tbuckley/cabot-search huggingface dataset:
The individual response to training and competition at altitude
Authors: Robert F Chapman
Journal: British Journal of Sports Medicine (2013)

Performance in athletic activities that include a significant aerobic component at mild or moderate altitudes shows a large individual variation. Physiologically, a large portion of the negative effect of altitude on exercise performance can be traced to limitations of oxygen diffusion, either at the level of the alveoli or the muscle microvasculature. In the lung, the ability to maintain arterial oxyhaemoglobin saturation (SaO 2 ) appears to be a primary factor, ultimately influencing oxygen delivery to the periphery. SaO 2 in hypoxia can be defended by increasing ventilatory drive; however, during heavy exercise, many athletes demonstrate limitations to expiratory flow and are unable to increase ventilation in hypoxia. Additionally, increasing ventilatory work in hypoxia may actually be negative for performance, if dyspnoea increases or muscle blood flow is reduced secondary to an increased sympathetic outflow (eg, the muscle metaboreflex response). Taken together, some athletes are clearly more negatively affected during exercise in hypoxia than other athletes. With careful screening, it may be possible to develop a protocol for determining which athletes may be the most negatively affected during competition and/or training at altitude.
Silencing of the Metastasis Suppressor RECK by RAS Oncogene Is Mediated by DNA Methyltransferase 3b–Induced Promoter Methylation
Authors: Hui-Chiu Chang, Chun-Yu Cho, Wen-Chun Hung
Journal: Cancer Research (2006)

Abstract RECK is a membrane-anchored glycoprotein that may negatively regulate matrix metalloproteinase activity to suppress tumor invasion and metastasis. Our previous study indicated that oncogenic RAS inhibited RECK expression via a histone deacetylation mechanism. In this study, we address whether DNA methyltransferases (DNMT) participate in the inhibition of RECK by RAS. Induction of Ha-RASVal12 oncogene increased DNMT3b, but not DNMT1 and DNMT3a, expression in 2-12 cells. In addition, induction of DNMT3b by RAS was through the extracellular signal-regulated kinase signaling pathway. Oncogenic RAS increased the binding of DNMT3b to the promoter of RECK gene and this binding induced promoter methylation, which could be reversed by 5′-azacytidine and DNMT3b small interfering RNA (siRNA). The MEK inhibitor U0126 also reversed RAS-induced DNMT3b binding and RECK promoter methylation. Treatment of 5′-azacytidine and DNMT3b siRNA restored RECK expression in 2-12 cells and potently suppressed RAS-stimulated cell invasion. In addition, the inhibitory effect of 5′-azacytidine on RAS-induced cell invasion was attenuated after knockdown of RECK by siRNA. Interestingly, human lung cancer cells harboring constitutively activated RAS exhibited lower RECK expression and higher promoter methylation of RECK gene. 5′-Azacytidine and DNMT3b siRNA restored RECK expression in these cells and effectively suppressed invasiveness. Collectively, our results suggest that RAS oncogene induces RECK gene silencing through DNMT3b-mediated promoter methylation, and DNMT inhibitors may be useful for the treatment of RAS-induced metastasis. (Cancer Res 2006; 66(17): 8413-20)
Prednisone-interferon combination in the treatment of chronic hepatitis B: Direct and indirect metanalysis
Authors: Marielle Cohard, Thierry Poynard, Philippe Mathurin, Jean Pierre Zarski
Journal: Hepatology (1994)

The aim of this study was to review all published randomized clinical trials evaluating the efficacy of a combination of prednisone and interferon in treatment of chronic hepatitis B and to subject these studies to metanalysis. Two types of metanalyses were carried out: direct metanalysis, comparing the prednisone-interferon combination with interferon on its own; and indirect metanalysis, comparing the treatment efficacy of prednisone-interferon and of interferon with control results. At the end of follow-up, four assessable end points were analyzed: HBeAg, hepatitis B virus DNA, HBsAg loss and serum ALT normalization rate. The direct metanalysis included seven trials comparing prednisone-interferon with interferon treatment. No significant differences were observed between the two types of therapy, for all the criteria given. However, in patients with low ALT levels, the prednisone-interferon combination gave significantly better results than interferon alone-HBeAg loss was 48% in the former group vs. 18.4% with interferon alone (p < 0.01). Fifteen trials compared interferon with control values; all end points were significantly improved. Seven trials compared prednisone-interferon with control results and showed all end points to be significantly improved by treatment. Indirect metanalysis showed that the differences in odds ratios for prednisone-interferon/control group and interferon/control group studies were negative for all assessable end points. In conclusion, the use of corticosteroids did not produce any significant increase in the efficacy of interferon treatment in adults with chronic hepatitis B and high initial ALT levels. However, it is possible that corticosteroids increased the HBeAg loss in the group of patients with low ALT levels. (Hepatology 1994;20:1390–1398).
Chlorination Disinfection By-Products and Risk of Congenital Anomalies in England and Wales
Authors: Mark J. Nieuwenhuijsen, Mireille B. Toledano, James Bennett, Nicky Best, Peter Hambly, Cornelis de Hoogh, Diana Wellesley, Patricia A. Boyd, Lenore Abramsky, Nirupa Dattani, John Fawell, David Briggs, Lars Jarup, Paul Elliott
Journal: Environmental Health Perspectives (2007)

BackgroundIncreased risk of various congenital anomalies has been reported to be associated with trihalomethane (THM) exposure in the water supply.ObjectivesWe conducted a registry-based study to determine the relationship between THM concentrations and the risk of congenital anomalies in England and Wales.MethodsWe obtained congenital anomaly data from the National Congenital Anomalies System, regional registries, and the national terminations registry; THM data were obtained from water companies. Total THM (&lt; 30, 30 to &lt; 60, ≥60 μg/L), total brominated exposure (&lt; 10, 10 to &lt; 20, ≥20 μg/L), and bromoform exposure (&lt; 2, 2 to &lt; 4, ≥4 μg/L) were modeled at the place of residence for the first trimester of pregnancy. We included 2,605,226 live births, stillbirths, and terminations with 22,828 cases of congenital anomalies. Analyses using fixed- and random-effects models were performed for broadly defined groups of anomalies (cleft palate/lip, abdominal wall, major cardiac, neural tube, urinary and respiratory defects), a more restricted set of anomalies with better ascertainment, and for isolated and multiple anomalies. Data were adjusted for sex, maternal age, and socioeconomic status.ResultsWe found no statistically significant trends across exposure categories for either the broadly defined or more restricted sets of anomalies. For the restricted set of anomalies with isolated defects, there were significant (p &lt; 0.05) excess risks in the high-exposure categories of total THMs for ventricular septal defects [odds ratio (OR) = 1.43; 95% confidence interval (CI), 1.00–2.04] and of bromoform for major cardiovascular defects and gastroschisis (OR = 1.18; 95% CI, 1.00–1.39; and OR = 1.38; 95% CI, 1.00–1.92, respectively).ConclusionIn this large national study we found little evidence for a relationship between THM concentrations in drinking water and risk of congenital anomalies.
Unknown primary carcinoma: natural history and prognostic factors in 657 consecutive patients.
Authors: J L Abbruzzese, M C Abbruzzese, K R Hess, M N Raber, R Lenzi, P Frost
Journal: Journal of Clinical Oncology (1994)

PURPOSE To evaluate the natural history, validate previous observations, and identify prognostic factors in patients with unknown primary carcinoma (UPC). PATIENTS AND METHODS Nine hundred twenty-seven consecutive patients referred to the M.D. Anderson Cancer Center with a preliminary diagnosis of UPC were prospectively identified. A standardized evaluation narrowed the study population to 657 patients with UPC. All data were recorded and computerized for storage, retrieval, and analysis. The primary end point for the study was survival, which was calculated from the first day of patient registration. Survival curves were estimated using the Kaplan-Meier method and compared using the Cox-Mantel log-rank test. To identify important prognostic factors, univariate and multivariate analyses were conducted. RESULTS The demographics of the UPC patient population mirrored those of the general population of patients referred to our cancer center except for an excess of men among the UPC patients. Most patients had histologic or cytologic evidence of adenocarcinoma and had more than one organ site metastatically involved. Univariate and multivariate analyses identified numerous important prognostic factors with a significant influence on survival, including sex, number of organ sites involved, specific organ sites involved, and pathologic subtypes. CONCLUSION This study validated previously identified important prognostic factors for survival in UPC. Additional variables that had an impact on survival were identified and the complex interaction of the factors was explored. As patient numbers increase, this database will be able to provide further analyses of patient subsets and potentially relate specific clinical features to the evolving molecular and biochemical understanding of these malignancies.
Comparison of registries of interstitial lung diseases in three European countries
Authors: M J Thomeer, U Costabe, G Rizzato, V Poletti, M Demedts
Journal: European Respiratory Journal (2001)

Few published studies have compared epidemiological data on the prevalence, incidence or relative frequency of the different interstitial lung diseases. In this review, the data of such registries from three countries in Europe (Belgium, Germany and Italy) are compared with those in the USA (Bernalillo County, NM). These registries show some striking similarities, but also discrepancies, which in part may be real, but may also be due to selection bias. Indeed, the registries in the European countries encompass the patients seen by pulmonologists, while the registry in Bernalillo County is based on a general population study in a limited area. In addition, in some studies, prevalences and incidences were registered, while in others, only prevalences or incidences were registered. Finally, most, but not all studies were prospective. Nonetheless, the different studies showed that sarcoidosis, idiopathic pulmonary fibrosis, hypersensitivity pneumonitis, interstitial lung diseases due to collagen vascular diseases and not-defined (or postinflammatory) fibrosis were most frequent. In the majority of disease entities a male predominance was found. Surprisingly large differences in the use of diagnostic techniques, such as high-resolution computed tomography, bronchoalveolar lavage, open lung biopsy and transbronchial lung biopsy, were noted between the different studies.
The Normal Child
Authors: I. Johnston
Journal: BMJ (2012)

Nuclear heme receptor reverse erythroblastosis virus (REV-ERB) <i>α</i> (a transcriptional repressor) is known to regulate cholesterol 7<i>α</i>-hydroxylase (CYP7A1) and bile acid synthesis. However, the mechanism for REV-ERB<i>α</i> regulation of CYP7A1 remains elusive. Here, we investigate the role of LRH-1 in REV-ERB<i>α</i> regulation of CYP7A1 and cholesterol metabolism. We first characterized the tertiary amine <i>N</i>-(4-chloro-2-methylbenzyl)-<i>N</i>-(4-chlorobenzyl)-1-(5-nitrothiophen-2-yl)methanamine (GSK2945) as a highly specific Rev-erb<i>α</i>/REV-ERB<i>α</i> antagonist using cell-based assays and confirmed expression of Rev-erb<i>α</i> in mouse liver. GSK2945 treatment increased hepatic mouse cholesterol 7<i>α</i>-hydroxylase (Cyp7a1) level and lowered plasma cholesterol in wild-type mice. Likewise, the compound increased the expression and microsomal activity of Cyp7a1 in hypercholesterolemic mice. This coincided with reduced plasma and liver cholesterol and enhanced production of bile acids. Increased levels of Cyp7a1/CYP7A1 were also found in mouse and human primary hepatocytes after GSK2945 treatment. In these experiments, we observed parallel increases in Lrh-1/LRH-1 (a known hepatic activator of Cyp7a1/CYP7A1) mRNA and protein. Luciferase reporter, mobility shift, and chromatin immunoprecipitation assays revealed that Lrh-1/LRH-1 was a direct Rev-erb<i>α</i>/REV-ERB<i>α</i> target gene. Furthermore, conditional deletion of Lrh-1 in the liver abrogated the regulatory effects of Rev-erb<i>α</i> on Cyp7a1 and cholesterol metabolism in mice. In conclusion, Rev-erb<i>α</i> regulates Cyp7a1 and cholesterol metabolism through its repression of the Lrh-1 receptor. Targeting the REV-ERB<i>α</i>/LRH-1 axis may represent a novel approach for management of cholesterol-related diseases.
Salicylates dilate blood vessels through inhibiting PYK2-mediated RhoA/Rho-kinase activation
Authors: Zhekang Ying, Fernanda R.C. Giachini, Rita C. Tostes, Robert Clinton Webb
Journal: Cardiovascular Research (2009)

Compared with other non-steroid anti-inflammatory drugs (NSAIDs), aspirin is not correlated to hypertension. It has been shown that aspirin has unique vasodilator action in vivo, offering an explanation for the unique blood pressure effect of aspirin. In the present study, we investigate the mechanism whereby salicylates (aspirin and sodium salicylate) dilate blood vessels. Rat aortic or mesenteric arterial rings were used to test the vascular effect of salicylates and other NSAIDs. RhoA translocation and the phosphorylation of MYPT1, the regulatory subunit of myosin light chain phosphatase, were measured by western blot, as evidenced for RhoA/Rho-kinase activation. Salicylates, but not other NSAIDs, relaxed contraction induced by most tested constrictors except for calyculin A, indicating that RhoA/Rho-kinase-mediated calcium sensitization is involved. The involvement of RhoA/Rho kinase in vasodilation by salicylates was confirmed by measurements of RhoA translocation and MYPT1 phosphorylation. The calculated half maximal inhibitory concentration (IC50) of vasodilation was apparently higher than that of cyclooxygenase inhibition, but comparable to that of proline-rich tyrosine kinase 2 (PYK2) inhibition. Over-expression of PYK2 induced RhoA translocation and MYPT1 phosphorylation, and these effects were markedly inhibited by sodium salicylate treatment. Consistent with the ex vitro vascular effects, sodium salicylate acutely decreased blood pressure in spontaneous hypertensive rats but not in Wistar Kyoto rats. Salicylates dilate blood vessels through inhibiting PYK2-mediated RhoA/Rho-kinase activation and thus lower blood pressure.
Estimation of heritability of different outcomes for genetic studies of TNFi response in patients with rheumatoid arthritis
Authors: Maša Umićević Mirkov, Luc Janss, Sita H Vermeulen, Mart A F J van de Laar, Piet L C M van Riel, Henk-Jan Guchelaar, Han G Brunner, Cornelis A Albers, Marieke J H Coenen
Journal: Annals of the Rheumatic Diseases (2014)

Pharmacogenetic studies of tumour necrosis factor inhibitors (TNFi) response in patients with rheumatoid arthritis (RA) have largely relied on the changes in complex disease scores, such as disease activity score 28 (DAS28), as a measure of treatment response. It is expected that genetic architecture of such complex score is heterogeneous and not very suitable for pharmacogenetic studies. We aimed to select the most optimal phenotype for TNFi response using heritability estimates.Using two linear mixed-modelling approaches (Bayz and GCTA), we estimated heritability, together with genomic and environmental correlations for the TNFi drug-response phenotype ΔDAS28 and its separate components: Δ swollen joint count (SJC), Δ tender joint count (TJC), Δ erythrocyte sedimentation rate (ESR) and Δ visual-analogue scale of general health (VAS-GH). For this, we used genome-wide single nucleotide polymorphism (SNP) data from 878 TNFi-treated Dutch patients with RA. Furthermore, a multivariate genome-wide association study (GWAS) approach was implemented, analysing separate DAS28 components simultaneously.The highest heritability estimates were found for ΔSJC (h(2)gbayz=0.76 and h(2)gGCTA=0.87) and ΔTJC (h(2)gbayz=0.62 and h(2)gGCTA=0.82); lower heritability was found for ΔDAS28 (h(2)gbayz=0.59 and h(2)gGCTA=0.71) while estimates for ΔESR and ΔVASGH were near or equal to zero. The highest genomic correlations were observed for ΔSJC and ΔTJC (0.49), and the highest environmental correlation was seen between ΔTJC and ΔVASGH (0.62). The multivariate GWAS did not generate excess of low p values as compared with a univariate analysis of ΔDAS28.Our results indicate that multiple SNPs together explain a substantial portion of the variation in change in joint counts in TNFi-treated patients with RA. In conclusion, of the outcomes studied, the joint counts are most suitable for TNFi pharmacogenetics in RA.
A critical role of serum response factor in myofibroblast differentiation during experimental oesophageal ulcer healing in rats
Authors: J. Chai, M. Norng, A. S Tarnawski, J. Chow
Journal: Gut (2006)

<b>Background:</b> Myofibroblast differentiation is a key event during wound healing and is triggered primarily by transforming growth factor β (TGFβ). Serum response factor (SRF) is a TGFβ-inducible transcription factor that is important for wound healing. Injection of SRF expression plasmid into rat gastric ulcers significantly accelerated restoration of epithelium and smooth muscle structures. <b>Aim:</b> To determine the role of SRF in oesophageal ulcer healing, especially in myofibroblast differentiation. <b>Subjects:</b> Rats (in vivo), oesophageal epithelial cells (Het1A) and fibroblasts (Rat1-R12) (in vitro) were used. <b>Methods:</b> Oesophageal ulcers were induced in rats with acetic acid and subsequently treated by local injection of plasmids expressing either SRF or SRF antisense sequence. Rats were killed at 1, 3, 6, 9 and 14 days after treatment and tissues collected. For in vitro studies, both Het1A and Rat1-R12 cells were transfected with the plasmids used in ulcer treatment. <b>Results:</b> Upregulation of SRF increased the myofibroblast population in ulcer granulation tissue; knockdown of SRF suppressed this event. In addition, ulceration induced SRF and TGFβ expression coordinately. In vitro studies showed that overexpression of SRF in either oesophageal epithelial cells or fibroblasts was sufficient to induce myofibroblast phenotype. Furthermore, the TGFβ-induced myofibroblast phenotype required integrin-linked kinase (ILK)-mediated SRF activation, as either knockdown of SRF or inactivation of ILK prevented this action. <b>Conclusions:</b> SRF is indispensable for myofibroblast differentiation during oesophageal ulcer healing and is required for TGFβ-induced myofibroblast transition from either epithelial cells or fibroblasts. ILK is a mediator in TGFβ-induced SRF activation and subsequent myofibroblast differentiation. ILK is associated with SRF, and TGFβ enhances this association.
Subcutaneous panniculitis-like T-cell lymphoma in a patient receiving etanercept for rheumatoid arthritis
Authors: C. Michot, V. Costes, D. Gerard-Dran, B. Guillot, B. Combes, O. Dereure
Journal: British Journal of Dermatology (2009)

Conflicts of interest: none declared. Sir, Etanercept, a tumour necrosis factor (TNF)‐α blocking agent, is currently used in inflammatory disorders including rheumatoid arthritis (RA), ankylosing spondylarthritis and psoriasis. A possibly higher risk of developing neoplasia including lymphoproliferative disorders cannot be ruled out.1 2–3 Indeed, an increasing number of systemic non‐Hodgkin lymphomas has been reported in patients receiving anti‐TNF‐α therapies, mainly of B‐cell phenotype, but there have also been individual cases of T‐cell lymphomas. Conversely, very few cases of cutaneous lymphoma have been reported in this setting, all of them of T‐cell phenotype.4–9 We report the first case of primary subcutaneous panniculitis‐like T‐cell lymphoma (SPTCL) in a patient treated with etanercept for RA. A 50‐year‐old women treated with etanercept during the past 6 years for aggressive RA with a good clinical result was referred for evaluation of multiple subcutaneous, indolent nodules of 1 year duration located on the limbs and the trunk. Clinical examination was otherwise unremarkable except for joint deformities. Biological tests showed leucopenia and erythropenia, a prominent inflammatory syndrome and normal lactate dehydrogenase, contrasting with a high β2‐microglobulin level (14·6 mg L−1). Histological examination of a subcutaneous nodule disclosed a proliferation of small, atypical cells bearing a α/β+ CD3+ CD8+ CD56− TIA‐1+ cytotoxic T‐cell phenotype and surrounding individual fat cells with occasional haemophagocytosis (Fig. 1a). A search for Epstein–Barr virus in lesions was negative. Bone marrow evaluation was normal. Positon emission tomography (PET) scan revealed numerous prominent hypermetabolic foci corresponding to inflammatory joints and subcutaneous nodules but no significant lymph node or visceral glucose uptake (Fig. 1b), whereas computed tomography (CT) scan did not show significant abnormality. A diagnosis of SPTCL was then established and etanercept was discontinued. After 3 months of treatment with bexarotene with poor tolerance, subsequent PET scan and CT scan led to a high suspicion of specific mediastinal infiltration and eight courses of systemic chemotherapy with cyclophosphamide, doxorubicin and vincristine were delivered with complete remission of both cutaneous and internal targets. The patient was alive and free of disease 16 months after initial diagnosis.
Anti-Ia antibody in the sera of normal subjects after in vivo antigenic stimulation.
Authors: K Okudaira, J S Goodwin, R C Williams
Journal: The Journal of Experimental Medicine (1982)

We showed that sera from normal subjects after antigenic challenge with intradermal PPD or Candida antigens or with subcutaneous tetanus vaccine contain a factor that blocks the binding of mouse monoclonal anti-Ia antibody to Ia-positive T cells or to B35 M cells, an Ia-positive human B cell line. The blocking activity appears 48 to 72 h after antigenic challenge and is gone by day 7. The appearance of the anti-Ia blocking activity coincided with a drop in the percentage of Ia-positive T cells and non-T cells in the peripheral blood of these subjects and also with a decrease in the density of surface Ia on the non-T cell population. The blocking was not genetically restricted; that is, serum from a given subject blocked anti-Ia binding to Ia-positive T cells of subjects with different DR haplotypes. The blocking activity was contained in the IgM fraction of the sera. The blocking activity of the sera was eliminated after absorption of the sera with Ia-positive but not with Ia-negative human cell lines. It would appear, therefore, that the blocking of monoclonal anti-Ia binding is caused by an IgM anti-Ia antibody that appears in normals after in vivo antigenic challenge.