as a reference ligand.
Keywords: antitumor; molecular docking; vascular endothelial growth factor receptor
J Cell Mol Med. 2020 Dec 21.
Zhang L, Ouyang P, He G, Wang X, Song D, Yang Y, He X.
microRNA-126 (miR-126), an endothelial-specific miRNA, is associated with vascular homeostasis and angiogenesis. However, the efficiency of miR-126-based treatment is partially compromised due to the low efficiency of miRNA delivery in vivo. Lately, exosomes have emerged as a natural tool for therapeutic molecule delivery. Herein, we investigated whether exosomes derived from bone marrow mesenchymal stem cells (BMMSCs) can be utilized to deliver miR-126 to promote angiogenesis. Exosomes were isolated from BMMSCs overexpressed with miR-126 (Exo-miR-126) by ultracentrifugation. In vitro study, Exo-miR-126 treatment promoted the proliferation, migration and angiogenesis of human umbilical vein endothelial cells (HUVECs). Furthermore, the gene/protein expression of angiogenesis-related vascular endothelial growth factor (VEGF) and angiotensin-1 (Ang-1) were up-regulated after incubation with Exo-miR-126. Additionally, the expression level of phosphoinositol-3 kinase regulatory subunit 2 (PIK3R2) showed an inverse correlation with miR-126 in HUVECs. Particularly, the Exo-miR-126 treatment contributed to enhanced angiogenesis of HUVECs by targeting PIK3R2 to activate the PI3K/Akt signalling pathway. Similarly, Exo-miR-126 administration profoundly increased the number of newly formed capillaries in wound sites and accelerated the wound healing in vivo. The results demonstrate that exosomes derived from BMMSCs combined with miR-126 may be a promising strategy to promote angiogenesis.
Keywords: angiogenesis; bone marrow mesenchymal stem cells; exosomes; microRNA-126
DOI: https://doi.org/10.1111/jcmm.16192
Ann Pharmacother. 2020 Dec 21. 1060028020983014
Shinn LT, Vo KA, Reeves DJ.
OBJECTIVE: To assess the clinical application of lurbinectedin and its role in the therapy of small-cell lung cancer (SCLC).DATA SOURCES: PubMed database and ClincialTrials.gov were utilized to perform a comprehensive literature search from August 2011 to mid-November 2020 with the terms lurbinectedin and PM01183.
STUDY SELECTION AND DATA EXTRACTION: English-language clinical trials of lurbinectedin were evaluated.
DATA SYNTHESIS: Lurbinectedin, as second-line therapy in SCLC, demonstrated an overall response (OR) rate of 35.2% and median overall survival of 9.3 months. Phase II studies in multiple cancers revealed myelosuppression (>95%), increased liver enzymes (>70%), nausea (up to 80%), vomiting (54%), and fatigue (>50%) as the most common adverse events associated with lurbinectedin. CYP3A4 drug interactions affect lurbinectedin exposure (severe pancytopenia occurred after coadministration with aprepitant), and protein binding can affect its clearance. Patients with cardiac comorbidities were not included in published lurbinectedin trials because of cardiotoxicity associated with trabectedin.
RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Lurbinectedin is an option in SCLC after failure of a platinum-based regimen. Dose adjustments, drug interactions, antiemetic regimen choice, and patient comorbidities are important clinical considerations with lurbinectedin use. Likewise, its place in therapy in the era of immune checkpoint inhibitors requires further exploration.
CONCLUSIONS: With a promising OR compared with other second-line options, lurbinectedin should be considered in patients who have failed first-line therapy. Studies are ongoing with lurbinectedin in combination with other agents in SCLC, and a phase III trial is assessing use in combination with doxorubicin compared with other second-line regimens.
Keywords: Zepzelca; extensive-stage; limited-stage; lurbinectedin; small-cell lung cancer
DOI: https://doi.org/10.1177/1060028020983014
Biomed Pharmacother. 2020 Dec 16. pii: S0753-3322(20)31284-1. [Epub ahead of print]134 111091
Saeed AFUH, Su J, Ouyang S.
The marine environment is an enormous source of marine-derived natural products (MNPs), and future investigation into anticancer drug discovery. Current progress in anticancer drugs offers a rise in isolation and clinical validation of numerous innovative developments and advances in anticancer therapy. However, only a limited number of FDA-approved marine-derived anticancer drugs are available due to several challenges and limitations highlighted here. The use of chitosan in developing marine-derived drugs is promising in the nanotech sector projected for a prolific anticancer drug delivery system (DDS). The cGAS-STING-mediated immune signaling pathway is crucial, which has not been significantly investigated in anticancer therapy and needs further attention. Additionally, a small range of anticancer mediators is currently involved in regulating various JAK/STAT signaling pathways, such as immunity, cell death, and tumor formation. This review addressed critical features associated with MNPs, origin, and development of anticancer drugs. Moreover, recent advances in the nanotech delivery of anticancer drugs and understanding into cancer immunity are detailed for improved human health.
Keywords: Anticancer drugs; Drug delivery system; JAK/STAT immune pathway; Marine-derived products; Nanotechnology; cGAS-STING
DOI: https://doi.org/10.1016/j.biopha.2020.111091
Biochem Pharmacol. 2020 Dec 18. pii: S0006-2952(20)30620-1. [Epub ahead of print] 114384
Adil MS, Khulood D, Somanath PR.
The uncontrolled growth and spread of abnormal cells because of activating protooncogenes and/or inactivating tumor suppressor genes are the hallmarks of cancer. The PI3K/Akt signaling is one of the most frequently activated pathways in cancer cells responsible for the regulation of cell survival and proliferation in stress and hypoxic conditions during oncogenesis. Non-coding RNAs are a large family of RNAs that are not involved in protein-coding, and microRNAs (miRNAs) are a sub-set of non-coding RNAs with a single strand of 18-25 nucleotides. miRNAs are extensively involved in the post-transcriptional regulation of gene expression and play an extensive role in the regulatory mechanisms including cell differentiation, proliferation, apoptosis, and tumorigenesis. The impact of cancer on mRNA stability and translation efficiency is extensive and therefore, cancerous tissues exhibit drastic alterations in the expression of miRNAs. miRNAs can be modulated by utilizing techniques such as miRNA mimics, miRNA antagonists, or CRISPR/Cas9. In addition to their capacity as potential targets in cancer therapy, they can be used as reliable biomarkers to diagnose the disease at the earliest stage. Recent evidence indicates that microRNA-mediated gene regulation intersects with the Akt pathway, forming an Akt-microRNA regulatory network. miRNAs and Akt in this network operate together to exert their cellular tasks. In the current review, we discuss the Akt-regulated miRNAs in several cancers, their molecular regulation, and how this newly emerging knowledge may contribute greatly to revolutionize cancer therapy.
Keywords: Akt; Biomarkers; Cancer; MicroRNAs; RNA-Therapeutics
DOI: https://doi.org/10.1016/j.bcp.2020.114384
Mol Cell Endocrinol. 2020 Dec 18. pii: S0303-7207(20)30424-X. [Epub ahead of print] 111122
Han YH, Kim HJ, Lee MO.
Nonalcoholic fatty liver diseases (NAFLDs) are characterized by excessive triacylglycerol (TAG) accumulation in the liver which contributes to hepatocyte dysfunction, inflammation, and fibrosis. Patatin-like phospholipase domain-containing 3 (PNPLA3; also known as adiponutrin) has emerged as an important enzyme leading to hepatic TAG hydrolysis. Because the I148M substitution in the PNPLA3 gene markedly reduces hepatic TAG hydrolase activity, this genetic variation is strongly associated with increased hepatic TAG in the full spectrum of NAFLDs. The Retinoic acid-related orphan receptor α (RORα) regulates various target genes related to lipid metabolism. Here, we investigated the role of RORα on PNPLA3-mediated hepatic lipid hydrolysis. With blockade of lipid esterification and β-oxidation, RORα enhanced TAG hydrolysis, resulting in increased free glycerol levels. We found a putative RORα response element on the upstream of PNPLA3 gene that was activated by RORα. Furthermore, the inhibitory action of cJUN on the RORα/PNPLA3 axis was enhanced under lipid stress and contributed to hepatic lipid accumulation. In summary, we showed for the first time that RORα activates the transcription of PNPLA3, which suggests that RORα and its ligands represent potential precision therapeutic approaches for NAFLDs.
Keywords: Lipolysis; Nonalcoholic fatty liver disease; PNPLA3; RORα; Triacylglycerol
DOI: https://doi.org/10.1016/j.mce.2020.111122
Brief Bioinform. 2020 Dec 22. pii: bbaa389. [Epub ahead of print]
Furlan M, de Pretis S, Pelizzola M.
Despite gene expression programs being notoriously complex, RNA abundance is usually assumed as a proxy for transcriptional activity. Recently developed approaches, able to disentangle transcriptional and post-transcriptional regulatory processes, have revealed a more complex scenario. It is now possible to work out how synthesis, processing and degradation kinetic rates collectively determine the abundance of each gene's RNA. It has become clear that the same transcriptional output can correspond to different combinations of the kinetic rates. This underscores the fact that markedly different modes of gene expression regulation exist, each with profound effects on a gene's ability to modulate its own expression. This review describes the development of the experimental and computational approaches, including RNA metabolic labeling and mathematical modeling, that have been disclosing the mechanisms underlying complex transcriptional programs. Current limitations and future perspectives in the field are also discussed.
Keywords: RNA degradation; RNA metabolic labeling; RNA processing; RNA synthesis; mathematical modeling; nascent RNA
DOI: https://doi.org/10.1093/bib/bbaa389
Physiol Genomics. 2020 Dec 21.
Drag MH, Kilpeläinen TO.
Circulating cell-free DNA (cfDNA) and RNA (cfRNA) hold enormous potential as a new class of biomarkers for the development of non-invasive liquid biopsies in many diseases and conditions. In recent years, cfDNA and cfRNA have been studied intensely as tools for non-invasive prenatal testing, solid organ transplantation, cancer screening, and monitoring of tumors. In obesity, higher cfDNA concentration indicates accelerated cellular turnover of adipocytes during expansion of adipose mass and may be directly involved in the development of adipose tissue insulin resistance by inducing inflammation. Furthermore, cfDNA and cfRNA have promising diagnostic value in a range of obesity-related metabolic disorders, such as non-alcoholic fatty liver disease, type 2 diabetes, and diabetic complications. Here, we review the current and future applications of cfDNA and cfRNA within clinical diagnostics, discuss technical and analytical challenges in the field, and summarise the opportunities of using cfDNA and cfRNA in the diagnostics and prognostics of obesity-related metabolic disorders.
Keywords: Cell-free DNA; cell-free RNA; diagnostics; metabolic disorders; obesity
DOI: https://doi.org/10.1152/physiolgenomics.00086.2020
Xu B, Mei J, Ji W, Huo Z, Bian Z, Jiao J, Li X, Sun J, Shao J.
Glioblastoma (GBM) is the most common primary malignant tumor in adults, and its morbidity and mortality are very high. Although progress has been achieved in the treatment of GBM, such as surgery, chemotherapy and radiotherapy, in recent years, the prognosis of patients with GBM has not improved significantly. MicroRNAs (miRNAs) are endogenous noncoding single-stranded RNAs consisting of approximately 20-22 nucleotides that regulate gene expression at the posttranscriptional level by binding to target protein-encoding mRNAs. Notably, miRNAs regulate various carcinogenic pathways, one of which is the epidermal growth factor receptor (EGFR) signaling pathway, which controls cell proliferation, invasion, migration, angiogenesis and apoptosis. In this review, we summarize the novel discoveries of roles for miRNAs targeting the factors in the EGFR signaling pathway in the occurrence and development of GBM. In addition, we describe their potential roles as biomarkers for the diagnosis and prognosis of GBM and for determining the treatment resistance of GBM and the efficacy of therapeutic drugs.
Keywords: EGFR signaling pathway; Glioblastoma; Predictive biomarkers; Treatment; microRNAs
Arch Med Res. 2020 Dec 17. pii: S0188-4409(19)30912-9. [Epub ahead of print]
Chen H, Chen J.
BACKGROUND: Osteosarcoma (OS) is commonly known as a bone malignancy, causing a mass of lethality worldwide. Long coding RNAs (lncRNAs) have been widely reported by documents that they exert important functions in the development of cancers. However, the relative mechanism of lncRNA SOX21-AS1 needs to be fully discovered in OS, as it has never been studied in the past.AIM OF THE STUDY: To find out how SOX21-AS1 materializes its function in OS.
METHODS: qRT-PCR detected RNA expression, and western blot tested the protein level. CCK8 and TUNEL assays were performed to assess cell viability and apoptosis. Next, Transwell analyses were applied to identify OS cell migration and invasion. Luciferase reporter, RIP and RNA pull-down experiments were employed for investigating the relationships among RNAs.
RESULTS: SOX21-AS1 had high expression in OS, and its presence accelerated OS cell proliferation, migration and invasion. Interestingly, we evidenced that SOX21-AS1 sponged miR-7-5p, which then targeted IRS2 in OS cells. SOX21-AS1 competed with IRS2 in binding to miR-7-5p, which formulated the ceRNA signaling in OS. SOX21-AS1 could negatively regulate miR-7-5p expression. Rescue experiments certified that the enhancement of IRS2 would neutralize the inhibition of SOX21-AS1 depletion on OS cell proliferation and metastasis.
CONCLUSIONS: SOX21-AS1 enhances IRS2 level by absorbing miR-7-5p, so as to boost the progression of OS.
Keywords: IRS2; Osteosarcoma; SOX21-AS1; miR-7-5p
DOI: https://doi.org/10.1016/j.arcmed.2020.11.007
Nucleic Acids Res. 2020 Dec 21. pii: gkaa1219. [Epub ahead of print]
Frigola J, Sabarinathan R, Gonzalez-Perez A, Lopez-Bigas N.
An abnormally high rate of UV-light related mutations appears at transcription factor binding sites (TFBS) across melanomas. The binding of transcription factors (TFs) to the DNA impairs the repair of UV-induced lesions and certain TFs have been shown to increase the rate of generation of these lesions at their binding sites. However, the precise contribution of these two elements to the increase in mutation rate at TFBS in these malignant cells is not understood. Here, exploiting nucleotide-resolution data, we computed the rate of formation and repair of UV-lesions within the binding sites of TFs of different families. We observed, at certain dipyrimidine positions within the binding site of TFs in the Tryptophan Cluster family, an increased rate of formation of UV-induced lesions, corroborating previous studies. Nevertheless, across most families of TFs, the observed increased mutation rate within the entire DNA region covered by the protein results from the decreased repair efficiency. While the rate of mutations across all TFBS does not agree with the amount of UV-induced lesions observed immediately after UV exposure, it strongly agrees with that observed after 48 h. This corroborates the determinant role of the impaired repair in the observed increase of mutation rate.
DOI: https://doi.org/10.1093/nar/gkaa1219
Front Genet. 2020 ;11 595550
Wang Y, Li J, Li J, Li P, Wang L, Di L.
Cancer is characterized by dysregulation at multiple levels, such as gene transcription. Enhancers are well-studied transcription regulators that can enhance target transcripts through DNA loop formation mediated by chromosome folding. The gain or loss of the interaction between an enhancer and its target gene has a critical effect on gene expression. In this study, we analyzed GRO-seq data to identify active enhancers from seven common cancer cell lines and studied the function of these enhancers across multiple cancer types. By constructing an "enhancer effect score" (EES), we found a significant correlation between EES and tumor-infiltrating lymphocytes (TILs) in prostate cancer. Further analysis revealed that androgen receptor (AR) plays an important role in regulating the immune checkpoint gene PVR via its enhancer. These results suggest that AR contributes to prostate cancer aggressiveness by promoting cancer cell immune evasion.
Keywords: GRO-seq; androgen receptor; enhancer; immune evading; prostate cancer
DOI: https://doi.org/10.3389/fgene.2020.595550
Badkas A, De Landtsheer S, Sauter T.
Drug repositioning has received increased attention since the past decade as several blockbuster drugs have come out of repositioning. Computational approaches are significantly contributing to these efforts, of which, network-based methods play a key role. Various structural (topological) network measures have thereby contributed to uncovering unintuitive functional relationships and repositioning candidates in drug-disease and other networks. This review gives a broad overview of the topic, and offers perspectives on the application of topological measures for network analysis. It also discusses unexplored measures, and draws attention to a wider scope of application efforts, especially in drug repositioning.
Keywords: computational methods; drug repositioning; networks; topological network measures; topology
Transl Oncol. 2020 Dec 15. pii: S1936-5233(20)30475-7. [Epub ahead of print]14(2): 100983
Younes AI, Barsoumian HB, Sezen D, Verma V, Patel R, Wasley M, Hu Y, Dunn JD, He K, Chen D, Menon H, Masrorpour F, Gu M, Yang L, Puebla-Osorio N, Cortez MA, Welsh JW.
Radiotherapy (RT) has been used to control tumors by physically damaging DNA and inducing apoptosis; it also promotes antitumor immune responses via neoantigens release and augmenting immune-oncology agents to elicit systemic response. Tumor regression after RT can recruit inflammatory cells, such as tumor-associated macrophages and CD11b+ myeloid cell populations, a major subset of which may actually be immunosuppressive. However, these inflammatory cells also express Toll-like receptors (TLRs) that can be stimulated to reverse suppressive characteristics and promote systemic antitumor outcomes. Here, we investigated the effects of adding CMP-001, a CpG-A oligodeoxynucleotide TLR9 agonist delivered in a virus-like particle (VLP), to RT in two murine models (344SQ metastatic lung adenocarcinoma and CT26 colon carcinoma). High-dose RT (12Gy x 3 fractions) significantly increased the percentages of plasmacytoid dendritic cells within the tumor islets 3- and 5-days post-RT; adding CMP-001 after RT also enhanced adaptive immunity by increasing the proportion of CD4+ and CD8+ T cells. RT plus CMP-001-mediated activation of the immune system led to significant inhibition of tumor growth at both primary and abscopal tumor sites, thereby suggesting a new combinatorial treatment strategy for systemic disease.
Keywords: Abscopal effect; CMP-001; Cancer; Radiotherapy; TLR9 agonist
DOI: https://doi.org/10.1016/j.tranon.2020.100983
Xu J, Kudron MM, Victorsen A, Gao J, Ammouri HN, Navarro FCP, Gevirtzman L, Waterston RH, White KP, Reinke V, Gerstein M.
Chromatin immunoprecipitation (IP) followed by sequencing (ChIP-seq) is the gold standard to detect transcription-factor (TF) binding sites in the genome. Its success depends on appropriate controls removing systematic biases. The predominantly used controls, i.e. DNA input, correct for uneven sonication, but not for nonspecific interactions of the IP antibody. Another type of controls, 'mock' IP, corrects for both of the issues, but is not widely used because it is considered susceptible to technical noise. The tradeoff between the two control types has not been investigated systematically. Therefore, we generated comparable DNA input and mock IP experiments. Because mock IPs contain only nonspecific interactions, the sites predicted from them using DNA input indicate the spurious-site abundance. This abundance is highly correlated with the 'genomic activity' (e.g. chromatin openness). In particular, compared to cell lines, complex samples such as whole organisms have more spurious sites-probably because they contain multiple cell types, resulting in more expressed genes and more open chromatin. Consequently, DNA input and mock IP controls performed similarly for cell lines, whereas for complex samples, mock IP substantially reduced the number of spurious sites. However, DNA input is still informative; thus, we developed a simple framework integrating both controls, improving binding site detection.


text:
Q: Excel file not opening in sharepoint 2013 I am using SP2013 & created a site. I have used document library to store the documents in my site but the excel documents doesn't open it shows this error:-   "We're sorry. We run into a problem please try again in sometime "
I don know why ! the word & pdf documents open normally. What shall I do ?

A: Can you check the advanced settings for your library? See if the library is configured to open documents in browser by default. If it is switch it to "Open in client application by default" which would fix the issue for time being.
For a proper fix you need to get ULS logs for the error and try to find the root cause there.

redpajama_set_name: RedPajamaStackExchange


text:
'use strict'

/* npm modules */
const defined = require('if-defined')
const httpError = require('immutable-app-http-error')
const httpRedirect = require('immutable-app-http-redirect')

/* application modules */
const loadRecordForUpdate = require('./load-record-for-update')

/* exports */
module.exports = initModelDelete

/**
 * @function initModelDelete
 *
 * delete record controller
 *
 * @param {object} args
 */
function initModelDelete (args) {
    var controller = this
    var model = this.model
    // if model does not have delete action then do not add
    if (!defined(model.columns.d)) {
        return
    }
    // if model does not have id column then cannot use default controller
    if (!model.columnName('id')) {
        return
    }
    // get accountId column
    var accountIdColumn = model.columnName('accountId')
    // set role to authenticated if model requires account id
    var role = args.defaultRole || (accountIdColumn && model.columns[accountIdColumn].null === false ? 'authenticated' : 'all')
    // index inputs
    var input = {
        // get current revision of record
        current: 'query.current',
        // get record even if deleted
        deleted: 'query.deleted',
        // ignore conflicts
        force: 'query.force',
        // record id
        id: 'params.id',
        // add option to set meta data for query
        meta: 'query.meta',
        // url to redirect to when done
        redirect: 'params.redirect',
        // http referrer
        referrer: 'headers.referer',
    }
    // record data is in body under model name
    input[model.name] = 'body.'+model.name
    // create path if it does not exist
    if (!defined(this.paths['/:id'])) {
        this.paths['/:id'] = {}
    }
    if (!defined(this.paths['/:id/delete'])) {
        this.paths['/:id/delete'] = {}
    }
    if (!defined(this.paths['/:id/undelete'])) {
        this.paths['/:id/undelete'] = {}
    }
    // add handler for GET /:id/delete and DELETE /:id to delete
    this.paths['/:id'].delete = this.paths['/:id/delete'].get = [
        {
            before: function (args) {
                // load record
                return loadRecordForUpdate(controller, args)
            },
            input: input,
            method: function (args) {
                // perform delete
                return deleteMethod(controller, 'delete', args)
            },
            role: role,
            methodName: 'delete',
        },
    ]
    // add handler for GET and POST /:id/undelete to undelete
    this.paths['/:id/undelete'].get = this.paths['/:id/undelete'].post = [
        {
            before: function (args) {
                // load record
                return loadRecordForUpdate(controller, args)
            },
            input: input,
            method: function (args) {
                // perform undelete
                return deleteMethod(controller, 'undelete', args)
            },
            role: role,
            methodName: 'undelete',
        },
    ]
}

/**
 * @function deleteMethod
 *
 * perform model action
 *
 * @param {ImmutableCoreController} controller
 * @param {string} actionName
 * @param {object} args
 *
 * @returns {Promise}
 */
function deleteMethod (controller, actionName, args) {
    // get model from controller
    var model = controller.model
    // get record loaded in before
    var record = args[`${model.name}Orig`]
    // perform action
    return record[actionName]()
    // do response
    .then(record => {
        // if request is in json mode the return record data
        if (args.json) {
            return record
        }
        // otherwise redirect
        else {
            // redirect url is either eplicity passed, from http referrer,
            // or to record url
            var url = args.redirect || args.referrer || '../'
            // do 302 redirect
            return httpRedirect(url)
        }
    })
    // catch errors
    .catch(err => {
        // throw 409 on duplicate key error
        if (record.isConflictError(err)) {
            // get current instance
            return record.current()
            // throw 409 conflic error with current instance data
            .then(current => {
                // check if current defined
                record.assert(defined(current), 'could not fetch current')
                // if in json mode return error with data
                if (args.json) {
                    httpError(409, undefined, current)
                }
                // otherwise redirect to current instance
                else {
                    httpRedirect(`../${current.id}?error=conflict`)
                }
            })
        }
        // throw original error
        else {
            throw err
        }
    })
}

redpajama_set_name: RedPajamaGithub


text:
Бон-Жезус-ду-Галью ()  —  муниципалитет в Бразилии, входит в штат Минас-Жерайс. Составная часть мезорегиона Вали-ду-Риу-Доси. Входит в экономико-статистический  микрорегион Каратинга. Население составляет 15 178 человек на 2006 год. Занимает площадь 590,971 км². Плотность населения — 25,7 чел./км².

История
Город основан 31 декабря 1943 года.

Статистика
 Валовой внутренний продукт на 2003 составляет 36.046.313,00 реалов (данные: Бразильский институт географии и статистики).
 Валовой внутренний продукт на душу населения на 2003 составляет 2.305,64 реалов (данные: Бразильский институт географии и статистики).
 Индекс развития человеческого потенциала на 2000 составляет 0,657 (данные: Программа развития ООН).

География
Климат местности: горный тропический.

Муниципалитеты штата Минас-Жерайс

redpajama_set_name: RedPajamaWikipedia


A number of years ago, the National Catholic Education Association entered onto a project to see what exactly priests, and especially pastors, do all day. The idea was that if they could determine what priests/pastors are called upon to do in their ministry, they could use this information to form courses within the seminary in order to better and more practically prepare seminarians for the practical aspects of their vocations.
The result of the study was In Fulfillment of their Mission. Incidentally, the study found that priest/pastors have 9 major areas of responsibility, each having between 6 – 11 tasks cross-graded by 5 different competency levels (from novice to expert). Thus an experienced priest/pastor could, theoretically, be responsible for almost 365 individual tasks, a seemingly daunting resume.
Actually, no person could do this task and no seminary-training program can prepare anyone for this scope of responsibility. Thus it is incumbent on the priest, after ordination, to make sure that he engages in some type of "on-going formation" in order to keep his skills up to date. Guidelines for this idea of "on-going formation" were originally proposed by Pope John Paul II in his 1992 document I Will Give You Shepherds. In the year 2000, US Bishops Conference published further, more detailed guidelines in their document, The Basic Plan for Ongoing Formation for Priests.
Recently, Mark Oppenheimer of the New York Times published an article entitled, "Helping Catholics by Teaching Priests How to Be the Boss." It reported on a retreat/workshop for pastors sponsored by the Leadership Roundtable on Church Management. The "Leadership Roundtable" which was founded in 2005 by lay Catholics to offer leadership expertise to the Catholic Church. The group is now active in about two-thirds of the 195 American dioceses.
Hiring, evaluating, coaching, and inspiring members of your parish team.
Each chapter is written by experts, both clergy and lay, with years of experience and leadership in their respective field.
I was associated with the "Roundtable" while Chaplain at the Penn Newman Center and got to meet a number of its members and see their work close up. They are a valuable gift to the Church and their work is providential. Personally I never attended this workshop but I know priests who have and have found the experience rewarding, helpful, hopeful and stimulating.
For pastors, CLI offers their "Good Leaders – Good Shepherds" model, which is a "world class curriculum… by which priests can minimize the frustration and energy that they spend on their administrative roles, and instead, maximize the joy and time spent on the pastoral duties for which they were uniquely ordained." A similar curriculum, entitled "Tending the Talents," exists for parish and diocesan leaders in their own unique role in ministry.
In 2007, I was invited by our own Matt Manion (President and CEO of CLI) to participate in a focus group, which was rewriting the curriculum for "Good Leaders-Good Shepherds." It was one of the most rewarding and helpful endeavors I have had in 20 years of priesthood. Along with CLI, "The Roundtable" and the "Pastors Toolbox," numerous high-quality, professional resources are being developed for the church to help them in addressing the challenges of the New Evangelization.


text:
Q: How to make a 2D array thread-safe? So I have a 2D array which will have moving Objects from one index to another index eg from index A - B. During the move no other Objects can be stored inside A or B.
Originally I was thinking to use ReentrantLocks but i'm apparently not allowed to. I was also worried about a performance bottleneck if every square had their own Lock.
Then I though about using AtomicReferences but it didn't seem to give me the functionality I was hoping for as I need a way to check to see if either of the indexes of the array are occupied.
One way I thought of would be to use a mutex.
But I got a bit confused on how I could use this mutex to lock specific indexes of an Array at a time.
If I was to use a mutex, this was how I was thinking.
So in this example I have an array of Objects, where each object will have their own synchronized set method. The object will be shown below.
public class ExampleObject {
    private Object monitor = new Object();
    private StoredObject storedObject;

    public void set(StoredObject inStoredObject) {
        boolean setStatus = false;
        synchronized (mutex) {
            if (storedObject == null) {
                storedObject = inStoredObject;
                setStatus = true;
            }
        }
        return setStatus;
    }

    public StoredObject get() {
        synchronized (mutex) {
            return storedObject;
        }
    }

    public void clear() {
        synchronized (mutex) {
            storedObject = null;
        }
    }
}

I had to check if the StoredObject is null as I don't want the StoredObject to be set if one already exists.
So I added the clear method as my idea was that if a StoredObject is moving from Index A -> B. It could leave a Copy of itself inside A and remove itself from A when it is successfully inside B (as transmission isn't instantaneous and takes 500 ms).
I am allowed to use Blocking Queues, monitors and volatile.


text:
Dental Practice Management Software
Hospital Information Software (HIS)
Radiology Information Software (RIS)
Case Management and Recruitment
Laboratory Information Software (LIS)
Cost effective and modern Medical Practice Management Software to manage patient, billing, health services and clinical data life cycle
The medical practice management software is core module of the Enterprise Resource Planning (ERP) software, a lightweight software designed to have small memory footprint (RAM usage) and low CPU usage, overall a low usage of system resources as a result of simple design and architecture.
Real-time processing, flexible workflow and robust automation are the elements of the medical practice management software to support broad range of use cases, business processes alignment and true flexible software implementation.
Applications and Modules
Minerva Data ERP covers a wide range of applications and provide sufficient resources to automate any business process in the following domains:
Patient Demographic
Patient Socioeconomic
Patient Evaluation
Patient Family History
Patient Vital Sign
Patient Diagnoses
Patient Medication
Patient Prescription
Patient Ophthalmology
Patient Pregnancies
Patient Certificates
Patient Insurance
Patient Communications
Patient Lab Requests
Patient Radiology Requests
Patient Insurance and Invoices
Payments, Receipts and Cash vouchers
Tax and currency managements
Recruitment and case management
Attendance and electronic signature
Payroll and payslips
Bill of materials (BoM)
Product life cycle management
Since 2006, we have been developing the medical practice management software to reflect our health professionals needs and requirements to include advanced and robust features to simplify and automate the workforce management for any medical centre, clinic or health care provider.
Patient Reporting and Dashboard
The medical practice patient management software is interactive and utilise modern web technology to present the patient medical records to the health professionals over the web in a secure environment.
Vital health and medical documents, health insurance, diagnosis and many more modules are seamlessly integrated with the patient record, one place to manage all the patient information.
Obstetrics and Gynecology (OB/GYN)
Minerva Data medical practice management software has a comprehensive obstetrics and gynecology (OB/GYN), pregnancy modules, fetal assessments, Induction and labour, delivery plans and antenatal management.
The obstetrics and gynecology (OB/GYN) module, is equipped with extensive capability to identify, diagnose and manage fetal weights, fetal growth and the Intrauterine growth restriction (IUGR).
Newborns and the APGAR (Appearance, Pulse, Grimace, Activity and Respiration) Score
Minerva Data medical practice management software has built in methodology and complete module to manage the APGAR score with the following measure:
Apgar score rate
Reflexes and responsiveness
Muscle tone
Breathing rate
Health and Medical Calendar, Appointment and Notification
Minerva Data medical practice management software has built in easy to use and intuitive calendar, appointment and SMS, Email and mobile notifications, to ensure interactive engagement among patients, health professionals and the medical clinics.
Prescription Medicine, Medicament and Medication
Minerva Data medical practice management software comes with built in prescription medicine, medicament and medication functions and procedures, easy to use and automated, medicament pregnancy warning and vaccine integration is one feature of the practice.
HL7 capable Medical Practice Management Software
Health Level Seven international (HL7) refers to a set of international standards for transfer of clinical and administrative data between software applications used by various healthcare providers.
Minerva Data medical practice management software implements the HL7 interface engine.
HL7 capable medical practice management software and Health Solutions and software enable health institutions to communicate and share patient information reliably and securely over the internet network.
ICD compliant Medical Practice Management Software
International Statistical Classification of Diseases and Related Health Problems (ICD) allows the systematic recording, analysis, interpretation and comparison of mortality and morbidity data collected in different countries or regions and at different times.
Minerva Data Electronic medical practice management software complies with the World Health Organisation (WHO) International Classification of Diseases (ICD) and Procedures and the International Health Regulations (IHR).
Simple design and mobile first modules
Minerva Data adopts responsive web design to make the medical practice management software pages to fit the screens of different devices automatically, displaying the content in a way that people feel comfortable, this capability reduces users' operations like panning, zooming and scrolling when using the different modules and pages in the ERP to ensure usability and satisfaction all time.
The medical practice management software is based on simple technology architecture to ensure high level of flexibility and scalability, the simple architecture contributes to more secure services, faster implementation and higher portability across different platforms.
The following diagram describes Minerva Data digital service high level architecture and the standard cloud service deployment on Amazon Web Services (AWS).
Elastic Load Balancing
Elastic Load Balancing (ELB) automatically distributes the incoming traffic across multiple application servers and IP addresses in more availability zones, ELB monitors the health of its registered targets, and routes traffic only to the healthy targets and scales the load balancer capacity automatically in response to changes in incoming traffic.
Minerva Data ELB distributes workloads across multiple compute resources to increases the availability and fault tolerance of the web services and cloud products.
Elastic Computing Resources
Minerva Data uses scalable computing capacity in the cloud to scale up and handle changes in requirements or spikes in popularity, reducing any down time due to heavy loads on the cloud services.
Multi-Deployment Relational Database
Minerva Data deploys primary databases and synchronously replicates the data to different databases in different locations, when database failure detected, Minerva Data services automatically failover with automatic database failover that completes as quickly as 60 seconds with zero data loss and no manual intervention.
Minerva Data digital services provide Web APIs Application Programming Interface (API) endpoints to integrate with other digital services by publishing and consuming events on the API's endpoints.
Web APIs are services accessed from client devices (Desktop, Server, Mobile Phone, Laptop, etc.) using the secure Hypertext Transfer Protocol (HTTPs), Minerva Data Web APIs are RESTful and implements the standard GET and POST. HTTP requests are used to access data or resources in the web application via URL-encoded parameters. Responses are generally formatted as either JSON or XML to transmit the data
Minerva Data has more than 1,300 API's endpoints to enable robust and asynchronous integration, with HTTPs requests made to a resource located on the server using the Unique Resource Identifier (URI) to receive the payload formatted in JavaScript Object Notation (JSON), this type of communication ensures fast performance, reliability, and the ability to scale end extend the digital services capabilities without affecting the system at run time.
Minerva Data implements a secure unified communication system to deliver notification to the system users, all communication messages are captured by the system audit trail.
Application Instant Messages via secure WebSocket protocol, WebSocket protocol was standardised by the IETF as RFC 6455 in 2011;
Email Services via TLS/SSL based communication with encrypted data;
SMS with encrypted data; and
Web Push Notification with encrypted data based on the Voluntary Application Server Identity Key (VAPID).
Protect the medical practice management software
Minerva Data implements NIST Cybersecurity Framework (NIST CSF) to protect all cloud services regardless of the technology used to power these services.
Created and established by the US National Institute of Standards and Technology (NIST), the framework addresses the lack of standards when it comes to cybersecurity and provides a uniform set of rules, guidelines, and standards for organisations to use across industries.
NIST Cybersecurity Framework is widely considered to be the gold-standard for building a cybersecurity program, by acting as a top-level security management tool that helps assess cybersecurity risk across the organisation.
NIST cybersecurity framework is a powerful framework to organise and improve Minerva Data cybersecurity program. Comprehensive guidelines and best practices to help our engineers to build and improve our cybersecurity state. The framework puts forth a set of recommendations and standards that enable us to be better prepared in identifying and detecting cyber-attacks, and also provides guidelines on how to respond, prevent, and recover from cyber incidents.
Minerva Data implements the 5 Core Functions of NIST Cybersecurity Framework as per the following section.
Medical Practice Management Software Cybersecurity Identification
Since 2006 and before the NIST time, Minerva Data has developed the following to identify the digital assets to be protected:
Robust Configuration Management Database (CMDB) for all data, personnel, devices, systems, and facilities that enables the digital services to achieve business purposes are identified and managed consistent with their relative importance to business objectives and our risk strategy.
Awareness of the business environment, Minerva Data motivation and mission, objectives, stakeholders, and activities are identified and prioritised; to inform Minerva Data cybersecurity roles, responsibilities, and risk management decisions.
Clear governance with the associated policies, procedures, and processes to manage and monitor Minerva Data legal, risk, and operational requirements to inform the management of cybersecurity risk.
Comprehensive Risk Assessment contributed to the understanding of the cybersecurity risk to the corporate and customers operations, including the significant impact on the clinical data and patient health and safety; and
Risk Management Strategy to support long term risk decisions.
Medical Practice Management Software Cybersecurity Protection
Minerva Data developed and implemented the following safeguards to ensure delivery of critical infrastructure services to our customers:
Fine-tuned permission and access control to ensure access to digital assets and associated facilities is limited to the authorised staff of Minerva Data;
Awareness and training program, Minerva Data personnel and partners are provided cybersecurity awareness education and information security-related induction;
Data Security: Health, clinical and Patient Information and records are managed consistent with Minerva Data risk strategy to protect the confidentiality, integrity, and availability of information.
Processes and procedures to maintain and manage the protections of information systems and digital assets; and
Robust technology to ensure the security and resilience of systems, consistent with Minerva Data policies, procedures, and agreements.
Medical Practice Management Software Cybersecurity Detection
To identify the occurrence of any cybersecurity event on our digital services, Minerva Data has developed and implemented the following activities:
Anomalies and Events Detection, to detected in a timely manner and to forecast the potential impact of events.
Security Continuous Monitoring on all Minerva Data cloud instances; and
Detection processes testing to verify the effectiveness of protective measures including network and physical activities.
Medical Practice Management Software Cybersecurity Response
Minerva Data has developed and implemented the following to respond to any detected cybersecurity incident:
Response Plan, automated ITIL based set of action to execute and maintain related processes and procedures to ensure timely response to detected cybersecurity events.
Robust Communications Channel with internal and external stakeholders to inform the cybersecurity events;
Mitigation activities to prevent expansion of the cybersecurity incident;
Improvements knowledge base to incorporate lessons learned from current and previous response activities.
Medical Practice Management Software Cybersecurity Recovery
In the case of successful cybersecurity attack and upon the compromise of any digital services, Minerva Data has developed and implemented appropriate activities to restore any capabilities or services that were impaired as per the following:
Recovery Plan, processes and procedures to be executed and maintained to ensure timely restoration of systems or assets affected by cybersecurity events.
Data Security, Isolation and Data Encryption
Minerva Data encrypts and digitally signs server-side data stored at rest and extends to the automated backups, read replicas, and snapshots, the signing operations using asymmetric key pairs to validate digital signatures and securely generate hash-based message authentication codes (HMACs) that ensure message integrity and authenticity.
Minerva Data cloud computing resources protected by security groups act as a firewall to control inbound and outbound traffic at the lowest computing level.
Minerva Data uses the industry standard AES-256 encryption algorithm to encrypted customer data.
Enhanced Technical Support
Business hours web access to Minerva Data Cloud Service Desk and Support Centre
1 case per month with 1 primary contact
24/7 web, and chat access to Minerva Data Cloud Service Desk and Support Centre
10 cases per month with 1 primary contact
Standard Priority
24/7 web, and chat access to Service Desk and Support Centre
Unlimited cases and unlimited contacts
Critical Priority
Case Severity / Response Times
General guidance < 48 hours
System impaired < 24 hours
System impaired < 6 hours
General guidance < 3 hours
System impaired < 1 hour
Business/Mission-critical system down < 15 minutes
Incident Resolution Time
System incident < 72 hours after the Response Time
All service and system incidents < 1 hour after the Response Time
Programmatic Case Management
Minerva Data ITSM Self-service only
ITSM Self-service only
ITSM Self-service
ITSM Service Calls
ITSM Change Management
ITSM API's
Service Integration and Third-Party Software Support
3 Hours per month
APIs Integration
30 Hours per month
Access to Minerva Data self-paced education portal
3 Hours online training session per month up to 10 users
20 Hours online training session per month up to 30 users
No cost option
$15 per user per month
Minimum 10 users
What is the Medical Practice Management Software?
The Medical Practice Management Software is a computer and electronic application and system empowers the health professionals to manage patient, billing, health services and clinical data life cycle with the capability of managing the medical and patient demographics, vital records, medical appointments, health insurance payors, invoices, billings and generate medical reports.
Who can use the Medical Practice Management Software?
The Cloud and Web based Medical Practice Management System can be used by the following audiences
Medical Centres
Health Professional
How much does the Cloud and Web based Medical Practice Management Software Cost?
The cost of the Cloud and Web based Medical Practice Management System is user based with the following cost schema as per the pricing page.
What is the user and who can be classified as user?
The user is any health professional has active account in the Cloud and Web based Medical Practice Management Software.
Do you count the patient who access the Online Medical Imaging and Radiology and the Online Medical Laboratory Results as a user?
No, any health institution, Clinic or the Medical Centre can have unlimited number of patients with active accounts without license and no cost associated.
Since 2006, Minerva Data has connected health professionals, doctors, general practitioners (GP) and medical clinics and centres with their patients through modern, cost effective and advanced digital services.
Our Electronic Medical Record (EMR), Radiology Information Software (RIS), Laboratory Information Software (LIS), Hospital Information Software (HIS) and Dental Practice Software and System have been widely adopted by regional and local health care providers.
Our software design and architecture simple approach and philosophy have contributed to the productivity and satisfaction of the health professionals and the medical staff who use Minerva Data software and services on daily basis.
We have become the strategic and trusted digital health service provider for local and regional health care providers to manage sensitive medical records and patients critical data in secure and reliable environment.
Minerva Data © 2022

redpajama_set_name: RedPajamaCommonCrawl


bigstrads wrote: Allocated my team................but heres my thinking now.
As I now look at it from a fantasy perspective, Im looking at the free agent list and I want to make LOADS of changes, because I picked from a team point of view, not a fantasy point of view.
For instance, no-one picked Dungleavy, Zach Randolph, Charlie V and many others because they werent good for team chemistry and other reasons...........but they are all going to have very good fantasy seasons............I wish wed have just done this as a fantasy game from the start, as then I wouldnt have bothered.
Whatever, Im just probably gonna leave this one alone and not bother swapping and changing all about.
Yeah, whatever, just another fantasy game...............I like that there isnt any bench spots, as atleast then I wont have to check it and swap players to being active every day.
Its just that I would have drafted VERY differently if Id have known it was going to end up like this.................wouldnt have gone so quirky and extreme.
Im just gonna leave it all year (unless someone gets horribly injured) and prove all the doubters wrong about my team!
First up to feel the wrath of my defensive juggernaught = TMC.
bigstrads wrote: First up to feel the wrath of my defensive juggernaught = TMC.
Great. Considering your offensive capabilities, I'll win 2-0.
You know what, I still have no idea how to score points (fantasy points I mean).............I still dont know how it works.
From the explanations Ive had, my understanding is that its ranked, so whoever's player had the most points gets a certain amount of points for that, and then staggered down.............and the same for every other catagory.
Is that right or have I got it COMPLETELY wrong? it might that I know how to actually score points I suppose.
We compete in several categories: points, rebounds, assists, steals, blocks, fg%... The one that has the biggest amount in each category, wins it (except steals, of course). The one that wins more categories, wins the weekly matchup.
Hmmmm, ok, I understand that................so you could have the highest scoring, 3 making, fg%, ft% players.........and I may have the highest rebounds, blks, stls.
I presume its a combined accumilation between all players active, is it decided who wins each catagory daily, then added up at the end of the week?
Thanks by the way for finally making me understand it.
Now y'all know why my teams might be a little off!!! because I had no idea really what I was looking for.
bigstrads wrote: is it decided who wins each catagory daily, then added up at the end of the week?
All the stats are added up during the whole week and the winner is decided after the last day of the week, not daily.
bigstrads wrote: Now y'all know why my teams might be a little off!!! because I had no idea really what I was looking for.
Don't worry, Bigs. I don't really care about fantasy drafting, anyway. I draft guys I like, and pass on great fantasy players that I dislike. That's why I never win in fantasy, I guess.
Cool, thanks alot man, think Ive got it now..............finally!!! youd think after drafting and commiting myself to 5 teams, that Id actually know what I was doing.
Well, it all starts tomorrow, should be a fun little extra thing for the season.
It isn't perfect, but it returns better results than standard leagues as far as who is performing better in the league. For instance, fantasy ranks Howard as the 77th best player overall but in real life we know is he is MUCH more valuable than that. I think in this system he comes out in the top 12 or so - still not a true value but closer to reality. Over the past years the best performers have been closer to who won the league MVP than in any other scoring system.
Not saying we should do it, but I just thought it'd be worth putting out there.
I keep seeing the stat lines next to players get filled up with infor during and right after games...............but then they are cleared, arent these supposed to stay? so we can see whos doing what in a total sense, or is it just there whilst and just after games are happening?
Id like to be there constantly, so I can see whos doing what.
The line that appears on your team screen next to the players name are the stats for the day. As you change to another day, the line is, obviously, cleared (or filled with the stats for that day, if we're talking about a previous one). You can change the day by clicking on a different one in the lineup line, right above stats.
If, instead, you want to see the accumulated stats, you can do so in the matchup screen.
Jeez..........now wasting a post is gay to you TMC, you see gay in everything!!!..........you need help bud.
And you may not call me gay because that answers my question and I now see what I want to see..........so thank you Mr TryingtogetoutofMyCloset.
Ps: Its ok man, we all understand, most of us are accepting, free thinking people.........its ok to admit it, we'll still like you.