Post-translational influences could underlie the ambiguous roles of monoamine oxidase-A (MAO-A) in pathologies such as depression, cancer and Alzheimer disease. In support of this, we recently demonstrated that the Ca²⁺-sensitive component of MAO-A catalytic activity is inhibited by a pro-survival p38 (MAPK)-dependent mechanism. We substituted three aspartic acid (D) residues in human MAO-A that reside in putative Ca²⁺-binding motifs and overexpressed the individual proteins in the human HEK293 cell line. We assayed the overexpressed proteins for catalytic activity and for their influence on cell viability (using MTT conversion and trypan blue exclusion) and proliferation/DNA synthesis [using bromodeoxyuridine (BrdU) incorporation]. Innate MAO-A catalytic activity (and the capacity for generating hydrogen peroxide) was unaffected by the D61A substitution, but inhibited moderately or completely by the D248A and D328G substitutions, respectively. The Ca²⁺-sensitive activities of wild-type and D248A MAO-A proteins were enhanced by treatment with the selective p38(MAPK) inhibitor, SB203580, but was completely abrogated by the D61A substitution. Monoamine oxidase-A(D61A) was toxic to cells and exerted no effect on cell proliferation, while MAO-A(D248A) was generally comparable to wild-type MAO-A. As expected, the catalytic-dead MAO-A(D328G) was not cytotoxic, but unexpectedly enhanced both MTT conversion and BrdU staining. Variant-dependent changes in Bax and Bcl-2/Bcl-XL protein expression were observed. A different pattern of effects in N2-a cells suggests cell line-dependent roles for MAO-A. A catalytic-dependent mechanism influences MAO-A-mediated cytotoxicity, whereas a catalytic-independent mechanism contributes to proliferation. Context-dependent inputs by either mechanism could underlie the ambiguous pathological contributions of MAO-A.
Background
In 2016, brain invasion was added as a standalone diagnostic criterion for Grade 2 meningiomas in the WHO Classification of Brain Tumors. The aim of this study was to compare the incidence and distribution of meningiomas, and agreement, between the 2007 and 2016 WHO criteria.
Methods
All cases of intracranial meningiomas diagnosed between 2007 and 2020 at a tertiary care academic hospital were identified. The incidence of each meningioma grade in the WHO 2007 and WHO 2016 cohorts were compared. Additionally, each case in the 2007 cohort was re-graded according to the WHO 2016 criteria to determine the intra-class correlation (ICC) between criteria.
Results
Of 814 cases, 532 (65.4%) were in the 2007 WHO cohort and 282 (34.6%) were in the 2016 WHO cohort. There were no differences in the distribution of meningioma grades between cohorts (p=0.11). Incidence rates were: 75.0% v. 75.2% for Grade 1, 22.7% v. 24.5% for Grade 2, and 2.3% v. 0.4% for Grade 3, for the 2007 and 2016 cohorts, respectively. Upon re-grading, 21 cases (3.9%) were changed. ICC between original and revised grade was 0.92 (95% CIs: 0.91-0.93). Amongst Grade 2 meningiomas with brain invasion, 75.8% had three or more atypical histologic features or an elevated mitotic index.
Conclusions
Including brain invasion as a standalone diagnostic criterion for Grade 2 meningiomas had minimal impact on the incidence of specific meningioma grade tumors. There is strong agreement between the 2007 and 2016 WHO criteria, likely due to cosegregation of grade elevating features.
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