Katarina Vukojević

The gradual deterioration of articular cartilage was thought to be the central event in osteoarthritis (OA), but recent studies demonstrated the importance of low-grade synovitis in the progression of OA. The Syndecan (SDC) family of membrane proteoglycans is known to be involved in the regulation of inflammation, but there is limited evidence considering the role of syndecans in OA synovitis. Our study aimed to investigate the hip OA synovial membrane expression patterns of SDC1, SDC2 and SDC4, as well as exostosins and sulfotransferases (enzymes involved in the polymerisation and modification of syndecans’ heparan sulphate chains). Synovial membrane samples of patients with OA (24) were divided into two groups according to their Krenn synovitis score severity. The immunohistochemical expressions of SDC1, SDC2, SDC4, EXT1, EXT2, NDST1 and NDST2 in synovial intima and subintima were then analysed and compared with the control group (patients with femoral neck fracture). According to our study, the immunoexpression of SDC1, NDST1 and EXT2 is significantly increased in the intimal cells of OA synovial membrane in patients with lower histological synovitis scores and SDC4 in patients with higher synovitis scores, in comparison with non-OA controls. The difference in the expression of SDC2 among the OA and non-OA groups was insignificant. SDC1, SDC4, NDST1 and EXT2 seem to be involved as inflammation moderators in low-grade OA synovitis and, therefore, should be further investigated as potential markers of disease progression and therapeutic goals.

Left-sided and right-sided colorectal cancer (L-CRC and R-CRC) have relatively different clinical pictures and pathophysiological backgrounds. The aim of this study was to investigate the presence of DAB adapter protein 2 (DAB2) as a potential molecular mechanism that contributes to this diversity in terms of malignancy and responses to therapy. The expression of the suppressor gene DAB2 in colon cancer has already been analyzed, but its significance has not been fully elucidated. Archived samples from 34 patients who underwent colon cancer surgery were included in this study, with 13 patients with low-grade CRC and 21 with high-grade CRC. Twenty of the tumors were R-CRC, while 14 were L-CRC. DAB2 expression was analyzed immunohistochemically in the tumor tissue and the colon resection margin was used as a control. Tumors were divided into L-CRC and R-CRC, with splenic flexure as the cutoff point for each side. The results showed that R-CRC had lower DAB2 protein expression compared to L-CRC (p = 0.01). High-grade tumors had reduced DAB2 expression compared to low-grade tumors (p = 0.02). These results are consistent with the analysis of DAB2 gene expression data that we exported from the TCGA Colon and Rectal Cancer Study (COADREAD). In 736 samples of colon cancer, lower DAB2 gene expression was found in R-CRC compared to L-CRC (p < 0.0001). DAB2 gene expression was significantly higher in the sigmoid colon than in the cecum and ascending colon (p < 0.01). The analysis confirmed a lower expression of the DAB2 in tumors with positive microsatellite instability (p < 0.001). In conclusion, DAB2 has a role in the biological differences between R-CRC and L-CRC and its therapeutic and diagnostic potential needs to be further examined.

Gastric cancer (GC) therapies include gastrectomy and chemoradiotherapy. The tumor immune microenvironment (TME) has implications for potential immunotherapy. We analyzed the expression of PD-L1, CD8, CTLA-4 and IFN-γ in the tumor and regional lymph node (LN) of patients with GC and compared it with clinical and pathological data. Paraffin blocks were collected from 97 patients undergoing gastrectomy/lymphadenectomy for GC. Double immunohistochemistry was performed for CD8 and PD-L1 and double immunofluorescence for CTLA-4 and IFN-γ. Statistical significance was set at p < 0.05. PD-L1 expression in tumor cells was associated with intestinal GC type (p = 0.046), the density of macrophages and CD8 + T cells (p < 0.001, both). The median number of CD8+ T cells was higher in PD-L1-positive than in -negative tumors. A cut-off of 28.5 CD8 + T cells in one high-magnification field predicted PD-L1-positive tumors (AUROC 0.797, sensitivity 74.2%, specificity 77.3%). IFN-γ expression in tumor cells was found in 37 GCs and was positively associated with CTLA4+ lymphocytes in the LN (p = 0.027) and CTLA4+/IFN-γ+ in tumors and the LN (all p < 0.001). The median overall survival (OS) was 17 months. In the group of deceased patients, IFN-γ expression in metastases correlated with lower OS (RHO = −0.314, p = 0.008). PD-L1 expression in tumor cells correlated with CD8 + T cells and macrophages in the TME and IFN-γ expression with suppressive CTLA4+/IFNγ+ immune cells in the TME and LN.