tbuckley/cabot-search huggingface dataset:
The Oncogenic BRAF Kinase Inhibitor PLX4032/RG7204 Does Not Affect the Viability or Function of Human Lymphocytes across a Wide Range of Concentrations
Authors: Begoña Comin-Anduix, Thinle Chodon, Hooman Sazegar, Douglas Matsunaga, Stephen Mock, Jason Jalil, Helena Escuin-Ordinas, Bartosz Chmielowski, Richard C Koya, Antoni Ribas
Journal: Clinical Cancer Research (2010)

Abstract Purpose: PLX4032 (RG7204), an oncogenic BRAF kinase inhibitor undergoing clinical evaluation, has high response rates in early clinical trials in patients with advanced BRAFV600E mutant melanoma. Combining PLX4032 with immunotherapy may allow expanding the durability of responses. The effects of PLX4032 on immune cells were studied to explore the feasibility of future combinatorial approaches with immunotherapy for melanoma. Experimental Design: Peripheral blood mononuclear cells (PBMC) and BRAFV600E mutant melanoma cells were exposed to increasing concentrations of PLX4032 and the cell viability, proliferation, cell cycle, apoptosis, and phosphorylation of signaling proteins were analyzed. Effects of PLX4032 on antigen-specific T-cell function were analyzed by specific cytokine release and cytotoxicity activity. Results: The 50% inhibition concentration (IC50) of PLX4032 for resting human PBMC was between 50 and 150 μmol/L compared with an IC50 below 1 μmol/L for sensitive BRAFV600E mutant melanoma cell lines. Activated lymphocytes were even more resistant with no growth inhibition up to concentrations of 250 μmol/L. PLX4032 had a marginal effect on cell-cycle arrest, apoptotic cell changes or alteration of phosphorylated signaling molecules in lymphocytes. Functional analysis of specific antigen recognition showed preserved T-cell function up to 10-μmol/L concentration of PLX4032, whereas the cytotoxic activity of PLX4032 was maintained up to high concentrations of 50 μmol/L. Conclusions: The preserved viability and function of lymphocytes exposed to high concentrations of PLX4032 suggest that this agent could be a potential candidate for combining with immunotherapy strategies for the treatment of patients with BRAFV600E mutant melanoma. Clin Cancer Res; 16(24); 6040–8. ©2010 AACR.
Sir Ernst Chain, FRS
Authors: A St. J. Dixon
Journal: Annals of the Rheumatic Diseases (1979)

Rheumatology has lost one of its greatest contri- butors, although few would recognise him under this description.Alexander Fleming discovered penicillin in 1929 but failed to realise its potential importance or exploit its capacity to cure human disease.Nine years later Ernst Chain, a refugee from Hitler's Germany who had arrived in Britain in 1933 at the age of 27, came across his paper and attempted to reproduce his results.It was no accident that Chain was working in this field, as he had already been studying lysozyme, an enzyme capable of destroying bacteria.Chain eventually concentrated the active substance produced by the mould penicillium and showed that it prevented death in mice injected with a fatal dose of streptococci.This simple experiment, which Fleming might have done but did not, eventually led to the virtual elimination from our rheumatology clinics of infective arthritis caused by penicillin-sensitive organisms-gono-
STUDIES ON THE GENERALIZED SHWARTZMAN REACTION
Authors: George D. Pappas, Michael H. Ross, Lewis Thomas
Journal: The Journal of Experimental Medicine (1958)

The intravascular fibrinoid which is deposited in glomerular capillaries of the rabbit during the generalized Shwartzman reaction has been studied with the aid of the electron microscope. In one group of animals the reaction was produced by two intravenous injections of Escherichia coli lipopolysaccharide endotoxin, spaced 24 hours apart. In another, a single dose of endotoxin was followed, 1 hour later, by intravenous liquoid (sodium polyanethol sulfonate). The appearance of fibrinoid was the same in the two groups. Initially, fibrinoid deposition occurred on the irregular, swollen surfaces of the endothelial cells within the capillary lumen. Subsequently, the fibrinoid mass increased to such proportions that the capillary lumen was completely occluded. Fibrinoid was found to be composed of unbranched fibrils, having a diameter of 200-300 angstroms and an axial repeating structure of 120 A. The basement membrane (lamina densa) underwent no change in appearance during the time when fibrinoid was being laid down. Balloon-like vesicles were consistently encountered in endothelial cells of glomerular capillaries after two doses of endotoxin, and also in animals given one injection of endotoxin followed by liquoid. The possible significance of the observations are discussed. It is suggested that they are compatible with the hypothesis, proposed earlier, that intravascular fibrinoid, in the generalized Shwartzman reaction, is derived from fibrinogen.
All Pre-Diabetes Is Not the Same: Metabolic and Vascular Risks of Impaired Fasting Glucose at 100 Versus 110 mg/dl
Authors: Lawrence S. Phillips, William S. Weintraub, David C. Ziemer, Paul Kolm, Jovonne K. Foster, Viola Vaccarino, Mary K. Rhee, Rahim K. Budhwani, Jane M. Caudle
Journal: Diabetes Care (2006)

The dramatic increase in incidence of diabetes (1) has prompted efforts to identify individuals who have milder glucose intolerance, because early management with lifestyle change and/or medication can delay progression to diabetes with its attendant morbidity, mortality, and cost (2). It has long been recognized that impaired glucose tolerance (IGT) is a diabetes precursor, but recognition of IGT requires oral glucose tolerance tests (OGTTs), which many health care providers are reluctant to order (3). As a more convenient alternative, the American Diabetes Association has emphasized screening by measurement of fasting plasma glucose (FPG) and lowered the cutoff for abnormal FPG progressively from 140 to 125 to 110 mg/dl. However, compared with IGT, an impaired fasting glucose (IFG) cutoff of 110 mg/dl provided good specificity but reduced sensitivity for detecting risk of developing diabetes (4–6).

To obtain increased sensitivity, the American Diabetes Association recently lowered the cutoff for IFG from 110 to 100 mg/dl (7), and application of this cutoff has increased the number of Americans thought to have “pre-diabetes” to 41 million (8). Although such individuals are considered candidates for management aimed at decreasing their risk of progressing to diabetes (9), the metabolic and cardiovascular risks of individuals with very modest abnormalities in FPG are not well understood. In this study, we compared measures of risk in individuals with fasting glucose 100–109 mg/dl (IFG100) with those with fasting glucose 110–125 mg/dl (IFG110).

The …
Molecular analysis of drug resistant TB
Authors: M Melzer
Journal: Thorax (2002)

Since the mid 1980s the number of notified cases of TB in the UK has continued to rise with the largest increases noted in London and inner city areas.1 King George Hospital in Goodmayes, Essex provides clinical services to a population of approximately 230 000; 17% are non-white subjects including immigrants from countries with high rates of M tuberculosis infection and drug resistance. From September 1996 to July 1997 47 adult cases of culture proven TB were identified including seven with drug resistant isolates. None was identified by contact tracing. A previous TB audit of African born patients revealed …
Magnesium Intake and Risk of Type 2 Diabetes in Men and Women
Authors: Ruy Lopez-Ridaura, Walter C. Willett, Eric B. Rimm, Simin Liu, Meir J. Stampfer, JoAnn E. Manson, Frank B. Hu
Journal: Diabetes Care (2004)

OBJECTIVE—To examine the association between magnesium intake and risk of type 2 diabetes. RESEARCH DESIGN AND METHODS—We followed 85,060 women and 42,872 men who had no history of diabetes, cardiovascular disease, or cancer at baseline. Magnesium intake was evaluated using a validated food frequency questionnaire every 2–4 years. After 18 years of follow-up in women and 12 years in men, we documented 4,085 and 1,333 incident cases of type 2 diabetes, respectively. RESULTS—After adjusting for age, BMI, physical activity, family history of diabetes, smoking, alcohol consumption, and history of hypertension and hypercholesterolemia at baseline, the relative risk (RR) of type 2 diabetes was 0.66 (95% CI 0.60–0.73; P for trend &amp;lt;0.001) in women and 0.67 (0.56–0.80; P for trend &amp;lt;0.001) in men, comparing the highest with the lowest quintile of total magnesium intake. The RRs remained significant after additional adjustment for dietary variables, including glycemic load, polyunsaturated fat, trans fat, cereal fiber, and processed meat in the multivariate models. The inverse association persisted in subgroup analyses according to BMI, physical activity, and family history of diabetes. CONCLUSIONS—Our findings suggest a significant inverse association between magnesium intake and diabetes risk. This study supports the dietary recommendation to increase consumption of major food sources of magnesium, such as whole grains, nuts, and green leafy vegetables.
Increased Expression of Tissue Transglutaminase in Pancreatic Ductal Adenocarcinoma and Its Implications in Drug Resistance and Metastasis
Authors: Amit Verma, Huamin Wang, Bramanandam Manavathi, Jansina Y. Fok, Aman P. Mann, Rakesh Kumar, Kapil Mehta
Journal: Cancer Research (2006)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive neoplastic diseases and is virtually incurable. The molecular mechanisms that contribute to the intrinsic resistance of PDAC to various anticancer therapies are not well understood. Recently, we have observed that several drug-resistant and metastatic tumors and tumor cell lines expressed elevated levels of tissue transglutaminase (TG2). Because PDAC exhibits inherent resistance to various drugs, we determined the constitutive expression of TG2 in 75 PDAC and 12 PDAC cell lines. Our results showed that 42 of 75 (56%) PDAC tumor samples expressed higher basal levels of TG2 compared with the normal pancreatic ducts [odds ratio (OR), 2.439; P = 0.012]. The increased expression of TG2 in PDAC was strongly associated with nodal metastasis (OR, 3.400; P = 0.017) and lymphovascular invasion (OR, 3.055; P = 0.045). Increased expression of TG2 was also evident in all 12 cell lines examined. The elevated expression of TG2 in PDAC cell lines was associated with gemcitabine resistance and increased invasive potential. Overexpression of catalytically active or inactive (C277S mutant) TG2 induced focal adhesion kinase (FAK) activation and augmented invasive functions in the BxPC-3 cell line. Conversely, down-regulation of TG2 by small interfering RNA attenuated FAK phosphorylation. Immunoprecipitation and confocal microscopy data revealed that TG2 was associated with FAK protein in PDAC cells. The activated FAK colocalized with TG2 at focal adhesion points. These results show for the first time that elevated expression of TG2 can induce constitutive activation of FAK and thus may contribute to the development of drug resistance and invasive phenotypes in PDAC. (Cancer Res 2006; 66(21): 10525-33)
Nasal continuous positive airway pressure: influence on digital volume pulse in obstructive sleep apnoea patients
Authors: Alexandra Scholze, Stephanie Lamwers, Martin Tepel, Bernd M. Sanner
Journal: European Respiratory Journal (2011)

Obstructive sleep apnoea (OSA) is linked to increased cardiovascular risk. This risk can be reduced by nasal continuous positive airway pressure (nCPAP) treatment. As OSA is associated with an increase of several vasoconstrictive factors, we investigated whether nCPAP influences the digital volume pulse wave. We performed digital photoplethysmography during sleep at night in 94 consecutive patients who underwent polysomnography and 29 patients treated with nCPAP. Digital volume pulse waves were obtained independently of an investigator and were quantified using an algorithm for continuous automated analysis. In patients with OSA and an apnoea/hypopnoea index (AHI) of >10 events · h(-1), a significant vasoconstriction was observed during the night (p<0.0001 by Friedman's test). A significant positive correlation existed between vasoconstriction and AHI (Spearman correlation, r = 0.27; p<0.01; n = 94) and the arousal index (Spearman correlation, r = 0.21; p < 0.05; n = 94). After 6 months of nCPAP treatment, the AHI was significantly reduced from 27 ± 3 events · h(-1) to 4 ± 2 events · h(-1) (each n = 29; p<0.001) and vasoconstriction during the night was significantly reduced from 10 ± 3% to 3 ± 1% (p<0.01). We show changes in the reflective index during the night consistent with vasoconstriction in patients with OSA, which are significantly reduced after 6 months of nCPAP treatment.
Monitoring Response to Anticancer Therapy by Targeting Microbubbles to Tumor Vasculature
Authors: Grzegorz Korpanty, Juliet G. Carbon, Paul A. Grayburn, Jason B. Fleming, Rolf A. Brekken
Journal: Clinical Cancer Research (2007)

Abstract Purpose: New strategies to detect tumor angiogenesis and monitor response of tumor vasculature to therapy are needed. Contrast ultrasound imaging using microbubbles targeted to tumor endothelium offers a noninvasive method for monitoring and quantifying vascular effects of antitumor therapy. We investigated the use of targeted microbubbles to follow vascular response of therapy in a mouse model of pancreatic adenocarcinoma. Experimental Design: Microbubbles conjugated to monoclonal antibodies were used to image and quantify vascular effects of two different antitumor therapies in s.c. and orthotopic pancreatic tumors in mice. Tumor-bearing mice were treated with anti-vascular endothelial growth factor (VEGF) monoclonal antibodies and/or gemcitabine, and the localization of microbubbles to endoglin (CD105), VEGF receptor 2 (VEGFR2), or VEGF-activated blood vessels (the VEGF-VEGFR complex) was monitored by contrast ultrasound. Results: Targeted microbubbles showed significant enhancement of tumor vasculature when compared with untargeted or control IgG–targeted microbubbles. Video intensity from targeted microbubbles correlated with the level of expression of the target (CD105, VEGFR2, or the VEGF-VEGFR complex) and with microvessel density in tumors under antiangiogenic or cytotoxic therapy. Conclusions: We conclude that targeted microbubbles represent a novel and attractive tool for noninvasive, vascular-targeted molecular imaging of tumor angiogenesis and for monitoring vascular effects specific to antitumor therapy in vivo.
Mapatumumab, an Antibody Targeting TRAIL-R1, in Combination With Paclitaxel and Carboplatin in Patients With Advanced Solid Malignancies: Results of a Phase I and Pharmacokinetic Study
Authors: Stephen Leong, Roger B. Cohen, Daniel L. Gustafson, Corey J. Langer, D. Ross Camidge, Kristin Padavic, Lia Gore, Margaret Smith, Laura Q. Chow, Margaret von Mehren, Cindy O'Bryant, Sujatha Hariharan, Sami Diab, Norma Lynn Fox, Renée Miceli, S. Gail Eckhardt
Journal: Journal of Clinical Oncology (2009)

A phase I study assessed the safety, tolerability, pharmacokinetics, and preliminary antitumor effect of mapatumumab, a fully-human agonist monoclonal antibody to the tumor necrosis factor-related apoptosis-inducing ligand receptor 1 (TRAIL-R1, DR4), in combination with paclitaxel and carboplatin.Patients with advanced solid malignancies received 3, 10, or 20 mg/kg of mapatumumab with standard doses of paclitaxel and carboplatin every 21 days for up to six cycles in the absence of disease progression. Additional cycles of paclitaxel and/or mapatumumab were permissible in selected cases.Twenty-seven patients (21 males), with a median age of 54 years, received mapatumumab in the following three cohorts: 3 mg/kg (n = 4), 10 mg/kg (n = 11), and 20 mg/kg (n = 12). The median number of cycles was four. Dose-limiting toxicities (DLTs) were grade 3 hypersensitivity reaction (n = 1) and neutropenic fever (n = 1), both at 10 mg/kg. Non-DLT treatment-related adverse events occurring in more than 10% of administered doses included alopecia, neutropenia, fatigue, nausea, anemia, thrombocytopenia, anorexia, and neuropathy. Paclitaxel and carboplatin exposures were similar in the presence or absence of mapatumumab. Plasma mapatumumab concentrations seemed similar to data from previous phase I monotherapy studies. Five patients (19%) achieved a confirmed radiologic partial response (including one pathologic complete response), and 12 patients (44%) had stable disease as their best response.Mapatumumab is well-tolerated up to 20 mg/kg in combination with paclitaxel and carboplatin. There are no apparent pharmacokinetic interactions among the drugs. Preliminary anticancer activity demonstrated clinical benefit for the majority of these patients.
Distinct Epigenomic Features in End-Stage Failing Human Hearts
Authors: Mehregan Movassagh, Mun-Kit Choy, David A. Knowles, Lina Cordeddu, Syed Haider, Thomas Down, Lee Siggens, Ana Vujic, Ilenia Simeoni, Chris Penkett, Martin Goddard, Pietro Lio, Martin R. Bennett, Roger S.-Y. Foo
Journal: Circulation (2011)

The epigenome refers to marks on the genome, including DNA methylation and histone modifications, that regulate the expression of underlying genes. A consistent profile of gene expression changes in end-stage cardiomyopathy led us to hypothesize that distinct global patterns of the epigenome may also exist.We constructed genome-wide maps of DNA methylation and histone-3 lysine-36 trimethylation (H3K36me3) enrichment for cardiomyopathic and normal human hearts. More than 506 Mb sequences per library were generated by high-throughput sequencing, allowing us to assign methylation scores to ≈28 million CG dinucleotides in the human genome. DNA methylation was significantly different in promoter CpG islands, intragenic CpG islands, gene bodies, and H3K36me3-enriched regions of the genome. DNA methylation differences were present in promoters of upregulated genes but not downregulated genes. H3K36me3 enrichment itself was also significantly different in coding regions of the genome. Specifically, abundance of RNA transcripts encoded by the DUX4 locus correlated to differential DNA methylation and H3K36me3 enrichment. In vitro, Dux gene expression was responsive to a specific inhibitor of DNA methyltransferase, and Dux siRNA knockdown led to reduced cell viability.Distinct epigenomic patterns exist in important DNA elements of the cardiac genome in human end-stage cardiomyopathy. The epigenome may control the expression of local or distal genes with critical functions in myocardial stress response. If epigenomic patterns track with disease progression, assays for the epigenome may be useful for assessing prognosis in heart failure. Further studies are needed to determine whether and how the epigenome contributes to the development of cardiomyopathy.
Nucleotide sequence of nifD from Frankia alni strain ArI3: phylogenetic inferences.
Authors: P Normand, M Gouy, B Cournoyer, P Simonet
Journal: Molecular Biology and Evolution (1992)

The complete nucleotide sequence of the nifD gene encoding the alpha subunit of component I of nitrogenase from Frankia alni strain ArI3 was determined. The coding region is 1,458 bp in length and encodes a polypeptide of 486 residues with a predicted molecular weight of 53,500. Phylogenetic inferences with 12 complete published nifD sequences were drawn using a variety of approaches. Frankia nifD clusters with proteobacteria rather than with Clostridium pasteurianum, the other Gram-positive bacterium studied. Extant eubacterial nif genes seem to have at least three distinct evolutionary origins as a result of ancient gene duplications. Within the Gram-positive bacterial phylum, functional nif genes descend from different duplicates.
The New Pharmacy
Authors: H. G. Lys
Journal: BMJ (1894)

<h3>Abstract</h3> The number of new daily infections is one of the main parameters to understand the dynamics of an epidemic. During the COVID-19 pandemic in 2020, however, such information has been underestimated. Here, we propose a retrospective methodology to estimate daily infections from daily deaths, because those are usually more accurately documented. This methodology is applied to Spain and its 19 administrative regions. Our results showed that probable infections during the first wave were between 35 and 42 times more than those officially documented on 14 March, when the national government decreed a national lockdown and 9 times more than those documented by the updated version of the official data. The national lockdown had a strong effect on the growth rate of virus transmission, which began to decrease immediately. Finally, the first inferred infection in Spain is about 43 days before it was officially reported during the first wave. The current official data show delays of 15-30 days in the first infection relative to the inferred infections in 63% of the regions. In summary, we propose a methodology that allows reinterpretation of official daily infections, improving data accuracy in infection magnitude and dates because it assimilates valuable information from the National Seroprevalence Studies.
Adolescent Personality Disorders Associated With Violence and Criminal Behavior During Adolescence and Early Adulthood
Authors: Jeffrey G. Johnson, Patricia Cohen, Elizabeth Smailes, Stephanie Kasen, John M. Oldham, Andrew E. Skodol, Judith S. Brook
Journal: American Journal of Psychiatry (2000)

OBJECTIVE: A community-based, longitudinal prospective study was conducted to investigate whether personality disorders during adolescence are associated with elevated risk for violent behavior during adolescence and early adulthood. METHOD: A community-based sample of 717 youths from upstate New York and their mothers were interviewed in 1983, 1985–1986, and 1991–1993. Axis I and II disorders were assessed in 1983 and 1985–1986. Antisocial personality disorder was not assessed because most participants were less than 18 years of age in 1983 and 1985–1986. Violent behavior was assessed in 1985–1986 and 1991–1993. RESULTS: Adolescents with a greater number of DSM-IV cluster A or cluster B personality disorder symptoms were more likely than other adolescents in the community to commit violent acts during adolescence and early adulthood, including arson, assault, breaking and entering, initiating physical fights, robbery, and threats to injure others. These associations remained significant after controlling for the youths’ age and sex, for parental psychopathology and socioeconomic status, and for co-occurring psychiatric disorders during adolescence. Paranoid, narcissistic, and passive-aggressive personality disorder symptoms during adolescence were independently associated with risk for violent acts and criminal behavior during adolescence and early adulthood after the covariates were controlled. CONCLUSIONS: Cluster A and cluster B personality disorders and paranoid, narcissistic, and passive-aggressive personality disorder symptoms during adolescence may increase risk for violent behavior that persists into early adulthood.
Human cardiomyocyte progenitor cell transplantation preserves long-term function of the infarcted mouse myocardium
Authors: Anke M. Smits, Linda W. van Laake, Krista den Ouden, Chantal Schreurs, Károly Szuhai, Cees J. van Echteld, Christine L. Mummery, Pieter A. Doevendans, Marie-José Goumans
Journal: Cardiovascular Research (2009)

AimsRecent clinical studies revealed that positive results of cell transplantation on cardiac function are limited to the short- and mid-term restoration phase following myocardial infarction (MI), emphasizing the need for long-term follow-up. These transient effects may depend on the transplanted cell-type or its differentiation state. We have identified a population of cardiomyocyte progenitor cells (CMPCs) capable of differentiating efficiently into beating cardiomyocytes, endothelial cells, and smooth muscle cells in vitro. We investigated whether CMPCs or pre-differentiated CMPC-derived cardiomyocytes (CMPC-CM) are able to restore the injured myocardium after MI in mice.