tbuckley/cabot-search huggingface dataset:
Coeliac disease-associated risk variants in TNFAIP3 and REL implicate altered NF- B signalling
Authors: G. Trynka, A. Zhernakova, J. Romanos, L. Franke, K. A. Hunt, G. Turner, M. Bruinenberg, G. A. Heap, M. Platteel, A. W. Ryan, C. de Kovel, G. K. T. Holmes, P. D. Howdle, J. R. F. Walters, D. S. Sanders, C. J. J. Mulder, M. L. Mearin, W. H. M. Verbeek, V. Trimble, F. M. Stevens, D. Kelleher, D. Barisani, M. T. Bardella, R. McManus, D. A. van Heel, C. Wijmenga
Journal: Gut (2009)

<h3>Objective:</h3> Our previous coeliac disease genome-wide association study (GWAS) implicated risk variants in the human leucocyte antigen (HLA) region and eight novel risk regions. To identify more coeliac disease loci, we selected 458 single nucleotide polymorphisms (SNPs) that showed more modest association in the GWAS for genotyping and analysis in four independent cohorts. <h3>Design:</h3> 458 SNPs were assayed in 1682 cases and 3258 controls from three populations (UK, Irish and Dutch). We combined the results with the original GWAS cohort (767 UK cases and 1422 controls); six SNPs showed association with p&lt;1×10<sup>−04</sup> and were then genotyped in an independent Italian coeliac cohort (538 cases and 593 controls). <h3>Results:</h3> We identified two novel coeliac disease risk regions: 6q23.3 (<i>OLIG3-TNFAIP3</i>) and 2p16.1 (<i>REL</i>), both of which reached genome-wide significance in the combined analysis of all 2987 cases and 5273 controls (rs2327832 p = 1.3×10<sup>−08</sup>, and rs842647 p = 5.2×10<sup>−07</sup>). We investigated the expression of these genes in the RNA isolated from biopsies and from whole blood RNA. We did not observe any changes in gene expression, nor in the correlation of genotype with gene expression. <h3>Conclusions:</h3> Both <i>TNFAIP3</i> (A20, at the protein level) and <i>REL</i> are key mediators in the nuclear factor kappa B (NF-κB) inflammatory signalling pathway. For the first time, a role for primary heritable variation in this important biological pathway predisposing to coeliac disease has been identified. Currently, the HLA risk factors and the 10 established non-HLA risk factors explain ∼40% of the heritability of coeliac disease.
Re: Hypertension as a Biomarker of Efficacy in Patients With Metastatic Renal Cell Carcinoma Treated With Sunitinib
Authors: A. H. van den Meiracker, A. H. J. Danser, S. Sleijfer, M. H. W. Kappers
Journal: JNCI Journal of the National Cancer Institute (2011)

Rini et al. (1) reported a large retrospective analysis that showed that patients with metastatic renal cell carcinoma who developed hypertension when treated with the tyrosine kinase inhibitor sunitinib have improved overall survival and progressionfree survival compared with patients who remained free of hypertension. The authors concluded that the development of hypertension is a potential valuable biomarker for the prediction of treatment response. However, we wonder whether a categorical division of patients is the most appro
Gene Transfer to Ovarian Cancer Versus Normal Tissues with Fiber-Modified Adenoviruses
Authors: Anna Kanerva, Minghui Wang, Gerd J. Bauerschmitz, John T. Lam, Renee A. Desmond, Snehal M. Bhoola, Mack N. Barnes, Ronald D. Alvarez, Gene P. Siegal, David T. Curiel, Akseli Hemminki
Journal: Molecular Therapy (2002)

Adenovirus serotype 5 (Ad5) displays unparalleled gene transfer efficacy to cells with high coxsackie-adenovirus receptor (CAR) expression. Unfortunately, cells isolated from clinical human cancers, both ovarian and other types, express highly variable and often low levels of CAR. Fortunately, native Ad5 tropism can be modified to circumvent CAR deficiency and to enhance infectivity. Ad5/3luc1 incorporates the serotype 3 fiber knob and binds to a receptor distinct from CAR, while the fiber of Ad5lucRGD is modified with an RGD-4C motif, allowing CAR-independent binding to integrins. We studied the liver tropism and blood clearance of these viruses after intravenous (i.v.) injection, and biodistribution after intraperitoneal (i.p.) injection to tumor-bearing mice. To estimate efficacy, we assessed gene transfer to purified human primary ovarian cancer cells, and in a mouse model of ovarian cancer. Ad5/3luc1 achieved improved gene transfer over Ad5lucRGD, and both infectivity-enhanced viruses were superior to the isogenic control with an unmodified Ad5 capsid. In the presence of malignant ascites, gene transfer was improved with both Ad5/3luc1 and Ad5lucRGD. Thus, retargeting to the Ad3 receptor enhances gene transfer to clinically relevant ovarian cancer substrates, while the mouse toxicity and biodistribution profile of both fiber-modified Ad vectors is comparable to Ad5.
Emergency treatment of hypercalcaemia.
Authors: J A Child
Journal: BMJ (1977)

biopsies are necessary if such a claim is to be made.The changes in subepidermal IgA deposition reported in the paper would thus provide a useful additional basis for the assessment of a patient's progress.However, one would need to know that the pattem of IgA deposition did not show spontaneous variation before changes occurring over a period of six months could be confidently accepted as evidence of improvement.In consequence we are not yet convinced that the changes represent "a more objective and sensitive index of improvement in the skin than the ability to reduce dapsone," though the need for such an index is undisputed.
Activation of Tumor-Associated Macrophages by the Vascular Disrupting Agent 5,6-Dimethylxanthenone-4-Acetic Acid Induces an Effective CD8+ T-Cell–Mediated Antitumor Immune Response in Murine Models of Lung Cancer and Mesothelioma
Authors: Arminder S. Jassar, Eiji Suzuki, Veena Kapoor, Jing Sun, Michael B. Silverberg, Lumei Cheung, Marie D. Burdick, Robert M. Strieter, Lai-Ming Ching, Larry R. Kaiser, Steven M. Albelda
Journal: Cancer Research (2005)

5,6-Dimethylxanthenone-4-acetic acid (DMXAA) is a small molecule in the flavanoid class that has antitumor activity thought to be due to ability to induce high local levels of tumor necrosis factor (TNF)-alpha that disrupt established blood vessels within tumors. The drug has completed phase 1 testing in humans and is currently in phase 2 trials in combination with chemotherapy. Although characterized as a "vascular disrupting agent," there are some studies suggesting that DMXAA also has effects on the immune system that are important for its efficacy. The goal of this study was to carefully define the immune effects of DMXAA in a series of murine lung cancer and mesothelioma cell lines with varying immunologic characteristics. We show that DMXAA efficiently activated tumor-associated macrophages to release a variety of immunostimulatory cytokines and chemokines, including TNF-alpha; IFN-inducible protein-10; interleukin-6; macrophage inflammatory protein-2; monocyte chemotactic protein-1; and regulated on activation, normal T-cell expressed, and secreted. DMXAA treatment was highly effective in both small and large flank tumors. Animals cured of tumors by DMXAA generated a systemic memory response and were resistant to tumor cell rechallenge. DMXAA treatment led to initial tumor infiltration with macrophages that was followed by an influx of CD8(+) T cells. These CD8(+) T cells were required for antitumor efficacy because tumor inhibitory activity was lost in nude mice, mice depleted of CD8(+) T cells, and perforin knockout mice, but not in CD4(+) T-cell-depleted mice. These data show that activation of tumor-associated macrophages by DMXAA is an efficient way to generate a CD8(+) T-cell-dependent antitumor immune response even in animals with relatively nonimmunogenic tumors. Given these properties, DMXAA might also be useful in boosting other forms of immunotherapy.
Prognostic impact of acquisition of cytogenetic abnormalities during the course of chronic myelomonocytic leukemia
Authors: Guilin Tang, Bing Fu, Shimin Hu, Xinyan Lu, Zhenya Tang, Shaoying Li, Kausar Jabbar, Joseph D. Khoury, L. Jeffrey Medeiros, Sa A. Wang
Journal: American Journal of Hematology (2015)

Karyotypic abnormalities are detected in 20-40% of chronic myelomonocytic leukemia (CMML) patients at initial diagnosis and have been shown to correlate with patients' outcome. The significance of acquisition of cytogenetic abnormalities (ACA) during the course of CMML, however, is largely unknown. In a cohort of 314 CMML patients, karyotypic abnormalities were detected in 106 (34%) patients at the time of diagnosis; and ACA were detected in 80 (25%) patients after a median interval of 17 months (range, 2-117 months). The most frequently observed ACA were a complex karyotype, followed by +21, -7/del(7q), del(20q), i(17q), and -17/del(17p). ACA appeared to occur more frequently in patients with a normal or lower risk karyotype. Progression to AML was seen in 44 of 80 (55%) patients with ACA versus 67 of 234 (29%) patients without ACA (P < 0.0001). Presence of ACA predicted an inferior leukemia-free survival (LFS) by univariate (P = 0.0435) and multivariate analysis (HR = 1.892, P = 0.006). While acquisition of a complex karyotype was positively correlated with AML progression (P = 0.0086), del(20q) was associated with a stable disease (P = 0.0198). We conclude that ACA occur in ∼20-30% of CMML patients during the course of disease, and are significantly associated with AML progression and a shorter LFS. Karyotypic abnormalities, either present at diagnosis or acquired during the course of disease, have prognostic implication in CMML patients.
Intravenous iloprost for treatment failure of aerosolised iloprost in pulmonary arterial hypertension: Table 1—
Authors: M.M. Hoeper, E. Spiekerkoetter, V. Westerkamp, R. Gatzke, H. Fabel
Journal: European Respiratory Journal (2002)

Treatment with aerosolised iloprost, a prostacyclin analogue, has beneficial effects in patients with pulmonary arterial hypertension (PAH). It is unclear if patients, whose clinical condition deteriorates under treatment with aerosolised iloprost, benefit from switching to continuous intravenous iloprost. The current authors report on 16 patients with severe PAH who received continuous intravenous iloprost after primary or secondary failure of treatment with aerosolised iloprost. Determinants of efficacy were survival, New York Heart Association (NYHA) class, and walking distance in the 6‐min walk test. Of 93 patients with PAH treated with aerosolised iloprost, 16 required switching to intravenous iloprost for clinical deterioration. These patients had severe right heart failure with a cardiac index of 1.6±0.2 L·min −1 ·m −2 and a mixed-venous oxygen saturation of 52±6%. Five of these patients showed no improvement and eventually died. Three patients had further deterioration in NYHA class and exercise capacity; two of them underwent lung transplantation; the third patient is still alive. Eight patients showed marked clinical improvement; one underwent lung transplantation and the others are currently alive and stable. In the latter group of patients, the walking distance in the 6‐min walk test increased from 205±94 to 329±59 m. It was not possible to identify clinical or haemodynamic factors that would predict whether switching from inhaled to intravenous iloprost would have a beneficial effect. In patients with pulmonary arterial hypertension who deteriorated while being treated with aerosolised iloprost, switching to continuous intravenous iloprost caused substantial improvement in exercise capacity in eight of 16 patients but could not prevent progression of pulmonary hypertension in the remaining eight patients. Since it was impossible to predict the individual effects of this approach, intravenous prostaglandin treatment should be considered in pulmonary arterial hypertension patients who deteriorate while receiving iloprost aerosol.
Posterior sternoclavicular dislocation: an American football injury.
Authors: L B Marker, B Klareskov
Journal: British Journal of Sports Medicine (1996)

Posterior dislocation of the sternoclavicular joint is uncommon, accounting for less than 0.1% of all dislocations. Since 1824 a little more than 100 cases have been reported, and the majority in the past 20 years. A review of published reports suggests that this injury is seen particularly in connection with American football. A typical case is described. The importance of this injury is that there is often a delay in diagnosis with potentially serious complications.
First pass metabolism of ethanol is strikingly influenced by the speed of gastric emptying
Authors: C M Oneta, U A Simanowski, M Martinez, A Allali-Hassani, X Parés, N Homann, C Conradt, R Waldherr, W Fiehn, C Coutelle, H K Seitz
Journal: Gut (1998)

Background —Ethanol undergoes a first pass metabolism (FPM) in the stomach and liver. Gastric FPM of ethanol primarily depends on the activity of gastric alcohol dehydrogenase (ADH). In addition, the speed of gastric emptying (GE) may modulate both gastric and hepatic FPM of ethanol. Aims —To study the effect of modulation of GE on FPM of ethanol in the stomach and liver. Methods —Sixteen volunteers (eight men and eight women) received ethanol (0.225 g/kg body weight) orally and intravenously, and the areas under the ethanol concentration time curves were determined to calculate FPM of ethanol. In seven of these subjects, FPM of ethanol was measured after the intravenous administration of 10 mg metoclopramide (MCP) and 20 mg N -butylscopolamine (NBS) in separate experiments to either accelerate or delay GE. GE was monitored sonographically by integration of the antral area of the stomach every five minutes for 90 minutes after oral ethanol intake. In addition, gastric biopsy specimens were taken to determine ADH activity and phenotype, as well as to evaluate gastric histology. Blood was also drawn for ADH genotyping. Results —GE time was significantly delayed by the administration of NBS as compared with controls (p&lt;0.0001) and as compared with the administration of MCP (p&lt;0.0001). This was associated with a significantly enhanced FPM of ethanol with NBS compared with MCP (p = 0.0004). A significant correlation was noted between GE time and FPM of ethanol ( r = 0.43, p = 0.0407). Gastric ADH activity did not significantly correlate with FPM of ethanol. Conclusion —FPM of ethanol is strikingly modulated by the speed of GE. Delayed GE increases the time of exposure of ethanol to gastric ADH and may therefore increase gastric FPM of ethanol. In addition, hepatic FPM of ethanol may also be enhanced as the result of slower absorption of ethanol from the small intestine. Thus a knowledge of GE time is a major prerequisite for studying FPM of ethanol in humans.
Dependence receptors and colorectal cancer
Authors: Patrick Mehlen, Servane Tauszig-Delamasure
Journal: Gut (2014)

The research on colorectal cancer (CRC) biology has been leading the oncology field since the early 1990s. The search for genetic alterations has allowed the identification of the main tumour suppressors or oncogenes. Recent work obtained in CRC has unexpectedly proposed the existence of novel category of tumour suppressors, the so-called 'dependence receptors'. These transmembrane receptors behave as Dr Jekyll and Mr Hyde with two opposite sides: they induce a positive signalling (survival, proliferation, differentiation) in presence of their ligand, but are not inactive in the absence of their ligand and rather trigger apoptosis when unbound. This trait confers them a conditional tumour suppressor activity: they eliminate cells that grow abnormally in an environment offering a limited quantity of ligand. This review will describe how receptors such as deleted in colorectal carcinoma (DCC), uncoordinated 5 (UNC5), rearranged during transfection (RET) or TrkC constrain CRC progression and how this dependence receptor paradigm may open up therapeutical perspectives.
THYROID HORMONES IN SERIOUS NON-THYROIDAL ILLNESS
Authors: D.G. Mclarty, J.G. Ratcliffe, D.J. Sammon, W.A. Ratcliffe, K.E.L. Mccoll, H. Meinhold, K.W. Wenzel, R. Naeije, N. Clumeck, G. Somers, L. Vanhaelst, J. Golstein, Edith Piroska, János Földes
Journal: The Lancet (1976)
Transdiagnostic Cognitive-Behavioral Therapy for Patients With Eating Disorders: A Two-Site Trial With 60-Week Follow-Up
Authors: Christopher G. Fairburn, Zafra Cooper, Helen A. Doll, Marianne E. O’Connor, Kristin Bohn, Deborah M. Hawker, Jackie A. Wales, Robert L. Palmer
Journal: American Journal of Psychiatry (2008)

Objective: The aim of this study was to compare two cognitive-behavioral treatments for outpatients with eating disorders, one focusing solely on eating disorder features and the other a more complex treatment that also addresses mood intolerance, clinical perfectionism, low self-esteem, or interpersonal difficulties. Method: A total of 154 patients who had a DSM-IV eating disorder but were not markedly underweight (body mass index over 17.5), were enrolled in a two-site randomized controlled trial involving 20 weeks of treatment and a 60-week closed period of follow-up. The control condition was an 8-week waiting list period preceding treatment. Outcomes were measured by independent assessors who were blind to treatment condition. Results: Patients in the waiting list control condition exhibited little change in symptom severity, whereas those in the two treatment conditions exhibited substantial and equivalent change, which was well maintained during follow-up. At the 60-week follow-up assessment, 51.3% of the sample had a level of eating disorder features less than one standard deviation above the community mean. Treatment outcome did not depend on eating disorder diagnosis. Patients with marked mood intolerance, clinical perfectionism, low self-esteem, or interpersonal difficulties appeared to respond better to the more complex treatment, with the reverse pattern evident among the remaining patients. Conclusions: These two transdiagnostic treatments appear to be suitable for the majority of outpatients with an eating disorder. The simpler treatment may best be viewed as the default version, with the more complex treatment reserved for patients with marked additional psychopathology of the type targeted by the treatment.
Evaluation of Subclinical Organ Damage for Risk Assessment and Treatment in the Hypertensive Patient
Authors: Roberto Pontremoli, Giovanna Leoncini, Francesca Viazzi, Elena Ratto, Valentina Vaccaro, Valeria Falqui, Angelica Parodi, Novella Conti, Cinzia Tomolillo, Giacomo Deferrari
Journal: Journal of the American Society of Nephrology (2006)

Microalbuminuria, i.e., abnormal urinary excretion of albumin, which is detectable by low cost and widely available tests, is a first-line tool for identifying hypertensive patients who are at higher cardiovascular (CV) risk. Numerous studies have provided evidence that microalbuminuria is a concomitant of cardiac and vascular damage as well as a strong, independent predictor of CV events. An important, emerging issue is that the risk for CV morbidity and mortality is linearly related to urinary albumin excretion and persists well below the currently used cutoff for defining microalbuminuria. Furthermore, late-breaking evidence suggests that a reduction of albuminuria under antihypertensive treatment is paralleled by changes in CV risk. The routine search for target organ damage by means of microalbuminuria could lead to a significant improvement in the evaluation and treatment of patients with primary hypertension.
Tumor masses support naive T cell infiltration, activation, and differentiation into effectors
Authors: Elizabeth D. Thompson, Hilda L. Enriquez, Yang-Xin Fu, Victor H. Engelhard
Journal: The Journal of Experimental Medicine (2010)

Studies of T cell responses to tumors have focused on the draining lymph node (LN) as the site of activation. We examined the tumor mass as a potential site of activation after adoptive transfer of naive tumor-specific CD8 T cells. Activated CD8 T cells were present in tumors within 24 h of adoptive transfer and proliferation of these cells was also evident 4-5 d later in mice treated with FTY720 to prevent infiltration of cells activated in LNs. To confirm that activation of these T cells occurred in the tumor and not the tumor-draining LNs, we used mice lacking LNs. Activated and proliferating tumor-infiltrating lymphocytes were evident in these mice 24 h and 4 d after naive cell transfer. T cells activated within tumors acquired effector function that was evident both ex vivo and in vivo. Both cross-presenting antigen presenting cells within the tumor and tumor cells directly presenting antigen activated these functional CD8 effectors. We conclude that tumors support the infiltration, activation, and effector differentiation of naive CD8 T cells, despite the presence of immunosuppressive mechanisms. Thus, targeting of T cell activation to tumors may present a tool in the development of cancer immunotherapy.
The NLRP3 inflammasome is released as a particulate danger signal that amplifies the inflammatory response
Authors: Alberto Baroja-Mazo, Fatima Martín-Sánchez, Ana I Gomez, Carlos M Martínez, Joaquín Amores-Iniesta, Vincent Compan, Maria Barberà-Cremades, Jordi Yagüe, Estibaliz Ruiz-Ortiz, Jordi Antón, Segundo Buján, Isabelle Couillin, David Brough, Juan I Arostegui, Pablo Pelegrín
Journal: Nature Immunology (2014)
Endothelin Receptor Type B Counteracts Tenascin-C–Induced Endothelin Receptor Type A–Dependent Focal Adhesion and Actin Stress Fiber Disorganization
Authors: Katrin Lange, Martial Kammerer, Monika E. Hegi, Stefan Grotegut, Antje Dittmann, Wentao Huang, Erika Fluri, George W. Yip, Martin Götte, Christian Ruiz, Gertraud Orend
Journal: Cancer Research (2007)

Tenascin-C, an extracellular matrix molecule of the tumor-specific microenvironment, counteracts the tumor cell proliferation-suppressing effect of fibronectin by blocking the integrin alpha(5)beta(1)/syndecan-4 complex. This causes cell rounding and stimulates tumor cell proliferation. Tenascin-C also stimulates endothelin receptor type A (EDNRA) expression. Here, we investigated whether signaling through endothelin receptors affects tenascin-C-induced cell rounding. We observed that endothelin receptor type B (EDNRB) activation inhibited cell rounding by tenascin-C and induced spreading by restoring expression and function of focal adhesion kinase (FAK), paxillin, RhoA, and tropomyosin-1 (TM1) via activation of epidermal growth factor receptor, phospholipase C, c-Jun NH(2)-terminal kinase, and the phosphatidylinositol 3-kinase pathway. In contrast to EDNRB, signaling through EDNRA induced cell rounding, which correlated with FAK inhibition and TM1 and RhoA protein destabilization in the presence of tenascin-C. This occurred in a mitogen-activated protein kinase/extracellular signal-regulated kinase kinase-dependent manner. Thus, tumorigenesis might be enhanced by tenascin-C involving EDNRA signaling. Inhibition of tenascin-C in combination with blocking both endothelin receptors could present a strategy for sensitization of cancer and endothelial cells toward anoikis.