tbuckley/cabot-search huggingface dataset:
Abstract 239: Sex and 17-beta Estradiol Regulate the Nuclear Translocation of the Cardiac L-type Calcium Channel C-terminus
Authors: Shokoufeh Mahmoodzadeh, Hannelore Haase, Anje Sporbert, Ingo Morano
Journal: Circulation Research (2016)

The cardiac L-type Ca 2+ channel (Cav1.2) constitutes the main entrance gate for Ca 2+ that triggers cardiac contraction. It has been shown that the distal C-terminus fragment of Cav1.2 α1C subunit (α1C-dCT) is proteolytically cleaved and shuttles between the plasma membrane and the nucleus, which is regulated both developmentally and by Ca 2+ . However, the effects of sex and sex hormone 17β-Estradiol (E2) on α1C-dCT nuclear translocation are still unexplored. To analyze the sexual disparity in the α1C-dCT nuclear translocation, we first generated an antibody directed against a synthetic peptide (GRRASFHLE) located in α1C-dCT, and used it to probe ventricular myocytes from adult female and male mice. Immunocytochemistry of isolated mouse primary adult ventricular myocytes revealed both nuclear staining and cytosolic punctuate staining around the T-tubules. The ratio of nuclear to cytosolic intensity (I nuc /I cyt ) was significantly higher in isolated female cardiomyocytes (1.42±0.05) compared to male cardiomyocytes (1.05±0.02). Western blot analysis of nuclear fraction confirmed these data. Furthermore, we found a significant decrease in nuclear staining intensity of α1C-dCT in both female and male cardiomyocytes upon serum withdrawal for 18h (I nuc /I cyt 1.05±0.02 and 0.89± 0.02, respectively). Interestingly, subsequent E2 treatment (10 -8 M) for 8h normalized the intracellular distribution of α1C-dCT in male cardiomyocytes (I nuc /I cyt 1.04±0.02), but not in female cardiomyocytes. Acute treatment of male cardiomyocytes with E2 for 45min revealed a similar effect. This effect of E2 was revised by ICI 182780, an estrogen receptor (ER) inhibitor, (10 -5 M), indicating the involvement of ER in this signaling pathway. Taken together, we showed for the first time that the shuttling of α1C-CT in cardiomyocytes is regulated in a sex-dependent manner, and E2-activated ER may play a role in the nuclear shuttling of α1C-dCT in male cardiomyocytes. We suggest that this identified novel signaling mechanism may explain, at least partly, the observed sex differences in the regulation of cardiac Cav1.2 channel activity.
Electronic and Tobacco Cigarettes Alter Polyunsaturated Fatty Acids and Oxidative Biomarkers
Authors: Rajat Gupta, Yan Lin, Karla Luna, Anjali Logue, Alexander J. Yoon, Kacey P. Haptonstall, Roya Moheimani, Yasmine Choroomi, Kevin Nguyen, Elizabeth Tran, Yifang Zhu, Kym F. Faull, Theodoros Kelesidis, Jeffrey Gornbein, Holly R. Middlekauff, Jesus A. Araujo
Journal: Circulation Research (2021)

[Figure: see text].
Rising antimicrobial resistance: an evolving epidemic in a pandemic
Authors: Abi Manesh, George M Varghese
Journal: The Lancet Microbe (2021)

While the second wave of the COVID-19 pandemic is sweeping through India, causing unprecedented human tragedy, the prescription of a plethora of unnecessary antibiotics—without regard for the potential for increased antimicrobial resistance—is widespread and unchecked. In The Lancet Microbe, Clark Russell and colleagues1 highlight the overuse of antimicrobials during the first wave of COVID-19 in the UK, despite the rare incidence of bacterial coinfections. This problem occurs to a greater magnitude in low-income and middle-income countries (LMICs).
A Randomized Trial of a Transglutaminase 2 Inhibitor for Celiac Disease
Authors: Detlef Schuppan, Markku Mäki, Knut E.A. Lundin, Jorma Isola, Tina Friesing-Sosnik, Juha Taavela, Alina Popp, Jari Koskenpato, Jost Langhorst, Øistein Hovde, Marja-Leena Lähdeaho, Stefano Fusco, Michael Schumann, Helga P. Török, Juozas Kupcinskas, Yurdagül Zopf, Ansgar W. Lohse, Mika Scheinin, Karin Kull, Luc Biedermann, Valerie Byrnes, Andreas Stallmach, Jørgen Jahnsen, Jonas Zeitz, Ralf Mohrbacher, Roland Greinwald
Journal: New England Journal of Medicine (2021)

In celiac disease, small intestinal transglutaminase 2 causes deamidation of glutamine residues in gluten peptides, which enhances stimulation of T cells and leads to mucosal injury. Inhibition of transglutaminase 2 is a potential treatment for celiac disease.In a proof-of-concept trial, we assessed the efficacy and safety of a 6-week treatment with ZED1227, a selective oral transglutaminase 2 inhibitor, at three dose levels as compared with placebo, in adults with well-controlled celiac disease who underwent a daily gluten challenge. The primary end point was the attenuation of gluten-induced mucosal damage, as measured by the ratio of villus height to crypt depth. Secondary end points included intraepithelial lymphocyte density, the Celiac Symptom Index score, and the Celiac Disease Questionnaire score (for assessment of health-related quality of life).Of the 41 patients assigned to the 10-mg ZED1227 group, the 41 assigned to the 50-mg group, the 41 assigned to the 100-mg group, and the 40 assigned to the placebo group, 35, 39, 38, and 30 patients, respectively, had adequate duodenal-biopsy samples for the assessment of the primary end point. Treatment with ZED1227 at all three dose levels attenuated gluten-induced duodenal mucosal injury. The estimated difference from placebo in the change in the mean ratio of villus height to crypt depth from baseline to week 6 was 0.44 (95% confidence interval [CI], 0.15 to 0.73) in the 10-mg group (P = 0.001), 0.49 (95% CI, 0.20 to 0.77) in the 50-mg group (P<0.001), and 0.48 (95% CI, 0.20 to 0.77) in the 100-mg group (P<0.001). The estimated differences from placebo in the change in intraepithelial lymphocyte density were -2.7 cells per 100 epithelial cells (95% CI, -7.6 to 2.2) in the 10-mg group, -4.2 cells per 100 epithelial cells (95% CI, -8.9 to 0.6) in the 50-mg group, and -9.6 cells per 100 epithelial cells (95% CI, -14.4 to -4.8) in the 100-mg group. Use of the 100-mg dose may have improved symptom and quality-of-life scores. The most common adverse events, the incidences of which were similar across all groups, were headache, nausea, diarrhea, vomiting, and abdominal pain. Rash developed in 3 of 40 patients (8%) in the 100-mg group.In this preliminary trial, treatment with ZED1227 attenuated gluten-induced duodenal mucosal damage in patients with celiac disease. (Funded by Dr. Falk Pharma; CEC-3 EudraCT number, 2017-002241-30.).
Duke University settles lawsuits alleging that patients were harmed in chemotherapy trials
Authors: C. Dyer
Journal: BMJ (2015)

Duke University in North Carolina has settled lawsuits alleging that patients with cancer were “fraudulently” entered into clinical trials that were based on flawed research by the oncologist Anil Potti.

Eight lawsuits were filed against Duke and Potti by patients or deceased patients’ estates, claiming that they were exposed to unnecessary and harmful chemotherapy during the trials, which were finally discontinued in 2010. …
Comprehensive Genetic Characterization of 63 Myeloid/Lymphoid Neoplasms Associated with Eosinophilia and Rearrangement of PDGFR-α, PDGFR-β, FGFR1 or PCM1-JAK2
Authors: Constance Regina Baer, Verena Muehlbacher, Wolfgang Kern, Claudia Haferlach, Torsten Haferlach
Journal: Blood (2017)
Abstract 12821: Home-Based Management for Chronic Heart Failure Reduces Recurrent Hospital Stay and Total Healthcare Costs Compared to a Clinic-Based Program: Results from the WHICH? Trial
Authors: Simon Stewart, Yih K Chan, Melinda J Carrington, Paul Scuffham, Which Trial Investigators
Journal: Circulation (2012)

BACKGROUND: Hospitalization is the most costly component of healthcare for chronic heart failure (CHF). The Which Heart failure Intervention is most Cost-effective & consumer friendly in reducing H...
A community-acquired Legionnaires’ disease outbreak caused by Legionella pneumophila serogroup 2: an uncommon event, Italy, August to October 2018
Authors: Maria Scaturro, Maria Cristina Rota, Maria Grazia Caporali, Antonietta Girolamo, Michele Magoni, Daria Barberis, Chiara Romano, Danilo Cereda, Maria Gramegna, Antonio Piro, Silvia Corbellini, Cinzia Giagulli, Giovanni Rezza, Arnaldo Caruso, Maria Luisa Ricci
Journal: Eurosurveillance (2021)

In September 2018 in Brescia province, northern Italy, an outbreak of Legionnaires' disease (LD) caused by Legionella pneumophila serogroup 2 ( Lp2 ) occurred. The 33 cases (two fatal) resided in seven municipalities along the Chiese river. All cases were negative by urinary antigen test (UAT) and most were diagnosed by real-time PCR and serology. In only three cases, respiratory sample cultures were positive, and Lp2 was identified and typed as sequence type (ST)1455. In another three cases, nested sequence-based typing was directly applied to respiratory samples, which provided allelic profiles highly similar to ST1455. An environmental investigation was undertaken immediately and water samples were collected from private homes, municipal water systems, cooling towers and the river. Overall, 533 environmental water samples were analysed and 34 were positive for Lp . Of these, only three samples, all collected from the Chiese river, were Lp2 ST1455. If and how the river water could have been aerosolised causing the LD cases remains unexplained. This outbreak, the first to our knowledge caused by Lp2 , highlights the limits of UAT for LD diagnosis, underlining the importance of adopting multiple tests to ensure that serogroups other than serogroup 1, as well as other Legionella species, are identified.
Germline POT1 variants can predispose to myeloid and lymphoid neoplasms
Authors: Tristan L. Lim, David B. Lieberman, Adam R. Davis, Alison W. Loren, Ryan Hausler, Ashkan Bigdeli, Yimei Li, Jacquelyn Powers, Anna Raper, None Regeneron Genetics Center, Shannon A. Carty, Katherine L. Nathanson, Adam Bagg, Elizabeth O. Hexner, Kara N. Maxwell, Jennifer J. D. Morrissette, Daria V. Babushok
Journal: Leukemia (2021)
Abstract 310: Beta-adrenergic Receptor/beta-arrestin-mediated MicroRNA Maturation Confers Cardiac Cell Survival
Authors: Jian-peng Teoh, Il-man Kim
Journal: Circulation Research (2016)

MicroRNAs (miRs) are small, non-coding RNAs that function to post-transcriptionally regulate gene expression. First transcribed as primary miR transcripts (pri-miRs), they are enzymatically processed in the nucleus by Drosha into hairpin-shaped premature miRs (pre-miRs) and further processed in the cytoplasm by Dicer into mature miRs. MiRs regulate cellular processes upon activation by various signals such as those stimulated by beta-adrenergic receptors (betaARs). Initially discovered to desensitize betaAR signaling, beta-arrestins are now appreciated to regulate diverse effector pathways independent of G protein-mediated second messenger accumulation, a concept known as biased signaling. Using the beta-arrestin-biased betaAR ligand carvedilol (Carv), we test whether Carv could modulate Dicer-mediated miR maturation, thereby providing a novel mechanism for its cardioprotective effects. In mouse hearts, Carv indeed upregulates 3 mature miRs, but not their pre-miRs and pri-miRs, in beta-arrestin1/2- and GPCR kinase 5/6-dependent manners. Interestingly, Carv-mediated activation of miR-466g and miR-532-5p is dependent on beta2AR while the activation of miR-674-5p by Carv is beta1AR-dependent. Mechanistically, beta-arrestins regulate miR maturation by associating with components of Dicer complex on these three pre-miRs (Figure A). Loss-of-function studies in cardiac cells show that miR-466g and miR-532-5p act as gatekeepers of cardiac endothelial cell survival (Figure B). Our findings indicate a novel role for betaAR-mediated beta-arrestin signaling activated by Carv in miR maturation, which may be linked, in part, to its cell survival mechanism.
A neural circuit for excessive feeding driven by environmental context in mice
Authors: Hasan Mohammad, Esra Senol, Martin Graf, Chun-Yao Lee, Qin Li, Qing Liu, Xin Yi Yeo, Menghan Wang, Achilleas Laskaratos, Fuqiang Xu, Sarah Xinwei Luo, Sangyong Jung, George J. Augustine, Yu Fu
Journal: Nature Neuroscience (2021)
Unique Inflammatory Signature in Hemophilic Arthropathy: Epigenetic Changes Due to Interaction between Blood and Fibroblast-like Synoviocytes
Authors: Sandra Mignot, Chantal Rothschild, Annie Harroche, Julien Even, Nicolas Cagnard, Richard Delarue, Benoit Albaut, Olivier Hermine, Laurent Frenzel
Journal: Blood (2017)
DOCK2/Rac依存経路を経たCD4(+)T細胞同時刺激を媒介するCCL21
Authors: Stein Jv, Donnadieu E, Fukui Y, Peterson, Vanhaesebroeck B, Okkenhaug K, Gollmer K, Asperti-Boursin F, Tanaka Y
Journal: Blood (2009)
Abstract 287: Obesity Accelerates T Cell Senescence
Authors: Kohsuke Shirakawa, Tsunehisa Yamamoto, Jin Enso, Keiichi Fukuda, Motoaki Sano
Journal: Circulation Research (2016)

Obesity is associated with accelerated biological aging and predisposes to the early onset of aging-related diseases. We investigate how obesity causes aging. Diet-induced adiposity was associated with an accumulation of programmed cell death-1 (PD-1)+ memory phenotype (MP) CD4+ T cells having features of cell senescence in visceral adipose tissue (VAT). The PD-1+ MP CD4+ T cells stimulated macrophage infiltration and promoted M1 macrophage polarization, while reducing regulatory T cells in VAT. High fat diet (HFD) induced conversion of naïve T cells to PD-1+ MP T cells in a macrophage- and B cell-dependent manner. Immunological depletion of PD-1+ T cells attenuated adipose inflammation and reversed insulin resistance in HFD-induced obese mice, while adoptive transfer of PD-1+ MP CD4+ T cells in VAT induced adipose inflammation and insulin resistance in non-obese mice. We propose that T cell senescence originating in VAT contributes to the mechanism of how obesity causes aging.
Abstract 11820: Outcomes in Anomalous Aortic Origin of a Coronary Artery Following Surgical Reimplantation in a Prospective Cohort
Authors: Carlos Bonilla-Ramirez, Binsalamah Ziyad, Prakash Masand, Shagun Sachdeva, Dana Reaves-O’Neal, Christopher Caldarone, Silvana M Molossi
Journal: Circulation (2019)

Introduction: Outcomes data is limited following coronary reimplantation in anomalous aortic origin of a coronary artery (AAOCA). Objective: To describe clinical, surgical, and outcome data in AAOC...
Treatment with HIV-Protease Inhibitor Nelfinavir Identifies Membrane Lipid Composition and Fluidity as a Therapeutic Target in Advanced Multiple Myeloma
Authors: Lenka Besse, Andrej Besse, Sara C. Stolze, Amin Sobh, Esther A. Zaal, Alwin J. van der Ham, Mario Ruiz, Santosh Phuyal, Lorina Büchler, Marc Sathianathan, Bogdan I. Florea, Jan Borén, Marcus Ståhlman, Julia Huber, Arnold Bolomsky, Heinz Ludwig, J. Thomas Hannich, Alex Loguinov, Bart Everts, Celia R. Berkers, Marc Pilon, Hesso Farhan, Christopher D. Vulpe, Herman S. Overkleeft, Christoph Driessen
Journal: Cancer Research (2021)

The HIV-protease inhibitor nelfinavir has shown broad anticancer activity in various preclinical and clinical contexts. In patients with advanced, proteasome inhibitor (PI)-refractory multiple myeloma, nelfinavir-based therapy resulted in 65% partial response or better, suggesting that this may be a highly active chemotherapeutic option in this setting. The broad anticancer mechanism of action of nelfinavir implies that it interferes with fundamental aspects of cancer cell biology. We combined proteome-wide affinity-purification of nelfinavir-interacting proteins with genome-wide CRISPR/Cas9-based screening to identify protein partners that interact with nelfinavir in an activity-dependent manner alongside candidate genetic contributors affecting nelfinavir cytotoxicity. Nelfinavir had multiple activity-specific binding partners embedded in lipid bilayers of mitochondria and the endoplasmic reticulum. Nelfinavir affected the fluidity and composition of lipid-rich membranes, disrupted mitochondrial respiration, blocked vesicular transport, and affected the function of membrane-embedded drug efflux transporter ABCB1, triggering the integrated stress response. Sensitivity to nelfinavir was dependent on ADIPOR2, which maintains membrane fluidity by promoting fatty acid desaturation and incorporation into phospholipids. Supplementation with fatty acids prevented the nelfinavir-induced effect on mitochondrial metabolism, drug-efflux transporters, and stress-response activation. Conversely, depletion of fatty acids/cholesterol pools by the FDA-approved drug ezetimibe showed a synergistic anticancer activity with nelfinavir in vitro. These results identify the modification of lipid-rich membranes by nelfinavir as a novel mechanism of action to achieve broad anticancer activity, which may be suitable for the treatment of PI-refractory multiple myeloma. SIGNIFICANCE: Nelfinavir induces lipid bilayer stress in cellular organelles that disrupts mitochondrial respiration and transmembrane protein transport, resulting in broad anticancer activity via metabolic rewiring and activation of the unfolded protein response.
APPLAUSE: Automatic Prediction of PLAcental health via U-net Segmentation and statistical Evaluation
Authors: Maximilian Pietsch, Alison Ho, Alessia Bardanzellu, Aya Mutaz Ahmad Zeidan, Lucy C. Chappell, Joseph V. Hajnal, Mary Rutherford, Jana Hutter
Journal: Medical Image Analysis (2021)

Purpose:Artificial-intelligence population-based automated quantification of placental maturation and health from a rapid functional Magnetic Resonance scan. The placenta plays a crucial role for any successful human pregnancy. Deviations from the normal dynamic maturation throughout gestation are closely linked to major pregnancy complications. Antenatal assessment in-vivo using T2* relaxometry has shown great promise to inform management and possible interventions but clinical translation is hampered by time consuming manual segmentation and analysis techniques based on comparison against normative curves over gestation. Methods:This study proposes a fully automatic pipeline to predict the biological age and health of the placenta based on a free-breathing rapid (sub-30 second) T2* scan in two steps: Automatic segmentation using a U-Net and a Gaussian process regression model to characterize placental maturation and health. These are trained and evaluated on 108 3T MRI placental data sets, the evaluation included 20 high-risk pregnancies diagnosed with pre-eclampsia and/or fetal growth restriction. An independent cohort imaged at 1.5 T is used to assess the generalization of the training and evaluation pipeline. Results: Across low- and high-risk groups, automatic segmentation performs worse than inter-rater performance (mean Dice coefficients of 0.58 and 0.68, respectively) but is sufficient for estimating placental mean T2* (0.986 Pearson Correlation Coefficient). The placental health prediction achieves an excellent ability to differentiate cases of placental insufficiency between 27 and 33 weeks. High abnormality scores correlate with low birth weight, premature birth and histopathological findings. Retrospective application on a different cohort imaged at 1.5 T illustrates the ability for direct clinical translation. Conclusion:The presented automatic pipeline facilitates a fast, robust and reliable prediction of placental maturation. It yields human-interpretable and verifiable intermediate results and quantifies uncertainties on the cohort-level and for individual predictions. The proposed machine-learning pipeline runs in close to real-time and, deployed in clinical settings, has the potential to become a cornerstone of diagnosis and intervention of placental insufficiency. APPLAUSE generalizes to an independent cohort imaged at 1.5 T, demonstrating robustness to different operational and clinical environments.
Short-term dose and duration-dependent glucocorticoid risk for cardiovascular events in glucocorticoid-naive patients with rheumatoid arthritis
Authors: Anthony James Ocon, George Reed, Dimitrios A Pappas, Jeffrey R Curtis, Joel M Kremer
Journal: Annals of the Rheumatic Diseases (2021)

Objectives Rheumatoid arthritis (RA), along with glucocorticoid use, is associated with cardiovascular disease. Cardiovascular safety of glucocorticoids in RA is controversial and may be related to dose and duration of use. We determined if initiating glucocorticoids in steroid-naive RA patients would increase cardiovascular event (CVE) risk in a dose and duration-dependent manner over short-term intervals. Methods Patients enrolled in CorEvitas (formerly Corrona) RA registry. Cox proportional-hazards models estimated adjusted HRs (aHR) for incident CVE in patients who initiated glucocorticoid treatment, adjusting for RA duration, traditional cardiovascular risk factors and time-varying covariates: Clinical Disease activity Index, disease-modifying antirheumatic drugs use and prednisone-equivalent use. Glucocorticoid use assessed current daily dose, cumulative dose and duration of use over rolling intervals of preceding 6 months and 1 year. Results 19 902 patients met criteria. 1106 CVE occurred (1.66/100 person-years). Increased aHR occurred at current doses of ≥5–9 mg 1.56 (1.18–2.06) and ≥10 mg 1.91 (1.31–2.79), without increased risk at 0–4 mg 1.04 (0.55–1.59). Cumulative dose over preceding 6 months showed increased aHR at 751–1100 mg 1.43 (1.04–1.98) and &gt;1100 mg 2.05 (1.42–2.94), without increased risk at lower doses; duration of use over preceding 6 months exhibited increased aHR for &gt;81 days of use 1.54 (1.08–2.32), without increased risk at shorter durations. One-year analyses were consistent. Conclusions Over preceding 6-month and 1-year intervals, initiating glucocorticoids in steroid-naïve RA patients is associated with increased risk of CVE at daily doses ≥5 mg and increased cumulative dose and duration of use. No association with risk for CVE was found with daily prednisone of ≤4 mg or shorter cumulative doses and durations.
The accuracy of forced vital capacity for diagnosing restrictive allograft syndrome and mixed phenotype of chronic lung allograft dysfunction
Authors: Liran Levy, Ella Huszti, Gregory Berra, Benjamin Renaud-Picard, Mitsuaki Kawashima, Akihiro Takahagi, Sajad Moshkelgosha, Rasheed Ghany, Eyal Fuchs, Chung-Wai Chow, Shaf Keshavjee, Lianne G. Singer, Jussi Tikkanen, Tereza Martinu
Journal: European Respiratory Journal (2021)

<b>In lung transplant recipients with suspected restrictive allograft syndrome/mixed phenotype and a preserved forced vital capacity, accurate phenotyping requires routine measurements of total lung capacity</b>https://bit.ly/3e2qxdP