tbuckley/cabot-search huggingface dataset:
Characterization of <i>TMPRSS2-ERG</i> Fusion High-Grade Prostatic Intraepithelial Neoplasia and Potential Clinical Implications
Authors: Juan-Miguel Mosquera, Sven Perner, Elizabeth M. Genega, Martin Sanda, Matthias D. Hofer, Kirsten D. Mertz, Pamela L. Paris, Jeff Simko, Tarek A. Bismar, Gustavo Ayala, Rajal B. Shah, Massimo Loda, Mark A. Rubin
Journal: Clinical Cancer Research (2008)

Abstract Purpose: More than 1,300,000 prostate needle biopsies are done annually in the United States with up to 16% incidence of isolated high-grade prostatic intraepithelial neoplasia (HGPIN). HGPIN has low predictive value for identifying prostate cancer on subsequent needle biopsies in prostate-specific antigen–screened populations. In contemporary series, prostate cancer is detected in ∼20% of repeat biopsies following a diagnosis of HGPIN. Further, discrete histologic subtypes of HGPIN with clinical implication in management have not been characterized. The TMPRSS2-ERG gene fusion that has recently been described in prostate cancer has also been shown to occur in a subset of HGPIN. This may have significant clinical implications given that TMPRSS2-ERG fusion prostate cancer is associated with a more aggressive clinical course. Experimental Design: In this study, we assessed a series of HGPIN lesions and paired prostate cancer for the presence of TMPRSS2-ERG gene fusion. Results: Fusion-positive HGPIN was observed in 16% of the 143 number of lesions, and in all instances, the matching cancer shared the same fusion pattern. Sixty percent of TMPRSS2-ERG fusion prostate cancer had fusion-negative HGPIN. Conclusions: Given the more aggressive nature of TMPRSS2-ERG prostate cancer, the findings of this study raise the possibility that gene fusion-positive HGPIN lesions are harbingers of more aggressive disease. To date, pathologic, molecular, and clinical variables do not help stratify which men with HGPIN are at increased risk for a cancer diagnosis. Our results suggest that the detection of isolated TMPRSS2-ERG fusion HGPIN would improve the positive predictive value of finding TMPRSS2-ERG fusion prostate cancer in subsequent biopsies.
Six Cycles of Doxorubicin and Cyclophosphamide or Paclitaxel Are Not Superior to Four Cycles As Adjuvant Chemotherapy for Breast Cancer in Women With Zero to Three Positive Axillary Nodes: Cancer and Leukemia Group B 40101
Authors: Lawrence N. Shulman, Constance T. Cirrincione, Donald A. Berry, Heather P. Becker, Edith A. Perez, Ruth O'Regan, Silvana Martino, James N. Atkins, Erica Mayer, Charles J. Schneider, Gretchen Kimmick, Larry Norton, Hyman Muss, Eric P. Winer, Clifford Hudis
Journal: Journal of Clinical Oncology (2012)

Purpose The ideal duration of adjuvant chemotherapy for patients with lower risk primary breast cancer is not known. Cancer and Leukemia Group B trial 40101 was conducted using a phase III factorial design to define whether six cycles of a chemotherapy regimen are superior to four cycles. We also sought to determine whether paclitaxel (T) is as efficacious as doxorubicin/cyclophosphamide (AC), but with reduced toxicity. Patients and Methods Between 2002 and 2008, the study enrolled women with operable breast cancer and zero to three positive nodes. Patients were randomly assigned to either four or six cycles of either AC or T. Study stratifiers were estrogen receptor/progesterone receptor (ER/PgR), human epidermal growth factor receptor 2 (HER2), and menopausal status. After 2003, all treatment was administered in dose-dense fashion. The primary efficacy end point was relapse-free survival (RFS). Results A total of 3,171 patients were enrolled; 94% were node-negative and 6% had one to three positive nodes. At a median follow-up of 5.3 years, the 4-year RFS was 90.9% and 91.8% for six and four cycles, respectively. The adjusted hazard ratio (HR) of six to four cycles regarding RFS was 1.03 (95% CI, 0.84 to 1.28; P = .77). The 4-year OS was 95.3% and 96.3% for six and four cycles, respectively, with an HR of six to four cycles of 1.12 (95% CI, 0.84 to 1.49; P = .44). There was no interaction between treatment duration and chemotherapy regimen, ER/PgR, or HER2 status on RFS or OS. Conclusion For women with resected primary breast cancer and zero to three positive nodes, we found no evidence that extending chemotherapy regimens of AC or single-agent T from four to six cycles improves clinical outcome.
MONILETHRIX: A SECOND GROUP OF FAMILIAL CASES
Authors: J. G. Tomkinson
Journal: BMJ (1935)

We submit: 1.That the term acidosis " is a very convenient one, and should be used to denote a biochemical phenomenon, in which the normal tendency of the body to form acid products of metabolism is enhanced; and that the pheno- menon is exactly comparable with such phenomena as elevated, tenmperature, accelerated pulse, and various rashes which may form integral parts of quite distinct symptom-complexes.This definition postulates that there can be no " types " of acidosis.2. That in acidosis the accumulation of acids in the blood is prevented -by compensatory mechanisms.When these mechanisms fail acidaemia supervenes.3. That the detection of acidosis by quantitative analysis of the early morning urine may furnish a valuable sign, and help in the construction of a definite disease syndrome.
Private providers must be stopped from skimming off easy cases
Authors: Rebecca Coombes
Journal: BMJ (2005)

The UK government needs to act urgently to stop private providers of NHS services “cream-skimming” the less difficult cases, MPs warned this week.

The House of Commons Public Administration Select Committee, in a report of its inquiry into choice in public services, said government plans to bring private companies to heel were so far “sketchy and inadequate.”

The concerns are about reforms due in December 2005 (although schemes are already in operation on a smaller scale), when all patients will be given a choice of hospital for elective treatment. The choice may include non-NHS facilities. Under the new funding system for acute hospital trusts, called payment by results, the NHS loses money if patients opt to go elsewhere. The new system lays down a fixed tariff for every operation, so a …
Inhibitory motor innervation of the gall bladder musculature by intrinsic neurones containing nitric oxide in the Australian Brush-tailed possum (Trichosurus vulpecula)
Authors: A C B Meedeniya
Journal: Gut (2001)

<h3>BACKGROUND</h3> Gall bladder functions are modulated by neurones intrinsic to the organ. Data are available on the neurochemical composition of intrinsic and extrinsic nerves innervating the gall bladder but are lacking on specific functional classes of gall bladder neurones. <h3>AIMS</h3> To characterise the intrinsic motor neurones of the gall bladder and identify their roles using pharmacological techniques. <h3>METHODS</h3> Retrograde tracing from the possum gall bladder muscle in vitro allowed identification of intrinsic motor neurones. Subsequently, their content of choline acetyltransferase and nitric oxide synthase, markers of acetylcholine and nitric oxide containing neurones, was established using immunohistochemical techniques. Organ bath pharmacology was used to evaluate neurotransmission by acetylcholine and nitric oxide in gall bladder muscle strips. <h3>RESULTS</h3> Innervation of the gall bladder musculature by neurones of both the muscular and serosal plexuses was demonstrated. A large proportion (62%) of these motor neurones were immunoreactive for nitric oxide synthase. All gall bladder neurones showed immunoreactivity for choline acetyltransferase. Organ bath pharmacology confirmed the neuroanatomical data, showing acetylcholine and nitric oxide mediating neurotransmission to the gall bladder musculature. <h3>CONCLUSIONS</h3> Neurones containing acetylcholine and nitric oxide, located within the muscular and serosal plexuses, provide excitatory and inhibitory motor innervation of the gall bladder, respectively. The large inhibitory innervation suggests active relaxation of the gall bladder during filling, mediated by intrinsic nerves.
Cardiovascular Disease in Survivors of Adolescent and Young Adult Cancer: A Danish Cohort Study, 1943–2009
Authors: Kathrine Rugbjerg, Lene Mellemkjær, John D. Boice, Lars Køber, Marianne Ewertz, Jørgen H. Olsen
Journal: JNCI Journal of the National Cancer Institute (2014)

BackgroundCardiovascular disease has emerged as a serious late effect in survivors of adolescent and young adult cancer, but risk has not been quantified comprehensively in a population-based setting.
Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies
Authors: N Sarwar, P Gao, S R Kondapally Seshasai, R Gobin, S Kaptoge, E Di Angelantonio, E Ingelsson, D A Lawlor, E Selvin, M Stampfer, C D A Stehouwer, S Lewington, L Pennells, A Thompson, N Sattar, I R White, K K Ray, J Danesh
Journal: The Lancet (2010)
Final results of the European Advanced Renal Cell Carcinoma Sorafenib (EU-ARCCS) expanded-access study: a large open-label study in diverse community settings
Authors: J. Beck, G. Procopio, E. Bajetta, U. Keilholz, S. Negrier, C. Szczylik, C. Bokemeyer, S. Bracarda, D.J. Richel, M. Staehler, U.P. Strauss, S. Mersmann, K. Burock, B. Escudier
Journal: Annals of Oncology (2011)
Mechanical bowel preparation for elective colorectal surgery: a multicentre randomised trial
Authors: Caroline ME Contant, Wim CJ Hop, Hans Pieter van 't Sant, Henk JM Oostvogel, Harm J Smeets, Laurents PS Stassen, Peter A Neijenhuis, Floris J Idenburg, Cees M Dijkhuis, Piet Heres, Willem F van Tets, Jos JGM Gerritsen, Wibo F Weidema
Journal: The Lancet (2007)
MOLECULAR MECHANISMS OF GENETIC POLYMORPHISMS OF DRUG METABOLISM
Authors: Urs A. Meyer, Ulrich M. Zanger
Journal: The Annual Review of Pharmacology and Toxicology (1997)

▪ Abstract One of the major causes of interindividual variation of drug effects is genetic variation of drug metabolism. Genetic polymorphisms of drug-metabolizing enzymes give rise to distinct subgroups in the population that differ in their ability to perform certain drug biotransformation reactions. Polymorphisms are generated by mutations in the genes for these enzymes, which cause decreased, increased, or absent enzyme expression or activity by multiple molecular mechanisms. Moreover, the variant alleles exist in the population at relatively high frequency. Genetic polymorphisms have been described for most drug metabolizing enzymes. The molecular mechanisms of three polymorphisms are reviewed here. The acetylation polymorphism concerns the metabolism of a variety of arylamine and hydrazine drugs, as well as carcinogens by the cytosolic N-acetyltransferase NAT2. Seven mutations of the NAT2 gene that occur singly or in combination define numerous alleles associated with decreased function. The debrisoquine-sparteine polymorphism of drug oxidation affects the metabolism of more than 40 drugs. The poor metabolizer phenotype is caused by several “loss of function” alleles of the cytochrome P450 CYP2D6 gene. On the other hand, “ultrarapid” metabolizers are caused by duplication or amplification of an active CYP2D6 gene. Intermediate metabolizers are often heterozygotes or carry alleles with mutations that decrease enzyme activity only moderately. The mephenytoin polymorphism affects the metabolism of mephenytoin and several other drugs. Two mutant alleles of CYP2C19 have so far been identified to cause this polymorphism. These polymorphisms show recessive transmission of the poor or slow metabolizer phenotype, i.e. two mutant alleles define the genotype in these individuals. Simple DNA tests based on the primary mutations have been developed to predict the phenotype. Analysis of allele frequencies in different populations revealed major differences, thereby tracing the molecular history and evolution of these polymorphisms.
Review of moderate alcohol consumption and reduced risk of coronary heart disease: is the effect due to beer, wine, or spirits?
Authors: E. B Rimm, A. Klatsky, D. Grobbee, M. J Stampfer
Journal: BMJ (1996)

<h3>Abstract</h3> <b>Objectives</b>: To review the effect of specific types of alcoholic drink on coronary risk. <b>Design</b>: Systematic review of ecological, case-control, and cohort studies in which specific associations were available for consumption of beer, wine, and spirits and risk of coronary heart disease. <b>Subjects</b>: 12 ecological, three case-control, and 10 separate prospective cohort studies. <b>Main outcome measures</b>: Alcohol consumption and relative risk of morbidity and mortality from coronary heart disease. <b>Results</b>: Most ecological studies suggested that wine was more effective in reducing risk of mortality from heart disease than beer or spirits. Taken together, the three case-control studies did not suggest that one type of drink was more cardioprotective than the others. Of the 10 prospective cohort studies, four found a significant inverse association between risk of heart disease and moderate wine drinking, four found such an association for beer, and four for spirits. <b>Conclusions</b>: Results from observational studies, where alcohol consumption can be linked directly to an individual9s risk of coronary heart disease, provide strong evidence that all alcoholic drinks are linked with lower risk. Thus, a substantial portion of the benefit is from alcohol rather than other components of each type of drink. <h3>Key messages</h3> Key messages We examined the relation between specific alcoholic drinks and reduction of risk of coronary heart disease by summarising published reports from ecological, case-control, and cohort studies Most ecological studies suggested that wine was more effective in reducing risk of mortality than beer or spirits, whereas the three case-control studies together did not suggest that one type of drink was more cardioprotective than others Of the 10 prospective cohort studies, four found a significant inverse association between risk of heart disease and moderate wine drinking, four found the association for beer, and four found it for spirits. The evidence suggests that all alcoholic drinks are linked with lower risk, so that much of the benefit is from alcohol rather than other components of each type of drink
Effects of Calcium Channel Blockers on Renal Function
Authors: L Chan, R W Schrier
Journal: Annual Review of Medicine (1990)

Calcium channel or entry blockers (CEBs) exert important vascular and tubular effects on the kidney. These renal effects include an enhancement of glomerular filtration rate (GFR), renal blood flow (RBF), and electrolyte excretion. Experimental studies in animals and humans indicate the potential therapeutic use of CEBs in several important clinical situations, for example attenuating the course of acute renal failure and slowing the progression of chronic renal failure. The latter effect appears to involve both the agent's antihypertensive effect and an additional cytoprotective effect. That CEBs help preserve renal function in renal transplantation has been shown in both animals and humans. In this setting, the effects of cyclosporine (CsA) and CEB on the immune system and on CsA hepatic metabolism are areas of importance for future research.
Alterations in the Renal Elastin-Elastase System in Type 1 Diabetic Nephropathy Identified by Proteomic Analysis
Authors: Visith Thongboonkerd, Michelle T. Barati, Kenneth R. McLeish, Charaf Benarafa, Eileen Remold-O’Donnell, Shirong Zheng, Brad H. Rovin, William M. Pierce, Paul N. Epstein, Jon B. Klein
Journal: Journal of the American Society of Nephrology (2004)

Diabetes now accounts for >40% of patients with ESRD. Despite significant progress in understanding diabetic nephropathy, the cellular mechanisms that lead to diabetes-induced renal damage are incompletely defined. For defining changes in protein expression that accompany diabetic nephropathy, the renal proteome of 120-d-old OVE26 transgenic mice with hypoinsulinemia, hyperglycemia, hyperlipidemia, and proteinuria were compared with those of background FVB nondiabetic mice (n = 5). Proteins derived from whole-kidney lysate were separated by two-dimensional PAGE and identified by matrix-assisted laser desorption ionization-time-of-flight (MALDI-TOF) mass spectrometry. Forty-one proteins from 300 visualized protein spots were differentially expressed in diabetic kidneys. Among these altered proteins, expression of monocyte/neutrophil elastase inhibitor was increased, whereas elastase IIIB was decreased, leading to the hypothesis that elastin expression would be increased in diabetic kidneys. Renal immunohistochemistry for elastin of 325-d-old FVB and OVE26 mice demonstrated marked accumulation of elastin in the macula densa, collecting ducts, and pelvicalyceal epithelia of diabetic kidneys. Elastin immunohistochemistry of human renal biopsies from patients with type 1 diabetes (n = 3) showed increased elastin expression in renal tubular cells and the interstitium but not glomeruli. These results suggest that coordinated changes in elastase inhibitor and elastase expression result in increased tubulointerstitial deposition of elastin in diabetic nephropathy. The identification of these coordinated changes in protein expression in diabetic nephropathy indicates the potential value of proteomic analysis in defining pathophysiology.
The Tricuspid Component of the First Heart Sound in Mitral Stenosis
Authors: HERBERT N. HULTGREN, THOMAS F. LEO
Journal: Circulation (1958)

The sound of tricuspid valve closure has been identified in 35 of 40 phonocardiograms of patients with mitral valve disease. Identification of the sound is facilitated by the delay of closure of the mitral valve thus separating these 2 components of the first heart sound. When the ventricular rhythm is irregular due to atrial fibrillation, the intensity of the sound is inversely proportional to the length of the preceding diastolic interval. When the sound of tricuspid closure is accentuated, it may be identified by auscultation as the initial component of a split first sound mesial to the apex. Measurement of the interval from the onset of the QRS complex of the electrocardiogram to the "first heart sound" should be made to the mitral component of the first sound when this can he identified on the phonocardiogram.
Transforming growth factor- type II receptor in pulmonary arteries of patients with very severe COPD
Authors: B. Beghe, E. Bazzan, S. Baraldo, F. Calabrese, F. Rea, M. Loy, P. Maestrelli, R. Zuin, L. M. Fabbri, M. Saetta
Journal: European Respiratory Journal (2006)

A mild-to-moderate increase in pulmonary arterial pressure is often associated with severe chronic obstructive pulmonary disease (COPD). Transforming growth factor (TGF)-β is a cytokine involved in the maintenance of integrity of vasculature. The aim of the study was to investigate whether the TGF-β pathway might be involved in the development of pulmonary hypertension associated with COPD. Surgical specimens from 14 patients undergoing lung transplantation for very severe COPD (forced expiratory volume in one second 17±2% of the predicted value) and from seven donors were examined. The expression of TGF-β1 and TGF-β type II receptor (TGF-βRII), cell proliferation index and structural changes in pulmonary arteries were quantified immunohistochemically. In severe COPD patients, increased expression of TGF-βRII was observed in both the tunica media and intima, which was associated with a normal proliferation index in both layers. Conversely, significant thickening of the tunica intima, which was not present in the tunica media, was observed, suggesting that mechanisms other than cell proliferation may be involved in intimal thickening. In conclusion, in the pulmonary arteries of patients with severe chronic obstructive pulmonary disease, there is upregulation of transforming growth factor-β type II receptor expression associated with a normal proliferation index. These findings suggest the activation of an antiproliferative pathway, which might explain the relatively low degree of pulmonary hypertension observed in these subjects.
NFATc1 self-promotes to build bone
Authors: Heather L. Van Epps
Journal: The Journal of Experimental Medicine (2005)

NFATc1 self-promotes to build boneSelf-promotion is the way to get ahead during bone development, according to Asagiri and colleagues.They show on page 1261 that the inducible transcription factor NFATc1 must turn on its own expression for bone-resorbing osteoclasts to form.NFATc1 drives osteoclast-specific gene expression and is essential for the development of these cells in vitro.But whether NFATc1 is required in vivo was unknown, as deletion of the NFATc1 gene is lethal in mice.Another open questions was whether NFATc2-NFATc1's closest relative-can drive osteoclast formation in the absence of NFATc1.Asagiri and colleagues now show that NFATc1 is indeed essential for osteoclast formation in vivo, as only NFATc1-expressing stem cells rescued osteoclast development when transferred into osteoclast-deficient mice.NFATc1-deficient stem cells failed at this task, despite having normal expression of NFATc2.Transcriptional regulation explained why only NFATc1 could do the job.Stimulation of bone marrow cells with the osteoclast growth factor RANKL (receptor activator of NF-B ligand) caused the NFATc2 protein in the cellalong with RANKL-induced NF-B proteins-to pile onto the NFATc1 promoter at the expense of the NFATc2 promoter.This binding induced the expression of NFATc1, which then bound back to its own promoter, thus amplifying NFATc1 production.The NFATc1 promoter also hoarded histone acetylases, whose DNA modifications facilitate transcription.The authors are now analyzing the chromatin structure of the two promoters, which might help explain why these proteins avoid the NFATc2 promoter.