tbuckley/cabot-search huggingface dataset:
Abstract 338: Cardioprotective Action of the Exosome Secreted From TGFbRI Inhibitor-primed Nkx2.5+ Cardiomyoblasts
Authors: Wen-Pin Chen, Wei-Feng Hsiao
Journal: Circulation Research (2017)

Using transgenic cardiac Nkx2.5 enhancer-eGFP mice to label Nkx2.5+ cardiomyoblasts, an embryonic Nkx2.5+ cell population representing the common precursor for cardiovascular lineages was identified in the developing heart and a residual small population was also found in the postnatal heart. Our previous study found that A83-01, an inhibitor of TGFb receptor type I (TGFbRI), could improve cardiac function in post-injured adult heart through inducing the proliferation of Nkx2.5+ cardiomyoblasts and enhancing paracrine benefit in the enhancement of myocardial survival. The aim of the present study is to examine whether the exosome secreted from A83-01-primed Nkx2.5+ cell (exo(Nkx-A83)) could increase cardiomyocyte survival and to investigate the cardioprotective mechanism of the exosomal molecules. Adult mice cardiomyocytes were isolated and cultured in IMDM medium in vitro . A83-01 alone did not directly affect myocyte viability. The myocyte viability was 33.3±2.0 % on day 5, and could be prominently increased to be 63.8 ±0.9% when co-cultured with Nkx2.5+ cell in the presence of A83-01. The effect was abolished by GW4869 to block exosome secretion. Moreover, treating cardiomyocyte with the purified exo(Nkx-A83) could markedly increase cell viability in vitro . The miRNA microarray and qPCR validation were performed to identify the different miRNAs in the exosome secreted from Nkx2.5+ cell treated with or without A83-01. It was found the marked increase of miR-30c, miR-489, miR-92b, and miR-98 in exo(Nkx-A83). Functional study demonstrated miRNA mimics of miR-30c and miR-92b could significantly enhance myocyte survival in vitro . Furthermore, administration of the purified exo(Nkx-A83) via intravenous injection in isoprenaline-induced heart injured mice could significantly improve cardiac function monitored by echocardiography. In conclusion, the findings revealed miR-30c and miR-92b in exo(Nkx-A83) could contribute to its cardioprotective action for the enhancement of myocardial survival.
Abstract 12948: Low Use of Statins in People With Type 2 Diabetes With or Without Cardiovascular Disease: A Capture Post Hoc Analysis
Authors: Jose Luis Arenas, Fahri Byram, Patrice Darmon, Timothy Davis, Guillermo Dieuzeide, Tianpei Hong, Margit S Kaltoft, Csaba Lengyel, ofri Mosenzon, Nicolai A Rhee, Giuseppina T Russo, Shinichiro Shirabe, Usha K Thamattoor, Katerina Urbancova, Sergio Vencio, Abdullah Alguwaihes
Journal: Circulation (2020)

Background and aim: The association between LDL levels, CVD and the benefits of statin use are well established. The CAPTURE study estimated the contemporary (2019) global prevalence of CVD and medication use in adults with type 2 diabetes across 13 countries. This post hoc analysis assessed serum lipid status and statin use in people with type 2 diabetes without CVD (NoCVD), with established CVD, and atherosclerotic CVD (AsCVD, a subgroup of CVD). Methods: CAPTURE was a multinational, cross-sectional and non-interventional study. Participant information on CVD status, serum lipid profiles, and medication use were ascertained during single routine clinical visit in primary or specialist setting. This analysis included people who had data on serum LDL-C and lipid-lowering therapies. LDL-C targets were set at &lt;100 mg/dL (&lt;2.6 mmol/L) and &lt;70 mg/dL (&lt;1.8 mmol/L) for people without and with CVD/AsCVD, respectively according to the ADA 2019 guidelines. Data were analyzed descriptively. Results: The CAPTURE study enrolled 9823 people aimed to be representative of the general type 2 diabetes population. Most (&gt;80%) had blood LDL-C information. Mean serum levels of lipids varied across 3 groups. (Table) The overall use of any statin was 38% in the NoCVD, 53% in CVD, and 55% in AsCVD groups. In those with documented serum LDL-C levels, 48% in the NoCVD, 67% in CVD, and 66% in AsCVD groups were above LDL-C targets with statin use of 34%, 57%, and 60%, respectively in these participants. Overall, the use of ezetimibe was 3-8% in all the groups and usually in combination with a statin. PCSK9 inhibitors use was &lt;0.1% and used only in participants with CVD. (Table) Conclusion: In conclusion, this CAPTURE post hoc analysis found that two-thirds of people with CVD and AsCVD had LDL-C levels above recommendations and only around 60% of them were on statins. Intolerability of statins might partly explain this lower than expected statin use.
The clinical and functional effects of <i>TERT</i> variants in myelodysplastic syndrome
Authors: Christopher R. Reilly, Mikko Myllymäki, Robert Redd, Shilpa Padmanaban, Druha Karunakaran, Valerie Tesmer, Frederick D. Tsai, Christopher J. Gibson, Huma Q. Rana, Liang Zhong, Wael Saber, Stephen R. Spellman, Zhen-Huan Hu, Esther H. Orr, Maxine M. Chen, Immaculata De Vivo, Daniel J. DeAngelo, Corey Cutler, Joseph H. Antin, Donna Neuberg, Judy E. Garber, Jayakrishnan Nandakumar, Suneet Agarwal, R. Coleman Lindsley
Journal: Blood (2021)
Inactivation of Pten cooperating with p53 loss induces malignant gliomas
Authors: Hongwu Zheng, Haoqiang Ying, Alec Kimmelman, Haiyan Yang, An-Jou Chen, Samuel Perry, Gerry Chu, Jeff Ding, Keith Ligon, Ruprecht Wiedemeyer, Yaoqi Wang, Lynda Chin, Ronald DePinho
Journal: Cancer Research (2008)

320  Malignant gliomas, due to their rapid growth and tendency to spread throughout the brain and spinal cord, remains one of the greatest clinical challenges and is considered to be among the deadliest human cancers. Like other malignancies, human gliomas have been associated with many molecular genetic abnormalities. Among them, alterations in the p53 and PI3K pathways have been found in virtually all high-grade gliomas. In this study, we have generated a malignant glioma mouse model with high penetrance that harbors both a conditional allele of p53 and a conditional allele of the Pten tumor suppressor gene that negatively regulates PI3K signaling. These tumors are highly aggressive, bearing striking resemblance clinically and pathologically to their human counterparts; namely uncontrolled cellular proliferation,diffuse infiltration, propensity for necrosis. We find that the earliest evidence of tumor formation localizes to different regions of the brain that contain progenitor populations. Additionally, the presence of extensive inter- and intra-tumoral histological heterogeneity suggests these tumors may originate from different progenitor linages. Furthermore, our in vivo and in vitro results indicate while Pten deletion promotes neural stem/progenitor cell early expansion, subsequent inactivation of p53 is required to maintain their progenitor activity and shift the homeostatic balance towards proliferation of this niche. Consistent with these findings, we find p53 is directed mutated in 40% our thirty-five analyzed human primary gliobastoma samples. Strikingly, Pten is concurrently mutated and/or deleted in 70% of these samples Together, this faithful mouse model may permit the systematic analysis of genetic lesions implicated in the human disease and serve as a platform for the identification of early disease markers and for the efficient testing of novel therapies.
Single-chain variable fragment antibody constructs neutralize measles virus infection in vitro and in vivo
Authors: Cyrille Mathieu, Marion Ferren, Olivia Harder, Francesca T. Bovier, Tara C. Marcink, Camilla Predella, Fabrizio Angius, Jennifer Drew-Bear, N. Valerio Dorrello, Alex L. Greninger, Anne Moscona, Stefan Niewiesk, Branka Horvat, Matteo Porotto
Journal: Cellular and Molecular Immunology (2021)
無症候性HTLV-1キャリアにおけるヒトT細胞白血病ウイルス1型(HTLV-1)プロウイルス負荷と疾患の進行: 日本全国前向き試験
Authors: Iwanaga Masako, Watanabe Toshiki, Utsunomiya Atae, Okayama Akihiko, Uchimaru Kaoru, Koh Ki-ryang, Ogata Masao, Kikuchi Hiroshi, Sagara Yasuko, Uozuml Kimiharu, Mochizuki Manabu, Tsukasaki Kunihiro, Saburi Yoshio, Yamamura Masaomi, Tanaka Junji, Morluchi Yukiyoshi, Hino Shigeo, Kamihira Shimeru, Yamaguchi Kazunari
Journal: Blood (2010)
Optimizing Nanopore sequencing-based detection of structural variants enables individualized circulating tumor DNA-based disease monitoring in cancer patients
Authors: Jose Espejo Valle-Inclan, Christina Stangl, Anouk C. de Jong, Lisanne F. van Dessel, Markus J. van Roosmalen, Jean C. A. Helmijr, Ivo Renkens, Roel Janssen, Sam de Blank, Chris J. de Witte, John W. M. Martens, Maurice P. H. M. Jansen, Martijn P. Lolkema, Wigard P. Kloosterman
Journal: Genome Medicine (2021)

Abstract Here, we describe a novel approach for rapid discovery of a set of tumor-specific genomic structural variants (SVs), based on a combination of low coverage cancer genome sequencing using Oxford Nanopore with an SV calling and filtering pipeline. We applied the method to tumor samples of high-grade ovarian and prostate cancer patients and validated on average ten somatic SVs per patient with breakpoint-spanning PCR mini-amplicons. These SVs could be quantified in ctDNA samples of patients with metastatic prostate cancer using a digital PCR assay. The results suggest that SV dynamics correlate with and may improve existing treatment-response biomarkers such as PSA. https://github.com/UMCUGenetics/SHARC .
入院高齢者における有害転帰の予測因子としての虚弱:系統的レビューとメタ分析【JST・京大機械翻訳】
Authors: Cunha Ana Izabel Lopes, Veronese Nicola, de Melo Borges Sheila, Ricci Natalia Aquaroni
Journal: Ageing Research Reviews (2019)
Local administration of liposomal-based Srpx2 gene therapy reverses pulmonary fibrosis by blockading fibroblast-to-myofibroblast transition
Authors: Qi Wang, Juan Liu, Yinan Hu, Ting Pan, Yongjian Xu, Jun Yu, Weining Xiong, Qing Zhou, Yi Wang
Journal: Theranostics (2021)

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive fatal interstitial lung disease characterized by abnormal transition and proliferation of fibroblasts. The uncontrolled transition of fibroblasts, commonly known as myofibroblasts, are the principal source of the enormous extracellular matrix (ECM) depositing in lung parenchyma, leading to gradual failure of gas exchange and mortality of the patients. However, up to now, rare effective therapeutic strategies have been developed to blockade fibroblast-to-myofibroblast transition (FMT) in IPF. Method: We illustrated that the lungs originated from IPF patients and mice with pulmonary fibrosis are characterized by the overexpression of sushi-repeat-containing protein, X-linked 2 (SRPX2). Further functionality studies identified the pivotal role of SRPX2 in FMT. Mechanistically, SRPX2 was involved in a TGFβR1/SMAD3/SRPX2/AP1/SMAD7 positive feedback loop. Specifically, SRPX2 was upregulated by TGF-β1 in a TGFβR1/SMAD3-dependent manner, after which SRPX2 in turn repressed the expression of AP1, subsequently minimized SMAD7 expression, through which it reduced the formation of inhibitory complex with TGFβR1 and enhanced SMAD signaling pathway to promote FMT and exacerbate pulmonary fibrosis. Notably, intratracheal administration of siRNA-loaded liposomes could effectively suppress the expression of Srpx2 in the lung and remarkably protect mice against BLM-induced pulmonary fibrosis, concomitant with a significant reduction of FMT. Results: Accordingly, these data indicate that Srpx2 plays an essential role in the pathogenesis of pulmonary fibrosis and suggests the strategy aiming at silencing Srpx2 could be a promising therapeutic approach against pulmonary fibrosis in clinical settings.
The 2020-2021 Residency Application Cycle
Authors: Maya M. Hammoud, Taylor C. Standiford, J. Bryan Carmody
Journal: JAMA (2021)

This Viewpoint summarizes lessons learned in the 2020-2021 US medical residency application cycle, when the COVID-19 pandemic forced a shorter season and virtual interviews, and discusses opportunities for improvement related to systems equity, efficiency, and more.
Abstract 15189: Impact of Revascularization Strategy on the Prognosis of Young and Middle-aged Patients With Coronary Artery Disease
Authors: Xiaoyan Liu, Chengyue Jin, Xinyu Liu, Yong Wang, Hong Qiu
Journal: Circulation (2020)

Introduction: Despite increasing incidence and mortality of CAD among young and mid-age patients (age ≤ 65), the optimum revascularization strategy remains unclear. We compared outcomes of PCI and CABG in this patient group. Methods: “Coronary artery bypass” and “percutaneous coronary intervention” were used to identify articles in PubMed and Cochrane database published prior to February 2, 2020. Both RCTs and observational studies (OSs) comparing PCI and CABG with data of patients or subgroups patients ≤ 65 years of age were included. The quality of study data was assessed by RoB2 and Newcastle-Ottawa Scale (NOS). The primary end point was all-cause mortality. Secondary endpoint includes MI, stroke, repeat revascularization (RR), and a composite endpoint of major adverse cardiac cerebral events (MACCE). We calculated odds ratio using Mantel-Haenszel method with random effects. Results: A total of 10 RCTs and 20 OSs with 31226 CAD patients were included in our analysis, of which 1 RCT and 4 OSs focused on population ≤ 65 years old while the rest provided subgroup data. The risk of bias RCTs were low to middle, and quality ratings of OSs were 4-8 by NOS. Compared to CABG, PCI was associated with a higher risk of mortality (OR 1.42, 95% CI 1.24-1.62, P&lt;0.001), MACCE (OR 1.99, P&lt;0.001), MI (OR 2.13, P = 0.011), and RR (OR 3.88, P&lt;0.001). The risk of stroke is similar in both groups (OR 0.883, P= 0.506). However, after stratification, mortality rate is similar in studies with follow-up period ≤ 3 years. (OR 1.27, P=0.255) but remain significant with longer follow-up (OR 1.41, P&lt;0.001). Conclusions: Compared to PCI, CABG is associated with lower all-cause mortality in young and middle-aged CAD patients, especially with long follow-up indicating superior long-term survival. Given the longer life-expectancy in this age group, the advantage of CABG is even more prominent. However, given the retrospective nature of this study, dedicated RCT is needed to further address this question.
PKM2-dependent metabolic skewing of hepatic Th17 cells regulates pathogenesis of non-alcoholic fatty liver disease
Authors: Maria E. Moreno-Fernandez, Daniel A. Giles, Jarren R. Oates, Calvin C. Chan, Michelle S.M.A. Damen, Jessica R. Doll, Traci E. Stankiewicz, Xiaoting Chen, Kashish Chetal, Rebekah Karns, Matthew T. Weirauch, Lindsey Romick-Rosendale, Stavra A. Xanthakos, Rachel Sheridan, Sara Szabo, Amy S. Shah, Michael A. Helmrath, Thomas H. Inge, Hitesh Deshmukh, Nathan Salomonis, Senad Divanovic
Journal: Cell Metabolism (2021)
Transparency, Accessibility, and Variability of US Hospital Price Data
Authors: Waqas Haque, Muzzammil Ahmadzada, Hassan Allahrakha, Eman Haque, David Hsiehchen
Journal: JAMA Network Open (2021)

This cross-sectional study evaluates the compliance of hospitals with a Centers for Medicare & Medicaid Services ruling mandating that hospital chargemasters be publicly available in a machine-readable file.
Abstract 003: Neighborhood Characteristics And Arterial Stiffness Among Black Adults - Results From The Jackson Heart Study &amp; Morehouse Emory Center For Health Equity
Authors: Shabatun Islam, Jeong Hwan Kim, Xiaona Li, Yi-An Ko, Peter Baltrus, Gary F Mitchell, Ervin R Fox, Mahasin S Mujahid, Viola Vaccarino, Tene T Lewis, Herman A Taylor, Mario Sims, Arshed A Quyyumi
Journal: Circulation (2021)

Introduction: Poor quality neighborhoods are independent risk factors for cardiovascular disease (CVD) but are understudied in Blacks, who face large CVD health disparities. Arterial stiffness (AS) precedes development of hypertension and adverse CVD events but the effect of neighborhood on AS among Blacks remain unknown. Objective: We compared the association between neighborhood environment and AS among Blacks in Jackson, MS and Atlanta, GA. Methods: We studied 1592 Blacks (age 58 ± 10, 38% male) living in Jackson, MS from the Jackson Heart Study (JHS) and 451 Blacks (age 53 ± 10, 39% male) living in Atlanta, GA from the Morehouse/Emory Center for Health Equity (MECA) study, without known CVD. Neighborhood problems (includes measures of aesthetic quality, walking environment, food access), social cohesion (includes activity with neighbors), and violence/safety were assessed using validated questionnaires. AS was measured as pulse wave velocity (PWV) using MRI in JHS and as PWV and augmentation index (AIx) using applanation tonometry (Sphygmocor Inc) in MECA. Multivariable linear regression models were used to examine the association between neighborhood characteristics and AS, adjusting for potential confounders. Results: Improved social characteristics, measured as social cohesion in JHS (β = -0.32 [-0.63, - 0.02], p=0.04) and activity with neighbors (β = -0.23 [-0.40, - 0.05] p=0.01) in MECA, were associated with lower PWV in both cohorts and lower AIx (β = -1.74 [-2.92, - 0.56], p=0.004) in MECA, after adjustment for CVD risk factors and income. Additionally, in MECA better food access (β = -1.18 [-2.35, - 0.01], p=0.05) was associated with lower AIx, and in JHS, lower neighborhood problems (β = -0.33 [-0.64, - 0.02], p=0.04) and lower violence (β = -0.30 [-0.61, 0.002], p=0.05) were associated with lower PWV (Fig). Conclusion: Neighborhood social characteristics show an independent association with vascular health of Blacks, findings that were reproducible in two distinct American cities.
Upregulation of VCAM-1 in lymphatic collectors supports dendritic cell entry and rapid migration to lymph nodes in inflammation
Authors: Jorge Arasa, Victor Collado-Diaz, Ioannis Kritikos, Jessica Danielly Medina-Sanchez, Mona Carina Friess, Elena Caroline Sigmund, Philipp Schineis, Morgan Campbell Hunter, Carlotta Tacconi, Neil Paterson, Takashi Nagasawa, Friedemann Kiefer, Taija Makinen, Michael Detmar, Markus Moser, Tim Lämmermann, Cornelia Halin
Journal: The Journal of Experimental Medicine (2021)

Dendritic cell (DC) migration to draining lymph nodes (dLNs) is a slow process that is believed to begin with DCs approaching and entering into afferent lymphatic capillaries. From capillaries, DCs slowly crawl into lymphatic collectors, where lymph flow induced by collector contraction supports DC detachment and thereafter rapid, passive transport to dLNs. Performing a transcriptomics analysis of dermal endothelial cells, we found that inflammation induces the degradation of the basement membrane (BM) surrounding lymphatic collectors and preferential up-regulation of the DC trafficking molecule VCAM-1 in collectors. In crawl-in experiments performed in ear skin explants, DCs entered collectors in a CCR7- and β1 integrin–dependent manner. In vivo, loss of β1-integrins in DCs or of VCAM-1 in lymphatic collectors had the greatest impact on DC migration to dLNs at early time points when migration kinetics favor the accumulation of rapidly migrating collector DCs rather than slower capillary DCs. Taken together, our findings identify collector entry as a critical mechanism enabling rapid DC migration to dLNs in inflammation.
An exhausted phenotype of T<sub>H</sub>2 cells is primed by allergen exposure, but not reinforced by allergen‐specific immunotherapy
Authors: Shu‐Hung Wang, Ulrich M. Zissler, Maren Buettner, Sonja Heine, Alexander Heldner, Sebastian Kotz, Lisa Pechtold, Josephine Kau, Mirjam Plaschke, Julia T. Ullmann, Ferdinand Guerth, Madlen Oelsner, Francesca Alessandrini, Simon Blank, Adam M. Chaker, Carsten B. Schmidt‐Weber, Constanze A. Jakwerth
Journal: Allergy (2021)

Studies show that proallergic TH 2 cells decrease after successful allergen-specific immunotherapy (AIT). It is likely that iatrogenic administration of allergens drives these cells to exhaustion due to chronic T-cell receptor stimulation. This study aimed to investigate the exhaustion of T cells in connection with allergen exposure during AIT in mice and two independent patient cohorts.OVA-sensitized C57BL/6J mice were challenged and treated with OVA, and the development of exhaustion in local and systemic TH 2 cells was analyzed. In patients, the expression of exhaustion-associated surface markers on TH 2 cells was evaluated using flow cytometry in a cross-sectional grass pollen allergy cohort with and without AIT. The treatment effect was further studied in PBMC collected from a prospective long-term AIT cohort.The exhaustion-associated surface markers CTLA-4 and PD-1 were significantly upregulated on TH 2 cells upon OVA aerosol exposure in OVA-allergic compared to non-allergic mice. CTLA-4 and PD-1 decreased after AIT, in particular on the surface of local lung TH 2 cells. Similarly, CTLA-4 and PD-1 expression was enhanced on TH 2 cells from patients with allergic rhinitis with an even stronger effect in those with concomitant asthma. Using an unbiased Louvain clustering analysis, we discovered a late-differentiated TH 2 population expressing both markers that decreased during up-dosing but persisted long term during the maintenance phase.This study shows that allergen exposure promotes CTLA-4 and PD-1 expression on TH 2 cells and that the dynamic change in frequencies of exhausted TH 2 cells exhibits a differential pattern during the up-dosing versus the maintenance phases of AIT.
Abstract 15301: Peripheral CD56 <sup>bright</sup> Natural Killer Cells Associate With Increased Atheroburden and Unstable Plaque Features in Humans
Authors: Hema Kothari, Fabrizio Drago, Chantel McSkimming, Coleen A McNamara
Journal: Circulation (2020)

Background: Atherosclerotic plaques in mice and humans contain natural killer (NK) cells. Data on the role of NK cells in atherosclerosis using different transgenic mice models is inconsistent. Some studies showed that NK cells augment atherosclerosis through their cytotoxic potential, while others reported no effect. Evidence in humans indicates that NK cells are atherogenic. Frequency of NK cells and expression of the activating NK cell receptors are associated with severe disease and symptomatic carotid atherosclerotic plaques in humans. Hypothesis: We tested if coronary artery disease (CAD) subjects with necrotic plaques have a higher frequency of the circulating NK cells. Methods: We performed mass cytometry on peripheral blood mononuclear cells from matched CAD subjects with low and high (n=9 each) necrotic plaque content as determined by intravascular ultrasound-virtual histology. Results: CAD subjects with high necrotic plaques have significantly higher atheroburden, stenosis, calcium, fatty plaque content, and lower plaque fibrosis. Interestingly, CAD subjects with high necrotic plaques exhibited a significantly higher frequency of the CD56 bright NK cells as compared to those with low necrotic plaques (4.618 ± 0.625 vs 2.481 ± 0.37; p=0.011). Moreover, frequency of CD25 + NK cells also trended to be higher in subjects with high necrotic plaques. The frequency of the cytotoxic CD56 dim NK cells did not differ between the two groups. Correlation analyses demonstrated a significant positive association of CD56 bright NK cells with atheroburden (r=0.43; p=0.04), stenosis (r=0.58; p=0.005), plaque necrotic (r=0.71; p=0.002), calcium contents (r=0.73; p=0.0001), and a negative association with the plaque fibrous content (r=0.71; p= 0.0003). CD25 + NK cells also showed similar trending associations with burden, stenosis and plaque features. Conclusions: Our data provides yet another evidence of the atherogenic role of NK cells in humans and indicates that the CD56 bright NK cells may contribute to the development of a vulnerable plaque. CD56 bright NK cells produce proinflammatory cytokines including IFN-γ and TNF-α and cytotoxic enzymes that may contribute to increased inflammation, cell activation, and apoptosis within the plaque.