tbuckley/cabot-search huggingface dataset:
Clinico-Molecular Features and Treatment Outcomes in Primary Myelofibrosis Phenotypes with Protracted Disease Dynamics
Authors: Luis E. Aguirre, Akriti G Jain, Somedeb Ball, Najla Al Ali, Sara Marie Tinsley-Vance, David A. Sallman, Kendra Sweet, Jeffrey E. Lancet, Eric Padron, Andrew T. Kuykendall, Rami S. Komrokji
Journal: Blood (2021)
G-CSF Upregulates the Expression of Aquaporin-9 through C/EBP-Beta to Enhance the Cytotoxic Activity of Arsenic Trioxide to Acute Myeloid Leukemia Cells
Authors: Wanbin Fu, Lan Xu, Jia Liu, Xiaofeng Han, Junying Wang, Xinpeng Wang, Huanbin Zhao, Jian Hou, Jiong Hu, Hua Zhong
Journal: Blood (2021)
Glutathione-responsive copper-disulfiram nanoparticles for enhanced tumor chemotherapy
Authors: Meixu Chen, Zeqian Huang, Meng Xia, Yaqing Ding, Ting Shan, Zilin Guan, Xiuling Dai, Xiaoyu Xu, Yanjuan Huang, Min Huang, Chunshun Zhao
Journal: Journal of Controlled Release (2021)
Promising Preliminary Activity of Optimized Affinity, CD38 CAR NK Cells Generated Using a Non-Viral Engineering Approach in Gene Edited Cord Blood Derived NK Cells for the Treatment of Multiple Myeloma
Authors: Rohit Duggal, Sumit Sen Santara, Myra Gordon, Aoife Kilgallon, David Hermanson, Richard W. Childs, Michael E. O'Dwyer
Journal: Blood (2021)
PATH-36. INTRATUMOR HETEROGENEITY AND BIOINFORMATIC DIFFERENCES INFLUENCE MENINGIOMA MOLECULAR CLASSIFICATION
Authors: Harish Vasudevan, Abrar Choudhury, Stephanie Hilz, Javier Villanueva-Meyer, William Chen, Calixto Lucas, Steve Braunstein, Nancy Ann Oberheim-Bush, Nicholas Butowski, Melike Pekmezci, Michael McDermott, Arie Perry, David Solomon, Stephen Magill, David Raleigh
Journal: Neuro-Oncology (2021)

Abstract Molecular alterations such as CDKN2A inactivation and TERT promoter mutation are new criteria for grade 3 meningiomas in the 5th edition of the WHO Classification of Tumors of the Central Nervous System. However, consensus approaches to identify copy number variants (CNVs) and short somatic variants in meningiomas are lacking. Here, we performed integrated DNA methylation profiling, RNA-sequencing, and targeted DNA mutational profiling on 10 stereotactically-collected, regionally-distinct samples from 4 meningiomas. Targeted DNA sequencing revealed numerous private short somatic variants from multiple sites within individual meningiomas, including a TERT promoter mutation in only 1 of 2 samples from the same tumor. DNA methylation profiling revealed differences in biologic groups and immune cell enrichment between regionally-distinct samples within individual meningiomas. CNV status was evaluated using DNA methylation profiling and RNA sequencing on 14 stereotactically-collected, regionally-distinct samples from 2 meningiomas. Phylogenetic architectures from DNA methylation profiling and targeted DNA sequencing were highly concordant and shared 99.12% of CNVs while RNA sequencing identified only 39% of the CNVs called from DNA based approaches. Finally, CNV analysis based on single-cell RNA sequencing revealed partially overlapping CNVs across meningioma cells within an individual tumor, suggesting subclonal populations may influence CNV-based meningioma molecular classification and underlie limitations in defining CNVs from bulk RNA-sequencing. In sum, these data highlight the relative strengths and weaknesses of various approaches for molecular analysis of meningiomas complicated by intratumor heterogeneity due to non-tumor cells and subclonal populations of meningioma cells. Future efforts to incorporate molecular analysis into the diagnostic paradigm for meningiomas may require orthogonal validation across multiple platforms or image-guided meningioma sampling to select the most aggressive regions for molecular profiling.
Abstract 14385: Genome Sequencing and Re-Engineered Heart Cell-Disease Modeling Identifies a Novel Deep Intronic Variant in a Multi-Generational Long QT Syndrome Pedigree
Authors: Kathryn E Tobert, David J Tester, Wei Zhou, Carla Haglund-Turnquist, John Giudicessi, Michael J Ackerman
Journal: Circulation (2021)

Introduction: Most of long QT syndrome (LQTS) is explained by pathogenic variants in KCNQ1 , KCNH2 , or SCN5A . However, ~10-20% of LQTS index cases remain genetically elusive following commercial genetic testing. Here, we identified and functionally characterized a novel LQTS genetic substrate in a multi-generational, “genotype negative” LQTS pedigree. Methods: The index case was a 40-year-old female with a history of syncope, seizures, ventricular fibrillation, and a family history of LQTS and sudden death. Although anticipated to have KCNH2- mediated LQT2, commercial genetic testing of all LQTS-causative genes was negative. Genome sequencing and variant analysis was performed on 6 affected family members. Patient-specific and CRISPR/Cas9 “gene-corrected” isogenic control induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) were generated. RT-PCR was used to determine the effects of the identified variant on splicing. Action potential duration (APD) and field potential duration (FPD) were measured using voltage-sensing dye (Fluovolt) and microelectrode array, respectively. Results: No ultra-rare, nonsynonymous heterozygous variants co-segregated among the 6 LQTS phenotype-positive individuals. Instead, a deep intronic KCNH2 variant (c.3331-316 G&gt;T) was present in all affected individuals. RT-PCR analysis of patient-specific iPSC-CM-derived RNA revealed that c.3331-316 G&gt;T creates a novel 89 base-pair exon residing between canonical exons 14 and 15 of KCNH2 that results in a frame-shift variant annotated as p.S1112Pfs*171. The APD 90 was significantly longer in p.S1112Pfs*171-iPSC-CMs (647 ± 12 ms, n=50) compared to isogenic control iPSC-CMs (412 ± 10 ms, n=50, p &lt; 0.0001). Further, the FPD was significantly longer in p.S1112Pfs*171-iPSC-CMs (349 ± 8 ms, n=48) compared to isogenic control iPSC-CMs (209 ± 10 ms, n=20, p &lt; 0.0001). Conclusions: A novel deep intronic KCNH2 variant was identified in a multi-generational genetically elusive LQTS pedigree. The patient-derived and isogenic control iPSC-CMs establish that the p.S1112Pfs*171-KCNH2 variant is the monogenetic cause for this family’s LQTS. As suggested by the phenotype, this family indeed has KCNH2 -mediated LQT2 albeit stemming from a deep intronic variant .
EPCO-02. GERMLINE SINGLE NUCLEOTIDE POLYMORPHISM rs55705857 AT 8q24 INTERACTS WITH SOMATIC IDH1 MUTATION TO ENHANCE HUMAN GLIOMA FORMATION
Authors: Kristen Drucker, Connor Yanchus, Thomas Kollmeyer, Asma Ali, Decker Paul, Matthew Kosel, Arijit Panda, Alissa Caron, Caterina Giannini, Terence Burns, Alexej Abyzov, Liguo Wang, Margaret Wrensch, John Wiencke, Jeanette Eckel-Passow, Daniel Lachance, Daniel Schramek, Robert Jenkins
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Determination of the causation of germline single nucleotide polymorphisms (SNPs) located in non-coding regions of the genome is challenging. The genomic region of 8q24 has been identified as important in many kinds of cancer, linked to a topologically associated domain (TAD) encompassing MYC; this TAD contains a GWAS SNP (rs55705857) associated with IDH-mutant glioma. METHODS Germline genotyping data from 622 IDH-mutant glioma and 668 controls were used to fine map the rs55705857 locus by detailed haplotype analysis. Chromatin immunoprecipitation sequencing (ChIP-seq) of histone markers H3K4me1, H3K4me3, H3K27ac and H3K36me3 was performed on normal brain samples (n=8) and human glioma samples (n=11 IDH-wt and 52 IDH-mut). RNAseq from 9 normal and 83 brain tumors (n=26 IDH-wt and 55 IDH-mut) were used to assess differential gene expression. RESULTS Fine-mapping identified rs55705857 SNP as the most likely causative allele (OR=8.69; p&amp;lt;0.001) within 8q24 for the development of IDH-mutant glioma. At rs55705857, both H3K27ac and H3K4me1 in IDH-mutant vs IDH-wt tumors were increased 3.05- and 1.58-fold, respectively (DiffBind; p=5.81×10-7 and p=2.31×10-3). ChromHMM analysis of the marks indicated that promoter and enhancer functions were significantly increased, and the activity broadened at rs55705857 in IDH-mut gliomas compared to IDH-wt tumors and normal brain samples. This enhancement correlated with significant increased MYC expression in IDH-mut gliomas (p=3.1×10-13), as well as alterations of Myc signaling targets. Publicly available ATACseq, ChIPseq and long-range DNA interaction data demonstrated that the rs55705857 locus is open and interacts with the MYC promoter. CONCLUSIONS Fine-mapping of the 8q24 locus provided strong evidence that rs55705857 is the causative 8q24 locus associated with IDH-mut glioma. Functional experiments suggest that IDH mutation facilitates rs55705857 interaction with MYC to alter downstream MYC targets.
Abstract 11889: A Novel Long Noncoding RNA FAF, Inhibits Apoptosis via Upregulating FGF9 Through PI3K/AKT Signaling Pathway in Ischemia-Hypoxia Cardiomyocytes
Authors: Lian-sheng Wang, Hao-jie Shi, Hao Wang
Journal: Circulation (2018)

Background: Ischemia and hypoxia in AMI is the main cause of cardiomyocytes loss, and cardiomyocyte apoptosis plays a significant role in pathogenesis of AMI. Recent studies have verified that long...
Abstract 6928: Trends and Mortality of Percutaneous and Open Cardiac Interventions in Diabetic Patients With Coronary Artery Disease: 18 Years National Perspective
Authors: Beka Aroshidze, Susan C Mirabal, Aaron Sircy, Srishti S Visen, Alexa B Kahn, Jilmil Raina, Junxin Shi, beka bakhtadze, Tamta Chkhikvadze
Journal: Circulation (2021)

Introduction: Coronary artery bypass grafting (CABG) is a preferred intervention in patients with diabetes and coronary artery disease (CAD). We aimed to analyze the trends and outcomes of interventions in diabetic patients with CAD and if there has been a shift in intervention types in this subset of patients. Methods: We queried Nationwide Inpatient Sample 2000-2018yy for adult patient discharged with associated ICD-9 and ICD-10 diagnosis and procedure codes for CAD and concomitant diabetes, who only underwent CABG or PCI and analyzed the procedure trend changes. Primary outcome was inpatient mortality. Results: A total of nationally estimated 42,887,309 adult hospitalizations were identified for diabetic patients with CAD from 2000-2018, with 3,653,882 PCI and 1,692,938 CABG procedures performed. Number of hospitalizations has gradually increased until 2011, and decreased afterwards. Although overall PCI numbers have dropped after 2015, likely related to ICD-9 to ICD-10 coding transition, the proportion of PCI procedures have followed the increasing trend of hospitalizations from 9.2% in 2000 to highest 11.3% in 2006 and 8% in 2018. Meanwhile the number of CABG has gradually decreased from 6.5% in 2000, reaching lowest &lt;3% in 2011 and 4% in 2018. Inpatient mortality has decreased for patients who only received CABG from 2.35% (95% CI:2.09-2.62) in 2000 to 1.69% (95% CI: 1.46-1.93) in 2018, while increased for PCI from 1.29% (95%CI: 1.12-1.46 in 2000) to 2.65% (95%CI: 2.45-2.85 in 2018) (Figure 1). Conclusion: While hospitalizations have increased for diabetic patients with CAD, the inpatient mortality for CABG has decreased as well as proportion of CABG performed. Meanwhile, the proportion of PCI has increased, whereas mortality for PCI has doubled. Further analysis is necessary in selection of interventions in these patients and evaluating the risks and benefits of PCI compared to CABG.
Abstract 9877: Burden and Predictors of Hypertensive Crisis-Related Hospitalizations and Outcomes in Young Cannabis Users: A Nationwide Multi-Center Analysis
Authors: Rupak Desai, Zainab J Gandhi, Geethu Jnaneswaran, Athul Raj Raju, Waleed Sultan, Charu Agarwal, Vivek Joseph Varughese, Gaurav Mudgal, Akhil Jain
Journal: Circulation (2021)

Introduction: With the increasing use of recreational cannabis in the youth and earlier reports suggesting its potential association with systolic hypertension, we planned to assess the burden with disparities, predictors and outcomes of hypertensive (HTN) crisis in young cannabis users vs. non-users. Methods: We queried the National Inpatient Sample (October2015-2017) to identify admissions among young (18-44 years) cannabis users with HTN crisis. Rates of HTN crisis admissions with racial/sex disparities were assessed in cannabis users vs. non-users. Multivariable analysis was performed adjusting for covariates to assess the predictors of HTN crisis in cannabis users and odds of inpatient mortality. Results: Of 623,715 admissions among young cannabis users, 4675 (0.7%) had HTN crisis. Among cannabis users, non-whites and females were more often admitted for HTN crisis cohort compared to non-users (Figure 1). Among young cannabis users, males (OR 1.12, CI 1.04-1.19), blacks (OR 3.28, CI 3.02-3.56), patients admitted non-electively (OR 3.09, CI 2.53-3.76) with comorbidities like chronic kidney disease (OR 8.83, CI 8.14-9.59), congestive heart failure (OR 3.35, CI 2.13-3.08), obesity (OR 2.83, CI 2.62-3.05), valvular diseases (OR 2.56, CI 2.13-3.08), fluid and electrolytes disorders (OR 2.25, CI 2.11-2.40), diabetes mellitus (OR 1.82, CI 1.67-1.97) and hyperlipidemia (OR 1.71, CI 1.56-1.87) predicted higher odds of HTN crisis (p&lt;0.001). Interestingly, cannabis users admitted for HTN crisis had lower odds of in-hospital mortality (OR 0.67, CI 0.45-0.99, p&lt;0.05) compared to non-users when adjusted for confounders. Conclusions: Non-white and male cannabis users had higher odds of HTN-crisis admissions. Cannabis users with preexisting cardiovascular and metabolic comorbidities had higher odds of developing HTN crisis. Lower risk of inpatient mortality following HTN-crisis in cannabis users warrants future prospective studies.
Abstract 14212: Relationship Between Baseline Frailty Status and Benefits of a Novel Multidomain Physical Rehabilitation Intervention Among Older Patients Hospitalized With Acute Decompensated Heart Failure: The REHAB-HF Trial
Authors: Ambarish Pandey, Amy M Pastva, Pamela W Duncan, Michael Nelson, Dalane W Kitzman, David J Whellan, Robert J Mentz, Haiying Chen, Bharathi Upadhya, Gordon R Reeves
Journal: Circulation (2021)

Background: Physical frailty is common among older patients with acute decompensated HF (ADHF) and is associated with worse quality of life (QOL) and a higher risk of adverse CV events. In the REHAB-HF trial, a 12-week, multidomain physical function intervention improved functional status and QOL in older ADHF patients. Whether baseline frailty status modifies the benefits of the intervention remains unclear. Objective: Evaluate the interaction between baseline frailty and treatment effects of the physical function intervention in the REHAB-HF trial. Methods: Frailty status was assessed by the modified Fried criteria. Outcomes were change in physical function (Short Physical Performance Battery [SPPB] score and 6-minute walk distance [6-MWD]), QOL (Overall KCCQ score), and Geriatric Depression Scale (GDS) score at the end of the 12-week intervention. Association between changes in frailty score and rates all-cause hospitalization were assessed using adjusted linear regression models. Results: At baseline, among 337 participants (age: 72 y, 54% women) 57% were frail, and 43% were prefrail. At 12-week f/u, both prefrail and frail groups improved with the intervention; however, the frail group had significantly greater improvements over the prefrail group in SPPB score, 6MWD, and KCCQ (Table). A significant improvement was also noted in the GDS score with the intervention among frail but not prefrail participants (Table). In adjusted analysis, an improvement in frailty score at 12-weeks was significantly associated with lower rates of all-cause hospitalization in the 3 months following the intervention period (rate ratio [95%CI] = 0.65[0.55-0.76], p&lt;0.001). Conclusion: ADHF patients with worse frailty status at baseline had greater improvement in functional status and QOL than those who were prefrail. Furthermore, improvement in frailty burden with the rehabilitation intervention was significantly associated with a lower risk of rehospitalization.
CBIO-14. SINGLE CELL RNA SEQUENCING ANALYSIS OF HUMAN GLIOBLASTOMA STEM-LIKE CELL CULTURES AND XENOGRAFT TUMORS
Authors: Sonali Arora, Anca Mihalas, John Bassett, Anoop Patel, Patrick Paddison
Journal: Neuro-Oncology (2021)

Abstract Single cell RNA-seq (scRNA-seq) studies for glioma have yielded critical insight into intratumoral heterogeneity and developmental gene expression patterns for primary gliomas. One key conclusion from these studies is that each tumor represents a complex, yet maligned, neuro-developmental ecosystem, harboring diverse cell types, which presumably contribute to tumor growth and homeostasis in specific ways (e.g., vascular mimicry, immune evasion, recreating NSC niches, neural injury responses, etc.). Here, to better understand experimental models of human glioblastoma (GB), we performed single cell RNA-seq analysis of human GB stem-like cells (GSCs) of distinct tumor subtypes (mesenchymal and proneural) during their in vitro culture in serum-free conditions and also during tumor formation in immunocompromised mice. This analysis revealed surprising differences between in vitro and in vivo grown GSCs. Among our results, we find that in vivo mesenchymal GSCs are capable of transitioning to proneural-like states, while proneural GSCs are capable of transitioning to mesenchymal states. We characterize cycling cells based on expression of and G2/M and S phase makers, estimate RNA velocity, and examine different developmental trajectories arising in vitro and in vivo. We also compare and discuss different analysis pipelines for scRNA-seq data.
Abstract 14414: Embryonic Stem Cell Derived Exosomes Enhance Anti-Tumor Efficacy of Doxorubicin and Improve Cardiac Function in Triple-Negative Breast Cancer Xenograft Mice
Authors: Arun Samidurai, Anindita Das, Donatas Kraskauskas, Bei Zhang, Amy L L Olex, Jinze Liu, Bin Hu, Jennifer Koblinski, Dinender K Singla, Rakesh C Kukreja
Journal: Circulation (2021)

Background: Doxorubicin (Dox) is a potent chemotherapeutic drug widely used for the treatment of triple negative breast cancer (TNBC). However, Dox treatment results in inadvertent cardiotoxic effects which often require supplemental therapy. We previously showed that treatment with embryonic stem cells derived exosomes (ES-Exos) enhanced chemosensitivity of Dox in breast cancer cells. Here we tested the hypothesis whether adjuvant therapy with ES-Exos in mice with orthotopic TNBC xenograft can enhance the anti-tumor effect of Dox and improve cardiac function. Methods and Results: Athymic female nude mice (6-wk old) were injected with human MDA-MB-231-Luc cell line in mammary intraductal T4 region to generate orthotopic xenografts of TNBC. After 2 weeks of tumor growth, mice (n=10/group) were treated for 4 weeks with: Saline (Con); Dox (5 mg/kg/week); ES-Exos (50 μg, twice a week); Dox+ES-Exos; and MEF (50 μg/twice a week; non-stem cell exosomes derived from mouse fibroblasts). ES-Exos were labelled with ExoGlow-Vivo near-IR dye to track the localization of exosomes in the tumor. Treatment with Dox+ES-Exos and Es-Exos showed improved survival as compared to Dox (2 deaths) and Con (3 deaths) (Fig.A) . Tumor size was significantly reduced with Dox+ES-Exos and ES-Exos treatments as compared to Con and Dox treatment (Fig.B) . Cardiac function measured by echocardiography showed improved ejection fraction in Dox+ES-Exos and ES-Exos as compared to Con group (Fig.C) . Cell proliferation rate assessed by Ki-67 score with immunofluorescence showed significantly higher rate in Con as compared to Dox and Dox+ES-Exos groups. RNA seq analysis identified upregulation of unique antitumorigenic regulators such as Semaphorin 5 (Sema5) and FOXO15 in ES-Exos compared to MEF, which may contribute to the therapeutic effect. Conclusion: Treatment with ES-Exos may be a promising novel strategy to improve chemosensitivity with attenuation of its cardiotoxic effect in TNBC.
Reply: Quality of Death Certificate Occupation Information
Authors: Robert Dubrow, M.D., Ph.D., David H. Wegman, M.D.
Journal: JNCI Journal of the National Cancer Institute (1985)

Reply: Quality of Death Certificate Occupation Information Get access Robert Dubrow, M.D., Ph.D., Robert Dubrow, M.D., Ph.D. Division of Surveillance, Hazard Eualuations and Field Studies, National Institute for Occupational Safety and Health, Public Health Service, U.S. Department of Health and Human Services, Cincinnati, Ohio 45226 Search for other works by this author on: Oxford Academic PubMed Google Scholar David H. Wegman, M.D. David H. Wegman, M.D. Diuision of Enuironmental and Occupational Health Sciences, School of Public Health, University of California, Los Angeles, Los Angeles, California 90024 Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 74, Issue 2, February 1985, Page 539, https://doi.org/10.1093/jnci/74.2.539-a Published: 01 February 1985
Abstract 10038: Cardiovascular Impact of Immune Checkpoint Inhibitors: A Systemic Review and Meta-Analysis
Authors: Muhammad Ayub, Muhammad Farooq, Abdul Wahab Arif, Sheeba Ba Aqeel, Muhammad Almani, Ankit Mangla, Tochi M Okwuosa, Annabelle Santos Volgman
Journal: Circulation (2021)

Introduction: Immune checkpoint inhibitors (ICIs) have become the cornerstone for treatment of advanced malignancies and have led to long-term tumor responses and improved survival. The body’s immune response to ICIs can lead to unintended consequences (immune-related cardiovascular adverse effects) sometimes involving the heart. Methods: Embase, Ovid, PubMed, and Scopus were searched for ICI randomized phase II or III clinical trials reporting adverse cardiovascular events with combination or monotherapy ICIs (experimental arm) and placebo or standard of care chemotherapy (control arm). The primary outcome was cumulative incidence of cardiovascular adverse effects, and secondary outcomes were isolated incidence of hypertension, myocardial infarction, myocarditis and pericardial effusion. Statistical heterogeneity was quantified using I 2 statistics. Publication bias was assessed with Egger’s regression test. P-value of 0.05 was deemed as statistically significant. Results: Twenty studies (N=13,525) met the inclusion criteria. The studies included 1 small cell and 8 non-small cell lung, 3 renal cell, 1 head &amp; neck, 1 colorectal and 1 prostate cancer with 2 malignant melanoma, 2 multiple myeloma, and 1 mesothelioma. There were 7434 (54.96%) and 6091 (45.04%) patients in the ICI and non-ICI arms, respectively. There was no statistically significant difference in reported cardiovascular toxicity with ICI compared to placebo or standard of care (OR 0.953 95% CI 0.542-1.675, I 2 =89.49 p&lt;0.001). There was no statistical difference in incidence of HTN (OR 0.543, 95% CI 0.219-1.346. I 2 =94.98, P&lt;0.001), pericardial effusion (OR 1.44, 95% CI 0.72-2.90. I 2 =0%, P=0.613), MI (OR 0.76, 95% CI 0.76-3.298 I 2 0%, P=0.83) and myocarditis (OR 2.12, CI 0.638-7.055, I 2 =0%, P=0.185). Conclusions: This meta-analysis demonstrates no significant difference in cardiovascular adverse effects in ICI group when compared to placebo or standard of care.