tbuckley/cabot-search huggingface dataset:
Abstract IA27: Protein methyltransferase inhibitors as precision cancer therapeutics: From bench to bedside to bench
Authors: Robert A. Copeland
Journal: Clinical Cancer Research (2017)

Abstract The protein methyltransferases (PMTs) constitute a class of enzymes that catalyze the methylation of lysine or arginine residues on histones and other proteins. A number of PMTs have been shown to be genetically altered in cancers through, for example, gene amplification, chromosomal translocations, point mutations and synthetic lethal relationships. The enzyme EZH2 provides a representative example of altered PMTs that act as genetic drivers of specific human cancers. Point mutations of EZH2 are found in a subset of non-Hodgkins lymphoma patients; the enzymatic activity of both wild type and mutant EZH2 are required for pathogenesis in these patients. Also, deletion of the INI1 or SMARCA4 subunit of the SWI/SNF chromatin-remodeling complex occur in a number of cancer types. For example, INI1 is deleted in nearly all malignant rhabdoid tumors (MRTs), a cancer found mainly in children that carries a particularly poor prognosis. Similarly, the SMARCA4 subunit of SWI/SNF is deleted, for example, in malignant rhabdoid tumor of the ovary (MRTO, also referred to as small cell carcinoma of the ovary hypercalcemic type), an aggressive cancer affecting young women. An antagonistic relationship has been demonstrated between the biochemical action on chromatin of the SWI/SNF complex and EZH2 (in the context of the polycomb repressive complex 2), that is relieved in MRTs due to the INI1 deletion. MRTs and other INI1- or SMARCA4-negative cancers therefore demonstrate increased reliance on the enzymatic activity of EZH2 for proliferation, and we have shown that MRT cells deficient in INI1 are selectively killed by inhibition of EZH2 in cell culture and in mouse xenograft models. Drug discovery efforts have yielded a potent, selective inhibitor of EZH2, tazemetostat (EPZ-6438), that has now transitioned into phase 2 clinical trials. This inhibitor affects the appropriate histone methyl marks in cells, leads to selective cell killing that is dependent on genetic lesions associated with EZH2 activity and effects tumor growth inhibition in xenograft models. Combining tazemetostat with other treatment modalities for non-Hodgkins lymphoma results in dramatic synergy of anti-proliferative activity in preclinical models. Results of preclinical and phase 1 clinical studies of tazemetostat will be presented. Citation Format: Robert A. Copeland. Protein methyltransferase inhibitors as precision cancer therapeutics: From bench to bedside to bench. [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 IA27.
Abstract #1352: ROR1 amplification and overexpression in ovarian cancer
Authors: Carl Miller, Christine Walsh, Xuan Xu, Quingjie Lu, Katy Ong, Beth Karlan, Sandra Orsulic
Journal: Cancer Research (2009)

ROR1 is a receptor tyrosine kinase-like orphan receptor that is abundantly expressed in B-cell leukemias. ROR1 and a related protein, ROR2, have frizzled domains and can sequester Wnts to mediate signaling in a non-canonical Wnt pathway. No specific ligand has yet been assigned to ROR1. Analysis of SNP array data from ovarian cancers frequently finds trisomy affecting the area including ROR1 on chromosome 1p31. Copy number peaks greater than 4 copies overlapped in one ovarian cancer cell line and four ovarian cancer patient samples. The peaks defined a minimum region of just under 1 megabase, amplifying two known genes: ROR1 and UBE2U. Expression analysis by real-time PCR showed that ROR1, but not UBE2U, is abundantly expressed in several ovarian cancer cell lines. Western blots confirmed the conclusion that the increased copy number was driving over-expression. The Catalogue of Somatic Mutations in Cancer (COSMIC) report 6 missense mutations affecting ROR1, two of which were found in ovarian cancer patient samples. The sequencing screen by COSMIC suggests that mutations of the ROR1 gene are clustered in two hotspots. The putative hotspots are being examined for mutations by sequencing amplified fragments in twelve cell lines. Results thus far have found no mutations. Continuing studies will address whether the ROR1 gene acts as an oncogene in ovarian cancer by examining its role in proliferation and differentiation in vitro and in mouse models.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 1352.
Accuracy of microRNA-based classification of metastases of unknown primary.
Authors: Nicholas Pavlidis, George E. Pentheroudakis, Brianna St. Cyr, Yael Spector, Eti Meiri, George Fountzilas, Anna Gousia, Hila Benjamin, Vassiliki Malamou-Mitsi, Vassiliki Kotoula, Aikaterini Stoyianni, Dimitrios Krikelis, Mats Olot Sanden, Karin Ashkenazi
Journal: Journal of Clinical Oncology (2012)

10575 Background: Identification of the tissue of origin of metastatic tumors is important for estimation of prognosis and patient management. Carcinoma of unknown primary (CUP) is not uncommon in oncology, representing 3-5% of all newly found malignancies. We used a microarray-based test that uses the expression of 64 microRNAs to retrospectively evaluate tumors from CUP patients. Methods: A cohort of resected metastatic lesions from patients diagnosed with CUP was studied blindly on the microRNA-based test. The cohort included 93 samples (from 92 patients) with tissue adequate for the test. Eight samples failed due to inadequate RNA quality; 85 samples (84 patients) were processed successfully. Test results were compared with clinical presentation including imaging, pathological data (histology and IHC) at initial CUP diagnosis and with clinical management and outcome data at the completion of each patient`s follow up. Results: The test results were fully concordant with the diagnosis based on all the clinical and pathological information available including follow-up and outcome in 92% of patients compared to ~70% agreement with the patients’ diagnosis at initial presentation, before additional data gathered throughout patient management. Two different metastases from the same patient yielded the same result. The microRNA test assigned a single tissue of origin for 51 patients and two tissues of origin in 33 patients, with the first being the more likely diagnosis. When comparing only the first (or single) diagnosis, a concordant level of 88% was achieved. Conclusions: In a retrospective, well studied cohort of metastases from CUP patients, a previously developed test based on the expression profile of 64 microRNAs allowed accurate identification of tissue of origin in 92% of the cases. This study validates the high accuracy of the test on real CUP patients. The high concordance of the test results to the final tissue of origin diagnosis of the patient, even in cases where the initial diagnosis at CUP presentation was discordant, demonstrates the importance of the test in yielding additional data valuable for patient management at an early stage of the patient’s treatment plan.
Efficacy and safety of sofosbuvir/velpatasvir in people with chronic hepatitis C virus infection and recent injecting drug use: the SIMPLIFY study
Authors: J. Grebely, O. Dalgard, B. Conway, E. Cunningham, P. Bruggmann, B. Hajarizadeh, J. Amin, P. Marks, S. Quiene, T.L. Applegate, T. Swan, J. Byrne, M. Lacalamita, A.J. Dunlop, J. Bruneau, M.E. Hellard, G.V. Matthews, J. Powis, D. Shaw, C.M. Thurnheer, M. Weltman, I. Kronborg, C. Cooper, J.J. Feld, C. Fraser, A. Litwin, J. Dillon, P. Read, E. Gane, G.J. Dore
Journal: Journal of Hepatology (2017)
SMYD2-Mediated Histone Methylation Contributes to HIV-1 Latency
Authors: Daniela Boehm, Mark Jeng, Gregory Camus, Andrea Gramatica, Roland Schwarzer, Jeffrey R. Johnson, Philip A. Hull, Mauricio Montano, Naoki Sakane, Sara Pagans, Robert Godin, Steven G. Deeks, Nevan J. Krogan, Warner C. Greene, Melanie Ott
Journal: Cell Host & Microbe (2017)
Regional Radiation Therapy Impacts Outcome for Node-Positive Cutaneous Melanoma
Authors: Tobin Strom, Javier F. Torres-Roca, Akash Parekh, Arash O. Naghavi, Jimmy J. Caudell, Daniel E. Oliver, Jane L. Messina, Nikhil I. Khushalani, Jonathan S. Zager, Amod Sarnaik, James J. Mulé, Andy M. Trotti, Steven A. Eschrich, Vernon K. Sondak, Louis B. Harrison
Journal: Journal of the National Comprehensive Cancer Network (2017)

Background: Regional radiation therapy (RT) has been shown to reduce the risk of regional recurrence with node-positive cutaneous melanoma. However, risk factors for regional recurrence, especially in the era of sentinel lymph node biopsy (SLNB), are less clear. Our goals were to identify risk factors associated with regional recurrence and to determine whether a radiosensitivity index (RSI) gene expression signature (GES) could identify patients who experience a survival benefit with regional RT. Methods: A single-institution, Institutional Review Board-approved study was performed including 410 patients treated with either SLNB with or without completion lymph node dissection (LND; n=270) or therapeutic LND (n=91). Postoperative regional RT was delivered to the involved nodal basin in 83 cases (20.2%), to a median dose of 54 Gy (range, 30-60 Gy) in 27 fractions (range, 5-30). Primary outcomes were regional control and overall survival by RSI GES status. Results: Median follow-up was 69 months (range, 13-180). Postoperative regional RT was associated with a reduced risk of regional recurrence among all patients on univariate (5-year estimate: 95.0% vs 83.3%; P=.036) and multivariate analysis (hazard ratio[HR], 0.15; 95% CI, 0.05-0.43; P<.001). Among higher-risk subgroups, regional RT was associated with a lower risk of regional recurrence among patients with clinically detected lymph nodes (n=175; 5-year regional control: 94.1% vs 69.5%; P=.003) and extracapsular extension (ECE) present (n=138; 5-year regional control: 96.7% vs 62.2%; P<.001). Among a subset of radiated patients with gene expression data available, a low RSI GES (radiosensitive) tumor status was associated with improved survival compared with a high RSI GES (5-year: 75% vs 0%; HR, 10.68; 95% CI, 1.24-92.14). Conclusions: Regional RT was associated with a reduced risk of regional recurrence among patients with ECE and clinically detected nodal disease. Gene expression data show promise for better predicting radiocurable patients in the future. In the era of increasingly effective systemic therapies, the value of improved regional control potentially takes on greater significance.
Ongoing Phase 1a/1b Dose-Finding Study of CWP232291 (CWP291) in Relapsed or Refractory Multiple Myeloma (MM)
Authors: Sung-Soo Yoon, Chang-Ki Min, Jin Seok Kim, Elisabet E. Manasanch, Robert Hauptschein, Jeongeun Choi, Kyoung-June Lee
Journal: Blood (2016)
Hepatitis C virus-induced epigenetic and transcriptional changes persist post cure
Authors: F. Jühling, S. Bandiera, N. Hamdane, C. Thumann, S.C. Durand, H.E. Saghire, I. Davidson, F. Habersetzer, P. Pessaux, N. Bardeesy, C. Schmidl, C. Bock, Y. Hoshida, M.B. Zeisel, T.F. Baumert
Journal: Journal of Hepatology (2017)
Overall survival in hormone-resistant prostate cancer patients with different transition of care within the Veterans Affairs (VA) system.
Authors: S Scott Sutton, Gowtham A Rao, LeAnn B. Norris, James Hardin, Sandip M. Prasad, Charles L. Bennett
Journal: Journal of Clinical Oncology (2013)

5091 Background: Prostate cancer patients with locally advanced /metastatic disease have a poor prognosis and although hormonal therapy can induce long-term remission, development of hormone-resistant prostate cancer (HRPC) is inevitable. The goal of this study is to evaluate overall survival in HRPC patients with different transition of care in the Veterans Affairs (VA) system. We hypothesized that prostate cancer patients with late referral to medical oncologists were more likely to have decreased overall survival. Methods: This is a retrospective, observational analysis of patients enrolled in the Veterans Health Administration system from October 2003 to March 2011. Patients were followed from initial evaluation and treatment by urology until an endpoint of death or the end of the study period. VA patients with a diagnosis of HRPC were identified; prostate specific antigen (PSA), medical and pharmacy records were collected. HRPC was defined as PSA doubling after treatment with hormonal therapy. Transition of care was defined as two encounters with the medical oncology service and at least one encounter was a medical oncologist. Three cohorts were created: patients transitioned to oncology before HRPC, those transitioned to oncology after HRPC, and patients who were never transitioned to oncology. Primary outcome was overall survival (OS). The Charlson score was utilized for comorbidity assessment. Statistical analysis was conducted using chi square test for categorical variables. Results: Total number of patients evaluated was 8,281; 2,168 in transition before HRPC (tbHRPC) cohort, 2,052 in transition after HRPC (taHRPC), and 4,061 patients that never transitioned (tnHPRC). The mean ages for the respective cohorts were: 69.35, 69.69, and 71.64. The Charlson comorbidity scores were 3.79 (tbHRPC), 3.06 (taHRPC), and 3.14 (tnHRPC); p-values &lt; 0.05. Mortality rates among the cohorts were 57% tbHRPC, 69% taHRPC, and 62% tnHRPC; p-values &lt;0.001. PSA doubling within 10 months were: 57% tbHRPC, 60% taHRPC, and 54% tnHRPC; p-values &lt; 0.05. Conclusions: Overall survival was improved among prostate cancer patients that transitioned to oncology before becoming HRPC.
Synergistic effects of aberrant expression of alpha-fetoprotein, annexin A10 and osteopontin at chromosome 4q in the tumor progression, early recurrence and poor prognosis of hepatocellular carcinoma
Authors: Shian-Yang Peng, Hung-Wei Pan, Shu-Hsiang Liu, Po-Lin Lai, Chin-Yuan Hsieh, Huei-Ying Li
Journal: Cancer Research (2004)

1468  Hepatocellular carcinoma (HCC) exhibits a unique feature of high frequency of allelic loss at chromosome 4q. Using mRNA differential display, we identified frequent overexpression of alpha-fetoprotein (AFP) at 4q11-q13 and osteopontin (OPN) at 4q21-q25, and downregulation of annexin A10 (ANXA10) at 4q33. This study is to elucidate the clinicopathological significance of the accumulation of the aberrant expressions of these three genes in the progression of HCC using reverse transcriptase polymerase chain reaction (RT-PCR) analyses and radioimmunoassay for AFP. We showed that high AFP levels (>200 ng/ml), OPN overexpression and ANXA10 downregulation had close association with more frequent large HCC (P=0.0002, P=0.0013, and P=0.007, respectively), grade II to IV (P=0.0000, P=0.0001, and P=0.0000, respectively), and portal vein invasion (stage IIIB and IV) (P=0.0000, P=0.0000, and P=0.0001, respectively). Besides, high AFP levels correlated with OPN overexpression (P=0.0001) and ANXA10 downregulation (P=0.0000), while OPN overexpression also correlated with ANXA10 downregulation (P=0.0011). We then analyzed their potential synergistic effects in the tumor progression. We showed that HCCs with all the three genetic aberrations had more frequent large tumors, portal vein invasion, and early tumor recurrence than the other groups (P
Retrospective indirect comparison of alectinib phase II data vs ceritinib real-world data in ALK+ NSCLC after progression on crizotinib
Authors: J. Davies, M. Martinec, R. Martina, P. Delmar, M. Coudert, W. Bordogna, S. Golding, G. Crane
Journal: Annals of Oncology (2017)
Abstract 32: Mitral Valve Interstitial Cells With the Serotonin Transporter (SERT)-LL Polymorphism are More Efficiently Activated by Serotonin
Authors: Kathryn H Driesbaugh, Juan B Grau, Joseph E Bavaria, Farrah Alkhaleel, Eric K Lai, Richard E Shaw, Robert C Gorman, Joseph H Gorman, Robert J Levy, Giovanni Ferrari
Journal: Circulation Research (2015)

Prolapse of the Mitral Valve (MV) leaflet is a hallmark of several cardiac disorders such as Myxomatous MV Disease (MMVD) or ischemic MV regurgitation (MR), and is only treated surgically. Elevated levels of serotonin (5HT) have been associated with valvulopathies. Ongoing studies in our laboratory suggest that 5HT signaling plays an important role in the progression of MMVD. In addition, a 44 base polymorphism in the promoter region of the 5HT transporter (SERT) gene, designated as short (S) or long (L) allele, has been reported with Mendelian distribution, with LL resulting in increased 5HT reuptake compared to SS. We hypothesized that patients with MMVD have enhanced 5HT signaling due to a high frequency of SERT-LL. DNA was extracted from 152 MMVD surgical patients, genomic fragment analysis performed to determine allelic frequencies, and a chi-square statistical test completed. We show that surgical patients with MMVD have a higher than expected frequency of SERT-LL (34% (52 of 152) vs. 25%). Notably, the frequency of SERT-LL is particularly enhanced (51% (21 of 41) vs. 25%) (p=0.009) in MMVD patients under 60 years old. Based on these findings, we tested whether MV interstitial cells (MVICs) expressing SERT-LL have increased susceptibility to 5HT-mediated activation. We demonstrate that SERT-LL MVICs respond to 5HT with a 4-fold increase in smooth muscle actin (SMA) mRNA expression, a marker of VIC activation, compared to a less than 1-fold increase in SERT-LS and SERT-SS cells. The SMA response is abrogated by specific pharmacological inhibitors of the 5HT receptors 5HTR2A and 5HTR2B, and SERT, as well as siRNA knockdown. Studies of 5HTR expression in cells of each genotype are in progress. Due to the enhanced frequency of the SERT-LL genotype among MMVD patients, particularly within the younger subset, and increased susceptibility of SERT-LL MVICs to 5HT, we postulate that the SERT-LL genotype may contribute to an increased risk of rapid disease progression by increasing the efficiency of 5HT signaling and uptake in MVICs resulting in extracellular matrix production leading to prolapse and impaired valve function. The SERT-genotype may constitute a novel means of identifying patients who may benefit from pharmacotherapy that alter 5HT-related mechanisms.
In hepatitis C infected patients with cirrhosis squamous cell carcinoma antigen (SCCA)-IgM levels may contribute to identify the individual risk of hepatocellular carcinoma development after antiviral therapy
Authors: G. Ricco, D. Cavallone, P. Pontisso, G. Fassina, A. Gallotta, P. Colombatto, F. Oliveri, V. Romagnoli, B. Coco, A. Salvati, F. Bonino, M.R. Brunetto
Journal: Journal of Hepatology (2017)
Early regression of liver fibrosis evaluated by non-invasive methods after successful antiviral therapy in patients with HCV genotype 1b compensated cirrhosis
Authors: A. Trifan, C.C. Prelipcean, L. Gheorghe, E. Miftode, S.A. Chiriac, T. Cuciureanu, I. Sporea, A. Goldis, S. Iacob, C. Cojocariu, G. Stefanescu, I. Girleanu, C. Mihai, I. Ciortescu, C. Stanciu
Journal: Journal of Hepatology (2017)
Hepatitis Delta Antigen (HDAg) is characterized by an extensive degree of genetic variability that correlates with elevated levels of serum HDV-RNA
Authors: L. Colagrossi, R. Salpini, R. Scutari, A. Battisti, L. Piermatteo, A. Bertoli, C. Menichini, P. Trimoulet, H. Fleury, E. Nebuloso, M. De Cristofaro, G. Cappiello, A. Spanò, V. Malagnino, T. Mari, A. Barlattani, N. Iapadre, M. Lichtner, C.M. Mastroianni, I. Lenci, C. Pasquazzi, G.M. De Sanctis, A.G. Lanza, M. Stanzione, G. Stornaiuolo, M. Marignani, L. Sarmati, M. Andreoni, M. Angelico, C.F. Perno, N. Coppola, V. Svicher
Journal: Journal of Hepatology (2017)
Therapeutic effect of cerium oxide nanoparticles (CeO2NPs) in rats with diet-induced non-alcoholic steatohepatitis
Authors: S. Carvajal, D. Oró, G. Fernández-Varo, T. Yudina, M. Perramón, L. Oller, G. Casals, B.G. de la Presa, V. Puntes, W. Jiménez
Journal: Journal of Hepatology (2017)
Workplace Factors Associated With Burnout of Family Physicians
Authors: Monee Rassolian, Lars E. Peterson, Bo Fang, H. Clifton Knight, Michael R. Peabody, Elizabeth G. Baxley, Arch G. Mainous
Journal: JAMA Internal Medicine (2017)

Taiwo Adesoye, MD, MPH; Christina Mangurian, MD, MAS; Esther K. Choo, MD, MPH; Christina Girgis, MD; Hala Sabry-Elnaggar, DO, MBA; Eleni Linos, MD, DrPH; for the Physician Moms Group Study Group
Treatment as prevention for hepatitis C in Iceland (TRAP HEP C). A real-world experience from a nationwide elimination program using direct acting antiviral agents
Authors: S. Olafsson, T. Tyrfingsson, V. Runarsdottir, O.M. Bergmann, E.S. Björnsson, B. Johannsson, B. Sigurdardottir, R.H. Fridriksdottir, A. Löve, T.J. Löve, G. Sigmundsdottir, M. Heimisdottir, M. Gottfredsson
Journal: Journal of Hepatology (2017)
RIG-I is a key antiviral interferon-stimulated gene against hepatitis E virus dispensable of interferon production
Authors: L. Xu, W. Wang, Y. Li, X. Zhou, Y. Yin, Y. Wang, R.A. de Man, L.J.W. Van Der Laan, F. Huang, N. Kamar, M.P. Peppelenbosch, Q. Pan
Journal: Journal of Hepatology (2017)
The health burden of primary biliary cholangitis in Switzerland: a cross-sectional study
Authors: B.C.T. Beretta-Piccoli, G. Stirnimann, A. Cerny, C. Khalid-de Bakker, D. Semela, R. Hessler, E. Giostra, B. Helbling, F. Stickel, F. Bihl, P. Invernizzi, J. Mertens, M. Carbone
Journal: Journal of Hepatology (2017)
Markedly improvement of glycaemic control in diabetic patients with chronic hepatitis C achieving sustained virologic response after direct acting antiviral therapy: results of a prospective controlled study
Authors: A. Ciancio, R. Bosio, S. Bo, M. Pellegrini, M. Sacco, E. Vogliotti, G. Fassio, A.B.M. Degerfeld, M. Gallo, C. Giordanino, L.T. Di Bergamo, A. Smedile, M. Rizzetto, G.M. Saracco
Journal: Journal of Hepatology (2017)