tbuckley/cabot-search huggingface dataset:
Abstract 4596: Early noninvasive prediction of response to targeted therapy in non-small cell lung cancer
Authors: Jillian A. Phallen, Alessandro Leal, Brian D. Woodward, Patrick M. Forde, Jarushka Naidoo, Kristen Marrone, Julie Brahmer, Jacob Fiksel, Doreen N. Palsgrove, Stephen Cristiano, Daniel Bruhm, Elizabeth Weihe, Vilmos Adleff, Parissa Keshavarzian, Valsamo Anagnostou, Robert B. Scharpf, Victor E. Velculescu, Hatim Husain
Journal: Cancer Research (2018)

Abstract There is an unmet need for improved methods of rapidly identifying responses to targeted therapies. Liquid biopsy approaches have potential as early biomarkers of response based on noninvasive, real-time monitoring of disease burden. We have used the ultrasensitive targeted error correction sequencing (TEC-Seq) approach to analyze 58 cancer driver genes in patients with metastatic non-small cell lung cancer undergoing treatment with targeted tyrosine kinase inhibitors. As a proof-of-principle study, liquid biopsies were obtained from sixteen patients immediately prior to treatment, 6-22 days after treatment, and at serial timepoints until disease progression. Tumor derived alterations and copy number changes were directly detected in plasma and tracked over timepoints analyzed. Based on the dynamics of cell-free circulating tumor DNA (ctDNA) mutations identified, we developed a noninvasive measure of cell-free clonal tumor load (cfTL) to evaluate real-time response to treatment. These analyses revealed that patients with a radiographic response to therapy had a significant drop in cfTL from an average mutant allele fraction of 3.59% to 0.13% within 6-22 days (P &amp;lt; 0.05) as well as in the number of detectable mutations and aneuploidy scores, while radiographic non-responders had limited to no changes. Analyses of residual cfTL 6-22 days after treatment stratified patients into ctDNA responders and ctDNA non-responders. ctDNA responders had improved progression-free survival (12.4 vs 1.7 months, P &amp;lt; 0.001), which was detected on average 38 days earlier and was as predictive as CT imaging. These analyses provide an approach for rapid evaluation of response to targeted therapies and have important clinical implications for the management of cancer patients. Citation Format: Jillian A. Phallen, Alessandro Leal, Brian D. Woodward, Patrick M. Forde, Jarushka Naidoo, Kristen Marrone, Julie Brahmer, Jacob Fiksel, Doreen N. Palsgrove, Stephen Cristiano, Daniel Bruhm, Elizabeth Weihe, Vilmos Adleff, Parissa Keshavarzian, Valsamo Anagnostou, Robert B. Scharpf, Victor E. Velculescu, Hatim Husain. Early noninvasive prediction of response to targeted therapy in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4596.
Cardiac Side Population Cells
Authors: KazumasaUnno, MohitJain, RonglihLiao
Journal: Circulation Research (2012)

Over the past decade, extensive work in animal models and humans has identified the presence of adult cardiac progenitor cells, capable of cardiomyogenic differentiation and likely contributors to cardiomyocyte turnover during normal development and disease. Among cardiac progenitor cells, there is a distinct subpopulation, termed “side population” (SP) progenitor cells, identified by their unique ability to efflux DNA binding dyes through an ATP-binding cassette transporter. This review highlights the literature on the isolation, characterization, and functional relevance of cardiac SP cells. We review the initial discovery of cardiac SP cells in adult myocardium as well as their capacity for functional cardiomyogenic differentiation and role in cardiac regeneration after myocardial injury. Finally, we discuss recent advances in understanding the molecular regulators of cardiac SP cell proliferation and differentiation, as well as likely future areas of investigation required to realize the goal of effec...
Abstract 3449: AGL loss promotes anchorage independent growth of non-small cell lung cancer by activating FAK
Authors: Sunny Guin, Craig Richmond
Journal: Cancer Research (2018)

Abstract Loss of glycogen debranching enzyme (AGL) has been shown to promote growth of bladder and non-small cell lung cancer. AGL loss predominantly assists anchorage independent growth of non-small cell lung cancer (NSCLC) cells. However the mechanism driving this anchorage independent growth with AGL loss is not well understood. To identify the driver pathways which contributions to increased anchorage independent growth with AGL loss, we carried out a phospho-kinase screen in A549 NSCLC cells with and without AGL expression. The kinase screen identified an increase in phospho-FAK (Tyr 576/577) levels with loss of AGL. The result of the screen was validated using separate independent Western blot experiments in A549 and other NSCLC cell lines which showed an increase in FAK activation at Tyr 576/577 with loss of AGL. We next treated NSCLC cells with and without AGL with FAK specific inhibitor (FAK inhibitor 14). Treatment with FAK inhibitor 14 had a greater cytotoxic effect (p&amp;lt;0.05) on NSCLC cells that have AGL loss. These data suggest that activation of FAK is a major driver of anchorage independent growth in NSCLC cells that have lost AGL expression and inhibition of FAK activity can serve as a therapeutic avenue for NSCLC patients with low tumor AGL expression. Citation Format: Sunny Guin, Craig Richmond. AGL loss promotes anchorage independent growth of non-small cell lung cancer by activating FAK [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3449.
Abstract MP44: Lifetime Marijuana Use is Not Associated with Incident Cardiovascular Disease in Middle-Age: The Coronary Artery Risk Development in Young Adults (CARDIA) Study
Authors: Jared P Reis, Reto Auer, David Goff, Cora Lewis, Mark Pletcher, Jamal Rana, Steve Sidney
Journal: Circulation (2016)

Background: Marijuana is the most frequently used illicit drug in the US. Its use is expected to rise given recent state policies that relax criminalization and permit medicinal use. Although several mechanisms exist by which marijuana might contribute to chronic cardiovascular conditions, few data are available. We sought to determine the association of lifetime marijuana use with the development of incident CHD and CVD. Methods: Participants were 5,114 white and black adults aged 18-30 years in 1985-86 from the multicenter, community-based CARDIA Study who have been followed for over 25 years. We estimated cumulative years of exposure in “marijuana-years,” with one marijuana-year equal to 365 days of marijuana use using repeated assessments every 2-5 years. Incident CHD included fatal or nonfatal myocardial infarction, angina, or CHD death. Incident CVD included CHD, stroke, hospitalized heart failure, and intervention for peripheral arterial disease. Cox proportional hazards models were used to estimate hazard ratios and 95% confidence intervals. Lifetime marijuana use and all time-varying covariates were entered as time-dependent variables. Results: Approximately 16% of the cohort were lifetime never users of marijuana, while 35%, 22%, 14%, and 13% reported lifetime use of &lt;0.5, 0.5-&lt;2, 2-&lt;5, and ≥5 marijuana-years, respectively. During a median of 26.9 years of follow-up (132,120 person-years), there were 104 and 216 cases of CHD and CVD, respectively. Compared to never use, categories of lifetime marijuana use showed no evidence for a higher or lower risk for CHD or CVD, regardless of the level of multivariable adjustment (Table). Findings did not vary significantly by age, sex, race, family history, 10-year risk of CVD, or use of other illicit drugs (p-interaction &gt;0.3, for all). Conclusions: In this long-term follow-up study of young adults at baseline, lifetime use of marijuana at these levels was not associated with incident CHD or CVD in middle-age.
Increased Carotid Wall Elastic Modulus and Fibronectin in Aldosterone-Salt–Treated Rats
Authors: PatrickLacolley, CarlosLabat, AlexPujol, ClaudeDelcayre, AthanaseBenetos, MichelSafar
Journal: Circulation (2002)

Background— Previous studies have demonstrated the development of cardiac fibrosis in aldosterone (Aldo)–salt hypertensive rats. Our aim was to determine the effects of Aldo and the Aldo receptor antagonist eplerenone (Epl) on in vivo mechanical properties of the carotid artery using echo-tracking system. Methods and Results— Aldo was administered (1 μg/h) in uninephrectomized Sprague-Dawley rats (SD) receiving a high-salt diet from 8 to 12 weeks of age. Uninephrectomized control SD rats received a normal salt diet without Aldo. Three groups of Aldo-salt rats were treated with 1, 10, or 30 mg/kg−1 · d−1 of Epl by gavage. Elasticity was measured by elastic modulus (Einc)-wall stress curves using medial cross-sectional area (MCSA). The structure of the arterial wall was analyzed by histomorphometry (elastin and collagen), immunohistochemistry (EIIIA fibronectin, Fn), and Northern blot (collagens I and III). Aldo produced increased systolic arterial pressure, pulse pressure, Einc, MCSA, and EIIIA Fn with no ...
Abstract CT155: Design of a dose escalation phase 1/2 trial for a novel combined cell and oncolytic viral therapy
Authors: Pamela R. Contag
Journal: Cancer Research (2018)

Abstract Ovarian cancer is the sixth most common malignancy in women and the leading cause of death from all gynecological cancers in the United States with epithelial ovarian cancer are often diagnosed with advanced- stage disease. Although clinically complete remissions are obtained in the majority of patients through a combination of cyto-reductive surgery and chemotherapy, relapse is common with 70% of patients exhibiting recurring disease and thus represents a high unmet need. Single-agent therapies used to treat the subset of patients with chemotherapy- resistant/refractory ovarian cancer include paclitaxel, PLD (peglyated liposomal doxorubicin) and topotecan. The response rate is in the 10-15% range and overall survival is approximately 12 months. Our immunotherapy is comprised of cytokine-induced NK-T cells which stealthily delivers a tumor selective vaccinia virus to the tumor microenvironment, attracted by chemokines released by the tumor and binding to tumor stress ligands. The virus is released in the tumor site and is synchronously released to kill tumor cells, reducing or eradicating the tumor. This therapeutic approach is multi-mechanistic and delivery of the oncolytic agent by the immune effector cells together may result in a durable immune response to ovarian tumor- specific antigens through a cytotoxic T-cell mechanism. The two components, vaccinia virus vvDD-CDSR and CIK cells have been tested and investigated in multiple pre-clinical and clinical studies that have demonstrated their antitumor efficacy and overall safety. In our proposed Open Phase I/II clinical study will be a dose escalation to determine a MFD/MTD. The maximum-feasible dose (MFD) will be defined as the top dose level if no MTD is defined. It is expected that a maximum of 22 patients will be required to establish the MTD for one infusion. Once an MFD/and or MTD is determined, the study moves onto Phase II part of the protocol design allowing multiple cycles up to 4, treating 6-22 patients in Arm 1 safety and 20 patients in Arm 2 efficacy. Citation Format: Pamela R. Contag. Design of a dose escalation phase 1/2 trial for a novel combined cell and oncolytic viral therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT155.
Abstract 5433: XRCC5 promotes tumor growth and progression via PDK-1 signaling and predicts poor prognosis in melanoma
Authors: Ge Qin, Tianze Liu, Wenbin Li, Yixin Li, Changlin Zhang, Qian Long, Dingbo Shi, Miao Chen, Shuting Huang, Wuguo Deng
Journal: Cancer Research (2018)

Abstract Melanoma is one of the most malignant and aggressive cancers with high cancer-related deaths. Patients with melanoma are often diagnosed at an advanced stage that has developed local or even remote metastasis due to its inapparent symptoms at early stages. Melanoma is often insensitive to chemotherapies, and most patients that respond well to targeted therapies or immunotherapies at first will develop resistance within several months. Therefore, it is of urgency to better understand the mechanisms of melanoma tumorigenesis, and to discover novel molecular targets for its effective treatment. In this study, we identified XRCC5 as a potential therapeutic target by siRNA library screening in A375 melanoma cells. We found that knockdown of XRCC5 inhibited cell growth, migration and invasion, and induced apoptosis in melanoma cells. Conversely,overexpression of XRCC5 significantly promoted the growth, migration and invasion of melanoma cells. We next analyzed the global transcriptome in A375 cells with XRCC5 knockdown, and identified PDK-1 as a candidate gene regulated by XRCC5. Further investigation revealed that XRCC5 cooperated with HIF-1α to bind at the promoter of PDK-1, and enhanced the expression of PDK-1. Consistently, overexpression of PDK-1 rescued the cell growth inhibition caused by XRCC5 knockdown. Our clinical data showed that the expression of XRCC5 and PDK-1 were positively correlated and elevated in melanoma samples, and high expression of XRCC5 predicted poor prognosis in melanoma patients. Collectively, our study discovered that XRCC5 bound to the promoter of PDK-1 to activate its expression, which promoted melanoma growth and progression. Our results indicated that the XRCC5/PDK-1 pathway could be a potential therapeutic target for melanoma. Citation Format: Ge Qin, Tianze Liu, Wenbin Li, Yixin Li, Changlin Zhang, Qian Long, Dingbo Shi, Miao Chen, Shuting Huang, Wuguo Deng. XRCC5 promotes tumor growth and progression via PDK-1 signaling and predicts poor prognosis in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5433.
Abstract 12292: Magnetocardiography Can Predict Reverse Remodeling and Long-Term Prognosis After Cardiac Resynchronization Therapy
Authors: Shunsuke Usami, Hiroshi Takaki, Shuji Hashimoto, Shogo Oishi, Yuko Yamada, Hideo Okamura, Takashi Noda, Kazuhiro Satomi, Takeshi Aiba, Wataru Shimizu, Naohiko Aihara, Shiro Kamakura, Masaru Sugimachi
Journal: Circulation (2011)

Background: Although cardiac resynchronization therapy (CRT), an established treatment for advanced heart failure (HF) with electromechanical dyssynchrony, is not effective in approximately one thi...
Abstract 18238: Markedly Elevated Pericardial Fluid Levels of N-terminal Probrain Natriuretic Peptide are Involved in Left Ventricular Systolic Dysfunction with Aortic Stenosis and Ischemic Heart Disease
Authors: ShoichiMiyamoto, ToshiakiIzumi, EisakuNakane, TakaoKatoh, MoritoshiFunasako, MasahiroKimura, KanaeSu, MitsumasaOkano, YukiKimura, TakayukiSekihara, HideyukiHayashi, JunIida, ManabuMorishima, KojiUeyama, TetsuyaHaruna, MasatoshiFujita, MoriakiInoko
Journal: Circulation (2014)

Background: Increasing evidence suggests that N-terminal probrain natriuretic peptide (NT-proBNP) may be a more discerning marker for the detection and evluation of heart failure than BNP. However, fundamental mechanisms that contribute to the heart failure in aortic stenosis (AS) and ischemic heart disease (IHD) via NT-proBNP remain unclear. Objectives: The purpose of this study was to investigate whether NT-proBNP represents autocrine/paracrine factors and are accumulated in pericardial fluid (PF) in patients with AS and IHD. Methods: With an electrochemiluminescent immunoassay, we measured the concentrations of NT-proBNP in serum and pericardial fluid simultaneously in 48 patients undergoing aortic valve replacement and 101 patients undergoing coronary artery bypass grafting. We investigated the correlation of NT-proBNP levels in serum or PF with hemodynamic variables. Results: In patients with AS, the PF levels of NT-proBNP were markedly elevated compared with serum levels (10747±17619 pg/ml vs. 2828±...
Abstract 19132: Urinary 8-hydroxy-2’-deoxyguanosine, a Biomarker of Oxidative Stress, Predicts Cardiac Events in Patients With Cardiac Sarcoidosis
Authors: TakekiMyoren
Journal: Circulation (2014)

Background: Enhanced production of reactive oxygen species plays a crucial role in the pathogenesis of cardiac sarcoidosis (CS). Here, we investigated whether urinary (U) 8-hydroxy-2’-deoxyguanosine (8-OHdG), a marker of oxidative DNA damage, predicts cardiac events in CS patients. Methods: Thirty consecutive patients were diagnosed as CS according to 2006 Japanese guideline, and they were divided into active CS group (n=20) and non-active CS group (n=10) based on the abnormal accumulation of isotope on heart by 18FDG-PET/CT. U-OHdG, cardiac function and other biomarkers were measured in 30 CS patients before discharge (mean age: 64.8 ± 11.1 years; male: 52%; LVEF: 35 ±13%; NYHA: 1.8 ± 0.6, BNP: 315.0 ± 352.7 pg/ml; U8-OHdG: 16.7 ± 7.0 ng/mg·creatinine). Then, we prospectively followed these patients for a median follow-up period of 48 month, with primary endpoints of cardiac events (death). Results: U-8OHdG (ng/mg·creatinine) in all CS patients was significantly increased as compared with control subject...
Abstract 2342: Digital gene expression of up to 96 targets in 96 samples for cell line screening with nCounter® PlexSet™
Authors: Giang T. Ong, Chris Merritt, Anisha Kharkia, Philippa Webster
Journal: Cancer Research (2018)

Abstract Cell line screening studies require highly efficient protocols for studying many samples in parallel. We have developed a lyse-and-go protocol for digital gene expression profiling of 96-samples by 96-genes in parallel. This protocol is based on nCounter® PlexSet™ Reagents, which enable multiplexing of samples and gene targets. The NanoString® nCounter Analysis platform uses a novel molecular barcoding technology to measure multiplexed gene expression. The assay counts fluorescent barcodes hybridized to targets to provide precise digital data. This platform is used in a wide variety of research applications. The standard nCounter gene expression assay can be used to process 12 samples per run. We recognize an additional need for a higher sample-throughput assay that would enable researchers to quickly evaluate up to 96 multiplexed targets in samples processed in a 96-well plate-based format. The PlexSet Reagent protocol is simple and fast and can be divided into 3 steps: 1) lyse cells, 2) set-up hybridization with crude lysate, 3) initiate automated post-hybridization processing and digital counting. The data presented are crude cells lysates from various PBMC cell types, two suspension cell lines, and two adherent cell lines using the IO Lymphocyte Activity Panel to measure the gene expression of 5 housekeeper genes and 91 lymphocyte activity genes (96 genes in total). The data demonstrate that up to 96 high-quality, digital data points for gene expression in each of 96 samples can be generated from crude cell lysates in an efficient, high-throughput protocol and that the cell lysate data correlate well with purified total RNA. Citation Format: Giang T. Ong, Chris Merritt, Anisha Kharkia, Philippa Webster. Digital gene expression of up to 96 targets in 96 samples for cell line screening with nCounter® PlexSet™ [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2342.
Abstract 4296: Cofilin-1 is associated with replicative origins licensing through regulation of MCM2-7 helicase
Authors: Yi-Jang Lee, Chun-Yuan Chang
Journal: Cancer Research (2018)

Abstract G1 to S phase transition is strictly regulated to avoid uncontrolled growth in mammalian cells. Although DNA replication initiates in S phase, licensing of DNA replicative origins substantially begins from late M to G1 phase. Interference of replicative origins licensing will lead to genomic instability and cell death. In addition, integral actin organization is required for G1 phase to S phase transition. Whether actin architectures will influence the licensing of DNA replicative origins is unclear. Previously, we found that over-expression of cofilin-1, a member of actin depolymerizing factor (ADF)/cofilin family could destabilize actin cytoskeleton and cause G1 phase arrest. The microarray assay further showed that minichromosome maintenance complex 2-7 (MCM2-7) helicase involved in the establishment of licensing was regulated by cofilin-1. In this study, we aim to investigate whether cofilin-1 would affect the expression of MCM2-7 complexes and the initiation of replicative origins licensing. First, we exploited a double thymidine blockage assay to demonstrate that the cofilin-1 expression was down-regulated during G1 to S phase transition. Use of H1299/tet-on-cofilin-1 cells, we also found that doxycycline induced exogenous cofilin-1 could inhibit the expression of MCM2-7 complex in both dose and time-dependent manners. Chromatin fractionation for analyzing the replicative origin licensing was performed to confirm these observations. DNA fiber analysis for determining the interorigin distance (IOD) was applied to investigate the IOD after the overexpression of cofilin-1 in H1299/tet-on-cofilin-1 cells. Taken together, current results revealed a novel finding that cofilin-1 could regulate MCM2-7 complex for mediating the replicative origin licensing and cell cycle progression. Since MCM2-7 complex has been regarded a prognostic marker of several human cancers, this study may contribute to designing of new therapeutic strategy for cancer treatment. Citation Format: Yi-Jang Lee, Chun-Yuan Chang. Cofilin-1 is associated with replicative origins licensing through regulation of MCM2-7 helicase [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4296.