tbuckley/cabot-search huggingface dataset:
Does Hemodialysis Increase Protein Breakdown? Dissociation between Whole-Body Amino Acid Turnover and Regional Muscle Kinetics
Authors: Victoria S. Lim, T. Alp Ikizler, Dominic S.C. Raj, Michael J. Flanigan
Journal: Journal of the American Society of Nephrology (2005)

Hemodialysis (HD) is a protein catabolic procedure. Whole-body amino acid turnover studies identify dialysate amino acid loss and reduced protein synthesis as the catabolic events; proteolysis is not increased. Regional amino acid kinetics, however, document enhanced muscle protein breakdown as the cause of the catabolism; muscle protein synthesis also increased but to a lesser magnitude than the increment in protein breakdown. This discordance between whole-body and regional kinetics is best explained by the contrasting physiology between the muscle and the liver. During HD, muscle releases amino acids, which then are taken up by the liver for de novo protein synthesis. There seems to be a somatic to visceral recycling of amino acids. Evidence supporting this concept includes the increased fractional synthesis of albumin and fibrinogen during HD. It should be emphasized that region- or organ-specific kinetics vary, and whole-body turnover is a composite of all of the visceral and somatic compartments taken together. Reduced whole-body protein synthesis may be a compensatory adaptation to dialysate amino acid loss with a consequent reduction in plasma amino acid concentration. Notwithstanding the protein catabolic nature of HD, evidence is accumulating that intradialytic nutritional supplementation may blunt its catabolic effect.
Role of increased cytosolic free calcium in the pathogenesis of rabbit proximal tubule cell injury and protection by glycine or acidosis.
Authors: J M Weinberg, J A Davis, N F Roeser, M A Venkatachalam
Journal: Journal of Clinical Investigation (1991)

To assess the role of increased cytosolic free calcium (Caf) in the pathogenesis of acute proximal tubule cell injury and the protection afforded by exposure to reduced medium pH or treatment with glycine, fura-2-loaded tubules were studied in suspension and singly in a superfusion system. The Ca2+ ionophore, ionomycin, increased Caf to micromolar levels and rapidly produced lethal cell injury as indicated by loss of lactate dehydrogenase to the medium by suspended tubules and accelerated leak of fura and failure to exclude Trypan blue by superfused tubules. Decreasing medium Ca2+ to 100 nM prevented the ionomycin-induced increases of Caf and the injury. Reducing medium pH from 7.4 to 6.9 or adding 2 mM glycine to the medium also prevented the cell death, but did not prevent the increase of Caf to micromolar levels. Cells treated with 1799, an uncoupler of oxidative phosphorylation which produced severe adenosine triphosphate (ATP) depletion, did not develop increases of Caf until just before loss of viability. Preventing these increases of Caf with 100 nM Ca2+ medium did not protect 1799-treated cells. Reduced pH and glycine protected 1799-treated cells without ameliorating the increases of Caf. These data demonstrate the toxic potential of increased Caf in the proximal tubule and show that Caf does sharply increase prior to loss of viability in an ATP depletion model of injury, but this increase does not necessarily contribute to the outcome. The potent protective actions of decreased pH and glycine allow the cells to sustain increases of Caf to micromolar levels in spite of severe, accompanying cellular ATP depletion without developing lethal cell injury.
<i>HLA-B*58:01</i>is a risk factor for allopurinol-induced DRESS and Stevens-Johnson syndrome/toxic epidermal necrolysis in a Portuguese population
Authors: M. Gonçalo, I. Coutinho, V. Teixeira, A.R. Gameiro, M.M. Brites, R. Nunes, A. Martinho
Journal: British Journal of Dermatology (2013)

HLA-B*58:01 is associated with allopurinol-induced severe cutaneous adverse drug reactions (sCADR) particularly in Han Chinese, but the risk in European populations has seldom been studied.To study the association of HLA-B*58:01 with allopurinol-induced sCADR in a Portuguese population.We studied 25 patients (11 male/14 female, mean age 67·4 years) with sCARD from allopurinol: 19 DRESS (drug reaction eosinophilia and systemic symptoms) and six Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). HLA was genotyped by reverse sequence-specific oligonucleotide-polymerase chain reaction and results compared statistically with a control group of 23 allopurinol-tolerant individuals and the control population.HLA-B*58:01 was present in 16 patients with sCADR (64%) [12 DRESS (63%), four SJS/TEN (67%)], one allopurinol-tolerant individual (4%) and 63 normal controls (1·96%), with a statistically significant difference between sCADR and the two control groups. When compared with the normal population, HLA-B*58:01 was associated with a higher risk of sCADR, both DRESS [odds ratio (OR) 85·36, 95% confidence interval (CI) 32·52-224·04] and SJS/TEN (OR 99·59, 95% CI 17·91-553·72). There was no statistically different risk between these two types of CADR.Portuguese patients with sCADR from allopurinol, both DRESS and SJS/TEN, have a high frequency of HLA-B*58:01, with an OR similar to European patients with SJS/TEN. This study also extends this association to DRESS in Europeans. The recommendation to genotype systematically before therapy is controversial, particularly when HLA-B*58:01 prevalence in the normal population is low, as in Europe. However it could be an option for patients with other risks factors.
Genomic Characterization of Non–Small-Cell Lung Cancer in African Americans by Targeted Massively Parallel Sequencing
Authors: Luiz H. Araujo, Cynthia Timmers, Erica Hlavin Bell, Konstantin Shilo, Philip E. Lammers, Weiqiang Zhao, Thanemozhi G. Natarajan, Clinton J. Miller, Jianying Zhang, Ayse S. Yilmaz, Tom Liu, Kevin Coombes, Joseph Amann, David P. Carbone
Journal: Journal of Clinical Oncology (2015)

Technologic advances have enabled the comprehensive analysis of genetic perturbations in non-small-cell lung cancer (NSCLC); however, African Americans have often been underrepresented in these studies. This ethnic group has higher lung cancer incidence and mortality rates, and some studies have suggested a lower incidence of epidermal growth factor receptor mutations. Herein, we report the most in-depth molecular profile of NSCLC in African Americans to date.A custom panel was designed to cover the coding regions of 81 NSCLC-related genes and 40 ancestry-informative markers. Clinical samples were sequenced on a massively parallel sequencing instrument, and anaplastic lymphoma kinase translocation was evaluated by fluorescent in situ hybridization.The study cohort included 99 patients (61% males, 94% smokers) comprising 31 squamous and 68 nonsquamous cell carcinomas. We detected 227 nonsilent variants in the coding sequence, including 24 samples with nonoverlapping, classic driver alterations. The frequency of driver mutations was not significantly different from that of whites, and no association was found between genetic ancestry and the presence of somatic mutations. Copy number alteration analysis disclosed distinguishable amplifications in the 3q chromosome arm in squamous cell carcinomas and pointed toward a handful of targetable alterations. We also found frequent SMARCA4 mutations and protein loss, mostly in driver-negative tumors.Our data suggest that African American ancestry may not be significantly different from European/white background for the presence of somatic driver mutations in NSCLC. Furthermore, we demonstrated that using a comprehensive genotyping approach could identify numerous targetable alterations, with potential impact on therapeutic decisions.
Human Bronchial Smooth Muscle Cell Lines Show a Hypertrophic Phenotype Typical of Severe Asthma
Authors: Limei Zhou, Jing Li, Adam M. Goldsmith, Dawn C. Newcomb, Diane M. Giannola, Robert G. Vosk, Eva M. Eves, Marsha R. Rosner, Julian Solway, Marc B. Hershenson
Journal: American Journal of Respiratory and Critical Care Medicine (2003)

We developed clonal cell lines of human bronchial smooth muscle origin by retroviral transduction of temperature-sensitive simian virus 40 large tumor (T) antigen. These cells show increased growth potential at 33 degrees C, but on shift to the nonpermissive temperature (39 degrees C), they show diminished or arrested growth. In addition to the expected reduction in the level of large T antigen, cells shifted to 39 degrees C show increased expression of the cyclin-dependent kinase inhibitor p21(Waf1/Cip1), characteristic of cells arrested in G1 of the cell cycle. Shifted cells undergo a process of cell hypertrophy, as demonstrated by increased time of flight and forward scatter, as well as increased expression of the contractile proteins alpha-smooth muscle actin, myosin light chain kinase, and SM22. Changes in contractile protein expression were regulated primarily in a posttranscriptional manner. Phosphatidylinositol 3-kinase activity was increased in shifted cells, and chemical inhibition of phosphatidylinositol 3-kinase attenuated alpha-actin and myosin light-chain kinase expression. We have developed clonal cell lines of human bronchial smooth muscle origin that may be useful for the study of airway smooth muscle biology. Furthermore, we demonstrate that arrest of airway smooth muscle cell cycle traversal can induce cellular hypertrophy, which parallels changes observed in the airways of patients with severe asthma.
Cofactor dependence and isotype distribution of anticardiolipin antibodies in viral infections
Authors: H Guglielmone
Journal: Annals of the Rheumatic Diseases (2001)

Antibodies to cardiolipin (aCLs) are often detected in patients with autoimmune disorders or infectious diseases.To investigate the distribution of aCL isotypes and requirement of protein cofactor in viral infections in order to establish the importance, if any, of these antibodies in these infectious diseases.The isotype distribution of aCLs in the sera from 160 patients with infection caused by HIV-1 (n=40), hepatitis A virus (n=40), hepatitis B virus (n=40), or hepatitis C virus (n=40) was studied by standardised enzyme linked immunosorbent assay (ELISA) in the presence and absence of protein cofactor (mainly beta2-glycoprotein I). Serum samples from healthy volunteers and patients with syphilis and antiphospholipid syndrome were also included and served as negative and positive control groups respectively.The prevalence of one or more aCL isotypes in serum of patients with HIV-1, hepatitis A virus, hepatitis B virus, or hepatitis C virus infection was 47%, 92%, 42%, and 17% respectively (principally IgM and/or IgA). Most of these antibodies were mainly cofactor independent.The presence of aCLs in viral infections is principally cofactor independent, suggesting that cofactor dependence of the aCLs should be assessed to distinguish subjects most likely to suffer from clinical symptoms observed in the presence of these antibodies.
Letrozole in the Extended Adjuvant Treatment of Postmenopausal Women with History of Early-Stage Breast Cancer Who Have Completed 5 Years of Adjuvant Tamoxifen
Authors: Bhupinder S. Mann, John R. Johnson, Roswitha Kelly, Rajeshwari Sridhara, Grant Williams, Richard Pazdur
Journal: Clinical Cancer Research (2005)

To present the basis of the decision of the Food and Drug Administration to grant accelerated approval for letrozole for extended adjuvant treatment of early-stage breast cancer in postmenopausal women after completion of adjuvant tamoxifen.The Food and Drug Administration reviewed the data from the MA17 trial, a single, multinational, randomized, double-blind, and placebo-controlled trial, submitted by the applicant to support the proposed new indication.MA17 consisted of a core study and Lipid and Bone Mineral Density safety substudies. It enrolled 5,187 patients. In the core study, median treatment duration was 24 months and median follow-up duration was 27.4 months. Using a conventional definition of disease-free survival, 122 events on letrozole and 193 events on placebo were observed (hazard ratio, 0.62; 95% confidence interval, 0.49-0.78; P = 0.00003). Distant disease-free survival also improved with letrozole, 55 versus 92 events (hazard ratio, 0.61; 95% confidence interval, 0.44-0.84; P = 0.003). No statistically significant improvement in overall survival was observed. Hot flushes, arthralgia/arthritis, myalgia, and new diagnosis of osteoporosis were more common on letrozole. Frequency of fractures and cardiovascular ischemic events was not significantly different. A statistically significant mean decrease in bone mineral density in the hip occurred at 24 months on letrozole.Letrozole administration led to a statistically significant prolongation in disease-free survival. Fractures and cardiovascular events were similar to placebo; however, new diagnoses of osteoporosis were more frequent. Short duration of treatment and follow-up precluded assessment of long-term safety and efficacy. Thus, accelerated approval was granted instead of regular approval.
Enhanced production of murine interferon gamma by T cells generated in response to bacterial infection.
Authors: E A Havell, G L Spitalny, P J Patel
Journal: The Journal of Experimental Medicine (1982)

Spleen cell cultures derived from animals infected 6 d earlier with Listeria monocytogenes produced 10-20-fold more murine interferon gamma (MuIFN gamma) than spleen cells from nonimmune mice in response to stimulation with T cell mitogens. A striking temporal association was found between the enhanced synthesis of MuIFN gamma and the development of anti-Listeria immunity in that both the potential for increased MuIFN gamma production and the generation of Listeria-protective T cells developed and then decayed in unison. Treatment of spleen cells with monoclonal anti-Thy-1.2 plus complement virtually abolished the ability of cells from Listeria-immune mice to synthesize MuIFN gamma. The T cells producing MuIFN gamma were found to be more susceptible to complement-mediated lysis with monoclonal anti-Lyt-1.2 than with monoclonal anti-Lyt-2.2. The production of MuIFN gamma was not affected by treating spleen cells with anti-IgG antisera or with a monoclonal antibody directed against I-A specificities. MuIFN gamma was detected 4 h after the beginning of mitogenic stimulation of spleen cell cultures, and peak levels of MuIFN gamma were reached by 18 h. The IFN synthesized by mitogen-induced spleen cells derived from Listeria-immune mice were relatively labile at pH 2.0 and neutralized by a rabbit anti-MuIFN gamma serum but not by an antiserum having specificities for MuIFN alpha and MuIFN beta. The apparent molecular weight of the MuIFN gamma, as estimated by molecular sieving on a Bio-gel P-60 column, was estimated to be 38,000, and the isoelectric point as determined by chromatofocusing was extremely heterogeneous, ranging between pH 5.0 and pH 7.0.
Small Is Beautiful: Insulin-Like Growth Factors and Their Role in Growth, Development, and Cancer
Authors: Robert G. Maki
Journal: Journal of Clinical Oncology (2010)

Insulin-like growth factors were discovered more than 50 years ago as mediators of growth hormone that effect growth and differentiation of bone and skeletal muscle. Interest of the role of insulin-like growth factors in cancer reached a peak in the 1990s, and then waned until the availability in the past 5 years of monoclonal antibodies and small molecules that block the insulin-like growth factor 1 receptor. In this article, we review the history of insulin-like growth factors and their role in growth, development, organism survival, and in cancer, both epithelial cancers and sarcomas. Recent developments regarding phase I to II clinical trials of such agents are discussed, as well as potential studies to consider in the future, given the lack of efficacy of one such monoclonal antibody in combination with cytotoxic chemotherapy in a first-line study in metastatic non-small-cell lung adenocarcinoma. Greater success with these agents clinically is expected when combining the agents with inhibitors of other cell signaling pathways in which cross-resistance has been observed.
Estimating Renal Survival Using the ANCA-Associated GN Classification
Authors: Marc Hilhorst, Benjamin Wilde, Peter van Breda Vriesman, Pieter van Paassen, Jan Willem Cohen Tervaert
Journal: Journal of the American Society of Nephrology (2013)

A histopathological classification system for ANCA-associated vasculitis was recently published, but whether this system predicts renal outcome requires validation. Here, we analyzed data from 164 consecutive patients with biopsy-proven renal involvement of ANCA-associated vasculitis. The ANCA-associated GN (AGN) classification categorizes patients as having focal, mixed, crescentic, or sclerotic GN. Five-year renal survival rates by categories of the AGN classification scheme were 91% for focal, 69% for mixed, and 64% for crescentic (log-rank P<0.0001). Only one patient was classified as sclerotic. Furthermore, the percentage of normal glomeruli found on biopsy estimated renal survival with the same precision as did the AGN classification scheme. Patients classified as crescentic or mixed, however, had worse survival when the percentage of normal glomeruli was <25%. In conclusion, the AGN classification for renal biopsy specimens is a practical and informative scheme with which to categorize patients with ANCA-associated vasculitis, but adding the percentage of normal glomeruli to the system seems to improve its predictive value.
The Problem of Rooting Rapid Radiations
Authors: Liat Shavit, David Penny, Michael D. Hendy, Barbara R. Holland
Journal: Molecular Biology and Evolution (2007)

There are many examples of groups (such as birds, bees, mammals, multicellular animals, and flowering plants) that have undergone a rapid radiation. In such cases, where there is a combination of short internal and long external branches, correctly estimating and rooting phylogenetic trees is known to be a difficult problem. In this simulation study, we tested the performances of different phylogenetic methods at estimating a tree that models a rapid radiation. We found that maximum likelihood, corrected and uncorrected neighbor-joining, and corrected and uncorrected parsimony, all suffer from biases toward specific tree topologies. In addition, we found that using a single-taxon outgroup to root a tree frequently disrupts an otherwise correct ingroup phylogeny. Moreover, for uncorrected parsimony, we found cases where several individual trees (in which the outgroup was placed incorrectly) were selected more frequently than the correct tree. Even for parameter settings where the correct tree was selected most frequently when using extremely long sequences, for sequences of up to 60,000 nucleotides the incorrectly rooted trees were each selected more frequently than the correct tree. For all the cases tested here, tree estimation using a two taxon outgroup was more accurate than when using a single-taxon outgroup. However, the ingroup was most accurately recovered when no outgroup was used.
Beneficial effects of weight loss associated with moderate calorie/carbohydrate restriction, and increased proportional intake of protein and unsaturated fat on serum urate and lipoprotein levels in gout: a pilot study
Authors: P H Dessein
Journal: Annals of the Rheumatic Diseases (2000)

<h3>OBJECTIVES</h3> Insulin resistance (IR) has been increasingly implicated in the pathogenesis of gout. The lipoprotein abnormalities described in hyperuricaemic subjects are similar to those associated with IR, and insulin influences renal urate excretion. In this study it was investigated whether dietary measures, reported to be beneficial in IR, have serum uric acid (SU) and lipid lowering effects in gout. <h3>METHODS</h3> Thirteen non-diabetic men (median age 50, range 38–62) were enrolled. Each patient had had at least two gouty attacks during the four months before enrolment. Dietary recommendations consisted of calorie restriction to 6690 kJ (1600 kcal) a day with 40% derived from carbohydrate, 30% from protein, and 30% from fat; replacement of refined carbohydrates with complex ones and saturated fats with mono- and polyunsaturated ones. At onset and after 16 weeks, fasting blood samples were taken for determination of SU, serum cholesterol (C), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), and triglycerides (TGs). Results were expressed as median (SD). <h3>RESULTS</h3> At onset, the body mass index (BMI) was 30.5 (8.1) kg/m<sup>2</sup>. Dietary measures resulted in weight loss of 7.7 (5.4) kg (p=0.002) and a decrease in the frequency of monthly attacks from 2.1 (0.8) to 0.6 (0.7) (p=0.002). The SU decreased from 0.57 (0.10) to 0.47 (0.09) mmol/l (p=0.001) and normalised in 7 (58%) of the 12 patients with an initially raised level. Serum cholesterol decreased from 6.0 (1.7) to 4.7 (0.9) mmol/l (p=0.002), LDL-C from 3.5 (1.2) to 2.7 (0.8) mmol/l (p=0.004), TGs from 4.7 (4.2) to 1.9 (1.0) mmol/l (p=0.001), and C:HDL-C ratios from 6.7 (1.7) to 5.2 (1.0) (p=0.002). HDL-C levels increased insignificantly. High baseline SU, frequency of attacks, total cholesterol, LDL-C and TG levels, and total C:HDL-C ratios correlated with higher decreases in the respective variables upon dietary intervention (p&lt;0.05). <h3>CONCLUSION</h3> The results suggest that weight reduction associated with a change in proportional macronutrient intake, as recently recommended in IR, is beneficial, reducing the SU levels and dyslipidaemia in gout. Current dietary recommendations for gout may need re-evaluation.
Tobacco and Cancer: The First Clinical Report, 1761
Authors: Donald Eugene Redmond
Journal: New England Journal of Medicine (1970)

Abstract The early participants in the tobacco controversy, beginning in the late sixteenth century, did not associate the use of tobacco with the production of cancers, although they credited it with causing or curing nearly every other known disease. Dr. John Hill, of London, a physician, botanist and prolific writer, first suggested the relation in 1761. In Cautions against the Immoderate Use of Snuff, he reported six cases of "polypusses" related to excessive indulgence in tobacco in the form of snuff. One such "polypus" was described as a swelling in one nostril that was hard, black and adherent on a . . .
Time from HIV-1 seroconversion to AIDS and death before widespread use of highly-active antiretroviral therapy: a collaborative re-analysis
Authors: A Babiker, S Darby, D De Angelis, D Kwart, K Porter, Beral, J Darbyshire, N Day, N Gill, R Coutinho, M Prins, B van Benthem, F Dabis, C Marimoutou, I Ruiz, J Tusell, C Altisent, B Evatt, H Jaffe, O Kirk, C Pedersen, P Rosenberg, J Goedert, R Biggar, M Melbye, R Brettie, A Downs, O Hamouda, G Touloumi, A Karafoulidou, O Katsarou, S Donfield, E Gomperts, M Hilgartner, K Hoots, E Schoenbaum, R Zangerle, J Del Amo, P Pezzotti, G Rezza, S Hutchinson, S Gore, L Kingsley, L Schrager, S Melnick, B Koblin, A Eskild, J Bruun, M Sannes, B Evans, AC Lepri, C Sabin, S Buchbinder, E Vittinghoff, A Moss, D Osmond, W Winkelstein, D Goldberg, F Boufassa, L Meyer, M Egger, P Francioli, M Rickenbach, D Cooper, B Tindall, T Sharkey, J Vizzard, J Kaldor, P Cunningham, P Vanhems, J Learmont, Farewell, O Berglund, J Mosley, E Operskalski, M van den Berg, D Metzger, D Tobin, G Woody, J Rusnak, C Hendrix, R Garner, C Hawkes, P Renzullo, F Garland, D Ewart, P Giangrande, C Lee, A Phillips, R Spooner, J Wilde, M Winter, A Johnson, JI Lorenzo, M Schechter, Collaborative Grp Aids Incubation
Journal: The Lancet (2000)