tbuckley/cabot-search huggingface dataset:
Abstract 443: Long-Term Testosterone Deficiency Modifies Frailty and Cardiac Structure and Function in Aging Male Mice
Authors: Shubham Banga, Stefan Heinze-Milne, Susan E Howlett
Journal: Circulation Research (2019)

Objective: Low circulating testosterone levels are correlated with heart diseases in older adults. The belief that low testosterone contributes to poor health and promotes frailty has dramatically increased testosterone prescriptions in recent years. Still links between low testosterone, frailty and the heart are unclear in part because preclinical studies typically use young, healthy animals. Here we investigated effects of chronic testosterone deficiency on frailty, body composition and cardiac structure/function in aging mice. Methods: Male C57BL/6 mice (18-21 mos) underwent a gonadectomy (GDX) or sham surgery (4-wks of age) and then were aged naturally. Sham (n=10-13) and GDX mice (n=11) were tested for frailty (frailty index (FI) tool), echocardiography, electrocardiography (ECG), blood pressure, and serum testosterone (ELISA, facial vein). Body composition was measured with dual-energy X-ray absorptiometry. Mice were anaesthetized (isoflurane) during all procedures except FI scoring. Results: Serum testosterone levels were lower in GDX mice than in sham controls (0.89±0.13 vs. 0.29±0.06 ng/mL; p&lt;0.05). Systolic and diastolic blood pressures were unchanged between groups. Interestingly, GDX mice had lower lean mass than sham mice (23.5±1.2 vs. 27.4±0.7 g; p&lt;0.05) but they were actually less frail (FI scores=0.17±0.05 vs. 0.23±0.01; p&lt;0.05). GDX also reduced heart mass (186±11 vs. 148±15 mg; p&lt;0.05) and prolonged the QRS complex (8.5±0.3 vs. 10.0±0.4 ms; p&lt;0.05) without altering heart rate. While end systolic volume was reduced by GDX (p&lt;0.05), ejection fraction, fractional shortening, and cardiac output remained unchanged. Conclusions: Chronic exposure to low circulating testosterone prolonged ventricular conduction time, reduced heart mass and lowered lean mass in aging male mice. This suggests that testosterone deficiency may promote electrical and contractile dysfunction in the setting of aging. However, despite adverse effects on the heart and lean muscle mass, frailty scores were actually lower in mice with chronic testosterone deficiency. This suggests that the impact of low testosterone on overall health is complex and raises questions about the benefits of testosterone supplementation in frail older adults.
T Repleted Haploidentical Mismatch Allogeneic Versus Autologous Hematopoietic Stem Cell Transplantation In Adult Patients With Acute Leukemia In Complete Remission (CR): A pair-Matched Analysis From The Acute Leukemia Working Party Of EBMT
Authors: Norbert Claude Gorin, Myriam Labopin, Fabio Ciceri, Simona Piemontese, William Arcese, Paolo Di Bartolomeo, Didier Blaise, Giovanna Meloni, He Huang, Depei Wu, Jia Chen, Andrea Bacigalupo, Attilio Olivieri, Mohamad Mohty
Journal: Blood (2013)
Transplantation of Peripheral Blood Cells As Compared with Bone Marrow From HLA-Identical Related Donors Is Associated with Superior Long-Term Outcomes
Authors: Marco Mielcarek, Barry Storer, Paul J. Martin, Robert S Negrin, Stephen J. Forman, Mary E.D. Flowers, Yoshihiro Inamoto, Thomas Chauncey, Rainer Storb, Frederick R. Appelbaum, William I Bensinger
Journal: Blood (2011)
OP0096 Transcriptome analysis in rheumatoid arthritis treated with a tnf neutralising tnf receptor: fusion protein (etanercept)
Authors: J Kekow, S Drynda, D Koczan, HJ Thiesen
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Treatment with etanercept (Enbrel) results in a rapid and sustained improvement of disease activity in patients with refractory rheumatoid arthritis (RA). Although changes in the expression of single proteins, particularly cytokines and proteases, could be demonstrated in the past at the protein and mRNA level, new methods are neccessary to provide insight into the complex mechanisms which occur after neutralisation of TNFα. <h3>Objectives</h3> Oligonucleotide arrays can provide a broad picture of the state of cells by monitoring the expression levels of thousands of genes at the same time. Here we report the application of DNA array technology (Affymetrix) to cover changes in the expression levels under etanercept treatment. <h3>Methods</h3> Mononuclear cells (PBMC) and neutrophils (PMN) from peripheral blood were prepared applying standard procedures, synovial fluid (SF) was obtained from both knees. Total RNA for analysis was isolated from PBMC, PMN and SF-cells at different time points in the course of treatment. <h3>Results</h3> The expression level of 5600 transcripts was analysed. The most expressed genes were found in SF-cells. About 3.3%, 2.4% and 0.2% of the assessed genes in PBMC, PMN and SF-cells, respectively, showed significant changes in gene expression in either direction (i.e. increase with a fold change &gt;/= 3, decrease with a fold change. <h3>Conclusion</h3> The group of genes which are up- or downregulated included a number of genes which are known to be involved in transcription, chemotaxis, cell adhesion as well as genes not previously examined in the context of rheumatoid arthritis. The results have to be considered preliminary and confirmed in further experiments.
A Genetically Engineered Primary Human Natural Killer Cell Platform for Cancer Immunotherapy
Authors: Emily J. Pomeroy, John T. Hunzeker, Mitchell G. Kluesner, Walker S. Lahr, Branden A. Smeester, Margaret R. Crosby, Cara-lin Lonetree, Kenta Yamamoto, Laura Bendzick, Jeffrey S. Miller, Melissa A. Geller, Bruce Walcheck, Martin Felices, Beau R. Webber, Timothy K. Starr, Branden S. Moriarity
Journal: Molecular Therapy (2019)
Developing a standardized approach to cancer medication-related infusion reaction prevention and management in Ontario.
Authors: Andrea Crespo, Daniela Gallo-Hershberg, Katherine Enright, Vishal Kukreti, Lorraine Martelli, Carlo DeAngelis, Anna Granic, Charmaine Mothersill, Ferid Rashid, Lily Spasic, Leslie Young, Jason Yu, Sarah McBain, Leta Marie Forbes
Journal: Journal of Clinical Oncology (2019)

255 Background: Cancer medication-related infusion reactions (CMIRs) can lead to treatment delays, switching to less optimal therapy, or discontinuation. Variation in the prevention, management and reporting of CMIRs was identified as a quality and safety gap by Ontario clinicians. This initiative aimed to facilitate a standardized approach to CMIRs in Ontario through the development of user-friendly health-care provider and patient resources. Methods: A multidisciplinary working group of 15 oncology clinicians (oncologists, pharmacists, nurses, administrators) with experience in the management of CMIRs reviewed available literature on CMIR assessment, prevention and management. Recommendations were based on best available evidence and group consensus when only low-level evidence was available. Final guideline content was reviewed and validated by external experts. Complementary patient information was created based on best practices in health literacy and input from patient education experts, patients and caregivers. A mechanism for system-wide reporting to track CMIRs was explored. Results: A CMIR clinical practice guideline was created. Definitions, risk factors, prophylaxis strategies, an acute management algorithm and desensitization protocols are described. A CMIR severity grading system was proposed. A toolkit was developed and contains a table outlining risk factors, mechanism, incidence, symptoms, onset, prophylaxis, acute management and re-challenge by specific drug and a tool for calculating a three-bag 12-step desensitization. Patient-friendly information was also created. A new data element for collection of CMIR incidence and severity was added to the provincial Activity Level Reporting (ALR) data set to track CMIR trends. Conclusions: A review of current evidence and expertise from oncology clinicians resulted in an evidence-informed, consensus-based guideline. This guideline and the accompanying resources can help to facilitate safe and standardized prevention and management of CMIRs across Ontario. The collection of system-wide CMIR data based on the proposed grading system will inform future quality and safety improvement initiatives.
Cell-of-Origin Identification and Prognostic Correlation in HIV-Associated Diffuse Large B-Cell Lymphomas: Results of an Italian Multicentric Study
Authors: Chiara Rusconi, Alessandro Re, Laura Bandiera, Lara Crucitti, Michele Spina, Guido Gini, Marco Paulli, Marco Lucioni, Fabio Facchetti, Gaia Goteri, Vincenzo Canzonieri, Luisa Lorenzi, Piera Balzarini, Simona Fisogni, Antonello Malfitano, Maurizio Bonfichi, Maria Cristina Moioli, Michele Nichelatti, Federica Melle, Giovanna Motta, Stefano A. Pileri, Roberto Cairoli
Journal: Blood (2018)
Abstract 240: Mistrafficking of Integrin β1d Contributes to Ca2+handling Disorder and Catecholaminergic Polymorphic Ventricular Tachycardia Under Cardiac Stress
Authors: Yihui Wang, Chunyan Li, Shi Ling, Long-Sheng Song, ShiHua Zhao
Journal: Circulation Research (2019)

Background: RyR2 hyper-phosphorylation has been identified as a contributing mechanism to arrhythmogenesis. The integrin β1D colocalized with RyR2 and stabilized phosphorylation of RyR2, which maintains the function of the RyR2 channel. Our objective is to investigate whether the alteration of β1D integrin is a novel mechanism to arrhythmogenesis under cardiac stress. Methods and Results: Using transgenic mouse model β1D-/- mice, which results in more uncoupling of β1D and RyR2, showed significantly increased the RyR2 ser2808 phosphorylation and Ca2+handling disorder and CPVT. Translocation of the β1D and uncoupling with RyR2 were discovered in the cardiac disease in human and animal model, instead of decreased β1D. KIF5B mediated β1D redistributed from the center to the periphery with hyper-phosphorylation of ser2808 and Ca2+handling dysfunction. Conclusions: These results discover that translocation of β1D and disassociation from RyR2, which leads to hyper-phosphorylation of the RyR2 ser2808, is a novel pathway to trigger CPVTunder cardiac disease.
Abstract 652: Increased Gα <sub>o</sub> Expression Plays a Pivotal Role in the Progression of Heart Failure by Impairing Ca <sup>2+</sup> Handling
Authors: Hideaki Inazumi, Koichiro Kuwahara, Yoshihiro Kuwabara, Yasuaki Nakagawa, Hideyuki Kinoshita, Kenji Moriuchi, Hiromu Yanagisawa, Toshio Nishikimi, Kazuwa Nakao, Takeshi Kimura
Journal: Circulation Research (2019)

Background: A transcriptional repressor, neuron restrictive silencer factor (NRSF), maintains normal cardiac function and electrical stability. Transgenic mice expressing a dominant-negative mutant of NRSF in their hearts (dnNRSF-Tg) exhibit systolic dysfunction and premature death due to lethal arrhythmias like human dilated cardiomyopathy(DCM). Underlining mechanisms remain to be elucidated, however. Purpose: To clarify how NRSF maintains normal cardiac homeostasis. Methods and Results: cDNA microarray analysis of dnNRSF-Tg and newly generated cardiac-specific NRSF knockout mice (NRSFcKO), which show similar cardiac phenotypes to those of dnNRSF-Tg, revealed that cardiac gene expression of GNAO1 that encodes Gα o , a member of inhibitory G protein Gα i family, is increased in both dnNRSF-Tg and NRSFcKO ventricles. ChIP-seq analysis, reporter assay and electrophoretic mobility shift assay identified that GNAO1 is a direct target of NRSF. In dnNRSF-Tg, pharmacological inhibition of Gα o by pertussis toxin improved systolic dysfunction and knockdown of Gα o by crossing with GNAO1 knockout mice improved not only systolic function but also frequency of ventricular arrhythmias and survival rates. Electrophysiological analysis in ventricular myocytes obtained from dnNRSF-Tg demonstrated that genetic reduction of Gα o ameliorated abnormalities in Ca 2 + handling, which include increased current density in surface sarcolemmal L-type Ca 2 + channel, reduced content of sarcoplasmic reticulum Ca 2+ and lowered peak of Ca 2+ transient. In addition, genetic reduction of Gα o attenuated increased phosphorylation levels of CAMKII and RyR2 in dnNRSF-Tg ventricles, which presumably underlies the improvement in Ca 2 + handling. Furthermore, we identified increased Gα o expression in ventricles of heart failure model mice induced by transverse aortic constriction and cardiac troponin T mutant DCM model mice, in both of which, genetic reduction of Gα o ameliorated cardiac dysfunction. Conclusions: We found that increased expression of Gα o , induced by attenuation of NRSF-mediated repression, plays a pivotal role in the progression of heart failure by evoking Ca 2+ handling abnormality. Gα o is a potential therapeutic target for heart failure.
Abstract 400: Enhanced Neovascularization by ETV2 via Angiogenesis in Myocardial Infarction Models
Authors: Seong-Ho Bae, Sangho Lee, Sangsung Kim, Young-sup Yoon
Journal: Circulation Research (2019)

Attempts to regenerate cardiac vessels in order to treat ischemic myocardial disease have continued to be an old goal in the field of gene therapy. However, most studies that have applied proangiogenic factors have shown that the effects were limited. We examined the therapeutic effects of the ETV2 gene, a factor induced by postnatal injury, which is involved in the differentiation and specification of endothelial cells in the developmental stages in animal models of ischemic myocardial infarction via the adenoviral expression system. The ETV2 gene, using adenoviral vectors, was efficiently delivered in normal heart and myocardial infarction models and induced gene expression. In the myocardial infarction model of the control group, the function of the heart deteriorated after induction over time, but deterioration in the adenoviral ETV2-treated myocardial infarction group was delayed. To confirm whether this effect was due to angiogenesis, the expression of proangiogenic factors was examined, and the expression of vascular endothelial growth factor and angiopoietin were significantly increased in the group treated with ETV2. This result was reproduced via ETV2 gene expression at the cellular level. In order to confirm the effects of angiogenesis more deeply, we confirmed that the dividing vascular endothelial cells expressed Ki67. As a result, it was confirmed that a significant number of Ki67-positive cells were present in the functional blood vessel region in the group treated with ETV2. Taken together, the results suggest that angiogenesis plays a role in regenerating cardiac vessels when the ETV2 gene is introduced into the myocardial infarction model, which may be considered as a candidate for treatment of ischemic heart disease.
Association of Open Approach vs Laparoscopic Approach With Risk of Surgical Site Infection After Colon Surgery
Authors: Daniel A. Caroff, Christina Chan, Ken Kleinman, Michael S. Calderwood, Robert Wolf, Elizabeth C. Wick, Richard Platt, Susan Huang
Journal: JAMA Network Open (2019)

<h3>Importance</h3> Colon surgery is associated with a high rate of surgical site infection (SSI), and there is an urgent need for strategies to reduce infection rates. <h3>Objective</h3> To assess whether laparoscopic colon surgery is associated with a lower surgical site infection rate than open-approach laparoscopy, especially in patients with medically complex conditions. <h3>Design, Setting, and Participants</h3> This cohort study used previously validated diagnosis and procedure codes from Medicare beneficiaries who underwent colon surgery from January 1, 2009, to November 30, 2013. Analyses were performed from August 1 to December 31, 2018. <h3>Main Outcomes and Measures</h3> Outcome measures were SSI events, medical comorbidities, and laparoscopic or open approach procedures. <h3>Results</h3> A total of 229 726 patients (mean [SD] age, 74.3 [9.4] years; 128 499 [55.9%] female) underwent colon procedures. There were 105 144 laparoscopic procedures and 124 582 open procedures. The overall mean SSI rate was 6.2%, varying by surgical procedure from 5.8% to 7.6%. Among the full study population, adjusted model results showed a significant association of laparoscopy with lower odds of SSI (odds ratio, 0.43; 95% CI, 0.41-0.46;<i>P</i> &lt; .001). When stratified by surgical approach, the mean SSI rates were 4.1% (procedure-specific range, 3.9%-5.1%) for the laparoscopic approach and 7.9% (procedure-specific range, 7.4%-10.2%) for the open approach. When stratified by Elixhauser score groups, the mean SSI rates were 6.2% (procedure-specific range, 3.2%-8.7%) for group 1 (0-1 comorbidity), 5.5% (procedure-specific range, 3.6%-11.1%) for group 2 (2 comorbidities), and 6.6% (procedure-specific range, 4.6%-10.6%) for group 3 (3-13 comorbidities). An interaction was also observed between laparoscopic approach and Elixhauser groups, with increased odds of SSI among patients who had 3 to 13 comorbidities present at the time of the procedure (odds ratio, 1.21; 95% CI, 1.11-1.32) compared with patient groups with fewer comorbidities. The population attributable fraction of SSIs for use of the open approach was 34.2%. A total of 2317 of 3882 hospitals (59.7%) performed few (0%-10%) or most (&gt;50%) procedures laparoscopically. <h3>Conclusions and Relevance</h3> Policy changes that promote surgical education and resources for laparoscopy, especially at low-adoption hospitals, may be associated with reduced colon SSI rates. Support of the development of innovative educational policies may help achieve improvement in patient outcomes and decreased health care use in colon surgery.
Abstract 702: Fusion of Cardiac Progenitor Cell and Cardiomyocyte Induces Cardiomyocyte Division
Authors: Zhongming Chen, Ingrid Bender, Jop van Berlo
Journal: Circulation Research (2019)

Recent evidence has shown that cardiac progenitor cells (CPCs) can fuse with existing cardiomyocytes (CMs). The fusion frequency significantly increases during heart injury or drug treatment, but the role of CPC-CM fusion in heart regeneration is largely unknown. In this study, we investigate CM-CPC fusion in vivo and its effects on CM proliferation in vitro using genetic lineage tracing and isolated cardiac cells from adult mice. To distinguish between nuclear fusion and membrane fusion, we utilized double fluorescent nuclear reporter mice. After one month of tamoxifen chow treatment, as many as 78% (n=4) of fused CMs displayed cytoplasm fusion, but not nuclear fusion. To further study the role of cytoplasm fusion in CM proliferation, we designed in vitro experiments where we either induce partial fusion or co-culture freshly isolated CMs with previously isolated c-kit+ cells. We find that 52% (387 of 741 cells, n=10) of the fused CMs maintain rod-shape morphology for over two months during culture, while all CMs ball up and dedifferentiate in co-culture controls (n=10) within 24 hours. Next, EdU was added to the culture media to assess DNA replication. EdU+ CMs were observed in both rod-shape and rounded CMs in 7 days. Finally, we monitored cell division of rod-shaped CMs fused with c-kit+ CPCs using intermittent live-cell imaging. We identified 2 cell division events from 20 randomly monitored rod-shape CMs in two months after fusion. These results demonstrate that fusion of c-kit+ cells with CMs are typically partial fusion events, that may play a role in regulating CM proliferation.
The Value of FDP/FIB and D-Dimer/FIB Ratios: Predicting High-Risk APL Related Thrombosis
Authors: Yanliang Bai, Mingyue Shi, Wanjun Zhang, Xiawan Yang, Hafiz Abdul Waqas Ahmed, Lei Huo, Yuqing Chen, Xiaona Niu, Honggang Guo, Fangfang Xu, Jing Yang, Yuzhu Zang, Shuangyin Han, Kai Sun
Journal: Blood (2018)
Abstract 123: Osteopontin Regulates Adult Cardiomyocyte Division in a Mouse Model of Pressure Overload Induced Heart Failure
Authors: Camila I Irion, Krista John-Williams, Ahmed Chahdi, Keyvan Yousefi, Yanelys R Fernandez, Konstantinos E Hatzistergos, Joshua M Hare, Keith Webster, Lina A Shehadeh
Journal: Circulation Research (2019)

Background: Our previous work showed that pharmacological blockade of Osteopontin (OPN) signaling can prevent and reverse heart failure induced by pressure overload in a transverse aortic construction (TAC) mouse model. Surprisingly, OPN Knockout (KO) mice subjected to 3 month TAC had worse cardiac function and bigger hearts than wild type (WT) TAC mice, despite lack of cardiomyocyte hypertrophy. We hypothesized that OPN KO increased adult cardiomyocyte proliferation in TAC-induced heart failure. Methods: Male C57Bl/6 (n=17) or OPN KO (n=11) mice were subject to TAC for 3 months. The protein levels of the mitosis marker H3P was quantified using immunofluorescence in paraffin-embedded myocardial sections. Myocytes were co-stained with WGA and MLC2 to count the number of myocytes per field. Adult primary cardiomyocytes from WT hearts were isolated and analyzed with co-imunoprecipitation (Co-IP) to study the interation between the regeneration factor YAP1, OPN and OPN-regulated proteins such as LDLR. For validation and mechanistic studies, more Co-IP experiments were performed in proliferative human liver HEPG2 cells. To study the effect of OPN blockade on YAP1 nuclear translocation, HEPG2 cells and human iPSC- derived cardiomyocytes (hiPS-CMs) were treated with an IgG or OPN blocking antibody for 24 hours followed by immunostaining for YAP1 and PITX2. Results: Nuclear H3P normalized to myocyte count was significantly increased in OPN KO relative to WT TAC hearts (Fold Change = 1.4; p=0,04). Co-IP results revealed a novel interaction between OPN, LDLR and YAP1. Stimulation of β2 adrenergic receptor increased the formation of this multi-molecular complex in a time-dependent manner. Blockade of OPN by a monocolonal antibody for 24 hours caused nuclear localization of YAP1 and PITX2 in HEPG2 cells and hiPS-CMs. Conclusion: OPN regulates the mitotic program in adult cardiomyocytes. Furthermore, the interaction of OPN with LDLR and YAP1 to form a new multi-molecular protein complex is regulated by β2-cAMP signaling pathway. Importantly, OPN regulates nuclear translocation of the regeneration factors YAP1 and PITX2, suggesting that OPN signaling may be important for adult cardiomyocyte division in TAC and potentially myocardial infarction and aging.
Recurrent Missense Mutations in the STAT3 Gene in LGL Leukemia Provide Insights to Pathogenetic Mechanisms and Suggest Potential Diagnostic and Therapeutic Applications
Authors: Hanna Koskela, Samuli Eldfors, Henrikki Almusa, Emma Andersson, Pekka Ellonen, Henrik Edgren, Pirjo Koistinen, Taru Kuittinen, Kati Penttinen, Jonathan Knowles, Janna Saarela, Olli Kallioniemi, Krister Wennerberg, Kimmo Porkka, Caroline Heckman, Satu Mustjoki
Journal: Blood (2011)
<i>Mycoplasma genitalium</i>infection
Authors: Nicolas Pinto-Sander, Suneeta Soni
Journal: BMJ (2019)

### What you need to know

Mycoplasma genitalium has been dubbed the latest superbug by the media.1 While the inference that this sexually transmitted infection is untreatable is incorrect, the relative ease by which M genitalium develops resistance is of great concern and presents challenges in treatment. This practice pointer provides an overview of M genitalium infection including practical advice for non-specialists on diagnosis and management.

M genitalium is the smallest known self replicating bacterium.2 It lacks a cell wall and hence cannot be detected on Gram staining of a specimen.2 M genitalium is predominantly found in the genitourinary tract of both sexes. It evades the adaptive immune system by establishing intracellular infection (possibly due to its tip-like structure), but also by antigenic and phase variation of its surface-expressed proteins.23

M genitalium infection may persist for months or years in asymptomatic individuals. It is found in genital specimens of 15-25% of men with non-gonococcal urethritis2 and 10-13% of women with pelvic inflammatory disease.45 Although the pathological consequences of M genitalium infection are thought mainly to be due to host response, M genitalium has been shown to directly cause cilial damage in human fallopian cell culture.26

The prevalence of M genitalium …