tbuckley/cabot-search huggingface dataset:
Abstract 17229: Synergistic Inhibition of Retinoblastoma1 and Meis2 Promotes Robust Proliferation of Adult Cardiomyocytes
Authors: Raghav Pandey, Jamie Fritz, Rafeeq P Ahmed
Journal: Circulation (2015)

Background: Cardiac remodeling and heart failure post myocardial Infarction (MI) is mainly due to inadequate regenerative capacity of mammalian heart, which is attributed to limited proliferative potential of adult cardiomyocytes (ACMs). In our recent study, we identified miR-1825 as a master regulator, which induces ACM proliferation through recruiting other proliferation inducing miRs, including miR-199a. In this study, we hypothesize that miR-1825 promotes proliferation through miR-199a mediated inhibition of cell cycle inhibitors Retinoblastoma1 (Rb1) and Meis2. Methods and Results: ACMs were isolated from 8-12 week old male rats and were transfected with cel-miR-67 (control), miR-1825, miR-199a, siRNA against Rb1 and Meis2 both individually and in combination (siRb1, siMeis2, siRb1+siMeis2). To label proliferating ACMs, EdU (5 μM) was added each day for 5 days and cells were harvested/fixed for staining, protein, and RNA analysis. Immuno-staining was performed for EdU, pH3 (mitotic marker), and Troponin-I. Similar to our previous reports, miR-1825 induced 23±0.4% and miR-199a induced 14.8±0.5% proliferation, as shown by EdU+ ACMs. In addition, we identified siRNA mediated silencing of Rb1 and Meis2 promoted 8.7±2.8% and 3.8±1.4% increase in proliferation, whereas simultaneous inhibition of both Rb1 and Meis2 induced robust (23±5.0%) proliferation of ACMs. Mitosis, as identified by p-H3+ACMs, following individual and combined silencing of Rb1 and Meis2 was observed to be 2.6%, 2.2%, and 7.6%, respectively. Western blotting confirmed silencing of Meis1/2 and Rb1 (0.14±0.02 fold) in miR-1825 transfected ACMs. Computational prediction and luciferase assay revealed a direct binding site for miR-199a on the 3’UTRs of both Rb1 and Meis2. Following miR-199a transfection, we found a 0.29±0.06 fold and 0.09±0.07 fold reduction of chemiluminescent activity with Rb1-3’UTR and Meis2-3’UTR, respectively. In addition, binding sites for miR-199a on both Rb1-3’UTR and Meis2-3’UTR are conserved across species as indicated by in-silico analysis. Conclusion: miR-1825 and miR-199a mediated simultaneous silencing of cell cycle inhibitors Rb1 and Meis2 promotes robust proliferation of ACMs. This can be used to regenerate ischemic myocardium.
CLK1/SRSF5 pathway induces aberrant exon skipping of METTL14 and Cyclin L2 and promotes growth and metastasis of pancreatic cancer
Authors: Shi Chen, Can Yang, Zu-Wei Wang, Jian-Fei Hu, Jing-Jing Pan, Cheng-Yu Liao, Jia-Qiang Zhang, Jiang-Zhi Chen, Yi Huang, Long Huang, Qian Zhan, Yi-Feng Tian, Bai-Yong Shen, Yao-Dong Wang
Journal: Journal of Hematology & Oncology (2021)

Both aberrant alternative splicing and m6A methylation play complicated roles in the development of pancreatic cancer (PC), while the relationship between these two RNA modifications remains unclear.RNA sequencing (RNA-seq) was performed using 15 pairs of pancreatic ductal adenocarcinoma (PDAC) tissues and corresponding normal tissues, and Cdc2-like kinases 1 (CLK1) was identified as a significantly upregulated alternative splicing related gene. Real-time quantitative PCR (qPCR) and western blotting were applied to determine the CLK1 levels. The prognostic value of CLK1 was elucidated by Immunohistochemistry (IHC) analyses in two independent PDAC cohorts. The functional characterizations and mechanistic insights of CLK1 in PDAC growth and metastasis were evaluated with PDAC cell lines and nude mice. SR-like splicing factors5250-Ser (SRSF5250-Ser) was identified as an important target phosphorylation site by phosphorylation mass spectrometry. Through transcriptome sequencing, Methyltransferase-like 14exon10 (METTL14exon10) and Cyclin L2exon6.3 skipping were identified as key alternative splicing events regulated by the CLK1-SRSF5 axis. RIP assays, RNA-pulldown and CLIP-qPCR were performed to confirm molecular interactions and the precise binding sites. The roles of the shift of METTL14exon 10 and Cyclin L2exon6.3 skipping were surveyed.CLK1 expression was significantly increased in PDAC tissues at both the mRNA and protein levels. High CLK1 expression was associated with poor prognosis. Elevated CLK1 expression promoted growth and metastasis of PC cells in vitro and in vivo. Mechanistically, CLK1 enhanced phosphorylation on SRSF5250-Ser, which inhibited METTL14exon10 skipping while promoted Cyclin L2exon6.3 skipping. In addition, aberrant METTL14exon 10 skipping enhanced the N6-methyladenosine modification level and metastasis, while aberrant Cyclin L2exon6.3 promoted proliferation of PDAC cells.The CLK1/SRSF5 pathway induces aberrant exon skipping of METTL14 and Cyclin L2, which promotes growth and metastasis and regulates m6A methylation of PDAC cells. This study suggests the potential prognostic value and therapeutic targeting of this pathway in PDAC patients.
Genetic analyses identify widespread sex-differential participation bias
Authors: Nicola Pirastu, Mattia Cordioli, Priyanka Nandakumar, Gianmarco Mignogna, Abdel Abdellaoui, Benjamin Hollis, Masahiro Kanai, Veera M. Rajagopal, Pietro Della Briotta Parolo, Nikolas Baya, Caitlin E. Carey, Juha Karjalainen, Thomas D. Als, Matthijs D. Van der Zee, Felix R. Day, Ken K. Ong, Michelle Agee, Stella Aslibekyan, Robert K. Bell, Katarzyna Bryc, Sarah K. Clark, Sarah L. Elson, Kipper Fletez-Brant, Pierre Fontanillas, Nicholas A. Furlotte, Pooja M. Gandhi, Karl Heilbron, Barry Hicks, Karen E. Huber, Ethan M. Jewett, Yunxuan Jiang, Aaron Kleinman, Keng-Han Lin, Nadia K. Litterman, Marie K. Luff, Matthew H. McIntyre, Kimberly F. McManus, Joanna L. Mountain, Sahar V. Mozaffari, Elizabeth S. Noblin, Carrie A. M. Northover, Jared O’Connell, Aaron A. Petrakovitz, Steven J. Pitts, G. David Poznik, J. Fah Sathirapongsasuti, Janie F. Shelton, Suyash Shringarpure, Chao Tian, Joyce Y. Tung, Robert J. Tunney, Vladimir Vacic, Xin Wang, Amir Zare, Preben Bo Mortensen, Ole Mors, Thomas Werge, Merete Nordentoft, David M. Hougaard, Jonas Bybjerg-Grauholm, Marie Bækvad-Hansen, Takayuki Morisaki, Eco de Geus, Rino Bellocco, Yukinori Okada, Anders D. Børglum, Peter Joshi, Adam Auton, David Hinds, Benjamin M. Neale, Raymond K. Walters, Michel G. Nivard, John R. B. Perry, Andrea Ganna
Journal: Nature Genetics (2021)
It is time to optimise the management of latent tuberculosis infection in children
Authors: Anne Christine Nordholm, Troels Lillebaek
Journal: European Respiratory Journal (2021)

<b>A world free of tuberculosis disease obliges us to join forces in low- and high-income countries, from stakeholders to clinicians, and take decisive action to reduce the burden of LTBI in children</b>https://bit.ly/3h8lUhz
Role of IgA in the early-life establishment of the gut microbiota and immunity: Implications for constructing a healthy start
Authors: Jielong Guo, Chenglong Ren, Xue Han, Weidong Huang, Yilin You, Jicheng Zhan
Journal: Gut Microbes (2021)

Colonization and maturation of the gut microbiota (GM) during early life is a landmark event that fundamentally influences the (early) immunity and later-life health of various mammals. This is a delicate, systematic process that is biologically actively regulated by infants and their mothers, where (secretory) IgA, an important regulator of microbes found in breast milk and generated actively by infants, may play a key role. By binding to microbes, IgA can inhibit or enhance their colonization, influence their gene expression, and regulate immune responses. IgA dysfunction during early life is associated with disrupted GM maturation and various microbe-related diseases, such as necrotizing enterocolitis and diarrhea, which can also have a lasting effect on GM and host health. This review discusses the process of early GM maturation and its interaction with immunity and the role of IgA (focusing on milk secretory IgA) in regulating this process. The possible application of this knowledge in promoting normal GM maturation processes and immune education has also been highlighted.
Nanomedicine Strategies for Anti‐Inflammatory Treatment of Noninfectious Arthritis
Authors: Long Chen, Yuanzheng Wang, Li Sun, Jerry Yan, Hai‐Quan Mao
Journal: Advanced Healthcare Materials (2021)

Abstract Noninfectious arthritis (NIA) comprises a class of chronic and progressive inflammatory disorders that require early‐stage management to prevent disease progression. The most common forms include osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, and gouty arthritis. Current treatments involve nonsteroidal anti‐inflammatory drugs, disease‐modifying antirheumatic drugs and glucocorticoids to alleviate clinical symptoms, although regular use of these can result in a high risk of chronic kidney disease and heart failure, as well as severe adverse gastrointestinal effects. Nanomedicine offers unique opportunities to address these challenges and improve therapeutic efficacy due to its ability to deliver therapeutics locally in a sustained manner, thus extending the half‐life, improving bioavailability, and reducing the side effects of these agents. This review includes a comprehensive analysis of the mechanisms of various treatment options for NIA and highlights recent progress and emerging strategies in treating NIA with nanomedicine platforms, particularly related to long‐term biosafety and nonspecific targeting in designing nanomedicine delivery systems.
The role and challenges of cluster randomised trials for global health
Authors: Louis Dron, Monica Taljaard, Yin Bun Cheung, Rebecca Grais, Nathan Ford, Kristian Thorlund, Fyezah Jehan, Etheldreda Nakimuli-Mpungu, Denis Xavier, Zulfiqar A Bhutta, Jay J H Park, Edward J Mills
Journal: The Lancet Global Health (2021)

SummaryEvaluating whether an intervention works when trialled in groups of individuals can pose complex challenges for clinical research. Cluster randomised controlled trials involve the random allocation of groups or clusters of individuals to receive an intervention, and they are commonly used in global health research. In this paper, we describe the potential reasons for the increasing popularity of cluster trials in low-income and middle-income countries. We also draw on key areas of global health research for an assessment of common trial planning practices, and we address their methodological shortcomings and pitfalls. Lastly, we discuss alternative approaches for population-level intervention trials that could be useful for research undertaken in low-income and middle-income countries for situations in which the use of cluster randomisation might not be appropriate. Evaluating whether an intervention works when trialled in groups of individuals can pose complex challenges for clinical research. Cluster randomised controlled trials involve the random allocation of groups or clusters of individuals to receive an intervention, and they are commonly used in global health research. In this paper, we describe the potential reasons for the increasing popularity of cluster trials in low-income and middle-income countries. We also draw on key areas of global health research for an assessment of common trial planning practices, and we address their methodological shortcomings and pitfalls. Lastly, we discuss alternative approaches for population-level intervention trials that could be useful for research undertaken in low-income and middle-income countries for situations in which the use of cluster randomisation might not be appropriate. This is the third in a Series of four papers about clinical trials in global health
Altered perivascular fibroblast activity precedes ALS disease onset
Authors: Anna Månberg, Nathan Skene, Folkert Sanders, Marta Trusohamn, Julia Remnestål, Anna Szczepińska, Inci Sevval Aksoylu, Peter Lönnerberg, Lwaki Ebarasi, Stefan Wouters, Manuela Lehmann, Jennie Olofsson, Inti von Gohren Antequera, Aylin Domaniku, Maxim De Schaepdryver, Joke De Vocht, Koen Poesen, Mathias Uhlén, Jasper Anink, Caroline Mijnsbergen, Hermieneke Vergunst-Bosch, Annemarie Hübers, Ulf Kläppe, Elena Rodriguez-Vieitez, Jonathan D. Gilthorpe, Eva Hedlund, Robert A. Harris, Eleonora Aronica, Philip Van Damme, Albert Ludolph, Jan Veldink, Caroline Ingre, Peter Nilsson, Sebastian A. Lewandowski
Journal: Nature Medicine (2021)
Achieving a Cure: The Next Frontier in Hepatitis B Treatment
Authors: Tina Boortalary, Brianna Shinn, Dina Halegoua-DeMarzio, Hie-Won Hann
Journal: Liver Cancer (2021)

Since the discovery of the hepatitis B virus (HBV) by Blumberg et al. in 1965, significant progress has been made in understanding the pathogenesis of the virus and creating an effective vaccine. In the past two decades, several antiviral therapies have reduced the incidence of HBV-related hepatocellular carcinoma. The nucleos(t)ide analogues have succeeded in decreasing the viral load to undetectable levels but have been unable to eradicate the virus due to the persistence of covalently closed circular DNA in the hepatocyte nucleus. Despite being on successful antiviral therapy for multiple years, patients are still at risk of developing hepatocellular carcinoma. Recently, a number of different drug targets have been identified that intervene on the viral replication cycle or host immune system. This chapter discusses the immunopathogenesis of the virus, the effectiveness of nucleos(t)ide analogues, and recent therapeutic developments. In light of robust progress achieved in antiviral therapy, the cure for hepatitis B is likely on the horizon.
表在性大腿動脈病変のためのS.M.A.R.T.制御 TM ステントの長期の結果,J-SMART登録
Authors: Suzuki Kenji, Iida Osamu, Soga Yoshimitsu, Hirano Keisuke, Inoue Naoto, Uematsu Masaaki, Yokoi Hiroyoshi, Muramatsu Toshiya, Nanto Shinsuke, Nobuyoshi Masakiyo, Meguro Taiichiro
Journal: Circulation (2011)
Extracellular vesicles derived from M1 macrophages deliver miR-146a-5p and miR-146b-5p to suppress trophoblast migration and invasion by targeting TRAF6 in recurrent spontaneous abortion
Authors: Jinli Ding, Yan Zhang, Xiaopeng Cai, Yi Zhang, Sisi Yan, Jiayu Wang, Sainan Zhang, Tailang Yin, Chaogang Yang, Jing Yang
Journal: Theranostics (2021)

Emerging evidence demonstrates that insufficient migration and invasion of trophoblasts play critical roles in the pathogenesis of recurrent spontaneous abortion (RSA). Cell-to-cell communication at the maternal-fetal interface is essential to maintain the invasion and migration of trophoblasts. M1 macrophages, important immune cellular components at the maternal-fetal interface, have been reported to be elevated in decidua tissues from patients with RSA. Recent studies indicate that M1 macrophages modulate trophoblast biological behaviors; however, the underlying mechanisms remain poorly understood.
The Novel Calcium Release-Activated Calcium (CRAC) Channel Inhibitor RP4010 Exerts Potent Antitumor Effects in NOD/SCID/IL2Rg-/- Mice with Diffuse Large B Cell Lymphoma (DLBCL) Cell Line Xenografts
Authors: Silvia Laura Locatelli, Giuseppa Careddu, Massimo Magagnoli, Martina di Trani, Lucia Morello, Srikant Viswanadha, Swaroop Kumar Vs Vakkalanka, Luca Castagna, Armando Santoro, Carmelo Carlo-Stella
Journal: Blood (2017)
Application of traction-method to hybrid endoscopic submucosal dissection for gastrointestinal tumors
Authors: Mitsuru Esaki, Ryosuke Maehara, Shuzaburo Nagatomo, Kei Nishioka, Yosuke Minoda, Haruei Ogino, Eikichi Ihara
Journal: Endoscopy (2021)

Hybrid endoscopic submucosal dissection (ESD) is a simplified endoscopic treatment for conventional ESD that consists of snaring of submucosal layer after completion of circumferential mucosal incision and subsequent partial submucosal dissection [1] Previous studies have revealed that hybrid ESD reduces the en bloc resection rate although it significantly shortens the treatment procedure time [2] [3]. To improve the en bloc resection rate, we proposed a traction-assisted hybrid ESD using the clip-with-thread technique and a multi-functional snare, SOUTEN (Kaneka Medix, Tokyo, Japan), in the porcine stomach model [4].
Low immunization rates among kidney transplant recipients who received 2 doses of the mRNA-1273 SARS-CoV-2 vaccine
Authors: Ilies Benotmane, Gabriela Gautier-Vargas, Noëlle Cognard, Jérôme Olagne, Françoise Heibel, Laura Braun-Parvez, Jonas Martzloff, Peggy Perrin, Bruno Moulin, Samira Fafi-Kremer, Sophie Caillard
Journal: Kidney International (2021)
Undifferentiated Embryonal Sarcoma of the Liver in Adults
Authors: Jingyang Huang
Journal: Liver Cancer (2021)

Undifferentiated embryonal sarcoma of the liver (UESL) is an aggressive malignancy that most commonly affects the pediatric age group. This tumor very rarely occurs in adults and, in such instances, can pose a considerable diagnostic challenge for the clinicians, radiologists, and pathologists involved. The clinical presentation is most often non-specific, and the radiology shows a solid and cystic liver mass which has a considerable differential on imaging. Especially in adult patients, UESL is a diagnosis of exclusion meaning that all other diagnostic possibilities must be excluded before the diagnosis of UESL can be confidently made. From a pathology perspective, this means careful examination of the histology along with a comprehensive panel of immunohistochemistry for almost all cases of newly diagnosed UESL. The prognosis of UESL used to be dismal, but with advances in treatment and the introduction of a multimodality approach, there has been considerable progress in improving outcomes and survival for patients with this aggressive tumor. This chapter outlines the clinical, radiological, and pathological features of UESL. An in-depth discussion is undertaken to describe the diagnostic approach and the differential diagnosis for this rare and challenging tumor.
Abstract 12520: Risk Stratification of Moderate Sized Pericardial Effusion: VGH Pericardiocentesis Prediction Score
Authors: Calvin Ka Wing Tong, Parvathy Nair, John Jue, Ken Gin, Pui Kee Lee, Elena Szefer, Darby Thompson, Michael Tsang, Teresa Tsang
Journal: Circulation (2018)

Introduction: Management of at least moderate pericardial effusion without hemodynamic compromise are often at the discretion of attending cardiologists. Objective scoring index (CHASER) was previo...
Navigating Attacks Against Health Care Workers in the COVID-19 Era
Authors: Howard Larkin
Journal: JAMA (2021)

Tricia R. Pendergrast, BA; Shikha Jain, MD; N. Seth Trueger, MD, MPH; Michael Gottlieb, MD; Nicole C. Woitowich, PhD; Vineet M. Arora, MD, MAPP
Population Bottlenecks Strongly Affect the Evolutionary Dynamics of Antibiotic Persistence
Authors: Etthel M Windels, Richard Fox, Krishna Yerramsetty, Katherine Krouse, Tom Wenseleers, Janne Swinnen, Paul Matthay, Laure Verstraete, Dorien Wilmaerts, Bram Van den Bergh, Jan Michiels
Journal: Molecular Biology and Evolution (2021)

Bacterial persistence is a potential cause of antibiotic therapy failure. Antibiotic-tolerant persisters originate from phenotypic differentiation within a susceptible population, occurring with a frequency that can be altered by mutations. Recent studies have proven that persistence is a highly evolvable trait and, consequently, an important evolutionary strategy of bacterial populations to adapt to high-dose antibiotic therapy. Yet, the factors that govern the evolutionary dynamics of persistence are currently poorly understood. Theoretical studies predict far-reaching effects of bottlenecking on the evolutionary adaption of bacterial populations, but these effects have never been investigated in the context of persistence. Bottlenecking events are frequently encountered by infecting pathogens during host-to-host transmission and antibiotic treatment. In this study, we used a combination of experimental evolution and barcoded knockout libraries to examine how population bottlenecking affects the evolutionary dynamics of persistence. In accordance with existing hypotheses, small bottlenecks were found to restrict the adaptive potential of populations and result in more heterogeneous evolutionary outcomes. Evolutionary trajectories followed in small-bottlenecking regimes additionally suggest that the fitness landscape associated with persistence has a rugged topography, with distinct trajectories toward increased persistence that are accessible to evolving populations. Furthermore, sequencing data of evolved populations and knockout libraries after selection reveal various genes that are potentially involved in persistence, including previously known as well as novel targets. Together, our results do not only provide experimental evidence for evolutionary theories, but also contribute to a better understanding of the environmental and genetic factors that guide bacterial adaptation to antibiotic treatment.
SARS-CoV-2–reactive cellular and humoral immunity in hemodialysis population
Authors: Moritz Anft, Arturo Blazquez-Navarro, Krystallenia Paniskaki, Sarah Skrzypczyk, Heiner Appel, Thiemo Pfab, Andrea Uhle, Michael Frahnert, Michael Barenbrock, Eckhart Büssemaker, Jan Hörstrup, Adrian Doevelaar, Felix S. Seibert, Bodo Hölzer, Ulrik Stervbo, Sebastian Dolff, Oliver Witzke, Nina Babel, Timm H. Westhoff
Journal: Kidney International (2021)
Acute Ischemic Stroke During the Convalescent Phase of Asymptomatic COVID-2019 Infection in Men
Authors: Tian Ming Tu, Christopher Ying Hao Seet, Jasmine Shimin Koh, Carol Huilian Tham, Hui Jin Chiew, Jasmyn Angon De Leon, Christopher Yuan Kit Chua, Andrew Che-Fai Hui, Shaun Shi Yan Tan, Shawn Sushilan Vasoo, Benjamin Yong-Qiang Tan, N. Thirugnanam Umapathi, Paul Anantharajah Tambyah, Leonard Leong Litt Yeo
Journal: JAMA Network Open (2021)

Acute ischemic stroke (AIS) is a known neurological complication in patients with respiratory symptoms of COVID-19 infection. However, AIS has not been described as a late sequelae in patients without respiratory symptoms of COVID-19.To assess AIS experienced by adults 50 years or younger in the convalescent phase of asymptomatic COVID-19 infection.This case series prospectively identified consecutive male patients who received care for AIS from public health hospitals in Singapore between May 21, 2020, and October 14, 2020. All of these patients had laboratory-confirmed asymptomatic COVID-19 infection based on a positive SARS-CoV-2 serological (antibodies) test result. These patients were individuals from South Asian countries (India and Bangladesh) who were working in Singapore and living in dormitories. The total number of COVID-19 cases (54 485) in the worker dormitory population was the population at risk. Patients with ongoing respiratory symptoms or positive SARS-CoV-2 serological test results confirmed through reverse transcriptase-polymerase chain reaction nasopharyngeal swabs were excluded.Clinical course, imaging, and laboratory findings were retrieved from the electronic medical records of each participating hospital. The incidence rate of AIS in the case series was compared with that of a historical age-, sex-, and ethnicity-matched national cohort.A total of 18 male patients, with a median (range) age of 41 (35-50) years and South Asian ethnicity, were included. The median (range) time from a positive serological test result to AIS was 54.5 (0-130) days. The median (range) National Institutes of Health Stroke Scale score was 5 (1-25). Ten patients (56%) presented with a large vessel occlusion, of whom 6 patients underwent intravenous thrombolysis and/or endovascular therapy. Only 3 patients (17%) had a possible cardiac source of embolus. The estimated annual incidence rate of AIS was 82.6 cases per 100 000 people in this study compared with 38.2 cases per 100 000 people in the historical age-, sex-, and ethnicity-matched cohort (rate ratio, 2.16; 95% CI, 1.36-3.48; P < .001).This case series suggests that the risk for AIS is higher in adults 50 years or younger during the convalescent period of a COVID-19 infection without respiratory symptoms. Acute ischemic stroke could be part of the next wave of complications of COVID-19, and stroke units should be on alert and use serological testing, especially in younger patients or in the absence of traditional risk factors.