tbuckley/cabot-search huggingface dataset:
THER-22. BROMODOMAIN INHIBITORS INDUCE DOWNREGULATION OF DNA DAMAGE REPAIR PATHWAYS AND OFFER NOVEL SYNERGISTIC COMBINATIONS WITH ENHANCED SAFETY PROFILES FOR THE TREATMENT OF MEDULLOBLASTOMA AND GLIOBLASTOMA
Authors: Fred C Lam, Tu-Lan Vu-Han, Bert Van de Kooj, Yi Wen Kong, Pratiti Bandopadhayay, Rameen Beroukhim, Jann Sarkaria, Paula Hammond, Michael Yaffe
Journal: Neuro-Oncology (2019)

Small molecule inhibitors targeting the BET bromodomain-containing protein BRD4 (BET inhibitors) are in early phase clinical develop for the treatment of several types of cancers, including CNS tumors. Studies have shed increasing insight into their anti-cancer mechanisms of action outside of its classical role in transcriptional downregulation of Myc. We recently reported additive effects between BET inhibitors and temozolomide in increasing DNA damage, tumor cell killing, and prolonging survival in intracranial mouse models of glioma. We now report that BET inhibition synergizes with PARP inhibition in an intracranial D458 patient-derived xenograft (PDX) model of type III medulloblastoma. Using a novel in-house cellular dual fluorescent reporter system of double-strand break repair called “DSB Spectrum” that detects a cell’s ability to repair by non-homologous end-joining (NHEJ) or homologous recombination (HR), we show that treatment of D458 cells with the BET inhibitor OTX-015 causes DNA damage and DSB formation but the inability to repair via NHEJ or HR due to transcriptional downregulation of key repair pathway proteins. This induced HR-deficiency synergizes cells to PARP inhibition and decreases tumor burden and prolongs survival in vivo. Mechanistically, BET inhibition causes replication stress-induced DNA damage by increasing collisions between the transcription and replication machinery with failure to activate the replication stress DNA damage checkpoint. Co-incidentally, this allows for further leveraging of BET inhibitors with PARP inhibitors and other DNA damaging agents at much lower doses in combination that avoids systemic toxicity, potently decreases tumor burden, and significantly increases survival in PDX models of medulloblastoma and glioblastoma. Taken together, our results suggest a novel role for BRD4 as a master regulator of the DNA damage response in cells that allows for the discovery of novel higher order synergistic drug combinations with enhanced safety profiles and translational potential.
PI3K-δ Inhibition Influences T-Cell Populations and Anti-Tumoral Immune Function in Preclinical Models
Authors: Annika Scheffold, Bola S Hanna, Philipp Roeßner, Yasmin Demerdash, Billy Michael Chelliah Jebaraj, Peter Lichter, Stephan Stilgenbauer, Martina Seiffert
Journal: Blood (2017)
Use of Platelet-Rich Plasma Injection for Rejuvenation of Photoaged Facial Skin?—Reply
Authors: Murad Alam
Journal: JAMA Dermatology (2019)

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TMOD-16. A NOVEL ALGORITHM FOR MANAGEMENT OF PEDIATRIC CRANIOPHARYNGIOMA
Authors: Mohammed Fouda, David Zurakowski, Liliana Goumnerova
Journal: Neuro-Oncology (2019)

INTRODUCTION: Pediatric craniopharyngioma is associated with significant long-term morbidities and high rate of recurrence despite the “benign” histopathologic nature of the tumor. Optimal management remains controversial. We propose a novel algorithm for the management of pediatric craniopharyngioma in the context of prevention of recurrence and long-term hypothalamic obesity. METHODS: A cohort study of all pediatric patients diagnosed and managed at Boston Children’s Hospital between 1985–2017. Chi-square, Fisher exact tests, logistic regression, and Cox-mantel models were used for the statistical analysis. IRB approval obtained. RESULTS: 90 patients met the inclusion and exclusion criteria (47 males, 43 females). Median age at the time of presentation was 8 years; median follow up was 10 years. 28 (31%) patients developed hypothalamic morbid obesity. 26 (29%) patients had a recurrence. Based on the univariate and multivariable logistic regression analysis for risk factors for the development of hypothalamic morbid obesity and recurrence we identified: 1) age at the time of presentation > 10 yrs. old (P-value 0.023), 2) preoperative obesity (P-value 0.006) and 3) preoperative papilledema (P-value < 0.0001) as significant risk factors for the development of hypothalamic morbid obesity while 1) extent of resection (P-value < 0.0001), 2) fine calcifications (P-value 0.025) and 3) maximum dimension of the lesion > 3.5 cm (P-value 0.008) were independent significant risk factors for recurrence. Based on the likelihood ratio tests and the weight of the risk factors for hypothalamic morbid obesity, we proposed a predictive score to differentiate patients with and without risk for hypothalamic morbid obesity. CONCLUSIONS: Based on these data we developed a novel algorithm for the management of pediatric craniopharyngioma using a new predictive score for hypothalamic morbid obesity and the probability of recurrence.
Digoxin with furosemide is efficacious in cutaneous warts
Authors: M. Rijsbergen, T. Niemeyer‐van der Kolk, G. Hogendoorn, S. Kouwenhoven, C. Lemoine, E.S. Klaassen, M. de Koning, S. Beck, J.N. Bouwes Bavinck, G. Feiss, J. Burggraaf, R. Rissmann
Journal: British Journal of Dermatology (2019)

This is a study of the effect of two topically‐applied (i.e. applied to the skin) drugs, digoxin and furosemide, on the healing of viral warts on the skin. It was performed by a group from the Netherlands and Pennsylvania, USA. The investigation is known as a proof of concept study, which is a preliminary experiment to show whether there is likely to be a benefit of a particular course of treatment. These two medicines are believed to improve healing rates of viral warts because they block the passage of potassium into cells, a process that is necessary for the growth of wart viruses in human skin. The team used a topically applied preparation containing the two medications and measured the size of warts, the presence of visible features on their surface and their disappearance; in addition, samples were taken for testing for the presence of wart virus. All the patients had warts that had not responded to other treatments. The study followed different groups of 20 patients who received either both medications combined, each singly or a placebo. This showed that after 6 weeks of daily treatment and a follow up of 14 weeks, only those patients who had received the treatment with both digoxin and furosemide together showed improvements, with some achieving elimination of the warts. This is an encouraging result, but the work should now be carried out on a larger number of patients with warts that have not been treated before as, although the new treatment led to greater improvement, the numbers of patients whose warts disappeared completely was small. There were no side effects associated with the treatment.
LGG-04. CLINICO-HISTO-MOLECULAR LANDSCAPE OF EIGHTY-TWO PEDIATRIC AND YOUNG ADULT DYSEMBRYOPLASTIC NEUROEPITHELIAL TUMORS
Authors: Mélanie Pagès, David T W Jones, Nathalie Boddaert, Arnault Tauziède-Espariat, Marie-Anne Debily, Thomas Blauwblomme, Dominique Figarella-Branger, Rameen Beroukhim, Pascale Varlet
Journal: Neuro-Oncology (2019)

Dysembryoplastic neuroepithelial tumor (DNT) belongs to low-grade neuroepithelial tumors, which encompasses a large spectrum of tumors, including recently genetically described entities. DNTs are stable tumors but rare progressive DNTs have been reported and the different histological subtypes recognized by the WHO classification (simple/complex specific DNT [spe-DNT]; non-specific DNT [ns-DNT]) have been depicted before the molecular biology era. The classification scheme for these tumors still needs to be clarified using the recent molecular advances. We subjected a monocentric series of 82 DNTs, including 22 spe-DNTs showing tumor progression,to DNA methylation profiling and searched for BRAF/FGFR1alterations. BRAF/FGFR1wild-type tumors and progressive DNTs were further analyzed by RNA/whole-exome sequencing, FISH and targeted sequencing. Integrative analyses along histopathology and imaging was performed.LGG-DNT methylation class was assigned to 92% of spe-DNTs. Clustering analysis identified a cluster enriched in progressive DNTs, harboring FGFR1disruption or not,showing histopathological and copy number changes at progression. The ns-DNT corresponded to a biologically heterogeneous group of tumors, with 25% lacking DNA-methylation class assignation and frequently harboring BRAF/MYBL1/FGFR2structural variants.
Abstract 20342: Outcomes of Children Supported With the HeartWare Ventricular Assist Device System: An Analysis of Pedimacs Registry
Authors: Christina J VanderPluym, Eric R Griffiths, Robert Niebler, A. Carolina Prada-Ruiz, Devin A Koehl, Ryan S Cantor, Angela Lorts
Journal: Circulation (2017)

Introduction: Over the last 5 years there has been increased utilization of the HeartWare® HVAD in children despite limited safety and efficacy data in this patient population. We sought to describ...
The epicardial adipose tissue and the coronary arteries: dangerous liaisons
Authors: Rosalinda Madonna, Marika Massaro, Egeria Scoditti, Irene Pescetelli, Raffaele De Caterina
Journal: Cardiovascular Research (2019)

The adipose tissue (AT) is an endocrine organ that produces adipocytokines (adipokines), able to influence metabolic homeostasis. In the conventional classification, there are two large AT depots, characterized by different paracrine activities: the subcutaneous AT, which would mostly produce cytokines with protective properties against cardiovascular disease; and the visceral AT, responsible for the secretion of cytokines with proinflammatory, prothrombotic, and proatherogenic effects. A third component, the epicardial AT (EAT) is now receiving increasing attention due to its unique anatomical and functional proximity to the myocardium and the coronary arteries. In rodents, the EAT protects the heart from exposure to high levels of free fatty acids, and provides energy to the myocardium under high metabolic demands. The observation that atherosclerotic plaques are more prevalent in regions of coronary arteries surrounded by the EAT, while they tend to be less present in segments penetrating the myocardium (the septal branches and segments under myocardial bridges), has led to the hypothesis of a possible role of the EAT in promoting the development of atherosclerosis through endocrine and paracrine effects, in addition to the role of biomechanical forces affecting transendothelial lipid permeability into the intima. In this article, we review the clinical and molecular evidence linking the EAT and coronary artery disease through a systematic review of the literature. We, here, discuss current diagnostic techniques in evaluating the interaction between EAT and the onset of coronary artery disease and ischaemic heart disease. Finally, we review current knowledge on the underlying mechanisms by which the EAT may affect coronary atherosclerosis, and potential clinical implications of this interaction, making the EAT an attractive target for new therapeutics in cardiovascular disease.
Single-Cell Lymphocyte Heterogeneity in Advanced Cutaneous T-cell Lymphoma Skin Tumors
Authors: Alyxzandria M. Gaydosik, Tracy Tabib, Larisa J. Geskin, Claire-Audrey Bayan, James F. Conway, Robert Lafyatis, Patrizia Fuschiotti
Journal: Clinical Cancer Research (2019)

Abstract Purpose: The heterogeneity of tumor cells presents a major challenge to cancer diagnosis and therapy. Cutaneous T-cell lymphomas (CTCL) are a group of T lymphocyte malignancies that primarily affect skin. Lack of highly specific markers for malignant lymphocytes prevents early diagnosis, while only limited treatment options are available for patients with advanced stage CTCL. Droplet-based single-cell transcriptome analysis of CTCL skin biopsies opens avenues for dissecting patient-specific T lymphocyte heterogeneity, providing a basis for identifying specific markers for diagnosis and cure of CTCL. Experimental Design: Single-cell RNA-sequencing was performed by Droplet-based sequencing (10X Genomics), focusing on 14,056 CD3+ lymphocytes (448 cells from normal and 13,608 cells from CTCL skin samples) from skin biopsies of 5 patients with advanced-stage CTCL and 4 healthy donors. Protein expression of identified genes was validated in advanced stage CTCL skin tumors by immunohistochemistry and confocal immunofluorescence microscopy. Results: Our analysis revealed a large inter- and intratumor gene expression heterogeneity in the T lymphocyte subset, as well as a common gene expression signature in highly proliferating lymphocytes that was validated in multiple advanced-stage skin tumors. In addition, we established the immunologic state of reactive lymphocytes and found heterogeneity in effector and exhaustion programs across patient samples. Conclusions: Single-cell analysis of CTCL skin tumor samples reveals patient-specific landscapes of malignant and reactive lymphocytes within the local microenvironment of each tumor, giving an unprecedented view of lymphocyte heterogeneity and identifying tumor-specific molecular signatures, with important implications for diagnosis and personalized disease treatment.
Metabolic reprogramming and redox adaptation in sorafenib‐resistant leukemia cells: detected by untargeted metabolomics and stable isotope tracing analysis
Authors: Xin You, Weiye Jiang, Wenhua Lu, Hui Zhang, Tiantian Yu, Jingyu Tian, Shijun Wen, Guillermo Garcia‐Manero, Peng Huang, Yumin Hu
Journal: Cancer Communications (2019)

Abstract Background Internal tandem duplications (ITD) within the juxtamembrane domain of FMS‐like tyrosine kinase 3 (FLT3) represent a poor prognostic indicator in acute myeloid leukemia (AML). Therapeutic benefits of tyrosine kinase inhibitors, such as sorafenib, are limited due to the emergence of drug resistance. While investigations have been conducted to improve the understanding of the molecular mechanisms underlying the resistance to this FLT3 inhibitor, a profile of cell functioning at the metabolite level and crosstalk between metabolic pathways has yet to be created. This study aimed to elucidate the alteration of metabolomic profile of leukemia cells resistant to the FLT3 inhibitor. Methods We established two sorafenib‐resistant cell lines carrying FLT3/ITD mutations, namely the murine BaF3/ITD‐R and the human MV4‐11‐R cell lines. We performed a global untargeted metabolomics and stable isotope‐labeling mass spectrometry analysis to identify the metabolic alterations relevant to the therapeutic resistance. Results The resistant cells displayed fundamentally rewired metabolic profiles, characterized by a higher demand for glucose, accompanied by a reduction in glucose flux into the pentose phosphate pathway (PPP); and by an increase in oxidative stress, accompanied by an enhanced glutathione synthesis. We demonstrated that the highest scoring network of altered metabolites in resistant cells was related to nucleotide degradation. A stable isotope tracing experiment was performed and the results indicated a decrease in the quantity of glucose entering the PPP in resistant cells. Further experiment suggested that the inhibition of major enzymes in the PPP consist of glucose‐6‐phosphate dehydrogenase deficiency (G6PD) in the oxidative arm and transketolase (TKT) in the non‐oxidative arm. In addition, we observed that chronic treatment with sorafenib resulted in an increased oxidative stress in FLT3/ITD‐positive leukemia cells, which was accompanied by decreased cell proliferation and an enhanced antioxidant response. Conclusions Our data regarding comparative metabolomics characterized a distinct metabolic and redox adaptation that may contribute to sorafenib resistance in FLT3/ITD‐mutated leukemia cells.
Morbidity and mortality after lifestyle intervention for people with impaired glucose tolerance: 30-year results of the Da Qing Diabetes Prevention Outcome Study
Authors: Qiuhong Gong, Ping Zhang, Jinping Wang, Jixiang Ma, Yali An, Yanyan Chen, Bo Zhang, Xinxing Feng, Hui Li, Xiaoping Chen, Yiling J Cheng, Edward W Gregg, Yinghua Hu, Peter H Bennett, Guangwei Li, Xin Qian, Lihong Zhang, Yuanchi Hui, Siyao He, Xuan Wang, Theodore J. Thompson, Robert B. Gerzoff, Pingan Liu, Yayun Jiang, Zexi Hu, Jixing Wang, Xigui Jiang, Jingling Zhang, Ruimin Xi, Chengyan Pang, Chunqin Li, Xiuying Hu, Wenying Yang, Zuoxin An, Xinquan Sun, Chuan Chen, Yong Gang, Juan Liu, Jianzhong Xiao, Huibi Cao, Hui Zheng, Hui Zhang, Hongliang Li, Jing Hong, Xueli Liu, Fang Zhao, Wenjuan Wang, Bo Chen, Barbara V. Howard, Michael M. Engelgau, Gojka Roglic
Journal: The Lancet Diabetes & Endocrinology (2019)
FDG PET/CT Demonstrated Precursor B-cell Lymphoblastic Lymphoma in a Pediatric Patient With Hemophilia B
Authors: Zhimou Liu, Xu Yang, Jie Liu, Jigang Yang
Journal: Clinical Nuclear Medicine (2019)

Abstract A 4-year-old boy with history of hemophilia B presented with increasingly enlarged scalp masses. Although they were initially thought as hematomas, unresponsiveness to the therapy lead to suspicion of malignancy, which prompted FDG PET/CT. The FDG PET/CT images demonstrated increased FDG uptake in the scalp masses and cervical lymph nodes. The pathology from the left scalp mass and the left cervical lymph nodes revealed precursor B-cell lymphoblastic lymphoma.
Correlation of Gut Microbiome Between ASD Children and Mothers and Potential Biomarkers for Risk Assessment
Authors: Ning Li, Junjie Yang, Jiaming Zhang, Cheng Liang, Ying Wang, Bin Chen, Changying Zhao, Jingwen Wang, Guangye Zhang, Dongmei Zhao, Yi Liu, Lehai Zhang, Jun Yang, Guimei Li, Zhongtao Gai, Lei Zhang, Guoping Zhao
Journal: Genomics Proteomics & Bioinformatics (2019)

Variation of maternal gut microbiota may increase the risk of autism spectrum disorders (ASDs) in offspring. Animal studies have indicated that maternal gut microbiota is related to neurodevelopmental abnormalities in mouse offspring, while it is unclear whether there is a correlation between gut microbiota of ASD children and their mothers. We examined the relationships between gut microbiome profiles of ASD children and those of their mothers, and evaluated the clinical discriminatory power of discovered bacterial biomarkers. Gut microbiome was profiled and evaluated by 16S ribosomal RNA gene sequencing in stool samples of 59 mother–child pairs of ASD children and 30 matched mother–child pairs of healthy children. Significant differences were observed in the gut microbiome composition between ASD and healthy children in our Chinese cohort. Several unique bacterial biomarkers, such as Alcaligenaceae and Acinetobacter, were identified. Mothers of ASD children had more Proteobacteria, Alphaproteobacteria, Moraxellaceae, and Acinetobacter than mothers of healthy children. There was a clear correlation between gut microbiome profiles of children and their mothers; however, children with ASD still had unique bacterial biomarkers, such as Alcaligenaceae, Enterobacteriaceae, and Clostridium. Candidate biomarkers discovered in this study had remarkable discriminatory power. The identified patterns of mother–child gut microbiome profiles may be important for assessing risks during the early stage and planning of personalized treatment and prevention of ASD via microbiota modulation.
clonealign: statistical integration of independent single-cell RNA and DNA sequencing data from human cancers
Authors: Kieran R. Campbell, Adi Steif, Emma Laks, Hans Zahn, Daniel Lai, Andrew McPherson, Hossein Farahani, Farhia Kabeer, Ciara O’Flanagan, Justina Biele, Jazmine Brimhall, Beixi Wang, Pascale Walters, IMAXT Consortium, Alexandre Bouchard-Côté, Samuel Aparicio, Sohrab P. Shah
Journal: Genome biology (2019)

Measuring gene expression of tumor clones at single-cell resolution links functional consequences to somatic alterations. Without scalable methods to simultaneously assay DNA and RNA from the same single cell, parallel single-cell DNA and RNA measurements from independent cell populations must be mapped for genome-transcriptome association. We present clonealign, which assigns gene expression states to cancer clones using single-cell RNA and DNA sequencing independently sampled from a heterogeneous population. We apply clonealign to triple-negative breast cancer patient-derived xenografts and high-grade serous ovarian cancer cell lines and discover clone-specific dysregulated biological pathways not visible using either sequencing method alone.
MEDU-36. BCL2 FAMILY MEMBERS ATTENUATE RESPONSE OF MYC-DRIVEN MEDULLOBLASTOMAS TO BET-BROMODOMAIN INHIBITION
Authors: Jessica Clymer, Gabrielle Gionet, Elizabeth Gonzalez, Graham Buchan, Kenin Qian, Patricia Ho, Ryan O’Rourke, Amanda Balboni-Iniguez, Kimberley Stegmaier, Keith Ligon, Federica Piccioni, Cory Johannessen, Rameen Beroukhim, Pratiti Bandopadhayay
Journal: Neuro-Oncology (2019)

BACKGROUND: BET-bromodomain proteins bind to H3K27ac enhancers and recruit transcriptional proteins to facilitate the expression of genes. Inhibition of BET-bromodomain proteins shows preclinical promise for MYC-driven tumors such as medulloblastoma (MB), however the mechanism of action and means of resistance are not well described. We hypothesized that genes required for MB cell growth and were sufficient to rescue the effects of BET-bromodomain inhibition (BETi) would signify key downstream effectors of this class of inhibitors. METHODS: We applied an integrative genomics approach: expression profiling of genes suppressed following BETi with JQ1, genome-scale CRISPR/Cas9 screens to determine which of the suppressed genes are also essential for cell viability, and a near-genome scale open reading frame (ORF) rescue screen to determine which of the suppressed genes are also sufficient to drive resistance to BETi. Genes that were nominated by all three data sets were considered BETi transcriptional targets responsible for BET-induced reduced cell viability. RESULTS: BETi in MYC-driven MB cell lines generated widespread changes in gene expression. Genes suppressed by BETi had the tendency to be essential to cell survival. The most frequently included pathways were cell-cycle, DNA replication, and RNA processing/transcription. In each cell line, we identified ORF constructs that significantly rescued cells from BETi which included BCL2 family proteins, which also represented genetic dependencies in treatment naïve cell. Overexpression of BCL2 family member BCL2L1 attenuated both apoptosis and JQ1 mediated cell cycle arrest and expression of the pro-apoptotic genes BAX and BAK were required for BETi response. BCL2 family genes were also validated in drug-tolerant cell lines as having been suppressed by BETi and re-expressed in drug-tolerant cells thus demonstrating their relevance in resistance. CONCLUSION: Integrative genomic analysis identifies BCL2 family members as key mediators of response of MB cells to BET-bromodomain inhibition and also mediate resistance to BETi.