tbuckley/cabot-search huggingface dataset:
Abstract 2252: Biomarkers for staging melanoma, a search at transcriptome level
Authors: Daniel Ortega-Bernal, Claudia Rangel-Escareño, Elena Arechaga-Ocampo, Claudia H. Gonzalez-De la Rosa
Journal: Cancer Research (2018)

Abstract Background: Melanoma represents one of the most aggressive malignancies and has a high tendency to metastasize. Metastatic potential may not be predicted from the morphologic features alone, and the use of routine histologic prognostic factors is insufficient for melanoma staging. Because metastatic melanoma remains extremely difficult to cure, there has been an urgent need to find new markers to identify tumors capable of metastasizing. Here, we used a computational strategy based on transcriptome meta-analysis for melanoma staging. We aimed to identify biomarkers that differentiate between non-metastatic and metastatic melanomas. Methods: Affymetrix HU 133A Plus 2.0 microarray data were obtained from the GEO database for the meta-analysis, representing benign nevi (N), stages I, II and III melanoma (EI-III), stage IV melanoma from primary site (EIV) and stage IV melanoma from metastatic site (Mm). Differential expression was analyzed using linear models (118 files) and time course (64 files). Transcripts with a log fold change of &amp;lt;-1/&amp;gt;1 and B-statistic &amp;gt;3 using linear models and evaluate by MB-statistic for Time Course were included in the study. The analysis focused on genes that encode secreted proteins, whose expression was upregulated throughout the progression of melanomas, starting at N and increasing gradually from EI-III to EIV and finally to Mm. Results: We obtained 6137 differentially expressed genes with linear models (between EI-III vs. N, EIV vs. EI-III, Mm vs. EIV, EIV vs. N and Mm vs. N contrasts) and took the top 6137 genes ranked with Time Course. Our results show 17 possible biomarkers that grouped into three types: 1) genes capable of differentiating between EIV/Mm and EI-III/N (SPP1); 2) genes capable of differentiating between Mm and EIV/EI-III/N (CXCR4, FCGR1B, NGRN, PHTF1, RAB8B, ARHGEF2, ARMC9, BCL2A1, CALU, DLGAP5, DMXL2, FKBP11 and STARD3NL); and 3) genes capable of differentiating between Mm/EIV/EI-III and N (ADAM10, CLIC4 and STK36). Conclusions: Our analyses, in agreement with previously reported results, identify SPP1 and CXCR4 as biomarkers of metastatic disease and poor clinical outcome, supporting the quality of our analysis. We also identified new biomarkers that may be used to predict undetectable metastasis. In order to provide a more precise evaluation, experimental validation or functional exploration of the reported gene expression differences is warranted. Citation Format: Daniel Ortega-Bernal, Claudia Rangel-Escareño, Elena Arechaga-Ocampo, Claudia H. Gonzalez-De la Rosa. Biomarkers for staging melanoma, a search at transcriptome level [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 2252.
Evaluating the replicability of social science experiments in Nature and Science between 2010 and 2015
Authors: Colin F. Camerer, Anna Dreber, Felix Holzmeister, Teck-Hua Ho, Jürgen Huber, Magnus Johannesson, Michael Kirchler, Gideon Nave, Brian A. Nosek, Thomas Pfeiffer, Adam Altmejd, Nick Buttrick, Taizan Chan, Yiling Chen, Eskil Forsell, Anup Gampa, Emma Heikensten, Lily Hummer, Taisuke Imai, Siri Isaksson, Dylan Manfredi, Julia Rose, Eric-Jan Wagenmakers, Hang Wu
Journal: Nature Human Behaviour (2018)
Attenuation of Ischemia/Reperfusion Injury in Rats by a Caspase Inhibitor
Authors: HiroyukiYaoita, KazueiOgawa, KazuhiraMaehara, YukioMaruyama
Journal: Circulation (1998)

Background—Z-Val-Ala-Asp(OMe)-CH2F (ZVAD-fmk), a tripeptide inhibitor of the caspase interleukin-1β–converting enzyme family of cysteine proteases, may reduce myocardial reperfusion injury in vivo by attenuating cardiomyocyte apoptosis within the ischemic area at risk. Methods and Results—Sprague-Dawley rats were subjected to a 30-minute coronary occlusion followed by a 24-hour reperfusion. An inert vehicle (dimethylsulfoxide; group 1, n=8) or ZVAD-fmk, at a total dose of 3.3 mg/kg (group 2, n=8), was administered intravenously every 6 hours starting at 30 minutes before coronary occlusion until 24 hours of reperfusion. At this 24-hour point, hemodynamics were assessed by means of cardiac catheterization; then, the rats were killed, and the left ventricle was excised and sliced. The myocardial infarct size/ischemic area at risk and the count of presumed apoptotic cardiomyocytes (terminal deoxynucleotidyl transferase–mediated dUTP-biotin nick end labeling [TUNEL]-positive cells) within the ischemic area at...
Moderate Aortic Enlargement and Bicuspid Aortic Valve Are Associated With Aortic Dissection in Turner Syndrome
Authors: MistyCarlson, NathanAirhart, LeoLopez, MichaelSilberbach
Journal: Circulation (2012)

Background—Girls and women with Turner syndrome are at risk for aortic dissection and rupture. However, the size of the aorta and the clinical characteristics among those with Turner syndrome and dissection have received little attention. Methods and Results—We obtained medical records from 20 individuals who voluntarily participated in the International Turner Syndrome Aortic Dissection Registry. Type A dissections occurred in 17 of 20 (85%) cases, and type B occurred in 3 cases of which 1 occurred after coarctation stent placement. Of those with spontaneous aortic dissections, 18 of 19 (95%) had an associated cardiac malformation that included a bicuspid aortic valve. In 1 individual there was no predisposing finding other than the presence of Turner syndrome. Associated pregnancy was documented in 1 of 19 (5%). More than half (13/19, 68%) came to medical attention >24 hours after the onset of symptoms. For those with type A dissections, the mean ascending aortic size index was 2.7±0.6 cm/m2 (n=9). Conc...
Abstract 1679: Interference of PD-1 and PD-L1 interaction with small-molecule inhibitors enhances the efficacy of tumor-specific CTLs
Authors: Priscilla S. Redd, Chunwan Lu, David Ostrov, Iryna Lebedyeva, Kebin Liu
Journal: Cancer Research (2018)

Abstract Programmed cell death-1 (PD-1) is an immunosuppressive receptor expressed on T cells upon activation. Once interacting with its ligands, programmed death ligand-1 (PD-L1), the PD-1:PD-L pathway curbs T cell activation and thereby serves as a natural protection mechanism against autoimmunity. However, this pathway has been hijacked by cancer cells in order to evade the immune system. In fact, PD-L1 is commonly overexpressed on the surface of tumor cells as well as other cells in the tumor microenvironment, such as myeloid-derived suppressor cells. This interface has already been recognized as an effective target for cancer therapy. Blocking the PD-1:PD-L axis would unleash T cells from suppression to maintain their effector function against tumor cells. At least two anti-PD-1 and three anti-PD-L1 blocking antibodies have been approved for human cancer immunotherapy. However, these drugs are only successful in a small number of cancers. Therefore, developing inhibitors that block this axis more effectively and have a wider scale of impact is necessary. We used a molecular docking model and performed virtual chemical library screening to identify small molecule inhibitors of PD-1 and PD-L1 interactions. To this end, we have identified 175 PD-L1 small molecule inhibitors. Functional assays were established with the 4T1 murine breast cancer cell line and a tumor-specific murine T cell line in the presence or absence of the PD-L1 small molecule inhibitors to test if these small molecule PD-L1 inhibitors can increase T cell killing of tumor cells. Cell viability assays were also done to test the toxicity of these inhibitors on tumor cells in the absence of T cells. From these studies, we have identified ten novel PD-L1 small molecule inhibitors that can significantly increase the lytic activity of the tumor-specific cytotoxic T lymphocytes (CTLs) to kill 4T1 tumor cells. These ten PD-L1 small molecule inhibitors show little to no cytotoxicity to 4T1 tumor cells in the absence of the antigen-specific T cells, suggesting that these small molecule inhibitors themselves are not cytotoxic, and therefore are potentially safe as therapeutic agents. These proof of concept studies indicate that these small molecule inhibitors are potentially potent agents for blocking PD-1 and PD-L1 interaction in cancer immunotherapy. Citation Format: Priscilla S. Redd, Chunwan Lu, David Ostrov, Iryna Lebedyeva, Kebin Liu. Interference of PD-1 and PD-L1 interaction with small-molecule inhibitors enhances the efficacy of tumor-specific CTLs [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 1679.
Serum Bioavailable and Free 25-Hydroxyvitamin D Levels, but Not Its Total Level, Are Associated With the Risk of Mortality in Patients With Coronary Artery Disease
Authors: Chao Yu, Hongliang Xue, Liqing Wang, Qian Chen, Xuechen Chen, Yuan Zhang, Gang Hu, Wenhua Ling
Journal: Circulation Research (2018)

Rationale: Bioavailable and free 25-hydroxyvitamin D (25(OH)D) are emerging measurements of vitamin D. Whether serum bioavailable or free 25(OH)D level is associated with mortality in patients with coronary artery disease (CAD) is unknown. Objective: Our aim is to determine the potential association between serum total, bioavailable, and free 25(OH)D levels and the risk of mortality among patients with CAD. Methods and Results: We measured serum 25(OH) levels in 1387 patients with angiographically confirmed CAD from the Guangdong Coronary Artery Disease Cohort. Serum DBP (vitamin D-binding protein) levels were measured using a polyclonal immunoassay, and serum-free 25(OH)D levels were measured using a 2-step immunoassay. Bioavailable 25(OH)D levels were calculated using a previously validated formula. By the median follow-up time of 6.7 years, 205 patients had died, including 134 deaths from cardiovascular diseases. In multivariate analyses, low serum bioavailable 25(OH)D level was significantly associated with increased risks of mortality, independent of established cardiovascular risk factors, features and treatments of CAD, factors associated with vitamin D and mineral metabolism, and CRP (C-reactive protein). The multivariable-adjusted hazard ratios across quartiles of bioavailable 25(OH)D were 1.79, 1.35, 1.36, and 1.00 for all-cause mortality ( P for trend=0.01) and 2.58, 1.85, 1.73, and 1.00 for cardiovascular mortality ( P for trend=0.001), respectively. Serum-free 25(OH)D level was inversely associated with the risk of mortality, with the extreme-quartile hazard ratios of 1.64 for all-cause mortality ( P for trend=0.024) and 1.97 for cardiovascular mortality ( P for trend=0.013). In contrast, serum total 25(OH)D level was not significantly associated with all-cause mortality or cardiovascular mortality. Conclusions: Lower serum bioavailable and free 25(OH)D levels rather than total 25(OH)D level are independently associated with an increased risk of all-cause mortality and cardiovascular mortality in a population-based CAD cohort.
Climatic drivers of melioidosis in Laos and Cambodia: a 16-year case series analysis
Authors: Philip L Bulterys, Michelle A Bulterys, Koukeo Phommasone, Manophab Luangraj, Mayfong Mayxay, Sabine Kloprogge, Thyl Miliya, Manivanh Vongsouvath, Paul N Newton, Rattanaphone Phetsouvanh, Christopher T French, Jeff F Miller, Paul Turner, David A B Dance
Journal: The Lancet Planetary Health (2018)

BackgroundBurkholderia pseudomallei is the cause of melioidosis, a serious and difficult to treat infection that is endemic throughout the tropics. Melioidosis incidence is highly seasonal. We aimed to identify the climatic drivers of infection and to shed light on modes of transmission and potential preventive strategies.MethodsWe examined the records of patients diagnosed with melioidosis at the Microbiology Laboratory of Mahosot Hospital in Vientiane, Laos, between October, 1999, and August, 2015, and all patients with culture-confirmed melioidosis presenting to the Angkor Hospital for Children in Siem Reap, Cambodia, between February, 2009, and December, 2013. We also examined local temperature, humidity, precipitation, visibility, and wind data for the corresponding time periods. We estimated the B pseudomallei incubation period by examining profile likelihoods for hypothetical exposure-to-presentation delays.Findings870 patients were diagnosed with melioidosis in Laos and 173 patients were diagnosed with melioidosis in Cambodia during the study periods. Melioidosis cases were significantly associated with humidity (p<0·0001), low visibility (p<0·0001), and maximum wind speeds (p<0·0001) in Laos, and humidity (p=0·010), rainy days (p=0·015), and maximum wind speed (p=0·0070) in Cambodia. Compared with adults, children were at significantly higher odds of infection during highly humid months (odds ratio 2·79, 95% CI 1·83–4·26). Lung and disseminated infections were more common during windy months. The maximum likelihood estimate of the incubation period was 1 week (95% CI 0–2).InterpretationThe results of this study demonstrate a significant seasonal burden of melioidosis among adults and children in Laos and Cambodia. Our findings highlight the risks of infection during highly humid and windy conditions, and suggest a need for increased awareness among at-risk individuals, such as children.FundingWellcome Trust.
Abstract 9777: Dietary Phosphatidylcholine and Risk of All-cause and Cardiovascular-specific Mortality Among Women and Men With Type 2 Diabetes
Authors: Yan Zheng, Yanping Li, Eric Rimm, Frank Hu, Christine Albert, Kathryn Rexrode, JoAnn Manson, Lu Qi
Journal: Circulation (2015)

Introduction: The trimethylamine-containing nutrient phosphatidylcholine is the major dietary source for gut microbiota metabolite trimethylamine-N-oxide, which has been related to cardiovascular diseases (CVD) and mortality. We recently found higher dietary phosphatidylcholine intake was associated with an increased risk of diabetes. No study has analyzed whether phosphatidylcholine intake is related to all-cause and CVD mortality in diabetic patients, who have a higher risk of CVD and premature mortality than the general population. Methods: In total, we included 10061 women and 3668 men with type 2 diabetes in the Nurses’ Health Study and Health Professionals Follow-up Study, respectively. Dietary intakes and potential confounders were assessed with regularly administered questionnaires. Results: We documented 2427 all-cause and 807 CVD deaths during up to 30-year follow-up. After multivariate adjustment for potential confounders, including age, smoking, body mass index, physical activity, dietary intakes and duration of diabetes, higher phosphatidylcholine intake was associated with an increased risk of all-cause and CVD mortality. The pooled relative risk comparing top to bottom quartiles of phosphatidylcholine intake was 1.22 (95%CI, 1.07-1.39; P for trend across quartiles=0.003) for all-cause mortality and 1.33 (1.04-1.69; P for trend=0.03) for CVD mortality. Conclusions: These data indicate that higher phosphatidylcholine consumption is associated with higher all-cause and CVD mortality in diabetic population, independent of other risk factors. Our findings suggest dietary modulation may be a potential interventional strategy to reduce mortality related to gut microbiota metabolites.
Efficacy of thalidomide, neurokinin-1 receptor antagonist, and olanzapine in combination with palonosetron plus dexamethasone in preventing chemotherapy-induced nausea and vomiting (CINV) induced by highly emetogenic chemotherapy (HEC): Bayesian network meta-analysis.
Authors: Abdullah Alhifany, Ali McBride, Abdulaali Almutairi, Hani M. Babiker, Karen MacDonald, Ivo Abraham
Journal: Journal of Clinical Oncology (2018)

e14514 Background: The combination of palonosetron and dexamethasone in the prevention of CINV has been the standard of care. Using a third agent is indicated for HEC. Several trials have examined adding thalidomide, neurokinin-1 receptor antagonist, and olanzapine to this combination regimen. In the absence of head-to-head trials, we conducted a Bayesian network meta-analysis to compare the efficacy of these additional agents in combination with palonosetron plus dexamethasone in preventing CINV induced by HEC. Methods: We identified 8 eligible studies involving 2859 patients through a search of PubMed/Medline and Embase databases. We conducted a Bayesian network meta-analysis using fixed and random effect models for Complete Response (CR) and Rate of No Nausea (RNN) in the acute, delayed, and overall phases. Results: Olanzapine-based regimens showed significantly greater CR than thalidomide-based (OR 3.59, 95% Cr.I 1.34-10.67) and NK-1-based regimens in the acute phase (OR 2.77, 95% Cr.I 1.31- 6.06), as well the overall phase (OR 1.80, 95% Cr.I 1.01- 3.45). There were no significant differences in CR in either of the three phases between the NK-1-based and thalidomide-based regimens. Olanzapine-based regimens showed a significantly better RNN than thalidomide-based and NK-1-based regimens in the delayed phase (OR 2.74, 95% Cr.I 1.37- 5.58; OR 3.37, 95% Cr.I 2.14-5.30, resp.). Conclusions: There was no significant difference between adding thalidomide or NK-1 as third agents to palonosetron plus dexamethasone to prevent CINV induced by HEC. However, the olanzapine-based triple regimen was better in terms of CR and RNN. Further clinical trials should focus on the optimal third agent to be added to the palonosetron and dexamethasone backbone in terms of safety, efficacy, tolerance, and economic value.
Abstract 4878: RMC-4550, an allosteric inhibitor of SHP2: Synthesis, structure, and anti-tumor activity
Authors: Elena S. Koltun, Naing Aay, Andreas Buckl, Ashutosh S. Jogalekar, Gert Kiss, Abby Marquez, Kevin T. Mellem, Kasia Mordec, Mae Saldajeno-Concar, Chris M. Semko, Nidhi Tibrewal, Christos Tzitzilonis, Walter Won, Jacqueline A. Smith, Susan E. Wilson, Robert J. Nichols, Zhengping Wang, David Wilds, Mallika Singh, Adrian L. Gill
Journal: Cancer Research (2018)

Abstract Genetic and pharmacologic evidence has shown that SHP2, a non-receptor protein tyrosine phosphatase (PTP) and scaffold protein encoded by the PTPN11 gene, is a convergent signal transduction node that integrates growth factor signals from multiple receptors to promote activation of RAS and its downstream effectors. Guided by structural insights from X-ray data, we describe a strategy aimed at the identification of a highly potent and selective allosteric SHP2 inhibitor series. Our efforts led to the discovery of RMC-4550, a potent and selective SHP2 inhibitor which exhibits a high quality, drug-like preclinical profile. RMC-4550 inhibits purified, activated full length human SHP2 with an IC50 of 1.55 nM, and has cellular IC50 of 39 nM in PC9 cells with a pERK readout. RMC-4550 has no detectable inhibitory activity up to 10 µM against the catalytic domain of SHP2, a panel of 14 additional protein phosphatases, and a panel of 468 protein kinases. RMC-4550 exhibits low to moderate cross species in vitro intrinsic clearance (3.6-24 µL/min/million cells) in hepatocytes, a high passive permeability (458 nm/s) and efflux ratio of 1. The ADME properties translate into favorable pharmacokinetic profiles in preclinical species. RMC-4550 has moderate to high bioavailability and has a half-life amenable for once daily oral administration. In the EGFR-driven KYSE-520 human esophageal cancer xenograft model, we observed a dose dependent efficacy consistent with target modulation, assessed by phospho-ERK inhibition in tumors. RMC-4550 is well tolerated at doses that achieved maximal and sustained efficacy in this model. RMC-4550 was synthesized in 5 linear (6 total) steps from the readily accessible or commercially available intermediates. The chemical structure and synthesis of RMC-4550, along with detailed structure-activity relationships will be presented. In summary, RMC-4550 exemplifies a novel class of potent allosteric inhibitors of SHP2 with an excellent drug like property profile. Citation Format: Elena S. Koltun, Naing Aay, Andreas Buckl, Ashutosh S. Jogalekar, Gert Kiss, Abby Marquez, Kevin T. Mellem, Kasia Mordec, Mae Saldajeno-Concar, Chris M. Semko, Nidhi Tibrewal, Christos Tzitzilonis, Walter Won, Jacqueline A. Smith, Susan E. Wilson, Robert J. Nichols, Zhengping Wang, David Wilds, Mallika Singh, Adrian L. Gill. RMC-4550, an allosteric inhibitor of SHP2: Synthesis, structure, and anti-tumor activity [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 4878.
Active Remodeling of the Coronary Arterial Lesions in the Late Phase of Kawasaki Disease
Authors: AtsukoSuzuki, SachikoMiyagawa-Tomita, KeikoKomatsu, ToshioNishikawa, YasunariSakomura, ToshinobuHorie, MakotoNakazawa
Journal: Circulation (2000)

Background—Remodeling of the coronary artery lesions in Kawasaki disease has been observed in longitudinal angiographic studies. However, mechanisms of such remodeling have not yet been elucidated. Methods and Results—We examined formalin-fixed specimens of the coronary arteries immunohistochemically by using antibodies against vascular growth factors (GFs) and their receptors in 7 children with Kawasaki disease, 9 children with no coronary disease, and 3 adults with atherosclerosis. In the thickened intima at stenotic sites and at recanalized vessels with Kawasaki disease, extensive expression of vascular GFs, such as transforming GF-β1, platelet-derived GF-A, and basic fibroblast GF, was observed both within and surrounding smooth muscle cells. Vascular endothelial GF was observed within smooth muscle cells. Furthermore, all of these GFs were strongly expressed in the newly formed microvessels within the intima. In the thinned media, these GFs were focally and weakly expressed. In contrast, these GFs we...
Metabolic glycan labeling and chemoselective functionalization of native biomaterials
Authors: Xi Ren, Daniele Evangelista-Leite, Tong Wu, Taufiek K. Rajab, Philipp T. Moser, Kentaro Kitano, Konstantinos P. Economopoulos, Daniel E. Gorman, Jordan P. Bloom, Jun Jie Tan, Sarah E. Gilpin, Haiyang Zhou, Douglas J. Mathisen, Harald C. Ott
Journal: Biomaterials (2018)
Atherogenic Lipoprotein Particles in Atherosclerosis
Authors: RafaelCarmena, PatrickDuriez, Jean-CharlesFruchart
Journal: Circulation (2004)

The importance of low-density lipoprotein (LDL) cholesterol in the development of atherosclerosis has long been recognized, and LDL cholesterol remains the primary target of therapy for the prevention of coronary heart disease. Nevertheless, increasing research attention over the past decade has been devoted to the heterogeneity of LDL particles and the atherogenicity of lipids and lipoproteins other than LDL. Particularly atherogenic forms of LDL include small, dense LDL particles and oxidized LDL. All lipoproteins that contain apolipoprotein B, such as LDL, very-low-density lipoprotein, and intermediate-density lipoprotein, tend to promote atherosclerosis; however, these particles differ in their apolipoprotein and triglyceride content. High levels of plasma triglycerides increase the risk of acute coronary events. Lipoprotein(a) is now considered an independent risk factor in both men and women. Ultimately, better understanding of the roles of these lipid particles and subfractions in the initiation an...
Hemodynamic and Hypotensive Effects of Long-term Therapy with Chlorothiazide
Authors: Jamesconway, Philiplauwers
Journal: Circulation (1960)

Long-term treatment of hypertension with chlorothiazide alone produces mioderate reduction in blood pressure in 66 per cent of patients with hypertension. This fall in pressure is due to a reduction in total peripheral resistance rather than a fall in cardiac output.