tbuckley/cabot-search huggingface dataset:
Pirfenidone attenuates expression of HSP47 in murine bleomycin-induced pulmonary fibrosis
Authors: T. Kakugawa, H. Mukae, T. Hayashi, H. Ishii, K. Abe, T. Fujii, H. Oku, M. Miyazaki, J. Kadota, S. Kohno
Journal: European Respiratory Journal (2004)

Heat shock protein (HSP) 47, a collagen-specific molecular chaperone, is involved in the processing and/or secretion of procollagen. The present study was undertaken to investigate whether treatment with the antifibrotic drug pirfenidone attenuates the bleomycin (BL)‐induced overexpression of HSP47 in the lungs. Male ICR mice were intravenously injected with BL or saline (SA). Pirfenidone or control drug (CD) was administered 14 days after commencement of BL or SA, and continued throughout the course of the experiment. The mice were randomly divided into three experimental groups: 1) SA‐treated with CD (SA group); 2) BL‐treated with CD (BL group); and 3) BL‐treated with pirfenidone (pirfenidone group). Lungs of the pirfenidone group showed a marked reduction of fibrotic lesions compared with the corresponding BL group. Immunohistochemical studies showed that BL treatment significantly increased the number of macrophages, myofibroblasts, HSP47‐positive type II pneumocytes and HSP47‐positive interstitial spindle-shaped cells. Treatment with pirfenidone significantly reduced the number of these cells compared with the corresponding BL group. Furthermore, treatment with pirfenidone significantly suppressed the BL‐induced increase of the positive ratio of HSP47 and α‐smooth muscle actin to interstitial spindle-shaped cells. The present study results showed that pirfenidone inhibited heat shock protein 47‐positive cells and myofibroblasts, the principal cells responsible for the accumulation and deposition of extracellular matrix seen in pulmonary fibrosis.
Multiple Horizontal Gene Transfers of Ammonium Transporters/Ammonia Permeases from Prokaryotes to Eukaryotes: Toward a New Functional and Evolutionary Classification
Authors: T. R. McDonald, F. S. Dietrich, F. Lutzoni
Journal: Molecular Biology and Evolution (2011)

The proteins of the ammonium transporter/methylammonium permease/Rhesus factor family (AMT/MEP/Rh family) are responsible for the movement of ammonia or ammonium ions across the cell membrane. Although it has been established that the Rh proteins are distantly related to the other members of the family, the evolutionary history of the AMT/MEP/Rh family remains unclear. Here, we use phylogenetic analysis to infer the evolutionary history of this family of proteins across 191 genomes representing all main lineages of life and to provide a new classification of the proteins in this family. Our phylogenetic analysis suggests that what has heretofore been conceived of as a protein family with two clades (AMT/MEP and Rh) is instead a protein family with three clades (AMT, MEP, and Rh). We show that the AMT/MEP/Rh family illustrates two contrasting modes of gene transmission: The AMT family as defined here exhibits vertical gene transfer (i.e., standard parent-to-offspring inheritance), whereas the MEP family as defined here is characterized by several ancient independent horizontal gene transfers (HGTs). These ancient HGT events include a gene replacement during the early evolution of the fungi, which could be a defining trait for the kingdom Fungi, a gene gain from hyperthermophilic chemoautolithotrophic prokaryotes during the early evolution of land plants (Embryophyta), and an independent gain of this same gene in the filamentous ascomycetes (Pezizomycotina) that was subsequently lost in most lineages but retained in even distantly related lichenized fungi. This recircumscription of the ammonium transporters/ammonia permeases family into MEP and AMT families informs the debate on the mechanism of transport in these proteins and on the nature of the transported molecule because published crystal structures of proteins from the MEP and Rh clades may not be representative of the AMT clade. The clades as depicted in this phylogenetic study appear to correspond to functionally different groups, with AMTs and ammonia permeases forming two distinct and possibly monophyletic groups.
Integrative Analysis Reveals an Outcome-Associated and Targetable Pattern of p53 and Cell Cycle Deregulation in Diffuse Large B Cell Lymphoma
Authors: Stefano Monti, Bjoern Chapuy, Kunihiko Takeyama, Scott J. Rodig, Yansheng Hao, Kelly T. Yeda, Haig Inguilizian, Craig Mermel, Treeve Currie, Ahmet Dogan, Jeffery L. Kutok, Rameen Beroukhim, Donna Neuberg, Thomas M. Habermann, Gad Getz, Andrew L. Kung, Todd R. Golub, Margaret A. Shipp
Journal: Cancer Cell (2012)
Sphingosine 1-Phosphate Produced by Sphingosine Kinase 2 Intrinsically Controls Platelet Aggregation In Vitro and In Vivo
Authors: Nicole Urtz, Florian Gaertner, Marie-Luise von Bruehl, Sue Chandraratne, Faridun Rahimi, Lin Zhang, Mathias Orban, Verena Barocke, Johannes Beil, Irene Schubert, Michael Lorenz, Kyle R. Legate, Andrea Huwiler, Josef M. Pfeilschifter, Christian Beerli, David Ledieu, Elke Persohn, Andreas Billich, Thomas Baumruker, Michael Mederos y Schnitzler, Steffen Massberg
Journal: Circulation Research (2015)

Platelets are known to play a crucial role in hemostasis. Sphingosine kinases (Sphk) 1 and 2 catalyze the conversion of sphingosine to the bioactive metabolite sphingosine 1-phosphate (S1P). Although platelets are able to secrete S1P on activation, little is known about a potential intrinsic effect of S1P on platelet function.To investigate the role of Sphk1- and Sphk2-derived S1P in the regulation of platelet function.We found a 100-fold reduction in intracellular S1P levels in platelets derived from Sphk2(-/-) mutants compared with Sphk1(-/-) or wild-type mice, as analyzed by mass spectrometry. Sphk2(-/-) platelets also failed to secrete S1P on stimulation. Blood from Sphk2-deficient mice showed decreased aggregation after protease-activated receptor 4-peptide and adenosine diphosphate stimulation in vitro, as assessed by whole blood impedance aggregometry. We revealed that S1P controls platelet aggregation via the sphingosine 1-phosphate receptor 1 through modulation of protease-activated receptor 4-peptide and adenosine diphosphate-induced platelet activation. Finally, we show by intravital microscopy that defective platelet aggregation in Sphk2-deficient mice translates into reduced arterial thrombus stability in vivo.We demonstrate that Sphk2 is the major Sphk isoform responsible for the generation of S1P in platelets and plays a pivotal intrinsic role in the control of platelet activation. Correspondingly, Sphk2-deficient mice are protected from arterial thrombosis after vascular injury, but have normal bleeding times. Targeting this pathway could therefore present a new therapeutic strategy to prevent thrombosis.
Defects in nuclear structure and function promote dilated cardiomyopathy in lamin A/C–deficient mice
Authors: Vesna Nikolova, Christiana Leimena, Aisling C. McMahon, Ju Chiat Tan, Suchitra Chandar, Dilesh Jogia, Scott H. Kesteven, Jan Michalicek, Robyn Otway, Fons Verheyen, Stephen Rainer, Colin L. Stewart, David Martin, Michael P. Feneley, Diane Fatkin
Journal: Journal of Clinical Investigation (2004)

Laminopathies are a group of disorders caused by mutations in the LMNA gene that encodes the nuclear lamina proteins, lamin A and lamin C; their pathophysiological basis is unknown. We report that lamin A/C-deficient (Lmna(-/-)) mice develop rapidly progressive dilated cardiomyopathy (DCM) characterized by left ventricular (LV) dilation and reduced systolic contraction. Isolated Lmna(-/-) myocytes show reduced shortening with normal baseline and peak amplitude of Ca(2+) transients. Lmna(-/-) LV myocyte nuclei have marked alterations of shape and size with central displacement and fragmentation of heterochromatin; these changes are present but less severe in left atrial nuclei. Electron microscopy of Lmna(-/-) cardiomyocytes shows disorganization and detachment of desmin filaments from the nuclear surface with progressive disruption of the cytoskeletal desmin network. Alterations in nuclear architecture are associated with defective nuclear function evidenced by decreased SREBP1 import, reduced PPARgamma expression, and a lack of hypertrophic gene activation. These findings suggest a model in which the primary pathophysiological mechanism in Lmna(-/-) mice is defective force transmission resulting from disruption of lamin interactions with the muscle-specific desmin network and loss of cytoskeletal tension. Despite severe DCM, defects in nuclear function prevent Lmna(-/-) cardiomyocytes from developing compensatory hypertrophy and accelerate disease progression.
Antisense Bcl-x oligonucleotide induces apoptosis and prevents arterial neointimal formation in murine cardiac allografts
Authors: J Suzuki
Journal: Cardiovascular Research (2000)

Cardiac allograft arteriosclerosis, which limits long-term survival of recipients, cannot be prevented by conservative therapies. The arteriopathy is characterized by diffuse intimal thickening comprised of proliferative smooth muscle cells (SMCs). Cell death is a prominent feature of atherosclerosis; Bcl-x is one of the anti-apoptotic mediators.To test the hypothesis that antisense bcl-x oligodeoxynucleotide (ODN) is effective in preventing intimal hyperplasia through enhancing apoptosis after cardiac transplantation, we performed single intraluminal delivery of antisense bcl-x ODN into murine cardiac allografts (n = 9). DBA/2 (H-2d) hearts were transplanted into B10.D2 (H-2d) mice. Sense bcl-x ODN (n = 8) and no treatment (n = 8) studies were also performed.Allografts were harvested at 4 weeks after transplantation; all allografts kept beating throughout the period. Coronary intimal thickening had developed in nontreated and sense ODN transfected allografts at 4 weeks after transplantation with enhanced expression of Bcl-x and cell adhesion molecules, and suppressed apoptosis. However, antisense bcl-x ODN prevented neointimal formation through enhanced apoptosis.These results indicate that apoptosis of vascular SMCs induced by Bcl-x is associated with initial hyperplasia after heart transplantation. Antisense bcl-x ODN inhibits SMC proliferation by inducing apoptosis in graft coronary arteries.
Independent changes in cardiac muscle fibres and connective tissue in rats with spontaneous hypertension, aortic constriction and hypoxia
Authors: D. D. LUND, T. A. TWIETMEYER, P. G. SCHMID, R. J. TOMANEK
Journal: Cardiovascular Research (1979)

The collagen content (hydroxyproline concentration) and muscle fibre diameter were determined in hearts of 16 week old spontaneously hypertensive, aortic constricted and normotensive rats and spontaneously hypertensive and aortic constricted groups exposed to 6 weeks of hypobaric hypoxia (simulated altitude of 6100 m). The early development of cardiomegaly associated with spontaneous hypertension is primarily caused by an increase in muscle mass with relatively less proliferation of the connective tissue elements. Although heart weight to body weight ratios and fibre diameter increase in the spontaneously hypertensive SHR compared with normotensive rats, the concentration of hydroxyproline decreases indicating that the connective tissue response in spontaneously hypertensive rats is less pronounced than the muscle response. Therefore, at 16 weeks of age, an increase in muscle mass is the primary contributor to cardiomegaly in spontaneously hypertensive rats. Hypobaric hypoxia induces increased collagen production in both the left and the right ventricles of spontaneously hypertensive rats. Unlike the spontaneously hypertensive rats, the collagen response in aortic constricted rats parallels the muscle response since cardiomegaly and increased left ventricular fibre diameter are associated with the maintenance of hydroxyproline concentration similar to that in normotensive rats. Hypoxia failed to activate collagen production further in aortic constricted rats. These findings suggest that the connective tissue response to cardiomegaly produced by aortic constriction is significantly different from the response produced by essential hypertension. The data also suggest that the factors governing connective tissue proliferation may be independent from those governing the muscle fibre hypertrophy.
Multicenter phase II trial of temozolomide in patients with glioblastoma multiforme at first relapse
Authors: M. Brada, K. Hoang-Xuan, R. Rampling, P.-Y. Dietrich, L.Y. Dirix, D. Macdonald, J.J. Heimans, B.A. Zonnenberg, J.M. Bravo-Marques, R. Henriksson, R. Stupp, N. Yue, J. Bruner, M. Dugan, S. Rao, S. Zaknoen
Journal: Annals of Oncology (2001)
Birth Weight: Genetic and Intrauterine Environment in Normal Pregnancy
Authors: Sara Fallucca, Mario Vasta, Ernesta Sciullo, Stefano Balducci, Francesco Fallucca
Journal: Diabetes Care (2009)

Recent meta-analysis (1) and systematic review (2) show that high and low birth weight are related in a U-shaped manner to later risk of type 2 diabetes. It is also interesting to denote the positive birth weight/type 2 diabetes associations within the normal weight range. It is now widely accepted that both genetic and environmental factors are engaged in intrauterine growth, glucose tolerance, and development of type 2 diabetes in later life. The polymorphisms of the insulin receptor substrate (IRS)-1 (3) and β3-adrenergic receptor (β3-AR) genes (4) are genetic risk factors that are associated with insulin resistance and predisposition to type 2 diabetes. …
The Effect of Benzophenone Sunscreen Lotion on Chlorpromazine-Treated Patients
Authors: CHARLES KORENYI
Journal: American Journal of Psychiatry (1969)

The protective effect of benzophenone lotion against ultraviolet irradiation was demonstrated with ten patients on chlorpromazine and ten controls taking no medication. All patients had histories of increased sensitivity to sunlight. Results indicate that benzophenone lotion was effective as a sunscreen and appears to have a useful place in psychiatry, where the use of phenothiazine derivates is extensive.
Operating theatre time, where does it all go? A prospective observational study
Authors: E. Travis, S. Woodhouse, R. Tan, S. Patel, J. Donovan, K. Brogan
Journal: BMJ (2014)

<b>Objective</b> To assess the accuracy of surgeons and anaesthetists in predicting the time it will take them to complete an operation or procedure and therefore explain some of the difficulties encountered in operating theatre scheduling. <b>Design</b> Single centre, prospective observational study. <b>Setting</b> Plastic, orthopaedic, and general surgical operating theatres at a level 1 trauma centre serving a population of about 370 000. <b>Participants</b> 92 operating theatre staff including surgical consultants, surgical registrars, anaesthetic consultants, and anaesthetic registrars. <b>Intervention</b> Participants were asked how long they thought their procedure would take. These data were compared with actual time data recorded at the end of the case. <b>Primary outcome measure</b> Absolute difference between predicted and actual time. <b>Results</b> General surgeons underestimated the time required for the procedure by 31 minutes (95% confidence interval 7.6 to 54.4), meaning that procedures took, on average, 28.7% longer than predicted. Plastic surgeons underestimated by 5 minutes (−12.4 to 22.4), with procedures taking an average of 4.5% longer than predicted. Orthopaedic surgeons overestimated by 1 minute (−16.4 to 14.0), with procedures taking an average of 1.1% less time than predicted. Anaesthetists underestimated by 35 minutes (21.7 to 48.7), meaning that, on average, procedures took 167.5% longer than they predicted. The four specialty mean time overestimations or underestimations are significantly different from each other (P=0.01). The observed time differences between anaesthetists and both orthopaedic and plastic surgeons are significantly different (P&lt;0.05), but the time difference between anaesthetists and general surgeons is not significantly different. <b>Conclusion</b> The inability of clinicians to predict the necessary time for a procedure is a significant cause of delay in the operating theatre. This study suggests that anaesthetists are the most inaccurate and highlights the potential differences between specialties in what is considered part of the "anaesthesia time."
Activin A Produced by Ureteric Bud Is a Differentiation Factor For Metanephric Mesenchyme
Authors: Akito Maeshima, Shin Yamashita, Kyoko Maeshima, Itaru Kojima, Yoshihisa Nojima
Journal: Journal of the American Society of Nephrology (2003)

The present study was conducted to investigate the role of the activin-follistatin system in the development of metanephros. Organ culture system and cultured metanephric mesenchymal cells were used to address this issue. Activin A was localized in ureteric bud. Activin type II receptor was localized in ureteric bud as well as metanephric mesenchyme. In an organ culture system, exogenous activin A reduced the size of cultured metanephroi, delayed ureteric bud branching, and enlarged the tips of ureteric bud. Follistatin, an antagonist of activin A was used to clarify the role of endogenous activin A. Exogenous follistatin enlarged the size of cultured metanephroi, increased ureteric bud branching, and promoted cell growth in ureteric bud. Blockade of activin signaling by adenoviral transfection of dominantly negative activin mutant receptor mimics the effect of follistatin. In cultured metanephric mesenchymal cells, activin A promoted cell growth; conversely, follistatin induced apoptosis. Furthermore, activin A induced the expressions of epithelial differentiation markers in these cells. These results suggest that activin A produced by ureteric bud is not only an important regulator of ureteric bud branching, but also a differentiation factor for metanephric mesenchyme during kidney development.
Management of malignant pleural effusions
Authors: V.B. Antony, R. Loddenkemper, P. Astoul, C. Boutin, P. Goldstraw, J. Hott, F. Rodriguez Panadero, S.A. Sahn
Journal: European Respiratory Journal (2001)

⇓Malignant pleural effusions are a common clinical problem in patients with neoplastic disease. In one post mortem series, malignant effusions were found in 15% of patients who died with malignancies 1. Although there have been no epidemiological studies, the annual incidence of malignant pleural effusions in the United States is estimated to be >150,000 cases (table 1⇓) 2–17. Malignant pleural effusion is also one of the leading causes of exudative effusion; studies have demonstrated that 42–77% of exudative effusions are secondary to malignancy 18, 19. Fig. 1.— Malignant pleural effusions: sensitivity (%) of different biopsy methods (cytological and histological results combined). Presented is a prospective simultaneous comparison (n=208). Fig. 2.— Diagnostic sensitivity of cytology (□) and medical thoracoscopy (![Graphic][1]</img>) in malignant pleural effusions. n-numbers are as follows: lung cancer, 67; non-lung primary, 154; mesothelioma, 66; total, 287. Fig. 3.— View this table: Table 1— Incidence of malignant pleural effusions (MPEs) Nearly all neoplasms have been reported to involve the pleura. In most studies, however, lung carcinoma has been the most common neoplasm, accounting for approximately one-third of all malignant effusions. Breast carcinoma is the second most common. Lymphomas, including both Hodgkin's disease and non-Hodgkin's lymphoma, are also an important cause of malignant pleural effusions. Tumours less commonly associated with malignant pleural effusions include ovarian and gastrointestinal carcinomas. In 5–10% of malignant effusions, no primary tumour is identified 12, 13. The incidence of mesothelioma varies according to the geographical location. Post mortem studies suggest that most pleural metastases arise from tumour emboli to the visceral pleural surface, with secondary seeding to the parietal pleura 1, 20. Other possible mechanisms include direct tumour invasion (in lung cancers, chest wall neoplasms, and breast carcinoma), haematogenous spread to parietal pleura, and lymphatic involvement. A malignant tumour can cause a pleural effusion, both directly and indirectly. … [1]: F2/embed/inline-graphic-1.gif
Control of myocardial oxygen consumption: relative influence of contractile state and tension development
Authors: Thomas P. Graham, James W. Covell, Edmund H. Sonnenblick, John Ross, Eugene Braunwald
Journal: Journal of Clinical Investigation (1968)

Myocardial oxygen consumption was measured in 11 anesthetized, open-chest dogs in order to compare in the same heart the relative influence on oxygen usage of tension development and the contractile or inotropic state, as reflected in Vmax. the maximum velocity of shortening of the unloaded contractile elements. The isovolumetrically contracting left ventricle was studied with left ventricular volume, heart rate, and systemic perfusion rate controlled. Wall tension, contractile element velocity, and Vmax were calculated. Peak developed tension was increased at a constant Vmax by increasing ventricular volume, and the effect on oxygen consumption was determined. Oxygen utilization was then redetermined at an increased Vmax but at a constant peak developed tension by infusing norepinephrine (0.76 to 7.6 μg/min) and decreasing ventricular volume to match the tension existing before norepinephrine infusion. Oxygen consumption consistently increased with increases in both developed tension and Vmax with the following multiple regression equation relating these variables: myocardial oxygen consumption (μl/beat per 100 g in LV) = K + 0.25 peak developed tension (g/cm2) + 1.43 Vmax (cm/sec). These data indicate that the oxygen cost of augmentation of contractility is substantial, can be independent of any change in fiber shortening, and is similar in order of magnitude to the effect of alterations in tension development
Inhibition of 5-lipoxygenase-activating protein (FLAP) reduces pulmonary vascular reactivity and pulmonary hypertension in hypoxic rats.
Authors: N F Voelkel, R M Tuder, K Wade, M Höper, R A Lepley, J L Goulet, B H Koller, F Fitzpatrick
Journal: Journal of Clinical Investigation (1996)

Chronically elevated shear stress and inflammation are important in hypertensive lung vessel remodeling. We postulate that 5-lipoxygenase (5-LO) is a molecular determinant of these processes. Immunohistology localized the 5-LO to macrophages of normal and chronically hypoxic rat lungs and also to vascular endothelial cells in chronically hypoxic lungs only. In situ hybridization of normal and chronically hypoxic lungs demonstrated that 5-LO mRNA is expressed in macrophages. Rats hypoxic for 4 wk-developed pulmonary hypertension increased translocation of the lung 5-LO from the cytosol to the membrane fraction and increased levels of lung tissue 5-lipoxygenase-activating protein (FLAP). A FLAP ligand, 3-[l-(4-chlorobenzyl)-3-t-butyl-thio-t-isopropylindol-2-yl]-2,2- dimethylpropanoic acid (MK-886), inhibited the acute angiotensin II and hypoxia-induced pulmonary vasoconstriction in vitro and the development of chronic hypoxic pulmonary hypertension in rats in vivo. Mice bred with the deletion of the 5-LO enzyme (5-LO knockout) developed less right heart hypertrophy than age-matched 5-LO competent mice. Our results support the hypothesis that the 5-LO is involved in lung vascular tone regulation and in the development of chronic pulmonary hypertension in hypoxic rodent models.