tbuckley/cabot-search huggingface dataset:
Chronic lymphocytic leukemia: 2017 update on diagnosis, risk stratification, and treatment
Authors: Michael Hallek
Journal: American Journal of Hematology (2017)

Chronic lymphocytic leukemia (CLL) is the commonest leukemia in western countries. The disease typically occurs in elderly patients and has a highly variable clinical course. Leukemic transformation is initiated by specific genomic alterations that impair apoptosis of clonal B cells.The diagnosis is established by blood counts, blood smears, and immunophenotyping of circulating B lymphocytes, which identify a clonal B-cell population carrying the CD5 antigen and B-cell markers.Two prognostic staging systems exist, the Rai and Binet staging systems, which are established by physical examination and blood counts. Various biological and genetic markers also have prognostic value. Deletions of the short arm of chromosome 17 (del(17p)) and/or mutations of the TP53 gene predict resistance to available chemotherapies. A comprehensive prognostic score (CLL-IPI) using genetic, biological, and clinical variables has recently been developed allowing to classify CLL into very distinct risk groups.Patients with active or symptomatic disease or with advanced Binet or Rai stages require therapy. For physically fit patients, chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab remains the current standard therapy. For unfit patients, currently available evidence supports two options for a first-line therapy: chlorambucil combined with an anti-CD20 antibody (obinutuzumab or rituximab or ofatumumab) or a continuous therapy with ibrutinib. At relapse, the initial treatment may be repeated, if the treatment-free interval exceeds 3 years. If the disease relapses earlier, therapy should be changed using alternative agents such as bendamustine (plus rituximab), alemtuzumab, lenalidomide, ofatumumab, ibrutinib, idelalisib, or venetoclax. Patients with a del(17p) or TP53 mutation can be treated with ibrutinib, venetoclax, or a combination of idelalisib and rituximab. An allogeneic SCT may be considered in relapsing patients with TP53 mutations or del(17p) or patients that are refractory to chemoimmunotherapy and the novel inhibitors.The new agents (ibrutinib, idelalisib, venetoclax, and obinutuzumab) hold the potential to significantly improve the outcome of CLL patients. However, their optimal use (in terms of combination, sequence, and duration) remains unknown. Therefore, CLL patients should be treated in clinical trials whenever possible.
Abstract 300: Protein Kinase G Positively Regulates Proteasome-mediated Degradation of Misfolded Proteins
Authors: Mark J Ranek, Erin J Terpstra, Jie Li, David A Kass, Xuejun Wang
Journal: Circulation Research (2013)

Objectives: Proteasome functional insufficiency is implicated in a large subset of cardiovascular diseases and may play an important role in their pathogenesis, evidenced by increased protein aggregates and ubiquitinated proteins. The regulation of proteasome function is poorly understood, hindering the development of effective strategies to improve proteasome function. We sought to establish the role of protein kinase G (PKG) in these debilitating conditions, for which there is currently no cure. Methods and Results: PKG was manipulated genetically and pharmacologically in cultured cardiomyocytes. Activation of PKG increased proteasome peptidase activities, facilitated proteasome-mediated degradation of surrogate (GFPu) and bona fide misfolded proteins (CryABR120G), and attenuated CryABR120G overexpression-induced accumulation of ubiquitinated proteins and cellular injury. PKG inhibition elicited the opposite responses. Differences in the abundance of the key 26S proteasome subunits Rpt6 and β5 between PKG manipulated and the control groups were not statistically significant, but the isoelectric points of were shifted by PKG activation. In transgenic mice expressing a surrogate substrate (GFPdgn), PKG activation by sildenafil increased myocardial proteasome activities and significantly decreased myocardial GFPdgn protein levels. Sildenafil treatment significantly increased myocardial PKG activity and significantly reduced myocardial accumulation of CryABR120G, ubiquitin conjugates, and aberrant protein aggregates in mice with CryABR120G-based desmin-related cardiomyopathy. No discernible effect on bona fide native substrates of the ubiquitin-proteasome system was observed from PKG manipulation in vitro or in vivo. Conclusions: PKG positively regulates proteasome activities and proteasome-mediated degradation of misfolded proteins likely through posttranslational modifications to proteasome subunits. Improved protein quality control is liekly a new mechanism underlying the benefit of PKG stimulation in treating cardiac diseases. Stimulation of PKG by measures such as sildenafil administration is potentially a novel therapeutic strategy to treat cardiac proteinopathies.
Anti-tumor activity of TAK-659, a dual inhibitor of SYK and FLT-3 kinases, in AML models.
Authors: Jie Yu, Jessica Huck, Matthew Theisen, Helen He, Stephen Tirrell, Mengkun Zhang, Karuppiah Kannan
Journal: Journal of Clinical Oncology (2016)

e14091 Background: TAK-659 is a reversible, dual inhibitor of SYK and FLT-3 being developed for oncology indications including Acute Myelogenous Leukemia (AML), a disease driven by SYK and/or FLT-3-mediated signaling. Loss of SYK in AML cell lines has been shown to induce myeloid differentiation. FLT-3 is a Class III receptor tyrosine kinase that is normally expressed only in hematopoietic stem and progenitor cells. However, its expression has been found in the blasts of a majority of patients with AML. Activating mutations of FLT-3, including internal tandem duplication (ITDs) within the juxtamembrane region of FLT-3 and point mutations in the FLT-3 activation loop, are observed in approximately 30% of AML patients. These FLT-3 mutations, associated with early relapse and poor survival, represent a critical prognostic factor for AML. Methods: TAK-659 is an investigational inhibitor of SYK and FLT-3 that is currently being evaluated in a Phase 1b/2 clinical trial of AML patients (NCT02323113). TAK-659 inhibits purified SYK and FLT-3 enzymes with concentrations producing 50% inhibition (IC50) of 4.3 and 4.6 nM, respectively. In cultured human tumor cells, TAK-659 potently inhibited the growth of hematopoietic-derived cell lines, with a concentration producing half-maximal response (EC50) ranging from 11 to 775 nM in sensitive cell systems (eg, diffuse large B-cell lymphoma, and AML). In a broad kinase panel, TAK-659 demonstrated a more than 50-fold selectivity for SYK and FLT-3 over 290 other protein kinases. Results: Daily oral administration of 60 mg/kg TAK-659 showed anti-tumor activity in AML cell-line xenograft models representing FLT-3-ITD (MV-4-11 (TGI 96%)), and WT FLT-3 (KG-1 (TGI 66%)). The time course of pSYK (pSYK525) and pFLT3 (pFLT3591) expression were assessed following a single dose of TAK-659. Time dependent inhibition of these phospho-proteins, and an increase in cleaved caspase 3 expression, was observed in the AML models studied here. TAK-659 treatment of primary AML patient blasts using Vivia's ExviTech platform also revealed inhibition of cell proliferation and increase in cell death. Conclusions: Taken together these data support the clinical investigation of TAK-659 in the treatment of AML.
stageR: a general stage-wise method for controlling the gene-level false discovery rate in differential expression and differential transcript usage
Authors: Koen Van den Berge, Charlotte Soneson, Mark D. Robinson
Journal: Genome biology (2017)

RNA sequencing studies with complex designs and transcript-resolution analyses involve multiple hypotheses per gene; however, conventional approaches fail to control the false discovery rate (FDR) at gene level. We propose stageR, a two-stage testing paradigm that leverages the increased power of aggregated gene-level tests and allows post hoc assessment for significant genes. This method provides gene-level FDR control and boosts power for testing interaction effects. In transcript-level analysis, it provides a framework that performs powerful gene-level tests while maintaining biological interpretation at transcript-level resolution. The procedure is applicable whenever individual hypotheses can be aggregated, providing a unified framework for complex high-throughput experiments.
HEAD INJURY EVENTS IN RUGBY UNION: DESCRIPTION OF HIGH RISK TACKLE EVENTS
Authors: Ross Tucker
Journal: British Journal of Sports Medicine (2017)

Background Head injuries are a concern in Rugby Union, accounting for 17% of injuries. Until the risk of specific game events is understood, effective interventions to reduce risk cannot be formulated. Objective To describe the relative risk of head injuries in rugby. Design Prospective cohort study. Setting 1,516 Rugby Union matches in six professional tournaments. Patients (or Participants) All players in the six professional tournaments were potential cases. Head injury events were identified by trained medical personnel using established Head Injury Assessment protocols. Assessment of Risk Factors A professional video analyst evaluated every head injury event, and characterized it according to a pre-determined classification framework of 25 variables. Main Outcome Measurements Head Injury Events characterized for relative risk by game event, playing position and match time. Results 611 Head Injury Events (HIEs) were documented. Tackles had the highest risk of any game event, with a propensity of 1.94 HIEs/1000 events, accounting for 464 (76%) HIEs at a rate of 1 HIE every 3.1 matches. The tackler was 2.6 times more likely to be injured than the ball-carrier. Other high risk events included kick contests (1.57 HIEs/1000 events), mauls (0.7 HIEs/1000 events) and rucks. Rucks accounted for the next highest number of HIEs (73 HIEs at a rate of 1 HIE/20.8 matches. The player most likely to sustain a head injury was the flyhalf (68.9 matches per HIE), with the least likely the wings. Within tackles, backline players have a greater propensity than forwards (220 HIAs, 2.62 HIAs/1000 tackles for backs vs 240 HIAs, 1.54 HIAs/1000 tackles for forwards). HIE risk was unaffected by match-time. Conclusions Tackles are the most injurious event, both by propensity and frequency. Tackling accounts for the greatest number of HIEs, and strategies to reduce the risk in tackles, with focus on the tackler, must be sought.
Telomere Length and Risk of Cancer and Non-neoplastic Diseases: Is Survivin the Ariadne's Thread?
Authors: Raffaella Mormile
Journal: JAMA Oncology (2017)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Oncology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Oncology journal
Mitochondrially targeted polypeptides have killing ability against cancer cells
Authors: Koji Yamamoto, Motohiro Mihara, Koji Kubota, Shinichi Miyagawa
Journal: Cancer Research (2008)

4385     Objective of the study   :  The tumor suppressor function of p53 is performed mainly by induction of apoptosis as a transcription factor, and also p53 has a direct apoptotic role at mitochondria. At mitochondria, p53 promotes oligomelization of the BH1,2,3 pro-apoptotic protein, leading outer mitochondrial membrane permeabilization and induces apoptosis as a result. One important mechanism by which p53 induces mitochondrial membrane permeabilization is that p53 forms a comprex with anti-apoptotic BclXL protein. Previously we reported that mitochondrially targeted p53 protein fused with protein transduction domain embedded in the human immunodeficiency virus TAT protein (TAT-PTD) had ability to induce apoptosis and tumor suppressor activity in the mouse-inoculated model of human colon cancer cell line. Here we generated polypeptides including BclXL binding domain, which consist of three parts of the DNA binding domain of p53, to investigate the apoptotic activity of each polypeptide and combination of these polypeptides.    Methods   :  The mitochondrially targeted polypeptides derived from p53 fused with TAT-PTD protein were administered to  human colon cancer cell line, LoVo. Apoptotic ability was evaluated at the time of 30 minutes, 1 hour and 2 hours after administration by TUNEL assay.    Resul    t:   Administration of single or combinated polypeptides including BclXL binding domains demonstrated killing ability against cells, while the polypeptide consisting of N-terminus or proline rich domain of p53 showed no apoptotic activity.    Conclusion :  The mitochondrially targeted polypeptides including BclXL binding domain of p53 can induce apoptosis and they could be applied for new treatment of cancer.
A Study of Safety and Efficacy of Anticoagulant Therapy in the Treatment of Atrial Fibrillation in Kanagawa (ASSAF-K)-The Second Announcement-
Authors: Kunishima Tomoyuki, Hatori Yutaka, Sakai Hiroyuki, Mitani Kazuhiko, Chin Keiichi, Hatori Nobuo, Sato Naoki
Journal: Circulation (2016)
02.17 Rheumatoid arthritis driven alteration in t-cell epigenetic programing
Authors: Rujiraporn Pitaksalee, Agata N Burska, Joshua Rogers, Paul Emery, Richard Hodgett, Frederique Ponchel
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Alteration in epigenetic patterns have been related to several diseases including RA. Early detection of RA will enable more effective treatment. The aim of our project is to identify the early changes in DNA methylation patterns of naïve and memory CD4<sup>+</sup>T-cells, and monocytes in Early RA patient to help understanding early disease pathology and to help finding the potential for biomarker development. <h3>Methods</h3> The methylation patterns of 480,000 CpGs were measured in 3 cell types (memory T-cell, naïve T-cell and monocytes) in 6 healthy control and 10 RA patients using an Illumina methylation genome-wide array (EWAS). Standard t-test were performed to associate p-value to CpG. Hierarchical clustering of CpG (p&lt;0.001) were performed and Heat maps were generated using R. Venn diagram were used to compare common CpG between cell types. Gene annotation and function analysis was performed using Panther. <h3>Results</h3> The analysis of the EWAS data showed 20,578 CpG sites differently methylated in RA for naïve T-cells, 15 794 for memory T-cells and 7180 for monocytes. Heat maps showed 42.97% over and 57.03% under methylated in RA for naïve T-cells, 89.95% over and 10.05% under methylated for memory T-cells, and 53.59% over and 46.41% under methylated for monocytes. The top 10 over and under methylated genes were identified with transcription factors, immunity-related protein/function, signalling protein, musculoskeletal protein, enzymes and activity related to nucleotides. Overlapping of 4 genes (ANKRD1, FAM20C, EFCAB1, HRAT92) were shown between 3 cell subsets. Venn diagrams showed 249 CpG common to all 3 subsets, 2662 common to the T-cell subsets, and 473 or 271 between monocytes and naïve or memory T-cells, respectively. A repeated Panther analysis of gene on the common 249 CpG showed genes to be related to HLA (1%), binding between protein DNA (17%), binding between proteins (19%), enzymatic activity (32%), receptors (9% of which 3% was associated with TNF signalling), and signalling (5%). <h3>Conclusion</h3> This analysis clearly demonstrate over and under methylation in several CpG islands in RA in all 3 subsets. The genes differentially methylated in all 3 subsets may offer potential for the development of biomarker for the early diagnosis of RA.
Abstract 061: Interstitial Matrix Flow-Regulation:Myocardial Fibroblasts Respond to Colloidosmotic Pressure
Authors: Maria P McGee, Michael Morykwas, Rui Wang, James Jordan, Louis Argenta
Journal: Circulation Research (2013)

Ischemia-reperfusion injury induces large differences in hydration potential between ischemic and nonischemic areas of the myocardium. They influence the rate and volume of fluid transfer in myocardial explants; temperature-dependent hydration-potential differences of approximately 100 mmHg in at-risk areas, as opposed to contiguous areas that are not at risk, suggest prompt interstitial fluid-transfer control mechanisms (Circ. Res . 2012;11:A235) . Aim: We adapted osmotic-stress techniques to determine whether myocardial fibroblasts, which are known to respond to mechanical and flow signals, also respond to hydration-potential changes. Methods: Fibroblasts were isolated from midwall regions of the left ventricles of healthy pigs using standard procedures. They were incorporated into 3-dimensional collagen gels of 500 mm 3 volume at 150 cells/mm 3 and equilibrated overnight in cultures using the nontoxic, inert polymer polyethylene glycol 8000 (molecular radius ~26.5 Å; concentration range 0-10% w/w) to adjust colloidosmotic pressure from approximately 5 to 205 mmHg . After the gels were detached from the dish, fluid flux was derived from any time-dependent changes in their dimensions. Results: The volume of gels without fibroblasts did not change significantly at any coloidosmotic pressure. In those with fibroblasts, the volume decreased, more slowly in those subjected to higher-than-plasma pressure levels. Progression curves conformed well to a two-exponential term model (R 2 &gt;0.9) suggesting that two parallel processes contribute to matrix efflux, one relatively fast, with decay constant 0.274 ± 0.014 (n = 3) , and another ~50-fold slower. Initial rates were calculated from the fitted curves, and linear regression analysis used to examine their dependence on colloidosmotic pressure. Initial efflux rates decreased with pressure, mean slope, - 0.29 ± 0.08 µl/h/mmHg (R 2 = 0.7; P-value = 0.006). Conclusion: In vitro , fibroblasts in collagen matrices regulate fluid efflux in response to colloidosmotic stresses within the range of hydration-potential differences measured in myocardial explants after ischemia-reperfusion injury.
THE SELF ASSESSMENT CORNER ( SAC METHOD): A NOVEL WAY TO SELF ASSESS SHOULDER ROTATOR CUFF STRENGTH: A RELIABILITY AND VALIDITY STUDY
Authors: Philippe Decleve, Ann Cools
Journal: British Journal of Sports Medicine (2017)

Background Risk factors among overhead athletes have been investigated in many studies. The rotator cuff external rotator weakness is associated with an increased probability of substantial shoulder problems and throwing related injury requiring surgical intervention. Objective To evaluate the relative and absolute reliability and the validity of the SAC method (SAC) that allows measurement of shoulder internal and external rotator isometric strength by the patient himself with the use of a hand-held dynamometer (HHD) fixed on a stabilization device. Design A two session measurement design was used. Setting laboratory setting. Patients (or Participants) 46 healthy adult participants (26 males and 20 females) aged between 18 and 25 years. Interventions (or Assessment of Risk Factors) Strength was measured using the SAC in a 0°0° and 90°90° shoulder position and compare to the HHD manual muscle testing in a standing (STAN) and sitting position (SIT). Main Outcome Measurements Relative reliability was determined by intraclass correlation coefficients (ICC). Absolute reliability was quantified by standard error of measurement (SEM) and minimal detectable change (MDC). Systematic differences among similar measurements under different testing circumstances, were analyzed with Related Samples Wilcoxon Signed Rank Test or Kruskall Wallis Test. Results Results showed relative reliability was good to excellent ranging from 0.85 (IR 0°0°) to 0.92(IR 90°90°). Absolute reliability showed MDC 90% varying from 8.06 N (IR 90°90°) to 15,69 N (IR 0°0°) and SEM varying from 3,45 N (IR 90°90°) to 6,72 N (IR 0°0°). Comparative analysis of similar measurements showed no statistically diferences between SAC and STAN in a 0°0° position as well as in a 90°90° position between SAC,STAN and SIT. Conclusions We demonstrated a clinically applicable method, reliable and valid for self assessing rotator cuff isometric strength.
ASSOCIATION BETWEEN HAND-HELD DYNAMOMETER MEASURES OF HAMSTRING STRENGTH AND FORCE OBTAINED FROM THE NORDIC HAMSTRING EXERCISE
Authors: Kate Evans, Morgan Williams
Journal: British Journal of Sports Medicine (2017)

Background The Nordic hamstring exercise (NHE) is included in many injury prevention programmes. Recently, a device that measures force at both ankles during the NHE has been introduced to help monitor and track an athlete's progress. Understanding the association between different hamstring strength protocols may reveal a better understanding of the NHE as an assessment and help practitioners to decide on its application. Objective To explore the associations between a series of hamstring strength measures obtained from a hand-held dynamometer with the force obtained during a NHE. Design This cross-sectional study involved participants being measured during a single session. Associations between all individual measures were assessed. In addition, the combined effect of the hand-held measures to predict Nordic eccentric strength (NES) were explored. Setting Professional team sports. Patients (or Participants) Seventy-nine professional male team sport athletes. Main Outcome Measurements NES obtained from a commercial device. Hand held dynamometry break assessments of hip extension (HE), hamstring inner range strength (HI) and hamstring strength at 30° knee flexion (H30). Results Based on the univariate correlations between variables (preferred limb only), the smallest association was between NES and HE (r 2 =0.02) and the largest association between NES and HI (r 2 =0.26). Using multiple regression, HI (P=0.0001) and H30 (P=0.0083) predicted NES (r 2 =0.32; RMSE=64N; P&lt;0.0001). The model was not improved with the addition of HE (r 2 =0.33; RMSE=64N; P&lt;0.0001). Conclusions Each hamstring strength assessment may offer unique information about the current hamstring strength quality of an athlete. Despite, HI having the largest effect, and the improved model with the addition of H30, handheld dynamometry replacing the using these measures in place of NES obtained from a commercial device is not advised.