tbuckley/cabot-search huggingface dataset:
A Common Gene Variant in Glucokinase Regulatory Protein Interacts With Glucose Metabolism on Diabetic Dyslipidemia: the Combined CODAM and Hoorn Studies
Authors: Nynke Simons, Jacqueline M. Dekker, Marleen M.J. van Greevenbroek, Giel Nijpels, Leen M. ’t Hart, Carla J.H. van der Kallen, Casper G. Schalkwijk, Nicolaas C. Schaper, Coen D.A. Stehouwer, Martijn C.G.J. Brouwers
Journal: Diabetes Care (2016)

OBJECTIVE Small molecules that disrupt the binding between glucokinase and glucokinase regulatory protein (GKRP) are potential new glucose-lowering targets. They stimulate hepatic glucose disposal by increasing glucokinase activity in the liver. It can, however, be anticipated that increased hepatic glucokinase activity might be accompanied by the development of hypertriglyceridemia, particularly in type 2 diabetes. We examined whether the strength of association between rs1260326, a common, functional gene variant in GKRP, and plasma lipids is affected by glucose metabolism. RESEARCH DESIGN AND METHODS rs1260326 was genotyped in subjects with normal glucose metabolism (n = 497), subjects with impaired glucose metabolism (n = 256), and patients with type 2 diabetes (n = 351) in the combined Hoorn and Cohort on Diabetes and Atherosclerosis Maastricht (CODAM) studies. RESULTS The strength of association between the rs1260326 minor T allele and plasma triglycerides increased from normal glucose metabolism to impaired glucose metabolism to type 2 diabetes (P for interaction = 0.002). The inverse relation between rs1260326 and plasma HDL cholesterol was again most prominent in type 2 diabetes (P for interaction = 0.004). Similar trends were observed when the Hoorn and CODAM cohorts were analyzed separately. Comparable results were obtained when glucose metabolism strata were replaced by continuous indices of glucose metabolism, i.e., HbA1c and fasting plasma glucose. CONCLUSIONS These findings illustrate that common gene variants, such as rs1260326, can have substantial effect sizes when they are studied in specific populations, such as type 2 diabetes. Moreover, our results shed light on potential side effects of small molecule disruptors of the GKRP-glucokinase complex, especially when glucose control is suboptimal.
Preclinical Characterisation of JNJ-54257099 – A Potent Uridine-Based Nucleotide Polymerase Inhibitor in Phase I Clinical Development for the Treatment of Chronic Hepatitis C
Authors: L. Tambuyzer, L. Vijgen, T.H. Jonckers, S. Lachau-Durand, J. Snoeys, L. Leclercq, J.M. Berke, J. Deval, P. Van Remoortere, K. Simmen, S. De Meyer, P. Raboisson
Journal: Journal of Hepatology (2016)
P0901 : The pan-genotypic NS3/4A protease inhibitor GS-9857 demonstrates potent antiviral activity in patients infected with HCV genotype 1, 2, 3 or 4 in a 3-day monotherapy study
Authors: M. Rodriguez-Torres, S. Glass, J. Hill, B. Freilich, D. Hassman, A. Di Bisceglie, J.G. Taylor, B. Kirby, J.C. Yang, L.M. Stamm, D.M. Brainard, S. Kim, D. Krefetz, W. Smith, T. Marbury, E. Lawitz
Journal: Journal of Hepatology (2015)
Role of tumor suppressor BARD1 in malignant transformation: Implications for therapeutic interventions
Authors: Jian-Yu Wu, Anis Feki, Charles Edward Efford, Irmgard Irminger-Finger
Journal: Cancer Research (2005)

5568   The BRCA1-associated protein BARD1 is regarded as tumor suppressor in conjunction with BRCA1. We have shown that repression of BARD1 leads to pre-malignant transformation and genomic instability (Irminger-Finger et al., 1998). However, endogenous or exogenous increase of BARD1 induces apoptosis in vivo and in vitro, while BARD1-repressed cells are resistant to apoptosis induced by hypoxia or genotoxic drugs (Irminger-Finger et al., 2001). The protein sequence required for apoptosis function of BARD1 coincides with tumor-associated missense mutations, thus confirming BARD1’s role in tumor suppression through induction of apoptosis (Jefford et al., 2004). Increased BARD1 expression might play a role in tissue homeostasis as observed in testis, spleen, or colon. Consistently, BARD1 expression is lost in some malignant tumors. However, in tumors expressing full length BARD1, it is cleaved during apoptosis, as it is in vitro, and the p67 cleavage product acts as immunogenic anti-tumorigenic agent in a rat animal model of colon cancer (Gautier et al. 2000; Jefford et al., 2004). To test the immunogenic and anti-tumorigenic activity of BARD1 we identified a rat ovarian cancer cell line, NuTu-19, which is deficient of BARD1, defective in apoptosis induction and upregulation of p53 protein levels in response to doxorubicin-induced genotoxic stress, in spite of a wild type p53. NuTu-19 cells, when injected intraperitoneally, induce tumors and metastasis leading to death of the animal 7 weeks after injection. We used this animal model to test the efficiency of virus-delivered BARD1 in tumor cell killing in vitro and in vivo by transduction of NuTu-19 cells with inducible BARD1. Induction of BARD1 either caused cell death or rendered cells hyper-sensitive to apoptosis-inducing agents, in vitro. To evaluate the effect of BARD1 expression on tumor cell proliferation in vivo, fluorescence-tagged NuTu-GFP cells were generated. Tumor formation was reduced or abrogated in animals injected with viable BARD1-expressing NuTu-19 cells. Tumor growth is slowed down by injection of retroviral BARD1 into subcutaneous tumors. Immunohistochemistry, performed on tumor samples, demonstrates increased immune response in tumors after lentiviral BARD1 injection. We conclude that BARD1 plays a role in tumorigenesis both as apoptosis inducer and as immunogenic agent.
Does PET/CT modify the therapeutic approach in medical oncology?
Authors: P. Manente, G. Vicario, F. Piazza, G. Vultaggio, M. Bortolin, G. Sgarbossa, L. Sartor, E. Scelzi, F. Chierichetti, V. Fiore, S. Bissoli
Journal: Journal of Clinical Oncology (2008)

17525 Background: the availability of PET/CT represents a progress in the diagnosis and therapy of a number of malignant tumors. In our institutions, PET has been available since 1993 and PET/CT since 2002. Thus, physicians were able to implement the use of this diagnostic tool. Here, we evaluated the advantages in the clinical management of the most frequent tumors for which PET/CT was utilized in our Institution. Methods: the case series considered PET/CT scans performed from our Medical Oncology Unit from 02/01/2006 to 31/12/2007. Overall, 403 patients underwent PET/CT: 37 Hodgkin's diseases, 37 Non Hodgkin Lymphomas, 47 NSCLC, 8 testicular carcinomas, 62 colo-rectal carcinomas, 80 breast carcinomas, 13 melanomas, 13 ovary carcinomas, 27 prostate cacinomas, 8 gastric carcinomas, 10 GIST, 4 cervix carcinomas, 12 head and neck cancers, 8 sarcomas, 2 esophageal carcinomas, 6 kidney carcinomas, 11 pancreatic carcinomas, 2 hepatocarcinomas, 1 urinary bladder carcinoma. Results: in NSCLC the procedure was employed for staging before surgery (38 cases) and before exclusive radiation therapy (8 cases). For colo-rectal tumors, PET/CT was done because of increased levels of CEA without evidence of new lesions at ultrasound or CT scan (13 cases); it was done before surgical removal of liver or lung metastasis (49 cases); it revealed additional metastasis controindicating the surgical intervention (25 cases). In 8 testicular tumors, the exam was done to plan surgical lyphoadenectomy or lung/liver metastasectomy. In melanomas, the procedure was employed for staging before surgical lymphadenectomy; for lymphomas, PET/CT was utilized mostly to evaluate the response to chemotherapy. For GISTs, to assess the response to imatinib or sunitinib. In the other cases, it was done before surgery. Conclusions: PET/CT appears essential in the staging of NSCLC before surgery and in the evaluation of the extent of the metastatic disease in those cases for which surgical removal of isolated metastasis could be attempted. Its role resulted also relevant to modify the radiation therapy in lung cancers and lymphomas. In lymphomas and GIST this exam is extremely significant for the early evaluation of the response to therapy. PET/CT could improve the multidisciplinary management of rarer diseases. No significant financial relationships to disclose.
Sofosbuvir/Velpatasvir Fixed Dose Combination for 12 Weeks in Patients Co-Infected with HCV and HIV-1: The Phase 3 Astral-5 Study
Authors: D. Wyles, N. Brau, S. Kottilil, E. Daar, K. Workowski, A. Luetkemeyer, O. Adeyemi, P. Ruane, B. Doehle, K.c Huang, A. Osinusi, J. McNally, D. Brainard, J. McHutchison, S. Naggie, M. Sulkowski
Journal: Journal of Hepatology (2016)
Titin-Based Cardiac Myocyte Stiffening Contributes to Early Adaptive Ventricular Remodeling After Myocardial Infarction
Authors: Sebastian Kötter, Malgorzata Kazmierowska, Christian Andresen, Katharina Bottermann, Maria Grandoch, Simone Gorressen, Andre Heinen, Jens M. Moll, Jürgen Scheller, Axel Gödecke, Jens W. Fischer, Joachim P. Schmitt, Martina Krüger
Journal: Circulation Research (2016)

Myocardial infarction (MI) increases the wall stress in the viable myocardium and initiates early adaptive remodeling in the left ventricle to maintain cardiac output. Later remodeling processes include fibrotic reorganization that eventually leads to cardiac failure. Understanding the mechanisms that support cardiac function in the early phase post MI and identifying the processes that initiate transition to maladaptive remodeling are of major clinical interest.To characterize MI-induced changes in titin-based cardiac myocyte stiffness and to elucidate the role of titin in ventricular remodeling of remote myocardium in the early phase after MI.Titin properties were analyzed in Langendorff-perfused mouse hearts after 20-minute ischemia/60-minute reperfusion (I/R), and mouse hearts that underwent ligature of the left anterior descending coronary artery for 3 or 10 days. Cardiac myocyte passive tension was significantly increased 1 hour after ischemia/reperfusion and 3 and 10 days after left anterior descending coronary artery ligature. The increased passive tension was caused by hypophosphorylation of the titin N2-B unique sequence and hyperphosphorylation of the PEVK (titin domain rich in proline, glutamate, valine, and lysine) region of titin. Blocking of interleukine-6 before left anterior descending coronary artery ligature restored titin-based myocyte tension after MI, suggesting that MI-induced titin stiffening is mediated by elevated levels of the cytokine interleukine-6. We further demonstrate that the early remodeling processes 3 days after MI involve accelerated titin turnover by the ubiquitin-proteasome system.We conclude that titin-based cardiac myocyte stiffening acutely after MI is partly mediated by interleukine-6 and is an important mechanism of remote myocardium to adapt to the increased mechanical demands after myocardial injury.
Value of Transient Elastography (Fibroscan®) in Patients with Autoimmune Hepatitis on Immunosuppressive Treatment
Authors: A.F. Stättermayer, M. Eder, S. Beinhardt, K. Kozbial, C. Freissmuth, R. Stern, F. Wrba, M. Trauner, P. Ferenci, H. Hofer
Journal: Journal of Hepatology (2016)
Cost-Effectiveness and Budget Impact of Interferon-Free Direct-Acting Antiviral (DAA)-Based Regimens for Chronic Hepatitis C Treatment. The French Case
Authors: S. Deuffic-Burban, D. Obach, V. Canva, S. Pol, F. Roudot-Thoraval, D. Dhumeaux, P. Mathurin, Y. Yazdanpanah
Journal: Journal of Hepatology (2016)
Ledipasvir/Sofosbuvir+/−Ribavirin in Patients Co-Infected with HCV and HIV: Real-World Heterogeneous Population from the Trio Network
Authors: D. Dieterich, B. Bacon, M. Curry, S. Flamm, L. Guest, K. Kowdley, Y. Lee, N. Tsai, Z. Younossi, N. Afdhal
Journal: Journal of Hepatology (2016)
NS3 Genetic Variability in HCV Genotype 1A Isolates from Liver Tissue and Serum Samples of Treatment-Naïve Patients with Chronic Hepatitis C
Authors: D. D’aliberti, I. Cacciola, S. Benfatto, F. Mannino, R. Filomia, C. Beninati, C. Saitta, G. Raimondo, T. Pollicino
Journal: Journal of Hepatology (2016)
Combined nasal exposure to sodium hypochlorite and ovalbumin induces airway hyperreactivity in mice through activation of the TRPA1 channel and mast cells
Authors: Valérie Hox, Jeroen Vanoirbeek, Ina Callebaut, Sonja Bobic, Vanessa De Vooght, Peter Hellings, Benoît Nemery
Journal: European Respiratory Journal (2011)
Increased Biomarkers of Cell Death are Associated with Development and Clinical Outcome in Patients with Cirrhosis and Hepatorenal Syndrome
Authors: M. Nguyen-Tat, T. Austgen, V. Sivanathan, J. Ahrens, D. Sollinger, J. Rey, M. Wörns, P. Galle, J. Marquardt
Journal: Journal of Hepatology (2016)
Achievement of Complete Hematological Remission and Reversal of High HTLV-1 Viral Loads with Anti CCR-4 Monoclonal Antibody Administration in Afro Caribbean Patients with Relapsed Chronic Adult T Cell Leukaemia (ATLL)
Authors: Paul Fields, Maria Demontis, Lucy Cook, Sasha Marks, David Wrench, Arief Gunawan, Claire Woodley, Graham Taylor
Journal: Blood (2014)
Total body metabolic tumor response in ALK-positive non-small cell lung cancer treated with crizotinib.
Authors: Gerald S.M.A. Kerner, Alexander Fischer, Michel J.B. Koole, Alfons H. H. Bongaerts, Jan Pruim, Harry J.M. Groen
Journal: Journal of Clinical Oncology (2014)

e19062 Background: In ALK-positive advanced NSCLC, crizotinib has a high response rate and effectively increases quality of life and progression-free survival. CT measurement of the tumor and RECIST evaluation may not reflect the actual tumor load changes. Therefore we explored whether 18F-FDG measured metabolic change per voxel in the primary tumor and largest metastatic sites during ALK inhibition is a more accurate measurement for tumor changes. Methods: 18F-FDG PET/CT was performed prior to and after 6 weeks of crizotinib treatment. Volumes of interest were drawn on the baseline scans of primary tumor and the 14 largest measurable metastases using the IMALYTICS research workstation. Using the elastix toolbox, scans performed after 6 weeks were non-rigidly aligned to the baseline scan in order to generate a target’ scan for voxel-by-voxel analysis. The differences in SUV between baseline and target’ were calculated. The percentage of the tumor of which the voxels exceeded the previously calculated reference values for image deformations was classified as decreasing partition (DP), stabile partition (SP) and increasing partition (IP), respectively. Tumor response on CT was classified with RECIST 1.1, while 18F-FDG PET response was assessed using the 1999 EORTC recommendations and the PERCIST criteria. Results: In this exploratory study 10 patients were analyzed. On CT, there were 8 partial responders (PR) and 2 patients had progressive disease (PD). After voxel-by-voxel analysis, PD patients had >20% IP and PR patients had < 2% IP. The 2 PD patients had 17 and 36% DP, respectively. Seven out of 8 PR had > 90% DP, 1 had 27% DP. IP between patients with PD and PR was statistically significant. Measured according to EORTC and PERCIST criteria, 8/10 patients were metabolic partial responders, 1 had stable metabolic disease and 1 had progressive metabolic disease. Conclusions: Most patients show a dramatic decrease in metabolic activity during crizotinib treatment. Metabolic response was different between the primary tumor and metastasis and was individually determined. In this small study, our new voxel-by-voxel technique corresponded better with RECIST response as the EORTC recommendations or PERCIST criteria did.
Changes in blood microbiota profiles associated with liver fibrosis in obese patients: A pilot analysis
Authors: Benjamin Lelouvier, Florence Servant, Sandrine Païssé, Anne‐Claire Brunet, Salah Benyahya, Matteo Serino, Carine Valle, Maria Rosa Ortiz, Josep Puig, Michael Courtney, Massimo Federici, José‐Manuel Fernández‐Real, Rémy Burcelin, Jacques Amar
Journal: Hepatology (2016)

The early detection of liver fibrosis among patients with nonalcoholic fatty liver disease (NAFLD) is an important clinical need. In view of the suggested role played by bacterial translocation in liver disease and obesity, we sought to investigate the relationship between blood microbiota and liver fibrosis (LF) in European cohorts of patients with severe obesity. We carried out a cross-sectional study of obese patients, well characterized with respect to the severity of the NAFLD, in the cohort FLORINASH. This cohort has been divided into a discovery cohort comprising 50 Spanish patients and then in a validation cohort of 71 Italian patients. Blood bacterial DNA was analyzed both quantitatively by 16S ribosomal DNA (rDNA) quantitative polymerase chain reaction and qualitatively by 16S rDNA targeted metagenomic sequencing and functional metagenome prediction. Spanish plasma bile acid contents were analyzed by liquid chromatography/mass spectrometry. The 16S rDNA concentration was significantly higher in patients of the discovery cohort with LF. By 16S sequencing, we found specific differences in the proportion of several bacterial taxa in both blood and feces that correlate with the presence of LF, thus defining a specific signature of the liver disease. Several secondary/primary bile acid ratios were also decreased with LF in the discovery cohort. We confirmed, in the validation cohort, the correlation between blood 16S rDNA concentration and LF, whereas we did not confirm the specific bacterial taxa signature, despite a similar trend in patients with more-severe fibrosis.Changes in blood microbiota are associated with LF in obese patients. Blood microbiota analysis provides potential biomarkers for the detection of LF in this population. (Hepatology 2016;64:2015-2027).
Long-Range Chromatin Interactions Drive Mutant <i>TERT</i> Promoter Activation
Authors: Semih Can Akıncılar, Ekta Khattar, Priscilla Li Shan Boon, Bilal Unal, Melissa Jane Fullwood, Vinay Tergaonkar
Journal: Cancer Discovery (2016)

Abstract Cancer-specific TERT promoter mutations (-146C&amp;gt;T and -124C&amp;gt;T) have been linked to reactivation of the epigenetically silenced telomerase reverse transcriptase gene (TERT). Understanding how these single-nucleotide alterations drive TERT reactivation is a fundamental unanswered question and is key for making successful therapeutics. We show that unlike wild-type promoters, recruitment of the transcription factor GABPA specifically to mutant TERT promoters mediates long-range chromatin interaction and enrichment of active histone marks, and hence drives TERT transcription. CRISPR-mediated reversal of mutant TERT promoters, or deletion of its long-range interacting chromatin, abrogates GABPA binding and long-range interactions, leading to depletion of active histone marks, loss of POL2 recruitment, and suppression of TERT transcription. In contrast, de novo introduction of a TERT promoter mutation enables GABPA binding and upregulation of TERT via long-range interactions, acquisition of active histone marks, and subsequent POL2 recruitment. This study provides a unifying mechanistic insight into activation of mutant TERT promoters across various human cancers. Significance: This study identifies a key mechanism by which cancer-specific mutant TERT promoters cause reactivation of TERT. Because the mechanism uncovered here is not utilized by promoters that drive TERT in normal cells, this mechanism could be exploited to make inhibitors which have the potential to block telomerase function and hence the progression of up to 90% of human cancers. Cancer Discov; 6(11); 1276–91. ©2016 AACR. See related commentary by Min and Shay, p. 1212. This article is highlighted in the In This Issue feature, p. 1197
Impact of the Combination of Dipeptidyl Peptidase IV Inhibitor and Angiotensin-II Type 1 Receptor Blocker on Hepatocarcinogenesis in a Rat Model of Nonalcoholic Steatohepatitis
Authors: Y. Okura, T. Namisaki, R. Noguchi, K. Takeda, K. Moriya, M. Kitade, N. Nishimura, S. Sato, Y. Sawada, H. Kawaratani, K. Seki, K. Kaji, H. Yoshiji
Journal: Journal of Hepatology (2016)
Canonical Correlation Analysis (CCA) of Imatinib Treatment (ImRx) Nonadherence (NA) with Associated Patient Variables (APVs) in Chronic Myeloid Leukemia (CML) - Results from the ADAGIO Study.
Authors: Marie-Anne van Lierde, Larissa De Rop, Filipo Serra, Eric Strobbe, Karen MacDonald, Stefaan Vancayzeele, Sabina De Geest, Laurie Letvak, Tara Albrecht, Ivo Abraham
Journal: Blood (2007)
Analysis of Molecular Mechanisms of 5-Fluorouracil Induced Steatosis and Inflammation in Vitro and in Mice
Authors: J. Sommer, A. Mahli, K. Freese, W. Thasler, F. Kuecuekoktay, A. Bosserhoff, M. Müller, C. Hellerbrand
Journal: Journal of Hepatology (2016)
Genotype-Phenotype Correlation of CTNNB1 Mutations Reveals Different B-Catenin Activation Levels in Hepatocellular Tumors with High Activity Associated with Malignancy
Authors: S. Rebouissou, A. Franconi, J. Calderaro, E. Letouzé, S. Imbeaud, C. Pilati, J.-C. Nault, G. Couchy, A. Laurent, C. Balabaud, P. Bioulac-Sage, J. Zucman-Rossi
Journal: Journal of Hepatology (2016)
P0417 : Nlrp3 inflammasome increases hepatic fibrosis by inducing inflammatory signals in hepatic stellate cells
Authors: C. Rychlicki, L. Agostinelli, E. Mingarelli, S. Saccomanno, C. Pinto, I. Pierantonelli, L. Trozzi, M. Marzioni, S. De Minicis, G. Svegliati-Baroni
Journal: Journal of Hepatology (2015)
Urethral Trauma After Foley Catheter Placement
Authors: Jana Bregman, Wade Iams, Cecelia Theobald
Journal: JAMA Internal Medicine (2016)

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