tbuckley/cabot-search huggingface dataset:
GENE-02. CHROMOSOME CONFORMATION ANALYSIS OF EPENDYMOMA IDENTIFIES PUTATIVE TUMOR DEPENDENCY GENES ACTIVATED BY DISTAL ONCOGENIC ENHANCERS
Authors: Konstantin Okonechnikov, Jens-Martin Hübner, Katerina Kraft, Rocio Acuna Hidalgo, Rosalind Bump, Sahaana Chandran, Stefan Mundlos, Jill Mesirov, Kristian Pajtler, Jesse Dixon, Stefan Pfister, Marcel Kool, Lukas Chavez
Journal: Neuro-Oncology (2019)

By profiling enhancers in primary ependymoma tumors, we have recently identified putative oncogenes, molecular targets, and functional pathways. Inhibition of selected targets diminished the proliferation of patient-derived neurospheres and increased survival in mouse models of ependymoma. To associate enhancers with their likely target genes, we previously relied on linear proximity and co-activation analysis. While enhancers frequently regulate the nearest gene, unambiguous identification of enhancer target genes remains to be a challenge in the absence of chromosome conformation information. Consequently, we have now used HiC to map the 3-dimensional organization of tumor chromatin in the two most common and aggressive ependymoma subgroups: posterior fossa group A (PF-EPN-A) and supratentorial ependymomas with gene fusions involving the NF-κB subunit gene RELA (ST-EPN-RELA). By an integrative analysis of enhancer and gene expression in the context of the newly derived HiC data, we find that a large amount of the previously predicted enhancer target genes can be confirmed by physical interactions. Importantly, we also identify many new putative tumor-dependency genes activated by long-range promoter-enhancer interactions. These distal regulatory dependencies could not be predicted previously by proximity or gene-enhancer co-activation analysis alone due to marked differences in ependymoma chromosome conformation compared to normal human cell types. Complementary to the analysis of gene-enhancer interactions, we have also leveraged the HiC data for resolving structural rearrangements underlying copy number alterations frequently observed in PF-EPN-A tumors. Especially copy number gains of the 1q arm of chromosome 1 are associated with poor survival. Our preliminary results reveal complex structural variants that underlie 1q gains, which lead to inter-chromosomal rearrangements and affect several genes that potentially contribute to poor survival. We now aim to test the relevance of the novel candidate tumor-dependency genes for tumor cell growth and proliferation in-patient derived ependymoma models.
An Endogenous Anti-aging Factor, Sonic Hedgehog, Suppresses Endometrial Stem Cell Aging through SERPINB2
Authors: Ara Cho, Se-Ra Park, Soo-Rim Kim, Seungyoon Nam, Soyi Lim, Chan Hum Park, Hwa-Yong Lee, In-Sun Hong
Journal: Molecular Therapy (2019)

Endometrial stem cells are located in the basal layer of the endometrium, and they are responsible for the cyclic regeneration of the uterus during the menstrual cycle. Recent studies have revealed that recurrent pregnancy loss is associated with an age-related stem cell deficiency in the endometrium. Therefore, intensive study of endometrial stem cell aging may provide new insights for preventing recurrent pregnancy loss. Sonic hedgehog (SHH) signaling has been identified as a morphogen during the embryonic development processes. In addition to this canonical function, we found that the age-associated decline in regenerative potential in the endometrium may be due to decreased SHH-signaling integrity in local stem cells with aging. Importantly, the current study also showed that SHH activity clearly declines with aging both in vitro and in vivo, and exogenous SHH treatment significantly alleviates various aging-associated declines in multiple endometrial stem cell functions, suggesting that SHH may act as an endogenous anti-aging factor in human endometrial stem cells. Moreover, we found that stem cell senescence may enhance SERPINB2 expression, which in turn mediates the effect of SHH on alleviating senescence-induced endometrial stem cell dysfunctions, suggesting that SERPINB2 is a master regulator of SHH signaling during the aging process. Endometrial stem cells are located in the basal layer of the endometrium, and they are responsible for the cyclic regeneration of the uterus during the menstrual cycle. Recent studies have revealed that recurrent pregnancy loss is associated with an age-related stem cell deficiency in the endometrium. Therefore, intensive study of endometrial stem cell aging may provide new insights for preventing recurrent pregnancy loss. Sonic hedgehog (SHH) signaling has been identified as a morphogen during the embryonic development processes. In addition to this canonical function, we found that the age-associated decline in regenerative potential in the endometrium may be due to decreased SHH-signaling integrity in local stem cells with aging. Importantly, the current study also showed that SHH activity clearly declines with aging both in vitro and in vivo, and exogenous SHH treatment significantly alleviates various aging-associated declines in multiple endometrial stem cell functions, suggesting that SHH may act as an endogenous anti-aging factor in human endometrial stem cells. Moreover, we found that stem cell senescence may enhance SERPINB2 expression, which in turn mediates the effect of SHH on alleviating senescence-induced endometrial stem cell dysfunctions, suggesting that SERPINB2 is a master regulator of SHH signaling during the aging process.
The BMJ Awards 2019: UK Research Paper of the Year
Authors: Jacqui Wise
Journal: BMJ (2019)

For the past 25 years, men with suspected prostate cancer on the basis of a raised prostate specific antigen (PSA) test have typically been offered standard transrectal ultrasonography (TRUS) guided biopsy of the prostate gland. However, this approach sometimes misses clinically significant tumours and can lead to the over-detection of low grade cancers.

The PRECISION trial1 was one of the first multicentre …
DIPG-08. THE ROLE OF KMT5B/C AND H4K20 DI/TRIMETHYLATION IN DIPG
Authors: Ketty Kessler, Alan Mackay, Valeria Molinari, Anna Burford, Lynn Bjerke, Sara Temelso, Mara Vinci, Chris Jones
Journal: Neuro-Oncology (2019)

Diffuse intrinsic pontine glioma (DIPG) are incurable childhood brain tumours marked by alterations in histone 3 in the form of somatic K27M mutations and loss of H3K27 trimethylation (H3K27me3). These highly aggressive tumours display extensive intratumoral heterogeneity, despite their relatively modest mutational burden. We recently proposed a model whereby co-operative subclonal interactions may exist to promote tumorigenesis in DIPG, and identified rare cancer stem cell populations to harbour mutations in the histone H4 lysine methyltransferase KMT5B. Although not previously described in glioma, loss of H4K20me2/3 caused by abrogated H4 methyltransferase function has been linked to defects in the DNA damage response and enhanced invasion in breast and pancreatic cancer. In order to explore whether dysregulation of H4 methylation may be directly responsible for tumorigenic phenotypes in DIPG, we targeted the methyltransferases by genetically engineering numerous isogenic cells from patient-derived in vitro models using CRISPR/Cas9 to knock out KMT5B and/or KMT5C, alongside pharmacological treatment with the small molecule KMT5B/C inhibitor A-196. We observed the expected reduction in H4K20me2 and H4K20me3 in response to inhibition of KMT5B/C, with an attendant increase in H3K27me3. Knock-out of KMT5B caused a significant increase in tumour cell migration and invasion in vitro, whilst KMT5C-deficient cells had reduced motility. Double knock-outs presented an intermediate phenotype. With H4K20me2/3 playing an important role in DNA repair via 53BP1 recruitment, we further observed a significantly enhanced efficacy of the PARP inhibitors olaparib and talazoparib in knock-out DIPG cells in vitro. Ongoing analysis of differential binding of post-translational modifications by ChIP-seq will provide important insights into the underlying mechanisms of epigenetic dysregulation, particularly in respect of the cross-talk between H3 and H4 marks. Although often present only in small tumour cell populations, H4K20me2/3 and KMT5B/C may represent an important novel aspect of DIPG tumorigenesis.
Abstract 18295: A Prospective Study of Pocket-carried Ultrasound Pre- and Post-Discharge Inferior Vena Cava Assessment for Risk Prediction of Heart Failure Re-hospitalization
Authors: Ehimare Akhabue, Jacob Pierce, Laura Davidson, Stuart Prenner, Kannan Mutharasan, Allen S Anderson, Sanjiv Shah, Jyothy Puthumana, James Thomas
Journal: Circulation (2017)

Introduction: Re-hospitalization for heart failure (HF) is common. Subclinical congestion may be present at the time of discharge (DC). The size and collapsibility of the inferior vena cava (IVC) c...
Inulin Can Alleviate Metabolism Disorders in <i>ob/ob</i> Mice by Partially Restoring Leptin-Related Pathways Mediated by Gut Microbiota
Authors: Xiaofeng Song, Liang Zhong, Na Lyu, Fei Liu, Boxing Li, Yanan Hao, Yong Xue, Jing Li, Yuqing Feng, Yue Ma, Yongfei Hu, Baoli Zhu
Journal: Genomics Proteomics & Bioinformatics (2019)

Abstract Inulin has been used as a prebiotic to alleviate glucose and lipid metabolism disorders in mice and humans by modulating the gut microbiota. However, the mechanism underlying the alleviation of metabolic disorders by inulin through interactions between the gut microbiota and host cells is unclear. We use ob/ob mice as a model to study the effect of inulin on the cecal microbiota by 16S rRNA gene amplicon sequencing and its interaction with host cells by transcriptomics. The inulin-supplemented diet improved glucose and lipid metabolism disorder parameters in ob/ob mice, alleviating fat accumulation and glucose intolerance. The α diversity of gut microbial community of ob/ob mice was reduced after inulin treatment, while the β diversity tended to return to the level of wild type mice. Interestingly, Prevotellaceae UCG 001 (family Prevotellaceae) was obviously enriched after inulin treatment. A comparative analysis of the gene expression profile showed that the cecal transcriptome was changed in leptin gene deficiency mice, whereas the inulin-supplemented diet partially reversed the changes in leptin gene-related signaling pathways, especially AMPK signaling pathway, where the levels of gene expression became comparable to those in wild type mice. Further analysis indicated that Prevotellaceae UCG 001 was positively correlated with the AMPK signaling pathway, which was negatively correlated with markers of glycolipid metabolism disorders. Our results suggest that the inulin-supplemented diet alleviates glucose and lipid metabolism disorders by partially restoring leptin related pathways mediated by gut microbiota.
DIPG-02. TRANSLATIONAL MR IMAGING CORRELATES FOR MOLECULAR ANALYSES IN DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)
Authors: Tina Young Poussaint, Sridhar Vajapeyam, Douglas Brown, Pei-Chi Kao, Clement Ma, Lianne Greenspan, Nalin Gupta, Liliana Goumnerova, Pratiti Bandopadhayay, Rameen Beroukhim, Keith Ligon, Mark Kieran, Susan Chi, Karen Wright
Journal: Neuro-Oncology (2019)

PURPOSE: To correlate MR imaging findings with molecular analyses in DIPG. METHODS: Baseline MR imaging studies, including standard pre- and post-contrast MR sequences, were reviewed from patients included in our multi-institutional, IRB-approved DIPG trial NCT01182350. Prospectively acquired imaging data were analyzed after study closure, including FLAIR/T2 tumor volume; tumor volume enhancement and cyst/necrosis; median, mean, mode, skewness, and kurtosis of apparent diffusion coefficient (ADC) tumor volume based on both FLAIR and enhancement at baseline. Whole-genome and RNA-sequencing identified histone mutations. We applied univariate Cox proportional-hazards regression modeling to test the association of imaging predictors with overall (OS) and progression-free survival (PFS). Wilcoxon rank-sum, Kruskal-Wallis, and Fisher’s exact tests compared imaging measures between groups. RESULTS: Fifty patients underwent biopsy and MRI. Median age at trial registration was 6 years (range,3.3–17.5 years); 52% of patients were female. Molecular subgroup study assignments for 48 patients’ tumors were as follows: 28 in MGMT-/EGFR-, 14 in MGMT-/EGFR+, 3 in MGMT+/EGFR-, and 3 in MGMT+/EGFR+. Further genetic testing identified mutations in histones, PDGFRA, ACVR1, TP53, EGFR, PPM1D, FGFR, and/or PI3K. Twenty-three tumors possessed histone mutations in H3F3A, 8 in HIST1H3B, and 3 in HISTH3C. Median follow-up time was 11 months (range,0.4–33 months). Poorer OS (p=0.01) and PFS (p=0.001) were significantly associated with increased enhancing tumor volume. Enhancing tumor volume also differed significantly across molecular subgroups (p=0.047). Tumor enhancement, mode, skewness, and kurtosis ADC-FLAIR differed significantly (p≤0.048) between patients with H3F3A and HIST1H3B mutations. Tumor enhancement, median, mode, skewness, and kurtosis ADC-FLAIR also differed significantly (p≤0.048) between patients with H3F3A and HIST1H3B or HISTH3C mutations. CONCLUSIONS: MR imaging features including enhancement and ADC histogram parameters correlate to molecular subgroups in DIPG. Further studies are required to verify and refine these findings in a larger cohort.
ATRT-11. MOLECULAR BACKGROUND AND SURVIVAL OF PATIENTS WITH ATRT AND RHABDOID TUMOURS; SINGLE CENTRE EXPERIENCE
Authors: Adela Misove, Marketa Vlckova, Josef Zamecnik, Lenka Krskova, Katerina Vanova, Jan Stary, Bela Malinova, Ivana Pernikova, Ales Vicha, Petr Liby, Michal Tichy, Martin Kyncl, Michal Zapotocky, David Sumerauer
Journal: Neuro-Oncology (2019)

Rhabdoid tumors (RTs) are frequent pediatric malignancies that are classified based on tumor localization: In the central nervous system, they are referred to as atypical teratoid/rhabdoid tumors (ATRTs) as compared to extra-cranial malignant RTs (MRTs).The common genetic hallmark of these tumors is the loss of SMARCB1 in 95% of all cases.Molecularly, RTs are heterogeneous.Previous studies reported molecular subgroups within RTs of the same anatomic compartment.However, biological similarities among RT subgroups of different sites, and molecular characteristics shared among them remained unknown.Investigating the similarity of RTs from different anatomic sites at a molecular level, we compared DNA methylation, gene expression, and H3K27ac profiles of 150 MRTs and 161 ATRTs generated by WGBS, 450K/850K-arrays, RNA-, and ChIP-Seq.Clustering of methylation data showed that a subset of MRTs (called Group1) clustered with the MYC-subgroup of ATRTs but not with SHH-and TYR-subgroups of ATRTs.Over-expression of MYC-ATRT representative genes, such as c-MYC and the non-coding regulatory RNA gene HOTAIR, was also observed in these MRTs.Transcription factor binding enrichment analyses displayed a high enrichment of transcription factors implicated in immune cell regulation such as GMEMB1/2, IRF5/8/9, and STAT1 in both ATRT-MYC and MRT.We therefore predicted the immune cell infiltration of RTs using the CIB-ERSORT and validated these in-silico analyses by immunohistochemistry (IHC) for CD3,CD8, CD68 and PD-L1.In line with the computational results, IHC demonstrated a high number of CD3+ and CD8+ in both MRT and ATRT-MYC, suggestive of abundant cytotoxic T-cell infiltration.Overall our analyses reveal a high degree of similarity between ATRT-MYC and (Group 1)-MRT not only at the epigenetic level, but also in the immune cell composition and underline the suitability of these tumors for a potential immunotherapy.
Abstract 13585: Non-Circular Shape of Right Ventricular Outflow Tract: A Real-Time Three-Dimensional Transesophageal Echocardiography Study
Authors: Masaki Izumo, Takeji Saitoh, Yoko Fukuoka, Jun Tanaka, Swaminatha Gurudevan, Kirsten Tolstrup, Robert J Siegel, Takahiro Shiota
Journal: Circulation (2011)
TMOD-05. C-MYC OVEREXPRESSION INDUCES CHOROID PLEXUS PAPILLOMAS THROUGH A T-CELL MEDIATED INFLAMMATORY MECHANISM
Authors: Ashirwad Merve, Xinyu Zhang, Nicola Pomella, Anaelle Dumas, Silvia Marino
Journal: Neuro-Oncology (2019)

Choroid plexus tumours (CPTs) account for up to 20% of brain tumours in children under 2 years of age. They can spread along the neuraxis and can recur after treatment. Little is known about the molecular mechanisms underlying their formation and only few high fidelity mouse models of p53-deficient malignant CPTs are available. We show here that c-Myc overexpression in the choroid plexus epithelium induces T-cell inflammation-dependent choroid plexus papillomas in a mouse model. We demonstrate that c-MYC is expressed in a substantial proportion of human choroid plexus tumours and that this subgroup of tumours is characterised by an inflammatory transcriptome and significant inflammatory infiltrates. Together with the deregulation of the IL36/IL1RL2 axis observed in c-Myc-dependent murine and c-MYC positive human CPTs, our data raise the possibility that benign choroid plexus tumours expressing c-MYC could be amenable to medical therapy with anti-inflammatory drugs rather than surgical therapy.
BIOL-02. CELLULAR HETEROGENEITY CONTRIBUTES TO THE AGGRESSIVE BEHAVIOR OF MYC-DRIVEN MEDULLOBLASTOMA
Authors: Nan Qin, Maike Langini, Daniel Picard, Eunice Paisana, Rita Cascão, Carlos Custódia, Frauke Meyer, Anja Stefanski, Kai Stühler, Guido Reifenberger, Arndt Borkhardt, Cláudia Faria, Marc Remke
Journal: Neuro-Oncology (2019)

INTRODUCTION: Medulloblastoma is the most common malignant brain tumor of childhood and is a genetically heterogeneous disease. Amongst all medulloblastoma subgroups, MYC-amplified medulloblastomas are associated with a particularly poor prognosis as they are commonly metastatic and resistant to standard therapy. However, MYC amplification is restricted to a cellular subpopulation within MYC-amplified tumors. The underlying mechanisms mediating this cellular heterogeneity remain poorly understood. HYPOTHESIS: We hypothesize that a secretome-dependent crosstalk between MYC-amplified and non-MYC-amplified cells shapes an intratumoral microenvironment that promotes medulloblastoma aggressiveness. METHODS AND RESULTS: We first demonstrate that MYC overexpressing (high-MYC) cells induce proliferation and invasive growth patterns in their isogenic counterparts with low MYC expression (low-MYC) using contacting and non-contacting co-culture systems in three different medulloblastoma cell lines (ONS76, DAOY and UW228-3). Secondly, we demonstrate that exosomes from high-MYC cells promote the migratory propensity of low-MYC cells in vitro. Importantly, we confirmed the pro-tumorigenic interaction of high-MYC and low-MYC cells using two orthotopic medulloblastoma xenograft models. We further demonstrate that low-MYC cells promote tumor angiogenesis in vivo. Using an unbiased proteomic discovery approach and targeted validation by Western blotting, we identified and verified secreted proteins that may mediate this interaction. Rescue experiments validated the relevance of these candidates using functional genomics approaches in vitro, with in vivo validation being currently ongoing. CONCLUSION: We demonstrate that the crosstalk between cellular subclones in MYC-driven medulloblastoma may promote tumor growth, metastasis and angiogenesis. Understanding the underlying secretory signaling networks may elucidate novel therapeutic vulnerabilities in this prognostically poor subgroup of medulloblastoma.
Abstract 22: Geographic Proximity of Automated External Defibrillators to Out-of-hospital Sudden Deaths in Wake County, North Carolina
Authors: Brittany M Bogle, Golsa Joodi, Ross Simpson
Journal: Circulation (2017)

Introduction: Survival rates for out-of-hospital sudden cardiac arrest are substantially improved by access to automated external defibrillators (AEDs) prior to Emergency Medical Services (EMS) arrival. However, AED use may be inhibited if their locations are unknown or far from the bystander. Objectives: We sought to classify out-of-hospital sudden death (OHSD) event locations, ascertain if bystanders utilized AEDs prior to EMS arrival, and calculate the distance to the nearest AED. Methods: From 2013 to 2015, we screened all EMS-reported out-of-hospital deaths aged 18-64 within Wake County, North Carolina to identify OHSDs. We geocoded event locations from EMS records and classified them as residential, commercial, public, or unknown using US Postal Service Residential Delivery Indicator, EMS narratives, and web searches. AED locations and installation dates, registered by law, were obtained from North Carolina Department of Health and Human Services. We used EMS narratives to determine AED use prior to EMS arrival. Walking distance between coordinates of an OHSD location and every AED installed prior to the death date was estimated using the Great-Circle distance. Results: Of 434 adjudicated OHSDs, 390 (90%) were residential, 31 (7%) were commercial, and 11 (2.5%) were public. Of commercial locations, 12 (39%) occurred in hotels. Of public locations, 6(46%) occurred in parking lots or parks. Wake County had 168 registered AEDs during the study period. The mean distance from OHSD to closest AED was 3.2 km (95% CI: 3.0-3.5 km). Only 20 (4.6%) of OHSDs were within 500 meters of an AED; the closest AED was 77 meters from an OHSD. Bystanders used AEDs prior to EMS arrival twice. Conclusions: While potentially lifesaving, AEDs are not placed optimally with respect to OHSD locations and are rarely utilized by bystanders, even in non-residential spaces. Public health strategies should be considered that incentivize optimal AED placement to witnessed cardiac arrest locations.
GENE-14. UNIQUE MOLECULAR AND CLINICAL FEATURES OF LI-FRAUMENI SYNDROME ASSOCIATED BRAIN TUMOURS
Authors: Michal Zapotocky, Adela Misove, Marketa Vlckova, Lenka Krskova, Josef Zamecnik, Katerina Vanova, Bela Malinova, Barbora Ondrova, Ivana Pernikova, Ales Vicha, Michal Tichy, Petr Liby, Martin Kyncl, Vijay Ramaswamy, David Sumerauer
Journal: Neuro-Oncology (2019)

Li-Fraumeni syndrome (LFS) is a condition characterized by germ-line TP53 mutation and predisposition to various types of malignant neoplasms in childhood. We aimed to characterize spectrum of brain tumours in children associated with LFS. We gathered clinical information on LFS patients treated since 1990 at our department. Where the tissue was available, we performed molecular analysis consisting of whole genome methylation array and/or sequencing. We identified 15 LFS patients diagnosed with brain tumours; six with choroid plexus carcinoma (CPC), four with glioma, three with medulloblastoma, one PNET and one spinal myxopapilary ependymoma. Twelve of these patients presented with brain tumour as their first malignancy. Two patients were previously treated for rhabdomyosarcoma and developed glioma in radiation field. One patient was diagnosed with medulloblastoma after adrenocortical carcinoma. Out of six patients with CPC, three are alive, with two treated with radiation therapy. Gliomas consisted of three diffuse astrocytomas (DA) and one glioblastoma. DAs were diagnosed at later age (14 to 18 years) and molecularly characterized by rare IDH1 R132G mutation. One glioblastoma was classified as GBM_other using NMP2.0. All four patients are alive with median 4 years from diagnosis of glioma, including the patient with glioblastoma. All medulloblastomas were SHH group with tumor location in the cerebellar hemisphere. Two patients treated with combined radiation and chemotherapy died of secondary malignancy 4 and 5 years from the primary diagnosis. Last patient is currently being treated with radiation sparing approach. In our cohort, majority of patients developed brain tumour as their first malignancy. Radiation sparing approaches need to be implemented to decrease risks of secondary cancers. Gliomas and medulloblastomas seem to harbour distinct molecular features compared to their sporadic counterparts.