tbuckley/cabot-search huggingface dataset:
Drug-Induced Long-QT Syndrome Associated With a Subclinical SCN5A Mutation
Authors: NaomasaMakita, MinoruHorie, TakeshiNakamura, TomohikoAi, KojiSasaki, HisatakaYokoi, MasayukiSakurai, IchiroSakuma, HideoOtani, HirofumiSawa, AkiraKitabatake
Journal: Circulation (2002)

Background— Subclinical mutations in genes associated with the congenital long-QT syndromes (LQTS) have been suggested as a risk factor for drug-induced LQTS and accompanying life-threatening arrhythmias. Recent studies have identified genetic variants of the cardiac K+ channel genes predisposing affected individuals to acquired LQTS. We have identified a novel Na+ channel mutation in an individual who exhibited drug-induced LQTS. Methods and Results— An elderly Japanese woman with documented QT prolongation and torsade de pointes during treatment with the prokinetic drug cisapride underwent mutational analysis of LQTS-related genes. A novel missense mutation (L1825P) was identified within the C-terminus region of the cardiac Na+ channel (SCN5A). The L1825P channel heterologously expressed in tsA-201 cells showed Na+ current with slow decay and a prominent tetrodotoxin-sensitive noninactivating component, similar to the gain-of-function phenotype most commonly observed for SCN5A-associated congenital LQTS...
Abstract 4423: MiR551b-mediated Oncostatin M signaling in breast cancer
Authors: Anjali Geethadevi, Deepak Parashar, Miriam Ragle-Aure, Bindu Nair, Yiling Lu, Vessela N. Kristensen, Ming You, Anil K. Sood, Gordon B. Mills, Sunila Pradeep, Pradeep Chaluvally Raghavan
Journal: Cancer Research (2018)

Abstract We have previously demonstrated that an oncogenic microRNA miR551b-3p (also known as miR551b) regulates STAT3 transcription thereby enhancing tumor growth and metastasis in ovarian cancer. Herein, we have identified that Oncostatin M (OSM) is upregulated through STAT3-driven transcription, which plays an important role in promoting migration and invasion of breast cancer cells. The purpose of this study was to evaluate the role of miR551b mediated STAT3 activation and the precise mechanism that regulates OSM-Receptor (OSMR) signaling for breast cancer growth and metastasis. MDA-MB231 cells were either overexpressed or silenced with miR551b and anti-miR551b respectively and the effects on proliferation, migration/invasion (Matrigel transwell assay), wound healing and expression of OSMR and its downstream targets (Western blotting, Quantitative RT-PCR) were assessed. Our data demonstrate that miR551b promoted survival, proliferation, invasion and migration and epithelial to mesenchymal transition (EMT) and spheroid formation of breast cancer cells. Our results also show that miR551b-mediated STAT3 activation upregulated the components of OSMR signaling through elevated expression of OSMR, Interleukin 31 receptor-alpha (IL31RA) and their ligands Oncostatin (OSM) and IL31 thereby inducing phosphorylation of STAT3 for tumor cell proliferation, migration and invasion. Conversely, anti-miR551b reduced the expression of OSMR, IL31R and their ligands OSM and IL31 as well as the phosphorylation of STAT3. Briefly, our results provide the first report indicating that miR551b regulates OSMR expression by activating STAT3 and thereby promoting tumor cell growth and metastasis in breast cancer cells through autocrine feed-forward signaling loop. A.G, D.P., contributed equally. Citation Format: Anjali Geethadevi, Deepak Parashar, Miriam Ragle-Aure, Bindu Nair, Yiling Lu, Vessela N. Kristensen, Ming You, Anil K. Sood, Gordon B. Mills, Sunila Pradeep, Pradeep Chaluvally Raghavan. MiR551b-mediated Oncostatin M signaling in breast cancer [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 4423.
Abstract 5278: Tobacco and areca nut use among Chuukese youth in Guam
Authors: Lilnabeth P. Somera, Brayan Simsiman, Grazyna Badowski, Hye-ryeon Lee, Kevin Cassel
Journal: Cancer Research (2018)

Abstract Background: Little is known regarding the tobacco use of Micronesian population in Guam. According to the Youth Risk Behavior Survey (YRBS) 2013, Micronesian youth have a higher prevalence rate of current smokers (27.2% vs. 15.7% for U.S.) and current smokeless tobacco users (39.7% vs. 8.8% for US) compared to the U.S. They also have the highest rate among all ethnic groups in Guam. This study aims to investigate tobacco use and areca nut use, which may explain high lung and bronchus cancer incidence and mortality rates among Micronesians. The survey in this study focuses on Chuukese youth, the largest group among Micronesians in Guam. Methods: Respondent-driven sampling method (RDS) was used to recruit 364 Chuukese youth (ages 13-19) to complete the survey. YRBS question items that measured cigarette, cigar, and smokeless tobacco use were included in the survey. Measures for areca nut use were also included. Chi-square tests were performed by bivariate analysis. Only high school-level youth are included in the analysis. Results: A total of 237 Chuukese high school students completed the survey. Fourteen percent of the participants currently smoke cigarettes, 6.4% currently smoke cigars, and 23.7% currently use smokeless tobacco. In addition, smokeless tobacco remains highest regarding daily use (11%) within the past 30 days prior the survey. Although there is high use of smokeless tobacco among participants, there are significant associations between gender and cigarette and gender and cigar use only. Boys smoke cigarettes and cigar at higher rates than girls. Among the recruited participants, 32% are areca nut users with tobacco product as an ingredient. There is significantly high association between smokeless tobacco users and areca nut with tobacco users. The majority of cigarette smokers (82.4%) have tried to quit smoking. Fifty-six percent of the smokeless tobacco users have tried to quit as well. However, only 17% of the participants are aware of the Guam Youth Quitline. Conclusion: Results suggest the need to raise awareness among Chuukese youth on tobacco cessation programs on Guam, particularly the smoking cessation quitline. Tobacco cessation efforts should not focus on cigarette use only, but must also be expanded to include the use of smokeless tobacco products and chewing areca nut. Future studies should investigate the roles and implications of tobacco as an ingredient of areca nut chewing among Micronesian youth. Citation Format: Lilnabeth P. Somera, Brayan Simsiman, Grazyna Badowski, Hye-ryeon Lee, Kevin Cassel. Tobacco and areca nut use among Chuukese youth in Guam [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 5278.
Fc Receptor–Mediated Inhibitory Effect of Immunoglobulin Therapy on Autoimmune Giant Cell Myocarditis
Authors: KeisukeShioji, ChiharuKishimoto, ShigetakeSasayama
Journal: Circulation Research (2001)

Abstract— In the present study, the mechanisms and importance of the Fc portion of immunoglobulin in experimental giant cell myocarditis were examined. Giant cell myocarditis was induced in rats by immunization of porcine cardiac myosin. Human intact immunoglobulin (1 g · kg−1 · d−1) or F(ab′)2 fragments of human immunoglobulin (1 g · kg−1 · d−1) were administered intraperitoneally daily on days 1 to 21. Intact immunoglobulin administration significantly ameliorated myocarditis, but F(ab′)2 fragments did not. The ribonuclease protection assay revealed that therapy with intact immunoglobulin, but not F(ab′)2 fragments, suppressed the mRNA expressions of inflammatory and proinflammatory cytokines. Immunohistochemical analysis showed that therapy with intact immunoglobulin, but not F(ab′)2 fragments, suppressed dendritic cell (DC) expression during both the early and the subsequent fulminant phases. Moreover, the early treatment of intact immunoglobulin until the 11th day or 14th day, when the expression of ...
A Single-Agent Dual-Specificity Targeting of FOLR1 and DR5 as an Effective Strategy for Ovarian Cancer
Authors: Gururaj Shivange, Karol Urbanek, Piotr Przanowski, Justin S.A. Perry, James Jones, Robert Haggart, Christina Kostka, Tejal Patki, Edward Stelow, Yuliya Petrova, Danielle Llaneza, Marty Mayo, Kodi S. Ravichandran, Charles N. Landen, Sanchita Bhatnagar, Jogender Tushir-Singh
Journal: Cancer Cell (2018)
Bone Marrow Cells Differentiate in Cardiac Cell Lineages After Infarction Independently of Cell Fusion
Authors: JanKajstura, MarcelloRota, BrianWhang, StefanoCascapera, ToruHosoda, ClaudiaBearzi, DariaNurzynska, HidekoKasahara, EliasZias, MassimilianoBonafé, BernardoNadal-Ginard, DanieleTorella, AngeloNascimbene, FedericoQuaini, KonradUrbanek, AnnarosaLeri, PieroAnversa
Journal: Circulation Research (2005)

Recent studies in mice have challenged the ability of bone marrow cells (BMCs) to differentiate into myocytes and coronary vessels. The claim has also been made that BMCs acquire a cell phenotype different from the blood lineages only by fusing with resident cells. Technical problems exist in the induction of myocardial infarction and the successful injection of BMCs in the mouse heart. Similarly, the accurate analysis of the cell populations implicated in the regeneration of the dead tissue is complex and these factors together may account for the negative findings. In this study, we have implemented a simple protocol that can easily be reproduced and have reevaluated whether injection of BMCs restores the infarcted myocardium in mice and whether cell fusion is involved in tissue reconstitution. For this purpose, c-kit–positive BMCs were obtained from male transgenic mice expressing enhanced green fluorescence protein (EGFP). EGFP and the Y-chromosome were used as markers of the progeny of the transplant...
Ultra‐small Albumin Templated Gd/Ru Composite Nanodots for In Vivo Dual modal MR/Thermal Imaging Guided Photothermal Therapy
Authors: Pengping Xu, Huihui Wu, Dongdong Wang, Gaozheng Zhao, Fenfen Li, Bensheng Qiu, Zhen Guo, Qianwang Chen
Journal: Advanced Healthcare Materials (2018)

Multifunctional theranostic nanoagents which realize precise diagnosis and treatment of tumors are attracting increasing interests in recent years. However, efficient and controlled synthesis of ultra-small noble metal nanoagents remains a challenge. Here, monodisperse Gd/Ru@BSA nanodots (GRBNDs) are successfully fabricated via a totally "green", "one-pot" protocol for in situ reduction of Ru(III) and biomineralization of Gd(III) in the presence of albumin. The as-prepared nanoagent possesses the features of being ultra small in size (≈6.7 nm), having strong colloidal stability, and thermal stability as well as high photothermal conversion efficiency (η = 50.7%). As expected, the GRBNDs achieve a significant efficacy of anticancer therapy under LASER activation both in vitro and in vivo. It also exhibits superior T1 -weighted magnetic resonance (MR) imaging ability due to its high longitudinal relaxivity value (r1 = 10.98 × 10-3 m-1 s-1 ). Moreover, it is demonstrated to be renal clearable with negligible systemic toxicity. This work highlights a straightforward and repeatable approach for synthesizing highly effective and multifunctional noble metal nanoagent of great clinical promising for cancer theranostics.
Abstract 2860: The chemosensitizing and oncolytic effects of Dihydrotanshinone in glioblastoma
Authors: Varun Kumar, Donna Leonardi
Journal: Cancer Research (2018)

Abstract Temozolomide is the primary chemotherapeutic agent used to treat glioblastoma. However, many tumors are initially resistant to or develop resistance to temozolomide, mainly due to high levels of O6-methylguanine DNA transferase (MGMT) which repairs DNA damage traditionally caused by temozolomide. Dihydrotanshinone (DHT) is extracted from Salvia miltiorrhiza, a Chinese medicinal plant, and has been shown to have antiproliferative effects on various cancer cell lines. DHT has also been to shown to induce apoptosis via induction endoplasmic reticulum stress, that can reportedly sensitize cells to temozolomide. MTS cellular proliferation assays or trypan blue viability assays were used to determine the effects of DHT/temozolomide combinatorial treatment. Enzyme-linked immunosorbent assay (ELISA) was used to determine effects on MGMT, P-glycoprotein, AKT, p65, and IlkB levels after singular and combinatorial treatment. DNA microarray was used to gauge gene expression and miRNA levels. Solute clearance of the blood-brain barrier was analyzed using a co-culture model system and confocal microscopy. DHT had a selectively cytotoxic synergistic oncolytic effect in a MGMT-deficient cell line and a sensitizing effect in a MGMT-expressing cell line. Cytotoxicity due to DHT was shown to be reactive oxygen species-dependent, while the combinatorial effect of DHT and temozolomide synergistically reduced MGMT and P-glycoprotein expression and protein levels. In addition, the NFkB complex was sensitive to combinatorial treatment, while AKT activity and gene expression was downregulated in response to treatment. DHT was shown to augment temozolomide efficacy, indicating that, since DHT can penetrate the blood–brain barrier, temozolomide in combination with DHT may represent a promising therapeutic option for glioblastoma. Citation Format: Varun Kumar, Donna Leonardi. The chemosensitizing and oncolytic effects of Dihydrotanshinone in glioblastoma [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 2860.
Abstract 1850: CDK inhibitor PHA-848125 preferentially inhibits proliferation of triple negative breast cancer and synergizes with cisplatin
Authors: Douglas G. Cheung, Marta Buzzetti, Carlo M. Croce, Gianpiero di Leva
Journal: Cancer Research (2018)

Abstract Triple-negative breast cancer (TNBC), defined by the lack of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), is highly aggressive with a poor prognosis as it lacks targeted therapies. Several inhibitors of the cyclin-dependent kinase 4 and 6 (CDK4/6) have been approved by the FDA for the treatment of ER-positive breast cancer. However, the effectiveness of these inhibitors against TNBC tumors is less than expected. Here, we tested the efficacy of PHA-848125, a potent ATP-competitive CDK2 inhibitor, on a panel of breast cancer cell lines showing a selective impaired proliferation in TNBC cells (IC50 of ER-positive MCF7 cells: 25.9 μM vs. IC50 of TNBC MDA-MB-231 cells: 430.8 nM). TNBC cells treated with PHA-848125 exhibited effects consistent with CDK2 inhibition, including G1 cell cycle arrest and reduced phosphorylation levels of the retinoblastoma protein (pRB) and CDK2. Interestingly, PHA-848125 was also effective against pRB-null TNBC cell lines, unlike other approved CDK inhibitors. Oral administration of PHA-848125 to TNBC xenograft mice and MMTV-PyMT transgenic mice impaired both tumor growth and metastasis at a tolerable dose (40 mg/kg), but not in ER-positive xenograft mice. A combination treatment of PHA-848125 and cisplatin inhibited tumor growth and induced apoptosis synergistically in vitro and in vivo. Thus, our preclinical experiments set the rationale for the clinical evaluation of PHA-848125, either alone or in combination with cisplatin, for the treatment of TNBC. Citation Format: Douglas G. Cheung, Marta Buzzetti, Carlo M. Croce, Gianpiero di Leva. CDK inhibitor PHA-848125 preferentially inhibits proliferation of triple negative breast cancer and synergizes with cisplatin [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 1850.
Glucocorticoid Excess Induces Superoxide Production in Vascular Endothelial Cells and Elicits Vascular Endothelial Dysfunction
Authors: TakahikoIuchi, MasashiAkaike, TakaoMitsui, YasushiOhshima, YasumiShintani, HiroyukiAzuma, ToshioMatsumoto
Journal: Circulation Research (2003)

Glucocorticoid (GC) excess often elicits serious adverse effects on the vascular system, such as hypertension and atherosclerosis, and effective prophylaxis for these complications is limited. We sought to reveal the mechanism underlying GC-induced vascular complications. Responses in forearm blood flow to reactive hyperemia in 20 GC-treated patients were significantly decreased to 43±8.9% (mean±SEM) from the values obtained before GC therapy (130±14%). An administration of vitamin C almost normalized blood flow responses. In human umbilical vein endothelial cells (HUVECs), production of hydrogen peroxide was increased up to 166.5±3.3% of control values by 10−7 mol/L dexamethasone (DEX) treatment (P<0.01). Concomitant with DEX-induced hydrogen peroxide production, intracellular amounts of peroxynitrite significantly increased and those of nitric oxide (NO) decreased, respectively (P<0.01). Immunoblotting analysis using anti-nitrotyrosine antibody showed that peroxynitrite formation was increased in DEX-tr...
Abstract 376: Sam68 Suppresses Autophagy in Macrophages and Promotes Atherosclerosis
Authors: Jiawei Shi, Shuling Han, Junlan Zhou, Liu Yang, Baron Arnone, Chan Boriboun, Congcong He, Gangjian Qin
Journal: Circulation Research (2016)

Background: Recent experimental evidence suggests that autophagy inhibits the pathogenesis of atherosclerosis. The Src-associated substrate during mitosis of 68 kDa (Sam68) belongs to the family of KH domain RNA binding protein; its role in macrophage autophagy and atherosclerosis has not been studied. Methods &amp; Results: In Raw264.7 macrophage cell line, lentivirus-shRNA mediated knockdown of Sam68 (Sam68-KDn) led to a reduced level of LC3-I, LC3-II, and p62/sqstm1 proteins at basal culture condition, however, to a faster accumulation of these proteins with Bafliomycin A1 (autolysosome inhibitor) treatment, indicating an accelerated autophagy flux. Consistently, Sam68-KDn HeLa/GFP-LC3 cells displayed more autophagosome punctae counts (by immuno-fluorescent microscopy) and greater LC3-II specific median fluorescent intensity (by flow cytometry) than control HeLa/GFP-LC3 cells when treated with Bafliomycin A1. Notably, quantitative RT-PCR analyses revealed that Sam68-KDn did not alter mRNA expression of known major autophagy related genes (MAP1LC3B, SQSTM1, BECN1, Atg5, Atg7 and Atg12). Following induction of autophagy with different treatments including starvation (EBSS), Rapamycin (100nM), LPS (10ng/ml) and ox-LDL (50μg/ml), the autophagy flux was increased to a greater extent in Sam68-KDn cells than in control non-targeting cells. When treated with oxLDL and AcLDL, Sam68-KDn Raw264.7 cells and Sam68-null (Sam68-/-) peritoneal macrophages formed fewer foam cells and produced lesser amount of pro-inflammatory cytokines (TNF-alpha, IL-1beta, and IL-6) than control cells with an intact Sam68. Furthermore, the Sam68-/- peritoneal macrophages displayed an enhanced cholesterol efflux as compared to wild-type control cells. Lastly, ApoE-/-Sam68-/- mice developed a significantly smaller area of atherosclerotic lesions in the aorta and aortic valves than ApoE-/- mice after Western diet feeding for 12 weeks. Conclusions: Sam68 suppresses autophagy in macrophages, which may contribute to the development of atherosclerosis.
Increased Risk of Left Heart Valve Regurgitation Associated With Benfluorex Use in Patients With Diabetes Mellitus
Authors: ChristopheTribouilloy, DanRusinaru, SylvestreMaréchaux, AntoineJeu, StéphaneEderhy, ErwanDonal, PatriciaRéant, EliseArnalsteen, JacquesBoulanger, Pierre-VladimirEnnezat, ThierryGarban, YannickJobic
Journal: Circulation (2012)

Background—Benfluorex was withdrawn from European markets in June 2010 after reports of an association with heart valve lesions. The link between benfluorex and valve regurgitations was based on small observational studies and retrospective estimations. We therefore designed an echocardiography-based multicenter study to compare the frequency of left heart valve regurgitations in diabetic patients exposed to benfluorex for at least 3 months and in diabetic control subjects never exposed to the drug. Methods and Results—This reader-blinded, controlled study conducted in 10 centers in France between February 2010 and September 2011 prospectively included 376 diabetic subjects previously exposed to benfluorex who were referred by primary care physicians for echocardiography and 376 diabetic control subjects. Through the use of propensity scores, 293 patients and 293 control subjects were matched for age, sex, body mass index, smoking, dyslipidemia, hypertension, and coronary artery disease. The main outcome ...
Ecto-5′-Nucleotidase on Immune Cells Protects From Adverse Cardiac Remodeling
Authors: FlorianBönner, NadineBorg, ChristophJacoby, SebastianTemme, ZhaopingDing, UlrichFlögel, JürgenSchrader
Journal: Circulation Research (2013)

Rationale:Ecto-5′-nucleotidase (CD73) on immune cells is emerging as a critical pathway and therapeutic target in cardiovascular and autoimmune disorders. Objective:Here, we investigated the role of CD73 in postinfarction inflammation, cardiac repair, and remodeling in mice after reperfused myocardial infarction (50-minute ischemia). Methods and Results:We found that compared with control mice (1) cardiac function in CD73−/− mice more severely declined after infarction (systolic failure with enhanced myocardial edema formation) as determined by MRI and was associated with the persistence of cardiac immune cell subsets, (2) cardiac adenosine release was augmented 7 days after ischemia/reperfusion in control mice but reduced by 90% in CD73 mutants, (3) impaired healing involves M1-driven immune response with increased tumor necrosis factor-α and interleukin-17, as well as decreased transforming growth factor-β and interleukin-10, and (4) CD73−/− mice displayed infarct expansion accompanied by an immature re...
Activation of Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1 Induces Apoptosis in Cultured Neonatal Rat Cardiac Myocytes
Authors: EriIwai-Kanai, KojiHasegawa, TatsuyaSawamura, MasatoshiFujita, TetsuhikoYanazume, ShinyaToyokuni, SouichiAdachi, YasukiKihara, ShigetakeSasayama
Journal: Circulation (2001)

Background— Lectin-like oxidized LDL receptor-1 (LOX-1) was originally identified as a receptor expressed predominantly in endothelial cells. LOX-1 can also be expressed in other cell types, and the activation of the LOX-1 pathway has been implicated in apoptosis. There have been no reports, however, about LOX-1 expression in cardiac myocytes or regulation of myocardial cell apoptosis by LOX-1. Methods and Results— In primary cardiac myocytes from neonatal rats, immunohistochemical analyses using a specific monoclonal antibody against LOX-1 demonstrated that LOX-1 expression was markedly induced by stimulation with norepinephrine and endothelin-1. LOX-1 expression was upregulated in cardiac myocytes as well as in vessel walls of failing rat hearts in vivo. In the presence of a low concentration of oxidized LDL that did not induce apoptosis by itself, artificial overexpression of LOX-1 in cardiac myocytes in culture resulted in apoptosis. LOX-1 overexpression induced activation of p38 mitogen-activated pro...
Accuracy and Methodologic Challenges of Volatile Organic Compound–Based Exhaled Breath Tests for Cancer Diagnosis
Authors: George B. Hanna, Piers R. Boshier, Sheraz R. Markar, Andrea Romano
Journal: JAMA Oncology (2018)

The detection and quantification of volatile organic compounds (VOCs) within exhaled breath have evolved gradually for the diagnosis of cancer. The overall diagnostic accuracy of proposed tests remains unknown.