tbuckley/cabot-search huggingface dataset:
A genome-wide association study reveals evidence of association with sarcoidosis at 6p12.1
Authors: S. Hofmann, A. Fischer, A. Till, J. Müller-Quernheim, R. Häsler, A. Franke, K.I. Gäde, H. Schaarschmidt, P. Rosenstiel, A. Nebel, M. Schürmann, M. Nothnagel, S. Schreiber
Journal: European Respiratory Journal (2011)

Sarcoidosis is a complex systemic inflammatory disease of unknown aetiology that is influenced by a variety of genetic and environmental factors. To identify further susceptibility loci for sarcoidosis, a genome-wide association study (GWAS) was conducted in 381 patients and 392 control individuals based on Affymetrix 100k GeneChip data. The top 25 single-nucleotide polymorphisms (SNPs) were selected for validation in an independent study panel (1,582 patients versus 1,783 controls). Variant rs10484410 on chromosome 6p12.1 was significantly associated, with a Bonferroni-corrected p-value of 2.90 × 10⁻² in the validation sample and a nominal p-value of 2.64 × 10⁻⁴ in the GWAS. Extensive fine mapping of the novel locus narrowed down the signal to a region comprising the genes BAG2, C6orf65, KIAA1586, ZNF451 and RAB23. Verification of the sarcoidosis-associated nonsynonymous SNP rs1040461 in a further independent case-control sample and quantitative mRNA expression studies point to the RAB23 gene as the most likely risk factor. RAB23 is proposed to be involved in antibacterial defence processes and regulation of the sonic hedgehog signalling pathway. The identified association of the 6p12.1 locus with sarcoidosis implicates this locus as a further susceptibility factor and RAB23 as a potential signalling component that may open up new perspectives in the pathophysiology of sarcoidosis.
A novel mechanism for the generation of superoxide anions in hematoporphyrin derivative-mediated cutaneous photosensitization. Activation of the xanthine oxidase pathway.
Authors: M Athar, C A Elmets, D R Bickers, H Mukhtar
Journal: Journal of Clinical Investigation (1989)

Prior studies, both in vitro and in vivo, have suggested that cutaneous porphyrin photosensitization requires the generation of superoxide anion (.O2-) and various other reactive oxygen metabolites. No unifying concept has emerged, however, that unequivocally demonstrates the source of generation of these species. Since xanthine oxidase is known to generate .O2- in reperfused ischemic tissue and in certain inflammatory disorders, we attempted to assess its role in porphyrin photosensitization. C3H mice were rendered photosensitive by the intraperitoneal administration of dihematoporphyrin ether (DHE) (5 mg/kg) followed by irradiation with visible light. Murine ear swelling was used as a marker of the acute photosensitization response and involvement of oxygen radicals was evaluated using electron spin resonance (ESR) spectroscopy. The administration of allopurinol, a potent inhibitor of xanthine oxidase, afforded 90% protection against DHE-mediated acute photosensitivity in vivo. Furthermore, xanthine oxidase activity was twofold higher in the skin of photosensitized mice than in unirradiated animals. ESR spectra of 5,5-dimethyl-1-pyrroline N-oxide-trapped radicals from the skin of photosensitized mice verified the presence of .O2- and .OH, while neither of these species was detected in the skin of control mice or mice receiving allopurinol. The administration of a soybean trypsin inhibitor or verapamil before irradiation also partially blocked the photosensitivity response, suggesting that calcium-dependent proteases play a role in the activation of xanthine oxidase in this photodynamic process. These data provide in vivo evidence for the involvement of .O2- in DHE-mediated cutaneous photosensitization and suggest that these radicals are generated through the activation of the xanthine oxidase pathway. The administration of allopurinol and calcium channel blockers may thus offer new approaches for the treatment of cutaneous porphyrin photosensitization.
Basal Supplementation of Insulin Lispro Protamine Suspension Versus Insulin Glargine and Detemir for Type 2 Diabetes
Authors: Katherine Esposito, Paolo Chiodini, Annalisa Capuano, Michela Petrizzo, Maria Rosaria Improta, Dario Giugliano
Journal: Diabetes Care (2012)

OBJECTIVE We compared the effect of insulin lispro protamine suspension (ILPS) with that of insulin glargine and insulin detemir, all given as basal supplementation, in the treatment of patients with type 2 diabetes. RESEARCH DESIGN AND METHODS We conducted an electronic search until February 2012, including online registries of ongoing trials and abstract books. All randomized controlled trials comparing ILPS with insulin glargine or detemir with a duration of ≥12 weeks were included. RESULTS We found four trials lasting 24–36 weeks involving 1,336 persons: three studies compared ILPS with glargine, and one trial compared ILPS with detemir. There was no significant difference in change in HbA1c level between ILPS and comparators, in the proportion of patients achieving the HbA1c goals of ≤6.5 or &amp;lt;7%, in weight change, or in daily insulin doses. There was no difference in overall hypoglycemia, but nocturnal hypoglycemia occurred significantly more with ILPS than with comparator insulins (mean difference 0.099 events/patient/30 days [95% CI 0.03–0.17]). In a prespecified sensitivity analysis comparing data obtained in patients who remained on their once-daily insulin regimen, not significantly different event rates for nocturnal hypoglycemia were observed between ILPS and comparator insulins (0.063 [−0.007 to 0.13]), and ILPS was associated with lower insulin dose (0.07 units/kg/day [0.05–0.09]). CONCLUSIONS There is no difference between ILPS and insulin glargine or detemir for targeting hyperglycemia, but nocturnal hypoglycemia occurred more frequently with ILPS than with comparator insulins. Nocturnal hypoglycemia was not significantly different in people who injected insulin once daily.
Prognostic Analysis of E-Cadherin Gene Promoter Hypermethylation in Patients with Surgically Resected, Node-Positive, Diffuse Gastric Cancer
Authors: Francesco Graziano, Federica Arduini, Annamaria Ruzzo, Italo Bearzi, Bostjan Humar, Helen More, Rosarita Silva, Pietro Muretto, Parry Guilford, Enrica Testa, Davide Mari, Mauro Magnani, Stefano Cascinu
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Recent investigations have demonstrated that hypermethylation is a frequent mechanism for silencing tumor suppressor genes. This is a potentially reversible epigenetic change, and it is the target of a novel class of anticancer compounds with demethylating activity. Better understanding of the clinical implications of hypermethylation will allow the optimal planning of future trials with demethylating drugs. In this perspective, we investigated whether hypermethylation in the CDH1 promoter region is correlated with poor prognosis of patients with surgically resected, node-positive, diffuse gastric cancer. Experimental Design: Consecutive cases of diffuse gastric cancer were considered eligible for study entry. Additional inclusion criteria were radical surgery with a minimum of D1 lymphadenectomy, complete follow-up information, and availability of tumor specimens for methylation-specific PCR and immunohistochemistry analyses. Results: CDH1 promoter hypermethylation was found in 40 of 73 cases (54%), and it was significantly associated with worse prognosis. In patients with and without hypermethylation, the 5-year event-free survival rate was 30% and 62%, respectively, and the 5-year overall survival rate was 35% and 67%, respectively. CDH1 promoter hypermethylation retained its prognostic role for disease-free survival (P &amp;lt; 0.001) and overall survival (P &amp;lt; 0.001) in multivariate analysis. Immunohistochemistry showed a significant association between CDH1 methylation and E-cadherin expression (P &amp;lt; 0.001). Conclusions: This study shows adverse prognostic effect of CDH1 promoter hypermethylation in patients with diffuse gastric cancer. This form of cancer, and other types with frequent hypermethylation and silencing of critical tumor suppressor genes, would make appropriate targets for the testing of novel compounds with demethylating activity.
KIT and PDGFRα mutations in 104 patients with gastrointestinal stromal tumors (GISTs): a population-based study
Authors: C. Braconi, R. Bracci, I. Bearzi, F. Bianchi, A. Costagliola, R. Catalani, A. Mandolesi, R. Ranaldi, E. Galizia, S. Cascinu, G. Rossi, L. Giustini, L. Latini, N. Valeri, R. Cellerino
Journal: Annals of Oncology (2008)
Expression of the thymus leukemia antigen by activated peripheral T lymphocytes.
Authors: R G Cook, N F Landolfi
Journal: The Journal of Experimental Medicine (1983)

Peripheral T lymphocytes activated in vitro with concanavalin A (Con A) or alloantigens express the thymus leukemia (TL) alloantigen as assessed by staining with the monoclonal antibody TL.m3 and flow cytometric analysis. The determinants detected by TL.m3 on activated cells are encoded within the Tla region and are detected as early as 48 h after activation with Con A. Several long-term cloned cytotoxic T lymphocyte lines were also examined and each expressed TL. By two-dimensional analysis, the TL isolated from activated peripheral cells was indistinguishable from that found on thymocytes and the leukemia cell line ASL-1.
Running on Empty: Cardiovascular Reserve Capacity and Late Effects of Therapy in Cancer Survivorship
Authors: Graeme J. Koelwyn, Michel Khouri, John R. Mackey, Pamela S. Douglas, Lee W. Jones
Journal: Journal of Clinical Oncology (2012)

Seminal investigations by Frank 1 and Starling 2 provided thefirst evidence that the heart possesses inherent reserve capacity—a key principle that is a pillar of modern cardiology research and practice. After 150 years of research, we now understand that cardiovascular reserve capacity (CVRC) is determined by the integrative ability of cross-system mechanisms (eg, neurohormonal, central, and peripheral oxygen delivery 3 ), which collectively possess remarkable adaptive capacity. Sequential as well as concurrent pathologic perturbations to either one or more of these mechanisms are offset by initial compensatory adaptive responses in other component systems to maintain whole-body homeostatic regulation—a process termed coordinated adaptation. 4 Unfortunately, CVRC is finite, and continued insults ultimately lead to overt dysfunction (eg, acute coronary syndromes, left ventricular dysfunction). Pathologic impairments in CVRC are etiologicinmanychronicdiseaseconditionsandarethusanintegralconsiderationindailypractice.Thepurposeofthiscommentaryistoprovidean overviewoftheguidingprinciplesandapplicationofCVRCintheoncology setting using early breast cancer as an illustrative model. Measurement of CVRC
Stimulation of soluble guanylate cyclase reduces experimental dermal fibrosis
Authors: Christian Beyer, Nicole Reich, Sonia C Schindler, Alfiya Akhmetshina, Clara Dees, Michal Tomcik, Claudia Hirth-Dietrich, Georges von Degenfeld, Peter Sandner, Oliver Distler, Georg Schett, Jörg H W Distler
Journal: Annals of the Rheumatic Diseases (2012)

Fibrosis and vascular disease are cardinal features of systemic sclerosis (SSc). Stimulators of soluble guanylate cyclase (sGC) are vasoactive drugs that are currently being evaluated in phase III clinical trials for pulmonary arterial hypertension.To study the antifibrotic potency of sGC stimulators.The effect of the sGC stimulator BAY 41-2272 on the release of collagen from dermal fibroblasts was examined. The antifibrotic effects of BAY 41-2272 on prevention and regression of fibrosis in bleomycin-induced dermal fibrosis and in Tsk-1 mice were also studied. Telemetric blood pressure studies in conscious mice were used to study potential hypotensive effects of sGC stimulation.sGC stimulation with BAY 41-2272 dose-dependently inhibited collagen release in dermal fibroblasts from patients with SSc and healthy individuals. Furthermore, BAY 41-2272 stopped the development of bleomycin-induced dermal fibrosis and skin fibrosis in Tsk-1 mice, preventing dermal and hypodermal thickening, reducing the numbers of myofibroblasts and reducing the hydroxyproline content. In addition, BAY 41-2272 was highly effective in the treatment of established fibrosis in the modified models of bleomycin-induced skin fibrosis and Tsk-1 mice. Treatment with sGC stimulators was well tolerated. Relevant antifibrotic doses of BAY 41-2272 did not affect systemic blood pressure and heart rate in mice.These findings demonstrate potent antifibrotic effects and good tolerability of sGC stimulators in various experimental models of SSc. Given their potential vasoactive properties, sGC stimulators may be promising candidates for the dual treatment of fibrosis and vascular disease in SSc.
Is there more than one inflammatory phenotype in asthma?
Authors: R A O'Donnell
Journal: Thorax (2002)

Circumstantial evidence suggests an important role for neutrophilic airways inflammation in addition to eosinophilic airways inflammation in non-severe asthma.

The existence of different clinical phenotypes of asthma is a concept that has excited considerable interest in academic, clinical, and pharmaceutical quarters. The source of this confusion goes back to the original Greek definition of asthma as a description for transient breathlessness. The ancients recognised that the symptoms of asthma could be triggered by cardiac or bronchial disease. The term “cardiac asthma” has been replaced by the physiological and pathological definitions of left ventricular failure and pulmonary oedema. Within bronchial asthma, definitions have continued to focus on physiological measurements and clinical context, including exercise induced asthma, nocturnal asthma, acute severe asthma, occupational asthma, etc. Implicit in these clinical phenotypes is the unspoken assumption that the clinical context dictates the pathophysiological mechanism. The demonstration that eosinophilic inflammation is a characteristic feature of many asthmatic airways led, during the 1990s, to the unhealthy and erroneous view that all asthma might be caused by eosinophils. Indeed, at one stage asthma was in danger of being defined for pharmaceutical purposes as eosinophilic airways inflammation. The few dissenting voices were drowned out by a series of studies showing the “anti-inflammatory” effects of anti-asthma drugs by virtue of a proxy effect on airways eosinophilic. Given the known dependence of eosinophils on T cells and cytokines such as interleukin 5 (IL-5), a further dogma arose that all asthma was orchestrated by T cells producing IL-5 and IL-4, the Th2 cytokines.

This issue of Thorax features a hypothesis paper by Douwes et al 1 that questions the assumption that Th2 driven allergic inflammation is the pathogenetic mechanism behind the majority of cases of asthma. Douwes and colleagues draw from several sources of evidence to argue that non-allergic, non-eosinophilic asthma …
Lower risk of atopic disorders in whole cell pertussis-vaccinated children
Authors: R.M.D. Bernsen, J.C. de Jongste, J.C. van der Wouden
Journal: European Respiratory Journal (2003)

This study addressed whether whole cell pertussis-vaccinated children have a different risk of atopic disorders compared with children who did not receive this vaccination. Data on vaccination status, atopic disorders and child and family characteristics of the children of 700 families were collected in this retrospective study. A minority of these 700 families refused vaccinations for religious reasons. The relation between pertussis-vaccination status and atopic disorders was analysed by means of adjusted logistic regression for repeated measurements in order to account for the correlation between sibship members. The 700 families included 1,961 children. Data on vaccination status and atopic disorders were available for 1,724 children. Vaccinated children had a reduced risk of atopic disorders. Whole cell pertussis vaccination is associated with a lower risk of atopic disorders, though other vaccine components (diphtheria, tetanus, poliomyelitis) or other vaccinations may also be involved.
Synergistic effects of angiotensin-converting enzyme and angiotensin-II type 1 receptor gene polymorphisms on risk of myocardial infarction
Authors: L Tiret, P Ducimetière, A Bonnardeaux, F Soubrier, O Poirier, S Ricard, F Cambien, P Marques-Vidal, A Evans, F Kee, D Arveiler, G Luc
Journal: The Lancet (1994)
SMAD4 Immunohistochemistry Reflects Genetic Status in Juvenile Polyposis Syndrome
Authors: Danielle Langeveld, W. Arnout van Hattem, Wendy W.J. de Leng, Folkert H. Morsink, Fiebo J.W. ten Kate, Francis M. Giardiello, G. Johan A. Offerhaus, Lodewijk A.A. Brosens
Journal: Clinical Cancer Research (2010)

Abstract Purpose: Juvenile polyposis syndrome (JPS) can be caused by a germline defect of the SMAD4 gene. Somatic inactivation of SMAD4 occurs in pancreatic and colorectal cancers and is reflected by loss of SMAD4 immunohistochemistry. Here, SMAD4 immunohistochemistry as a marker of SMAD4 gene status and the role of SMAD4 in the adenoma-carcinoma sequence in neoplastic progression in JPS are studied. Experimental Design: Twenty polyps with a SMAD4 germline defect and 38 control polyps were studied by SMAD4 immunohistochemistry. Inactivation of the SMAD4 wild-type allele was studied in dysplastic epithelium and in areas with aberrant SMAD4 expression. APC, β-catenin, p53, and K-ras were studied to evaluate the adenoma-carcinoma sequence. Results: Nine of 20 polyps with a SMAD4 germline defect showed loss of epithelial SMAD4 expression. Loss of heterozygosity of SMAD4 was found in five polyps and a somatic stop codon mutation was found in two polyps without loss of heterozygosity. Remarkably, somatic inactivation of epithelial SMAD4 did not always coincide with dysplasia and aberrant p53 staining was found in four of six dysplastic polyps with normal SMAD4 staining. One K-ras mutation was found in nine juvenile polyps with dysplasia. No evidence for Wnt activation was found. Conclusions: SMAD4 immunohistochemistry mirrors genetic status and provides a specific adjunct in the molecular diagnosis of JPS. However, epithelial SMAD4 inactivation is not required for polyp formation and is not obligatory for neoplastic progression in JPS. Instead, different routes to neoplasia in JPS caused by germline SMAD4 mutation seem to be operative, including somatic loss of SMAD4 and p53 inactivation without somatic loss of SMAD4. Clin Cancer Res; 16(16); 4126–34. ©2010 AACR.
Peripheral nerve injuries in the athlete
Authors: P McCrory
Journal: British Journal of Sports Medicine (2005)

Edited by J H Fienberg, N I Spielholz. Published by Human Kinetics, 2003, pp 280, £38.00, hardcover. ISBN 0736044906

Increasingly it has been recognised that neurological problems, such as nerve entrapment syndromes, contribute to a variety of exercise related problems in athletes. This increased awareness is reflected by the large number of books as well as review articles currently available on the topic of nerve injuries. This new book by Fienberg and Spielholz is yet another addition to this area. The book reads as being written primarily by rehabilitation physicians or physiatrists rather …
The prophet of nudge
Authors: L. Farrell
Journal: BMJ (2011)

“Life’s not fair,” I raged. “Why does god always take the smokers first?”

I was watching Joe’s funeral. The church is inconveniently situated beside our health centre, and I usually duck out of sight as the cortege looks over accusingly. If I’m spotted someone is sure to shout, “You should have sent him for that x ray” or “I told you he needed a strong antibiotic.” 

Strong? I feel like shouting back. “It was so strong we had to store it on …
High frequency of early colorectal cancer in inflammatory bowel disease
Authors: M W M D Lutgens, F P Vleggaar, M E I Schipper, P C F Stokkers, C J van der Woude, D W Hommes, D J de Jong, G Dijkstra, A A van Bodegraven, B Oldenburg, M Samsom
Journal: Gut (2008)

<h3>Background and aim:</h3> To detect precancerous dysplasia or asymptomatic cancer, patients suffering from inflammatory bowel disease often undergo colonoscopic surveillance based on American or British guidelines. It is recommended that surveillance is initiated after 8–10 years of extensive colitis, or after 15–20 years for left-sided disease. These starting points, however, are not based on solid scientific evidence. Our aim was to assess the time interval between onset of inflammatory bowel disease (IBD) and colorectal carcinoma (CRC), and subsequently evaluate how many patients developed cancer before their surveillance was recommended to commence. <h3>Methods:</h3> A nationwide automated pathology database (PALGA) was consulted to identify patients with IBD-associated colorectal carcinoma in seven university medical centres in The Netherlands between January 1990 and June 2006. Data were collected retrospectively from patient charts. Time intervals between onset of disease and cancer diagnosis were calculated in months. <h3>Results:</h3> 149 patients were identified with confirmed diagnoses of IBD and CRC (ulcerative colitis n = 89/Crohn's disease n = 59/indeterminate colitis n = 1). Taking <i>date of diagnosis</i> as the entry point, 22% of patients developed cancer before the 8 or 15 year starting points of surveillance, and 28% if surveillance was commenced 10 or 20 years after diagnosis for extensive or left-sided disease, respectively. Using <i>onset of symptoms</i> to calculate the time interval, 17–22% of patients would present with cancer prior to the surveillance starting points. <h3>Conclusions:</h3> These results show that the diagnosis of colorectal cancer is delayed or missed in a substantial number of patients (17–28%) when conducting surveillance strictly according to formal guidelines.
Specific plasma membrane receptors for reovirus on rat pituitary cells in culture.
Authors: E Maratos-Flier, C R Kahn, D R Spriggs, B N Fields
Journal: Journal of Clinical Investigation (1983)

Specific cellular and host tropism is a characteristic property of many viruses mediated by the interaction of viral attachment proteins with components of the plasma membrane of the cell. We have studied the binding of virus to cells quantitatively by using type 3 reovirus labeled with 125I and GH4C1 pituitary cells in culture. Binding was rapid at both 4 degrees and 15 degrees C and was stable over a 9-h period. Unlabeled virus inhibited binding of the labeled virus in a dose-dependent manner. Scatchard analysis revealed 4,200 viral binding sites/cell with an apparent affinity of 1.2 X 10(-11) M. Also, binding of type 3 reovirus was inhibited by antibodies directed against the viral hemagglutinin and partially inhibited by type 2 reovirus, but was unaffected by type 1 reovirus or a variety of other ligands that bind to receptors on GH4C1 cells. These data indicate that reovirus binds to a high affinity, specific receptor on target cells, which may control its tropism and ultimate disease expression.