tbuckley/cabot-search huggingface dataset:
KDM2B promotes pancreatic cancer via Polycomb-dependent and -independent transcriptional programs
Authors: Alexandros Tzatsos, Polina Paskaleva, Francesco Ferrari, Vikram Deshpande, Svetlana Stoykova, Gianmarco Contino, Kwok-Kin Wong, Fei Lan, Patrick Trojer, Peter J. Park, Nabeel Bardeesy
Journal: Journal of Clinical Investigation (2013)

Epigenetic mechanisms mediate heritable control of cell identity in normal cells and cancer. We sought to identify epigenetic regulators driving the pathogenesis of pancreatic ductal adenocarcinoma (PDAC), one of the most lethal human cancers. We found that KDM2B (also known as Ndy1, FBXL10, and JHDM1B), an H3K36 histone demethylase implicated in bypass of cellular senescence and somatic cell reprogramming, is markedly overexpressed in human PDAC, with levels increasing with disease grade and stage, and highest expression in metastases. KDM2B silencing abrogated tumorigenicity of PDAC cell lines exhibiting loss of epithelial differentiation, whereas KDM2B overexpression cooperated with KrasG12D to promote PDAC formation in mouse models. Gain- and loss-of-function experiments coupled to genome-wide gene expression and ChIP studies revealed that KDM2B drives tumorigenicity through 2 different transcriptional mechanisms. KDM2B repressed developmental genes through cobinding with Polycomb group (PcG) proteins at transcriptional start sites, whereas it activated a module of metabolic genes, including mediators of protein synthesis and mitochondrial function, cobound by the MYC oncogene and the histone demethylase KDM5A. These results defined epigenetic programs through which KDM2B subverts cellular differentiation and drives the pathogenesis of an aggressive subset of PDAC.
A 3-day short course of palifermin before HDT reduces toxicity and need for supportive care after autologous blood stem-cell transplantation in patients with multiple myeloma
Authors: G. Kobbe, I. Bruns, T. Schroeder, A. Czibere, J. Warnecke, N. Hieronimus, N. Safaian, M. Kondakci, C. Saure, U. Germing, R. Haas, R. Fenk
Journal: Annals of Oncology (2010)
Fruit and vegetable intake and incidence of type 2 diabetes mellitus: systematic review and meta-analysis
Authors: P. Carter, L. J. Gray, J. Troughton, K. Khunti, M. J. Davies
Journal: BMJ (2010)

<h3>Abstract</h3> The ongoing outbreak of COVID-19 challenges health systems and epidemiological responses of all countries worldwide. Although mitigation measures have been globally considered, the spatial heterogeneity of its effectiveness is evident, underscoring global health inequalities. Using Bayesian-based Markov chain Monte Carlo simulations, we evidenced that factors contributing to poverty are also risk factors for COVID-19 case-fatality, and unexpectedly, their impact on the case-fatality risk is comparable to that produced by health factors. Additionally, we confirm that both case-fatality risk and multidimensional poverty index have a heterogeneous spatial distribution, where the lastest consists of health, educational, dwelling, and employment dimensions. Spatio-temporal analysis reveals that the spatial heterogeneity in case-fatalities is associated with the percentage contribution of the health (RR 1.89 95%CI=1.43-2.48) and dwelling (RR 2.01 95%CI=1.37-2.63) dimensions to the multidimensional poverty, but also with the educational (RR 1.21 95%CI=1.03-1.49), and employment (RR 1.23 95%CI=1.02-1.47) dimensions. This spatial correlation indicates that the case-fatality risk increase by 189% and 201% in regions with a higher contribution of the health dimension (i.e., lack of health insurance and self-reporting) and dwelling dimension (i.e., lack of access to safe water, inadequate disposal of human feces, poor housing construction, and critical overcrowding), respectively. Furthermore, although a temporal decrease is evident, the relative risk of dying by COVID-19 in Colombia is still 200% higher than the established case-fatality risk based on the COVID-19 dynamics in Italy and China. These findings assist policy-makers in the spatial and temporal planning of strategies focused on mitigating the case-fatality risk in most vulnerable communities and preparing for future pandemics by progressively reducing the factors that generate health inequality.
Cost-Effectiveness of Novel Regimens for the Treatment of Hepatitis C Virus
Authors: Mehdi Najafzadeh, Karin Andersson, William H. Shrank, Alexis A. Krumme, Olga S. Matlin, Troyen Brennan, Jerry Avorn, Niteesh K. Choudhry
Journal: Annals of Internal Medicine (2015)

Background: New regimens for hepatitis C virus (HCV) have shorter treatment durations and increased rates of sustained virologic response compared with existing therapies but are extremely expensive. Objective: To evaluate the cost-effectiveness of these treatments under different assumptions about their price and efficacy. Design: Discrete-event simulation. Data Sources: Published literature. Target Population: Treatment-naive patients infected with chronic HCV genotype 1, 2, or 3. Time Horizon: Lifetime. Perspective: Societal. Intervention: Usual care (boceprevir–ribavirin–pegylated interferon [PEG]) was compared with sofosbuvir–ribavirin–PEG and 3 PEG-free regimens: sofosbuvir–simeprevir, sofosbuvir–daclatasvir, and sofosbuvir–ledipasvir. For genotypes 2 and 3, usual care (ribavirin–PEG) was compared with sofosbuvir–ribavirin, sofosbuvir–daclatasvir, and sofosbuvir–ledipasvir–ribavirin (genotype 3 only). Outcome Measures: Discounted costs (in 2014 U.S. dollars), quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios. Results of Base-Case Analysis: Assuming sofosbuvir, simeprevir, daclatasvir, and ledipasvir cost $7000, $5500, $5500, and $875 per week, respectively, sofosbuvir–ledipasvir was cost-effective for genotype 1 and cost $12 825 more per QALY than usual care. For genotype 2, sofosbuvir–ribavirin and sofosbuvir–daclatasvir cost $110 000 and $691 000 per QALY, respectively. For genotype 3, sofosbuvir–ledipasvir–ribavirin cost $73 000 per QALY, sofosbuvir–ribavirin was more costly and less effective than usual care, and sofosbuvir–daclatasvir cost more than $396 000 per QALY at assumed prices. Results of Sensitivity Analysis: Sofosbuvir–ledipasvir was the optimal strategy in most simulations for genotype 1 and would be cost-saving if sofosbuvir cost less than $5500. For genotype 2, sofosbuvir–ribavirin–PEG would be cost-saving if sofosbuvir cost less than $2250 per week. For genotype 3, sofosbuvir–ledipasvir–ribavirin would be cost-saving if sofosbuvir cost less than $1500 per week. Limitation: Data are lacking on real-world effectiveness of new treatments and some prices. Conclusion: From a societal perspective, novel treatments for HCV are cost-effective compared with usual care for genotype 1 and probably genotype 3 but not for genotype 2. Primary Funding Source: CVS Health.
Task Force on Strategic Research Direction
Authors: Lori Mosca, Donna K. Arnett, Kathleen Dracup, Barbara C. Hansen, Darwin R. Labarthe, James S. Marks, Karen A. Matthews, Thomas A. Pearson, William Weintraub, Walter Wilson
Journal: Circulation (2002)

S trategic research related to the prevention of cardiovas- cular disease (CVD) and improvement in quality of life encompasses a wide range of scientific disciplines.Experts from the fields of epidemiology, social sciences, health services and outcomes research, and preventive cardiology reached consensus with regard to five priority substantive areas of research to achieve the Healthy People 2010 objectives and to support the long-term goals and mission of the American Heart Association (AHA).The 2010 goals and objectives for heart disease and stroke are to guide the nation in achieving both increased quality and years of life and the elimination of health disparities among different segments of the population.Broadly, the Healthy People 2010 goals are prevention of the risk factors, detection and treatment of the risk factors, early identification and treatment of heart attacks and strokes, and prevention of recurrent cardiovascular events.Specific objectives include (but are not limited to) reduction in coronary heart disease mortality by 20%, reduction in stroke mortality by 20%, reduction in hospitalization rates for congestive heart failure by 50%, reduction in prevalence of high blood pressure to 16%, and reduction in prevalence of high total blood cholesterol concentration to 17%.Attainment of these goals and objectives will require increased investment of resources at the population level, through such strategies as are outlined below.Within each content area, the committee systematically identified specific research priorities using complementary scientific approaches: Prevention Research Priority Content AreasI. Methods to Improve Utilization and Quality of Preventive Services and Health Care II.Disparities in Cardiovascular Risk in Subpopulations III.Lifestyle and Metabolic Risk Factors IV.Psychosocial Risk Factors V. Population Genetics/Pharmacogenetics Related to Prevention Subcategories of Priority Prevention ResearchWithin each of the following categories, highest priority should be given to aspects closest to delivery of science to the population.• Effectiveness/outcomes research to determine the impact of interventions in real-world settings • Efficacy research to evaluate interventions in controlled trials • Early detection/subclinical measures • Etiologic research/surveillance I. Methods to Improve Utilization and Quality of Preventive Services and Health CareThe American Heart Association makes every effort to avoid any actual or potential conflicts of interest that may arise as a result of an outside relationship or a personal, professional, or business interest of a member of the writing panel.Specifically, all members of the writing group are required to complete and submit a Disclosure Questionnaire showing all such relationships that might be perceived as real or potential conflicts of interest.
CaMKII inhibition protects against necrosis and apoptosis in irreversible ischemia–reperfusion injury
Authors: Martin Vila-Petroff, Margarita A. Salas, Matilde Said, Carlos A. Valverde, Luciana Sapia, Enrique Portiansky, Roger J. Hajjar, Evangelia G. Kranias, Cecilia Mundiña-Weilenmann, Alicia Mattiazzi
Journal: Cardiovascular Research (2006)

Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) has been implicated in the regulation of cardiac excitation-contraction coupling (ECC) as well as in apoptotic signaling and adverse remodeling. The goal of the present study is to investigate the role of CaMKII in irreversible ischemia and reperfusion (I/R) injury.Isovolumic Langendorff perfused rat hearts were subjected to global no-flow I/R (45 min/120 min), and isolated myocytes were subjected to a protocol of simulated I/R (45 min simulated ischemia/60 min reoxygenation) either in the absence or presence of CaMKII inhibition [KN-93 (KN) or the CaMKII inhibitory peptide (AIP)].In I/R hearts, an increase in CaMKII activity at the beginning of reperfusion was confirmed by the significantly increased phosphorylation of the Thr(17) site of phospholamban. In the presence of KN, contractile recovery at the end of reperfusion was almost double that of I/R hearts. This recovery was associated with a significant decrease in the extent of infarction, lactate dehydrogenase release (necrosis), TUNEL-positive cells, caspase-3 activity, and an increase in the Bcl-2/Bax ratio (apoptosis). In isolated myocytes, both KN and AIP prevented simulated I/R-induced spontaneous contractile activity and cell mortality. Similar results were obtained when inhibiting the reverse mode Na(+)/Ca(2+) exchanger (NCX) with KB-R7943, sarcoplasmic reticulum (SR) function with ryanodine and thapsigargin, or SR Ca(2+) release with tetracaine. In contrast, overexpression of CaMKII decreased cell viability from 52+/-3% to 26+/-2%.Taken together, the present findings are the first to establish CaMKII as a fundamental component of a cascade of events integrating the NCX, the SR, and mitochondria that promote cellular apoptosis and necrosis in irreversible I/R injury.
P183Arginase inhibition protecs from ischemia-reperfusion injury in patients with coronary artery disease
Authors: O Kovamees, A Shemyakin, J Pernow
Journal: Cardiovascular Research (2014)

Background: Arginase is an important regulator of nitric oxide production by competing with nitric oxide synthase for their common substrate L-arginine. Up-regulation of arginase in patients with coronary artery disease (CAD) and diabetes mellitus (DM) may thereby be of major importance for the development of endothelial dysfunction and ischemia-reperfusion (IR) injury by reducing the bioavailability of nitric oxide. Accordingly, arginase inhibition reduces infarct size and improves endothelial function by nitric oxide synthase-dependent processes in animal models. Purpose: To investigate if arginase inhibition protects from endothelial dysfunction induced by IR in patients with CAD with and without DM. Methods: Male patients with CAD (n=12) or CAD + DM (n=12), were included in this cross-over study with blinded evaluation. Endothelium-dependent vasodilatation was assessed by flow-mediated dilatation (FMD) of the radial artery before and 20 min after a 20 min period of arm ischemia. The patients were given an intra-arterial infusion of the arginase inhibitor Nω-hydroxy-nor-arginine (nor-NOHA, 0.1 mg/min) or saline on the two occasions. The infusions were given for 20 min starting 5 min before reperfusion. Endothelium-independent vasodilatation was assessed by sublingual nitroglycerin. Results: IR decreased FMD in patients with CAD from 12.7±1.5% to 7.9±1.2% during saline administration. Nor-NOHA administration prevented the decrease in FMD in the CAD group (11.5±1.0% FMD at reperfusion, P<0.0.5 vs. saline). Baseline endothelium-dependent vasodilatation was significantly lower in the CAD+DM group (8.3±0.6%) than in the CAD group (P<0.05). IR induced a non-significant decrease in FMD in patients with CAD+DM. FMD at reperfusion was higher following nor-NOHA (11.2±1.0%) than following saline (7.2±1.0%) administration in the CAD + DM group (P<0.01). Endothelium-independent vasodilatation did not differ between the occasions in either group. Conclusions: Inhibition of arginase protects against endothelial dysfunction caused by IR in patients with CAD. Arginase may thereby be a promising therapeutic target in the treatment of IR injury.
Expression of a functional c-kit receptor on a subset of natural killer cells.
Authors: M E Matos, G S Schnier, M S Beecher, L K Ashman, D E William, M A Caligiuri
Journal: The Journal of Experimental Medicine (1993)

Natural killer (NK) cells are large granular lymphocytes thought to be important in the host's early immune response to viral infection and malignant transformation. NK cells proliferate and display enhanced cytotoxic activity in response to the T cell growth factor, interleukin 2 (IL-2). Stem cell factor or steel factor (SF) is the ligand for the c-kit receptor, and when combined with other hematopoietic growth factors, SF synergistically promotes the proliferation and differentiation of bone marrow stem cells. In the present study we show the c-kit receptor to be uniquely expressed on a subset of resting human NK cells (CD56bright) which constitutively expresses both the high affinity IL-2 receptor (IL-2R) and the intermediate affinity IL-2R. Other lymphocyte populations, including CD56dim NK cells, did not appear to express the c-kit receptor. Within the CD56bright NK cell subset, SF alone had no obvious effect on proliferation or cytotoxic activity. SF was shown to significantly augment the proliferative effect of IL-2, and caused a marked shift in the dose-response curve at IL-2 concentrations that selectively saturate the high affinity IL-2R. The potentiating effect of SF on NK cell proliferation was dependent on IL-2 binding to the high affinity IL-2R, and was blocked by a monoclonal antibody directed against the c-kit receptor. SF did not enhance proliferation at higher IL-2 concentrations that saturate the intermediate affinity IL-2R, nor did SF enhance IL-2-induced cytotoxic activity. Together, these data indicate that SF and IL-2 act synergistically to directly augment the proliferative capacity of a unique human NK cell subset constitutively expressing the high affinity IL-2R and the c-kit receptor. The implications of these findings on NK cell development and the host's early immune response to pathogen invasion are discussed.
Myocardial injury leads to a release of heat shock protein (hsp) 60 and a suppression of the anti-hsp65 immune response
Authors: G Schett
Journal: Cardiovascular Research (1999)

Objective: While atherosclerosis is associated with high titers of autoantibodies to bacterial hsp65 crossreacting with human hsp60 (anti-hsp60 autoantibodies), myocardial infarction entails decreased humoral immune response to hsp65. We previously hypothesized that myocardial ischemia and subsequent infarction not only induce myocardial hsp60 expression, but also trigger release of myocardial hsp60 into the circulation, influencing the systemic hsp immune response via immune complex formation. Methods: In the present study, organ culture of rat hearts under circulatory arrest provided a model of myocardiocyte injury due to ischemia. Results: Reperfusion of ischemic hearts confirmed the occurrence of myocardial injury by a rise of heart enzymes. Myocardial hsp60 expression was induced up to threefold in response to ischemia, and most of hsp60 expression was localized to the muscle fibers. Analysis of coronary eluate revealed release of hsp60 from myocardium. In addition, hsp60-containing, but not hsp60-free, coronary eluate was recognized by anti-hsp65 serum antibodies and induced proliferation of hsp65-specific T cells. When hsp60-containing coronary eluate was reinjected into an hsp65-primed rat, both humoral and cellular hsp65-immune responses were strongly downregulated. Conclusion: Our findings demonstrate the release of highly immunogenic and crossreactive hsp60 into the circulation in response to myocardial ischemia and myocardiocyte injury.
Expression of transforming growth factor-beta 1 in dystrophic patient muscles correlates with fibrosis. Pathogenetic role of a fibrogenic cytokine.
Authors: P Bernasconi, E Torchiana, P Confalonieri, R Brugnoni, R Barresi, M Mora, F Cornelio, L Morandi, R Mantegazza
Journal: Journal of Clinical Investigation (1995)

genetical criteria (20).Controls were also studied as were 11 spinal muscular atrophy (SMA) patients (seven type I, and four type Im), and 16 other subjects, who had undergone muscle biopsy for diagnosis but Transforming Growth Factor-/31 and Fibrosis in Xp2l Muscular Dystrophy 1137
Ohio runs out of execution drugs as manufacturers’ embargo bites across US
Authors: Owen Dyer
Journal: BMJ (2015)

Authorities in Ohio, the third most populous US state with the death penalty, have been unable to procure lethal injection drugs despite having 24 executions scheduled.

Ohio is the biggest state yet to be completely cut off from a supply of lethal injection drugs, evidence of the slow tightening of an embargo by drug manufacturers unwilling to see their products used in executions. In May Nebraska’s inability to reliably obtain drugs was a major factor in persuading Republican legislators to pass abolition of the death penalty.

In Ohio, too, the prospect of a de facto moratorium on executions has renewed debate about the viability of capital punishment. “I want to continue forward with the death penalty,” Ohio’s governor, John Kasich, said this week, “but if I don’t have the drugs it becomes very difficult.”

The statement was doubly significant, as Kasich is a candidate for the Republican presidential nomination and under pressure to show his conservative credentials.

Ohio’s …
Prognostic Factors in Patients With Aggressive Non-Hodgkin's Lymphoma Treated by Front-Line Autotransplantation After Complete Remission: A Cohort Study by the Groupe d'Etude des Lymphomes de l'Adulte
Authors: N. Mounier, C. Gisselbrecht, J. Brière, C. Haioun, P. Feugier, F. Offner, C. Recher, A. Stamatoullas, F. Morschhauser, M. Macro, C. Thieblemont, A. Sonet, B. Fabiani, F. Reyes
Journal: Journal of Clinical Oncology (2004)

Improved survival has been observed in aggressive non-Hodgkin's lymphoma (NHL) patients with adverse prognostic factors when autotransplantation (ASCT) was performed after complete remission. However, there is no agreement on the prognostic factors for patients treated with ASCT. We aimed to estimate the prognostic effect of clinical and biologic variables on relapse and survival rates by pooling the data from two trials.Of the patients treated in the LNH87 and LNH93 trials, 330 under age 60 years achieved complete remission after high-dose cyclophosphamide, doxorubicin, vincristine, and prednisone, and received consolidative ASCT; 16% of patients had T-cell NHL. The International Prognostic Index (IPI) score was 0 for 11%, 1 for 23%, 2 for 51%, and 3 for 15%. Univariate and Cox multivariate survival analyses were retrospectively performed on this population.Overall survival was 75 +/- 5% at 5 years and disease-free survival (DFS) 67 +/- 5%. For T-cell NHL, these scores were 54% and 44%, respectively. The IPI score had no prognostic value and only the following parameters adversely affected overall survival and DFS (P <.05): marrow involvement; more than one extranodal site; histology (nonanaplastic T-cell v others); and type of anthracycline (mitoxantrone v doxorubicin, for DFS only).These results suggest that ASCT can prevent relapse in patients with adverse IPI factors. However, patients presenting with a nonanaplastic T-cell phenotype, more than one extranodal site, or marrow involvement still have a higher risk of relapse. These factors should be taken into account when designing post-ASCT maintenance studies.
Phase I/II Trial of AEG35156 X-Linked Inhibitor of Apoptosis Protein Antisense Oligonucleotide Combined With Idarubicin and Cytarabine in Patients With Relapsed or Primary Refractory Acute Myeloid Leukemia
Authors: Aaron D. Schimmer, Elihu H. Estey, Gautam Borthakur, Bing Z. Carter, Gary J. Schiller, Martin S. Tallman, Jessica K. Altman, Judith E. Karp, Jeannine Kassis, David W. Hedley, Joseph Brandwein, Wei Xu, Duncan H. Mak, Eric LaCasse, Christine Jacob, Stephen J. Morris, Jacques Jolivet, Michael Andreeff
Journal: Journal of Clinical Oncology (2009)

X-linked inhibitor of apoptosis protein (XIAP) is an inhibitor of caspases 3 and 9 which are overexpressed in acute myeloid leukemia (AML) and may contribute to chemoresistance. We report on a phase I/II trial of the XIAP antisense oligonucleotide AEG35156 in combination with reinduction chemotherapy.Twenty-four patients with rapidly relapsed or refractory AML were treated with escalating doses of AEG35156 (12 to 250 mg/m(2)) as an intravenous solution over 2 hours and 32 patients were treated with the highest planned dose of 350 mg/m(2) in combination with idarubicin and high-dose cytarabine reinduction chemotherapy. Correlative studies were conducted to determine the effects of AEG35156 on levels of XIAP mRNA.Knockdown of XIAP mRNA during treatment increased with the dose of the antisense. All patients who received 350 mg/m(2) of AEG35156 had higher than 30% target knockdown with a median maximal knockdown of 90% (range, 48% to 100%). The overall response rate was higher among the patients receiving the highest dose of AEG35156. In this group, 15 (47%) of 32 patients achieved complete response (CR)/CR with incomplete platelet count recovery (CRp) compared with only one (4%) of 24 receiving 12 to 250 mg/m(2) AEG35156. Among the patients receiving 350 mg/m(2) of AEG35156 in combination with chemotherapy, 10 (91%) of 11 who were refractory to a single induction chemotherapy regimen achieved CR/CRp after reinduction with AEG35156 and chemotherapy. AEG35156 was well tolerated save for two cases of peripheral neuropathy in patients receiving multiple doses of AEG35156.At the highest dose tested, AEG35156 knocks down its target and appears very effective when combined with chemotherapy in patients with AML refractory to a single induction regimen.