tbuckley/cabot-search huggingface dataset:
Endothelial Dysfunction in Acute Renal Failure
Authors: FRANK RUSCHITZKA, SIDNEY SHAW, DANIEL GYGI, GEORG NOLL, MATTHIAS BARTON, THOMAS F. LÜSCHER
Journal: Journal of the American Society of Nephrology (1999)

Abstract. The kidney is an important target and source of the potent vasoconstrictor and mitogen endothelin-1 (ET-1). However, its exact role in acute renal failure (ARF) remains to be determined. ARF was induced in male Wistar-Kyoto rats ( n = 7) in a 2-kidney, 2-clip model of 30-min clamping. Twentyfour hours after clamp release, contractions to angiotensin I (AngI) and II, ET-1, and big ET-1 were studied in isolated aortic and renal artery rings. Endothelium-dependent and -independent relaxations were assessed by acetylcholine and sodium nitroprusside. ET-1 clearance, tissue uptake, plasma levels, and vascular and kidney content were investigated. In addition, ET A and Et B receptor mRNA expression was determined. Sham-operated animals served as controls ( n = 7). In ARF, ET-1 plasma levels and tissue content of the renal artery, the aorta, and the kidney markedly increased ( P &lt; 0.01). Plasma half-life of radiolabeled 125 I-ET-1 was markedly prolonged, whereas 125 I-ET-1 tissue uptake decreased in the kidney in ARF. Contractions to AngI and AngII were blunted ( P &lt; 0.05) and those to KC1 were unchanged, whereas vascular responses to big ET-1 and ET-1 were enhanced in the renal artery and also in the aorta in ARF ( P &lt; 0.05 to 0.001). Correspondingly, ET A and Et B receptor mRNA expression significantly increased in both vascular beds. In addition, endothelium-dependent relaxation to acetylcholine was diminished and inversely correlated with vascular ET-1 protein levels in the renal artery ( r = -0.827, P &lt; 0.001) and the aorta ( r = -0.812, P &lt; 0.001). In conclusion, the present study demonstrates that increase of circulating and tissue ET-1 protein levels and ET A and Et B receptor gene expression occurs, which induces endothelial dysfunction and enhanced vasoconstriction in different vascular beds in ARF.
High-Throughput Detection of Actionable Genomic Alterations in Clinical Tumor Samples by Targeted, Massively Parallel Sequencing
Authors: Nikhil Wagle, Michael F. Berger, Matthew J. Davis, Brendan Blumenstiel, Matthew DeFelice, Panisa Pochanard, Matthew Ducar, Paul Van Hummelen, Laura E. MacConaill, William C. Hahn, Matthew Meyerson, Stacey B. Gabriel, Levi A. Garraway
Journal: Cancer Discovery (2011)

Knowledge of "actionable" somatic genomic alterations present in each tumor (e.g., point mutations, small insertions/deletions, and copy-number alterations that direct therapeutic options) should facilitate individualized approaches to cancer treatment. However, clinical implementation of systematic genomic profiling has rarely been achieved beyond limited numbers of oncogene point mutations. To address this challenge, we utilized a targeted, massively parallel sequencing approach to detect tumor genomic alterations in formalin-fixed, paraffin-embedded (FFPE) tumor samples. Nearly 400-fold mean sequence coverage was achieved, and single-nucleotide sequence variants, small insertions/deletions, and chromosomal copynumber alterations were detected simultaneously with high accuracy compared with other methods in clinical use. Putatively actionable genomic alterations, including those that predict sensitivity or resistance to established and experimental therapies, were detected in each tumor sample tested. Thus, targeted deep sequencing of clinical tumor material may enable mutation-driven clinical trials and, ultimately, "personalized" cancer treatment.Despite the rapid proliferation of targeted therapeutic agents, systematic methods to profile clinically relevant tumor genomic alterations remain underdeveloped. We describe a sequencingbased approach to identifying genomic alterations in FFPE tumor samples. These studies affirm the feasibility and clinical utility of targeted sequencing in the oncology arena and provide a foundation for genomics-based stratification of cancer patients.
Recognition of Bacteria by Inflammasomes
Authors: Jakob von Moltke, Janelle S. Ayres, Eric M. Kofoed, Joseph Chavarría-Smith, Russell E. Vance
Journal: Annual Review of Immunology (2012)

Inflammasomes are cytosolic multiprotein complexes that assemble in response to a variety of infectious and noxious insults. Inflammasomes play a critical role in the initiation of innate immune responses, primarily by serving as platforms for the activation of inflammatory caspase proteases. One such caspase, CASPASE-1 (CASP1), initiates innate immune responses by cleaving pro-IL-1β and pro-IL-18, leading to their activation and release. CASP1 and another inflammatory caspase termed CASP11 can also initiate a rapid and inflammatory form of cell death termed pyroptosis. Several distinct inflammasomes have been described, each of which contains a unique sensor protein of the NLR (nucleotide-binding domain, leucine-rich repeat-containing) superfamily or the PYHIN (PYRIN and HIN-200 domain-containing) superfamily. Here we describe the surprisingly diverse mechanisms by which NLR/PYHIN proteins sense bacteria and initiate innate immune responses. We conclude that inflammasomes represent a highly adaptable scaffold ideally suited for detecting and initiating rapid innate responses to diverse and rapidly evolving bacteria.
Glomerular Permeability Is Altered by Loss of P0, a Myelin Protein Expressed in Glomerular Epithelial Cells
Authors: Emmanuelle Plaisier, Béatrice Mougenot, Marie Christine Verpont, Chantal Jouanneau, Joan J. Archelos, Rudolf Martini, Dontscho Kerjaschki, Pierre Ronco
Journal: Journal of the American Society of Nephrology (2005)

The myelin protein 0 (MPZ or P0) is a transmembrane glycoprotein that represents the most abundant myelin component. Mutations in the P0 gene are associated with one form of autosomal dominant demyelinating peripheral neuropathy, Charcot-Marie-Tooth disease type 1B (CMT1B). Because CMT1 may be associated with renal involvement, mostly focal segmental glomerulosclerosis, we hypothesized that P0 could be expressed in the kidney. P0 mRNA was detected by reverse transcriptase–PCR in the human and mouse renal cortex. P0 transcripts were identified by in situ hybridization at different stages of the mouse kidney development, especially in embryonic structures that give rise to the glomerulus. P0 protein was also detected by Western blot in human and rat glomerular extracts and in a human podocyte cell line using a monoclonal anti-P0 antibody. Immunofluorescence studies on human kidney sections showed that the podocytes were intensely labeled. Immunogold electron microscopy disclosed a predominant staining of the membranes of intracellular vesicles in podocytes. P0 was also detected in the podocyte cell membrane, including at the foot processes. P0−/− mice exhibited mild growth retardation and demyelinating neuropathy similar to the one observed in patients with CMT1B. They also presented mild albuminuria, without significant ultrastructural change of the glomerular basement membrane or the podocytes. These results demonstrate that P0, the major myelin protein, is also expressed during nephrogenesis and in mature kidney, mostly in podocytes. They suggest that P0 gene mutations might be involved in renal diseases.
Dendritic Cells Discriminate between Yeasts and Hyphae of the Fungus <i>Candida albicans</i>
Authors: Cristiana Fè d'Ostiani, Giuseppe Del Sero, Angela Bacci, Claudia Montagnoli, Antonio Spreca, Antonella Mencacci, Paola Ricciardi-Castagnoli, Luigina Romani
Journal: The Journal of Experimental Medicine (2000)

The fungus Candida albicans behaves as a commensal as well as a true pathogen of areas highly enriched in dendritic cells, such as skin and mucosal surfaces. The ability of the fungus to reversibly switch between unicellular yeast to filamentous forms is thought to be important for virulence. However, whether it is the yeast or the hyphal form that is responsible for pathogenicity is still a matter of debate. Here we show the interaction, and consequences, of different forms of C. albicans with dendritic cells. Immature myeloid dendritic cells rapidly and efficiently phagocytosed both yeasts and hyphae of the fungus. Phagocytosis occurred through different phagocytic morphologies and receptors, resulting in phagosome formation. However, hyphae escaped the phagosome and were found lying free in the cytoplasm of the cells. In vitro, ingestion of yeasts activated dendritic cells for interleukin (IL)-12 production and priming of T helper type 1 (Th1) cells, whereas ingestion of hyphae inhibited IL-12 and Th1 priming, and induced IL-4 production. In vivo, generation of antifungal protective immunity was induced upon injection of dendritic cells ex vivo pulsed with Candida yeasts but not hyphae. The immunization capacity of yeast-pulsed dendritic cells was lost in the absence of IL-12, whereas that of hypha-pulsed dendritic cells was gained in the absence of IL-4. These results indicate that dendritic cells fulfill the requirement of a cell uniquely capable of sensing the two forms of C. albicans in terms of type of immune responses elicited. By the discriminative production of IL-12 and IL-4 in response to the nonvirulent and virulent forms of the fungus, dendritic cells appear to meet the challenge of Th priming and education in C. albicans saprophytism and infections.
Child Development Following Exposure to Tricyclic Antidepressants or Fluoxetine Throughout Fetal Life: A Prospective, Controlled Study
Authors: Irena Nulman, Joanne Rovet, Donna E. Stewart, Jacob Wolpin, Pia Pace-Asciak, Samar Shuhaiber, Gideon Koren
Journal: American Journal of Psychiatry (2002)

Previous work suggested that first-trimester exposure to tricyclic antidepressants or fluoxetine does not affect adversely child IQ and language development. However, many women need antidepressants throughout pregnancy to avoid morbidity and suicide attempts. Little is known about the fetal safety of tricyclic antidepressants and fluoxetine when taken throughout pregnancy. The goal of this study was to assess the effects of tricyclic antidepressants and fluoxetine used throughout gestation on child IQ, language, and behavior.In a prospective study, mother-child pairs exposed throughout gestation to tricyclic antidepressants (N=46) or fluoxetine (N=40) and an unexposed, not depressed comparison group (N=36) were blindly assessed. The three groups were compared in terms of the children's IQ, language, behavior, and temperament between ages 15 and 71 months. The authors adjusted for independent variables such as duration and severity of maternal depression, duration of pharmacological treatment, number of depression episodes after delivery, maternal IQ, socioeconomic status, cigarette smoking, and alcohol use.Neither tricyclic antidepressants nor fluoxetine adversely affected the child's global IQ, language development, or behavior. IQ was significantly and negatively associated with duration of depression, whereas language was negatively associated with number of depression episodes after delivery.Exposure to tricyclic antidepressants or fluoxetine throughout gestation does not appear to adversely affect cognition, language development, or the temperament of preschool and early-school children. In contrast, mothers' depression is associated with less cognitive and language achievement by their children. When needed, adequate antidepressant therapy should be instituted and maintained during pregnancy and postpartum.
Phase III Trial of Carboplatin and Paclitaxel Compared With Cisplatin and Paclitaxel in Patients With Optimally Resected Stage III Ovarian Cancer: A Gynecologic Oncology Group Study
Authors: Robert F. Ozols, Brian N. Bundy, Benjamin E. Greer, Jeffrey M. Fowler, Daniel Clarke-Pearson, Robert A. Burger, Robert S. Mannel, Koen DeGeest, Ellen M. Hartenbach, Rebecca Baergen
Journal: Journal of Clinical Oncology (2003)

In randomized trials the combination of cisplatin and paclitaxel was superior to cisplatin and cyclophosphamide in advanced-stage epithelial ovarian cancer. Although in nonrandomized trials, carboplatin and paclitaxel was a less toxic and highly active combination regimen, there remained concern regarding its efficacy in patients with small-volume, resected, stage III disease. Thus, we conducted a noninferiority trial of cisplatin and paclitaxel versus carboplatin and paclitaxel in this population.
The role of vitamin D supplementation in the risk of developing pneumonia: three independent case–control studies
Authors: Hilde H F Remmelts, Simone M C Spoorenberg, Jan Jelrik Oosterheert, Willem Jan W Bos, Mark C H de Groot, Ewoudt M W van de Garde
Journal: Thorax (2013)

<h3>Background</h3> Vitamin D plays a role in host defence against infection. Vitamin D deficiency has been associated with an increased risk of respiratory tract infections in children and adults. This study aimed to examine whether vitamin D supplementation is associated with a lower pneumonia risk in adults. <h3>Methods</h3> Three independent case–control studies were performed including a total of 33 726 cases with pneumonia in different settings with respect to hospitalisation status and a total of 105 243 controls. Cases and controls were matched by year of birth, gender and index date. The major outcome measure was exposure to vitamin D supplementation at the time of pneumonia diagnosis. Conditional logistic regression was used to compute ORs for the association between vitamin D supplementation and occurrence of pneumonia. <h3>Results</h3> Vitamin D supplementation was not associated with a lower risk of pneumonia. In studies 1 and 2, adjustment for confounding resulted in non-significant ORs of 1.814 (95% CI 0.865 to 3.803) and 1.007 (95% CI 0.888 to 1.142), respectively. In study 3, after adjustment for confounding, the risk of pneumonia remained significantly higher among vitamin D users (OR 1.496, 95% CI 1.208 to 1.853). Additional analyses showed significant modification of the association through co-use of corticosteroids and drugs that affect bone mineralisation. For patients using these drugs, ORs below one were found combined with higher ORs for patients not using these drugs. <h3>Conclusions</h3> This study showed no preventive association between vitamin D supplementation and the risk of pneumonia in adults.
A New Semiempirical Codon Substitution Model Based on Principal Component Analysis of Mammalian Sequences
Authors: S. Zoller, A. Schneider
Journal: Molecular Biology and Evolution (2011)

Codon substitution models have traditionally been parametric Markov models, but recently, empirical and semiempirical models also have been proposed. Parametric codon models are typically based on 61×61 rate matrices that are derived from a small number of parameters. These parameters are rooted in experience and theoretical considerations and generally show good performance but are still relatively arbitrary. We have previously used principal component analysis (PCA) on data obtained from mammalian sequence alignments to empirically identify the most relevant parameters for codon substitution models, thereby confirming some commonly used parameters but also suggesting new ones. Here, we present a new semiempirical codon substitution model that is directly based on those PCA results. The substitution rate matrix is constructed from linear combinations of the first few (the most important) principal components with the coefficients being free model parameters. Thus, the model is not only based on empirical rates but also uses the empirically determined most relevant parameters for a codon model to adjust to the particularities of individual data sets. In comparisons against established parametric and semiempirical models, the new model consistently achieves the highest likelihood values when applied to sequences of vertebrates, which include the taxonomic class where the model was trained on.
Noncytotoxic suramin as a chemosensitizer in patients with advanced non-small-cell lung cancer: a phase II study
Authors: M.A. Villalona-Calero, G.A. Otterson, M.G. Wientjes, F. Weber, T. Bekaii-Saab, D. Young, A.J. Murgo, R. Jensen, T.-K. Yeh, Y. Wei, Y. Zhang, C. Eng, M. Grever, J. L.-S. Au
Journal: Annals of Oncology (2008)
Tumor Necrosis Factor and Lymphotoxin Alfa Genetic Polymorphisms and Outcome in Pediatric Patients With Non-Hodgkin’s Lymphoma: Results From Berlin-Frankfurt-Münster Trial NHL-BFM 95
Authors: Kathrin Seidemann, Martin Zimmermann, Marion Book, Ulrike Meyer, Birgit Burkhardt, Karl Welte, Alfred Reiter, Martin Stanulla
Journal: Journal of Clinical Oncology (2005)

Purpose To analyze the association of genetic variation within the tumor necrosis factor (TNF −308 [G→A]) and lymphotoxin alfa (LT-a +252 [A→G]) genes with outcome in non-Hodgkin's lymphoma of childhood and adolescence. Patients and Methods Genotyping of the TNF −308 (G→A) and LT-a +252 (A→G) polymorphisms in patients (n = 488) enrolled onto the German-Austrian-Swiss multicenter trial NHL-BFM 95 from April 1996 to January 2000 was performed by polymerase chain reaction with subsequent restriction fragment length polymorphism analysis on DNA from tumor-free specimen. Results In patients with Burkitt's lymphoma (BL) and B-cell acute lymphoblastic leukemia (B-ALL; n = 219, 211 eligible patients), patients carrying at least two variant alleles (high-producer haplotypes) had an increased risk of events: probability of event-free survival (pEFS) at 3 years was 81% (SE = 5%), compared with 91% (SE = 2%) in low-producer haplotypes (P = .018). In BL/B-ALL with high tumor load (lactate dehydrogenase [LDH] ≥ 500 U/L; n = 104), pEFS was 69% (SE = 8%) in high-producer versus 85% (SE = 4%) in low-producer haplotypes (P = .05). In multivariate analysis including risk factors for events (LDH ≥ 500 U/L, CNS involvement, methotrexate infusion regimen), TNF −308/LT-α +252 haplotype kept prognostic relevance: patients with high-producer haplotypes had a 2.34-fold increase in risk of events (P = .048). The TNF −308 (G→A) and LT-α +252 (A→G) polymorphisms were not associated with pEFS in lymphoblastic lymphoma (n = 101), anaplastic large-cell lymphoma (n = 67), or diffuse large B-cell lymphoma (n = 65), nor with therapy-related toxicity. Conclusion The TNF −308 (G→A) and LT-a +252 (A→G) polymorphisms were negative prognostic factors in pediatric BL/B-ALL. Among patients with serum LDH ≥ 500 U/L, haplotype analysis further determined patients at risk for events.
Obstructive sleep apnoea and hypertension: the ESADA study
Authors: R. Doug McEvoy
Journal: European Respiratory Journal (2014)

Population-based epidemiological studies strongly implicate obstructive sleep apnoea (OSA) as an independent risk factor for cardiovascular morbidity and mortality [1–7]. Final proof of a causal relationship between OSA and premature cardiovascular disease, and the true strength of that relationship, will depend on the results of large, well-designed randomised controlled trials of OSA treatment, several of which are ongoing [8]. In the meantime there is considerable interest in the various mechanistic pathways whereby OSA might lead to increased cardiovascular disease/events. A clearer understanding of these pathways will probably have practical therapeutic implications for reducing cardiovascular risk in OSA populations in the future. Devices such as continuous positive airway pressure (CPAP) and mandibular repositioning devices are effective treatments for OSA, but the reality is that they are found to be unacceptable or are used infrequently by many patients with OSA, particularly those who are minimally symptomatic. Other treatments directed specifically at mitigating cardiovascular risk in such patients may be needed and this will require a clear understanding of the dominant mechanisms for increased cardiovascular disease and/or cardiovascular events in OSA.

Systemic hypertension is the most important risk factor for cardiovascular disease. There is now strong evidence from randomised controlled trials of CPAP treatment of OSA that sleep apnoea is responsible for an increase in nocturnal and diurnal blood pressure, although to what extent OSA causes clinical hypertension is less certain. While early cross sectional data from community studies found a relatively robust independent association between OSA and prevalent hypertension [9–11], the results of longitudinal studies examining the role of OSA in the development of new hypertension have been less convincing. Some studies have shown an independent association between OSA and incident hypertension [12, 13], while others have not [ …
Ethnic Differences in Mortality, End-Stage Complications, and Quality of Care Among Diabetic Patients
Authors: Loes C. Lanting, Inez M.A. Joung, Johan P. Mackenbach, Steven W.J. Lamberts, Aart H. Bootsma
Journal: Diabetes Care (2005)

OBJECTIVE—To determine the influence of ethnic differences in diabetes care on inequalities in mortality and prevalence of end-stage complications among diabetic patients. The following questions were examined: 1) Are there ethnic differences among diabetic patients in mortality and end-stage complications and 2) are there ethnic differences among diabetic patients in quality of care? RESEARCH DESIGN AND METHODS—A review of the literature on ethnic differences in the prevalence of complications and mortality among diabetic patients and in the quality of diabetes care was performed by systematically searching articles on Medline published from 1987 through October 2004. RESULTS—A total of 51 studies were included, mainly conducted in the U.S. and the U.K. In general, after adjusting for confounders, diabetic patients from ethnic minorities had higher mortality rates and higher risk of diabetes complications. After additional adjustment for risk factors such as smoking, socioeconomic status, income, years of education, and BMI, in most instances ethnic differences disappear. Nevertheless, blacks and Hispanics in the U.S. and Asians in the U.K. have an increased risk of end-stage renal disease, and blacks and Hispanics in the U.S. have an increased risk of retinopathy. Intermediate outcomes of care were worse in blacks, and they were inclined to be worse in Hispanics. Likewise, ethnic differences in quality of care in the U.S. exist: process of care was worse in blacks. CONCLUSIONS—Given the fact that there are ethnic differences in diabetes care and that ethnic differences in some diabetes complications persist after adjustment for risk factors other than diabetes care, it seems the case that ethnic differences in diabetes care contribute to the more adverse disease outcomes of diabetic patients from some ethnic minority groups. Although no generalizations can be made for all ethnic groups in all regions for all kinds of complications, the results do implicate the importance of quality of care in striving for equal health outcomes among ethnic minorities.