tbuckley/cabot-search huggingface dataset:
Gastric acid secretion in sickle-cell anaemia
Authors: L. Wosornu, F. I. D. Konotey-Ahulu
Journal: Gut (1971)

The gastric acid response to the augmented histamine test was measured in 115 Ghanaian patients, including 45 cases of sickle-cell anaemia. Normal gastric acid responses were found in the patients with sickle-cell anaemia, suggesting that the frequent occurrence of indigestion in patients with this disorder is unlikely to be related to abnormal gastric acid secretion.
Durable efficacy of tipranavir-ritonavir in combination with an optimised background regimen of antiretroviral drugs for treatment-experienced HIV-1-infected patients at 48 weeks in the Randomized Evaluation of Strategic Intervention in multi-drug reSistant patients with Tipranavir (RESIST) studies: an analysis of combined data from two randomised open-label trials
Authors: Charles B Hicks, Pedro Cahn, David A Cooper, Sharon L Walmsley, Christine Katlama, Bonaventura Clotet, Adriano Lazzarin, Margaret A Johnson, Dietmar Neubacher, Douglas Mayers, Hernan Valdez
Journal: The Lancet (2006)
Voltage-dependent Na+ channel phenotype changes in myoblasts. Consequences for cardiac repair☆
Authors: R MARTINEZMARMOL, M DAVID, R SANCHES, M ROURAFERRER, N VILLALONGA, E SORIANELLO, S WEBB, A ZORZANO, A GUMA, C VALENZUELA
Journal: Cardiovascular Research (2007)

Objective Cellular cardiomyoplasty using skeletal myoblasts is a promising therapy for myocardial infarct repair. Once transplanted, myoblasts grow, differentiate and adapt their electrophysiological properties towards more cardiac-like phenotypes. Voltage-dependent Na+ channels (Nav) are the main proteins involved in the propagation of the cardiac action potential, and their phenotype affects cardiac performance. Therefore, we examined the expression of Nav during proliferation and differentiation in skeletal myocytes.
Positivity for anti-cyclic citrullinated peptide is associated with a better response to abatacept: data from the ‘Orencia and Rheumatoid Arthritis’ registry
Authors: J E Gottenberg, P Ravaud, A Cantagrel, B Combe, R M Flipo, T Schaeverbeke, E Houvenagel, P Gaudin, D Loeuille, S Rist, M Dougados, J Sibilia, X Le Loët, C Marcelli, T Bardin, I Pane, G Baron, X Mariette
Journal: Annals of the Rheumatic Diseases (2012)

Objectives Very limited data are available regarding the efficacy of abatacept (ABA) in real life. The aims of this study were to determine the efficacy of ABA in rheumatoid arthritis and predicting factors of efficacy in common practice. Methods The Orencia and Rheumatoid Arthritis” (ORA) prospective registry, promoted by the French Society of Rheumatology, has included 1003 patients with RA. Results 773 patients had already fulfilled the 6-month follow-up visit. Only 21.3% of patients would have fulfilled inclusion criteria used in pivotal controlled trials. The European League Against Rheumatism (EULAR) response, was observed in 330 (59.1%) of the 558 assessed patients (good response: 20.4%, moderate response: 38.7%) and was similar in patients who did and in patients who did not fulfill inclusion criteria of controlled trials. Among EULAR responders, initial 28-joint disease activity score (5.4 (4.7-6.5) in responders vs 4.9 (4.0-6.0) in non responders, p&lt; 0.0001), the proportion of rheumatoid factor (75.6% vs 66.7%, p= 0.03) and the proportion of anti-cyclic citrullinated peptide antibody (anti-CCP)-positivity (75.9% vs 62.2%, p= 0.001) were significantly higher. In multivariate analysis adjusted on initial 28-joint disease activity score and CRP, anti-CCP positivity was associated with EULAR response (OR=1.9;95% CI=1.2 to 2.9, p=0.007), but not rheumatoid factor (OR=1.0;95% CI=0.6 to 1.6, p=0.9). Anti-CCP positivity was also significantly associated with a higher ABA retention rate at 6 months. Conclusions Real life efficacy of ABA in the ORA registry was similar as that reported in clinical trials. Anti-CCP positivity was associated with a better response to ABA, independently from disease activity.
Unique Resistance of I/LnJ Mice to a Retrovirus Is Due to Sustained Interferon γ–dependent Production of Virus-neutralizing Antibodies
Authors: Alexandra Purdy, Laure Case, Melody Duvall, Max Overstrom-Coleman, Nilah Monnier, Alexander Chervonsky, Tatyana Golovkina
Journal: The Journal of Experimental Medicine (2003)

Selection of immune escape variants impairs the ability of the immune system to sustain an efficient antiviral response and to control retroviral infections. Like other retroviruses, mouse mammary tumor virus (MMTV) is not efficiently eliminated by the immune system of susceptible mice. In contrast, MMTV-infected I/LnJ mice are capable of producing IgG2a virus-neutralizing antibodies, sustain this response throughout their life, and secrete antibody-coated virions into the milk, thereby preventing infection of their progeny. Antibodies were produced in response to several MMTV variants and were cross-reactive to them. Resistance to MMTV infection was recessive and was dependent on interferon (IFN)-γ production, because I/LnJ mice with targeted deletion of the INF-γ gene failed to produce any virus-neutralizing antibodies. These findings reveal a novel mechanism of resistance to retroviral infection that is based on a robust and sustained IFN-γ–dependent humoral immune response.
Whole-genome sequencing identifies recurrent somatic NOTCH2 mutations in splenic marginal zone lymphoma
Authors: Mark J. Kiel, Thirunavukkarasu Velusamy, Bryan L. Betz, Lili Zhao, Helmut G. Weigelin, Mark Y. Chiang, David R. Huebner-Chan, Nathanael G. Bailey, David T. Yang, Govind Bhagat, Roberto N. Miranda, David W. Bahler, L. Jeffrey Medeiros, Megan S. Lim, Kojo S.J. Elenitoba-Johnson
Journal: The Journal of Experimental Medicine (2012)

Splenic marginal zone lymphoma (SMZL), the most common primary lymphoma of spleen, is poorly understood at the genetic level. In this study, using whole-genome DNA sequencing (WGS) and confirmation by Sanger sequencing, we observed mutations identified in several genes not previously known to be recurrently altered in SMZL. In particular, we identified recurrent somatic gain-of-function mutations in NOTCH2, a gene encoding a protein required for marginal zone B cell development, in 25 of 99 (∼25%) cases of SMZL and in 1 of 19 (∼5%) cases of nonsplenic MZLs. These mutations clustered near the C-terminal proline/glutamate/serine/threonine (PEST)-rich domain, resulting in protein truncation or, rarely, were nonsynonymous substitutions affecting the extracellular heterodimerization domain (HD). NOTCH2 mutations were not present in other B cell lymphomas and leukemias, such as chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL; n = 15), mantle cell lymphoma (MCL; n = 15), low-grade follicular lymphoma (FL; n = 44), hairy cell leukemia (HCL; n = 15), and reactive lymphoid hyperplasia (n = 14). NOTCH2 mutations were associated with adverse clinical outcomes (relapse, histological transformation, and/or death) among SMZL patients (P = 0.002). These results suggest that NOTCH2 mutations play a role in the pathogenesis and progression of SMZL and are associated with a poor prognosis.
One-Year Outcome of a Combination of Weight Loss Therapies for Subjects With Type 2 Diabetes
Authors: J. Bruce Redmon, Susan K. Raatz, Kristell P. Reck, Joyce E. Swanson, Christine A. Kwong, Qiao Fan, William Thomas, John P. Bantle
Journal: Diabetes Care (2003)

OBJECTIVE—The purpose of this study was to evaluate the effects of a combination weight loss program using intermittent low-calorie diets, energy-controlled meal replacement products, and sibutramine on weight loss, diabetes control, and cardiovascular risk factors in overweight or obese subjects with type 2 diabetes. RESEARCH DESIGN AND METHODS—Overweight or obese individuals with type 2 diabetes treated with diet or oral medication were randomly assigned to either a standard therapy or combination therapy group. Both groups received a standardized program to facilitate weight loss. The combination therapy group also received 10–15 mg sibutramine daily, low-calorie diets using meal replacement products for 1 week every 2 months, and between low-calorie diet weeks, once daily use of meal replacement product and snack bars to replace one usual meal and snack. Primary outcome measures were changes in body weight, glycemic control, plasma lipids, blood pressure, pulse, and body composition at 1 year. RESULTS—At 1 year, combination therapy, compared with standard therapy, resulted in significantly more weight loss (−7.3 ± 1.3 kg vs. −0.8 ± 0.9 kg, P &amp;lt; 0.001) and reduction in HbA1c (−0.6 ± 0.3 vs. 0.0 ± 0.2%, P = 0.05). Combination therapy resulted in reduced requirement for diabetes medications and decreased fat mass and lean body mass. A 5-kg decrease in weight at 1 year was associated with a decrease of 0.4% in HbA1c (P = 0.006). Changes in fasting glucose, lipids, pulse, and blood pressure did not differ between groups. CONCLUSIONS—This combination weight loss program resulted in greater weight loss and improved diabetes control compared with a standard weight loss program in overweight or obese subjects with type 2 diabetes.
IGF2 is an actionable target that identifies a distinct subpopulation of colorectal cancer patients with marginal response to anti-EGFR therapies
Authors: Eugenia R. Zanella, Francesco Galimi, Francesco Sassi, Giorgia Migliardi, Francesca Cottino, Simonetta M. Leto, Barbara Lupo, Jessica Erriquez, Claudio Isella, Paolo M. Comoglio, Enzo Medico, Sabine Tejpar, Eva Budinská, Livio Trusolino, Andrea Bertotti
Journal: Science Translational Medicine (2015)

Among patients with colorectal cancer who benefit from therapy targeted to the epidermal growth factor receptor (EGFR), stable disease (SD) occurs more frequently than massive regressions. Exploring the mechanisms of this incomplete sensitivity to devise more efficacious treatments will likely improve patients' outcomes. We tested therapies tailored around hypothesis-generating molecular features in patient-derived xenografts ("xenopatients"), which originated from 125 independent samples that did not harbor established resistance-conferring mutations. Samples from xenopatients that responded to cetuximab, an anti-EGFR agent, with disease stabilization displayed high levels of EGFR family ligands and receptors, indicating high EGFR pathway activity. Five of 21 SD models (23.8%) characterized by particularly high expression of EGFR and EGFR family members regressed after intensified EGFR blockade by cetuximab and a small-molecule inhibitor. In addition, a subset of cases in which enhanced EGFR inhibition was unproductive (6 of 16, 37.5%) exhibited marked overexpression of insulin-like growth factor 2 (IGF2). Enrichment of IGF2 overexpressors among cases with SD was demonstrated in the entire xenopatient collection and was confirmed in patients by mining clinical gene expression data sets. In functional studies, IGF2 overproduction attenuated the efficacy of cetuximab. Conversely, interception of IGF2-dependent signaling in IGF2-overexpressing xenopatients potentiated the effects of cetuximab. The clinical implementation of IGF inhibitors awaits reliable predictors of response, but the results of this study suggest rational combination therapies for colorectal cancer and provide evidence for IGF2 as a biomarker of reduced tumor sensitivity to anti-EGFR therapy and a determinant of response to combined IGF2/EGFR targeting.
Haptoglobin Genotype– and Diabetes-Dependent Differences in Iron-Mediated Oxidative Stress In Vitro and In Vivo
Authors: Rabea Asleh, Julia Guetta, Shiri Kalet-Litman, Rachel Miller-Lotan, Andrew P. Levy
Journal: Circulation Research (2005)

We have recently demonstrated in multiple independent population-based longitudinal and cross sectional analyses that the haptoglobin 2-2 genotype is associated with an increased risk for diabetic cardiovascular disease. The chief function of haptoglobin (Hp) is to bind to hemoglobin and thereby prevent hemoglobin-induced oxidative tissue damage. This antioxidant function of haptoglobin is mediated in part by the ability of haptoglobin to prevent the release of iron from hemoglobin on its binding. We hypothesized that there may be diabetes- and haptoglobin genotype-dependent differences in the amount of catalytically active redox active iron derived from hemoglobin. We tested this hypothesis using several complementary approaches both in vitro and in vivo. First, measuring redox active iron associated with haptoglobin-hemoglobin complexes in vitro, we demonstrate a marked increase in redox active iron associated with Hp 2-2-glycohemoglobin complexes. Second, we demonstrate increased oxidative stress in tissue culture cells exposed to haptoglobin 2-2-hemoglobin complexes as opposed to haptoglobin 1-1-hemoglobin complexes, which is inhibitable by desferrioxamine by either a chelation or reduction mechanism. Third, we demonstrate marked diabetes-dependent differences in the amount of redox active iron present in the plasma of mice genetically modified expressing the Hp 2 allele as compared with the Hp 1 allele. Taken together these data implicate redox active iron in the increased susceptibility of individuals with the Hp 2 allele to diabetic vascular disease.
Favourable medium term outcome following hepatic vein recanalisation and/or transjugular intrahepatic portosystemic shunt for Budd Chiari syndrome
Authors: C E Eapen
Journal: Gut (2005)

We report our experience with management of patients with Budd Chiari syndrome over the past two decades. In 1996 we described a novel approach involving recanalisation of hepatic veins by combined percutaneous and transvenous approaches. This was incorporated into an algorithm published in 1999 in which our preferred treatment for all cases of Budd Chiari syndrome with short segment occlusion or stenosis of the hepatic veins involves recanalisation of the hepatic veins by transvenous or combined percutaneous-transvenous approaches. In symptomatic Budd Chiari syndrome where recanalisation is not possible, we perform transjugular intrahepatic portosystemic shunts (TIPS) because TIPS decompresses the portal circulation directly in an adjustable way. In this series of patients with Budd Chiari syndrome treated with radiological interventions alone, we assess their medium term outcome using two independent objective prognostic indices.We retrospectively studied 61 patients with non-malignant Budd Chiari syndrome treated by radiological intervention alone in our centre.Actuarial survival for the entire cohort at one year and five years was 94% and 87%, respectively. Survival of our patients with mild disease (according to the Murad classification) was 100% at one year and at five years, with intermediate disease severity 94% at one year and 86% at five years, and with severe disease 85% at one year and 77% at five years.Management of Budd Chiari syndrome by interventional radiology resulted in excellent medium term survival for patients in all categories of disease severity.
The 1p-Encoded Protein Stathmin and Resistance of Malignant Gliomas to Nitrosoureas
Authors: T.-T B. Ngo, T. Peng, X.-J. Liang, O. Akeju, S. Pastorino, W. Zhang, Y. Kotliarov, J. C. Zenklusen, H. A. Fine, D. Maric, P. Y. Wen, U. De Girolami, P. McL. Black, W. W. Wu, R.-F. Shen, N. O. Jeffries, D.-W. Kang, J. K. Park
Journal: JNCI Journal of the National Cancer Institute (2007)

Malignant gliomas are generally resistant to all conventional therapies. Notable exceptions are anaplastic oligodendrogliomas with loss of heterozygosity on chromosome 1p (1p+/-). Patients with 1p+/- anaplastic oligodendroglioma frequently respond to procarbazine, 1-(2-chloroethyl)-3-cyclohexyl-l-nitrosourea, and vincristine. Because the underlying biologic basis for this clinical finding is unclear, we evaluated differentially expressed 1p-encoded proteins in 1p+/- and 1p+/+ malignant glioma cell lines and then examined whether their expression was associated with outcome of patients with anaplastic oligodendroglioma.We used a comparative proteomic screen of A172 (1p+/-) and U251 (1p+/+) malignant glioma cell lines to identify differentially expressed 1p-encoded proteins, including stathmin, a microtubule-associated protein. 1p+/- and 1p+/+ anaplastic oligodendroglioma specimens from 24 patients were assessed for stathmin expression by immunohistochemistry. The relationship between stathmin expression and clinical outcome was assessed with Kaplan-Meier analyses. RNA inhibition and cDNA transfection experiments tested effects of stathmin under- and overexpression, respectively, on the in vitro and in vivo resistance of malignant glioma cells to treatment with nitrosourea. For in vivo resistance studies, 36 mice with intracranial and 16 mice with subcutaneous xenograft tumor implants were used (one tumor per mouse). Flow cytometry was used for cell cycle analysis. Immunoblotting was used to assess protein expression. All statistical tests were two-sided.Decreased stathmin expression in tumors was statistically significantly associated with loss of heterozygosity in 1p (P<.001) and increased recurrence-free survival (P<.001). The median recurrence-free survival times for patients with tumors expressing low, intermediate, or high stathmin levels were 45 months (95% confidence interval [CI] = 0 to 90 months), 17 months (95% CI = 10.6 to 23.4 months), and 6 months (95% CI = 1.7 to 10.3 months), respectively. Expression of stathmin was inversely associated with overall survival of nitrosourea-treated mice carrying xenograft tumors. Median survival of mice with stathmin+/- tumors was 95 days (95% CI = 68.7 to 121.3 days) and that of mice with stathmin+/+ tumors was 64 days (95% CI = 58.2 to 69.8 days) (difference = 31 days, 95% CI = 4.1 to 57.9 days; P<.001, log-rank test). Nitrosoureas induced mitotic arrest in malignant glioma cells, and this effect was greater in cells with decreased stathmin expression.Loss of heterozygosity for the stathmin gene may be associated with improved outcomes of patients with 1p+/- anaplastic oligodendroglioma tumors.
Direct inhibitors of InhA are active against <i>Mycobacterium tuberculosis</i>
Authors: Ujjini H. Manjunatha, Srinivasa P. S. Rao, Ravinder Reddy Kondreddi, Christian G. Noble, Luis R. Camacho, Bee H. Tan, Seow H. Ng, Pearly Shuyi Ng, Ng L. Ma, Suresh B. Lakshminarayana, Maxime Herve, Susan W. Barnes, Weixuan Yu, Kelli Kuhen, Francesca Blasco, David Beer, John R. Walker, Peter J. Tonge, Richard Glynne, Paul W. Smith, Thierry T. Diagana
Journal: Science Translational Medicine (2015)

4-Hydroxy-2-pyridones, direct inhibitors of the mycobacterial protein InhA, are active against multidrug-resistant Mycobacterium tuberculosis .
Characterization and clonal distribution of four alleles of the speA gene encoding pyrogenic exotoxin A (scarlet fever toxin) in Streptococcus pyogenes.
Authors: K Nelson, P M Schlievert, R K Selander, J M Musser
Journal: The Journal of Experimental Medicine (1991)

Streptococcus pyogenes strains producing pyrogenic exotoxin A (scarlet fever toxin) have recently caused episodes of streptococcal toxic-shock-like syndrome (TSLS). We exploited knowledge of genetic diversity and relationships among exotoxin A-producing patient strains provided by multilocus enzyme electrophoresis to select strains for comparative sequencing of toxin genes. Our analysis identified four alleles of speA in natural populations, one of which (speA1) occurs in many distinct clonal lineages and is probably old. Two other alleles (speA2 and speA3), characterized solely by single amino acid substitutions, were each identified in single clones that together have caused the majority of TSLS episodes. It is unlikely that these alleles have had a long association with S. pyogenes clones. A fourth allele (speA4) also is present in a single phylogenetic lineage and is 9% divergent from the other three toxin alleles. An absence of synonomous (silent) nucleotide changes in speA2 and speA3 is unusual and suggests that the allelic variation is not selectively neutral, which implies that the toxins are not functionally equivalent. These results may be important in helping to understand the recent increase in frequency and severity of disease caused by S. pyogenes.
DNA methylation profiling in doxorubicin treated primary locally advanced breast tumours identifies novel genes associated with survival and treatment response
Authors: Emelyne Dejeux, Jo Anders Rønneberg, Hiroko Solvang, Ida Bukholm, Stephanie Geisler, Turid Aas, Ivo G. Gut, Anne-Lise Børresen-Dale, Per Eystein Lønning, Vessela N. Kristensen, Jörg Tost
Journal: Molecular Cancer (2010)

Abstract Background Breast cancer is the most frequent cancer in women and consists of a heterogeneous collection of diseases with distinct histopathological, genetic and epigenetic characteristics. In this study, we aimed to identify DNA methylation based biomarkers to distinguish patients with locally advanced breast cancer who may benefit from neoadjuvant doxorubicin treatment. Results We investigated quantitatively the methylation patterns in the promoter regions of 14 genes ( ABCB1 , ATM , BRCA1 , CDH3 , CDKN2A , CXCR4 , ESR1 , FBXW7 , FOXC 1, GSTP1 , IGF2 , HMLH1 , PPP2R2B , and PTEN ) in 75 well-described pre-treatment samples from locally advanced breast cancer and correlated the results to the available clinical and molecular parameters. Six normal breast tissues were used as controls and 163 unselected breast cancer cases were used to validate associations with histopathological and clinical parameters. Aberrant methylation was detected in 9 out of the 14 genes including the discovery of methylation at the FOXC1 promoter. Absence of methylation at the ABCB1 promoter correlated with progressive disease during doxorubicin treatment. Most importantly, the DNA methylation status at the promoters of GSTP1 , FOXC1 and ABCB1 correlated with survival, whereby the combination of methylated genes improved the subdivision with respect to the survival of the patients. In multivariate analysis GSTP1 and FOXC1 methylation status proved to be independent prognostic markers associated with survival. Conclusions Quantitative DNA methylation profiling is a powerful tool to identify molecular changes associated with specific phenotypes. Methylation at the ABCB1 or GSTP1 promoter improved overall survival probably due to prolonged availability and activity of the drug in the cell while FOXC1 methylation might be a protective factor against tumour invasiveness. FOXC1 proved to be general prognostic factor, while ABCB1 and GSTP1 might be predictive factors for the response to and efficacy of doxorubicin treatment. Pharmacoepigenetic effects such as the reported associations in this study provide molecular explanations for differential responses to chemotherapy and it might prove valuable to take the methylation status of selected genes into account for patient management and treatment decisions.