tbuckley/cabot-search huggingface dataset:
Oncogenic transformation of mesenchymal stem cells decreases Nrf2 expression favoring in vivo tumor growth and poorer survival
Authors: Juan M Funes, Stephen Henderson, Rachel Kaufman, James M Flanagan, Mathew Robson, Barbara Pedley, Salvador Moncada, Chris Boshoff
Journal: Molecular Cancer (2014)

The transcription factor Nrf2 is a key regulator of the cellular antioxidant response, and its activation by chemoprotective agents has been proposed as a potential strategy to prevent cancer. However, activating mutations in the Nrf2 pathway have been found to promote tumorigenesis in certain models. Therefore, the role of Nrf2 in cancer remains contentious.We employed a well-characterized model of stepwise human mesenchymal stem cell (MSC) transformation and breast cancer cell lines to investigate oxidative stress and the role of Nrf2 during tumorigenesis. The Nrf2 pathway was studied by microarray analyses, qRT-PCR, and western-blotting. To assess the contribution of Nrf2 to transformation, we established tumor xenografts with transformed MSC expressing Nrf2 (n = 6 mice per group). Expression and survival data for Nrf2 in different cancers were obtained from GEO and TCGA databases. All statistical tests were two-sided.We found an accumulation of reactive oxygen species during MSC transformation that correlated with the transcriptional down-regulation of antioxidants and Nrf2-downstream genes. Nrf2 was repressed in transformed MSC and in breast cancer cells via oncogene-induced activation of the RAS/RAF/ERK pathway. Furthermore, restoration of Nrf2 function in transformed cells decreased reactive oxygen species and impaired in vivo tumor growth (P = 0.001) by mechanisms that included sensitization to apoptosis, and a decreased hypoxic/angiogenic response through HIF-1α destabilization and VEGFA repression. Microarray analyses showed down-regulation of Nrf2 in a panel of human tumors and, strikingly, low Nrf2 expression correlated with poorer survival in patients with melanoma (P = 0.0341), kidney (P = 0.0203) and prostate (P = 0.00279) cancers.Our data indicate that oncogene-induced Nrf2 repression is an adaptive response for certain cancers to acquire a pro-oxidant state that favors cell survival and in vivo tumor growth.
A Novel K <sub>ATP</sub> Current in Cultured Neonatal Rat Atrial Appendage Cardiomyocytes
Authors: Anne Baron, Laurianne van Bever, Dominique Monnier, Angela Roatti, Alex J. Baertschi
Journal: Circulation Research (1999)

Abstract —The functional and pharmacological properties of ATP-sensitive K + (K ATP ) channels were studied in primary cultured neonatal rat atrial appendage cardiomyocytes. Activation of a whole-cell inward rectifying K + current depended on the pipette ATP concentration and correlated with a membrane hyperpolarization close to the K + equilibrium potential. The K ATP current could be activated either spontaneously or by a hypotonic stretch of the membrane induced by lowering the osmolality of the bathing solution from 290 to 260 mOsm/kg H 2 O or by the K + channel openers diazoxide and cromakalim with EC 50 ≈1 and 10 nmol/L, respectively. The activated atrial K ATP current was highly sensitive to glyburide, with an IC 50 of 1.22±0.15 nmol/L. Recorded in inside-out patches, the neonatal atrial K ATP channel displayed a conductance of 58.0±2.2 pS and opened in bursts of 133.8±20.4 ms duration, with an open time duration of 1.40±0.10 ms and a close time duration of 0.66±0.04 ms for negative potentials. The channel had a half-maximal open probability at 0.1 mmol/L ATP, was activated by 100 μmol/L diazoxide, and was inhibited by glyburide, with an IC 50 in the nanomolar range. Thus, pending further tests at low concentrations of K ATP channel openers, the single-channel data confirm the results obtained with whole-cell recordings. The neonatal atrial appendage K ATP channel thus shows a unique functional and pharmacological profile resembling the pancreatic β-cell channel for its high affinity for glyburide and diazoxide and for its conductance, but also resembling the ventricular channel subtype for its high affinity for cromakalim, its burst duration, and its sensitivity to ATP. Reverse transcriptase–polymerase chain reaction experiments showed the expression of Kir6.1, Kir6.2, SUR1A, SUR1B, SUR2A, and SUR2B subunits, a finding supporting the hypothesis that the neonatal atrial K ATP channel corresponds to a novel heteromultimeric association of K ATP channel subunits.
Allergen sensitization and exposure to irritants in infancy
Authors: V. Søyseth, J. Kongerud, J. Boe
Journal: Allergy (1996)

We investigated the relationship between residence in the neighbourhood of an aluminium smelter and the prevalence of atopy in schoolchildren (7–13 years of age). Atopy was assessed in 556 of the 620 participants by a skin prick test with eight common aeroallergens. The median exposures to sulphur dioxide and fluoride during the pollen season in the age interval 19–36 months were 24 and 3.1 μg/m 3 in the spring and 20 and 3.3 μg/m 3 in the summer, respectively. The odds ratio (OR) of having atopy was 2.0 (95% CI: 1.2–3.3) in those children who had lived in the index area for 7 years or more compared with those who had lived there less than 7 years (cumulative effect). The OR of atopy was 2.5 (1.44.4) in those who had lived in the index area during the age interval of 19–36 months compared with rural residence during this age‐interval (age‐specific effect). When the age‐specific effect and the cumulative effect were compared in the same logistic model, the former decreased to 1.1 (0.43.0), whereas the latter was 2.2 (0.7–6.6). The results indicate that exposure to these low levels of irritants during early childhood increases allergen sensitization in children.
Effect of arterial oxygen desaturation on six minute walk distance, perceived effort, and perceived breathlessness in patients with airflow limitation.
Authors: V H Mak, J R Bugler, C M Roberts, S G Spiro
Journal: Thorax (1993)

BACKGROUND: The effect of exercise induced hypoxaemia in determining submaximal exercise capacity, perceived breathlessness, and perceived exertion is not known. The purpose of this study was to investigate the relation of these variables to the results of lung function tests and the degree of hypoxaemia during submaximal exercise in patients with airflow limitation. METHODS: Forty two patients with chronic obstructive airways disease and 28 patients with chronic severe asthma were studied. Spirometry was performed and gas transfer (TLCO) and lung volumes were measured. Submaximal exercise capacity was assessed with a standardised six minute walk test. Arterial oxygen desaturation during the walk test was monitored by a portable pulse oximeter. Patients rated their perceived degree of respiratory impairment on a Medical Research Council (MRC) breathlessness scale before the walk. Perceived breathlessness was measured by means of a linear visual analogue scale and exertion on the Borg scale after the walk. RESULTS: The six minute walk distance was strongly correlated (r value) with TLCO (0.68), peak expiratory flow (PEF: 0.55), forced expiratory volume in one second (FEV1: 0.53), transfer coefficient KCO: 0.49), age (-0.49), and forced vital capacity (FVC: 0.48) but not with oxygen desaturation during the walk. Walk distance was also correlated with the breathlessness rating on the MRC scale (-0.52), but less strongly with perceived breathlessness (-0.35) and perceived exertion (-0.30). The prediction equation for the six minute walk distance in metres (6MD) generated by multiple regression analysis was 6MD = 387 + 29.7 (TLCO) -3.1 (age) + 0.35 (PEF 1/min), which accounted for 50% of the total variance in walk distance. The mean level of saturation during the walk correlated most significantly with TLCO (0.55), FEV1/FVC (0.54), and PEF (0.48), but not with walk distance or with the rating on any of the analogue scales. The prediction equation produced by multiple regression analysis for the mean level of saturation during the walk was MEANSAT(%) = 1.3(TLCO) + 1.5 (base-line saturation) - 0.01 (6MD) - 54. CONCLUSIONS: Oxygen desaturation during the six minute walk is not related to walk distance, nor does it determine the degree of perceived exertion or perceived breathlessness in patients with airflow limitation. Patients who consider themselves the most disabled by breathlessness have the shortest six minute walk distance but do not necessarily have appreciable desaturation.
Speed Limits, Enforcement, and Health Consequences
Authors: Rune Elvik
Journal: Annual Review of Public Health (2012)

This review summarizes current knowledge regarding the effects of speed limit enforcement on public health. Speed limits are commonly used around the world to regulate the maximum speed at which motor vehicles can be operated on public roads. Speed limits are statutory, and violations of them are normally sanctioned by means of fixed penalties (traffic tickets) or, in the event of serious violations, suspension of the driver's license and imposition of prison sentences. Speed limit violations are widespread in all countries for which statistics can be found. Speeding contributes more to the risk of traffic injury than do other risk factors for which estimates of population-attributable risk are available. Traffic speed strongly influences impact speed in crashes and therefore has major implications for public health.
Major histocompatibility complex class I-related chains A and B (MIC A/B): A novel role in nonalcoholic steatohepatitis
Authors: Alisan Kahraman, Martin Schlattjan, Peri Kocabayoglu, Sule Yildiz-Meziletoglu, Matthias Schlensak, Christian D. Fingas, Inga Wedemeyer, Guido Marquitan, Robert K. Gieseler, Hideo A. Baba, Guido Gerken, Ali Canbay
Journal: Hepatology (2009)

Stress-induced soluble major histocompatibility complex class I–related chains A/B (MIC A/B) are increased in chronic liver diseases and hepatocellular malignancy. We investigated the impact of these molecules on liver injury, apoptosis, and fibrosis in nonalcoholic steatohepatitis (NASH). Blood and liver tissue were obtained from 40 patients with NASH undergoing bariatric surgery for obesity. The control group consisted of 10 healthy individuals. We also investigated 10 patients with nonalcoholic fatty liver (NAFL). Polymerase chain reaction was used to measure messenger RNA (mRNA) transcripts of MIC A/B, natural killer cell receptor G2D (NKG2D), CD95/Fas, and tumor necrosis factor–related apoptosis-inducing ligand (TRAIL)–death receptor 5 (DR5). Apoptosis was quantified by way of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) (intrahepatic) and M30/M65 (systemic). Liver injury was assessed histopathologically and serologically (alanine aminotransferase/aspartate aminotransferase). Fibrosis was identified by Sirius red staining, quantitative morphometry, and α-smooth muscle actin and collagen 1α transcripts. Compared with controls, patients with NASH revealed significant increases in (1) NKG2D mRNA (13.1-fold) and MIC A/B mRNA (3.6-fold and 15.8-fold, respectively); (2) TRAIL–DR5 and CD95/Fas mRNA (2.7-fold and 3.6-fold, respectively); (3) TUNEL-positive hepatocytes (4.0-fold); and (4) M30 and M65 levels (4.6-fold and 3.4-fold, respectively). We found relevant correlations between MIC protein expression rates and NAS and fibrosis stages. In contrast, NKG2D and MIC A/B transcripts were attenuated in patients with NAFL compared with NASH. Histopathologically, NASH patients revealed increased NAS scores, an accumulation of natural killer cells, and 2.7-fold increased hepatic fibrosis by quantitative morphometry. Conclusion: Our findings suggest an important role for MIC A/B in liver injury. Therapeutic intervention aimed at reducing MIC A/B levels may beneficially affect the progression of NASH. (Hepatology 2009.)
B-Cell Receptor Translocation to Lipid Rafts and Associated Signaling Differ between Prognostically Important Subgroups of Chronic Lymphocytic Leukemia
Authors: David J. Allsup, Aura S. Kamiguti, Ke Lin, Paul D. Sherrington, Zoltan Matrai, Joseph R. Slupsky, John C. Cawley, Mirko Zuzel
Journal: Cancer Research (2005)

Abstract Chronic lymphocytic leukemia (CLL) is a highly heterogeneous disease in which interaction of the malignant cells with antigen is thought to play a key role. Individual CLL-cell clones markedly differ in their ability to respond to B-cell receptor ligation, but the mechanism underlying the frequent hyporesponsiveness is incompletely understood. Our aim was to further clarify the extent and cause of the B-cell receptor signaling abnormality in CLL and to assign pathophysiologic relevance to the presence or absence of B-cell receptor responsiveness. We show that extracellular signal-regulated kinase-2 phosphorylation, intracellular Ca2+ increases, CD79a phosphorylation, and translocation of the B-cell receptor to lipid rafts in response to ligation with anti–immunoglobulin M (as a surrogate for antigen) are features of CLL cells with relatively unmutated VH genes (&amp;lt;5% deviation from germ line) and a poor prognosis. B-cell receptor stimulation in these cases also promoted cell survival. In clones with mutated VH genes (&amp;gt;5% deviation from germ line), surface immunoglobulin M ligation failed to induce receptor translocation to rafts or to prolong cell survival. This failure of receptor translocation observed in mutated CLL cells was associated with the constitutive exclusion of the B-cell receptor from rafts by a mechanism involving src-dependent interactions between the B-cell receptor and the actin cytoskeleton. We conclude that exposure to antigen promotes the survival of unmutated CLL clones, contributing to the poor prognosis of this group. In contrast, hyporesponsive mutated CLL clones may have developed into a stage where continuous exposure to antigen results in relative tolerance to antigenic stimulation mediated by the exclusion of the B-cell receptor from lipid rafts.
Fotemustine Compared With Dacarbazine in Patients With Disseminated Malignant Melanoma: A Phase III Study
Authors: M.F. Avril, S. Aamdal, J.J. Grob, A. Hauschild, P. Mohr, J.J. Bonerandi, M. Weichenthal, K. Neuber, T. Bieber, K. Gilde, V. Guillem Porta, J. Fra, J. Bonneterre, P. Saïag, D. Kamanabrou, H. Pehamberger, J. Sufliarsky, J.L. Gonzalez Larriba, A. Scherrer, Y. Menu
Journal: Journal of Clinical Oncology (2004)

To compare fotemustine and dacarbazine (DTIC) in terms of overall response rate (ORR) as primary end-point and overall survival, duration of responses, time to progression, time to occurrence of brain metastases (BM), and to assess safety and quality of life in patients with disseminated cutaneous melanoma.Patients received either intravenous fotemustine 100 mg/m2 weekly for 3 weeks or DTIC 250 mg/m2/d for 5 consecutive days every 4 weeks (two cycles). Nonprogressive patients received a maintenance treatment every 4 weeks (fotemustine 100 mg/m2 or DTIC 250 mg/m2 for 5 days).Two hundred twenty-nine patients were randomly assigned to fotemustine or DTIC arms. The best ORR was higher in the fotemustine arm than in the DTIC arm in the intent-to-treat population (n=229; 15.2% v 6.8%; P=.043) and in full analysis set (n=221) (15.5% v 7.2%; P=.053). Similar median durations of responses (5.8 months with fotemustine v 6.9 months with DTIC) and time to progression (1.8 v 1.9 months, respectively) were observed. In patients without BM at inclusion, the median time to BM was 22.7 months with fotemustine versus 7.2 months with DTIC (P=.059). Median survival was 7.3 months with fotemustine versus 5.6 months with DTIC (P=.067). The main toxicity was grade 3 to 4 neutropenia (51% with fotemustine v 5% with DTIC) and thrombocytopenia (43% v 6%, respectively). No significant difference was noted for quality of life between arms.ORR was higher in the fotemustine arm compared to the DTIC arm in first-line treatment of disseminated melanoma. A trend in favor of fotemustine in terms of overall survival and time to BM was evidenced.
Thrombospondin 1 as a novel biological marker of obesity and metabolic syndrome
Authors: Yoshiyuki Matsuo, Masashi Tanaka, Hajime Yamakage, Yousuke Sasaki, Kazuya Muranaka, Hiroaki Hata, Iwao Ikai, Akira Shimatsu, Mayumi Inoue, Tae-Hwa Chun, Noriko Satoh-Asahara
Journal: Metabolism (2015)
Determinants of health-related quality of life in patients with chronic obstructive pulmonary disease.
Authors: C. A. Ketelaars, M. A. Schlosser, R. Mostert, H. Huyer Abu-Saad, R. J. Halfens, E. F. Wouters
Journal: Thorax (1996)

BACKGROUND: The consequences of chronic obstructive pulmonary disease (COPD) on daily life, encapsulated by the term "health-related quality of life" (HRQL), are important in determining appropriate home care. There is a need to understand the relative contribution of respiratory impairment, physical disability, coping, age, and socioeconomic variables on HRQL. METHODS: Patients with COPD were recruited on admission to a pulmonary rehabilitation centre. Respiratory impairment was assessed by lung function tests and physical disability was evaluated by a 12 minute walking test. HRQL was assessed by means of the St George9s Respiratory Questionnaire (SGRQ) measuring "symptoms", "activity", and "impact". Because the SGRQ does not include a measure of "well being", this was taken from the medical psychological questionnaire for lung diseases. The COPD coping questionnaire and a questionnaire covering basic socioeconomic variables were also used. RESULTS: One hundred and twenty six patients of mean (SD) age 65 (9) years and mean (SD) forced expiratory volume in one second (FEV1) 39 (9)% predicted were included. The scores on the SGRQ indicated severe impairment. Correlations were found between lung function parameters, 12 minute walking test, and the HRQL "activity" and "impact" components. Coping strategies were correlated with the "activity", "impact", and "well being" components. No correlations were found between age, socioeconomic variables, and HRQL. FEV1, 12 minute walking test, and the coping strategies "avoidance" and "emotional reaction" were the best predictors of HRQL. CONCLUSION: In patients with COPD methods of improving physical performance and teaching adequate coping strategies should be considered in order to improve HRQL.
P12. Combination of radiotherapy and chemotherapy with dendritic cell immunotherapy in glioblastoma patients induces NK and NKT cell responses
Authors: S Pellegatta, M Eoli, MG Bruzzone, S Cuzzubbo, E Anghileri, C Antozzi, S Frigerio, B Pollo, EA Parati, G Finocchiaro
Journal: Journal for ImmunoTherapy of Cancer (2014)

Meeting abstracts Two clinical studies including the treatment of first diagnosis and recurrent glioblastoma (GB) patients with dendritic cells (DCs) loaded with autologous tumour lysate (Nava et al, 2012) are currently active at Istituto Neurologico Besta, Milan. Our first results obtained on a
Hitchhiking Selection Is Driving Intron Gain in a Pathogenic Fungus
Authors: Patrick C. Brunner, Stefano F.F. Torriani, Daniel Croll, Eva H. Stukenbrock, Bruce A. McDonald
Journal: Molecular Biology and Evolution (2014)

The variability of intron density among eukaryotes is puzzling and still debated. Most previous studies have been limited because of the near absence of intron presence–absence polymorphism (IPAP) within species or because comparisons could be made only between distantly related species. We conducted population genetic analyses on eight loci showing IPAP to investigate the effect of natural selection on intron dynamics in a global collection of the panmictic fungal plant pathogen Zymoseptoria tritici and its very close relatives. Five of these loci likely represent recent intron gains because their absence is fixed among the closest relatives of Z. tritici, and three likely represent recent intron losses because their presence is fixed among the close relatives. We analyzed signatures of selection by comparing allele frequencies, nucleotide diversities, and rates of recombination and found compelling evidence that at least two out of the five intron-gain loci, a SWIM zinc-finger gene and a sugar transporter, are under directional selection favoring alleles that gained the intron. Our results suggest that the intron-present alleles of these loci are sweeping to fixation, providing a genetic hitchhiking mechanism to explain rapid intron gain in Z. tritici. The overall findings are consistent with the hypothesis that intron gains are more likely to be driven by selection while intron losses are more likely to be due to neutral processes such as genetic drift.
Consumption of a Diet Low in Advanced Glycation End Products for 4 Weeks Improves Insulin Sensitivity in Overweight Women
Authors: Alicja Budek Mark, Malene Wibe Poulsen, Stine Andersen, Jeanette Marker Andersen, Monika Judyta Bak, Christian Ritz, Jens Juul Holst, John Nielsen, Barbora de Courten, Lars Ove Dragsted, Susanne Gjedsted Bügel
Journal: Diabetes Care (2013)

OBJECTIVE High-heat cooking of food induces the formation of advanced glycation end products (AGEs), which are thought to impair glucose metabolism in type 2 diabetic patients. High intake of fructose might additionally affect endogenous formation of AGEs. This parallel intervention study investigated whether the addition of fructose or cooking methods influencing the AGE content of food affect insulin sensitivity in overweight individuals. RESEARCH DESIGN AND METHODS Seventy-four overweight women were randomized to follow either a high- or low-AGE diet for 4 weeks, together with consumption of either fructose or glucose drinks. Glucose and insulin concentrations-after fasting and 2 h after an oral glucose tolerance test-were measured before and after the intervention. Homeostasis model assessment of insulin resistance (HOMA-IR) and insulin sensitivity index were calculated. Dietary and urinary AGE concentrations were measured (liquid chromatography tandem mass spectrometry) to estimate AGE intake and excretion. RESULTS When adjusted for changes in anthropometric measures during the intervention, the low-AGE diet decreased urinary AGEs, fasting insulin concentrations, and HOMA-IR, compared with the high-AGE diet. Addition of fructose did not affect any outcomes. CONCLUSIONS Diets with high AGE content may increase the development of insulin resistance. AGEs can be reduced by modulation of cooking methods but is unaffected by moderate fructose intake.
The regulatory role of DR4 in a spontaneous diabetes DQ8 transgenic model
Authors: Li Wen, Ning-Yuan Chen, Jie Tang, Robert Sherwin, F. Susan Wong
Journal: Journal of Clinical Investigation (2001)

MHC class II molecules are critical determinants of genetic susceptibility to human type 1 diabetes. In patients, the most common haplotype contains the DRA1*0101-DRB1*0401 (DR4) and DQA1*0301-DQB1*0302 (DQ8) loci. To assess directly the relative roles of HLA-DQ8 and DR4 for diabetes development in vivo, we generated C57BL/6 transgenic mice that lack endogenous mouse MHC class II molecules but express HLA-DQ8 and/or DR4. Neither HLA-DQ nor HLA-DR transgenic mice developed insulitis or spontaneous diabetes. However, when they were crossed to transgenic mice (C57BL/6) expressing the B7.1 costimulatory molecules on pancreatic β cells that do not normally develop diabetes, T cells from these double transgenic mice were no longer tolerant to islet autoantigens. The majority of DQ8/RIP-B7 mice developed spontaneous diabetes, whereas only 25% of DR4/RIP-B7 mice did so. Interestingly, when DQ8 and DR4 were coexpressed (DQ8DR4/RIP-B7), only 23% of these mice developed diabetes, an incidence indistinguishable from the DR4/RIP-B7 mice. T cells from both DR4/RIP-B7 and DQ8DR4/RIP-B7 mice, unlike those from DQ8/RIP-B7 mice, exhibited a Th2-like phenotype. Thus, the expression of DR4 appeared to downregulate DQ8-restricted autoreactive T cells in DQ8DR4/RIP-B7 mice. Our data suggest that although both DQ8 and DR4 can promote spontaneous diabetes in mice with a non–autoimmune-prone genetic background, the diabetogenic effect of the DQ8 allele is much greater, whereas DR4 expression downregulates the diabetogenic effect of DQ8, perhaps by enhancing Th2-like immune responses.