tbuckley/cabot-search huggingface dataset:
Exercise and heart disease: cardiac findings in fatal cycle accidents.
Authors: A Kennedy
Journal: British Journal of Sports Medicine (1997)

Regular cyclists have been found to have a lower incidence of coronary events (CHD) than the general public. Non-invasive studies have found that competitive cyclists develop a cardiac hypertrophy that is physiological and reversible.To obtain pathological support for these observations, the postmortem findings of 32 cyclists killed in accidents have been compared with those in a control group of 32 other road traffic accidents, which were matched with the cyclists by sex, age, and year of death.Large myocardial scars and complete blockage of a coronary artery were only found in the controls; serious stenoses of coronary arteries (> 50%) were found in eight controls but in only one of the cyclists. Of the cyclists, 25 had normal coronary arteries as compared with 14 of the controls. The mean age of the cyclists with evidence of CHD was greater than that of similarly affected controls. The heart weights of the two groups were almost the same but heart weight varied with the degree of CHD. The heart weight of the healthy cyclists (389 g) was greater than that of the healthy controls (371 g) but this was not statistically significant.The results are in keeping with the concept that regular exercise provides some protection from the development of CHD and that cycling may be a valuable form of exercise in this respect. This may be of importance as the number of physically active occupations declines.
Deletion of a Small Consensus Region at 6q15, Including the<i>MAP3K7</i>Gene, Is Significantly Associated with High-Grade Prostate Cancers
Authors: Wennuan Liu, Bao-Li Chang, Scott Cramer, Patrick P. Koty, Tao Li, Jishan Sun, Aubrey R. Turner, Chris Von Kap-Herr, Peggy Bobby, Jianyu Rao, S. Lilly Zheng, William B. Isaacs, Jianfeng Xu
Journal: Clinical Cancer Research (2007)

Abstract Purpose: Chromosome 6q14-21 is commonly deleted in prostate cancers, occurring in ∼22% of all tumors and ∼40% of metastatic tumors. However, candidate prostate tumor suppressor genes in this region have not been identified, in part due to the large and broad nature of the deleted region implicated in previous studies. Experimental Design: We first used high-resolution Affymetrix single nucleotide polymorphism arrays to examine DNA from malignant and matched nonmalignant cells from 55 prostate cancer patients. We identified a small consensus region on 6q14-21 and evaluated the deletion status within the region among additional 40 tumors and normal pairs using quantitative PCR and fluorescence in situ hybridization. We finally tested the association between the deletion and Gleason score using the Fisher's exact test. Results: Tumors with small, interstitial deletions at 6q14-21 defined an 817-kb consensus region that is affected in 20 of 21 tumors. The MAP3K7 gene is one of five genes located in this region. In total, MAP3K7 was deleted in 32% of 95 tumors. Importantly, deletion of MAP3K7 was highly associated with higher-grade disease, occurring in 61% of tumors with Gleason score ≥8 compared with only 22% of tumors with Gleason score ≤7. The difference was highly significant (P = 0.001). Conclusion: Our study provides strong evidence for the first time that a small deletion at 6q15, including the MAP3K7 gene and four other genes, is associated with high-grade prostate cancers. Although the deletion may be a marker for high-grade prostate cancer, additional studies are needed to understand its molecular mechanisms.
How intestinal epithelial cells tolerise dendritic cells and its relevance to inflammatory bowel disease
Authors: M Shale, S Ghosh
Journal: Gut (2009)

Intestinal epithelial layer is an important barrier against antigen invasion. In addition to its barrier function, the immunomodulatory role of intestinal epithelium is attracting considerable attention. The intestinal epithelium may influence underlying immune cells including dendritic cells and lymphocytes and promote tolerogenic and regulatory responses in health. Breakdown of such regulatory influences may result in uncontrolled inflammation and tissue damage. The molecules mediating such regulation derived from intestinal epithelium and their interaction with immune cells may provide novel targets and therapeutic molecules that have translational potential in intestinal inflammation. Understanding the cross-talk between intestinal epithelium and immune cells has progressed from in vitro co-culture models to epithelial cell conditional knockout models.
Altered left ventricular diastolic properties during pacing-induced angina in patients with aortic stenosis.
Authors: M A Fifer, P D Bourdillon, B H Lorell
Journal: Circulation (1986)

An increase in left ventricular diastolic pressure has been repeatedly observed during angina in patients with coronary artery stenoses and regional demand ischemia, but the role of relaxation abnormalities versus left ventricular segmental dyssynchrony is controversial. In contrast, patients with angina due to aortic stenosis are likely to have diffuse rather than segmental ischemia and thus may provide an alternative model for examining the diastolic physiology of angina in man. Accordingly, we examined the hemodynamic manifestations of angina in eight patients with aortic stenosis without significant coronary artery disease. Angina was induced by pacing tachycardia, and hemodynamic and echocardiographic variables were measured in the control period and during angina in the beats immediately after cessation of pacing. Heart rate (control vs angina, 69 +/- 12 vs 70 +/- 11 beats/min, p = NS) and left ventricular peak systolic pressure (207 +/- 39 vs 222 +/- 22 mm Hg, p = NS) were similar in the control and postpacing angina periods. Left ventricular end-diastolic pressure, on the other hand, was significantly higher during postpacing angina (15 +/- 7 vs 28 +/- 8 mm Hg, p less than .01). The time constant of left ventricular pressure decline during isovolumetric relaxation (TL), calculated as the slope of a linear fit of the natural log of pressure vs time, increased from 44 +/- 5 to 51 +/- 7 msec (p less than .05); the time constant TD, derived from the slope of a linear fit of dP/dt vs pressure, also increased slightly, although the change was not statistically significant (69 +/- 5 vs 75 +/- 5 msec, p = .06).(ABSTRACT TRUNCATED AT 250 WORDS)
Angiotensin II Impairs the Insulin Signaling Pathway Promoting Production of Nitric Oxide by Inducing Phosphorylation of Insulin Receptor Substrate-1 on Ser <sup>312</sup> and Ser <sup>616</sup> in Human Umbilical Vein Endothelial Cells
Authors: Francesco Andreozzi, Emanuela Laratta, Angela Sciacqua, Francesco Perticone, Giorgio Sesti
Journal: Circulation Research (2004)

It has been suggested that serine (Ser) phosphorylation of insulin receptor substrate-1 (IRS-1) decreases the ability of IRS-1 to be phosphorylated on tyrosine, thereby attenuating insulin signaling. There is evidence that angiotensin II (AII) may impair insulin signaling to the IRS-1/phosphatydilinositol 3-kinase (PI 3-kinase) pathway by enhancing Ser phosphorylation. Insulin stimulates NO production by a pathway involving IRS-1/PI3-kinase/Akt/endothelial NO synthase (eNOS). We addressed the question of whether AII affects insulin signaling involved in NO production in human umbilical vein endothelial cells and tested the hypothesis that the inhibitory effect of AII on insulin signaling was caused by increased site-specific Ser phosphorylation in IRS-1. Exposure of human umbilical vein endothelial cells to AII resulted in inhibition of insulin-stimulated production of NO. This event was associated with impaired IRS-1 phosphorylation at Tyr612 and Tyr632, two sites essential for engaging the p85 subunit of PI3-kinase, resulting in defective activation of PI 3-kinase, Akt, and eNOS. This inhibitory effect of AII was reversed by the type 1 receptor antagonist losartan. AII increased c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) 1/2 activity, which was associated with a concomitant increase in IRS-1 phosphorylation at Ser312 and Ser616, respectively. Inhibition of JNK and ERK1/2 activity reversed the negative effects of AII on insulin-stimulated NO production. Our data suggest that AII, acting via the type 1 receptor, increases IRS-1 phosphorylation at Ser312 and Ser616 via JNK and ERK1/2, respectively, thus impairing the vasodilator effects of insulin mediated by the IRS-1/PI 3-kinase/Akt/eNOS pathway.
Tumour Necrosis Is an Indicator of Aggressive Biology in Patients with Urothelial Carcinoma of the Upper Urinary Tract
Authors: Richard Zigeuner, Shahrokh F Shariat, Vitaly Margulis, Pierre I Karakiewicz, Marco Roscigno, Alon Weizer, Eiji Kikuchi, Mesut Remzi, Jay D Raman, Christian Bolenz, Karim Bensalah, Umberto Capitanio, Theresa M Koppie, Wassim Kassouf, Kanishka Sircar, Jean-Jacques Patard, Mario I Fernández, Christopher G Wood, Francesco Montorsi, Philipp Ströbel, Jeffery C Wheat, Andrea Haitel, Mototsugu Oya, Charles C Guo, Casey Ng, Daher C Chade, Arthur Sagalowsky, Cord Langner
Journal: European Urology (2009)
Late CF caused by homozygous IVS8-5T CFTR polymorphism
Authors: V Cottin
Journal: Thorax (2005)

<h3>Abstract</h3> The quest to model and modulate embryonic development became a recent cornerstone of stem cell and developmental biology. Mammalian developmental timing is adjustable in vivo by preserving preimplantation embryos in a dormant state called diapause. Inhibition of the growth regulator mTOR (mTORi) pauses mouse development in vitro, yet constraints to pause duration are unrecognized. By comparing the response of embryonic and extraembryonic stem cells to mTORi-induced pausing, we identified lipid usage as a bottleneck to developmental pausing. Enhancing fatty acid oxidation (FAO) boosts embryo longevity, while blocking it reduces the pausing capacity. Genomic and metabolic analyses of single embryos point toward a deeper dormant state in FAO-enhanced pausing and reveal a link between lipid metabolism and embryo morphology. Our results lift a constraint on in vitro embryo survival and suggest that lipid metabolism may be a critical metabolic transition relevant for longevity and stem cell function across tissues. <h3>One-Sentence Summary</h3> Facilitating fatty acid oxidation by carnitine supplementation enhances mTOR inhibition-mediated developmental pausing.
Depressed contractile function due to canine mitral regurgitation improves after correction of the volume overload.
Authors: K Nakano, M M Swindle, F Spinale, K Ishihara, S Kanazawa, A Smith, R W Biederman, L Clamp, Y Hamada, M R Zile
Journal: Journal of Clinical Investigation (1991)

It is known that long-standing volume overload on the left ventricle due to mitral regurgitation eventually leads to contractile dysfunction. However, it is unknown whether or not correction of the volume overload can lead to recovery of contractility. In this study we tested the hypothesis that depressed contractile function due to volume overload in mitral regurgitation could return toward normal after mitral valve replacement. Using a canine model of mitral regurgitation which is known to produce contractile dysfunction, we examined contractile function longitudinally in seven dogs at baseline, after 3 mo of mitral regurgitation, 1 mo after mitral valve replacement, and 3 mo after mitral valve replacement. After 3 mo of mitral regurgitation (regurgitant fraction 0.62 +/- 0.04), end-diastolic volume had nearly doubled from 68 +/- 6.8 to 123 +/- 12.1 ml (P less than 0.05). All five indices of contractile function which we examined were depressed. For instance, maximum fiber elastance (EmaxF) obtained by assessment of time-varying elastance decreased from 5.95 +/- 0.71 to 2.25 +/- 0.18 (P less than 0.05). The end-systolic stiffness constant (k) was also depressed from 4.2 +/- 0.4 to 2.1 +/- 0.3. 3 mo after mitral valve replacement all indexes of contractile function had returned to or toward normal (e.g., EmaxF 3.65 +/- 0.21 and k 4.2 +/- 0.3). We conclude that previously depressed contractile function due to volume overload can improve after correction of the overload.
Inhibition of Interleukin 10 Signaling after Fc Receptor Ligation and during Rheumatoid Arthritis
Authors: Jong-Dae Ji, Ioannis Tassiulas, Kyung-Hyun Park-Min, Ani Aydin, Ingrid Mecklenbräuker, Alexander Tarakhovsky, Luminita Pricop, Jane E. Salmon, Lionel B. Ivashkiv
Journal: The Journal of Experimental Medicine (2003)

Interleukin-10 (IL-10) is a potent deactivator of myeloid cells that limits the intensity and duration of immune and inflammatory responses. The activity of IL-10 can be suppressed during inflammation, infection, or after allogeneic tissue transplantation. We investigated whether inflammatory factors suppress IL-10 activity at the level of signal transduction. Out of many factors tested, only ligation of Fc receptors by immune complexes inhibited IL-10 activation of the Jak-Stat signaling pathway. IL-10 signaling was suppressed in rheumatoid arthritis joint macrophages that are exposed to immune complexes in vivo. Activation of macrophages with interferon-γ was required for Fc receptor–mediated suppression of IL-10 signaling, which resulted in diminished activation of IL-10–inducible genes and reversal of IL-10–dependent suppression of cytokine production. The mechanism of inhibition involved decreased cell surface IL-10 receptor expression and Jak1 activation and was dependent on protein kinase C delta. These results establish that IL-10 signaling is regulated during inflammation and identify Fc receptors and interferon-γ as important regulators of IL-10 activity. Generation of macrophages refractory to IL-10 can contribute to pathogenesis of inflammatory and infectious diseases characterized by production of interferon-γ and immune complexes.
Acute Lower Respiratory Tract Infection
Authors: Joseph P. Mizgerd
Journal: New England Journal of Medicine (2008)

Acute lower respiratory tract infections are a major cause of death and disability, yet the mechanisms that make such infections so virulent are not entirely understood. This review emphasizes the roles of inflammation and the response of the innate immune system and explains how these two processes interact to rid the lung of microbes but also how they can bring the elimination of infection in the lung to a perilous climax.
Naturally Occurring Transposable Elements Disrupt hsp70 Promoter Function in Drosophila melanogaster
Authors: Daniel N Lerman, Martin E Feder
Journal: Molecular Biology and Evolution (2004)

Naturally occurring transposable element (TE) insertions that disrupt Drosophila promoters are correlated with modified promoter function and are posited to play a significant role in regulatory evolution, but their phenotypes have not been established directly. To establish the functional consequences of these TE insertions, we created constructs with either TE-bearing or TE-lacking hsp70 promoters fused to a luciferase reporter gene and assayed luciferase luminescence in transiently transfected Drosophila cells. Each of the four TEs reduces luciferase signal after heat shock and heat inducibility of the hsp70 promoter. To test if the differences in hsp70 promoter activity are TE-sequence dependent, we replaced each of the TEs with multiple intergenic sequences of equal length. These replacement insertions similarly reduced luciferase signal, suggesting that the TEs affect hsp70 promoter function by altering promoter architecture. These results are consistent with differences in Hsp70 expression levels, inducible thermotolerance, and fecundity previously associated with the TEs. That two different varieties of TEs in two different hsp70 genes have common effects suggests that TE insertion represents a general mechanism through which selection manipulates hsp70 gene expression.
Experiences with Liver Transplantation in Hannover
Authors: Rudolf Pichlmayr, C H. Brölsch, K. Wonigeit, P. Neuhaus, S. Siegismund, F.-W. Schmidt, M. Burdelski
Journal: Hepatology (1984)

Ninety orthotopic liver transplantations in 86 patients performed between 1972 and 1983 in the Medical University of Hannover are reviewed. Results in tumor patients (n = 46) are characterized by a high rate of early tumor recurrence. A few patients survived for prolonged periods, and some were cured. More experience is required to define more precisely suitable kinds and stages of malignancies so that liver grafting in tumor patients can be confined to situations with a favorable prognosis. The main problem of liver transplantation in cirrhotics (n = 40) is the appropriate time of indication. It is suggested that liver grafting be performed more often in an "elective" situation. This phase during the course of cirrhosis must be optimally defined by analysis of the underlying disease and by individual situation. Results of liver grafting in elective situations are better than those in emergency situations and may offer a tangible chance for cure. Liver grafting in pediatric patients gives the best results, although procurement of small donor organs is a major problem. More experience, better immunosuppression with cyclosporin A, and the search for the appropriate time of indication contribute to improvement in the results of liver grafting.
Randomized, Multicenter, Controlled Trial Comparing the Efficacy and Safety of Darbepoetin Alfa Administered Every 3 Weeks With or Without Intravenous Iron in Patients With Chemotherapy-Induced Anemia
Authors: Laurent Bastit, An Vandebroek, Sevilay Altintas, Bernd Gaede, Tamás Pintér, Tamas S. Suto, Tony W. Mossman, Kay E. Smith, Johan F. Vansteenkiste
Journal: Journal of Clinical Oncology (2008)

The concomitant use of intravenous (IV) iron as a supplement to erythropoiesis-stimulating agents in patients with chemotherapy-induced anemia is controversial. This study was designed to evaluate the efficacy and safety of darbepoetin alpha given with IV iron versus with local standard practice (oral iron or no iron).In this multicenter, randomized, open-label, phase III study, 396 patients with nonmyeloid malignancies and hemoglobin (Hb) less than 11 g/dL received darbepoetin alpha 500 microg with (n = 200) or without (n = 196) IV iron once every 3 weeks (Q3W) for 16 weeks.The hematopoietic response rate (proportion of patients achieving Hb >or= 12 g/dL or Hb increase of >or= 2 g/dL from baseline) was significantly higher in the IV iron group: 86% versus 73% in the standard practice group (difference of 13% [95% CI, 3% to 23%]; P = .011). Fewer RBC transfusions (week 5 to the end of the treatment period) occurred in the IV iron group: 9% versus 20% in the standard practice group (difference of -11% [95% CI, -18% to -3%]; P = .005). Both treatments were well tolerated with no notable differences in adverse events. Serious adverse events related to iron occurred in 3% of patients in the IV iron group and were mostly gastrointestinal in nature.Addition of IV iron to darbepoetin alpha Q3W in patients with chemotherapy-induced anemia was well tolerated, resulting in an improved hematopoietic response rate and lower incidence of transfusions compared with darbepoetin alpha alone.
Antigen Presentation and T Cell Stimulation by Dendritic Cells
Authors: Pierre Guermonprez, Jenny Valladeau, Laurence Zitvogel, Clotilde Théry, Sebastian Amigorena
Journal: Annual Review of Immunology (2002)

Dendritic cells take up antigens in peripheral tissues, process them into proteolytic peptides, and load these peptides onto major histocompatibility complex (MHC) class I and II molecules. Dendritic cells then migrate to secondary lymphoid organs and become competent to present antigens to T lymphocytes, thus initiating antigen-specific immune responses, or immunological tolerance. Antigen presentation in dendritic cells is finely regulated: antigen uptake, intracellular transport and degradation, and the traffic of MHC molecules are different in dendritic cells as compared to other antigen-presenting cells. These specializations account for dendritic cells' unique role in the initiation of immune responses and the induction of tolerance.
Overall Survival Benefit With Lapatinib in Combination With Trastuzumab for Patients With Human Epidermal Growth Factor Receptor 2–Positive Metastatic Breast Cancer: Final Results From the EGF104900 Study
Authors: Kimberly L. Blackwell, Harold J. Burstein, Anna Maria Storniolo, Hope S. Rugo, George Sledge, Gursel Aktan, Catherine Ellis, Allison Florance, Svetislava Vukelja, Joachim Bischoff, José Baselga, Joyce O'Shaughnessy
Journal: Journal of Clinical Oncology (2012)

Phase III EGF104900 data demonstrated that lapatinib plus trastuzumab significantly improved progression-free survival (PFS) and clinical benefit rate versus lapatinib monotherapy, offering a chemotherapy-free option for patients with heavily pretreated human epidermal growth factor receptor 2 (HER2) -positive metastatic breast cancer (MBC). Final planned overall survival (OS) analysis from EGF104900 is reported here.Patients with HER2-positive MBC whose disease progressed during prior trastuzumab-based therapies were randomly assigned to receive lapatinib monotherapy or lapatinib in combination with trastuzumab. OS and updated PFS data are presented using Kaplan-Meier curves and log-rank tests stratified for hormone receptor and visceral disease status. Subgroup analyses were conducted to identify characteristics of patients deriving the greatest clinical benefit.In this updated final analysis of all patients randomly assigned with strata (n = 291), lapatinib plus trastuzumab continued to show superiority to lapatinib monotherapy in PFS (hazard ratio [HR], 0.74; 95% CI, 0.58 to 0.94; P = .011) and offered significant OS benefit (HR, 0.74; 95% CI, 0.57 to 0.97; P = .026). Improvements in absolute OS rates were 10% at 6 months and 15% at 12 months in the combination arm compared with the monotherapy arm. Multiple baseline factors, including Eastern Cooperative Oncology Group performance status of 0, nonvisceral disease, < three metastatic sites, and less time from initial diagnosis until random assignment, were associated with improved OS. Incidence of adverse events was consistent with previously reported rates.These data demonstrated a significant 4.5-month median OS advantage with the lapatinib and trastuzumab combination and support dual HER2 blockade in patients with heavily pretreated HER2-positive MBC.
Neural Regulation of Insulin Secretion in the Dog
Authors: Daniel Porte, Lucien Girardier, Josianne Seydoux, Yasunori Kanazawa, Jean Posternak
Journal: Journal of Clinical Investigation (1973)

The effects of stimulation of the mixed autonomic nerve to the dog pancreas has been studied under conditions in which both pancreaticoduodenal vein blood flow and insulin concentration were determined. Stimulation resulted in increased insulin output, which was blocked by prior administration of atropine. Blood flow was reduced by stimulation in proportion to the rate of stimulation. At 40 stimuli/s a maximum effect was found at 1 min with a gradual return toward base line despite continued application of the stimulus. Atropinization had no effect on blood flow changes. Insulin responses to 0.1 g/kg glucose were reduced on the average 40% by simultaneous stimulation of the pancreatic nerve at 40 cycles/s in atropinized animals. These studies establish this preparation as a reproducible model for the direct examination of autonomic influences on endocrine pancreatic function. From them it is concluded that the nerve supply to the endocrine pancreas of the dog is sufficient to inhibit insulin secretion by activation of the sympathetic nerves and to stimulate insulin secretion by activation of the parasympathetic nerves.