tbuckley/cabot-search huggingface dataset:
TBIO-07. SINGLE-CELL TRANSCRIPTOMIC PROFILE REVEALS MACROPHAGE HETEROGENEITY IN SONIC-HEDGEHOG MEDULLOBLASTOMA AND THEIR DISTINCT RESPONSES TO DIFFERENT TREATMENT MODALITIES
Authors: Mai Dang, Malay Haldar
Journal: Neuro-Oncology (2020)

Abstract Tumor-associated macrophages (TAMs) are an important component of the tumor microenvironment. Pro-inflammatory macrophages can suppress while anti-inflammatory macrophages can promote tumor growth. Despite their abundance in many tumors, the origins and diversity of TAMs are not well understood, especially in pediatric brain tumors. Using single-cell RNA sequencing in a genetically engineered mouse model (Ptch+/-:p53-/-) of SHH-MB, we identified the dual microglia and monocytic origin of macrophage and their transcriptomic heterogeneity. We demonstrate differential recruitment and function of macrophages under distinct modalities of tumor therapy of molecular targeted hedgehog inhibition versus radiation. We additionally identify a monocytic macrophage population recruited post-radiation that is immune suppressive, suggesting a mechanism for radiation treatment failure. These insights uncover potential strategies for immunomodulation as adjunctive therapy for radiation.
The poly(ADP-ribosyl)ation of BRD4 mediated by PARP1 promoted pathological cardiac hypertrophy
Authors: Zhenzhen Li, Zhen Guo, Rui Lan, Sidong Cai, Zhirong Lin, Jingyan Li, Junjian Wang, Zhuoming Li, Peiqing Liu
Journal: Acta Pharmaceutica Sinica B (2020)

The bromodomain and extraterminal (BET) family member BRD4 is pivotal in the pathogenesis of cardiac hypertrophy. BRD4 induces hypertrophic gene expression by binding to the acetylated chromatin, facilitating the phosphorylation of RNA polymerases II (Pol II) and leading to transcription elongation. The present study identified a novel post-translational modification of BRD4: poly(ADP-ribosyl)ation (PARylation), that was mediated by poly(ADP-ribose)polymerase-1 (PARP1) in cardiac hypertrophy. BRD4 silencing or BET inhibitors JQ1 and MS417 prevented cardiac hypertrophic responses induced by isoproterenol (ISO), whereas overexpression of BRD4 promoted cardiac hypertrophy, confirming the critical role of BRD4 in pathological cardiac hypertrophy. PARP1 was activated in ISO-induced cardiac hypertrophy and facilitated the development of cardiac hypertrophy. BRD4 was involved in the prohypertrophic effect of PARP1, as implied by the observations that BRD4 inhibition or silencing reversed PARP1-induced hypertrophic responses, and that BRD4 overexpression suppressed the anti-hypertrophic effect of PARP1 inhibitors. Interactions of BRD4 and PARP1 were observed by co-immunoprecipitation and immunofluorescence. PARylation of BRD4 induced by PARP1 was investigated by PARylation assays. In response to hypertrophic stimuli like ISO, PARylation level of BRD4 was elevated, along with enhanced interactions between BRD4 and PARP1. By investigating the PARylation of truncation mutants of BRD4, the C-terminal domain (CTD) was identified as the PARylation modification sites of BRD4. PARylation of BRD4 facilitated its binding to the transcription start sites (TSS) of hypertrophic genes, resulting in enhanced phosphorylation of RNA Pol II and transcription activation of hypertrophic genes. The present findings suggest that strategies targeting inhibition of PARP1-BRD4 might have therapeutic potential for pathological cardiac hypertrophy.
Splicing and Dilated Cardiomyopathy: One Gene to Rule Them All?⁎⁎Editorials published in the Journal of the American College of Cardiologyreflect the views of the authors and do not necessarily represent the views of JACCor the American College of Cardiology.
Authors: Calum A. MacRae, William J. McKenna
Journal: Journal of the American College of Cardiology (2009)
Abstract 16098: Additional Predictive Value of Plasma C24:0/C16:0 Ceramide, and Its Modulation by BMI, Over NT-proBNP in the Prediction of Mortality
Authors: Linda R Peterson, Sharon Cresci, Jean E Schaffer, Xuntian Jiang, Daniel S Ory, Ramachandran Vasan, Vanessa Xanthakis, Meredith S Duncan, Marcus Dorr, Stefan Gross
Journal: Circulation (2020)

Introduction: NT-proBNP is a predictor of mortality in patients with or without HF. Ceramides are bioactive lipids involved in cell signaling and membrane structure. Our group showed that the ratio of specific plasma ceramides (C24:0/C16:0) is inversely related to death. However, NT-proBNP levels were not available for multivariate modeling of mortality in that cohort. Hypothesis: We hypothesized that plasma C24:0/C16:0 would add to a predictive model that includes NT-proBNP and classical cardiovascular risk factors (CVRs) of mortality. We also hypothesized that body mass index (BMI) modulates the predictive value of plasma C24:0/C16:0. Methods: We performed multivariable modeling on data from 2,760 Caucasian subjects in the SHIP (Study of Health in Pomerania) cohort from northern Europe. Plasma C24:0/C16:0 was measured using targeted liquid chromatograph/tandem mass spectrometry. CVRs in the modeling included: age, sex, systolic blood pressure, current smoking, diabetes, and total/high-density cholesterol. Model performance was evaluated using Akaike’s information criterion (AIC) and Harrel’s c-statistic. Results: There were 529 deaths over a median of 14.6 y. Model selection via AIC revealed that the best model with the least number of variables to predict mortality included plasma C24:0/16:0 and BMI (+ their interaction), CVRs, and NT-proBNP, P &lt; 0.001. The evidence ratio showed that this best model is 540 times more likely to be the ideal model than the model that only includes CVRs. The best model was also much more informative than a model that added only NT-proBNP to the CVRs (ΔAIC = 19.865, Akaike weight &lt; 0.001). With increasing BMI, the protective effect of plasma C24:0/16:0 on survival probability diminished. Post hoc analysis showed the best model predicted CVD mortality but not non-CVD mortality. Conclusions: A mortality prediction model that includes plasma C24:0/C16:0, NT-proBNP, and CVRs is superior to CVRs alone or CVRs + NT-proBNP and helps further stratify patients’ risk. BMI modifies the predictive value of plasma C24:0/C16:0. Plasma C24:0/C16:0 may be a novel target for modifying CVD mortality risk.
Effects of responsive caregiving and learning opportunities during pre-school ages on the association of early adversities and adolescent human capital: an analysis of birth cohorts in two middle-income countries
Authors: Angela C B Trude, Linda M Richter, Jere R Behrman, Aryeh D Stein, Ana M B Menezes, Maureen M Black
Journal: The Lancet Child & Adolescent Health (2020)

BackgroundMillions of children globally are at risk of not reaching their developmental potential because of early adversities. We hypothesised that responsive caregiving and learning opportunities, components of nurturing care, at pre-school ages might mitigate the effects of adversities.MethodsWe analysed longitudinal birth cohort data from Brazil (1993 Pelotas Birth Cohort, n=632) and South Africa (Birth to Twenty Plus [Bt20+] Birth Cohort, n=1130) to assess whether responsive caregiving and learning opportunities at pre-school ages (2–4 years) modified associations between cumulative early adversities and adolescent human capital. The cumulative adversities score (range 0–9) included household wealth and crowding; mothers' schooling, height, age, and mental health; and children's birthweight, gestational age, and length at age 12 months. We extracted data on responsive caregiving and learning opportunities from the Early Childhood Home Observation for Measurement of the Environment inventory, assessed at age 4 years (1993 Pelotas cohort) and 2 years (Bt20+ cohort). We examined three human capital indicators: intelligence quotient (IQ) assessed at age 18 years (1993 Pelotas cohort) and 16 years (Bt20+ cohort); psychosocial adjustment assessed at age 15 years and 14 years, respectively; and height assessed at age 18 years and 16 years, respectively. We used linear models with interaction terms between cumulative adversities, and responsive caregiving and learning opportunities, to predict adolescent human capital.FindingsFor each additional Z score of total cumulative adversity, adolescent IQ decreased by 5·89 (95% CI −7·29 to −4·50) points in the 1993 Pelotas cohort (p<0·0001) and 2·69 (–4·52 to −0·86) points in the Bt20+ cohort (p=0·0039). After adjusting for total cumulative adversities, adolescent IQ points increased by 5·47 (95% CI 4·20 to 6·74) with each additional Z score of learning opportunities and by 2·26 (0·93 to 3·59) with each additional Z score of responsive caregiving in the 1993 Pelotas cohort, but not in the Bt20+ cohort (0·86 [–0·12 to 1·83] and 0·65 [–0·32 to 1·61], respectively). Associations between early adversities and IQ were modified by learning opportunities in the 1993 Pelotas cohort (beta coefficient for interaction 1·74, 95% CI 0·43 to 3·04; p=0·0092) and by responsive caregiving in the Bt20+ cohort (2·24, 0·94 to 3·54; p=0·0075). High nurturing environment attenuated the negative effects of early cumulative adversities on IQ.InterpretationEarly nurturing home environments protect young children against effects of early adversities on adolescent IQ, with long-term positive associations on adolescent cognition in two middle-income countries.FundingBill & Melinda Gates Foundation.
VerSe: A Vertebrae labelling and segmentation benchmark for multi-detector CT images
Authors: Anjany Sekuboyina, Malek E. Husseini, Amirhossein Bayat, Maximilian Löffler, Hans Liebl, Hongwei Li, Giles Tetteh, Jan Kukačka, Christian Payer, Darko Štern, Martin Urschler, Maodong Chen, Dalong Cheng, Nikolas Lessmann, Yujin Hu, Tianfu Wang, Dong Yang, Daguang Xu, Felix Ambellan, Tamaz Amiranashvili, Moritz Ehlke, Hans Lamecker, Sebastian Lehnert, Marilia Lirio, Nicolás Pérez de Olaguer, Heiko Ramm, Manish Sahu, Alexander Tack, Stefan Zachow, Tao Jiang, Xinjun Ma, Christoph Angerman, Xin Wang, Kevin Brown, Alexandre Kirszenberg, Élodie Puybareau, Di Chen, Yiwei Bai, Brandon H. Rapazzo, Timyoas Yeah, Amber Zhang, Shangliang Xu, Feng Hou, Zhiqiang He, Chan Zeng, Zheng Xiangshang, Xu Liming, Tucker J. Netherton, Raymond P. Mumme, Laurence E. Court, Zixun Huang, Chenhang He, Li-Wen Wang, Sai Ho Ling, Lê Duy Huỳnh, Nicolas Boutry, Roman Jakubicek, Jiri Chmelik, Supriti Mulay, Mohanasankar Sivaprakasam, Johannes C. Paetzold, Suprosanna Shit, Ivan Ezhov, Benedikt Wiestler, Ben Glocker, Alexander Valentinitsch, Markus Rempfler, Björn H. Menze, Jan S. Kirschke
Journal: Medical Image Analysis (2021)
STEM-19. THE ISOLATION AND IDENTIFICATION OF GLIOMA STEM CELLS AND MESENCHYMAL STEM CELLS FROM HUMAN GLIOMA SPECIMENS
Authors: Yan-jiao Yu, Wang Jing, Zhong-ping Chen
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Glioma is the primary malignancy with the highest incidence in central nervous system. Studies have shown that glioma stem cell (GSC) is the important origin for recurrence and closely associated with tumor microenvironment. Glioma-associated human mesenchymal stem cells (GA-hMSCs), as an important part of the tumor microenvironment, might promote proliferation and invasion of GSC. We try to isolate GSCs and GA-hMSCs through glioma primary culture, and investigate the relationship between GSC and GA-hMSCs, as well as their roles in the recurrences of glioma. MATERIALS AND METHODS Five surgical specimens from patients with human high-grade glioma were collected for primary culture. The surgical specimens were cut up and digested with Dispase II (collagenase), terminated by adding plenty of DNase II. Cell suspension was collected and resuspended in conditional medium for MSC or GSC. After being cultured for several passages, GSCs were identified by immunofluorescence, and GA-hMSCs were identified by flow cytometry and in vitro differentiation assays. RESULTS Cell cultures were observed with an inverted phase-contrast microscope after 24 hours. Adherent GA-hMSCs were collected and the supernatant was discarded with non-adherent cells. GSC was cultured as neurospheres. The single-cell suspension was prepared from spheres of GSC to identify their surface expression profile by immunofluorescence assays after several passages. The results confirmed that GSCs positively expressed CD133, Nestin and SOX2, but did not express GFAP and Tublin III. GA-hMSCs positively expressed CD105, CD73, CD90 and negatively expressed CD45 and CD34. GA-hMSCs could differentiate into adipocytes, chondrocytes and osteocytes. CONCLUSION We isolated and identified GSCs and GA-hMSCs from glioma primary culture. Our future work will focus on the relationship between the two types of cells and their roles in the process of tumor recurrence based on the successful isolation of GSC and GA-hMSCs. Keywords: Glioma; Mesenchymal stem cells; Glioma stem cells; Recurrence
MBRS-12. A TRANSPOSON MUTAGENESIS SCREEN IDENTIFIES Rreb1 AS A DRIVER FOR GROUP 3 MEDULLOBLASTOMA
Authors: Meher Beigi Masihi, Catherine Lee, Grace A Furnari, Alexandra Garancher, Robert J Wechsler-Reya
Journal: Neuro-Oncology (2020)

Abstract Medulloblastoma (MB) is the most common malignant childhood brain tumor. MB can be divided into four major subgroups – WNT, Sonic hedgehog (SHH), Group 3 (G3), and Group 4 (G4) – that exhibit distinct genetic alterations, gene expression profiles, and clinical outcomes. Patients with G3-MB have the worst prognosis, and a deeper understanding of this disease is critical for development of new therapies. Most G3-MBs express high levels of the MYC oncogene, suggesting that MYC plays an important role in tumorigenesis. To identify genes that cooperate with MYC to promote formation of G3-MB, we performed an in vivo mutagenesis screen using mice expressing the Sleeping Beauty (SB) transposon. Cerebellar stem cells from transposon/transposase-expressing mice were infected with viruses encoding Myc, and transplanted into the cerebellum of adult hosts. The resulting tumors were sequenced to identify transposon-targeted genes, and these genes were functionally analyzed to determine whether they could cooperate with Myc to drive G3-MB. These studies identified the transcription factor Ras-responsive element binding protein 1 (Rreb1) as a potent Myc-cooperating gene. Tumors driven by Myc and Rreb1 resemble G3-MB at a histological and molecular level. Moreover, RREB1 is overexpressed in human G3-MB, and knockdown of RREB1 impairs growth of G3-MB cell lines and patient-derived xenografts. Ongoing studies are aimed at identifying the mechanisms by which Rreb1 contributes to tumor growth. Our studies demonstrate an important role for RREB1 in G3-MB, and provide a new model that can be used to identify therapeutic targets and develop more effective therapies for medulloblastoma.
EPEN-46. DNA METHYLATION LANDSCAPE OF RECURRENT PEDIATRIC EPENDYMOMA IDENTIFIES KEY DRIVER EVENTS
Authors: Sibo Zhao, Jia Li, Huiyuan Zhang, Lin Qi, Yuchen Du, Mari Kogiso, Frank Braun, Holly Lindsay, Paola Genevini, Anne-Clemence Veillard, Sol Schvartzman, Miklos Laczik, Geoffrey Berguet, Adekunle Adesina, Clifford Stephan, Murali Chintagumpala, Williams Parsons, Laszlo Perlaky, Yongcheng Song, Deqiang Sun, Xiao-Nan Li
Journal: Neuro-Oncology (2020)

Abstract Pediatric ependymoma has a propensity of developing late and multiple relapses over many years. About 50% of patients will experience relapses and eventually succumb to their disease. Our study is aimed to understand the mechanism of resistance and drivers associated with pediatric ependymoma relapse. We developed 10 sets of patient-derived orthotopic xenograft (PDOX) models of recurrent pediatric ependymoma from both RELA and PFA tumors. Time from primary tumor to last recurrence ranges from 2.75 – 13 years. Number of recurrences per patient ranges from 1 – 7 times. We performed Reduced Representation Bisulfite Sequencing (RRBS) and Whole Genome Bisulfite Sequencing (WGBS) to map the DNA methylation landscape of total of 30 samples of matched primary and recurrent tumors. Molecular subtypes and DNA methylation profiles were maintained, and RELA/PFA signature genes showed similar expression pattern during serial relapses. RELA- and PFA-specific Differentially Methylated CpGs (DMCs) are identified from primary tumors. During the recurrent process, individual patients displayed consistent changes of DMCs and shared DMCs among patients became convergent. We then identified shared common specific DMCs in recurrent RELA and PFA tumors that emerged as the driver signatures. We found that these recurrent DNA methylation signatures could be identified from primary tumors. Our analysis of the PDOX models showed that they can mostly recapitulate humor tumors’ DNA methylation and we were able to identify shared recurrent specific DMCs associated genes in PDOX models. Our comprehensive data is the first of its kind aimed to investigate the epigenetic mechanisms during pediatric ependymoma recurrence.
On the trail of blood doping—<scp>microRNA</scp> fingerprints to monitor autologous blood transfusions in vivo
Authors: Veronika Mussack, Georg Wittmann, Michael W. Pfaffl
Journal: American Journal of Hematology (2020)

Abstract Autologous blood doping refers to the illegal re‐transfusion of any quantities of blood or blood components with blood donor and recipient being the same person. The re‐transfusion of stored erythrocyte concentrates is particularly attractive to high‐performance athletes as this practice improves their oxygen capacity excessively. However, there is still no reliable detection method available. Analyzing circulating microRNA profiles of human subjects that underwent monitored autologous blood transfusions seems to be a highly promising approach to develop novel biomarkers for autologous blood doping. In this exploratory study, we randomly divided 30 healthy males into two different treatment groups and one control group and sampled whole blood at several time points at baseline, after whole blood donation and after transfusion of erythrocyte concentrates. Hematological variables were recorded and analyzed following the adaptive model of the Athlete Biological Passport. microRNA profiles were examined by small RNA sequencing and comprehensive multivariate data analyses, revealing microRNA fingerprints that reflect the sampling time point and transfusion volume. Neither individual microRNAs nor a signature of transfusion‐dependent microRNAs reached superior sensitivity at 100% specificity compared to the Athlete Biological Passport (≤11% 6 h after transfusion versus ≤44% 2 days after transfusion). However, the window of autologous blood doping detection was different. Due to the heterogenous nature of doping, with athletes frequently combining multiple medications in order to both gain a competitive advantage and interfere with known testing methods, the true applicability of the molecular signature remains to be validated in real anti‐doping testings.
Ischemic Time: The New Gold Standard for ST-Segment Elevation Myocardial Infarction Care⁎⁎Editorials published in the Journal of the American College of Cardiologyreflect the views of the authors and do not necessarily represent the views of JACCor the American College of Cardiology.
Authors: Richard W. Smalling
Journal: Journal of the American College of Cardiology (2009)
CBIO-18. G-QUADRUPLEX STABILIZATION TARGETS ATRX-DEFICIENT HIGH-GRADE GLIOMA VIA INDUCTION OF p53-INDEPENDENT APOPTOSIS
Authors: Sharvari Dharmaiah, Ahsan Farooqi, Christian Alvarez, Vladislav Sharin, David Irvin, Jason Huse
Journal: Neuro-Oncology (2020)

Abstract Gliomas are the most common primary malignant brain tumor in adults and mutational inactivation of histone chaperone ATRX is a critical molecular marker in the classification of high-grade glioma (HGG). ATRX loss occurs with concurrent mutations in TP53 and IDH1/2, altering genome-wide accessibility of chromatin and inducing replication stress and DNA damage via accumulations of abnormal G-quadruplex (G4) DNA secondary structures. While G4 stabilizers in particular hold strong therapeutic promise, the genomic consequences and efficacy of this treatment are poorly understood. We previously showed that chemical stabilization of G4s in ATRX-deficient normal human astrocytes (NHAs) results in lethality due to induction of replication stress, but it is unknown what drives this lethality in ATRX-deficient patient-derived preclinical models. We therefore sought to evaluate the mechanisms that underlie cell death in ATRX- and p53-deficient preclinical in vitro models following G4 stabilization. We found that ATRX-deficient glioma stem cells (GSCs) demonstrated dose-dependent enhanced sensitivity to G4 stabilization, compared to ATRX-intact controls. Evaluation of cell death mechanisms following G4 stabilization revealed a significant increase in cleaved caspase 3 expression and no p21 expression in ATRX-deficient GSCs, suggesting p53-independent apoptotic activation. Cell cycle flow analysis demonstrated G2/M checkpoint arrest in ATRX-deficient GSCs upon G4 stabilization, suggesting that p53 is nonfunctional at the G1/S checkpoint. Our preliminary findings now suggest that p73, a functional and structural homologue of p53, is activated and drives apoptosis in these ATRX-deficient GSCs. Furthermore, ATRX-deficient GSCs demonstrated upregulated expression of both pATR/pChk1 and pATM/pChk2, indicating enhanced replication stress and DNA damage via double-stranded breaks, respectively. These findings indicate that G4 stabilizers could potentially synergize with ionizing radiation, the current standard of care, as both therapies are DNA-damaging. Taken together, this study elucidates mechanisms of cytotoxicity and efficacy of a novel therapeutic strategy in ATRX-deficient preclinical models.
Reply to Firkins and Krishna
Authors: Bojan Kovacevic, Pia Klausen, Charlotte Vestrup Rift, Anders Toxværd, Hanne Grossjohann, John Gásdal Karstensen, Lene Brink, Hazem Hassan, Evangelos Kalaitzakis, Jan Storkholm, Carsten Palnæs Hansen, Jane Preuss Hasselby, Peter Vilmann
Journal: Endoscopy (2020)

See also:Clinical impact of endoscopic ultrasound-guided through-the-needle microbiopsy in patients with pancreatic cystsEndoscopy 2021; 53(01): 103-103DOI: 10.1055/a-1259-1409
The Importance of Studying Sex and Gender Differences in Opioid Misuse
Authors: R. Kathryn McHugh
Journal: JAMA Network Open (2020)

Sarah M. Bagley, MD, MSc; Mam Jarra Gai, MPH; Joel J. Earlywine, MS; Samantha F. Schoenberger, BA; Scott E. Hadland, MD, MPH, MS; Joshua A. Barocas, MD