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  • 11
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    Online Resource
    Neuro-Oncology Clinical Debate: PCV or temozolomide in combination with radiation for newly diagnosed high-grade oligodendroglioma
    Oxford University Press (OUP) ; 2019
    In:  Neuro-Oncology Practice Vol. 6, No. 1 ( 2019-01-30), p. 17-21
    Details
    In: Neuro-Oncology Practice, Oxford University Press (OUP), Vol. 6, No. 1 ( 2019-01-30), p. 17-21
    Abstract: The treatment of newly diagnosed oligodendroglioma has been revolutionized in the past decade by multiple studies demonstrating that the addition of chemotherapy to radiation therapy results in a significant survival benefit. While the most direct evidence comes from clinical trials that utilized PCV, a chemotherapy regimen consisting of procarbazine, CCNU (lomustine), and vincristine, there is circumstantial evidence suggesting that the oral agent temozolomide (TMZ), which is both better tolerated and logistically simpler than PCV, may also be effective. The lack of currently available direct comparative data for PCV vs TMZ results in a diversity of practice. In this article, Ruff and Buckner argue for PCV as part of the standard-of-care regimen for newly diagnosed anaplastic oligodendroglioma, while Geurts and van den Bent defend the use of TMZ.
    Type of Medium: Online Resource
    ISSN: 2054-2577 , 2054-2585
    URL: Article
    DOI: 10.1093/nop/npy044
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2019
    detail.hit.zdb_id: 2768945-1
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  • 12
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    Treatment restrictions in patients with severe stroke are associated with an increased risk of death
    SAGE Publications ; 2017
    In:  European Stroke Journal Vol. 2, No. 3 ( 2017-09), p. 244-249
    Details
    In: European Stroke Journal, SAGE Publications, Vol. 2, No. 3 ( 2017-09), p. 244-249
    Abstract: Treatment restrictions in the first 2 days after intracerebral haemorrhage have been independently associated with an increased risk of early death. It is unknown whether these restrictions also affect mortality if these are installed several days after stroke onset. Patients and methods Sixty patients with severe functional dependence at day 4 after ischaemic stroke or intracerebral haemorrhage were included in this prospective two-centre cohort study. The presence of treatment restrictions was assessed at the day of inclusion. Information about mortality, functional outcome (modified Rankin scale) score and quality of life (visual analogue scale) was recorded 6 months after stroke onset. Poor outcome was defined as modified Rankin scale 〉 3. Satisfactory quality of life was defined as visual analogue scale ≥ 60. Results At 6 months, 30 patients had died, 19 survivors had a poor functional outcome and 9 patients had a poor quality of life. Treatment restrictions were independently associated with mortality at 6 months (adjusted relative risk, 1.30; 95% confidence interval, 1.06–1.59; p = 0.01), but not with functional outcome. Discussion Our findings were observed in 60 selected patients with severe stroke. Conclusion The instalment of treatment restrictions by itself may increase the risk of death after stroke, even if the first 4 days have passed. In future stroke studies, this potential confounder should be taken into account. Quality of life was satisfactory in the majority of the survivors, despite considerable disability.
    Type of Medium: Online Resource
    ISSN: 2396-9873 , 2396-9881
    URL: Article
    DOI: 10.1177/2396987317704546
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2017
    detail.hit.zdb_id: 2851287-X
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  • 13
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    RDNA-14. RADIATION-INDUCED miR-4516 CONTRIBUTES TO RADIO-RESISTANCE AND PROMOTES AGGRESSIVE PHENOTYPE IN GLIOBLASTOMA
    Oxford University Press (OUP) ; 2019
    In:  Neuro-Oncology Vol. 21, No. Supplement_6 ( 2019-11-11), p. vi209-vi210
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 21, No. Supplement_6 ( 2019-11-11), p. vi209-vi210
    Abstract: Glioblastoma is the most aggressive brain tumor with poor prognosis despite the best available treatment. MicroRNAs (miRNAs) are emerging as promising, novel prognostic biomarkers and therapeutic targets in glioblastoma. In a previous study, we demonstrated that miR-4516 predicts poor prognosis and functions as an oncogene in glioblastoma. Aim of the current study is to examine the role miR-4516 in radiation resistance and identify downstream targets contributing to this phenotype METHODS Radiosensitization was evaluated by cell viability and clonogenic assays. Cell apoptosis was evaluated using flow cytometry and immunoblotting. Potential targets of miR-4516 were identified using bioinformatic analysis (Targetscan and miRDB) and confirmed by luciferase reporter assays. Results were validated using immunoblotting. miR-4516 expression in glioblastoma cell lines after radiation treatment was quantified by qRT-PCR. RESULTS Expression of miR-4516 was increased up to 15 fold following radiation treatment, peaking at around 15min-60 min in primary and established glioblastoma cell lines including GBM 08-387, GBM 30 and U87-MG. Furthermore, inhibition of miR-4516 sensitized GBM 08-387, GBM30 and U87-MG cells to radiation in comparison to control groups as determined by cell viability and clonogenic assays. Further, miR-4516 inhibition induced apoptosis in these cell lines following radiation treatment. While conducting mechanistic studies, we found that the tumor-promoting function of miR-4516 was, in part, mediated by inhibition of p21 and PTPN14, two direct targets of miR-4516 CONCLUSION Our data suggest that radiation induces the expression of miR-4516 in glioblastoma cell lines. This miRNA plays a critical role in radio-resistance and promotes aggressive phenotypes in glioblastoma and therefore, functional analyses of its target pathways may uncover novel therapeutically vulnerable target(s) in glioblastoma. FUNDING: R01CA108633, R01CA169368, RC2CA148190, U10CA180850-01(NCI), Brain Tumor Funders Collaborative Grant, and OSU-CCC (all to AC). The Ton and Patricia Bohnenn Fund for Neuro_Oncology Research (to PR).
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noz175.873
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2019
    detail.hit.zdb_id: 2094060-9
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  • 14
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    Timing of radiotherapy in newly diagnosed glioblastoma: no need to rush?
    Oxford University Press (OUP) ; 2018
    In:  Neuro-Oncology Vol. 20, No. 7 ( 2018-06-18), p. 868-869
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 20, No. 7 ( 2018-06-18), p. 868-869
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noy065
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2018
    detail.hit.zdb_id: 2094060-9
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  • 15
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    CSIG-24. miR-575 IS ASSOCIATED WITH WORSE SURVIVAL OF GBM PATIENTS AND ACTS AS A NOVEL ONCOGENE THROUGH TARGETING p27/CDKN1B AND BLID/BRCC2
    Oxford University Press (OUP) ; 2018
    In:  Neuro-Oncology Vol. 20, No. suppl_6 ( 2018-11-05), p. vi48-vi48
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 20, No. suppl_6 ( 2018-11-05), p. vi48-vi48
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noy148.190
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2018
    detail.hit.zdb_id: 2094060-9
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  • 16
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    CSIG-30. miR-146a INHIBITS TUMORIGENESIS AND INDUCES TEMOZOLOMIDE SENSITIVITY VIA AFFECTING CANCER STEM CELL PROPERTIES IN GBM
    Oxford University Press (OUP) ; 2019
    In:  Neuro-Oncology Vol. 21, No. Supplement_6 ( 2019-11-11), p. vi50-vi50
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 21, No. Supplement_6 ( 2019-11-11), p. vi50-vi50
    Abstract: Glioblastomas (GBMs) are the most aggressive primary brain tumors, with an average survival time of less than 15 months. miRNAs are emerging as promising and novel biomarkers in GBM. The aims of this study are: 1) to investigate novel miRNAs biomarkers that affect tumorigenesis and therapeutic sensitivity, and 2) to study the underlying molecular mechanisms in GBM. METHODS Nanostring v3 was performed followed by univariable (UVA) and multivariable (MVA) analyses. Functional studies were conducted to define the role of miR-146a in GBM tumorigenesis and therapeutic response and the molecular mechanisms were investigated. RESULTS UVA analyses demonstrated that miR-146a is one of the top miRNAs that correlated with better prognosis in GBM patients (p=9.21E-05), which was independent of MGMT promoter methylation by MVA analyses (p 〈 0.001). miR-146a expression was significantly downregulated in recurrent GBM tumors compared with the paired primary GBM tumors (p=0.003). Overexpression of miR-146a significantly inhibited tumor cell growth and sensitized patient-derived primary GBM cells to temozolomide (TMZ) treatment in vitro, and showed statistically significant smaller tumor size (p 〈 0.01) and prolonged survival (p=0.001) in vivo. In addition, miR-146a is downregulated in glioma cancer stem cells, and overexpression of miR-146a significantly affected glioma cancer stem cell self-renewal. We also found that overexpression of miR-146a significantly inhibited the NF-κB, AKT, and ERK pathways. CONCLUSION Our data suggest, for the first time, that miR-146a predicts favorable prognosis for GBM patients and sensitizes primary GBM cells to TMZ treatment in vitro and in vivo through regulating glioma stem cells. Importantly, miR-146a may prove to be a master switch shutting off AKT, NF-κB, as well as other pathways and may overcome redundancies among these pathways leading to resistance. FUNDING: Bohnenn Fund (to PR), R01CA108633, R01CA169368, U10CA180850-01(NCI), Brain Tumor Funders Collaborative Grant, and The Ohio State University CCC (all to AC).
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noz175.200
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2019
    detail.hit.zdb_id: 2094060-9
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  • 17
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    MPTH-50. AUTOMATED QUANTITATIVE ANALYSIS (AQUA) AS A RELIABLE METHOD TO ASSESS MGMT PROTEIN EXPRESSION IN GLIOBLASTOMAS
    Oxford University Press (OUP) ; 2016
    In:  Neuro-Oncology Vol. 18, No. suppl_6 ( 2016-11-01), p. vi116-vi117
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 18, No. suppl_6 ( 2016-11-01), p. vi116-vi117
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/now212.485
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2016
    detail.hit.zdb_id: 2094060-9
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  • 18
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    Therapeutic Hypothermia and the Risk of Infection : A Systematic Review and Meta-Analysis*
    Ovid Technologies (Wolters Kluwer Health) ; 2014
    In:  Critical Care Medicine Vol. 42, No. 2 ( 2014-02), p. 231-242
    Details
    In: Critical Care Medicine, Ovid Technologies (Wolters Kluwer Health), Vol. 42, No. 2 ( 2014-02), p. 231-242
    Type of Medium: Online Resource
    ISSN: 0090-3493
    URL: Article
    DOI: 10.1097/CCM.0b013e3182a276e8
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2014
    detail.hit.zdb_id: 2034247-0
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  • 19
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    Abstract 5726: A novel tumor-promoting role for miR-4516 in glioblastoma
    American Association for Cancer Research (AACR) ; 2017
    In:  Cancer Research Vol. 77, No. 13_Supplement ( 2017-07-01), p. 5726-5726
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 13_Supplement ( 2017-07-01), p. 5726-5726
    Abstract: Background: Glioblastomas are the most aggressive high-grade brain tumors, which are often life-threatening due to their location and rapid growth. Although survival rates differ depending on a variety of genetic and environmental factors, the average survival rate for a glioblastoma (GBM) patient is less than 15 months. Although the mechanisms of tumorigenesis are still being elucidated, miRNAs are promising candidates to explore as novel and prognostic biomarkers in GBM. Here we demonstrate a novel role for miR-4516 in promoting growth and migration of GBM and establish the molecular mechanisms mediating these functions. Methods: Formalin-fixed, paraffin-embedded tissue blocks (n=268) were collected for all patients and total RNA was isolated. miRNAs were analyzed simultaneously using the nCounter human miRNA v2 assay (NanoString Technologies; Seattle,WA). Functional characterization studies were conducted in vitro and in vivo. The effect of miR-4516 on GBM cell growth and motility were evaluated by cell proliferation assay, migration and invasion assay, and Annexin-V assay. Realtime PCR, immunoblotting, and 3’ untranslated region luciferase assays were used to analyze miR-4516 targets and signaling pathways. Intracranial injection will be performed to investigate the role of miR-4516 in tumor growth in vivo. Results: Univariate analysis showed that miR-4516 expression in GBM patients was inversely correlated with overall survival (FDR=0.002, p=1.02E-05). Knockdown of miR-4516 blocked tumor growth and induced cell apoptosis. Tumor cell growth, migration and invasion were induced in both transient miR-4516 overexpressed GBM cells (LN229, LN18, and U87) and stable miR-4516 overexpressed GBM cells (U87-EGFRvIII). These miR-4516 tumor-promoting effects were mediated in part via direct targeting PTPN14 and CDKN1A. Investigation of the other miR-4516 targets and in vivo functional study are in process. Conclusion: Taken together, these results suggest that miR-4516 acts as a prognostic biomarker for GBM patients. Funding Information: 1R01CA169368 (PI: Houghton; Co-I:Chakravarti); 1R01CA11522358 Multiple-PI R01: Chakravarti (PI); Xia (PI); 1R01CA1145128 Baroukhim (PI); Chakravarti (Co-PI) 7/2015-6/2020; R01CA108633 (PI:Chakravarti); 1RC2CA148190 (Scientific PI: Chakravarti) Citation Format: Tiantian Cui, Ashley Gray, Ziyan Liu, Marjolein Geurts, Pierre Robe, Joseph McElroy, Erica Hlavin Bell, Arnab Chakravarti. A novel tumor-promoting role for miR-4516 in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5726. doi:10.1158/1538-7445.AM2017-5726
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2017-5726
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 20
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    Abstract 1228: Spatial transcriptomics: Data processing revisited to address noise interference
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 12_Supplement ( 2022-06-15), p. 1228-1228
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. 1228-1228
    Abstract: Background: Spatially resolved transcriptomics is a novel and already highly recognized method that allows RNA sequencing results to be annotated with local tissue phenotypes. The NanoString GeoMx Digital Spatial Profiling (DSP) Platform allows users to collect RNA expression data from manually selected Regions of Interest (ROIs) on FFPE tissue sections. Here, we extensively evaluated data from the DSP platform with its associated pipeline and identify significant background noise interference issues which compromise data interpretation. Alternative and more suitable workflows are presented for correct data analysis. Methods: In this study, 12 paired tumor samples were collected from six glioma patients who underwent two separate resections. For all patients, the first resection was a low grade astrocytoma (WHO grade II or III) and the second resection was a high grade astrocytoma (WHO grade IV). The DSP platform was used to collect expression data of 1,800 genes from 72 ROIs (i.e. 6 per sample). Biological replicates were made of eight tumors from four patients. Gene expression data was normalized with both standard NanoString methods and several alternative methods (e.g. DeSeq2, gamma fit correction and quantile normalization). Weighted Gene Co-expression Network analysis (WGCNA) was used for biological validation. In addition to our own study, six publicly available NanoString DSP datasets were evaluated. Results: Data distributions of all glioma samples, when exposed to standard data processing, were burdened with significant background noise interference. Notably, differences in noise interference were largest between biologically distinct tumor subgroups (i.e. between first and second glioma resections), which was confirmed in replicate experiments. The noise interference patterns were also present in all six publicly available NanoString DSP datasets which will invariably lead to incorrect interpretation of the underlying biology. To correct for noise interference, we tested several normalization methods. The relatively crude quantile normalization method provided the least biased result and showed the highest concordance with bulk RNA sequencing data. To evaluate the biological validity of our alternative approach, we used T cell counts from our tissue regions as an independent parameter, that were quantified using immune fluorescence. Unsupervised WGCNA identified gene clusters enriched for lymphocyte genes that highly correlated with T cell quantities in ROIs, confirming that alternative normalization can extract a biological signal from the DSP platform. Conclusion: The DSP Platform platform suffers from significant noise interference when using standard analysis tools that obscure its results. Here, we revised the workflow and provide an alternative normalization that adequately addresses noise interference and enables correct interpretation of gene expression data. Citation Format: Levi van Hijfte, Marjolein Geurts, Wies R. Vallentgoed, Paul H. Eilers, Peter A. Sillevis Smitt, Reno Debets, Pim J. French. Spatial transcriptomics: Data processing revisited to address noise interference [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1228.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2022-1228
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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