tbuckley/cabot-search huggingface dataset:
Introduction: Utilization of higher plant systems as monitors of environmental mutagens
Authors: Frederick J. De Serres
Journal: Environmental Health Perspectives (1978)

Research over the past 10 years has clearly demonstrated the presence of mutagens among the numerous man-made and naturally occurring chemicals in our environment. These mutagens occur in all classes of chemicals, including foods, drugs, cosmetics, pesticides, household and industrial chemicals as well as in pollutants of both air and water. More recently, a high correlation has been found between carcinogenic and mutagenic activity; at least 90–95% of chemical carcinogens are mutagens. There is a widespread expectation that the discovery of mutagenic activity in chemical screening programs may alert us not only to mutagenic potential in man, but carcinogenic potential as well. The types of genetic damage which can be produced are numerous and the specificity of chemical mutagens makes it possible for one type of effect to be produced predominantly or exclusively. Thus, any screening program must consist of a battery of tests capable of detecting nondisjunction, chromosome aberrations, gene mutations (point mutations as well as interstitial deletion), in addition to more subtle effects of DNA repair. In addition, since innocuous chemicals can be converted by mammalian metabolism to potent mutagens and carcinogens, these metabolites must be evaluated as well as the parent compounds. Chemicals such as air pollutants present particular problems for mutagenicity testing using conventional microbial assays. Some of these problems can be overcome by using various higher plant systems. The general utility of these systems needs to be evaluated in terms of the types of genetic damage which can be detected, relative sensitivity, and general utility for use in mutagen screening and monitoring.
Regeneration and Repair of Myelinated Fibers in Sural-Nerve Biopsy Specimens from Patients with Diabetic Neuropathy Treated with Sorbinil
Authors: Anders A.F. Sima, Vera Bril, Virgil Nathaniel, Thomas AJ. McEwen, Morton B. Brown, Sarah A. Lattimer, Douglas A. Greene
Journal: New England Journal of Medicine (1988)

There is reason to believe that diabetic neuropathy may be related to the accumulation of sorbitol in nerve tissue through an aldose reductase pathway from glucose. Short-term treatment with aldose reductase inhibitors improves nerve conduction in subjects with diabetes, but the effects of long-term treatment on the neuropathologic changes of diabetic neuropathy are unknown. To determine whether more prolonged aldose reductase inhibition reverses the underlying lesions that accompany symptomatic diabetic peripheral polyneuropathy, we performed a randomized, placebo-controlled, double-blind trial of the investigational aldose reductase inhibitor sorbinil (250 mg per day). Sural-nerve biopsy specimens obtained at base line and after one year from 16 diabetic patients with neuropathy were analyzed morphometrically in detail and compared with selected electrophysiologic and clinical indexes. In contrast to patients who received placebo, the 10 sorbinil-treated patients had a decrease of 41.8±8.0 percent in nerve sorbitol content (P<0.01) and a 3.8-fold increase in the percentage of regenerating myelinated nerve fibers (P<0.001), reflected by a 33 percent increase in the number of myelinated fibers per unit of cross-sectional area of nerve (P = 0.04). They also had quantitative improvement in terms of the degree of paranodal demyelination, segmental demyelination, and myelin wrinkling. The increase in the number of fibers was accompanied by electrophysiologic and clinical evidence of improved nerve function. We conclude that sorbinil, as a metabolic intervention targeted against a specific biochemical consequence of hyperglycemia, can improve the neuropathologic lesions of diabetic neuropathy. (N Engl J Med 1988; 319:548–55.)
Chlamydia pneumoniae infection in acute exacerbations of COPD
Authors: F Blasi, D Legnani, VM Lombardo, GG Negretto, E Magliano, R Pozzoli, F Chiodo, A Fasoli, L Allegra
Journal: European Respiratory Journal (1993)

Chlamydia pneumoniae, strain TWAR, is a frequent causative agent of acute respiratory disease. We assessed the incidence and prevalence of Chlamydia pneumoniae infections in COPD. We studied, from January 1990 to May 1991, 142 out-patients with acute purulent exacerbations of chronic obstructive pulmonary disease (COPD) and 114 healthy control subjects. Oropharyngeal swab specimens were collected at each exacerbation and analysed using a high definition monoclonal indirect fluorescent antibody test for Chlamydia pneumoniae identification. Immunoglobulins G and M (IgG and IgM) fractions of antibodies to Chlamydia pneumoniae were studied by microimmunofluorescence test. Prevalence of specific IgG was 63% in COPD, and 46% in controls (Chi-squared test p = 0.007). Moreover, mean titre of IgG was significantly higher in COPD than in controls. Five patients were positive for specific IgM (&gt; or = = 1:16), and one had a fourfold increase of IgG titre; four of these patients had been treated with ciprofloxacin 1 g.day-1 for 10 days, and two with erythromycin, 3 g.day-1 for 14 days, with remission of signs and symptoms of exacerbation. Chlamydia pneumoniae identification was always negative. Our data suggest that Chlamydia pneumoniae infection is a rather frequent event in COPD, since at least 4% of exacerbations may be associated with it.
Experts warn rationing by GP consortiums could damage doctor-patient relationship
Authors: A. O'Dowd
Journal: BMJ (2011)

The need for GP commissioning consortiums to make rationing decisions could put a large strain on the doctor-patient relationship, experts have warned.

Decisions on rationing of NHS funds should be taken as far away as possible from the individual doctor level, witnesses told MPs on the parliamentary health select committee on 1 March as part of the committee’s inquiry into commissioning.

MPs asked whether or not patients would be better off as a result of GP commissioning consortiums and if there was a conflict of interest for GPs as commissioners and care providers.

Committee member Nadine Dorries, Conservative MP for Mid-Bedfordshire, said: “We hear so many conflicting stories that GPs may feel patients will …
Adenosine metabolism in phytohemagglutinin-stimulated human lymphocytes.
Authors: F F Snyder, J Mendelsohn, J E Seegmiller
Journal: Journal of Clinical Investigation (1976)

The association of a human genetic deficiency of adenosine deaminase activity with combined immunodeficiency prompted a study of the effects of adenosine and of inhibition of adenosine deaminase activity on human lymphocyte transformation and a detailed study of adenosine metabolism throughout phytohemagglutinin-induced blastogenesis. The adenosine deaminase inhibitor, coformycin, at a concentration that inhibited adenosine deaminase activity more than 95%, or 50 muM adenosine, did not prevent blastogenesis by criteria of morphology or thymidine incorporation into acid-precipitable material. The combination of coformycin and adenosine, however, substantially reduced both the viable cell count and the incorporation of thymidine into DNA in phytohemagglutinin-stimulated lymphocytes. Incubation of lymphocytes with phytohemagglutinin for 72 h produced a 12-fold increase in the rate of deamination and a 6-fold increase in phosphorylation of adenosine by intact lymphocytes. There was no change in the apparent affinity for adenosine with either deamination or phosphorylation. The increased rates of metabolism, apparent as early as 3 h after addition of mitogen, may be due to increased entry of the nucleoside into stimulated lymphocytes. Increased adenosine metabolism was not due to changes in total enzyme activity; after 72 h in culture, the ratios of specific activities in extracts of stimulated to unstimulated lymphocytes were essentially unchanged for adenosine kinase, 0.92, and decreased for adenosine deaminase, 0.44. As much as 38% of the initial lymphocyte adenosine deaminase activity accumulated extracellularly after a 72-h culture with phytohemagglutinin. In phytohemagglutinin-stimulated lymphocytes, the principal route of adenosine metabolism was phosphorylation at less than 5 muM adenosine, and deamination at concentrations greater than 5 muM. In unstimulated lymphocytes, deamination was the principal route of adenosine metabolism over the range of adenosine concentrations studied (0.5-250 muM). These studies demonstrate the dependence of both the unstimulated and stimulated lymphocyte on adenosine and may account for the observed sensitivity of mitogen-stimulated lymphocytes to the toxic effects of exogenously supplied adenosine in the presence of the adenosine deaminase inhibitor coformycin. A single case of immunodeficiency disease has been reported in association with purine nucleoside phosphorylase deficiency. The catabolism of guanosine was also found to be enhanced in stimulated normal lymphocytes; phosphorolysis of guanosine to guanine by intact lymphocytes increased six fold after 72-h culture with phytohemagglutinin. The specific activity of purine nucleoside phosphorylase in extracts, with guanosine as substrate, was essentially the same in stimulated and unstimulated lymphocytes after 72 h of culture.
ARHGDIA mutations cause nephrotic syndrome via defective RHO GTPase signaling
Authors: Heon Yung Gee, Pawaree Saisawat, Shazia Ashraf, Toby W. Hurd, Virginia Vega-Warner, Humphrey Fang, Bodo B. Beck, Olivier Gribouval, Weibin Zhou, Katrina A. Diaz, Sivakumar Natarajan, Roger C. Wiggins, Svjetlana Lovric, Gil Chernin, Dominik S. Schoeb, Bugsu Ovunc, Yaacov Frishberg, Neveen A. Soliman, Hanan M. Fathy, Heike Goebel, Julia Hoefele, Lutz T. Weber, Jeffrey W. Innis, Christian Faul, Zhe Han, Joseph Washburn, Corinne Antignac, Shawn Levy, Edgar A. Otto, Friedhelm Hildebrandt
Journal: Journal of Clinical Investigation (2013)

Nephrotic syndrome (NS) is divided into steroid-sensitive (SSNS) and -resistant (SRNS) variants. SRNS causes end-stage kidney disease, which cannot be cured. While the disease mechanisms of NS are not well understood, genetic mapping studies suggest a multitude of unknown single-gene causes. We combined homozygosity mapping with whole-exome resequencing and identified an ARHGDIA mutation that causes SRNS. We demonstrated that ARHGDIA is in a complex with RHO GTPases and is prominently expressed in podocytes of rat glomeruli. ARHGDIA mutations (R120X and G173V) from individuals with SRNS abrogated interaction with RHO GTPases and increased active GTP-bound RAC1 and CDC42, but not RHOA, indicating that RAC1 and CDC42 are more relevant to the pathogenesis of this SRNS variant than RHOA. Moreover, the mutations enhanced migration of cultured human podocytes; however, enhanced migration was reversed by treatment with RAC1 inhibitors. The nephrotic phenotype was recapitulated in arhgdia-deficient zebrafish. RAC1 inhibitors were partially effective in ameliorating arhgdia-associated defects. These findings identify a single-gene cause of NS and reveal that RHO GTPase signaling is a pathogenic mediator of SRNS.
Chromatin structure changes around satellite repeats on the Schistosoma mansoni female sex chromosome suggest a possible mechanism for sex chromosome emergence
Authors: Julie MJ Lepesant, Céline Cosseau, Jérome Boissier, Michael Freitag, Julien Portela, Déborah Climent, Cécile Perrin, Adhemar Zerlotini, Christoph Grunau
Journal: Genome biology (2012)

In the leuphotrochozoan parasitic platyhelminth Schistosoma mansoni, male individuals are homogametic (ZZ) whereas females are heterogametic (ZW). To elucidate the mechanisms that led to the emergence of sex chromosomes, we compared the genomic sequence and the chromatin structure of male and female individuals. As for many eukaryotes, the lower estimate for the repeat content is 40%, with an unknown proportion of domesticated repeats. We used massive sequencing to de novo assemble all repeats, and identify unambiguously Z-specific, W-specific and pseudoautosomal regions of the S. mansoni sex chromosomes.We show that 70 to 90% of S. mansoni W and Z are pseudoautosomal. No female-specific gene could be identified. Instead, the W-specific region is composed almost entirely of 36 satellite repeat families, of which 33 were previously unknown. Transcription and chromatin status of female-specific repeats are stage-specific: for those repeats that are transcribed, transcription is restricted to the larval stages lacking sexual dimorphism. In contrast, in the sexually dimorphic adult stage of the life cycle, no transcription occurs. In addition, the euchromatic character of histone modifications around the W-specific repeats decreases during the life cycle. Recombination repression occurs in this region even if homologous sequences are present on both the Z and W chromosomes.Our study provides for the first time evidence for the hypothesis that, at least in organisms with a ZW type of sex chromosomes, repeat-induced chromatin structure changes could indeed be the initial event in sex chromosome emergence.
Zerumbone Abolishes RANKL-Induced NF-κB Activation, Inhibits Osteoclastogenesis, and Suppresses Human Breast Cancer–Induced Bone Loss in Athymic Nude Mice
Authors: Bokyung Sung, Akira Murakami, Babatunde O. Oyajobi, Bharat B. Aggarwal
Journal: Cancer Research (2009)

Abstract Receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL) has emerged as a major mediator of bone resorption, commonly associated with cancer and other chronic inflammatory diseases. Inhibitors of RANKL signaling thus have potential in preventing bone loss. In the present report, the potential of zerumbone, a sesquiterpene derived from subtropical ginger, to modulate osteoclastogenesis induced by RANKL and breast cancer was examined. We found that zerumbone inhibited RANKL-induced NF-κB activation in mouse monocyte, an osteoclast precursor cell, through inhibition of activation of IκBα kinase, IκBα phosphorylation, and IκBα degradation. Zerumbone also suppressed RANKL-induced differentiation of these cells to osteoclasts. This sesquiterpene also inhibited the osteoclast formation induced by human breast tumor cells and by multiple myeloma cells. Finally, we examined whether zerumbone could prevent human breast cancer–induced bone loss in animals. We found that zerumbone decreased osteolysis in a dose-dependent manner in MDA-MB-231 breast cancer tumor-bearing athymic nude mice. These results indicate that zerumbone is an effective blocker of RANKL-induced NF-κB activation and of osteoclastogenesis induced by RANKL and tumor cells, suggesting its potential as a therapeutic agent for osteoporosis and cancer-associated bone loss. [Cancer Res 2009;69(4):1477–84]
Hypermethylation of the Death-Associated Protein (DAP) Kinase Promoter and Aggressiveness in Stage I Non-Small-Cell Lung Cancer
Authors: X. Tang
Journal: JNCI Journal of the National Cancer Institute (2000)

Background: Death-associated protein (DAP) kinase is a serine/threonine kinase that is important in ligand-induced programmed cell death and plays an important role in lung cancer metastasis in animal models. Hypermethylation of the promoter represses the expression of the DAP kinase gene. Our purpose was to determine whether the hypermethylation status of the DAP kinase promoter influences the prognosis of non-small-cell lung cancer (NSCLC). Methods: We retrospectively studied 135 patients with pathologic stage I NSCLC who had undergone curative surgery. Methylation-specific polymerase chain reaction was used to determine the methylation status of the DAP kinase promoter in resected specimens from patients with primary NSCLC. Statistical analyses, all two-sided, were performed to determine the prognostic effect of methylation status on various clinical parameters. Results: Hypermethylation of the DAP kinase promoter was found in 59 (44%) of the 135 tumors. Patients whose tumors exhibited such hypermethylation had a statistically significantly poorer probability of overall survival at 5 years after surgery than those without such hypermethylation (.46 versus .68; P = .007). Moreover, the groups with and without hypermethylation of the DAP kinase promoter showed a striking difference in the probability of disease-specific survival; i.e., among people who died of lung cancer-related causes specifically, the probability of 5-year survival was .56 for those with such hypermethylation and .92 for those without it (P<.001). Multivariate analysis indicated that hypermethylation of the DAP kinase promoter is the only independent predictor for disease-specific survival among clinical and histologic parameters tested. Conclusions: Hypermethylation of the DAP kinase promoter is a common abnormality in early-stage NSCLC. This abnormality is strongly associated with survival, suggesting that DAP kinase plays an important role in determining the biologic aggressiveness of early-stage NSCLC.
Modulation of cardiac contractility by 1 adrenoceptors
Authors: D. Fedida
Journal: Cardiovascular Research (1993)

Journal Article Modulation of cardiac contractility by α1 adrenoceptors Get access David Fedida David Fedida Department of Physiology, Botterell Hall, Queen's University, Kingston, Ontario, Canada K7L 3N6: Dr D Fedida. Search for other works by this author on: Oxford Academic PubMed Google Scholar Cardiovascular Research, Volume 27, Issue 10, October 1993, Pages 1735–1742, https://doi.org/10.1093/cvr/27.10.1735 Published: 01 October 1993 Article history Received: 29 December 1992 Accepted: 04 March 1993 Published: 01 October 1993
Gene-expression patterns reveal underlying biological processes in Kawasaki disease
Authors: Stephen J Popper, Chisato Shimizu, Hiroko Shike, John T Kanegaye, Jane W Newburger, Robert P Sundel, Patrick O Brown, Jane C Burns, David A Relman
Journal: Genome biology (2007)

Kawasaki disease (KD) is an acute self-limited vasculitis and the leading cause of acquired heart disease in children in developed countries. No etiologic agent(s) has been identified, and the processes that mediate formation of coronary artery aneurysms and abatement of fever following treatment with intravenous immunoglobulin (IVIG) remain poorly understood.In an initial survey, we used DNA microarrays to examine patterns of gene expression in peripheral whole blood from 20 children with KD; each was sampled during the acute, subacute, and convalescent phases of the illness. Acute KD was characterized by increased relative abundance of gene transcripts associated with innate immune and proinflammatory responses and decreased abundance of transcripts associated with natural killer cells and CD8+ lymphocytes. There was significant temporal variation in transcript levels during the acute disease phase and stabilization thereafter. We confirmed these temporal patterns in a second cohort of 64 patients, and identified additional inter-individual differences in transcript abundance. Notably, higher levels of transcripts of the gene for carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) were associated with an increased percentage of unsegmented neutrophils, fewer days of illness, higher levels of C-reactive protein, and subsequent non-response to IVIG; this last association was confirmed by quantitative reverse transcription PCR in a third cohort of 33 patients, and was independent of day of illness.Acute KD is characterized by dynamic and variable gene-expression programs that highlight the importance of neutrophil activation state and apoptosis in KD pathogenesis. Our findings also support the feasibility of extracting biomarkers associated with clinical prognosis from gene-expression profiles of individuals with systemic inflammatory illnesses.
Identification and Significance of Cell Markers in Leukemia and Lymphoma
Authors: Roger A. Warnke, Michael P. Link
Journal: Annual Review of Medicine (1983)

The identification of markers of human hematopoietic cell differentiation and function has revealed the nature of the proliferating cell in many lymphoid neoplasms and demonstrated marked phenotypie heterogeneity in traditional subgroups. Selected markers are described that define common subgroups of lymphoid leukemia and non-Hodgkin’s lymphoma. The identification of cell markers has significant implications for accuracy of diagnosis, for predicting clinical characteristics, and for understanding the biology of these diseases.
Press Release: Chemotherapy with Bevacizumab Increases Risk of Blood Clots in Arteries
Authors: L. Savage, A. Widener
Journal: JNCI Journal of the National Cancer Institute (2007)

Chemotherapy with Bevacizumab Increases Risk of Blood Clots in ArteriesTreatment with chemotherapy and bevacizumab, an anticancer drug, is associated with a greater risk of blood clots in patients' arteries compared with treatment with chemotherapy only, according to a study published online August 7 in the Journal of the National Cancer Institute .The combination of chemotherapy and bevacizumab has been shown to increase survival in patients with metastatic colorectal and non -small-cell lung cancer, but some previous studies suggest these patients are at an increased risk for blood clots in their arteries.Frank Scappaticci, M.D., Ph.D., of Genentech, Inc. in South San Francisco, Calif., and colleagues analyzed data from fi ve randomized controlled trials that included 1,745 patients with metastatic colorectal, breast, or non -small-cell lung cancer.Among patients treated with the combination therapy, 3.8 percent experienced blood clots in their arteries, compared with 1.7 percent of patients on chemotherapy alone.There was no statistically signifi cant difference in the incidence of blood clots in veins.Risk factors for blood clots in both arteries and veins included previous blood clots and older age (65 or older.)"The clinical benefi t associated with bevacizumab therapy was maintained for all subgroups.Although death from [a blood clot in the artery] was uncommon, we did not capture functional disabilities from these events, and the risk factors … identifi ed in this study should be considered when making treatment decisions for individual patients," the authors write.
The oxidation induced by antimyeloperoxidase antibodies triggers fibrosis in microscopic polyangiitis
Authors: P. Guilpain, C. Chéreau, C. Goulvestre, A. Servettaz, D. Montani, N. Tamas, C. Pagnoux, E. Hachulla, B. Weill, L. Guillevin, L. Mouthon, F. Batteux
Journal: European Respiratory Journal (2010)

Lung fibrosis is considered a severe manifestation of microscopic polyangiitis (MPA). Antimyeloperoxidase (anti-MPO) antibodies in MPA patients' sera can activate MPO and lead to the production of reactive oxygen species (ROS). While high levels of ROS are cytotoxic, low levels can induce fibroblast proliferation. Therefore, we hypothesised that the oxidative stress induced by anti-MPO antibodies could contribute to lung fibrosis. 24 MPA patients (45 sera) were enrolled in the study, including nine patients (22 sera) with lung fibrosis. Serum advanced oxidation protein products (AOPP), MPO-induced hypochlorous acid (HOCl) and serum-induced fibroblast proliferation were assayed. AOPP levels, MPO-induced HOCl production and serum-induced fibroblast proliferation were higher in patients than in healthy controls (p<0.0001, p=0.0001 and p=0.0005, respectively). Increased HOCl production was associated with active disease (p=0.002). Serum AOPP levels and serum-induced fibroblast proliferation were higher in patients with active MPA and lung fibrosis (p<0.0001). A significant linear relationship between fibroblast proliferation, AOPP levels and HOCl production was observed only in patients with lung fibrosis. Oxidative stress, in particular the production of HOCl through the interaction of MPO with anti-MPO antibodies, could trigger the fibrotic process observed in MPA.
Advanced chondrosarcomas: role of chemotherapy and survival
Authors: A. Italiano, O. Mir, A. Cioffi, E. Palmerini, S. Piperno-Neumann, C. Perrin, L. Chaigneau, N. Penel, F. Duffaud, J.E. Kurtz, O. Collard, F. Bertucci, E. Bompas, A. Le Cesne, R.G. Maki, I. Ray Coquard, J.Y. Blay
Journal: Annals of Oncology (2013)