tbuckley/cabot-search huggingface dataset:
Abstract 167: Increased Mitophagy and Lysophagy in High Fat Diet and Streptozotocin Induced Diabetic Cardiomyopathy
Authors: Joy R Patel, Satoru Kobayashi, Qiangrong Liang
Journal: Circulation Research (2019)

Heart disease and diabetes are among the leading causes of morbidity and mortality. Diabetes can result in diabetic cardiomyopathy, which further increases the risk of heart failure and mortality in diabetic patients. Diabetic cardiac injury has been associated with altered mitochondrial quality control mechanisms including mitophagy, a selective autophagy in which dysfunctional mitochondria are degraded through the lysosome. Lysophagy is the elimination of injured lysosomes by healthy lysosomes which is extremely important for all forms of autophagy. In the present study, we examined the functional status of mitophagy-lysosome system in the diabetic mouse heart. Cardiac mitophagy and lysophagy were determined by using novel dual fluorescent reporter mice, namely, mt-rosella that express mitochondria-targeted RFP-GFP fusion protein and tfgal3 that express RFP-GFP-galectin3, a galactoside-binding lectin. Mice were fed a high fat diet (60%calories by fat) for 1 month and then injected i.p. with streptozotocin (30 mg/kg/d for 3 days). Mice continued on HFD for additional 3 months. Echocardiographic data showed impaired cardiac function in the diabetic mice. Merged confocal images demonstrated that diabetes increased mitophagy flux in the heart as indicated by the red puncta from mt-Rosella and the mitochondrial LC3-II levels with and without lysosomal protease inhibitors pepstatin A and E64d. In addition, diabetes triggered lysosomal injury in the heart as shown by the increased total number of puncta (yellow plus red) from tfgal3 reporter on the merged confocal images. This was associated with accelerated lysophagy flux as shown by the red puncta, suggesting that the injured lysosomes were being actively degraded in the diabetic heart. The increased lysophagy may have contributed to the increased mitophagy flux since the enhanced elimination of injured lysosomes would be expected to help maintain a pool of healthy lysosomes which is essential for the efficient execution of all forms of autophagy. In summary, our results showed an enhanced mitophagy-lysosome system in the diabetic heart which may be an adaptive response that serves to limit diabetic cardiac injury.
Engraftment Syndrome After Allogeneic Hematopoietic Cell Transplantation: Relationship to Acute Gvhd and Impact on Transplant Outcomes
Authors: Aazim Kamal Omer, Bhargavi Yalamarti, Haesook Kim, Steven L. McAfee, Bimalangshu R. Dey, Karen K. Ballen, Eyal C. Attar, Yi-Bin A. Chen, Thomas R Spitzer
Journal: Blood (2011)
The Treatment of ECVP Plus G-Csf on Epstein–Barr Virus-Associated T Lymphoproliferative Disease (EBV+ T-LPD) in Adult
Authors: Meihua Qian, Wensong Wang, Manling Wang, Meijuan Wu, Zhongsheng Zhao, Tianxin Yang, Weiqun Jin, Sumei Zhan, Xiaogang Wang, Xing Jin, Ye Peng
Journal: Blood (2011)
Abstract 354: Golgi Localized β <sub>1</sub> -adrenergic Receptors Stimulate Golgi PI4P Hydrolysis by PLCε to Regulate Cardiac Hypertrophy
Authors: Wenhui Wei, Craig A Nash, Roshanak Irannejad, Alan V Smrcka
Journal: Circulation Research (2019)

Phospholipase C (PLC)-mediated PI4P hydrolysis pathway at the Golgi is important for regulating cardiac hypertrophy. cAMP stimulates this pathway via Epac-mediated activation of Rap1 which directly binds to and activates PLCε. Here, we demonstrate that a membrane permeant β-adrenergic agonist, dobutamine (dob), and the endogenous β-adrenergic agonist, norepinephrine (NE), induce Golgi PI4P hydrolysis in neonatal rat ventricular myocytes (NRVMs) and adult ventricular myocytes. However, a membrane impermeant β-adrenergic agonist, isoproterenol (iso), does not. In addition, a membrane permeant βAR antagonist, metoprolol, but not a membrane impermeant antagonist, sotalol, fully reverses dob-mediated PI4P hydrolysis. Taken together, this suggests that internal β-ARs are required for inducing PI4P hydrolysis. Subsequently,we used YFP-tagged mini Gs proteins that recruit to Gs-coupled receptors upon their activation, to monitor the location of activated receptors. Dob and NE induced robust and rapid recruitment of mini Gs to the plasma membrane and the Golgi, however, iso only induces recruitment to the plasma membrane. Additionally, inhibition of PLCεat the Golgi with either siRNA or the RA1 domain of PLCε, or the use of an Epac inhibitor also inhibits dob-mediated PI4P hydrolysis. This suggests that PI4P hydrolysis by dob requires Golgi-localized PLCεand Epac.Inhibition of the βAR with Golgi-targeted Nb80 prevented PI4P hydrolysis by both dob and NE confirming that Golgi-localized βARs are required for PI4P hydrolysis.Also, Oct3 transporter inhibitors prevent NE-induced PI4P hydrolysis but dyngo, an inhibitor of receptor internalization, had no effect. This indicates that agonist transport and not receptor internalization is required for NE-mediated Golgi βAR activation and PI4P hydrolysis. Furthermore, dob stimulates an increase in cell size and ANF expression in NRVMs that is significantly inhibited by metoprolol but less effectively by sotalol. Taken together, these data suggest that Golgi βARs are involved in mediating cardiomyocyte hypertrophy and may serve as a novel target for treating heart failure.
Expanding access to genetic evaluations in a large community oncology practice through a collaborative service delivery model.
Authors: Gayle Patel, Trisha Nichols, Ann Bunnell, Kate Principe, John F. Sandbach, Sara Toth, Monica White, Christine L. Long, Megan Jones, Ryan Sperl, Lalan S. Wilfong
Journal: Journal of Clinical Oncology (2019)

123 Background: Identifying individuals with inherited cancer susceptibility is critical to cancer treatment and prevention in patients and families. While the identification and management of inherited susceptibility to cancer is the standard of care, genetic testing rates are low; 1.2 million women with breast and/or ovarian cancer who qualify have yet to undergo genetic testing (Childers et al 2017). The Genetic Risk Evaluation and Testing Program (GREAT) formed to improve access to genetic evaluations and testing in Texas Oncology, a large, state-wide community oncology practice. Methods: The GREAT program is a collaborative service delivery model, utilizing 4 certified genetic counselors (CGC) to lead advanced practice providers and physicians in offering pre and post-test evaluations to oncology patients in their own community. Training involves 8-12 weeks of didactic lectures, precepting, and ongoing education and support. GREAT-trained providers then offer comprehensive genetic evaluations and testing to established oncology patients as well as at-risk individuals from the surrounding community. Results: The GREAT program has trained 72 providers at 52 cancer centers. Rates of genetic evaluations increased each year from 2012 to 2018. Overall findings: 19,129 unique patients received an evaluation; 17,305 genetic tests were completed; 2,597 pathogenic/likely pathogenic variants (P/VLP) have been identified. Conclusions: Despite guidelines recommending genetic evaluations for hereditary cancer syndromes, most patients are not receiving this service. A hybrid service delivery model utilizing regional CGCs to train providers in community oncology offices can significantly increase access to genetic services. The model described is an effective and expansive mechanism for the delivery of high-quality cancer genetics care. The GREAT program plans to hire additional CGCs to train more providers across Texas Oncology with the goal of expanding access. [Table: see text]
Integrative Analysis of Genomic Aberration and Gene Expression Suggests That MPD with Loss of Heterozygosity or Gain of Chromosome 9 Represents a Distinct Entity
Authors: Weijia Zhang, Benjamin L. Ebert, Windy Berkofsky-Fessler, Monica Buzzai, Yezhou Sun, Caixia Xi, Ross L Levine, D. Gary Gilliland, Jonathan D. Licht
Journal: Blood (2008)
Experiences of pediatric lymphoma patients undergoing treatment in Malawi across all PROMIS-25 domains.
Authors: Grace K Ellis, Bryce B Reeve, Salama Itimu, Ande Salima, Grace Banda, Agness Manda, Olivia Manthalu, Ryan Seguin, Satish Gopal, Katherine D Westmoreland
Journal: Journal of Clinical Oncology (2019)

203 Background: Health-related quality of life (HRQoL) is an important outcome in cancer care and research, but such data from sub-Saharan Africa are scant. We translated and validated the Pediatric Patient-Reported Outcome Measurement Information System (PROMIS)-25 questionnaire for use in Malawi. Methods: We administered the Pediatric PROMIS-25 at baseline, mid-treatment, treatment completion, and follow-up to pediatric lymphoma patients receiving care in Lilongwe. Domain scores were transformed into PROMIS T-scores. Differences in follow-up and baseline values were calculated and compared to published minimally important difference (MID) estimates of 3 points. Results: Eighty-one questionnaires were completed at diagnosis, 41 at mid-treatment, 24 at treatment completion, and 25 at follow-up [Table]. At baseline, 57 (70%) were male, median age was 11 (IQR 9-13), and 50 (62%) reported Pain Intensity ≥8. Mobility, Anxiety, Depressive Symptoms, and Pain Interference improved during treatment, but seemed to worsen at treatment completion. At follow-up, substantial improvements in HRQoL were reported [Table]. Conclusions: Despite poor HRQoL at baseline, improvements in all measured domains exceeded accepted MID thresholds. This suggests treatment led to meaningful improvements in HRQoL, but high mortality in data may reflect a survivor effect. Incorporating serial HRQoL assessments in emerging cancer programs in sub-Saharan Africa should be a regional priority. HRQoL T-scores during care, median (IQR). Lower Mobility and Peer Relationship scores reflect worse functioning; higher symptom scores reflect worse symptom burden. [Table: see text]
Artesunate Attenuate Chronic Graft-Versus-Host Disease By Regulating Th17/Treg Balance
Authors: Chen Xiaomei, Jianyu Weng, Peilong Lai, Xin Huang, Wang Yulian, Suxia Geng, Liyan Guo, Tian Huang, Lingji Zeng, Xin Du
Journal: Blood (2018)
Association of Cigarette Type With Lung Cancer Incidence and Mortality
Authors: Nichole T. Tanner, Nina A. Thomas, Ralph Ward, Alana Rojewski, Mulugeta Gebregziabher, Benjamin Toll, Gerard A. Silvestri
Journal: JAMA Internal Medicine (2019)

This study uses data from the National Lung Screening Trial to investigate the association of cigarette tar level, flavor, and filter status with lung cancer diagnosis, mortality, and all-cause mortality.
Abstract 15224: A Comparison of Biomarker Rise in Type 1 and Type 2 Myocardial Infarction
Authors: Amit K Pandey, Lori B Daniels
Journal: Circulation (2018)

Background: Cardiac troponin (cTn) is the primary biomarker used for the diagnosis of myocardial infarction (MI), though creatine kinase MB (CK-MB) is often used for infarct sizing. Type 2 MI occur...
Abstract 944: Differential Dna Methylation Co-segregates With the Severity of Heart Failure
Authors: Wilson Tan L Wen, Eleanor Wong, Thomas M Vondriska, Wang Yibin, Christoph D Rau, Roger Foo
Journal: Circulation Research (2019)

Heart failure (HF) is a leading cause of morbidity and mortality worldwide. As a potential epigenetic biomarker, DNA methylation differs between healthy and diseased hearts. However, its association according to disease severity has not yet been studied. Here, we sought to investigate how DNA methylation (DNAm) differs across HF disease severity, and study the use of a DNMT methyltransferase inhibitor RG108 on DNAm and its effect on heart function. A fixed dose of Isoprenaline (ISO), or saline control (SAL), administered to a hybrid mouse diversity panel (HMDP) consisting of 85 classical and recombinant inbred mouse strains produced a range of cardiac hypertrophy and/or LV dilatation. Left ventricles were harvested and subjected to genome-wide cardiac DNAm profiling by Reduced Representation Bisulfite Sequencing (RRBS). Unsupervised clustering of the top 1% most variable CpG methylation segregated strains to their genetic origin. Disregarding strain-specific methylation differences, differential methylation between ISO and SAL unexpectedly categorised mice into mild and severe disease responders. In the severe-responder strain BTBRT, the pharmacological DNMT methyltransferase inhibitor, RG108, rescued disease from ISO-response, with accompanying evidence of gene expression recovery. This work establishes the range of cardiac differential DNAm correlating according to disease severity. It displays the involvement of DNA methylation-dependent gene expression changes that turns out to be unique, despite different mouse strain backgrounds. This gives further proof of principle that cardiac DNAm changes represent novel biomarkers for disease stratification and consequent targeted therapy.
Longer Duration and Proper Titration of Low Molecular Weight Heparin (LMWH), Are Independent Factors for Successful Pregnancy Outcome. Retrospective Analysis from a Single Center
Authors: Maria Stamou, Stergios Intzes, Eleftheria Lamprianidou, Menelaos Konstantinos Papoutselis, Zoe Bezirgiannidou, Evangelia Nakou, Zafeirios Kartasis, Georgios Vrachiolias, Ioanna Bazntiara, Ioannis Kotsianidis, Emmanouil Spanoudakis
Journal: Blood (2018)
Exercise Intolerance, Mortality, and Organ System Impairment in Adult Survivors of Childhood Cancer
Authors: Kirsten K. Ness, Juan C. Plana, Vijaya M. Joshi, Russell V. Luepker, Jean B. Durand, Daniel M. Green, Robyn E. Partin, Aimee K. Santucci, Rebecca M. Howell, Deo Kumar Srivastava, Melissa M. Hudson, Leslie L. Robison, Gregory T. Armstrong
Journal: Journal of Clinical Oncology (2019)

PURPOSE Exercise intolerance, associated with heart failure and death in general populations, is not well studied in survivors of childhood cancer. We examined prevalence of exercise intolerance in survivors exposed or not to cardiotoxic therapy, and associations among organ system function, exercise intolerance, and mortality. METHODS Participants consisted of 1,041 people who had survived cancer ≥ 10 years (and had or did not have exposure to anthracyclines and/or chest-directed radiation) and 285 control subjects. Exercise intolerance was defined as peak oxygen uptake &lt; 85% predicted from maximal cardiopulmonary exercise testing; organ functions were ascertained with imaging or clinical testing. Multivariable regression of the data was performed to compare exercise capacity between survivors exposed or unexposed to cardiotoxic therapy and control subjects, and to evaluate associations between treatment and organ function, and organ function and exercise intolerance. Propensity score methods in time-to-event analyses evaluated associations between exercise intolerance and mortality. RESULTS Survivors (mean age ± standard deviation [SD], 35.6 ± 8.8 years) had lower mean (± SD) peak oxygen uptake (exposed: 25.74 ± 8.36 mL/kg/min; unexposed: 26.82 ± 8.36 mL/kg/min) than did control subjects (32.69 ± 7.75 mL/kg/min; P for all &lt; .001). Exercise intolerance was present in 63.8% (95% CI, 62.0% to 65.8%) of exposed survivors, 55.7% (95% CI, 53.2% to 58.2%) of unexposed survivors, and 26.3% (95% CI, 24.0% to 28.3%) of control subjects, and was associated with mortality (hazard ratio, 3.9; 95% CI, 1.09 to 14.14). Global longitudinal strain (odds ratio [OR], 1.71; 95% CI, 1.11 to 2.63), chronotropic incompetence (OR, 3.58; 95% CI, 1.75 to 7.31); forced expiratory volume in 1 second &lt; 80% (OR, 2.59; 95% CI, 1.65 to 4.09), and 1 SD decrease in quadriceps strength (OR, 1.49; 95% CI, 1.23 to 1.82) were associated with exercise intolerance. Ejection fraction &lt; 53% was not associated with exercise intolerance. CONCLUSION Exercise intolerance is prevalent among childhood cancer survivors and associated with all-cause mortality. Treatment-related cardiac (detected by global longitudinal strain), autonomic, pulmonary, and muscular impairments increased risk. Survivors with impairments may require referral to trained specialists to learn to accommodate specific deficits when engaging in exercise.
Pilot Study: Favorable Outcomes with Addition of Topotecan to Busulfan/Melphalan As High-Dose Myeloablative Therapy Followed by Autologous Hematopoietic Cell Transplantation
Authors: Joseph Rosenthal, Anna Pawlowska, Jerry Cheng, Steven Kechichian, Debbie Hitt, Mary Suarez, Ni-Chun Tsai, Joycelynne Palmer
Journal: Blood (2012)
Living systematic reviews: A novel mechanism for improving efficiency and quality of evidence synthesis in oncology.
Authors: Irbaz Bin Riaz, Rabbia Siddiqi, Noureen Asghar, Elizabeth Jane Cathcart-Rake, Vitaly Herasevich, Victor Montori, Zhen Wang, Ronald S. Go, S. Vincent Rajkumar, M. Hassan Murad
Journal: Journal of Clinical Oncology (2019)

241 Background: In a rapidly moving field, such as cancer immunotherapy, where immune checkpoint inhibitors (ICIs) are used across 14 different tumor types, patients may receive suboptimal treatment or even be harmed if information on toxicity is not readily translated for use in clinical practice. Every single systematic review and meta-analysis which attempted to summarize toxicity of immune checkpoint inhibitors (ICIs) quickly became outdated. A living systematic review, which is defined as a systematic review that is continually updated to incorporate relevant new evidence as it becomes available, is necessary in this situation. Methods: The process of creating a living systematic review started with the creation of a comprehensive search designed by a librarian experienced in systematic reviews in collaboration with the study’s principle investigator. Search was constantly updated every 3 months and evidence is synthesized in a series of steps (microtasks) using a combination of human and augmented intelligence. A complete infrastructure is being developed and it includes automated cumulative meta-analysis and an online reporting platform which will constantly update information for clinicians and patients in a live manner. Results: We screened 6746 studies during Sep 2018-March 2019 and identified 6746 studies and we were able to successfully maintain up-to-date toxicity estimates for immune mediated adverse events over this period while maintaining the rigor of a conventional systematic review. Eventually, we will integrate the steps of LSR into one, user-friendly, semi-automated format which can independently provide accurate estimates and feed into and support a living guidelines platform through shared Application Programing Interface (APIs). Conclusions: LSRs are feasible, efficient, and when fully developed can reduce redundancy and waste in medical research, improve the quality of evidence, reduce human effort and support living and dynamic guidelines to facilitate truly informed shared decision making.
Abstract 264: EPRS is a Critical Translational Control Factor in Cardiac Fibrosis
Authors: Jiangbin Wu, Kadiam C Venkata Subbaiah, Feng Jiang, Omar Hedaya, Peng Yao
Journal: Circulation Research (2019)

Increased protein synthesis of pro-fibrotic genes is a common feature of cardiac fibrosis, a major manifestation of heart failure (HF). Despite this observation, critical factors and molecular mechanisms for translational control of cardiac fibrosis remain underexplored. Here, we identify a critical house-keeping translational regulator, glutamyl-prolyl-tRNA synthetase (EPRS), which preferentially regulates the translation of proline-rich (PRR) pro-fibrotic genes. In mammals, EPRS catalyzes the attachment of two amino acids, glutamic acid and proline, to their cognate tRNAs for protein synthesis. By overlapping of aminoacyl-tRNA synthetases (ARSs) induced in TGF-β treated human cardiac fibroblasts, human ARSs with genetic mutations in the congenital heart disease, mouse ARSs associated with isoproterenol (ISO)-induced cardiomyopathy by GWAS, and ISO-induced ARSs in mouse failing hearts, we identified EPRS as the only ARS involved in various cardiac pathogenesis. EPRS is induced in failing human heart compared to non-failing donor heart and functions as an integrated node downstream of multiple hypertrophic and fibrotic stimuli in murine hearts, including ISO infusion and transverse aortic constriction (TAC) surgery. Low-dose halofuginone (Halo), a prolyl-tRNA synthetase (PRS)-specific inhibitor, as well as genetic knockout of one allele of EPRS in mouse genome, reduces cardiac hypertrophy and fibrosis in ISO- and TAC-induced HF mouse models. Using RNA-Seq and polysome profiling-Seq in Halo-treated fibroblasts, we identified several novel PRR genes, including Ltbp2, Furin and Sulf1, in addition to collagens, which are translationally regulated by EPRS. Inhibition of Furin by various inhibitors attenuates cardiac fibroblast activation and collagen deposition in vitro . Finally, we found that inactivation of EPRS reduced translational efficiency and enhanced mRNA decay of PRR genes. Taken together, our results indicate that EPRS controls the translational activation of PRR genes in cardiac fibroblasts, and these data provide novel insights into the translational control mechanisms of cardiac fibrosis, which may promote development of novel therapeutics by inhibiting pro-fibrotic translation factors.
Abstract 756: Sunitinib-Induced Cardiotoxicity in an Engineered Cardiac Microtissue Model With Dynamically Tunable Afterload
Authors: Carissa Livingston, Abhinay Ramachandran, Elise Corbin, Alexia Vite, Alexander Bennett, Kenneth B Margulies
Journal: Circulation Research (2019)

Introduction: Anti-angiogenic tyrosine kinase inhibitors (TKIs) have efficacy against many solid neoplasms. Unfortunately, their on- and off-target effects frequently cause hypertension (HTN) and heart failure. Nearly all cases of cardiac dysfunction are associated with HTN, but the mechanism for this association is unclear. Aims: We have developed a novel in vitro 3D tissue engineering platform that uses a magnetically tunable elastomer to create dynamic alterations in afterload felt by cardiac microtissues. We are using this platform to examine the impact of increased in vitro afterload (a proxy for HTN) on cardiotoxicity of the TKI sunitinib. Hypotheses: 1) Increased afterload augments sunitinib-induced cardiotoxicity 2) Repeat exposures to sunitinib and increased afterload will further augment this toxicity. Methods: Human induced pluripotent stem cell cardiomyocytes (96%) and human cardiac fibroblasts (4%) from a commercial vendor (NCardia, Inc.) were allowed to self-assemble and form cardiac microtissues. Microtissues were exposed to sunitinib (0μM-10μM) at differing levels of afterload for a minimum of 8 hours. After a washout period, tissues were either harvested for analysis or exposures to sunitinib and afterload were repeated. Outcomes measured after each drug exposure included caspase activation, contractile ability, and force generation. Results: The applied magnetic field produced increases in afterload from 0.509±0.032 to 0.698±0.031 μN/μm. At 36 hours after exposure to supratherapeutic concentrations of sunitinib, recovery of contractile function as measured by force generation of microtissues was greater under soft afterload conditions compared with stiff afterload conditions (2.52μN soft vs 1.16μN stiff). Conclusion: Our platform creates dynamic alterations in afterload in engineered cardiac microtissues. Use of this versatile platform to examine the cardiotoxic effects of sunitinib has given promising initial results. Future studies examining removal/application of afterload, repeat exposures to sunitinib, and exposure to cardioprotective drugs will allow for insight into the mechanisms, treatment, and prevention of sunitinib-induced cardiotoxicity.
Hematopoietic Stem Cell Transplantation for CNS Autoimmune Disorders for Adults and Children: Long-Term Outcomes - Experience of the Russian Federation
Authors: Kirill Kirgizov, Elena Skorobogatova, Denis Fedorenko, Elvira Volkova, Alexey Polushin, Ekaterina Pristanskova, Oksana Blagonravova, Sergey Piliya, Raisa Bembeeva, Ludmila Zubarovskaya, Axel Zander, Boris Afanasyev, Alexander Rumyantsev
Journal: Blood (2018)