tbuckley/cabot-search huggingface dataset:
Abstract 15267: Linear Growth and Adiposity Among Children and Adolescents With Obesity
Authors: Carter W English, Miranda L Ritterman Weintraub, Louise C Greenspan, June M Tester, Malini Chandra, Joan C Lo
Journal: Circulation (2017)

Introduction: Childhood obesity has been associated with accelerated growth, early maturation, and cardiometabolic risk. However, the association of stature and higher order obesity has not been examined in contemporary multi-racial/ethnic populations. We examined the relationship of adiposity and stature across the pediatric lifespan. Methods: Anthropometric data from a population of 7956 children age 3-17 years old (n=1130 age 3-5, n=3516 age 6-11, and n=3310 age 12-17 years) with obesity defined by body mass index (BMI) ≥95th percentile were assessed. Age- and sex-specific BMI and height percentiles were calculated using 2000 CDC reference data. Obesity severity was categorized as Class 1 (BMI 100-119%), Class 2 (BMI 120-139%), and Class 3 (BMI ≥140% of the 95th percentile). The association between height (percentile) and BMI class was examined by age group. Trend in height percentile across BMI categories was examined using a generalized linear model (trend test). Results: Tall stature was notable amo...
Abstract 2817: RAD6 promotes acquired chemoresistance and a poor prognostic marker in ovarian cancer
Authors: Chinnadurai Mani, David Clark, Ranganatha Somasagara, Sebastian Spencer, Kaushlendra Tripathi, Komariah Palle
Journal: Cancer Research (2018)

Abstract Ovarian cancer (OC) is deadly and incurable for patients who relapse after primary cancer is treated with surgery and platinum-based chemotherapy. Unfortunately, OC has a high rate of disease recurrence (70-80%) and most recurrent tumors are chemoresistant, causing deaths of nearly 15,000 women from this disease each year in U.S.A., which highlights the need for new therapeutic strategies. Platinum drug resistance and refractory disease pose major challenges in treating this disease and are major factors contributing to the poor survival rate of OC patients. Our studies demonstrated that RAD6 (an E2 ubiquitin conjugating enzyme) signaling is stimulated upon chemotherapeutic treatment and promotes expression of DNA repair proteins including Fanconi anemia (FA) pathway. Analysis of clinical samples revealed upregulation of RAD6 in ovarian tumors compared to normal ovarian tissues and RAD6 inhibition reduces cancer cell survival. In a pilot clinical study (n=26) comparing matched OC tumors from patients before and after carboplatin chemotherapy regimen, we found that RAD6 was upregulated after treatment and correlated with both chemoresistance and poor progression-free survival. Knockdown or inhibition of catalytic activity (small-molecule inhibitor) of RAD6 attenuated carboplatin-induced monoubiquitination of target proteins such as FANCD2, PCNA and histone 2B, thereby sensitizing OC cells to carboplatin. Interestingly, inhibition of RAD6 alone in OC cells induced replication stress and reduced cell survival and proliferation by arresting cells in the G2/M phase. Moreover, RAD6 plays an important role in the activation of the trans-lesion synthesis (TLS) pathway by monoubiquitinating PCNA and in the activation of the FA DNA repair pathway. These are critical mechanisms for cells to repair DNA crosslinks induced by platinum drugs. Together with these observations, our data suggest that inhibition of RAD6 could be a viable therapeutic target for overcoming platinum resistance and disease recurrence induced by FA pathway in ovarian cancer. Citation Format: Chinnadurai Mani, David Clark, Ranganatha Somasagara, Sebastian Spencer, Kaushlendra Tripathi, Komariah Palle. RAD6 promotes acquired chemoresistance and a poor prognostic marker in ovarian 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 2817.
Abstract 1900: Disruption of EGFR and integrin b1 signaling in triple-negative breast cancer through targeting SHC1
Authors: Ya-Fang Chang, Elizabeth Cordell, Yuhao Wang, Geoffrey Greene
Journal: Cancer Research (2018)

Abstract Triple-negative breast cancer (TNBC) accounts for 15-20% of breast cancer cases and is more prevalent among young women and African American women. SHC1 (Src Homology 2 Domain Containing Transforming Protein 1) is an adaptor protein that can transmit cell surface receptor signaling and activate the Ras-ERK pathway. SHC1 is found to be overexpressed in breast cancers and is important in the regulation of tumor progression and drug resistance in ER+ breast cancer. Elevated SHC1 correlates with poor prognosis in breast cancer patients. However, the biological significance of SHC1 in TNBC is not known. In this study, we performed siRNA-mediated knockdown to determine the importance of SHC1 in cell proliferation and drug response in TNBC. We found that although siSHC1 slightly inhibited the tumor growth of TNBC cells, siSHC1 + paclitaxel significantly decreased cell proliferation and increased caspase-3/7 activity in vitro. In invasion assays, siSHC1 significantly decreased the invasion of TNBC cells. To better understand the systemic regulation by SHC1, proteomic analysis was performed after siSHC1 or Scr transfection. Pathway analysis revealed the involvement of PI3K/AKT, FAK, and actin cytoskeleton pathways, by disruption of EGFR and integrin β1 signaling, in the control of TNBC progression and drug sensitivity. In tumor explant studies, siSHC1 significantly enhanced paclitaxel-induced tumor shrinkage and reduced lung metastasis. Our data suggest that SHC1 is a potential therapeutic target in TNBC. Citation Format: Ya-Fang Chang, Elizabeth Cordell, Yuhao Wang, Geoffrey Greene. Disruption of EGFR and integrin b1 signaling in triple-negative breast cancer through targeting SHC1 [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 1900.
Abstract LB-317: Anti-invasive effects of saracatinib in preclinical models of luminal bladder cancer
Authors: Bryan Wehrenberg, David Neal, Andrea Ochoa, Woonyoung Choi, David McConkey
Journal: Cancer Research (2018)

Abstract Bladder cancers (BC) form biologically and clinically distinct luminal and basal subtypes. In both subtypes, identifying treatments to prevent progression from non-muscle invasive to muscle invasive disease is a major clinical priority. Anti-invasive agents, such as the SRC and SRC-Family Kinase inhibitor, saracatinib, may benefit high risk non-muscle invasive BC patients. We hypothesized that SRC inhibition limits invasion in bladder tumor models. We examined SRC mRNA expression in the luminal and basal subtypes of BC using publicly available The Cancer Genome Atlas (TCGA) data. Using RNA-Seq expression data, we classified 30 human BC cell lines as luminal or basal and compared SRC expression between the subtypes. We then studied the effect of saracatinib in luminal and basal BC models. Proliferation was measured by MTT assay and invasion was measured using transwell assays. Transwells were either uncoated (modeling migration), matrigel coated (modeling basement membrane invasion) or collagen-1 coated (modeling muscle wall invasion). Luminal TCGA bladder tumors showed significantly enrichments in SRC mRNA expression (p&amp;lt;0.001). SRC expression was significantly higher in luminal than basal cell lines (p&amp;lt;0.05). Saracatinib had limited anti-proliferative activity in both luminal and basal models. All luminal models showed significantly decreased migration and collagen 1 invasion (p&amp;lt;0.05). Of the subset of luminal cell lines that invade matrigel, two thirds had significantly decreased invasion (p&amp;lt;0.05). Only one basal cell line exhibited significantly decreased invasion or migration (p&amp;lt;0.05). Invasion and migration in other basal models were not significantly altered or, in several case, were significantly increased (p&amp;lt;0.05), by saracatinib. Enrichment of SRC expression in luminal tumors and significant reductions in luminal cell line invasion after saracatinib treatment suggest SRC promotes invasion in luminal BC. The increase in basal cell line invasion, observed in a subset of these models, emphasizes the importance of considering subtype in studying the biology of BC. Though further validation in 3D culture and animal models is necessary, these results suggest saracatinib, and other SRC-Family Kinase inhibitors, could serve as effective anti-progression agents in luminal BC. Citation Format: Bryan Wehrenberg, David Neal, Andrea Ochoa, Woonyoung Choi, David McConkey. Anti-invasive effects of saracatinib in preclinical models of luminal bladder 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 LB-317.
Reduction of Circulating Soluble Fms-Like Tyrosine Kinase-1 Plays a Significant Role in Renal Dysfunction–Associated Aggravation of Atherosclerosis
Authors: KenjiOnoue, ShiroUemura, YukijiTakeda, SatoshiSomekawa, HajimeIwama, KeiichiImagawa, TakuNishida, YoshinobuMorikawa, YasuhiroTakemoto, OsamuAsai, TsunenariSoeda, SatoshiOkayama, KenichiIshigami, KimihikoNakatani, HiroyukiKawata, ManabuHorii, TamioNakajima, YasuhiroAkai, MasayukiIwano, YoshihikoSaito
Journal: Circulation (2009)

Background— Renal dysfunction is commonly accompanied by a worsening of atherosclerosis; however, the underlying molecular mechanism is not fully understood. We examined the role played by soluble fms-like tyrosine kinase-1 (sFlt-1), an endogenous antagonist of the proatherogenic cytokine placental growth factor (PlGF), in the worsening of atherosclerosis in patients with renal dysfunction and in an animal model of renal failure. Methods and Results— In this study, 329 patients who received cardiac catheterization and 76 patients who underwent renal biopsy were enrolled. Both plasma sFlt-1 levels and renal sFlt-1 mRNA expression were positively correlated with estimated glomerular filtration rate (P<0.01). The PlGF/sFlt-1 ratio was negatively correlated with estimated glomerular filtration rate (P<0.01), whereas plasma PlGF levels were not affected by it. The PlGF/sFlt-1 ratio was significantly higher in patients with multivessel coronary artery disease than in patients with single-vessel or no coronary a...
Interstitial Pneumonia With Autoimmune Features
Authors: Erin M. Wilfong, Robert J. Lentz, Adam Guttentag, James J. Tolle, Joyce E. Johnson, Jonathan A. Kropski, Peggy L. Kendall, Timothy S. Blackwell, Leslie J. Crofford
Journal: Arthritis & Rheumatology (2018)

Interstitial lung disease (ILD) remains a cause of significant morbidity and mortality in patients with connective tissue disease (CTD)–associated ILD. While some patients meet clear classification criteria for a systemic rheumatic disease, a subset of patients do not meet classification criteria but still benefit from immunosuppressive therapy. In 2015, the American Thoracic Society and European Respiratory Society described classification criteria for interstitial pneumonia with autoimmune features (IPAF) to identify patients with lung‐predominant CTD who lack sufficient features of a systemic rheumatic disease to meet classification criteria. Although these criteria are imperfect, they are an important attempt to classify the patient with undifferentiated disease for future study. Rheumatologists play a key role in the evaluation of potential IPAF in patients, especially as many patients with a myositis‐spectrum disease (e.g., non–Jo‐1 antisynthetase syndrome, anti–melanoma differentiation–associated protein 5 antibody inflammatory myositis, or anti–PM/Scl antibody–associated inflammatory myositis) would be classified under IPAF using the currently available criteria for inflammatory myositis, and would therefore benefit from rheumatologic comanagement. The aim of this review was to describe the historical context that led to the development of these criteria and to discuss the limitations of the current criteria, diagnostic challenges, treatment options, and strategies for disease monitoring.
Abstract 4372: SET/PP2A/SHP-1/Lyn oncogenic signaling contributes to tumor aggressiveness in diffuse large B cell lymphoma
Authors: Ji-Lin Chen, Wen-Chun Tsai, Tien-Yun Lan, Chun-Teng Huang, Pei-Yi Chu, Chia-Han Lee, Ka-Yi Lau, Wan-Lun Wang, Kuen-Feng Chen, Chung-Wai Shiau, Chun-Yu Liu
Journal: Cancer Research (2018)

Abstract Purpose: Diffuse large B-cell lymphoma (DLBCL) is aggressive non-Hodgkin lymphoma. It is a heterogeneous disease and is classified as germinal center B-cell like (GCB) and activated B-cell like (ABC) subtypes according to gene-expression profiling. The oncogenic pathways in DLBCL are potential targets for new therapies. In present study, the role and regulation of SET/PP2A/SHP-1/Lyn axis in DLBCL were investigated. Experimental design: U2932, OCL-Ly3, OCI-Ly7, SU-DHL-6 and DB DLBCL cell lines were used for this study. TD-19, a novel SET/PP2A protein-protein interaction inhibitor, was used to address the molecular events of SET signaling. Cell viability was measured by MTT assay. The apoptotic cells were examined by PI/Annexin V staining and Western blotting. SHP-1, Lyn and pLyn were analyzed by immunohistochemistry on lymphoma tissue microarrays from DLBCL patients. Results: We first examined the effects of two different SET inhibitors, TD-19 that is a SET/PP2A protein protein interaction inhibitor, and FTY720 which is a sphingosine analogue that targets SET, on DLBCL cells. TD-19 and FTY720 significantly decreased cell viability and induced apoptosis. SET inhibition activated PP2A and SHP-1 by reducing pPP2AY307 and pSHP-1S591 and inactivated Lyn by decreasing pLynY396. Overexpression of SET rescued these molecular events, and promoted cell growth and migration. Interestingly, we observed the level of SET was declined by TD-19 and TFY720 treatment. We hypothesized Lyn might up-regulate SET expression. Overexpression of Lyn increased SET level, and was accompanied with phosphorylation of PP2A (pPP2AY307) and SHP-1 (pSHP-1S591). Lyn elevated cell growth and migration and suppressed PP2A and SHP-1 activities. Moreover, exogenous SET restored the FTY720- and TD-19-suppressed pSHP-1 and pLyn. Immunohistochemically, high SHP-1 level was linked to low pLyn level of patient with DLBCL and vice versa. Conclusion: This study established the existence of positive feedback of SET/PP2A/SHP-1/Lyn axis in DLBCL cells, and targeting SET could disrupt this regulation. Citation Format: Ji-Lin Chen, Wen-Chun Tsai, Tien-Yun Lan, Chun-Teng Huang, Pei-Yi Chu, Chia-Han Lee, Ka-Yi Lau, Wan-Lun Wang, Kuen-Feng Chen, Chung-Wai Shiau, Chun-Yu Liu. SET/PP2A/SHP-1/Lyn oncogenic signaling contributes to tumor aggressiveness in diffuse large B cell lymphoma [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 4372.
Abstract 5840: Inhibition of cystathionine-β-synthase (CBS) sensitizes colon cancer cells to 5-FU via increasing apoptosis and inhibiting cellular bioenergetics
Authors: Shanwen Chen, Pengyuan Wang, Yisheng Pan, Yucun Liu
Journal: Cancer Research (2018)

Abstract Increased expression of cystathionine-β-synthase (CBS) has been validated in multiple kinds of tumor tissues, including colorectal cancer. Endogenous hydrogen sulfide (H2S), produced by CBS, was able to promote the proliferation and migration of colon cancer cells by inhibiting apoptosis and injuries caused by noxious environmental factors, including chemotherapeutic agents. Recently, overexpression of CBS has been reported to play a pivotal role in tumorigenesis of colon cancer cells, rendering the normal colon epithelial cell line acquiring the features of malignant cells. However, the potential role of CBS in the development of chemoresistance of colon cancer cells has not be illustrated. In the present study, overexpression of CBS in tumor tissues was further validated by realtime PCR and the effect of inhibition of both the activity and expression of CBS on the sensitivity to 5-fluorouracil (5-FU) was investigated in colon cancer cell lines. Inhibition of the activity of CBS by CBS inhibitor aminooxyacetate (AOAA) significantly increased the sensitivity of colon cancer cell lines to 5-FU, featured by decreased IC50 and colony forming efficiency. However, utilizing a slowly releasing H2S donor GYY4137, the present study suggested that exogenous hydrogen sulfide was able to increase the resistance to 5-FU in both colon cancer cell lines. What's intriguing was that, 5-FU, at clinically relevant concentrations, significantly inhibited the expression of CBS. Co-treatment of AOAA significantly increased the expression of Bax and decreased the expression of Bcl-2, indicating the involvement of increased apoptosis. AOAA also predisposed the colon cancer cells to the inhibition of cellular energetics induced by 5-FU, featured by the further reduced level of cellular ATP. These results suggested that inhibition of CBS promoted the sensitivity of colon cancer cells to 5-FU via increasing apoptosis and inhibiting cellular bioenergetics. Furthermore, inhibition of CBS expression by shRNA sensitizes the 5-FU resistant colon cancer cell line HCT-8/5-FU to treatment with 5-FU. The increased expression of CBS and the consequently increased level of endogenous H2S might be a potential therapeutic target for chemoresistance in colon cancer. Citation Format: Shanwen Chen, Pengyuan Wang, Yisheng Pan, Yucun Liu. Inhibition of cystathionine-β-synthase (CBS) sensitizes colon cancer cells to 5-FU via increasing apoptosis and inhibiting cellular bioenergetics [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 5840.
Clinical Implications of the ‘No Reflow’ Phenomenon
Authors: HiroshiIto, AtsushiMaruyama, KatsuomiIwakura, ShinTakiuchi, TohruMasuyama, MasatsuguHori, YorihikoHigashino, KenshiFujii, TakazoMinamino
Journal: Circulation (1996)

Background Recent studies demonstrated that the “no reflow” phenomenon after coronary reflow implies the presence of advanced myocardial damage. In this study, we verified the prognostic value of the detection of this phenomenon by studying complications, left ventricular morphology, and in-hospital survival after acute myocardial infarction (AMI). Methods and Results The study population consisted of 126 patients with a first anterior AMI. All patients received coronary reflow within 24 hours of onset of symptoms and underwent myocardial contrast echocardiography (MCE) before and shortly after coronary reflow with an intracoronary injection of sonicated microbubbles. From contrast reperfusion patterns, patients were divided into two subsets: those with MCE no reflow (47 patients, 37%) and those with MCE reflow (79 patients). There was no difference in the frequency of arrhythmia or coronary events between the two subsets. Pericardial effusion and early congestive heart failure were observed more frequent...
Natural Androgens Inhibit Male Atherosclerosis
Authors: PeterAlexandersen, JensHaarbo, IngerByrjalsen, HenrikLawaetz, ClausChristiansen
Journal: Circulation Research (1999)

Abstract—The effect of natural androgens on serum lipids and atherosclerosis is controversial. We therefore studied this important issue prospectively in an animal model of atherosclerosis. Eighty male rabbits were randomized to bilateral castration, and 20 animals were sham operated. The castrated rabbits were randomized to 500 mg oral dehydroepiandrosterone (DHEA) daily, 80 mg oral testosterone undecanoate (TU) daily, or 25-mg intramuscular injection of testosterone enanthate (TE) twice weekly, whereas the fourth castrated group (placebo) and the sham-operated rabbits did not receive any hormones. All animals were fed a cholesterol-rich diet during the 30-week treatment period. Average serum lipids and atherogenic lipoproteins were higher in the placebo group than in the other groups (ANOVA, P<0.0001). Aortic atherosclerosis, as evaluated by the cholesterol content (nmol/mg protein), was also highest in the placebo group (308±39) and lowest in the TE group (61±12), but was intermediate in the DHEA (155±...
Blood Coagulation and Thrombotic Disease
Authors: Benjaminalexander
Journal: Circulation (1962)

The role of blood coagulation in the pathogenesis of thrombotic disease as well as atherosclerosis is receiving renewed attention, and has been greatly extended into the area of therapy. The clotting mechanism has been delineated in accordance with most recent information, with particular reference to the early phases and the coagulation balance. The close relationship between clotting and proteolytic phenomena is considered, and the concept of hypercoagulability is critically scrutinized. Experimentally induced thrombosis by means of serum factors is reviewed in support of this concept. Also discussed is the place of lipids in coagulation and atherosclerosis in an attempt to embrace the lipid theory of the pathogenesis of atherosclerosis with current concepts of clotting. Finally, certain aspects of anticoagulant action are covered.
Abstract 14601: TRPC1 Channel Is Upregulated in Atria of Patients With Atrial Fibrillation
Authors: Kai Zhang, Feng Qiu, Qian Yang, Guo-Sheng Xiao, Gui-Rong Li, Yan Wang
Journal: Circulation (2016)

Introduction: Our previous study demonstrated that the non-selective cation current mediated by TRPC1 channels is present in human atrial myocytes and activated by endothelian-1 (ET-1). Hypothesis: Regulation of TRPC1 channels by ET-1 is related to activation of intracellular molecular signals and TRPC1 channels are upregulated in atria of patients with persistent atrial fibrillation (AF). Methods: A whole-patch voltage-clamp technique and molecular biological approaches were used to record TRPC1 current and to determine the related gene and protein expression in atrial myocytes and/or tissue specimens of sinus rhythm (SR, n=35) or AF (n=30) patients who underwent cardiac surgery. Results: It was found that ET-1 activated TRPC1 current more in AF myocytes than in SR myocytes (n=10, P<0.05 vs. control). ET-1-evoked TRPC1 current was inhibited by both ETA and ETB receptor antagonists BQ-123 and BQ788 or protein kinase C (PKC) inhibitor chelerythrine. ETA receptor-mediated TRPC1 channel activity was selectiv...
Systemic Infection Related to Endocarditis on Pacemaker Leads
Authors: DidierKlug, DominiqueLacroix, ChristineSavoye, LucGoullard, DanielGrandmougin, Jean LucHennequin, SalemKacet, JeanLekieffre
Journal: Circulation (1997)

Background Endocarditis related to pacemaker (PM)-lead infection is a rare but serious complication of permanent transvenous pacing. To determine in which situations the diagnosis should be evoked and to determine optimal management, we reviewed our experience with endocarditis related to PM-lead infection. Methods and Results Fifty-two patients were admitted for endocarditis related to PM-lead infection. The presentation was acute in 14 patients, with onset of symptoms in the first 6 weeks after the last procedure on the implant site, and chronic in 38 patients. Fever occurred in 86.5%. Clinical and/or radiological evidences of pulmonary involvement were observed in 38.4%. Pulmonary scintigraphy disclosed pulmonary infarcts in 31.2%. Local complications were found in 51.9%. Elevated C-reactive protein was found in 96.2%. A germ was isolated in 88.4% of patients and was a Staphylococcus in 93.5%. Transthoracic echocardiography demonstrated vegetations in only 23% of patients, whereas transesophageal echoc...