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  • 1
    Online Resource
    Online Resource
    The Significance of MGMT Promoter Methylation Status in Diffuse Glioma
    MDPI AG ; 2022
    In:  International Journal of Molecular Sciences Vol. 23, No. 21 ( 2022-10-27), p. 13034-
    Details
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 23, No. 21 ( 2022-10-27), p. 13034-
    Abstract: A single-institution observational study with 43 newly diagnosed diffuse gliomas defined the isocitrate dehydrogenase 1 and 2 (IDH1/2) gene mutation status and evaluated the prognostic relevance of the methylation status of the epigenetic marker O6-methylguanine-DNA methyltransferase (MGMT). Younger patients ( 〈 50 years) with surgically resected glioma and temozolomide (TMZ) adjuvant chemotherapy were associated with better prognosis, consistent with other studies. The methylation status depends on the chosen method and the cut-off value determination. Methylation-specific PCR (MSP) established the methylation status for 36 glioma patients (19 (52.8%) positively methylated and 17 (47.2%) unmethylated) without relevancy for the overall survival (OS) (p = 0.33). On the other side, real-time methylation-specific PCR (qMSP) revealed 23 tumor samples (54%) that were positively methylated without association with OS (p = 0.15). A combined MSP analysis, which included the homogenous cohort of 24 patients ( 〉 50 years with surgical resection and IDH1/2-wildtype diffuse glioma), distinguished 10 (41.6%) methylated samples from 14 (58.4%) unmethylated samples. Finally, significant correlation between OS and methylation status was noticed (p ≈ 0.05). The OS of the hypermethylated group was 9.6 ± 1.77 months, whereas the OS of the unmethylated group was 5.43 ± 1.04 months. Our study recognized the MGMT promoter methylation status as a positive prognostic factor within the described homogenous cohort, although further verification in a larger population of diffuse gliomas is required.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    URL: Article
    DOI: 10.3390/ijms232113034
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2019364-6
    SSG: 12
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  • 2
    Online Resource
    Online Resource
    Preferential Antibody and Drug Conjugate Targeting of the ADAM10 Metalloprotease in Tumours
    MDPI AG ; 2022
    In:  Cancers Vol. 14, No. 13 ( 2022-06-28), p. 3171-
    Details
    In: Cancers, MDPI AG, Vol. 14, No. 13 ( 2022-06-28), p. 3171-
    Abstract: ADAM10 is a transmembrane metalloprotease that sheds a variety of cell surface proteins, including receptors and ligands that regulate a range of developmental processes which re-emerge during tumour development. While ADAM10 is ubiquitously expressed, its activity is normally tightly regulated, but becomes deregulated in tumours. We previously reported the generation of a monoclonal antibody, 8C7, which preferentially recognises an active form of ADAM10 in human and mouse tumours. We now report our investigation of the mechanism of this specificity, and the preferential targeting of 8C7 to human tumour cell xenografts in mice. We also report the development of novel 8C7 antibody–drug conjugates that preferentially kill cells displaying the 8C7 epitope, and that can inhibit tumour growth in mice. This study provides the first demonstration that antibody–drug conjugates targeting an active conformer of ADAM10, a widely expressed transmembrane metalloprotease, enable tumour-selective targeting and inhibition.
    Type of Medium: Online Resource
    ISSN: 2072-6694
    URL: Article
    DOI: 10.3390/cancers14133171
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2527080-1
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  • 3
    Online Resource
    Online Resource
    A Comparison of MGMT Testing by MSP and qMSP in Paired Snap-Frozen and Formalin-Fixed Paraffin-Embedded Gliomas
    MDPI AG ; 2023
    In:  Diagnostics Vol. 13, No. 3 ( 2023-01-18), p. 360-
    Details
    In: Diagnostics, MDPI AG, Vol. 13, No. 3 ( 2023-01-18), p. 360-
    Abstract: Comparative analysis of the conventional methylation-specific PCR (MSP) vs. the quantitative MSP (qMSP) assessment of the O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status in 34 snap-frozen (SF) glioma samples was performed. The accuracy of the semi-quantitative MSP was compared with the corresponding qMSP semi-quantitative values using two semi-quantitative cut-off values (0—unmethylated and 1—weakly methylated) to discriminate methylated from unmethylated samples. In the case of the cut-off value 0, MSP test showed 80.0% sensitivity and 78.9% specificity compared to the reference qMSP analysis. However, when using the cut-off value 1, the diagnostic accuracy of the MSP test was significantly higher (85.7% sensitivity, 85.2% specificity). Fleiss’ Kappa statistical analyses indicated moderate agreement (Fleiss’ Kappa Coefficient = 0.509; 70.59% agreement) between MSP and qMSP semi-quantitative measurements of MGMT promoter methylation in glioma patients, justifying the conventional MSP use in diagnostics and confirming its high reliability. Further, we aimed to compare the validity of SF and formalin-fixed paraffin-embedded (FFPE) glioma samples for MGMT testing. Statistical analyses indicated moderate overall agreement of FFPE glioma samples and SF MSP semi-quantitative measurements (Fleiss’ Kappa Coefficient = 0.516/0.509; 70.0% agreement) and emphasized their low reliability in the assessment of highly methylated MGMT promoter samples.
    Type of Medium: Online Resource
    ISSN: 2075-4418
    URL: Article
    DOI: 10.3390/diagnostics13030360
    Language: English
    Publisher: MDPI AG
    Publication Date: 2023
    detail.hit.zdb_id: 2662336-5
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  • 4
    Online Resource
    Online Resource
    The Impact of MGMT Promoter Methylation and Temozolomide Treatment in Serbian Patients with Primary Glioblastoma
    MDPI AG ; 2019
    In:  Medicina Vol. 55, No. 2 ( 2019-02-01), p. 34-
    Details
    In: Medicina, MDPI AG, Vol. 55, No. 2 ( 2019-02-01), p. 34-
    Abstract: Background and objective: Despite recent advances in treatment, glioblastoma (GBM) remains the most lethal and aggressive brain tumor. A continuous search for a reliable molecular marker establishes the methylation status of the O6-methylguanine-DNA methyltransferase (MGMT) gene promoter as a key prognostic factor in primary glioblastoma. The aim of our study was to screen Serbian patients with primary glioblastoma for an MGMT promoter hypermethylation and to evaluate its associations with overall survival (OS) and sensitivity to temozolomide (TMZ) treatment. Materials and methods: A cohort of 30 Serbian primary glioblastoma patients treated with radiation therapy and chemotherapy were analyzed for MGMT promoter methylation and correlated with clinical data. Results: MGMT methylation status was determined in 25 out of 30 primary glioblastomas by methylation-specific PCR (MSP). MGMT promoter hypermethylation was detected in 12 out of 25 patients (48%). The level of MGMT promoter methylation did not correlate with patients’ gender (p = 0.409), age (p = 0.536), and OS (p = 0.394). Treatment with TMZ significantly prolonged the median survival of a patient (from 5 to 15 months; p 〈 0.001). Conclusions: Due to a small cohort of primary GBM patients, our study is not sufficient for definitive conclusions regarding the prognostic value of MGMT methylation for the Serbian population. Our preliminary data suggest a lack of association between MGMT promoter methylation and overall survival and a significant correlation of TMZ treatment with overall survival. Further population-based studies are needed to assess the prognostic value of the MGMT promoter methylation status for patients with primary glioblastoma.
    Type of Medium: Online Resource
    ISSN: 1648-9144
    URL: Article
    DOI: 10.3390/medicina55020034
    Language: English
    Publisher: MDPI AG
    Publication Date: 2019
    detail.hit.zdb_id: 2088820-X
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