tbuckley/cabot-search huggingface dataset:
Shared DNA methylation signatures in childhood allergy: The MeDALL study
Authors: Cheng-Jian Xu, Olena Gruzieva, Cancan Qi, Ana Esplugues, Ulrike Gehring, Anna Bergström, Dan Mason, Leda Chatzi, Daniela Porta, Karin C. Lodrup Carlsen, Nour Baïz, Anne-Marie Madore, Harri Alenius, Bianca van Rijkom, Soesma A. Jankipersadsing, Pieter van der Vlies, Inger Kull, Marianne van Hage, Mariona Bustamante, Aitana Lertxundi, Matias Torrent, Gillian Santorelli, Maria Pia Fantini, Vegard Hovland, Giancarlo Pesce, Nanna Fyhrquist, Tiina Laatikainen, Martijn C. Nawijn, Yang Li, Cisca Wijmenga, Mihai G. Netea, Jean Bousquet, Josep M. Anto, Catherine Laprise, Tari Haahtela, Isabella Annesi-Maesano, Kai-Håkon Carlsen, Davide Gori, Manolis Kogevinas, John Wright, Cilla Söderhäll, Judith M. Vonk, Jordi Sunyer, Erik Melén, Gerard H. Koppelman
Journal: Journal of Allergy and Clinical Immunology (2020)

Differential DNA methylation associated with allergy might provide novel insights into the shared or unique etiology of asthma, rhinitis, and eczema.We sought to identify DNA methylation profiles associated with childhood allergy.Within the European Mechanisms of the Development of Allergy (MeDALL) consortium, we performed an epigenome-wide association study of whole blood DNA methylation by using a cross-sectional design. Allergy was defined as having symptoms from at least 1 allergic disease (asthma, rhinitis, or eczema) and positive serum-specific IgE to common aeroallergens. The discovery study included 219 case patients and 417 controls at age 4 years and 228 case patients and 593 controls at age 8 years from 3 birth cohorts, with replication analyses in 325 case patients and 1111 controls. We performed additional analyses on 21 replicated sites in 785 case patients and 2124 controls by allergic symptoms only from 8 cohorts, 3 of which were not previously included in analyses.We identified 80 differentially methylated CpG sites that showed a 1% to 3% methylation difference in the discovery phase, of which 21 (including 5 novel CpG sites) passed genome-wide significance after meta-analysis. All 21 CpG sites were also significantly differentially methylated with allergic symptoms and shared between asthma, rhinitis, and eczema. The 21 CpG sites mapped to relevant genes, including ACOT7, LMAN3, and CLDN23. All 21 CpG sties were differently methylated in asthma in isolated eosinophils, and 10 were replicated in respiratory epithelium.Reduced whole blood DNA methylation at 21 CpG sites was significantly associated with childhood allergy. The findings provide novel insights into the shared molecular mechanisms underlying asthma, rhinitis, and eczema.
Racial Differences in Statewide Suicide Mortality Trends in Maryland During the Coronavirus Disease 2019 (COVID-19) Pandemic
Authors: Michael Johnathan Charles Bray, Nicholas Omid Daneshvari, Indu Radhakrishnan, Janel Cubbage, Michael Eagle, Pamela Southall, Paul Sasha Nestadt
Journal: JAMA Psychiatry (2020)

This cross-sectional study analyzes trends in suicidality by race/ethnicity during the coronavirus disease 2019 (COVID-19) pandemic.
Are mesenchymal stem cells and derived extracellular vesicles valuable to halt the COVID-19 inflammatory cascade? Current evidence and future perspectives
Authors: Marta Monguió-Tortajada, Antoni Bayes-Genis, Antoni Rosell, Santiago Roura
Journal: Thorax (2020)

Clinical management of patients suffering from COVID-19 includes infection prevention, control measures and supportive care, including supplemental oxygen and mechanical ventilatory support.1 2 If not expertly and individually managed with consideration for vasocentric features,3 20% of COVID-19 patients who exhibit acute respiratory distress syndrome (ARDS; 14.8% of hospitalised patients4) may eventually progress to multiorgan failure and death, even when not of advanced age or predisposed by pre-existing comorbidities or chronic diseases.5 In these patients, infection by SARS-CoV-2 activates both the innate and adaptive immune responses, provoking the production of large amounts of pro-inflammatory cytokines and chemokines, resulting in a clinical presentation (ie, unremitting high fever, lymphadenopathy, hepatosplenomegaly, cytopenia, hyperferritinaemia, central nervous system abnormalities, hypoalbuminaemia and capillary leak) similar to other systemic, uncontrolled cytokine release syndromes (CRS)(figure 1).6 7 Thus, at present, management of the potential inflammatory complications of COVID-19 by using appropriate immunosuppressive and immunomodulatory drugs is being explored.8 



Figure 1 
COVID-19 pathophysiology, potential disease mechanisms and treatment options. ACS, acute coronary syndrome; ARDS, acute respiratory distress syndrome; CRP, C reactive protein; DAMPs, danger-associated molecular patterns; IL, interleukin; LDH, lactate dehydrogenase; MSC, mesenchymal stem cell; MSC-EV, MSC-derived extracellular vesicles; PAMPs, pathogen-associated molecular patterns; TNFα: tumour necrosis factor alpha.



To date, a variety of novel and repurposed drugs with multiple pharmacological effects and therapeutic efficacies have been included in the potential armamentarium against COVID-19.9 10 For instance, among the antivirals preliminary tested, remdesivir has showing the best efficacy, with significant improvements in shortening the time to recovery and evidence of lower respiratory tract infection.11 It was issued an emergency use authorisation on 1 May 2020 for the treatment of COVID-19 patients hospitalised with severe disease by the Food and Drug Administration (FDA), and on 3 July 2020, it became the first treatment against …
BIOM-54. A RAPID GENOTYPING PANEL FOR SENSITIVE AND SPECIFIC SEGREGATION OF CNS PATHOLOGIES
Authors: Mihir Gupta, Evan Burns, Nicholas Georgantas, Julia Thierauf, Naema Nayyar, Ryan Burns, Jose Velarde, Priscilla Brastianos, Jorg Dietrich, Hetal Marble, Jochen Lennerz, Javier Romero, Kensuke Tateishi, Daniel Cahill, Ganesh Shankar
Journal: Neuro-Oncology (2020)

Abstract Primary central nervous system lymphoma (PCNSL) remains challenging to diagnose due to nonspecific clinical and radiologic features and low diagnostic yields of cerebrospinal fluid (CSF) studies. We sought to characterize the diagnostic approach of suspected PCNSL, in order to improve clinical workflow. We first reviewed 1,007 new brain lesions of unknown etiology that included PCNSL in the radiologic differential diagnosis. The most common final diagnoses included high-grade glioma (28.2%) and PCNSL (14.6%). Diagnostic biopsies were frequently performed for high-grade glioma (100%) and PCNSL (94.4%), while CSF was frequently sampled for PCNSL (78.7%). We next identified 159 patients with an established new diagnosis of PCNSL. CSF studies were non-diagnostic in 86.7% of cases, whereas biopsy was positive in 93%. However, intraoperative histopathology was inconclusive for PNCSL in 54.5%, likely contributing to 22% of patients undergoing surgical resection. These challenges resulted in 12 days median time to treatment initiation, and readmission for further workup or treatment initiation in 27% of patients. These results indicated the need for a rapid, sensitive and specific platform to segregate PCNSL and glioma using CSF and tissue samples. We developed a qPCR-based assay to genotype the MYD88 L265P hotspot mutation from CSF and plasma within 80 minutes of sample acquisition. Results were concordant with orthogonal DNA sequencing in extracts from 87 archived specimens, with detection limits of 490pg of input genomic DNA and 0.15% mutant allele frequency. When performed simultaneously with assays for TERT promoter, IDH1/2, H3F3A and BRAF point mutations, the resulting panel accurately segregated PCNSL and adult diffuse glioma molecular diagnoses in 87 archived specimens and 19 prospective liquid biopsies, including cases of lymphoma and glioma. We propose that inclusion of targeted analysis of these mutually exclusive recurrent molecular alterations characterizing gliomas and PCNSL will facilitate rapid, sensitive diagnosis from solid and liquid biopsies.
Navigating the Jargon of Molecular Testing in Non-Hodgkin Lymphoma
Authors: Eric D. Hsi
Journal: Journal of the National Comprehensive Cancer Network (2020)

The many different subtypes of non-Hodgkin lymphoma can be distinguished by histopathology, immunophenotype, and underlying genetic abnormalities. Molecular testing is routinely used by pathologists for diagnosis and prognosis, and to aid in guiding therapy selection (targeted or nontargeted). The different tools and techniques used for molecular testing are based on abnormality type and tissue available.
TAMI-56. HYPOXIA-DRIVEN NECROSIS DRIVES DYNAMIC TUMOR PROGRESSION IN GLIOBLASTOMA
Authors: Steven Markwell, Cheryl Olson, James Ross, Felix Nunez-Santana, Daniel Brat
Journal: Neuro-Oncology (2020)

Abstract The onset of necrosis correlates with aggressive malignant progression in solid tumors. Whether necrosis arises from or promotes accelerated tumor proliferation and progression remains unknown, primarily due to inadequate models systems that fail to induce or capture these dynamic changes as they develop. In glioblastoma (GBM; WHO grade IV), the most malignant primary brain tumor, vascular pathology and central necrosis precedes rapid, radial expansion resulting in patient mortality. While genetic alterations in GBM have been highly characterized, biological adaptations arising from sustained hypoxia/anoxia require further mechanistic investigation. This sustained nutrient deprivation leads to necrosis which dramatically changes the tumor microenvironment (TME). To reveal the dynamic temporal and spatial changes promoting expansive progression, we are generating mouse models that more appropriately capture events found in human gliomas, accounting for unique microenvironmental stressors often lacking in GBM animal models, specifically central necrosis. Combining hypoxia-induced focal necrosis within high grade gliomas with intravital microscopy captures TME restructuring to understand its impact on glioma progression. Our studies use both genetically characterized patient-derived orthotopic GBM xenografts, alongside an immunocompetent RCAS/tv-a model, to determine how antagonizing these processes impacts disease progression and outcomes across multiple GBM subtypes. Complementary to this, we are investigating how increasing hypoxia and necrosis-driven signaling events promotes tumor-associated macrophages (TAMs) influx and reprogramming during glioma progression. Our preliminary data indicate substantial differences pre- and post-necrosis regarding TAM enrichment, immunosuppressive phenotypic conversion and their biological impact, however these mechanisms have not yet been elucidated. Our models capture glioma growth dynamics, reactive neuroinflammation and therapeutic resistance, facilitating innovative pre-clinical interventions to improve patient outcome.
Abstract P406: Atrial Fibrillation (AF) and Stroke Symptoms in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study
Authors: Meghan Reading Turchioe, Elsayed Z Soliman, Hooman Kamel, Mary Cushman, Orysya Soroka, Ruth M Masterson Creber, Monika M Safford
Journal: Circulation (2020)

Background: AF-related thromboembolism increases risk of stroke. Stroke symptoms in the absence of a stroke diagnosis may represent “whispering strokes,” but their association with AF has not been well explored. Objective: To examine cross-sectionally the association between AF and self-reported stroke symptoms in the absence of a stroke diagnosis, and whether associations differ by anticoagulant use. Methods: We examined data from 27,072 REGARDS participants without a history of stroke or transient ischemic attack (TIA) at baseline. The presence, type, and cumulative number of self-reported stroke symptoms were compared between participants with and without self-reported history or ECG evidence of AF. Logistic regression models examined associations between AF and stroke symptoms, adjusting for sociodemographic, socioeconomic, stroke risk factors, and geographic characteristics. To investigate the possibility of stroke symptoms representing embolic stroke, results were stratified by anticoagulant or antiplatelet agent use. Results: The mean age of the sample was 64.4(±9.4), 55.3% were women, and 59.2% were black; 2,124 had evidence of AF. Twenty-nine percent of adults with AF and 17% of those without AF reported at least one stroke symptom. Compared to those without AF, the odds ratio (OR) of any stroke symptom was 2.21 (95% CI 1.88-2.58) among adults with AF not using an anticoagulant or antiplatelet agent and 1.93 (95% CI 1.62-2.30) for those on Aspirin or Plavix only ( Table 1 ). Associations were non-significant for those using Warfarin. Similar patterns were observed by each type and cumulative number of stroke symptoms. Conclusion: The association between AF and stroke symptoms suggests that some stroke symptoms in the absence of a stroke diagnosis may represent sub-clinical or “whispering strokes.” The attenuation of this association with Warfarin use but not antiplatelet agents supports the possibility that stroke symptoms in the absence of a stroke diagnosis represent undiagnosed embolic stroke.
ATRT-11. PREVALENCE OF GERMLINE VARIANTS IN SMARCB1 INCLUDING SOMATIC MOSAICISM IN AT/RT AND OTHER RHABDOID TUMORS
Authors: Ryota Shirai, Tomoo Osumi, Keita Terashima, Chikako Kiyotani, Meri Uchiyama, Shinichi Tsujimoto, Masanori Yoshida, Kaoru Yoshida, Toru Uchiyama, Daisuke Tomizawa, Yoko Shioda, Masahiro Sekiguchi, Kenichiro Watanabe, Dai Keino, Hitomi Ueno-Yokohata, Kentaro Ohki, Junko Takita, Shuichi Ito, Takao Deguchi, Nobutaka Kiyokawa, Hideki Ogiwara, Tomoro Hishiki, Seishi Ogawa, Hajime Okita, Kimikazu Matsumoto, Takako Yoshioka, Motohiro Kato
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Genetic hallmark of atypical teratoid/rhabdoid tumor (AT/RT) is loss-of-function variants or deletions in SMARCB1 gene on 22q11.2 chromosome, which is common to extracranial malignant rhabdoid tumors (MRT). Previous studies demonstrated that approximately one-thirds of AT/RT and extracranial MRT patients harbored germline SMARCB1 variants as the rhabdoid tumor predisposing syndrome. We studied herein intensive analysis of the SMARCB1 gene in AT/RT and extracranial MRT patients focusing on prevalence of germline genetic variants. PROCEDURE: In total, 16 patients were included. Both tumor-derived DNA and germline DNA were obtained from all patients. First, screening for SMARCB1 alterations in the tumor specimens was done by direct sequencing, ddPCR and SNP array analysis. Then, analysis of germline DNA samples focusing on the genomic abnormalities detected in the paired tumors in each case was performed. RESULTS In eight of 16 cases (50%), genomic alterations observed in the tumor-derived DNA were also detected in the germline DNA. It is worth noting that three patients had germline mosaicism. Two of three patients had mosaic deletion, including SMARCB1 region, and the average copy number of the deleted region in the SMARCB1 gene in the germline was 1.60 and 1.76. For another patient, the fraction of SMARCB1 variants in normal cells was as low as 1.7%. CONCLUSIONS Approximately half the MRT cases in this study had SMARCB1 germline alterations. Considering the presence of low-frequency mosaicisms which conventional methods might overlook, inherited germline variants in predisposition genes are more important than previously assumed for the pathogenesis of pediatric cancers.
SURG-18. THE IMPACT OF NEUROLOGIC IMPAIRMENTS ON THE RELATIVE BENEFIT OF MAXIMAL EXTENT OF RESECTION IN NEWLY DIAGNOSED IDH-WILD TYPE GLIOBLASTOMA
Authors: Shawn Hervey-Jumper, Annette Molinaro, Cecilia Dalle Ore, Desmond Brown, Yalan Zhang, Ramin Morshed, Marisa LaFontaine, Simon Ammanuel, Anny Shai, Gayathri Warrier, Terri Rice, Yi Lin, Jason Crane, Joanna Phillips, Margaret Wrensch, John Wiencke, Nancy Ann Oberheim Bush, Jennie Taylor, Nicholas Butowski, Jennifer Clarke, Susan Chang, Manish Aghi, Philip Theodosopoulos, Mitchel Berger
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND The prognostic importance of maximal resection of contrast enhancing and non-contrast enhancing disease has been established. Nonetheless, glioblastomas exist within the framework of complex neural circuitry serving cognition, movement, and behavior consequential leading to neurological impairments. The prognostic importance of neurological impairments on survival remains poorly understood. METHODS This is a retrospective, single cohort study from UCSF including 316 eligible patients diagnosed over 20 years with 9.6 years of follow-up. All patients underwent surgical resection for newly diagnosed glioblastoma for whom survival, molecular, preoperative and postoperative MRI images, and clinical data were available. All patients had chemoradiation treated IDH-wild-type glioblastoma with available preoperative and 1-month post-surgical resection neurological outcomes. We employed survival models and recursive partitioning (RPA) to investigate multivariate relationships of overall survival (OS). RESULTS Preoperative neurological impairments were present in 75.6% (n= 239) and new post resection impairments were identified in 37.3% (n=117). Univariate analysis confirmed that new postoperative cognitive impairment [HR 7.91, 95% CI 2.47-25.33] and hemiplegia [HR 3.38, 95% CI 0.83-13.67] (not hemiparesis) impact OS. Risk stratified grouping by RPA demonstrated that gross total resection of contrast enhancing tumor in patients with no new postoperative neurological impairments confers the longest OS (median OS 27.1 months 95%CI 21.5-33.7). Patients with any residual tumor volume after surgery but no new neurological deficits experience a similar survival to younger patients (under 65) with 1 or more new postoperative neurological deficits (median OS 16.6 months 95%CI 15.2-19.2). Shortest OS is identified in patients with any volume of residual tumor plus 1 or more new postoperative neurological deficits and age over 65 (median OS 11.4 months, 95%CI 9.3-13.5). CONCLUSIONS This study confirms that new postoperative neurological impairments impact overall survival in patients with chemoradiation treated IDH-wild-type glioblastoma.
Abstract 449: Cost Analysis of a Contextualized Cardiopulmonary Resuscitation Training for Orderlies Participating in In-Hospital Cardiac Arrests
Authors: Christian Vincelette, Catalina Sokoloff, François-Martin Carrier, Pierre Desaulniers, Nathalie Nadon
Journal: Circulation (2019)

Introduction: Basic life support (BLS) training poses challenges for healthcare organizations. It requires numerous resources, complicates scheduling and is expensive. Orderlies typically provide chest compressions during in-hospital cardiac arrests, and are therefore recertified in cardiopulmonary resuscitation (CPR) every 2 years. However, such time lapse between CPR certifications induces skills decay. Hypothesis: Based on the American Heart Association statement on resuscitation education science published in 2018, we aimed to train all orderlies (n= 900) in less than 1 year, in order to reach proficiency in chest compressions, at a fraction of the cost. Method: A shortened (20 minutes), and adapted version of CPR training was created. This training specifically addressed high quality chest compressions, the cornerstone skill relevant to the scope of practice of orderlies in CPR. It was delivered in situ during working hours, as a mass training program that spanned over a period of 1 week. The training was provided through Mastery Learning and Deliberate Practice with direct feedback and live coaching. The cost analysis aimed to compare the costs of the new approach as compared to BLS training. Results: With this innovative approach, 30 trainers were able to train 600 employees in only 5 days. Preliminary results suggest most were able to perform high quality compressions after training. The total cost of the activity was 2 347.21 $CAD which represents 3% (2 347 of 76 200) of what it would take to train 600 people in BLS (76 200$CAD), and 13% (2 347 of 18 000) of the budget planned per year for orderlies’ BLS training at our institution (~18 000$CAD). The individual cost of our initiative was 4.13$CAD per employee. This method allowed to train employees around the clock, to cover all working shifts, thereafter preventing the removal of employees from the rolling schedule. Also, this solution allows us to repeat the experience another time this year, to train all orderlies. Conclusions: Although further research is needed to assess if skills are sustained over time and comparable based on performance outcomes, our inquiry is an innovative, sustainable and cost-effective way to train specific CPR skills to large groups.
CTIM-29. CRUCIAL APPLICATION OF SINGLE CELL GENE EXPRESSION FOR MONITORING CHANGES IN GLIOBLASTOMA PATIENTS WITH SUSTAINED RADIOGRAPHIC RESPONSE TO CMV pp65-LAMP RNA-PULSED DENDRITIC CELL-BASED VACCINES
Authors: Oleg Yegorov, Changlin Yang, Anjelika Dechkovskaia, Maryam Rahman, Ashley Ghiaseddin, Duane Mitchell
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND The application of single cell sequencing as a novel immune monitoring platform can be used to identify the molecular mechanisms of immune response to dendritic cell- based vaccines, trace the cell types and states involved, and uncover novel biomarkers for immunotherapy. We applied single-cell RNA Seq analysis of longitudinal peripheral blood mononuclear cells (PBMCs) in patients with newly-diagnosed GBM enrolled on the ATTAC II clinical trial (FDA IND BB-16530; Clinicaltrials.gov # NCT02465268) who experienced a sustained radiographic response to autologous CMV pp65-LAMP RNA-pulsed DC vaccines plus GM-CSF and tetanus-diphtheria booster administered during adjuvant cycles of dose-intensified temozolomide. METHODS We constructed 5’ gene expression libraries and T cell receptor enriched libraries for 10x Genomics single-cell 5’ and VDJ sequencing, generated from PBMCs collected prior to and during patient immunization using dendritic cells loaded with messenger ribonucleic acid encoding the human cytomegalovirus (CMV) matrix protein pp65 conjugated with the lysosomal associated membrane protein (LAMP) sequence. RESULTS Overall, we sequenced a total of 189,808 single-cell transcriptomes from 5 patients. We leveraged these transcriptome-wide features to distinguish 15 peripheral immune cell subtypes in tested PBMCs. Analysis revealed dynamic changes in immune cell subsets over the course of first three vaccines, including increases in cytotoxic CD8 T cells, CD4 T cells, and NK cell subsets. Increased markers of T cell activation were observed during vaccination. Surprisingly, we observed a very high-level frequency of natural killer T (NKT) cells in the patient with a complete durable response compared to other patients. After three DC vaccines, the level of NKT cells in PBMC of this patient increased up to 10%. CONCLUSIONS These results emphasize the importance of subset specific profiling to achieve higher resolution in monitoring immune responses compared with bulk expression profiling in patients receiving immunotherapeutic treatment.