Search Results (3)

Ovarian cancer (OC) is a highly heterogeneous malignancy, often characterized by complex genomic alterations that drive tumor progression and therapy resistance. In this paper, we report a novel de novo BRCA2 germline variant NM_000059.3:c.(8693_8695delinsGT) associated with early-onset OC that featured two regions with differential MMR (Mismatch Repair) gene expression. To date, only six cases of de novo BRCA2 variants have been reported, none of which were associated with early-onset high-grade serous OC. The immunohistochemical analysis of MMR genes revealed two distinct tumor areas, separated by a clear topographic boundary, with the heterogeneous expression of MLH1 and PMS2 proteins. Seventy-five percent of the tumor tissue showed positivity, while the remaining 25% exhibited a complete absence of expression, underscoring the spatial variability in MMR gene expression within the tumor. Integrated comparative spatial genomic profiling identified several tumor features associated with the genetic variant as regions of loss of heterozygosity (LOH) that involved BRCA2 and MLH1 genes, along with a significantly higher mutational tumor burden in the tumor area that lacked MLH1 and PMS2 expression, indicating its further molecular evolution. The following variants were acquired: c.6572C>T in NOTCH2, c.1852C>T in BCL6, c.191A>T in INHBA, c.749C>T in CUX1, c.898C>A in FANCG, and c.1712G>C in KDM6A. Integrated comparative spatial proteomic profiles revealed defects in the DNA repair pathways, as well as significant alterations in the extracellular matrix (ECM). The differential expression of proteins involved in DNA repair, particularly those associated with MMR and Base Excision Repair (BER), highlights the critical role of defective repair mechanisms in driving genomic instability. Furthermore, ECM components, such as collagen isoforms, Fibrillin-1, EMILIN-1, Prolargin, and Lumican, were found to be highly expressed in the MLH1/PMS2-deficient tumor area, suggesting a connection between DNA repair deficiencies, ECM remodeling, and tumor progression. Thus, the identification of the BRCA2 variant sheds light on the poorly understood interplay between DNA repair deficiencies and ECM remodeling in OC, providing new insights into their dual role in shaping tumor evolution and suggesting potential targets for novel therapeutic strategies. Full article

This study aimed to assess the obesity effects on the proteomic profile of the periodontal ligament of rats submitted to obesity induction by a high-fat diet. Eight Holtzman rats were divided into control (n = 3) and obese (n = 5) groups. The maxillae were histologically processed for laser capture microdissection of the periodontal ligament of the first maxillary molars. Peptide mixtures were analyzed by LC-MS/MS. A total of 1379 proteins were identified in all groups. Among them, 335 (24.30%) were exclusively detected in the obese group, while 129 (9.35%) proteins were uniquely found in the control group. Out of the 110 (7.98%) differentially abundant proteins, 10 were more abundant and 100 had decreased abundance in the obese group. A gene ontology analysis showed some proteins related to obesity in the “extracellular exosome” term among differentially identified proteins in the gene ontology cellular component terms Prelp, Sec13, and Sod2. These three proteins were upregulated in the obese group (p < 0.05), as shown by proteomic and immunohistochemistry analyses. In summary, our study presents novel evidence that the proteomic profile of the periodontal ligament is altered in experimental obesity induction, providing a list of differentially abundant proteins associated with obesity, which indicates that the periodontal ligament is responsive to obesity. Full article

The full-length dystrophin protein isoform of 427 kDa (Dp427), the absence of which represents the principal abnormality in X-linked muscular dystrophy, is difficult to identify and characterize by routine proteomic screening approaches of crude tissue extracts. This is probably related to its large molecular size, its close association with the sarcolemmal membrane, and its existence within a heterogeneous glycoprotein complex. Here, we used a careful extraction procedure to isolate the total protein repertoire from normal versus dystrophic mdx-4cv skeletal muscles, in conjunction with label-free mass spectrometry, and successfully identified Dp427 by proteomic means. In contrast to a considerable number of previous comparative studies of the total skeletal muscle proteome, using whole tissue proteomics we show here for the first time that the reduced expression of this membrane cytoskeletal protein is the most significant alteration in dystrophinopathy. This agrees with the pathobiochemical concept that the almost complete absence of dystrophin is the main defect in Duchenne muscular dystrophy and that the mdx-4cv mouse model of dystrophinopathy exhibits only very few revertant fibers. Significant increases in collagens and associated fibrotic marker proteins, such as fibronectin, biglycan, asporin, decorin, prolargin, mimecan, and lumican were identified in dystrophin-deficient muscles. The up-regulation of collagen in mdx-4cv muscles was confirmed by immunofluorescence microscopy and immunoblotting. Thus, this is the first mass spectrometric study of crude tissue extracts that puts the proteomic identification of dystrophin in its proper pathophysiological context. Full article