tbuckley/cabot-search huggingface dataset:
How Sudden Is Sudden Cardiac Death
Authors: DirkMüller, RahulAgrawal, Hans-RichardArntz
Journal: Circulation (2006)

Background— Out-of-hospital sudden cardiac death (SCD) is a frequent cause of death. Survival rates remain low despite increasing efforts in medical care. Better understanding of the circumstances of SCD could be helpful in developing preventive measures and facilitating proper reactions to such a pending event. Methods and Results— Information on cases of out-of-hospital SCD was collected in the Berlin, Germany, emergency medical system via a questionnaire. Bystander interviews were performed by the emergency physician on scene immediately after declaration of death or return of circulation. Of 5831 rescue missions, 406 involved patients with presumed cardiac arrest. Sixty-six percent had a known cardiac disease. In 72%, the arrest occurred at home, and in 67%, it occurred in the presence of an eyewitness. Information on symptoms immediately preceding the arrest was available in 80% (n=323) of all 406 patients and in 274 of those with witnessed arrest. Symptoms were identical in the 2 groups. Typical ang...
Abstract 1317: Multi-scale mapping of the physical and functional architecture of the cancer cell
Authors: Fan Zheng, Michael K. Yu, Minkyu Kim, Keiichiro Ono, Mitchell Flagg, Jason F. Kreisberg, Nevan Krogan, Trey Ideker
Journal: Cancer Research (2018)

Abstract Cancer is governed by modular systems of genes, the composition and organization of which remains poorly understood. Here, we integrate physical and functional networks from a wide range of molecular studies to assemble a comprehensive multi-scale map of human cancer cell biology. This map consists of a hierarchical catalog of protein complexes, signaling pathways and inter-pathway crosstalk implicated in cancer, and it suggests many uncharacterized functional modules as intriguing hypotheses for further validation. Analysis of the pattern of somatic mutations in The Cancer Genome Atlas (TCGA) reveals that these mutations target systems of varying scales above the level of individual genes. The map also provides a platform to integrate and interpret new 'omics data; we integrate new protein-protein interactions identified using AP-MS in multiple breast cancer cell lines, revealing how different functional modules are rewired in cancer cells. A general model browsing tool has been created to visualize and navigate these hierarchical cancer maps. This multi-scale mapping approach elucidates the molecular heterogeneity of cancer, connects tumor genotypes to phenotypes and, ultimately, enables a platform for cancer precision medicine. Citation Format: Fan Zheng, Michael K. Yu, Minkyu Kim, Keiichiro Ono, Mitchell Flagg, Jason F. Kreisberg, Nevan Krogan, Trey Ideker. Multi-scale mapping of the physical and functional architecture of the cancer 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 1317.
Abstract 930: Targeted delivery of cytotoxic NAMPT inhibitors using antibody-drug conjugates
Authors: Christopher S. Neumann, Kathleen C. Olivas, Andrew B. Waight, David Meyer, Luke V. Loftus, Margo Zaval, Martha E. Anderson, Steven Jin, Julia H. Cochran, Jessica K. Simmons, Paul G. Pittman, Robert P. Lyon, Peter D. Senter
Journal: Cancer Research (2018)

Abstract Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme involved in the salvage biosynthetic pathway of NAD from nicotinamide. Small-molecule inhibitors of NAMPT lead to rapid depletion of NAD(H) and subsequent depletion of ATP as cellular energy metabolism is interrupted. While these inhibitors can be potently cytotoxic in vitro, their application as cancer chemotherapeutics is limited by toxicity upon systemic administration. We have developed NAMPT inhibitors that are suitable for targeted delivery to cancer cells using our antibody-drug conjugate (ADC) platform. The inhibitors retain impressive biochemical potency against purified NAMPT, as well as potent in vitro cytotoxicity. Cleavable drug linkers were constructed using an enzyme-labile glucuronic acid moiety as the trigger for drug release. The resulting linkers are relatively hydrophilic, allowing ADCs with eight drugs per antibody to be prepared with no aggregation and favorable pharmacokinetic profiles. In vitro, treatment of cells with ADCs leads to depletion of cellular NAD. This pharmacodynamic effect is also observed in xenografted L540cy tumors, where NAD(H) is not detected in excised tumors 4 days after dosing. Across multiple tumor xenograft models, treatment with NAMPT-based ADCs leads to tumor regression. Exploratory toxicology studies in rats show excellent single-dose tolerability, with recoverable anemia and lymphopenia noted. Importantly, retinal and cardiac toxicities associated with systemic administration of NAMPT inhibitors in rodents were not observed with NAMPT-based ADCs. These data demonstrate the ability of NAMPT inhibitors to serve as a novel payload class for ADCs, and the potential to reintroduce this unique mechanism of action to the clinic with improved therapeutic windows. Citation Format: Christopher S. Neumann, Kathleen C. Olivas, Andrew B. Waight, David Meyer, Luke V. Loftus, Margo Zaval, Martha E. Anderson, Steven Jin, Julia H. Cochran, Jessica K. Simmons, Paul G. Pittman, Robert P. Lyon, Peter D. Senter. Targeted delivery of cytotoxic NAMPT inhibitors using antibody-drug conjugates [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 930.
Abstract 3794: CCL5 from tumor-associated macrophages/microglia (TAMs) regulates glioma migration and invasion via calcium-dependent matrix metalloproteinase-2
Authors: Caren Yu-Ju Wu, Chia-Hua Chen, Chun-Yen Lin, Li-Ying Feng, Yung-Chang Lin, Kuo-Chen Wei, Chiung-Yin Huang, Jia-You Fang, Pin-Yuan Chen
Journal: Cancer Research (2018)

Abstract Tumor-associated macrophages/microglia (TAMs) are either macrophages of peripheral origin or brain-intrinsic microglia, and represent a considerable portion of the glioma mass, which facilitate gliomagenesis. Chemokine C-C motif ligand 5 (CCL5) is an inflammatory mediator produced by immune cells, and involves in tumor growth, and migration in serval cancers including glioma. However, the mechanism of how CCL5 facilitates glioma invasion remains largely unresolved. In this study, we demonstrate that CCL5 modulate human glioma cell lines, A172 and U87, migratory and invasive activities along with MMPs expression. In response to CCL5, glioma synchronized an increase of intracellular calcium levels, and kinase elevations including p-CaMKII, and p-Akt expressions in time and dosage manners. Importantly, glioma invasion along with MMPs elevation are dependent on CCL5-propogated p-CaMKII expression, and inhibition of p-CaMKII effectively reduced CCL5-directed glioma MMPs expression and invasion. Using three-dimensional cultures, we demonstrated that glioma cells tend to homing toward GM-CSF-activated TAM condition media. This homing effect associated with MMPs elevation which can be ameliorated either by controlling the intracellular and extracellular calcium levels or by CCL5 antagonism. Clinical results also reveal association of CCL5 with TAM activation, and patients' overall survival. Our results suggest that modulation of glioma CaMKII may restrict the effect of CCL5 on glioma migration and could be a potential therapeutic strategy for alleviating glioma invasion. Citation Format: Caren Yu-Ju Wu, Chia-Hua Chen, Chun-Yen Lin, Li-Ying Feng, Yung-Chang Lin, Kuo-Chen Wei, Chiung-Yin Huang, Jia-You Fang, Pin-Yuan Chen. CCL5 from tumor-associated macrophages/microglia (TAMs) regulates glioma migration and invasion via calcium-dependent matrix metalloproteinase-2 [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 3794.
Augmented Cardiac Hypertrophy in Response to Pressure Overload in Mice Lacking the Prostaglandin I2 Receptor
Authors: AkiyoshiHara, Koh-ichiYuhki, TakayukiFujino, TakehiroYamada, KojiTakayama, ShuhkoKuriyama, OsamuTakahata, HidejiKaribe, YujiOkada, Chun-YangXiao, HongMa, ShuhNarumiya, FumitakaUshikubi
Journal: Circulation (2005)

Background— In the heart, the expressions of several types of prostanoid receptors have been reported. However, their roles in cardiac hypertrophy in vivo remain unknown. We intended to clarify the roles of these receptors in pressure overload–induced cardiac hypertrophy using mice lacking each of their receptors. Methods and Results— We used a model of pressure overload–induced cardiac hypertrophy produced by banding of the transverse aorta in female mice. In wild-type mice subjected to the banding, cardiac hypertrophy developed during the observation period of 8 weeks. In mice lacking the prostaglandin (PG) I2 receptor (IP−/−), however, cardiac hypertrophy and cardiomyocyte hypertrophy were significantly greater than in wild-type mice at 2 and 4 weeks but not at 8 weeks, whereas there was no such augmentation in mice lacking the prostanoid receptors other than IP. In addition, cardiac fibrosis observed in wild-type hearts was augmented in IP−/− hearts, which persisted for up to 8 weeks. In IP−/− hearts,...
Reduced Coronary Flow Reserve in Hypercholesterolemic Patients Without Overt Coronary Stenosis
Authors: IkuoYokoyama, TohruOhtake, Shin-ichiMomomura, JunichiNishikawa, YasuhitoSasaki, MasaoOmata
Journal: Circulation (1996)

Background Reduced coronary flow reserve (CFR) in hypercholesterolemic patients without evidence of ischemia has been reported. However, it remains uncertain whether this abnormality occurs without overt coronary atherosclerosis. This study aimed to clarify whether CFR is impaired even in anatomically normal coronary arteries in hypercholesterolemic patients and to compare CFR between familial hypercholesterolemic (FH) patients and secondary hypercholesterolemic (SH) patients. Methods and Results Twenty-two patients with hypercholesterolemia (11 FH, 11 SH) and 11 control subjects were studied. Baseline myocardial blood flow (MBF) and MBF during dipyridamole loading were measured in segments perfused by angiographically normal coronary arteries with the use of positron emission tomography and 13N-ammonia, and CFR was calculated. Baseline MBF (mL/min per 100 g heart wt) in FH (81.3±31.4) and SH (70.0±20.7) patients was not different from that in control subjects (75.0±34.9). However, MBF during dipyridamole...
Long-Term Inhibition of RhoA Attenuates Vascular Contractility by Enhancing Endothelial NO Production in an Intact Rabbit Mesenteric Artery
Authors: NorikoShiga, KatsuyaHirano, MayumiHirano, JunjiNishimura, HajimeNawata, HideoKanaide
Journal: Circulation Research (2005)

RhoA plays a critical role in regulating NO production in cultured endothelial cells. To determine its role in in situ endothelial cells, we investigated the effects of 3-hydroxy-3-methyl-glutaryl coenzyme A reductase inhibitors and a RhoA-binding domain of Rho-kinase (RB) on vascular contractility in the isolated rabbit mesenteric artery. Ex vivo treatment of the strips with 3×10−5 mol/L simvastatin and fluvastatin for ≈24 to 30 hours significantly attenuated the contractile response to phenylephrine and high K+ in the presence of endothelium. The addition of Nω-nitro-l-arginine methyl ester and the removal of endothelium abolished the attenuation of the contractile response. The cotreatment with geranylgeranyl pyrophosphate prevented the statin-induced attenuation of the contractile response, whereas geranylgeranyl transferase inhibitor mimicked the effect of simvastatin. Treatment with simvastatin enhanced the bradykinin-induced endothelium-dependent relaxation in the mesenteric artery, whereas it had ...
Abstract 2023: RhebL1 is involved in epithelial mesenchymal transition of breast cancer cells
Authors: Hyunji KIM, Changhoon LEE
Journal: Cancer Research (2018)

Abstract RhebL1 belongs to the ras superfamily of G proteins and is highly conserved across many species. However, the cellular function of RhebL1 have not yet been reported especially in breast cancer. In this study, we found that RhebL1 is highly expressed in MDA-MB-231 and SK-BR-3 breast cancer cells. By using the public microarray data sets, we found that overall and relapse free survival were decreased in breast cancer patients with high expression of RhebL1. The involvement of RhebL1 in epithelial mesenchymal transition of breast cancer cells was examined. Gene silencing of RhebL1 decreased the expression of mesenchymal markers such as N-cadherin, Vimentin, snail and slug and increased the expression of epithelial marker E-cadherin in MDA-MB-231 and SK-BR-3 breast cancer cells. In contrast, overexpression of RhebL1 increased the expression of mesenchymal markers and decreased the expression of E-cadherin in MCF7 breast cancer cells. Next, we examined the effects of RhebL1 expression on migration and invasion since migratory and invasive capabilities were strongly related to EMT. RhebL1 overexpression significantly increased the migration and invasion of MCF7 cells and gene silencing of RhebL1 reduced the migration and invasion of MDA-MB-231 and SK-BR-3 cells. Furthermore, we identify a novel RhebL1-binding protein, RBP1, which mediates the segregation of protein phosphatase 2A from Akt, leading to induced Akt phosphorylation under conditions by binding to RhebL1. The collective results indicate that RhebL1 is involved in EMT of breast cancer cells via interaction with RBP1-Akt-PP2A complex. These results suggest that RhebL1 may be a key regulator modulating metastatic breast cancer cells. Citation Format: Hyunji KIM, Changhoon LEE. RhebL1 is involved in epithelial mesenchymal transition of breast 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 2023.
Abstract P026: Development of Autologous Tissue Small-Diameter Vascular Grafts (BIOTUBEs)
Authors: MasashiYamanami, TaijiWatanabe, KeiichiKanda, TomonoriOie, KeiichiTakamizawa, HatsueIshibashi-Ueda, HitoshiYaku, YasuhideNakayama
Journal: Circulation Research (2011)

Objectives: There are actually no small-caliber synthetic vascular grafts (< 6 mm) with acceptable patency rate for the use of coronary bypass or peripheral vascular repair below the knee in case the autologous vessels are not available. We developed autologous small-caliber vascular grafts “BIOTUBEs” using simple, safe and economical in vivo tissue engineering. In this study, we summarize the development of BIOTUBEs. Methods: Silicone rod molds (diameter: 1.5∼5 mm, length: 20∼50 mm) were placed into subcutaneous pouches of Wister rats, Japan white rabbits or Beagle dogs. After 1 month, BIOTUBEs formed around the molds were auto-implanted to the aorta (1.5 mm; rats) or the carotid arteries (2 mm; rabbits and 5 mm; dogs) of the respective animals. They were evaluated after determined period of implantation. Results: Irrespective of species, BIOTUBEs had thin wall (ca. 0.1mm) and mainly consisted of autologous fibroblasts and collagen fibers. Rats; After 12-week implantation, other than the oriented endothe...
Posttranscriptional upregulation of HER3 by HER2 mRNA induces trastuzumab resistance in breast cancer
Authors: Xin Li, Yuxiu Xu, Yun Ding, Changfei Li, Hong Zhao, Jiandong Wang, Songdong Meng
Journal: Molecular Cancer (2018)

HER2 gene amplification generates an enormous number of HER2 transcripts, but the global effects on endogenous miRNA targets including HER family members in breast cancer are unexplored. We generated a HER2–3’UTR expressing vector to test the tumor-promoting properties in HER2 low expressing T47D and MCF7 cells. Through microarray analysis and real-time PCR analysis we identified genes that were regulated by HER2–3’UTR. Positive and negative manipulation of miRNA expression, response element mutational studies and transcript reporter assays were performed to explore the mechanism of competitive sequestration of miR125a/miRNA125b by HER2 3’UTR. To investigate if trastuzumab-induced upregulation of HER3 is also mediated through miRNA de-repression, we used the CRISPR/cas9 to mutate the endogenous HER2 mRNA in HER2 over-expressing Au565 cells. Finally, we looked at cohorts of breast cancer samples of our own and the TCGA to show if HER2 and HER3 mRNAs correlate with each other. The HER2 3’UTR pronouncedly promoted cell proliferation, colony formation, and breast tumor growth. High-throughput sequencing revealed a significant increase in HER3 mRNA and protein levels by the HER2 3’untranslated region (3’UTR). The HER2 3’UTR harboring a shared miR-125a/b response element induced miR-125a/b sequestration and thus resulted in HER3 mRNA derepression. Trastuzumab treatment upregulated HER3 via elevated HER2 mRNA expression, leading to trastuzumab resistance. Depletion of miR-125a/b enhanced the antitumor activity of trastuzumab. Microarray data from HER2-overexpressing primary breast cancer showed significant elevation of mRNAs for predicted miR-125a/b targets compared to non-targets. These results suggest that HER2 3’UTR-mediated HER3 upregulation is involved in breast cell transformation, increased tumor growth, and resistance to anti-HER2 therapy. The combinatorial targeting of HER3 mRNA or miR-125a/b may offer an effective tool for breast cancer therapy.
Low Circulating Folate and Vitamin B6 Concentrations
Authors: KillianRobinson, KristopherArheart, HelgaRefsum, LarsBrattström, GodfriedBoers, PerUeland, PaoloRubba, RobertoPalma-Reis, RaymondMeleady, LeslieDaly, JacquelineWitteman, IanGraham
Journal: Circulation (1998)

Background—A high plasma homocysteine concentration is a risk factor for atherosclerosis, and circulating concentrations of homocysteine are related to levels of folate and vitamin B6. This study was performed to explore the interrelationships between homocysteine, B vitamins, and vascular diseases and to evaluate the role of these vitamins as risk factors for atherosclerosis. Methods—In a multicenter case-control study in Europe, 750 patients with documented vascular disease and 800 control subjects frequency-matched for age and sex were compared. Plasma levels of total homocysteine (before and after methionine loading) were determined, as were those of red cell folate, vitamin B12, and vitamin B6. Results—In a conditional logistic regression model, homocysteine concentrations greater than the 80th percentile for control subjects either fasting (12.1 μmol/L) or after a methionine load (38.0 μmol/L) were associated with an elevated risk of vascular disease independent of all traditional risk factors. In a...
Suppression of Atherosclerotic Development in Watanabe Heritable Hyperlipidemic Rabbits Treated With an Oral Antiallergic Drug, Tranilast
Authors: ToshiyukiMatsumura, KiyotakaKugiyama, SeigoSugiyama, YasutakaOta, HidekiDoi, NobuhikoOgata, HidekiOka, HirofumiYasue
Journal: Circulation (1999)

Background—Inflammatory and immunological responses of vascular cells have been shown to play a significant role in the progression of atheromatous formation. Tranilast [N-(3,4-dimethoxycinnamoyl) anthranillic acid] inhibits release of cytokines and chemical mediators from various cells, including macrophages, leading to suppression of inflammatory and immunological responses. This study tested whether tranilast may suppress atheromatous formation in Watanabe heritable hyperlipidemic (WHHL) rabbits. Methods and Results—WHHL rabbits (2 months old) were given either 300 mg · kg−1 · d−1 of tranilast (Tranilast, n=12) or vehicle (Control, n=13) PO for 6 months. Tranilast treatment was found to suppress the aortic area covered with plaque. Immunohistochemical analysis showed that there was no difference in the percentage of the RAM11-positive macrophage area and the frequency of CD5-positive cells (T cells) in intimal plaques between Tranilast and Control. Major histocompatibility complex (MHC) class II expres...
Chemoradiation Improves Survival Compared With Chemotherapy Alone in Unresected Nonmetastatic Gastric Cancer
Authors: Richard Li, Wei-Hsien Hou, Joseph Chao, Yanghee Woo, Scott Glaser, Arya Amini, Rebecca A. Nelson, Yi-Jen Chen
Journal: Journal of the National Comprehensive Cancer Network (2018)

Background: Limited data are available to guide management of patients with stage I–III gastric cancer not undergoing potentially curative surgical resection. We compared survival outcomes associated with chemotherapy alone versus chemoradiation (CRT) in the treatment of nonmetastatic gastric cancer. Methods: Patients with gastric adenocarcinoma from 2004 to 2015 were identified using the National Cancer Database. Patients were excluded if they had surgery, metastatic disease, or T0, Tis, or T1a disease. Logistic regression was used to evaluate predictors of CRT use. Cox proportional hazards modeling was performed to compare overall survival (OS) between chemotherapy alone and CRT in overall and propensity score–matched cohorts. Results: We identified 4,795 patients with stage I–III gastric adenocarcinoma who did not undergo surgery, at a median follow-up of 11.8 months. A total of 3,316 patients (69.2%) received chemotherapy alone and 1,479 patients (30.8%) received CRT. Predictors of increased CRT use were age ≥65 years (odds ratio [OR] 1.68; 95% CI, 1.43–1.99; P<.001), Charlson-Deyo comorbidity score ≥2 (OR, 1.46; 95% CI, 1.18–1.81), and treatment at a community facility (OR, 1.27; 95% CI, 1.07–1.51; P=.006). Patients receiving CRT had a 2-year OS rate of 28.3% compared with 21.5% among those receiving chemotherapy. Multivariate analysis showed that CRT was associated with improved OS (hazard ratio [HR], 0.82; 95% CI, 0.77–0.89; P<.001). After propensity score matching, a persistent survival benefit was observed (HR, 0.80; 95% CI, 0.74–0.88; P<.001). Conclusions: In patients with stage I–III gastric cancer not undergoing surgical resection, CRT was associated with improved survival compared with chemotherapy alone. However, only 30.8% of patients received CRT in this setting.
Abstract 4198: 2-Hydroxymelatonin shows antitumor activity against human colorectal cancer cells
Authors: Yi Yang, Rui Zhou, So-Yeon Park, Kyung Keun Kim, Hangun Kim
Journal: Cancer Research (2018)

Abstract 2-Hydroxymelatonin is a predominant hydroxylated melatonin metabolite in plants. To investigate whether it has potent cytotoxic effects on colorectal cancer cells, four colorectal cancer cell lines, Caco2, HCT116, DLD1, and CT26, were treated with 2-hydroxymelatonin and melatonin. 2-Hydroxymelatonin had a much lower IC50 value than melatonin in the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The cytotoxic effect of 2-hydroxymelatonin was much stronger than that of melatonin at high concentrations (1000 or 2000 μM) in HCT116, DLD1, and CT26 cells, but only at intermediate concentrations (250 or 500 μM) in Caco2 cells. The cytotoxicity of 2-hydroxymelatonin was induced through activation of the apoptotic signaling pathway, as confirmed by Hoechst staining and Annexin V-FITC/propidium iodide double labeling of cells treated with a lethal dose (1 mM). However, sub-lethal doses of 2-hydroxymelatonin inhibited the invasive ability of Caco2 cells. Epithelial-mesenchymal transition (EMT) markers were significantly regulated by 2-hydroxymelatonin. Overall, the anti-cancer activity of 2-hydroxymelatonin is more potent than that of melatonin. Taken together, 2-hydroxymelatonin exhibits potent anti-cancer activity against human colorectal cancer cells via induction of apoptosis and inhibition of EMT. Citation Format: Yi Yang, Rui Zhou, So-Yeon Park, Kyung Keun Kim, Hangun Kim. 2-Hydroxymelatonin shows antitumor activity against human colorectal 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 4198.