tbuckley/cabot-search huggingface dataset:
Relationship Between Progressive Microvascular Damage and Intramyocardial Hemorrhage in Patients With Reperfused Anterior Myocardial Infarction
Authors: ToshihikoAsanuma, KazuakiTanabe, KoichiOchiai, HiroyukiYoshitomi, KoNakamura, YoMurakami, KazuyaSano, ToshioShimada, RinjiMurakami, ShigefumiMorioka, ShintaroBeppu
Journal: Circulation (1997)

Background Recent studies indicated that ischemic microvascular damage may be reversible or progressive after coronary reflow. Intramyocardial hemorrhage is a phenomenon that reflects severe microvascular injury. We examined the relationship between temporal changes in microvascular perfusion patterns detected by myocardial contrast echocardiography (MCE) and intramyocardial hemorrhage detected by magnetic resonance imaging (MRI) in patients with acute myocardial infarction (AMI). Methods and Results The study population consisted of 24 patients with anterior AMI. All patients underwent MCE shortly after reflow and in the chronic stage (a mean of 31 days after reflow). Wall motion score (WMS) was determined as the sum of 16 segmental scores (dyskinetic/akinetic=3 to normal=0) at days 1 and 31. Gradient-echo acquisition and gadolinium-DTPA–enhanced spin-echo MRI were performed within 10 days after reflow. In MCE shortly after reflow, 16 patients (67%) showed contrast enhancement and the other 8 patients (3...
Abstract 11322: Multi-Institutional Analysis of Noninvasive Ventilation Practice After Infant Cardiac Surgery
Authors: Ryan Romans, Steven Schwartz, John Costello, Nikhil Chanani, Parthak Prodhan, David Cooper, Jeffrey Alten, Kshitij Mistry, Andrew H Smith, Avihu Gazit, Janet Donohue, Whenying Zhang, Michael Gaies
Journal: Circulation (2016)

Background: Hospitals performing infant cardiac surgery commonly use noninvasive ventilation (NIV) for postoperative respiratory support. The epidemiology of NIV use in this population remains unknown and it is unclear how practice varies across centers. Methods: We analyzed all infant surgical encounters (&lt;1 year) in the Pediatric Cardiac Critical Care Consortium (PC 4 ) registry from 10/2013--12/2015. NIV included high flow nasal cannula (HFNC) or positive airway pressure (PAP) support. We described patient, operative and postoperative characteristics of patients who did and did not received NIV. To examine casemix-adjusted duration of total respiratory support and the contribution of mechanical ventilation (MV) vs. NIV we created a model incorporating age, prematurity, extracardiac anomalies, surgical complexity and MV at preoperative admission. We calculated and compared adjusted mean duration of total support (MV + NIV), MV, and NIV across hospitals using observed-to-expected duration. Results: The cohort included 3708 encounters from 15 institutions: 2032 (55%) received NIV postoperatively, 40% were neonates, 36% were high complexity. Neonatal age group, extracardiac anomalies, single ventricle, procedure complexity, preoperative respiratory support, longer MV duration, and greater postoperative disease severity were all associated with NIV therapy vs. none (p&lt;0.001 for all). Of those receiving NIV, 93% and 43% received HFNC and PAP, respectively. Across hospitals, NIV use ranged from 32%-65%, and adjusted mean duration ranged from 1-4 days (3 days observed mean). Differences in total adjusted respiratory support were largely driven by duration of MV (Figure 1). Conclusions: NIV therapy is common after infant cardiac surgery, though use varies across hospitals. The analysis suggests that initiatives to reduce differences across hospitals in postoperative respiratory support time should initially focus on MV practices, not NIV.
Abstract 27: A Novel Variant Cell Cycle-related Kinase Provides Cardioprotection Upon Pressure Overload By Promoting Autophagy
Authors: HongyuQiu, LoLai
Journal: Circulation Research (2014)

Background: One approach to discovering novel targets for heart failure (HF) therapy is to determine which genes are down-regulated in HF. We found previously that cardiac cell cycle-related kinase (cCCRK), a novel variant of CCRK in heart, is down-regulated by 50% in failed heart vs control, and over-expression of the cCCRK decreases the susceptibility of cardiac myocytes to pro-apoptotic agents, indicating that cCCRK might be a potential target of HF. We tested here our hypothesis that cCCRK provides cardiaoprotection upon stress of pressure overload. Methods and Results: A transgenic (TG) mouse model with cardiac-specific over-expression of cCCRK was generated. Both wild type (WT) and TG mice were submitted to aortic banding for two weeks. In basal condition, no significant differences were found between TG and WT in left ventricular (LV) /body weight (3.5±0.3 in TG vs. 3.6±0.2 in WT) and contractility (LV ejection fraction (EF): 72.7±1 in TG vs 72.7±1 % in WT). After two weeks banding, EF was signific...
Abstract 2713: Preclinical development of first-in-class antibodies targeting Siglec-9 immune checkpoint for cancer immunotherapy
Authors: Olivier Bénac, Marion Gaudin, Mélody Ors, Aude Le Roy, Hélène Rispaud Blanc, Caroline Soulas, Stéphanie Chanteux, Benjamin Rossi, Laurent Gauthier, Carine Paturel, Yannis Morel, Ivan Perrot, Stéphanie Cornen
Journal: Cancer Research (2018)

Abstract Siglec-9 is a MHC class I-independent inhibitory receptor expressed on NK and myeloid cells (including dendritic cells, monocytes and neutrophils). Its ligands are sialic acid-containing carbohydrates which are over-expressed on various tumor types compared to normal tissues (1). Sialylation of tumor cells is involved in tumor cell malignancy and is reported for decades as a mechanism of escape from immune surveillance (2). The loss of beta-2-microglobulin, an essential component of MHC class I antigen presentation, was recently described as a common mechanism of resistance to checkpoint blockade in clinical trials and revealed the need for MHC class I-independent therapies (3-4). Thus, Siglec-9-sialic acid interaction disruption may promote anti-tumor immunity independently of MHC class I expression by tumors. Here, we describe the discovery and characterization of first-in class anti-human Siglec-9 antibodies as new checkpoint blockade therapy in a wide range of cancers. Antibodies were discovered that efficiently block the interaction between Siglec-9 and its ligands. Epitope mapping revealed that antibodies bind to distinct epitopes on Siglec-9 near the sialic acid binding site. In vitro assays showed that they potently reverse inhibitory functions of Siglec-9 on NK cells leading to subsequent sialic acid-expressing tumor cell killing. Interestingly, Siglec-9 is enhanced on both CD4+ and CD8+ T cells from RCC, melanoma and NSCLC PBMC patients suggesting a putative additional role on adaptive immunity. Siglec-9 was also co-expressed with other inhibitory receptors on NK cells and combination with other immune checkpoint blockers in in vitro assays is ongoing. The antibodies displaying the most interesting features were successfully humanized. (1) Pathol Oncol Res. 2016 Jul;22(3):443-7 (2) Nature. 1968 Jun 29;218(5148):1254-5 (3) Nat Commun. 2017 Oct 26;8(1):1136 (4) N Engl J Med. 2016 Sep 1;375(9):819-29 Citation Format: Olivier Bénac, Marion Gaudin, Mélody Ors, Aude Le Roy, Hélène Rispaud Blanc, Caroline Soulas, Stéphanie Chanteux, Benjamin Rossi, Laurent Gauthier, Carine Paturel, Yannis Morel, Ivan Perrot, Stéphanie Cornen. Preclinical development of first-in-class antibodies targeting Siglec-9 immune checkpoint for cancer immunotherapy [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 2713.
Aortic Event Rate in the Marfan Population
Authors: GuillaumeJondeau, DelphineDetaint, FlorenceTubach, FlorenceArnoult, OlivierMilleron, FrancoisRaoux, GabrielDelorme, LeaMimoun, LauraKrapf, DalilHamroun, ChristopheBeroud, CarineRoy, AlecVahanian, CatherineBoileau
Journal: Circulation (2012)

Background—Optimal management, including timing of surgery, remains debated in Marfan syndrome because of a lack of data on aortic risk associated with this disease. Methods and Results—We used our database to evaluate aortic risk associated with standardized care. Patients who fulfilled the international criteria, had not had previous aortic surgery or dissection, and came to our center at least twice were included. Aortic measurements were made with echocardiography (every 2 years); patients were given systematic β-blockade and advice about sports activities. Prophylactic aortic surgery was proposed when the maximal aortic diameter reached 50 mm. Seven hundred thirty-two patients with Marfan syndrome were followed up for a mean of 6.6 years. Five deaths and 2 dissections of the ascending aorta occurred during follow-up. Event rate (death/aortic dissection) was 0.17%/y. Risk rose with increasing aortic diameter measured within 2 years of the event: from 0.09%/y per year (95% confidence interval, 0.00–0.2...
Relationship between latent and rebound viruses in a clinical trial of anti–HIV-1 antibody 3BNC117
Authors: Yehuda Z. Cohen, Julio C.C. Lorenzi, Lisa Krassnig, John P. Barton, Leah Burke, Joy Pai, Ching-Lan Lu, Pilar Mendoza, Thiago Y. Oliveira, Christopher Sleckman, Katrina Millard, Allison L. Butler, Juan P. Dizon, Shiraz A. Belblidia, Maggi Witmer-Pack, Irina Shimeliovich, Roy M. Gulick, Michael S. Seaman, Mila Jankovic, Marina Caskey, Michel C. Nussenzweig
Journal: The Journal of Experimental Medicine (2018)

A clinical trial was performed to evaluate 3BNC117, a potent anti–HIV-1 antibody, in infected individuals during suppressive antiretroviral therapy and subsequent analytical treatment interruption (ATI). The circulating reservoir was evaluated by quantitative and qualitative viral outgrowth assay (Q2VOA) at entry and after 6 mo. There were no significant quantitative changes in the size of the reservoir before ATI, and the composition of circulating reservoir clones varied in a manner that did not correlate with 3BNC117 sensitivity. 3BNC117 binding site amino acid variants found in rebound viruses preexisted in the latent reservoir. However, only 3 of 217 rebound viruses were identical to 868 latent viruses isolated by Q2VOA and near full-length sequencing. Instead, 63% of the rebound viruses appeared to be recombinants, even in individuals with 3BNC117-resistant reservoir viruses. In conclusion, viruses emerging during ATI in individuals treated with 3BNC117 are not the dominant species found in the circulating latent reservoir, but frequently appear to represent recombinants of latent viruses.
Abstract 19234: Exercise Echocardiography is Efficacious With Superior Cost Profile Compared to Exercise ECG as First Line Test in Patients With no History of Coronary Artery Disease and New Suspected Stable Angina; A Randomized Prospective Study
Authors: Konstantinos Zacharias, Asrar Ahmed, Sothinathan Gurunathan, Benoy N Shah, Roxy Senior
Journal: Circulation (2015)

Introduction: Exercise ECG (ExECG) is the initial investigation of choice according to AHA/ACC guidelines in patients with suspected stable angina, normal ECG and able to exercise.We hypothesized that Exercise Stress Echo (ESE), given its high feasibility (with contrast use) and superior diagnostic accuracy would confer a cost advantage over ExECG. Methods: Consecutive consenting patients with no previous history of coronary artery disease (CAD) and a calculated pre-test CAD risk of &gt;10%, seen in our Rapid Access Clinic and able to exercise on the treadmill, were randomized into same day ExECG or ESE.Tests were classified as positive, negative or inconclusive for ischemia. Patients with negative tests were discharged from the clinic, with inconclusive tests were offered additional tests and with positive tests were offered Coronary Angiography (CA). Cost to diagnosis was calculated using the NHS tariff by adding the cost of all requested investigations up to an including CA on an intention to treat basis. Follow-up data on Death, Myocardial Infarction and Unplanned Revascularization were collected for a period of at least 1 year after the enrollment of the last study patient. Results: A total of 194 patients underwent ExECG (mean age 53, 66% male) and 191 patients ESE(mean age 55, 70% male).There were no significant differences in age, gender and in prevalence of diabetes mellitus, smoking and hyperlipidemia. Pre-test probability of CAD was also similar(39% vs. 40% p=0.6). Results of ExECG were:108(55.7% Negative), 14 (7.2%) Positive, 72(37.1%) Inconclusive and of ESE:191(94.8%) Negative, 9 (4.7%) Positive, 1(0.5%) Inconclusive. The positive predictive value for patients undergoing CA after a positive ESE was higher than that for positive ExECG (9/9 vs 9/14 p=0.04). Average cost to diagnosis was significantly lower for ESE vs Ex ECG ( £ 265 vs £ 331p=0.02). Over a mean follow-up period of 21±5 months there was no significant difference in cardiac event rates (1% vs. 0% p=0.1) in the ESE vs. ExECG groups. Conclusion: In this first randomized study, same day ESE was shown to be feasible, efficacious conferring superior cost advantage when compared to ExECG. This study suggests that ESE could be used as first line investigation in patients with suspected stable angina.
Abstract 2939: ETC159, a porcupine inhibitor, exhibits synergism with PI3K inhibitors in 3-dimensional cell culture
Authors: Sugunavathi Sepramaniam, Xin Hui Chew, Kao Chin Ngeow, May Ann Lee
Journal: Cancer Research (2018)

Abstract Aberrations in WNT signaling, a pathway regulated by a family of secreted glycoproteins known as WNTs, is implicated as a cause for cancer. Post-translational modification of WNTs by porcupine is critical for their activity and eventual activation of the WNT pathway. ETC-159 is an orally available, potent porcupine inhibitor. Addition of ETC-159 suppresses cancer proliferation in several cell lines by blocking the secretion and activity of all WNTs. Nevertheless, tumor growth is driven by complex molecular interactions that dysregulate several pathways at any one time. Thus, early drug discovery studies have increasingly evolved to target multiple molecules or pathways. As therapeutic approaches using combinations of drugs directed at multiple targets can improve treatment response, in this study we explored the possibility of identifying compounds that are synergistic with ETC-159. Unlike conventional two-dimensional combination drug screening, we used the three-dimensional soft agar colony formation assays for the study. Dose-response curves were first independently established to obtain the EC50 ranges for each drug, before proceeding to combination treatments. Using the Chou-Talalay Drug Combination Software, CompuSyn, we identified several inhibitors, which target the PI3K pathway, to act synergistically with ETC-159 in pancreatic cell lines HPAF-II, ASPC-1 and CFPAC-I. Similar treatments in nonpancreatic cell lines indicated that the observed synergism was not cell-line specific, hence highlighting the applicability of such combination treatments for different cancers. Citation Format: Sugunavathi Sepramaniam, Xin Hui Chew, Kao Chin Ngeow, May Ann Lee. ETC159, a porcupine inhibitor, exhibits synergism with PI3K inhibitors in 3-dimensional cell culture [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 2939.
Abstract 1294: Preoperative prediction of microvascular invasion in HCC using radiomics on multisequence gadoxetic acid-enhanced MR images
Authors: Jingwei Wei, Dongsheng Gu, Di Dong, Shuaitong Zhang, Yushen Jin, Jie Tian
Journal: Cancer Research (2018)

Abstract Micro-vascular invasion (MVI) is underscored as a judicious risk factor for early-stage recurrence and poor prognosis of hepatocellular carcinoma (HCC). Preoperative knowledge of MVI would assist in therapy decision making beforehand, thus prolong the survival of HCC patients. However, current diagnosis of MVI could only be obtained by pathological confirmation after the surgery or through punctures, which hinders timely therapeutic regime plan or causes needless suffering for the patients. In this study, we aimed to perform a preoperative prediction on MVI using multi-sequence Radiomics on gadoxetic acid-enhanced MR images, along with multi-variable clinical factor analysis. A cohort of 208 patients diagnosed with HCC was enrolled with institutional review board approval. Radiomic features including shape and size, intensity, textural and wavelet features were extracted on segmented region of interest. The least absolute regression modeling was used to select the most effective radiomic features which had potential for MVI identification. We finally utilized logistic regression modelling to generate the single radiomics signature for each sequence with Akaike information criteria as the stopping rule. Gadoxetic acid-enhanced hepatobiliary phase (HBP) T1-weighted image and HBP T1 map turned out to be the best-performed sequences with AUC over 0.7 on both training and validation cohorts. The fusion radiomics signature incorporating effective features from these two sequences achieved the optimal prediction with AUC of 0.895 on the training cohort and 0.837 on the validation cohort. Adding the pertinent clinical and radiological factors: AFP, irregular tumor border and arterial peritumoral enhancement, the final combined model could successfully predict the MVI with AUC of 0.943 on the training cohort and 0.861 on the validation cohort. Our study revealed the archetypal radiomic features related MVI and highlighted the fusion radiomics signature as a powerful imaging marker for MVI preoperative prediction. Radiomics combined with traditional clinic-radiological information would no doubt improve the clinical decision making in HCC therapy. Citation Format: Jingwei Wei, Dongsheng Gu, Di Dong, Shuaitong Zhang, Yushen Jin, Jie Tian. Preoperative prediction of microvascular invasion in HCC using radiomics on multisequence gadoxetic acid-enhanced MR images [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 1294.
Abstract 19085: Impact of Traditional Risk Factors for the Development and Outcomes of Atrial Fibrillation Across Racial and Gender Groups
Authors: Timothy Shih, Karina Ledezma, Benjamin Romer, Brandon Chalazan, Mark McCauley, Henry Huang, William Galanter, Dawood Darbar
Journal: Circulation (2017)

Introduction: Traditional risk factors for the development of atrial fibrillation (AF) and its outcomes are established in patients of European descent. However, there is a paucity of data regardin...
Abstract 3490: Mechanism of action for antioxidant Twendee X on hepatic cancer cell line HepG2
Authors: Haruhiko Inufusa
Journal: Cancer Research (2018)

Abstract [Purposes of the study] Reactive oxygen species (ROS) are associated with clinical condition of cancer patient, and closely involved in cancer growth and metastasis. Twendee X (TWX) is a composition consisting of Vitamin C, Glutamine, Cystine, Riboflavin, Succinic acid, Fumaric acid, Coenzyme Q10, and Niacin. TWX strongly reduces oxygen radicals or ROS in vitro and in vivo (World Intellectual Property Organization WO2013/072441 A1 COMPOSITION FOR PROTECTION AGAINST CELL-DAMAGING EFFECTS). TWX has significant effects of reducing tumor growth and inhibition metastasis. Hydrogen peroxide level (d-ROMs test) of tumor bearing nude mouse in serum was significantly reduced and increased NK-activity (2016 AACR meeting). Mechanism of action was examined for TWX using hepatic cancer cell line HepG2. [Experimental procedures] Human hepatic cancer cell line HepG2 was used in this study. Cell proliferation experiments of antioxidant by ICDD (France). Metabolome analysis was by Human Metabolome Technologies (Tokyo). In both experiments, HepG2 cell line treated one hour with TWX (60ug/ml). [Data] TWX inhibits the RAF-MEK-ERK pathway starting from ERK. Metabolome analysis shows total shift of metabolism, and especially increase mitochondrial metabolism and ATP production. [Conclusion] Effects of TWX on cancer cell line are not only increase immune activity, but also inhibit proliferation pathway, and mitochondrial metabolism change. Several publications using Vitamin-E or Cysteine as anti-oxidant showed cancer progression or increase metastasis. However, Vitamin-E or Cysteine has limited anti-oxidant effects and hydrogen peroxide level (d-ROMS test) dose not change. On the other hand, TWX has significant effects reduce hydrogen peroxide level, and Japanese Association for Dementia Prevention already started clinical trial for MCI and after stroke patients. For the cancer patients, clinical trial using TWX combination with standard therapy will be start soon. Citation Format: Haruhiko Inufusa. Mechanism of action for antioxidant Twendee X on hepatic cancer cell line HepG2 [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 3490.
Abstract 1654: Chemical and structure-guided optimization of BAX trigger site activators for cancer therapy
Authors: Denis E. Reyna, Felix Kopp, Evripidis Gavathiotis
Journal: Cancer Research (2018)

Abstract Cancer cells evade mitochondrial apoptosis most commonly by over-expressing anti-apoptotic BCL-2 proteins that suppress the activation of pro-apoptotic proteins. Pro-apoptotic BAX is a critical BCL-2 family effector protein that upon death stimuli is activated and induces mitochondrial outer membrane permeabilization that leads to cell death. The vast majority of cancer cells express wild-type BAX, therefore, direct BAX activation represents a potential therapeutic strategy in cancer. We previously presented the discovery of BTSA1 as a selective BAX activator with anti-leukemic activity and provided proof-of-concept for BAX as a druggable target in acute myeloid leukemia (AML) (Reyna et al, Cancer Cell, 2017). Here, we investigated chemical optimization of BTSA1 core scaffold to rationally optimize the potency and efficacy of the BAX trigger site activators in AML models. We designed compounds using a structural model of BTSA1 bound to the BAX trigger site that also fits with the previous established pharmacophore model. Synthesized compounds were evaluated for binding potency using a fluorescence polarization binding assay that measures compound competition of the fluorescein-label stapled BIM BH3 peptide from the BAX trigger site. Compounds with improved binding activity were evaluated for their potency in biochemical assays of BAX activation using isolated liposomal and mitochondrial membrane assays. Improved binding to BAX of BTSA1 derivatives correlated with better activation capacity. Moreover, compounds were evaluated for their efficacy in induction of BAX-mediated cell death in AML cell lines including Venetoclax-resistant cells. We have identified compounds with similar or superior cellular efficacy compared to BTSA1. Compounds were evaluated for ADME and in vivo pharmacokinetic profiles and these are compared to efficacy and pharmacodynamics data using in vivo AML xenograft models. Our work highlights our strategy for chemical and structure-guided optimization of BTSA1 demonstrating the potential for improved therapeutic induction of apoptosis in AML by BAX Trigger Site Activators. Citation Format: Denis E. Reyna, Felix Kopp, Evripidis Gavathiotis. Chemical and structure-guided optimization of BAX trigger site activators for cancer therapy [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 1654.