tbuckley/cabot-search huggingface dataset:
Abstract A30: Inhibiting histone methylation as an epigenetic therapeutic approach for pancreatic cancer
Authors: Rajgopal Govindarajan
Journal: Cancer Research (2013)

Abstract We evaluated the potential of an investigational histone methylation reversal agent, 3-deazaneplanocin A (DZNep), in improving the chemosensitivity of pancreatic cancer to nucleoside analogs (i.e., gemcitabine). DZNep brought delayed but selective cytotoxicity to pancreatic cancer cells without affecting normal human pancreatic ductal epithelial (HPDE) cells. Co-exposure of DZNep and gemcitabine induced cytotoxic additivity or synergism in both well- and poorly-differentiated pancreatic cell lines. In contrast, DZNep exerted antagonism with gemcitabine against HPDE cells with significant reduction in cytotoxicity compared with the gemcitabine-alone regimen. DZNep marginally depended on purine nucleoside transporters for its cytotoxicity, but the transport dependence was circumvented by acyl derivatization. Drug exposure studies revealed that a short priming with DZNep followed by gemcitabine treatment rather than co-treatment of both agents to produce a maximal chemosensitization response in both gemcitabine-sensitive and gemcitabine-resistant pancreatic cancer cells. DZNep rapidly and reversibly decreased trimethylation of histone H3 lysine 27 but increased trimethylation of lysine 9 in an EZH2- and JMJD1A/2C-dependent manner, respectively. However, DZNep potentiation of nucleoside analog chemosensitization was found to be temporally coupled to trimethylation changes in lysine 27 and not lysine 9. Polymeric nanoparticles engineered to chronologically release DZNep followed by gemcitabine produced pronounced chemosensitization and dose-lowering effects. Together, our results identify that an optimized DZNep exposure can presensitize pancreatic cancer cells to anticancer nucleoside analogs through the reversal of histone methylation, emphasizing the promising clinical utilities of epigenetic reversal agents in future pancreatic cancer combination therapies. Citation Format: Rajgopal Govindarajan. Inhibiting histone methylation as an epigenetic therapeutic approach for pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Jun 19-22, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2013;73(13 Suppl):Abstract nr A30.
Reproductive toxicity of ethylene glycol monoethyl ether tested by continuous breeding of CD-1 mice.
Authors: J C Lamb, D K Gulati, V S Russell, L Hommel, P S Sabharwal
Journal: Environmental Health Perspectives (1984)

The reproductive toxicity of ethylene glycol monoethyl ether (EGEE) was evaluated in the Fertility Assessment by Continuous Breeding protocol. Both male and female CD-1 mice were given 0, 0.5, 1.0 or 2% EGEE in the drinking water and were housed as breeding pairs continuously for 14 weeks. Significant adverse effects on fertility were seen at 1 and 2% but not at 0.5%. After the continuous breeding phase of this test was completed, treated males were housed with control females and treated females with control males and fertility and reproduction were compared to the corresponding pairs of control male and control female mice. Both males and females from the 1 and 2% groups were affected. Testicular atrophy, decreased sperm motility and increased abnormal sperm were noted in the treated males, but no specific anomalies were detected in the females.
Endoscopic Band Ligation of Bleeding Dieulafoy Lesions: The Best Therapeutic Strategy
Authors: J. M. Valera, R. Q. Pino, J. Poniachik, L. C. Gil, M. O’Brien, R. Sáenz, E. M. Quigley
Journal: Endoscopy (2006)

Dieulafoy’s lesion is a vascular lesion that is widely recognized as a persistently engorged, tortuous artery in the muscularis mucosa which is not associated with inflammation or atherosclerosis. The incidence of this lesion in patients with upper gastrointestinal bleeding has been estimated to be between 0.3 % and 6.7 %. Clinically, these lesions manifest as massive gastrointestinal hemorrhage, with no preceding symptoms. If the lesion is not treated, patients continue to bleed intermittently over the following days [1]. The advent of therapeutic endoscopic management has resulted in significantly improved outcomes. Success rates between 75 % and 96 % have been reported for endoscopic intervention [1] [2] [3]. As a result, endoscopic management has replaced surgery as the gold standard for the diagnosis and treatment of Dieulafoy lesions.
Symptoms of depression, prescription of benzodiazepines, and the risk of death in hemodialysis patients in Japan
Authors: S. Fukuhara, J. Green, J. Albert, H. Mihara, R. Pisoni, S. Yamazaki, T. Akiba, T. Akizawa, Y. Asano, A. Saito, F. Port, P. Held, K. Kurokawa
Journal: Kidney International (2006)
Candidate Genes on Chromosome 9q33-34 Involved in the Progression of Childhood Ependymomas
Authors: Stéphanie Puget, Jacques Grill, Alexander Valent, Ivan Bieche, Carmela Dantas-Barbosa, Audrey Kauffmann, Philippe Dessen, Ludovic Lacroix, Birgit Geoerger, Bastien Job, Clemens Dirven, Pascale Varlet, Mathieu Peyre, Peter B. Dirks, Christian Sainte-Rose, Gilles Vassal
Journal: Journal of Clinical Oncology (2009)

The molecular pathogenesis of pediatric ependymoma remains unclear. Our study was designed to identify genetic changes implicated in ependymoma progression.We characterized 59 ependymoma samples (33 at diagnosis and 26 at relapse) using array-comparative genomic hybridization (aCGH). Specific chromosomal imbalances were confirmed by fluorescent in situ hybridization, and candidate genes were assessed by real-time quantitative polymerase chain reaction (qPCR), immunohistochemistry, sequencing, and in vitro functional studies.aCGH analysis revealed a significant increase in genomic imbalances on relapse compared with diagnosis, such as gain of 9qter and 1q (54% v 21% and 12% v 0%, respectively) and loss of 6q (27% v 6%). Supervised tumor classification showed that gain of 9qter was associated with tumor recurrence, age older than 3 years, and posterior fossa location. Using a candidate-gene strategy, we found an overexpression of two potential oncogenes at the locus 9qter: Tenascin-C and Notch1. Moreover, Notch pathway analysis (qPCR) revealed overexpression of Notch ligands, receptors, and target genes (Hes-1, Hey2, and c-Myc), and downregulation of Notch repressor Fbxw7. We confirmed by immunohistochemistry the overexpression of Tenascin-C and Hes-1. We detected Notch1 missense mutations in 8.3% of the tumors (only in the posterior fossa location and in case of 9q33-34 gain). Furthermore, inhibition of Notch pathway with a gamma-secretase inhibitor impaired the growth of ependymoma stem cell cultures.The activation of the Notch pathway and Tenascin-C seem to be important events in ependymoma progression and may represent future targets for therapy. We report, to our knowledge for the first time, recurrent oncogenic mutations in pediatric posterior fossa ependymomas.
Roles of Achaete-Scute Homologue 1 in DKK1 and E-cadherin Repression and Neuroendocrine Differentiation in Lung Cancer
Authors: Hirotaka Osada, Shuta Tomida, Yasushi Yatabe, Yoshio Tatematsu, Toshiyuki Takeuchi, Hideki Murakami, Yutaka Kondo, Yoshitaka Sekido, Takashi Takahashi
Journal: Cancer Research (2008)

Abstract The proneural basic-helix-loop-helix protein achaete-scute homologue 1 (ASH1) is expressed in a very limited spectrum of normal and cancerous cells in a lineage-specific manner, including normal pulmonary neuroendocrine cells and lung cancer cells with neuroendocrine features. Our previous results indicated that ASH1 may play a crucial role in the growth and survival of lung cancers with neuroendocrine features, which prompted us to investigate the molecular function of ASH1 in relation to its involvement in carcinogenic processes. Herein, we report for the first time that ASH1 functions as a dual transcription factor by activating neuroendocrine differentiation markers and also repressing putative tumor suppressors. This protein was found to inactivate DKK1 and DKK3, negative regulators of Wnt/β-catenin signaling, E-cadherin, and integrin β1 through ASH1-mediated deacetylation and repressive trimethylation of lysine 27 (H3K27me3) of histone H3 in the promoter regions of DKK1 and E-cadherin. In addition, ASH1-transduced A549 adenocarcinoma cells exhibited markedly altered morphology characteristics compared with lung cancer cells with neuroendocrine features both in vitro and in vivo and also grew faster in vivo. Our results provide important clues for a better understanding of the molecular and cellular biological roles of ASH1 in the process of carcinogenesis of lung cancers with neuroendocrine features and warrant future investigations to shed light on the lineage-specific dependency of this transcription factor with dual functions. [Cancer Res 2008;68(6):1647–55]
Comparison of the rates of joint arthroplasty in patients with severe factor VIII and IX deficiency: an index of different clinical severity of the 2 coagulation disorders
Authors: Giuseppe Tagariello, Alfonso Iorio, Elena Santagostino, Massimo Morfini, Ruggero Bisson, Massimo Innocenti, Maria Elisa Mancuso, Maria Gabriella Mazzucconi, Gian Luigi Pasta, Paolo Radossi, Giuseppina Rodorigo, Cristina Santoro, Roberto Sartori, Antonio Scaraggi, Luigi Pier Solimeno, Pier Mannuccio Mannucci
Journal: Blood (2009)
Regulation of pancreatic and gallbladder functions by intraluminal fatty acids and bile acids in man.
Authors: J R Malagelada, E P DiMagno, W H Summerskill, V L Go
Journal: Journal of Clinical Investigation (1976)

The effects of intraduodenal glycerol, fatty acid (FA) chain length and FA loads, and bile acid (BA) concentrations on pancreatic and gallbladder function were investigated in 31 healthy volunteers by a perfusion method. FA absorption rates in the duodenum and proximal jejunum were measured simultaneously. Pancreatic and gallbladder responses were augmented by increasing FA chain length and FA loads until the "maximal" secretory capacity of the pancreas and gallbladder emptying was attained. Glycerol had no effect. Raising BA concentrations above the critical micellar concentration accelerated FA absorption rates but decreased the magnitude of pancreatic and gallbladder responses to FA. Higher BA concentrations exerted an opposite effect, slowing FA absorption and increasing pancreatic and gallbladder responses. Indeed, a significant, inverse correlation was found between FA absorption and pancreatic and gallbladder responses to FA, suggesting a relationship between the length of intestine exposed to FA and the amount of cholecystokinin (and/or other neurohormonal factors) released, which stimulates pancreatic secretion and gallbladder contraction.
RISK FACTORS FOR VERY LATE STENT THROMBOSIS AFTER SIROLIMUS–ELUTING STENT IMPLANTATION AND IMPACT OF DISCONTINUATION OF THIENOPYRIDINE THERAPY
Authors: Yasushi Fuku, Kazushige Kadota, yusuke hyodo, Koshi Miyake, Yuki Hayakawa, Naoki Saito, Hideaki Otsuji, Suguru Otsuru, Daiji Hasegawa, Yoshikazu Shigemoto, Seiji Habara, Takeshi Tada, Hiroyuki Tanaka, Hiroyuki Yamamoto, Tsuyoshi Goto, Kazuaki Mitsudo
Journal: Journal of the American College of Cardiology (2013)
Surveillance of invasive Neisseria meningitidis with a serogroup Y update, Sweden 2010 to 2012
Authors: B Törös, S Thulin Hedberg, S Jacobsson, H Fredlund, P Olcén, P Mölling
Journal: Eurosurveillance (2014)

An increase of invasive meningococcal disease caused by Neisseria meningitidis serogroup Y has been noted in Sweden since 2005, and to a lower extent throughout Europe. The present study describes the epidemiology of invasive N. meningitidis isolates in Sweden in the period between 2010 and 2012, with a focus on serogroup Y. We also aimed to find an optimal molecular typing scheme for both surveillance and outbreak investigations. All invasive N. meningitidis isolates in Sweden during the study period (n=208) were genetically characterised. Serogroup Y predominated with 22/57, 31/61 and 44/90 of all invasive isolates (incidence 0.23, 0.33 and 0.46 per 100,000 population) in 2010, 2011 and 2012 respectively. In each of these years, 15/22, 22/31 and 19/44 of serogroup Y isolates were genetically clonal (Y: P1.5–2,10–1,36–2: F4–1: ST-23(cc23), ‘porB allele 3–36, fHbp allele 25 and penA allele 22). Our findings further support those of others that currently recommended FetA typing could be replaced by FHbp. Moreover, in line with a previous study that we conducted, the current results indicate that highly variable multilocus variable-number tandem repeat analysis (HV-MLVA) can be used as a first-hand rapid method for small outbreak investigations.
An Orally Available Small-Molecule Inhibitor of c-Met, PF-2341066, Exhibits Cytoreductive Antitumor Efficacy through Antiproliferative and Antiangiogenic Mechanisms
Authors: Helen Y. Zou, Qiuhua Li, Joseph H. Lee, Maria E. Arango, Scott R. McDonnell, Shinji Yamazaki, Tatiana B. Koudriakova, Gordon Alton, Jingrong J. Cui, Pei-Pei Kung, Mitchell D. Nambu, Gerrit Los, Steven L. Bender, Barbara Mroczkowski, James G. Christensen
Journal: Cancer Research (2007)

The c-Met receptor tyrosine kinase and its ligand, hepatocyte growth factor (HGF), have been implicated in the progression of several human cancers and are attractive therapeutic targets. PF-2341066 was identified as a potent, orally bioavailable, ATP-competitive small-molecule inhibitor of the catalytic activity of c-Met kinase. PF-2341066 was selective for c-Met (and anaplastic lymphoma kinase) compared with a panel of >120 diverse tyrosine and serine-threonine kinases. PF-2341066 potently inhibited c-Met phosphorylation and c-Met-dependent proliferation, migration, or invasion of human tumor cells in vitro (IC(50) values, 5-20 nmol/L). In addition, PF-2341066 potently inhibited HGF-stimulated endothelial cell survival or invasion and serum-stimulated tubulogenesis in vitro, suggesting that this agent also exhibits antiangiogenic properties. PF-2341066 showed efficacy at well-tolerated doses, including marked cytoreductive antitumor activity, in several tumor models that expressed activated c-Met. The antitumor efficacy of PF-2341066 was dose dependent and showed a strong correlation to inhibition of c-Met phosphorylation in vivo. Near-maximal inhibition of c-Met activity for the full dosing interval was necessary to maximize the efficacy of PF-2341066. Additional mechanism-of-action studies showed dose-dependent inhibition of c-Met-dependent signal transduction, tumor cell proliferation (Ki67), induction of apoptosis (caspase-3), and reduction of microvessel density (CD31). These results indicated that the antitumor activity of PF-2341066 may be mediated by direct effects on tumor cell growth or survival as well as antiangiogenic mechanisms. Collectively, these results show the therapeutic potential of targeting c-Met with selective small-molecule inhibitors for the treatment of human cancers.
Direct demonstration of the identity of T cell growth factor binding protein and the Tac antigen.
Authors: R J Robb, W C Greene
Journal: The Journal of Experimental Medicine (1983)

Radiolabeled molecules from detergent-solubilized human T cell blasts were fractionated on affinity supports coupled with T cell growth factor (TCGF) and anti-Tac antibody. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis indicated that a glycoprotein of approximately 58,000 mol wt was bound in both cases. Sequential binding to the two affinity supports demonstrated that the molecules recognized in each instance were identical. Thus, the Tac antigen contains the cellular binding site for TCGF. Note added in proof: Preliminary binding experiments using high concentrations of [3H]leucine, lysine TCGF with a low specific radioactivity indicate the existence of a sizeable pool of receptor sites with an affinity 2,000-10,000 times lower than that of the high affinity receptors measured in Fig. 1. Such sites may explain the numerical discrepancy between early TCGF binding experiments (5) and the binding of the anti-Tac antibody. The hypothesis that the anti-Tac antibody apparently reacts with both classes of receptor would explain its effect on the physiological response (high affinity binding) and the high level of Tac antigen on the cell surface.
Are Medical Education Dollars Buying What They Should?
Authors: Joyce A. Lanning
Journal: JAMA (1977)

WHETHER or not it sticks in the craw, by federal mandate, health planning does exist, as do the specter of comprehensive national health insurance plans, and the Federal Trade Commission with its alledged assaults on professionalism. There are watch birds set up to control utilization and quality through Professional Standard Review Organizations, audits, and utilization review committees; the $2.7 billion authorized for health professions education by the new health manpower law comes with many strings attached. The public, at least in its federal form, has increasingly been involved in health care and medical education. I was asked to speak for the public interest. I cannot legitimately speak<i>for</i>all my fellow citizens. We even have difficulty according our highest popularly elected officials the power to speak<i>for</i>us. So, with that disclaimer, I will speak<i>about</i>medical education dollars and the public interest. <h3>DOLLARS, DISTRIBUTION, DISAFFECTION, AND QUALITY</h3> The key
Haemoglobinopathies and glycosylated haemoglobin estimation.
Authors: G Pulman, M F Laker, B Fail, K G Alberti
Journal: BMJ (1984)

practitioner (with hardware and software provided by the Greater London Council funded London New Technology Network), to encourage clinical review and regular assess- ment of biochemical control.If, as in the east London study,' most general practitioner supervised patients once attended a hospital diabetic clinic it should be possible to build most of the register from hospital records.The remainder may be provided by general practi- tioner disease lists and prescription returns for hypoglycaemic drugs and urine testing agents.
Comparison of carbamylated erythropoietin-FC fusion protein and recombinant human erythropoietin during porcine aortic balloon occlusion-induced spinal cord ischemia/reperfusion injury
Authors: Florian Simon, Angelika Scheuerle, Michael Gröger, Brigitta Vcelar, Oscar McCook, Peter Möller, Michael Georgieff, Enrico Calzia, Peter Radermacher, Hubert Schelzig
Journal: Intensive Care Medicine (2011)
Experimental models for study of common respiratory viruses.
Authors: W A Clyde
Journal: Environmental Health Perspectives (1980)

Numerous epidemiological studies have shown that there is excess respiratory disease morbidity in areas of high atmospheric pollution, implying an interactive effect on the clinical illness associated with these common infections. The principal etiologic agents of human respiratory infections are respiratory syncytial virus (RSV), influenza viruses (IV), parainfluenza virus types 1 and 3 (P1, P3), adenoviruses (AD), rhinoviruses (RV) and Mycoplasma pneumoniae (Mpn). Understanding the pathogenesis of the excess morbidity related to pollutants would facilitate detection of undesirable human health effects and provide a basis for intervention strategies. Through use of experimental model systems the mechanism of toxic effects could be defined (whether microbiological, immunological, pathological or physiological) to provide direction for appropriate studies in the human host. Small animal models of IV and Mpn infections have been available for many years; recently, experimental models of several more common viral diseases have been developed. A parallel to human RSV infections is provided by the ferret: virus replicates in the lungs of infant animals, but only in the noses of adults. The common cotton rat infected with RSV develops small airways lesions which may mimic the pathophysiologic changes of bronchiolitis. Both guinea pigs and Syrian hamsters are susceptible to human P3 virus, developing peribronchiolar and interstitial lesions. Practical small animal models for human AD and RV infections are not available because of the high host-specificity of these agents. Both the RSV and P3 model infections are nonlethal which enables study for long-term sequelae. Recent reports of pulmonary function abnormalities among children suffering bronchiolitis in infancy underscores the importance of defining toxic influences which could play a role by making the initial infections more severe.
WHO policy on antivenom provision in Africa and Asia may result in more deaths, report says
Authors: R. Dobson
Journal: BMJ (2009)

Treatment of snakebites has not improved for 30 years, with no significant reductions in mortality or morbidity, a new report says.

The authors criticise the World Health Organization for recommending that countries move to better quality antivenoms, when many countries cannot afford to do so and when the side effects of much cheaper antivenoms can often be tackled by inexpensive drugs ( Wilderness and Environmental Medicine 2009:20;43-56).

“The history of antivenom provision in the two key snakebite areas, Africa and Asia, comprises a record of 30 years of failure,” write the authors, from the Pakistan Medical Research Council and Stanford University Medical Center.

“The current World Health Organization approach to increase quality standards in an uncontrolled and …
Life threatening sickle chest syndrome treated with extracorporeal membrane oxygenation.
Authors: D S Gillett, K E Gunning, E H Sawicka, A J Bellingham, R J Ware
Journal: BMJ (1987)

A young West Indian woman with established sickle cell disease developed a severe episode of sickle chest syndrome. Conventional treatment including exchange transfusions and mechanical ventilation was to no avail, and an infusion of epoprostenol also failed to halt her worsening condition. When her arterial oxygen tension (PaO2) had fallen to 6.5 kPa (49 mm Hg) extracorporeal membrane oxygenation was instituted. Within two days her PaO2 was greatly improved (maximum 11.6 kPa; 87 mmHg), and by the sixth day pulmonary vascular resistance was reduced and angiography showed reperfusion of many vessels. The patient recovered and six months later showed a transfer factor close to the predicted range and normal spirometric values. Extracorporeal membrane oxygenation should be considered for severe sickle chest syndrome when conventional methods of artificial ventilation fail.
The Inhalation of Chloroform is always Attended with Danger
Authors: R. Martin
Journal: BMJ (1859)

inflammation of the veins, and occur under other circumstances, and which are supposed to depend upoIn the admixture of purulent, or other morbi(d fluids, with the circulating blood.In some instances, as in that first related, the affection is at- tended with uneasiniess, or pain, in the early stages.More commonly, it comes on insidiously and does not attract atten-