tbuckley/cabot-search huggingface dataset:
Abstract 2139: Evaluation of a novel hypoxia-activated prodrug strategy in colorectal cancer cells
Authors: Omar Hussain, Henrik Johansson, Simon J. Allison, Daniel S. Pedersen, Roger M. Phillips
Journal: Cancer Research (2018)

Abstract Introduction: Current chemotherapeutic drugs are often ineffective against cancer cells that reside within the tumor microenvironment due to contributing factors such as hypoxia (low O2 tension) and acidic extracellular pH (pHe). Hypoxia is known to drive the aggressive cancer phenotype in many solid tumors, making it a key component of drug development. The use of hypoxia-activated prodrugs (HAPs) has been extensively studied over 40 years but to date no HAP has been approved for use in humans, largely because of poor activity and toxicity profiles. The design of prodrugs that are activated by both hypoxia and acidic pHe may provide a greater degree of selectivity and activity than HAPs alone, and this study was designed to evaluate a series of novel bromosugar-based HAPs under hypoxic and acidic pHe conditions. Method: A library of 13 HAPs was evaluated against HCT116 colorectal cancer cells and ARPE-19 human retinal epithelial noncancerous cell line. Cytotoxicity was determined under (i) aerobic condition (21% oxygen) at pHe 7.4 or mild acidic conditions (pHe 6.5) and (ii) hypoxic condition (0.1% oxygen) at pHe 7.4 or mild acidic conditions (pHe 6.5). ARPE-19 cells were only tested under aerobic conditions and pHe 7.4 to reflect normal physiologic conditions. Compounds were tested at different concentrations ranging from 0.1-100µM from which an IC50 value was determined. Cell survival was measured after a 96-hour continuous drug exposure using the MTT assay. Results: Among the compounds screened, DS10 demonstrated the most enhanced potency against HCT116 cells under hypoxic conditions with an IC50 value of 28.18 ± 7.01 µM as compared to an IC50 value of 66.39 ± 8.10 µM under normoxic conditions at pHe 7.4. Potency was further increased when DS10 was evaluated under a combination of hypoxic and acidic pHe conditions with an IC50 value of 16.30 µM ± 4.11. ARPE-19 cells showed an IC50 value of 42.95 µM ± 5.03 under aerobic conditions. Discussion: The results of this study demonstrated that bromosugar derivatives may have the potential to selectively target hypoxic cancer cells in an acidic extracellular environment. Specifically, DS10 exhibited potential HAP properties with the ability to target cells that reside within the hypoxic and acidic microenvironment of tumors. Selectivity to tumor cells as opposed to noncancer cells was observed under these conditions, suggesting that DS10 is a promising compound to take forward for further evaluation. Citation Format: Omar Hussain, Henrik Johansson, Simon J. Allison, Daniel S. Pedersen, Roger M. Phillips. Evaluation of a novel hypoxia-activated prodrug strategy in colorectal 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 2139.
AMPKα2 Deletion Exacerbates Neointima Formation by Upregulating Skp2 in Vascular Smooth Muscle Cells
Authors: PingSong, ShuangxiWang, ChaoyongHe, ShaobinWang, BinLiang, BenoitViollet, Ming-HuiZou
Journal: Circulation Research (2011)

Rationale:Adenosine monophosphate-activated protein kinase (AMPK), a metabolic and redox sensor, is reported to suppress cell proliferation of nonmalignant and tumor cells. Whether AMPKα alters vascular neointima formation induced by vascular injury is unknown. Objective:The aim of this study was to determine the roles of AMPKα in the development of vascular neointima hyperplasia and to elucidate the underlying mechanisms. Methods and Results:Vascular smooth muscle cell (VSMC) proliferation and neointimal hyperplasia were evaluated in cultured VSMCs and wire-injured mouse carotid arteries from wild-type (WT, C57BL/6J), AMPKα2−/−, and AMPKα1−/− mice. Mouse VSMCs derived from aortas of AMPKα2−/− mice exhibited increased proliferation compared with either WT or AMPKα1−/− VSMCs. Further, deletion of AMPKα2 but not AMPKα1 reduced the level of p27Kip1, a cyclin-dependent kinase inhibitor, and increased the level of S-phase kinase-associated protein 2 (Skp2), a known E3 ubiquitin ligase for p27Kip1, through acti...
Abstract P080: Fructose Acutely Increases Size of Very Low Density Lipoprotein In Adolescents With Hepatic Steatosis
Authors: MirianVos, RanJin, JeanWelsh, Ngoc-AnhLe
Journal: Circulation (2014)

Introduction: Cardiovascular complications are a leading cause of mortality in nonalcoholic fatty liver disease (NAFLD). Fructose has been reported to be associated with dyslipidemia and increased cardiovascular risk in adults but its impact on adolescents with NAFLD is not well understood. We previously demonstrated that fructose disproportionately increased postprandial hypertriglyceridemia in pediatric NAFLD as compared to healthy children. However, the mechanism remains unclear. Hypothesis: We hypothesized that fructose would contribute to hypertriglyceridemia in pediatric NAFLD by increasing the size of VLDL particles. Methods: We examined the acute response to a single dose of fructose beverage in 50 Hispanic-American obese adolescents with varying degrees of hepatic steatosis. Those with hepatic fat >5% on MRI imaging were designated as presumed NAFLD. Subjects consumed a 12oz drink containing 33g of fructose and plasma samples were collected at baseline and 30, 60, and 90 minutes afterwards. Plasm...
Aortic Lipoprotein Lipase Activity in Relation to Species, Age, Sex, and Blood Pressure
Authors: Samuelmallov
Journal: Circulation Research (1964)

It has been suggested that lipoprotein lipase (LPL) activity may play a role in the etiology of atherosclerosis. To determine whether there is an inverse relationship between arterial LPL activity and the tendency for arteries to become atherosclerotic, determinations were made of the activities of the enzyme in homogenates of the aortas of animals under conditions associated with a greater or lesser tendency for atherosclerosis to develop. It was found that the LPL activities of the aortas of old rats and rabbits were significantly lower than those of young animals of the same species, respectively. Rats, which are resistant to the development of atherosclerosis, manifested about twice the aortic LPL activities that rabbits did, the latter animals being notorious for the ease with which they develop the disease. This was true regardless of the age and sex of the animals compared. These results support the hypothesis that low arterial LPL activity may be associated with increased atherogenesis. Aortas of ...
Effect of Hypothermia on Oxygen Consumption and Energy Utilization of Heart
Authors: Henrybadeer, AvedisKhachadurian
Journal: Circulation Research (1956)

The oxygen uptake of the denervated dog's heart doing constant work in a modified HLP appears to vary logarithmically with temperature between 36 and 26 C. Under these conditions hypothermia increases the mechanical efficiency of the heart. It is concluded that cold does not interfere with the conversion of aerobic energy into useful work done by the myocardium.
Comparative Effect of ACE Inhibition and Angiotensin II Type 1 Receptor Antagonism on Bioavailability of Nitric Oxide in Patients With Coronary Artery Disease
Authors: BurkhardHornig, UlfLandmesser, ChristophKohler, DorotheAhlersmann, StephanSpiekermann, AnnemarieChristoph, HelmaTatge, HelmutDrexler
Journal: Circulation (2001)

Background—Flow-dependent, endothelium-mediated vasodilation (FDD) and activity of extracellular superoxide dismutase (EC-SOD), the major antioxidative enzyme of the arterial wall, are severely impaired in patients with coronary artery disease (CAD). We hypothesized that both ACE inhibitor (ACEI) and angiotensin II type 1 receptor antagonist (AT1-A) increase bioavailability of nitric oxide (NO) by reducing oxidative stress in the vessel wall, possibly by increasing EC-SOD activity. Methods and Results—Thirty-five patients with CAD were randomized to 4 weeks of ACEI (ramipril 10 mg/d) or AT1-A (losartan 100 mg/d). FDD of the radial artery was determined by high-resolution ultrasound before and after intra-arterial N-monomethyl-l-arginine (L-NMMA) to inhibit NO synthase and before and after intra-arterial vitamin C to determine the portion of FDD inhibited by oxygen free radicals. EC-SOD activity was determined after release from endothelium by heparin bolus injection. FDD was improved after ramipril and lo...
Abstract 5244: Neratinib induced HER2 dependent and independent intracellular signaling events in human breast cancer cells and the clinical implications
Authors: W. G. Jiang, Tracey A. Martin, Sioned Owen, Ling Xin, Yinhua Liu, Fiona Ruge, Francesca Avogadri-Connors, Alshad S. Lalani, Richard P. Bryce, Eleri Davies
Journal: Cancer Research (2018)

Abstract Background. Neratinib is an orally available irreversible pan-HER receptor tyrosine kinase inhibitor that has clinical benefit in patients with HER2-positive and HER2-mutated breast cancer. Neratinib also targets the other two members of the HER family, namely EGFR and HER4. However, tentative evidence suggests that neratinib may affect kinases of non-HER family. In the present study, we aimed to explore the pattern of kinases targeted by neratinib, in the context of HER2 non-amplified cancer cells and explored the potential clinical implications. Method. A panel of HER2-low/medium-expressing (MCF-7 and ZR-75-1) and HER2- negative (MDA-MB-231 and BT549) human breast cancer cells were used. The response of a panel of 304 kinases to neratinib was screened using the kinase antibody array. Cellular toxicity was quantified using a colorimetric method. Candidate neratinib-responsive kinases were subject to analyses against the survival of a breast cancer cohort as well as a public database for additional validation. The protein expression level of the kinase targets identified was also validated on tissue arrays from breast cancer by immunohistochemistry. Result. Of all the kinases tested, thirty-six were found to be influenced by neratinib, either via activation or suppression of their phosphorylation. Based on the differential responses to neratinib in HER2 negative and positive breast cancer cells, a small panel of the kinases were classified as HER2 independent. Using clinical cohorts, these kinases collectively had predictive value for the overall survival of the patients (p&amp;lt;0.0001). We further analysed one of the candidate kinases, namely salt inducible kinase-1 (SIK1) and the SIK family in relation with HER2. HER2 expression was found significantly correlated with both SIK1 (r=0.46, p&amp;lt;0.001) and also other two SIK family members. SIK1 protein staining in the tissue array was found to be aberrant in breast tumours. Conclusion. Neratinib has an effect on a subset of HER2 independent kinases in breast cancer cells. These kinases had a prognostic value on patient's survival and correlated with HER2 expression, as in the case of the SIK family.This finding may have important implication in understanding the biology of HER2 inhibitors such as neratinib. Citation Format: W. G. Jiang, Tracey A. Martin, Sioned Owen, Ling Xin, Yinhua Liu, Fiona Ruge, Francesca Avogadri-Connors, Alshad S. Lalani, Richard P. Bryce, Eleri Davies. Neratinib induced HER2 dependent and independent intracellular signaling events in human breast cancer cells and the clinical implications [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 5244.
Abstract 1357: Functional characterization of FANCD2 in esophageal squamous cell carcinoma
Authors: Lisa Chan Lei, Valen Zhuoyou Yu, Lvwen Ning, Josephine Mun-Yee Ko, Li Dong Wang, Maria Li Lung
Journal: Cancer Research (2018)

Abstract Introduction: Esophageal squamous cell carcinoma (ESCC) has an especially high incidence in Northern China, where there is evidence for a significant familial association. We performed targeted next-generation sequencing (NGS) analysis on familial ESCC germline samples compared to non-cancer controls from the same high-risk region and compiled a list of candidate cancer predisposition genes. Interestingly, genes related to the Fanconi Anemia (FA) - BRCA pathway are enriched in the list. Among these FA-BRCA genes, Fanconi anemia complementation group D2 (FANCD2) was one of the top candidates, as it also had a high frequency of somatic mutations in ESCC tumor specimens. Therefore, we aim to characterize the role of FANCD2 in tumor development and explore its translational value. Methods: We knocked out the FANCD2 gene in ESCC cell lines using the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) technique to evaluate its potential oncogenic function in ESCC. Cell proliferation was measured by a MTT 2D clonogenic assay in vitro. Subcutaneous injection of the FANCD2 knockout ESCC cells into BALB/c-nude mice in vivo was performed to assess its functional impact on tumorigenesis. The single cell gel electrophoresis/comet assay was used to investigate the genome stability. Results: The FANCD2 knockout efficiency was confirmed by western blotting. Surprisingly, in vitro functional analyses showed that ESCC cells with FANCD2 knockout survive, with a greatly reduced growth rate and colony-forming ability. Consistent with the in vitro data, ESCC cells with FANCD2 knockout form significantly smaller subcutaneous tumors in nude mice. By applying the comet assay to examine the genome integrity, ESCC cells with FANCD2 knockout show significantly greater damage to the genome. Conclusion: These results suggest that FANCD2 plays an important role in supporting ESCC tumor growth. We attribute this to its core function in DNA repair ability and genome integrity maintenance. Acknowledgement: We acknowledge the grant support from the Hong Kong Research Grants Council Collaborative Research Fund (C7031.15G to M.L.L.). Citation Format: Lisa Chan Lei, Valen Zhuoyou Yu, Lvwen Ning, Josephine Mun-Yee Ko, Li Dong Wang, Maria Li Lung. Functional characterization of FANCD2 in esophageal squamous cell 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 1357.
Molecular Mechanisms of Mitochondrial Autophagy/Mitophagy in the Heart
Authors: ToshiroSaito, JunichiSadoshima
Journal: Circulation Research (2015)

Mitochondrial quality is a crucial determinant of cell viability, and mitochondrial autophagy plays a central role in this control mechanism. Based on studies in yeast, numerous investigations of this process have been conducted, and the framework of mammalian mitochondrial autophagy is progressively appearing. However, many enigmas about the molecular mechanisms involved remain unsolved. Furthermore, the pathological significance of mitochondrial autophagy in the heart remains largely unclear. In this review, we discuss the current understanding of mitochondrial autophagy in mammals with reference to that in yeast. Regarding the process in yeast, some points of uncertainty have arisen. We also summarize recent advances in the research of autophagy and mitochondrial autophagy in the heart. This article is a part of a review series on Autophagy in Health and Disease.
Control of Macrophage Activation and Function by PPARs
Authors: AjayChawla
Journal: Circulation Research (2010)

Abstract: Macrophages, a key component of the innate defense against pathogens, participate in the initiation and resolution of inflammation, and in the maintenance of tissues. These diverse and at times antithetical functions of macrophages are executed via distinct activation states, ranging from classical to alternative to deactivation. Because the dysregulation of macrophage activation is pathogenically linked to various metabolic, inflammatory and immune disorders, regulatory proteins controlling macrophage activation have emerged as important new therapeutic targets. Here, the mechanisms by which peroxisome proliferator-activated receptors (PPARs) transcriptionally regulate macrophage activation in health and disease states, including obesity, insulin resistance and cardiovascular disease, are reviewed.
Cardiac and Extracardiac Expression of Csx/Nkx2.5 Homeodomain Protein
Authors: HidekoKasahara, SoniaBartunkova, MartinaSchinke, MakotoTanaka, SeigoIzumo
Journal: Circulation Research (1998)

Abstract—Csx/Nkx2.5 is an evolutionary conserved homeobox gene related to the Drosophila tinman gene, which is essential for the dorsal mesoderm formation. Expression of Csx/Nkx2.5 mRNA is the earliest marker for heart precursor cells in all vertebrates so far examined. Previous studies have demonstrated that Csx/Nkx2.5 mRNA is highly expressed in the heart and at lower levels in the spleen, tongue, stomach, and thyroid in the murine embryo. Since some developmental genes are regulated by posttranscriptional mechanisms, we analyzed the developmental pattern of Csx protein expression at the single-cell level using Csx-specific antibodies. Immunohistochemical analysis of murine embryos at 7.8 days post coitum revealed that Csx protein is strongly expressed in the nucleus of endodermal and mesodermal cells in the cardiogenic plate. Subsequently, in the heart, Csx protein was detected only in the nucleus of myocytes of the atrium and the ventricle through the adult stage. During the fetal period, Csx protein ...
Abstract 17688: Soluble ST2 Concentration Predicts 1-Year Outcome in Patients Undergoing Transcatheter Aortic Valve Implantation (TAVI)
Authors: Bernhard Wernly, Michael Lichtenauer, Mathias Ausserwinkler, Sarah Eder, Uta C Hoppe, Christian Jung, Ulf Landmesser, Hans-Reiner Figulla, Alexander Lauten
Journal: Circulation (2016)

Introduction: Aortic valve stenosis due to calcification is the leading valvular heart disease in elderly patients. sST2 has been introduced as a novel biomarker in patients suffering from heart failure for better risk stratification. Here in this study we sought to investigate whether sST2 is useful for risk stratification and prediction of mortality in patients undergoing transcatheter aortic valve implantation (TAVI). Materials and Methods: A total of 274 patients undergoing TAVI were included in this study (149 female; age 80 years±0.5SEM; EUROSCORE 24±2SEM). Plasma samples were obtained pre-interventionally and analyzed for sST2 using commercially available ELISA kits. Patients were clinically followed-up regularly for one year after TAVI. Results: Median sST2 plasma concentration in these patients was high with 6370 pg/ml (IQR 4371-11721 pg/ml). In a Cox regression analysis sST2 plasma concentration evidenced to be associated with increased mortality (changes per pg/ml sST2 concentration; HR 1.00006...
Abstract LB-198: Novel somatic mutations of PRKAR1A in sporadic cardiac myxomacardiac myxoma
Authors: Jian He
Journal: Cancer Research (2018)

Abstract Background: Cardiac myxomas are benign tumors that commonly arise within the left atria. Familial cardiac myxomas are a part of Carney Complex (CNC), an autosomal dominant multiple neoplasia syndrome caused by germline mutations in PRKAR1A. Seven percent of cardiac myxomas are associated with CNC. To date, the genetic basis of isolated cardiac myxomas (ICM), however, has not been fully elucidated Methods: We investigated the genetic profile of ICM using whole exome sequencing (WES). Suspected mutations were confirmed using targeted sanger sequencing. To further examine the presence of PRKAR1A mutations in ICM, we performed targeted sequencing in an additional 61 ICM specimens. Results: 87.5% (7/8) of ICM harbored mutations in PRKAR1A. Three of the 8 ICM harbored biallelic somatic mutations of PRKAR1A, including c.607_610del:p. Leu203fs (pathogenic) + c.C896G:p.Ser299X (pathogenic), c.952delT:p.Leu318fs (pathogenic) + c.769-2 A&amp;gt;G (pathogenic) and c.178-1 G&amp;gt;C (pathogenic) + c. 550+1 G&amp;gt;C (pathogenic). Four of 8 tumors harbored monoallelic PRKAR1A mutations, including c.523_524insG:p.Tyr175_Val176delinsX (pathogenic), c.C920A:p.Ser307X (pathogenic), c.30delG:p.Glu10fs (pathogenic) and c.C289T:p.Arg97X (pathogenic). No identical variants were observed across the 8 ICM samples. Interestingly, none of these variants have been previously described in familial cardiac myxomas. In order to confirm our findings, directed sequencing of 61 ICM specimens was subsequently performed. Sixty-four percent (39/61) of ICMs tumors contained inactivating PRKAR1A mutations. Conclusion: Our findings suggest that loss-of-function mutations of PRKAR1A may play a vital role in the formation of isolated cardiac myxomas. Citation Format: Jian He. Novel somatic mutations of PRKAR1A in sporadic cardiac myxomacardiac myxoma [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 LB-198.
Underutilization of Combined-Modality Therapy in Limited-Stage Small Cell Lung Cancer—Reply
Authors: Stephen G. Chun, Todd A. Pezzi, David L. Schwartz
Journal: JAMA Oncology (2018)

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Artificial intelligence in retina
Authors: Ursula Schmidt-Erfurth, Amir Sadeghipour, Bianca S. Gerendas, Sebastian M. Waldstein, Hrvoje Bogunović
Journal: Progress in Retinal and Eye Research (2018)

Major advances in diagnostic technologies are offering unprecedented insight into the condition of the retina and beyond ocular disease. Digital images providing millions of morphological datasets can fast and non-invasively be analyzed in a comprehensive manner using artificial intelligence (AI). Methods based on machine learning (ML) and particularly deep learning (DL) are able to identify, localize and quantify pathological features in almost every macular and retinal disease. Convolutional neural networks thereby mimic the path of the human brain for object recognition through learning of pathological features from training sets, supervised ML, or even extrapolation from patterns recognized independently, unsupervised ML. The methods of AI-based retinal analyses are diverse and differ widely in their applicability, interpretability and reliability in different datasets and diseases. Fully automated AI-based systems have recently been approved for screening of diabetic retinopathy (DR). The overall potential of ML/DL includes screening, diagnostic grading as well as guidance of therapy with automated detection of disease activity, recurrences, quantification of therapeutic effects and identification of relevant targets for novel therapeutic approaches. Prediction and prognostic conclusions further expand the potential benefit of AI in retina which will enable personalized health care as well as large scale management and will empower the ophthalmologist to provide high quality diagnosis/therapy and successfully deal with the complexity of 21st century ophthalmology.