tbuckley/cabot-search huggingface dataset:
Chromosomal Location, Exon Structure, and Vascular Expression Patterns of the Human PDGFC and PDGFD Genes
Authors: MarkoUutela, JuhaLaurén, ErikaBergsten, XuriLi, NinaHorelli-Kuitunen, UlfEriksson, KariAlitalo
Journal: Circulation (2001)

Background—Platelet-derived growth factor (PDGF), which is a major mitogen for vascular smooth muscle cells and has been implicated in the pathogenesis of arteriosclerosis, is composed of dimers of PDGF-A and PDGF-B polypeptide chains, encoded by different genes. Here, we have analyzed the chromosomal localization, structure, and expression of 2 newly identified human genes of the PDGF family, called PDGFC and PDGFD. Methods and Results—We used fluorescence in situ hybridization to locate PDGFC and PDGFD in chromosomes 4q32 and 11q22.3 to 23.2, respectively. Exon structures of PDGFC and PDGFD were determined by sequencing from genomic DNA clones. The coding region of PDGFC consists of 6 and PDGFD of 7 exons, of which the last 2 encode the C-terminal PDGF cystine knot growth factor homology domain. An N-terminal CUB domain is encoded by exons 2 and 3 of both genes, and a region of proteolytic cleavage involved in releasing and activating the growth factor domain is located in exon 4 in PDGFC and exon 5 in ...
Abstract 1866: Small molecule NSC59984 is a radio-sensitizer dependent on ERK2 and DDR but independent of wild-type p53
Authors: Shengliang Zhang, Lanlan Zhou, Niklas Finnberg, Wafik El-Deiry
Journal: Cancer Research (2018)

Abstract Radiotherapy is a common and effective therapeutic strategy applied to various types of tumors. Mutations that commonly occur in p53 as a tumor suppressor gene, are a hallmark of tumor, and confer cellular radio-resistance. Targeted therapy is considered as a promising approach to increase efficacy and specificity of radiotherapy. We explore utilization of a small molecule targeting mutant p53 to enhance efficacy of radiotherapy in colorectal cancer. Colorectal cancer cells carrying with mutant p53 were treated with NSC59984 followed by ionizing radiation treatment. Combined NSC59984 with radiation significantly reduced colony formation in mutant p53-expressing colorectal cancer cells in a dose-dependent manner, suggesting that NSC59984 enhances the efficacy of radiotherapy. NSC59984 induces mutant p53 degradation via the ERK2 pathway. We investigated the role of ERK2 in the efficacy of the combination of NSC59984 and radiation treatment. ERK2 blockade partially abrogated the effect of NSC59984 on the radio-sensitivity, and this correlated with the rescue of mutant p53. Our results suggest that NSC59984 increases the efficacy of radiotherapy via activation of ERK2 or ERK2-dependant mutant p53 degradation. Mutant p53 and ERK2 are important regulators involved in repair of DNA double-strand breaks. We examined the DNA damage response (DDR) system and found that reduced Rad51 protein in cells treated with NSC59984, and the Rad51 protein was increased by the blockade of the ERK2 pathway. On the basis of the above results, we conclude that small-molecule NSC59984 enhances cancer cell sensitivity to radiotherapy via the ERK2 pathway and effects on DDR. Citation Format: Shengliang Zhang, Lanlan Zhou, Niklas Finnberg, Wafik El-Deiry. Small molecule NSC59984 is a radio-sensitizer dependent on ERK2 and DDR but independent of wild-type p53 [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 1866.
A collaborative translational research framework for evaluating and implementing the appropriate use of human genome sequencing to improve health
Authors: Muin J. Khoury, W. Gregory Feero, David A. Chambers, Lawrence E. Brody, Nazneen Aziz, Robert C. Green, A. Cecile J.W. Janssens, Michael F. Murray, Laura Lyman Rodriguez, Joni L. Rutter, Sheri D. Schully, Deborah M. Winn, George A. Mensah
Journal: PLoS Medicine (2018)

There is currently insufficient scientific evidence to support routine nondiagnostic use of germline genome sequencing in healthcare settings and population screening, but an increasing number of health systems are piloting genomic sequencing projects for clinical care.• In principle, numerous diagnostic or prognostic tests based on genes or variants could be used for different purposes across the life span, and an evidence-based approach is urgently needed to evaluate their possible clinical utility and facilitate appropriate implementation.• We discuss a translational research framework that features collaboration among multiple health systems with already available genome sequencing data, intervention information, and clinical outcomes.The framework is based on evaluating the impact of genetic information on improving health outcomes with study designs that depend on the evolving level of evidence for specific intended clinical uses.• In addition to observational studies, randomized controlled trials will be needed to assess health benefits, harms, and costs based on returning or not returning the results of selected genes/variants to patients, providers, or both, for specific clinical scenarios.
Abstract 3462: EGFRvIII-Stat5 signaling enhances glioblastoma cell invasion
Authors: Alison Roos, Harshil D. Dhruv, Sen Peng, Landon J. Inge, Serdar Tuncali, Michael Pineda, Nghia Millard, Jeffrey A. Winkles, Joseph C. Loftus, Nhan L. Tran
Journal: Cancer Research (2018)

Abstract Glioblastoma Multiforme (GBM) is the most common malignant brain tumor in adults. Most GBM patients succumb to the disease less than one-year post diagnosis due to the highly invasive nature of the tumor, which prevents complete surgical resection and gives rise to tumor recurrence. The invasive phenotype also confers radio and chemoresistant properties to the tumor cells; therefore, there is a need to develop new therapeutics that target drivers of GBM invasion. Amplification of EGFR is observed in over 50% of GBM tumors, of which half concurrently overexpress the variant EGFRvIII, and expression of both receptors confers a worse prognosis. EGFR and EGFRvIII cooperate to promote tumor progression and invasion, in part, through activation of the Stat-signaling pathway. Here we report that EGFRvIII activates Stat5 and GBM invasion, in part, by inducing the expression of a previously established mediator of glioma cell invasion and survival, fibroblast growth factor-inducible 14 (Fn14). EGFRvIII-mediated induction of Fn14 expression is dependent upon Stat5 and requires activation of Src, whereas EGFR regulation of Fn14 is dependent upon MEK/ERK-Stat3 activation. Notably, treatment of EGFRvIII expressing GBM cells with the FDA approved Stat5 inhibitor pimozide blocked Stat5 phosphorylation, Fn14 expression, and cell migration. Since EGFR inhibitors display limited therapeutic efficacy in GBM patients, we hypothesize that the EGFRvIII-Stat5-Fn14 signaling pathway represents a node of vulnerability in the invasive GB cell population and that targeting critical effectors in this pathway will limit GBM tumor dispersion, mitigate therapeutic resistance, and increase survival. Citation Format: Alison Roos, Harshil D. Dhruv, Sen Peng, Landon J. Inge, Serdar Tuncali, Michael Pineda, Nghia Millard, Jeffrey A. Winkles, Joseph C. Loftus, Nhan L. Tran. EGFRvIII-Stat5 signaling enhances glioblastoma cell invasion [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 3462.
Mechanisms of Atrial Tachyarrhythmias Associated With Coronary Artery Occlusion in a Chronic Canine Model
Authors: KunihiroNishida, Xiao YanQi, RezaWakili, PhilippeComtois, DenisChartier, MasahideHarada, Yu-kiIwasaki, PhilippeRomeo, AngeMaguy, DobromirDobrev, GeorghiaMichael, MarioTalajic, StanleyNattel
Journal: Circulation (2011)

Background—Coronary artery disease predisposes to atrial fibrillation (AF), but the effects of chronic atrial ischemia/infarction on AF-related substrates are unknown. Methods and Results—Regional right atrial myocardial infarction (MI) was created in 40 dogs by ligating an artery that supplies the right atrial free wall and not the ventricles; 35 sham dogs with the same artery isolated but not ligated were controls. Dogs were observed 8 days after MI and subjected to open-chest study, in vitro optical mapping, and/or cell isolation for patch-clamp and Ca2+ imaging on day 8. Holter ECGs showed more spontaneous atrial ectopy in MI dogs (eg, 662±281 on day 7 versus 34±25 ectopic complexes per day at baseline; 52±21 versus 1±1 atrial tachycardia episodes per day). Triggered activity was increased in MI border zone cells, which had faster decay of caffeine-evoked Ca2+ transients and enhanced (by ≈73%) Na+-Ca2+ exchange current. Spontaneous Ca2+ sparks (confocal microscopy) occurred under β-adrenergic stimulat...
Mogamulizumab versus vorinostat in previously treated cutaneous T-cell lymphoma (MAVORIC): an international, open-label, randomised, controlled phase 3 trial
Authors: Youn H Kim, Martine Bagot, Lauren Pinter-Brown, Alain H Rook, Pierluigi Porcu, Steven M Horwitz, Sean Whittaker, Yoshiki Tokura, Maarten Vermeer, Pier Luigi Zinzani, Lubomir Sokol, Stephen Morris, Ellen J Kim, Pablo L Ortiz-Romero, Herbert Eradat, Julia Scarisbrick, Athanasios Tsianakas, Craig Elmets, Stephane Dalle, David C Fisher, Ahmad Halwani, Brian Poligone, John Greer, Maria Teresa Fierro, Amit Khot, Alison J Moskowitz, Amy Musiek, Andrei Shustov, Barbara Pro, Larisa J Geskin, Karen Dwyer, Junji Moriya, Mollie Leoni, Jeffrey S Humphrey, Stacie Hudgens, Dmitri O Grebennik, Kensei Tobinai, Madeleine Duvic, Sunil Abhyankar, Oleg Akilov, Onder Alpdogan, Marie Beylot-Barry, Erin Boh, Dolores Caballero, Richard Cowan, Brigitte Dreno, Reinhard Dummer, Timothy Fenske, Francine Foss, Noriko Fukuhara, Pratyush Giri, Koji Habe, Toshihisa Hamada, Kiyohiko Hatake, Shinsuke Iida, Osamu Ishikawa, Lars Iversen, Eiji Kiyohara, Hiroshi Koga, Neil Korman, Bryone Jean Kuss, Zanetta Lamar, Frederick Lansigan, Mary Jo Lechowicz, Adam Lerner, Nina Magnolo, Lawrence Mark, Tomomitsu Miyagaki, Javier Munoz, Jan Peter Nicolay, Kaoru Nishiwaki, Hiroyuki Okamoto, Mikio Ohtsuka, Theresa Pacheco, Christiane Querfeld, Ronald Peter Rapini, Shigetoshi Sano, Maiko Tanaka, Michael D. Tharp, Jiro Uehara, Hidefumi Wada, Jillian Wells, Ryan A. Wilcox, Basem William, Kentaro Yonekura
Journal: The Lancet Oncology (2018)
Abstract 12554: Endothelial Dysfunction but not Vascular Smooth Muscle Dysfunction Plays Important Roles on Development of Acute Coronary Syndromes and Fatal Cardiovascular Events
Authors: Tatsuaki Murakami, Ikuo Moriuchi
Journal: Circulation (2011)

Background: Arterial dysfunction is thought to contribute to atherothrombogenic process, however we identify little about practical relationship between clinical evolution of acute coronary syndrom...
The Early and Late Phases of Ischemic Preconditioning
Authors: YuminQiu, Xian-LiangTang, Seong-WookPark, Jiang-ZhongSun, AnantharamKalya, RobertoBolli
Journal: Circulation Research (1997)

Abstract The effectiveness of the late phase of ischemic preconditioning (PC) in protecting against myocardial infarction and the concomitant contractile dysfunction after sustained ischemia remains unclear. The early and late phases of PC have not been compared using the same protocol in the same experimental model; furthermore, the late phase of PC has not been assessed in the conscious state in a large animal preparation. The goal of this study was to directly compare the effects of early and late PC on myocardial infarct size and postischemic dysfunction in chronically instrumented, conscious pigs. Four groups of pigs were subjected to a 40-minute coronary occlusion followed by 3 days of reperfusion. Group 1 (n=7) served as control. Group 2 (n=6) was subjected to ten 2-minute occlusion/2-minute reperfusion cycles 25 minutes before the 40-minute occlusion (early PC). Groups 3 (n=7) and 4 (n=4) were subjected to 10 and 25 cycles, respectively, of 2-minute occlusion/2-minute reperfusion 24 hours before t...
Abstract 4136: Marked decrease of BIRC5/Survivin by haploinsufficiency does not inhibit neuroblastoma in transgenic mice: Implications for survivin as a therapeutic target in neuroblastoma
Authors: Carmen Dorneburg, Volker Rasche, Andre Lechel, Sarah-Fee Katz, Klaus-Michael Debatin, Christian Beltinger
Journal: Cancer Research (2018)

Abstract Overexpression of survivin, a crucial regulator of the mitotic spindle checkpoint with additional antiapoptotic effects, is associated with poor prognosis in neuroblastoma (NB) and other cancers. Thus, survivin is a promising therapeutic target in NB. Transcriptional inhibitors of survivin show preclinical efficacy and have been tested in clinical trials. The results of these trials, however, have been disappointing, due to modest efficacy and unexpected off-target effects. We thus investigated the consequences of marked, yet incomplete decrease of survivin on NB in a novel transgenic mouse model. To this end, we crossed mice haploinsufficient for survivin with TH-MYCN mice to generate BIRC5+/- MYCN tg/+ mice. These mice developed NB with markedly decreased mRNA and protein expression of survivin. Surprisingly, incidence and latency of the NB that developed in the BIRC5+/- MYCN tg/+ mice were not different from those in the TH-MYCN mice. Growth of tumors was not decreased in BIRC5+/- MYCN tg/+ mice, as assessed by serial MRI imaging, and survival of the mice was not increased. Immunohistochemistry of the NB did not show decreased proliferation (Ki67), increased apoptosis (activated caspase 3) or a change in vascularity (CD31). No difference in copy number variations between the two NB mouse models was discernible using CGH arrays. To determine whether dysfunctional T cells described in mice haploinsufficient for survivin could have masked any loss of aggressiveness of NB cells haploinsufficient for survivin, NB of BIRC5+/- MYCN tg/+ mice were retransplanted into survivin sufficient mice. No difference in tumor incidence, latency and growth was detected. Taken together, despite a marked decrease in the expression of BIRC5/survivin by haploinsufficiency development and growth of NB were not inhibited. While a further decrease of survivin beyond that seen in haploinsufficiency will inhibit NB, it most likely will also elicit marked side effects, given that survivin is essential for normal cells. Our results cast doubt on the efficacy of inhibitors of survivin expression in NB and call for targeting survivin by alternative approaches, such as inhibiting protein-protein interactions of survivin. Citation Format: Carmen Dorneburg, Volker Rasche, Andre Lechel, Sarah-Fee Katz, Klaus-Michael Debatin, Christian Beltinger. Marked decrease of BIRC5/Survivin by haploinsufficiency does not inhibit neuroblastoma in transgenic mice: Implications for survivin as a therapeutic target in neuroblastoma [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 4136.
Abstract 385: HIF1A can regulate Wnt signaling in human colon cancer cells
Authors: Yung Lyou, George Chen, Marian Waterman
Journal: Cancer Research (2018)

Abstract Standard-of-care treatment for KRAS mutant metastatic colorectal cancer (mCRC) combines a cytotoxic chemotherapy backbone (FOLFOX) with an antiangiogenesis biologic agent (i.e., bevacizumab). Despite significant efforts to improve treatment, the prognosis for this type of cancer remains poor with an average 5-year overall survival of ~11%. Oncogenic KRAS mutations lead to the overactivation of RAS/ERK/MAPK pathwa,y driving many hallmarks of cancer such as cell proliferation, growth, and altered metabolism. In particular, several studies have shown that oncogenic activation of KRAS leads to normoxic stabilization of HIF1A protein, which can then reprogram cellular metabolism towards aerobic glycolysis. Our studies have discovered that overactive Wnt signaling can also reprogram cancer cell metabolism towards aerobic glycolysis. Of note, KRAS (~40%) and Wnt signaling (~90%) are very frequently coactivated in colorectal cancer. Interestingly, an important, key metabolic gene targeted by Wnt signaling, Pyruvate Dehydrogenase Kinase I (PDK1), is also directly regulated by HIF1A, suggesting there may be crosstalk between the HIF1A and Wnt pathways. Indeed, several published studies support the idea that HIF1A can influence Wnt signaling, and our data show this may occur through regulation of the Wnt mediating transcription factors LEF1 and TCF1 (TCF7 gene). Using luciferase reporters driven by LEF/TCF promoters, we observed significantly increased LEF1/TCF7 promoter activity in hypoxic colon cancer cells but not for other TCF family members (TCF7L1/TCF7L2). We identified putative hypoxia responsive elements (HREs) in the human LEF1 promoter, and deletion of these HREs reduced responsiveness to hypoxia. Furthermore, we have found that targeting glycolysis and Wnt can be synergistic in inhibiting colon cancer cell colony growth. We find that HIF1A and LEF/TCF/beta-catenin complexes coregulate gene expression of metabolic targets as well as Wnt signaling components (e.g., LEF1 and TCF7). These data suggest that cross-regulation between the HIF1A and Wnt signaling pathway is important and may be a potential Achilles heel for novel therapeutics in targeting KRAS mutant colon cancer. Current studies are under way to further investigate the mechanisms of crosstalk and joint regulation of metabolic reprogramming in KRAS mutant colon cancer cells. Citation Format: Yung Lyou, George Chen, Marian Waterman. HIF1A can regulate Wnt signaling in human colon 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 385.
Anti–Carbamylated Protein Antibodies and Higher Baseline Disease Activity in Rheumatoid Arthritis—A Replication Study in Three Cohorts: Comment on the Article by Truchetet et al
Authors: V. F. A. M. Derksen, H. Westerlind, S. Saevarsdottir, S. Ajeganova, L. A. Trouw, T. W. J. Huizinga, A. H. M. van der Helm‐van Mil, R. Knevel, D. van der Woude
Journal: Arthritis & Rheumatology (2018)
Abstract 1175: The establishment of single colorectal cancer organoid clones derived from regional biopsies for studying tumor heterogeneity
Authors: Myoung-Hyun Song, Ja-Lok Ku
Journal: Cancer Research (2018)

Abstract Nowadays, there is a spotlight on organoid culture, which is cultivated in 3D by using specimens derived from human or another mammalian. In addition, in the process of testing and screening anticancer drugs in vitro, the limitations of 2D culture have been pointed out because homogenous culture condition does not sufficiently represent the real environment in human body. Simultaneously, there has been consensus that 3D models such as spheroids and organoids are more physiologically similar to in vivo system when compared to 2D. In fact, tumor tissue grows in 3D and in heterogenous environment including extra-cellular matrix, immune cells and various lineage of cells differentiated from stem cells. To further comprehend complex in vivo tumor development pathway, new experimental model for mimicking real three-dimensional biopsy has been required and successfully become a part of biological field. Accordingly, organoid culture technic as an emerging next generation ex-vivo model has drawn tremendous attention for its advantages in lots of experimental and therapeutic application. Thus, we have established organoid (3D) lines by isolating tumor epithelium from colon cancer patient tissue and to look into the heterogenous environment of human intestine as well as investigating sensitivity in response to various stimulations such as anti-cancer reagents treatment and irradiation (professors Seung-Yong Jeong and Ji-Won Park contributed this work). And in particular, six to eight single organoids were isolated from the primary passage in each regional biopsy. 4 tumor tissues and 6 to 8 single organoids were obtained from a patient and each biopsy, respectively. In sum, more than 30 organoid lines from one patient were established and cultured to confirm both heterogeneity among regional biopsies and single organoids derived from each biopsy. Each single organoid was successfully isolated by using micromanipulator and micropipette without contamination. Then, we confirmed whether single clones were solely isolated. Furthermore, during the process of expansion of each organoid population, we observed differences in morphology and proliferation rate among organoid lines. However, distinct mechanisms that mainly influences on the tumor heterogeneity are still not fully understood. The technic of single organoid clone isolation could give insights for further studies on investigating heterogeneity among regional tumor biopsies. Citation Format: Myoung-Hyun Song, Ja-Lok Ku. The establishment of single colorectal cancer organoid clones derived from regional biopsies for studying tumor heterogeneity [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 1175.
Abstract 17495: Impact of Resting Pulmonary Hypertension on the Results of Percutaneous Mitral Balloon Valvuloplasty
Authors: Seung Mo Kang, Hyo In Choi, Pil Hyung Lee, Uk Jo, Jeong Yoon Jang, Byung Joo Sun, Won-Jang Kim, Dae Hee Kim, Young-Hak Kim, Jong-Min Song, Cheol Whan Lee, Duk-Hyun Kang, Jae-Kwan Song
Journal: Circulation (2013)

Background: Resting pulmonary hypertension has been considered as an unfavorable condition for percutaneous mitral balloon valvuloplasty (PMV), but its impact on immediate and long-term outcome nee...
Long-Term Patency Rate of Right Internal Thoracic Artery Bypass Via the Transverse Sinus
Authors: MasashiUra, RyuzoSakata, YoshihiroNakayama, YoshioArai, TaroSaito
Journal: Circulation (1998)

Background—Although concern regarding patency and possible compromise of graft blood flow by routing the right internal thoracic artery (RITA) through the transverse sinus has been raised, little is known about long-term patency. Methods and Results—To evaluate long-term patency of in situ RITA bypass via the transverse sinus, our first 115 patients (94 men, 21 women; mean age, 62.5 years; range, 13 to 77 years) who were alive in 1998 were enrolled for angiographic study. Only good-caliber grafts with no occlusion, string sign, or significant stenosis were considered patent. Early postoperative angiography had been performed 2 to 3 weeks after surgery in 114 patients. The early patency rates were 97.1% for RITA and 95.4% for left internal thoracic artery (LITA) grafts. Of 109 long-term survivors, 73 (67.0%) consented to have late angiographic restudy at a mean of 59 months (range, 9 to 93 months); 89.9% of RITA and 92.3% of LITA grafts were patent. Cumulative patency rates (actuarial curves) at 6 years we...