tbuckley/cabot-search huggingface dataset:
CSIG-45. RanBPM AS A PARTNER OF STAT5 REGULATES IFN-λ SIGNALING PATHWAY
Authors: Junwen Zhang, Wenhua Fan, Bo Zhang, Sheng Fang, Guishan Jin, Ruifang Mi, Mengmeng Zhang, Fusheng Liu
Journal: Neuro-Oncology (2018)

RanBPM (Ran-binding protein in the microtubule-organizing center, also known as Ranbp9) is a ubiquitous, nucleocytoplasmic protein whose function is poorly understood. RanBPM acts as a multi-modular scaffolding protein, bridging interactions between the cytoplasmic domains of a variety of membrane receptors and their intracellular signaling targets. In glioma rapid increases in the tyrosine phosphorylation of signal transducers and activators of transcription 5 (STAT5) proteins have been extensively documented in cells stimulated with cytokines and growth factors. However, the mechanisms by which STAT5 translocates to the nucleus and regulates proliferation in human glioblastoma multiforme cells have not been studied in detail. In this study, we are just discussing the interaction of RanBPM and STAT5. To confirm RanBPM as a binding partner of STAT5, GST pull-down and co-immunoprecipitation (Co-IP) assay were applied. And to map the binding site of the two proteins, various truncated plasmids were constructed and these plasmids were transfected with full length gene of RanBPM or STAT5, respectively. To reveal the biological function of RanBPM after interacting with STAT5A, we employed a luciferase reporter linked with a STAT5 binding element to examine the transcriptional activity of STAT5. In the GST pull-down and Co-IP assay, we confirm RanBPM can interact with STAT5. In the binding site experiment, the result revealed that the two domains of RanBPM, RanBPM-N and RanBPM-C were responsible for the linkage with STAT5. And the conserved binding sites of STAT5 take part in this association. In the dual-luciferase assay, the luciferase activity indicated that the overexpression of RanBPM enhanced the transcriptional activity of STAT5 in glioma cells (U87 MG and U251 MG). From these data, we conclude that RanBPM interact with STAT5 and plays a novel role in regulating transcriptional activity of STAT5.
NCMP-28. PTPRZ1-MET SIGNALING PROMOTES GLIOMA PROGRESSION THROUGH STIMULATION THE TRANSFORMATION FROM M1 TO M2 MACROPHAGE
Authors: Zhaoshi Bao, Zhiliang Wang
Journal: Neuro-Oncology (2018)

Tumor-associated macrophages (TAMs) have multiple functions in both inhibiting or promoting diversity tumors progression and correlated with increased intratumoral heterogeneity. PTPRZ1-MET (ZM) fusion has been implicated in the development of glioma and recently associated with an unfavorable prognosis for afflicted secondary glioblastoma (sGBM) patients, as well as temozolomide chemoresistance. The underlying mechanisms of ZM fusion and TAM in glioma still remain undefined. SsGSEA is a rank-based method that computes an overexpression measure for a gene list of interest relative to all other genes in the genome. The ssGSEA scores for M1-type and M2-type macrophage scores are standardized across all tumor with known M1-type and M2-type macrophage properties in previous reports. The influence of ZM fusion on macrophage conversion in glioma was explored by performing gene set enrichment analysis and in vitro and in vivo experiments. An orthotopic xenograft model was established in this study. Here, we first show that the ssGSEA score of M2-type macrophage is upregulated in ZM fusion positively gliomas and M2-type macrophage score is highly associated with glioma patient overall survival. Further studies illustrated that the abundant macrophages populations and M1–M2 polarization of macrophage are tightly controlled processes of the hyper-activation of PTPRZ1-MET signaling in vitro and in orthotopic xenograft model. Meanwhile, our data also indicate that distinct transcriptional networks in brain-resident microglia and recruited bone-marrow-derived macrophages (BMDMs) are influenced by PTPRZ1-MET signaling pathway. These data indicate that PTPRZ1-MET signaling contribute to glioma malignant progression by recruiting macrophages and facilitating M2-type to M1-type macrophages conversion and therefore provide a novel therapeutic target for the treatment of sGBM patients.
Abstract 17098: Evaluation of a Non-laboratory-based Cardiovascular Disease Risk Score in Predicting Cardiovascular Mortality in the Southern Community Cohort Study
Authors: Jai Singh, Edmond K Kabagambe, Meng Xu, Thomas A Gaziano, Thomas J Wang, William J Blot, Deepak K Gupta, Loren Lipworth
Journal: Circulation (2015)

Introduction: Cardiovascular disease (CVD) risk prediction guides clinical recommendations regarding primary prevention strategies. Recently, a non-laboratory-based CVD risk score was derived and validated in several populations. We evaluated the performance of the non-laboratory CVD risk score among individuals of low socioeconomic status in the southeastern US, with high CVD incidence rates. Methods: The Southern Community Cohort Study (SCCS) is a prospective cohort study of black and white adults enrolled primarily from community health centers in the southeastern US between 2002-2009. We calculated c-statistics and 95% confidence intervals (CI) to assess the performance of the non-laboratory risk score in discriminating 5- year risk of CVD death (ICD-10 I00-I99) in 14,243 participants (median enrollment age 51 yrs; 74% black, 71% female, 61% income &lt; $15,000 yr) with no history of MI/CABG or stroke at baseline and with complete data on all input variables (age, sex, smoking, diabetes mellitus, reported hypertension (HTN), measured SBP, and BMI). Reported HTN was substituted for anti-HTN therapy, used in the original risk score, because the latter was available only for a subset of the SCCS population. However, among this subset, 82% of individuals who reported HTN also reported use of anti-HTN drugs. Results: CVD risk factors were common: HTN (66%), smoking (59%), diabetes (29%), median SBP 130 mmHg, and median BMI 31 kg/m2. CVD death occurred in 263 participants (1.8%). The non-laboratory CVD risk score demonstrated poor discrimination for CVD mortality, with c-statistics of 0.65 (95% CI: 0.61-0.68) overall and 0.64 (0.59-0.69), 0.65 (0.6-0.7), 0.67 (0.63-0.71) and 0.58 (0.51-0.65) for males, females, blacks and whites, respectively. In an additional logistic regression model fit to the SCCS data, the inclusion of education and income did not substantially improve model performance; overall c-statistic 0.70 (0.67-0.73). Conclusion: In this population of predominantly low-income blacks and whites, a non-laboratory CVD risk score did not perform well in predicting CVD death in any of the race and gender groups. Future studies are warranted to develop algorithms for identifying individuals at increased CVD risk in low resource populations.
CMET-17. VENTRICULOMEGALY AFTER STEREOTACTIC RADIOSURGERY FOR BRAIN METASTASES
Authors: Ali Alattar, Brian Hirshman, Rushikesh Joshi, Clark Chen
Journal: Neuro-Oncology (2018)

Radiation therapy is a known risk factor for leukoencephalopathy and ventriculomegaly in patients with brain metastasis (BM). However, whether repeat stereotactic radiosurgery (SRS) contributes to these complications remains poorly studied. The question is pertinent since the cerebrum is exposed to a variable amount of radiation during each round of SRS. We performed a retrospective analysis of patients who underwent SRS for BM between 2007 and 2017 at our institution and had > 3 months of MRI follow-up. MRIs were assessed for ventriculomegaly based on published morphometric criteria. Statistical analysis was accomplished using Student’s t-test, Pearson’s chi-squared test, and univariate and multivariate logistic regression. We identified 214 patients who underwent 1,106 SRS for BM. Sixty-three patients (29%) presented with ventriculomegaly prior to SRS. Risk factors for presenting with ventriculomegaly prior to first SRS were female sex (odds ratio (OR) 0.373, 95% CI 0.176 - 0.767, p=0.008) and older age (OR 1.096, 95% CI 1.06 - 1.137, p< 0.001). Of the other 151 patients with normal ventricular size at the time of SRS, 29 patients (19%) developed ventriculomegaly after SRS. Of the 29 patients who developed ventriculomegaly, ten patients (34%) required operative CSF diversion for symptomatic relief. We identified two risk factors that were associated with increased odds of ventriculomegaly: receiving > 4 rounds of SRS (OR 4.1, 95% CI 0.8 - 20.6, p=0.038) and prior history of whole-brain radiation therapy (WBRT, OR 5.6, 95% CI 2.3 – 13.9, p< 0.001). The association between > 4 rounds of SRS and ventriculomegaly remained robust in patients without prior history of WBRT, which suggests that both forms of radiation contribute to the risk of developing new ventriculomegaly. Our results suggest that prior history of WBRT and > 4 rounds of SRS independently contribute to the risk of ventriculomegaly in SRS-treated BM patients.
ANGI-14. EPIGENETIC REACTIVATION OF BAI1 SUPPRESSES TUMOR INVASION BY PREVENTING TGFβ1-INDUCED MESENCHYMAL SWITCH IN GLIOBLASTOMA
Authors: Satoru Osuka, Liquan Yang, Dan Zhu, Narra Devi, Erwin Van Meir
Journal: Neuro-Oncology (2018)

Glioblastoma (GBM) is the most common and lethal type of malignant brain tumor in adults. GBM cells are highly invasive and diffusely infiltrate throughout the brain, which strongly restricts multimodal therapies. Acquiring a better knowledge of molecular defects underlying GBM invasion is essential for the development of effective therapies. Brain-specific Angiogenesis Inhibitor 1 (BAI1) is a transmembrane receptor of the adhesion GPCR family widely expressed in normal brain, but its expression is lost in the majority of human brain tumors. We have previously shown that BAI1 is epigenetically silenced in most GBM and restoration of its expression can inhibit glioma growth in vitro and in vivo (Zhu D. et al, Cancer Res, 2012). Recently, we reported that BAI1 protects p53 from Mdm2-mediated degradation and regulate tumor growth in medulloblastoma (Zhu D. et al, Cancer Cell, 2018). However, it is unclear whether BAI1 loss is important for tumor invasion in GBM. We found that restoration of BAI1 expression in GBM cells suppressed mesenchymal transition. Microarray analysis of the TCGA dataset revealed that BAI1 expression inversely correlates with the expression of many key mesenchymal genes, including Fibronectin1, SLUG, and TWIST1. Reduced BAI1 expression also correlates with poor outcome. Restoration of BAI1 expression suppresses mesenchymal gene expression and dramatically decreases GBM cell brain invasion in mice. Mechanistically, the N-terminal thrombospondin type 1 repeat (TSR#1) of BAI1 inhibits the maturation process of TGFβ1, a key growth factor involved in EMT. BAI1 is silenced epigenetically in GBM cells by MBD2, and its expression can be reactivated by KCC-07, a blood-brain barrier permeable MBD2 inhibitor. We found that GBM cells treated by KCC-07 exhibited decreased tumor invasion. These experiments demonstrate that epigenetic silencing of BAI1 is important for activation of the GBM invasive phenotype through TGFβ1 pathway activation. Epigenetic targeting of this process by KCC-07 can reduce GBM invasion.
CBMT-24. MITOCHONDRIAL DNA CONTENT IN GLIOBLASTOMA AND ITS CLINICAL SIGNIFICANCE
Authors: Palavalasa Sravya, Shilpa Rao, Vidya Nimbalkar, Nandaki Kanuri, Kruthika Banavathy, Arivazhagan Arimappamagan, Sampath Somanna, Vani Santosh
Journal: Neuro-Oncology (2018)

Evidence of altered mitochondrial DNA (mtDNA) content in several malignancies has surfaced in recent years. However, in glioblastoma, this aspect remains obscure. Hence, we have studied mtDNA content in glioblastoma at diagnosis and recurrence. Formalin fixed paraffin embedded tissue of newly diagnosed glioblastoma (n=100), paired recurrent glioblastoma (n=16 pairs) and non-neoplastic brain (n=30) archived in the department of Neuropathology, NIMHANS, were utilized for the study. Clinical details of the patients were obtained from files. IDH, ATRX and TERT promoter mutations, MGMT promoter methylation and EGFR amplification were assessed using immunohistochemistry, Sanger’s sequencing, methylation specific PCR and fluorescent insitu hybridization. mtDNA copy number was analyzed using quantitative real time PCR (relative quantification). The mtDNA content was calculated as percentage of normal using the formula 2- ΔΔCT x 100. Hence, for example, 20% mtDNA copy number means that if non-neoplastic brain tissue contains 100 copies of mtDNA, the tumor contains only 20 copies. mtDNA content was lower than non-neoplastic brain tissue (mean mtDNA copy number 19.8%) in all cases. Among them, the mtDNA content was significantly lower in older patients (p=0.04). Tumors expressing markers of aggressiveness had lower mtDNA content, though the difference was not statistically significant. Survival analysis using Cox regression showed that lower mtDNA copy number is associated with higher risk and hence poorer prognosis (Exp(B):0.97; p=0.045). Of the16 patients with recurrence studied, 7 had received radiation therapy (RT) while the others defaulted or recurred before initiation of RT. mtDNA content had increased at recurrence(mean:48.02%) when compared to the primary tumor(mean:20.32%) in all 7 cases who received RT. In the remaining 9 cases who did not receive RT, the difference was not statistically significant. Thus, for the first time, we show that lower mtDNA copy number is associated with poorer survival and earlier recurrence in glioblastoma and that RT may increase the mtDNA content.
Abstract 14746: Dynamic SIRTUIN1-modulated Lysine Acetylation of P66shc Governs Vascular Endothelial Oxidative Stress and Dysfunction of Diabetes
Authors: Santosh Kumar, Young Rae Kim, Ajit Vikram, Asma Naqvi, Ajay Kumar, Markus Bachschmid, Julia S Jacobs, Kaikobad Irani
Journal: Circulation (2014)

The SIRTUIN1 lysine deacetylase (SIRT1) ameliorates diabetic vascular dysfunction by epigenetically suppressing endothelial expression of the oxidative stress protein p66shc. However, whether SIRT1 modulates the oxidative function of p66shc by directly targeting it for lysine deacetylation is not known. Here we show that the oxidative function of p66shc is dynamically modulated by lysine acetylation. Mass spectroscopy identified lysine 81 in the unique CH2 domain of p66shc as the residue targeted by SIRT1. High glucose and SIRT1 knockdown stimulates acetylation of lysine 81 of endothelial p66shc. Compared to WT p66shc, non-acetylatable (K81R) p66shc is significantly handicapped in promoting endothelial hydrogen peroxide production stimulated by high glucose. Compared to WT p66shc, K81R p66shc is also less prone to serine 36 phosphorylation by high glucose, which is essential for the oxidative function of p66shc. Moreover, in contrast to WT p66shc which worsens endothelial dysfunction, expression of K81R p66shc does not impair endothelial function in wild type mice and rescues endothelium dysfunction of diabetic db+/db+ mouse aortas . These findings show that lysine 81 acetylation promotes the oxidative role of p66shc in hyperglycemic conditions, and is essential for p66shc-mediated endothelial dysfunction.
Efficacy and Safety of a Single Dose of Donor Lymphocytes Depleted of Alloreactive T-Cells (ATIR101) Following T-Cell-Depleted Haploidentical HSCT: A Pooled Analysis of Two Phase II Studies
Authors: Denis-Claude Roy, Irwin Walker, Johan Maertens, Philippe Lewalle, Eduardo Olavarria, Yves Beguin, Dominik Selleslag, Eva-Maria Wagner, Halvard Bonig, Gerard Bos, Stephan Mielke
Journal: Blood (2018)
TMOD-03. GLIOMAPDOX: A MOLECULARLY DIVERSE LIBRARY OF DIRECT-FROM-PATIENT ORTHOTOPIC GLIOMA XENOGRAFTS RECAPITULATES INTRATUMOR HETEROGENEITY
Authors: Nicholas Bayley, Lynn Baufeld, Laura Gosa, Danielle Morrow, Christopher Tse, Nikolas Balanis, Weihong Yan, Timothy Cloughesy, Linda Liau, Thomas Graeber, David Nathanson
Journal: Neuro-Oncology (2018)

The development of effective treatments for malignant brain tumors has been hampered by the lack of robust preclinical models that faithfully capture the high inter- and intra-tumor heterogeneity of the human disease. Conventional cell lines lose the most common genetic abnormalities of glioblastoma (GBM), while primary cultured cells do not account for the influences of the microenvironment and the blood brain barrier on tumor biology and drug efficacy. These systems are also under strong selection pressure divergent from that in vivo, leading to reduced heterogeneity between cultured tumor cells and an overall shift away from in vivo characteristics. Here we describe a biobank of direct-from-patient derived orthotopic xenografts (GliomaPDOX) that preserve the diverse genetic and transcriptional landscapes found in human GBMs. A paired comparison between matched patients, GliomaPDOX, and short-term primary cell cultures revealed transcriptional changes associated with altered nutrient availability and non-tumor cell interactions, emphasizing the impact of the tumor microenvironment on in vivo gene expression. Further, GliomaPDOX models preserved signatures of differentiated brain cell types recapitulating the intratumor heterogeneity of non-stem and stem-like cells found in patient tumors. These results are in contrast to those found in gliomapshere culture systems, where signatures of differentiated brain cells are abolished. Collectively these data show that GliomaPDOX is a model system that preserves defining molecular and anatomical characteristics of GBM and is well-suited for translational research investigations.
Utility of Gonadotropin-Releasing Hormone Agonists for Fertility Preservation: Lack of Biologic Basis and the Need to Prioritize Proven Methods
Authors: Volkan Turan, Giuliano Bedoschi, Kenny Rodriguez-Wallberg, Murat Sonmezer, Fernanda Silva Pacheco, Ozgur Oktem, Hugh Taylor, Kutluk Oktay
Journal: Journal of Clinical Oncology (2018)
CADD-33. PERSONALIZED PHARMACOGENOMICS USING GLIOMA PATIENT-DERIVED ORTHOTOPIC XENOGRAFTS (PDOXS)
Authors: Ann-Christin Hau, Anna Golebiewska, Anaïs Oudin, Linsey Houben, Daniel Stieber, Frank Hertel, Simone Niclou
Journal: Neuro-Oncology (2018)

It is well recognized that long term cell cultures are poor models to study human cancer, largely because of loss of clonal heterogeneity, accumulation or loss of genomic alterations and adaptation to a highly artificial environment. Patient-derived orthotopic xenografts (PDOX) based on organotypic three-dimensional tumor spheroids from human glioma samples are proposed to represent a reliable and clinically-relevant animal model. We have generated a living biobank of PDOX models from 34 glioma patients (grade III and IV), including longitudinal patient samples with matched recurrent tumors. Using an efficient orthotopic xenografting procedure we obtain an overall tumor take-rate of close to 80%. We show that our glioma PDOX retain the genetic and epigenetic profiles of primary patient biopsies throughout several generations of xenotransplantation. In particular they not only faithfully recapitulate gene amplification and expression of EGFR and EGFRvIII variant in a reproducible manner, also amplification and expression of rarer patient-specific EGFR variants is maintained. Overall genome-wide transcriptomic profiles of PDOX remain very similar to patient biopsies and correlate better with the GBM cohort of TCGA (538 GBM samples) than conventional cell lines. Observed differences at the transcriptomic level are largely based on the replacement of human to mouse stromal cells, which impacts on the molecular sub-classification of GBM. We conclude that glioma PDOX models closely reflect patient heterogeneity and treatment response, and thus represent appropriate avatars for reproducible pre-clinical trials. Furthermore, by combining profiling of the somatic mutational landscape with large-scale drug screening, PDOX-derived tumor organoids can elucidate druggable targets and tumor response profiles in a personalized patient-specific manner.
Hypertension—A Public Health Challenge of Global Proportions
Authors: Naomi D. L. Fisher, Gregory Curfman
Journal: JAMA (2018)

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TMIC-48. DYNAMIC OF MICROGLIA POLARIZATION IN GLIOMA TUMOR RESECTION AREA
Authors: Jescelica Ortiz, Gabriel Valentin-Guillama, Lidia Zuyeva, Lilia Kucheryavykh
Journal: Neuro-Oncology (2018)

All glioma tumors relapse after the surgical resection. Microglia is an important component of the tumor microenvironment and provides support for tumor growth. Both M1 pro-inflammatory and M2 pro-tumorigenic microglia were found in gliomas with predominance of M2. Surgical resection of brain tumors results in local tissue damage, causing microglial activation in the surgical area. We hypothesize that tumor resection provides signaling for microglial polarization modifications and exacerbates the malignant properties of the tumor cells that fail to be eliminated by resection, stimulating the tumor recurrence. The purpose of this study was to evaluate the dynamics of microglial polarization in the tumor resection area during the post-surgical period. C57BL/6/GL261 mouse glioma implantation model was used. M1 and M2 microglia were identified in area of tumor resection using western blot and immunofluorescent approaches (CD86, iNOS, CD206 and Arginase 1 were used as markers of M1 and M2 microglia). Study has been performed 0, 2 hours, 2, 6, and 10 days after the tumor resection. The dynamic shift in the immunological status of microglia have been found during the healing of the resected area. Up regulation of M2 microglia has been detected beginning 2 hours after tumor resection with further reduction by day 10. Same but less prominent dynamic of M1 microglia has been revealed. Electron microscopy demonstrated accumulation of phagocytic microglia in the immediate area of the resection edge with non-phagocytic microglia accumulated deeper in the tissue. These results suggest that the tumor resection procedure stimulates the polarization of both pro-tumorigenic M2 and inflammatory M1 microglia up to 10 days after tumor resection with the predominant accumulation of M1 microglia at the resection rim and accumulation of M2 deeper in the parenchyma. Acknowledgement: NIH Grants 1SC1GM122691 and R25GM110513.