tbuckley/cabot-search huggingface dataset:
Regulation of Cardiac Myocyte Protein Turnover and Myofibrillar Structure In Vitro by Specific Directions of Stretch
Authors: D. G. Simpson, M. Majeski, T. K. Borg, L. Terracio
Journal: Circulation Research (1999)

We have examined how different degrees (0.5%, 1.0%, 2.5%, 5.0%, and 10.0%) and directions of stretch regulate the turnover and accumulation of contractile proteins in cultured neonatal cardiac myocytes (NCMs). In pulse-chase experiments, stellate-shaped NCMs with random arrays of myofibrils (MFs) exhibited a threshold response to stretch. With respect to unstretched controls, the turnover of the contractile protein pool was suppressed 50% to 100% in stellate NCMs stretched 1.0% to 5.0% and was unaltered in stellate NCMs stretched 0.5% or 10.0%. The posttranslational metabolism of myosin heavy chain (MHC) and actin was regulated in parallel with the total contractile protein pool. The turnover of the cytoplasmic protein pool remained unchanged in response to stretch. NCMs plated onto an aligned matrix of type I collagen expressed an elongated, rod-like cell shape. The MFs of these cells were distributed in parallel with one another along a single unique axis. The tissue-like pattern of organization of these cultures made it possible to assay how specific directions of stretch affected cardiac protein turnover and MF organization. In pulse-chase experiments, stretch in parallel with the MFs did not alter the turnover of the total contractile protein pool, the cytoplasmic protein pool, MHC, or actin. The total cellular concentration of MHC and actin remained constant, and MF alignment was not overtly affected. In contrast, even modest degrees of stretch across the short axis of the MFs suppressed total contractile protein turnover, the turnover of MHC and actin, and promoted the accumulation of these MF subunits. The parallel alignment of MFs deteriorated in myocytes stretched greater than 5%. The characteristic response of aligned myocytes to stretch was not affected by the contractile state of the cells. Isoproterenol (ISO) treatment in concert with stretch in parallel with the MFs modestly accelerated contractile protein turnover. Conversely, contractile protein turnover was suppressed in cells treated with ISO and stretched across the short axis of the MFs. Contractile arrest with nifedipine (NIFED) accelerated total myofibrillar protein turnover. Stretch across the short axis, but not in parallel with the MFs, suppressed protein turnover in cells treated with NIFED. The turnover of the cytosolic proteins remained constant under all conditions assayed. These data suggest that specific directions of stretch may play a crucial role in regulating MF organization and the metabolism of contractile proteins in the cardiac myocyte.
Immune cell reservoirs of persisting hepatitis C virus
Authors: T. I. Michalak
Journal: Gut (2010)

Infection with hepatitis C virus (HCV) is a global health problem with more than 80% of those infected developing chronic hepatitis C (CHC) that tends to advance to liver cirrhosis and hepatocellular carcinoma. It is estimated that up to three-quarters of HCV-infected individuals are neither diagnosed nor aware that they are infected, and symptomatic liver damage may not appear for years or decades in many patients following virus exposure. The pathogenic and epidemiological significance of HCV could be further magnified by the existence of occult HCV infection (OCI), evidenced by small quantities of HCV RNA in plasma (usually below 100 virus genome copies/ml), liver and/or peripheral blood mononuclear cells (PBMCs), continuing in the context of essentially normal liver function tests after self-limited or therapeutically induced resolution of hepatitis C and OCI in which carriage of HCV RNA traces coincide with moderately elevated liver enzymes of unclear aetiology.1 Although HCV is conventionally known to target hepatocytes, a large and increasing body of experimental and clinical data provides cumulative, hence not yet commonly acknowledged evidence that HCV also propagates at extrahepatic locations, particularly in cells of the immune system.2 3

HCV is a positive single-stranded RNA virus of the Flaviviridae family that demonstrates remarkable genetic variability and typically exists in an infected host as a heterologous population of closely related quasispecies resulting from virus rapid replication driven by …
Endothelial Protection, AT <sub>1</sub> Blockade and Cholesterol-Dependent Oxidative Stress
Authors: Henning Morawietz, Sandra Erbs, Jürgen Holtz, Andreas Schubert, Michael Krekler, Winfried Goettsch, Oliver Kuss, Volker Adams, Karsten Lenk, Friedrich W. Mohr, Gerhard Schuler, Rainer Hambrecht
Journal: Circulation (2006)

Statins and angiotensin type 1 (AT1) receptor blockers reduce cardiovascular mortality and morbidity. In the Endothelial Protection, AT1 blockade and Cholesterol-Dependent Oxidative Stress (EPAS) trial, impact of independent or combined statin and AT1 receptor blocker therapy on endothelial expression of anti-atherosclerotic and proatherosclerotic genes and endothelial function in arteries of patients with coronary artery disease were tested.Sixty patients with stable coronary artery disease undergoing elective coronary artery bypass grafting (CABG) surgery were randomized 4 weeks before surgery to: (A) control without inhibition of renin-angiotensin system or statin; (B) statin (pravastatin 40 mg/d); (C) AT1 blockade (irbesartan 150 mg/d); or (D) combination of statin and AT1 blocker in same dosages. Primary end point was a priori therapy-dependent regulation of an anti-atherosclerotic endothelial expression quotient Q including mRNA expression (in arbitrary units measured by real-time polymerase chain reaction) of endothelial nitric oxide synthase and C-type natriuretic peptide, divided by expression of oxidized low-density lipoprotein receptor LOX-1 and NAD(P)H oxidase subunit gp91phox in left internal mammary arteries biopsies obtained by CABG surgery; 49 patients completed the study. Statin therapy increased lnQ from 3.2+/-0.4 to 4.4+/-0.4 significantly versus control. AT(1) blockade showed a trend to increase lnQ to 4.2+/-0.5. Combination of statin and AT1 blocker further increased lnQ to 5.1+/-0.6, but a putative interaction of both therapies in lnQ was not significant. Furthermore, preoperative therapy with statin, AT1 blocker and their combination improved endothelial function in internal mammary artery rings.Statin and AT1 blocker therapy independently and in combination improve an anti-atherosclerotic endothelial expression quotient and endothelial function.
Vaccination of Healthy Volunteers with Human Papillomavirus Type 16 L2E7E6 Fusion Protein Induces Serum Antibody that Neutralizes across Papillomavirus Species
Authors: Ratish Gambhira, Patti E. Gravitt, Ioannis Bossis, Peter L. Stern, Raphael P. Viscidi, Richard B.S. Roden
Journal: Cancer Research (2006)

Oncogenic human papillomavirus (HPV) infection is a necessary cause of cervical cancer. Therefore, vaccination to prevent or eliminate HPV infection could reduce the incidence of cervical cancer. A fusion protein comprising HPV16 L2, E6, and E7 is a candidate combination preventive and therapeutic HPV vaccine. The L1- and L2-specific and neutralizing serum antibody titers and peripheral blood mononucleocyte antigen-specific proliferative responses generated by vaccination thrice at monthly intervals with HPV16 L2E7E6 were compared in two studies: a phase I randomized double-blind placebo controlled dose escalation trial in 40 healthy volunteers and a phase II trial of HPV16 L2E7E6 at the maximum dose in 29 women with high-grade anogenital intraepithelial neoplasia (AGIN). Vaccination of healthy volunteers induced L2-specific serum antibodies that were detected 1 month after the final vaccination (P(binomial) < 0.001). There was a significant trend to seroconversion for HPV16 and HPV18 neutralizing antibodies with increasing vaccine dose (P = 0.006 and P = 0.03, respectively). Seroconversion for HPV18 neutralizing antibodies showed a significant positive trend with increasing dose (P = 0.03) and was associated with seroconversion for HPV16 neutralizing antibodies (P(exact) = 0.04). The antigen-specific proliferative response of vaccinated healthy volunteers also showed a significant trend with increasing vaccine dose (P = 0.04). However, AGIN patients responded less effectively to vaccination than healthy patients for induction of HPV16 L2-specific antibody (P < 0.001) and proliferative responses (P < 0.001). Vaccination of healthy volunteers thrice with 533-mug HPV16 L2E7E6 at monthly intervals induced L2-specific serum antibodies that neutralized across papillomavirus species. Responses in AGIN patients were infrequent.
Nonmutagenic mechanisms in carcinogenesis: role of protein kinase C in signal transduction and growth control.
Authors: I B Weinstein
Journal: Environmental Health Perspectives (1991)

There is accumulating evidence that the multistage carcinogenic process is associated with the progressive acquisition of mutations in cellular proto-oncogenes and in growth-suppressor genes. At the same time, several types of evidence indicate that nongenotoxic agents and epigenetic events also play an important role in the evolution of tumors. One of the most intensively studied nongenotoxic agents is the phorbol ester tumor promoter 12-O-tetradecanoyl-phorbol-13-acetate (TPA) and related compounds. Since TPA appears to exert its biologic effects through protein kinase C (PKC), a key enzyme in signal transduction, we have studied this enzyme in considerable detail. Our strategy has been to perturb signal transduction by developing cell lines that overexpress the beta 1 isoform of PKC. Such derivatives of rat fibroblasts display alterations in morphology and growth factors, altered expression of c-myc, ornithine decarboxylase, and phorbin, and increased susceptibility to transformation by certain oncogenes, H-ras, myc, and fos. These findings provide direct genetic evidence that PKC plays a critical role in growth control and the action of certain growth factors, tumor promoters, and oncogenes. In related studies, we have characterized the beta 1 isoform that is overproduced in the above cell systems in terms of its biochemical, kinetic, and immunologic properties. The enzyme has several properties characteristic of native PKCs. A surprising finding is that c-H-ras-transformed derivatives of the cells that overexpress PKC beta 1 display a several-fold increase in the expression of the endogenous alpha 1 isoform of PKC and a decrease in the expression of the endogenous epsilon isoform.(ABSTRACT TRUNCATED AT 250 WORDS)
Better Therapeutic Trials in Ovarian Cancer
Authors: M. A. Bookman, C. B. Gilks, E. C. Kohn, K. O. Kaplan, D. Huntsman, C. Aghajanian, M. J. Birrer, J. A. Ledermann, A. M. Oza, K. D. Swenerton
Journal: JNCI Journal of the National Cancer Institute (2014)

The Ovarian Task Force of the Gynecologic Cancer Steering Committee convened a clinical trials planning meeting on October 28–29, 2011, with the goals to identify key tumor types, associated molecular pathways, and biomarkers for targeted drug intervention; review strategies to improve early-phase screening, therapeutic evaluation, and comparison of new agents; and optimize design of randomized trials in response to an evolving landscape of scientific, regulatory, and funding priorities. The meeting was attended by international clinical and translational investigators, pharmaceutical industry representatives, government regulators, and patient advocates. Panel discussions focused on disease types, early-phase trials, and randomized trials. A manuscript team summarized the discussions and assisted with formulating key recommendations. A more integrated and efficient approach for screening new agents using smaller selective randomized trials in specific disease-type settings was endorsed, together with collaborative funding models between industry and the evolving national clinical trials network, as well as efforts to enhance public awareness and study enrollment through advocacy.
A multidisciplinary job retention vocational rehabilitation programme for patients with chronic rheumatic diseases: patients' and occupational physicians' satisfaction
Authors: P D M de Buck, J Breedveld, F J van der Giesen, T P M Vliet Vlieland
Journal: Annals of the Rheumatic Diseases (2004)

<h3>Abstract</h3> <i>Mycobacterium abscessus</i> is an emerging pathogen of concern in cystic fibrosis and immunocompromised patients and is considered one of the most drug-resistant mycobacteria. The majority of clinical <i>M. abscessus</i> isolates carry one or more prophages that are hypothesized to contribute to virulence and bacterial fitness. The prophage McProf was identified in the genome of the Bergey strain of <i>M. chelonae</i>, and is distinct from previously described prophages of <i>M. abscessus</i>. The McProf genome increases intrinsic antibiotic resistance of <i>M. chelonae</i> and drives expression of the intrinsic antibiotic resistance gene, <i>whi</i>B7, when superinfected by a second phage. The prevalence of McProf-like genomes was determined in sequenced mycobacterial genomes. Related prophage genomes were identified in the genomes of 25 clinical isolates of <i>M. abscessus</i> and assigned to the novel cluster, MabR. The MabR genomes share less than 10% gene content with previously described prophages; however, share features typical of prophages, including polymorphic toxin immunity (PT-Imm) systems.
Contribution of house and garden work to the association between physical activity and well-being in young, mid-aged and older women
Authors: Geeske Peeters, Yolanda R van Gellecum, Jannique G Z van Uffelen, Nicola W Burton, Wendy J Brown
Journal: British Journal of Sports Medicine (2012)

Objective Although physical activity occurs in leisure, transport, occupational and domestic domains of life, the contribution of house and garden work (HGW) to the association between total physical activity and well-being is not clear. The aim was to describe the contribution of HGW to total physical activity (TPA) in association with well-being in younger, mid-aged and older women. Design Younger (25–30 years), mid-aged (50–55 years) and older (76–81 years) participants in the Australian Longitudinal Study on Women's Health completed a mailed survey with questions about leisure, transport and house and garden activities. Well-being was assessed using the physical and mental components scores of the SF-36. Cross-sectional associations between the physical activity variables and well-being were modelled using General Additive Modelling. Results Correlations between HGW and leisure/transport activity (LTA) were low (r&lt;0.3, p&lt;0.001). Positive curvilinear associations were found between LTA and physical and mental well-being in all three cohorts, and between HGW and physical and mental well-being in mid-aged and older women. In the younger women, an inverse relationship was found between HGW and well-being. When HGW and LTA were summed (TPA), the associations between TPA and well-being were attenuated compared with those for LTA alone and well-being. Conclusions In mid-aged and older women, relationships between HGW and well-being were similar to, but weaker than seen for LTA and well-being. In young women, well-being declined with increasing HGW. Summing HGW to LTA led to attenuated relationships, suggesting that domains of physical activity should not be summed when studying relationships with well-being.
Efficacy of tacrolimus 0.1% ointment in cutaneous lupus erythematosus: A multicenter, randomized, double-blind, vehicle-controlled trial
Authors: Annegret Kuhn, Kristina Gensch, Merle Haust, Stefan W. Schneider, Gisela Bonsmann, Noemi Gaebelein-Wissing, Percy Lehmann, Annette Wons, Peter Reitmeir, Vincent Ruland, Thomas A. Luger, Thomas Ruzicka
Journal: Journal of the American Academy of Dermatology (2011)
Structural Analysis of the Synaptic Protein Neuroligin and Its β-Neurexin Complex: Determinants for Folding and Cell Adhesion
Authors: Igor P. Fabrichny, Philippe Leone, Gerlind Sulzenbacher, Davide Comoletti, Meghan T. Miller, Palmer Taylor, Yves Bourne, Pascale Marchot
Journal: Neuron (2007)
Prognostic Factors in Attempted Suicide
Authors: ARI KIEV
Journal: American Journal of Psychiatry (1974)

The author analyzes clinical and social data collected from 300 patients at the time of a suicide attempt and one year after the attempt. He was able to gather data for 299 patients at one-year follow-up. The results of the follow-up showed prognostic significance for three factors: interpersonal conflict, svmptom distress, and the social setting of the suicide attempt. The significance of these factors in predicting further suicide attempts calls attention to the need for psychiatrists to take cognizance of the social world of the patient following a suicide attempt.
THE QUANTITATIVE DETERMINATION OF GLUCOSE IN THE URINE BY A NEW MODIFICATION OF FEHLING'S SOLUTION.
Authors: J. RUDISCH
Journal: JAMA (1907)

In the volumetric determination of glucose in urine based on the property of sugar to reduce cupric oxid the end reaction is markedly obscured by the precipitation of insoluble red cuprous oxid. To find a solvent for it has been the object of most of the modifications of Fehling's method thus far proposed. The employment of an ammoniacal solution of cupric oxid to avoid this disturbing factor was first suggested by Pavy, whose method was subsequently modified by a number of investigators, including one of us (J. Rudisch). Such ammoniacal solutions, however, have not entirely accomplished their purpose. Not alone is the odor of ammonia obnoxious, but unless the determination proceeds rapidly the ammonia is driven off in sufficient quantity during the boiling to permit the deposit of the red oxid of copper before the end reaction is complete. These disadvantages are overcome in the method devised by Gerrard and
Extensive evaluation of a seronegative participant in an HIV-1 vaccine trial as a result of false-positive PCR
Authors: David H Schwartz, Oliver B Laeyendecker, Silvio Arango-Jaramillo, Renan C Castillo, Mary Jane Reynolds
Journal: The Lancet (1997)

In the USA, more than 2000 volunteers have received one or more experimental HIV-1 vaccines in phase I and II clinical trials, and there have been breakthrough HIV-1 infections among participants receiving vaccine and placebo. Serological diagnosis of new HIV-1 infections in vaccine-trial participants will become increasingly complicated as more viral components are used in vaccines. Recognition of this problem has led to a reliance on viral-genome measurement to distinguish vaccine-induced immunity from HIV-1 infection. Currently, quantitative RNA measurement is expensive, prone to contamination, and reliable only in laboratories certified by manufacturers or that have quality-control programmes.A high-risk vaccinee presented after an acute febrile episode and was tested for HIV-1 infection by reverse transcriptase (RT) PCR of viral RNA. Further extensive tests were required to clarify the HIV-1 infection and immune status of the vaccinee, including repeat RT-PCR, nested DNA PCR, western blot, lymphoproliferation assay, cytotoxic T-cell lysis, CD8-depleted co-culture, and HIV-1 challenge culture.Initial testing of plasma by RNA RT-PCR was reported as positive. This result was not confirmed by viral cultures, nested DNA PCR, western blot, or EIA. Additional RNA RT-PCR assays gave positive results from earlier occasions in the vaccine trial. Eventually, testing of all previously reactive samples by RNA RT-PCR was repeated in a quality-controlled laboratory, and confirmed the negative HIV-1 status of the individual.This case report exemplifies the difficulties with use of viral-genome measurement as a screening test to diagnose HIV-1 infection, particularly in individuals who have ever participated in HIV-1 vaccine trials. Monitoring of large numbers of phase III vaccinees by RNA RT-PCR will not be feasible. The design of efficacy trials for new vaccines should be in parallel with development of antibody-based diagnostic tests that are capable of differentiating between immunisation and true HIV-1 infection.
Colipase and maximally activated pancreatic lipase in normal subjects and patients with steatorrhea.
Authors: K J Gaskin, P R Durie, R E Hill, L M Lee, G G Forstner
Journal: Journal of Clinical Investigation (1982)

Human pancreatic lipase in duodenal secretions was studied under conditions of maximal activation by porcine colipase and maximal inhibition by sodium taurodeoxycholate. In almost all samples, total lipase activity in 4 mM sodium taurodeoxycholate was activated by the addition of porcine colipase. Activation was linear until saturation by cofactor was reached, and maximum activity was greater than that obtained in the absence of bile salts. At pH 8.0 in 4 mM sodium taurodeoxycholate, lipase activity was due to pancreatic lipase in samples from normal and steatorrheic individuals and was proportional to the concentration of endogenous colipase in samples that could be activated by exogenous colipase. In these samples, therefore, colipase activity could be conveniently assayed as the lipase activity at pH 0.8 in 4 mM sodium taurodeoxycholate. Colipase to total pancreatic lipase ratios varied widely from individual to individual and on average were significantly lower in steatorrheic patients. In individual samples, colipase secretion was stimulated by pancreozymin and secretin roughly in parallel with total pancreatic lipase, but some variation in the ratio of the two was often seen in successive collection periods. Because pancreatic lipase is usually unsaturated with respect to cofactor, lipolytic activity in duodenal secretions may be finely controlled by modulation of colipase secretion.
Genetic Basis of Cancer of the Kidney
Authors: W. Marston Linehan, James Vasselli, Ramaprasad Srinivasan, McClellan M. Walther, Maria Merino, Peter Choyke, Cathy Vocke, Laura Schmidt, Jennifer S. Isaacs, Gladys Glenn, Jorge Toro, Berton Zbar, Donald Bottaro, Len Neckers
Journal: Clinical Cancer Research (2004)

Abstract Studies during the past two decades have shown that kidney cancer is not a single disease; it is made up of a number of different types of cancer that occur in this organ. Clear cell renal carcinoma is characterized by mutation of the VHL gene. The VHL gene product forms a heterotrimeric complex with elongin C, elongin B, and Cul-2 to target hypoxia-inducible factors 1 and 2α for ubiquitin-mediated degradation. VHL−/− clear cell renal carcinoma overexpresses epidermal growth factor receptor and transforming growth factor α. Both hypoxia-inducible factor 1α and the epidermal growth factor receptor are potential therapeutic targets in clear cell renal carcinoma. Studies of the hereditary form of renal cell carcinoma (RCC) associated with hereditary papillary renal carcinoma (HPRC) determined that the c-Met proto-oncogene on chromosome 7 is the gene for HPRC and for a number of sporadic papillary RCCs. The HPRC c-Met mutations are activating mutations in the tyrosine kinase domain of the gene. The gene for a new form of hereditary RCC (Birt Hogg Dubé syndrome) associated with cutaneous tumors, lung cysts, and colon polyps or cancer has recently been identified. Studies are currently under way to determine what type of gene BHD is and how damage to this gene leads to kidney cancer. Individuals affected with hereditary leiomyomatosis renal cell carcinoma are at risk for the development of cutaneous leiomyomas, uterine leiomyomas (fibroids), and type 2 papillary RCC. The HLRC gene has been found to be the Krebs cycle enzyme, fumarate hydratase. Studies are under way to understand the downstream pathway of this cancer gene.