tbuckley/cabot-search huggingface dataset:
Abstract 326: FTO-mediated mRNA Demethylation Regulates Cardiac Contractile Protein Expression and Function
Authors: Prabhu Mathiyalagan, Marta Adamiak, Joshua Mayourian, Yassine Sassi, Yaxuan Liang, Neha Agarwal, Divya Jha, Shihong Zhang, Erik Kohlbrenner, Xiaoke Yin, Jiqiu Chen, Maria G Trivieri, Rihab Bouchareb, Rajvir Singh, Kenneth Fish, Kiyotake Ishikawa, Manuel Mayr, Djamel Lebeche, Roger J Hajjar, Susmita Sahoo
Journal: Circulation Research (2019)

Background: Exciting new discoveries in RNA biology underscore the importance of post-transcriptional chemical modifications to mRNAs (epitranscriptome) in regulating RNA stability, nuclear export, cellular compartmentalization, splicing, translation and degradation. The most abundant and functionally relevant modification in RNA, N6-methyladenosine (m6A) is reversibly demethylated by one of the m6A demethylases, fat mass and obesity-associated protein (FTO) whose function in the mammalian heart remains incompletely understood. Materials and Methods: We used clinical human samples, preclinical pig and mouse models and primary cardiomyocytes to study m6A and FTO in the heart and in cardiomyocytes. We modulated FTO expression using AAV9 (in vivo), adenovirus (in vivo and in vitro) and siRNAs (in vitro). We investigated m6A-induced changes to contractile protein expression using m6A RNA immunoprecipitation sequencing (MeRIP-seq) and stable isotope labeling of amino acids in cell culture (SILAC). Results: We discovered in human heart failure that reduced FTO expression is associated with aberrant increase in m6A mRNA methylation, which is conserved in swine and mouse models of myocardial ischemia (MI). AAV9-mediated FTO gene delivery in mouse MI attenuated m6A increase and improved cardiac function with enhanced contractility, angiogenesis and reduced fibrosis. At the molecular level, FTO-mediated mRNA demethylation serves to increase contractile protein expression in mouse hearts as well as in isolated primary cardiomyocytes. By comparing human and mouse transcriptome-wide m6A maps with SILAC proteomic profiling from cardiomyocytes, we identified FTO-mediated m6A demethylation is transcript-specific and leads to altered protein expression of several key contractile, angiogenic and regenerative proteins. Conclusion: Using new RNA-based investigations, we uncovered a novel regulatory layer beyond the genome working at the level of epitranscriptome governing cardiac function. Our findings on the dynamic nature of the cardiac m6A-epitranscriptome will lead to deeper understanding of the mechanism of cardiac remodeling on one hand and innovative therapeutic interventions on the other.
International travel as source of a hospital outbreak with an unusual meticillin-resistant Staphylococcus aureus clonal complex 398, Denmark, 2016
Authors: Jens Kjølseth Møller, Anders Rhod Larsen, Claus Østergaard, Camilla Holten Møller, Mette Assenholm Kristensen, Jesper Larsen
Journal: Eurosurveillance (2019)

In May 2016, an unusual outbreak with the Panton-Valentine leukocidin-positive human variant of meticillin-resistant Staphylococcus aureus (MRSA) clonal complex 398 occurred among mothers and infants in the maternity unit of a Danish hospital. MRSA sharing genotypic and phenotypic characteristics was confirmed in 36 cases, including 26 patients, nine household members and a healthcare worker (HCW) who had contact with all the patients. The national MRSA database contained 37 seemingly unlinked MRSA cases whose isolates shared the same genotypic and phenotypic characteristics as the outbreak strain. Whole genome sequencing showed that three of these isolates clustered together with the 36 outbreak isolates, suggesting spread outside the hospital. The HCW and 21 of 37 cases from the national MRSA database had links to south-eastern Asia, where the outbreak strain is endemic. These findings suggest that the HCW acquired the outbreak strain while travelling in south-eastern Asia and then introduced it into the hospital; from there, it spread within the patients' households and into the community. Screening of travellers returning from countries with high levels of MRSA could be an important intervention to prevent spread of these bacteria into hospitals via patients or HCWs.
Influence of FLT3-ITD Mutation and Length on the Treatment Response and Prognosis in Cytogenetically Normal AML Patients
Authors: Xuejie Jiang, Changxin Yin, Junya Sun, Jiaying Cheng, Qiang Wang, Guopan Yu, Ling Jiang, Dan Xu, Xiaoli Liu, Ru Feng, Qifa Liu
Journal: Blood (2018)
Differential Impact of Inhibitory and Activating Killer Ig-Like Receptors and HLA Ligand on Outcomes of Transplantation for Myeloid and Lymphoid Malignancies.
Authors: Vinod K. Prasad, Dong-Feng Chen, Gloria Broadwater, Nancy L Reinsmoen, Adella Clark, Nelson J Chao, David A. Rizzieri
Journal: Blood (2008)
Abstract 820: Enoxaparin Reverses Ventricular Tachycardia and Torsades de Pointes in Rat Isolated Heart Model
Authors: Enio R Vasques, Enio R Vasques, Ivarne L Tersariol, Helena B Nader, Carlos M Godoy
Journal: Circulation Research (2019)

Introduction: Enoxaparin (Enox) is used in cardiovascular emergency and coronary angiography due to its effects on coagulation mechanisms. However, its effect on changing the structure of the exchange-inhibiting peptide present in the sodium-calcium exchanger, leading to the acceleration of its function and withdrawing calcium from the cell in overload situations could lead to a new therapeutic function, where the intracellular calcium overload would be deleterious, as in cardiac arrhythmias and myocardial infarction. Objective: To analyze the action of Enox on cardiac arrhythmias induced by ischemia and reperfusion (IR) in isolated rat hearts. Materials and method. Adult Wistar rats were sacrificed, hearts isolated and placed under perfusion in Langhendorf Model with Krebs solution (KS) and monitoring of the electrocardiogram. After 30 minutes in sinus rhythm, ischemia was performed with discontinuation of the KS for 5 min and then reconnected. They were divided into 2 groups: Control (n = 10), with IR without medication and Enox Group, with infusion of 2mg / kg, in the cannula that perfuses the heart, soon after initiation and support for 30 seconds of Ventricular Tachycardia (VT) or Torsade de Pointes (TP). In case of reversal of the arrhythmia, a new arrhythmia induction will be attempted with the same protocol. Monitoring is continued until asystole or completion scheduled for 60 minutes of experimentation. Results: The control group presented VT in 70% of hearts and total atrioventricular block (TAVB) in 30% of hearts, followed by asystole after 7 minutes in 100% of hearts, and no further attempt of ischemia was possible. In the Enox group, 60% of VT, 30% of TP and 10% of TAVB were observed. All arrhythmias were reversed between 10 and 15 seconds after infusion of Enox, with return and maintenance of sinus rhythm after medication. In this group, a new attempt was made to induce arrhythmia due to IR without success after 10 minutes of interruption of the arrhythmia by Enox and sinus rhythm was maintained until the interruption of the experimental protocol. Conclusion: Enoxaparin reverses arrhythmias triggered by IR, with its effect prolonging and protecting new events after infusion, as well as decreasing organ mortality in isolated hearts of rats.
The Direction of KIR Ligand Incompatibility Is Associated with Graft Failure and May Predict the Dominant Donor Following Double Umbilical Cord Blood Transplantation
Authors: Lucy Li, Merle Kolk, Kirsten Marie Boughan, Paolo F Caimi, Molly M Gallogly, Jane Little, Ehsan Malek, Leland Metheny, Ben Tomlinson, Brenda Cooper, Marcos de Lima, Folashade Otegbeye
Journal: Blood (2018)
Quality improvements in palliative radiotherapy at end of life: The FutRE Study.
Authors: Siddhartha Goutam, Jordan Mark Stosky, Jackson S.Y. Wu, Alysa M. Fairchild, Marc Kerba
Journal: Journal of Clinical Oncology (2019)

306 Background: Palliative radiation therapy (RT) is offered to patients with cancer for symptom management. RT planning and delivery is resource intensive. Benefits may take weeks to develop. Palliative RT at the end of life may not be completed due to patient and disease factors. RT courses that are not completed may indicate a need for improved patient selection for RT and choice of RT prescription, minimizing the likelihood of delivering futile treatment. Methods: The FUTile Radiotherapy at End of life survey was implemented in the electronic RT workspace across Alberta in 2018. Radiation oncologists (ROs) were tasked with survey completion, at the time of palliative RT prescription approval, as part of their workflow on domains pertaining to patient and treatment decision-making. This survey data was linked to the cancer registry and date of death. Data association were examined among patients completing RT within 90 days of death for the accuracy of oncologist’s provided survival prognostication estimates, number of RT fractions prescribed, number of RT fractions completed, prescribing physician, including disease factors and treatment intent. Results were explored using descriptive statistics and tests of associations (STATA 11.1) Results: 1963 RT surveys were included in our analysis. Prescribing ROs overestimated patient survival 67% of the time, by a mean of 145 days, and underestimated survival 12% of the time by a mean of 109 days. Multi-fraction RT (1403 courses) was more frequently prescribed over single fraction (SF) RT (560 courses)(one-sample t-test, p≤0.001). SF treatments were more likely to be completed than MF treatments (RR = 10.3, 95% CI = [4.85, 21.7], p &lt; 0.0001). Treatments were less likely to be completed when survival was overestimated by 6 or more months and were over twice as likely to be completed than when patient survival was underestimated (RR = 2.6, 95% CI = [1.04, 6.50], p = 0.04). Conclusions: Survival among end of life patients is overestimated by ROs prescribing palliative MF RT treatments.
Postnatal probiotics and allergic disease in very preterm infants: Sub‐study to the <i>ProPrems</i> randomized trial
Authors: Erica L. Plummer, Adriana Chebar Lozinsky, Jacinta M. Tobin, Jessica B. Uebergang, Christine Axelrad, Suzanne M. Garland, Susan E. Jacobs, Mimi L. K. Tang
Journal: Allergy (2019)

Abstract Background Probiotic supplementation to mothers and/or their term‐born infants has been suggested to prevent allergic disease, in particular eczema; however, no studies have investigated probiotics for prevention of allergic diseases in very preterm infants. We evaluated the effect of a postnatal probiotic combination on development of allergic diseases in very preterm infants. Methods This sub‐study was an a priori secondary outcome of the ProPrems multi‐center, double‐blind, placebo‐controlled randomized trial (ANZCTR:12607000144415). ProPrems randomized 1099 very preterm infants to receive a probiotic combination or placebo from soon after birth until discharge from hospital or term corrected age (CA), whichever was earlier. Allergic disease (eczema, atopic eczema, food allergy, wheeze, atopic sensitization) was assessed in a subgroup of ProPrems infants (n = 281) as close to 12 months CA as possible by questionnaire, clinical examination, and skin prick tests to common allergens. Results There was no difference in eczema incidence between the probiotic and placebo groups (35[30%] of 118 infants vs 37[27%] of 137 infants, respectively, absolute difference 2.65%, 95% CI −8.45 to 13.75). Similarly, the incidence of atopic eczema (6[5%] of 118 vs 3[2%] of 137), food allergy (4[3%] of 124 vs 2[1%] of 154), wheeze (39[31%] of 127 vs 45[29%] of 154), and atopic sensitization (14[13%] of 106 vs 13[11%] of 123) were similar between the probiotic and placebo groups. Conclusion This study found no effect of postnatal administration of a probiotic combination on the incidence of allergic diseases or atopic sensitization in the first 2 years of life in children born very preterm. Evidence that probiotics are effective for prevention of allergic disease in premature infants remains lacking; adequately powered randomized controlled trials evaluating probiotic supplementation for allergy prevention in very preterm infants are needed.
Abstract 210: Transcriptomic Changes During Induced Pluripotent Stem Cell-derived Neural Crest Cell Differentiation Highlight Genes Involved in Endocardial Cushion and Cardiac Outflow Tract Development
Authors: Min Young Jang, Alexandre C Pereira, David M McKean, Joshua M Gorham, Daniel M DeLaughter, Radhika Agarwal, Arun Sharma, Tarsha L Ward, Daniel T Reichart, Christine E Seidman, J. G Seidman
Journal: Circulation Research (2019)

Rationale: Neural crest cells (NCCs) play a critical role in normal cardiac development, and defects in NCCs likely cause congenital heart disease (CHD). NCCs are transient and multipotent migratory stem cells that give rise to diverse tissues, including cardiac structures such as the smooth muscles of the great arteries and semilunar valves. Induced pluripotent stem cells (iPSC) can be differentiated into NCCs, as demonstrated by expression of several marker proteins including NGFR and HNK1. To better define iPSC-NCCs and to better understand the progression of iPSCs to NCCs, we have compared the transcriptomes of iPSC and iPSC-NCCs. We have also begun to investigate the consequences of loss-of-function mutations in genes implicated in CHD on the differentiation of iPSC-NCCs. Methods and Results: PGP1 iPSCs were differentiated to NCCs and RNA was collected at 0, 5, 10, and 15 days of differentiation. RNAseq analysis showed that by day 15, 6483 genes were upregulated in NCC vs iPSCs, 6406 downregulated, and 6715 unchanged (FDR 5%). Enrichment analysis for the top 500 upregulated genes showed 4 cardiac gene ontology (GO) terms in the top 10, including ‘endocardial cushion morphogenesis’ (fold enrichment 11.85, p = 0.012). Notably, of 45 genes under GO term ‘endocardial cushion development’, 38 (84%) differentially expressed in NCCs by day 15 (FDR 5%). Next, we compared this RNAseq data with that of iPSC-derived cardiomyocyte (CM) differentiation in a subset of 253 genes previously implicated in CHD. Of these, 143 genes were differentially expressed in both iPSC-CMs and iPSC-NCCs. However, 27 genes (10.6%) including MYH6, PITX2, and TBX5 were uniquely upregulated during CM differentiation, while 65 genes (25.7%) including CHD4 and NOTCH1 were uniquely upregulated during NCC differentiation. Conclusion: Transcriptomic changes during iPSC-NCC differentiation, assessed by both bulk and single cell RNAseq, reveal an upregulation of genes involved in cardiac development, particularly endocardial cushions and the outflow tract. Importantly, a subset of genes implicated in CHD are altered during iPSC-NCC differentiation but not in iPSC-CM differentiation. Thus, iPSC-NCCs offer a new model with which to investigate the pathogenesis and mechanisms of CHD.
Assessing advance directive (AD) completion rate in inpatient hematology unit.
Authors: Aneesha Ananthula, Manojna Konda, Issam Makhoul, Heather C Moore, Appalanaidu Sasapu
Journal: Journal of Clinical Oncology (2019)

42 Background: Advance Directive (AD) completion is particularly more important in patients with cancer given the higher mortality associated with the diagnoses as well as the treatments that patients receive. In reality AD discussion and completion rate is influenced by patient characteristics and disease status. We undertook a Quality improvement project to improve AD discussion and completion in inpatient hematology unit at our institution. Methods: Plan-Do-Study-Act (PDSA) methodology was used and the team consisted of residents and case managers. Each morning electronic medical record (EMR) was reviewed and new patients admitted to hematology unit were identified for a period of 1 month. Patients without an AD on file were educated by a designated resident and were given forms to file AD. Based on the patient’s willingness, the case manager was alerted with daily communication email to follow-up and assist in completion and filing of AD into EMRs. Results: AD on discharge on a randomly chosen pre-intervention month was 6.97% which improved to 42% post intervention. Conclusions: Compared to Oncology patients, Hematology patients have a lower rate of AD completion in general. Hematology patients are usually younger, have a higher chance of achieving remission, and usually have improved survival with stem cell transplant due to which AD discussion does not happen very often. The notion of having AD discussion only for patients with poor prognosis should change and must be offered to everyone. We found an improvement in AD filing rate by increasing physician involvement and streamlining the process with designated roles. It is the responsibility of physicians to discuss Advance Care Planning (ACP) with their patients and readdress them at appropriate intervals as disease status can change. [Table: see text]
Mutation in DNA Methyltransferase DNMT3A Confers Enhanced Self-Renewal Capacity Onto Multipotent Progenitor Cells and Predisposes to Acute Myeloid Leukemia (AML)
Authors: Matthew Loberg, Rebecca Bell, Tim Stearns, Leslie Goodwin, Kira Young, David Bergstrom, Rebekka Schneider, Jennifer J. Trowbridge
Journal: Blood (2018)
Abstract 215: Assessing the Efficacy of Novel RYR2 Inhibitor, EL20, in Induced Pluripotent Stem Cell Derived Cardiomyocytes from a Catecholaminergic Polymorphic Ventricular Tachycardia Patient
Authors: Tarah A Word, Andrew Landstrom, Ann Quick, Mayra Shak, Christina Miyake, Hugh D Allen, Xander Wehrens
Journal: Circulation Research (2019)

Background: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited cardiac arrhythmia syndrome that leads to sudden cardiac death in children and young adults. The most common form of CPVT is caused by autosomal-dominant mutations in the gene encoding cardiac ryanodine receptor type-2 ( RYR2) . Mutations in RYR2 promote excessive calcium (Ca 2+ ) leak from the sarcoplasmic reticulum (SR), triggering potentially lethal arrhythmias. Recently, we demonstrated that the tetracaine derivative EL20 specifically inhibits RYR2, normalizes Ca 2+ handling, and suppresses arrhythmias in a CPVT mouse model. We hypothesized that EL20 will also normalize Ca 2+ handling and arrhythmias in human induced pluripotent stem cell derived cardiomyocytes (iPSC-CMs). Materials/Methods: Blood samples from a child carrying RYR2 mutation R176Q/+ (RQ) and a mutation-negative relative (WT) were collected, processed into peripheral blood mononuclear cells (pBMCs), and reprogrammed into iPSCs using Sendai virus system. Functional iPSC-CMs were derived using Stemdiff TM kit. Differentiation of CMs was validated using qPCR and immunofluorescent staining. Confocal Ca 2+ imaging was used to monitor RyR2 activity. Axiom Biosystem TM microelectrode arrays (MEA) was used to assess arrhythmogenic action potential (AP) and rates. Results: Successfully differentiated CMs showed increased levels of Ca 2+ -handling markers and decreased levels of stem cell markers. Baseline Ca 2+ imaging revealed a 4-fold increase in calcium spark frequency (CaSpF) in RQ iPSC-CMs (3.08±0.58 a.u., n=12) vs. WT (0.69±0.22 a.u., n=13, p&lt;0.01). Strikingly, EL20 normalized CaSpF in RQ iPSC-CMs (0.60±0.16 a.u., n=9, p&lt;0.05 vs. baseline). Furthermore, EL20 decreased the erratic beat period rate of spontaneous APs occurring in RQ iPSC-CMs to a rate similar to WT. Importantly, EL20 had no significant effect on the beat period rate or field potential duration of WT iPSC-CMs. Conclusion: Our results demonstrate that EL20 normalizes Ca 2+ handling and AP beat rate frequency in patient-derived RYR2-R176Q/+ iPSC-CMs with no observed off-target effects, positioning this novel RyR2-inhibitor as a promising therapeutic candidate for treatment of CPVT.
Clinical characteristics, symptoms and burden of psoriasis and atopic dermatitis in adults
Authors: A. Egeberg, C.E.M. Griffiths, H.C. Williams, Y.M.F. Andersen, J.P. Thyssen
Journal: British Journal of Dermatology (2019)

There is debate as to whether psoriasis and atopic dermatitis (AD) belong to the same disease spectrum.To describe and compare disease characteristics, lifestyle factors and disease burden in adult patients with psoriasis and AD.We linked registry data with clinical and patient-reported outcomes from the Danish Skin Cohort, containing 3348 and 3834 adults with dermatologist-verified psoriasis or AD respectively, and 2946 adults from the general population.The participants were predominantly women and middle-aged. Patients with psoriasis mostly reported disease onset throughout adulthood, but with a distinct early incidence peak in those with a positive family history or severe disease. AD predominantly began in childhood, with only a very discrete incidence peak in adulthood. Scalp, extremity, chest and abdomen involvement was common to both diseases. Scalp/hairline, elbows, nails, intergluteal cleft, umbilicus, knees and legs were most frequently affected in patients with psoriasis. In AD, periocular, neck, antecubital fossae, back of the hands, interdigital areas and popliteal fossae were commonly affected. Patients with psoriasis (but not AD) were generally more overweight, obese and physically inactive, and had a positive smoking history, compared with the general population. Patients with both diseases experienced more frequent flares with increasing disease severity. Patients generally displayed uncontrolled disease despite being on systemic therapies. Itch and skin pain were much more severe in patients with AD, whereas joint pain was more common in patients with psoriasis.We identified important similarities and differences in the clinical characteristics of adults with psoriasis and AD; these should help clinicians to prioritize and improve patient management. What's already known about this topic? Psoriasis and atopic dermatitis in adults are increasingly being compared, and there is discussion as to whether they are part of the same disease spectrum. What does this study add? In this comparative study, patient-reported disease burden was markedly higher in atopic dermatitis than in psoriasis, whereas lifestyle-associated cardiometabolic risk factors were more frequent in psoriasis. In both disease groups, the condition in the majority of patients was uncontrolled even while they were on systemic therapy. The contrasting presentations highlight that these diseases are two distinct and different entities rather than belonging to the same spectrum.