tbuckley/cabot-search huggingface dataset:
Abstract 4179: A novel approach for antimetastatic therapies against TNBC utilizing a physiologic suppressor
Authors: Ali Ekrem Yesilkanal, Daniel C. Rabe, Payal Tiwari, Casey Frankenberger, Gary L. Johnson, Marsha Rosner
Journal: Cancer Research (2018)

Abstract Metastatic progression of tumors is the major cause of death in patients with triple-negative breast cancer (TNBC). However, since metastasis is a multistep process, unraveling its complexity is a major challenge. One effective way of tackling this question is to study natural blockers of the metastatic process, metastasis suppressors, and identify the mechanisms by which they regulate metastasis. Raf kinase inhibitory protein (RKIP), a protein that regulates kinase activity, is a suppressor of TNBC metastasis. Although RKIP inhibits the activity of key kinases such as Raf-1, GRK2, NIK/IKK in cultured cells, the kinase targets of RKIP in tumors are not known. To address this question, we used a mass spectrometry approach involving inhibitor-conjugated beads to identify kinases that are downregulated by RKIP in human TNBC xenograft tumors. Our results identified a network of stress kinases targeted by RKIP, including kinases that have not been previously reported as RKIP targets. In order to unravel the effect of this stress network on metastatic gene expression, we investigated genes that correlate with RKIP expression in TCGA breast cancer patient data set. We identified prometastatic genes such as APC and DOCK4 as novel RKIP targets in in vitro and in vivo models of TNBC. We also demonstrated these genes are downstream of the RKIP-stress network. Finally, by using a high-throughput invasion assay, we developed a low-dose multidrug cocktail of small-molecule kinase inhibitors that mimic RKIP's antimetastatic role in TNBCs. Elucidating RKIP function at a systems level reveals the interplay between key metastatic signaling cascades, particularly in relation to cell motility and invasion. Our findings suggest that the low-dose multidrug combination that targets a network of stress kinases is a viable antimetastatic therapy for TNBC patients. Citation Format: Ali Ekrem Yesilkanal, Daniel C. Rabe, Payal Tiwari, Casey Frankenberger, Gary L. Johnson, Marsha Rosner. A novel approach for antimetastatic therapies against TNBC utilizing a physiologic suppressor [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 4179.
Optimizing drug combinations against multiple myeloma using a quadratic phenotypic optimization platform (QPOP)
Authors: Masturah Bte Mohd Abdul Rashid, Tan Boon Toh, Lissa Hooi, Aleidy Silva, Yanzhou Zhang, Pei Fang Tan, Ai Ling Teh, Neerja Karnani, Sudhakar Jha, Chih-Ming Ho, Wee Joo Chng, Dean Ho, Edward Kai-Hua Chow
Journal: Science Translational Medicine (2018)

A drug discovery and optimization platform uncovered effective therapeutic combinations for bortezomib-resistant multiple myeloma.
Abstract 15465: Effect of Sitagliptin on Left Ventricular Function in Patients With Type 2 Diabetes a Sub Analysis of the PROLOGUE Study
Authors: Seno Hiromitsu, Hirotsugu Yamada, Kenya Kusunose, Rie Amano, Munehide Matsushita, Mamoru Nanasato, Toyoaki Murohara, Haruo Kamiya, Masataka Sata, Koichi Node
Journal: Circulation (2016)

Backgrounds: Effect of dipeptidyl peptidase 4 inhibitor on cardiac function has been issue of debate. We evaluated the effect of sitagliptin on echocardiographic systolic and diastolic parameters a...
Abstract 241: Contribution of female breast cancer predisposition SNPs to risk of male breast cancer
Authors: Nick Orr, Michael Jones, Sarah Maguire, Anthony Swerdlow
Journal: Cancer Research (2018)

Abstract Genome-wide association studies have identified more than 170 loci that confer susceptibility to breast cancer. Male breast cancer accounts for approximately 1% off all newly diagnosed cases of breast cancer and several reports have implicated germline genetic factors as significant in the aetiology of the disease. Inherited germline mutations in the BRCA2 gene are thought to account for up to 10% of cases. Here we demonstrate that there are substantial overlaps between polygenic susceptibility to male and female breast cancer and that a subset of shared predisposition loci confer significantly larger risk effects in males than in females. Men in the highest quintile of the distribution of risk allele count have a 2.7-fold (2.17-3.30) increased risk of breast cancer compared to those in the lowest quintile. Furthermore, comparisons of the risk allele distributions in male and female cases suggests that the overall impact of genetic predisposition to breast cancer may be greater in a susceptible minority of males from the general population than in females. Citation Format: Nick Orr, Michael Jones, Sarah Maguire, Anthony Swerdlow. Contribution of female breast cancer predisposition SNPs to risk of male 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 241.
Defining the Human Envirome
Authors: Daniel W. Riggs, Ray A. Yeager, Aruni Bhatnagar
Journal: Circulation Research (2018)

Both genetic and environmental factors contribute to the development of cardiovascular disease, but in comparison with genetics, environmental factors have received less attention. Evaluation of environmental determinants of cardiovascular disease is limited by the lack of comprehensive omics approaches for integrating multiple environmental exposures. Hence, to understand the effects of the environment as a whole (envirome), it is important to delineate specific domains of the environment and to assess how, individually and collectively; these domains affect cardiovascular health. In this review, we present a hierarchical model of the envirome; defined by 3 consecutively nested domains, consisting of natural, social, and personal environments. Extensive evidence suggests that features of the natural environment such as sunlight, altitude, diurnal rhythms, vegetation, and biodiversity affect cardiovascular health. However, the effects of the natural environment are moderated by the social environment comprised of built environments, agricultural and industrial activities, pollutants and contaminants, as well as culture, economic activities, and social networks that affect health by influencing access to healthcare, social cohesion, and socioeconomic status. From resources available within society, individuals create personal environments, characterized by private income, wealth and education, and populated by behavioral and lifestyle choices relating to nutrition, physical activity, sleep, the use of recreational drugs, and smoking. An understanding of the interactions between different domains of the envirome and their integrated effects on cardiovascular health could lead to the development of new prevention strategies and deeper insights into etiologic processes that contribute to cardiovascular disease risk and susceptibility.
Histone Deacetylase 7 Silencing Alters Endothelial Cell Migration, a Key Step in Angiogenesis
Authors: DenisMottet, AkeilaBellahcène, SophiePirotte, DavidWaltregny, ChristopheDeroanne, VirginieLamour, RosetteLidereau, VincentCastronovo
Journal: Circulation Research (2007)

Global inhibition of class I and II histone deacetylases (HDACs) impairs angiogenesis. Herein, we have undertaken the identification of the specific HDAC(s) with activity that is necessary for the development of blood vessels. Using small interfering RNAs, we observed that HDAC7 silencing in endothelial cells altered their morphology, their migration, and their capacity to form capillary tube-like structures in vitro but did not affect cell adhesion, proliferation, or apoptosis. Among several factors known to be involved in angiogenesis, platelet-derived growth factor-B (PDGF-B) and its receptor (PDGFR-β) were the most upregulated genes following HDAC7 silencing. We demonstrated that their increased expression induced by HDAC7 silencing was partially responsible for the inhibition of endothelial cell migration. In addition, we have also shown that treatment of endothelial cells with phorbol 12-myristate 13-acetate resulted in the exportation of HDAC7 out of the nucleus through a protein kinase C/protein k...
Abstract 4600: Biomarker analysis in circulating cell-free DNA in patients treated with sorafenib for advanced hepatocellular carcinoma
Authors: Sook Ryun Park, Chung Ryul Oh, Sun-Young Kong, Min Kyeong Kim, Kyong-Ah Yoon, Eun-Hae Cho, Junnam Lee, Jihoon Kang, Baek-Yeol Ryoo
Journal: Cancer Research (2018)

Abstract Purpose: We evaluated the potential role of Vascular Endothelial Growth Factor-A (VEGFA) amplification and genome-wide copy number variations (CNVs) using circulating cell-free DNA (cfDNA) as predictors of treatment outcome in hepatocellular carcinoma (HCC) patients treated with first-line sorafenib. Methods: Among 184 patients from a prospective biomarker cohort, who had started sorafenib between April 2015 and May 2016, 151 eligible patients were included in the analysis. Plasma cfDNA was extracted from peripheral blood in patients before starting sorafenib or healthy donors. Plasma VEGFA-to-EIF2C1 ratios (the VEGFA ratios) were determined using droplet digital polymerase chain reaction. We applied low depth whole genome sequencing in cfDNA to find CNVs and developed I-score to express genomic instability, which was defined as the sum of absolute Z-scores of sequenced reads on each chromosome. Results: The cfDNA concentrations were significantly higher in HCC patients than in healthy controls (0.71 vs. 0.34 ng/μL; p&amp;lt;0.0001). Patients who had progressive disease with sorafenib as best tumor response had significantly higher cfDNA levels (0.82 vs. 0.63 ng/μL; p=0.006) and I-scores (3,405 vs.1,024; p=0.0017) than those who achieved disease control. The disease control rate was 52.0% for the cfDNA-high group (above the median) vs. 75.0% for the cfDNA-low group (p=0.003), and 49.3% for the I-score-high group (above the median) vs. 77.6% for the I-score-low group (p=0.0003). The cfDNA-high group also had significantly worse TTP (median, 2.2 vs. 4.1 months; HR=1.71; p=0.002) and OS (median, 4.1 vs. 14.8 months; HR=3.50; p&amp;lt;0.0001) than the cfDNA-low group. Similarly, the I-score-high group had poorer TTP (median, 2.2 vs. 4.1 months; HR=2.09; p&amp;lt;0.0001) and OS (median, 4.6 vs. 14.8 months; HR=3.35; p&amp;lt;0.0001). In the multivariate analyses, cfDNA remained an independent prognostic factor for OS (p&amp;lt;0.0001), and I-score for both TTP (p=0.011) and OS (p=0.010). Although the VEGFA ratio was significantly higher in HCC patients than in healthy controls (2.50 vs. 2.17; p&amp;lt;0.0001), it was not significantly associated with treatment outcomes. Conclusions: Pretreatment cfDNA concentration and genome-wide CNVs in cfDNA are potential biomarkers predicting treatment outcomes in advanced HCC patients receiving first-line sorafenib. Citation Format: Sook Ryun Park, Chung Ryul Oh, Sun-Young Kong, Min Kyeong Kim, Kyong-Ah Yoon, Eun-Hae Cho, Junnam Lee, Jihoon Kang, Baek-Yeol Ryoo. Biomarker analysis in circulating cell-free DNA in patients treated with sorafenib for advanced hepatocellular carcinoma [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 4600.
Role of industry funders in oncology RCTs published in high-impact journals and its association with trial conclusions and time to publication
Authors: F. Liang, J. Zhu, M. Mo, C.M. Zhou, H.X. Jia, L. Xie, Y. Zheng, S. Zhang
Journal: Annals of Oncology (2018)

Previous studies have shown that industry funded trials are associated with pro-industry conclusions and publication bias. Less is known about the role of industry funders and their influence on trial conclusions and time to publication.We identified all industry funded RCTs published in six high-impact clinical journals between 2014 and 2016 to estimate the prevalence of the role of industry funders in trial design, data collection, data analyses, data interpretation and manuscript writing. Ordinal logistic regression was used to assess the association between the role of industry funders and trial conclusions, which was classified on a five-point scale. Cox proportional-hazards were used to examine the effect of role of funder on time to publication.Of the 255 eligible RCTs, industry funders had a role in trial design in 179 (70.2%) trials, data collection in 160 (62.7%) trials, data analyses in 173 (67.8%) trials, data interpretation in 135 (52.9%) trials and manuscript writing in 168 (65.9%) trials. Trials with any role of industry funders had 3.6 times (95% CI 2.0-6.6) higher odds of having positive conclusions compared with those without role of industry funders. In trials with any role of industry funders, positive trials were published more rapidly than negative trials (hazard ratio = 4.3; 95% CI 2.7-6.7, P < 0.001), while for trials without role of industry funders, there was no association (hazard ratio = 1.07; 95% CI 0.57-1.99, P = 0.84).The involvement of industry funders is common in all stages of clinical trials and was associated with more positive conclusions and more rapid publication of RCTs with positive results.
Abstract 13951: Impact of Obesity Control on Circulating Level of Endothelial Progenitor Cells and Angiogenesis in Response to Ischemic Stimulation
Authors: Hon Kan Yip, Tzu-Hsien Tsai, Sarah Chua, Steve Leu, Jiunn-Jye Sheu
Journal: Circulation (2012)

Background and Aim: We tested the hypothesis that obesity reduced circulating number of endothelial progenitor cells (EPCs), angiogenic ability, and blood flow in ischemic tissue that could be reve...
Apixaban in Comparison With Warfarin in Patients With Atrial Fibrillation and Valvular Heart Disease
Authors: Alvaro Avezum, Renato D. Lopes, Phillip J. Schulte, Fernando Lanas, Bernard J. Gersh, Michael Hanna, Prem Pais, Cetin Erol, Rafael Diaz, M. Cecilia Bahit, Jozef Bartunek, Raffaele De Caterina, Shinya Goto, Witold Ruzyllo, Jun Zhu, Christopher B. Granger, John H. Alexander
Journal: Circulation (2015)

Background— Apixaban is approved for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. However, the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial included a substantial number of patients with valvular heart disease and only excluded patients with clinically significant mitral stenosis or mechanical prosthetic heart valves. Methods and Results— We compared the effect of apixaban and warfarin on rates of stroke or systemic embolism, major bleeding, and death in patients with and without moderate or severe valvular heart disease using Cox proportional hazards modeling. Of the 18 201 patients enrolled in ARISTOTLE, 4808 (26.4%) had a history of moderate or severe valvular heart disease or previous valve surgery. Patients with valvular heart disease had higher rates of stroke or systemic embolism and bleeding than patients without valvular heart disease. There was no evidence of a differential effect of apixaban over warfarin in patients with and without valvular heart disease in reducing stroke and systemic embolism (hazard ratio [HR], 0.70; 95% confidence interval [CI], 0.51–0.97 and HR, 0.84; 95%, CI 0.67–1.04; interaction P =0.38), causing less major bleeding (HR, 0.79; 95% CI, 0.61–1.04 and HR, 0.65; 95% CI, 0.55–0.77; interaction P =0.23), and reducing mortality (HR, 1.01; 95% CI, 0.84–1.22 and HR, 0.84; 95% CI, 0.73–0.96; interaction P =0.10). Conclusions— More than a quarter of the patients in ARISTOTLE with nonvalvular atrial fibrillation had moderate or severe valvular heart disease. There was no evidence of a differential effect of apixaban over warfarin in reducing stroke or systemic embolism, causing less bleeding, and reducing death in patients with and without valvular heart disease. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00412984.
Physicochemical Amino Acid Properties Better Describe Substitution Rates in Large Populations
Authors: Claudia C Weber, Simon Whelan
Journal: Molecular Biology and Evolution (2019)

Substitutions between chemically distant amino acids are known to occur less frequently than those between more similar amino acids. This knowledge, however, is not reflected in most codon substitution models, which treat all nonsynonymous changes as if they were equivalent in terms of impact on the protein. A variety of methods for integrating chemical distances into models have been proposed, with a common approach being to divide substitutions into radical or conservative categories. Nevertheless, it remains unclear whether the resulting models describe sequence evolution better than their simpler counterparts. We propose a parametric codon model that distinguishes between radical and conservative substitutions, allowing us to assess if radical substitutions are preferentially removed by selection. Applying our new model to a range of phylogenomic data, we find differentiating between radical and conservative substitutions provides significantly better fit for large populations, but see no equivalent improvement for smaller populations. Comparing codon and amino acid models using these same data shows that alignments from large populations tend to select phylogenetic models containing information about amino acid exchangeabilities, whereas the structure of the genetic code is more important for smaller populations. Our results suggest selection against radical substitutions is, on average, more pronounced in large populations than smaller ones. The reduced observable effect of selection in smaller populations may be due to stronger genetic drift making it more challenging to detect preferences. Our results imply an important connection between the life history of a phylogenetic group and the model that best describes its evolution.
Intracoronary Stenting and Angiographic Results
Authors: AdnanKastrati, JulindaMehilli, JosefDirschinger, FranzDotzer, HelmutSchühlen, Franz-JosefNeumann, MartinFleckenstein, ConradPfafferott, MelchiorSeyfarth, AlbertSchömig
Journal: Circulation (2001)

Background—Increased thrombogenicity and smooth muscle cell proliferative response induced by the metal struts compromise the advantages of coronary stenting. The objective of this randomized, multicenter study was to assess whether a reduced strut thickness of coronary stents is associated with improved follow-up angiographic and clinical results. Methods and Results—A total of 651 patients with coronary lesions situated in native vessels >2.8 mm in diameter were randomly assigned to receive 1 of 2 commercially available stents of comparable design but different thickness: 326 patients to the thin-strut stent (strut thickness of 50 μm) and 325 patients to the thick-strut stent (strut thickness of 140 μm). The primary end point was the angiographic restenosis (≥50% diameter stenosis at follow-up angiography). Secondary end points were the incidence of reinterventions due to restenosis-induced ischemia and the combined rate of death and myocardial infarctions at 1 year. The incidence of angiographic resten...
Abstract 1666: Novel glucose transporter inhibitors decrease glioblastoma growth and glucose uptake
Authors: Catherine J. Libby, Sixue Zhang, Gloria A. Benavides, Yanjie Li, Matthew Redmann, Anh N. Tran, Arphaxad Otamias, Victor Darley-Usmar, Marek Napierala, Jianhua Zhang, Wei Zhang, Anita Hjelmeland
Journal: Cancer Research (2018)

Abstract Glioblastoma multiform (GBM) is the most common primary malignant adult brain tumor and one of the deadliest cancers. Patients with GBM typically undergo surgical resection, radiation and chemotherapy with temozolomide. Complete tumor resection is virtually impossible due to tumor location and the highly infiltrative nature of GBM, which leads to disease recurrence near the original tumor site. As such, these patients have a dramatically decreased life expectancy. Therapeutic development to prolong survival has been hampered by a high degree of inter- and intra-tumoral heterogeneity. Contributing to tumor heterogeneity is a subset of highly tumorigenic cells, termed brain tumor initiating cells (BTICs), that are able to self-renew and can be highly invasive and therapy resistant. BTICs are often enriched in perinecrotic regions, a GBM hallmark, where they can survive under nutrient restriction via increased glucose transporter 3 expression (GLUT3). GLUT3 has a 5-fold greater capacity for glucose transport than the other major glucose transporter isoform in the brain, GLUT1, and is typically restricted to neurons, testis, preimplantation embryos, and stem cells. GLUT3 expression is elevated in many solid tumor types, including GBM, and correlates with poor patient prognosis. Previously, we have shown that knockdown of GLUT3 in BTICs significantly inhibits their growth both in vitro and in vivo, indicating GLUT3 is a possible target for therapeutic intervention. Using structure based virtual screening, we have identified novel GLUT inhibitors that preferentially decrease the growth and glucose uptake of BTICs with minimal toxicity to non-malignant cells in vitro. Preliminary in vivo assessment of these compounds has not indicated toxicity. Our goal is to identify a potential new therapeutic option targeting metabolic reprogramming for the treatment of glioblastoma, as well as other tumor types. Citation Format: Catherine J. Libby, Sixue Zhang, Gloria A. Benavides, Yanjie Li, Matthew Redmann, Anh N. Tran, Arphaxad Otamias, Victor Darley-Usmar, Marek Napierala, Jianhua Zhang, Wei Zhang, Anita Hjelmeland. Novel glucose transporter inhibitors decrease glioblastoma growth and glucose uptake [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 1666.
A radiomics approach to assess tumour-infiltrating CD8 cells and response to anti-PD-1 or anti-PD-L1 immunotherapy: an imaging biomarker, retrospective multicohort study
Authors: Roger Sun, Elaine Johanna Limkin, Maria Vakalopoulou, Laurent Dercle, Stéphane Champiat, Shan Rong Han, Loïc Verlingue, David Brandao, Andrea Lancia, Samy Ammari, Antoine Hollebecque, Jean-Yves Scoazec, Aurélien Marabelle, Christophe Massard, Jean-Charles Soria, Charlotte Robert, Nikos Paragios, Eric Deutsch, Charles Ferté
Journal: The Lancet Oncology (2018)