tbuckley/cabot-search huggingface dataset:
Abstract LB-096: A gain-of-function screen identifies drivers of drug resistance in BRAFV600E melanoma cell lines
Authors: Charlotte R. Feddersen, Jacob L. Schillo, Hayley R. Vaughn, Andrew P. Voigt, Eliot Y. Zhu, Lexy S. Wadsworth, Christopher S. Stipp, Adam J. Dupuy
Journal: Cancer Research (2018)

Abstract Melanoma is the deadliest form of skin cancer, and until recently patients had few treatment options upon diagnosis. Fortunately, this lack of treatment options changed with the discovery of vemurafenib, a highly selective kinase inhibitor that specifically targets the BRAFV600E mutant protein, found in ~50% of all melanoma cases. Initially, the kinase inhibitor provided complete or partial response to over 50% of patients and prolonged progression-free survival. However, the majority of patients relapse once tumors acquire resistance to vemurafenib. Some of the genetic resistance mechanisms are known, including BRAF amplification, expression of truncated BRAF, and RAS mutation. However, a significant portion of vemurafenib resistance cases is unexplained. While drug resistance can be delayed by combining vemurafenib with cobimetinib, a MEK inhibitor, mechanisms of resistance to this drug combination are not well characterized. We performed a gain-of-function screen to identify drivers of drug resistance to vemurafenib or vemurafenib combined with cobimetinib. Briefly, A375 melanoma cells were engineered to express the hyperactive transposase SB100. These cells were then subsequently transfected with the mutagenic T2Onc3 transposon to produce a population of mutagenized A375 cells. Three weeks of vemurafenib treatment selected for cells with the acquired ability to grow in the presence of drug. Candidate driver mutations were then identified by profiling the sites of transposon insertion in drug-resistant cells to find genes that were recurrently over-expressed by transposon insertions. This led to the discovery of five genes that act as drivers of vemurafenib resistance when overexpressed in the human melanoma cell line A375. Candidate genes were then validated in multiple melanoma cell lines by assessing cell growth and viability in varying concentrations of vemurafenib. An analogous screen was performed in A375 to identify drivers of resistance to the combination of vemurafenib and cobimetinib. In addition, we are assessing the diversity of drug resistance mechanisms by performing mutagenesis in three additional human melanoma cell lines. The characterization of the novel drug resistance pathways identified here will improve treatment outcomes for patients with BRAFV600E mutant melanoma. Citation Format: Charlotte R. Feddersen, Jacob L. Schillo, Hayley R. Vaughn, Andrew P. Voigt, Eliot Y. Zhu, Lexy S. Wadsworth, Christopher S. Stipp, Adam J. Dupuy. A gain-of-function screen identifies drivers of drug resistance in BRAFV600E melanoma 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 LB-096.
Amiodarone Protects Cardiac Myocytes Against Oxidative Injury by its Free Radical Scavenging Action
Authors: TomomiIde, HiroyukiTsutsui, ShintaroKinugawa, HideoUtsumi, AkiraTakeshita
Journal: Circulation (1999)

Background—Oxidative stress plays an important role in the pathophysiology of ischemic heart disease and heart failure, and antioxidants might be beneficial in the treatment of these patients. This study was performed to determine the scavenging effects of amiodarone on oxygen free radicals and its protective effects against oxygen radical-mediated injury in cardiac myocytes. Methods and Results—The formation of the radical spin adduct with hydroxy radical (·OH) in the presence of H2O2 (10 mmol/L) and Fe3+-nitrilotriacetate (20 μmol/L) was monitored by electron paramagnetic resonance spectroscopy combined with a spin trapping agent, 5,5-dimethyl pyrroline-N-oxide (DMPO). Amiodarone decreased the intensity of the DMPO-OH signals in a dose-dependent manner (0.1 to 100 μmol/L), whereas other antiarrhythmia drugs such as disopyramide and atenolol had no such effects. Furthermore, amiodarone (10 μmol/L) protected intact adult canine cardiac myocytes against ·OH-mediated myocyte injury, as assessed by the degre...
Cutaneous malignant melanoma incidence and mortality trends in Canada: A comprehensive population-based study
Authors: Feras M. Ghazawi, Janelle Cyr, Rami Darwich, Michelle Le, Elham Rahme, Linda Moreau, Elena Netchiporouk, Andrei Zubarev, Osama Roshdy, Steven J. Glassman, Denis Sasseville, Ivan V. Litvinov
Journal: Journal of the American Academy of Dermatology (2018)
Regulation of Fibrillar Collagen Gene Expression and Protein Accumulation in Volume-Overloaded Cardiac Hypertrophy
Authors: TakashiNamba, HiroyukiTsutsui, HirofumiTagawa, MasaruTakahashi, KeikoSaito, ToshiyukiKozai, MakotoUsui, KyokoImanaka-Yoshida, TsutomuImaizumi, AkiraTakeshita
Journal: Circulation (1997)

Background Interstitial collagen accumulation has been extensively demonstrated to be increased at both mRNA and protein levels in pressure-overloaded cardiac hypertrophy. However, few data are available regarding the effects of volume overload on myocardial collagens. Methods and Results To determine whether the alterations of collagens may occur in volume-overloaded cardiac hypertrophy, we measured collagen types I and III mRNA levels and protein accumulation in left ventricular (LV) myocardium of rats at 3, 7, and 28 days after the creation of an aortocaval (AC) shunt. Eccentric LV hypertrophy was produced in rats with AC shunting. Northern blot analysis on RNA extracted from LV tissue indicated that the steady state mRNA levels for both type I and III collagen were persistently upregulated in AC shunt rats compared with sham-operated control rats. In contrast, the biochemical collagen protein concentration and morphometric collagen volume fraction were comparable between sham-operated control and AC s...
Abstract 4507: C-X-C motif ligand 1 from melanoma cells downregulates the invasion of their metastatic melanoma cells
Authors: Takaharu Hatano, Masakazu Yashiro, Hisashi Motomura, Heishiro Fujikawa, Shusaku Maeda
Journal: Cancer Research (2018)

Abstract [Introduction]The prognosis of patients with malignant melanoma is extremely poor because of the frequent metastasis. We have occasionally experienced the clinical cases that malignant melanoma patients rapidly developed distant metastases after the surgical resection of primary cancer lesion. These cases suggested that a primary tumor may control a metastatic tumor. We hypothesized that primary melanoma cells might produce a factor(s) which regulate the progression of metastatic melanoma cells. We reported that the conditioned medium from B16 cells significantly (p=0.02) suppressed the invasion ability of B16/BL6 cells, which is a subline of B16 melanoma and shows high metastatic potential to lung at the previous meeting. Then we investigated the growth and invasion interaction between primary malignant melanoma cells and high metastatic melanoma cells at the molecular level. [Materials and methods]We used two mouse melanoma cell lines, B16 and B16/BL6, that latter of which is a subline of B16 melanoma and shows high metastatic potential to lung. We investigated the interaction between the parent B16 cells and daughter B16/BL6 cells by invasion assay, cell morphology, cytokine array, RT-PCR, and gelatin-zymography. [Results]The conditioned medium (CM) from B16 cells significantly (p=0.02) inhibited the invasion ability of B16/BL6 cells. The morphology of the B16/BL6 cells was changed by the CM from bipolar in B16 cells to a multipolar shape. The B16 cells produced high levels of C-X-C motif ligand 1 (CXCL1), CXCL10, and M-CSF compared to the B16/BL6 cells. CXCL1 significantly (p=0.01) decreased the invasion ability of B16/BL6 cells, but CXCL10 and M-CSF did not. The invasion-inhibitory activity of the CM from B16 cells was significantly (p=0.046) suppressed following the addition of a neutralizing anti-CXCL1 antibody. The CM of B16 and CXCL1 increased the E-cadherin mRNA level and MMP2 activity of B16/BL6 cells. [Conclusion]Primary melanoma cells might down-regulate the invasion activity of metastatic melanoma cells through CXCL1 signaling. Citation Format: Takaharu Hatano, Masakazu Yashiro, Hisashi Motomura, Heishiro Fujikawa, Shusaku Maeda. C-X-C motif ligand 1 from melanoma cells downregulates the invasion of their metastatic melanoma 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 4507.
Coexistence of Single Ventricle with Atresia of One Atrioventricular Orifice
Authors: Manuelquero
Journal: Circulation (1972)

A new case of an unusual association of mitral atresia with single left ventricle is reported. The salient anatomic features include: (1) the right atrioventricular valve is atretic; (2) the left atrioventricular valve enters the large ventricle with morphologic characteristics of the left ventricle; and (3) this large ventricle communicates by way of an interventricular communication with a smaller left-sided ventricle, but with the morphologic characteristics of the right ventricle. Guidelines for the recognition of these uncommon malformations are given.
Rho/Rho-Kinase Pathway in Brain Stem Contributes to Blood Pressure Regulation via Sympathetic Nervous System
Authors: KojiIto, YoshitakaHirooka, KojiSakai, TakuyaKishi, KozoKaibuchi, HiroakiShimokawa, AkiraTakeshita
Journal: Circulation Research (2003)

Recent studies have demonstrated that the Rho/Rho-kinase pathway plays an important role in various cellular functions, including actin cytoskeleton organization and vascular smooth muscle contraction. This pathway is also present in the central nervous system and is involved in the maintenance of dendritic spines and axon outgrowth and in the regulation of neurotransmitter release. However, its role in central blood pressure regulation is unknown. In the present study, blockade of the Rho/Rho-kinase pathway in the nucleus tractus solitarii (NTS) of the brain stem by microinjection of a specific Rho-kinase inhibitor decreased blood pressure, heart rate, and renal sympathetic nerve activity in both Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). However, the magnitude of decreases in these variables was greater in SHR than in WKY rats. In addition, an adenovirus vector encoding dominant-negative Rho-kinase decreased blood pressure, heart rate, and urinary norepinephrine excretion in both...
Abstract 2061: Genipin inhibits invasion and migration of colon cancer cells by suppression of HIF1α accumulation and VEGF expression
Authors: Dae-Hee Lee, Sang-Choul Oh, Suk-young Lee, Hong Jun Kim
Journal: Cancer Research (2018)

Abstract Expression of hypoxia-inducible factor-1 (HIF-1) and vascular endothelial growth factor (VEGF) is known to play an important role in cancer progression in various cancer cell lines. Although genipin, a constituent of Gardenia fruit, has shown to have anti-tumor activity, its role in suppression of HIF-1 protein and downstream genes has yet to be clarified. We examined the effect of genipin on intracellular level of HIF-1α and extracellular level of VEGF proteins using colon cancer cell line HCT116. We observed genipin suppressed accumulation of HIF-1α under hypoxia in various cancer cell lines including HCT116. We found out suppressed accumulation of HIF-1α occurred through modulation of protein degradation. Genipin was also observed to suppress expression of VEGF and invasion of colon cancer cells through blocking of the ERK signaling pathway. Taken together, our results provide a new insight into the potential role of genipin in suppressing cancer progression of colon cancer cells. Citation Format: Dae-Hee Lee, Sang-Choul Oh, Suk-young Lee, Hong Jun Kim. Genipin inhibits invasion and migration of colon cancer cells by suppression of HIF1α accumulation and VEGF expression [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 2061.
The GSK-3 Family as Therapeutic Target for Myocardial Diseases
Authors: HindLal, FirdosAhmad, JamesWoodgett, ThomasForce
Journal: Circulation Research (2015)

Glycogen synthase kinase-3 (GSK-3) is one of the few signaling molecules that regulate a truly astonishing number of critical intracellular signaling pathways. It has been implicated in several diseases including heart failure, bipolar disorder, diabetes mellitus, Alzheimer disease, aging, inflammation, and cancer. Furthermore, a recent clinical trial has validated the feasibility of targeting GSK-3 with small molecule inhibitors for human diseases. In the current review, we will focus on its expanding role in the heart, concentrating primarily on recent studies that have used cardiomyocyte- and fibroblast-specific conditional gene deletion in mouse models. We will highlight the role of the GSK-3 isoforms in various pathological conditions including myocardial aging, ischemic injury, myocardial fibrosis, and cardiomyocyte proliferation. We will discuss our recent findings that deletion of GSK-3α specifically in cardiomyocytes attenuates ventricular remodeling and cardiac dysfunction after myocardial infar...
Abstract 12144: Impact of Left Ventricular Diastolic Dysfunction on Long-Term Outcomes Following Coronary Artery Bypass Grafting: 5-Year Outcomes of the CREDO-Kyoto CABG Registry Cohort-2
Authors: AkiraMarui, NoboruNishiwaki, TatsuhikoKomiya, MichiyaHanyu, ShiroTanaka, TakeshiKimura, RyuzoSakata
Journal: Circulation (2014)

Background: Left ventricular (LV) systolic dysfunction (heart failure [HF] with low ejection fraction [EF]) is regarded as an independent risk factor for poor outcomes after coronary artery bypass grafting (CABG). However, the impact of LV diastolic dysfunction (HF with normal LVEF) still has been unclear. Methods and Results: We identified 1877 patients who received isolated CABG among 15,939 patients undergoing first coronary revascularization enrolled in the CREDO-Kyoto Registry Cohort-2. Among them, 1489 patients had normal LV function (LVEF>50% without a history of HF; Normal group), 236 had LV systolic dysfunction (LVEF≤50% with HF; LVSD group), and 152 had LV diastolic dysfunction (LVEF>50% with HF; LVDD group). Preoperative LVEF in the LVSD group (36±9%) was markedly lower than the Normal (62±12%) and the LVDD groups (61±7%) (p<0.0001). [Table/Figure] In-hospital mortality in the LVDD group was equivalent to the Normal group (1.3% vs. 1.0%, p=0.72). However, cumulative all-cause mortality at 5-yea...
Abstract 4982: Oncogenic role of <i>THOR</i>, a conserved cancer/testis long noncoding RNA
Authors: Yashar Niknafs, Yasuyuki Hosono, Matthew K, John Prensner, Rohit Mehra, Sethuramasundaram Pitchiaya, Jean Tien, Rohit Malik, Weibin Zhao, Arul Chinnaiyan
Journal: Cancer Research (2018)

Abstract Large scale transcriptome sequencing efforts have vastly expanded the catalog of long non-coding RNAs (lncRNAs) with varying evolutionary conservation, lineage expression, and cancer specificity. Through a recent large-scale transcriptomic analysis over 6,500 tumor RNA-seq samples, we discovered over 50,000 lncRNAs in the human genome, many of which exhibited highly evolutionarily conserved sequence patterns. Building upon the discovery of these highly conserved lncRNAs, we functionally characterized a novel ultraconserved lncRNA, THOR, which exhibits expression exclusively in testis and a broad range of human cancers. We establish THOR as the first discovered cancer/testis lncRNA, and further investigated its functional significance. THOR knockdown and overexpression in multiple cell lines and animal models alters cell or tumor growth supporting an oncogenic role. Namely, we generated CRISPR knockout cell line models, showing a definitive role for THOR in cancer progression. Additionally, given the sequence conservation of THOR through the mouse and zebrafish, we generated a zebrafish knockout model, and also a zebrafish overexpression model for THOR. Through RNA-pulldown followed by mass spectrometry, we discovered a conserved interaction of THOR with the RNA binding protein, IGF2BP1, in both human and zebrafish cells. We further show that THOR contributes to the mRNA stabilization activities of IGF2BP1. These findings are corroborated by iCLIP data for IGF2BP1. Notably, transgenic THOR knockout produced fertilization defects in zebrafish and also conferred a resistance to melanoma onset in an NRAS K61-induced zebrafish melanoma model. Likewise, ectopic expression of human THOR in zebrafish accelerated the onset of melanoma. THOR represents a novel class of functionally important cancer/testis lncRNAs whose structure and function have undergone positive evolutionary selection. Citation Format: Yashar Niknafs, Yasuyuki Hosono, Matthew K, John Prensner, Rohit Mehra, Sethuramasundaram Pitchiaya, Jean Tien, Rohit Malik, Weibin Zhao, Arul Chinnaiyan. Oncogenic role of THOR, a conserved cancer/testis long noncoding RNA [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 4982.
Abstract 3956: Omomyc-based cell-penetrating peptides: From proof of concept to a clinically viable anti-Myc therapy
Authors: Marie-Eve Beaulieu, Toni Jauset, Daniel Massó-Vallés, Sandra Martínez-Martín, Peter Rahl, Löika Maltais, Mariano F. Zacarias-Fluck, Sílvia Casacuberta-Serra, Erika Serrano del Pozo, Christopher Fiore, Laia Foradada, Virginia Castillo Cano, Matthew Guenther, Eduardo Romero Sanza, Marta Oteo, Cynthia Tremblay Tremblay, Génesis Martín, Danny Letourneau, Martin Montagne, Miguel Ángel Morcillo Alonso, Jonathan R. Whitfield, Pierre Lavigne, Laura Soucek
Journal: Cancer Research (2018)

Abstract Deregulation of the MYC oncoprotein drives tumorigenesis in most–if not all–cancers and generally correlates with poor prognosis, suggesting that its inhibition would be a useful therapeutic strategy. Indeed, we have shown that Myc inhibition displays extraordinary therapeutic benefit in various transgenic mouse models of cancer (i.e., skin, lung, pancreatic cancer and glioma), without eliciting resistance to therapy, and causes only mild, well-tolerated and reversible side effects in normal tissues. For these studies we employed a dominant negative inhibitor of Myc, called Omomyc, which is an effective inhibitor of Myc transactivation function both in vitro and in vivo. Omomyc has so far been utilized exclusively as a transgene, as a successful proof of principle whose application was believed to be solely limited to gene therapy. Here, though, we show that the purified Omomyc polypeptide itself spontaneously transduces into cancer cells and effectively interferes with MYC transcription, abrogating cell cycle and promoting apoptosis in different cancer cells, independently of their mutational profile. Efficacy of the Omomyc polypeptide in two complementary murine models of non-small cell lung cancer (NSCLC) establishes its therapeutic potential through both direct tissue delivery (intranasal) and systemic intravenous administration, providing for the first time evidence that the Omomyc polypeptide is an effective MYC inhibitor worthy of clinical development. Citation Format: Marie-Eve Beaulieu, Toni Jauset, Daniel Massó-Vallés, Sandra Martínez-Martín, Peter Rahl, Löika Maltais, Mariano F. Zacarias-Fluck, Sílvia Casacuberta-Serra, Erika Serrano del Pozo, Christopher Fiore, Laia Foradada, Virginia Castillo Cano, Matthew Guenther, Eduardo Romero Sanza, Marta Oteo, Cynthia Tremblay Tremblay, Génesis Martín, Danny Letourneau, Martin Montagne, Miguel Ángel Morcillo Alonso, Jonathan R. Whitfield, Pierre Lavigne, Laura Soucek. Omomyc-based cell-penetrating peptides: From proof of concept to a clinically viable anti-Myc therapy [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 3956.
Tumor vasculature: a sally port for inhibiting cancer cell spreading
Authors: Chao‐Nan Qian, Francesco Pezzella
Journal: Cancer Communications (2018)

Abstract The close relationship between metastasis and establishment of tumor vasculature has inspired enormous research interests aiming to suppress metastasis via inhibiting the development of tumor vasculature. International experts gathered in Guangzhou, China on May 10–12, 2018 in The 4th International Meeting of Cancer and Blood Vessels to discuss the multiple ways for solid tumors to establish their vasculature. Vessel co‐option is a mean by which a solid tumor takes advantage of the existing or newly induced blood vessels in the surrounding normal tissues to sustain tumor growth and metastasis. The underlying mechanisms of vessel co‐option, the roles of pericyte, and the potential novel therapeutic targets have been discussed in the meeting.
Abstract 4932: Neuro-endocrine negative SCLC is mostly RB1 WT and may be sensitive to CDK4/6 inhibition, especially if CCND1 is amplified
Authors: Dmitriy Sonkin, Anish Thomas, Beverly A. Teicher
Journal: Cancer Research (2018)

Abstract Background: Small cell lung cancer (SCLC) is an aggressive form of lung cancer with limited therapeutic options, a very high mortality rate and is characterized, in most cases, by neuroendocrine features. A small but important subset of SCLC has intact RB1, however, other characteristics of this subset are not well-defined. Here we aim to characterize underlying genomics of SCLC cell lines with functional RB1. Methods: To comprehensively assess the underlying genomics of SCLC cell lines with functional RB1, we examined 52 SCLC cell lines from the Cancer Cell Line Encyclopedia (CCLE) collection. We also integrated CCLE SCLC genomics data with drug sensitivity data from NCI SCLC screen of 420 approved and investigational oncology drugs. Results: Out of 7 neuro-endocrine lineage marker-negative SCLC lines, 6 were RB1 WT. Out of 42 neuro-endocrine lineage marker-positive SCLC cell lines, 3 were RB1 WT. Two RB1 WT SCLC cell lines with CCND1 amplification were sensitive to CDK4/6 inhibitor. Oncogenic alterations in genes such as KRAS, NRAS, SMARCA4, and CDKN2A are rare in SCLC; however, these genes were altered in 7 of 9 RB1 WT SCLC cell lines. Conclusions: Neuro-endocrine lineage marker-negative SCLC are enriched for RB1 WT and may be sensitive to CDK4/6 inhibition especially in context of CCND1 amplification. Neuro-endocrine lineage marker-negative SCLC cell lines are associated with low DLL3 expression. Therefore, RB1 WT SCLC are less likely to respond to DLL3 targeted drugs. However, this may present the opportunity to identify patients with WT RB1 among patients screened for DLL3 ADC clinical trials and having no or very low DLL3 expression. Citation Format: Dmitriy Sonkin, Anish Thomas, Beverly A. Teicher. Neuro-endocrine negative SCLC is mostly RB1 WT and may be sensitive to CDK4/6 inhibition, especially if CCND1 is amplified [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 4932.