tbuckley/cabot-search huggingface dataset:
NIMG-22. INTEGRATION OF A RADIOMIC SIGNATURE, CLINICAL VARIABLES AND PLASMA CELL-FREE DNA IN ADULT PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA PREDICTS PATIENT SURVIVAL AND IMPROVES DISEASE STRATIFICATION
Authors: Anahita Fathi Kazerooni, Vishnu Bashyam, Hamed Akbari, Chiharu Sako, Elizabeth Mamourian, Jacob Till, Aseel Abdalla, Stephanie Yee, Zev Binder, Seyed Ali Nabavizadeh, Erica Carpenter, Christos Davatzikos, Stephen Bagley
Journal: Neuro-Oncology (2020)

Abstract PURPOSE We have previously demonstrated the potential role of liquid biopsy, specifically plasma cell-free DNA (cfDNA), as a non-invasive biomarker for prognostication in patients with glioblastoma. In separate prior studies, we have also developed MRI-based radiomic signatures to predict survival outcomes in glioblastoma. In this study, for the first time, we evaluated the potential of combining radiomic signatures, epidemiological and clinical variables, and plasma cfDNA quantification for upfront prediction of overall survival (OS) in patients with newly diagnosed glioblastoma. METHODS Quantitative radiomic features were extracted from multiparametric MRI (T1, T1Gd, T2, T2-FLAIR) scans of a discovery cohort of 505 and an independent replication cohort of 50 IDH-wildtype glioblastoma patients. For the independent replication cohort, pre-surgical plasma cfDNA was extracted and quantified. In the first stage, a radiomic signature was created for stratification of patients into categories of short (OS ≤ 6 months) and long (OS ≥ 18 months) survivors using a cross-validated XGBoost method based on the discovery cohort, which was tested independently on the replication cohort. In the second stage, the radiomic signature and clinical variables were integrated to build a second-stage signature using a cross-validated support vector machine (SVM) classifier to stratify the patients into short and long survivor categories. In the third stage, the value of the second-stage signature integrated with cfDNA concentration was assessed through a cross-validated SVM regression method. RESULTS The combination of radiomic, clinical, and cfDNA variables resulted in the best overall predictive accuracy, with Pearson’s correlation coefficient of 0.59 (p&amp;lt; 0.0001) between actual and predicted OS. CONCLUSION In this study, we evaluated the value of combining plasma cfDNA, radiomic, and clinical variables for predicting OS, and showed that it could act as an effective non-invasive prognostic and patient stratification tool in patients with newly diagnosed glioblastoma.
Abstract 409: Matrix Metalloproteinase-13 Inhibition is Protective in a Pressure Overload Model of Heart Failure
Authors: Allison E Schafer, Iñigo Valiente-Alandi, Burns C Blaxall
Journal: Circulation Research (2016)

Heart failure (HF), the leading cause of morbidity and mortality in the United States, is characterized by pathologic remodeling, fibrosis and deteriorating cardiac function. Cardiac fibrosis occurs due to imbalanced production and degradation of extracellular matrix (ECM) proteins. Cardiac fibroblasts (CF) are largely responsible for the secretion of ECM proteins in the heart, and upon injury, transition to a migratory and proliferative myofibroblast (MF) phenotype, leading to excess ECM deposition. Elevated expression of matrix metalloproteinases (MMPs), proteolytic enzymes responsible for degradation of the ECM, is common in HF. Specifically, MMP13 is known to be upregulated in human HF patients. Therefore, we hypothesized that MMP13 plays an important role in pathologic cardiac remodeling, and that inhibition of MMP13 would prevent the development of HF in a pressure overload model, transverse aortic constriction (TAC). Mice were subjected to TAC and treated with the MMP13 inhibitor, WAY170523 (WAY), or vehicle 4 weeks post-TAC until 12 weeks post-TAC. Mice treated with WAY display decreased cardiac hypertrophy and preserved cardiac function compared to vehicle treated mice. WAY treatment may also attenuate interstitial and perivascular fibrosis as well as expression of pro-fibrotic genes. To determine the effect of MMP13 inhibition in cardiac cells, CF and MF were isolated from healthy mice or mice 5 days post-ischemia/reperfusion injury, respectively, and treated with WAY. MMP13 inhibition led to decreased CF invasion but did not affect migration, proliferation or adhesion. Interestingly, inhibition of MMP13 in MF attenuated migration, proliferation and invasion. Moreover, WAY treatment reduced collagen and fibronectin deposition in the ECM of MF. MMP13 inhibition also appeared to decrease Angiotensin II-induced hypertrophy in ventricular cardiomyocytes (CM). These data suggest a role for MMP13 in pressure overload-induced HF, CM hypertrophy and CF behavior. MMP13 inhibition after injury may attenuate cardiac hypertrophy as well as the CF to MF transition, leading to decreased cardiac fibrosis and improved cardiac function. Further understanding of the role of MMP13 could lead to a novel therapeutic target in the treatment of HF.
Perceptions of Parenting Challenges and Career Progression Among Physician Faculty at an Academic Hospital
Authors: Helen Kang Morgan, Kanakadurga Singer, James T. Fitzgerald, Kirk J. Brower, Brooke M. Spencley, Lauren E. Owens, Heather L. Burrows
Journal: JAMA Network Open (2020)

This survey study compares the perceptions of male and female physician faculty members who have children regarding parenting challenges and career progression at an academic hospital.
CYP1A2 suppresses hepatocellular carcinoma through antagonizing HGF/MET signaling
Authors: Jianqing Yu, Xianfeng Xia, Yujuan Dong, Zhongqin Gong, Gang Li, George Gong Chen, Paul Bo San Lai
Journal: Theranostics (2020)

Rationale: Hyperactivation of HGF/MET signaling pathway is a critical driver in liver tumorigenesis. Cytochrome P450 1A2 (CYP1A2) was significantly down-regulated in hepatocellular carcinoma (HCC). However, little is explored about its tumor suppressive role in HCC. In this study, we examined the functional mechanisms and clinical implication of CYP1A2 in HCC. Methods: The clinical impact of CYP1A2 was evaluated in HCC patients in Hong Kong cohort. The biological functions of CYP1A2 were investigated in vitro and in vivo. A series of biochemical experiments including Western blot assay, immunohistochemistry, quantitative reverse transcription-polymerase chain reaction, and Co-immunoprecipitation assay were conducted. Results: CYP1A2 expression was prominently silenced in HCC tumor tissues and the high expression of CYP1A2 was significantly correlated with lower AFP level, less vascular invasion, and better tumor-free survival in local cohort of HCC patients. The overexpression of CYP1A2 inhibited HCC cell viability and clonogenicity, reduced cell migration and invasion abilities in vitro, and suppressed tumorigenicity in vivo, whereas CYP1A2 knockdown exhibited the opposite effects. CYP1A2 significantly hindered HGF/MET signaling and Matrix metalloproteinases (MMPs) expression in HCC cells. Mechanically, CYP1A2 decreased HGF level and diminished HIF-1α expression, both of which are recognized as key regulators of MET activation. As the transcriptional activator of MET, HIF-1α was identified as a binding partner of CYP1A2. Direct binding of CYP1A2 with HIF-1α induced ubiquitin-mediated degradation of HIF-1α, inhibiting HIF-1α-mediated transcriptions. Conclusions: In conclusion, our results have identified CYP1A2 as a novel antagonist of HGF/MET signaling, and CYP1A2 may serve as an independent new biomarker for the prognosis of HCC patients.
Abstract 15365: Natural History of Immune Checkpoint Inhibitor Associated Myocarditis With Preserved Ejection Fraction
Authors: Joseph Nowatzke, John R Power, Wouter C Meijers, Olusola Orimoloye, Charlotte Fenioux, Yuichi Tamura, Jennifer Cautela, Lorenz H Lehmann, Daniel Finke, Salim Hayek, Tariq U Azam, Aarti Asnani, Tyler Mehegan, Alison Weppler, Alan H Baik, Mandar A Aras, Anna Narezkina, Dimitri Arangalage, fanny rocher, Gerard Alexandre, Nicolas L Palaskas, Joe-elie Salem, Javid Moslehi
Journal: Circulation (2020)

Introduction: Immune Checkpoint Inhibitor (ICI)-associated myocarditis can be fatal, and is often characterized by arrhythmogenicity, although &gt; 50% present with preserved ejection fraction (pEF). The natural history of ICI-myocarditis with pEF is unknown. Methods: We utilized a multicenter network of ICI-myocarditis cases spanning 12 countries to identify 83 cases of definite or probable myocarditis presenting with an EF above 50% on initial echocardiography. We further stratified patients based on continued pEF or worsening EF (rEF) during hospitalization. We compared independent variables, vital signs on presentation, and laboratory values between the two groups. Mortality was defined as those who died or were discharged to hospice within 90 days from admission. Fulminant myocarditis was defined as need for circulatory support, atrioventricular block requiring electrical pacing, ventricular tachycardia or fibrillation, or cardiac arrest while in the hospital. Results: Of the 83 patients, 15 developed a rEF; 68 maintained pEF during hospitalization. Although no significant change in heart rate was noted on presentation, systolic blood pressure was lower in the rEF group (111 vs 129, p=0.010). The rEF cohort were more prone to have a peak troponin elevation (432 vs 41, p=0.021), and to develop fulminant myocarditis (73% vs 26%, p=&lt;0.001). Both in-hospital mortality (46% vs 17%, p=0.015) and 90-day all-cause mortality were significantly increased in those who develop a rEF (72% vs 29%, p=0.007). Overall, there was a 36.8% 90-day mortality rate for all those presenting with an initially normal EF. Conclusions: Patients with ICI-myocarditis can still have a fulminant course despite initial echocardiogram revealing EF&gt;50%. In our database, 18% go on to develop new rEF and 73% die in the following 90 days. Decreased BP and troponin on presentation may identify patients at risk of subsequent rEF and fulminant course.
Control strategy and methods for continuous direct compression processes
Authors: Yasuhiro Suzuki, Hirokazu Sugiyama, Manabu Kano, Ryutaro Shimono, Gosuke Shimada, Ryoichi Furukawa, Eichi Mano, Keiichi Motoyama, Tatsuo Koide, Yasuhiro Matsui, Kazuki Kurasaki, Issei Takayama, Shunin Hikage, Noriko Katori, Masahiko Kikuchi, Hiroshi Sakai, Yoshihiro Matsuda
Journal: Asian Journal of Pharmaceutical Sciences (2020)

We presented a control strategy for tablet manufacturing processes based on continuous direct compression. The work was conducted by the experts of pharmaceutical companies, machine suppliers, academia, and regulatory authority in Japan. Among different items in the process, the component ratio and blended powder content were selected as the items requiring the control method specific to continuous manufacturing different from the conventional batch manufacturing. The control and management of the Loss in Weight (LIW) feeder were deemed the most important, and the Residence Time Distribution (RTD) model were regarded effective for setting the control range and for controlling of the LIW feeder. Based on these ideas, the concept of process control using RTD was summarized. The presented contents can serve as a solid fundament for adopting a new control method of continuous direct compression processes in and beyond the Japanese market.
8P Immune cell subsets in peripheral blood are associated with primary resistance to immunotherapy as frontline treatment in NSCLC
Authors: H. Arasanz, M. Zuazo, L. Chocarro, A.I. Bocanegra Gondan, M. Martínez-Aguillo, I. Morilla, G. Fernández-Hinojal, E. Blanco, L. Teijeira, P. Morente, I. Pedroarena, R. Vera, G. Kochan, D. Escors
Journal: Annals of Oncology (2020)
ATRT-33. ENABLING RAPID CLASSIFICATION OF ATRT WITH NANOSTRING NCOUNTER PLATFORM
Authors: Ben Ho, Anthony Arnoldo, Yvonne Zhong, Mei Lu, Jonathon Torchia, Fupan Yao, Cynthia Hawkins, Annie Huang
Journal: Neuro-Oncology (2020)

Abstract In recent years, using gene expression and methylation array platform, multiple research groups have reported the presence of at least three major Atypical Teratoid Rhabdoid Tumor (ATRT) subtypes that exhibit distinct epigenetic, transcriptomic and clinical features. Yet, utilizing ATRT subtypes in a clinical setting remains challenging due to a lack of suitable biological markers, limited sample quantities and relatively high cost of current assays. To address this gap between research and clinical practice, we have designed an assay that utilizes a custom 35 signature genes panel for the NanoString nCounter System and have created a flexible machine learning classifier package for ATRT tumour subtyping. We have analyzed 71 ATRT primary tumours with matching gene expression data using the 35 genes panel. 60% of the data was used for models training (10 repeats of 10-fold cross validation with subgroup balanced sample splitting) resulting in overall 94.6% training accuracy. The remaining 40% of the samples were used for model validation and the assay was able to achieve 92–100% accuracy with no subgroup bias. To demonstrate the flexibility of the workflow, we have tested it against other transcriptome-based methods such as gene expression array and RNASeq. We have also demonstrated its use in samples that were not classifiable by methylation-based method. We are presenting here a rapid and accurate ATRT subtyping assay for clinical usage that is compatible with archived ATRT tissues.
Abstract 12705: Immune Checkpoint Inhibitor-Mediated Myocarditis in the US FDA Adverse Event Reporting System
Authors: Manuel Rivera, Gilson Fernandes, Leonardo Knijnik, Neal Olarte, Mauricio Cohen
Journal: Circulation (2018)

Introduction: Along with the increasing use of immune checkpoint inhibitors (ICI) for the management of advanced malignancies there has been an increase in the number of myocarditis events reported...
DIPG-42. TOWARD MULTIMODALITY THERAPY FOR DIPG/DMG: DEVELOPMENT AND INVESTIGATION OF CRANIOSPINAL IRRADIATION AND CONVECTION-ENHANCED DELIVERY PDX MODELS
Authors: Aaron J Knox, Ahmed Gilani, Benjamin van Court, Ayman Oweida, Patrick Flannery, John DeSisto, Rakeb Lemma, Hannah Chatwin, Fabia Gamboni, Benjamin Brown, Natalie Serkova, Rajeev Vibhakar, Kathleen Dorris, Michael Wempe, Julie A Reisz, Sana D Karam, Adam L Green
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Diffuse intrinsic pontine glioma (DIPG) and diffuse midline glioma (DMG) are metastatic diseases, as demonstrated by early convection-enhanced delivery (CED) clinical trials in which prolonged local tumor control can sometimes be achieved, but fatal disseminated disease then develops. We hypothesize that improvements in treatment of both focal disease and the entire neuraxis are necessary for long-term survival, and patient-derived xenograft (PDX) models can help advance these efforts. METHODS We used a BT245 murine orthotopic DIPG PDX model for this work. We developed a protocol and specialized platform to deliver craniospinal irradiation (CSI) with a pontine boost. We separately compared intratumoral drug concentration by CED and intraperitoneal delivery. In our CED model, mice receive gemcitabine 60 ug x1 in 15 ul at 0.5 ul/minute through a stepped catheter design with silica tubing extending 2mm beyond a 27G needle. RESULTS Mice receiving CSI (4 Gy x2d) plus boost (4 Gy x2d) showed minimal spinal and brain leptomeningeal metastatic disease by bioluminescence, MRI, and pathology compared to mice receiving radiation to the pons only (4 Gy x4d) or no radiation. CED achieved an intratumoral gemcitabine concentration 50-fold greater than intraperitoneal dosing when controlled for dose. CONCLUSIONS In a DIPG PDX model, CSI+boost minimizes tumor dissemination compared to focal radiation, and CED achieves clinically significant improvements in intratumoral chemotherapy concentration compared to systemic delivery. Adding these modalities to current treatment could improve both focal and metastatic tumor control, leading to meaningful improvements in survival.
<i>Notes from the Field:</i> Understanding Smoke Exposure in Communities and Fire Camps Affected by Wildfires— California and Oregon, 2020
Authors: Kathleen Navarro, Ambarish Vaidyanathan
Journal: MMWR Morbidity and Mortality Weekly Report (2020)

During 2020, the United States has experienced unseasonably higher fire activity than in past years, resulting in >7.8 million burned acres; as of December, wildfires were still active in the western United States (1).A major public health concern associated with wildfires is exposure to air pollutants, such as fine inhalable particles in smoke, with aerodynamic diameters ≤2.5 μm (particulate matter [PM] 2.5 ).Exposure to wildfire smoke can irritate the lungs, alter immune function, and increase susceptibility to respiratory infections.In addition, exacerbations of asthma, chronic obstructive pulmonary disease, cardiovascular disease, and possibly increased mortality are associated with smoke exposure* (2).Characterizing smoke exposure levels for communities located near the fires and personnel involved in response efforts is a critical public health function during wildfire episodes.To characterize smoke exposure levels, CDC deployed two staff members to support the Interagency Wildland Fire Air Quality Response Program (IWFAQRP) † as air resource advisors for wildfire incidents in California and Oregon.Air resource advisors are fully integrated into the wildfire incident management teams and provide insights into understanding and predicting air pollution exposures from wildfire smoke emissions.Air resource advisors interact with various stakeholders, including air quality regulators, fire personnel, public health practitioners, and community residents.A primary aspect of this engagement is to forecast smoke levels for areas immediately affected by fires and generate a daily smoke outlook § for keeping stakeholders informed of prevailing smoke levels.2020 is the first year during which CDC worked with IWFAQRP and deployed staff members as air resource advisors for wildfire incidents.From August 31 to September 14, 2020, one CDC staff member supported wildfire incidents in central Oregon's Cascade Range, which included Beachie Creek, Holiday Farm, Lionshead, and Riverside wildfires.Strong east winds across the Cascade Mountains resulted in >560,000 acres of fire growth during September 7-10 (1).Another CDC staff member was deployed for the Creek fire incident from September 20 to October 5, 2020.The Creek fire incident in the Southern Sierra Nevada region of California
BIOM-18. TUMOR LOCATION IS ASSOCIATED WITH CDKN2A STATUS IN IDH-MUTANT ASTROCYTOMAS
Authors: Jerome Graber, Patrick Cimino
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Astrocytomas with isocitrate dehydrogenase (IDH) mutations have a better prognosis and response to therapy than matching tumors without IDH mutations. IDH-mutant tumors of any grade or histology that carry homozygous deletions in cyclin-dependent kinase inhibitor (CDKN2A) have a worse prognosis compared to tumors with intact CDKN2A. Within a retrospective cohort of IDH-mutant astrocytomas with known CDKN2A status, we examined whether there was any correlation of CDKN2A status with anatomic location. METHODS Astrocytomas of any grade carrying IDH mutations with further molecular sequencing that included CDKN2A status were identified from a tissue database, as well as a clinical cohort of patients seen at the neuro-oncology clinic who had genomic analysis by clinical request. Imaging was reviewed for tumor location. Fisher’s exact test was used to analyze differences between groups. RESULTS Six of 35 IDH-mutant astrocytomas (17%) had CDKN2A deletions. None of the six patients with CDKN2A mutant tumors had contact with the insula, whereas 16 of 29 tumors (55%) with intact CDKN2A contacted the insula (p=0.02). The majority of tumors in both groups were located completely or partially in the frontal lobe, as is common in IDH-mutant astrocytomas, and all CDKN2A deleted tumors were in the frontal lobe. DISCUSSION Astrocytomas with IDH mutations that also carry CDKN2A deletions have been shown to have a worse prognosis than similar grade tumors with intact CDKN2A status. This has important prognostic implications, but CDKN2A testing is not standard currently or used to stratify patients in clinical trials. Our sample size is small, but if confirmed in a larger cohort could help guide efficient testing for CDKN2A status and improve prognostication.
MBRS-45. TWIST1 AND ABCB1 ARE FUNCTIONAL DETERMINANTS OF METASTASIS IN MEDULLOBLASTOMA
Authors: Alice Cardall, Franziska Linke, Ian Kerr, Beth Coyle
Journal: Neuro-Oncology (2020)

Abstract Paediatric medulloblastomas (MB) are frequently metastatic, resulting in a poor prognosis for the patient. Of the four MB subgroups, group 3 patients present with the highest rates of metastasis and worst outcomes. The mechanisms behind the metastatic process are poorly understood, limiting our ability to develop novel therapeutic treatments. We hypothesised that the epithelial-mesenchymal transition (EMT) transcription factor TWIST1 and the multidrug efflux pump ABCB1 (ATP-binding cassette subfamily B member 1) synergistically drive MB metastasis. TWIST1 protein expression was analysed in patient tissue microarrays by immunohistochemistry. High TWIST1 expression was associated with metastatic patients (p=0.041). Physical and functional interactions between TWIST1 and ABCB1 were investigated using chromatin immunoprecipitation (ChIP) and a 3D migration and invasion model. ChIP analysis confirmed TWIST1 binding to the ABCB1 promoter in SHH (ONS-76) and group 3 (D283MED and HD-MB03) metastatic cell lines. TWIST1 and ABCB1 were inhibited in HDMB03 cells with harmine and vardenafil respectively, resulting in attenuated cell migration in the 3D model. Western blot and qRT-PCR analysis of harmine treated cells confirmed a reduction in ABCB1 protein and gene expression. Overall our data reveals TWIST1 and ABCB1 to be key targets for MB metastatic disease. Using bioinformatics analysis and ChIP sequencing, additional TWIST1 downstream targets are now being identified and compared across the metastatic cell lines (ONS-76, D283MED and HD-MB03). This data will provide a deeper insight into the pathways associated with MB metastases, enabling personalised treatment approaches for patients with metastatic disease.