Tumor cells with neuronal intermediate progenitor features define a subgroup of 1p/19q co-deleted anaplastic gliomas.

The integrated diagnosis of anaplastic oligodendroglioma, IDH mutant and 1p/19q co-deleted, grade III (O3id ) is a histomolecular entity that WHO 2016 classification distinguished from other diffuse gliomas by specific molecular alterations. In contrast, its cell portrait is less well known. The present study is focused on intertumor and intratumor, cell lineage-oriented, heterogeneity in O3id . Based on pathological, transcriptomic and immunophenotypic studies, a novel subgroup of newly diagnosed O3id overexpressing neuronal intermediate progenitor (NIP) genes was identified. This NIP overexpression pattern in O3id is associated with: (i) morphological and immunohistochemical similarities with embryonic subventricular zone, (ii) proliferating tumor cell subpopulation with NIP features including expression of INSM1 and no expression of SOX9, (iii) mutations in critical genes involved in NIP biology and, (iv) increased tumor necrosis. Interestingly, NIP tumor cell subpopulation increases in O3id recurrence compared with paired newly diagnosed tumors. Our results, validated in an independent cohort, emphasize intertumor and intratumor heterogeneity in O3id and identified a tumor cell subpopulation exhibiting NIP characteristics that is potentially critical in oncogenesis of O3id . A better understanding of spatial and temporal intratumor cell heterogeneity in O3id will open new therapeutic avenues overcoming resistance to current antitumor treatments.

Age-related increase of protein glycation in peripheral blood lymphocytes is restricted to preferential target proteins.

Advanced glycation end products (AGE) have been analyzed in aging human peripheral blood lymphocytes since protein glycation and glycoxidation are believed to contribute to the intracellular age-related accumulation of damaged proteins, a process that has been associated with the cellular functional deficits that occur with age. The appearance of AGE in cell lysates was monitored with an enzyme-linked immunosorbent assay using an anti-AGE antibody raised against glycated RNAse. When lymphocyte cytosolic extracts from old donors (86-91 years old) were compared with those from young donors (20-25 years old), a small but significant 40% increase of protein glycation was observed. In both age groups, further analysis of the pattern of glycated proteins by two-dimensional gel electrophoresis followed by western blotting with the same anti-AGE antibody, showed that the protein silver stain and the immunoblot patterns were not superimposable indicating that glycoxidative modifications are targeting only a restricted set of proteins. Among these preferential protein targets, seven of them exhibited a significant age-related increased immunoreactivity with the anti-AGE antibody suggesting that the corresponding modified proteins might serve as biomarkers of aging lymphocytes.

Evidence of preferential protein targets for age-related modifications in peripheral blood lymphocytes.

Oxidatively modified proteins have been analyzed in aging human peripheral blood lymphocytes since protein modification by oxidation and other related pathways are believed to contribute to the intracellular age-related accumulation of damaged proteins, a process that has been associated with the cellular functional deficits that occur with age. Advanced glycation end products (AGE) were quantified and the pattern of glycated proteins analyzed by two-dimensional gel electrophoresis followed by Western blotting using an anti-AGE antibody raised against glycated RNAse. The protein silver stain and the immunoblot patterns were not superimposable, indicating that glycoxidative modifications are targeting only a restricted set of proteins. Modification of proteins with the lipid peroxidation product 4-hydroxy-2-nonenal has also been studied. The patterns of modified proteins have been analyzed using two- dimensional gel electrophoresis followed by Western blotting with an antibody recognizing 4-hydroxy-2-nonenal protein adducts using the same proteomic approach as for glycoxidative modifications. Specific protein targets for these modifications, that might serve as biomarkers of aging lymphocytes, are currently characterized and identified by mass spectrometry.

Algae extract protection effect on oxidized protein level in human stratum corneum.

Modification of proteins by reactive oxygen species is implicated in different disorders. The proteasome is a multicatalytic proteinase in charge of intracellular protein turnover and of oxidized proteins degradation. Consequently, proteasome function is very important in controlling the level of altered proteins in eukaryotic cells. Evidence for a decline in proteasome activity during skin photo-aging has been provided in Bulteau et al. in 2002. The ability of a lipid algae extract (Phaeodactylum tricornutum) to stimulate 20S proteasome peptidase activities was described by Nizard et al. in 2001. Furthermore, keratinocytes treated with Phaeodactylum tricornutum extract and then UVA and UVB irradiated, exhibited a sustained level of proteasome activity comparable to the one of nonirradiated cells. The level of modified proteins can be quantified by measurement of protein carbonyl content (Oxyblot technique), which has been shown to increase with aging and other disorders. In this paper, it is described that, in the presence of this lipid algae extract, the level of oxidized proteins is reduced, as assessed by the Oxyblot technique. These results are obtained both with culture of human keratinocytes and stratum corneum skin cells (obtained by stripping) from human volunteers. Altogether, these results argue for the presence of compounds in this algae extract that have a stimulating and/or protective effect on proteasome activity, resulting in a decreased level of protein oxidation.