tbuckley/cabot-search huggingface dataset:
Different definitions of atopic dermatitis: impact on prevalence estimates and associated risk factors
Authors: T. Nakamura, S. Haider, S. Colicino, C.S. Murray, J. Holloway, A. Simpson, P. Cullinan, A. Custovic
Journal: British Journal of Dermatology (2019)

There is no objective test that can unequivocally confirm the diagnosis of atopic dermatitis (AD), and no uniform clinical definition. To investigate to what extent operational definitions of AD cause fluctuation in the prevalence estimates and the associated risk factors. We first reviewed the operational definitions of AD used in the literature. We then tested the impact of the choice of the most common definitions of 'cases' and 'controls' on AD prevalence estimates and associated risk factors (including filaggrin mutations) among children aged 5 years in two population‐based birth cohorts: the Manchester Asthma and Allergy Study (MAAS) and Asthma in Ashford. Model performance was measured by the percentage of children within an area of clinical indecision (defined as having a posterior probability of AD between 25% and 60%). We identified 59 different definitions of AD across 45 reviewed studies. Of those, we chose four common 'case' definitions and two definitions of 'controls'. The prevalence estimates using different case definitions ranged between 22% and 33% in MAAS, and between 12% and 22% in Ashford. The area of clinical indecision ranged from 32% to 44% in MAAS and from 9% to 29% in Ashford. Depending on the case definition used, the associations with filaggrin mutations varied, with odds ratios (95% confidence intervals) ranging from 1·8 (1·1–2·9) to 2·2 (1·3–3·7) in MAAS and 1·7 (0·8–3·7) to 2·3 (1·2–4·5) in Ashford. Associations with filaggrin mutations also differed when using the same 'case' definition but different definitions of 'controls'. Use of different definitions of AD results in substantial differences in prevalence estimates, the performance of prediction models and association with risk factors. What's already known about this topic? There is no objective test that can unequivocally confirm the diagnosis of atopic dermatitis (AD) and no uniform clinical definition. This results in different definitions utilized in AD studies, raising concerns on the generalizability of the results and comparability across different studies. What does this study add? This study has shown that different definitions of 'cases' and 'controls' have major impacts upon prevalence estimates and associations with risk factors, including genetics, in two population‐based birth cohorts. These findings suggest the importance of developing a consensus on AD definitions of both 'controls' and 'cases' to minimize biases in studies.
Abstract OT1-12-02: Biomarker study of patients with HER2-negative metastatic breast cancer receiving combination therapy with nivolumab, bevacizumab and paclitaxel as first-line treatment (WJOG9917BTR)
Authors: Y Ozaki, S Kitano, K Matsumoto, M Takahashi, T Mukohara, M Futamura, N Masuda, J Tsurutani, K Yoshimura, H Minami, T Takano
Journal: Cancer Research (2019)

Abstract Background: In recent years, anti-PD-1 antibody, an immune checkpoint inhibitor, has been developed for the treatment of various types of cancer, including breast cancer. Synergistic effects of nivolumab, paclitaxel and bevacizumab are expected, based on various preclinical data, when these drugs are administered in combination. A biomarker study is ongoing to evaluate the immune status of patients participating in the NEWBEAT trial, which is a phase II trial of nivolumab + paclitaxel + bevacizumab therapy as first-line treatment for patients with metastatic or recurrent HER2-negative breast cancer. Methods: HER2-negative breast cancer patients from the WJOG9917B (NEWBEAT) trial are enrolled in this biomarker study. To explore new biomarkers for combined treatment of breast cancer with immune-checkpoint inhibitors and anti-vascular endothelial growth factor antibodies, we propose to conduct multicolor immunohistochemistry (IHC) assays for immunomonitoring of the intra-tumor environment, such as the expressions of PD-L1, CD4 and CD8. Blood samples are collected before the start of treatment and at four time-points during the treatment, to determine, using a multicolor flow cytometry panel, the numbers of circulating immunosuppressive cells, such as regulatory T cells, myeloid-derived suppressor cells and tumor-associated macrophages (M2). In the NEWBEAT trial, patients receive nivolumab 240 mg/body on days 1 and 15, paclitaxel 90 mg/m2 on days 1, 8 and 15, and bevacizumab 10 mg/kg on days 1 and 15 every 4 weeks until disease progression. The primary endpoint is the objective response rate, and the key secondary endpoints include progression-free survival, overall survival, and toxicity of the protocol treatment. A total of 51 patients will be enrolled and the enrollment period will be one year. This trial opened to accrual in February 2018. Clinical trial registry number: UMIN000029590 Citation Format: Ozaki Y, Kitano S, Matsumoto K, Takahashi M, Mukohara T, Futamura M, Masuda N, Tsurutani J, Yoshimura K, Minami H, Takano T. Biomarker study of patients with HER2-negative metastatic breast cancer receiving combination therapy with nivolumab, bevacizumab and paclitaxel as first-line treatment (WJOG9917BTR) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT1-12-02.
DOES PATHOLOGY ANTIBODY-MEDIATED REJECTION LEAD TO INTIMAL THICKENING IN THE FIRST-YEAR AFTER HEART TRANSPLANTATION?
Authors: Takuma Sato, Richard Cheng, Babak Azarbal, Ryan Levine, Sadia Dimbil, Jignesh Patel, Jon Kobashigawa
Journal: Journal of the American College of Cardiology (2019)
Abstract 21146: Late Pregnancy is Associated With a Decrease in Global Circumferential Strain and Tumor Necrosis Factor Receptor 2
Authors: Shayan Moazeni, Soban Umar, Emily Methangkool, Sheshanna Pham, Aman Mahajan, Mansoureh Eghbali
Journal: Circulation (2017)

Background: The hearts of pregnant women and rodents undergo physiological hypertrophy with preserved function. Recently, we have demonstrated that the hearts of late pregnant (LP) rodents are more prone to ischemia reperfusion injury compared to non-pregnant (NP) rodents. Currently, measurements such as ejection fraction (EF) are not sensitive enough to determine subclinical myocardial dysfunction. However, speckle-tracking echocardiography (STE), a novel imaging tool, has been demonstrated to assess myocardial function with greater sensitivity. Tumor Necrosis Factor Receptor 2 (TNFR2), a membrane receptor that has been implicated in cardioprotection and has been demonstrated as marker for subclinical myocardial dysfunction in patients. Thus, we hypothesized that global circumferential strain (GCS) measured by STE can detect subclinical myocardial dysfunction in pregnancy that is associated with a decrease in TNFR2 in rats. Methods: LP (20 days pregnant) and NP female Sprague-Dawley rats were used for the study (n=14). Left ventricular EF (LVEF, %), fractional shortening (FS, %), heart rate (HR, bpm), and GCS (%) were obtained using echocardiography (Visualsonics, Vevo 2100) (n=7/group). GCS was obtained with STE and was measured in triplicates. Total ventricular weight (VW) was recorded and LV was isolated to measure LV hypertrophy (LV/VW) (n=6/group). TNFR2 expression was measured using qPCR. Results: LP rats showed slightly reduced but insignificant LVEF (LP: 67.65+/-1.41% vs. NP: 71.35+/-1.52%, P=0.10) and FS (39.07+/-0.90 % vs. 42.643+/-1.76 %, P=0.09) compared to NP rats. Additionally, no difference in HR between LP and NP rats were found (352.50+/-16.36 bpm vs. 333.75+/-4.78 bpm, respectively, p=0.314).However, hearts from LP rats had evidence of hypertrophy evident by an increase in LV/VW compared to NP (0.57+/-0.03 g vs. 0.48+/-0.02 g). LP rats had a significantly reduced GCS compared to NP rats (-27.50+/-1.40 % vs. -34.375+/-1.95 %, p&lt;0.01) and reduced TNFR2 expression compared to NP. Conclusions: Our results demonstrate that late pregnancy is associated with a decrease in GCS with no significant change in EF and a decrease in TNFR2, which may be a subclinical marker for myocardial dysfunction.
SMALL HEART VOLUME PREDICTS ADVERSE CARDIAC EVENTS IN PATIENTS WITH NONOBSTRUCTIVE CORONARY ARTERY DISEASE: INSIGHTS FROM THE PROSPECTIVE MULTICENTER IMAGING STUDY FOR EVALUATION OF CHEST PAIN (PROMISE) TRIAL
Authors: Borek Foldyna, Parastou Eslami, Jan-Erik Scholtz, Thomas Mayrhofer, Maros Ferencik, Bálint Szilveszter, Julia Karady, Daniel Bittner, Nandini Meyersohn, Stefan Puchner, Hamed Emami, Pál Maurovich-Horvat, Pamela Douglas, Michael Lu, Udo Hoffmann
Journal: Journal of the American College of Cardiology (2019)
IN-HOSPITAL MANAGEMENT AND OUTCOMES IN PATIENTS WITH MARFAN SYNDROME ADMITTED WITH AORTIC DISSECTION: RESULTS FROM THE NATIONAL INPATIENT SAMPLE (NIS) DATABASE
Authors: Matthew Lippmann, Siva Sagar Taduru, Trip Zorn, Gregory Muehlebach, Emmanuel Daon, Travis Abicht, Jeffrey Kramer, Kamal Gupta
Journal: Journal of the American College of Cardiology (2019)
PULMONARY CONGESTION ASSESSED BY LUNG ULTRASOUND PREDICTS IN-HOSPITAL MORTALITY IN ACUTE HEART FAILURE
Authors: Diego Araiza Garaygordobil, Rodrigo Gopar-Nieto, Gabriela Alanis-Estrada, Juan Carlos De La Fuente Mancera, Jesús Martínez-Gutiérrez, Mario Javier Luna Carrera, Martinez-Amezcua Pablo, Cabello Lopez Alejandro, Grecia Iveth Maryelis Raymundo Martinez, Alexandra Arias-Mendoza, Jose Luis Briseño De La Cruz, Francisco Azar Manzur, Carlos Sierra, Hector Gonzalez-Pacheco, Carlos Martinez-Sanchez, Marco Antonio Martinez Rios
Journal: Journal of the American College of Cardiology (2019)
Abstract 234: Nrf2-Dependent Transcriptional and Post-Transcriptional Regulatory Responses in Reductive Stress Myocardium
Authors: Justin M Quiles, Mark E Pepin, Senthilkumar Cinghu, Anil Kumar Challa, Adam R Wende, David Crossman, Rajasekaran Namakkal-Soorappan
Journal: Circulation Research (2018)

Background: Transient activation of nuclear factor, erythroid 2 like 2 (Nfe2l2/Nrf2), a master regulator of antioxidant transcription, protects from oxidative insult. However, sustained Nrf2 signaling causes proteotoxic reductive stress (RS). Using Nrf2 - / - mice, we recently uncovered several cardiac microRNAs (miRNAs) potentially expressed in an Nrf2-dependent manner. Here, we utilized cardiac-specific constitutively active Nrf2 transgenic (caNrf2-Tg) mice to elucidate necessary and sufficient miRNAs, and hypothesized that miRNA dysregulation underlies RS. Methods: Next-generation RNA sequencing (RNAseq) was used to compare mRNA and miRNA transcriptomes of 6-month low (TgL) and high (TgH) transgene-expressing caNrf2-Tg mice to non-transgenic (NTg) controls (n=3-4/group). Differentially expressed genes (DEGs) were run through Ingenuity Pathway Analysis (IPA). Real-time qPCR validated RNAseq results (n=4-6/group). In silico target prediction correlated miRNA changes with corresponding mRNA levels. Results: Principal component and hierarchal clustering analyses revealed distinct TgL and TgH transcriptomes. Relative to NTg, TgL mice exhibited 246 DEGs, 214 of which were consistent in TgH hearts. Strikingly, TgH mice displayed 1031 DEGs. As expected, IPA of DEGs indicated enhanced free radical scavenging; however, caNrf2 expression also dose-dependently enriched hypertrophic signaling, protein ubiquitination and the unfolded protein response. While 16 miRNAs were significantly altered in TgL hearts, a total of 101 miRNAs were detected TgH mice, several of which were predicted to account for mRNA changes in RS pathways. Notably, miR-671-3p and miR-455-5p, two miRNAs decreased in Nrf2 - / - mice, were reciprocally increased in caNrf2-Tg mice suggesting that Nrf2 is necessary and sufficient for their function in the heart. Conclusion: While RS underlies human mutant protein aggregation cardiomyopathy, molecular determinants of pathogenesis downstream of Nrf2 remain unknown. Here, we identified key transcriptional responses and pathways associated with RS. These results link post-transcriptional regulation with redox imbalances in the heart, and highlight novel miRNAs for future mechanistic studies.
LONG-TERM OUTCOMES AND COMPLICATIONS OF ANTICOAGULANT THERAPY FOR BIOPROSTHETIC VALVE THROMBOSIS IN A LARGE MATCHED-COHORT STUDY
Authors: Ioana Petrescu, Filip Ionescu, Vuyisile Nkomo, Heidi Connolly, Patricia Pellikka, Cristina Pislaru, Alexander Egbe, Sorin Pislaru
Journal: Journal of the American College of Cardiology (2019)
INCIDENCE, TIMING, AND PREDICTORS OF PERMANENT PACEMAKER PLACEMENT FOLLOWING ALCOHOL SEPTAL ABLATION FOR HYPERTROPHIC CARDIOMYOPATHY
Authors: Matthew Lam, Dhaval Kolte, Kevin Kennedy, Srihari Naidu, Dmitriy Feldman, Antony Chu, Herbert Aronow
Journal: Journal of the American College of Cardiology (2019)
Abstract 11598: Coronary Flow Reserve in Patients With Prior Spontaneous Coronary Artery Dissection and Recurrent Angina
Authors: Tara Sedlak, Andrew Starovoytov, Karin H Humphries, Jacqueline Saw
Journal: Circulation (2017)

Background: Spontaneous coronary artery dissection (SCAD) is an important cause of myocardial infarction (MI) in young women. A significant proportion of SCAD patients have ongoing chronic chest pain despite healing of their dissection, the etiology of which is poorly understood. We sought to determine whether coronary microvascular dysfunction (CMD) contributes to post-SCAD chronic chest pain by performing coronary reactivity testing (CRT). Methods: Vancouver General Hospital is a quaternary referral center for SCAD patients and we prospectively follow over 350 SCAD patients. Patients with persistent chronic chest pain at least 3 months post-SCAD were eligible for our study. Eleven patients consented to having coronary angiography with CMD assessment. CRT was performed with the PressureWire wire (St Jude Medical) using thermodilution technique. Fractional flow reserve (FFR), coronary flow reserve (CFR), and index of microcirculatory resistance (IMR) were measured in two coronary arteries: a previously af...
PREDICTORS OF RECURRENT IN-STENT RESTENOSIS AFTER PACLITAXEL-COATED BALLOON ANGIOPLASTY IN PATIENTS WITH RENAL FAILURE RECEIVING HEMODIALYSIS
Authors: Atsushi Sakata, Kazushige Kadota, Yasushi Fuku, Hiroyuki Tanaka, Seiji Habara, Hidewo Amano, Shunsuke Kubo, Masanobu Ohya, Takenobu Shimada, Akimune Kuwayama, Kohei Osakada, Makoto Takamatsu, Koya Okabe
Journal: Journal of the American College of Cardiology (2019)
Elotuzumab Plus Pomalidomide and Dexamethasone for Relapsed/Refractory Multiple Myeloma: Initial Data from a Phase 2, Non-Comparative Study
Authors: Sundar Jagannath, Jesus G. Berdeja, Robert M Rifkin, Craig E. Cole, Michael Alan Thompson, Ravi Vij, Mihaela Popa-McKiver, Rao Saleem, Oumar Sy, William Bensinger
Journal: Blood (2018)
P038 In vivo demonstration of tmTNF reverse signaling: significance in the therapeutic response to anti-TNF agents during murine arthritis
Authors: B Rauwel, N simons, K Diallo, M Baron, Y Degboe, A kruglov, S Nedospasov, A Constantin, A Cantagrel, J-L Davignon
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Career situation of first and presenting author</h3> Post-doctoral fellow. <h3>Introduction</h3> Anti-TNF agents are widely used in rheumatoid arthritis (RA). Their effect on inflammation results from the neutralization of soluble TNF (sTNF), but also supposedly from the induction of reverse signaling through their binding to membrane TNF (tmTNF). Despite possible clinical relevance, reverse signaling has been described only <i>in vitro</i> but has not been proven <i>in vivo</i>. <h3>Objectives</h3> In this study we aim to demonstrate for the first time the existence of tmTNF reverse signaling <i>in vivo</i> and its importance in anti-TNF response during arthritis. <h3>Methods</h3> Triple transgenic mouse model (3TG), KO for TNFR1/TNFR2 and KI for tmTNF, thus secreting no sTNF was developed. To analyze reverse signaling, mice were injected either with etanercept (ETA, 10 mg/kg), an anti-mouse TNF antibody (MP6-XT22, rat IgG1, 10 mg/kg) or an anti-human IL17 antibody (secukinumab, SEC, 10 mg/kg) as a control. Daily clinical evaluation of K/BxN serum induced-arthritis was performed in 3TG as well as WT mice. Polarization of bone marrow-derived macrophages (BMDM) and cytokine production from non-arthritic WT and 3TG mice under the action of anti-TNF<i> in vitro</i> was evaluated by RT-qPCR, CBA and ELISA. <h3>Results</h3> <i>In vivo</i>, the administration of anti-TNF (ETA or MP6-XT22) decreased arthritic scores in WT mice (p=0.005) as well as in 3TG mice (p&lt;0.001), unlike SEC which had no effect, proving that anti-TNF binding of tmTNF decreased arthritis. <i>In vitro</i> effect of anti-TNF on BMDM from WT as well as 3TG mice induced a decrease in the expression of genes specific of inflammatory macrophages (CD38, GpR18 and FpR2), and an increase in the expression of genes specific of alternative macrophages (Arg1, EgR2, c-Myc). We also observed an inhibition of the secretion of pro-inflammatory cytokines (IL12p70 and IL-6) and an early peak of IL-10 secretion demonstrating an effect of reverse signaling on macrophage polarization and activation. This suggested a switch in macrophage polarization as a probable mechanism for modulation of inflammation during K/BxN serum-induced arthritis. <h3>Conclusions</h3> Our work provides <i>in vivo</i> evidence for the involvement of reverse signaling in the anti-TNF-mediated modulation of arthritis. Reverse signaling is expected to result in the modulation of macrophage polarization from an inflammatory to an alternative functional phenotype in arthritic mice. Our data prompt us to consider new interpretation of the effects of anti-TNF in the treatment of RA. <h3>Disclosure of Interest</h3> None declared.
Abstract 366: The Role of Mitochondrial Calcium Uniporter Complex in Cardiac Contractility and Function
Authors: Dhanendra Tomar, Santhanam Shanmughapriya, Rajika Roy, Xueqian Zhang, Jianliang Song, Sarah M Schumacher, Muniswamy Madesh, Joseph Y Cheung, Walter J Koch, Sudarsan Rajan
Journal: Circulation Research (2018)

Cardiac contractility is regulated by the intracellular Ca 2+ concentration fluxes which are maintained by multiple channels and transporters. Mitochondrial Calcium Uniporter (MCU) is the highly selective Ca 2+ ion channel responsible for the electrophoretic Ca 2+ uptake into the mitochondrial matrix. Earlier studies on the cardiac-specific acute MCU knockout and transgenic dominant-negative MCU mice have demonstrated that mitochondrial Ca 2+ ( m Ca 2+ ) signaling is necessary for cardiac ‘‘fight-or-flight’’ contractile response, however, the role of m Ca 2+ in the beat-to-beat regulation of cardiac contractility is highly debated. The MCU channel function is regulated by varied molecular regulatory components as well as ROS mediated modification at the Cys-96 residue of the core MCU protein. Our earlier studies have demonstrated that loss of MCU Regulator 1 (MCUR1) in cardiomyocytes results in the impaired m Ca 2+ uptake. To dissect the precise role of MCU in regulating cytosolic Ca 2+ transients associated with excitation-contraction (E-C) coupling and cardiac functions, we have employed the loss-of-function, cardiac-specific MCUR1 knockout mouse and a gain-of-function MCU C96A knockin mouse generated by CRISPR/Cas9 approach. Using these novel mouse models, both by in vivo analyses of cardiac physiology and in vitro experiments including single-cell cardiac contractility, calcium transients, and electrophysiology measurements, our study demonstrates that m Ca 2+ buffering actively participates in E-C coupling. MCUR1/MCU regulated m Ca 2+ buffering in cardiomyocytes, although insignificant under basal condition, becomes critical in stress-induced conditions and actively participates in regulating the c Ca 2+ transients during adrenergic stimulation. Our data indicate that MCUR1 ablation offers protection against pressure-overload cardiac hypertrophy and MCU C96A KI mice exhibit significantly decreased LV ejection fraction at baseline. In summary, our results provide critical insights into the mechanisms by which the MCU channel contributes in regulating the contractile function of the cardiomyocytes and the role of m Ca 2+ in the development and progression of heart failure.
IN-HOSPITAL OUTCOMES OF PERCUTANEOUS VENTRICULAR ASSIST DEVICE (PVAD) VERUS INTRAAORTIC BALLOON PUMP SUPPORT (IABP) IN INFARCTION-RELATED CARDIOGENIC SHOCK COMPLICATED BY ATRIAL FIBRILLATION: A PROPENSITY-MATCHED ANALYSIS OF THE NATIONAL INPATIENT SAMPLE (NIS)
Authors: Rupak Desai, Sonu Gupta, Abhishek Deshmukh, Saraschandra Vallabhajosyula, Bhrugesh Shah, Gautam Kumar, Adam Berman, Rajesh Sachdeva
Journal: Journal of the American College of Cardiology (2019)
IMPACT OF LESS INVASIVE VENTRICULAR ENHANCEMENT TM (LIVE TM) COMPARED TO OPTIMAL MEDICAL THERAPY ON CARDIAC OUTPUT IN PATIENTS WITH HFREF – PRELIMINARY RESULTS OF A 12-MONTH MULTI-CENTER CMR TRIAL
Authors: Felix Hennig, Lukas Stoiber, Tomas Lapinskas, Seyedeh Mahsa Zamani, Christoph Klein, Christoph Schmitz, Christoph Knosalla, Lon Annest, David Schickling, Volkmar Falk, Burkert Pieske, Sebastian Kelle
Journal: Journal of the American College of Cardiology (2019)
Tumor-stromal crosstalk in pancreatic cancer and tissue fibrosis
Authors: Divya Thomas, Prakash Radhakrishnan
Journal: Molecular Cancer (2019)

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with high morbidity and mortality worldwide. To date, limited therapeutic achievements targeting cell proliferation and related mechanisms has led researchers to focus on the microenvironment where pancreatic cancers develop. The anomalous proliferation of stromal cells, such as pancreatic stellate cells, and an increased deposition of altered matrix proteins create an environment that facilitates tumor growth, metastasis and drug resistance. Here, we summarize our understanding of recent advances in research about the role of fibrosis in pancreatic cancer progression, with particular emphasize on the involvement of fibrotic machineries such as wound healing, extra cellular matrix degradation, and epithelial-to-mesenchymal transition. The precise influence of these mechanisms on the biological behaviors and growth of cancer cells has great impact on clinical therapy and therefore deserves more attention. We also discuss the role of various stromal components in conferring drug resistance to PDAC which further worsening the pessimistic disease prognosis. A more in depth understanding of cancer-stroma crosstalk within the tumor microenvironment and stroma based clinical and translational therapies may provide new therapeutic strategies for the prevention of pancreatic cancer progression.