tbuckley/cabot-search huggingface dataset:
Spontaneous Coronary-Artery Dissection
Authors: Esther S.H. Kim
Journal: New England Journal of Medicine (2020)

Coronary-artery dissections account for less than 1% of acute myocardial infarctions, occur most commonly in women and most often between the ages of 47 and 53 years, may be associated with an underlying disorder such as fibromuscular dysplasia and other noncoronary arterial abnormalities, and are usually treated medically.
Long-term exposure to low-level air pollution and incidence of asthma: the ELAPSE project
Authors: Shuo Liu, Jeanette Therming Jørgensen, Petter Ljungman, Göran Pershagen, Tom Bellander, Karin Leander, Patrik K.E. Magnusson, Debora Rizzuto, Ulla A. Hvidtfeldt, Ole Raaschou-Nielsen, Kathrin Wolf, Barbara Hoffmann, Bert Brunekreef, Maciej Strak, Jie Chen, Amar Mehta, Richard W. Atkinson, Mariska Bauwelinck, Raphaëlle Varraso, Marie-Christine Boutron-Ruault, Jørgen Brandt, Giulia Cesaroni, Francesco Forastiere, Daniela Fecht, John Gulliver, Ole Hertel, Kees de Hoogh, Nicole A.H. Janssen, Klea Katsouyanni, Matthias Ketzel, Jochem O. Klompmaker, Gabriele Nagel, Bente Oftedal, Annette Peters, Anne Tjønneland, Sophia P. Rodopoulou, Evangelia Samoli, Doris Tove Kristoffersen, Torben Sigsgaard, Massimo Stafoggia, Danielle Vienneau, Gudrun Weinmayr, Gerard Hoek, Zorana Jovanovic Andersen
Journal: European Respiratory Journal (2020)

Background Long-term exposure to ambient air pollution has been linked to childhood-onset asthma, although evidence is still insufficient. Within the multicentre project Effects of Low-Level Air Pollution: A Study in Europe (ELAPSE), we examined the associations of long-term exposures to particulate matter with a diameter &lt;2.5 µm (PM 2.5 ), nitrogen dioxide (NO 2 ) and black carbon (BC) with asthma incidence in adults. Methods We pooled data from three cohorts in Denmark and Sweden with information on asthma hospital diagnoses. The average concentrations of air pollutants in 2010 were modelled by hybrid land-use regression models at participants’ baseline residential addresses. Associations of air pollution exposures with asthma incidence were explored with Cox proportional hazard models, adjusting for potential confounders. Results Of 98 326 participants, 1965 developed asthma during a mean follow-up of 16.6 years. We observed associations in fully adjusted models with hazard ratios of 1.22 (95% CI 1.04–1.43) per 5 μg·m −3 for PM 2.5 , 1.17 (95% CI 1.10–1.25) per 10 µg·m −3 for NO 2 and 1.15 (95% CI 1.08–1.23) per 0.5×10 −5 m −1 for BC. Hazard ratios were larger in cohort subsets with exposure levels below the European Union and US limit values and possibly World Health Organization guidelines for PM 2.5 and NO 2 . NO 2 and BC estimates remained unchanged in two-pollutant models with PM 2.5 , whereas PM 2.5 estimates were attenuated to unity. The concentration–response curves showed no evidence of a threshold. Conclusions Long-term exposure to air pollution, especially from fossil fuel combustion sources such as motorised traffic, was associated with adult-onset asthma, even at levels below the current limit values.
RARE-13. INFLAMMATORY MYOFIBROBLASTIC TUMOR MIMICKING DESMOPLASTIC INFANTILE GANGLIOGLIOMA (DIG) OF THE TEMPORAL LOBE
Authors: Ibrahim Abukhiran, Gino Bardi Lora, Patricia Kirby, Julia Shelton, Joel Shilyanski, Saul Wilson, Aaron Bossler, Yutaka Sato, Amani Bashir, Mariko Sato
Journal: Neuro-Oncology (2020)

Abstract Inflammatory myofibroblastic tumor (IMT) is a mesenchymal neoplasm composed of fascicles of myofibroblastic spindle cells in a background of prominent inflammatory infiltrate. It is categorized as ‘intermediate, rarely metastasizing’ in the World Health Organization classification of tumors of soft tissue and bone. We present a novel case of concurrent brain and lung tumor with diagnosis of TFG-ROS1-rearranged IMT in a 14 year old female patient, in which targeted next-generation sequencing became a powerful tool for detection of genomic alterations in both lung and brain tumors. At age 9, the patient’s lung mass was incidentally found and investigated for various infectious diseases with negative result. At age 14, she presented with seizure and was noted to have a stable size lung mass and a left temporal lobe tumor. The left temporal lobe tumor showed a desmoplastic spindle cell neoplasm involving the meninges and cerebral cortex and Desmoplastic Infantile Ganglioglioma (DIG) was considered one of differentials. Subsequently, her right lung mass was resected and showed a similar spindle cell neoplasm with a background of dense fibrosis and chronic inflammation, consistent with Inflammatory Myofibroblastic Tumor. Molecular microdissection revealed that both tumors shares TFG-ROS1 fusion which is associated with (t(3;6) (q12;q22)), thus it is strongly suggestive that two tumors arose from the same origin. No predisposition syndrome was identified.
Cardiopulmonary Impact of Particulate Air Pollution in High-Risk Populations
Authors: Jonathan D. Newman, Deepak L. Bhatt, Sanjay Rajagopalan, John R. Balmes, Michael Brauer, Patrick N. Breysse, Alison G.M. Brown, Mercedes R. Carnethon, Wayne E. Cascio, Gwen W. Collman, Lawrence J. Fine, Nadia N. Hansel, Adrian Hernandez, Judith S. Hochman, Michael Jerrett, Bonnie R. Joubert, Joel D. Kaufman, Ali O. Malik, George A. Mensah, David E. Newby, Jennifer L. Peel, Jeffrey Siegel, David Siscovick, Betsy L. Thompson, Junfeng Zhang, Robert D. Brook
Journal: Journal of the American College of Cardiology (2020)
Imaging temozolomide-induced changes in the myeloid glioma microenvironment
Authors: Claudia Foray, Silvia Valtorta, Cristina Barca, Alexandra Winkeler, Wolfgang Roll, Michael Müther, Stefan Wagner, Miranda L. Gardner, Sven Hermann, Michael Schäfers, Oliver Martin Grauer, Rosa Maria Moresco, Bastian Zinnhardt, Andreas H. Jacobs
Journal: Theranostics (2020)

Rationale: The heterogeneous nature of gliomas makes the development and application of novel treatments challenging. In particular, infiltrating myeloid cells play a role in tumor progression and therapy resistance. Hence, a detailed understanding of the dynamic interplay of tumor cells and immune cells in vivo is necessary. To investigate the complex interaction between tumor progression and therapy-induced changes in the myeloid immune component of the tumor microenvironment, we used a combination of [18F]FET (amino acid metabolism) and [18F]DPA-714 (TSPO, GAMMs, tumor cells, astrocytes, endothelial cells) PET/MRI together with immune-phenotyping. The aim of the study was to monitor temozolomide (TMZ) treatment response and therapy-induced changes in the inflammatory tumor microenvironment (TME). Methods: Eighteen NMRInu/nu mice orthotopically implanted with Gli36dEGFR cells underwent MRI and PET/CT scans before and after treatment with TMZ or DMSO (vehicle). Tumor-to-background (striatum) uptake ratios were calculated and areas of unique tracer uptake (FET vs. DPA) were determined using an atlas-based volumetric approach. Results: TMZ therapy significantly modified the spatial distribution and uptake of both tracers. [18F]FET uptake was significantly reduced after therapy (-53 ± 84%) accompanied by a significant decrease of tumor volume (-17 ± 6%). In contrast, a significant increase (61 ± 33%) of [18F]DPA-714 uptake was detected by TSPO imaging in specific areas of the tumor. Immunohistochemistry (IHC) validated the reduction in tumor volumes and further revealed the presence of reactive TSPO-expressing glioma-associated microglia/macrophages (GAMMs) in the TME. Conclusion: We confirm the efficiency of [18F]FET-PET for monitoring TMZ-treatment response and demonstrate that in vivo TSPO-PET performed with [18F]DPA-714 can be used to identify specific reactive areas of myeloid cell infiltration in the TME.
EXTH-12. INHIBITION OF CBP/p300 HISTONE ACETYLATION ACTIVITY ENHANCES TEMOZOLOMIDE ACTIVITY IN GLIOBLASTOMA PATIENT DERIVED XENOGRAFTS
Authors: Gaspar J Kitange, Danielle M Burgenske, Katrina K Bakken, Zeng Hu, Lihong He, Brett L Carlson, Jonathan Wilson, Archana Bommi-Reddy, Andy Conery, Jann Sarkaria
Journal: Neuro-Oncology (2020)

Abstract There is an unmet need to identify novel targets that can sensitize temozolomide (TMZ) or prevent resistance in GBM. We have demonstrated that retinoblastoma binding protein 4 (RBBP4) interacts with p300 to modulate expression of genes involved in homologous recombination (HR), including RAD51. In vitro, RBBP4- or p300-shRNA significantly sensitized TMZ in patient derived xenograft (PDX) GBM43 cells (relative fluorescence for 100µM TMZ treated control shNT cells was 0.89 ± 0.1 vs 0.47± 0.09 and 0.39 ± 0.01 for shRBBP4 and shp300, respectively (p&amp;lt; 0.01)). TMZ sensitization increased DNA damage signaling through phosphorylation of KAP1 (p-KAP1) and p-CHK1. Moreover, RBBP4- or p300-shRNA delayed the repair of TMZ-induced DSBs evidenced by persistent gH2AX. Silencing RBBP4 or p300 reduced acetylation of lysine 27 of histone H3 (H3K27Ac) within promoters of HR genes regulated by RBBP4/p300 complex. Thus, RBBP4/p300 complex controls gene expression through p300-mediated histone acetyltransferase (HAT) activity, suggesting that p300 inhibitors could sensitize GBM to TMZ. Accordingly, CBP/p300 inhibitor CPI1612 significantly suppressed H3K27Ac and HR repair genes, including RAD51. Moreover, CPI1612 sensitized TMZ in GBM43 (synergy score = 258), and TMZ/CPI1612 significantly suppressed growth of GBM39 PDX cells compared with either drug alone (confluence (%) was 92 ± 1.0 (DMSO), 76.5 ± 4.6 (10 µM TMZ), 62 ± 3.4 (10 nM CPI1612) and 21.9 ± 3.2 (TMZ 10 µM/CPI-CPI1612 10 nM). CPI1612 enhanced TMZ-induced DSBs with increased damage signaling through p- KAP1 and persistent gH2AX. Pharmacodynamics studies in GBM39 orthotopic mice models revealed that oral CPI1612 penetrates the brain and accumulate in tumor regions and suppresses H3K27Ac without significant weight loss in mice that received placebo, TMZ, CPI1612 alone or combined TMZ/CPI-1612, demonstrating good animal tolerability. Collectively, these findings are encouraging that CBP/p300 inhibition by the brain penetrant CPI-1612 is a potential strategy for enhancing the efficacy of TMZ in GBM.
SURG-22. PATTERN OF RECURRENCE ALONG EXTENT OF RESECTION IN PATIENTS WITH GLIOBLASTOMA, IDH-WILDTYPE: A RETROSPECTIVE STUDY
Authors: Jihwan Yoo, Seok-Gu Kang, Seon-Jin Yoon, Kyung Hwan Kim, Inho Jung, Woohyun Kim, Hong In Yoon, Se Hoon Kim, Ju Hyung Moon, Eui Hyun Kim, Jong Hee Chang
Journal: Neuro-Oncology (2020)

Abstract OBJECTIVE The concept for maximal resection of glioblastoma(GBM) is changing to resect not only contrast-enhanced (CE) tumor but non-contrast-enhanced (NCE) tumor. Although maximal resection is associated with longer survival, the pattern of recurrence in glioblastoma, isocitrate dehydrogenase (IDH)-wildtype patient is poorly understood. METHODS This retrospective, single-center study included 358 eligible patients through November 1, 2005 to December 31, 2018. Those patients were grouped along extent of resection (subtotal resection (STR, n=123), gross-total resection (GTR, n=194), and supratotal resection (SupTR, n=41)). The pattern of recurrence was classified based on the range of radiation treatment, into infield gross target volume (GTV), infield clinical target volume (CTV), marginal, outfield and CSF seeding. RESULTS Tumor recurrence was observed for each group as follows: STR group, 80.5%, GTR group, 75.3%, and SupTR group, 63.4%. Statistical differences in pattern of recurrence among each group were observed in infield GTV (STR group:75.8%, GTR group: 71.9%, and SupTR group: 42.3%, p=0.003) and Outfield (STR group:11.0%, GTR group: 21.2%, SupTR group: 34.6%, p=0.012) recurrence. The survival for SupTR group was significantly longer than that for the STR and GTR in terms of both overall survival (OS) and progression free survival (PFS) (OS, STR: 15.7m, GTR: 21.6m, SupTR: 44.7m, PFS, STR: 10.4m, GTR: 14.3m, SupTR: 35.5m) CONCLUSIONS As the extent of resection increased, local recurrence decreased and distant recurrence increased. During treatment of glioblastoma, expectation
UV Exposure and the Risk of Cutaneous Melanoma in Skin of Color
Authors: Fabiana C. P. S. Lopes, Marc G. Sleiman, Kate Sebastian, Roxanne Bogucka, Elizabeth A. Jacobs, Adewole S. Adamson
Journal: JAMA Dermatology (2020)

While current evidence supports UV exposure as an important risk factor for cutaneous melanoma in fair-skinned populations, the evidence for this association in skin of color is less certain.
Extracellular matrix scaffold crosslinked with vancomycin for multifunctional antibacterial bone infection therapy
Authors: Bin Fang, Pengcheng Qiu, Chen Xia, Dan Cai, Chenchen Zhao, Yan Chen, Haiping Wang, Shijie Liu, Haomai Cheng, Zhibin Tang, Bang Wang, Shunwu Fan, Xianfeng Lin
Journal: Biomaterials (2020)
PATH-13. PLEOMORPHIC XANTHOASTROCYTOMA INTEGRATED GENOMIC CHARACTERIZATION - WHAT HAVE WE LEARNED?
Authors: Rachael Vaubel, Valentina Zschernack, Alissa Caron, Dragana Milosevic, Robert Jenkins, Benjamin Kipp, Fausto Rodriguez, Quynh Tran, Brent Orr, Torsten Pietsch, Caterina Giannini
Journal: Neuro-Oncology (2020)

Abstract Pleomorphic xanthoastrocytoma (PXA) is a rare astrocytoma occurring predominantly in children and young adults. It is characterized histologically by large pleomorphic, spindled and lipidized cells with frequent eosinophilic granular bodies and pericellular reticulin deposition. BRAF p.V600E mutation and CKDN2A/B deletion are the most common genetic alterations. We report the integrated genomic characterization of a cohort of 67 patients (37 F, 30 M; median age 20.3 years (interquartile 13.4–32.9) with histologically defined PXA (52, 78%) or anaplastic PXA (A-PXA) (15, 22%), using genome-wide cytogenetic (ThermoFisher Oncoscan, n=67), methylation profiling (Illumina EPIC array, n=43), and targeted next generation sequencing (n=32). BRAF p.V600E mutation (n=51, 76.1%) and CDKN2A/B deletion (n=63; 94%) were the most frequent alterations. Of 16 BRAF p.V600E negative cases, 7 showed an alternative BRAF activating mutation (n=2), NF1 (n=3) mutation or ATG7-RAF1 fusion (n=2). Targeted TERT analysis found promoter mutations in 3 (of 58) cases, but TERT amplification was absent. Supervised and unsupervised methylation profiling against a comprehensive reference cohort demonstrated consensus grouping with the PXA class in 36 of 43 cases; while the minority grouped with a ganglioglioma class (n=3), with reactive brain or had no resolvable subgroup (n=4). Follow-up was available in 61 patients (91.0%) (median 63 months). Overall survival was significantly different between PXA and A-PXA (5-year:80.4% vs. 55.1%; p=0.001), but not progression-free survival (5-year:61.7% vs. 39.8%; p=0.128). Our data confirm the high frequency of MAP-K abnormalities and CDKN2A/B deletion in PXA. WHO grade remains a strong predictor of patient overall survival.
MDFI (MyoD family inhibitor), which regulates myogenic and Wnt/beta-catenin signaling pathways, is inactivated in human breast cancer by epigenetic gene silencing
Authors: Kazuaki Miyamoto, Masato Koseki, Yosuke Kawakami, Nobutaka Hatanaka, Wataru Kamiike, Toshikazu Ushijima, Kiyomi Taniyama
Journal: Cancer Research (2007)

1056  DNA methylation, a major epigenetic process, can affect every step in carcinogenesis, as well as genetic alterations. Aberrant methylation of CpG islands in promoter regions is known to be involved in the silencing of tumor-related genes. To identify CpG islands aberrantly methylated in human breast cancers, we performed a genome-wide search for aberrant methylation, using methylation-sensitive-representational difference analysis (MS-RDA). By MS-RDA, we identified MDFI (MyoD family inhibitor), which has been shown to negatively regulate myogenic regulatory factors and Wnt/beta-catenin signaling. By methylation-specific PCR, MDFI was methylated in 8 of the 8 breast cancer cell lines (100%), but not in normal human mammary epithelial cells (HMEC). MDFI expression was lost in the breast cancer cell lines that exhibited methylation, and its expression was restored by 5-aza-29-deoxycytidine, demonstrating its epigenetic silencing. In a series of 21 primary breast cancers, including early-stage cases,  MDFI was hypermethylated in 7 of 21 (33%) cases. Our results suggest that MDFI might play a role in human breast cancer development and progression.
Temporal Release of High-Sensitivity Cardiac Troponin T and I and Copeptin After Brief Induced Coronary Artery Balloon Occlusion in Humans
Authors: Ásthildur Árnadóttir, Sune Pedersen, Rasmus Bo Hasselbalch, Jens P. Goetze, Lennart J. Friis-Hansen, Anna-Marie Bloch-Münster, Jan Skov Jensen, Henning Bundgaard, Kasper Iversen
Journal: Circulation (2020)

Cardiac troponins (cTns) are the cornerstone of diagnosing acute myocardial infarction. There is limited knowledge on the duration of ischemia necessary to induce a measurable release of cTns or the very-early-release kinetics of cTns after an ischemic event. Copeptin may have a supplementary role in ruling out myocardial infarction early. We investigated the release of cTns and copeptin in the first hours after experimental balloon-induced ischemia in humans.Thirty-four patients (median age, 60 years [interquartile range, 51-64]; 15 men, 43%) with angiographically normal coronary arteries were randomly assigned into 4 groups with different durations of induced myocardial ischemia (0, 30, 60, 90 s). Ischemia was induced by inflating a balloon in the left anterior descending artery between the first and second diagonal branch. Blood was collected before balloon inflation (baseline) every 15 minutes for the first 3 hours, and every 30 minutes for the next 3 hours. The cTns were analyzed by 3 high-sensitivity (hs) cTn assays: hs-cTnT (Roche), hs-cTnI (Siemens), and hs-cTnI (Abbott). Copeptin was analyzed by a sandwich immunoluminometric assay.None of the patients had any complications. Increased cTn concentrations were detected by all 3 assays, and the magnitude of the increase was associated with the duration of ischemia. Increased hs-cTnI (Siemens) concentrations were first detectable 15 minutes after 90-s ischemia (median 43.7% increase) and increased more steeply and had a higher peak than the other assays. Copeptin levels did not significantly change. Using the cTnT, hs-cTnI (Siemens), and hs-cTnI (Abbott) concentrations at 0 and 180 minutes, 1 (11%), 0, and 0 patients from the 60-s ischemia group and 5 (63%), 2 (25%), and 1 (11%) from the 90-s ischemia group, respectively, fulfilled criteria for a biochemical myocardial infarction.This study is the first to report the early-release kinetics of cTn concentrations after different durations of experimental coronary balloon occlusion in humans. All assays detected a cTn increase after only 30 s of ischemia. hs-cTnI (Siemens) rose faster and reached a higher peak. Copeptin levels did not change significantly. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03203057.
Intronic tRNAs of mitochondrial origin regulate constitutive and alternative splicing
Authors: Simon M. Hoser, Anne Hoffmann, Andreas Meindl, Maximilian Gamper, Jörg Fallmann, Stephan H. Bernhart, Lisa Müller, Melanie Ploner, Matthias Misslinger, Leopold Kremser, Herbert Lindner, Stephan Geley, Heiner Schaal, Peter F. Stadler, Alexander Huettenhofer
Journal: Genome biology (2020)

Abstract Background The presence of nuclear mitochondrial DNA (numtDNA) has been reported within several nuclear genomes. Next to mitochondrial protein-coding genes, numtDNA sequences also encode for mitochondrial tRNA genes. However, the biological roles of numtDNA remain elusive. Results Employing in silico analysis, we identify 281 mitochondrial tRNA homologs in the human genome, which we term nimtRNAs (nuclear intronic mitochondrial-derived tRNAs), being contained within introns of 76 nuclear host genes. Despite base changes in nimtRNAs when compared to their mtRNA homologs, a canonical tRNA cloverleaf structure is maintained. To address potential functions of intronic nimtRNAs, we insert them into introns of constitutive and alternative splicing reporters and demonstrate that nimtRNAs promote pre-mRNA splicing, dependent on the number and positioning of nimtRNA genes and splice site recognition efficiency. A mutational analysis reveals that the nimtRNA cloverleaf structure is required for the observed splicing increase. Utilizing a CRISPR/Cas9 approach, we show that a partial deletion of a single endogenous nimtRNA Lys within intron 28 of the PPFIBP1 gene decreases inclusion of the downstream-located exon 29 of the PPFIBP1 mRNA. By employing a pull-down approach followed by mass spectrometry, a 3′-splice site-associated protein network is identified, including KHDRBS1, which we show directly interacts with nimtRNA Tyr by an electrophoretic mobility shift assay. Conclusions We propose that nimtRNAs, along with associated protein factors, can act as a novel class of intronic splicing regulatory elements in the human genome by participating in the regulation of splicing.
TAMI-16. BIOMATERIAL MATRICES TO STUDY GLIOBLASTOMA INVASION
Authors: Alireza Sohrabi, Elnaz Guivatchian, Weikun Xiao, Jesse Liang, Arshia Ehsanipour, Michael Condro, Harley Kornblum, Stephanie Seidlits
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Glioblastoma (GBM) is a highly infiltrative and lethal brain cancer. Previous studies have suggested that GBM tumors are stiffer than healthy brain tissues. We posit that local changes in the mechanical microenvironment near the tumor/tissue interface promote migration of GBM cells away from primary tumors. These studies seek to improve our understanding of how mechanical changes to the microenvironment of GBM tumors and surrounding brain tissue drive GBM progression using an in vitro, 3D model incorporating patient-derived primary GBM cells and a brain matrix-mimetic scaffold in which mechanical modulus can be varied. METHODS GBM xenografts were explanted and vibratome sectioning of fresh tissues for AFM. Hydrogels were fabricated by crosslinking thiolated hyaluronic acid (HA-SH), 8-arm polyethylene glycol (PEG)-norbornene and 4-arm PEG-thiol in the presence of photoinitiator UV light. Mechanical properties were measured using both rheology and AFM. Patient-derived GBM cells were maintained in 3D culture and migration monitored. RESULTS AND DISCUSSION AFM measurements of xenograft and brain tissue suggest that modulus is highest near the tumor center, decreases near the tumor border and is lowest in surrounding brain tissue. Hydrogels were tuned to match in vivo mechanics by altering total thiol content while matrix composition and effective pore size remained constant. GBM cells invaded readily in soft hydrogels, but were not able to migrate in stiff hydrogels. When cultured in platforms including defined regions in which moduli were varied, GBM cells seeded in stiffer regions readily migrated towards softer regions, while cells seeded into a softer matrix did not migrate to stiffer regions. Mechanical properties of the microenvironment appear to have marked effects on tumor cell migration and may drive GBM migration into surrounding tissues. In the long-term, we expect these studies to inform development of new therapeutics targeting GBM tumor invasion through improved understanding of underlying mechanisms.