tbuckley/cabot-search huggingface dataset:
Exosome-mediated improvement in membrane integrity and muscle function in dystrophic mice
Authors: Ling Leng, Xue Dong, Xianjun Gao, Ning Ran, Mengyuan Geng, Bingfeng Zuo, Yingjie Wu, Wei Li, Hua Yan, Gang Han, HaiFang Yin
Journal: Molecular Therapy (2020)

Duchenne muscular dystrophy (DMD) is a devastating genetic disorder that leads to compromised cellular membranes, caused by the absence of membrane-bound dystrophin protein. Muscle membrane leakage results in disrupted intracellular homeostasis, protein degradation, and muscle wasting. Improving muscle membrane integrity may delay disease progression and extend the lifespan of DMD patients. Here, we demonstrate that exosomes, membranous extracellular vesicles, can elicit functional improvements in dystrophic mice by improving muscle membrane integrity. Systemic administration of exosomes from different sources induced phenotypic rescue and mitigated pathological progression in dystrophic mice without detectable toxicity. Improved membrane integrity conferred by exosomes inhibited intracellular calcium influx and calcium-dependent activation of calpain proteases, preventing the degradation of the destabilized dystrophin-associated protein complex. We show that exosomes, particularly myotube-derived exosomes, induced functional improvements and alleviated muscle deterioration by stabilizing damaged muscle membrane in dystrophic mice. Our findings suggest that exosomes may have therapeutic implications for DMD and other diseases with compromised membranes.
DDRE-20. GENERATION OF A HIGH-AFFINITY EGFR/EGFRvIII-TARGETED D2C7 CAR-T CELL
Authors: Katherine Ryan, Daniel Wilkinson, Daniel Landi, Peter Fecci
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND The intent of this investigation is to validate a novel, high-affinity epidermal growth factor receptor (EGFR) chimeric antigen receptor (CAR) T-cell product for adoptive immunotherapy of EGFR-expressing malignancies of the central nervous system (CNS). Wild type EGFR is ubiquitously expressed on glial tumors in both children and adults, and the majority of solid tumors that metastasize to the CNS but is not expressed on healthy CNS tissues. EGFR and its isoform mutant, EGFRvIII, are hyperactivated or overexpressed receptor tyrosine kinases described in many human cancers. D2C7 is a recombinant monoclonal antibody short chain variable fragment (scFv) that binds to both wild type EGFR and EGFRvIII. We hypothesize that D2C7 adapted as a CAR on primary human T cells will generate potent, cytotoxic activity against EGFR-expressing tumors in vivo. METHODS In vitro interferon gamma release assays comparing the D2C7 CAR to the EGFRvIII CAR have proven that D2C7 CAR-T cells have high specificity and potent cytotoxicity against established murine glioblastoma (GBM) tumor cell lines, expressing both EGFR and EGFRvIII. Next steps include pre-clinical in vivo testing of the D2C7 CAR-T cells in murine models of CNS tumors expressing EGFR/EGFRvIII such as GBM, non-small cell lung carcinoma (NSCLC), breast carcinoma, and melanoma. CONCLUSIONS To improve and validate the effectiveness of CAR T-cell therapy for EGFR-expressing CNS tumors, our team has designed a high-affinity CAR-T cell that targets both EGFRvIII and wild-type EGFR, known as a D2C7 CAR-T cell. This investigation has established pre-clinical anti-tumor activity of D2C7-CAR T cells in vitro and we plan to present more mature data regarding efficacy in orthotopic murine models of GBM, NSCLC, breast carcinoma, and melanoma at the meeting this Fall.
Sixty seconds on . . . <i>Star Trek</i>
Authors: Mun-Keat Looi
Journal: BMJ (2020)

Victor Grech, a paediatric cardiologist at the University of Malta, has been exposed as having published 113 papers in a single Elsevier journal. Some 19 of them are entirely about the TV series Star Trek .1

Indeed. The discrepancy was spotted by an undergraduate student, Hampton Gaddy, at the University of Oxford. In a letter …
Abstract 12914: Multicenter Study of Diagnostic Performance of Noninvasive Coronary Angiography and Dynamic Myocardial Perfusion Imaging Using Dual Source Computed Tomography: The AMPLIFiED Study
Authors: Kakuya Kitagawa, Satoshi Nakamura, Hideki Ota, Ryo Ogawa, Takehito Shizuka, Tadahiro Kubo, Yan Yi, Tatsuro Ito, Naoki Nagasawa, Taku Omori, Shiro Nakamori, Tairo Kurita, Jun Sugisawa, Naoki Hatori, Hitoshi Nakashima, Yining Wang, Teruhito Kido, Kouki Watanabe, Yasuharu Matsumoto, Kaoru Dohi, Hajime Sakuma
Journal: Circulation (2020)

Introduction: Single-center studies indicated a high diagnostic accuracy of dynamic computed tomography perfusion (CTP) imaging in the diagnosis of hemodynamically significant coronary artery disease (CAD). However, no prospective multicenter study has assessed the performance of combined coronary computed tomography angiography (CTA) and dynamic CTP. Hypothesis: In this prospective multicenter study, we assessed the hypothesis that dynamic CTP can provide an incremental diagnostic value over CTA detecting hemodynamically significant CAD defined by invasive coronary angiography (ICA) with fractional flow reserve (FFR). Methods: Seven centers enrolled 165 patients with suspected or known CAD, who were clinically referred for ICA. CTA and dynamic CTP were performed using dual-source CT prior to ICA. FFR was done as part of ICA in case of 26-90% coronary diameter stenosis. Hemodynamically significant stenosis was defined as of FFR&lt;0.8 or ≥90% stenosis on ICA. Three blinded independent core laboratories analyzed CTA, CTP and ICA. Results: The study protocol was completed in 157 participants and hemodynamically significant stenosis was detected in 112 of 442 vessels (25%) and 123 of 157 patients (78%). According to receiver operating characteristic curve analysis, CTA showed an area under the curve (AUC) of 0.81 (95% confidence interval [CI], 0.73-0.86) on the patient level and 0.80 (95% CI, 0.76-0.84) on the vessel level. Adding dynamic CTP to CTA significantly increased the AUC to 0.85 (95% CI, 0.78-0.90; p=0.027) on the patient level and to 0.84 (95% CI, 0.80-0.87; p=0.002) on the vessel level. In the subgroups of patients with 1-, 2- and 3-vessel disease by CTA, the addition of dynamic CTP to CTA significantly increased AUC from 0.80 to 0.84 (p=0.041) in 2-vessel disease and from 0.65 to 0.73 (p=0.022) in 3-vessel disease, but not in 1-vessel disease (from 0.84 to 0.87, p=0.265). Conclusion: In this first prospective multicenter study on dynamic CTP, the combination of anatomical assessment with coronary CTA and functional evaluation with dynamic CTP allowed more accurate detection of hemodynamically significant coronary artery stenosis. Improved diagnostic performance with dynamic CTP was mainly obtained when multivessel disease was suspected by CTA.
TAMI-31. MACROPHAGE M1 INVASION PREDICTS POOR PROGNOSIS OF GLIOMA AND REVEALS A STRATEGY FOR GLIOBLASTOMA THERAPY
Authors: Zhaoming Zhou, Lei Wen, Changguo Shan, Mingyao Lai, Cheng Zhou, Linbo Cai
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Glioma is one of the most malignant tumors in the central neural system, due to a lack of efficient immune therapy targets. Here we explored the transcriptional information of gliomas with the aim to discover novel biomarkers for glioma classifying in the aspects of prognosis and immune therapy targets prediction. METHODS We explored the gene expression data from the Chinese Glioma Genome Atlas (CGGA). The extracellular matrix (ECM) and immune cells abundance of gliomas were evaluated on the transcriptional level by the ECM score and cell infiltration enrichment score. RESULTS Based on top differentially expressed genes (DEGs), ECM scores showed significantly differences between various grades (WHO II, III, and IV) of gliomas (p values &amp;lt; 0.0001). Cell infiltration enrichment scores of macrophages, macrophages M1, and monocytes showed positively correlated with the ECM scores by the linear regression analysis (r = 0.51, 0.54, and 0.62, respectively; p values &amp;lt; 0.0001). Variation-partitioning analysis indicated that macrophages, macrophages M1, and monocytes played dominant roles in the variances between WHO II, WHO III, and WHO IV gliomas. Survival association analysis showed that patients with higher infiltration of macrophages, macrophages M1, and monocytes shared shorter overall survival (OS). OS of glioblastoma (GBM) were determined to be shorter in high macrophages M1 enrichment group (p &amp;lt; 0.0001). Univariate and multivariate analysis of clinical characteristics with OS in GBM cohort demonstrated that macrophages M1 enrichment score was an independent survival risk factor for GBM patients. Further subgroup survival association analysis showed that the higher M1 macrophages enrichment score was associated with higher OS in IDH wildtype GBM patients (p = 0.011). CONCLUSIONS This study demonstrates Macrophages M1 infiltration level as a poor prognostic factor for glioma and suggests macrophages M1 could be the potential immune therapy targets for IDH-wild-type GBM patients.
QOLP-27. USE OF THE NEURO-QOL COGNITIVE FUNCTION SHORT-FORM AS A TOOL FOR ASSESSING PATIENT-PERCEIVED NEUROCOGNITION FOLLOWING RADIOTHERAPY
Authors: Sung Choi, Emily Kowalski, Rahul Khairnar, Mark Mishra
Journal: Neuro-Oncology (2020)

Abstract The Quality-of-Life in Neurological Disorders (Neuro-QOL) instruments are a practical set of validated tools utilized to measure a core set of health-related quality-of-life parameters that are relevant to patients with neurological disorders. The tools can be completed in approximately 1-minute. The primary objective of this study was to evaluate the feasibility of utilizing the eight-question Neuro-QoL Cognitive Function- Short Form (NCF-SF) tool (v2.0) to assess cognitive outcomes in patients with primary and secondary brain tumors undergoing radiotherapy. Patients completed the NCF-SF at baseline and during follow-up visits. Raw scores were converted to a standardized T-score that has been normalized to have mean score of 50 and standard deviation (SD) of 10. Descriptive statistical analyses were performed to assess the prevalence of baseline cognitive impairment (defined as &amp;gt; 1 SD below the normative mean), and to assess longitudinal changes in Neuro-QOL scores. A minimum clinically important difference (MCID) was defined as a change from baseline of &amp;gt;7.5, based on previously published literature. Ninety-one patients completed NCF-SF at baseline and at least one follow-up visit. The mean baseline score for the study cohort was 49.9 (SD 9.2). Nineteen percent of patients (n=17/91) had impaired function at baseline. Baseline scores did not differ based on tumor type (p=0.79): Glioma/ependymoma 49.6 (n=35); brain metastases 49.1 (n=24); Meningioma/benign 50.7 (n=32). Following radiation, 15% and 22% of patients experienced a MCID decline at 1- (n=60) and 3- months (n=65), respectively. However, 17% and 20% of patients demonstrated a MCID improvement at 1- and 3-months, respectively. In conclusion, this represents the first study to utilize the NCF-SF to measure cognitive function in patients undergoing brain radiotherapy. Use of NCG-SF was feasible, and identified patients with meaningful changes in cognitive function over time. Future clinical trials may consider use of Neuro-QOL to assess patient-perceived cognitive function.
TAMI-43. IMPACT OF SEX AND RADIATION ON IRON TRAFFICKING IN BONE MARROW DERIVED MACROPHAGES
Authors: Ganesh Shenoy, Amanda Snyder, Becky Slagle-Webb, Savannah Marshall, Todd Schell, Zissis Chroneos, Dimitrios Davalos, Michael Berens, Justin Lathia, Jill S Barnholtz-Sloan, Joshua Rubin, James Connor
Journal: Neuro-Oncology (2020)

Abstract The tumor microenvironment in glioblastoma provides cancer cells with favorable conditions to proliferate and invade surrounding tissues. Macrophages comprise a large portion of the glioblastoma tumor microenvironment (TME) both in terms of volume and function. These cells have been reported to influence tumor progression by modulating immune responses, remodeling extracellular matrix, and providing nutrients to cancer cells among numerous other functions. Radiation therapy forms one of the pillars of glioblastoma management along with surgical resection and chemotherapy. Here we investigated the effects of radiation on macrophage iron metabolism. Using mouse bone-marrow-derived macrophages (BMDMs) we performed in-vitro 59Fe radiotracer assays to study how radiation exposure modified iron trafficking in these cells. We found that low dose radiation at 0.25, 0.5, or 2 Gy from a 60Co source stimulated iron release from the BMDMs with maximal release occurring at 0.5 Gy. Moreover, we observed that iron release was dependent on the amount of serum present in culture media with cells cultured in 20% fetal bovine serum (FBS) showing reduced iron release profiles compared to those cultured in 10% or 1% FBS. Since glioblastoma patients exhibit sexually dimorphic survival outcomes, we investigated whether these radiation-induced responses occurred in a sexually dimorphic pattern. At radiation doses of 0.25 Gy we observed that male macrophages tended to release more iron than female macrophages despite no differences in iron uptake between the sexes – raising the question as to whether differential iron trafficking in response to treatment contributes to the poorer survival outcomes observed in males. Our data suggest that delineating how supporting cells such as macrophages respond to glioblastoma treatment regimens may provide insights into addressing mechanisms of treatment resistance and further our understanding of the sexual dimorphism observed in patient outcomes.
C-Reactive Protein to Identify Early Risk for Development of Calcific Aortic Stenosis: Right Marker? Wrong Time?⁎⁎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: Peter H. Stone
Journal: Journal of the American College of Cardiology (2007)
NCOG-31. DEVELOPMENT AND EVALUATION OF PROGNOSTIC MODELS TO PREDICT SURVIVAL OF PATIENTS WITH GLIOBLASTOMA MULTIFORME
Authors: John Lin, Michelle Mai, Saba Paracha
Journal: Neuro-Oncology (2020)

Abstract Glioblastoma multiforme (GBM), the most common form of glioma, is a malignant tumor with a high risk of mortality. By providing accurate survival estimates, prognostic models have been identified as promising tools in clinical decision support. In this study, we produced and validated two machine learning-based models to predict survival time for GBM patients. Publicly available clinical and genomic data from The Cancer Genome Atlas (TCGA) and Broad Institute GDAC Firehouse were obtained through cBioPortal. Random forest and multivariate regression models were created to predict survival. Predictive accuracy was assessed and compared through mean absolute error (MAE) and root mean square error (RMSE) calculations. 619 GBM patients were included in the dataset. There were 381 (62.9%) cases of recurrence/progression and 53 (8.7%) cases of disease-free survival. The MAE and RMSE values were 0.553 and 0.887 years respectively for the random forest regression model, and they were 1.756 and 2.451 years respectively for the multivariate regression model. Both models accurately predicted overall survival. Comparison of models through MAE, RMSE, and visual analysis produced higher accuracy values for random forest than multivariate linear regression. Further investigation on feature selection and model optimization may improve predictive power. These findings suggest that using machine learning in GBM prognostic modeling will improve clinical decision support. *Co-first authors.
Non-alcoholic fatty liver disease and risk of incident chronic kidney disease: an updated meta-analysis
Authors: Alessandro Mantovani, Graziana Petracca, Giorgia Beatrice, Alessandro Csermely, Amedeo Lonardo, Jörn M Schattenberg, Herbert Tilg, Christopher D Byrne, Giovanni Targher
Journal: Gut (2020)

Objective Studies reported a significant association between non-alcoholic fatty liver disease (NAFLD) and increased risk of chronic kidney disease (CKD). However, whether this risk changes with increasing severity of NAFLD remains uncertain. We performed a meta-analysis of observational studies to quantify the magnitude of the association between NAFLD and risk of incident CKD. Design We systematically searched PubMed, Web of Science and Scopus from January 2000 to August 2020 using predefined keywords to identify observational studies with a follow-up duration of ≥1 year, in which NAFLD was diagnosed by blood biomarkers/scores, International Classification of Diseases codes, imaging techniques or biopsy. Data from selected studies were extracted, and meta-analysis was performed using random-effects modelling. Results 13 studies with 1 222 032 individuals (28.1% with NAFLD) and 33 840 cases of incident CKD stage ≥3 (defined as estimated glomerular filtration rate &lt;60 mL/min/1.73 m 2 , with or without accompanying overt proteinuria) over a median follow-up of 9.7 years were included. NAFLD was associated with a moderately increased risk of incident CKD (n=10 studies; random-effects HR 1.43, 95% CI 1.33 to 1.54; I 2 =60.7%). All risks were independent of age, sex, obesity, hypertension, diabetes and other conventional CKD risk factors. Sensitivity analyses did not alter these findings. Funnel plot did not reveal any significant publication bias. Conclusion This large and updated meta-analysis indicates that NAFLD is significantly associated with a~1.45-fold increased long-term risk of incident CKD stage ≥3. Further studies are needed to examine the association between the severity of NAFLD and risk of incident CKD.
Cultivating Prognosis Following Percutaneous Coronary Intervention: The American College of Cardiology/National Cardiovascular Data Registry Risk Score⁎⁎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: Dean J. Kereiakes
Journal: Journal of the American College of Cardiology (2010)
RADT-30. COPLANAR AND NON-COPLANAR VMAT ARC SETTING FOR GLIOBLASTOMA MULTIFORME – DOSIMETRIC AND RADIOBIOLOGICAL COMPARISONS
Authors: Vanessa Moldoveanu, Mihai Dumitrache, Xenia Bacinschi, Luiza Serbanescu, Rodica Anghel
Journal: Neuro-Oncology (2020)

Abstract OBJECTIVES To evaluate three different arc arrangements in glioblastoma multiforme (GBM) treatment planning. METHODS Eighteen GBM patients were replanned by using one full arc (1FA), two full coplanar arcs (2FA), and three full non- coplanar arcs (3FA). Dose-volume histograms (DVHs) were used to calculate conformity (CI), homogeneity (HI) and gradient indices (GI), the dose received by 5% (D5%) and 95% (D95%) of the planning target volume (PTV) and maximum (Dmax) and minimum (Dmin) absorbed dose for organs at risk (OARs), including normal brain (brain excluding PTV). General equivalent uniform dose (gEUD) for both PTV and OARs and EUD based tumor control probability (TCP) and normal tissue control probability (NTCP) were calculated as radiobiological parameters. Monitor units (MUs) were also computed and compared. RESULTS All three plans resulted in similar conformity, while 2FA resulted in a better homogeneity than 1FA (0.06vs. 0.07, p=0.007). 2FA vs. 1FA dose analysis for PTV revealed a lower D5% (61.28 vs. 61.37 Gy, p=0.014), a higher D95% (58.7 vs. 58.47 Gy, p=0.008) and a higher TCP (37.73 vs.37.38%, p=0.008). The utilization of 3FA did not significantly change the outcome of PTV but managed to decrease GI in comparison to both 1FA and 2FA (4.11 vs. 5.19 and 5.49, p&amp;lt; 0.05). Regarding NB, 1FA scored a higher Dmax than 2FA (62.32 vs. 61.98 Gy, p=0.005), while 3FA scored a higher Dmin than 1FA and 2FA (2.52 vs. 1.08 and 1.10 Gy, p&amp;lt; 0.05). No difference in NB NTCP was noted between techniques. Furthermore, 3FA yielded more MUs when compared to coplanar patters (566.74 vs. 486.78, p= 0.015 for 1FA and 495.98, p=0.019 for 2FA). CONCLUSION Although all three approaches resulted in clinical admissible outcome, the utilization of complex non-coplanar arrangement resulted in a stepper dose fall off but did not improve PTV results and increased machine MUs.
Can We Predict Thromboembolic Events in Low-Risk Patients Undergoing Catheter Ablation of Atrial Fibrillation?: The Hanging CHAD**Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Authors: Ganesh Venkataraman, S. Adam Strickberger
Journal: Journal of the American College of Cardiology (2011)
STEM-07. IDENTIFICATION OF A NOVEL CSC SIGNALING AXIS CONTAINING JAM-A/SERPINB3/TGF-BETA
Authors: Adam Lauko, Soumya Turaga, Josephine Volovetz, Defne Bayik, Ulhas Naik, Justin Lathia
Journal: Neuro-Oncology (2020)

Abstract Despite therapeutic interventions including surgery, radiation, and chemotherapy, multiple clones of treatment resistant cells repopulate the tumor, resulting in recurrence and a high rate of mortality in glioblastoma. Effective targeting of these cancer stem cells (CSCs) has been limited by our incomplete understanding of the intracellular signaling mechanisms maintaining the CSC state. Our laboratory previously identified junctional adhesion molecule-A (JAM-A) on CSCs and, through functional studies, demonstrated that JAM-A is both necessary and sufficient for self-renewal and tumor growth. We determined that JAM-A signals via Akt in GBM CSCs to sustain pluripotency transcription factor activity; however, the intermediate signaling network is yet to be fully elucidated. Therefore, our goal was to delineate the pathway downstream of JAM-A. To achieve this, we immunoprecipitated JAM-A from GBM CSCs and performed mass spectrometry leading to the identification of the serine/cysteine protease inhibitor SerpinB3. While SerpinB3 has a functional role in lung adenocarcinoma, breast, pancreas, as well as in hepatocellular carcinoma, there is limited information in GBM or CSCs, and its relationship to JAM-A is yet to be elucidated. Using in vitro CSC functional assays, we observed that SerpinB3 is necessary for the maintenance of CSCs. Additionally, in an intracranial implantation model of GBM the knockdown of SerpinB3 extended the survival of mice. Knockdown of SerpinB3 in multiple GBM CSCs models also led to decreased expression of TGF-β, a known regulator of the CSC state. We also observed that SerpinB3 stabilizes JAM-A expression and further studies are investigating the mechanism of this stabilization, identifying the specific interaction sites of JAM-A and Serpin B3, and determining how TGF-β alters the association through positive and negative feedback mechanisms. Taken together, these data highlight the role of SerpinB3 in GBM CSCs and provides a novel target to inhibit the JAM-A-mediated CSC maintenance as a next-generation GBM therapy.
88P Identification of prognostic radio-immune-genetic profiles in patients affected by glioblastoma
Authors: G. Mazzaschi, A. Olivari, S. Dall'Asta, C.A. Lagrasta, C. Frati, D. Madeddu, A. Pavarani, M. Tiseo, M. Michiara, F. Quaini, P. Crafa
Journal: Annals of Oncology (2020)