tbuckley/cabot-search huggingface dataset:
Human Induced Pluripotent Stem Cell–Derived Cardiomyocytes as Models for Cardiac Channelopathies
Authors: Priyanka Garg, Vivek Garg, Rajani Shrestha, Michael C. Sanguinetti, Timothy J. Kamp, Joseph C. Wu
Journal: Circulation Research (2018)

Life threatening ventricular arrhythmias leading to sudden cardiac death are a major cause of morbidity and mortality. In the absence of structural heart disease, these arrhythmias, especially in the younger population, are often an outcome of genetic defects in specialized membrane proteins called ion channels. In the heart, exceptionally well-orchestrated activity of a diversity of ion channels mediates the cardiac action potential. Alterations in either the function or expression of these channels can disrupt the configuration of the action potential, leading to abnormal electrical activity of the heart that can sometimes initiate an arrhythmia. Understanding the pathophysiology of inherited arrhythmias can be challenging because of the complexity of the disorder and lack of appropriate cellular and in vivo models. Recent advances in human induced pluripotent stem cell technology have provided remarkable progress in comprehending the underlying mechanisms of ion channel disorders or channelopathies by modeling these complex arrhythmia syndromes in vitro in a dish. To fully realize the potential of induced pluripotent stem cells in elucidating the mechanistic basis and complex pathophysiology of channelopathies, it is crucial to have a basic knowledge of cardiac myocyte electrophysiology. In this review, we will discuss the role of the various ion channels in cardiac electrophysiology and the molecular and cellular mechanisms of arrhythmias, highlighting the promise of human induced pluripotent stem cell-cardiomyocytes as a model for investigating inherited arrhythmia syndromes and testing antiarrhythmic strategies. Overall, this review aims to provide a basic understanding of the electrical activity of the heart and related channelopathies, especially to clinicians or research scientists in the cardiovascular field with limited electrophysiology background.
LIGHT-HVEM Signaling in Innate Lymphoid Cell Subsets Protects Against Enteric Bacterial Infection
Authors: Goo-Young Seo, Jr-Wen Shui, Daisuke Takahashi, Christina Song, Qingyang Wang, Kenneth Kim, Zbigniew Mikulski, Shilpi Chandra, Daniel A. Giles, Sonja Zahner, Pyeung-Hyeun Kim, Hilde Cheroutre, Marco Colonna, Mitchell Kronenberg
Journal: Cell Host & Microbe (2018)
David Oliver: Can the extra funds for the NHS really transform care?
Authors: David Oliver
Journal: BMJ (2018)

The now departed health secretary, Jeremy Hunt, and NHS England’s chief executive, Simon Stevens, deserve praise for securing the promised 3.4% annual increase in funding for the NHS for five years from 2019-20.1 I see this as a victory, considering the backdrop of sustained cuts in other government departments, the reluctance to raise taxes, and the potential impact of Brexit on the economy.23 But it’s still less than the 4% annual increase that the King’s Fund, Nuffield Trust, Health Foundation, and Institute for Fiscal Studies have agreed that the NHS needs if it is to maintain even current service levels, let alone compensate for several years of funding increases …
The Control of Dicumarol Therapy in Myocardial Infarction by a Simple Blood Prothrombin Test
Authors: Benjaminmanchester, Borisrabkin
Journal: Circulation (1954)

Effective anticoagulant therapy is dependent upon adequate and reliable blood prothrombin determinations. The initiation of such therapy usually requires hospitalization. The currently available blood prothrombin tests require special laboratory facilities and trained personnel. The authors of this report present the results of Dicumarol in myocardial infarction and a simple blood prothrombin test for the control of such anticoagulant therapy. The test has been employed for more than eight years. The method has proved to be simple, accurate, and practical, and has made anticoagulants possible for patients at home as well as in the hospital.
Abstract 2019: Extracellular ATP induces EMT and metastatic activities in non-small cell lung cancer cells
Authors: Yanyang Cao, Xuan Wang, Xiaozhuo Chen
Journal: Cancer Research (2018)

Abstract Cancer is a leading cause of death worldwide. Metastasis, the spread of cancer cells from the primary tumors to distant organs, is responsible for approximately 90% of all cancer-related deaths. Metastasis is a multistep process in which loss of cell-cell adhesion, increased proteolysis, and cell motility have been shown to be critical steps. Recent studies have indicated that intratumoral ATP concentration is ~1,000 times higher than normal tissues of the same cell origins in the range of at least several hundred μM. Extracellular ATP (eATP), a tumor microenvironment molecule, potentially has a crucial role in supporting tumor invasion and metastasis. Our previous studies showed that eATP is internalized by cancer cells through macropinocytosis and other endocytosis and promotes cancer cell growth, survival, and drug resistance (1-4). Based on all these, we hypothesize that eATP functions as both a signaling molecule and an energy source to stimulate epithelial mesenchymal transition (EMT) and metastasis. Various bioassays were used in human non-small cell lung cancer (NSCLC) A549 and HOP-92 cells to test our hypothesis. Our results reveal that eATP treatment led to a substantially increased number of floating cancer cells, and these cells were viable and formed clones in clonogenic assays. Fence assay indicated that eATP not only induces cancer cell detachment but also increases the number of secondary colonies formed. Moreover, treatment of eATP induces a dose- and time-dependent increase in the migration and invasive capacities of the A549 and HOP-92 cells. Confocal images demonstrated that eATP induces the formation of F-actin-dependent filopodia necessary for cell migration. Using Western blot analysis, we found that the expression of epithelial markers was significantly reduced, while the mesenchymal markers were increased after eATP treatment. Purinergic receptor (PR) inhibitors and P2X7 receptor knockdown only slightly attenuated these effects, suggesting PR signaling is only partially responsible for eATP-induced migration and invasion. These results indicate eATP is an EMT and metastasis stimulator and imply novel targets for inhibiting/preventing metastasis. References: 1. Qian Y et al. Cancer Lett 2014;351:242-51. 2. Chen X, Qian Y, Wu S. Free Radical Biol Med 2015;79;253-63. 3. Qian Y et al. Mol Cancer Res 2016;14(11):1087-96. 4. Wang X et al. Oncotarget 2017;8:87860-77. Citation Format: Yanyang Cao, Xuan Wang, Xiaozhuo Chen. Extracellular ATP induces EMT and metastatic activities in non-small cell lung 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 2019.
Abstract 4607: G1/S transition-related gene mutations associated with survival of hepatocellular carcinoma patients
Authors: Bingyuan Zhang, Tianqiang Song, Pingzhou Yang, Songzhu Yang, Chao Guo, Lei Li, Shuang Ren, Maolin Yan, Weiyu Hu, Honglin Guo, Yongjian Zhang, Yanlin Li, Weifeng Wang, Kai Wang, Ming Yao
Journal: Cancer Research (2018)

Abstract Background: Hepatocellular carcinoma (HCC) is one of the most common malignancies in China and has limited therapeutic options. Genomic alterations in HCC had been widely explored and some prognostic genomic alterations were identified. Different etiologic characteristics were discovered in Chinese HCC patients compared with Western population; however, the genomic profiles of Chinese patients had not been thoroughly elucidated. Methods: FFPE tumor samples of 94 Chinese HCC patients, including 79 males and 15 females with a median age of 56, were collected for next-generation sequencing (NGS)-based 450 genes panel assay. Genomic alterations including single base substitution, short and long insertions/deletions, copy number variations, and gene rearrangement and fusions were assessed. Gene Ontology (GO) analysis was conducted with the genes whose variation rates were higher than 5% (N = 22). The TCGA HCC dataset with 198 patients was used to assess the prognostic value of the significantly enriched GO terms. Results: The top 10 highly mutant genes in the 94 Chinese HCC cohort were TP53 (64.9%), TERT (31.9%), CTNNB1 (23.4%), AXIN1 (16.0%), STK24 (12.8%), RB1 (11.7%), CCND1 (9.6%), ARID1A (9.6%), LRPIB (8.5%) and ARID2 (8.5%). The Gene Ontology analysis revealed these gene alterations were significantly associated with pivotal signal pathways and cell proliferation including phosphatidylinositol phosphorylation, protein kinase B signaling, cell cycle arrest, and G1/S transition of mitotic cell cycle. The G1/S transition-related genes included TP53, TERT, RB1, CCND1 and CDKN2A. Moreover, the TCGA HCC patients with mutations of G1/S phase transition and mitotic cell cycle-related genes had a poor survival (p = 0.029). Conclusions: Our study showed that Chinese HCC patients had different genomic alteration profile compared with Western population. The most frequent mutant gene in Chinese HCC was TP53 in 65% of the HCC patients, compared to 31% in the TCGA dataset (PMID:28622513). Genomic alterations in G1/S transition of mitotic cell cycle-related genes in Chinese HCC patients might be a negative prognostic factor. Our preliminary result suggested that functional analysis of HCC genomic alteration profile could have prognostic utility. Citation Format: Bingyuan Zhang, Tianqiang Song, Pingzhou Yang, Songzhu Yang, Chao Guo, Lei Li, Shuang Ren, Maolin Yan, Weiyu Hu, Honglin Guo, Yongjian Zhang, Yanlin Li, Weifeng Wang, Kai Wang, Ming Yao. G1/S transition-related gene mutations associated with survival of hepatocellular carcinoma patients [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 4607.
Abstract 18506: Management and Outcomes of Recalled Medtronic Sprint Fidelis and St Jude Riata ICD Leads at the Time of Generator Change or Lead Revision Surgery
Authors: Anub John, Philip Mar, Nevin Murthy, Praneeth Katrapati, Sarah Longserre, Rajesh Kabra, Rakesh Gopinathannair
Journal: Circulation (2017)

Introduction: Management options for recalled ICD leads include lead extraction with replacement, lead abandonment with replacement or continued use of the functional lead at time of generator chan...
m-Calpain Induction in Vascular Endothelial Cells on Human and Mouse Atheromas and Its Roles in VE-Cadherin Disorganization and Atherosclerosis
Authors: TakuroMiyazaki, YoshitakaTaketomi, MasafumiTakimoto, Xiao-FengLei, ShigekoArita, Joo-riKim-Kaneyama, SatoruArata, HisayukiOhata, HidekazuOta, MakotoMurakami, AkiraMiyazaki
Journal: Circulation (2011)

Background—Although dysfunction of VE-cadherin–mediated adherence junctions in vascular endothelial cells (ECs) is thought to be one of the initial steps of atherosclerosis, little is known regarding how VE-cadherin is disrupted during atherogenic development. This study focused on the role of calpain, an intracellular cysteine protease, in the proteolytic disorganization of VE-cadherin and subsequent progression of atherosclerosis. Methods and Results—Increased expression of m-calpain was observed in aortic ECs in atherosclerotic lesions in humans and low-density lipoprotein receptor–deficient (ldlr−/−) mice. Furthermore, proteolytic disorganization of VE-cadherin was shown in aortic ECs in ldlr−/− and apolipoprotein E–deficient (apoE−/−) mice. Long-term administration of calpain inhibitors into these mice attenuated atherosclerotic lesion development and proinflammatory responses, as well as VE-cadherin disorganization, without normalization of plasma lipid profiles. Furthermore, in vivo transfection of...
Abstract 4242: Ethnic disparities in the risk of cardiac death following cancer diagnosis: A population-based study
Authors: Mohamed M. Gad, Anas M. Saad, Muneer J. Al-Husseini, Abdelrahman I. Abushouk, Haitham M. Ahmed
Journal: Cancer Research (2018)

Abstract Background: Cancer-related cardiac complications and mortality have been well studied. However, the disparities among racial and ethnic groups have not been addressed on a large scale. In this study, we aimed to investigate the racial and ethnic disparities associated with cardiac death in cancer patients. Methods: Data were collected from The Surveillance, Epidemiology and End-Results program of the National Cancer Institute. We defined an "event" as death due to a cardiac cause within ten years after cancer diagnosis, and observed patients who experienced the event during that period. Then, we calculated the Observed/Expected (O/E) ratio and the excess risk per 10,000 person-years to estimate the change of risk following the diagnosis in different ethnicities, when compared to the general population. Results: We reviewed 4,671,989 cancer patients, of whom 163,255 died due to a cardiac cause within the ten years following cancer diagnosis. The overall risk of cardiac death increased significantly in this period with an O/E ratio of 1.16 and an excess risk of 11.66 per 10,000. The sample was divided into 2 groups: Whites with a total O/E ratio of 1.11, and non-Whites with a total O/E ratio of 1.38. When examined for the risk in the first 5 years after diagnosis, Whites and non-Whites demonstrated significant increase in the risk with O/E of 1.12 and 1.39, respectively. However, when examined for the long-term risk more than 5 years after diagnosis, only non-Whites had a significant increase with an O/E of 1.21, while Whites with a cancer diagnosis had the same risk of cardiac death as Whites without cancer diagnosis with an O/E of 1.00. The sample was then further subdivided according to ethnicity into non-Hispanic Whites, Blacks, American Indians (or Alaska natives), Asians (or Pacific islanders), and Hispanics. All groups showed a significantly increased risk of cardiac death following a cancer diagnosis (O/E=1.13, 1.36, 2.33, 1.44, and 1.05, respectively). Conclusion: Non-White patients with a prior cancer diagnosis had a significantly higher long-term risk of cardiac death compared to noncancer patients. Accordingly, careful attention should be paid to the cardiovascular status assessment of those patients to mitigate the added risk of cardiac mortality due to cancer-related morbidities. Further studies are warranted to determine why cardiac event risk increases at a discrepantly higher rate in minority patients with a cancer diagnosis. Citation Format: Mohamed M. Gad, Anas M. Saad, Muneer J. Al-Husseini, Abdelrahman I. Abushouk, Haitham M. Ahmed. Ethnic disparities in the risk of cardiac death following cancer diagnosis: A population-based study [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 4242.
Abstract 13830: Impact of Atrial Fibrillation on Clinical Outcome of Femoropopliteal Artery Intervention in Critical Limb Ischemia
Authors: HiroyukiJinnouchi, YoshimitsuSoga, YoheiKobayashi, YusukeTomoi
Journal: Circulation (2014)

Introduction: Clinical outcome of patients with atrial fibrillation (AF) after endovascular therapy for critical limb ischemia (CLI) is unclear. The aim of this study was to investigate if atrial fibrillation (AF) influences clinical outcomes after femoropopliteal artery intervention in patients with CLI. Methods: A retrospective review of all patients undergoing femoropopliteal artery intervention for CLI was performed. We compared clinical outcome between patients with and without AF. The primary endpoint was amputation free survival (AFS). The secondary endpoints were overall survival, limb salvage, freedom from repeat revascularization, and freedom from surgical conversion were compared between two groups. Kaplan-Meier analyses were performed to assess time-dependent outcomes. Factor analyses were performed using a Cox proportional hazard model for time-dependent variables. Results: A total of 398 limbs with 342 patients were performed with femoropopliteal artery intervention in patients with CLI. (ma...
Abstract 16816: Association of Exhaled Carbon Monoxide With Stroke Incidence and Subclinical Vascular Brain Injury: The Framingham Study
Authors: Matthew Nayor, Danielle Enserro, Alexa S Beiser, Susan Cheng, Charles DeCarli, Ramachandran S Vasan, Sudha Seshadri
Journal: Circulation (2015)

Introduction: Exhaled carbon monoxide (CO) is associated with cardiometabolic traits, subclinical atherosclerosis, and cardiovascular disease, but its specific relations with stroke have not been explored. Hypothesis: We hypothesized that exhaled CO is related to MRI measures of subclinical cerebrovascular disease cross-sectionally, and to incident stroke/ transient ischemic attack (TIA) prospectively in the Framingham Offspring Study. Methods: We measured exhaled CO in 3313 participants (age 59±10 years, 53% women) and Brain MRI imaging was available in 1982 individuals (age 58±10, 54% women). Participants were analyzed according to tertiles of exhaled CO concentration. Results: In age- and sex-adjusted models, the highest tertile of exhaled CO was associated with lower total cerebral brain volumes (TCBV), higher white matter hyperintensity volumes (WMHV), and greater prevalence of silent cerebral infarcts (p &lt;0.05 for all). The results for TCBV and WMHV were consistent after removing smokers from the sample, and the association with WMHV persisted after multivariable adjustment (p=0.04). In prospective analyses (mean follow-up 12.9 years), higher exhaled CO was associated with 67% (second tertile) and 97% (top tertile) increased incidence of stroke/TIA relative to the first tertile that served as referent (p &lt;0.01 for both), Table. These results were consistent in nonsmokers, and were partially attenuated upon adjustment for vascular risk factors, but were maintained after adjusting for circulating biomarkers B-type natriuretic peptide and C-reactive protein, Table. Conclusion: In this large, community-based sample of individuals free of clinical stroke/TIA at baseline, higher exhaled CO was associated with a greater burden of subclinical cerebrovascular disease cross-sectionally, and with increased risk of stroke/TIA prospectively. Further investigation is necessary to explore the biological mechanisms linking CO with stroke.
Low-Density Lipoproteins Inhibit the Na+/H+ Antiport in Human Platelets
Authors: Jerzy-RochNofer, MartinTepel, BeateKehrel, SonjaWierwille, MichaelWalter, UdoSeedorf, WalterZidek, GerdAssmann
Journal: Circulation (1997)

Background LDL have been reported to augment platelet activation, and increased platelet reactivity has been observed in familial hypercholesterolemia. However, the underlying mechanism of this putatively atherogenic effect is unknown. Because intracellular pH (pHi) may play an important role in platelet function, we examined the influence of LDL on pHi and Na+/H+antiport activity in human platelets and compared it with the effect of [3-methylsulfonyl-4-piperidinobenzoyl] guanidine hydrochloride (HOE 694), a selective Na+/H+ antiport inhibitor. Methods and Results Using a fluorescent dye technique, we demonstrated that incubation of platelets with physiological concentrations of LDL or with HOE 694 decreased pHi. In addition, both LDL and HOE 694 inhibited the Na+/H+ antiport in platelets treated with sodium propionate or thrombin. The inhibitory effect of LDL was observed both in normal and in glycoprotein (GP)IIb/IIIa- as well as in GPIIIb (CD36)-deficient platelets and was not influenced by the covalen...
Abstract 3496: GC1118, a novel anti-EGFR andtibody, shows more potent antitumor activity regardless of KRAS mutation or high-affinity lignad stimulation compared with cetuximab in gastric cancer
Authors: Ji Eun Park, Mei Hua Jin, Ah-Rong Nam, Ju-Hee Bang, Do-Youn Oh, Yung-Jue Bang
Journal: Cancer Research (2018)

Abstract Background: EGFR overexpression in gastric cancer (GC) has been reported in about 30% of patients. However, cetuximab and panitumulab, anti-EGFR antibodies, have failed to improve overall survival of GC patients compared with standard chemotherapy alone. GC1118 is a novel anti-EGFR antibody with distinct binding epitope compared to cetuximab or panitumumab, and has superior inhibitory activity against high-affinity EGFR ligands (Mol Cancer Ther 2016). In this study, GC1118 was tested to evaluate the antitumor effects in gastric cancer cells. Methods: Using a total of 15 kinds of GC cell lines (SNU-1, SNU-5, SNU-16, SNU-216, SNU-484, SNU-601, SNU-620, SNU-638, SNU-668, SNU-719, AGS, MKN-28, MKN-45, NCI-N87, and KATO-), GC1118, cetuximab, cisplatin, and 5-FU were tested. Cells were treated with or without high-affinity EGFR ligands, EGF 20ng/mL or HB-EGF 100ng/mL. Result: GC1118 exhibited more potent antigrowth effects in the majority of GC cells than cetuximab in colony forming assay and MTT assay, regardless of KRAS mutation status of cells. The synergistic efficacy was observed when cells were treated with GC1118 in combination with cytotoxic chemotherapeutic agents (cisplatin or 5FU) in colony formation assay and migration assay compared to each treatment alone, even under the EGFR-ligand stimulation condition. GC1118 significantly blocked the p-AKT or p-ERK signaling under the presence of ligand induced-EGFR activation. However, cetuximab failed to block p-AKT or p-ERK that was upregulated by EGF or HB-EGF. Moreover, this signal-blocking activity was more potent in case of GC1118 compared with cetuximab in the chemotherapy combination experiment. Conclusion: GC1118 showed more potent antitumor effects in GC compared with cetuximab. In combination with cytotoxic chemotherapy, GC1118 also has more potent activity compared with cetuximab regardless of KRAS mutation status or high-affinity ligand stimulation condition. This study supports further clinical development of GC1118 in gastric cancer. Citation Format: Ji Eun Park, Mei Hua Jin, Ah-Rong Nam, Ju-Hee Bang, Do-Youn Oh, Yung-Jue Bang. GC1118, a novel anti-EGFR andtibody, shows more potent antitumor activity regardless of KRAS mutation or high-affinity lignad stimulation compared with cetuximab in gastric 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 3496.