tbuckley/cabot-search huggingface dataset:
Wrinkle in the plan: miR-34a-5p impacts chemokine signaling by modulating CXCL10/CXCL11/CXCR3-axis in CD4<sup>+</sup>, CD8<sup>+</sup>T cells, and M1 macrophages
Authors: Martin Hart, Laura Nickl, Barbara Walch-Rueckheim, Lena Krammes, Stefanie Rheinheimer, Caroline Diener, Tanja Taenzer, Tim Kehl, Martina Sester, Hans-Peter Lenhof, Andreas Keller, Eckart Meese
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background In 2016 the first-in-human phase I study of a miRNA-based cancer therapy with a liposomal mimic of microRNA-34a-5p (miR-34a-5p) was closed due to five immune related serious adverse events (SAEs) resulting in four patient deaths. For future applications of miRNA mimics in cancer therapy it is mandatory to unravel the miRNA effects both on the tumor tissue and on immune cells. Here, we set out to analyze the impact of miR-34a-5p over-expression on the CXCL10/CXCL11/CXCR3 axis, which is central for the development of an effective cancer control. Methods We performed a whole genome expression analysis of miR-34a-5p transfected M1 macrophages followed by an over-representation and a protein–protein network analysis. In-silico miRNA target prediction and dual luciferase assays were used for target identification and verification. Target genes involved in chemokine signaling were functionally analyzed in M1 macrophages, CD4 + and CD8 + T cells. Results A whole genome expression analysis of M1 macrophages with induced miR-34a-5p over-expression revealed an interaction network of downregulated target mRNAs including CXCL10 and CXCL11. In-silico target prediction in combination with dual luciferase assays identified direct binding of miR-34a-5p to the 3′UTRs of CXCL10 and CXCL11 . Decreased CXCL10 and CXCL11 secretion was shown on the endogenous protein level and in the supernatant of miR-34a-5p transfected and activated M1 macrophages. To complete the analysis of the CXCL10/CXCL11/CXCR3 axis, we activated miR-34a-5p transfected CD4 + and CD8 + T cells by PMA/Ionomycin and found reduced levels of endogenous CXCR3 and CXCR3 on the cell surface. Conclusions MiR-34a-5p mimic administered by intravenous administration will likely not only be up-taken by the tumor cells but also by the immune cells. Our results indicate that miR-34a-5p over-expression leads in M1 macrophages to a reduced secretion of CXCL10 and CXCL11 chemokines and in CD4 + and CD8 + T cells to a reduced expression of CXCR3. As a result, less immune cells will be attracted to the tumor site. Furthermore, high levels of miR-34a-5p in naive CD4 + T cells can in turn hinder Th1 cell polarization through the downregulation of CXCR3 leading to a less pronounced activation of cytotoxic T lymphocytes, natural killer, and natural killer T cells and possibly contributing to lymphocytopenia.
SLAM family receptors control pro-survival effectors in germinal center B cells to promote humoral immunity
Authors: Ming-Chao Zhong, Yan Lu, Jin Qian, Yingzi Zhu, Lingli Dong, Astrid Zahn, Javier M. Di Noia, Danielle Karo-Atar, Irah L. King, André Veillette
Journal: The Journal of Experimental Medicine (2020)

Expression of the signaling lymphocytic activation molecule (SLAM)–associated protein (SAP) is critical for the germinal center (GC) reaction and T cell–dependent antibody production. However, when SAP is expressed normally, the role of the associated SLAM family receptors (SFRs) in these processes is nebulous. Herein, we established that in the presence of SAP, SFRs suppressed the expansion of the GC reaction but facilitated the generation of antigen-specific B cells and antibodies. SFRs favored the generation of antigen-reactive B cells and antibodies by boosting expression of pro-survival effectors, such as the B cell antigen receptor (BCR) and Bcl-2, in activated GC B cells. The effects of SFRs on the GC reaction and T cell–dependent antibody production necessitated expression of multiple SFRs, both in T cells and in B cells. Hence, while in the presence of SAP, SFRs inhibit the GC reaction, they are critical for the induction of T cell–mediated humoral immunity by enhancing expression of pro-survival effectors in GC B cells.
Abstract 14785: Podocan a Novel Circulating Wnt-Pathway Inhibitor Predicts Major Adverse Cardiovascular Events in Patients With Coronary Artery Disease Independent of Framingham Cardiovascular Risk Factors in Synergy With Dickkopf-1
Authors: Kanramon Watthanasuntorn, Bishesh Shrestha, Nancy Bethuel, Charat Thongprayoon, Kanjit Leungsuwan, Jennifer Victory, Paul Jenkins, Deborah Hyink, Daniel H Katz, Paul Klotman, Jagdesh Kandala, Randolph Hutter
Journal: Circulation (2019)

Introduction: Smooth muscle cell (SMC) function determines the clinical course of vascular disease via fibrous cap stability. Podocan is a potent suppressor of SMC function by inhibiting SMC Wnt-pa...
Integrated analysis of microbiome and host transcriptome reveals correlations between gut microbiota and clinical outcomes in HBV-related hepatocellular carcinoma
Authors: Hechen Huang, Zhigang Ren, Xingxing Gao, Xiaoyi Hu, Yuan Zhou, Jianwen Jiang, Haifeng Lu, Shengyong Yin, Junfang Ji, Lin Zhou, Shusen Zheng
Journal: Genome Medicine (2020)

Abstract Background The gut-liver axis plays a pivotal role in the pathogenesis of hepatocellular carcinoma (HCC). However, the correlations between the gut microbiome and the liver tumor transcriptome in patients with HCC and the impact of the gut microbiota on clinical outcome are less well-understood. Methods Fecal samples collected from HBV-related HCC patients ( n = 113) and healthy volunteers ( n = 100) were subjected to 16S rRNA sequencing of the microbiome. After a rigorous selection process, 32 paired tumor and adjacent non-tumor liver tissues from the HCC group were subjected to next-generation sequencing (NGS) RNA-seq. The datasets were analyzed individually and integrated with clinical characteristics for combined analysis using bioinformatics approaches. We further verified the potential of the gut microbiota to predict clinical outcome by a random forest model and a support vector machine model. Results We found that Bacteroides , Lachnospiracea incertae sedis , and Clostridium XIVa were enriched in HCC patients with a high tumor burden. By integrating the microbiome and transcriptome, we identified 31 robust associations between the above three genera and well-characterized genes, indicating possible mechanistic relationships in tumor immune microenvironment. Clinical characteristics and database analysis suggested that serum bile acids may be important communication mediators between these three genera and the host transcriptome. Finally, among these three genera, six important microbial markers associated with tumor immune microenvironment or bile acid metabolism showed the potential to predict clinical outcome (AUC = 81%). Conclusions This study revealed that changes in tumor immune microenvironment caused by the gut microbiota via serum bile acids may be important factors associated with tumor burden and adverse clinical outcome. Gut microbes can be used as biomarkers of clinical features and outcomes, and the microbe-associated transcripts of host tumors can partly explain how gut microbiota promotes HCC pathogenesis.
What to Do With Sideline Guilt—Reply
Authors: David B. Reuben
Journal: JAMA Internal Medicine (2020)

To the Editor The Physician Perspective by Reuben 1 on sideline guilt should strike a deep chord for many of us.I am a family physician, 72 years old, 6 years retired after an episode of ill health from which I have recovered.So I have my health, food in the refrigerator, enough money in the bank, and a spouse who still puts up with me.The only hardship we face is that coronavirus disease 2019 (COVID-19) has kept us from seeing our far-flung children and grandchildren and forced us to socialize distantly with our friends.Many of my prepandemic activities-working as a nursing home ombudsman, teaching medical students, serving on hospital committees-have been curtailed completely or relegated to virtual visits.That I, as a noncritical care specialist, could meaningfully replace a frontline worker is a dubious proposition at best.As Reuben 1 points out, staying away from hospitals may be the most constructive thing some of us can do.But beyond the world of medicine, there is so much more to feel guilty about.The COVID-19 pandemic and current events have brought into sharp focus the long-standing racial and class inequities from which I and so many who might read this have undoubtedly benefited in one way or another.I would add 2 suggestions to those Reuben 1 has proposed.First, allow yourself to experience gratitude if you float in the same guilty boat as I do: gratitude that you have the boat.Second, get angry about the state of the world and get motivated.The Viewpoint by Berwick 2 on the moral determinants of health is a good place to start.There is much that those of us who are blessed not to be suffering in these difficult times can do to help make sure the new normal will better than the old.
Safety and efficacy of quavonlimab, a novel anti-CTLA-4 antibody (MK-1308), in combination with pembrolizumab in first-line advanced non-small-cell lung cancer
Authors: R. Perets, J. Bar, D.W. Rasco, M.-J. Ahn, K. Yoh, D.-W. Kim, A. Nagrial, M. Satouchi, D.H. Lee, D.R. Spigel, D. Kotasek, M. Gutierrez, J. Niu, S. Siddiqi, X. Li, J. Cyrus, A. Chackerian, A. Chain, R.A. Altura, B.C. Cho
Journal: Annals of Oncology (2020)

Quavonlimab (MK-1308), a novel anti-CTLA-4 antibody, in combination with pembrolizumab was investigated in a phase I study.Dose-escalation (DE) phase: patients with advanced/metastatic solid tumors received an initial flat dose of quavonlimab as monotherapy [25 mg (cohort 1), 75 mg (cohort 2), or 200 mg (cohort 3)] followed by four treatments of the same quavonlimab dose plus pembrolizumab every 3 weeks (Q3W). Dose-confirmation phase (DC): patients with stage IIIB/IV non-small-cell lung cancer (NSCLC) received first-line quavonlimab [25 mg Q3W (arm A), 25 mg Q6W (arm B), 75 mg Q6W (arm C), or 75 mg Q3W (arm E)] plus pembrolizumab. Primary objectives were safety and tolerability and establishment of the recommended phase II dose (RP2D) of quavonlimab when used with pembrolizumab. Objective response rate (ORR) was a secondary endpoint. Efficacy based on PD-L1 expression, tumor mutational burden (TMB), and changes in circulating CD4+/CD8+ cells were exploratory endpoints.Thirty-nine patients were enrolled in DE [n = 14 (cohort 1); n = 17 (cohort 2); n = 8 (cohort 3)] and 134 in DC [n = 40 (arm A); n = 40 (arm B); n = 40 (arm C); n = 14 (arm E)]. Maximum-tolerated dose was not reached. Grade 3-5 treatment-related adverse events (AEs; graded according to NCI CTCAE v4.03) occurred in 0%, 23.5%, and 75.0% of patients in DE cohorts 1, 2, and 3, respectively, and 35.0%, 30.0%, 35.0%, and 57.1% of patients in DC arms A, B, C, and E, respectively. Efficacy was observed at all dose levels/schedules in patients with NSCLC. ORRs were 40.0% [95% confidence interval (CI), 24.9-56.7; arm A], 37.5% (95% CI, 22.7-54.2; arm B), 27.5% (95% CI, 14.6-43.9; arm C), and 35.7% (95% CI, 12.8-64.9; arm E). PD-L1 expression and total number of circulating CD4+ cells correlated with ORR.Quavonlimab 25 mg Q6W plus pembrolizumab demonstrated similar efficacy and a better safety profile among all quavonlimab doses/schedules evaluated; this regimen was the chosen RP2D.
In Situ Nucleic Acid Amplification and Ultrasensitive Colorimetric Readout in a Paper‐Based Analytical Device Using Silver Nanoplates
Authors: Akkapol Suea‐Ngam, Ilada Choopara, Shangkun Li, Mathias Schmelcher, Naraporn Somboonna, Philip D. Howes, Andrew J. deMello
Journal: Advanced Healthcare Materials (2020)

Abstract A rapid, highly sensitive, and quantitative colorimetric paper‐based analytical device (PAD) based on silver nanoplates (AgNPls) and loop‐mediated isothermal amplification (LAMP) is presented. It is shown that cauliflower‐like concatemer LAMP products can mediate crystal etching of AgNPls, with a threefold signal enhancement versus linear dsDNA. Methicillin‐resistant Staphylococcus aureus (MRSA), an antimicrobial resistant bacterium that poses a formidable risk with persistently high mortality, is used as a model pathogen. Due to the excellent color contrast provided by AgNPls, the PAD allows qualitative analysis by the naked eye and quantitative analysis using a smartphone camera, with detection limits down to a single copy in just 30 min, and a linear response from 1 to 10 4 copies ( R 2 = 0.994). The entire assay runs in situ on the paper surface, which drastically simplifies operation of the device. This is the first demonstration of single copy detection using a colorimetric readout, and the developed PAD shows great promise for translation into an ultrasensitive gene‐based point‐of‐care test for any infectious disease target, via modification of the LAMP primer set.
Endothelial Dysfunction: A Pathophysiologic Factor in Heart Failure With Preserved Ejection Fraction⁎⁎Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Authors: Carolyn S.P. Lam, Dirk L. Brutsaert
Journal: Journal of the American College of Cardiology (2012)
Oral berotralstat for the prophylaxis of hereditary angioedema attacks in patients in Japan: A phase 3 randomized trial
Authors: Isao Ohsawa, Daisuke Honda, Yusuke Suzuki, Tomoo Fukuda, Keisuke Kohga, Eishin Morita, Shinichi Moriwaki, Osamu Ishikawa, Yoshihiro Sasaki, Masaki Tago, Greg Chittick, Melanie Cornpropst, Sharon C. Murray, Sylvia M. Dobo, Eniko Nagy, Sharon Van Dyke, Lacy Reese, Jessica M. Best, Heather Iocca, Phil Collis, William P. Sheridan, Michihiro Hide
Journal: Allergy (2020)

With no approved treatments in Japan for the prevention of hereditary angioedema (HAE) attacks, there is a significant unmet need for long-term prophylactic therapies for Japanese patients with HAE. Berotralstat (BCX7353) is an oral, once-daily, highly selective inhibitor of plasma kallikrein in development for prophylaxis of angioedema attacks in HAE patients.APeX-J is a phase 3, randomized, double-blind, placebo-controlled, parallel-group, 3-part trial conducted in Japan (University Hospital Medical Information Network identifier, UMIN000034869; ClinicalTrials.gov identifier, NCT03873116). Patients with a clinical diagnosis of type 1 or 2 HAE underwent a prospective run-in period of 56 days to determine eligibility, allowing enrollment of those with ≥2 expert-confirmed angioedema attacks. Patients were randomly assigned (1:1:1) and stratified by baseline attack rate (≥2 vs. <2 expert-confirmed attacks/month between screening and randomization) to receive once-daily berotralstat 110 mg, berotralstat 150 mg, or placebo. The primary endpoint was the rate of expert-confirmed angioedema attacks during dosing in the 24-week treatment period.Nineteen patients were randomized to receive once-daily berotralstat 110 mg (n = 6), berotralstat 150 mg (n = 7), or placebo (n = 6). Treatment with berotralstat 150 mg significantly reduced HAE attacks relative to placebo (1.11 vs. 2.18 attacks/month, p = .003). The most frequently reported treatment-emergent adverse events (TEAEs) in berotralstat-treated patients (n = 13) were nasopharyngitis (n = 4, 31%), abdominal pain, cough, diarrhea, and pyrexia (n = 2 each, 15%).Orally administered, once-daily berotralstat 150 mg significantly reduced the frequency of HAE attacks and was safe and well tolerated, supporting its use as a prophylactic therapy in patients with type 1 or 2 HAE in Japan.
17999 Evaluation of ascorbic acid and a capsulated ascorbic acid-containing serum for protection against ambient particulate matter &lt;2.5 μm and ultraviolet radiation
Authors: Anne Yuqing Yang, Mallory Hamilton, Sonia Trehan, Michael Chang, Star Walsh, Thierry Oddos, Katharine Martin, Michael Southall, Fang Liu-Walsh
Journal: Journal of the American Academy of Dermatology (2020)
Sequential Combination of Pharmacotherapy and Psychotherapy in Major Depressive Disorder
Authors: Jenny Guidi, Giovanni A. Fava
Journal: JAMA Psychiatry (2020)

The sequential model emerged from the awareness that the persistence of residual symptoms and the frequent occurrence of psychiatric comorbidity were both associated with poor long-term outcome of major depressive disorder (MDD).To conduct an updated meta-analysis to examine the association of the sequential combination of pharmacotherapy and psychotherapy with reduced risk of relapse and recurrence in MDD.Keyword searches were conducted in PubMed, PsycInfo, Web of Science, and the Cochrane Library from inception of each database through November 2019. Reference lists from relevant studies were examined using the following keywords: sequential treatment, drugs and psychotherapy, combined treatment, continuation or maintenance, relapse or recurrence and prevention, and depress* or major depress*, selecting adults and randomized controlled trials as additional limits. Authors of selected articles were contacted if needed.Randomized clinical trials examining the effectiveness of the sequential use of psychotherapy following response to acute-phase pharmacotherapy in the treatment of adult remitted patients with MDD were selected independently by 2 reviewers.The methods used fulfilled the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. Data extraction and methodologic quality assessment were conducted independently by the reviewers. Examination of the pooled results was performed based on the random-effects model. Heterogeneity between study results and likelihood of significant publication bias were assessed. Sensitivity analyses and meta-regressions were also run.The primary outcome measures were relapse or recurrence rates of MDD, as defined by study investigators, at the longest available follow-up.Seventeen randomized clinical trials met criteria for inclusion in the meta-analysis, with 1 study yielding 2 comparisons (2283 patients overall, with 1208 patients in a sequential treatment arm and 1075 in a control arm). The pooled risk ratio for relapse/recurrence of MDD was 0.84 (95% CI, 0.74-0.94), suggesting a relative advantage in preventing relapse/recurrence for the sequential combination of treatments compared with control conditions.The results of this systematic review and meta-analysis indicate that the sequential integration of psychotherapy following response to acute-phase pharmacotherapy, alone or combined with antidepressant medication, was associated with reduced risk of relapse and recurrence in MDD. The preventive value of the sequential strategy relies on abatement of residual symptoms and/or increase in psychological well-being. The steps for implementing the sequential approach in remitted patients with recurrent MDD are provided.
271P Cost-effectiveness of pembrolizumab as monotherapy or in combination with chemotherapy versus EXTREME regimen for the first-line treatment of recurrent or metastatic head and neck squamous cell carcinoma in Taiwan
Authors: C.H. Wang, H.L. Lei, R. Borse, D. Chirovsky, L. Chien, S.C. Tan, C. Spiteri
Journal: Annals of Oncology (2020)
Endoscopy-Related Bleeding and Thromboembolic Events in Patients on Direct Oral Anticoagulants or Vitamin K Antagonists
Authors: Enrique Rodríguez de Santiago, Rubén Sánchez Aldehuelo, Fausto Riu Pons, Carlos Rodríguez Escaja, Gloria Fernández-Esparrach, Ángel Cañete-Ruiz, Carlos Ferre Aracil, Daniel Pérez-Corte, Raquel Ríos León, Héctor Miguel Marcos-Prieto, Pedro G. Delgado-Guillena, Ana García-Rodríguez, Charly Guarner-Argente, Alfonso Muriel, Elsa de la Fuente-Briongos, Ana García García de Paredes, Sofía Parejo-Carbonell, Luis Téllez, Carla Senosiaín-Lalastra, Diego Burgos-Santamaría, Marta Aicart-Ramos, Beatriz Mateos Muñoz, Beatriz Peñas-García, Giulia Pagano, Gemma Casals Urquiza, Miguel Urpi Ferreruela, Miguel Ángel de Jorge-Turrión, Eva Barreiro-Alonso, Miguel Fraile-López, Ana Gómez-Outomuro, María Isabel Altamirano, Matilde Núñez Esteban, Mireia Ruiz-Andreu, Julia Arribas-Anta, Diego de Frutos, Alberto Herreros-de-Tejada, María Luisa Arias-Rivera, Marta Roldán-Fernández, Ángel F. Marcos Martín, Javier Zamora, Enrique Vázquez-Sequeiros, Agustín Albillos, José Ramón Foruny-Olcina, Aida Argüelles Longoria, Carmen María González González, Juan Ángel González-Martín, Eduardo Tavío-Hernádez, Alba Martínez-Sánchez, Sergio López-Duran, Francisco Mesonero-Gismero, Pablo Pérez Riveras, Ana García Cid, Marta Rodríguez-Carrasco, Teresa Álvarez-Nava Torrego, David Rafael de la Cruz Esteban, María López-Cerón
Journal: Clinical Gastroenterology and Hepatology (2020)
Novel therapeutics in myeloproliferative neoplasms
Authors: Sangeetha Venugopal, John Mascarenhas
Journal: Journal of Hematology & Oncology (2020)

Abstract Hyperactive signaling of the Janus-Associated Kinase/Signal Transducers and Activators of Transcription (JAK/STAT) pathway is central to the pathogenesis of Philadelphia-chromosome-negative myeloproliferative neoplasms (MPN), i.e., polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) which are characterized by inherent biological and clinical heterogeneity. Patients with MPNs suffer from substantial symptom burden and curtailed longevity due to thrombohemorrhagic complications or progression to myelofibrosis or acute myeloid leukemia. Therefore, the management strategies focus on thrombosis risk mitigation in PV/ET, alleviation of symptom burden and improvement in cytopenias and red blood cell transfusion requirements, and disease course alteration in PMF. The United States Food and Drug Administration’s (USFDA) approval of two JAK inhibitors (ruxolitinib, fedratinib) has transformed the therapeutic landscape of MPNs in assuaging the need for frequent therapeutic phlebotomy (PV) and reduction in spleen and symptom burden (PV and PMF). Despite improving biological understanding of these complex clonal hematopoietic stem/progenitor cell neoplasms, none of the currently available therapies appear to modify the proclivity of the disease per se, thereby remaining an urgent unmet clinical need and an ongoing area of intense clinical investigation. This review will highlight the evolving targeted therapeutic agents that are in early- and late-stage MPN clinical development.
Recovery of Regional Left Ventricular Dysfunction After Coronary Revascularization: Impact of Myocardial Viability Assessed by Nuclear Imaging and Vessel Patency at Follow-Up Angiography11This study was supported by Collaborative Research Grant 910576 from the North Atlantic Treaty Organization. It was presented in part at the 43rd Annual Scientific Session of the American College of Cardiology, Atlanta, Georgia, March 1994.
Authors: Juergen vom Dahl, Carsten Altehoefer, Petra Buechin, Rainer Uebis, Bruno J Messmer, Udalrich Buell, Peter Hanrath, Florence H Sheehan
Journal: Journal of the American College of Cardiology (1996)
Abstract 14703: Do Fractional Flow Reserve and Instantaneous Wave Free Ratio Correlate With Exercise Coronary Physiology?
Authors: Matthew Ryan, Bhavik Modi, Haseeb Rahman, Rupert Williams, Satpal Arri, Kaleab N Asrress, Matthew Lumley, Howard Ellis, Brian Clapp, Michael Marber, Simon R Redwood, Divaka Perera
Journal: Circulation (2019)

Introduction: Invasive pressure-derived indices are widely used to discern the functional significance of coronary lesions, but it is not known whether these accurately reflect hemodynamic changes ...
15328 Efficacy and safety of mirikizumab in patients with moderate to severe plaque psoriasis: 104-week results from a randomized phase 2 study
Authors: Robert Bissonnette, Catherine Maari, M. Alan Menter, Chika Ohata, Kim Alexander Papp, Jay L. Tuttle, Paul Klekotka, Karen Huayu Liu, Dipak R. Patel, Kristian Reich
Journal: Journal of the American Academy of Dermatology (2020)