tbuckley/cabot-search huggingface dataset:
Abstract 847: Optimization of radiation regimen in a carcinogen-induced mouse model for lung cancer
Authors: Sagar Bhayana, Joseph Liu, Arnab Chakravarti, Naduparambil K. Jacob
Journal: Cancer Research (2018)

Abstract Purpose: Lung cancer remains the most common cause of cancer-related mortality in United States and worldwide. The major cause of lung cancer is attributed to carcinogens present in tobacco smoke, air pollution, diet and food supplements, occupational and other environmental exposures. Lung Cancer Mutation Consortium has identified many recognized “driver mutations” in nearly two-thirds of the patients who developed advanced form of lung cancer. Our primary goal is to understand the mechanism underlying the variations in radiation sensitivity with driver mutations and optimize radiation dose and treatment regimen. A better understanding of the most frequent driving mutations is required for progression towards personalized therapy. Methods: Urethane, a carcinogen injected via intraperitoneal route into A/J mice induced multiple lung tumors by week 25 that resembled non-small cell lung carcinoma. These lung tumors were assessed via MRI and each tumor was longitudinally tracked via surface rendered 3D imaging following X-ray exposure using small animal radiation research platform (SARRP). We employed acute high single dose (12 Gy) and clinically relevant fractionated dose (3 X 5 Gy). Individual lung tumor was also dissected from non-irradiated and irradiated mice followed by collagenase digestion and then cultured in a specific media for in-vitro mutational analysis. Results: Urethane induced multiple lung tumors (20-25 tumors with 1mg/kg urethane) of varying size (0.5 - 2mm) were detectable by MRI at 25 week following injection. Longitudinal MRI performed on irradiated tumor bearing mice showed significant regression after radiation with commitment survival benefit. Mice performed better when exposed to fractionated regimen than high single dose with relatively low level radiation toxicity. Primary lung cancer cells were prepared from the explanted tumors for prospectively examining relevant driver mutations and studying the genetic determinants of resistance and to identify novel targets. We also have collected body fluids for investigating changes in molecular profile of exosomes at time points after irradiation. Conclusions: Our study thus far set up a platform for longitudinal 3D tracking of individual lung tumors following treatment and recurrence. Tumor regression was evident after a week of radiation exposure. Primary lung tumor cell cultures were successfully established for molecular analysis and mechanistic studies Citation Format: Sagar Bhayana, Joseph Liu, Arnab Chakravarti, Naduparambil K. Jacob. Optimization of radiation regimen in a carcinogen-induced mouse model for 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 847.
From design to the clinic: practical guidelines for translating cardiovascular nanomedicine
Authors: Iwona Cicha, Cédric Chauvierre, Isabelle Texier, Claudia Cabella, Josbert M Metselaar, János Szebeni, László Dézsi, Christoph Alexiou, François Rouzet, Gert Storm, Erik Stroes, Donald Bruce, Neil MacRitchie, Pasquale Maffia, Didier Letourneur
Journal: Cardiovascular Research (2018)

Cardiovascular diseases (CVD) account for nearly half of all deaths in Europe and almost 30% of global deaths. Despite the improved clinical management, cardiovascular mortality is predicted to rise in the next decades due to the increasing impact of aging, obesity, and diabetes. The goal of emerging cardiovascular nanomedicine is to reduce the burden of CVD using nanoscale medical products and devices. However, the development of novel multicomponent nano-sized products poses multiple technical, ethical, and regulatory challenges, which often obstruct their road to successful approval and use in clinical practice. This review discusses the rational design of nanoparticles, including safety considerations and regulatory issues, and highlights the steps needed to achieve efficient clinical translation of promising nanomedicinal products for cardiovascular applications.
T−786→C Mutation in the 5′-Flanking Region of the Endothelial Nitric Oxide Synthase Gene Is Associated With Coronary Spasm
Authors: MasafumiNakayama, HirofumiYasue, MichihiroYoshimura, YukioShimasaki, KiyotakaKugiyama, HisaoOgawa, TakeshiMotoyama, YoshihikoSaito, YoshihiroOgawa, YoshihiroMiyamoto, KazuwaNakao
Journal: Circulation (1999)

Background—Coronary spasm plays an important role in the pathogenesis of ischemic heart diseases in general. However, the precise mechanism(s) responsible for coronary spasm remains to be elucidated, and we examined the molecular genetics of coronary spasm. Methods and Results—We searched for the possible mutations in the endothelial nitric oxide synthase (eNOS) gene in patients with coronary spasm. In this study, we demonstrate the existence of 3 linked mutations in the 5′-flanking region of the eNOS gene (T−786→C, A−922→G, and T−1468→A). The incidence of the mutations was significantly greater in patients with coronary spasm than in the control group (P<0.0001). Multiple logistic regression analysis with forward stepwise selection using the environmental risk factors and the eNOS gene variant revealed that the most predictive independent risk factor for coronary spasm was the mutant allele (P<0.0001). As assessed by luciferase reporter gene assays, the T−786→C mutation resulted in a significant reductio...
Abstract 5213: HRH1 inhibition enhances antitumor therapeutic responses through ERK activation in breast cancer
Authors: Patricia Fernandez-Nogueira, Aleix Noguera Castells, Gemma Fuster Orellana, Leire Recalde Percaz, Nuria Moragas Garcia, Anna Lopez Plana, Patricia Jauregui Jimenez, Maria Neus Carbó Carbó, Pedro Gascon Villaplana, Paloma Bragado Domingo, Mario Mancino
Journal: Cancer Research (2018)

Abstract Histamine receptor 1 (HRH1) belongs to the rhodopsin-like G-protein-coupled receptor family. Its activation by histamine, a ubiquitous messenger molecule released mostly from mast cells, has been demonstrated to be involved in cell proliferation, embryonic development, and tumor growth. In particular, high levels of HRH1 have been associated with dual behavior in the regulation of several tumors. Most of the physiological and pathological actions of HRH1 have been shown to depend strictly on its level of expression and the tumor cell type under study. We recently established that HRH1 is upregulated in patients with basal and HER2-enriched breast tumors and that its expression correlates with a worse prognosis. Despite this, the functional role of HRH1 basal and HER2 targeted therapies for resistant breast cancer (BC) progression has not so far been addressed. We assessed HRH1 expression in a wide panel of breast cancer cell lines and found HRH1 overexpressed in basal and HER2-targeted therapy resistant to BC cell lines at the protein and mRNA levels, corroborating data previously published using patient databases. Using terfenadine, a selective chemical inhibitor of HRH1, we showed that inhibition of HRH1 activity in basal BC cells leads to sub-G0 accumulation, suppresses proliferation, promotes cell motility and triggers the activation of ERK signaling, initiating the mitochondrial pathway of caspase cascade activation, inducing apoptosis. Moreover, in vivo experiments showed that terfenadine therapy reduced basal and HER2-targeted therapies for resistant BC cell tumor growth but does not affect luminal and parental tumor growth. In conclusion, our results suggest that targeting HRH1 might be an effective therapeutic treatment in patients with basal and HER2-targeted resistant BC tumors. Citation Format: Patricia Fernandez-Nogueira, Aleix Noguera Castells, Gemma Fuster Orellana, Leire Recalde Percaz, Nuria Moragas Garcia, Anna Lopez Plana, Patricia Jauregui Jimenez, Maria Neus Carbó Carbó, Pedro Gascon Villaplana, Paloma Bragado Domingo, Mario Mancino. HRH1 inhibition enhances antitumor therapeutic responses through ERK activation in breast 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 5213.
Survival and Risk Factors for Death After Cardiac Transplantation in Infants
Authors: CharlesCanter, DavidNaftel, RandallCaldwell, RichardChinnock, ElfriedePahl, ElizabethFrazier, JamesKirklin, MarkBoucek, RobertMorrow
Journal: Circulation (1997)

Background Despite the increasing application of cardiac transplantation in infants, reported survival rates vary, and risk factors for death are poorly understood. Methods and Results To examine early survival and risk factors for death in infants (<1 year of age) undergoing cardiac transplantation, 141 infants (36 <1 month of age) underwent primary cardiac transplantation between January 1, 1993, and January 1, 1995, at 23 centers in the Pediatric Heart Transplant Study (PHTS). Diagnoses were hypoplastic left heart syndrome (66%), other congenital heart disease (17%), cardiomyopathy (14%), and other (3%). Actuarial survival after cardiac transplantation was 84% at 1 month, 70% at 1 year, and 69% at 2 years, with the greatest hazard for death within the first 3 months. The principal cause of death was early graft failure in 20 patients (52% of deaths), infection in 10 (26% of deaths), and rejection in 4 (10%). On the basis of multivariate analysis, risk factors for early mortality were history of previou...
Astronaut Cardiovascular Health and Risk Modification (Astro-CHARM) Coronary Calcium Atherosclerotic Cardiovascular Disease Risk Calculator
Authors: Amit Khera, Matthew J. Budoff, Christopher J. O’Donnell, Colby A. Ayers, James Locke, James A. de Lemos, Joseph M. Massaro, Robyn L. McClelland, Allen Taylor, Benjamin D. Levine
Journal: Circulation (2018)

Background: Coronary artery calcium (CAC) is a powerful novel risk indicator for atherosclerotic cardiovascular disease (ASCVD). Currently, there is no available ASCVD risk prediction tool that integrates traditional risk factors and CAC. Methods: To develop a CAC ASCVD risk tool for younger individuals in the general population, subjects aged 40 to 65 without prior cardiovascular disease from 3 population-based cohorts were included. Cox proportional hazards models were developed incorporating age, sex, systolic blood pressure, total and high-density lipoprotein cholesterol, smoking, diabetes mellitus, hypertension treatment, family history of myocardial infarction, high-sensitivity C-reactive protein, and CAC scores (Astro-CHARM model [Astronaut Cardiovascular Health and Risk Modification]) as dependent variables and ASCVD (nonfatal/fatal myocardial infarction or stroke) as the outcome. Model performance was assessed internally, and validated externally in a fourth cohort. Results: The derivation study comprised 7382 individuals with a mean age 51 years, 45% women, and 55% nonwhite. The median CAC was 0 (25th, 75th [0,9]), and 304 ASCVD events occurred in a median 10.9 years of follow-up. The c-statistic was 0.784 for the risk factor model, and 0.817 for Astro-CHARM ( P &lt;0.0001). In comparison with the risk factor model, the Astro-CHARM model resulted in integrated discrimination improvement (0.0252), and net reclassification improvement (0.121; P &lt;0.0001), as well. The Astro-CHARM model demonstrated good discrimination (c=0.78) and calibration (Nam-D’Agostino χ 2 , 13.2; P =0.16) in the validation cohort (n=2057; 55 events). A mobile application and web-based tool were developed to facilitate clinical application of this tool ( www.AstroCHARM.org ). Conclusion: The Astro-CHARM tool is the first integrated ASCVD risk calculator to incorporate risk factors, including high-sensitivity C-reactive protein and family history, and CAC data. It improves risk prediction in comparison with traditional risk factor equations and could be useful in risk-based decision making for cardiovascular disease prevention in the middle-aged general population.
Abstract 17504: Time-dependent Association of Circulating microRNAs With Death and Myocardial Infarction After Non-ST Elevation Acute Coronary Syndrome
Authors: Mark Y Chan, Megan L Neely, Lydia Kwee, Keith A Fox, Elizabeth Burns, Simon Gregory, Paul Armstrong, E. Magnus Ohman, Harvey White, Matthew T Roe, Svati Shah
Journal: Circulation (2016)

Background: Clinical risk scores for risk stratification of non-ST elevation acute coronary syndrome (NSTE-ACS) accurately predict death but not myocardial infarction (MI) events. Circulating micro...
Abstract 19554: N-myc Downstream Regulated Gene-1 Regulates Endothelial Inflammation and Thrombotic Function
Authors: Guan-Xin Zhang, Qing Qin, Zhi-Fu Guo, Bing Yi, Litian Yin, Yongqiang Yin, Jihui Chen, Fang Cheng, Yang Wang, Lin Han, Shengdong Huang, Zhiyun Xu, Jianxin Sun
Journal: Circulation (2016)

Introduction: N-myc downstream-regulated gene 1 (NDRG-1) is a member of NDRG family that plays essential roles in cell differentiation, proliferation, and stress responses. The expression of NDRG1 ...
Locum oncologist is struck off over death of patient in India
Authors: Clare Dyer
Journal: BMJ (2018)

A locum consultant oncologist working in the UK has been struck off the UK medical register over a patient’s death that occurred four years ago in India.

A medical practitioners’ tribunal concluded that Pantula Sastry had knowingly given high dose BEAM chemotherapy followed by autologous stem cell transplantation to a patient with lymphoma whose test results suggested she would not survive it when he was working at Kokilaben Dhirubhai Ambani Hospital, Mumbai.

The therapy destroys bone marrow, and patient survival depends on bone marrow regenerating from stem cells that are harvested from the patient before treatment and infused afterwards. The patient needs time between treatments …
Abstract 3391: Comparison of gene copy number variations (CNV) in primary and metastatic lung cancers
Authors: Yunfei Shi, Naiquan Mao, Xiao Ding, Jianji Guo, Gang Guo, Zheng Chen, Weiguang Gu, Lei Dai, Shiwang Wen, Hui Jia, Ziqiang Tian, Junping Shi, Taiyan Guo, Jicheng Yao, Fei Pang, Gungwei Chirn, Ming Yao
Journal: Cancer Research (2018)

Abstract Background: Characterization of genomic alterations that drive patient disease development is critical in cancer management. The genomic alteration and population characteristics between the primary tumors and metastases in patients with non-small cell lung cancer (NSCLC) is still unclear. Here we evaluated the frequency and distribution of all classes of genomic alterations in both primary and metastatic NSCLC by comprehensive genomic profiling approach. Methods: FFPE tumor and matched blood samples of 1135 Chinese NSCLC patients (female:male is 670: 465), including 954 primary tumors and 181 metastases, were collected for next-generation sequencing (NGS) based panel assay. Gene copy number variations (CNV) including gene amplifications and deletions, short variants, and gene fusions were assessed. Results: On average, 0.65 gene copy number variations were detected in the 181 metastatic lesions, which is higher than 0.43 CNVs per sample in the primary lesions (p value is 0.003). No significant difference was found in short variants (2.48 vs 2.31), fusions (0.27 vs 0.20) and germline mutations (0.26 vs 0.31) between the primary and metastatic NSCLC. In the top-ranked genes with copy number alterations, EGFR amplifications were detected in 11% of the primary and 15% in metastases. MET amplifications, CDKN2A/B deletions, and PMS2 deletions were more frequently found in metastatic lesions: MET (7.7% vs 1.7%, p=0.0001), CDKN2A (5.5% vs 1.5%, p=0.002), CDKN2B (5.0% vs 1.9%, p=0.0007), and PMS2 (3.9% vs 1.2%, p=0.016). Conclusions: Copy number variations are common driver mutations in NSCLC. We reported here that the prevalence of copy number variations between primary and metastatic lung cancers was different, including driver genes MET, CDKN2A/B, and PMS2. No difference was observed in terms of frequency on short variants or gene fusions in NSCLC. Citation Format: Yunfei Shi, Naiquan Mao, Xiao Ding, Jianji Guo, Gang Guo, Zheng Chen, Weiguang Gu, Lei Dai, Shiwang Wen, Hui Jia, Ziqiang Tian, Junping Shi, Taiyan Guo, Jicheng Yao, Fei Pang, Gungwei Chirn, Ming Yao. Comparison of gene copy number variations (CNV) in primary and metastatic lung cancers [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 3391.
Abstract 1923: Identification and validation of Integrin-Linked Kinase (ILK) signaling as a therapeutic target for ovarian cancer
Authors: Michael A. Ulm, Suriyan Ponnusamy, Adam C. ElNaggar, Ramesh Narayanan
Journal: Cancer Research (2018)

Abstract Ovarian cancer affects approximately 25,000 women and contributes to around 14,000 deaths in the United States each year. Although significant advances have been made in the discovery of molecular diagnostics and therapeutics for other cancers, ovarian cancer still lacks reliable diagnostic and prognostic markers as well as appropriate targeted therapeutics. A major reason for the lagging development of targeted therapeutics is the molecular heterogeneity of high grade serous ovarian cancer and the lack of better understanding of driver mutations and pathogenesis. Although gene expression data sets are available, most of them lack appropriate pair-matched controls to define the alterations that result in the transformation of normal ovarian cells to highly proliferative cancerous cells. We compared differential gene expression of high-grade treatment-naïve ovarian cancer tissue samples to matched-pair adjacent benign ovarian tissue specimens from 24 patients. A significant upregulation of the integrin-linked kinase (ILK) pathway was identified in 22 of the 24 cancer specimens, identifying a potential player that could contribute to the transformation of normal ovarian cells to cancerous cells. To determine the therapeutic potential of ILK inhibition, ILK expression was reduced using siRNA in SKOV3 cells, which resulted in decreased cell proliferation. This is consistent with prior studies demonstrating reduced adhesion to and invasion of collagen gels and organotypic meso-mimetic ovarian cancer cultures with down-regulating ILK using siRNA resulted in. We then assessed the ability of a targeted agent, compound 22, a small molecule ILK-selective inhibitor, to inhibit proliferation in various ovarian cancer cell lines with different phenotypic characteristics (SKOV3, OVCAR3, OVCAR8, OV90). Compound 22 reduced the phosphorylation of Akt, a downstream target of ILK, and also inhibited cellular proliferation. Our initial findings validate ILK as a potential therapeutic target for molecular inhibition in ovarian cancer and warrants further investigation. Citation Format: Michael A. Ulm, Suriyan Ponnusamy, Adam C. ElNaggar, Ramesh Narayanan. Identification and validation of Integrin-Linked Kinase (ILK) signaling as a therapeutic target for ovarian 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 1923.
Abstract 2130: Novel ADAM9 variant induces prostate cancer metastasis
Authors: Chia-Ling Hsieh, Shian-Ying Sung
Journal: Cancer Research (2018)

Abstract Prostate cancer often progresses from an androgen to castration-refractory prostate cancer and metastasizes to the bone and lymph nodes. However, there is no biomarker to predict the initiation of cancer metastasis. Therefore, it is an unmet need to understand molecules which induce metastasis to replace the prediction by PSA. Previous studies by us demonstrate the elevation of ADAM9 in PCa malignant progression. However, the role of ADAM9 in the tumor microenvironment is still not fully understood. Using laser capture microdissection of prostate tumor and stromal cells, indicating the increased of ADAM9 and reactive oxygen species in tumor-associated stromal cells. These inductions correlated with the increased expression of SOD-2 in tumor-associated stromal cells. Both electron microscope analysis and conditioned medium of stromal cells demonstrated the increased of soluble ADAM9 level in the medium. ELISA analysis of patient serum confirmed the increased of ADAM9 serum levels in prostate cancer patients. PCR and sequencing analysis confirmed a novel soluble ADAM9 (sADAM9v2) with deletion of membrane domain that induces cell migration through the activation of FAK and AKT phosphorylation. Our studies demonstrated the release of sADAM9 in tumor microenvironment correlated with reactive oxygen stress and regulate prostate cancer migration and metastasis. In conclusion, our studies showed that sADAM9 release by cancer-associated stromal cells could be a potential biomarker for prostate cancer progression. Citation Format: Chia-Ling Hsieh, Shian-Ying Sung. Novel ADAM9 variant induces prostate cancer metastasis [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 2130.
Sedentary Behaviors in Today’s Youth: Approaches to the Prevention and Management of Childhood Obesity: A Scientific Statement From the American Heart Association
Authors: Tracie A. Barnett, Aaron S. Kelly, Deborah Rohm Young, Cynthia K. Perry, Charlotte A. Pratt, Nicholas M. Edwards, Goutham Rao, Miriam B. Vos
Journal: Circulation (2018)

This scientific statement is about sedentary behavior and its relationship to obesity and other cardiometabolic outcomes in youth. A deleterious effect of sedentary behavior on cardiometabolic health is most notable for screen-based behaviors and adiposity; however, this relation is less apparent for other cardiometabolic outcomes or when sedentary time is measured with objective movement counters or position monitors. Increasing trends of screen time are concerning; the portability of screen-based devices and abundant access to unlimited programming and online content may be leading to new patterns of consumption that are exposing youth to multiple pathways harmful to cardiometabolic health. This American Heart Association scientific statement provides an updated perspective on sedentary behaviors specific to modern youth and their impact on cardiometabolic health and obesity. As we reflect on implications for practice, research, and policy, what emerges is the importance of understanding the context in which sedentary behaviors occur. There is also a need to capture the nature of sedentary behavior more accurately, both quantitatively and qualitatively, especially with respect to recreational screen-based devices. Further evidence is required to better inform public health interventions and to establish detailed quantitative guidelines on specific sedentary behaviors in youth. In the meantime, we suggest that televisions and other recreational screen-based devices be removed from bedrooms and absent during meal times. Daily device-free social interactions and outdoor play should be encouraged. In addition, parents/guardians should be supported to devise and enforce appropriate screen time regulations and to model healthy screen-based behaviors.