tbuckley/cabot-search huggingface dataset:
CSIG-11. TARGETING PD-L1 IN GLIOBLASTOMA USING NANOPARTICLE-BASED GENE EDITING
Authors: An Tran, Javier Fierro, Huanyu Dou
Journal: Neuro-Oncology (2020)

Abstract Glioblastoma multiforme (GBM) is an astrocyte derived brain tumor with very poor prognosis, usually with a less than one year survival rate. Immunotherapy has shown promising therapeutic potentials in research and clinical application, however, GBM associated immunosuppressive microenvironment creates a significant barrier for effective anti-GBM immune responses. The immune checkpoint PD-1/PD-L1 pathways play a critical role in tumor-induced immunosupression to evade immune surveillance. Gene-editing tools targeting PD-1/PD-L1 pathway have gained increased research attention, however the major challenge is how to effectively deliver gene-editing tools without causing adverse effects for clinical translation. We have developed a nanoparticle (NP) delivery system from a low molecular weight PEI lipid shell and a PLGA core that can package PD-L1 gRNA-CRISPR/Cas9 plasmid to transfect human U87 glioma cells overexpressing PD-L1. PD-L1 gRNA-CRISPR/Cas9 plasmid is constructed by inserting single guide targeting PD-L1 sequence into GFP CRISPR/Cas9 plasmid for visualizing transfection efficacy. NP is labelled with Rhodamine 6G to monitor cellular uptake and trafficking. Fluorescence microscopy shows human U87 glioma cells can quickly uptake PD-L1 GFP-CRISPR/Cas9 plasmid-NPs within 2 hours as indicated by the Rhodamine 6G. GFP expression was obtained after 48 hours of transfection and maintained up to 7 days without causing toxicity. Western blot analysis confirmed successful knockdown of PD-L1 in U87 cells. These findings reveal that NPs made by a cationic branched PEI lipid shell and a PLGA core are non-toxic and efficient in delivering CRISPR/Cas9 system to U87 cells. Editing of pathological gene in human glioma cells with PD-L1 GFP-CRISPR/Cas9 plasmid using NPs as a delivery system may provide a novel immunotherapy platform to treat GBM.
Abstract 10446: The Ceramide-based Coronary Event Risk Test (CERT) Predicts Cardiovascular Mortality in Cardiovascular Disease Patients With Type 2 Diabetes Mellitus as Well as in Those Without Diabetes
Authors: Andreas Leiherer, Axel Muendlein, Christoph H Saely, Reijo Laaksonen, Mitja Lääperi, Alexander Vonbank, Arthur Mader, Iris Baumgartner, Peter Fraunberger, Heinz Drexel
Journal: Circulation (2019)

Introduction: The recently introduced Coronary Event Risk Test (CERT) is a validated cardiovascular risk predictor that uses circulating ceramide concentrations to allocate patients into one of fou...
SURG-02. SURVIVAL PREDICTION AFTER NEUROSURGICAL RESECTION OF BRAIN METASTASES: A MACHINE LEARNING APPROACH
Authors: Alexander Hulsbergen, Yu Tung Lo, Vasileios Kavouridis, John Phillips, Timothy Smith, Joost Verhoeff, Kun-Hsing Yu, Marike Broekman, Omar Arnaout
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Survival prediction in brain metastases (BMs) remains challenging. Current prognostic models have been created and validated almost completely with data from patients receiving radiotherapy only, leaving uncertainty about surgical patients. Therefore, the aim of this study was to build and validate a model predicting 6-month survival after BM resection using different machine learning (ML) algorithms. METHODS An institutional database of 1062 patients who underwent resection for BM was split into a 80:20 training and testing set. Seven different ML algorithms were trained and assessed for performance. Moreover, an ensemble model was created incorporating random forest, adaptive boosting, gradient boosting, and logistic regression algorithms. Five-fold cross validation was used for hyperparameter tuning. Model performance was assessed using area under the receiver-operating curve (AUC) and calibration and was compared against the diagnosis-specific graded prognostic assessment (ds-GPA); the most established prognostic model in BMs. RESULTS The ensemble model showed superior performance with an AUC of 0.81 in the hold-out test set, a calibration slope of 1.14, and a calibration intercept of -0.08, outperforming the ds-GPA (AUC 0.68). Patients were stratified into high-, medium- and low-risk groups for death at 6 months; these strata strongly predicted both 6-months and longitudinal overall survival (p &amp;lt; 0.001). CONCLUSIONS We developed and internally validated an ensemble ML model that accurately predicts 6-month survival after neurosurgical resection for BM, outperforms the most established model in the literature, and allows for meaningful risk stratification. Future efforts should focus on external validation of our model.
Abstract 15161: A Comparison of Hemodynamic Parameter & Mortality Between Temporary Mechanical Circulatory Support & Intra-Aortic Balloon Pump in Refractory Cardiogenic Shock - A Systematic Review and Meta-Analysis
Authors: Monil Majmundar, Abdullah Zoheb Azhar, Palak Shah, Rajkumar P Doshi, Tikal Kansara
Journal: Circulation (2019)

Introduction: Refractory cardiogenic shock (CS) is associated with higher mortality. Temporary mechanical circulatory support (MCS) devices such as intra-aortic balloon pump (IABP), Extracorporeal ...
Abstract 15104: Malignant Neoplasms of the Heart in the United States
Authors: Neiberg A Lima, Kamil Cwikla, Kristina Byers-Spencer, Cuyler Huffman, Mireya Diaz, Thomas Melgar, Nicholas Helmstetter
Journal: Circulation (2020)

Introduction: Malignant cardiac neoplasms (MCN) are rare and deadly. Metastatic cardiac tumors are known to be more frequent than primary neoplasms of the heart. Due to the uncommon nature of this disease, there are few data-driven studies examining the incidence in the United States or analyzing rates and types of complications. The purpose of our study was to better describe the types, characteristics and trends of MCN in the United States. Methods: This study is a retrospective review of data from the HCUP-NIS Database from 2002-2014. Inclusion criteria consisted of the presence of indication for MCN. Additionally, we queried the database for MCN-associated comorbidities and procedures. SAS studio was utilized for analysis. Results: The data consists of 482,872,274 weighted hospital discharges, 5,610 of which had MCN. Fifty three percent were male. Eighty percent had a metastatic cardiac tumor and twenty percent had a primary neoplasm of the heart (Figure 01). Median cost of admission was 35,855 USD, three times higher than the national average. A total of 568 (10.12%) patients died during the admission. Stroke and arterial embolization were reported in 192 (3.42%) and 54 (0.96%) cases, respectively. Weight loss, fever and endocarditis were reported in 70 (1.24%), 162 (2.89%) and 53 (0.94%) patients, respectively. Pulmonary hypertension co-occurred in 225 (4.01%) patients. Atrial tachyarrhythmias, ventricular arrhythmias, syncope and cardiac arrest were reported in 1,119 (19.95%), 185 (3.30%), 39 (0.70%), and 88 (1.57%) cases. Sinus node dysfunction and severe AV nodal block co-occurred in 46 and 50 patients. Conclusions: Morbidity and mortality are high in patients with MCN. The majority of MCN are associated with metastatic disease, with especially lung, skin/bone/soft tissue and gastrointestinal being the commonest.
Propranolol inhibits cavernous vascular malformations by β1 adrenergic receptor antagonism in animal models
Authors: Wenqing Li, Robert Shenkar, Mathew R. Detter, Thomas Moore, Christian Benavides, Rhonda Lightle, Romuald Girard, Nicholas Hobson, Ying Cao, Yan Li, Erin Griffin, Carol Gallione, Joseph M. Zabramski, Mark H. Ginsberg, Douglas A. Marchuk, Issam A. Awad
Journal: Journal of Clinical Investigation (2020)

Propranolol, a pleiotropic β-adrenergic blocker, has been anecdotally reported to reduce cerebral cavernous malformations (CCMs) in humans. However, propranolol has not been rigorously evaluated in animal models, nor has its mechanism of action in CCM been defined. We report that propranolol or its S(-) enantiomer dramatically reduced embryonic venous cavernomas in ccm2 mosaic zebrafish, whereas R-(+)-propranolol, lacking β antagonism, had no effect. Silencing of the β1, but not β2, adrenergic receptor mimicked the beneficial effects of propranolol in a zebrafish CCM model, as did the β1-selective antagonist metoprolol. Thus, propranolol ameliorated cavernous malformations by β1 adrenergic antagonism in zebrafish. Oral propranolol significantly reduced lesion burden in 2 chronic murine models of the exceptionally aggressive Pdcd10/Ccm3 form of CCM. Propranolol or other β1-selective antagonists may be beneficial in CCM disease.
BIOM-40. ANALYSIS OF SERUM MIRNA IN GLIOBLASTOMA PATIENTS: TARGETED ENRICHMENT OF EXTRACELLULAR VESICLES ENHANCES SPECIFICITY FOR PROGNOSTIC SIGNATURE
Authors: Theophilos Tzaridis, Johannes Weller, Daniel Bachurski, Niklas Schäfer, Christina Schaub, Michael Hallek, Björn Scheffler, Martin Glas, Gunther Hartmann, Ulrich Herrlinger, Stefan Wild, Christoph Coch, Katrin Reiners
Journal: Neuro-Oncology (2020)

Abstract Glioblastoma is a devastating disease, for which biomarkers allowing a prediction of prognosis are urgently needed. microRNAs have been described as potentially valuable biomarkers in cancer. Here, we studied a panel of microRNAs in extracellular vesicles (EV) from the serum of glioblastoma patients and also in total serum without prior EV separation, and evaluated their correlation with the survival of these patients. Our study included 55 patients in total, 26 (47.3%) of which were treated within the multicenter Phase III CeTeG/NOA-09 trial and 29 (52.7%) in the Division of Clinical Neurooncology of the University Hospital of Bonn, as well as 10 healthy volunteers (HV). Blood was drawn from patients during the adjuvant chemotherapeutic treatment. A panel of 15 microRNAs was studied by quantitative real-time PCR in EV that were separated by size-exclusion chromatography, followed by CDxx* immunoprecipitation (SEC+CDxx*), and compared with those from total serum of glioblastoma patients and HV. Comparing SEC+CDxx* to total serum, we found evidence for enrichment of miR-21-3p and miR-106a-5p and, conversely, lower levels of miR-15b-3p in SEC+CDxx* EV. miR-15b-3p and miR-21-3p were upregulated in serum of glioblastoma patients compared to healthy subjects. Significant correlation with survival of the patients was found for levels of miR-15b-3p in total serum and miR-15b-3p, miR-21-3p, miR-106a-5p and miR-328-3p in SEC+CDxx* EV. Combining miR-15b-3p in serum or miR-106a-5p in SEC+CDxx* EV with any one of the other three microRNAs in SEC+CDxx* EV allowed for a prognostic stratification of glioblastoma patients. We have thus identified four microRNAs whose levels, in combination, can predict the prognosis for these patients. *=Cluster of Differentiation xx (CDxx); Molecule cannot be specifically mentioned due to pending patent.
Reply to comment on “The natural history of progressive fibrosing interstitial lung diseases”
Authors: Kevin K. Brown, Rozsa Schlenker-Herceg, Athol U. Wells
Journal: European Respiratory Journal (2020)

No set of criteria will cover all patients, but the inclusion criteria used in the INBUILD trial were effective at identifying a population of patients with progressive ILDhttps://bit.ly/3mKkzzi
HGG-11. HIGH-GRADE GLIOMAS IN ADOLESCENTS AND YOUNG ADULTS HIGHLIGHT HISTOMOLECULAR DIFFERENCES WITH THEIR ADULT AND PAEDIATRIC COUNTERPARTS
Authors: Alexandre Roux, Johan Pallud, Raphaël Saffroy, Myriam Edjlali-Goujon, Marie-Anne Debily, Nathalie Boddaert, Marc Sanson, Stéphanie Puget, Steven Knafo, Clovis Adam, Thierry Faillot, Dominique Cazals-Hatem, Emmanuel Mandonnet, Marc Polivka, Georges Dorfmüller, Aurélie Dauta, Mathilde Desplanques, Albane Gareton, Mélanie Pages, Arnault Tauziède-Espariat, Jacques Grill, Franck Bourdeaut, François Doz, Frédéric Dhermain, Karima Mokhtari, Fabrice Chrétien, Dominique Figarella-Branger, Pascale Varlet
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Considering that paediatric high-grade gliomas (HGGs) are biologically distinct from their adult counterparts, the objective of this study was to define the landscape of HGGs in adolescents and young adults (AYAs). METHODS We performed a multicentric retrospective study of 112 AYAs from adult and paediatric Ile-de-France neurosurgical units, treated between 1998 and 2013 to analyse their clinicoradiological and histomolecular profiles. The inclusion criteria were age between 15 and 25-years, histopathological HGG diagnosis, available clinical data, pre-operative and follow-up MRI. MRI and tumoral samples were centrally reviewed. Immunohistochemistry and complementary molecular techniques such as targeted/next generation sequencing, whole exome sequencing and DNA-methylation analyses were performed to achieve an integrated diagnosis according to the 2016 WHO classification. RESULTS Based on 80 documented AYA patients, HGGs constitute heterogeneous clinicopathological and molecular groups, with a predominant representation of paediatric-subtypes (Histone H3-mutants, 40%) but also adult-subtypes (IDH-mutants, 28%) characterized by the rarity of oligodendrogliomas, IDH-mutant and 1p/19q co-deleted and the relative high frequency of “rare adult IDH mutations” (20%). H3G34-mutants (14%) represent the most specific subgroup in AYAs. In the H3K27-mutant subgroup, the non-brainstem diffuse midline gliomas are more frequent (66.7%) than diffuse intrinsic pontine gliomas (23.8%), contrary to children. We found that WHO grade has no prognostic value, but molecular subgrouping has major prognostic importance. CONCLUSIONS HGGs in AYAs could benefit from a more personalized neuro-oncological management, driven by molecular subtyping rather than age group. Collaborative efforts are needed from paediatric and adult neuro-oncology teams to improve the management of HGGs in AYAs.
Gut microbiota signatures are associated with toxicity to combined CTLA-4 and PD-1 blockade
Authors: Miles C. Andrews, Connie P. M. Duong, Vancheswaran Gopalakrishnan, Valerio Iebba, Wei-Shen Chen, Lisa Derosa, Md Abdul Wadud Khan, Alexandria P. Cogdill, Michael G. White, Matthew C. Wong, Gladys Ferrere, Aurélie Fluckiger, Maria P. Roberti, Paule Opolon, Maryam Tidjani Alou, Satoru Yonekura, Whijae Roh, Christine N. Spencer, Irina Fernandez Curbelo, Luis Vence, Alexandre Reuben, Sarah Johnson, Reetakshi Arora, Golnaz Morad, Matthew Lastrapes, Erez N. Baruch, Latasha Little, Curtis Gumbs, Zachary A. Cooper, Peter A. Prieto, Khalida Wani, Alexander J. Lazar, Michael T. Tetzlaff, Courtney W. Hudgens, Margaret K. Callahan, Matthew Adamow, Michael A. Postow, Charlotte E. Ariyan, Pierre-Olivier Gaudreau, Luigi Nezi, Didier Raoult, Catalin Mihalcioiu, Arielle Elkrief, Rossanna C. Pezo, Lauren E. Haydu, Julie M. Simon, Hussein A. Tawbi, Jennifer McQuade, Patrick Hwu, Wen-Jen Hwu, Rodabe N. Amaria, Elizabeth M. Burton, Scott E. Woodman, Stephanie Watowich, Adi Diab, Sapna P. Patel, Isabella C. Glitza, Michael K. Wong, Li Zhao, Jianhua Zhang, Nadim J. Ajami, Joseph Petrosino, Robert R. Jenq, Michael A. Davies, Jeffrey E. Gershenwald, P. Andrew Futreal, Padmanee Sharma, James P. Allison, Bertrand Routy, Laurence Zitvogel, Jennifer A. Wargo
Journal: Nature Medicine (2021)
Urinary Arsenic and Cadmium Associations with Findings from Cranial MRI in American Indians: Data from the Strong Heart Study
Authors: Astrid Suchy-Dicey, Carolyn Noonan, Ekaterina Burduli, Farrah J. Mateen, W.T. Longstreth, Dedra Buchwald, Ana Navas-Acien
Journal: Environmental Health Perspectives (2020)

Background: Arsenic and cadmium are known cardiovascular toxicants that pose disproportionate risk to rural communities where environmental exposures are high. American Indians have high vascular risk, which may be attributable in part to these exposures. Objective: We examined urine metal concentrations in association with magnetic resonance imaging findings of vascular brain injury or cerebral atrophy in adult American Indians. Methods: We measured arsenic and cadmium in American Indian participants from the Strong Heart Study (1989–1991) and evaluated these associations with later (2010–2013) measures of infarct, hemorrhage, white matter hyperintensity (WMH) grade, brain and hippocampal volume, and sulcal and ventricle atrophy using nested multivariate regression analyses. Results: Among participants with available data (N=687), the median urine arsenic:creatinine ratio was 7.54μg/g [interquartile range (IQR): 4.90–11.93] and the cadmium:creatinine ratio was 0.96μg/g (IQR: 0.61–1.51). Median time between metal measurement and brain imaging was 21 y (range: 18–25 y). Statistical models detected significant associations between arsenic and higher burden of WMH [grade increase=0.014 (95% CI: 0.000, 0.028) per 10% increase in arsenic]; and between cadmium and presence of lacunar infarcts [relative risk (RR)=1.024 (95% CI: 1.004, 1.045) per 10% increase in cadmium]. Discussion: This population-based cohort of American Indian elders had measured values of urine arsenic and cadmium several times higher than previous population- and clinic-based studies in the United States and Mexico, and comparable values with European industrial workers. Our findings of associations for arsenic and cadmium exposures with vascular brain injury are consistent with established literature. Environmental toxicant accumulation is modifiable; public health policy may benefit from focusing on reductions in environmental metals. https://doi.org/10.1289/EHP6930
Addressing Social Needs in Health Care Settings: Evidence, Challenges, and Opportunities for Public Health
Authors: Matthew W. Kreuter, Tess Thompson, Amy McQueen, Rachel Garg
Journal: Annual Review of Public Health (2020)

There has been an explosion of interest in addressing social needs in health care settings. Some efforts, such as screening patients for social needs and connecting them to needed social services, are already in widespread practice. These and other major investments from the health care sector hint at the potential for new multisector collaborations to address social determinants of health and individual social needs. This article discusses the rapidly growing body of research describing the links between social needs and health and the impact of social needs interventions on health improvement, utilization, and costs. We also identify gaps in the knowledge base and implementation challenges to be overcome. We conclude that complementary partnerships among the health care, public health, and social services sectors can build on current momentum to strengthen social safety net policies, modernize social services, and reshape resource allocation to address social determinants of health.
EAACI Biologicals Guidelines—dupilumab for children and adults with moderate‐to‐severe atopic dermatitis
Authors: Ioana Agache, Cezmi A. Akdis, Mubeccel Akdis, Knut Brockow, Tomas Chivato, Stefano del Giacco, Thomas Eiwegger, Kilian Eyerich, Ana Giménez‐Arnau, Jan Gutermuth, Emma Guttman‐Yassky, Marcus Maurer, Graham Ogg, Peck Y. Ong, Liam O’Mahony, Jürgen Schwarze, Amena Warner, Thomas Werfel, Oscar Palomares, Marek Jutel
Journal: Allergy (2020)

Abstract Atopic dermatitis imposes a significant burden on patients, families and healthcare systems. Management is difficult, due to disease heterogeneity, co‐morbidities, complexity in care pathways and differences between national or regional healthcare systems. Better understanding of the mechanisms has enabled a stratified approach to the management of atopic dermatitis, supporting the use of targeted treatments with biologicals. However, there are still many issues that require further clarification. These include the definition of response, strategies to enhance the responder rate, the duration of treatment and its regimen (in the clinic or home‐based), its cost‐effectiveness and long‐term safety. The EAACI Guidelines on the use of dupilumab in atopic dermatitis follow the GRADE approach in formulating recommendations for each outcome and age group. In addition, future approaches and research priorities are discussed.
PATH-25. EXPERIENCE WITH AN RNA FUSION TRANSCRIPT PANEL FOR DETECTION OF POTENTIAL THERAPEUTIC TARGETS IN GLIOMAS
Authors: Shawn Kothari, Stephen Bagley, Arati Desai, Jennifer Morrisette, Robyn Sussman, Nasrallah MacLean
Journal: Neuro-Oncology (2020)

Abstract Next-generation sequencing to identify fusion proteins is increasingly employed across oncology to identify therapeutic targets.1 The clinical relevance of detecting fusion transcripts is well described in the pediatric glioma population, but similar reports for adult patients are scant.2 The University of Pennsylvania Health System (UPHS) has implemented routine use of an RNA fusion transcript panel (ArcherDX, Boulder, CO) on resected brain tumors since August 2017. Here we report the results of this analysis for adult patients with gliomas and highlight potentially targetable fusions. Over the period of August 2017 through December 2019, fusion analysis was performed on resected gliomas of over 200 patients. Ninety-seven patients were found to have a detected fusion protein. Eighty-three of the 97 patients (86%) had glioblastoma and 14 (14%) had lower grade gliomas. A total of 26 unique fusions were found. The most common (n=55) was EGFRvIII. NTRK fusions were of special interest as FDA-approved agents are available for patients harboring this genetic alteration.3 We identified 8 patients (8%) with NTRK fusions including ARHGEFF2:NTRK1, BNA: NTRK1, BCR: NTRK2, PDE5A/NTRK2, SKAP2/NTRK2, and STRN: NTRK2. Several of these patients went on to receive TRK kinase inhibitors with clinical benefit. Of the 97 patients with a detected fusion, 24 (25%) were found to have a potentially targetable fusion other than EGFRvIII, with inhibitors available in clinical trials or as off-label therapy. These fusions included BRAF (n=5; BRAF: LHFPL3, KIAA1549:BRAF), FGFR (n=9; FGFR3:BRAP, FGFR3:RENBP, FGFR3:TACC3), MET (n=7; CAPZA2-MET, KLF12:MET, PTPRZ1:MET, ST7:MET), and ROS1 (n=3; DLL: ROS1, GOPC: ROS1). In sum, routine clinical use of an RNA-based fusion transcript panel for adult patients with glioma may allow for detection of therapeutically targetable alterations in a meaningful proportion of cases. Prospective trials are needed to determine whether targeting specific fusions is beneficial for adult patients with glioma.