tbuckley/cabot-search huggingface dataset:
Synergistic Activation of Vascular TRPC6 Channel by Receptor and Mechanical Stimulation via Phospholipase C/Diacylglycerol and Phospholipase A <sub>2</sub> /ω-Hydroxylase/20-HETE Pathways
Authors: Ryuji Inoue, Lars J. Jensen, Zhong Jian, Juan Shi, Lin Hai, Andrew I. Lurie, Freja H. Henriksen, Max Salomonsson, Hiromitsu Morita, Yasuhiro Kawarabayashi, Masayuki Mori, Yasuo Mori, Yushi Ito
Journal: Circulation Research (2009)

TRPC6 is a non-voltage-gated Ca(2+) entry/depolarization channel associated with vascular tone regulation and remodeling. Expressed TRPC6 channel responds to both neurohormonal and mechanical stimuli, the mechanism for which remains controversial. In this study, we examined the possible interactions of receptor and mechanical stimulations in activating this channel using the patch clamp technique. In HEK293 cells expressing TRPC6, application of mechanical stimuli (hypotonicity, shear, 2,4,6-trinitrophenol) caused, albeit not effective by themselves, a prominent potentiation of cationic currents (I(TRPC6)) induced by a muscarinic receptor agonist carbachol. This effect was insensitive to a tarantula toxin GsMTx-4 (5 mumol/L). A similar extent of mechanical potentiation was observed after activation of I(TRPC6) by GTPgammaS or a diacylglycerol analog 1-oleoyl-2-acetyl-sn-glycerol (OAG). Single TRPC6 channel activity evoked by carbachol was also enhanced by a negative pressure added in the patch pipette. Mechanical potentiation of carbachol- or OAG-induced I(TRPC6) was abolished by small interfering RNA knockdown of cytosolic phospholipase A(2) or pharmacological inhibition of omega-hydroxylation of arachidonic acid into 20-HETE (20-hydroxyeicosatetraenoic acid). Conversely, direct application of 20-HETE enhanced both OAG-induced macroscopic and single channel TRPC6 currents. Essentially the same results were obtained for TRPC6-like cation channel in A7r5 myocytes, where its activation by noradrenaline or Arg8 vasopressin was greatly enhanced by mechanical stimuli via 20-HETE production. Furthermore, myogenic response of pressurized mesenteric artery was significantly enhanced by weak receptor stimulation dependently on 20-HETE production. These results collectively suggest that simultaneous operation of receptor and mechanical stimulations may synergistically amplify transmembrane Ca(2+) mobilization through TRPC6 activation, thereby enhancing the vascular tone via phospholipase C/diacylglycerol and phospholipase A(2)/omega-hydroxylase/20-HETE pathways.
Design of anticancer prodrugs for reductive activation
Authors: Yu Chen, Longqin Hu
Journal: Medicinal Research Reviews (2008)

Abstract Anticancer prodrugs designed to target specifically tumor cells should increase therapeutic effectiveness and decrease systemic side effects in the treatment of cancer. Over the last 20 years, significant advances have been made in the development of anticancer prodrugs through the incorporation of triggers for reductive activation. Reductively activated prodrugs have been designed to target hypoxic tumor tissues, which are known to overexpress several endogenous reductive enzymes. In addition, exogenous reductive enzymes can be delivered to tumor cells through fusion with tumor‐specific antibodies or overexpressed in tumor cells through gene delivery approaches. Many anticancer prodrugs have been designed to use both the endogenous and exogenous reductive enzymes for target‐specific activation and these prodrugs often contain functional groups such as quinones, nitroaromatics, N‐oxides, and metal complexes. Although no new agents have been approved for clinical use, several reductively activated prodrugs are in various stages of clinical trial. This review mainly focuses on the medicinal chemistry aspects of various classes of reductively activated prodrugs including design principles, structure‐activity relationships, and mechanisms of activation and release of active drug molecules. © 2008 Wiley Periodicals, Inc. Med Res Rev, 29, No. 1, 29–64, 2009
Detection of Enhancer-Associated Rearrangements Reveals Mechanisms of Oncogene Dysregulation in B-cell Lymphoma
Authors: Russell J.H. Ryan, Yotam Drier, Holly Whitton, M. Joel Cotton, Jasleen Kaur, Robbyn Issner, Shawn Gillespie, Charles B. Epstein, Valentina Nardi, Aliyah R. Sohani, Ephraim P. Hochberg, Bradley E. Bernstein
Journal: Cancer Discovery (2015)

Abstract B-cell lymphomas frequently contain genomic rearrangements that lead to oncogene activation by heterologous distal regulatory elements. We used a novel approach called “pinpointing enhancer-associated rearrangements by chromatin immunoprecipitation,” or PEAR-ChIP, to simultaneously map enhancer activity and proximal rearrangements in lymphoma cell lines and patient biopsies. This method detects rearrangements involving known cancer genes, including CCND1, BCL2, MYC, PDCD1LG2, NOTCH1, CIITA, and SGK1, as well as novel enhancer duplication events of likely oncogenic significance. We identify lymphoma subtype–specific enhancers in the MYC locus that are silenced in lymphomas with MYC-activating rearrangements and are associated with germline polymorphisms that alter lymphoma risk. We show that BCL6-locus enhancers are acetylated by the BCL6-activating transcription factor MEF2B, and can undergo genomic duplication, or target the MYC promoter for activation in the context of a “pseudo-double-hit” t(3;8)(q27;q24) rearrangement linking the BCL6 and MYC loci. Our work provides novel insights regarding enhancer-driven oncogene activation in lymphoma. Significance: We demonstrate a novel approach for simultaneous detection of genomic rearrangements and enhancer activity in tumor biopsies. We identify novel mechanisms of enhancer-driven regulation of the oncogenes MYC and BCL6, and show that the BCL6 locus can serve as an enhancer donor in an “enhancer hijacking” translocation. Cancer Discov; 5(10); 1058–71. ©2015 AACR. See related commentary by Mack et al., p. 1018. This article is highlighted in the In This Issue feature, p. 1005
Paclitaxel-Eluting versus Everolimus-Eluting Coronary Stents in Diabetes
Authors: Upendra Kaul, Sripal Bangalore, Ashok Seth, Priyadarshini Arambam, Rajpal K. Abhaichand, Tejas M. Patel, Darshan Banker, Atul Abhyankar, Ajit S. Mullasari, Sanjay Shah, Rajneesh Jain, Premchand R. Kumar, C.G. Bahuleyan
Journal: New England Journal of Medicine (2015)

The choice of drug-eluting stent in the treatment of patients with diabetes mellitus and coronary artery disease who are undergoing percutaneous coronary intervention (PCI) has been debated. Previous studies comparing paclitaxel-eluting stents with stents eluting rapamycin (now called sirolimus) or its analogues (everolimus or zotarolimus) have produced contradictory results, ranging from equivalence between stent types to superiority of everolimus-eluting stents.We randomly assigned 1830 patients with diabetes mellitus and coronary artery disease who were undergoing PCI to receive either a paclitaxel-eluting stent or an everolimus-eluting stent. We used a noninferiority trial design with a noninferiority margin of 4 percentage points for the upper boundary of the 95% confidence interval of the risk difference. The primary end point was target-vessel failure, which was defined as a composite of cardiac death, target-vessel myocardial infarction, or ischemia-driven target-vessel revascularization at the 1-year follow-up.At 1 year, paclitaxel-eluting stents did not meet the criterion for noninferiority to everolimus-eluting stents with respect to the primary end point (rate of target-vessel failure, 5.6% vs. 2.9%; risk difference, 2.7 percentage points [95% confidence interval, 0.8 to 4.5]; relative risk, 1.89 [95% confidence interval, 1.20 to 2.99]; P=0.38 for noninferiority). There was a significantly higher 1-year rate in the paclitaxel-eluting stent group than in the everolimus-eluting stent group of target-vessel failure (P=0.005), spontaneous myocardial infarction (3.2% vs. 1.2%, P=0.004), stent thrombosis (2.1% vs. 0.4%, P=0.002), target-vessel revascularization (3.4% vs. 1.2%, P=0.002), and target-lesion revascularization (3.4% vs. 1.2%, P=0.002).In patients with diabetes mellitus and coronary artery disease undergoing PCI, paclitaxel-eluting stents were not shown to be noninferior to everolimus-eluting stents, and they resulted in higher rates of target-vessel failure, myocardial infarction, stent thrombosis, and target-vessel revascularization at 1 year. (Funded by Boston Scientific; TUXEDO-India Clinical Trials Registry-India number, CTRI/2011/06/001830).
The normoglycaemic biobreeding rat: a spontaneous model for impaired gastric accommodation
Authors: Christophe Vanormelingen, Tim Vanuytsel, Tatsuhiro Masaoka, Gert De Hertogh, Hanne Vanheel, Pieter Vanden Berghe, Ricard Farré, Jan Tack
Journal: Gut (2014)

Impaired gastric accommodation is reported in patients with functional dyspepsia (FD). Previous findings in postinfectious patients with FD suggest that low-grade inflammation and dysfunction of nitrergic nerves play a role in impaired accommodation. To date, spontaneous animal models to study the relationship between these changes are lacking. We hypothesise that the normoglycaemic BioBreeding diabetes-prone (BB-DP) rat provides an animal model of inflammation-induced impaired gastric motor function.Control diabetes-resistant biobreeding, normoglycaemic and hyperglycaemic BB-DP rats were sacrificed at the age of 30, 70 and 220 days and gastric fundus tissue was harvested to study nitrergic motor control, inflammation and expression of neuronal isoform of nitric oxide synthase (nNOS) and inducible isoform of nitric oxide synthase (iNOS). Nutrient-induced changes in intragastric pressure (IGP) were measured in normoglycaemic BB-DP rats to study accommodation.No differences in nitrergic function and inflammation were observed between BB-DP and control rats at 30 days. The nitrergic component of the fundic muscle relaxation was reduced in BB-DP rats of 70 and 220 days. This was accompanied by a significant loss of nNOS proteins. IGP significantly increased during nutrient infusion in BB-DP rats of 220 days, indicating impaired accommodation. Infiltration of polymorphonuclear cells, increased myeloperoxidase activity and increased expression of iNOS was observed in the fundic mucosa and muscularis propria of 70-day-old and 220-day-old BB-DP rats.BB-DP rats of 220 days display altered fundic motor control and impaired accommodation, which is least partially explained by loss of nitrergic function. This may be related to inflammatory changes in the neuromuscular layer, suggesting that normoglycaemic BB-DP rats provide a spontaneous model for inflammation-induced impaired gastric accommodation.
A Modular Analysis Framework for Blood Genomics Studies: Application to Systemic Lupus Erythematosus
Authors: Damien Chaussabel, Charles Quinn, Jing Shen, Pinakeen Patel, Casey Glaser, Nicole Baldwin, Dorothee Stichweh, Derek Blankenship, Lei Li, Indira Munagala, Lynda Bennett, Florence Allantaz, Asuncion Mejias, Monica Ardura, Ellen Kaizer, Laurence Monnet, Windy Allman, Henry Randall, Diane Johnson, Aimee Lanier, Marilynn Punaro, Knut M. Wittkowski, Perrin White, Joseph Fay, Goran Klintmalm, Octavio Ramilo, A. Karolina Palucka, Jacques Banchereau, Virginia Pascual
Journal: Immunity (2008)
Mars and Venus in the GP's office
Authors: C. Jenkins
Journal: European Respiratory Journal (2006)

Discussions about the differences between men and women are age-old, but usually of great interest to both sexes and, despite our increasing understanding of gender psychology, likely to be prone to bias and misconstruction for centuries to come. The mix of gender differences in the pathogenesis, perception and presentation of disease is a potent brew for confusion, but needs further research if we are to completely understand the variety of ways in which nature and nurture interact in the development and manifestations of obstructive lung disease.

For some time, it has been known that men and women perceive and relate their symptoms differently 1. For many diseases, it is also becoming clear that males and females develop different symptoms and clinical manifestations, at different stages of a disease, and respond differently to treatment 2, 3. Traditionally, women have been considered to be more likely to report symptoms and to be more sensitive to changes in underlying disease 4, 5. In relation to the presenting features of chronic obstructive pulmonary disease (COPD) in males and females, two papers published in the present issue of the European Respiratory Journal have some important contributions to make.

In the first of these papers, Watson et al. 6 investigated predictors for the presence, development and remission of COPD symptoms in participants completing 3 yrs of the European Respiratory Society Study on Chronic Obstructive Pulmonary Disease (EUROSCOP). Over these 3 yrs similar proportions of males and females reported symptoms, although in males better lung function was associated with a reduction in new symptoms of wheeze and dyspnoea, and symptom prevalence reduced with annual improvement of forced expiratory volume in one second (FEV1). The prevalence of phlegm was reduced with budesonide treatment, an effect seen only in males. An increase in …
Ubiquitinated deiodinase: not dead yet
Authors: Ronald J. Koenig
Journal: Journal of Clinical Investigation (2003)

Originating in the thyroid, the prohormone thyroxine is converted to triiodothyronine, which is essential in brain development, growth, and metabolism. A study in this issue reveals a novel mechanism for controlling triiodothyronine production that provides the first example of enzyme activity being restored by deubiquitination.
Time Dependency of Molecular Rate Estimates and Systematic Overestimation of Recent Divergence Times
Authors: Simon Y W Ho, Matthew J Phillips, Alan Cooper, Alexei J Drummond
Journal: Molecular Biology and Evolution (2005)

Studies of molecular evolutionary rates have yielded a wide range of rate estimates for various genes and taxa. Recent studies based on population-level and pedigree data have produced remarkably high estimates of mutation rate, which strongly contrast with substitution rates inferred in phylogenetic (species-level) studies. Using Bayesian analysis with a relaxed-clock model, we estimated rates for three groups of mitochondrial data: avian protein-coding genes, primate protein-coding genes, and primate d-loop sequences. In all three cases, we found a measurable transition between the high, short-term (<1–2 Myr) mutation rate and the low, long-term substitution rate. The relationship between the age of the calibration and the rate of change can be described by a vertically translated exponential decay curve, which may be used for correcting molecular date estimates. The phylogenetic substitution rates in mitochondria are approximately 0.5% per million years for avian protein-coding sequences and 1.5% per million years for primate protein-coding and d-loop sequences. Further analyses showed that purifying selection offers the most convincing explanation for the observed relationship between the estimated rate and the depth of the calibration. We rule out the possibility that it is a spurious result arising from sequence errors, and find it unlikely that the apparent decline in rates over time is caused by mutational saturation. Using a rate curve estimated from the d-loop data, several dates for last common ancestors were calculated: modern humans and Neandertals (354 ka; 222–705 ka), Neandertals (108 ka; 70–156 ka), and modern humans (76 ka; 47–110 ka). If the rate curve for a particular taxonomic group can be accurately estimated, it can be a useful tool for correcting divergence date estimates by taking the rate decay into account. Our results show that it is invalid to extrapolate molecular rates of change across different evolutionary timescales, which has important consequences for studies of populations, domestication, conservation genetics, and human evolution.
α1-Antitrypsin Precursor in Gastric Juice Is a Novel Biomarker for Gastric Cancer and Ulcer
Authors: Ping-I Hsu, Chung-Hsuan Chen, Chieu-Shia Hsieh, Wei-Chao Chang, Kwok-Hung Lai, Gin-Ho Lo, Ping-Ning Hsu, Feng-Woei Tsay, Yu-Shan Chen, Michael Hsiao, Hui-Chun Chen, Pei-Jung Lu
Journal: Clinical Cancer Research (2007)

Abstract Purpose: To search for novel disease-specific markers in gastric juice by investigating the protein concentrations and components in gastric juice from patients with various gastroduodenal diseases. Experimental Design: Protein concentrations and pH values in fasting gastric juice were examined in 120 healthy subjects and 39 gastric ulcer, 38 duodenal ulcer, and 31 gastric cancer patients. The protein components in gastric juice were studied by two-dimensional PAGE and mass spectrometric analysis. Results: Protein concentrations in gastric juice of patients with gastric ulcers and gastric cancer were significantly higher than those in healthy subjects (1.06 and 2.61 mg/mL versus 0.48 mg/mL; P = 0.001 and P &amp;lt; 0.001, respectively), and duodenal ulcer patients had lower gastric juice protein concentrations compared with healthy subjects (0.26 versus 0.48 mg/mL; P &amp;lt; 0.05). Gastric hypoacidity and advanced age were independent factors affecting the protein concentrations in gastric juice with odds ratios of 32.9 (95% confidence interval, 11.8-90.9) and 3.2 (95% confidence interval, 1.3-8.3), respectively. Each electrophoresis images of gastric juice could be classified into one of three patterns: basic band, specific band, or nonspecific band. The frequencies of specific band pattern in healthy subjects, gastric ulcer, duodenal ulcer, and gastric cancer patients were 6%, 42%, 6%, and 93%, respectively. Proteomic analysis revealed that α1-antitrypsin precursor was the principal peptide in the specific band. Conclusions: α1-antitrypsin precursor in gastric juice is a novel biomarker for gastric cancer and ulcer. A noninvasive method to obtain gastric juice followed by proteomic analysis may serve as a new tool to screen for gastric malignancies.
Association between β-blocker therapy and outcomes in patients hospitalised with acute exacerbations of chronic obstructive lung disease with underlying ischaemic heart disease, heart failure or hypertension
Authors: Mihaela S Stefan, Michael B Rothberg, Aruna Priya, Penelope S Pekow, David H Au, Peter K Lindenauer
Journal: Thorax (2012)

<h3>Background</h3> β-Blocker therapy has been shown to improve survival among patients with ischaemic heart disease (IHD) and congestive heart failure (CHF) and is underused among patients with chronic obstructive pulmonary disease (COPD). Evidence regarding the optimal use of β-blocker therapy during an acute exacerbation of COPD is particularly weak. <h3>Methods</h3> We conducted a retrospective cohort study of patients aged ≥40 years with IHD, CHF or hypertension who were hospitalised for an acute exacerbation of COPD from 1 January 2006 to 1 December 2007 at 404 acute care hospitals throughout the USA. We examined the association between β-blocker therapy and in-hospital mortality, initiation of mechanical ventilation after day 2 of hospitalisation, 30-day all-cause readmission and length of stay. <h3>Results</h3> Of 35 082 patients who met the inclusion criteria, 29% were treated with β blockers in the first two hospital days, including 22% with β1-selective and 7% with non-selective β blockers. In a propensity-matched analysis, there was no association between β-blocker therapy and in-hospital mortality (OR 0.88, 95% CI 0.71 to 1.09), 30-day readmission (OR 0.96, 95% CI 0.89 to 1.03) or late mechanical ventilation (OR 0.98, 95% CI 0.77 to 1.24). However, when compared with β1 selective β blockers, receipt of non-selective β blockers was associated with an increased risk of 30-day readmission (OR 1.25, 95% CI 1.08 to 1.44). <h3>Conclusions</h3> Among patients with IHD, CHF or hypertension, continuing β1-selective β blockers during hospitalisation for COPD appears to be safe. Until additional evidence becomes available, β1-selective β blockers may be superior to treatment with a non-selective β blocker.
Gene Signature–Guided Dasatinib Therapy in Metastatic Breast Cancer
Authors: Lajos Pusztai, Stacy Moulder, Mehmet Altan, Danielle Kwiatkowski, Vicente Valero, Naoto T. Ueno, Francisco J. Esteva, Rony Avritscher, Yuan Qi, Lewis Strauss, Gabriel N. Hortobagyi, Christos Hatzis, W. Fraser Symmans
Journal: Clinical Cancer Research (2014)

Dasatinib has limited single-agent activity in unselected patients with metastatic breast cancer. Several gene signatures predictive of dasatinib response in vitro have been reported. The purpose of this three-arm, phase II study was to prospectively assess the utility of three previously published gene signatures to select patients with clinical benefit from dasatinib.Patients with metastatic breast cancer underwent biopsy for gene expression profiling in an academic CLIA laboratory; those who were positive for any one of three predictive gene signatures (dasatinib sensitivity signature, SRC pathway activity signature, and dasatinib target index) received dasatinib 100 mg orally daily. The three marker-defined cohorts were analyzed separately, using early stopping rules for futility.Ninety-seven patients were enrolled, 93 underwent biopsy, and 80% of the biopsies were sufficient for molecular testing. Thirty patients were positive for at least one signature and received treatment. Only 1 patient experienced clinical benefit and had stable disease over 300 days. All three arms were closed early for futility. There was one serious biopsy-related adverse event (hematoma and pain following a liver biopsy). There were no unexpected toxicities from dasatinib.None of the three predictive gene signatures, although supported by preclinical evidence, defined tumors clinically sensitive to dasatinib as a single agent.
Impact of azathioprine and tumour necrosis factor antagonists on the need for surgery in newly diagnosed Crohn's disease
Authors: L. Peyrin-Biroulet, A. Oussalah, N. Williet, C. Pillot, L. Bresler, M.-A. Bigard
Journal: Gut (2011)

<h3>Objective</h3> The aim of the study was to assess whether azathioprine and antitumour necrosis factor (TNF) treatment decrease the long-term need for surgery in patients with Crohn9s disease. <h3>Methods</h3> This was an observational study of a referral centre cohort. The cumulative incidence of the first Crohn9s disease-related major abdominal surgery was estimated using the Kaplan–Meier method, and independent predictors of surgery were identified using Cox proportional hazards regression with propensity scores adjustment. Receiver operating characteristic (ROC) analysis was used to identify optimal cut-offs for duration of maintenance treatments. The electronic charts of 296 incident cases of Crohn9s disease from Nancy University Hospital, France, diagnosed between 2000 and 2008, were reviewed through January 2010. <h3>Results</h3> The median follow-up time per patient was 57 months. Seventy-six patients (26%) underwent at least one major abdominal surgical procedure. The cumulative probabilities of the first Crohn9s disease-related major abdominal surgery were 6.5, 25.9 and 44.3 at 1, 5 and 9 years, respectively. In the ROC analysis, the duration of anti-TNF and azathioprine treatment had significant cut-off values (≤475 days ∼16 months and ≤45 days ∼1.5 months, respectively) with positive likelihood ratios (PLRs) of 1.52 (p&lt;0.0001) and 1.51 (p=0.003) for the first Crohn9s disease-related major abdominal surgery. Using multivariate Cox proportional hazards regression analysis (after propensity score adjustment), independent positive predictors of major abdominal surgery were stricturing (HR=12.01; 95% CI 5.97 to 24.17) or penetrating (HR=10.77; 95% CI 4.87 to 23.80) disease behaviour at diagnosis, duration of anti-TNF treatment of &lt;16 months (HR=3.86; 95% CI 1.77 to 8.45) and duration of azathioprine treatment of &lt;1.5 months (HR=2.00; 95% CI 1.20 to 3.34). <h3>Conclusions</h3> Non-complicated inflammatory disease behaviour and long-term anti-TNF treatment are associated with a lower risk for surgery whereas azathioprine only modestly lowers this risk.