tbuckley/cabot-search huggingface dataset:
Abstract IA12: Targeting DNA repair in cancer therapy
Authors: Alan D. D'Andrea
Journal: Clinical Cancer Research (2017)

Abstract Human cancer cells have genomic instability resulting from germline or acquired defects in DNA repair. One DNA repair pathway—the Fanconi Anemia/BRCA pathway (D'Andrea, A., N Engl J Med 362:1909, 2010)—is defective in many human cancers, including breast, ovarian, and pancreatic neoplasms. Disruption of the FA/BRCA Pathway results in the characteristic chromosome instability and radiation/crosslinker hypersensitivity of these tumors. In general, loss of one DNA repair pathway often leads to hyperdependence on another pathway for tumor cell survival. This hyperdependence offers a unique opportunity for the development of anticancer therapeutics. For instance, FA/BRCA pathway deficient tumors are hyperdependent on Base Excision Repair (BER) and, accordingly, these tumors are hypersensitive to single agent treatment with PARP1 inhibitors, which block BER, or with ATM inhibitors. Our research program is focused on profiling the FA/BRCA pathway and the other five major DNA repair pathways in tumor cells (Kennedy and D'Andrea, JCO 24: 3799, 2006). Each DNA repair pathway has a characteristic biomarker and repairs a specific type of DNA lesion. By profiling these pathways in primary tumor samples with activation-specific antibodies to DNA repair proteins, we have been able (1) to predict the sensitivity of tumors to conventional chemotherapy and radiation (2) to subset tumors for their sensitivity to novel classes of DNA repair inhibitors, (i.e., PARP1, Chk1, ATM, and proteasome inhibitors) and (3) to screen for new small molecule inhibitors of other DNA repair pathways. This combination of novel DNA repair inhibitors, conventional DNA damaging agents, and DNA repair biomarkers offers new opportunities for developing more effective anticancer therapy. In my presentation, I will also discuss novel approaches to sensitizing Triple Negative Breast Cancers (TNBCs) and Ovarian Tumors (OCs) to PARP1 inhibitors. We have previously shown that exposure of these tumors to either a CDK inhibitor or a proteasome inhibitor can block homologous recombination (HR) repair and thereby sensitize the tumor cells to PARP1 inhibitor. The CDK inhibitor/PARP1 inhibitor combination has been examined in orthotopic primary TNBC and OC xenograft models. Finally, we have identified an additional PARP1-dependent DNA repair mechanism in TNBCs and OCs. This pathway is driven by a novel alternative end-joining polymerase, POLθ. These tumors are hypersensitive to inhibitors of this new pathway, suggesting a new target for DNA repair therapies. Citation Format: Alan D. D'Andrea. Targeting DNA repair in cancer therapy. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr IA12.
Arthroscopic surgery for degenerative knee arthritis and meniscal tears: a clinical practice guideline
Authors: Reed A C Siemieniuk, Ian A Harris, Thomas Agoritsas, Rudolf W Poolman, Romina Brignardello-Petersen, Stijn Van de Velde, Rachelle Buchbinder, Martin Englund, Lyubov Lytvyn, Casey Quinlan, Lise Helsingen, Gunnar Knutsen, Nina Rydland Olsen, Helen Macdonald, Louise Hailey, Hazel M Wilson, Anne Lydiatt, Annette Kristiansen
Journal: BMJ (2017)

#### What you need to know What is the role of arthroscopic surgery in degenerative knee disease? An expert panel produced these recommendations based on a linked systematic review triggered by a randomised trial published in The BMJ in June 2016, which found that, among patients with a degenerative medial meniscus tear, knee arthroscopy was no better than exercise therapy. The panel make a strong recommendation against arthroscopy for degenerative knee disease. Box 1 shows all of the articles and evidence linked in this Rapid Recommendation package. The infographic provides an overview of the absolute benefits and harms of arthroscopy in standard GRADE format. Table 2 below shows any evidence that has emerged since the publication of this article. #### Box 1: Linked articles in this BMJ Rapid Recommendations cluster
Tumour recurrence after Interferon-free treatment for hepatitis C in patients with previously treated hepatocellular carcinoma discloses a more aggressive pattern and faster tumour growth
Authors: M. Reig, Z. Mariño, C. Perelló, M. Iñarrairaegui, S. Lens, A. Díaz, R. Vilana, A. Darnell, M. Varela, B. Sangro, J.L. Calleja, X. Forns, J. Bruix
Journal: Journal of Hepatology (2017)
Impact of elbasvir/grazoprevir (EBR/GZR) on health-related quality of life (HRQOL) and fatigue in patients with chronic hepatitis C virus (HCV) infection and inherited blood disorders (IBLD): data from the C-EDGE IBLD study
Authors: J.M. Vierling, A. Sobhonslidsuk, G. Papatheodoridis, N. Assy, W. Rosenberg, D. Guyader, A. Dev, S.C. Gordon, S. Pol, V.A. Luketic, S. Khemichian, B. Evans, L. Morgan, M. Li, R. Talwani, J.M. Arduino, P. Kwo
Journal: Journal of Hepatology (2017)
The bile acid receptor TGR5 regulates paracellular permeability and protects the liver through an impact on the tight junction protein JAM-A
Authors: G. Merlen, J. Ursic-Bedoya, N. Kahale, H. Simerabet, I. Doignon, Z. Tanfin, N. Péan, J. Gautherot, C. Ullmer, L. Humbert, D. Rainteau, D. Cassio, T. Tordjmann
Journal: Journal of Hepatology (2017)
First-in-Human Phase 1a Study of the Safety, Pharmacokinetics, and Pharmacodynamics of the Noncovalent Bruton Tyrosine Kinase (BTK) Inhibitor SNS-062 in Healthy Subjects
Authors: Linda L. Neuman, Renee Ward, David Arnold, Daniel L. Combs, Deena Gruver, Wendy Hill, Josué Mfopou Kunjom, Langdon L. Miller, Judith A. Fox
Journal: Blood (2016)
The diagnostic accuracy of vibration controlled transient elastography for cirrhosis in subjects with nonalcoholic fatty liver disease
Authors: M.S. Siddiqui, R. Vuppulanchi, M. Van Natta, D. Brandman, J.T. Tonascia, N. Chalasani, M.S. Middleton, A.J. Sanyal
Journal: Journal of Hepatology (2017)
Long term quinine for muscle cramps may increase death risk
Authors: Jacqui Wise
Journal: BMJ (2017)

Long term use of quinine, prescribed off label for muscle cramps or restless leg syndrome, is associated with increased mortality, says a study of UK GP prescribing published in JAMA .1

The British National Formulary (BNF) says that quinine salts such as quinine sulfate 200-300 mg at bedtime are effective in reducing nocturnal leg cramps by about 25%.2 Because of potential toxicity, however, quinine is not recommended for routine treatment and is advised only when cramps are very painful or frequent, …
An miRNA Expression Signature for the Human Colonic Stem Cell Niche Distinguishes Malignant from Normal Epithelia
Authors: Vignesh Viswanathan, Shirish Damle, Tao Zhang, Lynn Opdenaker, Shirin Modarai, Monica Accerbi, Skye Schmidt, Pamela Green, Deni Galileo, Juan Palazzo, Jeremy Fields, Sepehr Haghighat, Isidore Rigoutsos, Greg Gonye, Bruce M. Boman
Journal: Cancer Research (2017)

Abstract Malignant transformation of tissue stem cells (SC) may be the root of most cancer. Accordingly, we identified miRNA expression patterns in the normal human colonic SC niche to understand how cancer stem cells (CSC) may arise. In profiling miRNA expression in SC-enriched crypt subsections isolated from fresh, normal surgical specimens, we identified 16 miRNAs that were differentially expressed in the crypt bottom, creating an SC signature for normal colonic epithelia (NCE). A parallel analysis of colorectal cancer tissues showed differential expression of 83 miRNAs relative to NCE. Within the 16 miRNA signature for the normal SC niche, we found that miR-206, miR-007-3, and miR-23b individually could distinguish colorectal cancer from NCE. Notably, miR-23b, which was increased in colorectal cancer, was predicted to target the SC-expressed G protein-coupled receptor LGR5. Cell biology investigations showed that miR-23b regulated CSC phenotypes globally at the level of proliferation, cell cycle, self-renewal, epithelial–mesenchymal transition, invasion, and resistance to the colorectal cancer chemotherapeutic agent 5-fluorouracil. In mechanistic experiments, we found that miR-23b decreased LGR5 expression and increased ALDH+ CSCs. CSC analyses confirmed that levels of LGR5 and miR-23b are inversely correlated in ALDH+ CSCs and that distinct subpopulations of LGR5+ and ALDH+ CSCs exist. Overall, our results define a critical function for miR-23b, which, by targeting LGR5, contributes to overpopulation of ALDH+ CSCs and colorectal cancer. Cancer Res; 77(14); 3778–90. ©2017 AACR.
Loss of TOSO Promotes Richter's Transformation of TCL1A Driven CLL
Authors: Alexandra da Palma Guerreiro, Cornelia Dorweiler, Laurent Kintzelé, Dunja Baatout, Malte Huelsemann, Valeska Berg, Olaf Merkel, Nina Reinart, Guenter Fingerle-Rowson, Gero Knittel, Christian Pallasch, Hans Christian Reinhardt, Clemens Martin Wendtner, Michael Hallek, Lukas P. Frenzel
Journal: Blood (2016)
Investigations of a new diagnostics technology for hepatocellular carcinoma screening.
Authors: Jiasong Ji, Jingjing Song, Zhongwei Zhao, Jianfei Tu, Xiaoxi Fan, Xing Tang, Da Lou, Hongmei Tao, Yue Lin, Xuedong Du, Chris Chang Yu
Journal: Journal of Clinical Oncology (2015)

e22171 Background: A newly developed diagnostic technology named Cancer Differentiation Analysis Technology (CDA) was investigated for hepatocellular carcinoma (HCC) screening. The CDA technology is a blood-sample based, multi-level, multi-parameter diagnostic method which detects signals from both proteins and cells, in which multiple aspects of information collected to improve diagnostic accuracy. Methods: Blood samples from patients with HCC (n = 511), cirrhosis (n = 71) and other benign liver diseases (BLD) (n = 46), as well as control subjects (n = 79) were collected in EDTA tubes. CDA values were measured using a CDA device. After removing outliers, the final valid CDA data came from 485 HCC patients, 64 cirrhosis, 44 other benign liver diseases, and 75 controls. All data were analyzed and the results were shown in the table below. Results: The average CDA of HCC, cirrhosis, BLD, and controls were 53.14, 44.04, 41.90, and 33.90 (rel. units), respectively. The results indicated that HCC could be significantly distinguished from the control, BLD, and cirrhosis (all p < 0.001), and the control could be distinguished from BLD and cirrhosis (both p < 0.001). The false positives in HCC diagnostic tests could possibly be reduced with this new technology, given statistically significant difference between HCC , and cirrhosis and BLD. Conclusions: Initial results showed that CDA technology could be a potential candidate for HCC screening. Table 1 Summary of CDA Test Results. Group Number of CDA Data Set Gender (Male %) Age Range (year) Average Age (year) Median Age (year) Average CDA (rel. units) Median CDA (rel. units) SD of CDA (rel. units) HCC 485 87 32 - 87 58 58 53.14 53.49 4.03 Hepatocirrhosis 64 83 19 - 81 55 54 44.04 43.83 5.74 BLD 44 68 24 - 75 54 51 41.90 43.43 6.05 Control 75 57 23 - 89 50 49 34.24 33.90 4.76
Post-prandial serum bile acid concentration change after bariatric surgery and is associated with weight loss and glucose metabolism improvement in obese human subjects
Authors: L. Parlati, F. Ferri, E. Poli, F. Leonetti, D. Capoccia, G. Silecchia, M. Ståhlman, A. Molinaro, S.G. Corradini, F. Backhed
Journal: Journal of Hepatology (2017)
Prolonged-release pirfenidone is a dual activator for PPARalpha and PPARgamma and improves NASH features induced by high fat/carbohydrate diet
Authors: J. Armendariz-Borunda, R. Rodriguez-Echevarria, J. Macias-Barragan, E. Mendivil-Rangel, J. Vera-Cruz, J. Garcia-Banuelos
Journal: Journal of Hepatology (2017)
Evaluation of non-classical response by immune-modified RECIST and efficacy of atezolizumab beyond disease progression in advanced NSCLC: Results from the randomized Phase II study POPLAR
Authors: A. Artal-Cortes, J. Mazieres, L. Fehrenbacher, A. Rittmeyer, A.I. Spira, K. Park, C. Lewanski, S. Liu, M. Ballinger, J. Vansteenkiste
Journal: Annals of Oncology (2017)
Registries: An essential tool for maximising the health benefits of immunisation in the 21st century
Authors: N S Crowcroft, D Levy-Bruhl
Journal: Eurosurveillance (2017)

Preview this article: Registries: An essential tool for maximising the health benefits of immunisation in the 21st century, Page 1 of 1 < Previous page | Next page > /docserver/preview/fulltext/eurosurveillance/22/17/eurosurv-22-30523-1-1.gif
Increase in age at diagnosis of Primary Biliary Cholangitis over the last 40 years
Authors: C.F.M. Perez, W.J. Lammers, J.C. Goet, H.L. Janssen, H.R. van Buuren, A. Mason, C. Corpechot, P. Invernizzi, M.J. Mayo, P.M. Battezzati, A. Floreani, A. Pares, F. Nevens, K.V. Kowdley, C.Y. Ponsioen, T. Bruns, G.N. Dalekos, D. Thorburn, G. Hirschfield, N.F. LaRusso, K.D. Lindor, K. Zachou, R. Poupon, P.J. Trivedi, M. Carbone, X. Verhelst, A. Gulamhusein, B.E. Hansen
Journal: Journal of Hepatology (2017)
Suitability of HCV treatment in primary care settings for individuals with HIV/hepatitis C coinfection
Authors: J.S. Doyle, A.L. Bowring, D.M. Iser, J. Sasadeusz, J. Roney, M. O’Reilly, C. Fairley, E. Gane, J. Hoy, G.V. Matthews, N. Medland, R. Moore, M. Prins, M. Stoové, T. Ban-Kiem, M.E. Hellard
Journal: Journal of Hepatology (2017)
Limited Effect of TET2 Mutations on Promoter DNA Methylation in Chronic Myelomonocytic Leukemia
Authors: Jumpei Yamazaki, Rodolphe F Taby, Aparna Vasanthakumar, Trisha Macrae, Kelly R Ostler, Lanlan Shen, Hagop M. Kantarjian, Marcos R Estecio, Jaroslav Jelinek, Lucy Godley, Jean-Pierre Issa
Journal: Blood (2011)
Simvastatin ameliorates the sinusoidal microcirculatory phenotype, fibrosis and portal hypertension in aged cirrhotic rats
Authors: R. Maeso-Diaz, M. Ortega-Ribera, A. Fernandez-Iglesias, L. Muñoz, S. Vila, A. Albillos, J.C. Garcia-Pagan, J. Bosch, J. Gracia-Sancho
Journal: Journal of Hepatology (2017)
Abstract B45: Endometrial cancer microbiome signature and its implications for carcinogenesis
Authors: Marina Walther-Antonio, Jun Chen, Francesco Multinu, Alexis Hokenstad, Tammy Distad, Heidi Cheek, Gary Keeney, Douglas Creedon, Heidi Nelson, Andrea Mariani, Nicholas Chia
Journal: Clinical Cancer Research (2017)

Abstract Endometrial cancer studies have led to a number of well-defined but mechanistically unconnected genetic and environmental risk factors. One of the emerging modulators between environmental triggers and genetic expression is the microbiome. Because of the inflammatory display in endometrial cancer, we set out to inquire about the composition of the uterine microbiome and its putative role in endometrial cancer. We undertook a pilot study of the microbiome in 238 samples taken from different locations along the entire female reproductive tract in hysterectomy patients with endometrial cancer (n=17), patients with endometrial hyperplasia (n=4) and patients afflicted with a benign uterine condition (n=10). Samples were collected aseptically both in the operating room and the pathology laboratory. Following DNA extraction, the 16S rDNA (V3-V5 region) microbial gene was amplified and sequenced to identify the microbiota present. The microbiome sequencing revealed a structural microbiome shift in the cancer and hyperplasia cases, distinguishable from the benign cases (p=0.01). Several taxa were found to be significantly enriched in samples belonging to the endometrial cancer cohort: Firmicutes (Anaerostipes, ph2, Dialister, Peptoniphilus, 1-68, Ruminococcus, and Anaerotruncus), Spirochaetes (Treponema), Actinobacteria (Atopobium), Bacteroidetes (Bacteroides and Porphyromonas), and Proteobacteria (Arthrospira). Of particular relevance, the simultaneous presence of Atopobium vaginae and an uncultured representative of the Porphyromonas sp. (99% match to P.somerae) were found to be predictive of the disease status (sensitivity 73-93%; specificity 67-90%, AUC 0.918). Sensitivity is increased to 100% if combined with a high vaginal pH (&amp;gt;4.5), although specificity is decreased to 60%. Although our numbers are low, the microbiome signature of hyperplasia was even more distinct from benign disease than endometrial cancer itself. This is suggestive of an early microbiome role in the disease. Given the pathogenic profile of the identified microorganisms these findings raise the possibility of a microbiome role in the etiology or progression of endometrial cancer that should be further investigated. Citation Format: Marina Walther-Antonio, Jun Chen, Francesco Multinu, Alexis Hokenstad, Tammy Distad, Heidi Cheek, Gary Keeney, Douglas Creedon, Heidi Nelson, Andrea Mariani, Nicholas Chia. Endometrial cancer microbiome signature and its implications for carcinogenesis. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr B45.
Suboptimal MMR2 vaccine coverage in six counties in Norway detected through the national immunisation registry, April 2014 to April 2017
Authors: Maria Hagerup-Jenssen, Sigrun Kongsrud, Øystein Rolandsen Riise
Journal: Eurosurveillance (2017)

In 2014, Norway became aware of potential low vaccination coverage for the second dose of measles-mumps-rubella vaccine (MMR2) in six of 19 counties. This was detected by comparing the national coverage (NC) for 16-year-olds extracted from the national immunisation registry SYSVAK with the annual status update for elimination of measles and rubella (ASU) reported to the World Health Organization (WHO). The existing method for calculating NC in 2014 did not show MMR2 coverage. ASU reporting on MMR2 was significantly lower then the NC and below the WHO-recommended 95% coverage. SYSVAK is based on the Norwegian personal identification numbers, which allows monitoring of vaccinations at aggregateded as well as individual level. It is an important tool for active surveillance of the performance of the Norwegian Childhood Immunisation Programme (NCIP). The method for calculating NC was improved in 2015 to reflect MMR2 coverage for 16-year-olds. As a result, Norway has improved its real-time surveillance and monitoring of the actual MMR2 coverage also through SYSVAK (the annual publication of NC). Vaccinators receive feedback for follow-up if 15-year-olds are missing MMR2. In 2017, only three counties had an MMR2 coverage below 90%.
Simultaneous blocking of factor H and CD59 activities strongly sensitizes lung cancer cells to complement-mediated lysis
Authors: Daniel Ajona, Luis M. Montuenga, Ruben Pio
Journal: Cancer Research (2005)

565   Many molecular targeted therapeutic strategies against cancer are based on monoclonal antibodies to tumor associated antigens. Among other mechanisms, monoclonal antibodies can initiate complement-dependent cell lysis. However, malignant cells are usually resistant to complement through the enhanced expression of complement control proteins. In previous studies we have shown that non small cell lung cancer (NSCLC) cells produce and bind factor H, an inhibitor of complement activation, as a mechanism to escape the activation of the alternative pathway of complement. In this study, we examine the role of factor H and CD59, a cell membrane complement inhibitor, in the regulation of the classical complement pathway. First, we generated polyclonal antisera to NSCLC cell lines A549 and H1264 by immunizing rabbits with these cell extracts. Flow cytometry studies revealed that both cell lines reacted with their respective antiserum. Single-cell suspensions of both cell lines were first treated with their corresponding rabbit antiserum and, in a second step, with normal human serum. To evaluate the activation of complement, we examined by flow cytometry the deposition of C3 (a key element in the complement cascade). We also analyzed complement-mediated lysis by a calcein-AM cytotoxicity assay. Our study revealed deposition of C3 fragments on both cancer cell lines but a limited cell lysis (less than 10%). These results are in agreement with previous studies in which a high resistance to complement-mediated lysis in NSCLC cells had been described. However, when factor H activity was blocked by neutralizing antibodies (MoAb OX-24), deposition of C3 fragments from normal human serum was more efficient, and the susceptibility to complement-mediated lysis increased moderately. On the other hand, when CD59 activity was blocked by neutralizing antibodies (MoAb YTH53.1), cells were more susceptible to complement-mediated lysis, enabling lysis of up to 50% of H1264 cells and 75% of A549 cells. A combined treatment with anti-factor H and anti-CD59 antibodies was much more effective in increasing cell susceptibility to lysis, with up to 90% of the cells lysed by complement. Finally, in order to evaluate the in vivo role of factor H, we knocked down factor H expression on A549 cells using shRNA silencing of the gene. In vitro growth of these cells was not affected when compared to cells transfected with an siRNA targeted to a scramble sequence. However, growth of xenograft tumors in athymic mice was reduced to 50%. In summary, we have shown that lung cancer cells are able to prevent significant complement activation upon their cell membrane. Furthermore, we demonstrate that lack of activation can be prevented by combined factor H and CD59 inhibition. Our results suggest that complement-mediated immunotherapy based on modulation of complement activation is an attractive strategy for lung cancer treatment.
Toll-like receptor 5 polymorphism at position c. 1846T &gt; C is associated with the development of hepatocellular carcinoma in caucasians with chronic hepatitis B infection
Authors: E. Koukoulioti, J. Fischer, E. Schott, B. Fueloep, R. Heyne, T. Berg, F. van Bömmel
Journal: Journal of Hepatology (2017)
Atezolizumab as first-line (1L) therapy for advanced non-small cell lung cancer (NSCLC) in PD-L1–selected patients: Efficacy data from the BIRCH trial
Authors: S. Peters, E. Carcereny Costa, M.C. Garassino, D. Christoph, T. Kurata, J. Chaft, M.L. Johnson, S. Mocci, S.N. Gettinger, E. Felip
Journal: Annals of Oncology (2017)
PreS1/PreS2/S and precore/core mutations related with major risk of hepatocellular carcinoma in patients with “grey-zone” chronic hepatitis B
Authors: A.I. Gil, I. Francisco-Recuero, A. Madejón, M. Romero, A. García, M.S. Carrillo, P. Castillo, J.C. Erdozaín, A. Olveira, R. Mena, J. García-Samaniego
Journal: Journal of Hepatology (2017)