tbuckley/cabot-search huggingface dataset:
Detection of γH2AX foci as a marker for repair of radiation-induced DNA damage in vitro and in vivo
Authors: Andreas Rimner, Marija Drobnjak, Adriana Haimovitz-Friedman, Carlos Cordon-Cardo, Richard N. Kolesnick, Zvi Fuks
Journal: Cancer Research (2005)

1660   H2AX is a member of the H2 histone protein family that is known to be rapidly phosphorylated following ionizing radiation (γH2AX). Several candidate kinases including ATM and ATR as well as PI3K have been suggested as involved in this phosphorylation process. Binding of γH2AX precedes the recruitment of repair proteins like Rad51 and the Mre11 complex, which form foci at the sites of DNA double-strand breaks. This study addresses whether γH2AX foci might be used as a marker for radiation damage in tumor cell lines and mouse tumor models. Using FACS the half-life of γH2AX foci was evaluated in a panel of six cell lines that vary in radiosensitivity. The foci were quantified as a function of time and delivered radiation dose. We found that H2AX was rapidly phosphorylated and incorporated into foci in vitro following ionizing radiation. The half-life of γH2AX foci correlated strongly with the SF2 (r2 = 0.8947), the D0 (r2 = 0.8696) and the Dq (r2 = 0.9842), as assessed by clonogenic survival assays. No good correlation was found for parameters like the alpha/beta ratio or N. We then developed a staining protocol to quantify γH2AX foci in paraffin-embedded tumor tissue using confocal microscopy. We were able to detect γH2AX foci in MCA129 mouse fibrosarcomas as early as 30 minutes after irradiation. The Abercrombie-corrected half-life in vivo was comparable to the in vitro data. We have previously shown that the ASM genotype of the tumor vasculature affects tumor growth (Garcia-Barros et al., Science, 2003). We are currently testing whether the ASM status of the tumor vasculature influences the repair efficiency of the tumor cells and thus mediates tumor growth delay and regression. We will further attempt to investigate with this technology the role of other proteins like Rad51, Mre 11 and Rad 17 in irradiation-induced foci as markers for repair and radiosensitivity.
Role of Id2 in the regulation of fatty acid metabolism
Authors: Joana Murad, Nathan Watson, William Kinlaw, Mark Israel
Journal: Cancer Research (2008)

2728   In normal and malignant tissues, fatty acids (FA) have a spectrum of functions that range from energy storage and membrane synthesis to participation in signal transduction cascades. A hallmark of the highly malignant phenotype is an increase in the carbon flux through glycolysis and an increased reliance on FA metabolism for energy production. This change can confer significant growth and survival advantages in addition to functioning as an anabolic energy-storage pathway. We have identified a key regulatory role for Id2 in mediating the balance between glycolysis and fatty acid metabolism for energy production. Id2, an endogenous dominant negative regulator of bHLH transcription factors, has been shown to inhibit differentiation, increase proliferation, and promote invasion in both normal and malignant cells.  In mouse embryonic fibroblasts from animals in which the Id2 gene had been deleted (Id2-/- MEFs) we observed an increase in glucose uptake and an increase in the expression of genes related to mitochondrial fatty acid oxidation. Id2-/- MEFs display increased glucose uptake, decreased pyruvate utilization, and a three-fold increase in lactic acid production under normoxic conditions. The phenotype seen in Id2-/- MEFs was due to an increase in Hif-2a levels. In addition to ineffective glucose utilization, these cells exhibited an increase in fatty acid oxidation, in which we demonstrated that peroxisome proliferator-activated receptor alpha (PPARa) plays a key role. Importantly, we also found that Hif-2a is responsible for the high levels of PPARa in these cells. To elucidate the importance of Id2 as a regulator of the metabolic switch in cancer cells, we first evaluated a nonaggressive and differentiated breast cancer cell line (T47D) and an aggressive and metastatic breast cancer cell line (MDA-MB-231). The levels of Id2 and markers of fatty acid metabolism were measured in both cells lines, and we identified a direct correlation between them. Other studies are being conducted to explore further this relationship. In normoxic conditions, MDA-MB-231 cells were highly dependent on anaerobic glycolysis, a phenotype comparable to the one observed on the Id2 -/- MEFs and indistinguishable from the Warburg effect. Based on these results, we propose a model for the regulation of tumor metabolism in which Id2 plays a central role in energy metabolism, shunting ineffective glucose metabolism to more efficient metabolism of fatty acids.
Abstract 11163: Abi Gene Family, Member 3 (NESH) Binding Protein (ABI3bp) Regulates Cardiac Progenitor Cell (CPC) Differentiation and Proliferation
Authors: Conrad Hodgkinson, Jose Gomez, Alan Payne, Richard Pratt, Victor Dzau
Journal: Circulation (2013)

INTRODUCTION: The mammalian heart contains three major cell types, cardiomyocytes, smooth muscle cells, and endothelial cells, all of which are believed to derive from a common cardiac progenitor c...
Late Clinical Events After Clopidogrel Discontinuation May Limit the Benefit of Drug-Eluting Stents
Authors: Matthias Pfisterer, Hans Peter Brunner-La Rocca, Peter T. Buser, Peter Rickenbacher, Patrick Hunziker, Christian Mueller, Raban Jeger, Franziska Bader, Stefan Osswald, Christoph Kaiser
Journal: Journal of the American College of Cardiology (2006)
Predictors of Catastrophic Adverse Outcomes in Children With Pulmonary Hypertension Undergoing Cardiac Catheterization
Authors: Michael L. O’Byrne, Andrew C. Glatz, Brian D. Hanna, Russell T. Shinohara, Matthew J. Gillespie, Yoav Dori, Jonathan J. Rome, Steven M. Kawut
Journal: Journal of the American College of Cardiology (2015)
Income distribution, socioeconomic status, and self rated health in US
Authors: J. Milyo, B. P Kennedy, I. Kawachi, R. Glass, D. Prothrow-Stith
Journal: BMJ (1999)

Proportions of cases (babies with neonatal encephalopathy) and controls having complicated* and uncomplicated † deliveries in Badawi et al's study No (%) of cases (n=164) No (%) of controls (n=400) Unadjusted odds ratio (95% CI) Complicated delivery 79 (48) 101 (25) 2.75 (1.88 to 4.02) Uncomplicated delivery 85 (52) 299 (75) 0.36 (0.25 to 0.53) *Complicated deliveries: instrumental deliveries
Estrogens and Endometrial Cancer-Reply
Authors: Donald F. Austin
Journal: JAMA (1977)

This letter is critical of 2 previous articles in which the incidence of endometrial cancer among postmenopausal women and associated with estrogen therapy is considered to be too low. Unpublished data indicate that, in the population reported on, at least 1/3 of postmenopausal women may have had a hysterectomy. Therefore they should not be included in the incidence rate for endometrial cancer. The real risk for endometrial cancer among postmenopausal women with an intact uterus is estimated to be at least 50% higher than reported in these articles.
Changes in brain glucose metabolism in cocaine dependence and withdrawal
Authors: N D Volkow, J S Fowler, A P Wolf, R Hitzemann, S Dewey, B Bendriem, R Alpert, A Hoff
Journal: American Journal of Psychiatry (1991)

The authors investigated changes in brain function associated with cocaine dependence and withdrawal to provide clues regarding the processes that lead to the uncontrollable self-administration of cocaine.They measured regional brain metabolism with [18F]-fluorodeoxyglucose (FDG) and positron emission tomography in 15 outpatients with the diagnosis of cocaine abuse and 17 normal comparison subjects. Ten of the patients were studied less than 1 week after they had last had cocaine, and five were studied 2-4 weeks after withdrawal.Patients studied within 1 week of cocaine withdrawal but not those studied within 2-4 weeks of cocaine withdrawal had higher levels of global brain metabolism as well as higher levels of regional brain metabolism in the basal ganglia and orbitofrontal cortex than did normal subjects, probably as a consequence of less brain dopamine activity. There was also a significant relationship between the number of days since cocaine withdrawal and regional brain glucose metabolism in the orbitofrontal cortex and in the basal ganglia, and the correlations between cocaine craving and metabolic activity were significant in the prefrontal cortex and the orbitofrontal cortex.Although the time-dependent fall in metabolic activity suggests that the higher metabolic activity observed less than a week after cocaine withdrawal may represent a nonspecific expression of drug withdrawal, the selectivity of changes in glucose metabolism for the basal ganglia and for the orbitofrontal cortex suggests that the regional metabolic changes seen in cocaine abusers during detoxification are related to changes in brain dopamine activity.
Phase 2 study of MKC-1 in patients (pts) with metastatic breast cancer (MBC) who have failed prior therapy with an anthracycline (A) and taxane (T)
Authors: L. Sylvester, L. Laufman, K. Jabboury, M. Saleh, K. Tkaczuk, F. Volterra, J. Arnott, A. Hannah, C. Sidor, K. Miller
Journal: Journal of Clinical Oncology (2007)

11508 Background: MKC-1 (previously Ro 31–7453) is a novel cell cycle inhibitor with significant in vitro and in vivo activity against a wide range of tumor cell lines, including multi-drug resistant cell lines. Proteins identified as binding targets of MKC-1 include microtubules (colchicine binding site) and members of the importin-β family (proteins that play a critical role in nuclear transport and spindle formation). Objective responses (ORs) were observed in heavily pre-treated breast and NSCLC pts (Trigo Perez ASCO’03 A62; Kurup ASCO’03 A2725) treated at a dose of 95 mg/m 2 BID given 14 days every 4 weeks with little toxicity. Salazar et al (2004 CCR 10:4374) recommended a higher oral dose (125 mg/m 2 BID) on this schedule for further studies. This phase 2 trial is exploring the higher dose to maximize potential anticancer activity. Methods: Pts with MBC who had failed prior A and T and met eligibility criteria received MKC-1 at 125mg/m 2 BID x 14d every 4 weeks. Pts with known treated and stable CNS metastases could enroll. Primary objective: OR by RECIST. Should 2 or more of the first 23 evaluable pts have an OR, enrollment will continue to 53 pts. Dose escalation/reductions are required based on toxicity (primarily neutropenia). Results: To date, a total of 20 pts have been enrolled (4 active in Cycles 1–5+). All female; median age/KPS of 60/90. 19% / 13% had received A / T in the neo/adjuvant setting; others had received A / T for metastatic disease. To date, a total of 48 cycles (median 2, range 1–8) were administered; of pts proceeding into Cycle 2, 40% and 20% had the dose increased or reduced, respectively. Severe drug-related toxicity (n=17) was observed in 3 pts (18%): ↑AST/ALT in 2 pts and parathesias in 1 pt. Drug related toxicity: nausea (47%), ↑ALT, diarrhea (both 24%), anemia, ↑AST, cough, fatigue, neutropenia and vomiting (all 18%). Two pts discontinued due to toxicity. One pt had complete resolution of measurable disease (1 st observed after Cycle 4, confirmed after Cycle 6 with withdrawal for a new lesion at Cycle 8). An additional 2 pts had stable disease for 5 cycles (1 pt remains active). Conclusions: MKC-1 is well tolerated at the initial recommended dose for this schedule. Activity is observed in pts previously treated with A/T for MBC. No significant financial relationships to disclose.
Abstract 11748: Pre-Procedural Glucose Levels and the Risk for Contrast-Induced Acute Kidney Injury in Patients Undergoing Emergency Coronary Intervention Whose Contrast Volume Was Below Maximum Allowable Contrast Dose
Authors: Kenji Shiino, Junnichi Ishii, Hiroyuki Naruse, Shigeru Matsui, Tousei Hashimoto, Tomoko Kawai, Kousuke Hattori, Masanori Okumura, Sadako Motoyama, Hideo Izawa, Masanori Nomura, Yukio Ozaki
Journal: Circulation (2011)
Phase 1/2 Study in Pediatric Patients with Relapsed/Refractory B-Cell Precursor Acute Lymphoblastic Leukemia (BCP-ALL) Receiving Blinatumomab Treatment
Authors: Arend von Stackelberg, Franco Locatelli, Gerhard Zugmaier, Rupert Handgretinger, Tanya M. Trippett, Carmelo Rizzari, Christian M. Zwaan, Deepa Bhojwani, Steven G. Dubois, Peter Bader, Arndt Borkhardt, Maureen O'Brien, Susan R. Rheingold, Todd Michael Cooper, Kuolung Hu, Noemi Mergen, Anja Fischer, Min Zhu, Youssef Hijazi, James Whitlock, Lia Gore
Journal: Blood (2014)
Registering a fetus papyraceus
Authors: P O D Pharoah, R W I Cooke, M. Griffiths
Journal: BMJ (1997)

Basic helix-loop-helix (bHLH) transcription factors are known to play important roles in neuronal determination and differentiation. However, their exact roles in neural development still remain to be determined because of the functional redundancy. Here, we examined the roles of neural bHLH genes <i>Mash1</i> and <i>Math3</i> in the development of trigeminal and facial branchiomotor neurons, which derive from rhombomeres 2-4. In <i>Math3</i>-null mutant mice, facial branchiomotor neurons are misspecified, and both trigeminal and facial branchiomotor neurons adopt abnormal migratory pathways. In <i>Mash1;Math3</i> double-mutant mice, trigeminal and facial branchiomotor neurons are severely reduced in number partly because of increased apoptosis. In addition, neurons with migratory defects are intermingled over the midline from either side of the neural tube. Furthermore, oligodendrocyte progenitors of rhombomere 4 are reduced in number. In the absence of <i>Mash1</i> and <i>Math3</i>, expression of Notch signaling components is severely downregulated in rhombomere 4 and neural progenitors are not properly maintained, which may lead to intermingling of neurons and a decrease in oligodendrocyte progenitors. These results indicate that <i>Mash1</i> and <i>Math3</i> not only promote branchiomotor neuron development but also regulate the subsequent oligodendrocyte development and the cytoarchitecture by maintaining neural progenitors through Notch signaling.
Abstract 238: Emergency Extracorporeal Life Support Versus Conventional Cardiopulmonary Resuscitation for Refractory Cardiac Arrest: An Emergency Department Registry Analysis
Authors: Andreas Schober, Fritz Sterz, Michael Holzer, Christian Wallmueller, Peter Stratil, Alexander Landerl, Christoph Weiser, Raphael Van Tulder, Anton Laggner, Christoph Testori
Journal: Circulation (2014)

Background: Outcome after cardiac arrest is poor. In refractory cardiac arrest, with cardiopulmonary resuscitation (CPR) for more than 30 minutes, chances of survival decrease even further. Emergency extracorporeal life support (E-ECLS) has become an option for a highly selected population of cardiac arrest patients. Aim of this study was to evaluate the potential effects on outcome of E-ECLS in refractory cardiac arrest compared to ongoing standard CPR at an emergency department of a tertiary care center.

Methods: Anonymized data, of adult patients suffering cardiac arrest, treated between 2002 and 2012 and transported to our department in refractory cardiac arrest (more than 30 minutes) with ongoing hemodynamic instability and CPR were analyzed.

Results: Overall 269 patients fulfilled the inclusion criteria. Baseline parameters and outcomes are displayed in Table 1. E-ECLS was initiated in 12 patients. They were younger, but otherwise did not differ significantly in cardiac arrest specific criteria. Overall survival to discharge in good neurologic condition (defined as cerebral performance category 1 or 2) was achieved in 18 (7%) patients and was significantly higher in the group of patients receiving E-ECLS (25% vs. 6% of patients p=0.038). Correcting for age in regression analysis we still found E-ECLS to be significantly associated with survival (OR 0.65 95%CI 0.04-0.94) p=0.041).

Conclusions: Emergency extracorporeal life support for patients in refractory cardiac arrest, deployed at an emergency department with critical care capability seems to be superior to standard CPR in terms of neurologic intact survival. Randomised controlled trials are urgently needed to verify these findings.

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Ultraconserved non-coding RNA expression profiles in human prostate cancer
Authors: Robert Hudson, Ming Yi, Robyn Prueitt, Tiffany Howe, Tiffany Wallace, Chang-Gong Liu, Robert Stephens, George Calin, Carlo Croce, Stefan Ambs
Journal: Cancer Research (2008)

345  Completely conserved among human, rat, and mouse genomes, ultraconserved regions (UCRs) act as transcriptional enhancers and have been found to be associated with alternative splicing events. The data indicate that UCRs contribute to RNA surveillance in mammalian cells. A recent study has shown that transcripts encoded by UCRs are expressed in human tissues and their expression is altered in human cancer. Thus, these RNAs (ucRNAs) have been hypothesized to have a role in the pathogenesis, diagnosis, and prognosis of cancer. In this study we explored the role of ucRNAs in human prostate cancer by examining genome wide ucRNA expression patterns in resected prostate adenocarcinomas and also in androgen (AR) insensitive (DU-145) and sensitive (LNCaP) prostate cells lines stimulated with the synthetic AR ligand R1881. Usinga microarray containing 962 UCR probes, we identified expression patterns of ucRNAs that differentiate tumor tissues from non-tumor tissues and found association of ucRNA expression patterns with several phenotypes related to poor outcome including Gleason score, extraprostatic extension, and race/ethnicity. We also identified several ucRNAs that are differentially expressed upon AR stimulation. Lastly, we compared the expression of ucRNA with global mRNA and microRNA expression patterns to examine host, mRNA, and microRNA relationships that may yield novel insight into the function of transcripts derived from UCRs. Taken together this study suggests a significant association of ucRNAs with the pathogenesis of human prostate cancer.
Histone deacetylases at the interface between aging and development of resistance to chemotherapy in cancer
Authors: Fei Chu, Xin Zheng, Bernard L. Mirkin, Abdelhadi Rebbaa
Journal: Cancer Research (2006)

4040  Cancer cells have superior adaptability to stress a characteristic that is viewed as a major obstacle for successful chemotherapy. Recent evidence has shown that the ability of cancer cells to escape irreversible growth arrest (senescence) is a pre-requisite for the onset of drug resistance. We have demonstrated that expression of the histone deacetylase Sirt1, known for inducing resistance to caloric restriction and extending life span through inhibition of cellular senescence, was up-regulated in cancer cells selected for resistance to doxorubicin and cisplatin. Further characterization of Sirt1’s role in drug resistance indicated that this molecule was a positive regulator of the multidrug resistance gene mdr1. In the present study, we have investigated whether selection for resistance to histone deacetylase (HDAC) inhibitors could affect the development of resistance to classical chemotherapeutic agents and expression of sirtuins. Our data indicate that development of resistance to Trichostatin A (TSA) was indeed associated with resistance to doxorubicin and that expression of the mdr1 gene was up-regulated in the TSA resistant cells. Comparison of HDAC profiles between drug-sensitive and resistant cells revealed that expression of both HDAC1 and the sirtuin (Sirt5) was enhanced in association with resistance to TSA. Paralleling the role of sirtuins in protecting cells against caloric restriction, the TSA resistant cells survived longer than their parental cells in glucose depleted culture medium. Overall, these findings shed light on the implication of histone deacetylases in resistance to DNA-damaging, chromatin-targeting, and caloric restriction-induced stresses. Considering the role some of these enzymes in life span extension, their implication in development of drug resistance in cancer may interfere with healthy aging.
Abstract 12651: Atrium Fibrosis and Inflammation: Impaired Atrial Natriuretic Peptide System in Experimental Heart Failure
Authors: Tomoko Ichiki, Brenda K Huntley, S Jeson Sangaralingham, Gail J Harty, John C Burnett
Journal: Circulation (2014)

Introduction: The cardiac atrium is an important endocrine organ which also releases natriuretic peptides (NPs). We reported that dysregulation of the proNP convertases, furin and corin, may disrupt NP progressing, causing atrial fibrosis in experimental heart failure (HF). Atrial fibrosis results in atrial arrhythmias and impairs the prognosis of human HF, therefore understanding mechanisms of atrial fibrosis may help in designing treatment strategies for HF. We sought to extend our studies into the entire NP system and global gene profiles including fibrotic and inflammatory pathways in experimental HF. Hypothesis: Components of the NP, pro-fibrotic and inflammatory system will be up-regulated in the atrium in HF. Methods: Experimental canine HF was induced by rapid right ventricular pacing at 240 bpm for 10 days. We examined hemodynamics, echo parameters, circulating neurohumoral factors, and global gene profiles using RT-PCR microarrays related to the NP system, fibrosis, growth factors, inflammation and cardiac hypertrophy in left atrium (LA) from normal and HF canines (n=4 of each). Results: Experimental HF was characterized by decreased % EF and LV radial strain, and increased circulating ANP, cGMP and aldosterone levels. HF LA weight significantly increased with fibrosis and interstitial edema compared to normals. Gene profile analyses showed increases in profibrotic cytokines and extracellular matrix related genes in LA. Increased ANP expression but also increased ANP degrading enzyme IDE and decreased proANP processing enzyme corin were also observed. Genes related to inflammatory cytokines such as TNF-alpha, members of the IL-6 family, MCP-1, and cell adhesion molecules were up-regulated in LA compared to normals. Conclusions: Experimental HF was characterized by on-going atrial fibrosis with increased circulating ANP levels. Although ANP gene expression increased in failing LA, impaired proANP processing and accelerated ANP degradation may impair any anti-fibrotic ANP effects. Further, atrium may be a source of inflammatory cytokines and pro-fibrotic growth factors which may advance organ damage in HF. Our studies suggest NP treatment, perhaps in a form less susceptible to IDE degradation, may be a novel therapeutic for HF.
There is a place for a combined treatment approach
Authors: M. G Smyth
Journal: BMJ (1995)

Definition ofdepression is questionable EDITOR,-Mynors-Wallis and colleagues claim that problem solving treatment and amitriptyline are equally effective in major depressive disorder.'Even though they required their patients to meet the research diagnostic criteria for depression, just how severely depressed they were comes into question.To be eligible to take part in the study patients had to score just 13 on the Hamilton depression rating scale.Drug licensing authorities, such as the Committee on Safety of Medicines and the Food and Drug Administration, and most
Website of the week: Genes and insurance
Authors: D. Carnall
Journal: BMJ (1999)

Last week, the inaugural meeting of the UK Forum for Genetics and Insurance (UKFGI) addressed “the complex issues on the use of genetic testing on the assessment of people's insurability” (see p 273). Even for single gene disorders this is not a straightforward matter: 13% of family members with a family history of a single gene disorder were wrongly rated by life insurers in …