tbuckley/cabot-search huggingface dataset:
PATH-17. NOVEL DUAL HISTONE 3 K27M AND G34R POINT MUTATIONS IN A MIDLINE GLIOMA
Authors: Peter Pan, Tejus Bale, Alexandra Miller, Marc Ladanyi, Marc Rosenblum, Aya Haggiagi
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Histone H3 alterations due to mutations on H3F3A and HIST1H3B genes, have in recent years been associated with distinct entities and tumor locations within the context of infiltrative gliomas. H3K27M is associated with a midline location and is included in the WHO 2016 as the diffuse midline glioma H3K27M-mutant, a specific diagnostic entity. H3G34R, thought to be a mutually exclusive alteration, is less common but has been associated with a cerebral hemispheric location. We report the first case to our knowledge with both of these alterations in the same tumor. METHODS Clinical and pathologic records of the patient were reviewed and presented. RESULTS A 39-year-old man presented with acute right face, arm, and leg numbness and mild weakness; examination was notable for right lower motor neuron facial nerve palsy and numbness, along with numbness and subtle slowing of rapid alternating movements in the left arm and leg. A non-enhancing left thalamic mass was identified and stereotactically biopsied. Infiltrative glial neoplasm with moderately-increased cellularity was seen, with ovoid cells, enlarged nuclei, apoptotic bodies, and mitotic figures. No necrosis or microvascular proliferation seen. Immunostain was positive for H3K27M. O6-methylguanine-methyltransferase (MGMT) promoter was not methylated. Next-generation sequencing showed dual in cis H3 point mutations in K27M (HIST1H3B c.83A &amp;gt;T) and G34R (HIST1H3B c.103G &amp;gt;C). Additional alterations were noted in NF1, PIK3CA, ATRX, FGFR3, and NSD1. Isocitrate dehydrogenase (IDH1/2) mutations were not identified. CONCLUSION This case of a young man with a midline glioma is novel for carrying both H3K27M and H3G34R alterations and indicates these alterations are not mutually exclusive. The interaction seen here suggests H3K27M dominance for a midline phenotype.
EPID-23. A SYSTEMIC REVIEW OF CENTRAL NERVOUS SYSTEM TUMORS IN AFRICA FROM 1960 – 2017 AND THE NEED FOR A CENTRAL BRAIN TUMOR REGISTRY IN AFRICA
Authors: Marilyn Mbi Feh, Ankita Brahmaroutu, Kristopher Lyon, Ekokobe Fonkem
Journal: Neuro-Oncology (2020)

Abstract PURPOSE Central Nervous System (CNS) tumors pose a substantial health problem. Although data on specific time periods and regions of Africa has been previously reported, no study has yet to provide a systemic review on the frequency of CNS tumors for the entire continent of Africa. This study aims to analyze the frequency of CNS tumors in Africa from 1960 to 2017. METHODS A comprehensive literature search on CNS tumors in Africa was performed using multiple online scientific databases. The following keywords were queried in combination with the phrase “CNS tumors in Africa”: incidence, frequency, epidemiology, prevalence, brain, and cancer. A total of 26 articles met the inclusion criteria. Each selected article reported incidence and mortality rates from different regions of Africa between 1960 to 2017. SPSS21 statistical software was used to analyze the data. RESULTS Nigeria, Egypt, and Uganda were found to have the highest incidence of CNS tumors in Africa. Total incidence was 5902, the majority were males, 3190 with mean rate 122.67 (95% CI: 29.27, 216.07) compared to females, 2501 with a mean rate of 96.19 (95% CI: 26.24, 166.15). The most common CNS tumors found were astrocytoma (24.70%), meningioma (22.22%), pituitary adenoma (8.4%), medulloblastoma (4.26%), craniopharyngioma (4.07%), and other not specified (25.17%). CONCLUSION Given the large population of Africa, the reported total incidence may be underestimated when compared to other continents due to the lack of a central brain tumor registry in Africa. Comprehensive knowledge of CNS tumors in Africa is critical to research and the entire healthcare system.
Substitution of Fractionated for Unfractionated Heparin During High-Risk Percutaneous Coronary Intervention: Has the Problem Been Solved?⁎⁎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: Mark J. Eisenberg
Journal: Journal of the American College of Cardiology (2007)
STEM-12. ZIKA VIRUS TARGETS GLIOBLASTOMA STEM CELLS THROUGH A SOX2-INTEGRIN α vβ 5 AXIS
Authors: Clark Chen, Sanjay Dhawan, Zhe Zhu, Pinar Mesci, Jeremy Rich
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Oncolytic virus hold great promise as a platform for glioblastoma therapeutic development. Zika virus (ZIKV) is an oncolytic virus with exquisite selectivity for infecting and killing glioblastoma stem cells (GSCs). Here, we delineate the molecular determinant of this selectivity. METHODS cell-based glioblastoma models, glioblastoma organoid assays, in vivo murine glioblastoma models, ZIKV infectivity assays, gene silencing, ChIP-seq studies. RESULTS In independent models, ZIKV preferentially infected and lysed SOX2+ GSCs. Silencing of SOX2 expression attenuated this preferential infectivity. Of note, ZIKV infection of GSCs was independent of AXL, its putative receptor in normal brain. ChIP-seq experiments revealed that SOX2 bound within the ITGAV locus (encoding the integrin av subunit), and this binding was associated with accumulation of the active chromatin mark H3K27ac. Silencing of SOX2 suppressed ITGAV expression as well as ZIKV infectivity against GSCs, indicating that integrin is required for ZIKV infection. Of integrin b units, only silencing of integrin b5 prevented the killing of GSCs by ZIKV infection, suggesting ZIKV infection required the avb5 integrin. Supporting this hypothesis, blockade of the avb5 integrin substantially reduced ZIKV infection of GSCs in glioblastoma organoid assays and in clinical glioblastoma specimens. Sox2 expression additionally suppress GSC expression of all members of the interferon-stimulated genes (ISG family), thereby suppressing innate anti-viral response to facilitate ZIKV infection. CONCLUSIONS Collectively, our results reveal that ZIKV infection of GSCs is mediated by integrin α vβ 5 leading to SOX2 expression which negatively regulates antiviral immunity thereby facilitating ZIKV infection.
IMMU-05. CSF METABOLOMICS AS A PREDICTOR OF SURVIVAL IN PATIENTS WITH BRAIN METASTASIS RECEIVING IMMUNOTHERAPY
Authors: Sasmit Sarangi, Devin Zhang, Anita Dong, Edwin Lok, Eric Wong
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Checkpoint inhibitors show a positive intracranial response in around 20–50% of patients with metastatic melanoma and non-small cell lung cancer (NSCLC). There is a current paucity of biomarkers to prospectively identify these patients. We hypothesize that CSF would provide useful data on tumor-related metabolites to help stratify responders and non-responders. We focused on adenosine and related nucleotides based on their role in creating an immunosuppressive tumor microenvironment. METHODS Fifty-one patients (43 with melanoma and 8 with NSCLC) received immunotherapies. The CSF samples from this cohort were compared to 30 controls and 60 non-immunotherapy-treated patients (13 with melanoma and 47 with NSCLC) using liquid chromatography/tandem mass spectrometry for quantitative assessment of metabolites. RESULTS The age and sex distribution were comparable in both cohorts. The most common immunotherapy regimens were ipilimumab, α-interferon and IL-2, while the most common non-immunotherapy regimens were carboplatin/taxol, carboplatin/pemetrexed and pemetrexed alone. CSF AMP, but not adenosine, ADP or ATP, from the immunotherapy cohort was higher in comparison to the non-immunotherapy cohort (P=0.0495). An adenosine/AMP ratio (AAR) was used to quantify relative adenosine production from AMP. AAR of 3.5–7 was associated with lower median survival from diagnosis of brain metastasis in immunotherapy-treated patients (9.1 months, log-rank P=0.0197). AAR below or above this range had significantly higher median survival (27.7 and 24.2 months, respectively). The same AARs could not stratify for survival in non-immunotherapy-treated patients (log-rank P=0.3039). Compared to the non-immunotherapy cohort, the immunotherapy cohort had higher kynurenine, glyceraldehyde 3-phosphate, pyruvate and lactate, as well as succinate, fumarate, malate, oxaloacetate, aconitate and isocitrate (all P&amp;lt; 0.05). CONCLUSION AAR of 3.5–7 could indicate an immunosuppressive microenvironment and needs further investigation to identify immunotherapy non-responders. The presence of elevated kynurenine, succinate, fumarate, malate and oxaloacetate suggests glutaminolysis related to immunotherapy. Research supported by the 2019 AACR-Bayer Innovation and Discovery Grant.
CSIG-20. L3MBTL3 SUPPRESSES MEDULLOBLASTOMA TUMORIGENESIS THROUGH MODULATION OF THE NOTCH/RBPJ SIGNALING PATHWAY
Authors: Honglai Zhang, Tao Xu, Claire Peabody, Ester Calvo Fernández, Rashmi Budhathoki, Philip Chi-En Huang, Elizabeth D Hughes, Thomas L Saunders, Rork Kuick, Brian Magnuson, Sandra Camelo-Piragua, Jean-François Rual
Journal: Neuro-Oncology (2020)

Abstract The NOTCH/RBPJ pathway governs cell proliferation in many biological contexts, including SHH and Group#3medulloblastoma (MB) tumorigenesis. Using our proteomic platform, we discovered an interaction between RBPJ, a key co-factor of NOTCH for the modulation of the NOTCH/RBPJ signaling pathway, and L3MBTL3, a methyllysine reader. L3MBTL3 is recruited by RBPJ on chromatin at the enhancers of NOTCH/RBPJ target genes to repress their expression. Deletions of the L3MBTL3 locus are observed in patients with WNT and Group#3 MB and expression of L3MBTL3 in the SHH MB-derived cell DAOY inhibits cell growth, suggesting a putative tumor suppressor role for L3MBTL3 in MB. To further investigate the putative role of L3MBTL3 as a suppressor of MB tumorigenesis, we used our novel L3mbtl3 KO mouse in combination with a genetically engineered ND2:SmoA1 mouse model of SHH MB in a survival analysis. Furthermore, to identify the biological processes regulated by L3mbtl3 in MB, we analyzed by RNA-seq the transcriptome of L3mbtl3 KO mouse cerebella. Our survival analysis validated in vivo our hypothesis that L3mbtl3 is a tumor suppressor in this disease context. Indeed, our data show that [ND2:SmoA1; L3mbtl3+/-] mice have a significantly lower survival rate than ND2:SmoA1 mice (P = 0.032; Log-rank test). Moreover, our RNA-seq studies showed that L3MBTL3 regulates cell fate in the cerebellum via modulation the NOTCH/RBPJ signaling pathway. Hence, the RBPJ-L3MBTL3 interaction is at the heart of a molecular mechanism governing the repression of NOTCH/RBPJ target genes and malfunction of this molecular mechanism contributes to L3MBTL3’s tumor suppressor role in MB through aberrant “de-repression” of NOTCH/RBPJ target genes. Our discovery provides insights into the tumor suppressor role of the L3MBTL3 in MB that could be harnessed in the future for the therapeutic benefit of patients with MB.
CBIO-07. CELL DEATH INDUCED BY AN OSCILLATING MAGNETIC FIELD IN PATIENT DERIVED GLIOBLASTOMA CELLS IS MEDIATED BY REACTIVE OXYGEN SPECIES
Authors: Shashank Hambarde, Martyn Sharpe, David Baskin, Santosh Helekar
Journal: Neuro-Oncology (2020)

Abstract Noninvasive cancer therapy with minimal side effects would be ideal for improving patient outcome in the clinic. We have developed a novel therapy using strong rotating magnets mounted on a helmet. They generate oscillating magnetic fields (OMF) that penetrate through the skull and cover the entire brain. We have demonstrated that OMF can effectively kill patient derived glioblastoma (GBM) cells in cell culture without having cytotoxic effects on cortical neurons and normal human astrocytes (NHA). Exposure of GBM cells to OMF reduced the cell viability by 33% in comparison to sham-treated cells (p&amp;lt; 0.001), while not affecting NHA cell viability. Time lapse video-microscopy for 16 h after OMF exposure showed a marked elevation of mitochondrial reactive oxygen species (ROS), and rapid apoptosis of GBM cells due to activation of caspase 3. Addition of a potent antioxidant vitamin E analog Trolox effectively blocked OMF-induced GBM cell death. Furthermore, OMF significantly potentiated the cytotoxic effect of the pro-oxidant Benzylamine. The results of our studies demonstrate that OMF-induced cell death is mediated by ROS generation. These results demonstrate a potent oncolytic effect on GBM cells that is novel and unrelated to any previously described therapy, including a very different mechanism of action and different technology compared to Optune therapy. The effect is very powerful, and unlike Optune, can be seen within hours after initiation of treatment. We believe that this technology holds great promise for new, effective and nontoxic treatment of glioblastoma.
Targeting therapy-resistant prostate cancer via a direct inhibitor of the human heat shock transcription factor 1
Authors: Bushu Dong, Alex M. Jaeger, Philip F. Hughes, David R. Loiselle, J. Spencer Hauck, Yao Fu, Timothy A. Haystead, Jiaoti Huang, Dennis J. Thiele
Journal: Science Translational Medicine (2020)

Heat shock factor 1 (HSF1) is a cellular stress-protective transcription factor exploited by a wide range of cancers to drive proliferation, survival, invasion, and metastasis. Nuclear HSF1 abundance is a prognostic indicator for cancer severity, therapy resistance, and shortened patient survival. The HSF1 gene was amplified, and nuclear HSF1 abundance was markedly increased in prostate cancers and particularly in neuroendocrine prostate cancer (NEPC), for which there are no available treatment options. Despite genetic validation of HSF1 as a therapeutic target in a range of cancers, a direct and selective small-molecule HSF1 inhibitor has not been validated or developed for use in the clinic. We described the identification of a direct HSF1 inhibitor, Direct Targeted HSF1 InhiBitor (DTHIB), which physically engages HSF1 and selectively stimulates degradation of nuclear HSF1. DTHIB robustly inhibited the HSF1 cancer gene signature and prostate cancer cell proliferation. In addition, it potently attenuated tumor progression in four therapy-resistant prostate cancer animal models, including an NEPC model, where it caused profound tumor regression. This study reports the identification and validation of a direct HSF1 inhibitor and provides a path for the development of a small-molecule HSF1-targeted therapy for prostate cancers and other therapy-resistant cancers.
COVID-19 stokes inflammasomes
Authors: Clare Bryant
Journal: The Journal of Experimental Medicine (2020)

The poor success rate of treating patients with aggressive sepsis in SARS-CoV-2 infections has highlighted again the challenges of managing systemic inflammatory conditions. In this issue of JEM, Rodrigues et al. (https://doi.org/10.1084/jem.20201707) discuss the role of inflammasome activation in COVID-19 disease severity, opening new possibilities for therapeutic management of sepsis syndromes.
SURG-29. A SINGLE CENTRE EXPERIENCE OF USING INTRA-OPERATIVE MRI IN MANAGING PEDIATRIC CRANIAL NEURO-ONCOLOGY CASES
Authors: Dharmendra Ganesan, Nor Faizal Ahmad Bahuri, Revathi Rajagopal, Jasmine Loh PY, Kein Seong Mun, Raja Rizal Azman Raja Aman
Journal: Neuro-Oncology (2020)

Abstract The University of Malaya Medical Centre, Kuala Lumpur had acquired a intraoperative MRI (iMRI) brain suite via a public private initiative in September 2015. The MRI brain suite has a SIEMENS 1.5T system with NORAS coil system and NORAS head clamps in a two room solution. We would like to retrospectively review the cranial paediatric neuro-oncology cases that had surgery in this facility from September 2015 till December 2019. We would like to discuss our experience with regard to the clear benefits and the challenges in using such technology to aid in the surgery. The challenges include the physical setting up the paediatric case preoperatively, the preparation and performing the intraoperative scan, the interpretation of intraoperative images and making a decision and the utilisation of the new MRI data set to assist in the navigation to locate the residue safely. Also discuss the utility of the intraoperative images in the decision of subsequent adjuvant management. The use of iMRI also has other technical challenges such as ensuring the perimeter around the patient is free of ferromagnetic material, the process of transfer of the patient to the scanner and as a consequence increased duration of the surgery. CONCLUSION: Many elements in the use of iMRI has a learning curve and it improves with exposure and experience. In some areas only a high level of vigilance and SOP (Standard operating procedure) is required to minimize mishaps. Currently, the iMRI gives the best means of determining extent of resection before concluding the surgery.
Chemotherapy strategies for young children newly diagnosed with desmoplastic/extensive nodular medulloblastoma up to the era of molecular profiling – a comparative outcomes analysis of prospective multi-center European and North American trials.
Authors: Jonathan Finlay, Martin Mynarek, Girish Dhall, Lucie Lafay-Cousin, Claire Mazewski, David Ashley, Sarah Leary, Bruce H Cohen, Giles Robinson, Russell Geyer, Diana Tait, Joseph Stanek, Amar Gajjar, Stefan Rutkowski
Journal: Neuro-Oncology (2021)

Abstract Aims Survival has been poor in several multi-center/national trials since the 1980s, either delaying, avoiding or minimizing brain irradiation in young children with medulloblastoma. The introduction of German regimens supplementing “standard” chemotherapy with both intravenous high-dose (HD-MTX) and intraventricular (IVENT-MTX) methotrexate, and North American regimens incorporating marrow-ablative chemotherapy with autologous hematopoietic cell rescue (HDCx+AuHCR), have reported encouraging outcomes. We performed a comparative outcomes analysis of these differing strategies for young children with desmoplastic/extensive nodular medulloblastoma. Method Data from 12 trials reported between 2005 and 2020 for children &amp;lt;six-years-old with desmoplastic/extensive nodular medulloblastoma were reviewed; event-free (EFS) survival+/-standard errors were compared. Results The German HIT-SKK’92 and HIT-SKK’00 trials incorporating HD-MTX and IVENT-MTX reported 85+/-8% and 95+/-5% 5-10-year EFS respectively; a third trial (ACNS1221) incorporating HIT-SKK therapy but without IVENT-MTX reported only 49+/-10% EFS. Three trials (Head Start I and II combined and CCG-99703) employing induction chemotherapy without HD-MTX, followed by one or three HDCx+AuHCR cycles, reported 3-5-year EFS of 67+/-16% and 79+/-11%. Two trials employing HD-MTX-containing induction chemotherapy (Head Start III and ACNS0334), followed by one or three HDCx+AuHCR cycles, reported 3-5-year EFS of 89+/-6% and 100%, respectively. Finally, four trials utilizing neither IVENT-MTX nor HDCx+AuHCR (UK-CNS-9204, CCG-9921, COG-P9934 and SJYC07) reported 2-5 year EFS of 35+/-11%, 77+/-9%, 58+/-8% and 53+/-9% respectively. Conclusion A trend towards better EFS for young children with desmoplastic/extensive nodular medulloblastoma is observed in trials including eitherHD-MTX and IVENT-MTX or including HD-MTX-containing induction chemotherapy and HDCx+AuHCR. Trials excluding HD-MTX, IVENT-MTX and HDCx+AuHCR have poorer outcomes.
The words that shaped COVID-19
Authors: Amesh Adalja
Journal: The Lancet Infectious Diseases (2020)

As someone who has been immersed in the COVID-19 pandemic since January of 2020, looking back on all that has happened since the emergence of severe acute respiratory syndrome coronavirus 2 is an extreme challenge. Trying to keep the full context of all the events, the new discoveries, the policies, and the rhetoric is almost a specialty in its own right. That's why a book like Unprepared: America in the Time of Coronavirus by Jon Sternfeld has such value. There will be many books written on this pandemic, but I suspect none that provide such a unique service as Unprepared does.
Performance of Salamanca refinement of the T3-AJCC8 versus the Brigham and Women's Hospital and Tübingen alternative staging systems for high-risk cutaneous squamous cell carcinoma
Authors: Laura Puebla-Tornero, Luis Antonio Corchete-Sánchez, Alberto Conde-Ferreirós, Natalia García-Sancha, Roberto Corchado-Cobos, Concepción Román-Curto, Javier Cañueto
Journal: Journal of the American Academy of Dermatology (2020)
Association between new-onset liver cirrhosis and suicide risk in South Korea: A nationwide cohort study
Authors: Suk-Yong Jang, Woo Sun Rou, Seok Hyun Kim, Byung Seok Lee, Hyuk Soo Eun
Journal: Clinical and Molecular Hepatology (2020)

Background/Aims: Current evidence suggests that liver cirrhosis (LC) causes severe psychological stress and depression, which are risk factors for suicide. Although previous studies reported the association between LC and suicidal thoughts, little is known of its effect on suicidal deaths. Therefore, this study was undertaken to investigate the effect of new-onset LC on suicide.Methods: From the National Health Insurance Service-National Sample Cohort of South Korea, 5,809 incident LC patients and 11,618 risk-set controls matched by propensity score were selected for follow-up. The incidence rate of suicide was estimated using a generalized estimating equation with a Poisson distribution. Effect size was presented as a hazard ratio (HR) using Cox’s proportional hazards model.Results: The incidence rate of suicide was 143.3 cases per 100,000 person years (95% confidence interval [CI], 100.2–205.1) among the LC cohort. The LC patients were 2.37 times more likely to commit suicide compared with matched controls (HR, 2.37; 95% CI, 1.44–3.88). Increased suicide risk was evident within the first 2 years of the follow-up period (HR, 2.59; 95% CI, 1.20–5.60) and among the 18–49-year-old age group (HR, 3.72; 95% CI, 1.45–9.56).Conclusions: Our study found increased risk of suicide in patients with new onset LC, especially during the early period following diagnosis and in younger patients. To decrease this suicide risk, a regular and continuous social support system is required.
Bendamustine, Gemcitabine and Dexamethasone Chemotherapy Is Effective Salvage and Stem-Cell Mobilization Regimen in Patients with Relapsed or Refractory Hodgkin Lymphoma — Early Results of the Polish Lymphoma Research Group Study
Authors: Ewa Paszkiewicz-Kozik, Jan Zaucha, Agata Tyczyńska, Marcin Szymanski, Lukasz Targonski, Joanna Drozd-Sokolowska, Elżbieta Wojciechowska-Lampka, Joanna Tajer, Pawel Kurczab, Joanna Romejko-Jarosinska, Michal Osowiecki, Jan Walewski
Journal: Blood (2017)
Obesity and the Heart: A Weighty Issue⁎⁎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: Stephan von Haehling, Wolfram Doehner, Stefan D. Anker
Journal: Journal of the American College of Cardiology (2006)