tbuckley/cabot-search huggingface dataset:
Stromal Cell–Derived Factor-1 and CXCR4 Interaction Is Critical for Development of Transplant Arteriosclerosis
Authors: HideyasuSakihama, TaroMasunaga, KenichiroYamashita, TakuHashimoto, ManabuInobe, SatoruTodo, ToshimitsuUede
Journal: Circulation (2004)

Background— Posttransplant chronic allograft deterioration associated with development of transplant arteriosclerosis (TA) remains an unresolved problem. Recent studies suggest that the smooth muscle cells (SMCs) constituting the neointima are derived from recipient hematopoietic stem cells (HSCs). However, the underlying mechanisms of the process are not yet fully elucidated. Methods and Results— We examined the genes expressed in allografts at different stages of TA development using a mice aortic transplantation model. Genes were analyzed by a differential mRNA display technique. We show that stromal cell–derived factor-1α (SDF-1α) is a critical molecular target for the treatment of TA. During the course of TA, intragraft SDF-1α expression was upregulated with time, and the circulating HSCs expressing its counterreceptor CXCR4 increased in the recipients receiving allografts. CXCR4-positive HSCs, derived from transplant recipients, migrated into allografts via microvessels in the adventitia and then to...
Myocardial Regeneration Therapy for Heart Failure
Authors: ShigeruMiyagawa, YoshikiSawa, SatoshiTaketani, NaomasaKawaguchi, ToshikazuNakamura, NariakiMatsuura, HikaruMatsuda
Journal: Circulation (2002)

Background— We hypothesized that transfection of the gene for human hepatocyte growth factor (hHGF) combined with cellular cardiomyoplasty might regenerate the impaired myocardium. Methods and Results— We used a ligation model of proximal left anterior descending coronary artery (LAD) of Lewis rats. Two weeks after LAD ligation, 3 different treatments were conducted: (1) neonatal rat cardiomyocytes group (106 cells, T group, n=11), (2) HVJ-liposomes bearing the hHGF gene group (H group, n=10), and (3) combined (T-H group, n=10). The injection site was the scar area of myocardial infarction. For control, culture medium was injected (C group, n=13). Echocardiography demonstrated that cardiac performance was significantly ameliorated in the T-H group 4 and 8 weeks after injection. Contrast echocardiography also showed a marked increase in myocardial perfusion in the T-H group but not in the other groups. In the T-H group, neovascularization and a marked reduction of fibrosis were observed histologically. In ...
Abstract 4293: Glycogen synthase kinase 3 b maintains mitotic arrest by regulating mitotic checkpoint complex levels
Authors: Maisha S. Rashid, William R. Taylor
Journal: Cancer Research (2018)

Abstract The cell cycle is regulated by checkpoints that ensure genomic integrity and proper cell division. We are investigating the role of a multifunctional ser/thr kinase, glycogen synthase kinase 3 (GSK3), in the regulation of the mitotic checkpoint. Our data show that spindle toxin-induced mitotic arrest is relieved in multiple cancer cell lines by the GSK3 inhibitors, SB 415286 (SB), RO-81220 (RO) and lithium chloride. Additionally, the mitotic index is reduced in CRISPR-generated GSK3β knockout human cells and GSK3β knockout mouse embryo fibroblasts compared to wild type cells in the presence of taxol. Mitotic arrest is dependent on the mitotic checkpoint complex (MCC), composed of Mad2, BubR1, Cdc20 and Bub1. GSK3 appears to target the MCC to regulate mitotic arrest. For example, Mad2, BubR1 and Bub1 localization at kinetochores and MCC assembly were both reduced by co-treatment of GSK3 inhibitors and spindle toxin compared to spindle toxin alone. These data imply that GSK3β plays a role in maintaining the mitotic checkpoint. The strength of the checkpoint was determined to act like a rheostat rather than a toggle-switch, as cells undergo mitotic slippage after prolonged arrest in spindle toxins. Our data indicates that GSK3 regulates the strength of the checkpoint, as illustrated by time lapse-imaging. GSK3-inhibition induced exit was observed to be dependent on how long the cells were arrested in mitosis prior to GSK3-inhibitor addition. GSK3 inhibition in taxol also decreases the amount of KnL1, part of the KMN network forming the kinetochore, at the centromeres. This indicates a regulatory role of GSK3 in kinetochore assembly and function. The Wnt-signaling pathway and the PI3K/Akt signaling pathway are known upstream regulators of GSK3β, negatively regulating GSK3β activity. Our data shows that inhibiting Wnt-signaling and PI3K/Akt-signaling in the presence of taxol, induces a longer mitotic arrest compared to taxol alone. This suggests that GSK3β is regulated upstream by the Wnt- and the PI3K/Akt signaling archs to control mitosis. Finally, our data implicated that de-acetylase sirtuin2 is a downstream target of GSK3 in its mitotic regulatory role. Our observations indicate a novel regulator of the checkpoint and novel insight in connecting growth-signaling pathways with mitosis. Citation Format: Maisha S. Rashid, William R. Taylor. Glycogen synthase kinase 3 b maintains mitotic arrest by regulating mitotic checkpoint complex levels [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 4293.
Abstract 4433: Upregulation of <i>BLU</i> tumor suppressor gene by miR-34a
Authors: Shinichiro Ohno, Yoshihiro Sambu, Keiki Oikawa, Yoshitaka Naito, Yuichirou Harada, Masahiko Kuroda
Journal: Cancer Research (2018)

Abstract miR-34a is down-regulated in several tumor tissues and well known as strong tumor suppresser miRNA. However, the mechanisms of tumor suppression by miR-34a remain unclear. To elucidate the mechanisms of tumor suppression by miR-34a, we performed microarray analysis of miR-34a transfected cells. Interestingly, we found that the number of up-regulated genes was larger than down-regulated genes by the transfection of miR-34a. The tumor suppresser BLU (ZMYND10) is strongly up-regulated by miR-34a that primarily expressed in the normal lung and down-regulated in non-small cell lung cancer (NSCLC). Therefore, we investigated the possibility that miR-34a inhibits lung cancer development through inducing BLU expression. It was recently reported that miRNA also regulate transcription in the nucleus through binding to the lncRNA from promoter locus. Because, the predicted two binding sites of miR-34a are located in the BLU promoter locus, we searched the lncRNA expressed from the BLU promoter locus. As a result, we identified the lncRNA from the BLU promoter and siRNA against the lncRNA also induced BLU expression. These results suggest that miR-34a induced tumor suppresser BLU through the binding to the promoter-associated lncRNA. Citation Format: Shinichiro Ohno, Yoshihiro Sambu, Keiki Oikawa, Yoshitaka Naito, Yuichirou Harada, Masahiko Kuroda. Upregulation of BLU tumor suppressor gene by miR-34a [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 4433.
Regulation of Vascular Inflammation and Remodeling by ETS Factors
Authors: PeterOettgen
Journal: Circulation Research (2006)

The ETS (E26 Transformation-specific Sequence) factors are comprised of a family of transcription factors that share a highly conserved DNA binding domain. Although originally described for their role as protooncogenes in the development of several types of human cancer, they have subsequently been shown to regulate a wide variety of biological processes including cellular growth and differentiation under normal and pathological conditions. As transcription factors, they can either function as activators or repressors of gene expression. Several ETS family members are expressed in cells of vascular origin, including endothelial cells and vascular smooth muscle cells, where they regulate the expression of a number of vascular-specific genes. In the past few years, emerging evidence supports a novel role for selected ETS family members in the regulation of vascular inflammation and remodeling. ETS factor expression can be induced by proinflammatory cytokines, growth factors, and vasoactive peptides. Example...
Abstract 4674: IL-35 regulates anti-tumor immune response in pancreatic ductal adenocarcinoma
Authors: Bhalchandra Mirlekar, Ryan Searcy, Yuliya Pylayeva-Gupta
Journal: Cancer Research (2018)

Abstract Despite advances in our understanding of the mutational landscape in pancreatic ductal adenocarcinoma (PDA), this devastating disease is now the third-leading cause of U.S. cancer-related deaths. While recent successes of cancer immunotherapy have generated considerable excitement, this form of treatment has been largely ineffective in patients with pancreatic cancer. A major barrier for immunotherapeutic approaches is marked immunosuppression within the PDA milieu. We have previously identified a novel role for IL-35 producing B regulatory cells in the pathogenesis of pancreatic cancer. However, little is known about the mechanisms behind IL-35 activity in cancer. The overarching goal of this project is to elucidate molecular and cellular mechanisms by which IL-35 facilitates the emergence of pancreatic cancer. Our results demonstrate that IL-35, but not IL-10, potentiates PDA growth. This correlates with induction of immunosuppressive T regulatory cells (Treg) and suppression of T effector cell (Teff) and cytotoxic CD8+ T cell activity, suggesting that IL-35 controls anti-tumor immune responses in PDA. Remarkably, while PDA is typically resistant to anti-PD1 immunotherapy, IL-35 deficiency converted PDA from immunologically ‘cold' to ‘hot' tumor, which allowed for a robust synergistic reduction in tumor growth in response to anti-PD-1 treatment. Insights gleaned from these and further mechanistic studies of IL-35 in PDA may be expeditiously translated into IL-35 targeted combination immunotherapy. Citation Format: Bhalchandra Mirlekar, Ryan Searcy, Yuliya Pylayeva-Gupta. IL-35 regulates anti-tumor immune response in pancreatic ductal adenocarcinoma [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 4674.
Abstract 12692: Contemporary Evidence on the Risks of Early Carotid Revascularization After Stroke in Evolution
Authors: Paola De Rango, Martin Brown, Seemant Chaturvedi, Virginia Howard, Tudor Jovin, Michael Mazya, Maurizio Paciaroni, Luca Farchioni, Valeria Caso
Journal: Circulation (2015)

Introduction: Current stroke guidelines suggest performing carotid endarterectomy (CEA) within 2 weeks after an ischemic stroke or TIA caused by severe carotid stenosis. However, early carotid revascularization in patients in unstable neurological condition after acute stroke (“stroke in evolution”, SIE) is controversial because of the risk of new ischemic stroke, intracerebral hemorrhage (ICH) and death. Published studies have not found a consistent benefit in this cohort. Hypothesis: The aim of this systematic review and meta-analysis was to document outcomes after urgent carotid intervention performed within 2 weeks from SIE. Methods: A systematic review of studies published in the last 8 years (2008-2015) reporting the risk of stroke, death and ICH following carotid intervention performed within 2 weeks from acute stroke in patients with SIE, was undertaken. Pooled proportion of periprocedural stroke, stroke or death and ICH were obtained with proportion meta-analysis and random effects model. Results: Out of 47 published series reporting on 2-week timing of carotid intervention after ischemic neurological event, only 15 separately described periprocedural risks for patients with SIE. In 8 studies patients underwent thrombolysis for acute stroke management of SIE before carotid revascularization. The pooled proportion of periprocedural stroke was 5.0% (95% Confidence Intervals, CI, 3.3 - 7.1), ranging 0 -14.2% among different studies. Figure. The pooled proportion of periprocedural risk for the combined of stroke or death was 4.7% (95% CI 2.9 -7.0) and that of periprocedural ICH, 1.2% (95% CI 0.4-2.4). Conclusions: The current risk of stroke, death and ICH after urgent carotid revascularization performed within 2 weeks for patients with stroke in evolution is lower than that anticipated in previous studies. Nevertheless, due to the heterogeneity in reporting and differential in patient selection, these findings should be interpreted with caution.
Abstract 5154: Semaphorin 6A attenuates the migration capability of lung cancer cells via the NRF2/HMOX1 axis
Authors: Li-Han Chen, Che-Yu Liao, Eric Y. Chuang, Mong-Hsun Tsai
Journal: Cancer Research (2018)

Abstract Cell migration is a fundamental feature of cancer recurrence. Since recurrence is correlated with high mortality in lung cancer, it follows that reducing cell migration would decrease recurrence and increase survival rates. The goal of this study was to determine the role of SEMA6A in cell migration. Semaphorin 6A (SEMA6A), a protein initially known as a regulator of axonal guidance, is down-regulated in lung cancer tissue, and low levels of SEMA6A are associated with cancer recurrence. Thus, we hypothesized that SEMA6A could suppress cancer cell migration. In this study, we found that the migration capability of H1299 lung cancer cells decreased with SEMA6A overexpression, while it increased with SEMA6A silencing. Reduction in migration was observed only with the full length protein and not with the extracellular ectodomain construct, suggesting that a reverse signaling mechanism is used to mediate the effects of SEMA6A on migration. Moreover, silencing of the cellular homeostasis protein HMOX1 and/or the transcription factor NRF2 reversed the migration-suppressing effect of SEMA6A and the SEMA6A-driven alterations in expression of PLAU and IGFBP3, both downstream effectors of HMOX1. Taken together, these results demonstrate that SEMA6A is a potential suppressor of migration that functions through the NRF2/HMOX1 axis. Our results explain why low SEMA6A is linked to high recurrence in the clinical setting and suggest that SEMA6A could be useful as a biomarker or target in lung cancer therapy. Citation Format: Li-Han Chen, Che-Yu Liao, Eric Y. Chuang, Mong-Hsun Tsai. Semaphorin 6A attenuates the migration capability of lung cancer cells via the NRF2/HMOX1 axis [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 5154.
Vectorcardiographic Investigations on the Auricles
Authors: Rudolfwenger, Klemenshupka, Erwinwick
Journal: Circulation (1955)

Vectorcardiography demonstrates very clearly the method of auricular activation and shows its spatial development. This is illustrated and discussed in this paper as it occurs in normal subjects, in a patient with an ectopic auricular pacemaker, and in patients with pulmonary heart disease. Changes similar to those seen in patients with cor pulmonale have been observed in dogs after partial occlusion of the pulmonary artery. Remarkable alterations of the auricular vectorcardiogram have been seen in patients with mitral heart disease after commissurotomy.
T-Tubule Function in Mammalian Cardiac Myocytes
Authors: FabienBrette, CliveOrchard
Journal: Circulation Research (2003)

The transverse tubules (t-tubules) of mammalian cardiac ventricular myocytes are invaginations of the surface membrane. Recent studies have suggested that the structure and function of the t-tubules are more complex than previously believed; in particular, many of the proteins involved in cellular Ca2+ cycling appear to be concentrated at the t-tubule. Thus, the t-tubules are an important determinant of cardiac cell function, especially as the main site of excitation-contraction coupling, ensuring spatially and temporally synchronous Ca2+ release throughout the cell. Changes in t-tubule structure and protein expression occur during development and in heart failure, so that changes in the t-tubules may contribute to the functional changes observed in these conditions. The purpose of this review is to provide an overview of recent studies of t-tubule structure and function in cardiac myocytes.
Left Ventricular Fibromuscular Band Is Not a Specific Substrate for Idiopathic Left Ventricular Tachycardia
Authors: Fun-ChungLin, Ming-ShienWen, Chun-ChiehWang, San-JouYeh, DelonWu
Journal: Circulation (1996)

Background A fibromuscular band has been detected in patients with idiopathic left ventricular tachycardia, and this band has been suggested to be the anatomic substrate for the arrhythmia. Whether the fibromuscular band is a specific substrate for the tachycardia was systematically evaluated in a large group of consecutive patients with and without idiopathic left ventricular tachycardia. Methods and Results Conventional transthoracic two-dimensional echocardiography and multiplane transesophageal echocardiography were performed in 18 patients with idiopathic left ventricular tachycardia that was responsive to calcium blockers (group 1, tachycardia patients) and 40 patients with paroxysmal supraventricular tachycardia (group 2, control patients). There were 17 men and 1 woman, with a mean age of 29±11 years, in group 1 patients, and 21 men and 19 women, with a mean age of 42±12 years, in group 2 patients. The QRS morphology during tachycardia in group 1 patients displayed a pattern of right bundle-branch...
Abstract 1857: Hydrophilic As4S4 nanoparticles inhibit K562 cell activity through ROS modulation and autophagy induction
Authors: Tao Wang, Tao Wen, Jie Meng, Jian Liu, Haiyan Xu
Journal: Cancer Research (2018)

Abstract Realgar is crystalized As4S4 that has been demonstrated to be effective in treating hematologic malignancies by oral administration [1]. Nevertheless, the low bioavailability due to its poor solubility in neutral or acidic aqueous solution not only leads to the over dose administration of arsenic in clinical practice but also hinders the study of pharmaceutical mechanism for realgar. We previously reported a solid dispersion of realgar (e-As4S4), in which the crystal realgar (r-As4S4) was fabricated into nanoparticles encapsulated by the hydrophilic polymer using the hot melting co-extrusion technique [2]. The e-As4S4 exhibited much higher bioavailability and improved treatment efficacy in the acute myeloid leukemia (AML) animal model compared with r-As4S4. This study investigated the effect of e-As4S4 has inhibitory on K562 cells and the underlying mechanisms. We showed that e-As4S4 down regulated the cellular ROS and HIF1-alpha in a concentration dependent manner. The low concentration of e-As4S4 induced both erythroid and megakaryocytic differentiation in the cells, evidenced by the up-regulation of CD235a and CD41 respectively, and the higher concentration induced cell cycle arrested in G2/M phase and apoptosis. Consistently, the proliferation rate and oxygen-consuming rate of the cells were reduced. Meanwhile the autophagy was detected when the cells were treated with e-As4S4, as well as the variation phosphorylation for p38 and Erk. These effects together induced the significant elimination of Bcr-Abl. In conclusion, e-As4S4 induced the bi-direction differentiation by modulating cellular ROS and inducing autophagy of the cells. These results therefore suggest that e-As4S4 represents a promising orally administrated drug for the treatment of CML. Reference 1. Zhu HH et al. Oral tetra-arsenic tetra-sulfide formula versus intravenous arsenic trioxide as first-line treatment of acute promyelocytic leukemia: a multicenter randomized controlled trial. J Clin Oncol. 2013; 31:4215-21. 2. Ma Q et al. Fabrication of water-soluble polymer-encapsulated As4S4 to increase oral bioavailability and chemotherapeutic efficacy in AML mice. Sci Rep. 2016; 6: 29348. Acknowledgement This work was supported by National Key R&amp;D Program of China (2017YFA0205504) and CAMS Innovation Fund for Medical Sciences (CIFMS, 2016-I2M-3-004). Citation Format: Tao Wang, Tao Wen, Jie Meng, Jian Liu, Haiyan Xu. Hydrophilic As4S4 nanoparticles inhibit K562 cell activity through ROS modulation and autophagy induction [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 1857.
Abstract 3356: The EWS/FLI1 transcriptome is characterized by marked heterogeneity across Ewing sarcoma cell lines
Authors: Susan M. Kitchen-Goosen, Megan J. Bowman, Marie Adams, Penny Berger, Patrick J. Grohar
Journal: Cancer Research (2018)

Abstract BACKGROUND: Ewing sarcoma (ES) is the second most common pediatric bone cancer. ES cells are dependent on the activity of the EWS/FLI1 transcription factor for cell survival. EWS/FLI1 drives proliferation, dysregulates the cell cycle and establishes a block in differentiation. Despite the known dependence of Ewing sarcoma on EWS/FLI1, the exact identity of all the downstream targets of EWS/FLI1 is not known. While gene signatures have been reported for EWS/FLI1, these fail to capture the marked heterogeneity in the EWS/FLI1 transcriptome or correlate these expression changes with cellular phenotype. METHODS: Next generation RNA sequencing with deep coverage was used to generate a comprehensive analysis of the EWS/FLI1 transcriptome by silencing EWS/FLI1 in 5 different ES cell lines at two different time points. These results were organized into gene expression networks and signaling nodes were identified by weighted correlation network analysis (WGCNA). The networks were validated by a 500-gene signature of EWS/FLI1 targets using a next generation sequencing capture assay and the Illumina platform. The cellular endpoint of EWS/FLI1 silencing was evaluated by caspase 3,7 cleavage to measure apoptosis, BGAL staining to measure senescence and scratch assays to capture migration. RESULTS: Next generation RNA sequencing with siRNA silencing of EWS/FLI1 revealed marked heterogeneity in the EWS/FLI1 transcriptome among cell lines. Targets of EWS/FLI1 that were common across cell lines exhibited small magnitude gene expression changes (log fold &amp;lt;2), while large magnitude gene expression changes were unique to individual cell lines (log fold&amp;gt;2). When the log fold change in expression was restricted to greater than 2, only 13 common repressed targets and 4 common induced targets were identified in all 5 cell lines. In addition, silencing of EWS/FLI1 induced dramatically different phenotypes across cell lines, where p53 wild-type cell lines underwent senescence and the p53 mutant cell lines did not. Most cell lines did not continue to proliferate with EWS/FLI1 silencing with the exception being the widely used A673 cell line. Cellular migration did not change with EWS/FLI1 silencing in many of the cell lines in contrast to A673 cells. CONCLUSIONS: EWS/FLI1 drives different gene expression signatures and different phenotypes in unique cell lines. This diversity needs to be considered as EWS/FLI1 directed therapies are developed. Citation Format: Susan M. Kitchen-Goosen, Megan J. Bowman, Marie Adams, Penny Berger, Patrick J. Grohar. The EWS/FLI1 transcriptome is characterized by marked heterogeneity across Ewing sarcoma cell lines [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 3356.