tbuckley/cabot-search huggingface dataset:
Measles outbreak in Gothenburg urban area, Sweden, 2017 to 2018: low viral load in breakthrough infections
Authors: Nicklas Sundell, Leif Dotevall, Martina Sansone, Maria Andersson, Magnus Lindh, Thomas Wahlberg, Tobias Tyrberg, Johan Westin, Jan-Åke Liljeqvist, Tomas Bergström, Marie Studahl, Lars-Magnus Andersson
Journal: Eurosurveillance (2019)

In an outbreak of measles in Gothenburg, Sweden, breakthrough infections (i.e. infections in individuals with a history of vaccination) were common. The objective of this study was to compare measles RNA levels between naïve (i.e. primary) and breakthrough infections. We also propose a fast provisional classification of breakthrough infections. Medical records were reviewed and real-time PCR-positive samples genotyped. Cases were classified as naïve, breakthrough or vaccine infections. We compared clinical symptoms and measles RNA cycle threshold (Ct) values between breakthrough and naïve infections. Sixteen of 28 confirmed cases of measles in this outbreak were breakthrough infections. A fast provisional classification, based on previous history of measles vaccination and detectable levels of measles IgG in acute serum, correctly identified 14 of the 16 breakthrough infections, confirmed by IgG avidity testing. Measles viral load was significantly lower in nasopharyngeal samples from individuals with breakthrough compared with naïve infections (median Ct-values: 32 and 19, respectively, p &lt; 0.0001). No onward transmission from breakthrough infections was identified. Our results indicate that a high risk of onward transmission is limited to naïve infections. We propose a fast provisional classification of breakthrough measles that can guide contact tracing in outbreak settings.
EPEN-09. PRECLINICAL MODELS REVEAL SUBGROUP-STRATIFIED TARGETED THERAPY OPTIONS FOR CHILDHOOD SUPRATENTORIAL EPENDYMOMA
Authors: Vladimir Amani, Andrew Donson, Andrea Griesinger, Davis Witt, Jean Mulcahy Levy, Lindsey Hoffman, Todd Hankinson, Michael Handler, Rajeev Vibhakar, Kathleen Dorris, Nicholas Foreman
Journal: Neuro-Oncology (2019)

Treatment of ependymoma has changed little over the years and is essentially limited to surgery and radiation. Limited preclinical testing has hindered the development of targeted therapies. Our group has identified a variety of potential therapy options for ependymoma based on drug screening using novel human posterior fossa ependymoma cell lines with chromosome 1q gain. Whether these agents were also effective in RELA fusion-driven supratentorial ependymoma was not determined due to of a lack of available supratentorial ependymoma cell lines. Recently we were able to generate a novel supratentorial cell line – MAF1329 - harboring 1q+ as well as the RELA-C11orf95 fusion. Paired with a supratentorial ependymoma cell line (EP1NS) obtained from collaborators, we were able to perform an in vitro screen and to identify supratentorial ependymoma-selective therapies in a panel of 124 FDA-approved oncology drugs, for streamlined clinical application. Additionally, we are able to compare drug sensitivities between supratentorial and posterior fossa ependymoma. Our initial findings indicate that the two ependymoma subgroups differ in response to therapy options with some overlap, notably RTKIs imatinib and pazopanib. We also noted that carmofur, a lypophilic-masked analog of 5-FU, was effective in treating both subgroups. Conversely, 5-FU itself, a top hit in posterior fossa ependymoma, showed very little effect in supratentorial models. Early phase trials of 5-FU resulted in a lack of survival benefit in supratentorial tumors enrolled in the study, and this preclinical finding may explain this lack of response. These data suggest that supratentorial and posterior fossa ependymoma may require subgroup specific targeted therapy options. Further comparative drug screening of other supratentorial cell lines and short term cultures, combined with in vivo testing, will address the need for subgroup-stratified preclinical data to better inform design of clinical trials in ependymoma.
Lamin B1 loss promotes lung cancer development and metastasis by epigenetic derepression of RET
Authors: Yanhan Jia, Joaquim Si-Long Vong, Alina Asafova, Boyan K. Garvalov, Luca Caputo, Julio Cordero, Anshu Singh, Thomas Boettger, Stefan Günther, Ludger Fink, Till Acker, Guillermo Barreto, Werner Seeger, Thomas Braun, Rajkumar Savai, Gergana Dobreva
Journal: The Journal of Experimental Medicine (2019)

Although abnormal nuclear structure is an important criterion for cancer diagnostics, remarkably little is known about its relationship to tumor development. Here we report that loss of lamin B1, a determinant of nuclear architecture, plays a key role in lung cancer. We found that lamin B1 levels were reduced in lung cancer patients. Lamin B1 silencing in lung epithelial cells promoted epithelial-mesenchymal transition, cell migration, tumor growth, and metastasis. Mechanistically, we show that lamin B1 recruits the polycomb repressive complex 2 (PRC2) to alter the H3K27me3 landscape and repress genes involved in cell migration and signaling. In particular, epigenetic derepression of the RET proto-oncogene by loss of PRC2 recruitment, and activation of the RET/p38 signaling axis, play a crucial role in mediating the malignant phenotype upon lamin B1 disruption. Importantly, loss of a single lamin B1 allele induced spontaneous lung tumor formation and RET activation. Thus, lamin B1 acts as a tumor suppressor in lung cancer, linking aberrant nuclear structure and epigenetic patterning with malignancy.
Post-traumatic stress disorder (PTSD) and other trauma-related mental disorders in elite athletes: a narrative review
Authors: Cindy Miller Aron, Sydney Harvey, Brian Hainline, Mary E Hitchcock, Claudia L Reardon
Journal: British Journal of Sports Medicine (2019)

This narrative review examines post-traumatic stress disorder (PTSD) and other trauma-related disorders—mental health conditions with complex diagnosis and treatment considerations—in elite athletes. Athletes may exhibit greater rates of PTSD (up to 13%–25% in some athlete populations) and other trauma-related disorders relative to the general population. We describe common inciting events leading to symptoms of PTSD in elite athletes, including trauma incurred in sports participation through direct physical injury, secondary/witnessed traumatic events, or abusive dynamics within sports teams. Symptoms of PTSD may significantly impact athletes’ psychosocial and sport-related function through avoidance, hypervigilance and dissociative behaviours, which, in turn, may delay recovery from musculoskeletal injury. While PTSD may be common among elite athletes, recognition by providers who do not routinely screen for trauma-related disorders may be challenging because of the tendency of athletes to mask symptoms of PTSD and other trauma-related disorders. Early identification of athletes suffering from trauma-related symptoms, including those of acute stress disorder, may prevent progression to PTSD, while treatment of athletes already meeting criteria for PTSD may improve life functioning and sports performance outcomes. Current evidence supports increasing awareness of PTSD in athletes and use of screening tools to identify athletes who may benefit from trauma-informed medical or psychotherapeutic interventions.
Abstract 16597: Free-of-acrylamide SDS-based Tissue Clearing (FASTClear) for Three Dimensional Imaging of Collagen Content and Vascular Organization in Adult Ventricular Tissue
Authors: Filippo Perbellini, Alan K Liu, Samuel A Watson, Ifigeneia Bardi, Cesare M Terracciano
Journal: Circulation (2017)

Introduction: Cardiac fibrosis and new vessels formation are very important phenomena occurring during cardiac tissue remodelling. Three-dimensional (3D) collagen and vascular imaging of laboratory...
GENE-21. PEDIATRIC BRAIN TUMORS WITH FGFR1 MUTATIONS: A SERIES OF 14 CASES ASSESSING THE MORPHOLOGIC SPECTRUM AND ASSOCIATED GENETIC ALTERATIONS
Authors: Bonnie Cole, Christina Lockwood, Vera Paulson, Sarah Leary
Journal: Neuro-Oncology (2019)

BACKGROUND: Recurrent somatic mutations in FGFR1 have been identified in a subset of pediatric glial and glioneuronal tumors. Here we describe the morphologic spectrum and associated genetic alterations in a series of pediatric CNS tumors with activating FGFR1 mutations. METHODS: Genetic alterations in pediatric brain tumors were identified on a clinically validated next-generation sequencing platform that detects single nucleotide variants, insertions and deletions, and selected gene fusions in 262 cancer related genes. The clinical, radiologic, and histologic features of tumors with FGFR1 alterations were reviewed. RESULTS: Sequencing identified activating FGFR1 alterations in fourteen patients, including single nucleotide variants (n=7), tandem duplications (n=4), and FGFR1-TACC1 fusions (n=3). Six tumors with activating single nucleotide variants contained additional genetic alterations, including PTPN11 (n=2), NF1 (n=2), and TP53 (n=1). One contained two different FGFR1 point mutations. Tumors with fusions or tandem duplications lacked other genetic alterations. Tumors displayed varied clinical, radiologic, and histologic features. Age at diagnosis ranged from 3 to 17 years. Tumor locations included spinal cord, thalamus, suprasellar, cerebellum, frontal, parietal, and temporal lobes. Four tumors recurred after initial resection. Ten tumors were low grade, two were not graded, and two were high grade. Morphologic findings included oligodendroglial histology (n=7), infiltration (n=5), vascular proliferation (n=5), eosinophilic granular bodies (n=4) and one case with perivascular nuclear free zones suggestive of ependymoma morphology. CONCLUSIONS: Tumors with activated FGFR1 signaling demonstrate a wide spectrum of clinical, histologic and cooperating genetic features. It will be important to evaluate these factors as potential predictors of response to FGFR targeted therapy.
Post Hoc Bayesian Analyses
Authors: David Ferreira, Nicolas Meyer
Journal: JAMA (2019)

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GENE-08. THE MNP 2.0 STUDY: PROSPECTIVE INTEGRATION OF DNA METHYLATION PROFILING IN CNS TUMOR DIAGNOSTICS
Authors: Dominik Sturm, Felix Sahm, Felipe Andreiuolo, Agata Rode, Kerstin Grund, Steffen Hirsch, Stefan Rutkowski, Brigitte Bison, Marco Gessi, Monika Warmuth-Metz, Andreas von Deimling, Torsten Pietsch, Stefan M Pfister, David T W Jones
Journal: Neuro-Oncology (2019)

There is a broad variety of CNS tumor entities that can affect children and adolescents, associated with divergent clinical outcomes. We have recently proposed a DNA methylation-based classification to distinguish biologically distinct CNS tumor classes within and across neuropathological entities. The Molecular Neuropathology 2.0 study integrates genome-wide (epi-)genetic diagnostics with reference neuropathological assessment for newly-diagnosed pediatric CNS tumors in Germany. From 04/2015 to 09/2017, 607 patients with sufficient tissue were enrolled from 51 German centers. A reference neuropathological diagnosis according to the WHO classification was established for 95% of tumors and reflected the distribution of known histological CNS tumor entities in a pediatric population. Using 10 FFPE sections for DNA extraction, a DNA methylation-based molecular diagnosis was established in 95% of cases, of which 83% were assigned to a distinct CNS tumor methylation class. The remaining 17% did not match any of 82 currently established classes, but revealed evidence for novel rare molecular entities. Gene panel sequencing of >130 genes performed for 88% of patients with matched blood samples indicated diagnostically, prognostically, or therapeutically relevant somatic alterations in 47%. Germline DNA sequencing indicated potential predisposition syndromes in ~10% of patients, leading to human genetic counselling of affected families. Discrepant results by neuropathological and (epi-)genetic classification (~20%) were discussed in a weekly multi-disciplinary tumor board including reference neuroradiological evaluation. The majority of clinically-relevant discrepancies (67%) involved tumors neuropathologically diagnosed as high-grade gliomas, of which 25% were showed discrepant results. Clinical follow-up of enrolled patients through the German HIT study centers is ongoing. The MNP 2.0 study adds a valuable layer of information to clinical neuropathological diagnostics and has expanded to an international registry for molecular data analysis for pediatric CNS tumors. The results provide insight into tumors with divergent neuropathological and molecular classification with potential implications for patient management.
Exosomal tRNA-derived small RNA as a promising biomarker for cancer diagnosis
Authors: Lei Zhu, Jiao Li, Youling Gong, Qingbin Wu, Shuangyan Tan, Dan Sun, Xiaomin Xu, Yuanli Zuo, Yun Zhao, Yu-Quan Wei, Xia-Wei Wei, Yong Peng
Journal: Molecular Cancer (2019)

tRNA-derived small RNA (tsRNA) is a novel regulatory small non-coding RNA and participates in diverse physiological and pathological processes. However, the presence of tsRNAs in exosome and their diagnostic potential remain unclear. In this study, we took advantage of small RNA-seq technology to profile exosomal tsRNAs from cell culture medium and plasma, and found ubiquitous presence of tsRNAs in exosome. To explore the potential value of tsRNA for cancer diagnosis, we compared exosomal tsRNA levels between liver cancer patients and healthy donors, revealing that tsRNAs were dramatically increased in plasma exosomes of liver cancer patients. Importantly, patients with liver cancer exhibited significantly higher levels of four tsRNAs (tRNA-ValTAC-3, tRNA-GlyTCC-5, tRNA-ValAAC-5 and tRNA-GluCTC-5) in plasma exosome, demonstrating that plasma exosomal tsRNA could serve as a novel diagnostic biomarker. Taken together, our results not only expand non-coding RNA species in exosome, but also highlight the potential of tsRNAs as a promising biomarker for cancer diagnosis.
Gut Microbiota Regulation of T Cells During Inflammation and Autoimmunity
Authors: Eric M. Brown, Douglas J. Kenny, Ramnik J. Xavier
Journal: Annual Review of Immunology (2019)

The intestinal microbiota plays a crucial role in influencing the development of host immunity, and in turn the immune system also acts to regulate the microbiota through intestinal barrier maintenance and immune exclusion. Normally, these interactions are homeostatic, tightly controlled, and organized by both innate and adaptive immune responses. However, a combination of environmental exposures and genetic defects can result in a break in tolerance and intestinal homeostasis. The outcomes of these interactions at the mucosal interface have broad, systemic effects on host immunity and the development of chronic inflammatory or autoimmune disease. The underlying mechanisms and pathways the microbiota can utilize to regulate these diseases are just starting to emerge. Here, we discuss the recent evidence in this area describing the impact of microbiota-immune interactions during inflammation and autoimmunity, with a focus on barrier function and CD4+ T cell regulation.
MEDU-13. FUNCTIONAL CRISPR-CAS9 SCREEN IDENTIFIES DRUGGABLE DEPENDENCIES IN MYC-DRIVEN MEDULLOBLASTOMA
Authors: Bethany Veo, Susan Fosmire, Dong Wang, Krishna Madhavan, Angela Pierce, Sujatha Venkataraman, Rajeev Vibhakar
Journal: Neuro-Oncology (2019)

Myc-driven Medulloblastoma remains a major therapeutic challenge due to frequent metastasis and a poor 5-year survival rate. Myc overexpression results in transcriptional dysregulation, proliferation, and survival of malignant cells. However direct inhibition of Myc remains an obstacle to therapeutic interventions. To identify therapeutic targets in Myc amplified medulloblastoma we performed a CRISPR-Cas9 essentiality screen targeting 1140 genes annotated as the druggable genome. A strand guide library (4–10 Sg/gene) was transduced along with Cas9 into 3 different Myc amplified medulloblastoma cell lines in triplicate and DNA extracted and sequenced 18 days after transduction. Analysis of the resultant data revealed multiple gene networks as essential for Myc-medulloblastoma. The cyclin-dependent kinase, CDK7, was identified as a top candidate. CDK7 phosphorylates the c-terminal domain of RNA Pol II facilitating transcriptional initiation and elongation. We found that CDK7 expression is elevated in Myc-medulloblastoma patient samples and cell lines compared to other subgroups and normal pediatric cerebellum. Genetic depletion of CDK7 suppressed medulloblastoma cell clonogenicity in vitro. Recently a covalent inhibitor, THZ1, with high potency for CDK7 was identified and shown to efficiently reduce tumor growth in several pediatric cancers. To evaluate whether CDK7 is a therapeutic target in Myc-driven medulloblastoma we treated Myc-amplified medulloblastoma cells with THZ1. We observed a significant inhibition of clonogenic potential and induction of apoptosis in Myc-medulloblastoma cells in vitro. Using RNA-seq-based gene set enrichment analysis we show that THZ1 decreases c-Myc driven transcriptomic programs and enhanced inflammatory and apoptotic responses. Further studies established that chemical inhibition of CDK7 enhanced radiation sensitivity of Myc MB cells by potentiating DNA damage. Furthermore, CDK7 inhibition with THZ2 suppresses medulloblastoma tumor formation in vivo. Our studies are the first demonstration of CDK7 inhibition as a viable therapeutic strategy alone or in combination with radiation for Myc-amplified medulloblastoma.
Right subdiaphragmatic renal ectopia mimicking lung tumour
Authors: Ichiro Hirayama, Ryota Inokuchi, Masataka Fukue, Kent Doi
Journal: Thorax (2019)

A 76-year-old Japanese man was transported to our emergency room in summer with a coma and fever. His Glasgow coma scale score was E4V2M4, and his body temperature was 37.8°C. As part of a clinical workup, a pulmonary examination was performed, which revealed reduced breath sounds in the right basal hemithorax. Chest radiography revealed a round lesion on the right inferior lobe (figure 1). Lung tumour or abscess was suspected, but blood examination revealed renal dysfunction; thus, …
Abstract P100: Long-Term Exposures to Community Noise and Blood Pressure Levels in Chicago, Illinois
Authors: Jennifer C D'Souza, Jennifer Weuve, Robert D Brook, Denis A Evans, Joel D Kaufman, Sara D Adar
Journal: Circulation (2018)

Objectives: Over half the US population experiences noise levels above WHO recommendations yet little research within the US has examined the health effects of these exposures. Our objective is to investigate the associations between community noise and blood pressure in residents of Chicago. Methods: Participants were from two prospective cohort studies: the Multi Ethnic Study of Atherosclerosis (MESA) and the Chicago Health and Aging Project (CHAP). MESA is a multi-site study of persons aged 45-84 years and free of clinical cardiovascular disease. CHAP is an open cohort initiated to study chronic conditions of aging among persons aged ≥65 years. This analysis focuses on the 5,167 participants of these cohorts living in Chicago with an average of 2.5 (CHAP) and 4.5 (MESA) assessments per participant, for systolic (SBP) and diastolic (DBP) blood pressure between 1999-2011. In both cohorts, hypertension was defined as taking antihypertensive medication, SBP ≥140 or DBP ≥ 90 mmHg. We estimated noise at participant addresses using land use regression models weighted according to participants’ 5-year residential history before each exam. Among those taking antihypertensive medication, blood pressure was adjusted using multiple imputation. Associations between noise and blood were estimated using linear mixed models. A Cox proportional hazards model was used to estimate relative risk (RR) of incident hypertension. All models included calendar time, age, sex, race, income, education, neighborhood socioeconomic score, smoking, cohort, interaction between cohort and age, race, and gender, and NO x (a traffic-related air pollutant). Findings : At baseline, MESA participants were younger (63 vs 73 years) and more educated (36 vs. 3% with ≥graduate degree) than CHAP participants. MESA participants had higher noise levels (60 vs 56 dB) and lower blood pressures (e.g. SBP: 124 vs 135 mmHg) than CHAP participants. After adjusting for cohort and other confounders, we found that 10 dB higher residential noise levels were associated with 0.9 (95% CI: -0.2, 0.2; p=0.1) and 0.5 mmHg greater (95% CI: -0.1, 0.11; p=0.08) SBP and DBP, respectively. Similar associations were found within each cohort. Noise was not associated with incident hypertension overall (RR: 1.00; 95% CI: 0.8, 1.3, p=0.98) or within cohort. Conclusions: We found a suggestive association between noise and blood pressure levels, but no association with hypertension. This could be due to the lack of nighttime noise information, which has been shown to be more strongly associated with blood pressure outcomes than daytime levels or with the selection of healthy older participants.
How does your fat affect your liver when you drink?
Authors: Seonghwan Hwang, Bin Gao
Journal: Journal of Clinical Investigation (2019)

White adipose tissue (WAT) dysfunction is generally thought to promote the development of alcoholic liver disease (ALD) in alcoholics by releasing free fatty acids and inflammatory mediators. This explains, at least in part, the synergistic or additive effects of alcohol and obesity on liver disease progression. In this issue of the JCI, Shen et al. establish a previously unrecognized concept that brain alcohol sensing enhances thermogenesis of brown adipose tissue (BAT) through sympathetic nerve activation. BAT functions as hepatoprotective machinery to counteract the development of ALD, implying a therapeutic potential of BAT activity modulation for the treatment of ALD.