tbuckley/cabot-search huggingface dataset:
TMIC-24. TUMOR-SUPPRESSIVE AND ANTI-INFLAMMATORY microRNA-93 IS DECREASED IN GLIOBLASTOMA PATIENTS
Authors: Max Hübner, David Effinger, Christian Hinske, Nicholas Möllhoff, Friedrich-Wilhelm Kreth, Simone Kreth
Journal: Neuro-Oncology (2018)

Differential expression of microRNAs (miRs) during inflammation and hypoxia is increasingly appreciated as central driver of glioblastoma (GBM) progression. As miR-93 inhibits expression Interleukin(IL)-8, we hypothesized that miR-93 might be a key regulator of inflammation within the GBM microenvironment. Stereotactically obtained GBM specimens were analysed by qRT-PCR. U87 cells were transfected with miR-93 by electroporation and subsequently incubated with IL1b in 5% O2 to mimic the GBM microenvironment. Whole transcriptome microarrays were processed and analyzed by bioinformatics. Invasion and angiogenesis were studied using U87 cell migration and endothelial tube formation assays. Expression levels were measured by qRT-PCR, multiplex assays, and SDS-PAGE (HIF1A, MAP3K2). Binding of miR-93 to 3`UTRs was analysed by luciferase reporter assays. Experiments were performed in triplicates at least 4 times. Results are presented as mean±SEM. P-Values were calculated using Student’s t-test. GBM specimens (n=33) and primary cell lines (n=5) revealed decreased levels of miR-93 compared to normal brain tissue (-55.6%±14% and -72.2%±22.3% p<0.05). Supernatants of miR-93-transfected U87 cells impaired U87 cell migration and attenuated angiogenesis of endothelial cells (migration:-58%±12.2%; angiogenesis:-62.4%±19.1%, n=5, p<0.05). Transfection of miR-93 resulted in strong repression of inflammatory genes as shown by transcriptome analyses and qRT-PCR (IL6:-89.6%±15.6%; IL8:-86.4%±16.5%; IL1b:-69.8%±13%; LIF:-59.7%±5.,9%, CSF3:-88.8%±17.9%; COX2:-76.3%±14.2%, CXCL5:-74.2%±13.8%, MAP3K2:-39.5%±20.9%; HIF1A:-15.4%±1.5%; n=4, p<0.05). Luciferase activity of five 3`UTR reporters were significantly quenched after miR-transfection (IL6:-29.2%±10.8%; LIF:-22%%±6.5%; CSF3:-31.8%±10.7%, MAP3K2:-45.3%±21.7%; HIF1A:-32.9%±8.4%, n=5, p<0.05), while COX2, CXCL5 exhibited no decrease. Combined knockdown of MAP3K2 and HIF1A significantly reduced COX2- and CXCL5 levels thus proving indirect regulation (-39%±4.3% and -25.9%±7.1%, respectively, n=8, p<0.05). These results suggest an anti-inflammatory and tumor suppressive role of miR-93. Through direct targeting of proinflammatory cytokines, MAP3K2, and HIF1A, miR-93 reduces tumor-initiated inflammation and inhibits shaping of a tumorigenic microenvironment. MiR-93 thus might be a promising target in new GBM treatment strategies.
Abstract 16157: Single Measurement of GDF-15 Provides Reliable Prognostication of Stroke and Major Bleeding in Atrial Fibrillation
Authors: Lars Wallentin, Ziad Hijazi, Ulrika Andersson, Bertil Lindahl, Christopher B Granger, John H Alexander, Dan Atar, Bernard J Gersh, Michael Hanna, Veli-Pekka Harjola, John D Horowitz, Steen Husted, Elaine M Hylek, Renato D Lopes, John J McMurray, Agneta Siegbahn
Journal: Circulation (2014)

BACKGROUND: GDF-15 level was recently shown to predict stroke, mortality and bleeding in anticoagulated patients with atrial fibrillation (AF). However, the variability in GDF-15 levels over time a...
SURG-14. ANALYSIS OF TREATMENT RESULTS FOR RECURRENT GLIOBLASTOMA INCLUDING IMMUNE STATUS ALTERATION
Authors: Kyoung Su Sung, Tae Hoon Roh, Ju Hyung Moon, Eui Hyun Kim, Seok-Gu Kang, Se Hoon Kim, Jong Hee Chang
Journal: Neuro-Oncology (2018)

This study was designed to analyze our treatment results for recurrent GBM (rGBM) and to investigate the change of molecular expression, including C3, programmed death-1 (PD-1), and programmed death-ligand 1 (PD-L1) on paired primary and recurrent tumor specimens of GBMs and to evaluate the influence of their changes for patients survival. From 2004 to 2015, 170 patients with rGBM were included. Forty-three patients (25.3%) were selected for 2nd operation upon recurrent disease (re-operated group) and 127 patients did not undergo 2nd operation (non-operated group). We also evaluated immunohistochemical expression of immunologic markers of 43 paired surgical specimens from the 1st and 2nd operation. Median overall survival after recurrence (rOS) of re-operated group showed significant longer than that of non-operated group (median: 9.1 months vs 5.6 months, P=0.024), The re-operated group showed relative younger age, better Karnofsky performance scale (KPS), and lower rate of leptomeningeal seeding, and eloquent area involvement. In re-operated group, higher KPS and extent of resection was significantly associated with longer rOS. Among 43 paired surgical specimens from the 1st and 2nd operation, positive expression of PD-L1 was 17 patients (39.5%) after 1st operations and 6 patients (13.9%) after 2nd operations. Changes of PD-L1 expression rate after recurrence were as follows; increased group (n=5, 11.6%), decreased group (n=13, 30.2%), and no change group (n=25, 58.1%). The PD-L1 expression and changes of PD-L1 expression did not affect the survival after recurrence. C3 and PD-1 tumor infiltrating mononuclear cells were not detected in almost all initial and secondary specimens. In some selected patients with a recurred GBM, re-operation could be good treatment option. The PD-L1 expression from the 1st and 2nd operation and changes of PD-L1 expression after recurrence did not influence on survival for GBM patients. However, it needs further investigations to reveal the role of immunity in GBM.
HOUT-15. CIRCULATING BLOOD CELL COUNTS AS POTENTIAL BIOMARKERS OF OUTCOMES IN RECURRENT GLIOBLASTOMA PATIENTS TREATED WITH BEVACIZUMAB
Authors: Eugene Vaios, Sebastian Winter, Alona Muzikansky, Brian Nahed, Jorg Dietrich
Journal: Neuro-Oncology (2018)

There is a lack of biomarkers to identify patients who may benefit from specific salvage therapies in glioblastoma (GBM), such as from the anti-angiogenic agent bevacizumab. We have recently shown that leukopenia is a potential biomarker for overall survival (OS) in patients with newly diagnosed glioblastoma treated with chemoradiation. We hypothesize that circulating blood counts may also serve as a potential biomarker of overall outcome in patients with progressive GBM treated with bevacizumab. Complete blood counts (WBC, RBC, and PLT, and relative blood counts of monocytes, neutrophils, eosinophiles and basophiles) and clinical and radiographic information were collected retrospectively from GBM patients with progressive disease and treated with bevacizumab monotherapy. 92 patients (60.87% male and 39.13% female) with progressive GBM were identified. The length of bevacizumab (10mg/kg q2 weeks) ranged from 21 to 984 days (M = 152.48d SD = 158.67d). OS following initiation of bevacizumab ranged from 41 to 984 days (M = 233.94d SD = 176.42d). Using a cox proportional hazard model, we found no significant changes in total white blood counts, red blood counts, lymphocytes, neutrophils, basophils, eosinophiles and monocytes over the course of bevacizumab therapy. Unlike our prior findings in newly diagnosed GBM, WBCs did not show any correlation with overall outcome (OS, PFS). However, we found that increases in platelet counts during bevacizumab therapy were associated with a strong trend in improved OS (p=0.059). Age, sex, and steroid use during treatment were not predictive of clinical outcomes. Consistent with the literature, MGMT promotor methylation was associated with improved OS (p=0.0103). Changes in circulating blood counts might serve as biomarkers of response to bevacizumab and overall outcome. The correlation of improved OS in patients with recurrent GBM and increases in platelet counts during bevacizumab therapy warrants further investigation and prospective studies.
Abstract 16487: Effectiveness and Safety of Apixaban versus Other Oral Anticoagulants in Older Adults With Non-Valvular Atrial Fibrillation and Concomitant Coronary Artery Disease or Peripheral Arterial Disease
Authors: Renato D Lopes, Manuela Di Fusco, Allison Keshishian, Xuemei Luo, Xiaoyan Li, Cristina Masseria, Melissa Hamilton, Keith Friend, Kiran Gupta, Jack Mardekian, Xianying Pan, Onur Baser, W Schuyler Jones
Journal: Circulation (2017)

Introduction: Coronary artery disease (CAD) and peripheral arterial disease (PAD) are common comorbidities that are often presented in conjunction with non-valvular atrial fibrillation (NVAF) and h...
P14.124 EORTC 1709/CCTG CE.8: A phase III trial of marizomib in combination with standard temozolomide-based radiochemotherapy versus standard temozolomide-based radiochemotherapy alone in patients with newly diagnosed glioblastoma
Authors: P Roth, J Reijneveld, T Gorlia, F Dhermain, F De Vos, M Vanlancker, C O’Callaghan, E Le Rhun, M van den Bent, W Mason, M Weller
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND The standard of care for patients with newly diagnosed glioblastoma includes maximal debulking surgery followed by radiotherapy (RT), and concomitant as well as maintenance therapy with the alkylating agent, temozolomide (TMZ). However, the prognosis remains poor and novel treatment strategies are urgently needed. Targeting the proteasome has been considered a promising anti-cancer approach for several years. Marizomib is a novel, irreversible and pan-proteasome inhibitor, which crosses the blood-brain barrier and has been assessed in phase I trials in patients with newly diagnosed or recurrent glioblastoma. MATERIAL AND METHODS EORTC 1709/CCTG CE.8 is a randomized, controlled, open label phase III superiority trial. Patients with histologically confirmed newly diagnosed glioblastoma and a performance status &gt;70 are eligible. Patients are randomized in a 1:1 ratio to receive standard of care (TMZ/RT→TMZ) alone or TMZ/RT→TMZ plus marizomib. The study aims at enrolling 750 patients. Stratification factors include study site, age, performance status and extent of resection. The primary objective of this trial is to compare overall survival in patients receiving marizomib in addition to standard of care with those receiving standard treatment only. The testing strategy specifies the determination of this objective in the intent-to-treat population as well as the subgroup of patients with MGMT-unmethylated tumors. Secondary endpoints include progression-free survival, safety, neurocognitive function and quality of life. A translational research program has been set up. The study will be activated at approximately 50 EORTC sites across Europe, 25 sites in Canada and additional sites in the US. Patient recruitment started in June 2018 and as of April 29, 2019, a total of 164 patients have been randomized. An update on the enrolment status will be provided at the EANO meeting. ClinicalTrials.gov Identifier: NCT03345095
NIMG-29. IN SILLICO BRAIN TUMOR MODELS FOR VALIDATING NEW DYNAMIC MR IMAGING METHODS PRIOR TO CLINICAL TRIALS
Authors: Junzhou Chen, Leah Henze Bancroft, Jorge Jimenez, Roberta Strigel, Azam Ahmed, Walter Block
Journal: Neuro-Oncology (2018)

New dynamic MRI methods hold promise in better characterization of the complex structure and heterogeneous treatment response of brain tumors. These methods utilize assumptions to reduce the data samples needed to produce high temporal and spatial resolution images with complex, iterative reconstructions. Determining how these methods depict actual brain tumor pathology is difficult due to lack of a gold standard. We therefore tailor an existing digital tool, built originally to simulate dynamic MRI breast studies, to assess the performance of new dynamic methods if applied to brain cancer. The tool permits a tumor of customizable shape featuring an inner core and an adjustable surrounding rim to be overlaid on a digital 3-D brain model, which we acquired from an online database called BrainWeb, with segmented brain tissue layers. We used existing capabilities in the tool to assign pharmacokinetic parameters to each tumor region to simulate necrotic cores and rims of varying width that represent spatially varying levels of enhancement due to tumor pathology and/or radiation necrosis. The tool then computes the corresponding MR k-space data for any proposed MR sampling trajectory during a simulated passage of a contrast agent. The simulated MR k-space data can then be input to any proposed reconstruction to produce a simulated time course of image volumes. Performance of proposed dynamic MR imaging methods can be measured against the digital truth prior to clinical trials through methods including: the structural similarity (SSIM) index over the lesion region-of-interest, comparing calculated vs. assigned pharmacokinetic parameters, and root-mean-square error. We are using this tool to estimate the performance, in brain applications, of a 3-D radial acquisition and reconstruction method with compressed sensing and local low rank that was previously demonstrated to produce 0.8 mm resolution in a 10 second frame rate in bilateral breast screening.
COMP-15. META-ANALYSIS OF CANCER CELL LINES BASED ON THEIR RESPONSE TO TUMOR TREATING FIELDS (TTFIELDS)
Authors: Moshe Giladi, Gitit Lavy-Shahaf, Rosa S Schneiderman, Karnit Gotlieb, Einav Zeevi, Yaara Porat, Mijal Munster, Uri Weinberg, Eilon Kirson
Journal: Neuro-Oncology (2018)

Tumor Treating Fields (TTFields) therapy (low intensity, intermediate frequency (100–300 kHz alternating electric fields) is an approved modality for the treatment of glioblastoma. TTFields were shown to exert an inhibitory effect on numerous cancer cell lines with some variability in the response of different cell lines. The goal of the present study is to compare characteristics of cell lines based on their response pattern to TTFields. Forty different human cancerous cell lines were treated for 72 hours with TTFields at optimal cell-specific frequency at the same nominal intensity (1.7 V/cm). Cell survival and clonogenicity were determined. Functional analysis of differentially expressed genes and mutations associated with response to TTFields was performed based on the Cancer Cell Line Encyclopedia (CCLE) database. Sensitivity to TTFields was compared with pharmacological profiling (CCLE). TTFields application demonstrated varying degree of cytotoxic effect in all cell lines tested. The inhibitory response to TTFields was found to be distributed around an average of 50% with a cytotoxic effects ranging between 14% and 86% reductions in cell counts, and a clonogenic effect ranging between no effect and 88% reduction in the number of colonies. Pharmacological profiling based on IC50 values, revealed increased sensitivity to: Lapatinib, PHA-665752 and PLX-4720 within the group of cell lines which were less sensitive to TTFields. Functional analysis of cell line gene expression and mutation data revealed enriched pathways related to DNA damage repair response, cell migration, hypoxia signaling and oxidative stress. This meta-analysis of cancerous cell line response to TTFields demonstrates the broad effectiveness of TTFields in various cell lines and define the optimal frequency to be applied for each. The data presented in this work suggest that beside their anti-mitotic properties, TTFields may have effects on other cellular pathways. Pharmacological profiling may offer a rational for combining specific agents with TTFields.
An LC/MS/MS based method to analyze tissue eicosanoids: Application to EPA-mediated alteration of prostaglandin metabolism
Authors: Peiying Yang, Russell D. Klein, Edward Felix, Diana Chan, Timothy Madden, Robert A. Newman
Journal: Cancer Research (2004)

3912  While specific eicosanoid metabolites have clearly been shown to contribute to tumor cell growth and proliferation in vitro, the role of eicosanoids in etiology and progression of cancer in vivo is far from clear. To approach this problem, it was necessary to develop an analytical method capable of accurately determining multiple eicosanoids within tissues and tumor specimens. Previously, we reported rapid, specific and sensitive LC/MS/MS methods to simultaneously analyze major COX and LOX metabolites in cancer cell lines (Kempen et al., Anal. Biochem. 297: 183, 2001; Yang et al., Anal. Biochem. 308: 168, 2002). We now report a modification of this method to examine endogenous levels of eicosanoids of interest in tissues. Frozen tissues were pulverized followed by homogenization with an ultrasonic processor. Homogenates were subjected to extraction by hexane:ethyl acetate and eicosanoids were quantified by LC/MS/MS. Using this method, we are able to identify various prostaglandins (PGE2, PGE3, PGD2, PGA2, 15-deoxy-12,14 delta-PGJ2), HETEs (5-, 8-, 12-, 15-) and HODEs (9- and 13-) in a variety of tissues, including mouse prostate, skin, and various human xenograft tumors. Extraction efficiency for PGE2, 15-, 12-, 5-HETEs and 13-HODEs from tissue homogenates ranged from 51.2% to 91.0%. Quantitative determination is linear (r2 & congruent; 0.99) for the above five metabolites in the range tested (1 to 100 ng/ml) with CVs ranging from 9.8 to 18.8%. To demonstrate this method, mice (wild type and TRAMP) were fed on a modified AIN-diet with either high corn oil or high menhaden oil (rich in EPA and DHA) for 2 weeks. Prostate lobes were collected and tissues were subjected to extraction and analysis for eicosanoid profiles. As reported previously, the mean endogenous levels of PGE2 were found to be significantly lower in the dorsal prostates of TRAMP mice compared to their wild type (1.24 versus 6.83 ng/mg protein, respectively). By comparison, levels of PGE3 were significantly increased (3-fold) in the prostates of both TRAMP and wild type mice receiving the fish oil diet for two weeks (P
Interleukin-12p35 knockout promotes macrophage differentiation, aggravates vascular dysfunction, and elevates blood pressure in angiotensin II-infused mice
Authors: Jing Ye, Bin Que, Ying Huang, Yingzhong Lin, Jiangbin Chen, Ling Liu, Ying Shi, Yuan Wang, Menglong Wang, Tao Zeng, Zhen Wang, Haiying Hu, Yao Xu, Lei Shi, Di Ye, Jianfang Liu, Huimin Jiang, Jun Wan, Qingwei Ji
Journal: Cardiovascular Research (2018)

Numerous studies have demonstrated that inflammation is involved in the progression of hypertension. Inflammatory cytokines interleukin (IL)-12 and IL-35 belong to the IL-12 cytokine family and share the same IL-12p35 subunit. Accumulating evidence has demonstrated that IL-12p35 knockout (IL-12p35 KO) leads to cardiovascular disease by regulating the inflammatory response. This study aimed to investigate whether IL-12p35 KO elevates blood pressure in a hypertension mouse model. Mice with angiotensin (Ang) II infusion showed marked aortic IL-12p35 expression; thus, aortic macrophages may be the main source of IL-12p35. Wild-type and IL-12p35 KO mice were infused with Ang II or saline. IL-12p35 KO promoted M1 macrophage differentiation, amplified the inflammatory response, aggravated vascular dysfunction, and elevated blood pressure in Ang II-treated mice. Then, some Ang II-infused mice were given phosphate buffer saline, mouse recombinant IL-12 (rIL-12), or rIL-35, and the results showed that rIL-12 but not rIL-35 treatment had an antihypertensive effect on Ang II-infused mice. In addition, detection of human plasma IL-12 levels in hypertensive patients and control subjects showed that IL-12 was significantly increased in hypertensive patients when compared with control subjects. In hypertensive patients, IL-12 levels were positively correlated with blood pressure. IL-12p35 KO amplifies the inflammatory response and promotes blood pressure elevation in Ang II-treated mice. In addition, IL-12, but not IL-35, plays a protective role in the Ang II-induced hypertension model. Thus, IL-12 may be a novel therapeutic agent for the prevention and treatment of clinical hypertension.
ANGI-03. PSA-NCAM IN GLIOBLASTOMA – A NEGATIVE PROGNOSTIC MARKER AND A THERAPEUTIC TARGET?
Authors: Thomas Park, Bernard Kim, Jena Macapagal, Birger Dieriks, Patrick Schweder, Peter Heppner, Clinton Turner, Maurice Curtis, Mike Dragunow
Journal: Neuro-Oncology (2018)

Glioblastoma (GBM) is the most common and aggressive primary brain tumour in adults. Despite the current clinical management of surgical resection, followed by radiation and chemotherapy, the median survival time is still a dismal 15 months. This may be due to treatment-resistant GBM stem cells (GSCs) that survive and migrate, resulting in tumour recurrence. Therefore, elucidating the mechanisms of GSC migration and studying ways of limiting this process will be beneficial in the treatment of GBM. A key molecule of interest is polysialylated neural cell adhesion molecule (PSA-NCAM). During normal development and adult neurogenesis, its presence on the cell surface reduces interactions with the extracellular matrix and aids in cellular migration. However, it has also been associated with malignant brain tumours and with negative patient prognosis. We investigated PSA-NCAM’s role in tumour recurrence by immunohistologically evaluating over 160 surgically resected brain tumour specimens for PSA-NCAM expression and correlating this with patient outcomes. We also utilized GSCs isolated from the same patient specimens to investigate the role of PSA-NCAM in tumour cell migration. Univariate and Cox proportional hazard analysis showed that PSA-NCAM expression was a strong predictor of rapid tumour progression, even more so than the cell proliferation marker Ki67, which is often used to assess tumour grade. In addition, high-content image analysis revealed that PSA-NCAM was highly expressed by migrating patient-derived GSCs in vitro, and drugs that limited their migration also decreased PSA-NCAM expression. This led to investigations that aimed to elucidate the effects of PSA-NCAM removal on GSC migration. SUMMARY: Our work highlights the potential role of PSA-NCAM in GSC migration and tumour progression. This opens up avenues to pharmacologically and genetically manipulate PSA-NCAM to reduce GBM cell migration and curb tumour recurrence.