tbuckley/cabot-search huggingface dataset:
The DEK oncoprotein binds to highly and ubiquitously expressed genes with a dual role in their transcriptional regulation
Authors: Carl Sandén, Linnea Järvstråt, Andreas Lennartsson, Per Brattås, Björn Nilsson, Urban Gullberg
Journal: Molecular Cancer (2014)

The DEK gene is highly expressed in a wide range of cancer cells, and a recurrent translocation partner in acute myeloid leukemia. While DEK has been identified as one of the most abundant proteins in human chromatin, its function and binding properties are not fully understood. We performed ChIP-seq analysis in the myeloid cell line U937 and coupled it with epigenetic and gene expression analysis to explore the genome-wide binding pattern of DEK and its role in gene regulation. We show that DEK preferentially binds to open chromatin, with a low degree of DNA methylation and scarce in the heterochromatin marker H3K9me3 but rich in the euchromatin marks H3K4me2/3, H3K27ac and H3K9ac. More specifically, DEK binding is predominantly located at the transcription start sites of highly transcribed genes and a comparative analysis with previously established transcription factor binding patterns shows a similarity with that of RNA polymerase II. Further bioinformatic analysis demonstrates that DEK mainly binds to genes that are ubiquitously expressed across tissues. The functional significance of DEK binding was demonstrated by knockdown of DEK by shRNA, resulting in both significant upregulation and downregulation of DEK-bound genes. We find that DEK binds to transcription start sites with a dual role in activation and repression of highly and ubiquitously expressed genes.
Role of PP2Cα in cell growth, in radio- and chemosensitivity, and in tumorigenicity
Authors: Twan Lammers, Peter Peschke, Volker Ehemann, Jürgen Debus, Boris Slobodin, Sara Lavi, Peter Huber
Journal: Molecular Cancer (2007)

PP2Cα is the representative member of the type 2C family of protein phosphatases, and it has recently been implicated in the regulation of p53-, TGFβ-, cyclin-dependent kinase- and apoptosis-signaling. To investigate the role of PP2Cα in cell growth and in radio- and chemosensitivity, wild type and PP2Cα siRNA-expressing MCF7 cells were subjected to several different viability and cell cycle analyses, both under basal conditions and upon treatment with radio- and chemotherapy. By comparing the growth of tumors established from both types of cells, we also evaluated the involvement of PP2Cα in tumorigenesis. It was found that knockdown of PP2Cα did not affect the proliferation, the clonogenic survival and the membrane integrity of MCF7 cells. In addition, it did not alter their radio- and chemosensitivity. For PP2Cα siRNA-expressing MCF7 cells, the number of cells in the G0/G1 phase of the cell cycle was reduced, the induction of the G1 block was attenuated, the number of cells in G2/M was increased, and the induction of the G2 block was enhanced. The tumorigenic potential of PP2Cα siRNA-expressing MCF7 cells was found to be higher than that of wild type MCF7 cells, and the in vivo proliferation of these cells was found to be increased. Based on these findings, we conclude that PP2Cα is not involved in controlling cell growth and radio- and chemosensitivity in vitro. It does, however, play a role in the regulation of the cell cycle, in the induction of cell cycle checkpoints and in tumorigenesis. The latter notion implies that PP2Cα may possess tumor-suppressing properties, and it thereby sets the stage for more elaborate analyses on its involvement in the development and progression of cancer.
Endocrine Effects of Adjuvant Letrozole + Triptorelin Compared With Tamoxifen + Triptorelin in Premenopausal Patients With Early Breast Cancer
Authors: Emanuela Rossi, Alessandro Morabito, Ermelinda De Maio, Francesca Di Rella, Giuseppe Esposito, Adriano Gravina, Vincenzo Labonia, Gabriella Landi, Francesco Nuzzo, Carmen Pacilio, Maria Carmela Piccirillo, Giuseppe D'Aiuto, Massimiliano D'Aiuto, Massimo Rinaldo, Gerardo Botti, Ciro Gallo, Francesco Perrone, Andrea de Matteis
Journal: Journal of Clinical Oncology (2007)

Purpose To compare the endocrine effects of 6 months of adjuvant treatment with letrozole + triptorelin or tamoxifen + triptorelin in premenopausal patients with early breast cancer within an ongoing phase 3 trial (Hormonal Adjuvant Treatment Bone Effects study). Patients and Methods Prospectively collected hormonal data were available for 81 premenopausal women, of whom 30 were assigned to receive tamoxifen + triptorelin and 51 were assigned letrozole + triptorelin ± zoledronate. Serum 17-β-estradiol (E2), follicle-stimulating hormone (FSH), luteinizing hormone (LH), Δ4-androstenedione, testosterone, dehydroepiandrosterone-sulfate, progesterone, adrenocorticotropic hormone (ACTH), and cortisol were measured at baseline and after 6 months of treatment. For each hormone, 6-month values were compared between treatment groups by the Wilcoxon-Mann-Whitney exact test. Results Median age was 44 years for both groups of patients. Letrozole + triptorelin (± zoledronate) induced a stronger suppression of median E2 serum levels (P = .0008), LH levels (P = .0005), and cortisol serum levels (P &lt; .0001) compared with tamoxifen + triptorelin. Median FSH serum levels were suppressed in both groups, but such suppression was lower among patients receiving letrozole, who showed significantly higher median FSH serum levels (P &lt; .0001). No significant differences were observed for testosterone, progesterone, ACTH, androstenedione, and dehydroepiandrosterone between the two groups of patients. Conclusion Letrozole in combination with triptorelin induces a more intense estrogen suppression than tamoxifen + triptorelin in premenopausal patients with early breast cancer.
A Phase I Study of Oral ARRY-614, a p38 MAPK/Tie2 Dual Inhibitor, in Patients with Low or Intermediate-1 Risk Myelodysplastic Syndromes
Authors: Guillermo Garcia-Manero, Hanna J. Khoury, Elias Jabbour, Jeffrey Lancet, Shannon L. Winski, LouAnn Cable, Selena Rush, Lara Maloney, Grant Hogeland, Mieke Ptaszynski, Monica Cabrero Calvo, Zach Bohannan, Alan List, Hagop Kantarjian, Rami Komrokji
Journal: Clinical Cancer Research (2014)

Abstract Purpose: Data suggest that activity of p38 MAPK and Tie2 kinases is dysregulated in myelodysplastic syndromes (MDS) and may be targets for novel therapies. A phase I study of ARRY-614, an oral dual inhibitor of p38 MAPK and Tie2, was conducted in patients with low or intermediate-1 International Prognostic Scoring System risk MDS to evaluate safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary responses by International Working Group 2006 criteria. Experimental Design: Forty-five patients received ARRY-614 either once daily or twice daily in dose escalation (400, 600, 900, or 1,200 mg once daily; 200 or 300 mg twice daily) or expansion cohorts. Results: The 300 mg twice daily schedule was not tolerated, and an MTD was not reached for once daily dosing. Treatment-related adverse events were primarily grade 1–2, with the most common being rash, diarrhea, dry skin, fatigue and anorexia. Interpatient PK variability was high, although exposure was sufficient to achieve reduction in p38 MAPK activation in bone marrow and in the levels of circulating biomarkers. Disease responses were observed in 14 of 44 (32%) evaluable patients, 13 (93%) of whom had previously been treated with a hypomethylating agent. Responses were observed in all lineages, with 5 patients experiencing bilineage responses. Three of 25 red blood cell transfusion-dependent (TD) patients achieved transfusion independence (TI) and 5 of 7 platelet TD patients achieved TI. Conclusions: ARRY-614 was well tolerated and has sufficient activity to warrant further evaluation in this patient population. We recommend 1,200 mg once daily as the optimal dose for further study. Clin Cancer Res; 21(5); 985–94. ©2014 AACR.
Environmental pleural plaques in an asbestos exposed population of northeast Corsica
Authors: F Rey, C Boutin, J Steinbauer, J R Viallat, P Alessandroni, P Jutisz, D Di Giambattista, M A Billon-Galland, P Hereng, P Dumortier
Journal: European Respiratory Journal (1993)

The purpose of this study was to determine whether the inhabitants of villages environmentally exposed to asbestos, in northeast Corsica, had a higher incidence of pleural plaques. X-rays were obtained from subjects aged over 50 yrs, with no occupational exposure to asbestos or history of pleural disease, in one village exposed to asbestos, Murato, and a nonexposed, control village, Vezzani. In addition, the mineral content of the air and parietal pleura of animals in the exposed zone was studied, using transmission electron microscopy. The incidence of bilateral pleural plaques in the exposed population was 41%, as compared to 7.5% in the nonexposed population (p < 0.00001). The levels of airborne tremolite were higher in Murato (6-72 ng.m-3) than in Vezzani (< 1 ng.m-3), but chrysotile levels were similar. Significant numbers of chrysotile and tremolite fibres were identified in the parietal pleura of animals from the exposed village. This study confirms the well-known correlation between bilateral pleural plaques and environmental exposure to low levels of asbestos.
Abstract 10441: Latent Genetic Backgrounds and Molecular Pathogenesis in Acquired Long QT Syndrome with Distinct Arrhythmic Triggers
Authors: Hideki Itoh, Yuko Oka, Wei-Guang Ding, Tomoko Sakaguchi, Hiromi Kimura, Yuka Mizusawa, Akashi Miyamoto, Jie Wu, Seiko Ohno, Takeru Makiyama, Makoto Ito, Hiroshi Matsuura, Minoru Horie
Journal: Circulation (2010)

Introduction: A part of patients with acquired long QT syndrome (aLQTS) has been shown to carry mutations in cardiac ion channel genes similar to those identified in congenital long QT syndrome (cLQTS). Drugs and bradycardia are typical triggers for aLQTS, but it remains unknown whether these 2 subtypes of aLQTS have distinct genetic backgrounds. Methods: Genetic testing was carried out for cLQTS-related genes (KCNQ1 , KCNH2 , SCN5A , KCNE1 , and KCNE2 ) in 34 subjects (20 drug-induced aLQTS and 14 bradycardia-induced aLQTS). Biophysical characteristics of the identified aLQTS-associated mutations were analyzed using a heterologous expression system (CHO cell line) and a computer simulation model. Results: Bradycardia-induced aLQTS displayed significantly longer QTc interval than those with drug-induced aLQTS when without ventricular arrhythmias (495±42 vs. 446±29 ms, p<0.05). On the other hand, the positive-mutation rates were similar between the 2 groups (drug-induced aLQTS vs. bradycardia-induced aLQTS...
Systemic Inflammatory Response and Progression to Severe Sepsis in Critically Ill Infected Patients
Authors: Corinne Alberti, Christian Brun-Buisson, Sylvie Chevret, Massimo Antonelli, Sergey V. Goodman, Claudio Martin, Rui Moreno, Ana R. Ochagavia, Mark Palazzo, Karl Werdan, Jean Roger Le Gall
Journal: American Journal of Respiratory and Critical Care Medicine (2004)

Rationale: The systemic inflammatory response syndrome has low specificity to identify infected patients at risk of worsening to severe sepsis or shock. Objective: To examine the incidence of and risk factors for worsening sepsis in infected patients. Methods: A 1-year inception cohort study in 28 intensive care units of patients (n = 1,531) having a first episode of infection on admission or during the stay. Measurements and main results: The cumulative incidence of progression to severe sepsis or shock was 20% and 24% at Days 10 and 30, respectively. Variables independently associated (hazard ratio [HR]) with worsening sepsis included: temperature higher than 38.2°C (1.6), heart rate greater than 120/minute (1.3), systolic blood pressure higher than 110 mm Hg (1.5), platelets higher than 150 × 109/L (1.5), serum sodium higher than 145 mmol/L (1.5), bilirubin higher than 30 μmol/L (1.3), mechanical ventilation (1.5), and five variables characterizing infection (pneumonia [HR 1.5], peritonitis [1.5], primary bacteremia [1.8], and infection with gram-positive cocci [1.3] or aerobic gram-negative bacilli [1.4]). The 12 weighted variables were included in a score (Risk of Infection to Severe Sepsis and Shock Score, range 0–49), summarized in four classes of "low" (score 0–8) and "moderate" (8.5–16) risk (9% and 17% probability of worsening, respectively), and of "high" (16.5–24) and "very high" (score > 24) risk (31% and 55% probability, respectively). Conclusions: One of four patients presenting with infection/sepsis worsen to severe sepsis or shock. A score estimating this risk, using objectively defined criteria for systemic inflammatory response syndrome, could be used by physicians to stratify patients for clinical management and to test new interventions.
Function-Specific Accelerations in Rates of Sequence Evolution Suggest Predictable Epistatic Responses to Reduced Effective Population Size
Authors: T. Warnecke, E. P. C. Rocha
Journal: Molecular Biology and Evolution (2011)

Changes in effective population size impinge on patterns of molecular evolution. Notably, slightly deleterious mutations are more likely to drift to fixation in smaller populations, which should typically also lead to an overall acceleration in the rates of evolution. This prediction has been validated empirically for several endosymbiont and island taxa. Here, we first show that rate accelerations are also evident in bacterial pathogens whose recent shifts in virulence make them prime candidates for reduced effective population size: Bacillus anthracis, Bordetella parapertussis, Mycobacterium leprae, Salmonella enterica typhi, Shigella spp., and Yersinia pestis. Using closely related genomes to analyze substitution rate dynamics across six phylogenetically independent bacterial clades, we demonstrate that relative rates of coding sequence evolution are biased according to gene functional category. Notably, genes that buffer against slightly deleterious mutations, such as chaperones, experience stronger rate accelerations than other functional classes at both nonsynonymous and synonymous sites. Although theory predicts altered evolutionary dynamics for buffer loci in the face of accumulating deleterious mutations, to observe even stronger rate accelerations is surprising. We suggest that buffer loci experience elevated substitution rates because the accumulation of deleterious mutations in the remainder of the genome favors compensatory substitutions in trans. Critically, the hyper-acceleration is evident across phylogenetically independent clades, supporting the hypothesis that reductions in effective population size predictably induce epistatic responses in genes that buffer against slightly deleterious mutations.
Cyclin D1 Proteolysis: a Retinoid Chemoprevention Signal in Normal, Immortalized, and Transformed Human Bronchial Epithelial Cells
Authors: J. O. Boyle, J. Langenfeld, F. Lonardo, D. Sekula, P. Reczek, V. Rusch, M. I. Dawson, E. Dmitrovsky
Journal: JNCI Journal of the National Cancer Institute (1999)

Retinoids (derivatives of vitamin A) are reported to reduce the occurrence of some second primary cancers, including aerodigestive tract tumors. In contrast, beta-carotene does not reduce the occurrence of primary aerodigestive tract cancers. Mechanisms explaining these effective retinoid and ineffective carotenoid chemoprevention results are poorly defined. Recently, the all-trans-retinoic acid (RA)-induced proteolysis of cyclin D1 that leads to the arrest of cells in G1 phase of the cell cycle was described in human bronchial epithelial cells and is a promising candidate for such a mechanism. In this study, we have investigated this proteolysis as a common signal used by carotenoids or receptor-selective and receptor-nonselective retinoids.We treated cultured normal human bronchial epithelial cells, immortalized human bronchial epithelial cells (BEAS-2B), and transformed human bronchial epithelial cells (BEAS-2BNNK) with receptor-selective or receptor-nonselective retinoids or with carotenoids and studied the effects on cell proliferation by means of tritiated thymidine incorporation and on cyclin D1 expression by means of immunoblot analysis. We also examined whether calpain inhibitor I, an inhibitor of the 26S proteasome degradation pathway, affected the decline (i.e., proteolysis) of cyclin D1.Receptor-nonselective retinoids were superior to the carotenoids studied in mediating the decline in cyclin D1 expression and in suppressing the growth of bronchial epithelial cells. Retinoids that activated retinoic acid receptor beta or retinoid X receptor pathways preferentially led to a decrease in the amount of cyclin D1 protein and a corresponding decline in growth. The retinoid-mediated degradation of cyclin D1 was blocked by cotreatment with calpain inhibitor I.Retinoid-dependent cyclin D1 proteolysis is a common chemoprevention signal in normal and neoplastic human bronchial epithelial cells. In contrast, carotenoids did not affect cyclin D1 expression. Thus, the degradation of cyclin D1 is a candidate intermediate marker for effective retinoid-mediated cancer chemoprevention in the aerodigestive tract.
Effects of nabumetone compared with naproxen on platelet aggregation in patients with rheumatoid arthritis
Authors: E. A J Knijff-Dutmer, A. Martens, M. A F J v. Laar
Journal: Annals of the Rheumatic Diseases (1999)

<h3>OBJECTIVE</h3> To test the hypothesis that nabumetone (a partially selective cyclo-oxygenase-(COX)-2 inhibitor) has less effect on platelet aggregation than naproxen (a non-selective COX-inhibitor) in patients with rheumatoid arthritis (RA). <h3>METHODS</h3> A crossover study in 10 RA patients was performed, using either nabumetone or naproxen for two weeks, and, after a washout period of two weeks, the other drug during another two weeks. Platelet aggregation studies were performed and bleeding time was assessed before and after each treatment period. <h3>RESULTS</h3> Maximum platelet aggregation induced by epinephrine and by collagen was significantly more reduced after the use of naproxen than of nabumetone; secondary aggregation induced by ADP and epinephrine disappeared more often by naproxen than by nabumetone. Bleeding times were not influenced. <h3>CONCLUSION</h3> COX dependent platelet aggregation in RA patients seems to be more inhibited by naproxen than by nabumetone. This may be relevant for patients requiring non-steroidal anti-inflammatory drug treatment but who have an increased risk of bleeding as well.
Effect of ACE inhibitors on angiographic restenosis after coronary stenting (PARIS): a randomised, double-blind, placebo-controlled trial
Authors: Thibaud Meurice, Christophe Bauters, Xavier Hermant, Valérie Codron, Eric VanBelle, Eugène P Mc Fadden, Jean-Marc Lablanche, Michel E Bertrand, Philippe Amouyel
Journal: The Lancet (2001)
Some Coronary Risk Factors Related to the Insulin Resistance Syndrome and Treatment With Gemfibrozil
Authors: Leena Tenkanen, Matti Mänttäri, Vesa Manninen
Journal: Circulation (1995)

Background Coronary risk factors related to the insulin resistance syndrome tend to cluster in the same individual. Our previous studies have shown that the dyslipidemia characteristic of this syndrome—low HDL cholesterol and high triglyceride (TG) levels—responds well to treatment with gemfibrozil. Most factors related to insulin-resistance syndrome decrease fibrinolytic capacity, whereas a recent study showed that gemfibrozil improves it and thus may attenuate thrombotic events. To discover whether subjects with clustering of factors related to this resistance might in particular benefit from gemfibrozil, we reanalyzed the Helsinki Heart Study data. Methods and Results We used Cox regression models to explore the effects of gemfibrozil among overweight subjects with additional coronary risk factors in this hypercholesterolemic male population of 2046 subjects randomized to gemfibrozil and 2035 to placebo. The effect of gemfibrozil was largely confined to overweight subjects: among those with body mass index (BMI) &gt;26 kg/m 2 , the net difference in cardiac end points between gemfibrozil and placebo groups was 21 (25 of 1119 versus 46 of 1081), and in those with BMI ≤26 kg/m 2 , it was 7 (31 of 927 versus 38 of 954). The risk reduction with gemfibrozil was 78% ( P =.002) among those with BMI &gt;26 kg/m 2 and dyslipidemia (TG ≥2.3 mmol/L and HDL cholesterol &lt;1.08 mmol/L). Among those with BMI &gt;26 kg/m 2 and three or four of the following factors present—smoking, sedentary lifestyle, blood pressure ≥140/90 mm Hg, or blood glucose &gt;4.4 mmol/L—the risk reduction was 68% ( P =.03). Conclusions Gemfibrozil reduced the coronary risk mainly in overweight subjects with additional risk factors known to contribute to the insulin-resistance syndrome or predispose to it.
Characterization of resident and migratory dendritic cells in human lymph nodes
Authors: Elodie Segura, Jenny Valladeau-Guilemond, Marie-Hélène Donnadieu, Xavier Sastre-Garau, Vassili Soumelis, Sebastian Amigorena
Journal: The Journal of Experimental Medicine (2012)

Dendritic cells (DCs) initiate adaptive immune responses in lymph nodes (LNs). In mice, LN DCs can be divided into resident and tissue-derived populations, the latter of which migrate from the peripheral tissues. In humans, different subsets of DCs have been identified in the blood, spleen, and skin, but less is known about populations of resident and migratory tissue-derived DCs in LNs. We have analyzed DCs in human LNs and identified two populations of resident DCs that are present in all LNs analyzed, as well as in the spleen and tonsil, and correspond to the two known blood DC subtypes. We also identify three main populations of skin-derived migratory DCs that are present only in skin-draining LNs and correspond to the DC subsets found in the skin. Resident DCs subsets induce both Th1 and Th2 cytokines in naive allogeneic T lymphocytes, whereas the corresponding blood subsets failed to induce efficient Th2 polarization. LN-resident DCs also cross-present antigen without in vitro activation, whereas blood DCs fail to do so. Among migratory DCs, one subset was poor at both CD4+ and CD8+ T cell activation, whereas the other subsets induced only Th2 polarization. We conclude that in humans, skin-draining LNs host both resident and migratory DC subsets with distinct functional abilities.
Cellular senescence and the senescent secretory phenotype: therapeutic opportunities
Authors: Tamara Tchkonia, Yi Zhu, Jan van Deursen, Judith Campisi, James L. Kirkland
Journal: Journal of Clinical Investigation (2013)

Aging is the largest risk factor for most chronic diseases, which account for the majority of morbidity and health care expenditures in developed nations. New findings suggest that aging is a modifiable risk factor, and it may be feasible to delay age-related diseases as a group by modulating fundamental aging mechanisms. One such mechanism is cellular senescence, which can cause chronic inflammation through the senescence-associated secretory phenotype (SASP). We review the mechanisms that induce senescence and the SASP, their associations with chronic disease and frailty, therapeutic opportunities based on targeting senescent cells and the SASP, and potential paths to developing clinical interventions.