tbuckley/cabot-search huggingface dataset:
Abstract 288: Mitoq Regulates Redox-related Non-coding Rnas to Improve Mitochondrial Network in Pressure Overload Heart Failure
Authors: Jiajia Song, Seulhee Kim, Mary N Latimer, Kah Yong Goh, Sumanth D Prabhu, Gangjian Qin, Victor Darley-Usmar, Xiaoguang Liu, Adam R Wende, Martin E Young, Lufang Zhou
Journal: Circulation Research (2019)

Background: Previous studies show that mitochondrial network excitability, or the propagation of ROS signals, is impaired in cardiomyocytes from failing hearts. While oxidative stress has been implicated in heart failure (HF)-associated mitochondrial network abnormality, the effect of mitochondrial-targeted antioxidant, such as mitoquinone (MitoQ), on mitochondrial network in pressure overload hearts has not been demonstrated. We hypothesize that MitoQ improves mitochondrial networks in HF via regulation of redox-related cardiac remodeling-associated non-coding RNAs. Methods and results: To test the hypothesis, C57BL/6J mice were subjected to ascending aortic constriction (AAC) to induce left ventricular (LV) pressure overload, followed by 7 days of MitoQ treatment (2 μmol). Doppler echocardiography revealed severe LV dilation and decreased ejection fraction following AAC, which were attenuated by MitoQ. Electron microscopy and immunostaining showed that inter-mitochondrial and mitochondria-sarcoplasmic reticulum (SR) network structure were altered in HF myocardium, in parallel with reduced expression of mitofusin proteins (e.g., MFN1 and MFN2) compared to sham-operated animals. MitoQ blunted mitofusin protein downregulation and improved mitochondrial networks. Our data also identified a MitoQ-mediated mechanism of mitofusin expression in HF by ameliorating the dysregulation of redox-related cardiac remodeling-associated long non-coding RNAs and microRNAs (i.e. Plscr4-miR-214 axis). Conclusion: The present study indicates that MitoQ improves inter-mitochondrial and mitochondrial-SR structural organization in pressure overload hearts by attenuating the dysregulation of cardiac remodeling-associated non-coding RNAs.
Histopathologist features predictive of diagnostic concordance at expert level among a large international sample of pathologists diagnosing Barrett’s dysplasia using digital pathology
Authors: Myrtle J van der Wel, Helen G Coleman, Jacques J G H M Bergman, Marnix Jansen, Sybren L Meijer
Journal: Gut (2019)

Guidelines mandate expert pathology review of Barrett's oesophagus (BO) biopsies that reveal dysplasia, but there are no evidence-based standards to corroborate expert reviewer status. We investigated BO concordance rates and pathologist features predictive of diagnostic discordance.
Incorporation of Evidence Based Guidelines on Bleeding Risk Assessment PRIOR to Ent Surgery into Practice: Real Time Experience
Authors: Nada Al-Marhoobi, Manar Maktoom, Fatma Bulushi, Mohamed Ebrahim Mohamed Ebrahim Elshinawy, Hanan Nazir, Rashid Al-abri, Khalil Macki, Abdul Hakim Al-Rawas, Khalid Al Hashmi, Murtadha K. Al-Khabori, Yasser Ahmed Mohamed Soliman Wali
Journal: Blood (2018)
Secondary Malignancies after Treatment of Aggressive Non-Hodgkin Lymphoma: A GISL Cohort Study on 1259 Patients.
Authors: Stefano Sacchi, Luigi Marcheselli, Alessia Bari, Raffaella Marcheselli, Samantha Pozzi, Giovanni Quarta, Nicola Di Renzo, Alberto Fragasso, Francesco Angrilli, Massimo Federico
Journal: Blood (2007)
The Genotype of the Donor for the (GT)n Polymorphism in the Promoter/Enhancer of the FOXP3 Gene Influences Graft Versus Host Disease without Affecting Graft Versus Leukemia Effect After Myeloablative HLA-Identical Allogeneic Stem Cell Transplantation
Authors: Victor Noriega, Carolina Martinez-Laperche, Leyre Bento, Noemi Sanchez-Hernandez, Milagros Gonzalez-Rivera, Pascual Balsalobre, Mi Kwon, Jorge Gayoso, Jose Luis Diez-Martin, Ismael Buno
Journal: Blood (2011)
Many Ways to Build a Polyp
Authors: Detlev Arendt
Journal: Trends in Genetics (2019)

The freshwater cnidarian Hydra has been studied for centuries for its unique regenerative capacities. Whole-body single-cell transcriptomics now reveal cellular lineages and gene regulatory networks that build the Hydra polyp. For the first time, transcription factor signatures allow direct comparison of the polyp body plan between Hydra and sea anemone.
The Immunomodulatory Drug Lenalidomide (CC5013; Revlimid), Enhances Antigen-Presenting Cell’s Function Leading to Effective Priming of CD4+ T-Lymphocytes.
Authors: Hongwei Wang, Aung Naing, Fengdong Cheng, Pedro Horna, Ildelfonso Suarez, Jason Brayer, Alan F. List, Eduardo M. Sotomayor
Journal: Blood (2005)
Abstract 279: Increased Drp1 Acetylation Mediates Lipid Overload-induced Cardiomyocyte Death &amp; Heart Dysfunction
Authors: Qingxun Hu, Huiliang Zhang, Nicolás G Cortés, Dan Wu, Pei Wang, Eric Smith, Mingyi Wang, Shey-Shing Sheu, Wang Wang
Journal: Circulation Research (2019)

Rationale: Lipid overload can cause diabetic cardiomyopathy (DCM), which is characterized by cardiomyocyte death, myocardial remodeling, and eventually contractile dysfunction. How excessive lipid supply impacts cardiac metabolism leading to DCM remains poorly understood. Objective: To investigate the role and mechanism of a mitochondrial fission protein, dynamin-related protein 1 (Drp1), in lipid overload-induced cardiomyocyte death and DCM. Methods and Results: Mice fed with high fat diet (HFD) for 18 weeks exhibited DCM phenotype including myocardial insulin resistance, fibrosis, hypertrophy, cardiomyocyte death and mild contractile dysfunction. Cultured adult cardiomyocytes incubated with high levels of palmitate also exhibited increased cell death and openings of the mitochondrial permeability transition pore. Mitochondrial fission was stimulated by HFD in the heart or by palmitate incubation in cultured adult cardiomyocytes. Mechanistically, lipid overload increased acetyl-CoA level and decreased NAD + level in the heart and in adult cardiomyocytes, leading to upregulation of Drp1 acetylation at lysine 642 (K642). Elevated Drp1 acetylation increased Drp1 protein level, its oligomerization and its phosphorylation at the activating serine 616 (S616) site. The excessively activated Drp1 translocated to mitochondria, induced fission, and bound with VDAC1 to promote cardiomyocyte death. Preventing Drp1 acetylation (K642R mutation), inhibiting Drp1 activity, or supplementing NAD + ameliorated palmitate-induced fission and cardiomyocyte death. In the hearts of HFD-fed monkeys, we observed increased Drp1 acetylation, oligomerization, and phosphorylation, which were accompanied with markers of DCM. Conclusions: These findings uncover a novel mechanism mediating lipid overload-induced heart hypertrophy and dysfunction. Excessive lipid supply created an intracellular environment that facilitated Drp1 acetylation, which increased its activity and mitochondrial translocation causing cardiomyocyte death. Thus, Drp1 could be a critical mediator for metabolic stress-induced heart dysfunction as well as a potential target for therapy.
Interim Results of the Observational Study Caro: Twice Weekly Carfilzomib Is a Convenient Treatment Option for Patients with Multiple Myeloma Who Have Received at Least One Prior Therapy
Authors: Wolfgang Knauf, Andreas Ammon, Jens Uhlig, Marie Merling, Hans-Juergen Hurtz, Corinne Vannier, Holger Schulz, Norbert Marschner, Tamara Riedt, Karin Potthoff
Journal: Blood (2018)
Both Tissue-Derived and Bone Marrow-Derived Host IL-17 Producing Cells Are Required for Preventing Acute Graft-Versus-Host Disease
Authors: Rie Kuroda, Hideaki Maeba, Katsuaki Sato, Kazuhito Naka, Shintaro Mase, Raita Araki, Toshihiro Fujiki, Yoichiro Iwakura, Akihiro Yachie, Shoichi Koizumi, Ryosei Nishimura
Journal: Blood (2011)
Synthetic Lethality of Wnt Pathway Activation and Asparaginase in Drug-Resistant Acute Leukemias
Authors: Laura Hinze, Maren Pfirrmann, Salmaan Karim, James Degar, Connor McGuckin, Divya Vinjamur, Sacher Joshua, Kristen E. Stevenson, Donna S Neuberg, Daniel E. Bauer, Florence Wagner, Kimberly Stegmaier, Alejandro Gutierrez
Journal: Blood (2018)
Chemogenomic Approach Unveils the Increased Susceptibility of RUNX1-Mutated AML to Glucocorticoids
Authors: Laura Simon, Vincent-Philippe Lavallee, Marie-Eve Bordeleau, Bernhard Lehnertz, Tara MacRae, Jalila Chagraoui, Jean-Francois Spinella, Geneviève Boucher, Thierry Bertomeu, Jasmin Coulombe-Huntington, Mike Tyers, Sébastien Lemieux, Anne Marinier, Josée Hébert, Guy Sauvageau
Journal: Blood (2018)
Exploratory analysis of barriers and facilitators to cervical cancer care in rural Tamil Nadu, India.
Authors: Shruthi Rajashekara, Malliga J Subramanian, Swaminathan Rajaraman, Jessica Davila, Sharmila Anandasabapathy
Journal: Journal of Clinical Oncology (2019)

125 Background: Approximately 20% of cervical cancer deaths worldwide occur in India, most notably in rural areas. The key to addressing the cervical cancer epidemic is early detection and treatment of precancerous cervical lesions. Many studies that assess barriers to cervical cancer care in India focus on individual level factors, such as awareness and education. Given the disparities in cervical cancer in India, particularly between rural and urban settings, a comprehensive, multi-level approach to evaluating barriers and facilitators to care is needed. Methods: In December 2018, we used semi-structured interviews and direct observation of 15 community health workers, medical officers and gynecologic oncologists to explore the multi-level barriers and facilitators to cervical cancer care in rural Tamil Nadu. Data collection occurred within an existing organized cervical cancer screening program and was guided by the social-ecological model. Results: Barriers and facilitators to cervical cancer screening and treatment of precancerous lesions were identified at all levels of the social-ecological model. Barriers included fear of and travel distance to urban centers for treatment (individual), limited social support (interpersonal), lack of rural clinical facilities that provide treatment (organizational), competing community health initiatives (community), and lack of cohesive national screening and treatment guidelines (policy). Facilitators included travel distance to local screening services (individual), access to community health workers (interpersonal), institutional initiatives to increase screening access (organizational), mass awareness campaigns (community), and Tamil Nadu State priorities to improve cervical cancer care (policy). Conclusions: This assessment underscores the gap between cervical cancer screening and treatment in rural Tamil Nadu. This data will inform the development of a multi-faceted intervention, targeting all levels of the social-ecological model, to improve the linkage between cervical cancer screening and treatment for precancerous cervical lesions to decrease the burden of disease and mortality in India.
Abstract 122: Reliability Analysis for Image-based Non-invasive Pressure Quantification in Aortorenal Artery Systems
Authors: Hao Wu, Monsurul Khan, Xiaoping Du, Alan P Sawchuk, Huidan W YU
Journal: Circulation Research (2019)

Non-invasive quantification of fractional flow reserve (FFR) based on CT angiography has great potential to replace invasive catheterization for quantifying the amount of ischemia caused by a specific arterial stenosis (AS), promising for lower medical cost and better patient care. In clinical practice, the reliability of quantifying the 4-D approximate pressure (p a ) and distal pressure (p d ) across an AS is critical since FFR=p d /p a by definition. The objective of this work is to assess the effects of uncertainties (empiricalness) in the 3-element Windkessel model (WK3) used as exit boundary conditions (BC) on the quantification of p d and p a in aortorenal artery systems. A developed and validated in-house software ( InVascular , see Fig. 1(a)), featured with revolutionarily fast speed for image-based computational hemodynamics, is used for the uncertainty quantification analysis. Fifteen total aortic and renal arteries were studies in five male patients aged 64 to 83. In each case, the effects of the uncertainty on the 4-D pressure quantification are assessed using the First Order Second Moment method. We conduct analyses where the input variables are normally distributed with their coefficients of variation being 3%. Figure 1(b) shows the effects of uncertainty on the systolic pressure (SP) with their means, standard deviations, and 95% confident intervals. The results indicate that the uncertainty (measured by standard deviation) in SP in the aorta is higher than that in the renal arteries. The uncertainty is minimal for the severe stenosis (in red), implying more reliable noninvasive pressure quantification in stenosed arteries.
Abstract 757: β-arrestin-Biased β2-Adrenergic Receptor Signaling Mediates Novel Mechanisms of Cardiomyocyte Contractility
Authors: Ama Dedo Okyere, Claudio de Lucia, Jianliang Song, Rhonda L Carter, Jeffrey L Benovic, Walter J Koch, Joseph Y Cheung, Douglas G Tilley
Journal: Circulation Research (2019)

During heart failure, chronically decreased cardiac output can be treated with positive inotropes, but classic inotropes such as β-adrenergic receptor (βAR) agonists that increase cAMP-dependent Ca 2+ mobilization and contractility ultimately enhance patient mortality. Thus, an alternate approach would be to enhance cardiomyocyte contractility without alterations in cAMP and Ca 2+ levels, such as regulation of sarcomeric proteins. Recently, we demonstrated that a small lipidated pepducin designed from the 1 st intracellular loop of β2AR (ICL1-9) enhanced cardiomyocyte contractility in a Ca 2+ -independent, β-arrestin-dependent manner, yet the complete mechanisms remained unclear. We also showed that β2AR stimulation in hearts in vivo or neonatal rat ventricular myocytes (NRVM) in vitro activated RhoA in a βarr-dependent manner. Therefore, we sought to determine both the proximal and distal mechanisms by which ICL1-9 enhances cardiomyocyte contractility. Using adult murine cardiomyocytes isolated from wild-type C57Bl/6J mice, we measured basal, ICL1-9- and isoproterenol (ISO, as a positive control)-promoted contractility either alone or in the presence of inhibitors of Gα i activity (Pertussis toxin), ROCK1 (Y-27632), myosin light chain kinase (ML7), and protein kinase D (CID755673). Inhibition of Gα i activity prior to ICL1-9 stimulation led to a decreased contractile response. Consistent with RhoA activation by ICL1-9, ROCK1 inhibition was able to attenuate ICL1-9-mediated contractility, as was inhibition of MLCK. Interestingly, we observed that inhibition of PKD also attenuated ICL1-9-mediated contractility. These data suggest that ICL1-9 acts proximally to engage a β2AR/Gα i /βarr signaling axis, which may distally increase the activation of kinases including PKD, MLCK, and ROCK to alter the regulation of sarcomeric proteins.
Novel Hermanksky-Pudlak Syndrome Type 6 Missense Variant Associated with Subclinical Oculocutaneous Albinism and Mild Bleeding
Authors: Nagabhishek Moka, Dong Chen, Chen Han, Kevin J O'Brien, Sara Haroutinian, Laryssa Huryn, Wendy Introne, Ellen Macnamara, William A. Gahl, May Christine Malicdan, Bernadette Gochuico, Koyamangalath Krishnan
Journal: Blood (2018)
HIV transmission links between past and newly diagnosed infections: a molecular epidemiology study
Authors: Tsz Ho Kwan, Ngai Sze Wong, Grace Chung Yan Lui, Kenny Chi Wai Chan, Owen Tak Yin Tsang, Wai Shing Leung, Kai Man Ho, Man Po Lee, Wilson Lam, Sze Nga Chan, Denise Pui Chung Chan, Sabrina Wai Chi To, Wing Cheong Yam, Shui Shan Lee
Journal: The Lancet (2019)
Abstract 630: Txlnb-Deficient Mice Reveal That Ubiquitin-Proteosome-System Dysfunction is Not Sufficient to Impair Cardiac Performance
Authors: Jared M McLendon, Xiaoming Zhang, Colleen S Stein, Nathan H Witmer, Gabrielle M Abouassaly, Ryan L Boudreau
Journal: Circulation Research (2019)

Prior reports show that impaired cardiac function is associated with, if not caused by, Ubiquitin-Proteasome-System (UPS) dysfunction. Rodent loss-of-function studies for proteins involved in protein folding/ER stress responses, ubiquitin ligation, and proteasomal degradation are frequently associated with accumulation of misfolded/ubiquitinated proteins, decreased proteasomal activities, worse outcomes to cardiac stress, and premature death. By contrast, gain of function models that improve protein folding/trafficking or activate the proteasome prevent these molecular phenotypes and improve cardiac function. We have recently found an exception to this association while characterizing beta-taxilin (TXLNB), an understudied muscle- and heart-enriched protein with unknown function. In cardiomyocytes, TXLNB overexpression decreased ubiquitinated proteins and increased proteasome activity, whereas knockdown promotes proteasomal insufficiency. Similarly, hearts from TXLNB knockout (TXLNB-KO) mice show increased ubiquitinated proteins (&gt;2-fold, n=8, p=.007) and decreased 26SB5 proteasome activity (~40%, n=8, p=.025), starting by 12 weeks of age and persisting through life. Despite robust cardiac proteasomal insufficiency, TXLNB-KO mice surprisingly exhibit normal cardiac function [echo/ekg measures done in several independent cohorts (n&gt;7 per sex/genotype) up to ~24 months of age]. In addition, these mice do not show worse responses to mild pressure-overload induced by thoracic aortic constriction (n&gt;13 per sex/genotype). While their cardiac function is normal, TXLNB-KO males do display slight reductions in heart growth with age (10 months, p=.023, n=7; 18 months, p=.07, n=11-17; 24 months, p=.026, n=3-4), suggesting that TXLNB function may interface with hypertrophic signaling. Together, our findings indicate that TXLNB serves to bolster cardiac UPS, and more importantly, that UPS dysfunction and proteasomal insufficiency is not sufficient to cause cardiac dysfunction in mice. Future studies will need to examine if the incongruency with prior reports relates to distinct proteosomal pools (e.g. sarcomeric vs. nuclear vs. ER-associated) and/or the specific identities of the accumulated ubiquitinated proteins.
Abstract 933: Integrated Omics Analysis of Diabetic Heart Failure in Human Myocardium
Authors: Stephani Page, Lydia Kwee, William Kraus, Phillip White, Adam Devore, Robert Mentz, Michael Bristow, Carmelo Milano, Dawn Bowles, Olga Ilkayeva, G. Michael Felker, Bridgette Christopher, Christopher Holley, Robert McGarrah, Svati Shah
Journal: Circulation Research (2019)

Background: Patients with diabetes mellitus (DM) have a higher risk of heart failure (HF). While metabolic dysregulation has been well-established in HF and DM separately, molecular mechanisms associated with diabetic HF are incompletely understood. Thus, we sought to test the overarching hypothesis that cardiac metabolic programming is distinct in diabetic HF compared to DM and HF individually. Methods: RNA-sequencing and targeted metabolomics profiles were completed on human myocardial tissue from 54 unique individuals received from the Duke Human Heart Biorepository and the University of Colorado. Multi-omics profiles of cardiac tissue from 4 groups were compared: a) controls with no clinical evidence of DM or HF (n = 12), b) DM-only (n = 15), c) HF-only (n = 10), and d) HF+DM (n = 17). Results: After using statistical criteria to prioritize genes, we looked for genes that function together or modulate the same activity. Genes encoding producers of reactive oxygen species (ROS), DUOX2, DUOXA2, and DUOXA1, were differentially upregulated in diabetic-HF, compared to DM or HF alone (FDR HF+DM vs DM-only/HF-only = 6.6 x 10 -7 /2.2 x 10 -4 , 7.7 x 10 -3 /6.7 x 10 -3 , and 3.6 x 10 -6 /0.013, respectively). Modulators of mTOR signaling, ERBB3, ERBB4, and PIK3R3, were also differentially regulated in diabetic-HF (FDR HF+DM vs DM-only/HF-only = 1.4 x 10 -3 /0.010, 0.012/7.4 x 10 -3 , and 0.011/9.3 x 10 -3 , respectively). Gene set enrichment analysis supported our focus on these genes; top enriched gene sets included mTOR signaling and processes related to oxidative stress response. In our metabolomics data, long chain acylcarnitines (AC) and ceramides (Cer) are decreased in diabetic-HF. For example, C20:1 AC can be converted to C20:1 Cer and accumulation of both is diminished in diabetic-HF (FDR = 0.0032 and 0.035, respectively). Conclusions: We found that diabetic-HF was characterized by a distinct omics profile consistent with increased ROS production, diminished AC and Cer accumulation, and modulation of mTOR signaling. The fact that ceramide accumulation has been previously associated with oxidative stress and also linked to ERBB and PI3K pathways suggests that these data may reveal a unique regulation of these pathways in diabetic-HF.
Abstract 195: Epigenetic Mechanisms Underlying Anthracycline-Induced Cardiotoxicity
Authors: Ching Kit Chen, Yee Phong Lim, Wilson Lek Wen Tan, George C Anene-Nzelu, Shi Ling Ng, Yiqing Li, Tuan L Danh, Roger Sik Yin Foo
Journal: Circulation Research (2019)

Anthracycline-induced cardiotoxicity (AC) is a major cause of morbidity in childhood cancer survivors. Doxorubicin cardiotoxicity however, is consistently observed to develop chronically over time. We sought to develop a mouse model of pediatric AC to test our hypothesis for an epigenetic mechanism, which may be operating to explain delayed-onset AC. Three week-old male and female C57Bl/6J mice were administered 5 weekly injections with doxorubicin (1mg/kg) (n=24) or saline (n=8). The dosage used was intended to closely mimic the clinical scenario. Half of the doxorubicin-treated (DOX) mice (n=12) and all controls (n=8) were sacrificed 1 week after the last injection; the rest of DOX mice (n=12) were given 4 weeks of drug-free holiday before sacrifice. Echocardiographic measurements were obtained before the first injection, 1 week after the final injection, and before sacrifice. Gene expression profiles were assessed by RNA-sequencing, reduced representation bisulphite sequencing (RRBS), and by ATAC-seq. These analyses were performed on purified pools of isolated cardiac myocytes, procured using a published Langendorff-free method. There was no death in the cohort. LV chamber dimension and wall thickness as well as fractional shortening did not differ between DOX and controls, implying the lack of obvious functional insufficiency from this dose. Similarly, DOX mice did not differ in body weight, heart weights (HW), and HW-to-tibia length ratios compared with controls. Cardiomyocyte dimensions and myocardial interstitial fibrosis were the same between groups. Despite the lack of echo and histological changes in DOX mice, RNA-seq analysis revealed profound and significant differentially expressed genes between the DOX mice and controls. Importantly, a significant proportion of downregulated and upregulated genes persisted, despite the period of drug-free holiday. Moreover, despite being taken off DOX, cardiomyocytes appeared to display new gene expression changes taking place even 4 weeks after stopping DOX. Detailed results of RNA-sequencing, RRBS and ATAC-Seq will be presented during the meeting. These results suggest that cardiomyocytes display DOX-related epigenetic alterations, which may implicate the basis for delayed-onset AC.