bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2024‒03‒10
thirteen papers selected by
Oltea Sampetrean, Keio University
  1. ACTION: A randomized phase 3 study of ONC201 (dordaviprone) in patients with newly diagnosed H3 K27M-mutant diffuse glioma.
  2. LncRNA LUCAT1 Promotes Glioblastoma Progression by Enhancing HIF1α Activity.
  3. Evolving concepts in margin strategies and adaptive radiotherapy for glioblastoma: A new future is on the horizon.
  4. Response rate and molecular correlates to encorafenib and binimetinib in BRAF-V600E mutant high-grade glioma.
  5. HIF1α/ATF3 partake PGK1 K191/K192 succinylation by modulating P4HA1/succinate signaling in glioblastoma.
  6. Trans-lesion synthesis and mismatch repair pathway crosstalk defines chemoresistance and hypermutation mechanisms in glioblastoma.
  7. Harnessing Generative AI for Glioma Diagnosis: A Step Forward in Neuro-Oncologic Imaging.
  8. Integrating multi-modal imaging in radiation treatments for glioblastoma.
  9. Generation of immunocompetent somatic glioblastoma mouse models through in situ transformation of subventricular zone neural stem cells.
  10. Lactate dehydrogenase A regulates tumor-macrophage symbiosis to promote glioblastoma progression.
  11. Locoregional delivery of IL-13Rα2-targeting CAR-T cells in recurrent high-grade glioma: a phase 1 trial.
  12. Proneural-mesenchymal antagonism dominates the patterns of phenotypic heterogeneity in glioblastoma.
  13. Single-cell nanobiopsy enables multigenerational longitudinal transcriptomics of cancer cells.
  1. Neuro Oncol. 2024 Mar 06. pii: noae031. [Epub ahead of print]
    ACTION: A randomized phase 3 study of ONC201 (dordaviprone) in patients with newly diagnosed H3 K27M-mutant diffuse glioma.
    Isabel Arrillaga-Romany, Andrew Lassman, Susan L McGovern, Sabine Mueller, Burt Nabors, Martin van den Bent, Michael Vogelbaum, Joshua E Allen, Allen S Melemed, Rohinton S Tarapore, Patrick Y Wen, Timothy Cloughesy.
      BACKGROUND: H3 K27M-mutant diffuse glioma primarily affects children and young adults, is associated with a poor prognosis, and no effective systemic therapy is currently available. ONC201 (dordaviprone) has previously demonstrated efficacy in patients with recurrent disease. This phase 3 trial evaluates ONC201 in patients with newly diagnosed H3 K27M-mutant glioma.METHODS: ACTION (NCT05580562) is a randomized, double-blind, placebo-controlled, parallel-group, international Phase 3 study of ONC201 in newly diagnosed H3 K27M-mutant diffuse glioma. Patients who have completed standard frontline radiotherapy are randomized 1:1:1 to receive placebo, once-weekly dordaviprone, or twice-weekly dordaviprone on two consecutive days. Primary efficacy endpoints are overall survival (OS) and progression-free survival (PFS); PFS is assessed by response assessment in neuro-oncology-high grade glioma criteria (RANO-HGG) by blind independent central review. Secondary objectives include safety, additional efficacy endpoints, clinical benefit, and quality of life. Eligible patients have histologically confirmed H3 K27M-mutant diffuse glioma, a Karnofsky/Lansky performance status ≥70, and completed first-line radiotherapy. Eligibility is not restricted by age; however, patients must be ≥10 kg at time of randomization. Patients with a primary spinal tumor, diffuse intrinsic pontine glioma, leptomeningeal disease, or cerebrospinal fluid dissemination are not eligible. ACTION is currently enrolling in multiple international sites.
    Keywords:  H3 K27M; ONC201; Phase 3; diffuse glioma; dordaviprone
    DOI:  https://doi.org/10.1093/neuonc/noae031
  2. Neuro Oncol. 2024 Mar 08. pii: noae036. [Epub ahead of print]
    LncRNA LUCAT1 Promotes Glioblastoma Progression by Enhancing HIF1α Activity.
    Haidong Huang, Hariti Shah, Jing Hao, Jianhong Lin, Richard A Prayson, Liangqi Xie, Shideng Bao, Abhishek A Chakraborty, Eckhard Jankowsky, Jianjun Zhao, Jennifer S Yu.
      BACKGROUND: Hypoxia is associated with poor prognosis in many cancers including glioblastoma (GBM). Glioma stem-like cells (GSCs) often reside in hypoxic regions and serve as reservoirs for disease progression. Long non-coding RNAs (lncRNAs) have been implicated in GBM. However, the lncRNAs that modulate GSC adaptations to hypoxia are poorly understood. Identification of these lncRNAs may provide new therapeutic strategies to target GSCs under hypoxia.METHODS: lncRNAs induced by hypoxia in GSCs were identified by RNAseq. LUCAT1 expression was assessed by qPCR, RNAseq, Northern blot, single molecule FISH in GSCs, and interrogated in IvyGAP, TCGA, and CGGA databases. LUCAT1 was depleted by shRNA, CRISPR/Cas9, and CRISPR/Cas13d. RNAseq, Western blot, immunohistochemistry, co-IP, ChIP, ChIPseq, RNA immunoprecipitation, and proximity ligation assay were performed to investigate mechanisms of action of LUCAT1. GSC viability, limiting dilution assay, and tumorigenic potential in orthotopic GBM xenograft models were performed to assess the functional consequences of depleting LUCAT1.
    RESULTS: A new isoform of Lucat1 is induced by HIF1α and NRF2 in GSCs under hypoxia. LUCAT1 is highly expressed in hypoxic regions in GBM. Mechanistically, LUCAT1 formed a complex with HIF1α and its co-activator CBP to regulate HIF1α target gene expression and GSC adaptation to hypoxia. Depletion of LUCAT1 impaired GSC self-renewal. Silencing LUCAT1 decreased tumor growth and prolonged mouse survival in GBM xenograft models.
    CONCLUSIONS: A HIF1α-LUCAT1 axis forms a positive feedback loop to amplify HIF1α signaling in GSCs under hypoxia. LUCAT1 promotes GSC self-renewal and GBM tumor growth. LUCAT1 is a potential therapeutic target in GBM.
    Keywords:  HIF1α; LUCAT1; glioma stem-like cells; hypoxia; lncRNA
    DOI:  https://doi.org/10.1093/neuonc/noae036
  3. Neuro Oncol. 2024 Mar 04. 26(Supplement_1): S3-S16
    Evolving concepts in margin strategies and adaptive radiotherapy for glioblastoma: A new future is on the horizon.
    Chia-Lin Tseng, K Liang Zeng, Eric A Mellon, Scott G Soltys, Mark Ruschin, Angus Z Lau, Natalia S Lutsik, Rachel W Chan, Jay Detsky, James Stewart, Pejman J Maralani, Arjun Sahgal.
      Chemoradiotherapy is the standard treatment after maximal safe resection for glioblastoma (GBM). Despite advances in molecular profiling, surgical techniques, and neuro-imaging, there have been no major breakthroughs in radiotherapy (RT) volumes in decades. Although the majority of recurrences occur within the original gross tumor volume (GTV), treatment of a clinical target volume (CTV) ranging from 1.5 to 3.0 cm beyond the GTV remains the standard of care. Over the past 15 years, the incorporation of standard and functional MRI sequences into the treatment workflow has become a routine practice with increasing adoption of MR simulators, and new integrated MR-Linac technologies allowing for daily pre-, intra- and post-treatment MR imaging. There is now unprecedented ability to understand the tumor dynamics and biology of GBM during RT, and safe CTV margin reduction is being investigated with the goal of improving the therapeutic ratio. The purpose of this review is to discuss margin strategies and the potential for adaptive RT for GBM, with a focus on the challenges and opportunities associated with both online and offline adaptive workflows. Lastly, opportunities to biologically guide adaptive RT using non-invasive imaging biomarkers and the potential to define appropriate volumes for dose modification will be discussed.
    Keywords:  MR-Linac; adaptive radiotherapy; glioblastoma; radiotherapy margins
    DOI:  https://doi.org/10.1093/neuonc/noad258
  4. Clin Cancer Res. 2024 Mar 06.
    Response rate and molecular correlates to encorafenib and binimetinib in BRAF-V600E mutant high-grade glioma.
    Karisa C Schreck, Roy E Strowd, Louis B Nabors, Benjamin M Ellingson, Michael Chang, Sze K Tan, Zied Abdullaev, Rust Turakulov, Kenneth Aldape, Neeraja Danda, Serena Desideri, Joy Fisher, Michaella Iacoboni, Trisha Surakus, Michelle A Rudek, Chetan Bettegowda, Stuart A Grossman, Xiaobu Ye.
      PURPOSE: While fewer than 5% of high-grade gliomas (HGG) are BRAF-V600E mutated, these tumors are notable as BRAF-targeted therapy shows efficacy for some populations. The purpose of this study was to evaluate response to the combination of encorafenib with binimetinib in adults with recurrent BRAF-V600 mutated HGG.PATIENTS AND METHODS: In this phase 2, open-label, Adult Brain Tumor Consortium (ABTC) trial (NCT03973918), encorafenib and binimetinib were administered at their FDA-approved doses continuously in 28-day cycles. Eligible patients were required to have high-grade glioma or glioblastoma with a BRAF-V600E alteration that was recurrent following at least one line of therapy including radiation.
    RESULTS: Five patients enrolled between January 2020 and administrative termination in November 2021 (due to closure of the ABTC). Enrolled patients received treatment for 2-40 months; currently one patient remains on treatment. Centrally determined radiographic response rate was 60%, with one complete response and two partial responses. Methylation profiling revealed all tumors cluster most closely with anaplastic PXA. Transcriptional profile for MAPK-response signature was similar across all tumors at baseline and did not correlate with response in this small population. Circulating tumor DNA measured in plasma samples prior to treatment, during response, and upon progression showed feasibility of detection for the BRAF-V600E alteration. No new safety signal was detected.
    CONCLUSIONS: Encorafenib and binimetinib exhibit positive tumor responses in patients with recurrent BRAF-V600E mutant HGG in this small series, warranting therapeutic consideration. Although toxicity remains a concern for BRAF-targeted therapies, no new safety signal was observed in these patients.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-23-3241
  5. Neuro Oncol. 2024 Mar 05. pii: noae040. [Epub ahead of print]
    HIF1α/ATF3 partake PGK1 K191/K192 succinylation by modulating P4HA1/succinate signaling in glioblastoma.
    Yang Shixue, Zhan Qi, Su Dongyuan, Cui Xiaoteng, Zhao Jixing, Wang Qixue, Hong Biao, Ju Jiasheng, Cheng Chunchao, Yang Eryan, Chunsheng Kang.
      BACKGROUND: Hypoxia is a pathological hallmark in most cancers, including glioblastoma (GBM). Hypoxic signaling activation and posttranslational modification (PTM) of oncogenic proteins are well-studied in cancers. Accumulating studies indicate glycolytic enzyme PGK1 plays a crucial role in tumorigenesis, yet the underlying mechanisms remain unknown.METHODS: We first used ChIP assays to uncover the crosstalk between HIF1α and ATF3 and their roles in P4HA1 regulation. Protein degradation analysis, LC-MS/MS, and in vitro succinate production assays were performed to examine the effect of protein succinylation on GBM pathology. Seahorse assay measured the effects of PGK1 succinylation at K191/192 or its mutants on glucose metabolism. We utilized an in vivo intracranial mouse model for biochemical studies to elucidate the impact of ATF3 and P4HA1 on aerobic glycolysis and the tumor immune microenvironment.
    RESULTS: We demonstrated that HIF1α and ATF3 positively and negatively regulate the transcription of P4HA1, respectively, leading to an increased succinate production and increased activation of HIF1α signaling. P4HA1 expression elevated the succinate concentration, resulting in the enhanced succinylation of PGK1 at the K191 and K192 sites. Inhibition of proteasomal degradation of PGK1 by succinylation significantly increased aerobic glycolysis to generate lactate. Furthermore, ATF3 overexpression and P4HA1 knockdown reduced succinate and lactate levels in GBM cells, inhibiting immune responses and tumor growth.
    CONCLUSION: Together, our study demonstrates that HIF1α/ATF3 participated in P4HA1/succinate signaling, which is the major regulator of succinate biosynthesis and PGK1 succinylation at K191 and K192 sites in GBM. The P4HA1/succinate pathway might be a novel and promising target for aerobic glycolysis in GBM.
    Keywords:  ATF3; HIF1α; P4HA1; PGK1; Succinylation
    DOI:  https://doi.org/10.1093/neuonc/noae040
  6. Nat Commun. 2024 Mar 04. 15(1): 1957
    Trans-lesion synthesis and mismatch repair pathway crosstalk defines chemoresistance and hypermutation mechanisms in glioblastoma.
    Xing Cheng, Jing An, Jitong Lou, Qisheng Gu, Weimin Ding, Gaith Nabil Droby, Yilin Wang, Chenghao Wang, Yanzhe Gao, Jay Ramanlal Anand, Abigail Shelton, Andrew Benson Satterlee, Breanna Mann, Yun-Chung Hsiao, Chih-Wei Liu, Kun Lu, Shawn Hingtgen, Jiguang Wang, Zhaoliang Liu, C Ryan Miller, Di Wu, Cyrus Vaziri, Yang Yang.
      Almost all Glioblastoma (GBM) are either intrinsically resistant to the chemotherapeutical drug temozolomide (TMZ) or acquire therapy-induced mutations that cause chemoresistance and recurrence. The genome maintenance mechanisms responsible for GBM chemoresistance and hypermutation are unknown. We show that the E3 ubiquitin ligase RAD18 (a proximal regulator of TLS) is activated in a Mismatch repair (MMR)-dependent manner in TMZ-treated GBM cells, promoting post-replicative gap-filling and survival. An unbiased CRISPR screen provides an aerial map of RAD18-interacting DNA damage response (DDR) pathways deployed by GBM to tolerate TMZ genotoxicity. Analysis of mutation signatures from TMZ-treated GBM reveals a role for RAD18 in error-free bypass of O6mG (the most toxic TMZ-induced lesion), and error-prone bypass of other TMZ-induced lesions. Our analyses of recurrent GBM patient samples establishes a correlation between low RAD18 expression and hypermutation. Taken together we define molecular underpinnings for the hallmark tumorigenic phenotypes of TMZ-treated GBM.
    DOI:  https://doi.org/10.1038/s41467-024-45979-5
  7. Neuro Oncol. 2024 Mar 05. pii: noae043. [Epub ahead of print]
    Harnessing Generative AI for Glioma Diagnosis: A Step Forward in Neuro-Oncologic Imaging.
    Matthew D Lee, Rajan Jain.
      
    DOI:  https://doi.org/10.1093/neuonc/noae043
  8. Neuro Oncol. 2024 Mar 04. 26(Supplement_1): S17-S25
    Integrating multi-modal imaging in radiation treatments for glioblastoma.
    William G Breen, Madhava P Aryal, Yue Cao, Michelle M Kim.
      Advances in diagnostic and treatment technology along with rapid developments in translational research may now allow the realization of precision radiotherapy. Integration of biologically informed multimodality imaging to address the spatial and temporal heterogeneity underlying treatment resistance in glioblastoma is now possible for patient care, with evidence of safety and potential benefit. Beyond their diagnostic utility, several candidate imaging biomarkers have emerged in recent early-phase clinical trials of biologically based radiotherapy, and their definitive assessment in multicenter prospective trials is already in development. In this review, the rationale for clinical implementation of candidate advanced magnetic resonance imaging and positron emission tomography imaging biomarkers to guide personalized radiotherapy, the current landscape, and future directions for integrating imaging biomarkers into radiotherapy for glioblastoma are summarized. Moving forward, response-adaptive radiotherapy using biologically informed imaging biomarkers to address emerging treatment resistance in rational combination with novel systemic therapies may ultimately permit improvements in glioblastoma outcomes and true individualization of patient care.
    Keywords:  MRI; PET; glioblastoma; radiomics; radiotherapy
    DOI:  https://doi.org/10.1093/neuonc/noad187
  9. STAR Protoc. 2024 Mar 01. pii: S2666-1667(24)00093-5. [Epub ahead of print]5(1): 102928
    Generation of immunocompetent somatic glioblastoma mouse models through in situ transformation of subventricular zone neural stem cells.
    Melanie Clements, Holly Simpson Ragdale, Claudia Garcia-Diaz, Simona Parrinello.
      Disease-relevant in vivo tumor models are essential tools for both discovery and translational research. Here, we describe a highly genetically tractable technique for generating immunocompetent somatic glioblastoma (GBM) mouse models using piggyBac transposition and CRISPR-Cas9-mediated gene editing in wild-type mice. We describe steps to deliver plasmids into subventricular zone endogenous neural stem cells by injection and electroporation, leading to the development of adult tumors that closely recapitulate the histopathological, molecular, and cellular features of human GBM. For complete details on the use and execution of this protocol, please refer to Garcia-Diaz et al.1.
    Keywords:  CRISPR; Cancer; Model Organisms; Stem Cells
    DOI:  https://doi.org/10.1016/j.xpro.2024.102928
  10. Nat Commun. 2024 Mar 05. 15(1): 1987
    Lactate dehydrogenase A regulates tumor-macrophage symbiosis to promote glioblastoma progression.
    Fatima Khan, Yiyun Lin, Heba Ali, Lizhi Pang, Madeline Dunterman, Wen-Hao Hsu, Katie Frenis, R Grant Rowe, Derek A Wainwright, Kathleen McCortney, Leah K Billingham, Jason Miska, Craig Horbinski, Maciej S Lesniak, Peiwen Chen.
      Abundant macrophage infiltration and altered tumor metabolism are two key hallmarks of glioblastoma. By screening a cluster of metabolic small-molecule compounds, we show that inhibiting glioblastoma cell glycolysis impairs macrophage migration and lactate dehydrogenase inhibitor stiripentol emerges as the top hit. Combined profiling and functional studies demonstrate that lactate dehydrogenase A (LDHA)-directed extracellular signal-regulated kinase (ERK) pathway activates yes-associated protein 1 (YAP1)/ signal transducer and activator of transcription 3 (STAT3) transcriptional co-activators in glioblastoma cells to upregulate C-C motif chemokine ligand 2 (CCL2) and CCL7, which recruit macrophages into the tumor microenvironment. Reciprocally, infiltrating macrophages produce LDHA-containing extracellular vesicles to promote glioblastoma cell glycolysis, proliferation, and survival. Genetic and pharmacological inhibition of LDHA-mediated tumor-macrophage symbiosis markedly suppresses tumor progression and macrophage infiltration in glioblastoma mouse models. Analysis of tumor and plasma samples of glioblastoma patients confirms that LDHA and its downstream signals are potential biomarkers correlating positively with macrophage density. Thus, LDHA-mediated tumor-macrophage symbiosis provides therapeutic targets for glioblastoma.
    DOI:  https://doi.org/10.1038/s41467-024-46193-z
  11. Nat Med. 2024 Mar 07.
    Locoregional delivery of IL-13Rα2-targeting CAR-T cells in recurrent high-grade glioma: a phase 1 trial.
    Christine E Brown, Jonathan C Hibbard, Darya Alizadeh, M Suzette Blanchard, Heini M Natri, Dongrui Wang, Julie R Ostberg, Brenda Aguilar, Jamie R Wagner, Jinny A Paul, Renate Starr, Robyn A Wong, Wuyang Chen, Noah Shulkin, Maryam Aftabizadeh, Aleksandr Filippov, Ammar Chaudhry, Julie A Ressler, Julie Kilpatrick, Paige Myers-McNamara, Mike Chen, Leo D Wang, Russell C Rockne, Joseph Georges, Jana Portnow, Michael E Barish, Massimo D'Apuzzo, Nicholas E Banovich, Stephen J Forman, Behnam Badie.
      Chimeric antigen receptor T cell (CAR-T) therapy is an emerging strategy to improve treatment outcomes for recurrent high-grade glioma, a cancer that responds poorly to current therapies. Here we report a completed phase I trial evaluating IL-13Rα2-targeted CAR-T cells in 65 patients with recurrent high-grade glioma, the majority being recurrent glioblastoma (rGBM). Primary objectives were safety and feasibility, maximum tolerated dose/maximum feasible dose and a recommended phase 2 dose plan. Secondary objectives included overall survival, disease response, cytokine dynamics and tumor immune contexture biomarkers. This trial evolved to evaluate three routes of locoregional T cell administration (intratumoral (ICT), intraventricular (ICV) and dual ICT/ICV) and two manufacturing platforms, culminating in arm 5, which utilized dual ICT/ICV delivery and an optimized manufacturing process. Locoregional CAR-T cell administration was feasible and well tolerated, and as there were no dose-limiting toxicities across all arms, a maximum tolerated dose was not determined. Probable treatment-related grade 3+ toxicities were one grade 3 encephalopathy and one grade 3 ataxia. A clinical maximum feasible dose of 200 × 106 CAR-T cells per infusion cycle was achieved for arm 5; however, other arms either did not test or achieve this dose due to manufacturing feasibility. A recommended phase 2 dose will be refined in future studies based on data from this trial. Stable disease or better was achieved in 50% (29/58) of patients, with two partial responses, one complete response and a second complete response after additional CAR-T cycles off protocol. For rGBM, median overall survival for all patients was 7.7 months and for arm 5 was 10.2 months. Central nervous system increases in inflammatory cytokines, including IFNγ, CXCL9 and CXCL10, were associated with CAR-T cell administration and bioactivity. Pretreatment intratumoral CD3 T cell levels were positively associated with survival. These findings demonstrate that locoregional IL-13Rα2-targeted CAR-T therapy is safe with promising clinical activity in a subset of patients. ClinicalTrials.gov Identifier: NCT02208362 .
    DOI:  https://doi.org/10.1038/s41591-024-02875-1
  12. iScience. 2024 Mar 15. 27(3): 109184
    Proneural-mesenchymal antagonism dominates the patterns of phenotypic heterogeneity in glioblastoma.
    Harshavardhan Bv, Mohit Kumar Jolly.
      The aggressive nature of glioblastoma (GBM) - one of the deadliest forms of brain tumors - is majorly attributed to underlying phenotypic heterogeneity. Early attempts to classify this heterogeneity at a transcriptomic level in TCGA GBM cohort proposed the existence of four distinct molecular subtypes: Proneural, Neural, Classical, and Mesenchymal. Further, a single-cell RNA sequencing (scRNA-seq) analysis of primary tumors also reported similar four subtypes mimicking neurodevelopmental lineages. However, it remains unclear whether these four subtypes identified via bulk and single-cell transcriptomics are mutually exclusive or not. Here, we perform pairwise correlations among individual genes and gene signatures corresponding to these proposed subtypes and show that the subtypes are not distinctly mutually antagonistic in either TCGA or scRNA-seq data. We observed that the proneural (or neural progenitor-like)-mesenchymal axis is the most prominent antagonistic pair, with the other two subtypes lying on this spectrum. These results are reinforced through a meta-analysis of over 100 single-cell and bulk transcriptomic datasets as well as in terms of functional association with metabolic switching, cell cycle, and immune evasion pathways. Finally, this proneural-mesenchymal antagonistic trend percolates to the association of relevant transcription factors with patient survival. These results suggest rethinking GBM phenotypic characterization for more effective therapeutic targeting efforts.
    Keywords:  Cancer; Expression study; Mathematical biosciences; Transcriptomics
    DOI:  https://doi.org/10.1016/j.isci.2024.109184
  13. Sci Adv. 2024 Mar 08. 10(10): eadl0515
    Single-cell nanobiopsy enables multigenerational longitudinal transcriptomics of cancer cells.
    Fabio Marcuccio, Chalmers C Chau, Georgette Tanner, Marilena Elpidorou, Martina A Finetti, Shoaib Ajaib, Morag Taylor, Carolina Lascelles, Ian Carr, Iain Macaulay, Lucy F Stead, Paolo Actis.
      Single-cell RNA sequencing has revolutionized our understanding of cellular heterogeneity, but routine methods require cell lysis and fail to probe the dynamic trajectories responsible for cellular state transitions, which can only be inferred. Here, we present a nanobiopsy platform that enables the injection of exogenous molecules and multigenerational longitudinal cytoplasmic sampling from a single cell and its progeny. The technique is based on scanning ion conductance microscopy (SICM) and, as a proof of concept, was applied to longitudinally profile the transcriptome of single glioblastoma (GBM) brain tumor cells in vitro over 72 hours. The GBM cells were biopsied before and after exposure to chemotherapy and radiotherapy, and our results suggest that treatment either induces or selects for more transcriptionally stable cells. We envision the nanobiopsy will contribute to transforming standard single-cell transcriptomics from a static analysis into a dynamic assay.
    DOI:  https://doi.org/10.1126/sciadv.adl0515
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