tbuckley/cabot-search huggingface dataset:
Cellular Mechanisms of Aortic Aneurysm Formation
Authors: Raymundo Alain Quintana, W. Robert Taylor
Journal: Circulation Research (2019)

Aortic aneurysms are a common vascular disease in Western populations that can involve virtually any portion of the aorta. Abdominal aortic aneurysms are much more common than thoracic aortic aneurysms and combined they account for >25 000 deaths in the United States annually. Although thoracic and abdominal aortic aneurysms share some common characteristics, including the gross anatomic appearance, alterations in extracellular matrix, and loss of smooth muscle cells, they are distinct diseases. In recent years, advances in genetic analysis, robust molecular tools, and increased availability of animal models have greatly enhanced our knowledge of the pathophysiology of aortic aneurysms. This review examines the various proposed cellular mechanisms responsible for aortic aneurysm formation and identifies opportunities for future studies.
Peripheral blood minimal/measurable residual disease assessed in flow cytometry in acute myeloblastic leukemia
Authors: Cécile Guénot, Francis Lacombe, Kaoutar Allou, Florent Dumezy, Jean Feuillard, Franck Geneviève, Estelle Guérin, Julien Guy, Marc Maynadié, Orianne Wagner Ballon, Claude Preudhomme, André Baruchel, Hervé Dombret, Norbert Ifrah, Marie C. Béné
Journal: Leukemia (2019)
Surveillance and outcomes after curative resection for gastroesophageal adenocarcinoma (GEAC).
Authors: Di Maria Jiang, Chihiro Suzuki, Osvaldo Espin-Garcia, Melania Pintilie, Charles Henry Lim, Lucy Xiaolu Ma, Peiran Sun, Hao-Wen Sim, Akina Natori, Bryan Anthony Chan, Daniel Yokom, Stephanie Moignard, Eric Xueyu Chen, Geoffrey Liu, Carol Jane Swallow, Gail Elizabeth Darling, Rebecca Wong, Raymond Woo-Jun Jang, Elena Elimova
Journal: Journal of Clinical Oncology (2019)

162 Background: Although commonly performed, the benefit of routine surveillance testing (SvT) following curative resection of GEAC is undefined. We aimed to determine frequency of successful salvage therapy (SST) in patients (pts) with relapsed GEAC who were surveyed post curative therapy. Methods: Between 2011 and 2016, 210 consecutive pts with locally advanced GEAC underwent curative surgery and subsequent surveillance at Princess Margaret Cancer Center. SST was defined as any potentially curative therapy for recurrence which resulted in post-recurrence survival (PRS) two years without further relapse. Time-to-event outcomes were analyzed using Kaplan-Meier and Cox regression methods. Results: Median age was 64.1 years. Esophageal (14%), gastroesophageal junction (41%), and gastric adenocarcinomas (45%) were included. Pts received surgery alone (29%), surgery with perioperative chemotherapy (26%) or perioperative chemoradiation (45%) as primary curative therapy. At median follow-up of 33.6 months (m, range 6.0-122.4), 3- and 5-year overall survival (OS) rates were 68% (95% CI 61-75%) and 59% (95% CI 51-68%) respectively. SvT modalities included imaging (69%), endoscopy (19%), tumor markers (4%), and clinical visits only (9%). Recurrences occurred in 95 (45%) pts, 51% were surveillance-detected (SvDR), and 47% were non-SvDR. Types of recurrences included locoregional only (4%), distant (87%) or both (9%). Salvage therapy was attempted in 14 pts (7%) with SvDR and 1 with non-SvDR. In four pts with SvDR (1.9%) salvage therapy was successful with chemoradiation or surgery perioperative chemotherapy, six were unsuccessful, and 5 had immature follow-up. Compared with pts with non-SvDR, pts with SvDR had longer median OS (34.8 vs. 24.0m, p=0.03) and PRS (14.4 vs. 4.8m, p &lt; 0.001), and similar time-to-relapse (15.6 vs. 12.0m, p = 0.67). Palliative chemotherapy was administered in 25 pts with SvDR and 18 pts with non-SvDR with similar median duration (3.5m vs. 3.3m, p=0.64). Conclusions: Following curative therapy, 96% of relapses were distant. SvT enabled SST in only 1.9% of pts, and did not extend duration of palliative chemotherapy. These data do not support the use of routine SvT in resected GEAC.
Thrombospondin-1, Platelet Factor 4, and Galectin-1 Are Associated with Engraftment in Patients with Sickle Cell Disease Who Underwent Haploidentical HSCT
Authors: Ahmad Shaikh, Purevdorj Olkhanud, Marjan Gucek, Sajni Patel, Courtney D. Fitzhugh
Journal: Blood (2018)
Clinical Course and Significance of Hypertrophic Cardiomyopathy Without Left Ventricular Hypertrophy
Authors: Niccolò Maurizi, Michelle Michels, Ethan J. Rowin, Christopher Semsarian, Francesca Girolami, Benedetta Tomberli, Franco Cecchi, Martin S. Maron, Iacopo Olivotto, Barry J. Maron
Journal: Circulation (2019)
Abstract B36: Targeting MDM4 in neuroblastoma to reactivate p53 signaling
Authors: Sarah E. Woodfield, Roma H. Patel, Aryana M. Ibarra, Zhenghu Chen, Sanjeev A. Vasudevan
Journal: Cancer Research (2018)

Abstract Introduction: Neuroblastoma is the most common pediatric extracranial solid tumor. Despite aggressive therapeutic regimens, long-term survival of patients with high-risk disease is less than 50%. The TP53 tumor suppressor gene is wild-type and functional in 99% of neuroblastoma cases at diagnosis. Thus, we hypothesized that targeting the p53 regulator MDM4 to reactivate p53 signaling would be effective in neuroblastoma. Methods: Levels of gene expression of MDM4 and its association with event-free and overall survival in neuroblastoma patients were analyzed using the publically available patient datasets in the R2 Genomics Analysis and Visualization Platform. MDM4 gene and protein expression were also examined in five neuroblastoma cell lines (IMR-32, SH-SY5Y, NB-19, SK-N-AS, and LAN-1) with qPCR and immunoblotting assays. The effects of MDM4 inhibitor NSC207895 on TP53 wild-type IMR-32 and SH-SY5Y, TP53 mutant SK-N-AS, and TP53 null LAN-1 cells were analyzed with MTT assays for cytotoxicity and qPCR experiments to look at p53 targets. Results: MDM4 expression is significantly correlated with both event-free and overall survival of neuroblastoma patients in the Kocak (n=476) and Oberthuer (n=251) datasets in the R2 Genomics Analysis and Visualization Platform, with lower expression correlated with increased survival (p&amp;lt;0.01). All five neuroblastoma cell lines showed gene and protein expression of MDM4. NSC207895 had strong cytotoxic effects at very low concentrations (0.08-0.09 μM) after only 24 hours of treatment with TP53 wild-type IMR-32 and SH-SY5Y cells. NSC207895 exposure also led to upregulation of p53 targets Bax (3.7- to 4.3-fold), Puma (5.7- to 21.6-fold), and CDKN1A (14.5- to 53.1-fold) in these cells but not in TP53 mutant SK-N-AS or TP53 null LAN-1 cells. Conclusions: Inhibition of MDM4 shows efficacy in preclinical models of neuroblastoma by upregulating p53 tumor suppressor signaling in TP53 wild-type cells and is a promising therapeutic strategy for high-risk patients with wild-type TP53. Citation Format: Sarah E. Woodfield, Roma H. Patel, Aryana M. Ibarra, Zhenghu Chen, Sanjeev A. Vasudevan. Targeting MDM4 in neuroblastoma to reactivate p53 signaling [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr B36.
Intestinal Microbiota at Neutrophil Engraftment Can Predict Acute Graft-Versus-Host Disease in the Recipients of Allogeneic Hematopoietic Stem Cell Transplantation
Authors: Lijie Han, Zhiping Fan, Hua Jin, Li Xuan, Min Dai, Fen Huang, Ren Lin, Jing Sun, Qifa Liu
Journal: Blood (2018)
Early Use of Norepinephrine in Septic Shock Resuscitation (CENSER). A Randomized Trial
Authors: Chairat Permpikul, Surat Tongyoo, Tanuwong Viarasilpa, Thavinee Trainarongsakul, Tipa Chakorn, Suthipol Udompanturak
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

Rationale: Recent retrospective evidence suggests the efficacy of early norepinephrine administration during resuscitation; however, prospective data to support this assertion are scarce. Objectives: To conduct a phase II trial evaluating the hypothesis that early low-dose norepinephrine in adults with sepsis with hypotension increases shock control by 6 hours compared with standard care. Methods: This single-center, randomized, double-blind, placebo-controlled clinical trial was conducted at Siriraj Hospital, Bangkok, Thailand. The study enrolled 310 adults diagnosed with sepsis with hypotension. The patients were randomly divided into two groups: early norepinephrine (n = 155) and standard treatment (n = 155). The primary outcome was shock control rate (defined as achievement of mean arterial blood pressure ≥65 mm Hg, with urine flow ≥0.5 ml/kg/h for 2 consecutive hours, or decreased serum lactate ≥10% from baseline) by 6 hours after diagnosis. Measurements and Main Results: The patients in both groups were well matched in background characteristics and disease severity. Median time from emergency room arrival to norepinephrine administration was significantly shorter in the early norepinephrine group (93 vs. 192 min; P < 0.001). Shock control rate by 6 hours was significantly higher in the early norepinephrine group (118/155 [76.1%] vs. 75/155 [48.4%]; P < 0.001). The 28-day mortality was not different between groups: 24/155 (15.5%) in the early norepinephrine group versus 34/155 (21.9%) in the standard treatment group (P = 0.15). The early norepinephrine group was associated with lower incidences of cardiogenic pulmonary edema (22/155 [14.4%] vs. 43/155 [27.7%]; P = 0.004) and new-onset arrhythmia (17/155 [11%] vs. 31/155 [20%]; P = 0.03). Conclusions: Early norepinephrine was significantly associated with increased shock control by 6 hours. Further studies are needed before this approach is introduced in clinical resuscitation practice. Clinical trial registered with www.clinicaltrials.gov (NCT01945983) (CENSER trial).
Eosinophil Count and Serum Immunoglobulin E Levels in Atopic Dermatitis: Analysis of Upadacitinib Phase 2 Study Findings
Authors: Lisa A. Beck, Jonathan I. Silverberg, Kristie Grebe, Feng Hong, Julie Parmentier, Henrique Teixeira, Emma Guttman-Yassky
Journal: Journal of Allergy and Clinical Immunology (2019)
Abstract A62: In vivo electroporation improves the immune responses induced by a DNA vaccine and confers complete antitumor protection against HPV-associated tumors
Authors: Natiely Silva Sales, Mariana de Oliveira Diniz, Jamile Ramos Silva, Mariângela de Oliveira Silva, Bruna F. M. M. Porchia, Luana R. M. M. Aps, Luis Carlos Souza Ferreira
Journal: Clinical Cancer Research (2018)

Abstract Cervical cancer associated with persistent papilloma virus infections (HPV) is a public health problem and represents the third most frequent type of cancer in women. Our group developed a DNA vaccine against HPV-induced tumors based on the expression of the HPV-16 E7 oncoprotein genetically fused to the HSV-1 glycoprotein D (gD) (pgDE7h). This vaccine is capable of promoting antitumoral effects against tumor cells expressing HPV-16 E6 and E7 proteins (TC-1 cells) and induces specific cellular immune responses. In view of the low success rate of DNA vaccines in clinical trials, in vivo electroporation (EP) is a promising strategy for plasmid delivery, leading to increased cellular transfection and enhanced immune responses. In this study, C57BL/6 mice were inoculated with TC-1 cells subcutaneously and immunized 3 days later with pgDE7h intramuscularly, associated or not with EP. Immune responses were analyzed 14 days after vaccination and tumor growth was monitored for 60 days. Similar antitumor effects were obtained with 10-fold less DNA associated with EP when compared to the group that was inoculated only with DNA, reaching around 20% of tumor-free mice. Dose-response curves indicated that maximum protective immunity was achieved with 50 ug of vaccine inoculated with EP, promoting 100% of antitumor protection. This group also had enhanced frequencies of cytotoxic lymphocytes expressing the degranulation marker CD107a and high in vivo cytotoxic activities. Besides that, a delayed vaccination performed 10 days after the TC-1 injection led to 70% of tumor-free mice until the end of the observed period. Collectively, these data confirmed that EP can be used as an efficient method of DNA vaccine delivery and should be further studied to improve the chances of cancer vaccine success in clinical trials. Citation Format: Natiely Silva Sales, Mariana de Oliveira Diniz, Jamile Ramos Silva, Mariângela de Oliveira Silva, Bruna F. M. M. Porchia, Luana R. M. M. Aps, Luis Carlos Souza Ferreira. In vivo electroporation improves the immune responses induced by a DNA vaccine and confers complete antitumor protection against HPV-associated tumors [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; São Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr A62.
Abstract 24033: Regional Assessment of Pyruvate Metabolism in the Remodeled Heart Using Dynamic Nuclear Polarization Carbon13 Magnetic Resonance
Authors: James J Pilla, Terence Gade, Gabor Mizsei, Norman Butler, Yoshiaki Saito, Akito Imai, Keitaro Okamoto, Christopher L Gade, Gabrielle Pilla, Jerry Zsido, Joseph H Gorman, Robert C Gorman
Journal: Circulation (2017)

Introduction: After infarction compensated remodeling of the left ventricular (LV) may be followed by adverse remodeling leading to heart failure. The mechanism of adverse remodeling maybe linked to the elevated wall stress in the dysfunctional myocardium adjacent to the infarct (border zone BZ). We hypothesize that increased BZ stress results in altered metabolism which could drive the transition from compensated to adverse remodeling. To evaluate BZ and remote metabolism we compared the regional uptake and intracellular conversion of 1-13C-pyruvate using hyperpolarized (HP) 13 C MR. Methods: An established pre-clinical posterolateral infarct model of LV remodeling was used to investigate region metabolism. To accurately measure regional metabolism, we developed implantable carbon-tuned surface coils placed on the epicardium over the BZ and remote regions (Fig. Top). A coronary catheter was placed for direct injection of the HP substrate to maximize deliver and eliminate cavity blood pool signal. MR was performed at 6-weeks post infarct with a spectra acquired every 1.5s for each region simultaneously during HP infusion under physiologic and DOB stress conditions. The resulting spectra from each coil were analyzed to measure lactate, alanine, bicarb, and total flux. Results: Under physiologic (Pre-DOB) conditions the percent difference between remote and BZ lactate, alanine, and total flux was only slightly elevated in the remote region whereas bicarb flux was greater in BZ compared to remote (Fig. Bottom). DOB stress produced an increase in remote metabolite flux compared to BZ with lactate, alanine and total flux reaching significance and bicarb flux shifting from greater in BZ Pre-DOB to greater in remote. Conclusion: These findings demonstrate an impaired metabolic response to pharmacologic stress in BZ myocardium which may provide a mechanism for the established association of mechanical stress and adverse cardiac remodeling following infarct.
Abstract 20925: Transverse Tubular Network Structures in the Genesis of Intracellular Calcium Alternans and Triggered Activity in Cardiac Cells
Authors: Zhen Song, Michael Liu, Zhilin Qu
Journal: Circulation (2017)

Introduction: The major role of a transverse-tubular (TT) network in a cardiac cell is to facilitate effective excitation-contraction coupling and signaling. The TT network structures are heterogeneous within a single cell, and vary between different types of cells and species. They are also remodeled in cardiac diseases. However, how different TT network structures predispose cardiac cells to arrhythmogenesis remains to be revealed. Methods: Based on recent experimental observations, different TT network structures, including uniform and non-uniform random (including patchy, hollow, and sheet-like) TT structures (see Figure), were modeled in a cardiac cell model consisting of a three-dimensional network of Ca 2+ release units (CRUs). We used this model to carry out simulations to systematically investigate the roles of TT network structures and the underlying mechanisms in the genesis of intracellular calcium (Ca 2+ ) alternans and triggered activity (TA). Results: Our simulations showed that both Ca 2+ alternans and Ca 2+ wave-mediated TA were promoted when the fraction of orphaned CRUs was in an intermediate range, but suppressed in cells exhibiting either well-organized TT networks or low TT densities. Ca 2+ alternans and TA could be promoted by low TT densities when the cells were small or the CRU coupling was strong. Both alternans and TA occurred more easily in uniform TT networks than in non-uniform TT networks. Subcellular spatially discordant Ca 2+ alternans was promoted by non-uniform TT networks but suppressed by increasing CRU coupling strength. These mechanistic insights provide a holistic understanding of the effects of TT network structure on the susceptibility to arrhythmogenesis. Conclusions: The TT network plays important roles in promoting Ca 2+ alternans and TA, and different TT network structures may predispose cardiac cells differently to arrhythmogenesis.
Abstract 16500: CSL112 Restores Cholesterol Efflux in Patients Immediately After Acute Myocardial Infarction
Authors: Andreas Gille, Samuel D Wright, Michael Tortorici, Danielle Duffy, Charlie Liss, Megan K Yee, Lawrence I Deckelbaum, Denise M D'Andrea, C M Gibson
Journal: Circulation (2017)

Introduction: CSL112 is human apolipoprotein A-I (apoA-I), currently in development for reduction of cardiovascular (CV) risk in the subacute period after acute myocardial infarction (AMI). Infusio...
Abstract 12862: Predictors of Hospitalization and Effects of Dabigatran and Warfarin on Hospitalization Rates: An Analysis From The Re-ly Trial
Authors: Ali-Reza Merali, Aiman Alak, Stuart J Connolly, Mandy Fraessdorf, Martina Brueckmann, Michael D Ezekowitz, Paul Reilly, Salim Yusuf, Lars Wallentin
Journal: Circulation (2015)

Introduction: Hospitalization is common in patients with atrial fibrillation (AF), and predicts poor prognosis, but is poorly understood. Aim: We evaluated predictors of hospitalization in patients with AF treated with dabigatran etexilate (DE) or warfarin in RE-LY to understand predictors of hospitalization and to further evaluate the effects of anticoagulant choices on hospitalization. Methods: A multivariate regression model was developed to determine predictors of hospitalization. Hospitalization due to bleeding events were identified and rates were compared between DE and warfarin. Results: Of 18,113 patients in RE-LY, 7,200 (39.8%) were hospitalized at least once during mean follow up of 2 years, with 14,025 total hospitalizations. Compared to patients not hospitalized, patients with hospitalizations were older, more often had coronary artery disease, prior MI, a history of heart failure, moderate renal impairment, hypertension, diabetes and higher CHADS 2 scores. Multivariate analysis identified peripheral artery disease (PAD; HR 1.44, 95% CI 1.22-1.69), a CHADS 2 score of ≥ 3 (HR 1.29, CI 1.11-1.51), VKA-naïve (HR 1.28, CI 1.19-1.37), left ventricular ejection fraction (EF) ≤ 40% (HR 1.24, CI 1.12-1.36), and renal impairment with CrCL ≤ 50mL/min (HR 1.12, CI 1.02-1.23) as predictors of hospitalization. First hospitalization rates were 39.5%, 41.6% and 42.6% for DE 110 mg bid, DE 150 mg bid and warfarin, respectively. The treatment effects of both DE doses compared to warfarin were consistent, between patients hospitalized and those not. Hospitalization occurred less often with DE 110 compared to warfarin (RR = 0.93, CI 0.87-0.99) and compared to DE 150 (RR=0.95, CI 0.89-1.01). Hospitalizations for bleeding events occurred less often with DE 110 (3.5%) compared both to warfarin (4.6%) (p=0.02) and to DE 150 (5.2%) (p&lt;0.001); rates were statistically similar between DE 150 and warfarin (p=0.07). Conclusion: Predictors of hospitalization included common comorbidities of an elderly AF population, such as PAD, higher CHADS 2 scores, low EF and renal impairment. DE 110 mg bid was associated with significantly fewer hospitalizations compared to both warfarin and DE 150 bid; in part due to reduction in hospitalizations for bleeding events.
Disparities associated with the receipt of palliative care in patients with metastatic gastric cancer.
Authors: Subhadeep Paul, Caitlin Hester, Sam C. Wang, Patricio Polanco, Adam Charles Yopp, Mathew M Augustine, John C. Mansour, Herbert Zeh, Matthew R. Porembka
Journal: Journal of Clinical Oncology (2019)

28 Background: Metastatic gastric adenocarcinoma (mGA) is frequently associated with debilitating symptoms that negatively impact quality of life. We aim to determine the rate of palliative care (PC) use in mGA and the factors which are associated with receipt of PC. Methods: Using the National Cancer Database, mGA patients were selected. Receipt of PC as defined by the NCDB participant use file was correlated to demographic and clinicopathologic factors. As defined according to NCDB, PC treatment included surgery, radiation, systemic therapy, and pain management to alleviate symptoms. Logistic regression was performed to assess the impact of factors on the likelihood of receiving PC. Overall survival was estimated using the Kaplan-Meier method and compared using log-rank tests. Results: Between 2004 and 2013, 45519 patients with mGA and reported PC status were identified. Median age was 66 years (IQR: 55-76 years) and 64% were male. 7365 (16.2%) patients received PC. PC utilization increased over time (2004-6 13.4%, 2007-10 15.8%, 2011-13 19.1%; p &lt; 0.001). Factors associated with PC on univariate analysis included insurance status, education level, income, sex, race, Charlson/Deyo comorbidity score, and year of diagnosis (all p &lt; 0.001). On multivariate analysis, female sex (0.87, 95%CI: 0.83-0.92) and minority race were associated with less receipt of PC (Hispanic 0.73, 95%CI: 0.66-0.80, Black 0.87, 95%CI: 0.80-0.95, Asian 0.89, 95%CI: 0.77-0.98 compared to non-Hispanic White patients). Higher education level was associated with greater receipt of PC (1.46, 95%CI: 1.31-1.62). Receipt of PC was associated with decreased overall survival (PC 4.8 months vs no PC 6.0 months; p &lt; 0.001). Conclusions: Although use of PC has increased over time, PC is underutilized in mGA. Disparities exist in receipt of PC in regard to race, gender, and education. Additional research is necessary to better optimize PC use in mGA and mitigate potential disparities.