tbuckley/cabot-search huggingface dataset:
Transforming growth factor-β1 and ultraviolet A1 radiation increase production of vascular endothelial growth factor but not endothelin-1 in human dermal fibroblasts
Authors: S. Trompezinski, I. Pernet, C. Mayoux, D. Schmitt, J. Viac
Journal: British Journal of Dermatology (2000)

Normal and dysregulated wound healing involves fibroblast activation and angiogenesis, in which polypeptide factors such as transforming growth factor (TGF)-beta, vascular endothelial growth factor (VEGF) and endothelin-1 (ET-1) play an important part. Ultraviolet (UV) A1 (365 nm) has recently received attention as a possible treatment for some dermal fibrotic disorders.The aim of this study was to evaluate the effects of TGF-beta1 and UVA1 radiation, as well as that of cobalt chloride, reported to mimic hypoxia both in vivo and in vitro, on the expression of VEGF and ET-1 by cultured human dermal fibroblasts.Levels of VEGF and ET-1 were measured by enzyme-linked immunosorbent assay and expression of neutral endopeptidase (NEP, CD10), known to degrade ET-1, was quantified by flow cytometric analysis after cell trypsinization.Our results showed that the cells released minor amounts of VEGF and ET-1. Both TGF-beta1 and UVA1 strongly increased VEGF secretion in a dose- and time-dependent manner, without significantly affecting ET-1 release. Irradiation of TGF-beta1-stimulated fibroblasts resulted in a synergistic effect on increasing levels of VEGF but not ET-1 after 48 h. Cobalt chloride stimulated the secretion of VEGF by fibroblasts; the effects of TGF-beta1 and cobalt were additive. However, no significant effect of cobalt chloride on ET-1 secretion was observed, suggesting that ET-1 production in fibroblasts is not oxygen-sensitive. The expression of NEP was not modified by TGF-beta1 or UVA1 radiation. Addition of a neutralizing anti-CD10 antibody to fibroblast cultures downregulated CD10 expression at the cell surface without changing ET-1 levels in cell supernatants after 24 or 48 h. This suggests that membrane-bound NEP has minimal or no activity against secreted ET-1.Taken together, these results underline the major role played by TGF-beta1 in increasing VEGF secretion by fibroblasts. This, as well as the documented effect of UVA1 on increasing VEGF production, may have implications for wound healing in vivo.
Pamela June Alexander (née Tyson)
Authors: Rosemary Alexander
Journal: BMJ (2007)

Pioneered the first successful bone marrow transplants in children with primary immunodeficiency and became a fearless university administratorThe dreadful death of Roland Levinsky has shocked the world of paediatric oncology and genetics.He was an immunologist of international renown who performed the UK's first successful bone marrow transplant in children with primary immunodeficiency in 1979 at Great Ormond Street children's hospital.He went on to perform the UK's first successful attempts at gene therapy in children with fatal inherited diseases.He transformed the Institute of Child Health in London into a topclass research institution.Later, he did a similar makeover at Plymouth University, sending it soaring up the league tables.Levinsky was born in South Africa to a British-born mother and Polish/Lithuanian father.His father, died when Roland was 13.Two years later his mother returned to England with her three children.
Hospital Variation in Thrombolysis Times Among Patients With Acute Ischemic Stroke
Authors: Kori Sauser, Deborah A. Levine, Adrienne V. Nickles, Mathew J. Reeves
Journal: JAMA Neurology (2014)

Given the limited time window available for treatment with tissue plasminogen activator (tPA) in patients with acute ischemic stroke, guidelines recommend door-to-imaging time (DIT) within 25 minutes of hospital arrival and door-to-needle (DTN) time within 60 minutes for patients with acute ischemic stroke. Despite improvements in DITs, DTN times for tPA treatment in patients with acute ischemic stroke remain suboptimal.To examine the contributions of DIT and imaging-to-needle (ITN) time to delays in timely delivery of tPA to patients with acute ischemic stroke and to assess between-hospital variation in DTN times.A cohort analysis of 1193 patients having acute ischemic stroke treated with intravenous tPA between January 2009 and December 2012. Multilevel linear regression models included random effects for 25 Michigan hospitals participating in the Paul Coverdell National Acute Stroke Registry.The primary outcome was a continuous measure of DTN time, in minutes, from emergency department arrival to thrombolytic delivery.The mean age was 68.1 years, the median National Institutes of Health Stroke Scale score was 11.0 (interquartile range, 6-17), 51.4% were female, and 37.5% were of nonwhite race/ethnicity.The mean (SD) DTN time was 82.9 (35.4) minutes, the mean (SD) DIT was 22.8 (15.9) minutes, and the mean (SD) ITN time was 60.1 (32.3) minutes. Most patients (68.4%) had DIT within 25 minutes, while 28.7% had DTN time within 60 minutes. Hospital variation accounted for 12.7% of variability in DTN times. Neither annual stroke volume nor primary stroke center designation was a significant predictor of shorter DTN time. Patient factors (age, sex, race/ethnicity, arrival mode, onset-to-arrival time, and stroke severity) explained 15.4% of the between-hospital variation in DTN times. After adjustment for patient-level factors, DIT explained 10.8% of the variation in hospital risk-adjusted DTN times, while ITN time explained 64.6%.Compared with DIT, ITN time is a much greater source of variability in hospital DTN times and is a more common contributor to delays in timely tPA therapy for acute ischemic stroke. More attention is needed to determine systems changes that can decrease ITN time for patients with acute ischemic stroke.
Nineteen cases of the t(1;22)(p13;q13) acute megakaryblastic leukaemia of infants/children and a review of 39 cases: report from a t(1;22) study group
Authors: J Bernstein, N Dastugue, OA Haas, J Harbott, NA Heere, JL Huret, J Landman-Parker, MM LeBeau, C Leonard, G Mann, MP Pages, C Perot, H Pirc-Danoewinata, B Roitzheim, CM Rubin, M Slociak, F Viguie
Journal: Leukemia (2000)
Skeletal muscle blood flow and neurovascular reactivity in liver disease
Authors: M. Lunzer, S. P. Newman, S. Sherlock
Journal: Gut (1973)

There was no significant difference in forearm muscle blood flow, measured by the clearance of (133)Xenon when 38 patients with liver disease were compared with 38 normal subjects. Patients with a clinically hyperdynamic circulation, finger clubbing, and previous portocaval anastomoses were included in the study. The changes in forearm skeletal muscle blood flow and pulse rate caused by a head-up tilt of 70 degrees were measured in 15 patients with chronic liver disease and 15 age-matched controls. Head-up tilting resulted in significantly less peripheral vasoconstriction and tachycardia in the group with liver disease than in the control group. These results suggest an impairment of baroreceptor-mediated sympathetic reactivity in liver disease. Such a defect might explain the relative rarity of hypertension in patients with cirrhosis.
Film: Nurse Betty
Authors: S. A Spence
Journal: BMJ (2000)

Directed by Neil LaBute, Pathé Productions, on worldwide general release Rating: ![Graphic][1]</img> ![Graphic][2]</img> ![Graphic][3]</img> Betty Sizemore lives in Kansas and works in a diner. Her husband Del is a car salesman and is having an affair with his secretary. He treats Betty badly and she retreats into an inner life focused on the plot of a TV soap opera. She thinks she is in love with the soap's central character, Doctor David Ravell. From these unremarkable beginnings this accomplished film catapults its heroine into a hugely entertaining, yet subtle and thought provoking journey across western America, culminating in Hollywood. … [1]: /embed/inline-graphic-1.gif [2]: /embed/inline-graphic-2.gif [3]: /embed/inline-graphic-3.gif
In Memoriam Norman J. Siegel, MD 1943–2006
Authors: William G. Couser, Allison A. Eddy
Journal: Journal of the American Society of Nephrology (2006)

![Figure][1]</img> The members of the American Society of Nephrology (ASN) and the international nephrology community were deeply shocked and saddened by the untimely death of a recent past president of the ASN, Dr. Norman Siegel, on April 28, 2006. Dr Siegel died unexpectedly while attending the
SUCCESSFUL RESTORATION OF HEART RATE RESPONSIVENESS TO EXERCISE USING CARDIAC RESYNCHRONIZATION THERAPY DELAYS ANAEROBIC THRESHOLD IN PATIENTS WITH ADVANCED HEART FAILURE
Authors: Daniel Sims, Andrea Mignatti, Paolo C. Colombo, Pierantonio Laveneziana, Nir Uriel, Frederick A. Ehlert, Ulrich P. Jorde
Journal: Journal of the American College of Cardiology (2010)
Evidence for Preserved Cardiopulmonary Baroreflex Control of Renal Cortical Blood Flow in Humans With Advanced Heart Failure
Authors: Holly R. Middlekauff, Egbert U. Nitzsche, Michèle A. Hamilton, Heinrich R. Schelbert, Gregg C. Fonarow, Jaime D. Moriguchi, Antoine Hage, Saleh Saleh, G. Gary Gibbs
Journal: Circulation (1995)

Background The effect of cardiopulmonary baroreflexes on the renal circulation in healthy humans and patients with heart failure is unknown because of the technical limitations of studying the renal circulation. Positron emission tomography (PET) imaging is a new method to measure renal cortical blood flow in humans that is precise, rapid, reproducible, and noninvasive. The purpose of this study was to compare the effect of acute cardiopulmonary baroreceptor unloading by phlebotomy on regional blood flow in healthy humans and humans with advanced heart failure. Methods and Results We compared renal cortical blood flow and forearm blood flow in 10 healthy volunteers and 8 patients with heart failure (left ventricular ejection fraction, 0.24±0.02) during cardiopulmonary baroreceptor unloading with phlebotomy (450 mL). The major findings of this study are: (1) At rest, renal cortical blood flow is markedly diminished in humans with heart failure compared with healthy humans (heart failure, 2.4±0.1 versus healthy, 4.3±0.2 mL · min −1 · g −1 , P &lt;.001). (2) In healthy humans, during phlebotomy, forearm blood flow decreased substantially (basal, 3.3±0.4 versus phlebotomy, 2.6±0.3 mL · min −1 · 100 mL −1 , P =.02) and renal cortical blood flow decreased slightly but significantly (basal, 4.3±0.2 versus phlebotomy, 4.0±0.3 mL · min −1 · g −1 , P =.01). (3) The small magnitude of reflex renal vasoconstriction is not explained by the inability of the renal circulation to vasoconstrict, since the cold pressor stimulus induced substantial decreases in renal cortical blood flow in healthy subjects (basal, 4.4±0.1 versus cold pressor, 3.7±0.1 mL · min −1 · g −1 , P =.003). (4) In humans with heart failure, during phlebotomy, forearm blood flow did not change (basal, 2.6±0.3 versus phlebotomy, 2.7±0.2 mL · min −1 · 100 mL −1 , P =NS), but renal cortical blood flow decreased slightly but significantly (basal, 2.4±0.1 versus phlebotomy, 2.1±0.1 mL · min −1 · g −1 , P =.01). (5) The cold pressor stimulus induced substantial decreases in renal cortical blood flow in patients with heart failure (basal, 2.9±0.1 versus cold pressor, 2.3±0.1 mL · min −1 · g −1 , P =.008). Thus, in patients with heart failure, there is an abnormality in cardiopulmonary baroreflex control of the forearm circulation but not the renal circulation. Conclusions This study demonstrates the power of PET imaging to study normal physiological and pathophysiological reflex control of the renal circulation in humans and describes the novel finding of selective dysfunction of cardiopulmonary baroreflex control of one vascular region but its preservation in another in patients with heart failure.
Abstract 1886: Activation of IL-6R/JAK1/STAT3 signaling induces de novo resistance to irreversible EGFR inhibitors in non-small cell lung cancer with T790M resistance mutation
Authors: Byoung Chul Cho, Sun Mi Kim, Flavio Solca, Joo-Hang Kim
Journal: Cancer Research (2012)

Abstract Advanced non-small cell lung cancers (NSCLCs) with activating epidermal growth factor receptor (EGFR) mutation respond preferentially to reversible first-generation EGFR tyrosine kinase inhibitors (TKIs) gefitinib or erlotinib, but drug resistance invariably emerges. Acquisition of secondary T790M mutation in EGFR is the most common mechanism of acquired resistance to EGFR TKIs in these tumors. Although second-generation irreversible EGFR TKIs, such as BIBW2992 or PF00299804, have been introduced to overcome acquired resistance by the T790M mutation, showing they showed a limited clinical activity in patients with T790M mutant tumors. In this study, we first demonstrated in vitro and in vivo that JAK1-dependent STAT3 activation via autocrine IL-6 production was the key mechanism of de novo resistance to the irreversible EGFR TKIs in NSCLC cells harboring T790M mutation. Both BIBW2992 and PF00299804 induced STAT3 activation via JAK1, but not JAK2 or TYK2, and inhibition of JAK1/STAT3 signaling by small interfering RNA or pyridone 6 (P6, pan-JAK inhibitor) significantly increased sensitivity to BIBW2992 in H1975 or PC9-GR cells. BIBW2992-induced JAK1/STAT3 activation is mediated by interleukin-6 receptor (IL-6R) signaling pathway via autocrine IL-6 production. Cancer cells showed a stronger STAT3 activation and enhanced resistance to BIBW2992 in the presence of conditioned medium from MRC-5 (MRC5-CM) fibroblasts. Blocking of IL-6R/JAK1 signaling significantly inhibited MRC5-CM-induced STAT3 activation and increased the sensitivity to BIBW2992 in the presence of MRC5-CM, suggesting a critical role of IL-6R/JAK1/STAT3 signaling between fibroblasts and cancer cells in the development of drug resistance. Treatment of PC9-GR cells with BIBW2992 for 10 days in the presence of MRC5-CM significantly increased expression of several mesenchymal markers including snail, twist, vimentin, and N-cadherin. The epithelial-mesenchymal transition (EMT) upon short-term BIBW2992 treatment was not suppressed by the addition of P6, but was prevented by early concurrent administration of P6 with BIBW2992. In PC9-GR xenograft model, combination treatment with BIBW2992 and P6 showed a synergistic anti-tumor activity compared with BIBW2992 or P6 alone. Taken together, we suggest that inhibition of IL-6R/JAK1/STAT3 signaling can be a potential target to enhance therapeutic efficacy of irreversible EGFR TKIs in patients with a T790M resistance mutation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1886. doi:1538-7445.AM2012-1886
Fabry Nephropathy and the Case for Adjunctive Renal Therapy
Authors: Christoph Wanner, Frank Breunig
Journal: Journal of the American Society of Nephrology (2007)

Proteinuria in advanced Fabry nephropathy does not respond to enzyme replacement therapy (ERT) alone using recombinant agalsidase-α or -β. In this issue of JASN , Tahir et al. [1][1] describe a series of patients who had Fabry nephropathy and achieved sustained reductions in proteinuria and
Iron and coronary heart disease. Control for haematological variables.
Authors: I F Godsland, R Bruce, M Worthington, J C Stevenson
Journal: BMJ (1993)

and greatly inhibit atherogenesis.Interactions in vivo between iron and low density lipoprotein are not well defined.The apparent lack of increased atherosclerosis in haemochromatosis may simply mean that modification of low density lipoprotein catalysed by iron is maximal or nearly maximal at a low level ofexcess iron.
Glycosylated haemoglobin in rheumatoid arthritis.
Authors: D Lewis, H.A Capell, D.K Talwar, D.A Robb
Journal: Annals of the Rheumatic Diseases (1983)

One possible explanation for the variance of their results with ours after trypsin and hyaluronidase digested synovial fluid on the frictional resistance of joints may be that they did not appear to deactivate the enzymes before performing the lubrication tests.These enzymes have well known effects on articular cartilage, and we think it likely that the authors would have obtained similar results to what we reported previously if they had taken the above precaution.
The Golden Age of CME Is Yet to Come
Authors: Len Scarpinato
Journal: JAMA (1988)

<h3>To the Editor.</h3> —We read with interest "The Past, Present, and Future of Continuing Medical Education [CME]" by Drs Manning and Petit<sup>1</sup>and the accompanying editorial by Wilbur.<sup>2</sup>However, they do not mention the influence of the pharmaceutical industry on CME. Involvement includes monetary support for educational programs, travel expenses for selected speakers, and free trips to conferences held in vacation spots for "educationally influential physicians."<sup>3</sup>The pharmaceutical industry's effect on CME is uncertain and unstudied. Formal studies might compare the content of CME programs that accept or reject the pharmaceutical industry's support. One might compare the quantity of CME concerning specific diagnoses before and after the availability of pharmaceuticals that are used to treat these diagnoses. We suspect that significant differences could be found, but the effect on the knowledge base of physicians and subsequent patient care would be more difficult to determine. We suspect that
Conditional mating strategies are contingent on return from investment
Authors: Elizabeth M. Hill
Journal: Behavioral and Brain Sciences (2000)

Gangestad &amp; Simpson present an evolutionary functional analysis of mating strategies. This commentary interprets their argument using a central concept from life history theory, return from investment. Incorporating return from investment allows further specification of costs and benefits from short-term mating in women as well as men and in ecological settings of high environmental variation in mortality and resource availability.
Neuropilin and liver fibrosis: Hitting three birds with one stone?
Authors: Juliane S. Troeger, Robert F. Schwabe
Journal: Hepatology (2011)

PDGF-dependent hepatic stellate cell (HSC) recruitment is an essential step in liver fibrosis and the sinusoidal vascular changes that accompany this process. However, the mechanisms that regulate PDGF signaling remain incompletely defined. Here, we found that in two rat models of liver fibrosis, the axonal guidance molecule neuropilin-1 (NRP-1) was upregulated in activated HSCs, which exhibit the highly motile myofibroblast phenotype. Additionally, NRP-1 colocalized with PDGF-receptor beta (PDGFRbeta) in HSCs both in the injury models and in human and rat HSC cell lines. In human HSCs, siRNA-mediated knockdown of NRP-1 attenuated PDGF-induced chemotaxis, while NRP-1 overexpression increased cell motility and TGF-beta-dependent collagen production. Similarly, mouse HSCs genetically modified to lack NRP-1 displayed reduced motility in response to PDGF treatment. Immunoprecipitation and biochemical binding studies revealed that NRP-1 increased PDGF binding affinity for PDGFRbeta-expressing cells and promoted downstream signaling. An NRP-1 neutralizing Ab ameliorated recruitment of HSCs, blocked liver fibrosis in a rat model of liver injury, and also attenuated VEGF responses in cultured liver endothelial cells. In addition, NRP-1 overexpression was observed in human specimens of liver cirrhosis caused by both hepatitis C and steatohepatitis. These studies reveal a role for NRP-1 as a modulator of multiple growth factor targets that regulate liver fibrosis and the vascular changes that accompany it and may have broad implications for liver cirrhosis and myofibroblast biology in a variety of other organ systems and disease conditions.
Abstract 5871: Chronic Organic Mitral Regurgitation Results in Myofibrillar Degeneration and Oxidative Stress with Post-Surgical Left Ventricular Impairment Despite Pre-Surgical Left Ventricular Ejection Fraction &gt; 60%
Authors: Mustafa I Ahmed, James D Gladden, Steven G Lloyd, Silvio H Litovsky, Himanshu Gupta, Seidu Inusah, Thomas Denney, David C McGiffin, Louis J Dell’Italia
Journal: Circulation (2008)

Background: Current guidelines recommend valve repair for chronic organic mitral regurgitation (MR) if LVEF drops below 60% to preserve LV function and maximize outcome. Post-operative drop in LVEF is typical, and widely believed to be due to alteration in loading conditions. Here we address whether cardiomyocyte damage may contribute to postoperative dysfunction. Methods: Three-dimensional magnetic resonance imaging (3D-MRI) with tissue tagging was performed in 23 MR patients, prior to and six months following mitral valve repair. LV biopsy was obtained from all MR patients at time of surgery. Immunohistochemistry was performed to assess for signs of oxidative stress, specifically lipofuscin deposition, and presence and quantity of xanthine oxidase (XO). Plasma XO levels were measured before, and six months post-surgery. Results: MR patients (n=23) demonstrated decreased LVEF (62 ± 1 to 54 ± 2% p=0.0002) and LV end-diastolic volume (116 ± 5 to 79 ± 5 ml/m 2 p&lt;0.0001) six months after mitral valve (MV) repair. LV circumferential and longitudinal strain rates decreased below normal (6.54 ± 0.21 vs. 5.24 ± 0.24 p=0.0001, and 6.56 ± 0.26 vs. 5.41 ± 0.27 p=0.0084) despite no change in blood pressure and 3-dimensional LV end-systolic radius/wall thickness ratios. LV biopsies demonstrated marked cardiomyocyte myofibrillar degeneration vs. normals (2.32 ± 1.09 vs. 1.25 ± 0.45, p=0.0016, mean degeneration grade [1–4]). Immunostaining for xanthine oxidase (XO), a prominent oxidative enzyme, was increased in MR vs. normals (88 ± 7 vs. 33 ± 4%, p &lt;0.01), as plasma XO decreased post-MV repair (2.12 ± 0.46 to 0.49 ± 0.25 μU/mL, p=0.008). Lipofuscin deposition, a product of oxidative stress, was increased in cardiomyocytes of MR vs. normals (0.62 ± 0.04 vs. 0.33 ± 0.04%, p &lt;0.01). Conclusions: Decreased LV strain rates 6 months post MV repair indicate myocyte contractile dysfunction in chronic MR patients despite pre-surgical LVEF &gt;60%. This is supported by marked cardiomyocyte myofibrillar degeneration and oxidative damage at the time of surgery. While raising questions regarding timing of surgery for MR, these findings generate hypothesis concerning XO and oxidative stress-related myocyte damage in the pathophysiology of LV contractile dysfunction in MR.
Reduced p21WAF1/CIP1 expression and p53 mutation in hepatocellular carcinomas
Authors: A M Hui, Y Kanai, M Sakamoto, H Tsuda, S Hirohashi
Journal: Hepatology (1997)

p21WAF1/CIP1 is a universal cyclin–dependent kinase (cdk) inhibitor, the expression of which is regulated by p53–dependent and p53–independent pathways. We examined p21WAF1/CIP1 expression in and p53 status of 21 primary hepatocellular carcinomas (HCCs) by reverse–transcriptase polymerase chain reaction (RT–PCR) and by PCR single–strand conformation polymorphism (PCR–SSCP) analysis. p21WAF1/CIP1 messenger RNA expression was reduced markedly in 8 of 21 HCCs (38.1%) and 5 of these 8 HCCs bore p53 mutations. The relative p21WAF1/CIP1 messenger RNA expression value of HCCs with p53 mutations (.73 ± .13 U, n = 6) was significantly lower than that of HCCs with wild–type p53 (1.00 ± 0.21 U, n = 14; P &lt; .01). The p21WAF1/CIP1 expression levels in cancerous tissues (.73 ± .13 U) were significantly reduced in comparison with those in noncancerous tissues (.97 ± .13 U) (P &lt; .01) in the 6 cases with p53 mutations. These data indicate that p21WAF1/CIP1 expression in HCCs is predominantly regulated by dependence on p53 and that reduced p21WAF1/CIP1 expression may participate in hepatocarcinogenesis.