RESUMO
The significant heterogeneity in clinical outcomes among patients with bladder cancer has highlighted the existence of different biological subtypes of muscle-invasive bladder cancer (MIBC) and non-muscle-invasive bladder cancer (NMIBC). Meanwhile, immune checkpoint proteins and their interference with tumor-related immune-evasive strategies has led to the development of several immunotherapeutic drugs targeting programmed death-1 (PD-1) or programmed death ligand-1 (PD-L1). However, the lack of any known biomarker that could predict responses to immunotherapy has led to a more agnostic therapeutic approach. Here, we present a study conducted in 77 bladder cancer (BC) patients (n = 77), ranging from stages pTa to pT2. Tumor specimens were resected via transurethral resection of bladder tumor (TURBT) and consistuted of 24 low-grade (LG) and 53 high-grade (HG) tumors. Patients' tumors were then categorized into molecular subtypes, via immunohistochemistry (CK5/6 and GATA3). Furthermore, all tumor specimens were stained with anti-PD-L1 and demonstrated significant correlations with basal immunophenotype, stage pT2 and HG tumors. As such, we attempted to stratify patients into groups of likely-responders and likely-not-responders to immunotherapy with anti-PD-L1, based on their molecular phenotype. Finally, in acknowledging the fact that there is a universal lack of biomarkers associated with predicting BC response to immunotherapeutic drugs, we tested all tumors for deficiency of mismatch repair proteins (MMR).
RESUMO
The present study investigated the effects of two expired commercial medicines, like Buscopan Plus and Mesulid, commonly classified as household medical wastes, on hemocytes of mussel Mytilus galloprovincialis. Mussel hemocytes' lysosomal membrane stability (in terms of neutral red retention assay), superoxide anions (O2·-) and nitric oxides (NO, in terms of nitrites) production, lipid peroxidation (in terms of malondialdehyde/MDA content) and the formation of nuclear abnormalities (using the micronucleus/MN assay) were assessed in hemocytes of mussels treated for 7 days with appropriate amounts of each drug (the concentrations of active substances were considered in each case, due to the absence of data related with the excipients) as well as in hemocytes of post-treated/recovered mussels (7 days post-treatment/recovery period). According to the results, treated mussels showed significantly decreased NRRT values, enhanced O2·-, NO and MDA levels, as well as high frequencies of nuclear abnormalities in both cases. Thοse effects showed a drastic reduction in almost all cases, after the post-treatment/recovery period. Moreover, the "stress on stress" method, commonly performed for estimating mussels' ability to survive in air, showed significantly reduced LT50 values in challenged mussels, compared to values observed in control mussels. The current findings revealed for the first time that both expired commercial drugs could affect mussels, probably via the formation of active substances bioactivated metabolites, as well as excipients, such as TiO2 and SiO2, at least in case of Buscopan plus. Although further research is needed, the current findings indicate the environmental impact of expired commercial drugs, thus revealing the need for the proper disposal of household medical wastes.
