tbuckley/cabot-search huggingface dataset:
Low-Gradient Aortic Stenosis
Authors: Jean-LucMonin, Jean-PaulQuéré, MehranMonchi, HélènePetit, SergeBaleynaud, ChristopheChauvel, CaméliaPop, PatrickOhlmann, ClaudeLelguen, PatrickDehant, ChristopheTribouilloy, PascalGuéret
Journal: Circulation (2003)

Background— The prognostic value of dobutamine stress hemodynamic data in the setting of low-gradient aortic stenosis has been addressed in small, single-center studies. Larger studies are needed to define the criteria for selecting the patients who will benefit from valve replacement. Methods and Results— Six centers prospectively enrolled 136 patients with aortic stenosis (96 men; median age, 72 years [range, 65 to 77 years]; median aortic valve area, 0.7 cm2 [range, 0.6 to 0.8]; mean transaortic gradient, 29 mm Hg [range, 23 to 34 mm Hg]; cardiac index, 2.11 L · min−1 · m−2 [range, 1.75 to 2.55 L · min−1 · m−2]). Left ventricular contractile reserve on the dobutamine stress Doppler study was present in 92 patients (group I) and absent in 44 patients (group II). Operative mortality was 5% (3 of 64 patients) in group I compared with 32% (10 of 31 patients) in group II (P=0.0002). Predictors for operative mortality were the lack of contractile reserve (odds ratio, 10.9; 95% confidence interval [CI], 2.6 t...
Evolution of Spontaneous Atherosclerotic Plaque Rupture With Medical Therapy
Authors: GillesRioufol, MartineGilard, GérardFinet, IsabelleGinon, JacquesBoschat, XavierAndré-Fouët
Journal: Circulation (2004)

Background— Ruptured coronary atheromatous plaque is generally considered to involve a high risk of subsequent clinical events. Few data are available on the natural evolution of non–culprit-lesion ruptured plaque. We therefore used serial intravascular ultrasound (IVUS) to study how such lesions, detected in the context of a first acute coronary syndrome with elevated troponin I levels, develop. Methods and Results— Fourteen patients with 28 distinct plaque ruptures (2±1 per patient) without significant associated stenosis (minimal lumen cross-sectional area >4 mm2) were included and systematically treated with 40 mg statin and antiplatelet agent (clopidogrel and aspirin for ≥9 months). Mean clinical and IVUS follow-up was 22±13 months (median, 22 months). No clinical event related to the lesion under study occurred. On final IVUS examination, half (14 of 28) of the ruptured plaques had healed, and the degree of stenosis tended to diminish (stenosis, 22±17% versus 29±17% at baseline; P=0.056). No healing...
Application of Percutaneous Transluminal Coronary Angioplasty to Coronary Arterial Stenosis in Kawasaki Disease
Authors: ToshihiroIno, KatsumiAkimoto, MataichiOhkubo, KeiNishimoto, KeijiroYabuta, JunjiTakaya, HiroshiYamaguchi
Journal: Circulation (1996)

Background Percutaneous transluminal coronary angioplasty (PTCA) has rarely been performed on patients with coronary lesions that result from Kawasaki disease. In this study, we retrospectively evaluated the effectiveness of PTCA in five patients with coronary arterial stenosis that resulted from Kawasaki disease and reviewed previous reports for possible indicators of PTCA effectiveness. Methods and Results Five patients, ranging in age from 2 to 16 years (median, 8 years), underwent conventional PTCA for localized stenosis. The lesion targeted for PTCA was located in the middle right coronary artery of three patients and in the left anterior descending artery in two patients. In four of the five patients, PTCA was angiographically effective, with stenosis rates improving from 84±10% to 33±11% (P<.05). When the previously reported cases of six similar patients were taken into consideration, the only predictor of successful PTCA seemed to be the time elapsed between the onset of Kawasaki disease and perfo...
Successive Action of Meprin A and Neprilysin Catabolizes B-Type Natriuretic Peptide
Authors: KristinPankow, YongWang, FlorianGembardt, EberhardKrause, XiaoouSun, GerdKrause, Heinz-PeterSchultheiss, Wolf-EberhardSiems, ThomasWalther
Journal: Circulation Research (2007)

Natriuretic peptides such as B-type natriuretic peptide (BNP) are important cardioprotective hormones with essential functions in sodium excretion, water balance and blood pressure regulation. Consequently, the catabolism of these peptides is in the focus of clinical research. In previous studies, we demonstrated that BNP, in contrast to the structurally related atrial and C-type natriuretic peptide, was not hydrolyzed by neprilysin (NEP). Because membrane preparations of several organs of NEP-knockout mice rapidly degrade BNP, the aim of this study was to identify BNP-catabolizing peptidases responsible for this fast clearance. Using kidney membranes of wild-type and NEP-knockout mice, as well as several peptidase inhibitors, we monitored the catabolism of BNP and analyzed its degradation products. We identified meprin A, a multimeric metalloprotease expressed in the brush borders of kidney proximal tubules, to initially truncate mouse BNP in the N terminus to mBNP7-32, a BNP metabolite with conserved bi...
The fragile X mutation impairs homeostatic plasticity in human neurons by blocking synaptic retinoic acid signaling
Authors: Zhenjie Zhang, Samuele G. Marro, Yingsha Zhang, Kristin L. Arendt, Christopher Patzke, Bo Zhou, Tyler Fair, Nan Yang, Thomas C. Südhof, Marius Wernig, Lu Chen
Journal: Science Translational Medicine (2018)

Fragile X syndrome (FXS) is an X chromosome-linked disease leading to severe intellectual disabilities. FXS is caused by inactivation of the fragile X mental retardation 1 (FMR1) gene, but how FMR1 inactivation induces FXS remains unclear. Using human neurons generated from control and FXS patient-derived induced pluripotent stem (iPS) cells or from embryonic stem cells carrying conditional FMR1 mutations, we show here that loss of FMR1 function specifically abolished homeostatic synaptic plasticity without affecting basal synaptic transmission. We demonstrated that, in human neurons, homeostatic plasticity induced by synaptic silencing was mediated by retinoic acid, which regulated both excitatory and inhibitory synaptic strength. FMR1 inactivation impaired homeostatic plasticity by blocking retinoic acid-mediated regulation of synaptic strength. Repairing the genetic mutation in the FMR1 gene in an FXS patient cell line restored fragile X mental retardation protein (FMRP) expression and fully rescued synaptic retinoic acid signaling. Thus, our study reveals a robust functional impairment caused by FMR1 mutations that might contribute to neuronal dysfunction in FXS. In addition, our results suggest that FXS patient iPS cell-derived neurons might be useful for studying the mechanisms mediating functional abnormalities in FXS.
Abstract 1672: Preclinical evaluation of WXFL1024H251, a potent second-generation HSP90 inhibitor
Authors: Xiaobing yan, Charles Z. Ding, Lihong Hu, Wei Huang, Shuhui Chen, Dongdong Wu, Jiahu Wu, Guoqiang Ma, Qiyao Zhang, Rui Gao, Yusong Zhu, Tiantian Dong, Yizhong Zhu, Caixia Yan, Yan Yan
Journal: Cancer Research (2018)

Abstract Objective: Heat Shock Protein 90 (Hsp90) is a molecular chaperone that mediates the post-translational stability of its protein substrates, many of which are onco-proteins. Hsp90 is emerging as an important target for cancer therapy because its inactivation may abrogate multiple signaling pathways simultaneously, irrespective of the mutational status of proteins involved. We disclose here our clinical candidate WXFL1024H251, a novel second-generation small-molecule Hsp90 inhibitor with a chemical structure unrelated to the first generation, the ansamycin family of Hsp90 inhibitors. Method: The anti-proliferative activity of WXFL1024H251 was evaluated in a variety of cancer cell lines in a 96-hour viability assay. QW, Q2W or TIW intravenous administration of at doses of 5~50 mg/kg was used to evaluate the in vivo anti-tumor activity of WXFL1024H251 in BT474 cell line-derived xenograft (CDX) breast cancer model. Effects of WXFL1024H251 on HSP90 function were assessed by western blot analysis of PD markers HSP70, Her2 and p-Her2 in the BT474 tumors. Result: A panel of 20 cancer cell lines were screened for sensitivity to WXFL1024H251. Proliferation of 2 cancer cell lines A549 and BT474 were potently inhibited by WXFL1024H251, with IC50 of 0.007 μM and 0.009 μM, respectively. A549 cell line has KRAS mutation and medium to high EGFR expression. BT474 is an ER+ and ERBB2+ breast cancer cell line. In the BT474 tumor model, 3 week treatment with WXFL1024H251 showed good antitumor efficacy with T/C values of 36% at 7.5 mg/kg Q2W and 45% at 10 mg/kg QW; toxicity were acceptable with both dosing regiments. Conclusion: These preclinical studies showed good antitumor efficacy of WXFL1024H251, which was associated with client protein maturation and HSP70 up-regulation in the tumor tissue. WXFL1024H251 may represent a novel promising clinical antitumor agent for treating breast cancer and other cancer types with high expression of HSP90. Citation Format: Xiaobing yan, Charles Z. Ding, Lihong Hu, Wei Huang, Shuhui Chen, Dongdong Wu, Jiahu Wu, Guoqiang Ma, Qiyao Zhang, Rui Gao, Yusong Zhu, Tiantian Dong, Yizhong Zhu, Caixia Yan, Yan Yan. Preclinical evaluation of WXFL1024H251, a potent second-generation HSP90 inhibitor [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 1672.
Abstract 12102: Use of Mean Platelet Volume to Predict Significant Coronary Artery Disease in Patients With Non-ST Elevation Acute Coronary Syndromes
Authors: Tuncay Taskesen, Harsimran Sekhon, Igor Wroblewski, Mikhail Goldfarb, Muhammad B Ahmad, Quang Nyguen, Adi Gidron, Dadkhah Shahriar
Journal: Circulation (2016)

Background: Acute coronary syndrome (ACS) is characterized by unstable plaque and thrombotic process involving central role of platelets (PLT). Significant number of patients undergoing cardiac catheterization with non-STE ACS have non-significant coronary artery disease (CAD). It is postulated that an increase in Mean platelet volume (MPV) signifies an increase in inflammation during ACS, and thus, a higher risk of significant CAD. Method: This retrospective study enrolled patients with non-STE ACS who underwent coronary angiography from two teaching hospitals from 2011 to 2016. Significant CAD was defined &gt;70% stenosis in at least one coronary artery. Exclusion criteria included patients with known CAD, hematologic disease, and on anticoagulant medication. Hematologic and angiographic data were collected by independent observers. Results: A total of 213 patients were enrolled (male 53%, mean age 61± 12.3). Mean MPV level was 8.9 fl and 45% of patients had significant CAD. When comparing patients with high MPV (MPV&gt;=9 fl) vs low MPV (MPV&lt;9 fl), high MPV group had significantly more significant CAD (55% vs 35% p =0.005) and higher HbA1c (6.9 vs 6.4 p =0.02). Both groups had similar DM, HTN, smoking, and obesity rates. Patients with significant CAD had high MPV level (9.2± 1.07 fl vs 8.6 ± 1.03 fl p =0.001), high MPV/PLT (0.46 vs 0.40 p =0.01), older age (64.5±11 vs 59.2 ± 12 p =0.02), low HDL level (42±12 vs 47 ±16 p =0.01), and non-significantly low PLT count (219 vs 230 p =0.2). Multivariate analysis showed that increased age (AOR 1.04 95% CI 1.01-1.07, p =0.002), high MPV (AOR 1.46, 95% CI 1.01-1.076, p =0.01), high troponin (AOR 3.01, 95% CI 1.40-6.46, p =0.005), and low HDL levels (AOR 0.96, 95% CI 0.94-0.99, p =0.005) were associated with significant CAD. High MPV along with high troponin level was associated with a 4.8-fold increased risk for significant CAD as compared with normal MPV with high troponin (OR 4.8, 95% CI 1.31-17.6, p =0.001). Conclusion: Non-STE ACS patients with high MPV had significantly more significant CAD. Adding high MPV level to troponin level increased the predictive value of significant CAD. This result may help determine who would benefit from cardiac catheterization. This finding needs to be further validated in larger, prospective studies.
Platelets and Chemokines in Atherosclerosis
Authors: ChristianWeber
Journal: Circulation Research (2005)

It becomes increasingly evident that blood platelets do not only exert important functions in hemostasis and thrombus formation but are also involved in atherosclerotic vascular disease. A major portion of the underlying mechanisms is related to an intricate functional interaction of platelets with chemokines, which have also been implicated in atherogenesis and neointima formation: (1) Platelets can induce the secretion of chemokines in different cells of the vascular wall; (2) In combination with primary agonists, certain chemokines can potentiate platelet aggregation and adhesion; (3) Activated platelets can release and deposit chemokines and precursors on vascular cell surfaces, which trigger atherogenic recruitment of vascular cells or modulate crucial processes such as angiogenesis and lipoprotein metabolism; (4) Surface-adherent platelets can bind and present vascular cell-derived chemokines to trigger arrest of circulating mononuclear cells. The close linkage between platelets and chemokines as cu...
Abstract 1583: Clinical significance of <i>PIK3CA</i>, <i>AKT1</i>, and <i>ESR1</i> mutation in plasma cell-free DNA from estrogen receptor-positive breast cancer patients
Authors: Takashi Takeshita, Mai Tomiguchi, Aiko Sueta, Mutsuko Yamamoto-Ibusuki, Yutaka Yamamoto, Hirotaka Iwase
Journal: Cancer Research (2018)

Abstract Background: In endocrine therapy (ET) resistance mechanisms, PI3K / AKT pathway abnormality and ESR1 mutation are drawing attention. In recent large-scale clinical trials, it was revealed that identification of these genetic abnormalities in cell-free DNA (cfDNA) was useful for rapid assessment and monitoring of the therapeutic effect in ET-resistant breast cancer (BC). However, the frequency of them per treatment line and its clinical significance have not been verified. Here we studied the clinical significance of PIK3CA, AKT1, and ESR1 mutation according to the treatment line in estrogen receptor (ER)-positive BC. METHODS: From 2003 to 2017, a total of 251 plasma specimens were collected from 128 patients with ER positive BC treated at our hospital. The breakdown were 133 plasma samples from 73 primary BC (PBC) patients and 118 plasma samples from 68 metastatic BC (MBC) patients. CfDNA was extracted from 500 μL of plasma. The hotspot of PIK3CA, AKT1, and ESR1 mutation in plasma cfDNA was verified using multiplex digital PCR method. RESULTS: In the PBC patient group, PIK3CA mutation was recognized at 15.1%, AKT1 mutation at 1.4%, and ESR1 mutation at 2.7%. The presence or absence of PIK3CA mutation did not affect clinical outcome. In the MBC patient group, the frequency of PIK3CA mutation increased from 16% to 32% and that of ESR1 mutation increased from 23% to 41.9% as the treatment line advanced. Furthermore, we examined the time to treatment failure (TTF) by dividing into early treatment line and late treatment line. In the early treatment group, patients with PIK3CA mutation had significantly shorter TTF (P = 0.035). However, the presence or absence of ESR1 mutation did not affect TTF. On the other hand, in the late treatment group, patients with ESR1 mutation had significantly shorter TTF (P = 0.048). However, the presence or absence of PIK3CA mutation did not affect TTF. Since AKT1 mutation was rare in both PBC patients and MBC patients, its clinical significance was unknown. CONCLUSION: We showed clinical significance of verification of PIK3CA, AKT1, and ESR1 mutation in cfDNA according to treatment line in ER positive BC patients. Citation Format: Takashi Takeshita, Mai Tomiguchi, Aiko Sueta, Mutsuko Yamamoto-Ibusuki, Yutaka Yamamoto, Hirotaka Iwase. Clinical significance of PIK3CA, AKT1, and ESR1 mutation in plasma cell-free DNA from estrogen receptor-positive breast cancer 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 1583.
Abstract 2056: CPAP promotes angiogenesis via interacting with and enhancing the activity of STAT3 in HCC
Authors: Ruo Yu Chen
Journal: Cancer Research (2018)

Abstract Hepatocellular carcinoma (HCC) is one of the malignant hypervascular tumors in which angiogenesis plays a vital role in tumor growth and metastasis. Our previous studies indicated that CPAP is overexpressed in HCC, and is positively correlated with recurrence and vascular invasion. In this study, we demonstrated that overexpressed CPAP increases tumor growth, angiogenesis, as well as metastasis ex vivo and in vivo. The expression level of CPAP has a positive correlation with activated STAT3 in HCC. Mechanistically, CPAP can act as a transcriptional co-activator of STAT3 to enhance IL-6-induced STAT3 activation by directly binding with STAT3. Overexpressed CPAP up-regulates several target gene expressions of STAT3 that are involved in angiogenesis, such as IL-8, CD44 and MCAM. The expression of CPAP mRNA is positively correlated with the levels of IL-8, CD44 and MCAM mRNAs in HCC. Importantly, IL-6/STAT3-mediated angiogenesis is significantly increased by overexpressed CPAP, and can be blocked by decreased expression of IL-8. Taken together, our results suggest that overexpressed CPAP interacts with STAT3 to enhance its activity and therefore leads to angiogenesis. Our findings shed light on the importance of CPAP to act as a potential therapeutic target in inhibiting the angiogenesis pathway. Citation Format: Ruo Yu Chen. CPAP promotes angiogenesis via interacting with and enhancing the activity of STAT3 in HCC [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 2056.
Longitudinal Phenotypes of Respiratory Health in a High-Risk Urban Birth Cohort
Authors: Leonard B. Bacharier, Avraham Beigelman, Agustin Calatroni, Daniel J. Jackson, Peter J. Gergen, George T. O’Connor, Meyer Kattan, Robert A. Wood, Megan T. Sandel, Susan V. Lynch, Kei E. Fujimura, Douglas W. Fadrosh, Clark A. Santee, Homer Boushey, Cynthia M. Visness, James E. Gern, R. Wood, E. Matsui, H. Lederman, F. Witter, S. Leimenstoll, D. Scott, M. Cootauco, P. Jones, G. O’Connor, W. Cruikshank, M. Sandel, A. Lee-Parritz, C. Jordan, E. Gjerasi, P. Price-Johnson, L. Gagalis, L. Wang, N. Gonzalez, M. Tuzova, D. Gold, R. Wright, M. Kattan, C. Lamm, N. Whitney, P. Yaniv, M. Pierce, H. Sampson, R. Sperling, N. Rivers, G. Bloomberg, L. Bacharier, Y. Sadovsky, E. Tesson, C. Koerkenmeier, R. Sharp, K. Ray, J. Durrange, I. Bauer, A. Freie, V. Morgan. C. Visness, P. Zook, M. Yaeger, J. Martin, A. Calatroni, K. Jaffee, W. Taylor, R. Budrevich, H. Mitchell, W. Busse, J. Gern, P. Heinritz, C. Sorkness, K. Hernandez, Y. Bochkov, K. Grindle, A. Dresen, T. Pappas, M. Renneberg, B. Stoffel, P. Gergen, A. Togias, E. Smartt, K. Thompson
Journal: American Journal of Respiratory and Critical Care Medicine (2018)

Characterization of patterns of wheezing and allergic sensitization in early life may allow for identification of specific environmental exposures impacting asthma development.
Abstract 4678: High-throughput single-cell linking of antigen specificities with T cell receptor sequences using de novo generated DNA-linked MHC tetramers
Authors: Ning Jiang, Shu-qi Zhang, Chenfeng He, Eric Sun, Mingliang Zhang, Weiping Jia
Journal: Cancer Research (2018)

Abstract Identification of correlated antigens recognized by T cell and its T cell receptor (TCR) sequences at single cell level is extremely useful to the understanding and treating immune-related diseases. Although mass cytometry, CyTOF, has pushed the number of antigenic peptides that can be interrogated at once to around 100, the destructive nature of CyTOF prohibits linking pMHCs recognized by a T cell with its TCR receptor sequences. In addition, the high cost associated with peptide synthesis process prevents the quick generation of a peptide library that can be tailored to any pathogens or diseases. Here we describe a new technology, TetATCR-Seq for Tetramer Associated TCR sequencing, that is capable of de novo generating a large amount of peptides and mapping antigen recognition with single cell TCR sequences by DNA barcoded tetramers. It evolves three major steps: 1) de novo peptide generation, 2) DNA barcoded tetramer generation, and 3) single cell sequencing of tetramer DNA barcode and TCR sequences. By spiking in 5 altered peptide ligands (APL) that are known to bind to a HCV T cell clone with other 90 irrelevant peptides, we showed that the binding of all these 5 APLs can be faithfully detected by sequencing while non-specific binding is minimum. Using a published set of cancer neo-antigen sequences, we showed that these peptides and their wild type counterparts can be quickly generated. Resulted tetramers can be used to clearly identify a population of neo-antigen only or wild type antigen only or double positive T cells. Subsequent single cell TCR sequencing showed that TCR paired α and β chain sequences can be obtained in more than 80% of single sorted T cells. Simultaneous tetramer DNA barcode sequencing showed that many T cells are found to cross-reactive to both neo-antigen and its wild type counterpart, suggesting the necessity of strict screening for neo-antigen only TCR in adoptive cell transfer therapy. In summary, the TetaTCR-seq tool we developed here enables one to quickly survey antigen repertoire again TCR repertoire at single cell level for a large number of peptides. This is an extremely useful tool in profiling T cell repertoire reactivity in infection and vaccination. It is also a useful tool to screen for T cell cross-reactivity and select neo-antigen specific TCR for cancer immunotherapy. Citation Format: Ning Jiang, Shu-qi Zhang, Chenfeng He, Eric Sun, Mingliang Zhang, Weiping Jia. High-throughput single-cell linking of antigen specificities with T cell receptor sequences using de novo generated DNA-linked MHC tetramers [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 4678.