tbuckley/cabot-search huggingface dataset:
Abstract 9632: A Functional Role of Tenascin-C in Angiotensin II-Induced Cardiac Fibrosis
Authors: NaoshiShimojo, RyotaroHashizume, KazukiKanayama, YukaSuzuki, MariHara, TomohiroNishioka, ToshimichiYoshida, KyokoImanaka-Yoshida
Journal: Circulation (2014)

Introduction: tenascin-C is sparsely detected in normal adult heart but becomes expressed in the pathological myocardium closely associated with inflammation and tissue remodeling. We have previously reported about enhanced TN-C production and macrophages accumulation in the perivascular fibrosis of angiotensin II (AngII)-induced mouse hypertensive heart. Hypothesis: The aim of study was to clarify the role of TN-C in progression of hypertensive cardiac fibrosis using TN-C knock-out (TNKO) mouse, and to evaluate whether TN-C is involved in macrophage activation. Methods: Balb/c WT and TNKO mice (8 week-old) were subcutaneously implanted with an osmotic minipump which released AngII (560 ng/kg body weight/min) for 4 weeks (WT/AngII and TNKO/AngII). In vitro, to test the direct effects of TN-C on macrophage activation, macrophages were isolated from WT mice, seeded in culture well. They were subsequently analyzed using histological and molecular biological approaches. Results and Conclusions: AngII treatmen...
Hyperhomocysteinemia Exaggerates Adventitial Inflammation and Angiotensin II−Induced Abdominal Aortic Aneurysm in Mice
Authors: ZiyiLiu, HongzhiLuo, LuZhang, YaqianHuang, BoLiu, KongyangMa, JuanFeng, JinshengXie, JingangZheng, JingHu, SiyanZhan, YiZhu, QingboXu, WeiKong, XianWang
Journal: Circulation Research (2012)

Rationale:A number of epidemiological studies have suggested an association of hyperhomocysteinemia (HHcy) and abdominal aortic aneurysm (AAA), but discrepancies exist. In addition, we lack direct evidence supporting a causal role. Objective:We determined the association and contribution of HHcy to AAA formation. Methods and Results:We first performed a meta-analysis of studies involving 1489 subjects and found a strong association of HHcy and AAA (odds ratio, 7.39). Next, we used angiotensin II–infused male apolipoprotein E–deficient mice and tested whether HHcy contributes to AAA pathogenesis. Homocysteine (Hcy) supplement (1.8 g/L) in drinking water resulted in mild HHcy. Intriguingly, HHcy greatly increased the incidence of angiotensin II–induced AAA and aortic dissection in apolipoprotein E–deficient mice (vehicle versus Hcy: 50% versus 100%; P<0.05). Histology indicated HHcy markedly exaggerated aortic adventitial inflammation. Increased levels of proinflammatory interleukin-6 and monocyte chemoattr...
Abstract 11438: Thyroid Hormones and Changes in Body Weight and Metabolic Parameters in Response to Weight-Loss Diets: The POUNDS LOST Trial
Authors: Gang Liu, Liming Liang, George A Bray, Lu Qi, Frank B Hu, Frank Sacks, Qi Sun
Journal: Circulation (2016)

Context: The role of thyroid hormones in diet-induced weight loss and subsequent weight regain is largely unknown. Objective: To examine the relationship between baseline thyroid hormones and subsequent changes in body weight and resting metabolic rate (RMR) in a diet-induced weight-loss setting. Methods: In the 2-year POUNDS LOST randomized clinical trial that tested 4 weight-loss diets, thyroid hormones (free triiodothyronine [T3], free thyroxine [T4], total T3, total T4, and thyroid stimulating hormone [TSH]), and resting metabolic rate (RMR), as well as anthropometric and biochemical parameters, were determined at baseline, 6 months, and 2 years among 569 overweight and obese participants aged 30-70 years with normal thyroid function. Results: Participants lost an average of 6.6 kg of body weight during the first 6 months and subsequently regained an average of 2.7 kg of body weight over the remaining period from 6-24 months. Baseline free T3 and total T3 levels were positively associated with baseline body mass index and RMR, whereas free T4, total T4, and TSH did not demonstrate a clear pattern of correlations with these parameters. After multivariate adjustment including dietary intervention groups and baseline body weight, higher baseline free T3 and free T4 levels were significantly associated with a greater decrease in body weight in the first 6 months. Comparing extreme tertiles, the weight loss was -5.39±0.9 vs -3.87±0.9 for free T3 (P trend=0.02) and -5.88±0.9 vs -4.09±0.9 for free T4 (P trend=0.004). The thyroid hormones did not predict weight regain between 6 and 24 months. The associations were attenuated after further adjusting for changes in RMR. Conclusion: In this diet-induced weight-loss setting, higher baseline free T3 and free T4 predict more weight loss, but not weight regain among overweight and obese adults with normal thyroid function. In addition, changes in RMR may partially mediate the observed associations. These findings reveal a novel role of thyroid hormones in body weight regulations and may help identify individuals more responsive to weight-loss diets.
Abstract 288: Genomic profiling of metastatic gastric adenocarcinoma
Authors: Kazuto Harada, Shumei Song, Yan Xu, Brain D. Bagewell, Melissa P. Pizzi, Jiankang Jin, Ying Wang, Ailing W. Scott, Lang Ma, Fatemeh G. Amlashi, Makoto Kobayashi, Jody V. Vykoukal, Cristina Ivan, Jeannelyn S. Estrella, Sinchita R. Chowdhuri, George A. Calin, Samir Hanash, Ju-Seog Lee, Bin Liu, Jaffer A. Ajani
Journal: Cancer Research (2018)

Abstract Objectives: Metastatic gastric adenocarcinoma (mGAC) is highly resistant to therapy and is incurable. Particularly, peritoneal carcinomatosis leads to severe morbidities and short survival. The genome wide approaches have been conducted in primary GAC and have uncovered useful information. However, detailed understanding of mGAC is limited. Thus, we aimed to characterize the genomic landscape of mGAC. Methods: Thirty-four malignant ascites specimens were prospectively collected from at The University of Texas MD Anderson Cancer Center (Houston, USA) from February 2016. 25 specimens had whole exome sequencing and 30 specimens had RNA sequencing. Results: The top highly mutated genes in mGAC were TP53, ATM, SYNE2, TTN, CDH11, FAT4/3, KMT2C, FGF23, NCOR1, RP1, CYP2A, and ADAMTS8/9. Compared with mutations in primary GAC (TCGA and TMUCIH), mutations in mGAC shared only 13.7% with TCGA and 10.9% with TMUCIH data. The commonly shared mutations in all three sets were TP53, ATM, FAT4, CDH1, SYNE1, PLEC, PRKDC, and ZFHX3, while unique mutations in mGAC were TTN, SYNE2, ZNF503, PUS7L, PPP2R5C, NBPF12, MROH1, IFNL1, and COL18A1. Furthermore, RNA- sequencing revealed two frequent fusions; 36.7% of samples with C15orf57-CBX3 (t(15;7)) fusion and 10% with SLC35A1-TSHZ2 (t(6;20)). We explored gene signatures in C15orf57-CBX3 fusion subgroup and C15orf57-CBX3 non-fusion subgroup. Gene set enrichment analysis revealed that C15orf57-CBX3 fusion group had enrichment of immune-response related genes, while non-fusion subgroup had enrichment of genes related to the segregation of chromatid, DNA replication, and histone exchange. The clustering analysis of RNA expression using the top 2000 genes with most median absolute deviation identified two subgroups that correlated either with C15orf57-CBX3 fusion or mutations. Conclusions: We have identified a novel genomic landscape of mGAC, such as unique mutation and fusions. Further studies are needed to gain insights into the mechanism of progression and resistance phenotype of mGAC. Citation Format: Kazuto Harada, Shumei Song, Yan Xu, Brain D. Bagewell, Melissa P. Pizzi, Jiankang Jin, Ying Wang, Ailing W. Scott, Lang Ma, Fatemeh G. Amlashi, Makoto Kobayashi, Jody V. Vykoukal, Cristina Ivan, Jeannelyn S. Estrella, Sinchita R. Chowdhuri, George A. Calin, Samir Hanash, Ju-Seog Lee, Bin Liu, Jaffer A. Ajani. Genomic profiling of metastatic gastric adenocarcinoma [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 288.
Abstract P381: Overlap of Echocardiographic Diastolic Dysfunction Definitions in the Cardia Study
Authors: LauraRasmussen-Torvik, LauraColangelo, JoaoLima, DavidJacobs, CarlosRodriguez, DonaldLloyd-Jones, SanjivShah
Journal: Circulation (2015)

Background: Existing echocardiographic criteria for diastolic dysfunction differ widely. We examined overlap in definitions proposed by the American Society of Echocardiography (ASE), Rochester County Epidemiology Project (Redfield), and the VALIDD trial of diastolic dysfunction among middle-aged individuals undergoing echocardiographic examination in CARDIA. Methods: 3474 CARDIA participants had echocardiographic data at Y25. At each center, trained echo techs obtained images by a standardized protocol and scans were read centrally. Standard 2D and M-mode assessments were obtained. Published binary definitions of diastolic dysfunction were applied; pulmonary venous flow and mitral inflow at peak Valsalva maneuver measures were not available in CARDIA, so the (modified) Redfield definition of diastolic dysfunction was based on two of the four variables included in the definition. Results: The mean age in the sample was 50.2 years, mean BMI was 30.2 kg/m2, 46.7% of the sample was African American and 53.3%...
Abstract 15528: Myocardial Deformation Imaging and Obstruction in Hypertrophic Cardiomyopathy, Insights from Cross-sectional and Post-myectomy Analysis
Authors: YukariKobayashi, GherardoFinocchiaro, GenevieveGiraldeau, DavidBoulate, YuheiKobayashi, RichardHa, DavidLee, DavidLiang, IngelaSchittger, FrancoisHaddad, EuanAshley
Journal: Circulation (2014)

Background: Hypertrophic cardiomyopathy (HCM) has been reported to alter left ventricular deformation. However, little is known about the differences of left ventricular (LV) strain values among healthy and varying levels of HCM patients including non-obstructive and obstructive, nor about the impact of septal reduction therapy on strain values. Methods: Age- and sex matched patients with HCM and varying degree of obstruction as well as 48 healthy controls were studied. Among HCM patients, 28 subjects had non-obstructive HCM, 27 had mildly symptomatic obstructive HCM, and 34 had HCM requiring septal reduction therapy (either myectomy or alcohol ablation). LV global longitudinal strain (LV-GLS) and circumferential strain as well as routine echocardiography were evaluated. Detailed LV longitudinal strain was assessed with septal and lateral longitudinal strain (Sept.-LS and Lat.-LS). In HCM patients treated with septal reduction, echocardiography was performed before, 3-months, and 1-year after the procedur...
Characterization of Low Right Atrial Isthmus as the Slow Conduction Zone and Pharmacological Target in Typical Atrial Flutter
Authors: Ching-TaiTai, Shih-AnnChen, Chern-EnChiang, Shih-HuangLee, Kwo-ChangUeng, Zu-ChiWen, Jin-LongHuang, Yi-JenChen, Wen-ChungYu, An-NingFeng, Chuen-WangChiou, Mau-SongChang
Journal: Circulation (1997)

Background Previous electrophysiological studies in patients with typical atrial flutter suggested that the slow conduction zone might be located in the low right atrial isthmus, which is a path formed by orifice of inferior vena cava, eustachian valve/ridge, coronary sinus ostium, and tricuspid annulus. The conduction characteristics during atrial pacing and responses to antiarrhythmic drugs of this anatomic isthmus were unknown. Methods and Results Forty-four patients, 20 patients with paroxysmal supraventricular tachycardia (group 1) and 24 patients with clinically documented paroxysmal typical atrial flutter (group 2), were studied. A 20-pole halo catheter was situated around the tricuspid annulus. Incremental pacing from the low right atrium and coronary sinus ostium was performed to measure the conduction time and velocity along the isthmus and lateral wall in the baseline state and after intravenous infusion of procainamide or sotalol. In both groups, conduction velocity in the isthmus during incre...
Interventional Treatment for Children With Severe Coronary Artery Stenosis With Calcification After Long-term Kawasaki Disease
Authors: TetsuSugimura, HiroyoshiYokoi, NoboruSato, TeijiAkagi, TakeshiKimura, MotohumiIemura, MasakiyoNobuyoshi, HirohisaKato
Journal: Circulation (1997)

Background About 4% of children with Kawasaki disease (KD) eventually develop ischemic heart disease, which is often associated with calcified stenosis. We assessed the utility of the percutaneous transluminal coronary rotational ablation (PTCRA) in children with coronary artery stenosis after KD. Methods and Results Four children (three boys and one girl; age, 12 to 13 years) with coronary artery stenosis underwent percutaneous transluminal coronary angioplasty (PTCA) and PTCRA 11.8±0.9 years after the onset of KD. Morphology of the coronary artery wall was evaluated by intravascular ultrasound imaging. In one patient, the targeted lesion for intervention was in the left anterior descending artery (90% stenosis); in the other three patients, it was in the middle of the right coronary artery (75% to 90% stenosis). PTCA failed in three patients because of severe stenosis with calcification. However, PTCRA proved effective, with stenosis rates reduced from 90% to 25%. Follow-up coronary angiography performe...
Abstract 5502: Characterization of a hotspotPTENmutation in endometrial cancer
Authors: Ye Wang, Charles Jakubik, Rachel Peterson, Cyril Benes, Wilhelm Haas, Jeffrey Engelman, Carlotta Costa
Journal: Cancer Research (2018)

Abstract Endometrial cancer is the most common gynecologic malignancy in the developed world. These cancers harbor the highest rates of PI3K pathway alterations reported, with PTEN being the most frequently altered gene. Differently from other cancer types, in endometrial cancer a specific hotspot mutation in the lipid phosphatase domain of PTEN is present at residue 130. This hotspot mutation significantly co-occurs with other mutations in the PI3K pathway, such as PIK3CA and PIK3R1. Interestingly, in the TCGA data we also found a positive correlation between this mutation and the expression level of the estrogen receptor alpha. Although it has been reported that the PTEN-R130 mutant loses its lipid phosphatase activity in vitro, little is known regarding the other unconventional functions of PTEN, such as its protein phosphatase activity. We performed unbiased phospho-proteomics experiments in order to explore the impact of this specific mutation in multiple endometrial cancer cell models. Citation Format: Ye Wang, Charles Jakubik, Rachel Peterson, Cyril Benes, Wilhelm Haas, Jeffrey Engelman, Carlotta Costa. Characterization of a hotspot PTEN mutation in endometrial 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 5502.
Abstract 19190: Effectiveness of Supervised Exercise Therapy for the Treatment of Intermittent Claudication in Real-world Clinical Practice
Authors: Ellen Rouwet, Karin Weststrate, Lidia Bons, Hence Verhagen, Sanne Hoeks
Journal: Circulation (2015)

Introduction: Guidelines recommend supervised exercise therapy (SET) as a first-line treatment for patients with intermittent claudication. In trials, SET has indeed been shown to be equally effective as endovascular revascularization in improving walking performance and quality of life. However, SET is an underutilized treatment and the effectiveness of a SET-first approach outside a trial setting is unknown. Hypothesis: We assessed the hypothesis that SET is an effective treatment for intermittent claudication in real-world clinical practice. Methods: In a single-center prospective cohort study, 204 patients with newly diagnosed intermittent claudication were referred to a physiotherapist for SET between August 2009 and December 2013. All patients underwent lower extremity CTA or MRA imaging. Significant stenosis was defined as ≥50% reduction in luminal diameter. Community-based SET was provided according to national guidelines. Freedom from endovascular or open surgical intervention at the last outpatient visit was considered as the primary outcome. Kaplan Meier estimate was used to determine freedom from intervention at 1 year. Results: Mean age was 70±10 years with 59% men and the common risk factors (77% hypertension, 31% diabetes, 46% smoking, 10% obesity) and comorbidities (32% and 23% history of ischemic heart or cerebrovascular disease, resp.). Median maximum walking distance on treadmill testing at baseline visit was 320 m (IQR 150-510 m). The majority (88%) of patients had significant femoropopliteal and/or crural disease. Only 4% had isolated aortoiliac and/or common femoral artery stenoses. Of the 204 referred patients, 84% followed the SET program. After 1 year follow up, 88% of patients were still free from endovascular or surgical intervention. Conclusions: In a real-world clinical setting, a SET-first approach is an effective treatment for intermittent claudication, preventing invasive treatment in most patients.
Aspirin cooperates with p300 to activate the acetylation of H3K9 and promote FasL-mediated apoptosis of cancer stem-like cells in colorectal cancer
Authors: Zhigang Chen, Wenlu Li, Fuming Qiu, Qi Huang, Zhou Jiang, Jun Ye, Pu Cheng, Cho Low, Yikun Guo, Xinchi Yi, Wenteng Chen, Yongpin Yu, YueHua Han, Jun Wu, Shenghang Jin, Dong Kong, Jian Huang
Journal: Theranostics (2018)

Cancer stem-like cells (CSCs) have been proposed as a key driving force of tumor growth and relapse in colorectal cancer (CRC), and therefore, they are promising targets for cancer therapy. Epidemiological evidence has suggested that the daily use of aspirin reduces overall mortality of CRC and the risk of distant metastasis. We investigated the effect and mechanism of aspirin on CSCs in CRC. Methods: The ratio of CSCs was analyzed after aspirin treatment both in a cell model and patient samples. Chemically modified aspirin and immunoprecipitation were adopted to detect the target proteins of aspirin. A locus-specific light-inducible epigenetic modification system based on CRISPR technology was constructed to verify the causal relationship in these molecular events. In vivo characterization was performed in a xenograft model. Results: We found that aspirin induces apoptosis in enriched colorectal CSCs, inhibits tumor progression, and enhances the anti-neoplastic effects of chemotherapeutic agents. Furthermore, aspirin directly interacts with p300 in the nucleus, promotes H3K9 acetylation, activates FasL expression, and induces apoptosis in colorectal CSCs. Notably, these effects of aspirin are absent in non-CSCs since H3K9 is hypermethylated in non-CSCs and the effects are not induced by other NSAIDs. In addition, aspirin can suppress oxaliplatin-enriched CSCs and serve as an adjuvant therapy. Conclusions: Taken together, we revealed a unique epigenetic and cox-independent pathway (p300-AcH3K9-FasL axis) by which aspirin eliminates colorectal CSCs. These findings establish an innovative framework of the therapeutic significance of aspirin.
Abstract 465: Regulation of HMGB1 release protects chemoradiotherapy-associated mucositis
Authors: Keon-Il Im, Young-Sun Nam, Nayoun Kim, YuneJin Song, Young-Woo Jeon, Jung-Yeon Lim, Seok-Goo Cho
Journal: Cancer Research (2018)

Abstract Oral mucositis (OM) is a common complication in cancer patients undergoing anticancer treatment. Despite the clinical and economic consequences of OM, there are no drugs available for its fundamental control. Here, we show that high-mobility group box 1 (HMGB1), a “danger signal” that acts as a potent innate immune mediator, plays a critical role in the pathogenesis of OM. In addition, we investigated treatment of OM through HMGB1 blockade using NecroX-7 (tetrahydropyran-4-yl)-[2-phenyl-5-(1,1-dioxo-thiomorpholin-4-yl)methyl-1Hindole-7-yl]amine). NecroX-7 ameliorated basal-layer epithelial cell death and ulcer size in OM induced by chemotherapy or radiotherapy. This protective effect of NecroX-7 was mediated by inhibition of HMGB1 release and downregulation of mitochondrial oxidative stress. Additionally, NecroX-7 inhibited the HMGB1-induced release of TNF-α, IL-1β and MIP-1β, as well as the expression of p53-upregulated modulator of apoptosis (PUMA) and the excessive inflammatory microenvironment, including nuclear factor kB (NF-kB) pathways. In conclusion, our findings suggest that HMGB1 plays a key role in the pathogenesis of OM; therefore, blockade of HMGB1 by NecroX-7 may be a novel therapeutic strategy for OM. Citation Format: Keon-Il Im, Young-Sun Nam, Nayoun Kim, YuneJin Song, Young-Woo Jeon, Jung-Yeon Lim, Seok-Goo Cho. Regulation of HMGB1 release protects chemoradiotherapy-associated mucositis [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 465.
Abstract B14: A restricted cell population propagates MPNST growth after treatment
Authors: Daochun Sun, Luis Parada
Journal: Clinical Cancer Research (2018)

Abstract Malignant peripheral nerve sheath tumor is a type of soft-tissue sarcoma that arises from the neural crest lineage and is commonly associated with nerve trunks. Surgical removal is the major treatment conjugated with chemo/radiation therapy when applicable. However, the complete tumor clearance is limited by the resectability, especially when tumor is associated with large peripheral nerve such as sciatic nerve, brachial plexus, and sacral plexus. The local recurrence of MPNST is 40-45% and distal recurrence is 40-48%. By harnessing our Nes-hsvTK-GFP transgene that successfully labeled the cancer stem cells in glioblastoma, we identified a small quiescent cell population in MPNSTs from both cisNf1+/-;Trp53+/- (cisNP) spontaneous model and skin progenitor (SKP)-based allograft model. Inhibition of these cells by feeding mice ganciclovir chow significantly decreased the tumor growth in both cisNP model and allograft model. We also found that the transgene-labeled GFP+ cells enrich in the sciatic nerve region compared to the distal tumor mass in MPNST allograft model. Tumor primary culture from the sciatic nerve vicinity forms significantly larger and more spheres in vitro than the distal tumor mass. The BrdU-EdU sequential labeling assay after chemotherapy in MPNST allograft model shows that the GFP+ cells can continuously repopulate tumor. These results indicate that the transgene-labeled GFP+ cells may serve as a source of tumor growth and, at the same time, a novel target to reduce MPNST relapse after treatment. Citation Format: Daochun Sun, Luis Parada. A restricted cell population propagates MPNST growth after treatment [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(2_Suppl):Abstract nr B14.