tbuckley/cabot-search huggingface dataset:
Ionic Mechanism of Action Potential Prolongation in Ventricular Myocytes From Dogs With Pacing-Induced Heart Failure
Authors: Stefan Kääb, H. Bradley Nuss, Nipavan Chiamvimonvat, Brian O’Rourke, Peter H. Pak, David A. Kass, Eduardo Marban, Gordon F. Tomaselli
Journal: Circulation Research (1996)

Abstract Membrane current abnormalities have been described in human heart failure. To determine whether similar current changes are observed in a large animal model of heart failure, we studied dogs with pacing-induced cardiomyopathy. Myocytes isolated from the midmyocardium of 13 dogs with heart failure induced by 3 to 4 weeks of rapid ventricular pacing and from 16 nonpaced control dogs did not differ in cell surface area or resting membrane potential. Nevertheless, action potential duration (APD) was significantly prolonged in myocytes isolated from failing ventricles (APD at 90% repolarization, 1097±73 milliseconds [failing hearts, n=30] versus 842±56 milliseconds [control hearts, n=25]; P &lt;.05), and the prominent repolarizing notch in phase 1 was dramatically attenuated. Basal L-type Ca 2+ current and whole-cell Na + current did not differ in cells from failing and from control hearts, but significant differences in K + currents were observed. The density of the inward rectifier K + current (I K1 ) was reduced in cells from failing hearts at test potentials below −90 mV (at −150 mV, −19.1±2.2 pA/pF [failing hearts, n=18] versus −32.2±5.1 pA/pF [control hearts, n=15]; P &lt;.05). The small outward current component of I K1 was also reduced in cells from failing hearts (at −60 mV, 1.7±0.2 pA/pF [failing hearts] versus 2.5±0.2 pA/pF [control hearts]; P &lt;.05). The peak of the Ca 2+ -independent transient outward current (I to ) was dramatically reduced in myocytes isolated from failing hearts compared with nonfailing control hearts (at +80 mV, 7.0±0.9 pA/pF [failing hearts, n=20] versus 20.4±3.2 pA/pF [control hearts, n=15]; P &lt;.001), while the steady state component was unchanged. There were no significant differences in I to kinetics or single-channel conductance. A reduction in the number of functional I to channels was demonstrated by nonstationary fluctuation analysis (0.4±0.03 channels per square micrometer [failing hearts, n=5] versus 1.2±0.1 channels per square micrometer [control hearts, n=3]; P &lt;.001). Pharmacological reduction of I to by 4-aminopyridine in control myocytes decreased the notch amplitude and prolonged the APD. Current clamp–release experiments in which current was injected for 8 milliseconds to reproduce the notch sufficed to shorten the APD significantly in cells from failing hearts. These data support the hypothesis that downregulation of I to in pacing-induced heart failure is at least partially responsible for the action potential prolongation. Because the repolarization abnormalities mimic those in cells isolated from failing human ventricular myocardium, canine pacing-induced cardiomyopathy may provide insights into the development of repolarization abnormalities and the mechanisms of sudden death in patients with heart failure.
Nitric oxide inhibitable isoforms of adenylate cyclase mediate epithelial secretory dysfunction following exposure to ionising radiation
Authors: S L Freeman
Journal: Gut (2004)

<b>Background:</b> Hyporesponsiveness of the intestinal epithelium to secretagogues occurs in different models of intestinal injury, including radiation enteropathy, and in human disease. While this impairment of barrier function has been linked to increased inducible nitric oxide synthase (iNOS) activity, the cellular target of NO in this phenomenon is not known, although recent studies suggest that some isoforms of adenylate cyclase are inhibited by NO. <b>Aims:</b> To determine adenylate cyclase isoform distribution in colonic epithelial cells and, in particular, the physiological significance of NO inhibitable adenylate cyclase isoforms 5 and 6 in radiation induced epithelial secretory dysfunction. <b>Methods:</b> Reverse transcription-polymerase chain reaction (RT-PCR), immunocytochemistry, and immunohistochemistry were used to examine adenylate cyclase expression. The responsiveness of mouse colon to secretagogues 72 hours post-15 Gy gamma radiation or following in vitro exposure to NO donors was measured in Ussing chambers. Also, cAMP, cGMP, and ATP levels were measured. <b>Results:</b> RT-PCR, immunocytochemistry, and immunohistochemistry showed that adenylate cyclase 5 was expressed in mouse colon, and isoforms 5 and 6 were expressed in human biopsies and intestinal epithelium. Pharmacological studies showed that these isoforms are functionally important in chloride secretion. NO mediated hyporesponsiveness to secretagogues is primarily a result of decreased adenylate cyclase activity, and not G<sub>i</sub> activation or decreased cellular ATP levels. <b>Conclusions:</b> NO inhibitable isoforms of adenylate cyclase are expressed in mouse and human secretory colonic epithelia, and appear to be the target of radiation induced NO to reduce the responsiveness to cAMP dependent secretagogues.
Antibodies to nuclear lamin C in chronic hepatitis delta virus infection
Authors: Józefa Węsierska-Gądek, Edward Penner, Eva Hitchman, Georg Sauermann
Journal: Hepatology (1990)

Sera of patients with chronic hepatitis delta virus infection stained the nuclear periphery in indirect immunofluorescence. Using proteins of isolated nuclei, isolated nuclear matrices, the nuclear pore complex-lamina fraction and purified lamins A and C as antigen source in immunoblotting experiments, nuclear lamin C was identified as the reactive antigen. Most sera tested (8 of 10) recognized nuclear lamin C exclusively, but not the nuclear lamins A and B. Antibodies reacting with both nuclear lamins A and C, which share extensive sequence homologies, have been reported to occur in autoimmune hepatitis and primary biliary cirrhosis. The present findings suggest that the novel autoantibody associated with chronic hepatitis delta virus infection recognizes an epitope localized in the short carboxyterminal region of nuclear lamin C.
Multicenter, Double-Blind, Placebo-Controlled, Randomized Phase II Trial of Gemcitabine/Cisplatin Plus Bevacizumab or Placebo in Patients With Malignant Mesothelioma
Authors: Hedy L. Kindler, Theodore G. Karrison, David R. Gandara, Charles Lu, Lee M. Krug, James P. Stevenson, Pasi A. Jänne, David I. Quinn, Marianna N. Koczywas, Julie R. Brahmer, Kathy S. Albain, David A. Taber, Samuel G. Armato, Nicholas J. Vogelzang, Helen X. Chen, Walter M. Stadler, Everett E. Vokes
Journal: Journal of Clinical Oncology (2012)

Gemcitabine plus cisplatin is active in malignant mesothelioma (MM), although single-arm phase II trials have reported variable outcomes. Vascular endothelial growth factor (VEGF) inhibitors have activity against MM in preclinical models. We added the anti-VEGF antibody bevacizumab to gemcitabine/cisplatin in a multicenter, double-blind, placebo-controlled randomized phase II trial in patients with previously untreated, unresectable MM.Eligible patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 and no thrombosis, bleeding, or major blood vessel invasion. The primary end point was progression-free survival (PFS). Patients were stratified by ECOG performance status (0 v 1) and histologic subtype (epithelial v other). Patients received gemcitabine 1,250 mg/m(2) on days 1 and 8 every 21 days, cisplatin 75 mg/m(2) every 21 days, and bevacizumab 15 mg/kg or placebo every 21 days for six cycles, and then bevacizumab or placebo every 21 days until progression.One hundred fifteen patients were enrolled at 11 sites; 108 patients were evaluable. Median PFS time was 6.9 months for the bevacizumab arm and 6.0 months for the placebo arm (P = .88). Median overall survival (OS) times were 15.6 and 14.7 months in the bevacizumab and placebo arms, respectively (P = .91). Partial response rates were similar (24.5% for bevacizumab v 21.8% for placebo; P = .74). A higher pretreatment plasma VEGF concentration (n = 56) was associated with shorter PFS (P = .02) and OS (P = .0066), independent of treatment arm. There were no statistically significant differences in toxicity of grade 3 or greater.The addition of bevacizumab to gemcitabine/cisplatin in this trial did not significantly improve PFS or OS in patients with advanced MM.
Evolution of immunoglobulin VH pseudogenes in chickens.
Authors: T Ota, M Nei
Journal: Molecular Biology and Evolution (1995)

In chickens, there is a single functional gene (VH1) coding for the heavy chain variable region of immunoglobulins, and immunoglobulin diversity is generated by gene conversion of the VH1 gene by many variable region pseudogenes (psi VH's) that exist on the 5' side of the VH1 gene. To understand the evolution of this unique genetic system, we conducted statistical analyses of VH1 and psi VH genes together with functional VH genes from other higher vertebrate species. The results indicate, first, that chicken VH genes are all closely related to one another and were derived relatively recently from an ancestral gene belonging to one of the three major groups of VH genes in higher vertebrates. Second, the rate of nonsynonymous substitution is slightly higher than that of synonymous substitution in the complementarity-determining regions (CDRs), which suggests that diversity-enhancing selection has operated in the CDRs even for pseudogenes. However, both the rates of synonymous and nonsynonymous substitution are higher in the CDRs than in the framework regions (FRs), apparently because of an interaction between positive selection and meiotic gene conversion in the CDRs. Third, a dot matrix analysis of the psi VH genes and genomic diversity (D) genes has indicated that the 3' end of psi VH genes is attached by D-gene-like sequences, and this region of psi VH genes has high similarity with D gene sequences. This suggests that V and D genes were fused at some point of evolutionary time and this fused element multiplied by gene duplication. Finally, two alternative hypotheses of explaining the evolution of the chicken VH gene system are presented.
Biological and clinical characteristics of the European Friedreich's Ataxia Consortium for Translational Studies (EFACTS) cohort: a cross-sectional analysis of baseline data
Authors: Kathrin Reetz, Imis Dogan, Ana S Costa, Manuel Dafotakis, Kathrin Fedosov, Paola Giunti, Michael H Parkinson, Mary G Sweeney, Caterina Mariotti, Marta Panzeri, Lorenzo Nanetti, Javier Arpa, Irene Sanz-Gallego, Alexandra Durr, Perrine Charles, Sylvia Boesch, Wolfgang Nachbauer, Thomas Klopstock, Ivan Karin, Chantal Depondt, Jennifer Müller vom Hagen, Ludger Schöls, Ilaria A Giordano, Thomas Klockgether, Katrin Bürk, Massimo Pandolfo, Jörg B Schulz
Journal: The Lancet Neurology (2015)
Normothermic Ex Vivo Lung Perfusion in Clinical Lung Transplantation
Authors: Marcelo Cypel, Jonathan C. Yeung, Mingyao Liu, Masaki Anraku, Fengshi Chen, Wojtek Karolak, Masaaki Sato, Jane Laratta, Sassan Azad, Mindy Madonik, Chung-Wai Chow, Cecilia Chaparro, Michael Hutcheon, Lianne G. Singer, Arthur S. Slutsky, Kazuhiro Yasufuku, Marc de Perrot, Andrew F. Pierre, Thomas K. Waddell, Shaf Keshavjee
Journal: New England Journal of Medicine (2011)

More than 80% of donor lungs are potentially injured and therefore not considered suitable for transplantation. With the use of normothermic ex vivo lung perfusion (EVLP), the retrieved donor lung can be perfused in an ex vivo circuit, providing an opportunity to reassess its function before transplantation. In this study, we examined the feasibility of transplanting high-risk donor lungs that have undergone EVLP.In this prospective, nonrandomized clinical trial, we subjected lungs considered to be high risk for transplantation to 4 hours of EVLP. High-risk donor lungs were defined by specific criteria, including pulmonary edema and a ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen (PO(2):FIO(2)) less than 300 mm Hg. Lungs with acceptable function were subsequently transplanted. Lungs that were transplanted without EVLP during the same period were used as controls. The primary end point was primary graft dysfunction 72 hours after transplantation. Secondary end points were 30-day mortality, bronchial complications, duration of mechanical ventilation, and length of stay in the intensive care unit and hospital.During the study period, 136 lungs were transplanted. Lungs from 23 donors met the inclusion criteria for EVLP; in 20 of these lungs, physiological function remained stable during EVLP and the median PO(2):FIO(2) ratio increased from 335 mm Hg in the donor lung to 414 and 443 mm Hg at 1 hour and 4 hours of perfusion, respectively (P<0.001). These 20 lungs were transplanted; the other 116 lungs constituted the control group. The incidence of primary graft dysfunction 72 hours after transplantation was 15% in the EVLP group and 30% in the control group (P=0.11). No significant differences were observed for any secondary end points, and no severe adverse events were directly attributable to EVLP.Transplantation of high-risk donor lungs that were physiologically stable during 4 hours of ex vivo perfusion led to results similar to those obtained with conventionally selected lungs. (Funded by Vitrolife; ClinicalTrials.gov number, NCT01190059.).
Burdens and Benefits of Adjuvant Cyclophosphamide, Methotrexate, and Fluorouracil and Tamoxifen for Elderly Patients With Breast Cancer: The International Breast Cancer Study Group Trial VII
Authors: Diana Crivellari, Marco Bonetti, Monica Castiglione-Gertsch, Richard D. Gelber, Carl-Magnus Rudenstam, Beat Thürlimann, Karen N. Price, Alan S. Coates, Christoph Hürny, Jürg Bernhard, Jurij Lindtner, John Collins, Hans-Jörg Senn, Franco Cavalli, John Forbes, Anne Gudgeon, Edda Simoncini, Hernan Cortes-Funes, Andrea Veronesi, Martin Fey, Aron Goldhirsch
Journal: Journal of Clinical Oncology (2000)

PURPOSE: Information on the tolerability and efficacy of adjuvant chemoendocrine therapy for older women is limited. We studied these issues using the data collected as part of the International Breast Cancer Study Group Trial VII. PATIENTS AND METHODS: Postmenopausal women with operable, node-positive breast cancer were randomized to receive either tamoxifen alone for 5 years (306 patients) or tamoxifen plus three consecutive cycles of classical cyclophosphamide (100 mg/m 2 orally days 1 to 14), methotrexate (40 mg/m 2 intravenous days 1 and 8), and fluorouracil (600 mg/m 2 intravenous days 1 and 8) every 28 days (CMF; 302 patients). The median follow-up was 8.0 years. RESULTS: Among the 299 patients who received at least one dose of CMF, women 65 years of age or older (n = 76) had higher grades of toxicity compared with women less than 65 years old (n = 223) (P = .004). More women in the older age group compared with the younger women experienced grade 3 toxicity of any type (17% v 7%, respectively), grade 3 hematologic toxicity (9% v 5%, respectively), and grade 3 mucosal toxicity (4% v 1%, respectively). Older patients also received less than their expected CMF dose compared with younger postmenopausal women (P = .0008). The subjective burdens of treatment, however, were similar for younger and older patients based on quality-of-life measures (performance status, coping, physical well-being, mood, and appetite). For older patients, the 5-year disease-free survival (DFS) rates were 63% for CMF plus tamoxifen and 61% for tamoxifen alone (hazards ratio [HR], 1.00; 95% confidence interval [CI], 0.65 to 1.52; P = .99). For younger patients, the corresponding 5-year DFS rates were 61% and 53% (HR, 0.70; 95% CI, 0.53 to 0.91; P = .008), but the test for heterogeneity of CMF effect according to age group was not statistically significant. The reduced effectiveness of CMF among older women could not be attributed to dose reductions according to dose received. CONCLUSION: CMF tolerability and effectiveness were both reduced for older patients compared with younger postmenopausal node-positive breast cancer patients who received tamoxifen for 5 years. The development and evaluation of less toxic and more effective chemotherapy regimens are required for high-risk elderly patients.
A Micropuncture Study of Postobstructive Diuresis in the Rat
Authors: William E. Yarger, Hagop S. Aynedjian, Norman Bank
Journal: Journal of Clinical Investigation (1972)

In order to investigate the syndrome of postobstructive diuresis, clearance and micropuncture studies were carried out in rats after relief of 24 hr of bilateral (BUL) or unilateral (UUL) ureteral ligation. In rats with BUL, a striking diuresis and natriuresis occurred when the obstruction to one kidney (the experimental kidney) was relieved. The results were not influenced by administration of vasopressin or d-aldosterone. Whole kidney clearances of inulin and p-aminohippuric acid (PAH) in the experimental kidney were reduced to 10% and 20% of normal, respectively. Superficial nephron inulin and PAH clearances were also reduced, but only to 40% and 45%, respectively. These findings suggest a heterogeneity of nephron function in which deep nephrons were functioning poorly or not at all. To investigate the site of impaired tubular reabsorption in the surface nephrons, absolute and fractional water reabsorption was measured. Absolute reabsorption was found to be decreased all along the nephron. Fractional reabsorption in proximal tubules was normal, as indicated by an average endproximal tubular fluid per plasma inulin (TF/P(In)) of 2.16 vs. 2.30 in controls. TF/P(In) was markedly decreased in distal tubules (2.91 vs. 8.02) and final urine (5.56 vs. 263). These observations indicate that the major sites of impaired sodium reabsorption leading to the diuresis were beyond the proximal tubule.Rats with 24 hr of UUL did not demonstrate a comparable natriuresis or diuresis either spontaneously when the obstruction was relieved or after i.v. infusion of urea. A major difference between the BUL and UUL rats was that prerelease intrarenal hydrostatic pressure was markedly elevated (30.1 mm Hg) in the former but was below normal free-flow values (9.2 mm Hg) in the latter. Thus, elevation of intrarenal pressure during the period of obstruction may be causally related to the natriuresis and diuresis which occurs after the obstruction is relieved.
Erythropoietin prevents PC12 cells from beta-amyloid-induced apoptosis via PI3K⁄Akt pathway
Authors: Sun Zhi-Kun, Yang Hong-Qi, Wang Zhi-Quan, Pan Jing, Hong Zhen, Chen Sheng-Di
Journal: Translational Neurodegeneration (2012)

Abstract Background Several studies indicated that Erythropoietin (Epo) may provide remarkable neuroprotection in some neurological diseases. It also showed the significant decrease of Epo immunoreactivity in the cerebral cortex and hippocampus in aged rats, suggesting the role of Epo in the pathogenesis of age-related neurodegenerative diseases such as AD. Methods The protective effect of Epo was studied in differentiated PC12 cells treated with Abeta. The viability of the cells, the apoptosis of the cells and the level of Bax, Bcl-2, cleaved caspase-3 and cleaved PARP expression were detected by MTT, Hoechst 33258 staining and Western blotting respectively. Results 20 μM Abeta (25-35) could induce a decreased viability and a increased apoptosis in PC12 cell in a time-dependent manner. However, 20 μM Abeta (35-25) had no effect on cell viability and apoptosis. Western blot analysis also showed that Abeta (25-35) treatment could decrease the expression of Bcl-2 ( P &lt; 0.05) and increase the expression of Bax ( P &lt; 0.05), Cleaved casapase-3 ( P &lt; 0.05), and Cleaved PARP ( P &lt; 0.05). The pretreatment of Epo could effectively reverse all the above changes induced by Abeta (25-35 ) ( P &lt; 0.05). Furthermore, the protective effect of Epo could be blocked by PI3K inhibitor LY294002 ( P &lt; 0.05). Conclusions Epo prevented cell injuries in PC12 cells exposed to the Abeta (25-35) and this effect may depend on the PI3K⁄Akt pathway. Our study provided an important evidence for the potential application of Epo in the therapy of Alzheimer's disease.
VEGF165 mediates glomerular endothelial repair
Authors: Tammo Ostendorf, Uta Kunter, Frank Eitner, Anneke Loos, Heinz Regele, Dontscho Kerjaschki, Dwight D. Henninger, Nebojsa Janjic, Jürgen Floege
Journal: Journal of Clinical Investigation (1999)

VEGF165, the most abundant isoform in man, is an angiogenic cytokine that also regulates vascular permeability. Its function in the renal glomerulus, where it is expressed in visceral epithelial and mesangial cells, is unknown. To assess the role of VEGF165 in glomerular disease, we administered a novel antagonist — a high-affinity, nuclease-resistant RNA aptamer coupled to 40-kDa polyethylene glycol (PEG) — to normal rats and to rats with mesangioproliferative nephritis, passive Heymann nephritis (PHN), or puromycin aminonucleoside nephrosis (PAN). In normal rats, antagonism of VEGF165 for 21 days failed to induce glomerular pathology or proteinuria. In rats with mesangioproliferative nephritis, the VEGF165 aptamer (but not a sequence-scrambled control RNA or PEG alone) led to a reduction of glomerular endothelial regeneration and an increase in endothelial cell death, provoking an 8-fold increase in the frequency of glomerular microaneurysms by day 6. In contrast, early leukocyte influx and the proliferation, activation, and matrix accumulation of mesangial cells were not affected in these rats. In rats with PHN or PAN, administration of the VEGF165 aptamer did not influence the course of proteinuria using various dosages and administration routes. These data identify VEGF165 as a factor of central importance for endothelial cell survival and repair in glomerular disease, and point to a potentially novel way to influence the course of glomerular diseases characterized by endothelial cell damage, such as various glomerulonephritides, thrombotic microangiopathies, or renal transplant rejection.
Transgenic triadin 1 overexpression alters SR Ca2+ handling and leads to a blunted contractile response to β-adrenergic agonists
Authors: U Kirchhefer
Journal: Cardiovascular Research (2004)

Ca2+ release from the cardiac junctional sarcoplasmic reticulum (SR) is regulated by a complex of proteins, including the ryanodine receptor (RyR), calsequestrin (CSQ), junctin (JCN), and triadin 1 (TRD). Moreover, triadin 1 appears to anchor calsequestrin to the ryanodine receptor.To determine whether triadin 1 overexpression alters excitation-contraction coupling, we examined the effects of cardiac-specific overexpression of triadin 1 on SR Ca2+ handling and contractility in transgenic (TG) compared to wild-type (WT) mice.The overexpression of triadin 1 was associated with an enhanced SR Ca2+ load, reflected by a 22% higher amplitude of caffeine-induced Ca2+ transients. The decline of Ca2+ transients during caffeine exposure was prolonged by 57%. The detection of resting spontaneous SR Ca2+ release events (Ca2+ sparks) revealed an increased amplitude (by 16%), decline (by 47%), and width (by 47%) in TG. This was associated with a redistribution of Ca2+ spark amplitudes from one population to two populations. Measurement of cardiac function by echocardiography and left ventricular (LV) catheterization revealed a decreased cardiac contractility in vivo. The impaired response to beta-adrenergic receptor (beta-AR) stimulation in TG hearts was associated with an increased protein expression of beta-AR kinase 1. In addition, the increase of the L-type Ca2+ peak current and the increase of phospholamban (PLB) phosphorylation at Thr17 were reduced under beta-AR stimulation.Taken together, our data suggest that triadin 1 overexpression results in a complex modulation of SR Ca2+ handling, which may contribute, at least in part, to the depressed basal contractility and the blunted response to beta-adrenergic agonists in TG mice.