tbuckley/cabot-search huggingface dataset:
Mutational Analysis of Thirty-two Double-Strand DNA Break Repair Genes in Breast and Pancreatic Cancers
Authors: Xianshu Wang, Csilla Szabo, Chiping Qian, Peter G. Amadio, Stephen N. Thibodeau, James R. Cerhan, Gloria M. Petersen, Wanguo Liu, Fergus J. Couch
Journal: Cancer Research (2008)

Inactivating mutations in several genes that encode components of the DNA repair machinery have been associated with an increased risk of breast cancer. To assess whether alterations in other DNA repair genes contribute to breast cancer and to further determine the relevance of these genes to pancreatic cancer, we performed mutational analysis of 32 DNA double-strand break repair genes in genomic DNA from 38 breast tumors, 48 pancreatic tumors, and 10 non-BRCA1/BRCA2 hereditary breast cancer patients. A total of 494 coding exons were screened by denatured high-performance liquid chromatography and direct DNA sequencing. Two inactivating mutations were identified in breast tumor samples, a germline single-nucleotide deletion in POLQ (c.3605delT) and a somatic nonsense change in PRKDC (c.2408C>A, p.Ser803X). Two germline-inactivating mutations in RAD50 (c.1875C>G, p.Tyr625X and IVS14+1G>A) were also detected in separate pancreatic tumor samples. In addition, 35 novel nonsynonymous amino acid substitutions, resulting from two in-frame deletions and 33 single nucleotide alterations, were identified. Seven of these were predicted to influence protein function. A separate analysis of the CLSPN c.3839C>T (rs35490896) variant that was observed more frequently in breast tumors than in pancreatic tumors or normal controls failed to detect a significant association with breast cancer risk in a Mayo Clinic breast cancer case-control study. In conclusion, this screen of DNA repair genes implicates PRKDC and POLQ as candidate tumor suppressor genes involved in breast cancer and suggests that inactivating mutations in RAD50 predispose to pancreatic cancer as well as breast cancer.
Activation of Transient Receptor Potential Vanilloid Type-1 Channel Prevents Adipogenesis and Obesity
Authors: Li Li Zhang, Dao Yan Liu, Li Qun Ma, Zhi Dan Luo, Ting Bing Cao, Jian Zhong, Zhen Cheng Yan, Li Juan Wang, Zhi Gang Zhao, Shan Jun Zhu, Mark Schrader, Florian Thilo, Zhi Ming Zhu, Martin Tepel
Journal: Circulation Research (2007)

We tested the hypothesis that activation of transient receptor potential vanilloid type-1 (TRPV1) by capsaicin prevents adipogenesis. TRPV1 channels in 3T3-L1-preadipocytes and visceral adipose tissue from mice and humans were detected by immunoblotting and quantitative real-time RT-PCR. The effect of TRPV1 on cytosolic calcium was determined fluorometrically in 3T3-L1-preadipocytes and in human visceral fat tissue. Adipogenesis in stimulated 3T3-L1-preadipocytes was determined by oil red O-staining of intracellular lipid droplets, triglyceride levels, expression of peroxisome proliferator-activated receptor-γ, and expression of fatty acid synthase. Long-term feeding experiments were undertaken in wild-type mice and TRPV1 knockout mice. We detected TRPV1 channels in 3T3-L1-preadipocytes and visceral adipose tissue from mice and humans. In vitro, the TRPV1 agonist capsaicin dose-dependently induced calcium influx and prevented the adipogenesis in stimulated 3T3-L1-preadipocytes. RNA interference knockdown of TRPV1 in 3T3-L1-preadipocytes attenuated capsaicin-induced calcium influx, and adipogenesis in stimulated 3T3-L1-preadipocytes was no longer prevented. During regular adipogenesis TRPV1 channels were downregulated which was accompanied by a significant and time-dependent reduction of calcium influx. Compared with lean counterparts in visceral adipose tissue from obese db/db and ob/ob mice, and from obese human male subjects we observed a reduced TRVP1 expression. The reduced TRPV1 expression in visceral adipose tissue from obese humans was accompanied by reduced capsaicin-induced calcium influx. The oral administration of capsaicin for 120 days prevented obesity in male wild type mice but not in TRPV1 knockout mice assigned to high fat diet. We conclude that the activation of TRPV1 channels by capsaicin prevented adipogenesis and obesity.
Does a positive Heaf test reaction in Asian schoolchildren predict later breakdown of tuberculosis?
Authors: J B Cookson, A G Cookson
Journal: Thorax (1992)

Some authorities advise giving prophylactic antituberculosis treatment to those with a grade 3 or 4 reaction to Heaf tests performed as part of the schools' BCG programme. This is not done in Leicestershire, which because of its large Asian population would require considerable resources to do so. A calculation of the "breakdown" rate, and thus the potential value of chemoprophylaxis, in these children would therefore be valuable.Lists of names of Asian children who had a grade 3 or 4 Heaf test reaction in 1982 and 1983 were compared with lists of notifications for the five years 1983 to 1987. Those who were on both lists were considered to have tuberculosis that had "broken down."Of the 760 children with positive Heaf test reactions, only four were on the subsequent notification lists. The chest radiograph obtained because of the Heaf test result showed evidence of active tuberculosis in only three of these. Only one child had infection that "broke down" later.The benefit of chemoprophylaxis seems likely to be limited in these Asian children, most of whom had received BCG early in life.
Mycobacterium tuberculosis DNA in tissues affected by sarcoidosis
Authors: M L Wilsher, R E Menzies, M C Croxson
Journal: Thorax (1998)

<h3>BACKGROUND</h3> Although some studies have reported the presence of <i>Mycobacterium tuberculosis</i> (MTb) DNA in tissues affected by sarcoidosis, the data are conflicting. The aim of this study was to collect prospectively tissue from patients with sarcoidosis in whom tuberculosis had been excluded, and to use polymerase chain reaction (PCR) to search for DNA sequences specific for MTb. <h3>METHODS</h3> Fresh tissue samples (node or lung biopsy) taken from 23 patients with newly diagnosed sarcoidosis, 10 with other respiratory disease, and four patients with culture positive tuberculosis were analysed using PCR to amplify a 123 bp fragment of IS6110, the insertion element present in MTb, and nested PCR to further amplify an 85 bp sequence within the 123 bp product. DNA was also extracted from formalin fixed tissue from eight additional patients with sarcoidosis. <h3>RESULTS</h3> MTb DNA was not detected in any of the tissue samples from patients with sarcoidosis or other respiratory disease but was found in all four patients with tuberculosis. <h3>CONCLUSIONS</h3> This study has shown the absence of MTb DNA in lymph node and lung biopsy samples from patients with sarcoidosis. MTb is therefore unlikely to be a factor in the pathogenesis of this disease.
Interventions in children with Prader-Willi syndrome and their effect on sleep related breathing disorders, a retrospective review
Authors: Oneza Ahmareen, Rioghnach Sinead O'Neill, David F. Burke, Peter Greally
Journal: European Respiratory Journal (2013)

Introduction: Limited evidence exists regarding effect of interventions on sleep related breathing disorders (SRBD) in children with Prader-willi syndrome (PWS).

Aim: Evaluate results of polysomnograms (PSG) in children with PWS and assess impact of intervention adenotonsillectomy (AT), continuous positive airways pressure (CPAP) and/or growth hormone (GH) therapy on SRBD.

Methods: Retrospective chart review of all PWS patients. Those who had initial PSG as part of assessment for suitability for GH and consequently had repeat PSG between April 2004 and July 2012 were included in study.

Results: Sixteen patients met the inclusion criteria . Five had GH, 2 had CPAP and GH, 1 had AT and GH, 6 had AT and 2 had no intervention. Median AHI was 6.4/hour for the initial PSG, this decreased to 3.15/hour in subsequent PSG. Median desaturation index for the group improved from 11.5/hour to 8/hour. Median Sp02 nadir increased from 79% to 85%.

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Conclusion: Data shows that PSG results with each intervention are highly variable from patient to patient with no pattern indentified. Given the sporadic nature of outcomes, we conclude that each patient be evaluated on an individual basis.
Cortical spreading depression activates and upregulates MMP-9
Authors: Yasemin Gursoy-Ozdemir, Jianhua Qiu, Norihiro Matsuoka, Hayrunnisa Bolay, Daniela Bermpohl, Hongwei Jin, Xiaoying Wang, Gary A. Rosenberg, Eng H. Lo, Michael A. Moskowitz
Journal: Journal of Clinical Investigation (2004)

Cortical spreading depression (CSD) is a propagating wave of neuronal and glial depolarization and has been implicated in disorders of neurovascular regulation such as stroke, head trauma, and migraine. In this study, we found that CSD alters blood-brain barrier (BBB) permeability by activating brain MMPs. Beginning at 3–6 hours, MMP-9 levels increased within cortex ipsilateral to the CSD, reaching a maximum at 24 hours and persisting for at least 48 hours. Gelatinolytic activity was detected earliest within the matrix of cortical blood vessels and later within neurons and pia arachnoid (≥3 hours), particularly within piriform cortex; this activity was suppressed by injection of the metalloprotease inhibitor GM6001 or in vitro by the addition of a zinc chelator (1,10-phenanthroline). At 3–24 hours, immunoreactive laminin, endothelial barrier antigen, and zona occludens-1 diminished in the ipsilateral cortex, suggesting that CSD altered proteins critical to the integrity of the BBB. At 3 hours after CSD, plasma protein leakage and brain edema developed contemporaneously. Albumin leakage was suppressed by the administration of GM6001. Protein leakage was not detected in MMP-9–null mice, implicating the MMP-9 isoform in barrier disruption. We conclude that intense neuronal and glial depolarization initiates a cascade that disrupts the BBB via an MMP-9–dependent mechanism.
Concentration of amoxycillin and clavulanate in lung compartments in adults without pulmonary infection.
Authors: P J Cook, J M Andrews, J Woodcock, R Wise, D Honeybourne
Journal: Thorax (1994)

The efficacy of an antibiotic is usually predicted from serum levels and MIC90 values for likely pathogens, but in the lung tissue concentrations may be more informative. This study compares concentrations of amoxycillin and clavulanate in serum, epithelial lining fluid (ELF), alveolar macrophages, and bronchial mucosa in 15 adults.Amoxycillin 500 mg and clavulanic acid 250 mg were given 1-2 hours before diagnostic bronchoscopy for haemoptysis or radiological abnormality. Mucosal biopsy samples were taken from macroscopically normal sites, alveolar macrophages harvested by lavage, and ELF volume derived from urea concentrations in bronchial lavage fluid and blood. Amoxycillin was assayed by inhibition of growth of Micrococcus lutea, and clavulanate (in serum, ELF, and bronchial mucosa) by inhibition of growth of Klebsiella pneumoniae; in macrophages clavulanate was measured by high performance liquid chromatography.The median concentrations in serum were 6.90 mg/l for amoxycillin and 5.25 mg/l for clavulanate. The median bronchial mucosal concentration of amoxycillin was 2.99 mg/l and of clavulanate was 1.65 mg/l; the median concentrations in ELF were 0.89 and 0.96 mg/l, and in macrophages 0 and 0.76 mg/l, respectively. In macrophages amoxycillin levels were undetectable in 10 of 14 subjects (71%); by contrast, only 6 of 14 subjects (43%) had no detectable clavulanate.Clavulanate levels exceeded quoted MIC90 values (around 0.25 mg/l) for Legionella pneumophila both in ELF and in macrophages. Amoxycillin-clavulanate may therefore have a clinical role in infections with Legionella pneumophila.
Prevention and Treatment of Papillomavirus-Related Cancers Through Immunization
Authors: Ian H. Frazer, Graham R. Leggatt, Stephen R. Mattarollo
Journal: Annual Review of Immunology (2011)

Cervical and other anogenital cancers are initiated by infection with one of a small group of human papillomaviruses (HPV). Virus-like particle-based vaccines have recently been developed to prevent infection with two cancer-associated HPV genotypes (HPV16, HPV18) and have been ∼95% effective at preventing HPV-associated disease caused by these genotypes in virus-naive subjects. Although immunization induces virus-neutralizing antibody sufficient to prevent infection, persistence of antibody as measured by current assays does not appear necessary to maintain protection over time. Investigators have not identified a reliable surrogate immunological marker of protection against disease following immunization. The prophylactic vaccines are not therapeutic for existing infection. Trials of HPV-specific immunotherapy have shown some efficacy for existing disease, although animal modeling suggests that a combination of immunization and local enhancement of innate immunity may be necessary for optimal therapeutic outcome. HPV prophylactic vaccines are the first vaccines designed to prevent a human cancer and are the practical outcome of a global collaborative effort between basic and applied scientists, clinicians, and industry.
Sensitivity of Human Carcinoma Cell Lines to Lysis by Blood Natural Killer Cells Correlating With Surface Expression of Carcinoembryonic Antigen&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: D A Clark, P B McCulloch, S K Liao, P B Dent, A Fuks
Journal: JNCI Journal of the National Cancer Institute (1984)

The HCT-8R clone of the HCT-8 human colon tumor line, which expresses increased quantities of carcinoembryonic antigen (CEA) on its surface, was discovered to have an enhanced susceptibility to lysis by natural killer (NK) cells in human peripheral blood. This increase in susceptibility to lysis by peripheral blood mononuclear cells was not explained by stimulation of interferon release by HCT-8R cells but rather was found to be attributable to an increased susceptibility of HCT-8R cells to lysis by those NK cells that bind to sheep erythrocytes (E-RFC). Cold target competition experiments and single-cell assay for cytotoxic cells suggested that the presence of surface CEA did not increase lysis of HCT-8R by facilitating "recognition" by E-RFC-type cytotoxic cells but by rendering HCT-8R cells more susceptible to the lytic mechanism of NK cells. The magnitude of expression of surface CEA by a variety of human carcinoma cell lines with a few exceptions and subclones of HCT-8 also correlated with increased susceptibility to lysis by blood mononuclear cells. The possible clinical significance of these findings was discussed.
Time-Series Studies of Particulate Matter
Authors: Michelle L. Bell, Jonathan M. Samet, Francesca Dominici
Journal: Annual Review of Public Health (2004)

Studies of air pollution and human health have evolved from descriptive studies of the early phenomena of large increases in adverse health effects following extreme air pollution episodes to time-series analyses based on the use of sophisticated regression models. In fact, advanced statistical methods are necessary to address the challenges inherent in the detection of a relatively small pollution risk in the presence of potential confounders. This paper reviews the history, methods, and findings of the time-series studies estimating health risks associated with short-term exposure to particulate matter (PM), though much of the discussion is applicable to epidemiological studies of air pollution in general. We review the critical role of epidemiological studies in setting regulatory standards and the history of PM epidemiology and time-series analysis. We also summarize recent time-series results and conclude with a discussion of current and future directions of time-series analysis of particulates, including research on mortality displacement and the resolution of results from cohort and time-series studies.
Pharmacogenetics of Capecitabine in Advanced Breast Cancer Patients
Authors: Rémy Largillier, Marie-Christine Etienne-Grimaldi, Jean-Louis Formento, Joseph Ciccolini, Jean-François Nebbia, Aurélie Ginot, Mireille Francoual, Nicole Renée, Jean-Marc Ferrero, Cyril Foa, Moïse Namer, Bruno Lacarelle, Gérard Milano
Journal: Clinical Cancer Research (2006)

Abstract Purpose: Germinal gene polymorphisms can explain a part of the interpatient pharmacodynamic variability of anticancer drugs, particularly fluoropyrimidines. Genes for which polymorphisms may potentially influence pharmacodynamics of fluoropyrimidines, including capecitabine, are thymidylate synthase (TS), methylenetetrahydrofolate reductase (MTHFR), and dihydropyrimidine dehydrogenase (DPD). Experimental design: The aim of this prospective pilot study was to analyze the effect of TS, MTHFR, and DPD gene polymorphisms on toxicity and efficacy in advanced breast cancer patients receiving capecitabine as monotherapy. Germinal polymorphisms of TS (6 bp deletion in the 3′ region and 28 bp repeats, including G&amp;gt;C mutation in the 5′ region), MTHFR (677C&amp;gt;T and 1298A&amp;gt;C), and DPD (IVS14 + 1G&amp;gt;A) were determined in 105 consecutive patients. Results: A trend toward a higher global toxicity grade 3 and 4 was observed in patients homozygous for the TS 3RG allele compared with patients heterozygous for the 3RG allele or patients not carrying the 3RG allele (50% versus 19% versus 13% respectively, P = 0.064). The sole patient bearing the DPD IVS14 + 1G&amp;gt;A mutation (heterozygous) deceased from hematologic toxicity. The median response duration was 5.8 months (95% confidence interval, 4.3-7.2). Duration of response was significantly shortened in patients homozygous for the 3RG allele compared with others (P = 0.037). Conclusions: The present data suggest that 3RG3RG breast cancer patients are not good candidates for capecitabine therapy. In addition, attention should be paid to DPD deficiency in breast cancer patients receiving capecitabine. These preliminary data require further confirmation on a larger number of patients.
Vitamin E in the Prevention of Prostate Cancer: Where Are We Today?
Authors: I-Min Lee, J. Michael Gaziano, Julie E. Buring
Journal: JNCI Journal of the National Cancer Institute (2006)

In their landmark study in 1981, Doll and Peto estimated that 35% of cancer deaths in the United States could be attributed to dietary factors ( 1 ) . One of the mechanisms they proposed for this association was “ deactivation, or prevention of formation, of short-lived intracellular species ” by antioxidants in the diet. At that time, the National Cancer Institute had also begun its focus on cancer prevention ( 2 ) and had funded large-scale randomized clinical trials to test antioxidant vitamins and minerals in cancer prevention ( 3 – 11 ) . Among the antioxidant vitamins of great interest, both among scientists and the general public, was vitamin E. The results of these vitamin E trials ( 3 – 5 , 9 – 11 ) , however, have generally been disappointing because they have indicated that intake of this vitamin provides little protection against cancer overall in well-nourished populations. To date, few completed trials have provided data on vitamin E intake and prostate cancer risk. The Alpha-Tocopherol, BetaCarotene Prevention (ATBC) Study reported that among male smokers, those assigned to receive 50 mg of α -tocopherol daily had a statistically signifi cant 32% lower prostate cancer incidence (specifi cally observed only for clinical but not latent disease) and a statistically signifi cant 41% lower prostate cancer mortality than those assigned to receive placebo ( 11 ) . However, the Heart Outcomes Prevention Evaluation — The Ongoing Outcomes (HOPE-TOO) trial, which enrolled men with or at high risk for cardiovascular disease, observed no effect of supplemental vitamin E at 400 IU/day on prostate cancer incidence ( 10 ) . A study ( 12 ) in this issue of the Journal provides additional information on the possible role of antioxidant intake, including vitamin E intake, in the reduction of prostate cancer risk. In a prospective analysis of data from 29 361 men in the screening arm of the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, Kirsh et al. ( 12 ) report no overall associations between intakes of dietary or supplemental vitamin E and prostate cancer risk, a fi nding that is consistent with data from the HOPE-TOO trial ( 10 ) and several other observational studies ( 13 – 14 ) . However, Kirsh et al. ( 12 ) reported an intriguing subgroup fi nding: Among men who were current smokers or who had quit smoking within the past 10 years, those with supplemental
Progesterone as a mediator of gonadotrophin action in the corpus luteum: beyond steroidogenesis
Authors: R. L. Stouffer
Journal: Human Reproduction Update (2003)

Studies using newer, potent GnRH antagonists and pure gonadotrophins have clarified the importance of: (i) the strength-duration of the midcycle surge of pituitary gonadotrophins (LH, FSH) in follicle rupture and conversion to the corpus luteum; (ii) the continued requirement for pituitary LH throughout development and the functional lifespan of the primate corpus luteum in the menstrual cycle; and (iii) the exponential secretion of chorionic gonadotrophin (CG) by the developing placenta to extend the functional lifespan of the primate corpus luteum in early pregnancy. Although studies continue to increase current understanding of the cellular and molecular actions of LH/CG to stimulate luteal steroidogenesis, knowledge of the processes whereby these gonadotrophins promote the development and maintenance of the functional corpus luteum remains limited. This review summarizes evidence that the primate ovulatory follicle and corpus luteum is a target for the primary steroid produced by luteinizing/luteal tissue (i.e. progesterone). With evidence for dynamic expression of genomic progesterone receptors (PRA/B), and possibly other progesterone-receptor systems, recent studies addressed the hypothesis that progesterone is a critical 'local luteotrophin' that promotes luteal development and sustains luteal structure-function during the menstrual cycle and early pregnancy. Specific progesterone actions to regulate tissue remodelling (via protease expression), health (anti-apoptotic effects) and sensitivity to other local factors (e.g. via estrogen receptor expression) are discussed. The collective data suggest that there are gonadotrophin-stimulated, progesterone-dependent processes that promote luteotrophic and suppress luteolytic pathways in the primate corpus luteum. However, further studies are needed to verify their role in normal ovarian function and relevance to possible ovarian defects in natural and assisted reproduction technique-related cycles.
Myocardial lipid peroxidation in rats after chronic alcohol ingestion and the effects of different antioxidants
Authors: I. EDES, A. TOSZEGI, M. CSANADY, B. BOZOKY
Journal: Cardiovascular Research (1986)

Journal Article Myocardial lipid peroxidation in rats after chronic alcohol ingestion and the effects of different antioxidants Get access ISTVÁN ÉDES, ISTVÁN ÉDES **From the Second Department of Medicine, Division of Cardiology, Debrecen, Hungary‡From the BIOGAL Pharmaceutical Works, Medical Division, Debrecen, Hungary Search for other works by this author on: Oxford Academic PubMed Google Scholar ANNA TÓSZEGI, ANNA TÓSZEGI †From the Department of Pathology, University Medical School, Szeged, Debrecen, Hungary Search for other works by this author on: Oxford Academic PubMed Google Scholar MIKLÓS CSANADY, MIKLÓS CSANADY **From the Second Department of Medicine, Division of Cardiology, Debrecen, Hungary Search for other works by this author on: Oxford Academic PubMed Google Scholar BÉLA BOZÓKY BÉLA BOZÓKY †From the Department of Pathology, University Medical School, Szeged, Debrecen, Hungary Search for other works by this author on: Oxford Academic PubMed Google Scholar Cardiovascular Research, Volume 20, Issue 7, July 1986, Pages 542–548, https://doi.org/10.1093/cvr/20.7.542 Published: 01 July 1986