tbuckley/cabot-search huggingface dataset:
Regional, Layer, and Cell-Type-Specific Connectivity of the Mouse Default Mode Network
Authors: Jennifer D. Whitesell, Adam Liska, Ludovico Coletta, Karla E. Hirokawa, Phillip Bohn, Ali Williford, Peter A. Groblewski, Nile Graddis, Leonard Kuan, Joseph E. Knox, Anh Ho, Wayne Wakeman, Philip R. Nicovich, Thuc Nghi Nguyen, Cindy T.J. van Velthoven, Emma Garren, Olivia Fong, Maitham Naeemi, Alex M. Henry, Nick Dee, Kimberly A. Smith, Boaz Levi, David Feng, Lydia Ng, Bosiljka Tasic, Hongkui Zeng, Stefan Mihalas, Alessandro Gozzi, Julie A. Harris
Journal: Neuron (2020)

The evolutionarily conserved default mode network (DMN) is a distributed set of brain regions coactivated during resting states that is vulnerable to brain disorders. How disease affects the DMN is unknown, but detailed anatomical descriptions could provide clues. Mice offer an opportunity to investigate structural connectivity of the DMN across spatial scales with cell-type resolution. We co-registered maps from functional magnetic resonance imaging and axonal tracing experiments into the 3D Allen mouse brain reference atlas. We find that the mouse DMN consists of preferentially interconnected cortical regions. As a population, DMN layer 2/3 (L2/3) neurons project almost exclusively to other DMN regions, whereas L5 neurons project in and out of the DMN. In the retrosplenial cortex, a core DMN region, we identify two L5 projection types differentiated by in- or out-DMN targets, laminar position, and gene expression. These results provide a multi-scale description of the anatomical correlates of the mouse DMN.
HGG-52. SUSTAINED RESPONSE TO CRIZOTINIB MONOTHERAPY IN AN INFANT WITH GOPC-ROS1 FUSED CONGENITAL HEMISPHERIC GLIOMA
Authors: Rishi Lulla, Konstantina Svokos, Kristine Pelton, Douglas Anthony, Mehdi Touat, Keith L Ligon
Journal: Neuro-Oncology (2020)

Abstract Recent studies identified the presence of ALK/ROS/NTRK/MET alterations in a subset of infantile hemispheric gliomas. We report a case of GOPC-ROS1 fused congenital hemispheric glioma with a sustained response to crizotinib. An infant born at 28 weeks gestation was diagnosed with a large hemispheric mass at 2 weeks of life. The tumor was partially resected at 7 weeks of life. Histological evaluation confirmed a neoplasm with a spindle cell growth pattern, hypercellularity, nuclear pleomorphism, endothelial proliferation and necrosis consistent with glioblastoma. Fresh tissue was submitted for targeted panel sequencing (Oncopanel) which identified the presence of a GOPC-ROS1 fusion (exon 36:intron 4). This was confirmed by copy number analysis which showed a focal intragenic deletion with a breakpoint in ROS1 on 6q22. Given the lack of preclinical native models for ROS1 and other congenital kinase-driven gliomas, live cells were utilized to attempt to establish a patient derived cell line (organoid/neurosphere model) and intracranial patient derived xenograft model, the results of which are pending and will be reported. The GOPC-ROS1 rearrangement was structurally predicted to respond to kinase inhibitors with activity against ROS1 and crizotinib was started at 280 mg/m2/dose twice daily at 6 months of life with progressive tumor noted on imaging. Three months after initiating therapy, a 56% reduction in the tumor size and subsequent imaging revealed additional response. Our report is the first to demonstrate clinical response to crizotinib in a GPOC-ROS1 fused congenital glioblastoma and describe the development of a renewable resources for future analysis.
FAN-C: a feature-rich framework for the analysis and visualisation of chromosome conformation capture data
Authors: Kai Kruse, Clemens B. Hug, Juan M. Vaquerizas
Journal: Genome biology (2020)

Chromosome conformation capture data, particularly from high-throughput approaches such as Hi-C, are typically very complex to analyse. Existing analysis tools are often single-purpose, or limited in compatibility to a small number of data formats, frequently making Hi-C analyses tedious and time-consuming. Here, we present FAN-C, an easy-to-use command-line tool and powerful Python API with a broad feature set covering matrix generation, analysis, and visualisation for C-like data ( https://github.com/vaquerizaslab/fanc ). Due to its compatibility with the most prevalent Hi-C storage formats, FAN-C can be used in combination with a large number of existing analysis tools, thus greatly simplifying Hi-C matrix analysis.
Left Atrial Roof Ablation Is More Important Than Pulmonary Vein Isolation in Terminating Persistent Atrial Fibrillation in a Canine Model: Should We Perform a Left Atrial Roof Line in All Atrial Fibrillation Ablations?**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: J. Paul Mounsey
Journal: Journal of the American College of Cardiology (2010)
LGG-35. FUNCTIONAL GENOMIC APPROACHES TO IDENTIFY THERAPEUTIC TARGETS IN <i>MYB</i> AND <i>MYBL1</i> EXPRESSING PEDIATRIC LOW-GRADE GLIOMAS
Authors: Alexandra-Larisa Condurat, Annika Wefers, Elizabeth Gonzalez, Jeyna Doshi, Prasidda Khadka, Selin Jessa, Jessica Tsai, Graham Buchan, Cecile Rouleau, Tanaz Abid, Amy Goodale, Nicole Persky, Rameen Beroukhim, David Root, Keith Ligon, Nada Jabado, Clauda L Kleinman, Federica Piccioni, David T W Jones, Pratiti Bandopadhayay
Journal: Neuro-Oncology (2020)

Abstract AIM Recurrent structural variants involving MYB and MYBL1 transcription factors were recently identified in pediatric low-grade gliomas (pLGGs), such as the MYB-QKI rearrangement in Angiocentric Gliomas and truncations of MYBL1 (MYBL1tr) in Diffuse Astrocytomas. However, therapeutic dependencies induced by these alterations remain unexplored. METHODOLOGY We have generated in vitro pLGG mouse neural stem cell (NSCs) models engineered to harbor distinct MYB/MYBL1 genomic alterations. We used single cell RNA sequencing approaches to determine the transcriptional profile and dissect the central regulatory networks of our in vitro pLGG models over time. To identify specific genetic dependencies associated with MYB/MYBL1 mutations, we employed the Brie genome-wide mouse CRISPR lentiviral knockout pooled library, consisting of 78,637 single guide RNAs (sgRNAs) targeting 19,674 mouse genes. RESULTS MYB/MYBL1 expression in neural stem cells induced activation of cell-cycle related, glioma-related and senescence-related pathways that are involved in normal development, including activation of MAPK and mTOR signaling which are also activated in human pLGG samples. Genome-scale CRISPR-cas9 screens in isogenic NSCs expressing MYB-QKI or MYBL1tr identified differential genetic dependencies relative to GFP controls. These included regulators of cell-cycle progression and several modulators of the ubiquitin-proteasome degradation pathway. Analysis of RNA-sequencing data from human tumors revealed several of these dependencies identified in the cell line model to be differentially expressed in MYB-altered pLGG tumors relative to normal brain. CONCLUSION Expression of MYB family alterations induces expression of key developmental and oncogenic pathways and genetic dependencies that represent potential therapeutic targets for MYB or MYBL1 rearranged pLGGs.
DNA Sensing in Mismatch Repair-Deficient Tumor Cells Is Essential for Anti-tumor Immunity
Authors: Changzheng Lu, Junhong Guan, Steve Lu, Qihuang Jin, Benoit Rousseau, Tianshi Lu, Dennis Stephens, Hongyi Zhang, Jiankun Zhu, Mingming Yang, Zhenhua Ren, Yong Liang, Zhida Liu, Chuanhui Han, Longchao Liu, Xuezhi Cao, Anli Zhang, Jian Qiao, Kimberly Batten, Mingyi Chen, Diego H. Castrillon, Tao Wang, Bo Li, Luis A. Diaz, Guo-Min Li, Yang-Xin Fu
Journal: Cancer Cell (2020)
Pure redox-sensitive paclitaxel–maleimide prodrug nanoparticles: Endogenous albumin-induced size switching and improved antitumor efficiency
Authors: Xinyu Lou, Dong Zhang, Hao Ling, Zhonggui He, Jin Sun, Mengchi Sun, Dongchun Liu
Journal: Acta Pharmaceutica Sinica B (2020)

A commercial albumin-bound paclitaxel nano-formulation has been considered a gold standard against breast cancer. However, its application still restricted unfavorable pharmacokinetics and the immunogenicity of exogenous albumin carrier. Herein, we report an albumin-bound tumor redox-responsive paclitaxel prodrugs nano-delivery strategy. Using diverse linkages (thioether bond and disulfide bond), paclitaxel (PTX) was conjugated with an albumin-binding maleimide (MAL) functional group. These pure PTX prodrugs could self-assemble to form uniform and spherical nanoparticles (NPs) in aqueous solution without any excipients. By immediately binding to blood circulating albumin after intravenous administration, NPs are rapidly disintegrated into small prodrug/albumin nanoaggregates in vivo, facilitating PTX prodrugs accumulation in the tumor region via albumin receptor-mediated active targeting. The tumor redox dual-responsive drug release property of prodrugs improves the selectivity of cytotoxicity between normal and cancer cells. Moreover, disulfide bond-containing prodrug/albumin nanoaggregates exhibit long circulation time and superior antitumor efficacy in vivo. This simple and facile strategy integrates the biomimetic characteristic of albumin, tumor redox-responsive on-demand drug release, and provides new opportunities for the development of the high-efficiency antitumor nanomedicines.
EPCO-29. EPIGENOMICS OF THE GLIOMA LONGITUDINAL ANALYSIS (GLASS) CONSORTIUM
Authors: Thais Sabedot, Michael Wells, Indrani Datta, Tathiane Malta, Ana Valeria Castro, Laila M Poisson, Roel Verhaak, Antonio Iavarone, Houtan Noushmehr
Journal: Neuro-Oncology (2020)

Abstract Adult diffuse gliomas are central nervous system (CNS) tumors that arise from the malignant transformation of glial cells. Nearly all gliomas will recur despite standard treatment however, current histopathological grading fails to predict which of them will relapse and/or progress. The Glioma Longitudinal AnalySiS (GLASS) consortium is a large-scale collaboration that aims to investigate the molecular profiling of matched primary and recurrent glioma samples from multiple institutions in order to better understand the dynamic evolution of these tumors. At this time, the cohort comprises 946 samples across 11 institutions and among those, 864 have DNA methylation data available. The current molecular classification based on 7 subtypes published by TCGA in 2016 was applied to the dataset. Among the IDH wildtype tumors, 33% (16/49) of the patients showed a change of subtype upon recurrence, whereas most of them (9/16) were Classic-like at the primary stage but changed to either Mesenchymal-like or PA-like at the recurrent level. Among the IDH mutant tumors, 15% (22/142) showed a change of subtype at recurrent stage, in which 16 out of 22 progressed from G-CIMP-high to G-CIMP-low. Although some tumors progressed to a different subtype upon recurrence, an unsupervised analysis showed that the samples tend to cluster by patient instead of by subtype. By estimating the copy number alterations of these tumors using DNA methylation, the overall copy number profile of the recurrent samples remains similar to their primary counterpart. From this initial analysis using epigenomic data, we were able to characterize some aspects of glioma evolution and how the DNA methylation is associated with the progression of these tumors to different subtypes. These findings corroborate the importance of epigenetics in gliomas and can potentially lead to the identification of new biomarkers that can reflect tumor burden and predict its development.
COVID-19 Pandemic Health Disparities and Pediatric Health Care—The Promise of Telehealth
Authors: Deepa U. Menon, Harolyn M. E. Belcher
Journal: JAMA Pediatrics (2020)

This Viewpoint examines the association between the COVID-19 pandemic and how the changes to telehealth are helping close the gap between clinicians and pediatric physical and mental health care patients.
ETMR-20. IMPACT OF HIGH DOSE CHEMOTHERAPY WITH AND WITHOUT METHOTREXATE (MTX) ON OUTCOME OF PATIENTS WITH EMBRYONAL TUMORS WITH MULTI-LAYERED ROSETTES (ETMRs): A REPORT FROM CHILDREN’S ONCOLOGY GROUP PHASE III TRIAL ACNS0334
Authors: Claire Mazewski, Guolian Kang, Stewart Kellie, Jeffrey Gossett, Sarah Leary, Bryan Li, Paul Aridgides, Laura Hayes, Alyssa Reddy, Dennis Shaw, Peter Burger, Alexander Judkins, Jeffrey Russell Geyer, Maryam Fouladi, Annie Huang
Journal: Neuro-Oncology (2020)

Abstract Infant embryonal brain tumors comprise a spectrum of histologic and molecular entities including medulloblastoma (MB) and tumors collectively called CNS PNET’s, including supratentorial PNET (sPNET), pineoblastoma and other less common histologic entities. Non-MB embryonal tumors, historically considered high risk disease, were included in ACNS0334, A Children’s Oncology Group prospective phase III trial which compared efficacy of an induction regimen with and without methotrexate combined with high dose chemotherapy and stem cell rescue; no radiation was mandated. Molecular testing performed after ACNS0334 closure identified 14 patients with embryonal tumors with multi-layered rosettes (ETMRs), a new molecular entity previously classified under various diagnostic categories. ETMR patients made up 20% of the molecularly analyzed ACNS0334 cohort and were predominantly females. Tumors were largely non-metastatic (10/14 M0, 1 M1, 3 M2/M3) and originated in the cerebrum (8), cerebellum (3) and pineal gland (3). Gross total tumor resection was achieved in 5/11 patients with M0/M1 disease; 9/14 patients completed full treatment with 5 randomized to MTX induction and 9 to no-MTX. Five of 14 patients progressed on treatment, one had a toxic death. Disease progression was primarily local (88 %). No difference by methotrexate randomization was observed. Four patients are alive without progression 5–10+ years off therapy, none received radiation. No patients received radiation prior to progression. Four were irradiated after progression and died from disease within 3 to 13 months. Our study, a first report on ETMRs prospectively treated on a clinical trial, suggests high dose chemotherapy benefits a portion of ETMR patients.
High-Risk Coronary Plaque Regression After Intensive Lifestyle Intervention in Nonobstructive Coronary Disease
Authors: Jan Henzel, Cezary Kępka, Mariusz Kruk, Magdalena Makarewicz-Wujec, Łukasz Wardziak, Piotr Trochimiuk, Zofia Dzielińska, Marcin Demkow
Journal: JACC. Cardiovascular imaging (2020)
Implantable Cardioverter-Defibrillators for Primary Prevention of Sudden Death: The Quest to Identify Patients Most Likely to Benefit⁎⁎Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Authors: Alfred E. Buxton
Journal: Journal of the American College of Cardiology (2012)
Abstract P348: Long-term Cognitive Decline in Older Adults After Incident Coronary Heart Disease or After First Receipt of Coronary Artery Bypass Grafting Surgery or Percutaneous Coronary Intervention
Authors: Jacqueline E Kunzelman, Rachel M Gabor, Monica Scrobotovici, Natalie J Blades, W T Longstreth, Susan R Heckbert, Bruce M Psaty, Alice M Arnold, Annette L Fitzpatrick, David J Llewellyn, Elzbieta Kuzma, Hooman Kamel, Mandip S Dhamoon, Sarwat I Chaudhry, John A Dodson, Dawson W Hedges, Shawn D Gale, Lance D Erickson, Bruce L Brown, Evan L Thacker
Journal: Circulation (2020)

Objective: We investigated two hypotheses: First, incident CHD, defined as myocardial infarction or definite angina, leads to faster long-term cognitive decline. Second, among those with CHD, treatment with CABG surgery or PCI leads to slower long-term cognitive decline. Methods: The Cardiovascular Health Study is a cohort of US adults aged 65+. Global cognitive ability was assessed annually up to 9 times from 1990 to 1998 with the 100-point Modified Mini-Mental State Examination (3MS). We estimated trajectories of 3MS scores in the absence of stroke, adjusting for demographics, health behaviors, and comorbidities. For hypothesis 1, we compared 3MS trajectory after incident CHD with 3MS trajectory in the absence of CHD, censoring at first receipt of CABG/PCI. For hypothesis 2, among participants with CHD, we compared 3MS trajectory after first receipt of CABG/PCI with 3MS trajectory without CABG/PCI. Results: For hypothesis 1, of 4,122 participants, 398 had incident CHD during a mean of 5.9 years of follow-up. Figure Panel A shows model-predicted mean 3MS trajectories without CHD (blue) and after incident CHD (red) diagnosed at ages 70, 75, 80, or 85. Model-predicted 3MS score declined faster after incident CHD, especially for CHD diagnosed at age 80 or later. For example, after incident CHD at age 85, predicted 5-year decline in mean 3MS score through age 90 was 13.9 points (95% CI: 11.0, 16.7) versus 8.9 points (95% CI: 8.1, 9.7) among those without CHD. For hypothesis 2, of 1,183 participants who had prevalent or incident CHD, 118 had their first CABG/PCI during a mean of 4.1 years of follow-up. Model-predicted 3MS score declined faster after first receipt of CABG/PCI ( Figure Panel B ). Conclusions: Older adults diagnosed with incident CHD had faster average cognitive decline than those without CHD. However, treatment with CABG/PCI did not slow cognitive decline among those with CHD. This finding may be due to adverse effects of CABG/PCI on brain health or CABG/PCI recipients having more severe CHD or more cerebral atherosclerosis.
The Effects of Four Doses of Vitamin D Supplements on Falls in Older Adults
Authors: Lawrence J. Appel, Erin D. Michos, Christine M. Mitchell, Amanda L. Blackford, Alice L. Sternberg, Edgar R. Miller, Stephen P. Juraschek, Jennifer A. Schrack, Sarah L. Szanton, Jeanne Charleston, Melissa Minotti, Sheriza N. Baksh, Robert H. Christenson, Josef Coresh, Lea T. Drye, Jack M. Guralnik, Rita R. Kalyani, Timothy B. Plante, David M. Shade, David L. Roth, James Tonascia
Journal: Annals of Internal Medicine (2020)

Background: Vitamin D supplementation may prevent falls in older persons, but evidence is inconsistent, possibly because of dosage differences. Objective: To compare the effects of 4 doses of vitamin D3 supplements on falls. Design: 2-stage Bayesian, response-adaptive, randomized trial. (ClinicalTrials.gov: NCT02166333) Setting: 2 community-based research units. Participants: 688 participants, aged 70 years and older, with elevated fall risk and a serum 25-hydroxyvitamin D [25-(OH)D] level of 25 to 72.5 nmol/L. Intervention: 200 (control), 1000, 2000, or 4000 IU of vitamin D3 per day. During the dose-finding stage, participants were randomly assigned to 1 of the 4 vitamin D3 doses, and the best noncontrol dose for preventing falls was determined. After dose finding, participants previously assigned to receive noncontrol doses received the best dose, and new enrollees were randomly assigned to receive 200 IU/d or the best dose. Measurements: Time to first fall or death over 2 years (primary outcome). Results: During the dose-finding stage, the primary outcome rates were higher for the 2000- and 4000-IU/d doses than for the 1000-IU/d dose, which was selected as the best dose (posterior probability of being best, 0.90). In the confirmatory stage, event rates were not significantly different between participants with experience receiving the best dose (events and observation time limited to the period they were receiving 1000 IU/d; n = 308) and those randomly assigned to receive 200 IU/d (n = 339) (hazard ratio [HR], 0.94 [95% CI, 0.76 to 1.15]; P = 0.54). Analysis of falls with adverse outcomes suggested greater risk in the experience-with-best-dose group versus the 200-IU/d group (serious fall: HR, 1.87 [CI, 1.03 to 3.41]; fall with hospitalization: HR, 2.48 [CI, 1.13 to 5.46]). Limitations: The control group received 200 IU of vitamin D3 per day, not a placebo. Dose finding ended before the prespecified thresholds for dose suspension and dose selection were reached. Conclusion: In older persons with elevated fall risk and low serum 25-(OH)D levels, vitamin D3 supplementation at doses of 1000 IU/d or higher did not prevent falls compared with 200 IU/d. Several analyses raised safety concerns about vitamin D3 doses of 1000 IU/d or higher. Primary Funding Source: National Institute on Aging.
Long non-coding RNA NEAT1 promotes bone metastasis of prostate cancer through N6-methyladenosine
Authors: Simeng Wen, Yulei Wei, Chong Zen, Wei Xiong, Yuanjie Niu, Yu Zhao
Journal: Molecular Cancer (2020)

Abstract Background N6-methyladenosine (m6A) is the most prevalent messenger RNA modification in mammalian cells. However, the disease relevant function of m6A on specific oncogenic long non-coding RNAs (ncRNAs) is not well understood. Methods We analyzed the m6A status using patients samples and bone metastatic PDXs. Through m6A high-throughput sequencing, we identified the m6A sites on NEAT1–1 in prostate bone metastatic PDXs. Mass spec assay showed interaction among NEAT1–1 , CYCLINL1 and CDK19. RNA EMSA, RNA pull-down, mutagenesis, CLIP, western blot, ChIP and ChIRP assays were used to investigate the molecular mechanisms underlying the functions of m6A on NEAT1–1 . Loss-of function and rescued experiments were executed to detect the biological roles of m6A on NEAT1–1 in the PDX cell phenotypes in vivo. Results In this study, we identified 4 credible m6A sites on long ncRNA NEAT1–1. High m6A level of NEAT1–1 was related to bone metastasis of prostate cancer and m6A level of NEAT1–1 was a powerful predictor of eventual death. Transcribed NEAT1–1 served as a bridge to facility the binding between CYCLINL1 and CDK19 and promoted the Pol II ser2 phosphorylation. Importantly, depletion of NEAT1–1 or decreased m6A of NEAT1–1 impaired Pol II Ser-2p level in the promoter of RUNX2 . Overexpression of NEAT1–1 induced cancer cell metastasis to lung and bone; xenograft growth and shortened the survival of mice, but NEAT1–1 with m6A site mutation failed to do these. Conclusion Collectively, the findings indicate that m6A on ncRNA NEAT1–1 takes critical role in regulating Pol II ser2 phosphorylation and may be novel specific target for bone metastasis cancer therapy and diagnosis. New complex CYCLINL1/CDK19/ NEAT1–1 might provide new insight into the potential mechanism of the pathogenesis and development of bone metastatic prostate cancer.