tbuckley/cabot-search huggingface dataset:
Quality of life with talazoparib versus physician’s choice of chemotherapy in patients with advanced breast cancer and germline BRCA1/2 mutation: patient-reported outcomes from the EMBRACA phase III trial
Authors: J. Ettl, R.G.W. Quek, K.-H. Lee, H.S. Rugo, S. Hurvitz, A. Gonçalves, L. Fehrenbacher, R. Yerushalmi, L.A. Mina, M. Martin, H. Roché, Y.-H. Im, D. Markova, H. Bhattacharyya, A.L. Hannah, W. Eiermann, J.L. Blum, J.K. Litton
Journal: Annals of Oncology (2018)

In the EMBRACA phase III trial, talazoparib (1 mg daily, orally) demonstrated a statistically significant improvement in PFS versus physician's choice of chemotherapy (PCT; capecitabine, eribulin, gemcitabine, or vinorelbine) in patients with HER2-negative advanced breast cancer carrying a germline BRCA1/2 mutation; we evaluated patient-reported outcomes (PROs).Patients were randomized 2 : 1 to receive talazoparib or PCT. PROs were assessed at day 1 (baseline), the start of each treatment cycle (every 3 weeks), and at the end of treatment, using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-30) and its breast cancer module, QLQ-BR23. Prespecified exploratory analyses included a longitudinal mixed-effect model comparing treatment arms and a time to definitive clinically meaningful deterioration (TTD) analysis carried out in the global health status/quality of life (GHS/QoL), and all functional and symptom scales from the EORTC QLQ-C30 and -BR23 questionnaires. Between-arm TTD comparisons were made using a stratified log-rank test and a Cox proportional hazards model.Baseline scores were similar between arms. Statistically significant estimated overall improvement from baseline in GHS/QoL was seen for talazoparib compared with statistically significant deterioration for PCT {3.0 [95% confidence interval (CI) 1.2, 4.8] versus -5.4 [95% CI -8.8, -2.0]; between arms, P < 0.0001}. A statistically significant greater delay was observed in TTD in GHS/QoL, favoring talazoparib over PCT [hazard ratio, 0.38 (95% CI 0.26, 0.55; median, 24.3 versus 6.3 months, respectively; P < 0.0001)]. A statistically significant overall change and a statistically significant delay in TTD, all favoring talazoparib, were also observed in multiple functions and symptoms.Patients who received talazoparib had significant overall improvements and significant delay in TTD in multiple cancer-related and breast cancer-specific symptoms, functions, and GHS/QoL.NCT01945775.
Sustained Increase in Aortic Endothelial Nitric Oxide Synthase Expression In Vivo in a Model of Chronic High Blood Flow
Authors: SophieNadaud, MoniquePhilippe, Jean-FrancoisArnal, Jean-BaptisteMichel, FlorentSoubrier
Journal: Circulation Research (1996)

Physiological adaptation of normal blood vessels to acute or chronic changes in blood flow is endothelium dependent. In vitro studies have shown that, among other genes, NO synthase (NOS) 3 mRNA and protein expression is enhanced by acute elevation of shear stress in endothelial cells. We have investigated the effect of chronic high blood flow on NOS3 mRNA and protein expression in rat aorta. NOS3 mRNA levels were measured by quantitative polymerase chain reaction (PCR) in the aortas of 12 rats with arteriovenous fistulas and 9 sham-operated control rats. The PCR assay indicated that NOS3 mRNA levels were significantly enhanced (twofold) during high blood flow. Western blots showed that immunoreactive NOS3 levels were also increased to a similar extent. Furthermore, the Ca2+-dependent NOS activity, measured by the l-arginine to l-citrulline conversion assay, and the cGMP content were also significantly increased in the proximal aortic wall submitted to the arteriovenous shunt. These results indicate that ...
Meeting report: a close look at oral biofilms and microbiomes
Authors: Xin Xu, Feng Chen, Zhengwei Huang, Lvyan Ma, Li Chen, Yaping Pan, Jian Xu, Syngcuk Kim, Denis Kinane, Hyun Koo, Xuedong Zhou
Journal: International Journal of Oral Science (2018)

Abstract The “Biofilms, Microbiomes and Oral Diseases: Challenges and Future Perspectives” symposium jointly organized by Penn Dental Medicine and West China School of Stomatology was held on 30 September 2017 at Penn Wharton China Center (PWCC) in Beijing, China. The topics included the pathogenicity of oral biofilms, novel strategies for the control of biofilm-related diseases, oral microbiome and single-cell approaches, and the link between oral diseases and overall health. Researchers from a number of disciplines, representing institutions from China and Penn Dental Medicine, gathered to discuss advances in our understanding of biofilms, as well as future directions for the control of biofilm-related oral and systemic diseases.
Abstract 3412: Androgen receptor binding sites are highly mutated in prostate cancer
Authors: Tunc Morova, Mehmet Gonen, Attila Gursoy, Ozlem Keskin, Nathan A. Lack
Journal: Cancer Research (2018)

Abstract Androgen receptor (AR) signaling is essential to nearly all prostate cancer cells. Any alterations to AR-mediated transcription can have a profound effect on prostate carcinogenesis and tumor growth. While the AR protein has been extensively studied, little is know about those mutations to non-coding regions where AR binds to DNA. Using whole genome sequencing from 197 primary prostate cancer patients, we demonstrate that AR binding sites have a dramatically increased rate of mutations that is greater than any other transcription factor. This is not due to the specific chromosomal region as increased mutation were only observed in prostate cancer. The rate of mutations correlated with AR occupancy and did not cluster with any histone mark or transcription factor. Suggesting that this may occur with other lineage-specific transcription factors, we observed that estrogen receptor binding sites also had an elevated rate of mutations in breast cancer. Interestingly, the mutations at AR binding sites had a high frequency of TpG-&amp;gt;ApG. These uncommon purine transversions have been shown to occur when abasic sites are incorrectly repaired. Based on the mutations observed at the binding site of AR and other related transcription factors, we propose that AR occupancy impairs access of base excision repair enzymes to endogenous DNA damage. Overall, this work demonstrates that non-coding AR binding sites are frequently mutated in prostate cancer and may potentially act as driver mutations. Citation Format: Tunc Morova, Mehmet Gonen, Attila Gursoy, Ozlem Keskin, Nathan A. Lack. Androgen receptor binding sites are highly mutated in prostate 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 3412.
Evaluation of Myocardial Blood Perfusion in Man with Radioactive Potassium or Rubidium and Precordial Counting
Authors: Luigidonato, Giancarlobartolomei, Robertogiordani
Journal: Circulation (1964)

The myocardial clearance of potassium may be obtained by precordial counting after a single intravenous injection of K42Cl or Rb86Cl. The theoretical foundations of the method and the technic developed have been presented and discussed. The distribution of the values obtained in normal subjects and in subjects with coronary insufficiency is in agreement with the clinical expectancy, and changes of the observed MCK after nitroglycerin agree with the results obtained by other investigators who measured coronary blood flow by the indirect Fick method. In agreement with the observations of other investigators in rats and dogs, the amount of K42 or Rb86 in the myocardium was found to change very little for an appreciable time interval after the first circulation, despite the significant recirculation and the decreasing arterial concentration. This observation and the fact that MCK values in normal subjects closely agree with the accepted values for coronary blood flow confirm Sapirstein's findings in rats and ...
Abstract 2681: Antiproliferative effects of the naturally occurring solamargine and related glycoalkaloids against liver cancer cells
Authors: Mostafa I. Fekry, Shahira M. Ezzat, Maha M. Salama, Ahmed M. Al-Abd
Journal: Cancer Research (2018)

Abstract Hepatocellular carcinoma (HCC) is progressively increasing tumor with lack of accurate prognosis and inadequate systemic treatment approaches. Solanum sp. (such as Solanum melongena) is a folk herb which is reported to possess anticancer properties. In a continuity for our interest in pursuing the anticancer activity of compounds isolated from the fruit peels of Solanum melongena, the HPLC profiling and ESI-MS assessment for the methanolic extract evidenced the presence of bioactive glycoalkaloids (solasonine, solasodine and solamargine). These glycoalkaloids were isolated, purified and proved to possess in vitro cytotoxicity against human liver cancer cell lines (Huh7 and HepG2). Herein, we investigated the potential mechanism of action of these compounds using DNA content flow-cytometry and apoptosis/necrosis differential anaylsis using annexin-V/FITC staining. Solasonine, solasodine and solamargine inducd significant antiproliferative effect against liver cancer cells (Huh7 and HepG2) which was attributed to cell cycle arrest at S-phase. Solamargine, solasodine and solasonine induced significant apoptosis in Huh7 cells. Only solamargine-induced cell cycle arrest, was reflected as apoptotic cell killing effect against HepG2 cells. In conclusion, glycoalkaloids derived from Solanum melongena and particularly, solamargine are promising antiproliferative agents with potential anticancer effects. Citation Format: Mostafa I. Fekry, Shahira M. Ezzat, Maha M. Salama, Ahmed M. Al-Abd. Antiproliferative effects of the naturally occurring solamargine and related glycoalkaloids against liver cancer cells [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 2681.
Translational insights into gastrointestinal stromal tumor and current clinical advances
Authors: M.L. Hemming, M.C. Heinrich, S. Bauer, S. George
Journal: Annals of Oncology (2018)

Gastrointestinal stromal tumor (GIST) is the most common soft tissue sarcoma of the gastrointestinal tract and, in the vast majority of cases, is characterized by activating mutations in KIT or, less commonly, PDGFRA. Mutations in these type III receptor tyrosine kinases (RTKs) account for over 85% of GIST cases, and the majority of KIT primary mutations respond to treatment with the tyrosine kinase inhibitor (TKI) imatinib. However, drug resistance develops over time, most commonly due to secondary kinase mutations. Sunitinib and regorafenib are approved for the treatment of imatinib-resistant GIST in the second and third lines, respectively. However, resistance to these agents also develops and new therapeutic options are needed. In addition, a small number of GISTs harbor primary activating mutations that are resistant to currently available TKIs, highlighting an additional unmet medical need. Several novel and selective TKIs that overcome known mechanisms of resistance in GIST have been developed and show promise in early clinical trials. Additional emerging targeted therapies in GIST include modulation of cellular signaling pathways downstream of KIT, antibodies targeting KIT and PDGFRA and immune checkpoint inhibitors. These advancements highlight the rapid evolution in the understanding of this malignancy and provide perspective on the encouraging horizon of current and forthcoming therapeutic strategies for GIST.
Persistent Supraventricular Tachycardia
Authors: Normanshachnow, Stanleyspellman, Irarubin
Journal: Circulation (1954)

A summary of all reported cases of persistent supraventricular tachycardia, as contrasted with paroxysmal and repetitive tachycardia, is presented, along with an additional well-documented instance covering an 11-year period. The distinctive features of persistent tachycardia are included.
Association of Neighborhood Geographic Spatial Factors With Rates of Childhood Obesity
Authors: Di Fang, Michael R. Thomsen, Rodolfo M. Nayga, Anthony Goudie
Journal: JAMA Network Open (2018)

<h3>Importance</h3> Childhood obesity is a principal public health concern. Understanding the geographic distribution of childhood obesity can inform the design and delivery of interventions. <h3>Objective</h3> To better understand the causes of spatial dependence in rates of childhood obesity across neighborhoods. <h3>Design, Setting, and Participants</h3> This cohort study used data from a legislatively mandated body mass index screening program for public school children in Arkansas from the 2003-2004 through 2014-2015 academic years. Spatial autoregressive moving average (SARMA) models for panel data were used to estimate spatial dependency in childhood obesity at 2 levels of spatial aggregation. Data were analyzed from August 2017 to February 2018. <h3>Exposures</h3> The SARMA models included geographic fixed effects to capture time-invariant differences in neighborhood characteristics along with controls for the mean age of children and the proportion of children by race/ethnicity, school meal status, and sex. <h3>Main Outcomes and Measures</h3> The proportion of obese schoolchildren in Arkansas neighborhoods by year, defined at larger (census tract) and smaller (census block group) spatial scales. <h3>Results</h3> The geographic aggregations were based on 935 800 children with a mean (SD) age of 132 (39) months. Of these children, 51% were male; 65% were white, 21% were black, 10% were Hispanic, 2% were Asian, and the remainder were of other or unidentified race/ethnicity. In models without geographic fixed effects, there was evidence of positive and significant spatial autocorrelation in obesity rates across tracts (ρ = 0.511; 95% CI, 0.469-0.553) and block groups (ρ = 0.569; 95% CI, 0.543-0.595). When geographic fixed effects were included, spatial autocorrelation diminished at the census tract level (ρ = 0.271; 95% CI, 0.147-0.396) and disappeared at the census block group level (ρ = −0.075; 95% CI, −0.264 to 0.114). <h3>Conclusions and Relevance</h3> Because block groups are smaller than tracts, children in neighboring block groups were more likely to attend the same schools and interact through neighborhood play. Thus, geographic-based social networks were more likely to span block group boundaries. The lack of evidence of spatial autocorrelation in block group–level models suggests that social contagion may be less important than differences in neighborhood context across space. Caution should be used in interpreting significant spatial autocorrelation as evidence of social contagion in obesity.
Abstract 18762: Adherence to Appropriate Use Criteria for Transesophageal Echocardiography Use in Suspected Infective Endocarditis
Authors: Christopher M Bianco, Ashley E Burch, Yara L Cameron, Deepinder S Grewal, Singh P Puneet, Samuel F Sears, Rajasekhar Nekkanti
Journal: Circulation (2016)

Introduction: AHA appropriate use criteria (AUC) and valvular heart disease guidelines help direct appropriate utilization of transesophageal echocardiography (TEE) in suspected infective endocarditis (IE). A limitation of previous literature examining TEE AUC adherence was underrepresentation of studies performed in suspected IE. Hypothesis: We hypothesized that TEE was often inappropriately utilized in the evaluation of low pretest probability patients, defined as those without high risk predisposing factors and a low modified duke score following quality TTE. Methods: Clinical information retrieved from the electronic medical record was used to retrospectively analyze 229 consecutive TEE studies performed in the evaluation of suspected IE between 7/1/2013-12/31/2015 at a large academic center. Results: Inappropriate TEE use was determined in 14% of studies. All inappropriate studies failed to show TEE evidence of IE. About two thirds (67%) of inappropriate studies were ordered by three groups - Interna...
Implications of the New American College of Cardiology Guidelines for Hypertension Prevalence in India
Authors: Nikhil Srinivasapura Venkateshmurthy, Pascal Geldsetzer, Lindsay M. Jaacks, Dorairaj Prabhakaran
Journal: JAMA Internal Medicine (2018)

This study analyzes whether the lowered blood pressure threshold for hypertension in the 2017 American College of Cardiology/American Heart Association guidelines vs the JNC7 guidelines are associated with diagnosis prevalence of hypertension among adults in India.
Inhibition of Endogenous Mst1 Prevents Apoptosis and Cardiac Dysfunction Without Affecting Cardiac Hypertrophy After Myocardial Infarction
Authors: MariOdashima, SoichiroUsui, HiromitsuTakagi, ChullHong, JingLiu, MitsuhiroYokota, JunichiSadoshima
Journal: Circulation Research (2007)

Mammalian sterile 20–like kinase-1 (Mst1) plays an important role in mediating cardiac myocyte apoptosis in response to ischemia/reperfusion. Whether or not Mst1 is also involved in the long-term development of heart failure after myocardial infarction (MI) is unknown. We addressed this issue using transgenic mice with cardiac specific overexpression of dominant negative Mst1 (Tg-DN-Mst1). The left coronary artery was permanently ligated, and the size of MI was similar between Tg-DN-Mst1 and nontransgenic controls (NTg). After 4 weeks, Mst1 was significantly activated in the remodeling area in NTg, but not in Tg-DN-Mst1. Although left ventricular (LV) enlargement was significantly attenuated in Tg-DN-Mst1 compared with NTg, neither LV weight/body weight nor myocyte cross sectional area was statistically different between Tg-DN-Mst1 and NTg. LV ejection fraction was significantly greater in Tg-DN-Mst1 than in NTg (53 versus 38%, P<0.01), whereas LV end-diastolic pressure (6 versus 12 mm Hg, P<0.05) and lun...
The Heart and Pulmonary Circulation at High Altitudes
Authors: DantePenaloza, JavierArias-Stella
Journal: Circulation (2007)

More than 140 million people worldwide live >2500 m above sea level. Of them, 80 million live in Asia, and 35 million live in the Andean mountains. This latter region has its major population density living above 3500 m. The primary objective of the present study is to review the physiology, pathology, pathogenesis, and clinical features of the heart and pulmonary circulation in healthy highlanders and patients with chronic mountain sickness. A systematic review of worldwide literature was undertaken, beginning with the pioneering work done in the Andes several decades ago. Original articles were analyzed in most cases and English abstracts or translations of articles written in Chinese were reviewed. Pulmonary hypertension in healthy highlanders is related to a delayed postnatal remodeling of the distal pulmonary arterial branches. The magnitude of pulmonary hypertension increases with the altitude level and the degree of exercise. There is reversal of pulmonary hypertension after prolonged residence at ...
Abstract 2497: Inhibitors of RNA Pol I and an aminoacyl-tRNA synthetase result in MYC and MYCN downregulation in MYC family protein-driven neuroblastoma cells
Authors: Naohiko Ikegaki, Jasmine Zeki, Bill Chiu, Hiroyuki Shimada
Journal: Cancer Research (2018)

Abstract We have previously reported histologic variants among unfavorable histology neuroblastomas (NB), having large cell appearance with vesicular nuclei and or prominent nucleolar (PN) formation, indicating hyperactive rRNA synthesis and protein translation. These features appear to be associated with dismal outcome and high-level MYC family protein expression. PN formation could provide critical prognostic and risk-stratification information for NB. At the same time, this observation could open up an opportunity for innovative therapy for aggressive NB. To assess this possibility, we examined the effect of two potent and specific small-molecule inhibitors of RNA Pol I activity and an aminoacyl tRNA synthetase (CX-5461 and Halofuginone, respectively) on growth and MYC family protein expression in NB cell lines. These small-molecule inhibitors inhibited growth of NB cell lines at low to submicromolar concentrations in vitro in 48 hours. Moreover, the inhibitors destabilized MYC and MYCN proteins in NB cells. Interestingly, halofuginone showed a rapid effect on the stability of MYC family proteins at 500 nM-1 uM (&amp;lt;3 hours). In contrast, CX-5461 at 1 uM was less effective at the 3-hour time. At the concentration of 100 nM-250 nM for halofuginone and 1 uM for CX-5461 for up to 48 hours of the drug treatments, MYC and MYCN expression were both downregulated. We further examined the preclinical efficacy of halofuginone in orthotopic Kelly human NB xenografts in mice using a silk film as the drug delivery device. Halofuginone showed a significant growth-suppressive effect on the xenografts, as indicated by the time periods to reach certain tumor sizes being significantly longer in the halofuginone-treated group than those in the control group. Moreover, histologic examination of the xenografts showed a marked suppression of MYCN protein expression in the halofuginone-treated xenograft at day 17 of the drug treatment. Specific inhibition of hyperactive rRNA synthesis and protein translation was shown to be an effective way to suppress MYC/MYCN protein expression and NB growth. Together, MYC-family protein overexpression and PN formation should be included in new NB risk stratification and considered for potential therapeutic targets. Citation Format: Naohiko Ikegaki, Jasmine Zeki, Bill Chiu, Hiroyuki Shimada. Inhibitors of RNA Pol I and an aminoacyl-tRNA synthetase result in MYC and MYCN downregulation in MYC family protein-driven neuroblastoma cells [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 2497.