tbuckley/cabot-search huggingface dataset:
Abstract 505: Adenovirus Targets Connexin43 Gap Junction Expression and Function During Infection
Authors: Jordan D Taylor, Patrick J Calhoun, Carissa C James, Allen V Phan, James W Smyth
Journal: Circulation Research (2019)

Introduction: Myocarditis leads to pathologic remodeling of the myocardium and arrhythmia. A leading etiological agent of viral myocarditis is human Adenovirus type 5 (Ad5). Individuals affected are at a higher risk of arrhythmogenesis which can lead to sudden cardiac death. Gap junctions, comprised of connexin proteins, provide direct intercellular communication between cardiomyocytes to facilitate electrical coupling. Connexin43 (Cx43) is the predominant connexin expressed in the working myocardium and is tightly regulated by post-translational modifications. Gap junctions are also known to propagate the innate antiviral immune response but the impact of Ad5 infection on Cx43 expression and function is essentially unexplored. Hypothesis: During Ad5 infection Cx43 gap junctions are directly targeted to limit intercellular communication thus precipitating an arrhythmogenic substrate. Methods: Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), keratinocytes (HaCaT), and lentivirus-transduced HaCaTs stably overexpressing Cx43 were infected with Ad5. Biochemical fractionation and pulse chase assays were implemented to determine gap junction and Cx43 stability. Cx43 protein levels and phosphorylation status were determined by western blotting and immunoprecipitation experiments. Confocal immunofluorescence microscopy was employed determine localization and functional of Cx43 during Ad5 infection. Results: Cx43 expression is targeted early in infection with remaining protein localized at the cell-cell boarder during infection. Phosphorylation of Cx43-Ser368 was detected during early Ad5 infection implicating reduced gap junction conductance. In contrast phosphorylation of Cx43-Ser262 is reduced during Ad5 infection with a concomitant increase in protein half-life despite losses in functional gap junction intercellular communication. Conclusion: Cx43 gap junction structures are stabilized during Ad5 infection but directly targeted by specific phosphorylation events to effect channel closure. Insight provided into mechanisms by which Ad5 manipulates Cx43 regulation will provide novel therapeutic avenues to target gap junction function in a broad spectrum of heart disease states.
<i>Man’s 4th Best Hospital</i>
Authors: Samuel Shem
Journal: JAMA (2019)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Single Centre Experience in Treating Elderly Patients with Acute Myeloid Leukaemia or High Risk Myelodysplastic Syndrome with a Combination of Low Dose Cytarabine, Venetoclax and Fluconazole (VeLDAC-F)
Authors: Lauren Child, Henry Chan, Ross Alistair Henderson, Anna Elinder, Eileen Merriman, Merit Hanna, David Simpson
Journal: Blood (2018)
Abstract 857: MCUB Regulates the Molecular Composition of the Mitochondrial Calcium Uniporter Channel During Cardiac Stress to Limit Mitochondrial Calcium Overload
Authors: Jonathan P Lambert, Timothy S Luongo, Dhanendra Tomar, Pooja Jadiya, Erhe Gao, Xueqian Zhang, Anna M Lucchese, Devin W Kolmetzky, Neil Shah, John W Elrod
Journal: Circulation Research (2019)

The mitochondrial calcium uniporter (mtCU) is a ~700 kD multi-subunit channel residing in the inner mitochondrial membrane required for mitochondrial Ca 2+ ( m Ca 2+ ) uptake. Mitochondrial Calcium Uniporter B ( MCUB ) is reported to negatively regulate m Ca 2+ uptake, but its precise functional role and contribution to cardiac physiology remain unresolved. Size exclusion chromatography of ventricular mitochondria revealed MCUB was absent from high-molecular weight (MW) mtCU complexes in sham animals, but present 24 hours following myocardial ischemia-reperfusion injury (IR). To investigate MCUB ’s contribution to mtCU regulation we created a MCUB -/- cell line by CRISPR-Cas9n. MCUB deletion increased histamine-mediated [ m Ca 2+ ] transient amplitude by ~50% vs. WT controls (mito-R-GECO1). MCUB deletion increased mtCU capacitance (mitoplast patch-clamp) and rate of [ m Ca 2+ ] uptake. Size-exclusion chromatography revealed loss of MCUB increased MCU incorporation into high-MW mtCU, suggesting stoichiometric replacement and overall more functional mtCU’s. To examine MCUB’s role in cardiac physiology we generated a cardiac-specific, tamoxifen-inducible MCUB mouse model (CAG-CAT-MCUB x MCM; MCUB-Tg). FPLC revealed MCUB was undetected in high-MW mtCU complexes of Cre controls, but enriched in MCUB-Tg hearts. MCUB incorporation decreased the presence of channel gatekeepers, MICU1/2, and decreased the MW of the mtCU complex. Immunoprecipitations suggest MCUB interacts with MCU but not MICU1/2. MCUB-Tg adult cardiomyocytes (ACMs) expressing AAV9-mitycam ( m Ca 2+ reporter) were paced and displayed a ~30% decrease in m Ca 2+ transient peak amplitude with significantly reduced m Ca 2+ uptake rates vs controls. A reduction in OxPhos reserve capacity correlated with a severe impairment in cardiac contractile reserve (LV invasive hemodynamics during isoproterenol infusion). MCUB-Tg cardiac mitochondria were resistant to Ca 2+ -induced permeability transition and MCUB-Tg mice displayed ~50% decrease in infarct size per area-at-risk after in vivo IR-injury. These data suggest MCUB regulation of the mtCU is an endogenous compensatory mechanism to decrease m Ca 2+ overload during ischemic injury, but maladaptive to cardiac energetic responsiveness.
Abstract 422: Placental Cdx2 Cells Regenerate Injured Myocardium
Authors: Sangeetha Vadakke-madathil, Gina Larocca, Koen Raedschelders, Jesse Yoon, Joseph Tripodi, Vesna Najfeld, Jennifer E Van-Eyk, Hina W Chaudhry
Journal: Circulation Research (2019)

The limited regeneration of adult mammalian heart has prompted the need to recognize novel strategies that can restore contractile function in heart disease. However, in cell-based therapies the lack of an appropriate cell-type that can differentiate to cardiomyocytes in vivo persists as an ultimate unmet need. Our prior study demonstrates that experimental myocardial injury in pregnant mice triggers the flux of fetal cells via the maternal circulation into the injured heart where they undergo differentiation into diverse cardiac cell fates. Among those fetal cells, the expression of Caudal type homeobox2 (Cdx2); a trophoblast stem cell marker was unique. To understand the intriguing role of placental Cdx2 cells in cardiomyogenesis, we utilized a lineage-tracing strategy to label fetal-derived Cdx2 cells with enhanced green fluorescent protein (Cdx2-eGFP). Cdx2-eGFP cells were characterized and assayed for cardiac differentiation in vitro and in vivo using a mouse model of myocardial infarction. Cdx2-eGFP cells clonally proliferated and differentiated into spontaneously beating cardiomyocytes and vascular cells in vitro , signifying a multipotent nature compared to the Cdx2 negative cell population. When administered via tail vein to infarcted wild-type male mice, Cdx2-eGFP cells selectively and robustly homed to the injured heart and differentiated to cardiomyocytes and blood vessels, significantly improving the contractility noted by magnetic resonance imaging. Proteomics and immune transcriptomics studies of Cdx2-eGFP cells compared to embryonic stem (ES) cells reveal that they appear to retain ‘stem’-related functions of ES cells, but exhibit unique signatures for homing and survival in addition to being immunologically naive. Blocking CXCR4, during the migration of Cdx2-eGFP cells to SDF1α suggested a possible role for SDF1-CXCR4 signaling in the mechanistic basis of homing. Advancing towards a translational role, we demonstrate that CDX2 expressing cells can be isolated from the chorionic region of human term placenta. Our results herein may represent a paradigmatic shift in the way we approach early embryonic lineages and cell fate choices and will establish the translational potential of placental Cdx2 cells for cardiac repair.
Abstract 515: WNT the Right Ventricle’s Had Enough
Authors: Jonathan J Edwards, Jeffrey Brandimarto, Kenneth Bedi, Kenneth B Margulies, Zoltan P Arany
Journal: Circulation Research (2019)

Background: A greater understanding of the gene programs that drive adaptive and pathologic right ventricle (RV) remodeling are needed given the poor response of the RV to standard reverse remodeling agents and the absence of RV-specific therapies. Left ventricular failure (LVF) provides an ideal model to study human RV remodeling given the spectrum of secondary RV involvement. Methods: Dilated (DCM) and ischemic cardiomyopathy (ICM) hearts in the Penn Human Heart Tissue Bank were identified as having preserved RV function (pRV) or RVF using preexplant right atrial to wedge pressure ratio. Using RT-PCR and a candidate gene approach, we assessed RV differential expression of 28 WNT -related genes and NPPA/NPPB as positive controls between nonfailing (NF, n= 29), DCM-pRV (n = 47), DCM-RVF (n = 26), ICM-pRV (n = 31), and ICM-RVF (n = 10). Genes which met significance for differential expression between NF, pRV, and RVF for both DCM and ICM using Kruskal-Wallis were further assessed by Mann Whitney U comparing pRV to RVF after combining ICM and DCM groups (Benjamini-Hochberg p &lt; 0.05 for significance). Results: Most (20/28) WNT -related genes were differentially expressed in at least one cardiomyopathy group, but only 13, as well as NPPA, were significant for both DCM and ICM. Only, CREBBP, NFATC2, and ROR2 were differentially expressed between pRV and RVF (Table). Discussion: WNT -related genes show significant DGE in RV remodeling. But, of those tested, only CREBBP, NFATC2, and ROR2 appear to be implicated in the progression from adaptive to pathologic RV remodeling. Additional studies are underway to confirm differential protein expression.
Atiprimod Blocks STAT3 and STAT5 Phosphorylation, Inhibits Proliferation, and Induces Apoptosis in Acute Myeloid Leukemia (AML) but Not Normal Cells.
Authors: Stefan Faderl, Alessandra Ferrajoli, David Harris, Quin Van, Hagop M. Kantarjian, Zeev Estrov
Journal: Blood (2005)
Benefit of Two Additional Cycles of Bortezomib/Thalidomide/Dexamethasone (VTD) Induction Therapy Compared to Four Cycles of VTD for Newly Diagnosed Multiple Myeloma
Authors: Yoojin Lee, Kihyun Kim, Sang Kyun Sohn, Dongwon Back, Joon Ho Moon, Je-Jung Lee, Jae-Cheol Jo, Won-Sik Lee, Ho-Jin Shin, Sung-Hyun Kim, Ji Hyun Lee, Sung Hwa Bae, Min Kyoung Kim, Ho Sup Lee, Chang-Ki Min
Journal: Blood (2018)
Abstract 560: Differences in GCN5L1 Expression Between Male and Female Hearts Are Associated With Increased Mitochondrial Protein Acetylation
Authors: Janet R Manning, Dharendra Thapa, Manling Zhang, Michael Stoner, Iain Scott
Journal: Circulation Research (2019)

Introduction: Historically, most preclinical heart research has relied predominantly on male subjects, despite the identification of significant differences in signaling, metabolism, and pathology between males and females. Delineating the mechanisms behind these sex differences is critical to the effective application of novel findings to the general population as a whole. GCN5L1 is a mitochondrial-targeted protein that drives the acetylation and activation/deactivation of several metabolic proteins, and which has recently been reported to regulate cardiac metabolism and recovery from ischemia-reperfusion. It is unknown whether GCN5L1 plays a role in sex-specific differences in the myocardium. Hypothesis: Differential regulation of myocardial GCN5L1 expression between male and female animals results in differences in the acetylation and activity of proteins that regulate glucose and fatty acid oxidation. Methods: Heart lysates from male and female mice were probed for the expression of GCN5L1, and the acetylation status of whole cell and mitochondrial protein fractions was analyzed. Proliferating cardiac cells were treated with 17β-estradiol, and the expression of GCN5L1 was evaluated by immunoblotting. The acetylation status of mitochondrial proteins was measured using immunoblotting and immunoprecipitation. Results and Conclusions: Significant differences in cardiac GCN5L1 protein expression were found between male and female mice. In contrast, there was no difference in the protein expression of SIRT3, the mitochondrial deacetylase enzyme previously shown to counter GCN5L1 activity. Mitochondrial acetylation levels were found to be different between male and female mice. Treatment of cardiac cells with estradiol resulted in increased GCN5L1 expression, with a concurrent increase in the acetylation status of GCN5L1 targets localized to mitochondria. We conclude that sex-based differences in mitochondrial protein acetylation may be mediated by hormone-induced changes in GCN5L1 expression.
Is it the shoes? A simple proposal for regulating footwear in road running
Authors: Geoffrey T Burns, Nicholas Tam
Journal: British Journal of Sports Medicine (2019)

In 2018, runners wearing the new Nike Vaporfly 4% running shoe broke world records over the 100 km, marathon, half-marathon and 15 km distances. This shoe has advanced the benefit of footwear further and more substantially than any other previous shoe. When Nike compared its energetic cost (running economy) to contemporary elite racing shoes, the Vaporfly provided a 4% improvement in economy (hence the shoe’s moniker) and an estimated 3.4% increase in running speed.1 Subsequent independent laboratory testing2 and big-data performance analyses3 have corroborated the benefit.

The International Association of Athletics Federations (IAAF) rule 143.2 stipulates that shoes ‘must not be constructed so as to give athletes any unfair assistance or advantage’.4 While the Vaporfly gives runners an advantage, it does not violate current IAAF rules. However, many in the running community debate whether this shoe blurs the line between physiological and technological performance, and many have called for more explicit regulations.

The Vaporfly deviates from conventional running shoes in three ways: (1) an embedded carbon-fibre plate, (2) its midsole material, and (3) its midsole thickness (figure 1). Each of these components has design features that reduce energy loss in isolation and, perhaps more-so, in combination.



Figure 1 
Schematic of the Nike Vaporfly 4% (images adapted from Nike.com)



### Carbon-fibre plate

The full-length embedded carbon-fibre plate increases the longitudinal bending stiffness of …
Development of a multidisciplinary approach to supportive care for patients with genitourinary cancers.
Authors: Liana Yocavitch, Gregory D. Garber, Alison Petok, Brooke Worster, Nathan Handley
Journal: Journal of Clinical Oncology (2019)

88 Background: Patients with cancer who engage early with palliative care may experience improved quality of life (QOL), increased overall survival (OS), and decreased acute care utilization. The Neu Center for Supportive Medicine and Cancer Survivorship (NCSMC) at Thomas Jefferson University is a program designed to identify patients who would benefit from early intervention palliative and supportive care and deliver appropriate services. After initial experience with the model in patients with gastrointestinal and head and neck malignancies, the NCSMC is expanding to patients with genitourinary cancers. Methods: A multidisciplinary team consisting of palliative care physicians, social work, psychology, and navigation conducts biopsychosocial screening (using the NCCN Distress Thermometer) and initiates a personalized care plan for each patient to clarify treatment goals and offer assistance. Prior to deploying the program, multiple stakeholders were engaged to discuss optimal screening points in the patient journey. Patients with a new cancer diagnosis are approached at a post-operative visit in the urology clinic; patients with high distress or significant barriers are discussed at a weekly interdisciplinary meeting with a team of physicians, nurses, social workers, and psychiatry. Patients are subsequently referred to services identified as potentially beneficial. Results: In the first 10 weeks of the program, 67 patients with new diagnoses of bladder (28, 41.8%), prostate (21, 31.3%), kidney (12, 17.9%), urothelial (5, 7.5%), and testicular (1, 1.5%) cancers were screened. 38 (59.4%) patients were identified as low distress; 24 patients (36%) were identified as high distress and offered NCSMC services. Two patients utilized services. Conclusions: Distress and barriers to care amongst patients with newly diagnosed genitourinary cancers are highly variable. While evaluating all patients in the immediate post-operative period is effective at identifying affected patients, the process is resource intensive. An iterative approach testing the intervention at different points in the patient journey is ongoing. As the program matures, impact on QOL, OS, and utilization will be measured.
Unsuspected Pulmonary Emboli Identified on Routine Cancer Staging MDCT Scans: Impact on Cancer Survival
Authors: Casey L O’Connell, Mohammad Ghalichi, Soames Boyle, Sheila Vasan, William Boswell, Pedram Razavi, Kristen Grabow, Lisa Mark, Amy Caton, Howard Liebman
Journal: Blood (2008)
Abstract 261: Excessive O-GlcNAcylation Causes Heart Failure
Authors: Mahaa Umapathi, Olurotimi Mesubi, Jon Granger, Qinchuan Wang, Yuejin Wu, Elizabeth Luczak, Gerald Hart, Mark Anderson
Journal: Circulation Research (2019)

Increased protein O -GlcNAcylation (OGN) is a common feature of failing heart muscle. However, it is unknown if excessive OGN contributes to cardiomyopathy and heart failure. OGN levels are determined by the net activity of two enzymes: OGT ( O -GlcNAc transferase, adds OGN) and OGA ( O -GlcNAcase, removes OGN). We hypothesized that excessive myocardial OGN is a cause of cardiomyopathy. To test for a role of OGN in cardiomyopathy we developed new transgenic (TG) mouse models with myocardial overexpression of OGT or OGA. The OGT-TG hearts showed progressive decline in left ventricular (LV) systolic function, dilation, increased mass (Figure A, B) (Statistical Analysis ANOVA - *** = p&lt;0.001) and increased OGN (Figure C) . OGT-TG mice showed premature mortality compared to WT littermates (Figure D). In contrast, OGA-TG mice exhibit normal contractility, do not have significantly different OGN and have normal lifespan compared to WT littermates. Hearts from OGT-TG and OGA-TG interbred mice have marked improvement of LV systolic function, lower OGN and normal lifespan. We next tested if attenuation of myocardial OGN was beneficial in acquired cardiomyopathy by performing transverse aortic constriction surgery (TAC) on OGA-TG and WT littermates. The OGA-TG hearts had lower OGN, improved LV systolic function, less hypertrophy, and lower expression of heart failure genes compared to WT littermates after TAC. Our data identify excessive OGN as an independent mechanism for cardiomyopathy, and suggest attenuation of OGN may be an effective therapy for heart failure.
EBV-Related Post-Transplant Lymphoproliferative Disease in Allogeneic Hematopoietic Cell Transplantation: Single-Center Experience and Considerations Regarding CNS Involvement
Authors: Anna Vardi, Ioanna Sakellari, Andriana Lazaridou, Apostolia Papalexandri, Ioannis Batsis, Despina Mallouri, Anastasia Marvaki, Tasoula Touloumenidou, Evangelia Yannaki, Michalis Iskas, Varnavas Constantinou, Eleni Gavriilaki, Styliani Papaemmanouil, Achilles Anagnostopoulos
Journal: Blood (2018)
Presurgical evaluation of basal cell carcinoma using combined reflectance confocal microscopy–optical coherence tomography: A prospective study
Authors: Saud Aleissa, Cristian Navarrete-Dechent, Miguel Cordova, Aditi Sahu, Stephen W. Dusza, William Phillips, Anthony Rossi, Erica Lee, Kishwer S. Nehal
Journal: Journal of the American Academy of Dermatology (2019)
Prognostic Impact of MYC Oncoprotein Expression on Survival Outcome in Secondary AML Patients
Authors: Seongseok Yun, Rohit Sharma, David A Sallman, Nicole D. Vincelette, Kendra L. Sweet, Eric Padron, Rami S. Komrokji, Jeffrey E. Lancet, Lynn C. Moscinski, John Cleveland, Alan F. List, Ling Zhang
Journal: Blood (2018)
Lucitanib for the Treatment of HR+/HER2− Metastatic Breast Cancer: Results from the Multicohort Phase II FINESSE Study
Authors: Rina Hui, Alex Pearson, Javier Cortes, Christine Campbell, Camille Poirot, Hatem A. Azim, Debora Fumagalli, Matteo Lambertini, Fergus Daly, Amal Arahmani, José Perez-Garcia, Philippe Aftimos, Philippe L. Bedard, Laura Xuereb, Elsemieke D. Scheepers, Malou Vicente, Theodora Goulioti, Sibylle Loibl, Sherene Loi, Marie-Jeanne Pierrat, Nicholas C. Turner, Fabrice Andre, Giuseppe Curigliano
Journal: Clinical Cancer Research (2019)

The FGFR1 gene is amplified in 14% of patients with HR + /HER2 - breast cancer. Efficacy and safety of lucitanib, an inhibitor of VEGFR1-3, FGFR1-3, and PDGFRα/β, were assessed.Patients with HR + /HER2 - metastatic breast cancer (MBC) received oral lucitanib in three centrally confirmed cohorts: (i) FGFR1 amplified, (ii) FGFR1 nonamplified, 11q13 amplified, and (iii) FGFR1 and 11q13 nonamplified. Key inclusion criteria included Eastern Cooperative Oncology Group Performance Status ≤2, ≥1 line of anticancer therapy, but ≤2 lines of chemotherapy. Primary endpoint was overall response rates (ORR) by RECIST1.1. Simon's two-stage design was used: If ≥2 patients responded among 21 patients, 20 additional patients could be enrolled in each cohort. FGFR1 copy-number variation (CNV) was determined by FISH and droplet digital PCR, whereas FGFR1 expression was determined by IHC.Seventy-six patients (32/18/26 in cohorts 1/2/3) from nine countries were enrolled. The prespecified primary endpoint was met in cohort 1 with ORR of 19% [95% confidence interval (CI), 9%-35%], but not in cohorts 2 and 3 with ORR of 0% (95% CI, 0%-18%) and 15% (95% CI, 6%-34%), respectively. Frequent adverse events included hypertension (87%), hypothyroidism (45%), nausea (33%), and proteinuria (32%). Exploratory biomarker analyses suggested higher ORR in patients with high FGFR1 amplification (≥4 CNV) than those without high amplification (22% vs. 9%). ORR in patients with FGFR1-high tumors (IHC, H-score ≥50) was 25% versus 8% in FGFR1-low cancers.Lucitanib had modest antitumor activity and significant hypertension-related toxicity in patients with HR + /HER2 - MBC. Although based on small sample sizes, exploratory biomarker analyses suggested that patients with high FGFR1 amplification or expression might derive greater benefit.
Anti-IL5 and anti-IL5Rα therapy for clinically significant bronchiectasis with eosinophilic endotype: a case series
Authors: Jessica Rademacher, Stefanie Konwert, Jan Fuge, Sabine Dettmer, Tobias Welte, Felix C. Ringshausen
Journal: European Respiratory Journal (2019)

<b>Patients with clinically significant bronchiectasis featuring an eosinophilic inflammatory endotype who were treated with add-on mepolizumab or benralizumab showed a significant improvement of FEV<sub>1</sub>, symptom burden and quality of life</b>http://bit.ly/2AZvBLm