tbuckley/cabot-search huggingface dataset:
Abstract LB-093: ERK mutations and amplification confer resistance to ERK-inhibitor therapy
Authors: Bijay S. Jaiswal, Steffen Durinck, Eric W. Stawiski, Jianping Yin, Weiru Wang, Eva Lin, John Moffat, Scott E. Martin, Zora Modrusan, Somasekar Seshagiri
Journal: Cancer Research (2018)

Abstract MAPK pathway inhibitors targeting BRAF and MEK have shown clinical efficacy in patients with RAF and/or RAS mutated tumors. However, acquired resistance to these agents has been an impediment to improved long-term survival in the clinic. In such cases, targeting ERK downstream of BRAF/MEK has been proposed as a potential strategy for overcoming acquired resistance. Preclinical studies suggest that ERK inhibitors are effective at inhibiting BRAF/RAS mutated tumor growth and overcome BRAF or/and MEK inhibitor resistance. However, as with other MAPK pathway inhibitors, treatment with ERK inhibitors is likely to cause resistance in the clinic. In this study, we have used in vitro modeling, structural biology and genomic analysis to understand development of resistance to ERK inhibitors and the mechanisms leading to it. We have identified mutations in ERK1/2, amplification and overexpression of ERK2, and overexpression of EGFR/ERBB2 as mechanisms of acquired resistance. Structural analysis of ERK showed that specific compounds that induced on-target ERK mutations were impaired in their ability to bind mutant ERK. We show that in addition to MEK inhibitor, ERBB-receptor and PI3K/mTOR pathway inhibitors are effective in overcoming ERK-inhibitor resistance. These findings suggest that combination therapy with MEK or ERBB-receptor or PI3K/mTOR and ERK inhibitors may be an effective strategy for managing the emergence of resistance in the clinic. Citation Format: Bijay S. Jaiswal, Steffen Durinck, Eric W. Stawiski, Jianping Yin, Weiru Wang, Eva Lin, John Moffat, Scott E. Martin, Zora Modrusan, Somasekar Seshagiri. ERK mutations and amplification confer resistance to ERK-inhibitor 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 LB-093.
Opportunities for Early Detection of Endometrial Cancer in Women With Postmenopausal Bleeding
Authors: Kristen A. Matteson, Katina Robison, Vanessa L. Jacoby
Journal: JAMA Internal Medicine (2018)

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Abstract 19165: Improving Accuracy of Cardiac Output Estimates Using the Fick Principle - Oxygen versus Carbon Dioxide
Authors: Dorothy A Perry, Lindsay M Thomson, Abigail R Moore, Aditya K Kaza, John N Kheir
Journal: Circulation (2016)

Introduction: The Fick principle is frequently used to estimate cardiac output (CO) in critically ill patients. These data are used to guide patient management and to estimate vascular resistance. Oxygen-based Fick (FickO2) has been shown to systematically overestimate CO. The substitution of all O2 parameters with CO2 parameters may improve the accuracy of Fick. Objective: To compare CO as measured by (1) FickO2, (2) carbon dioxide-based Fick (FickCO2), and (3) aortic flow probe at varying O2 and CO2 tensions. Methods: Yorkshire swine (n=8, 29-30kg) were anesthetized, intubated, and paralyzed. Instrumentation included a femoral arterial and pulmonary arterial catheters, myocardial tissue PO2 probe (Oxford Optronix), and a transit time flow probe (Transonic, Inc) placed on the aortic root via sternotomy. Indexed oxygen consumption (VO2) and carbon dioxide production (VCO2) were continuously measured (E-CAiOVX module, GE Healthcare). In separate experiments, PaO2 was varied between 100-650 mmHg, and PaCO2 ...
Two Cases of Calcified Amorphous Tumor Mimicking Mitral Valve Vegetation
Authors: MikikoFujiwara, HiroyukiWatanabe, TakakoIino, YusukeKobukai, KazuyukiIshibashi, HiroshiYamamoto, KenjiIino, FumioYamamoto, HiroshiIto
Journal: Circulation (2012)
Resection of an Aneurysm of the Arch of the Aorta with Preservation of the Lumen of the Vessel
Authors: Oliviermonod, Andrémeyer
Journal: Circulation (1950)

A case is reported of a 20 year old woman, without history, stigmata, or serologic evidence of syphilis, who presented a mediastinal mass just above and lateral to the arch of the aorta which was originally mistaken for tuberculous lymph nodes. The diagnosis of saccular aneurysm was made after direct puncture of this mass under pleuroscopy. Exploratory thoracotomy was performed and a saccular aneurysm of the terminal part of the arch of the aorta was found. The aneurysm was removed and the aorta sutured without interrupting the continuity of the artery or narrowing its lumen. The authors believe that this is the second successful resection of an aortic aneurysm and the first in which resection was accomplished with preservation of the lumen of the aorta.
Efficacy and tolerability of trabectedin in elderly patients with sarcoma: subgroup analysis from a phase III, randomized controlled study of trabectedin or dacarbazine in patients with advanced liposarcoma or leiomyosarcoma
Authors: R.L. Jones, G.D. Demetri, S.M. Schuetze, M. Milhem, A. Elias, B.A. Van Tine, J. Hamm, S. McCarthy, G. Wang, T. Parekh, R. Knoblauch, M.L. Hensley, R.G. Maki, S. Patel, M. von Mehren
Journal: Annals of Oncology (2018)

Treatment options for soft tissue sarcoma (STS) patients aged ≥65 years (elderly) can be limited by concerns regarding the increased risk of toxicity associated with standard systemic therapies. Trabectedin has demonstrated improved disease control in a phase III trial (ET743-SAR-3007) of patients with advanced liposarcoma or leiomyosarcoma after failure of anthracycline-based chemotherapy. Since previous retrospective analyses have suggested that trabectedin has similar safety and efficacy outcomes regardless of patient age, we carried out a subgroup analysis of the safety and efficacy observed in elderly patients enrolled in this trial.Patients were randomized 2 : 1 to trabectedin (n = 384) or dacarbazine (n = 193) administered intravenously every-3-weeks. The primary end point was overall survival (OS); secondary end points were progression-free survival (PFS), time-to-progression, objective response rate (ORR), duration of response, symptom severity, and safety. A post hoc analysis was conducted in the elderly patient subgroup.Among 131 (trabectedin = 94; dacarbazine = 37) elderly patients, disease characteristics were well-balanced and consistent with those of the total study population. Treatment exposure was longer in patients treated with trabectedin versus dacarbazine (median four versus two cycles, respectively), with a significantly higher proportion receiving prolonged therapy (≥6 cycles) in the trabectedin arm (43% versus 23%, respectively; P = 0.04). Elderly patients treated with trabectedin showed significantly improved PFS [4.9 versus 1.5 months, respectively; hazard ratio (HR)=0.40; P = 0.0002] but no statistically significant improvement in OS (15.1 versus 8.0 months, respectively; HR = 0.72; P = 0.18) or ORR (9% versus 3%, respectively; P = 0.43). The safety profile for elderly trabectedin-treated patients was comparable to that of the overall trabectedin-treated study population.This subgroup analysis of the elderly population of ET743-SAR-3007 suggests that elderly patients with STS and good performance status can expect clinical benefit from trabectedin similar to that observed in younger patients.www.clinicaltrials.gov, NCT01343277.
Abstract 16038: Oscillatory Gene Promoter Regulation by Pgc-1α and Sirt1 in Cardiac Energy Metabolism
Authors: Shinichi Oka, Peiyong Zhai, Takanobu Yamamoto, Yoshiyuki Ikeda, Akihiro Shirakabe, Santosh Bhat, Kevin Schesing, Shohei Ikeda, Ji Yeon Park, Bin Tian, Maha Abdellatif, Junichi Sadoshima
Journal: Circulation (2016)

Impaired energy metabolism is a hallmark of heart failure. PGC-1α is a transcriptional coactivator that stimulates energy metabolism through activation of target transcription factors such as PPARα...
Association Between Temporal Changes in Neonatal Mortality and Spontaneous and Clinician-Initiated Deliveries in the United States, 2006-2013
Authors: Cande V. Ananth, Alexander M. Friedman, Robert L. Goldenberg, Jason D. Wright, Anthony M. Vintzileos
Journal: JAMA Pediatrics (2018)

Preterm and postterm deliveries have declined since 2005 in the United States, but the association between these changes and neonatal mortality remains unknown.To estimate changes in the gestational age distribution among spontaneous and clinician-initiated deliveries between 2006 and 2013 and associated changes in neonatal mortality.A retrospective cohort analysis was conducted of 22 million singleton live births without major malformations in the United States from 2006 to 2013. Data analysis was performed from August to October 2017.Changes in gestational age distribution among spontaneous and clinician-initiated deliveries at extremely preterm (20-27 weeks), very preterm (28-31 weeks), moderately preterm (32-33 weeks), late preterm (34-36 weeks), early term (37-38 weeks), term (39-40), late term (41 weeks), and postterm (42-44 weeks) gestations and changes in neonatal mortality rates at less than 28 days between 2006 and 2013. These changes were estimated from log-linear Poisson regression models with robust variance, adjusted for confounders.Among 22 million births, 12 493 531 (56.7%) were spontaneous and 9 557 815 (43.3%) were clinician-initiated deliveries. Among spontaneous deliveries, the proportion of births at 20 to 27, 28 to 31, 32 to 33, 34 to 36, and 37 to 38 weeks declined. Among clinician-initiated deliveries, the proportion of births at 34 to 36 and 37 to 38 weeks declined and the proportion at 39 to 40 weeks increased. Among spontaneous deliveries, overall neonatal mortality rates declined from 1.8 to 1.3 per 1000 live births, mainly at 20 to 27 weeks (adjusted annual decline, 1%; 95% CI, -2% to -1%) and 28 to 31 weeks (adjusted annual decline, 6%; 95% CI, -8% to -5%). Among clinician-initiated deliveries, overall mortality rates remained unchanged (2.1 to 2.2 per 1000 live births). However, mortality rates declined (0.6 to 0.5 per 1000 live births) at 39 to 40 weeks by 1% (95% CI, -3% to -0.4%) annually, adjusted for confounders.In the United States, there was a decline in spontaneous deliveries associated with an overall decline in neonatal mortality. Although clinician-initiated deliveries increased at 39 to 40 weeks, neonatal mortality at that gestation declined.
Abstract 17591: Impact of Renal Dysfunction on Clinical Outcomes in Patients Undergoing Percutaneous Coronary Intervention Who Have Concomitant Atrial Fibrillation: From the CREDO-Kyoto Registry Cohort-2
Authors: Koji Goto, Satoshi Shizuta, Kentaro Nakai, Takeshi Morimoto, Hiroki Shiomi, Masahiro Natsuaki, Yoshihisa Nakagawa, Yutaka Furukawa, Takeshi Kimura
Journal: Circulation (2013)

Background: Clinical outcomes in patients undergoing percutaneous coronary intervention (PCI) with atrial fibrillation (AF) and chronic kidney disease (CKD) have not yet been fully elucidated. Methods and Results: Among 12716 patients undergoing PCI in the CREDO-Kyoto Registry Cohort-2, 1057 (8.3%) had AF. The AF patients were divided into 3 groups according to estimated glomerular filtration rate (eGFR); non-CKD (eGFR>=60, n=491), mild-CKD (eGFR=30-60, n=448), and severe-CKD (eGFR<30 or on hemodialysis, n=107) groups. Compared with non-CKD patients, mild- and severe-CKD patients were older (70.1±9.2, 74.8±8.7, and 74.2±9.5, P<0.001). Prevalence of oral anticoagulation (OAC) with warfarin at hospital discharge was 48%, 49%, and 44%, respectively (P=NS). Median follow-up duration was 5.1 years. AF was independently associated with stroke (adjusted hazard ratio [HR] 2.00, 95% confidence interval [CI] 1.65-2.43). The 5-year risk of stroke in AF patients with non-, mild-, and severe-CKD was 8.9%, 13.7%, and 3...
Protection Against Oxidized Low-Density Lipoprotein–Induced Vascular Endothelial Cell Death by Integrin-Linked Kinase
Authors: XiuwuZhang, KangHu, Chuan-YuanLi
Journal: Circulation (2001)

Background Integrin-linked kinase (ILK) is a protein that plays important roles in extracellular matrix-mediated signaling. It has been shown that ILK is expressed preferentially in cardiac and skeletal muscles. Evidence points to its role as an upstream regulator of protein kinase B, a critical player in apoptosis. Because oxidized LDL (oxLDL) is thought to promote atherogenesis by causing the apoptosis of endothelial cells, we investigated the potential roles that ILK may play in oxLDL-induced apoptosis in vascular endothelial cells. Methods and Results Transcriptional and translational levels of ILK were investigated with reverse-transcriptase polymerase chain reaction and Western analysis. oxLDL treatment induced both the transcription and the translation of the ILK gene in endothelial cells. A recombinant adenovirus vector encoding the ILK gene was constructed to investigate its potential role in oxLDL-induced apoptosis in human umbilical vein endothelial cells and mouse lymphoid vein endothelial cel...
Vascular Remodeling Induced by Naturally Occurring Unsaturated Lysophosphatidic Acid In Vivo
Authors: KenjiYoshida, WataruNishida, Ken’ichiroHayashi, YasuyukiOhkawa, AkiraOgawa, JunkenAoki, HiroyukiArai, KenjiSobue
Journal: Circulation (2003)

Background— We previously identified unsaturated (16:1, 18:1, and 18:2) but not saturated (12:0, 14:0, 16:0, and 18:0) lysophosphatidic acids (LPAs) as potent factors for vascular smooth muscle cell (VSMC) dedifferentiation. Unsaturated LPAs strongly induce VSMC dedifferentiation via the coordinated activation of the extracellular signal–regulated kinase (ERK) and p38 mitogen–activated protein kinase (p38MAPK), resulting in the proliferation and migration of dedifferentiated VSMCs. Here, we investigated the effects of 18:1 and 18:0 LPAs (as representative unsaturated and saturated LPAs, respectively) on the vasculature in vivo. Methods and Results— Rat common carotid arteries (CCAs) were treated transiently with 18:1 or 18:0 LPA and then examined by histological and biochemical analyses. The 18:1 but not 18:0 LPA potently induced vascular remodeling that was composed primarily of neointima. The incorporation of [3H]18:1 LPA into the CCAs revealed that a sufficient amount of unmetabolized [3H]18:1 LPA to i...
Abstract 4394: Novel edible medicinal plant induced cytotoxic and apoptotic effects on ovarian cancer cells
Authors: Ariane T. Mbemi
Journal: Cancer Research (2018)

Abstract Ovarian cancer (OC) is the leading cause of death in gynecologic cancer and the fifth most common form of cancer diagnosed among women. Caucasians have a higher incidence and mortality rate compared to African-Americans. The low survival rate of ovarian cancer among patients is caused by the fact that ovary organs are located inside the pelvic region in the female reproductive system; many cases are diagnosed in advanced stage, when cancer has already metastasized beyond the ovaries. Consequently, there is an urgent need to prevent ovarian cancer at the early stage and provide effective treatment. Herbal medicine with lesser or no side effect is currently considered as an alternative cancer treatment because it possesses many bioactive compounds essential to destroy cancer cells. A preliminary study in our laboratory demonstrates that extracts of Vernonia species have antitumor activities against cancer cells. Therefore, our overall goal in this study was to test the therapeutic mechanisms of a Vernonia species (an edible medical plant) in the treatment of ovarian cancer. To reach our goal, we tested the cytototic and apoptotic effects of the Vernonia species on OVCAR-3 cells. Data generated from the trypan blue test and MTT assay demonstrated that extracts of Vernonia species exhibited significant growth-inhibitory effects on OVCAR-3 cells. Oxidative stress biomarkers showed slight decrease in the production of malondialdehyde (MDA) levels and an increase in catalase activity and glutathione peroxidase in treated cells compared to the control group. Further experiments, including cell morphology and apoptosis analysis, showed that VA caused growth-inhibitory effects on OVCAR-3 cells through cell cycle arrest at the Go/G1 checkpoint and activation of caspase-3 activity leading to apoptosis. Collectively, findings from this study provide convincing scientific evidence that the Vernonia species tested here may represent a potential anticancer candidate against ovarian cancer. This research work was supported by a grant from the National Institutes of Health (Grant No. NIMHD-G12MD007581). Citation Format: Ariane T. Mbemi. Novel edible medicinal plant induced cytotoxic and apoptotic effects on ovarian 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 4394.
Papillary Muscle Dyssynchrony-Mediated Functional Mitral Regurgitation
Authors: Philipp E. Bartko, Henrike Arfsten, Gregor Heitzinger, Noemi Pavo, Guido Strunk, Marianne Gwechenberger, Christian Hengstenberg, Thomas Binder, Martin Hülsmann, Georg Goliasch
Journal: JACC. Cardiovascular imaging (2018)
Application of Nanoparticle Technology for the Prevention of Restenosis After Balloon Injury in Rats
Authors: ToyokazuUwatoku, HiroakiShimokawa, KohtaroAbe, YasuharuMatsumoto, TsuyoshiHattori, KeijiOi, TakehisaMatsuda, KazunoriKataoka, AkiraTakeshita
Journal: Circulation Research (2003)

Restenosis after percutaneous coronary intervention continues to be a serious problem in clinical cardiology. Recent advances in nanoparticle technology have enabled us to deliver an antiproliferative drug selectively to the balloon-injured artery for a longer time. NK911, which is a core-shell nanoparticle of polyethyleneglycol-based block copolymer encapsulating doxorubicin, accumulates in vascular lesions with increased permeability. We first confirmed that balloon injury caused a marked and sustained increase in vascular permeability (as evaluated by Evans blue staining) for a week in the rat carotid artery. We then observed that intravenous administration of just 3 times of NK911, but not doxorubicin alone, significantly inhibited the neointimal formation of the rat carotid artery at 4 weeks after the injury in both a single- and double-injury model. Immunostaining demonstrated that the effect of NK911 was due to inhibition of vascular smooth muscle proliferation but not to enhancement of apoptosis o...
Abstract 3114: In vitro culture system for circulating tumor cell
Authors: Chen Yin-Ju, Long-Sheng Lu, Hsin-Lun Lee, Lai-Lei Ting, Jeng-Fong Chiou
Journal: Cancer Research (2018)

Abstract Circulating tumor cells (CTCs) detection could be considered a real-time “liquid biopsy” approach and contains several advantages such as being minimally invasive, easy and safe to perform, multiple samples can be taken over time, better prognosis to indicate an elevated risk of metastases, improved therapy monitoring, and providing live disease status information. CTC analysis is a promising new diagnostic field for estimating the risk for metastatic relapse and metastatic progression in patients with cancer. However, the number of CTCs is very low so the establishment of cell culture from CTCs becomes the most challenging over the past year. In this study, we development a cost-effective and reproducible in vitro system for primary CTC cultures or established cell lines from CTCs. 8 CTC cell lines were generated from patients including breast cancer, small cell lung cancer, pancreatic cancer and expanded for more than one year. These cell lines exhibit the tissue-specific markers and also correlated with clinical treatment response from patients. This system provides an opportunity for broad applications of CTCs for personalized oncology and advancing precision medicine. Citation Format: Chen Yin-Ju, Long-Sheng Lu, Hsin-Lun Lee, Lai-Lei Ting, Jeng-Fong Chiou. In vitro culture system for circulating tumor cell [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 3114.
SAT0060 Proteomic analysis of osteoblasts secretome provides new insights in mechanisms underlying osteoarthritis subchondral bone sclerosis
Authors: C. Sanchez, G. Mazzucchelli, F. Comblain, C. Lambert, E. DePauw, Y. Henrotin
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Osteoarthritis (OA) is characterised by cartilage degradation but also by other joint tissues modification like subchondral bone sclerosis <h3>Objectives</h3> In this study, we used a proteomic approach to compare secretome of osteoblasts isolated from sclerotic (SC) or non sclerotic (NSC) area of OA subchondral bone <h3>Methods</h3> Secretome was analysed using differential quantitative and relative label free analysis on nanoUPLC G2 HDMS system. mRNA of the more differentially secreted proteins were then quantified by RT-PCR and the most relevant proteins identified using western-blotting and immunoassays <h3>Results</h3> 175 proteins were identified in NSC osteoblasts secretome. Compared to NSC osteoblasts secretome, 13 proteins were significantly less secreted (Osteomodulin, CSF-1, IGFBP5, VCAM-1, IGF2, 78 kDa glucose-regulated protein, versican, calumenin, IGFBP2, thrombospondin-4, periostin, reticulocalbin 1 and osteonectin), and 12 proteins significantly more secreted by SC osteoblasts (CHI3L1, fibulin-3, SERPINE2, IGFBP6, SH3BGRL3, SERPINE1, reticulocalbin3, alpha-2-HS-glycoprotein, TIMP-2, IGFBP3, TIMP-1, SERPINF1). Similar changes in periostin, osteomodulin, SERPINE1, IGFBP6, fibulin-3 and CHI3L1 mRNA levels were observed. Finally, osteomodulin and fibulin-3 specific sequences were quantified by western blot and immunoassays in serum and osteoblasts conditioned culture supernatants. <h3>Conclusions</h3> We highlighted some proteins differentially secreted by NSC and SC osteoblasts of OA subchondral bone sclerosis. These changes contribute to explain some features observed in OA subchondral bone, like the increase of bone remodelling or abnormalities in bone matrix mineralization. Among identified proteins, osteomodulin was found decreased and fibulin-3 increased in serum of OA patients. These findings suggest that osteomodulin and fibulin-3 fragments could be biomarkers to monitor early changes in subchondral bone metabolism in OA. <h3>Acknowledgements</h3> The D-Board project has received funding from the European Union's Seventh Framework Programme for research, technological development and demonstration under grant agreement No. 3 05 815. <h3>Disclosure of Interest</h3> None declared