tbuckley/cabot-search huggingface dataset:
Mobilized Endothelial Progenitor Cells by Granulocyte-Macrophage Colony-Stimulating Factor Accelerate Reendothelialization and Reduce Vascular Inflammation After Intravascular Radiation
Authors: Hyun-JaiCho, Hyo-SooKim, Myoung-MookLee, Dae-HeeKim, Hyun-JuYang, JinHur, Kyoung-KookHwang, SeilOh, Young-JinChoi, In-HoChae, Byung-HeeOh, Yun-ShikChoi, KennethWalsh, Young-BaePark
Journal: Circulation (2003)

Background— Endothelial progenitor cells (EPCs) play a pivotal role in repair and regeneration of damaged vessels. We investigated the role of mobilized EPCs in the healing process after intravascular radiation therapy. Methods and Results— One iliac artery of hypercholesterolemic rabbits was subjected to balloon injury and intravascular radiation with a Re-188 balloon and the contralateral iliac artery to balloon injury only. Rabbits received granulocyte-macrophage colony-stimulating factor (recombinant human GM-CSF) (60 μg/d subcutaneously) daily for 1 week, either 7 days before the angioplasty or at the time of angioplasty. Control rabbits received human albumin. GM-CSF significantly increased the double-positive (CD31+ and KDR+) fraction in peripheral blood monocytes and showed a higher number of EPCs than albumin after culture and, furthermore, enhanced migration and incorporation of EPCs. In the albumin group, intravascular radiation therapy reduced neointimal hyperplasia but delayed reendothelializ...
The Study of Left Ventricular Function in Man by Increasing Resistance to Ventricular Ejection with Angiotensin
Authors: Johnross, Eugenebraunwald
Journal: Circulation (1964)

The performance of the left ventricle was studied in 18 patients by determining the effects of increasing the resistance to left ventricular ejection with graded infusions of angiotensin. By this means, left ventricular function curves, i.e., the relationship between ventricular end-diastolic pressure and stroke work, were constructed. In patients without left ventricular disease the ventricular function curves exhibited steep ascending limbs, large increases in stroke work occurring with small elevations of left ventricular end-diastolic pressure; in contrast, in patients with cardiac disease, the ventricular function curves were either flat, i.e., small changes in stroke work occurred with large elevations in left ventricular end-diastolic pressure, or the function curves exhibited descending limbs. Prior to the infusion of angiotensin many patients with and without depression of their left ventricular function curves had comparable values of left ventricular end-diastolic pressure and stroke work. Thus...
Selection-driven cost-efficiency optimization of transcripts modulates gene evolutionary rate in bacteria
Authors: Emily A. Seward, Steven Kelly
Journal: Genome biology (2018)

Most amino acids are encoded by multiple synonymous codons. However, synonymous codons are not used equally, and this biased codon use varies between different organisms. It has previously been shown that both selection acting to increase codon translational efficiency and selection acting to decrease codon biosynthetic cost contribute to differences in codon bias. However, it is unknown how these two factors interact or how they affect molecular sequence evolution. Through analysis of 1320 bacterial genomes, we show that bacterial genes are subject to multi-objective selection-driven optimization of codon use. Here, selection acts to simultaneously decrease transcript biosynthetic cost and increase transcript translational efficiency, with highly expressed genes under the greatest selection. This optimization is not simply a consequence of the more translationally efficient codons being less expensive to synthesize. Instead, we show that transfer RNA gene copy number alters the cost-efficiency trade-off of synonymous codons such that, for many species, selection acting on transcript biosynthetic cost and translational efficiency act in opposition. Finally, we show that genes highly optimized to reduce cost and increase efficiency show reduced rates of synonymous and non-synonymous mutation. This analysis provides a simple mechanistic explanation for variation in evolutionary rate between genes that depends on selection-driven cost-efficiency optimization of the transcript. These findings reveal how optimization of resource allocation to messenger RNA synthesis is a critical factor that determines both the evolution and composition of genes.
Abstract 40: Investigation into Heart Aging
Authors: Kai Chen, Shirley Wang, Jianglei Chen, Wilton Sun, Fnu M Ullha, Zhongjie Sun
Journal: Circulation Research (2017)

Background: Aging is a well-known contributing factor for heart failure, which is the leading cause of death world-wide. However, the underlying mechanisms of heart aging are less clear. Methods and Results: We found that the overall heart size, heart weight, and cardiomyocyte size were increased in aged mice (24 months). Cardiac fibrosis was also found in old mice. Therefore, aging induced cardiac hypertrophy and remodeling. Concomitantly, heart function declined significantly in aged mice, as evidenced by decreases in fraction shorting, ejection fraction, left ventricular stroke volume, and cardiac output. Renal and circulating Klotho levels were dramatically decreased, suggesting that there may be association between a decrease in Klotho and heart failure in aged mice. Using Klotho mutant homozygous (KL-/-) mice, we found that Klotho deficiency caused cardiac hypertrophy and heart failure. Interestingly, treatment with secreted Klotho prevented cardiac hypertrophy, remodeling and heart failure in aged mice and KL (-/-) mice. Secreted Klotho treatment attenuated excessive cardiac oxidative stress and apoptosis in old mice and KL (-/-) mice. In this study, all KL (-/-) mice were fed with low-phosphate diet which maintained serum phosphate at the normal level, suggesting that the cardioprotective effects of secreted Klotho were independent of phosphate metabolism. Mechanistically, Klotho deficiency suppressed glutathione reductase (GR) expression and activity in the heart through downregulation of a transcription factor Nrf2. Furthermore, heart-specific overexpression of GR prevented aging- and Klotho deficiency-induced heart failure, excessive cardiac oxidative stress and apoptosis in old mice and KL (-/-) mice. Conclusions: Klotho deficiency plays an important role in aging-related heart failure. Secreted Klotho protects against heart aging via activation of glutathione reductase which attenuates cardiac oxidative stress, apoptosis and fibrosis.
Anti-Folate Receptor Alpha–Directed Antibody Therapies Restrict the Growth of Triple-negative Breast Cancer
Authors: Anthony Cheung, James Opzoomer, Kristina M. Ilieva, Patrycja Gazinska, Ricarda M. Hoffmann, Hasan Mirza, Rebecca Marlow, Erika Francesch-Domenech, Matthew Fittall, Diana Dominguez Rodriguez, Angela Clifford, Luned Badder, Nirmesh Patel, Silvia Mele, Giulia Pellizzari, Heather J. Bax, Silvia Crescioli, Gyula Petranyi, Daniel Larcombe-Young, Debra H. Josephs, Silvana Canevari, Mariangela Figini, Sarah Pinder, Frank O. Nestle, Cheryl Gillett, James F. Spicer, Anita Grigoriadis, Andrew N.J. Tutt, Sophia N. Karagiannis
Journal: Clinical Cancer Research (2018)

Abstract Purpose: Highly aggressive triple-negative breast cancers (TNBCs) lack validated therapeutic targets and have high risk of metastatic disease. Folate receptor alpha (FRα) is a central mediator of cell growth regulation that could serve as an important target for cancer therapy. Experimental Design: We evaluated FRα expression in breast cancers by genomic (n = 3,414) and IHC (n = 323) analyses and its association with clinical parameters and outcomes. We measured the functional contributions of FRα in TNBC biology by RNA interference and the antitumor functions of an antibody recognizing FRα (MOv18-IgG1), in vitro, and in human TNBC xenograft models. Results: FRα is overexpressed in significant proportions of aggressive basal like/TNBC tumors, and in postneoadjuvant chemotherapy–residual disease associated with a high risk of relapse. Expression is associated with worse overall survival. TNBCs show dysregulated expression of thymidylate synthase, folate hydrolase 1, and methylenetetrahydrofolate reductase, involved in folate metabolism. RNA interference to deplete FRα decreased Src and ERK signaling and resulted in reduction of cell growth. An anti-FRα antibody (MOv18-IgG1) conjugated with a Src inhibitor significantly restricted TNBC xenograft growth. Moreover, MOv18-IgG1 triggered immune-dependent cancer cell death in vitro by human volunteer and breast cancer patient immune cells, and significantly restricted orthotopic and patient-derived xenograft growth. Conclusions: FRα is overexpressed in high-grade TNBC and postchemotherapy residual tumors. It participates in cancer cell signaling and presents a promising target for therapeutic strategies such as ADCs, or passive immunotherapy priming Fc-mediated antitumor immune cell responses. Clin Cancer Res; 24(20); 5098–111. ©2018 AACR.
Genome-scale CRISPR-Cas9 knockout screening in gastrointestinal stromal tumor with Imatinib resistance
Authors: Jie Cao, Jianchang Wei, Ping Yang, Tong Zhang, Zhuanpeng Chen, Feng He, Fang Wei, Huacui Chen, He Hu, Junbin Zhong, Zhi Yang, Wensong Cai, Wanglin Li, Qiang Wang
Journal: Molecular Cancer (2018)
Role of Endothelin-1 in Beagles With Dehydromonocrotaline-Induced Pulmonary Hypertension
Authors: MorihitoOkada, ChojiroYamashita, MasayoshiOkada, KenjiOkada
Journal: Circulation (1995)

Background Although plasma levels of endothelin-1 (ET-1) increase in patients with pulmonary hypertension (PH), its role in PH is unknown. We investigated the contribution of endogenous ET-1 to cardiopulmonary changes in beagles with dehydromonocrotaline (DMCT)-induced PH. Methods and Results Eight 3-month-old beagles were given a single injection of 3 mg/kg DMCT via the right atrium. During the 8 weeks after injection, the mean pulmonary arterial pressure (PAP) and plasma ET-1 level increased significantly from 11.6±2.3 to 35.9±7.1 mm Hg and from 1.24±0.25 to 3.25±0.94 pg/mL, respectively. In controls, ET-1 infusion elevated the systemic arterial pressure (SAP) but did not alter PAP. In PH beagles, ET-1 infusion increased SAP, which was attenuated by FR139317 (an endothelin type [ET] A receptor antagonist), and produced a dose-dependent decrease in PAP, which was attenuated by RES-701-1 (an ETB receptor antagonist). In PH beagles, FR139317 infusion decreased PAP, and RES-701-1 infusion increased PAP. Sar...
Abstract 1312: Predicting ligand-dependent tumors from multi-dimensional signaling features
Authors: Helge Hass, Kristina Masson, Sibylle Wohlgemuth, Violette Paragas, John E. Allen, Mark Sevecka, Emily Pace, Jens Timmer, Joerg Stelling, Gavin MacBeath, Birgit Schoeberl, Andreas Raue
Journal: Cancer Research (2018)

Abstract Receptor tyrosine kinases (RTKs) are high-affinity cell surface receptors for growth factors that are frequently deregulated in cancer. Signaling through these receptors has been associated with increased cancer cell proliferation and resistance to cytotoxic therapies. To block this detrimental signaling, many companies are developing inhibitory antibodies against various RTKs. A key challenge in clinical studies is the optimal stratification of patients who may benefit from these therapies. For an RTK targeted antibody, the detection of the respective growth factor in the tumor microenvironment may be an important bio-marker. Beyond the physical presence of the growth factor, the decision whether a cancer cell will respond to growth factor-induced signals is governed by complex intra-cellular signaling networks. We compared different approaches to predict cellular responses and will highlight a hybrid approach that combines mechanistic modeling based on ordinary differential equations with a machine learning algorithm. The models are trained on in vitro drug response screens and then applied to predict response in patient samples. The mechanistic models are trained on quantitative data from signal transduction studies as well as RNAseq data for cellular characterization. Using the hybrid approach, a correlation between growth factor expression in the tumor microenvironment and its predicted response was identified. This supports the hypothesis of addiction of tumors to growth factors abundant in the tumor microenvironment, and might enable more robust patient stratification in the future. Citation Format: Helge Hass, Kristina Masson, Sibylle Wohlgemuth, Violette Paragas, John E. Allen, Mark Sevecka, Emily Pace, Jens Timmer, Joerg Stelling, Gavin MacBeath, Birgit Schoeberl, Andreas Raue. Predicting ligand-dependent tumors from multi-dimensional signaling features [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 1312.
Abstract 2280: Systematic analysis of causal noncoding mutations in pediatric B-cell acute lymphoblastic leukemia
Authors: Bing He, Peng Gao, Yang Ding, Chia-Hui Chen, Hannah Kim, Stephen P. Hunger, Sarah K. Tasian, Kai Tan
Journal: Cancer Research (2018)

Abstract B cell acute lymphoblastic leukemia (B-ALL) is the most prevalent childhood hematological malignancy and the leading cause of childhood cancer-related mortality. To date, the molecular pathogenesis of B-ALL has not been completely defined, limiting our ability to develop targeted therapies. Despite great advances in identifying mutations in cancer patients, the functional consequences of noncoding mutations are still difficult to interpret. Transcriptional enhancers are key determinants of tissue-specific gene expression. Several recent studies have reported novel mutations in cancer genome that disrupt enhance function and thus expression of their target genes. However, systematic detection of noncoding mutations that perturb either enhancer sequence or enhancer-promoter (EP) interaction is still challenging. Such analysis can help to identify novel driver mutations and improve our understanding of the disease. Here we introduce a novel algorithm for identifying causal mutations that disrupt enhancer function and target gene expression in B-ALL. The algorithm takes as input whole genome sequencing (WGS) and RNA-Seq data to predict causal noncoding mutations. We apply the algorithm to analyze data from 163 B-ALL patients and identify 332 noncoding mutations that disrupt EP interactions and gene expression. Our analysis recapitulate previously known translocations such as t(14;X) that leads to CRLF2 overexpression, as well as novel causal translocations that leads to deregulation of TMEM106A and MIR663B. Systematic analysis of the identified mutations indicated that SNVs in enhancer region have a higher variant allele frequency (VAF), suggesting enhancer mutations likely occur earlier than coding mutations during oncogenesis. In addition, pathway analysis show that the majority (57%) of mutations perturbing metabolic pathways are noncoding mutations. Further analysis and experimental follow-up of the predicted noncoding mutations may reveal novel insights into the pathogenesis of B-cell ALL. Citation Format: Bing He, Peng Gao, Yang Ding, Chia-Hui Chen, Hannah Kim, Stephen P. Hunger, Sarah K. Tasian, Kai Tan. Systematic analysis of causal noncoding mutations in pediatric B-cell acute lymphoblastic leukemia [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 2280.
Abstract 3932: Metabolic biomarkers predict the sensitivity to phosphatidylinositol 3-kinase pathway inhibitor in small-cell lung carcinoma
Authors: Shigeki Umemura, Hideki Makinoshima, Genichiro Ishii, Takehiko Sasaki, Hiroyasu Esumi, Koichi Goto, Katsuya Tsuchihara
Journal: Cancer Research (2018)

Abstract Comprehensive genomic analysis has revealed that the PI3K/AKT/mTOR pathway is a feasible therapeutic target in small-cell lung carcinoma (SCLC). However, biomarkers to identify patients likely to benefit from inhibitors of this pathway have not been identified. Here we show that metabolic features determine sensitivity to the PI3K/mTOR dual inhibitor gedatolisib in SCLC cells. We analyzed the phosphatidyl lipid profile including the acyl groups of 11 SCLC cell lines using electrospray ionization mass spectrometry. We found that a specific phosphatidylinositol (3,4,5)-triphosphate (PIP3) subspecies lipid product, PIP3 (38:4), is predictive in assessing sensitivity to gedatolisib. We generated a large-scale metabolomic dataset for 28 SCLC cell lines. Notably, we found that higher amounts of purine-related aqueous metabolites such as hypoxanthine led to resistance to PI3K pathway inhibition. The levels of the mRNA encoding hypoxanthine phosphoribosyl transferase 1 (HPRT1), a key component of the purine salvage pathway, differed significantly between SCLC cells sensitive or resistant to gedatolisib. Loss of HPRT1 in SCLC cells decreased cellular proliferation in the presence of gedatolisib compared with a control. Further, complementation with purine metabolites could reverse the vulnerability to targeting of the PI3K pathway in SCLC cells normally sensitive to gedatolisib. These results indicate that the mechanism of resistance to PI3K pathway inhibitors is mediated by activation of the purine salvage pathway, which supplies purine resources for nucleotide biosynthesis. Metabolic profiles of clinical samples of SCLC revealed that purine-related metabolites were higher in SCLC tumor tissues, suggesting that higher amounts of purine-related aqueous metabolites might be characteristic of SCLC biology. Metabolomics is a powerful approach for identifying novel therapeutic biomarkers applicable to SCLC treatment. Citation Format: Shigeki Umemura, Hideki Makinoshima, Genichiro Ishii, Takehiko Sasaki, Hiroyasu Esumi, Koichi Goto, Katsuya Tsuchihara. Metabolic biomarkers predict the sensitivity to phosphatidylinositol 3-kinase pathway inhibitor in small-cell lung 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 3932.
Weaning From Mechanical Cardiac Support in Patients With Idiopathic Dilated Cardiomyopathy
Authors: JohannesMüller, GerdWallukat, Yu-GuoWeng, MichaelDandel, SusanneSpiegelsberger, SabineSemrau, KerstenBrandes, VassilisTheodoridis, MatthiasLoebe, RudolfMeyer, RolandHetzer
Journal: Circulation (1997)

Background Implantation of mechanical cardiac support systems (MCSS) in patients with idiopathic dilated cardiomyopathy (IDC) may improve cardiac function and allow explantation of the device. We report of long-term effects of ventricular unloading on cardiac function, humoral anti-β1-adrenoceptor autoantibodies (A-β1-AABs), and myocardial fibrosis. Methods and Results Seventeen patients in New York Heart Association functional class IV with nonischemic IDC received MCSS. All had a cardiac index of  68 mm and tested positive for A-β1-AABs. Echocardiographic evaluation, serum tests for A-β1-AABs, and histological assessment of myocardial fibrosis were performed before and after MCSS implantation. The mean support duration was 230±201 days. Six patients died, four were transplanted, and two are still on MCSS. Five patients with significant cardiac re...
Prevalence and Long-Term Outcome of Aortic Prosthesis–Patient Mismatch in Patients With Paradoxical Low-Flow Severe Aortic Stenosis
Authors: DaniaMohty, CyrilleBoulogne, JulienMagne, PhilippePibarot, NajmeddineEchahidi, ElisabethCornu, JeanDumesnil, MarcLaskar, PatriceVirot, VictorAboyans
Journal: Circulation (2014)

Background—Patients with severe aortic stenosis (AS) and paradoxical low flow (PLF) have worse outcome compared with those with normal flow. Furthermore, prosthesis–patient mismatch (PPM) after aortic valve replacement is a predictor of reduced survival. However, the prevalence and prognostic impact of PPM in patients with PLF-AS are unknown. We aimed to analyze the prevalence and long-term survival of PPM in patients with PLF-AS. Methods and Results—Between 2000 and 2010, 677 patients with severe AS, preserved left ventricular ejection fraction, and aortic valve replacement were included (74±8 years; 42% women; aortic valve area, 0.69±0.16 cm2). A PLF (indexed stroke volume ≤35 mL/m2) was found in 26%, and after aortic valve replacement, 54% of patients had PPM, defined as an indexed effective orifice area ≤0.85 cm2/m2. The combined presence of PLF and PPM was found in 15%. Compared with patients with noPLF/noPPM, those with PLF/PPM were significantly older, with more comorbidities. They also received sm...
Abstract 1996: Nuclear factor (erythroid-derived 2)-like 2 promotes tumor-initiating cell lineage and drug resistance in hepatocellular carcinoma
Authors: Hoi Wing Leung, Terence Kin Wah Lee
Journal: Cancer Research (2018)

Abstract Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide. The long-term prognosis of HCC remains unsatisfactory due to high recurrence rates and chemoresistance. The efficacy of sorafenib, the only FDA-approved molecularly targeted drug in advanced hepatocellular carcinoma (HCC) is limited by acquired resistance. Increasing evidences showed that liver tumor-initiating cells (T-ICs) is the source of acquired resistance and metastasis. We have previously established sorafenib-resistant HCC cells both in vitro and PDTX models and demonstrated that these cells are endowed with enhanced T-IC properties. Interestingly, nuclear factor (erythroid-derived 2)-like 2 (NRF2) expression was elevated in these resistant cells. The transcription factor NRF2 has long been considered as a tumour suppressor, as it can regulate cellular antioxidant response to protect cells from oxidative stress, chemotherapeutic agents and radiotherapy. In HCC, NRF2 level was up-regulated, and its expression was correlated with tumor differentiation, metastasis, and tumor size, revealing its oncogenic role. By lentiviral based knockdown approach, we found that NRF2 repression suppressed liver T-IC properties including self-renewal, in vivo tumorigenicity, HCC invasiveness and expression of liver T-IC markers. In addition, we found that NRF2 repression not only sensitized HCC cells to sorafenib but also to other chemotherapeutic drugs including doxorubicin and fluorouracil. Mechanistically, the signaling cascade related to sonic hedgehog pathway was greatly suppressed in NRF2 knockdown HCC cells, when compared with control counterparts. Collectively, NRF2 was involved in drug resistance, invasion and migration, tumorigenicity and self-renewal via regulating T-IC properties at least in part through direct regulation of sonic hedgehog pathway in HCC. Targeting NRF2 mediated signaling cascade alone or in combination with other treatment modalities may be a new a potential therapeutic approach for treatment of HCC. Citation Format: Hoi Wing Leung, Terence Kin Wah Lee. Nuclear factor (erythroid-derived 2)-like 2 promotes tumor-initiating cell lineage and drug resistance in 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 1996.