tbuckley/cabot-search huggingface dataset:
Recurrent Mutations of <i>MYD88</i> and <i>TBL1XR1</i> in Primary Central Nervous System Lymphomas
Authors: Alberto Gonzalez-Aguilar, Ahmed Idbaih, Blandine Boisselier, Naïma Habbita, Marta Rossetto, Alice Laurenge, Aurélie Bruno, Anne Jouvet, Marc Polivka, Clovis Adam, Dominique Figarella-Branger, Catherine Miquel, Anne Vital, Hervé Ghesquières, Rémy Gressin, Vincent Delwail, Luc Taillandier, Olivier Chinot, Pierre Soubeyran, Emmanuel Gyan, Sylvain Choquet, Caroline Houillier, Carole Soussain, Marie-Laure Tanguy, Yannick Marie, Karima Mokhtari, Khê Hoang-Xuan
Journal: Clinical Cancer Research (2012)

Abstract Purpose: Our objective was to identify the genetic changes involved in primary central nervous system lymphoma (PCNSL) oncogenesis and evaluate their clinical relevance. Experimental Design: We investigated a series of 29 newly diagnosed, HIV-negative, PCNSL patients using high-resolution single-nucleotide polymorphism (SNP) arrays (n = 29) and whole-exome sequencing (n = 4) approaches. Recurrent homozygous deletions and somatic gene mutations found were validated by quantitative real-time PCR and Sanger sequencing, respectively. Molecular results were correlated with prognosis. Results: All PCNSLs were diffuse large B-cell lymphomas, and the patients received chemotherapy without radiotherapy as initial treatment. The SNP analysis revealed recurrent large and focal chromosome imbalances that target candidate genes in PCNSL oncogenesis. The most frequent genomic abnormalities were (i) 6p21.32 loss (HLA locus), (ii) 6q loss, (iii) CDKN2A homozygous deletions, (iv) 12q12-q22, and (v) chromosome 7q21 and 7q31 gains. Homozygous deletions of PRMD1, TOX, and DOCK5 and the amplification of HDAC9 were also detected. Sequencing of matched tumor and blood DNA samples identified novel somatic mutations in MYD88 and TBL1XR1 in 38% and 14% of the cases, respectively. The correlation of genetic abnormalities with clinical outcomes using multivariate analysis showed that 6q22 loss (P = 0.006 and P = 0.01) and CDKN2A homozygous deletion (P = 0.02 and P = 0.01) were significantly associated with shorter progression-free survival and overall survival. Conclusions: Our study provides new insights into the molecular tumorigenesis of PCNSL and identifies novel genetic alterations in this disease, especially MYD88 and TBL1XR1 mutations activating the NF-κB signaling pathway, which may be promising targets for future therapeutic strategies. Clin Cancer Res; 18(19); 5203–11. ©2012 AACR.
M1/MUC5AC mucin released by human airways in vitro
Authors: C. Labat, J. Bara, J-P. Gascard, H. Sosse-Alaoui, V. Thomas de Montpreville, M. Yeadon, C. Brink
Journal: European Respiratory Journal (1999)

A series of monoclonal antibodies which bind to a mucin known as M1 (anti-M1 MAbs) have also been shown to detect the product of the human gene MUC5AC. The aim of this investigation was to determine the concentration of the M1 mucin in the surface epithelium of human bronchial preparations by means of immunohistochemistry and in the bronchial fluid derived from human airways by means of an immunoradiometric assay. Human bronchial ring preparations from the resection material of 20 patients were challenged with methacholine, leukotriene D4, or anti-immunoglobulin E. Experiments were performed in preparations with an intact epithelium as well as in tissues in which the epithelium had been mechanically removed. The anti-M1 MAbs stained the goblet cells in the epithelium intensely and there was also light and less uniform staining in the submucosa. The M1/MUC5AC mucin in the fluids secreted by the bronchial preparations was not modified during either the experimental protocol or stimulation with the different secretagogues. However, in preparations in which the epithelium had been removed, there was a significant reduction in the amount of M1/MUC5AC mucin detected. These data suggest that the M1/MUC5AC mucin detected in the biological fluids produced by human airways in vitro may be released constantly, and principally from the goblet cells in the epithelial layer.
Increased Prevalence of Dihydropyrimidine Dehydrogenase Deficiency in African-Americans Compared with Caucasians
Authors: Lori Kay Mattison, Jeanne Fourie, Renee A. Desmond, Anil Modak, Muhammad Wasif Saif, Robert B. Diasio
Journal: Clinical Cancer Research (2006)

Abstract Purpose: African-American patients with colorectal cancer were observed to have increased 5-fluorouracil (5-FU)–associated toxicity (leukopenia and anemia) and decreased overall survival compared with Caucasian patients. One potential source for this disparity may be differences in 5-FU metabolism. Dihydropyrimidine dehydrogenase (DPD), the initial and rate-limiting enzyme of 5-FU catabolism, has previously been shown to have significant interpatient variability in activity. Several studies have linked reduced DPD activity to the development of 5-FU toxicity. Although the distribution of DPD enzyme activity and the frequency of DPD deficiency have been well characterized in the Caucasian population, the distribution of DPD enzyme activity and the frequency of DPD deficiency in the African-American population are unknown. Experimental Design: Healthy African-American (n = 149) and Caucasian (n = 109) volunteers were evaluated for DPD deficiency using both the [2-13C]uracil breath test and peripheral blood mononuclear cell DPD radioassay. Results: African-Americans showed significantly reduced peripheral blood mononuclear cell DPD enzyme activity compared with Caucasians (0.26 ± 0.07 and 0.29 ± 0.07 nmol/min/mg, respectively; P = 0.002). The prevalence of DPD deficiency was 3-fold higher in African-Americans compared with Caucasians (8.0% and 2.8%, respectively; P = 0.07). African-American women showed the highest prevalence of DPD deficiency compared with African-American men, Caucasian women, and Caucasian men (12.3%, 4.0%, 3.5%, and 1.9%, respectively). Conclusion: These results indicate that African-Americans, particularly African-American women, have significantly reduced DPD enzyme activity compared with Caucasians, which may predispose this population to more 5-FU toxicity.
Dealcoholized Red Wine Decreases Systolic and Diastolic Blood Pressure and Increases Plasma Nitric Oxide
Authors: Gemma Chiva-Blanch, Mireia Urpi-Sarda, Emilio Ros, Sara Arranz, Palmira Valderas-Martínez, Rosa Casas, Emilio Sacanella, Rafael Llorach, Rosa M. Lamuela-Raventos, Cristina Andres-Lacueva, Ramon Estruch
Journal: Circulation Research (2012)

Experimental studies have shown a potential blood pressure (BP) lowering effect of red wine polyphenols, whereas the effects of ethanol and polyphenols on BP in humans are not yet clear.The aim of the present work was to evaluate the effects of red wine fractions (alcoholic and nonalcoholic) on BP and plasma nitric oxide (NO) in subjects at high cardiovascular risk.Sixty-seven men at high cardiovascular risk were studied. After a 2-week run-in period, subjects were randomized into 3 treatment periods in a crossover clinical trial, with a common background diet plus red wine (30g alcohol/day), the equivalent amount of dealcoholized red wine, or gin (30g alcohol/day), lasting 4 weeks each intervention. At baseline and after each intervention, anthropometrical parameters, BP and plasma NO were measured. Systolic and diastolic BP decreased significantly after the dealcoholized red wine intervention and these changes correlated with increases in plasma NO.Dealcoholized red wine decreases systolic and diastolic BP. Our results point out through an NO-mediated mechanism. The daily consumption of dealcoholized red wine could be useful for the prevention of low to moderate hypertension. Trial registered at controlled-trials.com: ISRCTN88720134.
U.S. Food and Drug Administration Approval: Ruxolitinib for the Treatment of Patients with Intermediate and High-Risk Myelofibrosis
Authors: Albert Deisseroth, Edvardas Kaminskas, Joseph Grillo, Wei Chen, Haleh Saber, Hong L. Lu, Mark D. Rothmann, Satjit Brar, Jian Wang, Christine Garnett, Julie Bullock, Laurie B. Burke, Atiqur Rahman, Rajeshwari Sridhara, Ann Farrell, Richard Pazdur
Journal: Clinical Cancer Research (2012)

On November 16, 2011, the U.S. Food and Drug Administration (FDA) granted full approval to ruxolitinib, (Jakafi; Incyte Corp.), an inhibitor of the Janus kinases 1 and 2, for the treatment of patients with intermediate- or high-risk myelofibrosis, including primary myelofibrosis, postpolycythemia vera myelofibrosis, and postessential thrombocythemia myelofibrosis. This approval was based on the results of 2 large randomized phase III trials that enrolled patients with intermediate-2 or high-risk myelofibrosis and compared ruxolitinib with placebo (study 1) or best available therapy (study 2). The primary efficacy endpoint was the proportion of patients who experienced a reduction in spleen volume of ≥ 35% at 24 weeks (study 1) or 48 weeks (study 2). The key secondary endpoint in study 1 was the proportion of patients who experienced a ≥ 50% improvement from baseline in myelofibrosis total symptom score at 24 weeks. The results of these studies showed that a greater proportion of patients treated with ruxolitinib experienced a ≥ 35% reduction in spleen volume as compared with those treated with placebo (42% vs. 1%, P < 0.0001) or best available therapy (29% vs. 0%, P < 0.0001). A greater proportion of patients in study 1 experienced a ≥ 50% reduction in the myelofibrosis total symptom score during treatment with ruxolitinib than with placebo (46% vs. 5%, P < 0.0001). Ruxolitinib treatment was associated with an increased incidence of grades III and IV anemia, thrombocytopenia, and neutropenia. This is the first drug approved for myelofibrosis.
Intronic SMAD7 Gene Polymorphisms, RS12953717 and RS4464148, in Association with Risk of Colorectal Cancer
Authors: Derakhshani Shaghayegh, Damavand Behzad, Saeedi Nastaran, Mohebbi Seyed Reza, Milanizadeh Saman, Azimzadeh Pedram, Asadzadeh Aghdaei Hamid, Zali Mohammad Reza
Journal: Annals of Oncology (2014)
Adenocarcinoma of the upper small bowel complicating coeliac disease.
Authors: G K Holmes, G I Dunn, R Cockel, V S Brookes
Journal: Gut (1980)

Adenocarcinoma of the small intestine complicating coeliac disease is uncommon. Only 14 cases have been reported, and in only one of these was a jejunal biopsy carried out more than eight months before the diagnosis of malignancy. We describe four more patients with this association, all with long histories of coeliac disease, confirmed in three by jejunal biopsy over five years before the diagnosis of malignancy. Important presenting features of carcinoma were abdominal pain, anaemia, occult gastrointestinal bleeding, abdominal mass, and intestinal obstruction, and these were the main indications for operation. After resection of the tumour survival may be prolonged, as evidenced by one of our cases who remains well eight years after surgery.
Responses of coronary arteries of cardiac transplant patients to acetylcholine.
Authors: R D Fish, E G Nabel, A P Selwyn, P L Ludmer, G H Mudge, J M Kirshenbaum, F J Schoen, R W Alexander, P Ganz
Journal: Journal of Clinical Investigation (1988)

Accelerated coronary atherosclerosis is a major cause of graft failure after heart transplantation. Graft atherosclerosis is typically diffuse and difficult to detect even with coronary arteriography. Recently, acetylcholine was shown to dilate blood vessels by releasing a vasorelaxant substance from the endothelium (endothelium-derived relaxing factor). We have demonstrated paradoxical vasoconstriction induced by acetylcholine both early and late in the course of coronary atherosclerosis in patients, suggesting an association of endothelial dysfunction and atherosclerosis. In this report, we tested the hypothesis that coronary arteries of heart transplant patients can show endothelial dysfunction before or in the early stages of angiographically evident coronary atherosclerosis. Acetylcholine was infused into the left anterior descending artery of 13 heart transplant patients at 12 (n = 9) and 24 (n = 4) mo after transplantation. Vascular responses were evaluated by quantitative angiography. Among patients with angiographically smooth coronary arteries, relatively few (6/25) arterial segments had preserved vasodilator responses, while the majority failed to dilate (10/25) or paradoxically constricted (9/25). Angiographically irregular coronary arteries were present in three patients, in whom 8/10 segments showed marked paradoxical constriction and the remaining 2/10 failed to dilate. Only 1 of 13 patients retained appropriate dilation to acetylcholine in all segments. Nitroglycerin, which acts directly on vascular smooth muscle, dilated nearly all segments. No clinical features of the patients, including myocardial rejection appeared to correlate with the impaired functional response of vessels. Thus impaired response to acetylcholine is a common early finding in heart transplant patients and emphasizes the potential importance of endothelial dysfunction in the development of atherosclerosis.
Pharmacological Inhibition of the Wnt Acyltransferase PORCN Prevents Growth of WNT-Driven Mammary Cancer
Authors: Kyle David Proffitt, Babita Madan, Zhiyuan Ke, Vishal Pendharkar, Lijun Ding, May Ann Lee, Rami N. Hannoush, David M. Virshup
Journal: Cancer Research (2012)

Abstract Porcupine (PORCN) is a membrane bound O-acyltransferase that is required for Wnt palmitoylation, secretion, and biologic activity. All evaluable human Wnts require PORCN for their activity, suggesting that inhibition of PORCN could be an effective treatment for cancers dependent on excess Wnt activity. In this study, we evaluated the PORCN inhibitor Wnt-C59 (C59), to determine its activity and toxicity in cultured cells and mice. C59 inhibits PORCN activity in vitro at nanomolar concentrations, as assessed by inhibition of Wnt palmitoylation, Wnt interaction with the carrier protein Wntless/WLS, Wnt secretion, and Wnt activation of β-catenin reporter activity. In mice, C59 displayed good bioavailability, as once daily oral administration was sufficient to maintain blood concentrations well above the IC50. C59 blocked progression of mammary tumors in MMTV-WNT1 transgenic mice while downregulating Wnt/β-catenin target genes. Surprisingly, mice exhibit no apparent toxicity, such that at a therapeutically effective dose there were no pathologic changes in the gut or other tissues. These results offer preclinical proof-of-concept that inhibiting mammalian Wnts can be achieved by targeting PORCN with small-molecule inhibitors such as C59, and that this is a safe and feasible strategy in vivo. Cancer Res; 73(2); 502–7. ©2012 AACR.
Socioeconomic status, occupation, and risk of hospitalisation due to coxarthrosis in Denmark 1981-99
Authors: F Tuchsen
Journal: Annals of the Rheumatic Diseases (2003)

<b>Objectives:</b> To predict the relative risk and time trend in hospitalisation due to coxarthrosis (CA) among groups of different socioeconomic status and occupations in order to test existing aetiological hypotheses. <b>Methods:</b> Four consecutive cohorts of all gainfully employed Danish men were followed up for CA. Standardised hospitalisation ratios (SHR) and time trends were calculated. <b>Results:</b> Self employed men had an SHR due to CA of 140 (95% confidence interval (CI) 130 to 151) in 1994−99. It changed −1.2% (95% CI −2 to −0.4) annually from 1981 to 1999. Self employed farmers had an SHR of 286 (95% CI 262 to 313) during 1994–99, increasing 0.14% a year (95% CI −0.9 to 1.1) from 1981 to 1999. Unskilled men had an SHR of 121 (95% CI 113 to 130) in 1994−99. The SHR increased 1.6% annually (95% CI 0.7 to 2.4) from 1981 to 1999. Employed agricultural workers had an SHR of 189 (95% CI 158 to 227) from 1994 to 1999. The SHR increased 3.7% annually (95% CI 1.2 to 6.2) from 1981 to 1999. <b>Conclusions:</b> The relative risk of hospitalisation due to CA was consistently high among farmers in four successive analyses spanning an 18 year period. The relative risks remained stable over time despite the fact that the number of farmers decreased. The risk increased among employed workers in agriculture and horticulture over that period, and an increased risk was also found among tractor drivers and a few other occupations.
Long term effects of azithromycin in patients with cystic fibrosis: a double blind, placebo controlled trial
Authors: Clement A, Tamalet A, Leroux E, Ravilly S, Fauroux B, Jais Jp
Journal: Thorax (2006)

Macrolides display immunomodulatory effects that may be beneficial in chronic inflammatory pulmonary diseases. The aim of the study was to document whether long term use of azithromycin may be associated with respiratory benefits in young patients with cystic fibrosis.A multicentre, randomised, double blind, placebo controlled trial was conducted from October 2001 to June 2003. The criteria for enrollment were age older than 6 years and forced expiratory volume in 1 second (FEV1) of 40% or more. The active group received either 250 mg or 500 mg (body weight < or > or =40 kg) of oral azithromycin three times a week for 12 months. The primary end point was change in FEV1.Eighty two patients of mean (SD) age 11.0 (3.3) years and mean (SD) FEV1 85 (22)% predicted were randomised: 40 in the azithromycin group and 42 in the placebo group. Nineteen patients were infected with Pseudomonas aeruginosa. The relative change in FEV1 at month 12 did not differ significantly between the two groups. The number of pulmonary exacerbations (count ratio 0.50 (95% CI 0.32 to 0.79), p < 0.005), the time elapsed before the first pulmonary exacerbation (hazard ratio 0.37 (95% CI 0.22 to 0.63), p < 0.0001), and the number of additional courses of oral antibiotics were significantly reduced in the azithromycin group regardless of the infectious status (count ratio 0.55 (95% CI 0.36 to 0.85), p < 0.01). No severe adverse events were reported.Long term use of low dose azithromycin in young patients with cystic fibrosis has a beneficial effect on lung disease expression, even before infection with Pseudomonas aeruginosa.
Cost-Effective Screening for the Metabolic Syndrome in Patients Treated With Second-Generation Antipsychotic Medications
Authors: David Straker, Christoph U. Correll, Elisse Kramer-Ginsberg, Nasreen Abdulhamid, Fiju Koshy, Elayna Rubens, Robert Saint-Vil, John M. Kane, Peter Manu
Journal: American Journal of Psychiatry (2005)

OBJECTIVE: Despite concerns about the adverse effects of second-generation antipsychotics on weight regulation and glucose and lipid metabolism, little is known about the relationship between these agents and the metabolic syndrome. Because the metabolic syndrome is more strongly associated with cardiovascular morbidity and mortality than its individual components, attention to the full syndrome is important. The authors' goal was to explore the relationship between second-generation antipsychotics and the metabolic syndrome. METHOD: They assessed the prevalence of metabolic syndrome in a nearly consecutive group of 89 acutely admitted psychiatric inpatients treated with at least one second-generation antipsychotic for different psychiatric disorders. Patients' waist circumference and blood pressure were measured as well as their fasting blood glucose and lipid levels. RESULTS: Twenty-six (29.2%) of the 89 patients fulfilled criteria for the metabolic syndrome. Presence of the syndrome was associated with older age, higher body mass index, and higher values for each individual criterion of the metabolic syndrome but not with specific diagnoses or antipsychotic treatment regimens. Presence of abdominal obesity was most sensitive (92.0%), while fasting glucose >110 mg/dl was most specific (95.2%) in correctly identifying the presence of metabolic syndrome. Combining abdominal obesity and elevated fasting blood glucose had 100% sensitivity. CONCLUSIONS: The measurement of both abdominal obesity and fasting blood glucose is a simple, cost-effective screening test to detect patients at high risk for future cardiovascular morbidity.
<i>Bordetella</i> evades the host immune system by inducing IL-10 through a type III effector, BopN
Authors: Kanna Nagamatsu, Asaomi Kuwae, Tadashi Konaka, Shigenori Nagai, Sei Yoshida, Masahiro Eguchi, Mineo Watanabe, Hitomi Mimuro, Shigeo Koyasu, Akio Abe
Journal: The Journal of Experimental Medicine (2009)

The inflammatory response is one of several host alert mechanisms that recruit neutrophils from the circulation to the area of infection. We demonstrate that Bordetella, a bacterial pathogen, exploits an antiinflammatory cytokine, interleukin-10 (IL-10), to evade the host immune system. We identified a Bordetella effector, BopN, that is translocated into the host cell via the type III secretion system, where it induces enhanced production of IL-10. Interestingly, the BopN effector translocates itself into the nucleus and is involved in the down-regulation of mitogen-activated protein kinases. Using pharmacological blockade, we demonstrated that BopN-induced IL-10 production is mediated, at least in part, by its ability to block the extracellular signal-regulated kinase pathway. We also showed that BopN blocks nuclear translocation of nuclear factor κB p65 (NF-κBp65) but, in contrast, promotes nuclear translocation of NF-κBp50. A BopN-deficient strain was unable to induce IL-10 production in mice, resulting in the elimination of bacteria via neutrophil infiltration into the pulmonary alveoli. Furthermore, IL-10–deficient mice effectively eliminated wild-type as well as BopN mutant bacteria. Thus, Bordetella exploits BopN as a stealth strategy to shut off the host inflammatory reaction. These results explain the ability of Bordetella species to avoid induction of the inflammatory response.
β <sub>1</sub> Integrins Participate in the Hypertrophic Response of Rat Ventricular Myocytes
Authors: Robert S. Ross, Can Pham, Shaw-Yung Shai, Joshua I. Goldhaber, Csilla Fenczik, Chris C. Glembotski, Mark H. Ginsberg, Joseph C. Loftus
Journal: Circulation Research (1998)

Abstract —Multiple signaling pathways have been implicated in the hypertrophic response of ventricular myocytes, yet the importance of cell-matrix interactions has not been extensively examined. Integrins are cell-surface molecules that link the extracellular matrix to the cellular cytoskeleton. They can function as cell signaling molecules and transducers of mechanical information in noncardiac cells. Given these properties and their abundance in cardiac cells, we evaluated the hypothesis that β 1 integrin function is involved in the α 1 -adrenergic mediated hypertrophic response of neonatal rat ventricular myocytes. The hypertrophic response of this model required interaction with extracellular matrix proteins. Specificity of these results was confirmed by demonstrating that ventricular myocytes plated onto an anti–β 1 integrin antibody supported the hypertrophic gene response. Adenovirus-mediated overexpression of β 1 integrin augmented the myocyte hypertrophic response when assessed by protein synthesis and atrial natriuretic factor production, a marker gene of hypertrophic induction. DNA synthesis was not altered by integrin overexpression. Transfection of cultured cardiac myocytes with either the ubiquitously expressed β 1A integrin or the cardiac/skeletal muscle–specific β 1 isoform (β 1D ) activated reporter expression from both the atrial natriuretic factor and myosin light chain-2 ventricular promoters, genetic markers of ventricular cell hypertrophy. Finally, suppression of integrin signaling by overexpression of free β 1 integrin cytoplasmic domains inhibited the adrenergically mediated atrial natriuretic factor response. These findings show that integrin ligation and signaling are involved in the cardiac hypertrophic response pathway.