tbuckley/cabot-search huggingface dataset:
Abstract MP071: Genetic Modification of Triggers of Acute Myocardial Infarction: Results From a Case-crossover Study in Costa Rica
Authors: Dongqing Wang, Elizabeth Mostofsky, Murray Mittleman, Sharon L Kardia, Hannia Campos, Ana Baylin
Journal: Circulation (2017)

Background: Coffee intake and heavy physical exertion are triggers of acute myocardial infarction (AMI). It is hypothesized that their triggering effects can be modified by genetic variation. Methods: The study population consisted of incident cases (n=1354 for coffee intake, and n=1101 for heavy physical exertion) of nonfatal AMI recruited in Costa Rica between 1994 and 2004. Coffee intake and heavy physical exertion were assessed with validated questionnaires. Blood samples were collected and genotyping was conducted. We used a case-crossover design to estimate the relative risks (RRs) and 95% confidence intervals (CIs) of AMI associated with each trigger stratified by the genotypes of each SNP included. Chi-square tests of homogeneity of RR across genotypic strata were used to assess effect modification by genetic factors. We included SNPs from both candidate genes (candidate SNPs) and previous genome-wide association studies (GWAS SNPs) related to the pathophysiological pathways of the triggering effects. Specifically, the candidate SNPs were from select genes related to sympathetic nervous system, renin-angiotensin system, caffeine metabolism, and habitual coffee consumption. The GWAS SNPs were those previously found to be associated with AMI/coronary artery disease, lipid metabolism, blood pressure, heart rate, blood coagulation, matrix metalloproteinase, and adhesion molecules. A p-value of 0.05 was considered statistically significant at first. We then performed Bonferroni correction and false discovery rate (FDR) adjustment to account for multiple testing. Results: Among the SNPs associated with AMI/coronary artery disease, rs10483853 significantly modified the triggering effect of coffee, and rs10507130 was significant for heavy physical exertion. Among the SNPs associated with blood pressure, rs935334 was significant for both triggers. Among the SNPs associated with heart rate, rs9398652, rs1541010 and rs1395479 were significant for coffee intake, and rs17287293 and rs223116 were significant for heavy physical exertion. Among the SNPs associated with blood coagulation, rs4460176, rs565229, and rs12367822 were significant for coffee intake, and rs2731672, rs10489087, rs647316, rs2138852, rs1473247, rs12367822 and rs1671152 were significant for heavy physical exertion. The two SNPs associated with serum matrix metalloproteinase (rs11225434 and rs495366) both significantly modified the triggering effect of heavy physical exertion. No SNPs remained statistically significant after Bonferroni correction or FDR adjustment. Conclusions: We identified several potential genetic modifiers of the triggering effects of coffee intake and heavy physical exertion on AMI. Among them, heart rate and blood coagulation traits appeared to be more important. Replication studies in other populations will help confirm and expand our findings.
Peripheral Cellular Immunome Reveals Heterogeneity Spanning Myeloma Spectrum Diseases
Authors: Manisha Bhutani, David M Foureau, Qing Zhang, Myra M Robinson, Adina Wynn, Nury M Steuerwald, Lawrence J Druhan, Fei Guo, Katherine Rigby, Mitchell Turner, Reed Friend, Shebli Atrash, Ami Ndiaye, Chelsea Sprouse, James T Symanowski, Belinda Rene Avalos, Edward A Copelan, Peter M. Voorhees, Saad Z Usmani
Journal: Blood (2017)
THER-07. A PHASE 0 PHARMACODYNAMIC AND PHARMACOKINETIC STUDY OF EVEROLIMUS IN VESTIBULAR SCHWANNOMA (VS) AND MENINGIOMA PATIENTS
Authors: Matthias Karajannis, Shiyang Wang, Judith Goldberg, Thomas Roland, Chandranath Sen, Dimitris Placantonakis, John Golfinos, Jeffrey Allen, Erin Dunbar, Scott Plotkin, Srivandana Akshintala, Robert Schneider, Jingjing Deng, Thomas Neubert, Filippo Giancotti, Jaishri Blakeley
Journal: Neuro-Oncology (2019)

BACKGROUND: Inhibition of mTORC1 signaling has been shown to diminish growth of NF2 deficient tumors in preclinical studies, and clinical data suggest that everolimus, an orally administered mTORC1 inhibitor, may slow tumor progression in a subset of adult and pediatric NF2 patients with VS. To assess the pharmacokinetics, pharmacodynamics and potential mechanisms of treatment resistance, we performed a pre-surgical (“phase 0”) clinical trial of everolimus in patients undergoing surgery for VS or meningiomas. METHODS: Eligible patients with meningioma or VS requiring tumor resection received everolimus 10 mg daily for 10 days immediately prior to surgery. Everolimus blood levels were determined immediately prior to and after surgery. Tumor samples were collected intraoperatively. RESULTS: Ten patients completed protocol therapy, including 5 patients with NF2-related meningioma, 3 patients with sporadic meningioma, and 2 patients with NF2-related VS. Median pre- and post-operative plasma levels of everolimus were found to be in a high therapeutic range (17.4 ng/ml and 9.4 ng/ml, respectively). Median tumor tissue drug concentration determined by mass spectrometry was 24.3 ng/g (range 9.2–169.2), and median tumor tissue to post-operative plasma drug concentration ratio was 0.39. We observed only partial inhibition of phospho-S6 in the treated tumors, indicating incomplete target inhibition compared to matched control tissues from untreated patients (p = 0.005). Consistent with prior observations that inhibition of mTORC1 may lead to MAPK pathway activation through a PI3K-dependent feedback loop, we observed a statistically significant increase of phospho-ERK (p < 0.03) versus untreated controls. CONCLUSIONS: In patients with meningioma or VS, treatment with everolimus leads to incomplete inhibition of mTORC1 signaling and upregulation phospho-ERK. These data may explain the limited anti-tumor effect of everolimus observed in clinical studies for NF2 patients and identify upregulation of phospho-ERK as a likely resistance mechanism that could be addressed with combination therapies.
Mutations in NUP160 Are Implicated in Steroid-Resistant Nephrotic Syndrome
Authors: Feng Zhao, Jun-yi Zhu, Adam Richman, Yulong Fu, Wen Huang, Nan Chen, Xiaoxia Pan, Cuili Yi, Xiaohua Ding, Si Wang, Ping Wang, Xiaojing Nie, Jun Huang, Yonghui Yang, Zihua Yu, Zhe Han
Journal: Journal of the American Society of Nephrology (2019)

Studies have identified mutations in >50 genes that can lead to monogenic steroid-resistant nephrotic syndrome (SRNS). The NUP160 gene, which encodes one of the protein components of the nuclear pore complex nucleoporin 160 kD (Nup160), is expressed in both human and mouse kidney cells. Knockdown of NUP160 impairs mouse podocytes in cell culture. Recently, siblings with SRNS and proteinuria in a nonconsanguineous family were found to carry compound-heterozygous mutations in NUP160.We identified NUP160 mutations by whole-exome and Sanger sequencing of genomic DNA from a young girl with familial SRNS and FSGS who did not carry mutations in other genes known to be associated with SRNS. We performed in vivo functional validation studies on the NUP160 mutations using a Drosophila model.We identified two compound-heterozygous NUP160 mutations, NUP160R1173× and NUP160E803K . We showed that silencing of Drosophila NUP160 specifically in nephrocytes (fly renal cells) led to functional abnormalities, reduced cell size and nuclear volume, and disorganized nuclear membrane structure. These defects were completely rescued by expression of the wild-type human NUP160 gene in nephrocytes. By contrast, expression of the NUP160 mutant allele NUP160R1173× completely failed to rescue nephrocyte phenotypes, and mutant allele NUP160E803K rescued only nuclear pore complex and nuclear lamin localization defects.Mutations in NUP160 are implicated in SRNS. Our findings indicate that NUP160 should be included in the SRNS diagnostic gene panel to identify additional patients with SRNS and homozygous or compound-heterozygous NUP160 mutations and further strengthen the evidence that NUP160 mutations can cause SRNS.
DIPG-09. CRISPR GENE EDITING OF ENDOGENOUS MUTANT FORMS OF H3.3 DEFINES ONCOHISTONE MECHANISMS AND NEW THERAPEUTIC APPROACHES
Authors: Michael Chen, Kelly Bush, Rachel Klein, Vanessa Cervantes, Nichole Lewis, Aasim Naqvi, Angel Montero Carcaboso, Paul Knoepfler
Journal: Neuro-Oncology (2019)

Pediatric high-grade gliomas often contain mutations in the H3F3A gene encoding the histone variant H3.3 and more rarely in canonical histone H3 family genes, a feature distinguishing them from adult gliomas. To define specific functionally significant changes in epigenomic states driven by mutant H3.3, we have utilized CRISPR-Cas9 to introduce specific H3.3 mutations (K27M, G34R) into formerly H3.3 wildtype (WT) brain and glioma cells, while in parallel also precisely reverting the pre-existing K27M and G34R mutations in patient-derived glioma cells to WT. In each case, gene editing was conducted on endogenous H3F3A alleles. Analyses of this overall panel of H3.3 gene-edited cells indicate that CRISPR-introduced K27M or G34R mutations within formerly H3.3 WT cells leads to increased gliomatypic signatures: elevated expression of specific oncogenes as well as neurogenesis and Notch signaling pathway genes, and perturbation of specific histone post-translational marks. Conversely, gene editing-based reversion of histone mutations to WT in primary glioma cells partially reverses glioma-associated phenotypes. Gene editing of K27M also yields coherent phenotype changes in xenograft assays. K27M and G34R mutations appear to function via both shared and unique epigenomic mechanisms. Targeting the mutant H3.3 effector pathways identified by our analyses in our full panel of cells with specific inhibitory drugs plus or minus irradiation defines differential, largely opposite responses of the parental and gene-edited cells. These defined pathways may serve as entry points for development of novel therapies specific for H3.3-mutant pediatric glioma. Overall, this system of gene editing gain and loss of mutant H3.3 provides new insights into oncohistone mechanisms and therapeutic strategies.
Automation of the kidney function prediction and classification through ultrasound-based kidney imaging using deep learning
Authors: Chin-Chi Kuo, Chun-Min Chang, Kuan-Ting Liu, Wei-Kai Lin, Hsiu-Yin Chiang, Chih-Wei Chung, Meng-Ru Ho, Pei-Ran Sun, Rong-Lin Yang, Kuan-Ta Chen
Journal: npj Digital Medicine (2019)

Prediction of kidney function and chronic kidney disease (CKD) through kidney ultrasound imaging has long been considered desirable in clinical practice because of its safety, convenience, and affordability. However, this highly desirable approach is beyond the capability of human vision. We developed a deep learning approach for automatically determining the estimated glomerular filtration rate (eGFR) and CKD status. We exploited the transfer learning technique, integrating the powerful ResNet model pretrained on an ImageNet dataset in our neural network architecture, to predict kidney function based on 4,505 kidney ultrasound images labeled using eGFRs derived from serum creatinine concentrations. To further extract the information from ultrasound images, we leveraged kidney length annotations to remove the peripheral region of the kidneys and applied various data augmentation schemes to produce additional data with variations. Bootstrap aggregation was also applied to avoid overfitting and improve the model's generalization. Moreover, the kidney function features obtained by our deep neural network were used to identify the CKD status defined by an eGFR of <60 ml/min/1.73 m2. A Pearson correlation coefficient of 0.741 indicated the strong relationship between artificial intelligence (AI)- and creatinine-based GFR estimations. Overall CKD status classification accuracy of our model was 85.6% -higher than that of experienced nephrologists (60.3%-80.1%). Our model is the first fundamental step toward realizing the potential of transforming kidney ultrasound imaging into an effective, real-time, distant screening tool. AI-GFR estimation offers the possibility of noninvasive assessment of kidney function, a key goal of AI-powered functional automation in clinical practice.
GPA: A Microbial Genetic Polymorphisms Assignments Tool in Metagenomic Analysis by Bayesian Estimation
Authors: Jiarui Li, Pengcheng Du, Adam Yongxin Ye, Yuanyuan Zhang, Chuan Song, Hui Zeng, Chen Chen
Journal: Genomics Proteomics & Bioinformatics (2019)

Abstract Identifying antimicrobial resistant (AMR) bacteria in metagenomics samples is essential for public health and food safety. Next-generation sequencing (NGS) technology has provided a powerful tool in identifying the genetic variation and constructing the correlations between genotype and phenotype in humans and other species. However, for complex bacterial samples, there lacks a powerful bioinformatic tool to identify genetic polymorphisms or copy number variations (CNVs) for given genes. Here we provide a Bayesian framework for genotype estimation for mixtures of multiple bacteria, named as Genetic Polymorphisms Assignments (GPA). Simulation results showed that GPA has reduced the false discovery rate (FDR) and mean absolute error (MAE) in CNV and single nucleotide variant (SNV) identification. This framework was validated by whole-genome sequencing and Pool-seq data from Klebsiella pneumoniae with multiple bacteria mixture models, and showed the high accuracy in the allele fraction detections of CNVs and SNVs in AMR genes between two populations. The quantitative study on the changes of AMR genes fraction between two samples showed a good consistency with the AMR pattern observed in the individual strains. Also, the framework together with the genome annotation and population comparison tools has been integrated into an application, which could provide a complete solution for AMR gene identification and quantification in unculturable clinical samples. The GPA package is available at https://github.com/IID-DTH/GPA-package.
Evaluation and Treatment of Patients With Bradycardia and Cardiac Conduction Delay
Authors: Keith Oken, Mark H. Schoenfeld, Fred Kusumoto
Journal: JAMA Cardiology (2019)

This article describes the 2018 American College of Cardiology, American Heart Association, and Heart Rhythm Society Guideline on Bradycardia and Conduction Delay for patients who may need permanent pacing.
Abstract 2221: Long-Term Administration of Thiazolidinedione Provides Multiple Ultrasonic Manifested Antiatherosclerotic Effects Independent of Diabetic Improvement for Type-2 Diabetics Receiving Angiotensin-II Receptor Blocker
Authors: Tatsuaki Murakami, Katsushi Misawa
Journal: Circulation (2008)

Background: Insulin resistance and type-2 diabetes mellitus are thought to be highly involved in complex atherothrombogenic processes, but the long-term effects of insulin sensitizing agents remain partially clarified. We assessed hypothesis that long-term use of thiazolidinedione, an insulin sensitizer, pleiotropically inhibits atherosclerotic progression in patients treated with angiotensin-II receptor blocker, one of the best possible antiatherosclerotic therapies. Methods: Thirty-two type-2 diabetic patients treated with angiotensin-II receptor blocker were randomized to group-T where they received troglitazone (400mg/day) or pioglitazone (30mg/ day), or to group-C where they continued therapy without thiazolidinedione for more than 2 years. We quantified flow-mediated dilation of brachial artery after 5 minutes forearm occlusion (FMD), dilation of brachial artery after sublingual administration of nitroglycerin (TNG), and intima-media thickness of common carotid artery (IMT) using high-resolution ultrasonography. Changes in FMD, TNG, and IMT were compared between the 2 groups. Results: Group-T (n=16) manifested improvements in diabetic variables while group-C showed no improvement. FMD (%) increased after medication in group-T (p&lt;0.01) but remained unchanged in group-C (p=0.86). TNG (%) remained unchanged in both groups. IMT (mm) decreased in group-T (p=0.03) but remained unchanged in group-C (p=0.12). Changes of FMD or IMT in group-T did not correlate to those of HbA1c (FMD: r=0.21, p=0.70, IMT: r=0.22, p=0.62). Conclusion: These results indicate long-term therapy with thiazolidinedione in diabetic patients receiving angiotensin-II receptor blocker additionally improves endothelial function, and reduces arterial wall thickness independent of reversal for diabetic status, which may have novel potential benefit for management of atherosclerosis in type-2 diabetics treated with standard antiatherosclerotic therapies.
Early myeloid-derived suppressor cells (HLA-DR−/lowCD33+CD16−) expanded by granulocyte colony-stimulating factor prevent acute graft-versus-host disease (GVHD) in humanized mouse and might contribute to lower GVHD in patients post allo-HSCT
Authors: Ke Wang, Meng Lv, Ying-Jun Chang, Xiang-Yu Zhao, Xiao-Su Zhao, Yuan-Yuan Zhang, Yu-Qian Sun, Zhi-Dong Wang, Pan Suo, Yang Zhou, Dan Liu, Shu-Zhen Zhai, Yan Hong, Yu Wang, Xiao-Hui Zhang, Lan-Ping Xu, Kai-Yan Liu, Xiao-Jun Huang
Journal: Journal of Hematology & Oncology (2019)

Myeloid-derived suppressor cells (MDSCs) are proposed to control graft-versus-host disease (GVHD) in allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, the definition of human MDSCs has not yet reached consensus, and the mechanism of MDSCs to control GVHD remains unclear. Immature myeloid cells (HLA-DR−/lowCD33+CD16−) were tested before and after granulocyte colony-stimulating factor (G-CSF) administration in healthy donor and isolated for suppression assays and co-culture with T cells in vitro. Isolated cells were infused in humanized mice for a xenogeneic model of acute GVHD. One hundred allo-HSCT recipients were enrolled prospectively to assess the role of HLA-DR−/lowCD33+CD16− cells in grafts on the occurrence of acute GVHD. In the present study, G-CSF mobilized HLA-DR−/lowCD33+CD16− cells with immunosuppressive properties in donor peripheral blood. These cells contained more interleukin-10+ and transforming growth factor-beta (TGF-β)+ cells after G-CSF administration and inhibited the proliferation of autologous donor T cells in a TGF-β-dependent manner. Meanwhile, these immature myeloid cells promoted regulatory T cell expansion and induced Th2 differentiation. Importantly, these cells prevented acute GVHD in a humanized mouse model. Moreover, clinical cohort results showed that the number of HLA-DR−/lowCD33+CD16− cells in the donor graft was the only independent risk factor inversely correlated with the incidence of grade II–IV acute GVHD in the recipients (HR 0.388, 95% CI 0.158–0.954, p = 0.039). HLA-DR−/lowCD33+CD16− cells represent functional MDSCs that may control acute GVHD in allo-HSCT.
GENE-11. SHARED LONG NON-CODING RNA DYSREGULATION IN HISTONE H3 K27M GLIOMAS AND PF-A EPENDYMOMAS
Authors: Lauren Sanders, Allison Cheney, Andrew Field, Holly Beale, Ellen Kephart, Katrina Learned, Isabel Bjork, Ann Durbin, Geoff Lyle, Jacob Pfeil, Sofie Salama, David Haussler, Olena Vaske
Journal: Neuro-Oncology (2019)

Diffuse pediatric gliomas harboring a Histone H3 K27M mutation are significantly more aggressive than H3-wild type gliomas and demonstrate global hypomethylation at the K27 residue1. As a result, these tumors show global aberrant gene expression, resulting in a primitive, stem-like proliferative cell population2. Posterior fossa (PF) ependymomas, on the other hand, harbor few significantly recurrent somatic mutations, but PF-A and PF-B subgroups have been defined on the basis of epigenetic differences3. Compared to PF-B, the PF-A subgroup demonstrates H3K27 hypomethylation, aberrant gene expression and aggressive tumor growth4,5. We recently identified a set of long non-coding RNA (lncRNA) that are transiently expressed in early brain development6, and hypothesized that H3K27M gliomas and PF-A ependymomas may share methylation-related dysregulation of long non-coding RNA (lncRNA) networks responsible for maintaining normal differentiation programs. Here we describe a network of regulatory lncRNA with increased expression in both H3K27M gliomas and PF-A ependymomas, as compared to H3-WT gliomas and PF-B ependymomas. We demonstrate that increased expression of this lncRNA network correlates with the over-expression of signaling pathways involved in maintaining a non-differentiated, proliferative phenotype and driving tumorigenesis. We hypothesize that in both H3K27M gliomas and PF-A ependymomas, aberrant global methylation may be driving lncRNA to activate and maintain stem-like states in early neural development, suggesting similarities in epigenetically driven, developmental origins for both tumor types. References: 1. Chan KM, Fang D, Gan H, et al. Genes Dev. 2013;27(9):985–90; 2. Filbin MG, Tirosh I, Hovestadt V, et al. Science. 2018;360(6386):331–5; 3. Witt H, Mack SC, Ryzhova M, et al. Cancer cell. 2011;20(2):143–57; 4. Bayliss J, Mukherjee P, Lu C, et al. Sci. Transl. Med. 2016;8(366):366ra161; 5. Mack SC, Witt H, Piro RM, et al. Nature. 2014;506(7489):445; 6. Field AR, Jacobs FM, Fiddes IT, et al. bioRxiv. 2017:232553.
Potential Role of Febrile Seizures and Other Risk Factors Associated With Sudden Deaths in Children
Authors: Laura Gould Crandall, Joyce H. Lee, Rebecca Stainman, Daniel Friedman, Orrin Devinsky
Journal: JAMA Network Open (2019)

<h3>Importance</h3> Sudden unexplained death in childhood (SUDC) is the fifth leading category of death among toddlers but remains underrecognized and inadequately studied. <h3>Objective</h3> To assess the potential role of febrile seizures (FS) and other risk factors associated with SUDC and describe the epidemiology, mechanisms, and prevention of SUDC. <h3>Design, Setting, and Participants</h3> This case series study reviewed 622 consecutive sudden child death cases aged 1 to 17 years from 2001 to 2017 from 18 countries. Data were collected from family members of children who died suddenly; these families voluntarily registered with the SUDC Foundation. Data analysis was conducted from November 2017 to February 2019. <h3>Main Outcome Measures</h3> Certified manner of death characterized as accident, natural, or undetermined. <h3>Results</h3> A total of 391 families with decedents aged 1 to 6 years completed a comprehensive interview on medical and social histories, and circumstances of death with forensic evaluations revealing a cause of death (sudden explained death in childhood [SEDC]) or no cause of death (SUDC). Of these children, 231 (59.1%) were male, the mean (SD) age at death was 24.9 (12.8) months, and 104 (26.6%) had a history of FS. Compared with the general population FS prevalence (2%-5%), FS prevalence among SUDC (28.8%; 95% CI, 23.3%-34.2%) and SEDC (22.1%; 95% CI, 14.8%-29.3%) were elevated. The odds of death during sleep was 4.6-fold higher in SUDC than in SEDC cases (odds ratio, 4.61; 95% CI, 1.92-11.09; adjusted<i>P</i> = .008). The siblings of SUDC cases were followed up for 3144 life-years, and none died prematurely from SUDC. <h3>Conclusions and Relevance</h3> This analysis of the largest SUDC cohort confirmed an increased FS rate and found significantly increased rates of FS among SEDC. This study suggests that seizures may contribute to some SUDC and SEDC deaths. The risk of sudden death in a sibling was low. To develop and assess preventive strategies, population-based studies are needed to define the epidemiology and spectrum of risk factors and identify biomarkers of patients with FS at high risk of sudden death.