tbuckley/cabot-search huggingface dataset:
Abstract 5473: Towards a better understanding of MTH1 as a therapeutic target in RAS-driven cancer
Authors: Govindi J. Samaranayake, Clara I. Troccoli, Mai Q. Huynh, Andrew Win, Debin Ji, Eric T. Kool, Priyamvada Rai
Journal: Cancer Research (2017)

Abstract Oncogenic RAS signaling-generated reactive oxygen species (ROS) drive tumor progression by the hyperactivation of proliferative, anti-apoptotic, and metastatic pathways. Elevated ROS levels however can also cause oxidative DNA damage, leading to oncogene-induced senescence (OIS) and cell death. To avoid such tumor-suppressive outcomes, RAS-driven tumors often upregulate redox-protective proteins. The collective research from our group over the last few years has shown that oncogenic RAS elevates expression of the mammalian 8-oxo-dGTPase MutT Homolog 1 (MTH1), which in turn enables evasion of OIS, promotes transformation efficiency, and facilitates tumorigenicity. Our prior work has therefore demonstrated that MTH1 is beneficial to the spectrum of RAS-driven transformation, and that its shRNA-mediated targeting in oncogenic RAS-harboring lung cancer cells produces robust tumor-suppressive outcomes. However the first wave of chemical MTH1 inhibitors has led to controversial and conflicting results regarding MTH1 as a chemotherapeutic target. Here we evaluate the benefit of MTH1 inhibitors in wildtype. vs. oncogenic KRAS expressing cells, and directly assess the effects of oncogenic KRAS as well as three recently developed inhibitors on MTH1 8-oxo-dGTPase activity. Our results support that introduction of oncogenic KRAS elevates both MTH1 expression and activity, presumably through its elevation of ROS levels, and thus sensitizes cells to MTH1 inhibitors. The degree of this sensitization has a complex dependence on residual 8-oxodGTPase activity in the different cells following treatment with the MTH1 inhibitors, alternate antioxidant responses, and induction of different tumor suppressor pathways. Our data therefore highlight the importance of evaluating the molecular contexts and outcomes of MTH1 inhibition when determining its utility as a chemotherapeutic target. Citation Format: Govindi J. Samaranayake, Clara I. Troccoli, Mai Q. Huynh, Andrew Win, Debin Ji, Eric T. Kool, Priyamvada Rai. Towards a better understanding of MTH1 as a therapeutic target in RAS-driven cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5473. doi:10.1158/1538-7445.AM2017-5473
THU0129 Cd8+cd28- t-lymphocytes are associated with subclinical atherosclerosis in patients with rheumatoid arthritis
Authors: B Wahlin, AE Fasth, K Karp, K Lejon, A Södergren, S Wållberg-Jonsson
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Patients with rheumatoid arthritis (RA) have an increased mortality and morbidity due to cardiovascular disease and accelerated progression of atherosclerosis. Altered populations of T-lymphocytes are associated with atherosclerosis, and chronic infection with cytomegalovirus (CMV) affects the T-cell-population. <h3>Objectives</h3> To study the association between subsets of T-lymphocytes, subclinical atherosclerosis assessed by intima-media thickness (IMT) and antibodies against CMV in patients with RA. <h3>Methods</h3> Patients with new-onset RA (n=71), aged ≤60 years at diagnosis, were consecutively included in a study of development of atherosclerosis. Ultrasound measurement of IMT of a. carotis communis was undertaken at inclusion (T0), after five years (T5) and after 11 years (T11) (n=54). At T11, flow-cytometry was undertaken to investigate subsets of T-lymphocytes (CD45+CD3+), where CD4, CD8, CD28, CD56 and CX3CR1 was studied. CX3CR1 is the ligand of fractalkine, an adhesion molecule expressed on activated endothelial cells to attract leukocytes. Serological analysis for CMV was undertaken from samples collected at T0, T5 and T11. <h3>Results</h3> The percentage of CD8+T-lymphocytes lacking the co-stimulatory molecule CD28 (CD8+CD28-) was significantly (standardized beta coefficient 0.39, p-value 0.01) associated with IMT at T11 in a linear regression model including T0 variables smoking, systolic blood pressure and cholesterol. No association with IMT was seen for CD4+CD28- T-lymphocytes. CX3CR1 was expressed in 71% of CD8+CD28- T-lymphocytes, compared with 8.2% of CD8+CD28+. The prevalence of immunoglobulin G seropositivity for CMV was 47/70 (67%), 42/66 (57%) and 34/56 (52%) at T0, T5 and T11 respectively. Patients with constantly positive CMV serologies (T0, T5 and T11) had a significantly higher percentage of CD8+CD28- and CD4+CD28- T-lymphocytes. Also the proportion of cells expressing CX3CR1 was in both CD4+ and CD8+ T-lymphocytes associated with constantly positive serologies for CMV. <h3>Conclusions</h3> Subclinical atherosclerosis in patients with RA was associated with CD8+CD28- T-lymphocytes in a regression model adjusted for traditional cardiovascular risk factors. Positive serologies for CMV were associated with an increased proportion of CD8+CD28- T-lymphocytes and T-lymphocytes expressing CX3CR1. <h3>Disclosure of Interest</h3> B. Wahlin: None declared, A. Fasth Employee of: Novartis Sweden AB, K. Karp: None declared, K. Lejon: None declared, A. Södergren: None declared, S. Wållberg-Jonsson: None declared
Abstract 40: Development of a novel antibody-drug conjugate targeting endosialin/TEM-1: potent antitumor activity in sarcoma
Authors: Gianluca Sala, Stefano Iacobelli, Emily Capone, Enza PIccolo, Jean-Fred Sauniere, Vanessa Vannucci Douet
Journal: Cancer Research (2017)

Abstract The TEM-1/Endosialin/CD248 receptor is expressed in the cell surface of tumor-associated stroma cells, as well as in sarcoma and neuroblastoma cells. This receptor is emerging as an attractive molecule in diagnostics and therapeutics because of its expression across the stroma of many human tumors, the low to absent expression in normal tissues and accessibility from the vascular circulation. In this study, we present evidence of the preclinical efficacy of a novel Antibody-Drug Conjugate (ADC). It consists of a humanized TEM-1 monoclonal antibody (E.8-3) conjugated to a highly potent payload (TEM-1-ADC). In TEM-1 expressing cancer cell lines, this TEM-1-ADC demonstrated a powerful, specific and target-dependent killing activity. High expression levels of TEM-1 in cells correlated with efficient internalization, efficacy, and cytotoxic effects in vitro. Efficacy studies demonstrated that TEM-1-ADC treatment leads to a long lasting tumor growth inhibition of cell line-based models of human sarcoma. Taken together, our results demonstrated that TEM-1 is an attractive target in sarcoma and suggest that TEM-1-ADC has the potential to be developed into a biotherapeutic agent in these malignancies. Citation Format: Gianluca Sala, Stefano Iacobelli, Emily Capone, Enza PIccolo, Jean-Fred Sauniere, Vanessa Vannucci Douet. Development of a novel antibody-drug conjugate targeting endosialin/TEM-1: potent antitumor activity in sarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 40. doi:10.1158/1538-7445.AM2017-40
Abstract 5908: Cancer-associated fibroblast driven drug resistance in colorectal cancer
Authors: Colleen M. Garvey, Oscar Chen, Shannon M. Mumenthaler
Journal: Cancer Research (2017)

Abstract Drug resistance remains a major problem in the treatment of most cancers. For example, KRAS wild-type colorectal cancers (CRCs) are typically treated with the anti-epidermal growth factor receptor (EGFR) therapy cetuximab in combination with standard chemotherapy; however, of the 40% of patients that do respond, virtually all relapse within 3-12 months. Additionally, around 25% of nonresponders have no identifiable resistance mechanisms. This suggests that it is not just cell-intrinsic mechanisms that result in resistance, but that extrinsic factors play a role. The purpose of this study was to investigate how the dynamics of the tumor microenvironment, specifically cancer-associated fibroblasts (CAFs) and hypoxia, modify the response of CRC cells to cetuximab. We used a novel high-content imaging platform to generate quantitative phenotypic data (i.e. morphology, birth/death rates) of cellular co-cultures perturbed by multiple, co-occurring microenvironmental conditions. Preliminary data demonstrated reduced sensitivity of tumor cells to cetuximab in the presence of CAFs, which was dependent on patient specifics and time scale of co-culture. Additionally, we found that low oxygen conditions altered the effect of CAFs on tumor cell phenotypes, which highlights the importance of studying co-occurring microenvironmental factors. This work underlies the importance of considering not just the genetic makeup of patient tumors, but also the heterogeneity of the surrounding microenvironment when designing personalized treatment strategies. Citation Format: Colleen M. Garvey, Oscar Chen, Shannon M. Mumenthaler. Cancer-associated fibroblast driven drug resistance in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5908. doi:10.1158/1538-7445.AM2017-5908
Abstract 80: Mechanical vs Manual Chest Compressions in Out-of-Hospital Cardiac Arrest: Meta-analysis on the Effects on Return of Spontaneous Circulation
Authors: Mark Westfall, Steve Krantz, Christopher Kaufman, Christopher Mullin
Journal: Circulation (2011)

Background: Morbidity and mortality rates for out-of-hospital cardiac arrest (OHCA) remain high. A load-distributing band (LDB-CPR) device that provides circumferential thoracic compressions and a piston-driven device with active compression/decompression (PD-CPR) that provides sternal compressions are commercially available automated mechanical chest compression devices designed to supplement conventional CPR (C-CPR). To date, short-term survival data of LDB-CPR and PD-CPR vs. C-CPR are limited and inconclusive. A larger body of data exists on the effects of return of spontaneous circulation (ROSC) for these devices. Methods: A meta-analysis was performed to compare LDB-CPR and PD-CPR to C-CPR with the primary endpoint of ability to achieve ROSC. Selection criteria for the meta-analysis required that studies must be human controlled (randomized, phased, historical or case-control) investigations with confirmed OHCA cases. Random effects models were used to assess the relative effect of treatments on ROSC. Result: A total of 13 studies (LDB-CPR vs. C-CPR = 8, PD-CPR vs. C-CPR = 5), comprising a total of 6664 subjects with 1884 ROSC events, met the selection criteria. When compared to C-CPR, LDB-CPR had a significantly greater odds of ROSC (odds ratio (OR) = 1.62; 95CI%= 1.36, 1.92, p&lt;0.001) (Figure). The treatment effect for PD-CPR was not significant (OR = 1.15; 95CI%= 0.87, 1.51, p=0.331). Conclusion: The ability to achieve ROSC with general automated mechanical chest compression devices is, at the least, comparable to C-CPR. In the case of LDB-CPR, it was superior to C-CPR as the odds of ROSC were over 1.5 times greater and statistically significant. The robustness of these findings should be confirmed in large randomized controlled clinical trials.
State-Dependent Cross-Brain Information Flow in Borderline Personality Disorder
Authors: Edda Bilek, Gabriela Stößel, Axel Schäfer, Laura Clement, Matthias Ruf, Lydia Robnik, Corinne Neukel, Heike Tost, Peter Kirsch, Andreas Meyer-Lindenberg
Journal: JAMA Psychiatry (2017)

<h3>Importance</h3> Although borderline personality disorder (BPD)—one of the most common, burdensome, and costly psychiatric conditions—is characterized by repeated interpersonal conflict and instable relationships, the neurobiological mechanism of social interactive deficits remains poorly understood. <h3>Objective</h3> To apply recent advancements in the investigation of 2-person human social interaction to investigate interaction difficulties among people with BPD. <h3>Design, Setting, and Participants</h3> Cross-brain information flow in BPD was examined from May 25, 2012, to December 4, 2015, in pairs of participants studied in 2 linked functional magnetic resonance imaging scanners in a university setting. Participants performed a joint attention task. Each pair included a healthy control individual (HC) and either a patient currently fulfilling<i>DSM-IV</i>criteria for BPD (cBPD) (n = 23), a patient in remission for 2 years or more (rBPD) (n = 17), or a second HC (n = 20). Groups were matched for age and educational level. <h3>Main Outcomes and Measures</h3> A measure of cross-brain neural coupling was computed following previously published work to indicate synchronized flow between right temporoparietal junction networks (previously shown to host neural coupling abilities in health). This measure is derived from an independent component analysis contrasting the time courses of components between pairs of truly interacting participants compared with bootstrapped control pairs. <h3>Results</h3> In the sample including 23 women with cBPD (mean [SD] age, 26.8 [5.7] years), 17 women with rBPD (mean [SD] age, 28.5 [4.3] years), and 80 HCs (mean [SD] age, 24.0 [3.4] years]) investigated as dyads, neural coupling was found to be associated with disorder state (<i>η</i><sup>2</sup> = 0.17;<i>P</i> = .007): while HC-HC pairs showed synchronized neural responses, cBPD-HC pairs exhibited significantly lower neural coupling just above permutation-based data levels (η<sup>2</sup> = 0.16;<i>P</i> = .009). No difference was found between neural coupling in rBPD-HC and HC-HC pairs. The neural coupling in patients was significantly associated with childhood adversity (<i>T</i> = 2.3;<i>P</i> = .03). <h3>Conclusions and Relevance</h3> This study provides a neural correlate for a core diagnostic and clinical feature of BPD. Results indicate that hyperscanning may deliver state-associated biomarkers for clinical social neuroscience. In addition, at least some neural deficits of BPD may be more reversible than is currently assumed for personality disorders.
Abstract 1266: Metformin represses esophageal carcinogenesis in NMBzA-treated rat model through inhibiting AMPK/mTOR and Stat3 signaling pathways
Authors: Hongjun Fan, Zhigeng Zou, Xiying Yu, Liping Guo, Wei Jiang, Shih-Hsin Lu
Journal: Cancer Research (2017)

Abstract Esophageal cancer is one of the most aggressive tumor types because of its invasiveness and metastatic potential. Metformin is one of the most used diabetic drugs for the management of type 2 diabetes mellitus in the world. The role of metformin in prevention of the development and progression of a variety of human tumors has been studied. However, the detailed mechanisms have not yet been fully understood. In the present study, we investigated the effects of metformin on the suppression of esophageal carcinogenesis in a rat model, in which F344 rats were treated with N-nitroso-N-methylbenzylamine (NMBzA 0.30 mg/kg s.c.) three times per week for 35 weeks to induce esophageal tumors. To monitor the effects of metformin in this model, one group of rats were administered with metformin (3 g/L) in the drinking water at the first NMBzA injection. Our results showed that although there was no significant difference in body weight in rats of different groups, rats treated with NMBzA and metformin together significantly reduced the tumor formation and tumor volume when compared with rats treated with NMBzA alone. Statistic analyses demonstrated that the tumor numbers was reduced in NMBzA-treated rats received metformin to an average of 1.85 ± 1.09 tumors per rat when compared with 10.85 ± 3.86 (P &amp;lt; 0.001) in rats without metformin, while the tumor volume was decreased from 70.79 ± 41.65 mm3 per rat without metformin administration to 8.64 ± 13.45 mm3 (P &amp;lt; 0.001) with metformin administration. In addition, 7 out of 24 rats in the NMBzA-treated group died before week 35 but no rats died in the other groups. Furthermore, immunoblotting analysis indicated that p-mTORSer2448, p-Stat3Tyr705, and Cyclin D1 protein levels significantly decreased, while p-AMPKThr172 significantly increased in tumors obtained from rats treated with NMBzA and metformin when compared with tumors obtained from rats treated with NMBzA alone. Thus, our results indicated that metformin suppressed NMBzA-induced esophageal carcinogenesis via inhibition of the AMPK/mTOR and Stat3 signaling pathways. Together, our study suggested that metformin might have a potential use for treatment and prevention of esophageal cancer. Citation Format: Hongjun Fan, Zhigeng Zou, Xiying Yu, Liping Guo, Wei Jiang, Shih-Hsin Lu. Metformin represses esophageal carcinogenesis in NMBzA-treated rat model through inhibiting AMPK/mTOR and Stat3 signaling pathways [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1266. doi:10.1158/1538-7445.AM2017-1266
Abstract 4660: HPRT as a biomarker for tumor classification and its variability of expression in breast cancer
Authors: Michelle H. Townsend, Abigail M. Felsted, Jacob Clarke, Richard A. Robison, Kim L. O'Neill
Journal: Cancer Research (2017)

Abstract The purpose of this study is to investigate the differential expression of HRPT between various breast cancer tissues in comparison to healthy breast tissue in order to evaluate its potential use as a diagnostic tool. Breast cancer is the most common malignancy diagnosed in women and remains incurable in the metastatic setting requiring accurate and reliable tools for early diagnosis. We analyzed HPRT, a purine salvage pathway enzyme responsible for synthesizing 90% of the available GMP and IMP in cellular maintenance. Due to its critical role in maintaining necessary nucleotides for cell proliferation, we hypothesized an increase in the expression of HPRT in cancer. Tissues from 48 patients with breast carcinoma were stained using standard immunohistochemistry (IHC) techniques. We examined infiltrating ductal carcinoma, margin of carcinoma, hyperplasia, atypical hyperplasia, adenosis, collagen fibers tissues, and normal breast tissue in order to determine expression between various breast cancers. Briefly, tissues were treated with a polyclonal anti-HPRT antibody along with a GADPH positive control and a universal negative control. Tissues were incubated with an HRP-polymer conjugated antibody, and DAP substrate which reacts to antibody-antigen binding sites and results in a color change. Adenosis and hyperplasia are benign breast conditions and are early signs of breast carcinoma development. Hyperplasia tissues, which are in a state of rapid proliferation, showed significant upregulation of HPRT and adenosis tissues showed approximately 42% upregulation. This HPRT upregulation in pre-stage 1 tissues indicates that it may be used as a biomarker to detect early stages of breast cancer. Expression of HPRT was also found to be upregulated in 65% of infiltrating duct carcinoma showing high expression in active malignant areas. In marginal tissue located on the perimeter of primary tumors only 31% of tissues show upregulation of the protein. Because the levels of HPRT in marginal tissue is significantly lower than those found in primary tumors, HPRT may serve as a useful diagnostic tool when evaluating successful tumor removal. These data suggests HPRT as a useful diagnostic tool when identifying tissue with a high proliferation rate indicative of potential cancer development. Additionally, HPRT may also be used as a tool for pathologists to evaluate the success of tumor removal. Citation Format: Michelle H. Townsend, Abigail M. Felsted, Jacob Clarke, Richard A. Robison, Kim L. O'Neill. HPRT as a biomarker for tumor classification and its variability of expression in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4660. doi:10.1158/1538-7445.AM2017-4660
Abstract 1872: Fluorescence-guided surgery in the tumor microenvironment in a syngeneic mouse model of EL-4 lymphoma
Authors: Kosuke Hasegawa, Atsushi Suetsugu, Miki Nakamura, Takuro Matsumoto, Takahiro Kunisada, Masahito Shimizu, Shigetoyo Saji, Hisataka Moriwaki, Michael Bouvet, Robert M. Hoffman
Journal: Cancer Research (2017)

Abstract We report fluorescence-guided surgery (FGS) of the tumor microenvironment of the EL-4-RFP lymphoma cells growing subcutaneously in C57/BL6 GFP transgenic mice. Using a portable hand-held Dino-Lite digital imaging system, subcutaneous tumors were resected by FGS. The tumor surface contained both RFP cancer cells and GFP stromal cells. The tumor microenvironment was clearly visualized and resected with the Dino-Lite. Host stromal cells, including adipocyte-like cells and blood vessels with lymphocytes, were observed along the tumor by confocal microscopy in addition to cancer cells by color-coded confocal imaging. Stromal cells were within the tumor and that cancer cells also invaded the TME. Color-coded FGS, which distinguished cancer and stroma, significantly prevented local recurrence, which bright-light surgery or single-color FGS could not. Citation Format: Kosuke Hasegawa, Atsushi Suetsugu, Miki Nakamura, Takuro Matsumoto, Takahiro Kunisada, Masahito Shimizu, Shigetoyo Saji, Hisataka Moriwaki, Michael Bouvet, Robert M. Hoffman. Fluorescence-guided surgery in the tumor microenvironment in a syngeneic mouse model of EL-4 lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1872. doi:10.1158/1538-7445.AM2017-1872
Abstract 3504: High expression of lncRNA-ATB and miR-21 as a biomarker in human hepatocellular carcinoma
Authors: Eunhye Lee, Gyeonghwa Kim, Se Young Jang, Yong-Hun Choi, Yu Rim Lee, Won Young Tak, Young Oh Kweon, Soo Young Park, Keun Hur
Journal: Cancer Research (2017)

Abstract Non-coding RNAs (ncRNAs) including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) have emerged as novel gene-regulators. The aim of this study was to determine the clinical relevancies of 2 lncRNAs (lncRNA-ATB and MEG3) and 2 miRNAs (miR-21 and miR-31) in hepatocellular carcinoma (HCC). We analyzed clinical specimens from 100 pairs of HCC and matched normal liver (NL) tissues. MiRNAs and lncRNAs expression levels were evaluated by quantitative real-time PCR. In addition, we determined the clinical significance of the ncRNAs expression in matching tissue and serum exosome samples from HCC patients. MiR-21 significantly increased in HCC (P&amp;lt;0.01) compared to corresponding NL tissues. LncRNA-ATB was significantly up-regulated in HCC (P&amp;lt;0.05); however, lncRNA-MEG3 was down-regulated in HCC (P&amp;lt;0.05) tissues. In addition, expression of miR-21 and lncRNA-ATB was significantly associated with the tumor size and poor prognosis of HCC patients. More importantly, expression of serum exosomal lncRNA-ATB and miR-21 was more significantly associated with HCC progression and poor patients survival compared to its’ tissue expression. We conclude that non-coding RNAs (lncRNA-ATB and miR-21) expression has the potential to serve as biomarkers for prognosis and targeted therapy in HCC patients. Citation Format: Eunhye Lee, Gyeonghwa Kim, Se Young Jang, Yong-Hun Choi, Yu Rim Lee, Won Young Tak, Young Oh Kweon, Soo Young Park, Keun Hur. High expression of lncRNA-ATB and miR-21 as a biomarker in human hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3504. doi:10.1158/1538-7445.AM2017-3504