tbuckley/cabot-search huggingface dataset:
Abstract 13677: Left Atrial Structure and Function in Relation to Incident Stroke/TIA and Dementia: The Multi-ethnic Study of Atherosclerosis
Authors: Mohammadali Habibi, Mytra Zareian, Bharath Ambale Venkatesh, Sanaz Samiei, Elzbieta Chamera, Kevin Rezzadeh, Colin Wu, Lenore J Launer, Ana Diez Roux, Steven Shea, Susan R Heckbert, David A Bluemke, Joao A Lima
Journal: Circulation (2015)

Introduction: Increased left atrial (LA) size and reduced LA function are known predictors of atrial fibrillation (AF). Evidence also links increased LA size and stroke. We sought to examine the association of LA function, measured with cardiac magnetic resonance imaging (CMR) and incident stroke/TIA and dementia. Methods: This case-cohort study compared LA size and function in 180 MESA participants with incident Stroke/TIA and 95 with incident dementia, over a median follow up of 10.7 years, to 550 participants randomly selected from the whole MESA cohort. All individuals were free of clinical cardiovascular and major valvular heart disease. Phasic LA volumes, LA emptying fractions (LAEF) and peak strain were quantified in sinus rhythm using tissue-tracking CMR. Vascular neurologists adjudicated stroke events by medical record review. Dementia cases were identified using ICD9 codes from hospital records. Modified Cox proportional hazard models weighted for the stratified case-cohort sampling design was used to examine the associations. Results: Incident Stroke/TIA (age 67 ± 9 years, 45% male) and dementia cases (age 74 ± 6 years, 58% male) were older than the subcohort population (age: 61 ± 10, 49% male). In multivariable analysis adjusted for standard cardiovascular risk factors and left ventricular ejection fraction, lower peak LA strain and passive LAEF were associated with both incident stroke/TIA and dementia. After further adjustment for incident AF, the associations were attenuated for peak LA strain but remained significant for passive LAEF (HR for incident Stroke/TIA: 0.72 per SD 95% CI: 0.55-0.93, p=0.013 and for incident dementia: 0.59 per SD 95% CI: 0.37-0.95, p=0.031). Conclusions: Reduced LA conduit function was associated with incident Stroke/TIA and dementia independent of other cardiovascular risk factors and incident AF. Assessment of LA function may add further information in risk stratifying individuals at risk for stroke and dementia.
Abstract IA07: Cancer drug target identification using domain-focused CRISPR screening
Authors: Christopher Vakoc
Journal: Clinical Cancer Research (2018)

Abstract In my presentation, I will describe an experimental strategy to reveal actionable protein domains that sustain the growth of cancer cells, which relies on CRISPR-Cas9-based indel mutagenesis of exons encoding protein domains. Citation Format: Christopher Vakoc. Cancer drug target identification using domain-focused CRISPR screening [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(2_Suppl):Abstract nr IA07.
Abstract 4849: Targeting the lethal pediatric atypical teratoid/rhabdoid tumors with the DNA minor-groove binding agent quinacrine
Authors: Harpreet Kaur, Huizi Guo, Charles G. Eberhart, Eric H. Raabe
Journal: Cancer Research (2018)

Abstract Atypical teratoid/rhabdoid tumors (AT/RT) are rare, incurable, and highly proliferative pediatric brain tumors. Discovering new targets and developing novel therapeutics are urgently needed for this devastating tumor. We have previously shown that AT/RT tumors and cell lines express increased amounts of the epigenetic modifier high mobility group AT-hook 2 (HMGA2). HMGA2 is a DNA-binding oncoprotein that regulates transcription during normal embryogenesis and in cancer stem cells. Targeting HMGA2 using short hairpins significantly decreased AT/RT cell growth and increased survival of xenografted mice in our studies. We hypothesized that pharmacological inhibition of HMGA proteins using DNA minor-groove binding drugs will decrease growth of AT/RT cell lines due to displacement of HMGA proteins from the DNA. We used the minor-groove binding agent quinacrine to test our hypothesis in 3 different AT/RT cell lines (BT37, CHLA-06 and CHLA-04). Quinacrine has been used in millions of humans to treat malaria and other parasitic infections and has a well known safety profile. Quinacrine penetrates the brain, and we can achieve micromolar levels of quinacrine in brain after oral administration. Quinacrine causes a dose-dependent reduction in AT/RT cell growth (MTS assay) and proliferation (BrdU incorporation) compared to vehicle-treated cells (P&amp;lt;0.05). Additionally, treatment of AT/RT cells with quinacrine significantly increased apoptotic cell death (increased cleaved caspase-3 and cleaved PARP expression) in a dose-dependent manner compared to vehicle-treated cells (P&amp;lt;0.05). Our results suggest that minor groove binding drugs like quinacrine are a viable potential treatment strategy for AT/RT. Future studies are aimed at testing the in vivo efficacy and validating the mechanism of action of quinacrine in AT/RT. Citation Format: Harpreet Kaur, Huizi Guo, Charles G. Eberhart, Eric H. Raabe. Targeting the lethal pediatric atypical teratoid/rhabdoid tumors with the DNA minor-groove binding agent quinacrine [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 4849.
Abstract 3933: Circadian timing regimen for alpelisib (NVP-BYL719), a selective inhibitor of the class Ia PI3K isoform alpha to maximize therapeutic index
Authors: Christian R. Schnell, Thomas Ferrat, Daniel Wyss, Walter Tinetto, Sonja Tobler, Christine Fritsch, Michael Jensen
Journal: Cancer Research (2018)

Abstract The gene encoding for the catalytic subunit of the phosphatidylinositol-3-kinase (PI3K), p110a (PIK3CA) is the most frequently mutated kinase in cancer. This discovery triggered the development of small molecule anti-PI3K inhibitors, such as NVP-BYL719. However, the PI3K / Akt signaling pathway plays not only an important role in promoting cell growth, proliferation and survival but also in regulating glucose homeostasis by directly mediating insulin-stimulated glucose uptake into insulin sensitive tissues (adipocytes and muscles). NVP-BYL719 (a selective inhibitor of the class Ia PI3K isoform alpha) given in the morning is facing on-target tolerability challenge (hyperglycemia) in clinical trials limiting the dose being administered to patient (1). As glucose metabolism is highly impacted by circadian rhythms in patients and rodents, we have decided to adopt an integrative circadian-timing approach in our pre-clinical models to interrogate the benefit of morning vs evening dosing for BYL719. By using a newly developed radio-telemetry technology (2), we were able to record in real time and 'around-the-clock' blood glucose levels in stress-free, freely moving rats dosed with NVP-BYL719 at different regimens. The dynamic profile of hyperglycemia observed after active or inactive period dosing of NVP-BYL719 (50 mg/kg qd p.o.) were similar. Dosing before the inactive phase (10 a.m.) allowed blood glucose to normalize in between 2 doses, which could not be achieved when dosing before the active phase (5 p.m.). After treatment discontinuation a significant hyperglycemia remained for a period up to 12h in the group dosed before the active phase (5 p.m.). Circadian “evening” NVP-BYL719 dosing is associated with a better control of glycaemia. Clinically this could potentially translate to better compliance and longer time on treatment hence better efficacy for patient. Based on these findings we could recommend optimized treatment schedules for future combination experiments in the clinic with NVP-BYL719. 1) Juric et al, “Phase I study of the PI3Kα Inhibitor BYL719, as a Single Agent in Patients with Advanced Solid Tumors (AST)”, Annals of Oncology (2014), 25 (Supp. 4) 2) Brockway et al, “Fully Implantable Arterial Blood Glucose Device for Metabolic Research Applications in Rats for Two Months”, J Diabetes Sci Technol (2015), 9(4):771-81 Citation Format: Christian R. Schnell, Thomas Ferrat, Daniel Wyss, Walter Tinetto, Sonja Tobler, Christine Fritsch, Michael Jensen. Circadian timing regimen for alpelisib (NVP-BYL719), a selective inhibitor of the class Ia PI3K isoform alpha to maximize therapeutic index [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 3933.
N-Terminal–Pro-Brain Natriuretic Peptide Predicts Outcome After Hospital Discharge in Heart Failure Patients
Authors: PauloBettencourt, AnaAzevedo, JoanaPimenta, FernandoFriões, SusanaFerreira, AntónioFerreira
Journal: Circulation (2004)

Background— Heart failure (HF) is responsible for a huge burden in hospital care. Our goal was to evaluate the value of N-terminal–pro-brain natriuretic peptide (NT-proBNP) in predicting death or hospital readmission after discharge of HF patients. Methods and Results— We included 182 patients consecutively admitted to hospital because of decompensated HF. Patients were followed up for 6 months. The primary end point was death or readmission. Twenty-six patients died in hospital. The median admission NT-proBNP level was 6778.5 pg/mL, and the median level at discharge was 4137.0 pg/mL (P<0.001). Patients were classified into 3 groups: (1) decreasing NT-proBNP levels by at least 30% (n=82), (2) no significant modifications on NT-proBNP levels (n=49), and (3) increasing NT-proBNP levels by at least 30% (n=25). The primary end point was observed in 42.9% patients. Variables associated with an increased hazard of death and/or hospital readmission in univariate analysis were length of hospitalization, heart rat...
Abstract P118: County-Level Disparities in the Availability of Farmers Markets in the United States: An Ecological Study
Authors: ChelseaSingleton, OliviaAffuso, BisakhaSen
Journal: Circulation (2014)

Introduction: Farmers markets (FM) have been hypothesized to be a potential community-level obesity prevention strategy for populations at risk for chronic diseases because they provide a mechanism for communities to purchase healthy locally grown produce. This study aimed to identify county-level factors associated with FM availability in an effort to determine if disparities in availability exist in the US. Hypothesis: Increased FM availability will be associated with higher median household income, lower % minority residents, lower % obese residents and a higher number of grocery stores and recreation centers per 100,000 residents. Methods: An ecological study was conducted using 2009 data from the USDA Food Environment Atlas on 3,135 US counties. Crude and multivariable adjusted logistic regression models where used to determine associations between having at least one FM available and county-level variables such as % African American (AA) residents, % Hispanic residents, median household income, % WI...
Letter by Settergren et al Regarding Article, “Evidence for Statin Pleiotropy in Humans: Differential Effects of Statins and Ezetimibe on Rho-Associated Coiled-Coil Containing Protein Kinase Activity, Endothelial Function, and Inflammation”
Authors: MagnusSettergren, LarsRydén, JohnPernow
Journal: Circulation (2009)
Abstract 1074: Expression of p39 and Rb in lung cancer and its correlation with clinicopathologic parameters
Authors: Jaileene Perez-Morales, Stephanie Rivera, Bryan Torres, Xavier Rodriguez, Angel Isidro, Pedro Santiago-Cardona
Journal: Cancer Research (2018)

Abstract Lung cancer is characterized by its aggressiveness and proclivity for early metastasis. A predictor of metastasis of NSCLC rely on post-resection evaluation of tumor histology, which is a severe limitation since only 15% of the patients are diagnosed with resectable disease. Hence, there is a need to characterize biomarkers with metastasis-predicting value in pre-resection small biopsy specimens. Rb is a tumor suppressor inactivated due to hyper-phosphorylation in NSCLC. Our preliminary data relates the Rb S249 phosphorylation to an epithelial-to-mesenchymal transition (EMT), a trait strongly associated to metastasis and increase in CDK5 activator p39. Here, we examined the prognostic significance of Rb S249 and p39 as biomarkers of metastasis staging in non-small cell lung cancer. Our hypothesis is that Rb hyper-phosphorylation in S249 can have prognostic value by being associated with a metastatic phenotype and EMT. To determine p39 and Rb phosphorylation in lung cancer, immunohistochemistry analysis was performed on two lung cancer microarrays. Three pathologists observed the microarrays and scored them using the all-red scoring system. P39 and Rb phosphorylation in S249 were more present in lung tumors than adjacent normal tissue. P39 positive expression had a positive correlation with staging, lymph node involvement, and metastasis. Rb phosphorylation in residue S249 had a positive correlation with histological grading. Using general linear model, we determined that staging can be predicted when combining phosphorylation of Rb S249 and p39. Our analysis suggests that p39 and Rb S249 are likely to be diagnostic biomarkers for lung cancer metastasis. Citation Format: Jaileene Perez-Morales, Stephanie Rivera, Bryan Torres, Xavier Rodriguez, Angel Isidro, Pedro Santiago-Cardona. Expression of p39 and Rb in lung cancer and its correlation with clinicopathologic parameters [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 1074.
Abstract 2228: Differential expression of MT-ATPase and COXIV genes in colorectal adenopolyps
Authors: Lashanale Wallace, Anju Cherian, Felix Aikhionbare
Journal: Cancer Research (2018)

Abstract Therapeutic decisions in colorectal cancer (CRC) will be enhanced if guided by more accurate prognostic and predictive biomarkers during the progression of adenomas to CRC. Given that most CRCs develop from adenopolyps via the adenoma-carcinoma sequence, a mechanism for the inhibition of this sequence in patients with a high risk of developing CRC is a pressing need. Variants in mitochondrial (mt) protein expressions have been correlated with several clinico-pathological features of cancers as the majority of energy for tumor transformation are of mitochondrial origin. Differences in mitochondrial efficiency may be reflected as in adenoma-carcinoma sequence. Reports have shown that cytochrome c oxidase (COX) is a key player in oxidative phosphorylation and reactive oxygen species (ROS) formation. In addition ATPase subunits are also associated with ROS formation and mtDNA maintenance. Here, we specifically searched for differentially expressed ATPase and COX subunits in early adenomas of CRC tissues as compared to late stages of CRC tissues. In addition mitochondria variants were analyzed in mitochondrial encoded subunits of complexes IV and V of the electron transport chain. Direct sequencing, high resolution restriction digestion, RT-qPCR and western blot techniques were used to assess differences in colorectal tumors. Tissue samples used included early adenomas classified as tubular adenoma (TA), tubulovillous adenoma (TV), and villous adenomas (v); cancer tissues, and normal surrounding tissues. Results suggest that most variants of complex IV were found in mitochondrial encoded cytochrome c oxidase subunit III (9207-9990). Of these variants 9414delC found in 60% TA and 20% CA samples was predicted to be disease causing. Furthermore, ATPase6 variant G9055A found abundantly in TA and V samples was confirmed using high resolution restriction digestion. Expression levels of ATPase6 progressively increased from early adenomas to late stage adenomas and cytochrome c oxidase mitochondrial subunits also varied within the adenoma carcinoma sequence. Interestingly, COX subunit 4 isoform 1 protein expression decreased by five-fold in cancer samples when compared to normal tissue and by three-fold when compared to TA. Therefore, this study suggest an important role of ATPase and COX IV-1 in tumor CRC progression in respect to the impact on mitochondrial ROS production and oxidative phosphorylation regulation. Citation Format: Lashanale Wallace, Anju Cherian, Felix Aikhionbare. Differential expression of MT-ATPase and COXIV genes in colorectal adenopolyps [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 2228.
2-Pyridone-functionalized Aza-BODIPY photosensitizer for imaging-guided sustainable phototherapy
Authors: Wanyue Xiao, Peng Wang, Changjin Ou, Xiaoyu Huang, Yunyun Tang, Meiyan Wu, Weili Si, Jinjun Shao, Wei Huang, Xiaochen Dong
Journal: Biomaterials (2018)
N9741: Survival update and prognostic factor analysis of oxaliplatin (Ox) and irinotecan (Iri) combinations for metastatic colorectal cancer (MCRC)
Authors: H. K. Sanoff, D. J. Sargent, M. E. Campbell, R. F. Morton, C. S. Fuchs, R. K. Ramanathan, S. K. Williamson, B. P. Findlay, H. C. Pitot, R. M. Goldberg
Journal: Journal of Clinical Oncology (2007)

4067 Background: N9741 randomized 1691 patients (pts) to seven 5FU, Ox and Iri containing regimens for MCRC. After 20.4 months median follow-up, FOLFOX and IROX improved time to progression (TTP) and overall survival (OS) compared to IFL. Here we update OS and TTP, and report an analysis of factors prognostic of pt outcome. Methods: 5 yr OS and TTP were calculated by Kaplan-Meier per treatment (rx) arm. Pt factors [rx arm, age, gender, prior adjuvant rx, body mass index (BMI), performance status (PS), number of disease sites (#sites), neutrophil count (ANC), hemoglobin, platelets, bilirubin, alkaline phosphatase (ALK), aspartate aminotransferase (AST)] were assessed for univariate association with OS, TTP, response rate (RR), and any grade =3 toxicity. Associated factors were included in multivariate Cox and logistic regression models. Results: After a median follow-up of 4.3 yrs, FOLFOX treated pts were more likely to live 5 yrs, 9.2% versus 5.4% for IROX (p=.016) and 3.8% for IFL (p&lt;.001). Median TTP was also significantly longer in the FOLFOX arm, 9.2 mo vs 6.5 mo for IROX (p=&lt;.001) and 6.0 mo for IFL (p=&lt;.001). The prognostic model found higher PS, ANC and ALK, and more disease sites were prognostic of worse OS (see table ). Age = 70 was associated with poorer survival (HR death 1.33, p=.03), but not TTP, RR, or grade =3 toxicity. FOLFOX rx was the most powerful prognostic factor for TTP and OS. The odds of grade =3 toxicity were significantly higher in FOLFOX treated pts (OR 1.65, p&lt;.001) and lower in men (OR .63, p&lt;.001). No significant interactions between rx arm and pt factors were present, suggesting no factor examined is predictive of rx-specific outcome. Conclusions: 9% 5 yr OS in MCRC pts treated with first-line FOLFOX sets a new benchmark. We confirmed pre-rx PS, WBC, and ALK are prognostic for OS, though FOLFOX rx was the strongest prognostic factor. No factor was associated with differential outcome or toxicity by rx arm, thus these factors cannot be used to guide rx selection. [Table: see text] [Table: see text]
Abstract 3011: Determinants and prognostic value of quality of life in patients with pancreatic ductal adenocarcinoma
Authors: Yang Deng, Huakang Tu, Jeanne A. Pierzynski, Ethan Miller, Maosheng Huang, Xiangjun Gu, David W. Chang, Yuanqing Ye, Michelle A. Hildebrandt, Alison P. Klein, Scott M. Lippman, Xifeng Wu
Journal: Cancer Research (2018)

Abstract Background Quality of life (QOL) is impaired in pancreatic cancer patients. Our aim was to investigate the determinants and prognostic value of QOL after diagnosis in a hospital-based cohort of racially/ethnically diverse patients with pancreatic ductal adenocarcinoma (PDAC). Patients and methods QOL was prospectively assessed using the Short Form-12 version 1 in 2478 PDAC patients. The Physical Component Summary (PCS) and Mental Component Summary (MCS) were categorized into tertiles based on their distribution. Ordered logistic regression was adopted to compare the risk of having lower PCS and MCS by patient sociodemographic and clinical characteristics. The association of PCS and MCS with mortality was assessed by Cox regression. Results Compared with non-Hispanic whites, Hispanics were at significantly higher risk of having lower PCS (odds ratio [95%CI], 1.69 [1.26-2.26]; P &amp;lt; .001) and lower MCS (1.66 [1.24-2.23]; P &amp;lt; .001). Patients diagnosed with stage III (1.80 [1.10-2.94]; P = .02) and stage IV (2.32 [1.50-3.59]; P &amp;lt; .001) were more likely to have lower PCS than were patients diagnosed with stage I. Other determinants included sex, age, drinking, smoking, education level, and comorbidities. The low tertile of PCS (hazard ratio [95%CI], 1.94 [1.72-2.18]; P &amp;lt; .001) and MCS (1.42 [1.26-1.59]; P &amp;lt; .001) were each related to poor prognosis. Similar results were found for non-Hispanic Whites as compared to African Americans/Hispanics/others. Conclusion QOL after diagnosis is a significant prognostic indicator for patients with PDAC, and multiple factors determine QOL, suggesting possible means of intervention to improve QOL and outcomes of PDAC patients. Citation Format: Yang Deng, Huakang Tu, Jeanne A. Pierzynski, Ethan Miller, Maosheng Huang, Xiangjun Gu, David W. Chang, Yuanqing Ye, Michelle A. Hildebrandt, Alison P. Klein, Scott M. Lippman, Xifeng Wu. Determinants and prognostic value of quality of life in patients with pancreatic ductal adenocarcinoma [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 3011.