tbuckley/cabot-search huggingface dataset:
PTU-030 Obesity: a risk factor for Crohn's disease or a distinct obesity-related enteropathy?
Authors: M Mendall, A V Gunasekera, J B John, D Kumar
Journal: Gut (2010)

<h3>Introduction</h3> Obesity is a rapidly increasing problem with an increasing number of adverse health consequences being discovered. It is associated with a pro-inflammatory state.1 In epidemiological studies obesity has been associated with diarrhoeal symptoms,2 and increased levels of a marker of inflammation, calprotectin, in the faeces.3 The objective was to determine whether obesity at diagnosis is a risk factor for Crohn9s disease vs ulcerative colitis and also vs community controls. <h3>Methods</h3> 524 consecutive patients attending gastroenterology clinics at Mayday University Hospital and St George9s Medical School were administered a questionnaire enquiring about weight at diagnosis if not available from the notes and height as well as other risk factors for inflammatory bowel disease. 480 community controls aged 50–70 were randomly selected from the registers of 4 local general practices as part of another study. Outcome measures: odds ratio of association of obesity at diagnosis with Crohn9s disease vs ulcerative colitis at all ages and Crohn9s disease vs community controls in the 50–70-year age group as a secondary analysis. <h3>Results</h3> Obesity at diagnosis was more common in subjects with Crohn9s disease vs ulcerative colitis odds ratio 2.017 (1.18–3.43) p=0.01 and also Crohn9s disease vs community controls in the 50–70-year age group odds ratio 3.22 (1.59–6.52) p=0.001 after controlling for age at diagnosis, sex and smoking at the time of diagnosis. The strength of association for CD vs UC was increased further after adjustment for weight and height at diagnosis to odds ratio 3.84 (1.83–8.15) p=0.0003 as was the case when BMI and BMI squared were modelled as the explanatory variables. This reflects a U shaped relationship between BMI at diagnosis and risk of Crohn9s vs ulcerative colitis. <h3>Conclusion</h3> Obesity may play a role in the pathogenesis of Crohn9s disease and it maybe that an obesity related enteropathy is a distinct entity.
Abstract 3133: Deciphering the novel role and underlying mechanism of let-7i repression in stem-like properties of head and neck cancer cells
Authors: Tsai-Tsen Liao, Muh-Hwa Yang
Journal: Cancer Research (2015)

Abstract Background: Head and neck squamous cell carcinoma (HNSCC) is one of the major male cancers worldwide, and the main therapeutic strategies include surgery, radiotherapy and chemotherapy. Cancer stem cells are a small population of tumor cells that are responsible for tumorigenesis, tumor recurrence and treatment resistance. let-7 family microRNAs have been shown to function as a tumor suppressor. Here we aim to investigate the role of let-7i in regulating stem cell properties in HNSCC. Methods: Luciferase reporter assay were used to identify the targets of let-7i; Western blot to analysis the correlation between ARID3B and Oct4; ChIP assay confirm the binding of ARID3B to Oct4 proximal promoter; Quantitative RT-PCR to analyzed the level of ARID3B, Oct4, and let-7i in the 52 pairs of samples containing primary tumor tissues and adjacent normal epithelium from head and neck cancer patients with different stage receiving surgery. Results: ARID3B, a member of the AT-rich interaction domain family proteins which plays an essential role during embryogenesis, is a bona fide target of let-7i. ARID3B promotes stem-like properties of HNSCC cells and upregulates a panel of stemness genes, and Oct4 is one of the most prominent ones to be upregulated. ARID3B direct binds to the AT-rich region of Oct4 promoter to activate its transcription. Downregulation of let-7i in HNSCC samples correlates with a corresponding upregulation of Oct4 and ARID3B. Conclusions: We propose a mechanism of let-7i repression-mediated stem-like properties through releasing the suppression of a novel let-7i target ARID3B, which leads to transcriptional activation of stemness genes. Let-7i coordinates the function of ARID3B through repressing targets related to ARID3B activity, such as ARID3A and KPNA4. Furthermore, we elucidate of the regulatory mechanism of the stemness factors by ARID3B through epigenetic regulation. The results provide useful information in elucidating the mechanism of HNSCC progression and also provide potential targets in developing HNSCC-specific treatment. Citation Format: Tsai-Tsen Liao, Muh-Hwa Yang. Deciphering the novel role and underlying mechanism of let-7i repression in stem-like properties of head and neck cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3133. doi:10.1158/1538-7445.AM2015-3133
Reduced-Intensity Versus Myeloablative Conditioning for Unrelated Cord Blood Transplantation in Adults with Acute Leukemia: A Report from Eurocord, the Acute Leukemia Working Party and the Cord Blood Committee of the Cellular Therapy &amp; Immunobiology Working Party of the European Group for Blood and Marrow Transplantation
Authors: Frederic Baron, Ruggeri Annalisa, Eric Beohou, Myriam Labopin, Guillermo Sanz, Noel Milpied, Mauricette Michallet, Andrea Bacigalupo, Gerard Socie, Didier Blaise, Jorge Sierra, Jan Cornelissen, Mohamad Mohty, Christoph Schmid, Sebastian Giebel, Norbert Claude Gorin, Jordi Esteve, Fabio Ciceri, Bipin N. Savani, Eliane Gluckman, Arnon Nagler
Journal: Blood (2015)
Targeting Myeloma Cells and Their Progenitors By Pim Kinase Inhibition
Authors: Shiro Fujii, Hirokazu Miki, Asuka Oda, Keiichiro Watanabe, Ryota Amachi, Hikaru Yagi, Kimiko Sogabe, Mamiko Takahashi, Tomoko Maruhashi, Kengo Udaka, Shingen Nakamura, Kumiko Kagawa, Shuji Ozaki, Toshio Matsumoto, Masahiro Abe
Journal: Blood (2014)
Highly pathogenic avian influenza A(H5N8) outbreaks: protection and management of exposed people in Europe, 2014/15 and 2016
Authors: Cornelia Adlhoch, Ian H. Brown, Svetla G. Angelova, Ádám Bálint, Ruth Bouwstra, Silke Buda, Maria R. Castrucci, Gavin Dabrera, Ádám Dán, Christian Grund, Timm Harder, Wim van der Hoek, Katalin Krisztalovics, Frances Parry-Ford, Rodica Popescu, Anders Wallensten, Anna Zdravkova, Siamak Zohari, Svetla Tsolova, Pasi Penttinen
Journal: Eurosurveillance (2016)

Introduction of highly pathogenic avian influenza (HPAI) virus A(H5N8) into Europe prompted animal and human health experts to implement protective measures to prevent transmission to humans. We describe the situation in 2016 and list public health measures and recommendations in place. We summarise critical interfaces identified during the A(H5N1) and A(H5N8) outbreaks in 2014/15. Rapid exchange of information between the animal and human health sectors is critical for a timely, effective and efficient response.
CpG Island Methylation Is a Poor Prognostic Factors in Myelodysplastic Syndrome Patients and Is Reversed by Decitabine Therapy-Results of a Phase III Randomized Study.
Authors: Lanlan Shen, Hagop Kantarjian, Hussain Saba, E. Lin, Don Berry, Saira Ahmed, Jaroslav Jelinek, Jean-Pierre J. Issa
Journal: Blood (2005)
Executive Summary: Trends in U.S. Cardiovascular Care
Authors: Frederick A. Masoudi, Angelo Ponirakis, James A. de Lemos, James G. Jollis, Mark Kremers, John C. Messenger, John W.M. Moore, Issam Moussa, William J. Oetgen, Paul D. Varosy, Robert N. Vincent, Jessica Wei, Jeptha P. Curtis, Matthew T. Roe, John A. Spertus
Journal: Journal of the American College of Cardiology (2016)
Randomized Trial of GM-CSF and G-CSF Following High-Dose Cytarabine and Mitoxantrone Chemotherapy for Relapsed and Refractory Acute Leukemia.
Authors: Maria R. Baer, Laurie A. Ford, Brian N. Bundy, Sheila M. Tighe, Kieran L. O’Loughlin, James L. Slack, Meir Wetzler, Paul K. Wallace
Journal: Blood (2006)
Prospective Evaluation of An Agvhd-Specific Proteomic Pattern in More Than 340 Patients.
Authors: Eva M. Mischak-Weissinger, Ernst Holler, Michael Schleuning, Gernot Beutel, Hildegard Greinix, Anne M Dickinson, James LM Ferrara, Stefanie Buchholz, Annika Krons, Julia Kontsendorn, Norbert Hahn, Axel R. Zander, Hans-Jochem Kolb, Jochen Metzger, Arnold Ganser
Journal: Blood (2009)
A rare cause of GI bleeding in a 56-year-old man
Authors: Pao-Ying Lin, Jui-Hsiang Tang, Chun-Chao Chang
Journal: Gut (2016)

A 56-year-old man, with a known history of diabetes for 1 year, presented with a 5-day history of melena that was associated with one episode of haematemesis. One month prior, he had completed a course of oral amoxicillin for a dental infection that occurred after a tooth extraction. The only other significant past medical problem was hypertension for 10 years. Physical examination only showed pallor and abdominal examination was normal. Laboratory investigations revealed haemoglobin level of 8.4 g/dL and HbA1C of 7.8%. His upper GI endoscopy showed a diffuse irregular friable exudative ulcerative lesion involving the gastric fundus (figure 1). Endoscopic ultrasonography (EUS) demonstrated disrupted gastric wall layers with wall thickening of 5.1 mm and regional lymph nodes (figure …
Incomplete inhibition by eculizumab: mechanistic evidence for residual C5 activity during strong complement activation
Authors: Markus J. Harder, Nadine Kuhn, Hubert Schrezenmeier, Britta Höchsmann, Inge von Zabern, Christof Weinstock, Thomas Simmet, Daniel Ricklin, John D. Lambris, Arne Skerra, Markus Anliker, Christoph Q. Schmidt
Journal: Blood (2016)
630. Cytotoxicity by Adenovirus Replications is Associated with DNA Damages and the Activated P53 Pathways and Is Dependent on Reactive Oxygen Species
Authors: Masatoshi Tagawa, Kiyoko Kawamura, Shinya Okamoto, Yuanyuan Jiang, Zhihan Li, Takao Morinaga, Shuji Kubo, Masato Shingyoji, Ikuo Sekine, Yuji Tada, Koichiro Tatsumi, Hideaki Shimada, Kenzo Hiroshima
Journal: Molecular Therapy (2015)

Adenovirus (Ad) replications induce cytotoxicity to the infected targets but a possible mechanism of replication-induced cell death is not well characterized. We examined cytotoxicity of replication-competent Ads which were activated by an exogenous regulatory region to human pancreatic carcinoma cells with defective p53 pathways. The cytotoxicity was not correlated with infectivity of the Ad vectors or a transcriptional activity of the regulatory regions used to activate the E1 region. Cells infected with the Ads showed cytopathic effects and increased sub-G1 fractions. Caspase-9, less significantly caspase-8 and poly (ADP-ribose) polymerase, but not caspase-3 was cleaved, and expression of the molecules involved in autophagy and caspase-independent cell death pathways, Beclin-1, Atg5, LC3A/B I/II, Endo G, Bid and AIF, remained unchanged. H2A histone family member X molecules were however phosphorylated at Ser 139 after the infection with the Ads, and N-acetyl-L-cystein, an inhibitor for reactive oxygen species, suppressed the Ads-mediated cytotoxicity. We also examined the Ads-mediated cytotoxicity to human esophageal carcinoma cells with mutated p53 gene. Infection with the Ads induced cleavage of caspase-8, -9, -3 and poly (ADP-ribose) polymerase, and increased sub-G1 fractions in the target cells, whereas the infection did not activate autophagy pathways. Transduction with Ads expressing the wild-type p53 gene (Ad-p53) in combination with the replication-competent Ads further enhanced the Ads-mediated cytotoxicity in a synergistic manner. Transduction with Ad-p53 was however inhibitory to production of replication-competent Ad progenies, but the combination augmented Ad-p53-induced p53 expression levels and the phosphorylation. These data collectively showed that an involvement of caspase-dependent apoptosis in the Ads-induced cell death were dependent on cells tested, and that the cell death was linked with DNA damages and actions of reactive oxygen species. Moreover, Ad replications augmented cell death through activation of the p53 pathways.
Abstract 833: Persistent alterations of gene expression profiling of human peripheral blood mononuclear cells from smokers
Authors: Daniel Y. Weng, Jinguo Chen, Cenny Taslim, Ping-Ching Hsu, Catalin Marian, Sean P. David, Christopher A. Loffredo, Peter G. Shields
Journal: Cancer Research (2015)

Abstract The number of validated biomarkers of tobacco smoke exposure is limited, and none exist for tobacco-related cancer. Additional biomarkers for smoke effects on cellular systems in vivo are needed to improve early detection of lung cancer, and to assist the Food and Drug Administration in regulating exposures to tobacco products. We assessed the effects of smoking on the gene expression in vitro and in vivo using human cell cultures and blood from a cross-sectional study. We profiled global transcriptional changes in cultured smokers’ peripheral blood mononuclear cells (PBMCs) treated with cigarette smoke condensate (CSC) in vitro and from well-characterized smokers’ blood (n = 36). ANOVA and linear regression with adjustment for covariates were used for statistical analysis. CSC in vitro altered the expression of 1178 genes (177 genes with &amp;gt; 1.5 fold-change) at P &amp;lt; 0.05. Phase I and II metabolizing enzyme genes were up-regulated, cytokines and chemokines were down-regulated. Nine putative oncogenes and 5 tumor suppressor genes were dysregulated. In vivo, PBMCs of heavy and light smokers differed for 614 genes (29 with &amp;gt; 1.5 fold-change) at P &amp;lt; 0.05 (309 remaining significant after adjustment for age, race and gender). Seventy eight genes had a significant linear correlation (P &amp;lt; 0.01) with cigarettes per day and 28 genes were linearly correlated with cumulative pack-year smoking. Forty-one genes were persistently altered both in vitro and in vivo, 22 having the same expression pattern reported for non-small cell lung cancer. Our data provides evidence that persistent alterations of gene expression in vitro and in vivo may relate to carcinogenic effects of cigarette smoke, and the identified genes may serve as potential biomarkers for cancer. The use of an in vitro model to corroborate results from human studies provides direct evidence for a cause and effect. Citation Format: Daniel Y. Weng, Jinguo Chen, Cenny Taslim, Ping-Ching Hsu, Catalin Marian, Sean P. David, Christopher A. Loffredo, Peter G. Shields. Persistent alterations of gene expression profiling of human peripheral blood mononuclear cells from smokers. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 833. doi:10.1158/1538-7445.AM2015-833
Prostaglandin E2 (PGE2) Regulates Osteoblastic Jagged1 and Expands Primitive Hematopoietic Cells In Vivo.
Authors: Laura M. Calvi, Benjamin J. Frisch, Benjamin J. Gigliotti, Christina A. Christianson, Jonathan M. Weber, Craig T. Jordan, Regis J. O’Keefe
Journal: Blood (2006)
A Phase 1 first-in-human trial to evaluate the safety and tolerability of CCT3833, an oral panRAF inhibitor, in patients with advanced solid tumours, including metastatic melanoma.
Authors: Emma Jane Dean, Udai Banerji, Romina Girotti, Ion Niculescu-Duvaz, Filipa Lopes, Lawrence Davies, Dan Niculescu-Duvaz, Natalie Dhomen, Sally Ellis, Zohra Ali, Brent O'Carrigan, Louise Carter, Luke Chisolm, Caroline Dive, Heidi A Lane, Paul Lorigan, Martin Eric Gore, James Larkin, Richard Marais, Caroline Springer
Journal: Journal of Clinical Oncology (2016)

TPS9597 Background: Over 70,000 patients are diagnosed with malignant melanoma in the USA every year with a high proportion occurring in young people. Although treatments targeting the mitogen activated protein kinase signal transduction pathway including BRAF inhibitors have improved survival for patients with BRAF mutated melanoma, their utility is limited by intrinsic and acquired resistance of diverse mechanisms. Patients with a RAS mutated melanoma also represent a current unmet need. CCT3833 is a potent inhibitor of mutant BRAF, CRAF and SRC kinases. Preclinical data using CCT3833 in a range of mutant RAF or RAS cell lines in vitro and human tumour xenograft models in vivo demonstrated activity, including melanoma patient-derived xenografts with intrinsic or acquired resistance to selective BRAF inhibitors. These data support clinical development of CCT3833 in humans. Methods: This ongoing open-label, multi-centre Phase I trial of CCT3833 is in two parts; an initial dose escalation stage (Part A) in a rolling six design, followed by a dose expansion (Part B). The primary objectives are to evaluate the safety and tolerability profile of CCT3833 and establish the Recommended Phase 2 Dose (RP2D). CCT3833 is administered orally once daily on a continuous basis over a 28-day cycle. In Part A, a single dose is administered for safety and pharmacokinetic (PK) purposes prior to commencing continuous dosing. Secondary objectives include characterisation of the PK profile and correlation with tolerability / efficacy of CCT3833 in humans and assessment of response (radiological or clinical), supported by PD analyses. Eligible subjects include patients with advanced solid malignancies with performance status 0 to 1, fit for entry into a Phase 1 clinical trial. Part B will enrol patients with BRAF- or RAS- mutated metastatic melanoma into 3 cohorts i) treatment naïve V600E BRAF mutant melanoma ii) V600E BRAF mutant melanoma with progression on BRAF inhibitor therapy or iii) RAS mutant melanoma. Three cohorts of the dose escalation have been completed without DLT. Enrolment to cohort 4 began in January 2016. Clinical trial information: NCT02437227. Clinical trial information: NCT02437227.
Risk Factors in Childhood Acute Lymphoblastic Leukemia: A Single Center Experience in a Developing Country.
Authors: Sema S. Anak, Leyla Agaoglu, Arzu Akcay, Ebru T. Saribeyoglu, Didem Y. Atay, Mesut Garipardic, Aysegul Unuvar, Zeynep Karakas, Omer Devecioglu, Gulyuz Ozturk, Gunduz Gedikloglu
Journal: Blood (2005)
The Effect of Eplerenone versus Placebo on Cardiovascular Mortality or Heart Failure Hospitalization in Subjects With NYHA Class II Chronic Systolic Heart Failure. EMPHASIS-HF
Authors: Faiez Zannad, McMurray J. John, Drexler Helmut, Krum Henry, Van Veldhuisen J. Dirk, Swedberg Karl, Pitt Bertram
Journal: Circulation (2010)
Lenalidomide, Bortezomib, and Dexamethasone (Rev/Vel/Dex) in Patients with Relapsed or Relapsed/Refractory Multiple Myeloma (MM): Preliminary Results of a Phase II Study.
Authors: Paul Richardson, Sundar Jagannath, Noopur Raje, Andrzej Jakubowiak, Sagar Lonial, Irene Ghobrial, Robert Schlossman, Amitabha Mazumder, Nikhil Munshi, Kathleen Colson, Mary McKenney, Melissa Farrell, Laura Lunde, Lawrence Giove, Sarah Kaster, Constantine Mitsiades, Teru Hideshima, Robert Knight, Dixie-Lee Esseltine, Kenneth Anderson
Journal: Blood (2007)
686. Gene Correction of IL2RG in Human Hematopoietic Stem and Progenitor Cells
Authors: Anthony Conway, Dmitry Y. Guschin, Pietro Genovese, Angelo Lombardo, Luigi Naldini, Philip D. Gregory, Michael C. Holmes, Gregory J. Cost
Journal: Molecular Therapy (2015)

Mutations in the IL2RG gene may result in X-linked severe combined immunodeficiency (X-SCID), an immunodeficiency disorder in which the body produces very few T cells and natural killer cells, resulting in premature death due to opportunistic infections. At present, allogeneic hematopoietic stem cell transplant (HSCT) is the standard of care and results in full immune reconstitution if engraftment is successful. However, the search for a compatible donor is not always successful and transplantation from a non MHC-identical donor carries the risk of graft-versus-host disease. An autologous HSCT containing a replaced or corrected IL2RG gene would avoid these risks. Previous autologous gene therapy for X-SCID successfully treated the disease but relied on early generation gene replacement retroviral vectors and resulted in insertional oncogenesis and leukemia development in some treated subjects. Here we report a gene correction approach to X-SCID gene therapy involving targeted integration (TI) of a corrective IL2RG donor DNA cassette (cDNA from exons 2-8) into intron 1 of the IL2RG gene. This strategy has the advantage of retaining the endogenous IL2RG promoter and enhancer and allows treatment of patients with almost all X-SCID causing IL2RG mutations (excluding only those affecting the gene upstream of intron 1). Using engineered zinc-finger nucleases (ZFNs) delivered as mRNA and IL2RG donor DNA delivered as adeno-associated virus (AAV) to CD34+ human hematopoietic stem and progenitor cells (HSPCs) cultured ex vivo, we have achieved TI of the corrective IL2RG donor in up to 25% of alleles. These cells differentiate normally in vitro and retain consistent levels of TI in both erythroid and myeloid lineages. IL2RG mRNA expression was successfully restored in an IL2RG knockout model human cell line, validating this strategy. Coupled with the strong, intrinsic in vivo selection for cells with IL2RG activity, our data are a promising advance towards an autologous HSPC-based gene therapy for the treatment of X-SCID.
483. Epigenetic Silencing of Hepatitis B cccDNA In Vitro and In Vivo Using AAV-Delivered Engineered Repressor Transcription Activator-Like Effector
Authors: Buhle Moyo, Samantha Nicholson, Ilke Roelofse, Carol Crowther, Kristie Bloom, Claudio Mussolino, Toni Cathomen, Koichi Watashi, Abdullah Ely, Patrick Arbuthnot
Journal: Molecular Therapy (2015)

Hepatitis B virus (HBV) infection is hyper-endemic (>8 % chronic carriers) to parts of Asia and sub-Saharan Africa. Persistent HBV infection predisposes to liver diseases such as cirrhosis and hepatocellular carcinoma. Current anti-HBV therapies face several limitations. RNA interference-based therapies lack the robustness and specificity required for therapeutic effect while interferon-α and nucleotide/side analogs function post-transcriptionally and thus allow for the persistence of the covalently closed circular (cccDNA). cccDNA may persist indefinitely and enables re-initiation of HBV replication after withdrawal of treatment. Disabling the cccDNA is essential for the successful treatment of chronic HBV. Our group previously described effective anti-HBV transcription activator-like effector (TALE) nucleases (TALENs). Although potentially useful to counter HBV replication, one drawback is that viral sequences integrated into the host genome may be susceptible to digestion by the TALENs. Transcriptional silencing, rather than cleavage, of cccDNA may therefore be preferable to avoid causing undesirable mutations in the host. To this end, TALE binding domains designed to target the viral preS2 promoter and the basic core promoter/enhancer II regions were fused to a Krüppel-associated box repressor domain to generate repressor-TALEs (rTALEs). These rTALEs were shown to inhibit viral replication in vitro and in vivo without inducing significant toxicity. In an in vivo murine model using hydrodynamic transfection with an HBV replication-competent plasmid, a reduction in secreted HBV surface antigen (HBsAg) of 97% and 98% was seen at day 3 and 93% and 96% at day 5 for P1L and P1R respectively. To develop this approach as a feasible therapy, rTALE-encoding sequences were incorporated into recombinant adeno-associated viruses (rAAVs) and assessed in the HepG2.hNTCP-C4 cell line. These cells overexpress the HBV receptor, human sodium taurocholate co-transporting peptide (hNTCP). The HepG2.NTCP-C4 cell line is infectable with HBV and viral gene expression is dependent on formation of cccDNA. Measurement of viral markers of replication may thus be used as an indicator of inhibitory effects on cccDNA. The anti-HBV efficacy of the rTALEs and epigenetic modification of the targeted HBV DNA was characterized. Chromatin immunoprecipitation assays determined the binding of the rTALEs to the cccDNA and induction of epigenetic markers of viral gene suppression. Mobility shift assays confirmed specificity of rTALE binding. In vivo efficacy of rAAV-delivered rTALEs was evaluated in transgenic HBV mice. Our study provides valuable information on the potential therapeutic utility of rTALEs and demonstrates the feasibility of the approach for treatment of HBV.