tbuckley/cabot-search huggingface dataset:
Eliminating Atherogenesis in Mice by Switching Off Hepatic Lipoprotein Secretion
Authors: Hsiao D. Lieu, Shannon K. Withycombe, Quinn Walker, James X. Rong, Rosemary L. Walzem, Jinny S. Wong, Robert L. Hamilton, Edward A. Fisher, Stephen G. Young
Journal: Circulation (2003)

LDL receptor-deficient "apolipoprotein (apo)-B100-only" mice (Ldlr-/-Apob100/100 have elevated LDL cholesterol levels on a chow diet and develop severe aortic atherosclerosis. We hypothesized that both the hypercholesterolemia and the susceptibility to atherosclerosis could be eliminated by switching off hepatic lipoprotein production.We bred Ldlr-/-Apob100/100 mice that were homozygous for a conditional allele for Mttp (the gene for microsomal triglyceride transfer protein) and the inducible Mx1-Cre transgene. In these animals, which we called "Reversa mice," the hypercholesterolemia could be reversed, without modifying the diet or initiating a hypolipidemic drug, by the transient induction of Cre expression in the liver. After Cre induction, hepatic Mttp expression was virtually eliminated (as judged by quantitative real-time PCR), hepatic lipoprotein secretion was abolished (as judged by electron microscopy), and LDLs were virtually eliminated from the plasma. Intestinal lipoprotein production was unaffected. In mice fed a chow diet, Cre induction reduced plasma cholesterol levels from 233.9+/-46.0 to 37.2+/-6.5 mg/dL. In mice fed a high-fat diet, cholesterol levels fell from 525.7+/-32.2 to 100.6+/-14.3 mg/dL. The elimination of hepatic lipoprotein production completely prevented both the development of atherosclerosis and the changes in gene expression that accompany atherogenesis.We developed mice in which hypercholesterolemia can be reversed with a genetic switch. These mice will be useful for understanding gene-expression changes that accompany the reversal of hypercholesterolemia and atherosclerosis.
Balance and Gait Deficits in Schizophrenia Compounded by the Comorbidity of Alcoholism
Authors: Edith V. Sullivan, Margaret J. Rosenbloom, Adolf Pfefferbaum
Journal: American Journal of Psychiatry (2004)

Alcoholism carries a liability of balance and gait instability that persists with sobriety. Such deficits are less well documented in schizophrenia and may be compounded by comorbidity with alcoholism, which is prevalent in schizophrenia.The authors administered quantitative ataxia tests to 10 patients comorbid for schizophrenia and alcohol dependence/abuse, 10 nonalcoholic patients with schizophrenia, 24 nonschizophrenic patients with alcohol dependence, and 27 age-matched comparison men.All three patient groups were impaired relative to the comparison subjects. The comorbid group was significantly more impaired than the alcoholic group on most tests and was more impaired than the schizophrenia patients, especially when tested with eyes open.Rigorous quantitative testing revealed gait and balance deficits in schizophrenia, even without alcohol dependence, and exacerbated deficits in schizophrenia comorbid with alcoholism. The enhancement of postural stability expected with visual information was dampened in comorbid patients, implicating compromised sensorimotor integrative abilities.
Glucose-stimulated insulin secretion correlates with changes in mitochondrial and cytosolic Ca2+ in aequorin-expressing INS-1 cells.
Authors: E D Kennedy, R Rizzuto, J M Theler, W F Pralong, C Bastianutto, T Pozzan, C B Wollheim
Journal: Journal of Clinical Investigation (1996)

Nutrient-stimulated insulin secretion is dependent upon the generation of metabolic coupling factors in the mitochondria of the pancreatic B cell. To investigate the role of Ca2+ in mitochondrial function, insulin secretion from INS-1 cells stably expressing the Ca2+-sensitive photoprotein aequorin in the appropriate compartments was correlated with changes in cytosolic calcium ([Ca2+]c) and mitochondrial calcium ([Ca2+]m). Glucose and KCl, which depolarize the cell membrane, as well as the Ca2+-mobilizing agonist, carbachol (CCh), cause substantial increases in [Ca2+]m which are associated with smaller rises in [Ca2+]c. The L-type Ca2+-channel blocker, SR7037, abolished the effects of glucose and KCl while attenuating the CCh response. Glucose-induced increases in [Ca2+]m, [Ca2+]c, and insulin secretion all demonstrate a pronounced initial peak followed by a sustained plateau. All three parameters are increased synergistically when glucose and CCh are combined. Finally, [Ca2+]m, [Ca2+]c, and insulin secretion also display desensitization phenomena following repeated additions of the three stimuli. The high sensitivity of [Ca2+]m to Ca2+ influx and the desensitization-resensitization effects can be explained by a model in which the mitochondria of INS-1 cells are strategically located to sense Ca2+ influx through plasma membrane Ca2+ channels. In conclusion, the correlation of [Ca2+]m and [Ca2+]c with insulin secretion may indicate a fundamental role for Ca2+ in the adaptation of oxidative metabolism to the generation of metabolic coupling factors and the energy requirements of exocytosis.
Interleukin-13 and transforming growth factor β synergise in the pathogenesis of human intestinal fistulae
Authors: Michael Scharl, Sandra Frei, Theresa Pesch, Silvia Kellermeier, Joba Arikkat, Pascal Frei, Michael Fried, Achim Weber, Ekkehard Jehle, Anne Rühl, Gerhard Rogler
Journal: Gut (2012)

<h3>Objective</h3> Epithelial to mesenchymal transition (EMT) seems to play an important role in the pathogenesis of fistulae, a common clinical complication of Crohn9s disease (CD). TGFβ and interleukin-13 (IL-13) have been correlated with the onset of EMT-associated organ fibrosis and high levels of TGFβ have been shown in transitional cells (TCs) lining CD fistula tracts. This study investigated whether IL-13 could be involved in the pathogenesis of CD-associated fistulae. <h3>Design</h3> Protein or mRNA levels in HT29 intestinal epithelial cells (IECs) or colonic lamina propria fibroblasts (CLPFs) were studied by western blotting or real-time PCR. CLPFs were isolated from non-inflammatory disease controls or patients with CD with or without fistulae and IL-13 levels were analysed in surgically removed fistula specimens by immunohistochemistry. <h3>Results</h3> TGFβ induced IL-13 secretion in CLPFs from patients with fistulising CD. In fistula specimens high levels of IL-13 were detected in TCs covering fistula tracts. In HT29 IEC monolayers, IL-13 induced SLUG and β6-integrin mRNA, which are associated with cell invasion. HT29 spheroids completely disintegrated when treated with TGFβ for 7 days, whereas IL-13-treated spheroids did not show morphological changes. Here, TGFβ induced mRNA expression of SNAIL1 and IL-13, whereas IL-13 elevated SLUG and β6-integrin mRNA. An anti-IL-13 antibody was able to prevent IL-13-induced SLUG expression in HT29 IECs. <h3>Conclusions</h3> TGFβ induces IL-13 expression and an EMT-like phenotype of IECs, while IL-13 promotes the expression of genes associated with cell invasion. These findings suggest that TGFβ and IL-13 play a synergistic role in the pathogenesis of fistulae and inhibition of IL-13 might represent a novel therapeutic approach for fistula treatment.
Structure and function of cardiac potassium channels
Authors: D Snyders
Journal: Cardiovascular Research (1999)

Recent advances in molecular biology have had a major impact on our understanding of the biophysical and molecular properties of ion channels. This review is focused on cardiac potassium channels which, in general, serve to control and limit cardiac excitability. Approximately 60 K+ channel subunits have been cloned to date. The (evolutionary) oldest potassium channel subunits consist of two transmembrane (Tm) segments with an intervening pore-loop (P). Channels formed by four 2Tm–1P subunits generally function as inwardly rectifying K+-selective channels (KirX.Y): they conduct substantial current near the resting potential but carry little or no current at depolarized potentials. The inward rectifier IK1 and the ligand-gated KATP and KACh channels are composed of such subunits. The second major class of K+ channel subunits consists of six transmembrane segments (S1–S6). The S5–P–S6 section resembles the 2Tm–1P subunit, and the additional membrane-spanning segments (especially the charged S4 segment) endow these 6Tm–1P channels with voltage-dependent gating. For both major families, four subunits assemble into a homo- or heterotetrameric channel, subject to specific subunit–subunit interactions. The 6Tm–1P channels are closed at the resting potential, but activate at different rates upon depolarization to carry sustained or transient outward currents (the latter due to inactivation by different mechanisms). Cardiac cells typically display at least one transient outward current and several delayed rectifiers to control the duration of the action potential. The molecular basis for each of these currents is formed by subunits that belong to different Kvx.y subfamilies and alternative splicing can contribute further to the diversity in native cells. These subunits display distinct pharmacological properties and drug-binding sites have been identified. Additional subunits have evolved by concatenation of two 2Tm–1P subunits (4Tm–2P); dimers of such subunits yield voltage-independent leak channels. A special class of 6Tm–1P subunits encodes the 'funny' pacemaker current which activates upon hyperpolarization and carries both Na+ and K+ ions. The regional heterogeneity of K+ currents and action potential duration is explained by the heterogeneity of subunit expression, and significant changes in expression occur in cardiac disease, most frequently a reduction. This electrical remodelling may also be important for novel antiarrhythmic therapeutic strategies. The recent crystallization of a 2Tm–1P channel enhances the outlook for more refined molecular approaches.
Evaluation of a Worldwide Spontaneous Reporting System With Cimetidine
Authors: Thomas G. Davis
Journal: JAMA (1980)

Adverse reactions to cimetidine have been identified through the manufacturer's Worldwide Spontaneous Reporting System. Reactions not observed during clinical trials—mental confusion, interstitial nephritis, and potentiation of oral anticoagulants—were identified and added to the prescribing information for cimetidine while further studies were undertaken. The monitoring of the drug's adverse reaction profile is ongoing so that new types of reactions can be identified. (<i>JAMA</i>243:1912-1914, 1980)
Initiation of hormone replacement therapy after acute myocardial infarction is associated with more cardiac events during follow-up
Authors: Karen P Alexander, L.Kristin Newby, Anne S Hellkamp, Robert A Harrington, Eric D Peterson, Steve Kopecky, Antoly Langer, Patrick O’Gara, Christopher M O’Connor, Robert N Daly, Robert M Califf, Steven Khan, Valentin Fuster
Journal: Journal of the American College of Cardiology (2001)
Visualizing and Assessing Phylogenetic Congruence of Core Gene Sets: A Case Study of the γ-Proteobacteria
Authors: E. Susko, J. Leigh, W. F. Doolittle, E. Bapteste
Journal: Molecular Biology and Evolution (2006)

Here, we address a much-debated topic: is there or is there not an organismal tree of γ-proteobacteria that can be unambiguously inferred from a core of shared genes? We apply several recently developed analytical methods to this problem, for the first time. Our heat map analyses of P values and of bootstrap bipartitions show the presence of conflicting phylogenetic signals among these core genes. Our synthesis reconstruction suggests that at least 10% of these genes have been laterally transferred during the divergence of the γ-proteobacteria, and that for most of the rest, there is too little phylogenetic signal to permit firm conclusions about the mode of inheritance. Although there is clearly a central tendency in this data set (it is far from random), lateral gene transfers cannot be ruled out. Instead of an organismal tree, we propose that these core genes could be used to define a more subtle and partially reticulated pattern of relationships.
Does hospital at home for palliative care facilitate death at home? Randomised controlled trial
Authors: G. E Grande, C. J Todd, S. I G Barclay, M. C Farquhar
Journal: BMJ (1999)

<h3>Abstract</h3> <b>Objective:</b> To evaluate the impact on place of death of a hospital at home service for palliative care. <b>Design:</b> Pragmatic randomised controlled trial. <b>Setting:</b> Former Cambridge health district. <b>Participants:</b> 229 patients referred to the hospital at home service; 43 randomised to control group (standard care), 186 randomised to hospital at home. <b>Intervention:</b> Hospital at home versus standard care. <b>Main outcome measures:</b> Place of death. <b>Results:</b> Twenty five (58%) control patients died at home compared with 124 (67%) patients allocated to hospital at home. This difference was not significant; intention to treat analysis did not show that hospital at home increased the number of deathsat home. Seventy three patients randomised to hospital at home were not admitted to the service. Patients admitted to hospital at home were significantly more likely to die at home (88/113; 78%) than control patients. It is not possible to determine whether this was due to hospital at home itself or other characteristics of the patients admitted to the service. The study attained less statistical power than initially planned. <b>Conclusion:</b> In a locality with good provision of standard community carewe could not show that hospital at home allowed more patients to die at home, although neither does the study refute this. Problems relating to recruitment, attrition, and the vulnerability of the patient group make randomised controlled trials in palliative care difficult. Whilethese difficulties have to be recognised they are not insurmountable with the appropriateresourcing and setting. <h3>Key messages</h3> Terminally ill patients allocated to hospital at home were no more likely to die at home than patients receiving standard care Although the subsample of patients actually admitted to hospital at home did show a significant increase in likelihood of dying at home, whether this was due to theservice itself or the characteristics of patients admitted to hospital at home could not be determined The need to balance ideal research design against the realities of evaluation of palliative care had the effect that the trial achieved less statistical power than originally planned Particular problems were that many patients failed to receive the allocatedintervention because of the unpredictable nature of terminal illness, inclusion of other service input alongside hospital at home, and the wide range of standard care available The trial illustrated problems associated with randomised controlled trialsin palliative care, none of which are insurmountable but which require careful consideration and resourcing before future trials are planned
Serial Changes of the Electrocardiogram During the Progression of Subarachnoidal Hemorrhage
Authors: Moriaki Inoko, Junji Nakashima, Tetsuya Haruna, Kimisato Nakano, Tetsuhiko Yanazume, Eisaku Nakane, Toru Kinugawa, Hisataka Ohwaki, Masatsune Ishikawa, Ryuji Nohara
Journal: Circulation (2005)
Simultaneous Generation of CD8+ and CD4+ Melanoma-Reactive T Cells by Retroviral-Mediated Transfer of a Single T-Cell Receptor
Authors: Jeffrey J. Roszkowski, Gretchen E. Lyons, W. Martin Kast, Cassian Yee, Koen Van Besien, Michael I. Nishimura
Journal: Cancer Research (2005)

Abstract Adoptive immunotherapy of cancer requires the generation of large numbers of tumor antigen–reactive T cells for transfer into cancer patients. Genes encoding tumor antigen–specific T-cell receptors can be introduced into primary human T cells by retroviral mediated gene transfer as a potential method of providing any patient with a source of autologous tumor-reactive T cells. A T-cell receptor–specific for a class I MHC (HLA-A2)–restricted epitope of the melanoma antigen tyrosinase was isolated from a CD4+ tumor-infiltrating lymphocyte (TIL 1383I) and introduced into normal human peripheral blood lymphocytes by retroviral transduction. T-cell receptor–transduced T cells secreted various cytokines when cocultured with tyrosinase peptide–loaded antigen-presenting cells as well as melanoma cells in an HLA-A2-restricted manner, and could also lyse target cells. Furthermore, T-cell clones isolated from these cultures showed both CD8+ and CD4+ transduced T cells could recognize HLA-A2+ melanoma cells, giving us the possibility of engineering class I MHC–restricted effector and T helper cells against melanoma. The ability to confer class I MHC–restricted tumor cell recognition to CD4+ T cells makes the TIL 1383I TCR an attractive candidate for T-cell receptor gene transfer–based immunotherapy.
A British Medical Association Lecture on CARCINOMA OF THE STOMACH
Authors: A. J. Walton
Journal: BMJ (1929)

OF the £62 patieot,s w-itlh careilloma of the stomaclh that have soulght inr advice, 9, and 9 on1lv, lhave survived for lonig enougzh time for me to regard them as probable cures.These figTules are s'ufficiently startling to make us realize tllat all is rot wi-ell w-itlh our metlhods of diagnosis and treatmen-t of thois disease.In other varieties of carcinoma somewllat L,etter resuilts arle clbtained, but they are far fromn satisfactorv, andl for this reasoni ino one lias at any stag,e in the hiistor-of the mnedical world attracted so much attention as lhas caneer to-day.I tlhere- fore feel very sensible of the lhonour whlicih our committee lhas done m e ( o in askinig me to conisider with'you somue of the problems wh-Iichl confrolnit uis in dealin(r with tlhe difficult suibject of carcinoma of the stomachi.Oni all sides efforts wvhiclh are almost feverislh in their activity are being miiacle to (liscov-er its cause and cure, anid althouglh there hiave been nio startling discoveries, it satisfactoryv to r ealize that miethods wvhich aSre more or less empiric are little bw l,ittle adding to our store of knowledge anid are steadilyimproving our esuilts.In some for-ms of canieer, indeed, tlle use of radium andx rays has been a gcreat advance oni the older metlhods. ETIOLOGY.Carcinoma of the stomachb is so difficult to diagnnose in its early stages that any-i plovement in our results must of necessitv be slow, andl can only be recogniiized if we have accuirate statistical kniowledge of the presenit-day position of the disease.It is generally believed that it is inicreasing in frequency, but, as T hoave previously pointed out,6 my figures do nlot suplh)ort this v'iewv.Thiey are small in mLniber, but ar e of value, in that ever-v case hlas been proved by operation, siiupIpoitefl eitloer bv micirosopic examination or bv ca, rfrle obser-ation of the after-p0-ogress of tle patienit.The figures (see Clhart 1) show 1913 1i1 5l 9156
The Obesity-Associated Peptide Leptin Induces Hypertrophy in Neonatal Rat Ventricular Myocytes
Authors: Venkatesh Rajapurohitam, Xiaohong Tracey Gan, Lorrie A. Kirshenbaum, Morris Karmazyn
Journal: Circulation Research (2003)

One of the major manifestations of obesity is increased production of the adipocyte-derived 16-kDa peptide leptin, which is also elevated in heart disease, including congestive heart failure. However, whether leptin can directly alter the cardiac phenotype is not known. We therefore studied the effect of leptin as a potential hypertrophic factor in cultured myocytes from 1- to 4-day-old neonatal rat heart ventricles. Using RT-PCR, we demonstrate that these cells express the short-form (OB-Ra) leptin receptor. Twenty-four hours of exposure to leptin (0.31 to 31.3 nmol/L) produces a significantly increased cell surface area that peaked at 0.63 nmol/L. Subsequent experiments were done with 3.1 nmol/L leptin, which significantly increased cell area by 42%, protein synthesis by 32%, and α-skeletal actin and myosin light chain-2 expression by 250% and 300%, respectively. These events occurred in the absence of any increased cell death. Hypertrophy was preceded by rapid activation of the mitogen-activated protein kinase system including p38 and p44/42 as early as 5 minutes after leptin addition, whereas hypertrophy was inhibited by the p38 inhibitor SB203580 but not by the p44/42 inhibitor PD98059. Our results demonstrate a direct hypertrophic effect of leptin and may offer a biological link between hypertrophy and hyperleptinemic conditions such as obesity.
Splenomegaly in myelofibrosis—new options for therapy and the therapeutic potential of Janus kinase 2 inhibitors
Authors: Jasleen Randhawa, Alen Ostojic, Radovan Vrhovac, Ehab Atallah, Srdan Verstovsek
Journal: Journal of Hematology & Oncology (2012)

Abstract Splenomegaly is a common sign of primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (post-PV MF), and post-essential thrombocythemia myelofibrosis (post-ET MF) that is associated with bothersome symptoms, which have a significant negative impact on patients’ quality of life. It may also be present in patients with advanced polycythemia vera (PV) or essential thrombocythemia (ET). Until recently, none of the therapies used to treat MF were particularly effective in reducing splenomegaly. The discovery of an activating Janus kinase 2 (JAK2) activating mutation (JAK2V617F) that is present in almost all patients with PV and in about 50-60 % of patients with ET and PMF led to the initiation of several trials investigating the clinical effectiveness of various JAK2 (or JAK1/JAK2) inhibitors for the treatment of patients with ET, PV, and MF. Some of these trials have documented significant clinical benefit of JAK inhibitors, particularly in terms of regression of splenomegaly. In November 2011, the US Food and Drug Administration approved the use of the JAK1- and JAK2-selective inhibitor ruxolitinib for the treatment of patients with intermediate or high-risk myelofibrosis, including PMF, post-PV MF, and post-ET MF. This review discusses current therapeutic options for splenomegaly associated with primary or secondary MF and the treatment potential of the JAK inhibitors in this setting.
Outcome of children with hypodiploid ALL treated with risk-directed therapy based on MRD levels
Authors: Charles G. Mullighan, Sima Jeha, Deqing Pei, Debbie Payne-Turner, Elaine Coustan-Smith, Kathryn G. Roberts, Esmé Waanders, John K. Choi, Xiaotu Ma, Susana C. Raimondi, Yiping Fan, Wenjian Yang, Guangchun Song, Jun J. Yang, Hiroto Inaba, James R. Downing, Wing H. Leung, W. Paul Bowman, Mary V. Relling, William E. Evans, Jinghui Zhang, Dario Campana, Ching-Hon Pui
Journal: Blood (2015)