tbuckley/cabot-search huggingface dataset:
Abstract 402: Multiplex TaqMan assays for rare mutation analysis using digital PCR
Authors: Marion -. Laig, Frances Chan, Le Lac, Ted Straub, Kamini Varma, David Keys
Journal: Cancer Research (2016)

Abstract Introduction Detection of rare mutations for research purposes in tumor tissue and cell free DNA (cfDNA) allows for monitoring of tumor progression and regression. cfDNA isolated from plasma combined with a sensitive detection method like digital PCR is non-invasive and enables earlier detection compared to conventional imaging techniques. Building on the TaqMan based Rare Mutation assay set for detection of rare mutations using digital PCR on the QuantStudio 3D Digital PCR System, we are now developing multiplex assays for simultaneous detection of several mutations. We selected relevant mutations in the EGFR and KRAS genes for our initial multiplex application: EGFR G719, EGFR exon 19 deletions, and KRAS G12/G13. These mutations may have implications for potential future targeted therapy. Methods Primers and probes of singleplex Rare Mutation Assays were reformulated to generate multiplex assays detecting the EGFR and KRAS mutations. All multiplex assays were tested on template composed of wild-type genomic DNA background mixed with mutant plasmid reflecting each of the mutations detected by the multiplex assays. Summary Initial experimental results were successful and showed excellent signal intensity and clear cluster separation when analyzed with the QuantStudio 3D AnalysisSuite™ Cloud Software. The EGFR G719 mutations (COSM6239, COSM6253, COSM6252) were detected using a 3plex assay, EGFR exon 19 deletions (COSM12383, COSM12422, COSM12678, COSM6223, COSM6254, COSM6255) were detected using a 6plex assay, and KRAS G12/G13 mutations (COSM516, COSM517, COSM518, COSM520, COSM521, COSM522, COSM527, COSM532) were detected using an 8plex. Conclusion Multiplexing assays for three relevant mutation loci proved feasible and presents an efficient way to assess the presence and the percentage of mutations at these loci. Citation Format: Marion -. Laig, Frances Chan, Le Lac, Ted Straub, Kamini Varma, David Keys. Multiplex TaqMan assays for rare mutation analysis using digital PCR. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 402.
Long Noncoding RNA <i>GCASPC</i>, a Target of miR-17-3p, Negatively Regulates Pyruvate Carboxylase–Dependent Cell Proliferation in Gallbladder Cancer
Authors: Ming-zhe Ma, Yan Zhang, Ming-zhe Weng, Shou-hua Wang, Ye Hu, Zhao-yuan Hou, Yi-yu Qin, Wei Gong, Yong-Jie Zhang, Xiang Kong, Jian-dong Wang, Zhi-wei Quan
Journal: Cancer Research (2016)

Abstract Long noncoding RNAs (lncRNA) are being implicated in the development of many cancers. Here, we report the discovery of a critical role for the lncRNA GCASPC in determining the progression of gallbladder cancer. Differentially expressed lncRNAs and mRNAs between gallbladder cancer specimens and paired adjacent nontumor tissues from five patients were identified and validated by an expression microarray analysis. Quantitative real-time PCR was used to measure GCASPC levels in tissues from 42 gallbladder cancer patients, and levels of GCASPC were confirmed further in a separate cohort of 89 gallbladder cancer patients. GCASPC was overexpressed or silenced in several gallbladder cancer cell lines where molecular and biological analyses were performed. GCASPC levels were significantly lower in gallbladder cancer than adjacent nontumor tissues and were associated with tumor size, American Joint Committee on Cancer tumor stage, and patient outcomes. GCASPC overexpression suppressed cell proliferation in vitro and in vivo, whereas GCASPC silencing had opposite effects. By RNA pull-down and mass spectrometry, we identified pyruvate carboxylase as an RNA-binding protein that associated with GCASPC. Because GCASPC is a target of miR-17-3p, we confirmed that both miR-17-3p and GCASPC downregulated pyruvate carboxylase level and activity by limiting protein stability. Taken together, our results defined a novel mechanism of lncRNA-regulated cell proliferation in gallbladder cancer, illuminating a new basis for understanding its pathogenicity. Cancer Res; 76(18); 5361–71. ©2016 AACR.
Incretin-based drugs were not linked to HF hospitalization compared with other oral antidiabetic drug combinations
Authors: Donald A. Smith
Journal: Annals of Internal Medicine (2016)

ACP Journal Club19 July 2016Incretin-based drugs were not linked to HF hospitalization compared with other oral antidiabetic drug combinationsDonald A. Smith, MD, MPHDonald A. Smith, MD, MPHMount Sinai Heart, New York, New York, USA (D.A.S.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/ACPJC-2016-165-2-011 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Source CitationFilion KB, Azoulay L, Platt RW, et al; CNODES Investigators. A multicenter observational study of incretin-based drugs and heart failure. N Engl J Med. 2016;374:1145-54. https://pubmed.ncbi.nlm.nih.gov/27007958Clinical Impact RatingsGIM/FP/GP: Cardiology: Endocrinology: References1 Bertoni AG, Hundley WG, Massing MW, et al. Heart failure prevalence, incidence, and mortality in the elderly with diabetes. Diabetes Care. 2004;27:699-703. [PMID: 14988288] Google Scholar2 Iribarren C, Karter AJ, Go AS, et al. Glycemic control and heart failure among adult patients with diabetes. Circulation. 2001;103:2668-73. [PMID: 11390335] Google Scholar3 Turnbull FM, Abraira C, Anderson RJ, et al; Control Group. Intensive glucose control and macrovascular outcomes in type 2 diabetes. Diabetologia. 2009;52:2288-98. [PMID: 19655124] Google Scholar4 Udell JA, Cavender MA, Bhatt DL, et al. Glucose-lowering drugs or strategies and cardiovascular outcomes in patients with or at risk for type 2 diabetes: a meta-analysis of randomised controlled trials. Lancet Diabetes Endocrinol. 2015;3:356-66. [PMID: 25791290] Google Scholar5 Green JB, Bethel MA, Armstrong PW, et al; TECOS Study Group. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2015;373:232-42. [PMID: 26052984] Google Scholar6 US Food and Drug Administration. FDA drug safety communication: FDA adds warnings about heart failure risk to labels of type 2 diabetes medicines containing saxagliptin and alogliptin. April 2016. www.fda.gov/Drugs/DrugSafety/ucm486096.htm (accessed 13 May 2016). Google Scholar Author, Article, and Disclosure InformationAffiliations: Mount Sinai Heart, New York, New York, USA (D.A.S.)This article was published at Annals.org on 5 July 2016. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 19 July 2016Volume 165, Issue 2Page: JC11KeywordsCohort studiesCongestive heart failureDatabasesDrugsHeart failureHospitalizationsHypoglycemicsInformation storage and retrievalMortalityType 2 diabetes ePublished: 19 July 2016 Issue Published: 19 July 2016 Copyright & PermissionsCopyright © 2016 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Abstract 3032: A novel compound ARN-3236 inhibits SIK2 and sensitizes ovarian cancer to paclitaxel
Authors: Jinhua Zhou, Albandri Alfredi, Shu Zhang, Janice M. Santiago-O’Farrill, Ahmed A. Ahmed, Hailing Yang, Weiqun Mao, Yan Wang, Hariprasad Vankayalapati, Zhen Lu, Robert C. Bast
Journal: Cancer Research (2016)

Abstract Ovarian carcinomas account for 4% of total cancers in women in the United States. Improved outcomes might be attained if sensitivity to primary chemotherapy were enhanced. A recent study discovered that the salt inducible kinase 2 (SIK2) plays a key role in the initiation of mitosis and regulates paclitaxel sensitivity. Here we show that SIK2 is overexpressed in 30% ovarian cancer specimens, associated with a poor prognosis. ARN-3236, a selective, highly potent small molecule SIK2 inhibitor with function similar to SIK2 siRNA, blocks cell proliferation in a panel of ovarian cancer cell lines, where the IC50 of ARN-3236 was inversely correlated with endogenous SIK2 expression. ARN-3236 also enhanced response to paclitaxel in ovarian cancer cells (OC316, SKOv3, A2780, HEY, ES2 and UPN251). Similar to the function of SIK2 siRNA, ARN-3236 effectively inhibits AKT phosphorylation at Ser473 and Tyr308, as well as the expression of the downstream effector survivin. ARN-3236 uncouples the centrosome from the nucleus in interphase, and blocks centrosome separation in mitosis, resulting in the accumulation of cells in prometaphase. In addition, ARN-3236 enhances tumor growth inhibition of paclitaxel in ovarian cancer xenograft models. Thus, functional inhibition of SIK2 with ARN-3236 had the same effects on ovarian cancer cell function as knockdown of SIK2 with siRNA. ARN-3236 deserves further study as a SIK2 inhibitor that significantly improves the sensitivity to paclitaxel for treatment of human ovarian cancer cells and xenografts. Citation Format: Jinhua Zhou, Albandri Alfredi, Shu Zhang, Janice M. Santiago-O’Farrill, Ahmed A. Ahmed, Hailing Yang, Weiqun Mao, Yan Wang, Hariprasad Vankayalapati, Zhen Lu, Robert C. Bast Jr. A novel compound ARN-3236 inhibits SIK2 and sensitizes ovarian cancer to paclitaxel. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3032.
Association of Reference Pricing for Diagnostic Laboratory Testing With Changes in Patient Choices, Prices, and Total Spending for Diagnostic Tests
Authors: James C. Robinson, Christopher Whaley, Timothy T. Brown
Journal: JAMA Internal Medicine (2016)

<h3>Importance</h3> Prices for laboratory and other clinical services vary widely. Employers and insurers increasingly are adopting "reference pricing" policies to create incentives for patients to select lower-priced facilities. <h3>Objective</h3> To measure the association between implementation of reference pricing and patient choice of laboratory, test prices, patient out-of-pocket spending, and insurer spending. <h3>Design, Setting, and Participants</h3> We conducted an observational study of changes in laboratory pricing and selection by employees of a large national grocery firm (n = 30 415) before and after the firm implemented a reference pricing policy for laboratory services and compared the findings with changes over the same period for policy holders of a large national insurer that did not implement reference pricing (n = 181 831). The grocery firm established a maximum payment limit at the 60th percentile of the distribution of prices for each laboratory test in each region. Employees were provided with data on prices at all laboratories through a mobile digital platform. Patients selecting a laboratory that charged more than the payment limit were required to pay the full difference themselves. A total of 2.13 million claims were analyzed for 285 types of in vitro diagnostic tests between 2010 and 2013. <h3>Main Outcomes and Measures</h3> Patient choice of laboratory, price paid per test, patient out-of-pocket costs, and employer spending. <h3>Results</h3> Compared with trends in prices paid by insurance policy holders not subject to reference pricing, and after adjusting for characteristics of tests and patients, implementation of reference pricing was associated with a 31.9% reduction (95% CI, 20.6%-41.6%) in average price paid per test by the third year of the program. In these 3 years, total spending on laboratory tests declined by $2.57 million (95% CI, $1.59-$3.35 million). Out-of-pocket costs by patients declined by $1.05 million (95% CI, $0.73-$1.37 million). Spending by the employer declined by $1.70 million (95% CI, $0.92-$2.48 million). <h3>Conclusions and Relevance</h3> When combined with access to price information, reference pricing was associated with patient choice of lower-cost laboratories and reductions in prices and payments by both employer and employees.
Activation of Wnt signaling promotes hippocampal neurogenesis in experimental autoimmune encephalomyelitis
Authors: Reiner Schneider, Barbara Koop, Friederike Schröter, Jason Cline, Jens Ingwersen, Carsten Berndt, Hans-Peter Hartung, Orhan Aktas, Tim Prozorovski
Journal: Molecular Neurodegeneration (2016)

Disease progression in multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE), as one of its animal models, is characterized by demyelination and neuronal damage in white and gray matter structures, including the hippocampus. It is thought that dysfunction of the hippocampus, a primary locus of learning and memory consolidation, may contribute to cognitive impairment in MS patients. Previously, we reported an increased generation of hippocampal neuronal progenitors in the acute stage of EAE, whereas the microenvironmental signals triggering this process remained uninvestigated. In the present study, we used the Wnt signaling reporter mouse Axin2LacZ, to elucidate the molecular mechanisms underlying the activation of the hippocampal neurogenic niche upon autoimmune neuroinflammation. Histological and enzymatic examinations of β-gal during the disease course of EAE, allowed us to survey hippocampal Wnt/β-catenin activity, one of the key signaling pathways of adult neurogenesis. We found that Wnt signaling is transiently upregulated in the acute stage of disease, consistent with a timely induction of canonical Wnt ligands. The enhancement of signaling coincided with hippocampal neuronal damage and local expression of immune cytokines such as TNFα and IFNγ, implicating the role of the inflammatory milieu in activation of the Wnt/β-catenin pathway. Supporting this finding, we show that transient exposure to pro-inflammatory cytokine TNFα triggers Wnt signaling in hippocampal organotypic slice cultures. Importantly, inflammation-mediated activation of the Wnt/β-catenin pathway was associated with enhanced neurogenesis in vitro and in vivo, indicating its potential role in hippocampal tissue regeneration and repair. This study raises the possibility that enhancement of Wnt signaling may support neurogenic processes to cope with neuronal deficits upon immune-mediated neuroinflammation.
Abstract 2154: TX1111: a peptide homologue of Topoisomerase-1 sensitizes pancreatic cancer cells to gemcitabine
Authors: Manu Gnanamony, Victoria Stepanova, Lily Criscione, Jerusha Boyineni, Stephen J. Marshall, AiXuan Holterman, Christopher S. Gondi
Journal: Cancer Research (2016)

Abstract Pancreatic Ductal Adeno Carcinoma (PDAC) is the fourth most common cause of cancer deaths in the United States and accounts for over 95% of all pancreatic cancers. The combined 1- and 5-year survival rates for PDAC are very poor, at 25% and 6% respectively. A major hallmark of pancreatic cancer is tumor recurrence and extremely poor response to chemotherapy. The current standard of care for patients with advanced pancreatic cancer is a chemotherapy regimen that includes gemcitabine. This treatment results in a modest benefit i.e., an increase in survival of only 5 weeks. The high mortality in patients diagnosed with this pancreatic cancer is primarily due to its drug-resistant nature and the lack of effective therapeutic strategies to overcome drug resistance. This disappointing situation strongly suggests that an improved and increased understanding of drug resistance mechanisms could lead to the development of novel therapeutic strategies for the successful treatment of patients with pancreatic cancer. Our studies have shown that one of the contributing factors that lead to chemotherapy resistance is the protease activator urokinase plasminogen activator (uPA). To validate the contribution of uPA in chemoresistance, we overexpressed uPA in MIAPaCa-2 and PANC-1 cells and determined chemoresistance. We observed that uPA overexpressed cells showed increased chemoresistance in both Mia PaCa-2 (&amp;gt;25 fold) and PANC-1 (&amp;gt;6 fold). Mass-Spec analysis of nuclear uPA-IP from pancreatic cancer cells revealed that uPA interacts with Topoisomerase-1 (TOPO-1). This was further validated by western blot analysis of nuclear co-IP in pancreatic cancer cells. Further the binding domains of TOPO-1 to uPA were identified using overlapping a peptides array (PepSpot-JPT) followed by synthesis of these peptides. We observed that a TOPO-1 homologous peptide designated TX1111 was capable of significantly suppressing gemcitabine resistance in pancreatic cancer cells. Our observations show that the specific peptide TX1111 suppresses chemoresistance by 45% in Mia Paca-2 cells (p&amp;lt;0.001) and by 40% in PANC cells (p = 0.002). These results demonstrate that: 1. Overexpression of uPA promotes gemcitabine resistance in pancreatic cancer cells 2. uPA and TOPO-1 interact in the nucleus of pancreatic cancer cells 3. The peptide homologue of TOPO-1, TX1111 sensitizes gemcitabine resistant pancreatic cancer cells. Citation Format: Manu Gnanamony, Victoria Stepanova, Lily Criscione, Jerusha Boyineni, Stephen J. Marshall, AiXuan Holterman, Christopher S. Gondi. TX1111: a peptide homologue of Topoisomerase-1 sensitizes pancreatic cancer cells to gemcitabine. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2154.
Abstract 2465: Spleen tyrosine kinase (SYK) in neuroblastoma tumorigenesis
Authors: Conny Tuemmler, Gianina Dumitriu, Julia Cserna, Ugo L. Moens, Per Kogner, John Inge Johnsen, Baldur Sveinbjørnsson
Journal: Cancer Research (2016)

Abstract Tyrosine kinases play an important role in tumorigenesis by contributing to the regulation of cell proliferation and survival, and are therefore among the most attractive drug targets. SYK is a non-receptor tyrosine kinase highly expressed in cells of hematopoietic origin where it contributes to immune receptor signaling. The role of SYK in cancer is best understood in hematological malignancies where it promotes survival, and SYK inhibition has been shown to be a promising therapeutic approach. For solid tumors the role of SYK remains double-edged, as it has been found to promote but also suppress tumor development dependent on the cancer type. Besides its role in survival signaling SYK has also been found to contribute to drug resistance in several malignancies. Neuroblastoma (NB) is a malignancy of early childhood. Although there have been great advances in the treatment of NB during the past 30 years, the prognosis for high- risk patients remains poor. In this study we have evaluated SYK as a potential drug target in NB. Examination of gene expression datasets indicated a correlation between high expression of SYK and poor prognosis in NB. Screening of NB cell lines showed that SYK mRNA was present in the majority of NB cells lines whereas the SYK protein was detected less frequently. However, SYK was detectable in NB tumor tissue using immunohistochemistry. The efficacy of different, commercially available, SYK inhibitors was evaluated by comparing the neuroblastoma cell lines SH-SY5Y (high SYK expression) and SK-N-BE(2) (low SYK expression) using a cell viability assay. While one inhibitor displayed a markedly stronger effect on the viability of SH-SY5Y cells compared to SK-N-BE(2) the effect of the other inhibitors appears to be less specific. To confirm that SYK inhibition leads to decreased cell proliferation SYK specific siRNA was used. After 48h incubation the cell viability of SH-SY5Y cells was decreased by approximately 25%. Our findings indicate that SYK may be a possible drug target in neuroblastoma. To further evaluate its potential, combination studies using SYK inhibitors and cytostatic drugs will be performed. Citation Format: Conny Tuemmler, Gianina Dumitriu, Julia Cserna, Ugo L. Moens, Per Kogner, John Inge Johnsen, Baldur Sveinbjørnsson. Spleen tyrosine kinase (SYK) in neuroblastoma tumorigenesis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2465.
High-Throughput Molecular Profiling of Multiple Myeloma (MM) Clonotypic CD19+ B Cells Highlights Pathways Potentially Involved in the Disease Endurance
Authors: Marina Martello, Angela Flores Dico, Daniel Remondini, Giovanni Martinelli, Enrica Borsi, Barbara Santacroce, Lucia Pantani, Elena Zamagni, Paola Tacchetti, Annamaria Brioli, Anna Beatrice Zannetti, Katia Mancuso, Serena Rocchi, Annalisa Pezzi, Nicoletta Testoni, Giulia Marzocchi, Gaia Ameli, Michele Cavo, Carolina Terragna
Journal: Blood (2014)
The effects of preoperative oral antibiotic use on the development of surgical site infection after elective colorectal resections: A retrospective cohort analysis in consecutively operated 90 patients
Authors: Suleyman Ozdemir, Kamil Gulpinar, S. Erpulat Ozis, Zafer Sahli, S. Altug Kesikli, Atila Korkmaz, I. Ethem Gecim
Journal: International Journal of Surgery (2016)
Prognostic importance of social and economic resources among medically treated patients with angiographically documented coronary artery disease
Authors: R. B. Williams
Journal: JAMA (1992)

<h3>Objective.</h3> —To evaluate the hypothesis that diminished social and economic resources impact adversely on cardiovascular mortality in patients with coronary artery disease. <h3>Design.</h3> —Inception cohort study of patients undergoing cardiac catheterization from 1974 through 1980 and followed up through 1989. <h3>Setting.</h3> —Tertiary care university medical center. <h3>Patients.</h3> —Consecutive sample of 1965 medically treated patients with stenosis 75% or greater of at least one major coronary artery. Five hundred patients were not enrolled due to logistic problems; 33 refused; 64 had missing data on key medical variables. The final study population included 1368 patients, 82% male, with a median age of 52 years. <h3>Main Outcome Measure.</h3> —Survival time until cardiovascular death. <h3>Results.</h3> —Independent of all known baseline invasive and noninvasive medical prognostic factors, patients with annual household incomes of $40 000 or more had an unadjusted 5-year survival of 0.91, compared with 0.76 in patients with incomes of $10000 or less (Cox model adjusted hazard ratio, 1.9; 95% confidence interval, 1.57 to 2.32;<i>P</i>=.002). Similarly, unmarried patients without a confidant had an unadjusted 5-year survival rate of 0.50, compared with 0.82 in patients who were married, had a confidant, or both (adjusted hazard ratio, 3.34; 95% confidence interval, 1.84 to 6.20;<i>P</i>&lt;.0001). <h3>Conclusions.</h3> —Low levels of social and economic resources identify an important high-risk group among medically treated patients with coronary artery disease, independent of important medical prognostic factors. Additional study will be required to see if interventions to increase these resources improve prognosis. (<i>JAMA</i>. 1992;267:520-524)