tbuckley/cabot-search huggingface dataset:
EXTH-54. ENHANCED SENSITIVITY OF HUMAN GLIOMA CELLS FOR TEMOZOLOMIDE (TMZ) BY COMBINING THERAPY WITH HEAT SHOCK PROTEIN 90
Authors: Pratibha Sharma, Lakshmi Shree K Mahadevan, Aaron Argall, Jihong Xu, Deepa Sampath, Vinay Puduvalli
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Heat-shock protein 90 (HSP90) is a molecular chaperone involved in the conformational maturation of many client proteins that regulate cell proliferation, survival, and apoptosis. Due to the limited solubility of natural Hsp90 inhibitors, synthetic inhibitors with a more potent impact are being developed. In this study we examined the biological activity of a potent synthetic small molecule Hsp90 inhibitor, SNX-5422 (PF-04929113)and assessed its ability of to inhibit the growth of glioma and to synergize with temozolomide. We also examined the ability of SNX-5422 to cross the blood brain barrier (BBB) and to achieve target inhibition in vivo. METHODS Using a combination of in vitro techniques, the effect of SNX-5422 on the biological impact and HSP90 client protein signaling were studied in glioma lines and patient-derived glioma stem like cells. Its efficacy as a single agent or in combination with TMZ was also assessed in vitro. To assess SNX-5422 ability to cross blood brain barrier, brain and plasma pharmacokinetics was performed in non-tumor bearing mice. RESULTS SNX-5422 exhibited potent growth inhibition in both glioma cells and GSCs with an IC50 range of 100-500nM, and inhibited pro-survival signal kinases, phospho-Akt, p-ERK1/2 and p-S6 following treatment in GSC262 and GSC811. This was accompanied by accumulation of apoptotic cells following SNX-5422 exposure. Combination studies with TMZ showed a synergestic impact on glioma cell proliferation. Pharmacokinetics studies showed a significant drug penetrance into the intact brain further supported by elevated levels of HSP70 (molecular maker for HSP90 inhibition) by IHC. CONCLUSIONS SNX-5422 is effective in downregulating Hsp90 client proteins required for glioma cell survival. In addition, SNX-5422 inhibits tumor growth by promoting apoptosis through modulation of several key signaling pathways and sensitizes glioma cells to TMZ. Given also that SNX-5422 crosses BBB, it warrants further investigation as a clinical agent for treatment of gliomas.
HGG-35. PEDIATRIC PLEOMORPHIC XANTHOASTROCYTOMA WITH ANAPLASIA TREATED WITH SURGERY AND ADJUVANT CHEMOTHERAPY: A CASE SERIES OF 3 LONG-TERM SURVIVORS
Authors: Rebecca Ronsley, Christopher Dunham, Stephen Yip, Juliette Hukin, Sylvia Cheng
Journal: Neuro-Oncology (2020)

Abstract OBJECTIVE Pleomorphic xanthoastrocytoma (PXA) with anaplasia is a rare histological subtype of central nervous system astrocytoma and generally treated as high grade gliomas. The optimal extent of therapy required is unknown. Here we report on 3 pediatric cases of PXA with anaplasia. We also describe molecular features and methylation profile of PXA with anaplasia compared to age-matched PXA without anaplasia. METHODS Our institutional database was queried for cases of PXA since 1998 and 3 cases with anaplasia were identified and records reviewed. RESULTS 2/3 patients were male and all were aged 12 at diagnosis. All underwent a gross total resection (GTR), where the diagnosis of PXA with anaplasia was made. Immunohistochemistry demonstrated that two cases were BRAF V600E positive and two were CD34 positive. Methylation profiling revealed unique pattern of CpG methylation/unmethylation. All patients underwent 5400cGy radiation to the surgical bed. 2/3 patients received concurrent temozolamide with radiation followed by maintenance chemotherapy with temozolamide and lomustine for 6 cycles as per the Children’s Oncology Group Protocol ACNS0423. These two patients had a continued complete response. The third patient received temozolamide following radiation and subsequently had recurrent disease at the end of treatment and went on to have a re-resection GTR and achieved complete response after 6 cycles of lomustine, vincristine and procarbazine. All are alive with no evidence of disease at more than 2 years post treatment completion (OS=100%,EFS=67%). CONCLUSIONS This rare pediatric tumor is not well understood. The genetic landscape may be informative for optimizing treatment and prognosis.
PATH-19. MOLECULAR, HISTOLOGIC AND CLINICAL CHARACTERISTICS OF OLIGODENDROGLIOMAS: A MULTI-INSTITUTIONAL RETROSPECTIVE STUDY
Authors: Antonio Dono, Kristin Alfaro-Munoz, Yuanqing Yan, Carlos Lopez-Garcia, Zaid Soomro, Garret Williford, Takeshi Takayasu, Lindsay Robell, Nazanin Majd, John de Groot, Yoshua Esquenazi, Carlos Kamiya-Matsuoka, Leomar Y Ballester
Journal: Neuro-Oncology (2020)

Abstract In the 2016 WHO classification of CNS tumors, oligodendrogliomas are molecularly defined by IDH1 or IDH2 mutations and 1p/19q co-deletion. Some reports suggest that PI3K pathway alterations may confer increased risk of progression and poor prognosis in oligodendroglioma. However, factors that influence prognosis in molecularly defined oligodendroglioma (mOGD) have not been thoroughly studied. Also, the benefits of adjuvant radiation and temozolomide in mOGDs remain to be determined. 107 mOGDs diagnosed between 2008-2018 at the University of Texas Health Science Center at Houston (n= 39) and MD Anderson Cancer Center (n= 68) were included. A retrospective review of the demographic, clinical, histologic, molecular, and outcomes were performed. Median age at diagnosis was 37 years and 61 (57%) patients were male. There were 64 (60%) WHO Grade 2 and 43 (40%) WHO Grade 3 tumors. Ninety-five (88.8%) tumors were IDH1-mutant and 12 (11.2%) were IDH2-mutant. Eighty-two (77%) patients were stratified as high-risk: older than 40-years and/or subtotal resection (RTOG 9802). Gross-total resection was achieved in 47 (45%) patients. Treatment strategies included observation (n= 15), temozolomide (n= 11), radiation (n= 13), radiation with temozolomide (n= 62) and other (n= 6). Our results show a benefit of temozolomide vs. observation in progression-free survival (PFS). However, no benefit in PFS or overall survival (OS) was observed when comparing radiation vs. radiation with temozolomide. PIK3CA mutations were detected in 15 (14%) cases, and patients with PIK3CA-mutant mOGDs showed worse OS (10.7-years vs 15.1-years, p= 0.009). Patients with WHO Grade 3 tumors had shorter PFS but no significant difference in OS was observed compared to grade 2. Our findings suggest that mOGDs harboring PIK3CA mutations have worse OS. Except for an advantage in PFS in temozolomide treated patients, adjuvant treatment with radiation or the combination of both, showed no significant advantage in terms of OS.
A biomimetic model of 3D fluid extracellular macromolecular crowding microenvironment fine-tunes ovarian cancer cells dissemination phenotype
Authors: Rümeyza Bascetin, Carine Laurent-Issartel, Cécile Blanc-Fournier, Charlotte Vendrely, Sabrina Kellouche, Franck Carreiras, Olivier Gallet, Johanne Leroy-Dudal
Journal: Biomaterials (2020)
HGG-04. ZINC ENHANCES TEMOZOLOMIDE CYTOTOXICITY IN PEDIATRIC GLIOBLASTOMA MULTIFORME MODEL SYSTEM
Authors: Amos Toren, Michal Yalon, Aner Dafni, Ruty Mehrian-Shai
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Temozolomide (TMZ) is an alkylating agent that has become the mainstay treatment of the most malignant brain cancer, glioblastoma multiforme (GBM). Unfortunately only a limited number of patients respond to it positively. We have shown that zinc metal reestablishes chemosensitivity in adult GBM in vitro and also in vivo but this effect has not been tested with pediatric GBM. METHODS Using Human pediatric glioblastoma cell lines- KNS42 (mutant p53/ MGMT [+]) and SF188 (mutant p53/ MGMT [-]), we investigated whether addition of zinc to TMZ enhances its cytotoxicity against GBM. RESULTS In vitro cell viability analysis showed that the cytotoxic activity of TMZ was substantially increased with addition of zinc and this response was accompanied by an elevation of p21, PUMA, BAX and a decrease in growth fraction as manifested by low ki67. Beta gal analysis showed that most of the remaining cells after the combination therapy are in senescence state. In order to eliminate the senescent population created as a result of the combined treatment of TMZ and Zinc, we decided to use a senolytic agent Navitoclax (ABT-263) that was demonstrated to be effective in reducing senescent cells by specific inhibition of Bcl-2, Bcl-XL and Bcl-w. Following the addition of Navitoclax to the combined treatment, SF188 cells, but not KNS42, show a significance reduction in viability compare to the combination treatment. CONCLUSIONS Our results suggest that zinc may serve as a potentiator of TMZ therapy in pediatric GBM patients and using a second hit with senolytic drug in some cases may be even more beneficial.
BIOM-13. DNA METHYLATION MARKS GLUCOCORTICOID PATHWAY RESPONSE IN DEXAMETHASONE-TREATED BRAIN TUMOR PATIENTS
Authors: John Wiencke, Annette Molinaro, Gayathri Warrier, Terri Rice, Jennifer Clarke, Jennie Taylor, Margaret Wrensch, Stanley Tamaki, JiYoon Lee, Helen Hansen, Lucie McCoy, Paige Bracci, Lucas Salas, Devin Koestler, Brock Christensen, Karl Kelsey
Journal: Neuro-Oncology (2020)

Abstract Dexamethasone (DEX) is routinely prescribed in brain tumor patients to limit vasogenic edema but may also exacerbate immunosuppression and adversely affect survival. The wide spectrum of dosing and individual variation in glucocorticoid (GC) response makes it difficult to assess the impact of DEX exposures. A potential marker of steroid pathway activation and GC load affecting the immune system are induced changes in chromatin structure marked by DNA methylation. We identified DEX-responsive DNA methylation sites in blood leukocytes from glioma patients treated with the drug at various doses and times during the course of their disease. Using weighted co-methylation network analysis, we show that DEX-induced hypomethylation includes well-known regulators of GC receptor (GR) sensitivity (e.g., FK506 binding protein 51: FKBP5) and inflammation (e.g., myeloperoxidase: MPO) and is enriched at genomic locations containing glucocorticoid receptor (GR) binding sites. Elastic net regression modeling was used to train a multilocus GC methylation index (GCMI) that discriminates current DEX users and non-users. GCMI scores showed wide interindividual variation among cases and DEX naïve control subjects. Using independent samples of DEX naïve and exposed glioma patients we show that the GCMI is a sensitive and specific indicator of DEX exposure. GCMI measured in non-glioma controls indicated sensitivity to non-DEX steroid treatments (e.g. prednisolone, fluticasone). Subjects with elevated neutrophil and decreased lymphocyte counts demonstrated high GCMI scores, reflecting the clinically relevant in vivo impact of this marker. Among 195 IDH wildtype and hTERT non-mutant glioma subjects, the GCMI was associated with a HR of 1.11 (95% CI 1.06–1.17) p&amp;lt; 0.0001 in Cox survival models that included age and tumor grade. We conclude that epigenetic remodeling in the peripheral immune compartment in response to DEX exposures is a rich source of potentially powerful markers of individual response to GC pathway activation and associated alterations in the immune response.
MBRS-18. TUMOR SUPPRESSOR p53 DEFINES THE THERAPEUTIC RESPONSES IN TREATMENT OF MEDULLOBLASTOMA
Authors: Avinash L Mohan, Anubhav G Amin, Michael E Tobias, Mohan K Das, Raphael S S de Medeiros, Nelci Zanon, Chirag D Gandhi, Sidnei Epelman, Meena Jhanwar-Uniyal
Journal: Neuro-Oncology (2020)

Abstract Medulloblastoma (MB) is the most common primary pediatric malignant brain tumor. Current molecular analysis classifies MB into 4 groups, classic (WNT), sonic hedgehog (Shh), group 3, and group 4. Furthermore, atypical p53 signaling is associated with disease progression and confers poor prognosis. This study investigated the correlation of mutational status of p53 and iSO17q with disease progression and metastatic potential. In addition, we used small molecule inhibitors of PI3K (Buparlisib; BKM120) and HDAC (LBH-589) on a p53-mutant MB cell line to find novel therapeutic targets. Efficacy of these drugs were assessed using functional assays (cell proliferation, migration, cell cycle and drug resistance). MB tumors (n=53) were evaluated for GLI-1, GAB-1, NPR, KV1, YAP expression and mutant p53 via immunohistochemistry and correlated to patient outcomes. Results demonstrated that: 1) high expression of GAB-1 and YAP were found in the Shh group, while KV1 expression was present in all subtypes; 2) mutant p53 expression was present in various subsets of MB with no apparent correlation with metastasis or disease progression; 3) patients displaying iSO17q (determined by fluorescence in situ hybridization (FISH) technique) exhibited metastatic disease; 4) LBH-589 and BKM120 caused both time and dose-dependent inhibition of MB cell proliferation and migration; 5) combined treatment of BKM120 and LBH-589 had a synergistic effect; 6) MB cells demonstrated drug-resistance to BKM120. In conclusion, these findings underscore use of Buparlisib and LBH-589 in treatment of MB. Further, the role of mutant p53 in disease progression remains elusive, whereas presence of iSO17q defines metastatic potential.
TAMI-60. EXPLORING METABOLIC DIFFERENCES IN VARYING GRADES OF MENINGIOMAS THROUGH NONTARGETED MASS SPECTROMETRY
Authors: Zach Rabow, Taryn Morningstar, Mirna Lechpammer, Oliver Fiehn
Journal: Neuro-Oncology (2020)

Abstract Emerging molecular data demonstrates the importance of genomic and epigenetic factors in pathogenesis of meningioma. Understanding the metabolic landscape using mass spectrometry is needed to overcome significant uncertainty in predicting tumor behavior and the risk of recurrence. Current technologies lack sensitivity and selectivity, which hinders the discovery of potential novel diagnostic and prognostic features. Here, we present a nontargeted metabolomics approach applied to meningiomas for biomarker discovery and identification of potential therapeutic targets. Fresh frozen tissue from 36 patients (57% women, 43% men; mean age: 48) who underwent surgical resection for newly diagnosed meningiomas and 9 patient samples with non-neoplastic dura were used for case/control comparison. Additionally, 16 patient-derived meningioma cell lines (Grade I-III), 2 immortalized human cell lines (IOMM-Lee and Ch157MN) and immortalized arachnoid cells were used to further explore metabolic changes in meningiomas. Metabolites were extracted from tissue and cells for GC-TOF (primary metabolism), RPLC ESI (±) (lipidomics) and HILIC ESI (±) (biogenic amines) coupled to high-resolution mass spectrometry for analysis. Metabolites were identified using authentic standards, retention time, and MS2 fragmentation. Over one thousand known metabolites were identified and annotated as well as over 300 unknown metabolites. Metabolites were grouped into one of fifteen classes based on chemical ontology and function. Bis(monoacylglycero)phosphates were over 2-fold increase in atypical (Grade II) meningiomas versus Grade I, indicating lysosomal activation. One carbon metabolism pathway showed significant upregulation in neoplastic tissue vs. tumor involved dura, as well as neoplastic cells compared to arachnoid cells, indicating folate-dependent pathways as a potential therapeutic target. Using novel combined untargeted metabolomics, we found multiple classes of metabolites that were either enriched or suppressed in neoplastic tissue and cells compared to non-neoplastic cells. Further studies are warranted for a better understanding of possible oncogenic signaling pathways and to detect potential biomarkers useful for diagnosis and treatment.
Abstract P218: Dietary Prescription in the Coronary Care Unit, Missed Opportunity to Improve Care?
Authors: Mohammed Al-Sadawi, Muhammad Ihsan, Adekunle Kiladejo, Judith E Mitchell
Journal: Circulation (2020)

Introduction: A notable portion of the excess burden of cardiovascular disease [CVD] risk factors in African Americans [AA] is believed secondary to the diet. Hypothesis: Dietary assessment and prescribed diets are inadequate in patients admitted to the coronary care unit [CCU]. Results: Cohort: 267 consecutively patients, AA 83%, male 55%, mean age 65 yrs, were assessed for cardiovascular [CV] risk factors, clinical status and appropriateness of prescribed diets. Patients were at increased CV risk as evidenced by 65% older than 60 yrs, Body Mass Index (BMI) &gt;30 in 40% with women almost twice as likely to be obese [p&lt;0.006], history of smoking 55%, hypertension 90%, diabetes 54%, and mean ejection fraction 43%. Established CAD acknowledged in 60%. Breakdown of diet orders: normal diet 11%, diabetic diet 38% and a form of low sodium, low cholesterol diet in 51%. CCU length of stay: 2.5 days with no significant difference by sex, diabetic or obesity status. Dietary assessment documentation was missing in 40% of the CCU admissions. A significant percentage of the patients missing this documentation were women [45%], diabetics [47%], obese--BMI&gt;30 [42%] and older--age &gt;60 [68%]. Incongruence is seen between the disease burden and the appropriate dietary order. For example, 54% of patients had DM. However, only 38% were given a diabetic diet. A form of low Na diet was provided to 51% of the patients yet 90% of them were hypertensive or had a history of hypertension. The statistic, dietary assessment not recorded in 40% of the patients, may have been affected by the relatively short CCU stay. One limitation of our study is that we did not examine if this decreased dietary assessment rate was affected by week-day vs. weekend stay in the CCU or by the severity of the patient’s illness. Conclusion: Dietary assessment and appropriate dietary prescription matters. Recent studies show that dietary pattern is one of the largest mediating factors for differences in the incidence of CV risks, i.e. hypertension, in blacks vs. whites accounting for some of the excess risk among blacks. Not adequately addressing nutrition in a CCU setting leads to the loss of a critical teachable moment.
CBIO-08. ASTROCYTE SENESCENCE CONTRIBUTES TO SEX DIFFERENCES IN GLIOBLASTOMA INCIDENCE AND OUTCOME
Authors: Lauren Broestl, Gina Rhee, Lucia Grandison, Jasmin Sponagel, Najla Kfoury, Cameron Hill, Joshua Rubin
Journal: Neuro-Oncology (2020)

Abstract Sex differences in incidence and outcome are consistently observed in cancer, including in the most common malignant brain tumor – glioblastoma (GBM). Women are less likely to develop GBM and have a survival advantage compared to men. Previous research from our lab identified the proteins Rb, p16, and p21 as key mediators of female protection against cellular transformation. Strikingly, these proteins are all primary components of the senescence response, a potent cell-intrinsic anti-cancer mechanism that results in permanent cell cycle arrest, preventing proliferation of damaged cells. We hypothesized that sex differences in GBM incidence and outcome are mediated by differences in senescence induction after DNA damage in male and female cells. Using both wildtype astrocytes and a GBM model, we found that females have a lower threshold for senescence induction in response to oxidative stress, telomere shortening, and treatment with chemotherapy or radiation. Following irradiation, female GBM model cells had higher levels of p21 expression, and p21 levels correlated with the percentage of senescent cells. Knocking out p21 eliminated sex differences in the senescence response following irradiation. Achieving a better understanding of mechanisms of senescence and how they differ in male and female cells could advance development of senescence-directed therapies and potentially improve treatment for brain tumors.
急性心筋梗塞の日本人患者における冠再疎通効果に関する組換え組織型プラスミノゲン-アクチベータ(RT-PA、アルテプラーゼ)の最初のボーラス投与量の差異
Authors: Ogawa H, Oshima S, Ogata Y
Journal: Circulation (1993)
TMOD-10. EFFECT OF BRAIN TUMORIGENESIS ON CEREBRAL CORTICAL FUNCTIONAL CONNECTIVITY IN THE MOUSE
Authors: Samuel Cramer, Laurentiu Popa, Samuel Haley, Sanjay Dhawan, Russell Carter, Jianfang Ning, Justin Aronson, Suhasa Kodandaramaiah, Timothy Ebner, Clark Chen
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Neuro-cognitive decline is near universal in glioblastoma patients and negatively impacts the quality of life for afflicted patients. Yet, there is little information on longitudinal effects of brain tumor growth on cerebral cortical function and network connectivity. OBJECTIVE To address this knowledge gap, we examined in vivo Ca2+ imaging in a transgenic murine glioblastoma model. METHODS Mesoscopic Ca2+ imaging was performed after implant of GL261 glioblastoma cells into a transgenic mice strain (Thy1-GCaMP6f) that expresses the fast calcium indicator GCaMP6f in Layer II/III and Layer V pyramidal neurons. Independent component analysis (ICA), correlation matrix and graph theory approaches were used to assess changes in network connectivity. RESULTS ICA defined canonical cerebral network consisting of nodal convergence and connectivity between nodes. The overall network structure remained unaltered after tumor implant. A decrease in the strength of connectivity was observed immediately following tumor implant. This temporary suppression was followed by progressive, global increase in the strength of nodal connectivity (p &amp;lt; 0.0001). By two weeks post-tumor implant, 50% of the nodes exhibited increased connectivity compared to baseline. Progressive activation of select nodes was also observed in the weeks following tumor implant (p &amp;lt; 0.01). In aggregate, these results suggest that activation of select network nodes as well as enhanced connectivity as means to compensate for the deleterious effects of glioblastoma growth. CONCLUSIONS Our results indicate that focal brain tumor growth induces a reorganization of both local and remote cortical activity. The finding bears pertinence to the pathogenesis of neuro-cognitive decline and tumor-associated epilepsy.