tbuckley/cabot-search huggingface dataset:
MODL-11. COMPARISON OF HUMAN &amp; MURINE PA/PXA CHARACTERISTICS
Authors: Alexander C Sommerkamp, Pengbo Sun, Annika K Wefers, Britta Ismer, Kathrin Schramm, Andrea Wittmann, Jan Gronych, Andrey Korshunov, Andreas von Deimling, Natalie Jäger, Stefan M Pfister, David T W Jones
Journal: Neuro-Oncology (2020)

Abstract Pediatric low-grade gliomas (pLGGs) are the most common brain tumors in children. Despite recent advances in the molecular characterization of this heterogeneous set of tumors, the separation of specific tumor types is still not fully established. Pilocytic astrocytoma (PA; WHO grade I) and pleomorphic xanthoastrocytoma (PXA; WHO grade II) are two pLGG types that can be difficult to distinguish based on histology alone. Even though their clinical course is different, they are often grouped as ‘pLGG’ in clinical trials (and therefore treated similarly). Based on a cohort of 89 human pediatric tumor samples, we show that PAs and PXAs have clearly distinct methylation and transcriptome profiles. The difference in gene expression is mainly caused by cell cycle- and development-associated genes, suggesting a key difference in the regulatory circuits involved in tumor growth. In addition to BRAF V600E, we found NTRK fusions and a previously unknown EGFR:BRAF fusion as mutually exclusive driving events in PXAs. Both tumor types show marked signs of immune cell infiltration, but with significant qualitative differences, which might represent therapeutic vulnerabilities. To pave the way for further research on PA and PXA, we developed corresponding mouse models using the virus-based RCAS system, which allows introduction of an oncogenic driver into immunocompetent mice for molecular and preclinical research. The murine tumors do not only histologically resemble their human counterparts but also show a similar growth behavior. Expression analysis revealed that the murine PXAs have a stronger gene signature of proliferation and immune cell infiltration compared to PAs.
MBRS-71. ATAXIA TELANGIECTASIA AND RAD3-RELATED PROTEIN ATTENUATES DNA DAMAGE AND IS A THERAPEUTIC TARGET IN Myc-DRIVEN MEDULLOBLASTOMA
Authors: Ahmed Abdel-Hafiz, Krishna Madhavan, Ilango Balakrishnan, Angela Pierce, Dong Wang, Etienne Danis, Natalie Serkova, Sujatha Venkataraman, Rajeev Vibhakar
Journal: Neuro-Oncology (2020)

Abstract Group 3 medulloblastoma tumors (Myc-MB), and particularly the 3γ subtype, have the worst prognosis and show a 5-year overall survival of less than 40%. Group 3 tumors are often accompanied by Myc amplification and have a higher rate of metastatic disease and relapse. Unfortunately, therapeutic strategies to target Mychave remained elusive. Further, the relapse of the MB has been linked to DNA replication stress. Ataxia telangiectasia and Rad3-related protein (ATR) senses persistent DNA damage, which arises due to replication stress, and activates damage checkpoints, thereby leading to increased cell survival. ATR is highly expressed in MB and is thought to contribute to undisturbed DNA replication to protect genomic integrity. Yet, the exact underlying mechanisms involving ATR are still unclear in MB. Inhibition of ATR (ATRi) using the ATR inhibitor, AZD6738, suppressed clonogenicity and cell self-renewal in Myc-MB. ATRi in Myc-MB cell lines downregulated Chk1 and upregulated P21. ATRi also induced cell cycle arrest and increased apoptosis in Myc-MB cell lines. Further, mice with orthotopic xenografts treated with ATR inhibitor survived significantly longer than control mice. High-throughput drug screening showed ATRi to be synergistic with chemotherapeutic agents including gemcitabine, cisplatin and topotecan. The treatment of Myc-MB cells with ATR inhibitor in combination with gemcitabine and with radiation increased in expression of DNA damage markers. These findings emphasize the role of ATR in alleviating DNA replication stress and that its inhibition is critical to the treatment of Myc-MB.
NCOG-33. HEMATOLOGIC PREDICTORS OF OUTCOMES IN GLIOBLASTOMA TREATED WITH SURGERY AND CHEMORADIATION
Authors: Nicholas Damico, Theresa Elder, Michael Kharouta, Anthony Sloan, Amber Kerstetter-Fogle, Peggy Harris, Aryavarta Kumar, David Mansur, Mitchell Machtay, Aashish Bhatt, Robin Buerki, Andrew E Sloan, Serah Choi
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND There are conflicting reports regarding the prognostic value of platelet and other blood counts in glioblastoma. However, few series have looked at all hematologic parameters simultaneously. METHODS We performed a retrospective chart review of patients diagnosed with supratentorial glioblastoma from 2014-2019 who started conventional chemoradiation following initial surgical biopsy and/or resection. Hematologic parameters were collected at baseline, in the preoperative and postoperative periods and at the initiation and completion of chemoradiation. This included platelet counts, hemoglobin levels, white blood cell counts (WBC), neutrophil and lymphocyte counts with neutrophil:lymphocyte (NLR) and platelet:lymphocyte ratios (PLR) calculated at each time point. Cox regression was performed to assess the association between each hematologic parameter and both overall survival (OS) and progression free survival (PFS). A multivariate Cox proportional hazards model adjusted for all hematologic parameters, age, sex, race and KPS was generated for each time point. All hematologic parameters were modeled as continuous variables. RESULTS A total of 58 patients met inclusion criteria. 18 were female and 40 male. The median age was 59.5 (range 43-82). Median follow up for all patients was 15.3 months. A total of 52 patients completed radiation therapy and 18 completed 6 cycles of adjuvant chemotherapy. Hemoglobin and neutrophil counts at the conclusion of chemoradiation were associated with OS and PFS on univariate and multivariate analyses. The HR for OS were 0.74 (95% CI 0.5807-0.9313) and 1.28 (1.143-1.441) respectively. The HR for PFS were 0.70 (0.5531-0.8881) and 1.16 (1.05-1.271) respectively. Postoperative lymphocyte and platelet counts at initiation of chemoradiation were both associated with OS with unadjusted HR of 3.2 (1.037-9.960) and HR of 0.99 (0.9898-0.9999) respectively, which remained significant on multivariate analysis. However, neither were associated with PFS. CONCLUSION Several hematologic parameters are associated with glioblastoma outcomes in these initial analyses. Further analyses with additional patients are ongoing.
CD10 reduces inhibitory effect of Met-enkephalin in colon cancer
Authors: Yukiko Moriwaka, Toshio Kuwai, Tomonori Sasahira, Hitoshi Ohmori, Yasuhiko Kitadai, Hiroki Kuniyasu
Journal: Cancer Research (2008)

1159  CD10 is a neutral endopeptidase expressed in small intestine, immune cells, and lung endothelial cells. We examined the role of CD10 in liver metastasis of colon cancer. CD10-positive human colon cancer cell line, HT29 showed inhibition of growth, migration, invasion, and survival by CD10 antisense treatment. Number and size of metastatic foci in nude mice liver were reduced in CD10 antisense-treated HT29 cells. Thiorphan, a specific CD10 inhibitor reduced growth, invasion, survival in in vitro and liver metastasis in nude mice. Met-enkephalin (ENK), one of substrates of CD10 suppresses growth in HT29 cells by activation of delta opioid receptor (DOR) in a dose-dependent manner. Inhibition of CD10 activity by thiorphan treatment increased apoptosis in HT29 cells. In human colon cancer, concurrent expression of ENK, DOR, and CD10 was found in 4 of 5 liver metastasis positive cases, whereas the concurrent expression was found in only one of 16 liver metastasis-negative cases (P
Abstract 17194: Clinically Successful Percutaneous Treatment of Platypnea Orthodeoxia Syndrome in Patients With Patent Foramen Ovale
Authors: Gerard Marti Aguasca, Alvaro Calabuig Goena, Enric Domingo Ribas, Bernat Serra Creus, Imanol Otaegui Irurueta, Vicens Serra Garcia, Neus Bellera Gotarda, Bruno Garcia del Blanco, Ignacio Ferreira Gonzalez
Journal: Circulation (2019)

Introduction: Platypnea-orthodeoxia syndrome (POS) is a rare clinical entity, characterized by dyspnea and desaturation while in the upright position, relieved in the supine position. POS can be ca...
18F-FDG PET/CT for Monitoring of Disease Progression in Metastatic Perivascular Epithelioid Cell Tumor
Authors: Adrien Holzgreve, Matthias P. Fabritius, Thomas Knösel, Bernhard W. Renz, Lars H. Lindner, Dorit Di Gioia, Peter Bartenstein, Johannes Rübenthaler, Reinhold Tiling
Journal: Clinical Nuclear Medicine (2020)

Abstract A 38-year-old woman presented for 18 F-FDG PET/CT after multiple intra-abdominal surgical resections of a rare recurrent perivascular epithelioid cell tumor of the gastrointestinal tract. A solitary pelvic metastasis was detected, but surprisingly exhibited neither increased glucose consumption nor contrast enhancement on CT. Follow-up 18 F-FDG PET/CT staging in the further disease course revealed multiple abdominal metastases, now, however, with markedly increased 18 F-FDG uptake and intraoperatively correlating widespread peritoneal sarcomatosis. This case gives preliminary insight into monitoring of disease progression in metastatic perivascular epithelioid cell tumor, although the underlying pathophysiological bases for varying 18 F-FDG uptake in PET/CT are not yet fully understood.
Fully end-to-end deep-learning-based diagnosis of pancreatic tumors
Authors: Ke Si, Ying Xue, Xiazhen Yu, Xinpei Zhu, Qinghai Li, Wei Gong, Tingbo Liang, Shumin Duan
Journal: Theranostics (2020)

Artificial intelligence can facilitate clinical decision making by considering massive amounts of medical imaging data.Various algorithms have been implemented for different clinical applications.Accurate diagnosis and treatment require reliable and interpretable data.For pancreatic tumor diagnosis, only 58.5% of images from the First Affiliated Hospital and the Second Affiliated Hospital, Zhejiang University School of Medicine are used, increasing labor and time costs to manually filter out images not directly used by the diagnostic model.Methods: This study used a training dataset of 143,945 dynamic contrast-enhanced CT images of the abdomen from 319 patients.The proposed model contained four stages: image screening, pancreas location, pancreas segmentation, and pancreatic tumor diagnosis.Results: We established a fully end-to-end deep-learning model for diagnosing pancreatic tumors and proposing treatment.The model considers original abdominal CT images without any manual preprocessing.Our artificial-intelligence-based system achieved an area under the curve of 0.871 and a F1 score of 88.5% using an independent testing dataset containing 107,036 clinical CT images from 347 patients.The average accuracy for all tumor types was 82.7%, and the independent accuracies of identifying intraductal papillary mucinous neoplasm and pancreatic ductal adenocarcinoma were 100% and 87.6%, respectively.The average test time per patient was 18.6 s, compared with at least 8 min for manual reviewing.Furthermore, the model provided a transparent and interpretable diagnosis by producing saliency maps highlighting the regions relevant to its decision.Conclusions: The proposed model can potentially deliver efficient and accurate preoperative diagnoses that could aid the surgical management of pancreatic tumor.
Abstract 13283: Treatment Pathways of Oral Anticoagulants for Stroke Prevention in Atrial Fibrillation Patients - Clinical Landscape From Multiple Countries
Authors: Pareen Vora, Henry Morgan Stewart, Beth Russell, Alex Asiimwe, Gunnar Brobert
Journal: Circulation (2019)

Introduction: Gradual introduction of non-vitamin K antagonist oral anticoagulants (NOACs) provided new treatment options for stroke prevention of atrial fibrillation (SPAF). Hypothesis: To charact...
Anti-fibrotic treatments for chronic liver diseases: The present and the future
Authors: Naoshi Odagiri, Tsutomu Matsubara, Misako Sato-Matsubara, Hideki Fujii, Masaru Enomoto, Norifumi Kawada
Journal: Clinical and Molecular Hepatology (2020)

Liver fibrosis reflects tissue scarring in the liver due to the accumulation of excessive extracellular matrix in response to chronically persistent liver injury. Hepatocyte cell death can trigger capillarization of liver sinusoidal endothelial cells, stimulation of immune cells including macrophages and Kupffer cells, and activation of hepatic stellate cells (HSCs), resulting in progression of liver fibrosis. Liver cirrhosis is the terminal state of liver fibrosis and is associated with severe complications, such as liver failure, portal hypertension, and liver cancer. Nevertheless, effective therapy for cirrhosis has not yet been established, and liver transplantation is the only radical treatment for severe cases. Studies investigating HSC activation and regulation of collagen production in the liver have made breakthroughs in recent decades that have advanced the knowledge regarding liver fibrosis pathophysiology. In this review, we summarize molecular mechanisms of liver fibrosis and discuss the development of novel anti-fibrotic therapies.
Circular RNA: metabolism, functions and interactions with proteins
Authors: Wei-Yi Zhou, Ze-Rong Cai, Jia Liu, De-Shen Wang, Huai-Qiang Ju, Rui-Hua Xu
Journal: Molecular Cancer (2020)

Circular RNAs (CircRNAs) are single-stranded, covalently closed RNA molecules that are ubiquitous across species ranging from viruses to mammals. Important advances have been made in the biogenesis, regulation, localization, degradation and modification of circRNAs. CircRNAs exert biological functions by acting as transcriptional regulators, microRNA (miR) sponges and protein templates. Moreover, emerging evidence has revealed that a group of circRNAs can serve as protein decoys, scaffolds and recruiters. However, the existing research on circRNA-protein interactions is quite limited. Hence, in this review, we briefly summarize recent progress in the metabolism and functions of circRNAs and elaborately discuss the patterns of circRNA-protein interactions, including altering interactions between proteins, tethering or sequestering proteins, recruiting proteins to chromatin, forming circRNA-protein-mRNA ternary complexes and translocating or redistributing proteins. Many discoveries have revealed that circRNAs have unique expression signatures and play crucial roles in a variety of diseases, enabling them to potentially act as diagnostic biomarkers and therapeutic targets. This review systematically evaluates the roles and mechanisms of circRNAs, with the hope of advancing translational medicine involving circRNAs.
Assessment of Machine Learning to Estimate the Individual Treatment Effect of Corticosteroids in Septic Shock
Authors: Romain Pirracchio, Alan Hubbard, Charles L. Sprung, Sylvie Chevret, Djillali Annane
Journal: JAMA Network Open (2020)

<h3>Importance</h3> The survival benefit of corticosteroids in septic shock remains uncertain. <h3>Objective</h3> To estimate the individual treatment effect (ITE) of corticosteroids in adults with septic shock in intensive care units using machine learning and to evaluate the net benefit of corticosteroids when the decision to treat is based on the individual estimated absolute treatment effect. <h3>Design, Setting, and Participants</h3> This cohort study used individual patient data from 4 trials on steroid supplementation in adults with septic shock as a training cohort to model the ITE using an ensemble machine learning approach. Data from a double-blinded, placebo-controlled randomized clinical trial comparing hydrocortisone with placebo were used for external validation. Data analysis was conducted from September 2019 to February 2020. <h3>Exposures</h3> Intravenous hydrocortisone 50 mg dose every 6 hours for 5 to 7 days with or without enteral 50 μg of fludrocortisone daily for 7 days. The control was either the placebo or usual care. <h3>Main Outcomes and Measures</h3> All-cause 90-day mortality. <h3>Results</h3> A total of 2548 participants were included in the development cohort, with median (interquartile range [IQR]) age of 66 (55-76) years and 1656 (65.0%) men. The median (IQR) Simplified Acute Physiology Score (SAPS II) was 55 [42-69], and median (IQR) Sepsis-related Organ Failure Assessment score on day 1 was 11 (9-13). The crude pooled relative risk (RR) of death at 90 days was 0.89 (95% CI, 0.83 to 0.96) in favor of corticosteroids. According to the optimal individual model, the estimated median absolute risk reduction was of 2.90% (95% CI, 2.79% to 3.01%). In the external validation cohort of 75 patients, the area under the curve of the optimal individual model was 0.77 (95% CI, 0.59 to 0.92). For any number willing to treat (NWT; defined as the acceptable number of people to treat to avoid 1 additional outcome considering the risk of harm associated with the treatment) less than 25, the net benefit of treating all patients vs treating nobody was negative. When the NWT was 25, the net benefit was 0.01 for the treat all with hydrocortisone strategy, −0.01 for treat all with hydrocortisone and fludrocortisone strategy, 0.06 for the treat by SAPS II strategy, and 0.31 for the treat by optimal individual model strategy. The net benefit of the SAPS II and the optimal individual model treatment strategies converged to zero for a smaller number willing to treat, but the individual model was consistently superior than model based on the SAPS II score. <h3>Conclusions and Relevance</h3> These findings suggest that an individualized treatment strategy to decide which patient with septic shock to treat with corticosteroids yielded positive net benefit regardless of potential corticosteroid-associated side effects.
Abstract 12542: Intraventricular Flow Profile in Young Adults With Single Left Ventricle Fontan Using Echocardiographic Contrast Particle Imaging Velocimetry
Authors: Ling Li, Andreas Schuster, Mary Craft, Joan Olson, Gianni Pedrizzetti, Shelby Kutty
Journal: Circulation (2018)

Background: The purpose of this investigation was to test the hypothesis that intraventricular flow patterns in the palliated single left ventricle (SLV) differs from the normal LV. High-resolution...
IMMU-16. TWO DISTINCT SUBSETS OF NATURAL KILLER CELLS ARE ENRICHED IN THE TUMOR MICROENVIRONMENT AND CORRELATE WITH SURVIVAL OUTCOME IN HUMAN GLIOBLASTOMA.
Authors: Todd Bartkowiak, Sierra Barone, Madeline Hayes, Caroline Roe, Justine Sinnaeve, Akshitkumar Mistry, Nalin Leelatian, Allison Greenplate, Bret Mobley, Lola Chambless, Reid Thompson, Kyle Weaver, Rebecca Ihrie, Jonathan Irish
Journal: Neuro-Oncology (2020)

Abstract Glioblastomas (GBM) account for up to 60% of all adult primary brain tumors. With few advances in therapeutics, median overall survival (mOS) remains at 15-months post diagnosis. Success of immunotherapy in peripheral solid tumors may offer an alternative therapeutic approach for patients with GBM tumors; however, no predictive immune features currently inform therapeutic stratification for GBM. Recently, we have identified radiographic tumor contact with the lateral ventricle (LV) as a prognostic indicator of OS, as patients with LV+ GBM survive 7 months less than patients with LV- gliomas. This disparity was independent of known prognostic factors (e.g. KPS, extent of resection). Further, we have identified a correlation between greater immune infiltration and the frequency of tumor subtypes with more favorable prognosis. We therefore hypothesized that differences in overall survival between patients with LV+ and LV- are due, in part, to a uniquely immunosuppressive microenvironment within the LV. Using 35-parameter single-cell mass cytometry (CyTOF) we profiled the immune infiltrate of human GBM tissue acquired in accordance with the Declaration of Helsinki and with the approval of the institutional review board (IRB #131870). Computational approaches (tSNE, Citrus, RAPID) correlated natural killer (NK) cell populations correlating with prognosis. NK cells made of 1–14% of the total immune infiltrate in GBM. Ninety percent of NK cells infiltrating LV- tumors were CD16+CD56dim cytotoxic NK cells (cNK). LV+ gliomas, however, were enriched in CD16+CD56bright immunoregulatory NK cells (irNK). The presence of cNK cells correlated with a 2.5-fold improvement of OS, whereas irNK cells correlated with a 2.2-fold reduction in OS. Further, 30–60% of NK cells infiltrating LV+ tumors expressed checkpoint receptors (TIGIT, TIM3, B7-H3) compared to only 10–20% in LV- tumors. These results suggest that NK cells contribute to immunosuppression in the LV and may serve as alternative targets to T cell-based therapies for GBM.
HGG-21. GERMLINE MUTATIONS IN <i>MSH2</i> GENE IN PEDIATRIC PATIENTS WITH CONGENITAL AND SPORADIC GLIOBLASTOMA
Authors: Maria Ejmont, Małgorzata Rydzanicz, Wiesława Grajkowska, Marta Perek-Polnik, Agnieszka Sowińska, Magdalena Kozłowska, Maria Łastowska, Maciej Pronicki, Rafał Płoski, Bożenna Dembowska-Bagińska, Joanna Trubicka
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Glioblastoma (GBM) remains one of the biggest therapeutic challenges in neuro-oncology. In spite of multimodal treatment approaches the prognosis of GBM is extremely poor, median survival is estimated about 12–16 months. Although GBM is one of the most common and malignant primary brain tumors, pediatric glioblastoma, including congenital is a very rare tumor, with an incidence of about 1.1–3.4 per million live births. Moreover, the mode of presentation, behavior, response to therapy and molecular background of pediatric glioblastomas differs from adult type of GBM. Until now, about ten patients with congenital glioblastoma have been described and in none of them germline markers were examined. Here we report two patients with GBM, one with congenital tumor with germline mutations in MSH2 gene. METHODS Targeted Next-Generation Sequencing (NGS) of the probands DNA extracted from leucocytes was performed using the TruSight One sequencing panel on an Illumina HiSeq 1500. Applied gene panel investigated the coding sequence and splice sites of 4813 genes associated with known disease phenotypes. The NGS data were analyzed using an in-house procedure. Identified variants were validated by Sanger sequencing. RESULTS NGS analysis of patients constitutional DNA revealed know, pathogenic variants c.940C&amp;gt;T and c.942 + 3A&amp;gt;T in MSH2 gene (NM_000251.3) associated with MMR-dependent hereditary cancer syndromes. CONCLUSION Molecular analysis are heavily needed for better understanding of pediatric GBM etiology and new treatment modality implementation. Identification of this oncogenic driver may provide insight into the pathogenesis of GBM, including congenital cases. Funded by National Science Centre, Poland (2016/23/B/NZ2/03064 and 2016/21/B/NZ2/01785).
Mast cell–derived IL-13 downregulates IL-12 production by skin dendritic cells to inhibit the TH1 cell response to cutaneous antigen exposure
Authors: Juan Manuel Leyva-Castillo, Mrinmoy Das, Emilie Artru, Juhan Yoon, Claire Galand, Raif S Geha
Journal: Journal of Allergy and Clinical Immunology (2020)