Malignant pleural mesothelioma (MPM) is an aggressive cancer with poor prognosis. The main treatment for MPM is doublet chemotherapy with Cisplatin and Pemetrexed, while ongoing trials test the efficacy of pemetrexed monotherapy. However, there is lack of evidence regarding the effects of Cisplatin and Pemetrexed on MPM cell phenotypes, especially in three-dimensional (3D) cell cultures. In this study, we evaluated the effects Cisplatin and Pemetrexed on cell viability using homologous cell derived extracellular matrix (hECM) as substratum and subsequently in the following 3D cell culture phenotypes: tumor spheroid formation, tumor spheroid invasion, and collagen gel contraction. We used benign mesothelial MeT-5A cells as controls and the MPM cell lines M14K (epithelioid), MSTO (biphasic), and ZL34 (sarcomatoid). Cell viability of all cell lines was significantly decreased with all treatments. Mean tumor spheroid perimeter was reduced after treatment with Pemetrexed or the doublet therapy in all cell lines, while Cisplatin reduced the mean spheroid perimeter of MeT-5A and MSTO cells. Doublet treatment reduced the invasive capacity of spheroids of cell lines into collagenous matrices, while Cisplatin lowered the invasion of the MSTO and ZL34 cell lines, and Pemetrexed lowered the invasion of MeT-5A and ZL34 cell lines. Treatment with Pemetrexed or the combination significantly reduced the collagen gel contraction of all cell lines, while Cisplatin treatment affected only the MeT-5A and M14K cells. The results of the current study can be used as an in vitro 3D platform for testing novel drugs against MPM for ameliorating the effects of first line chemotherapeutics.

Healthcare access and a high quality of the provided services to healthcare users are fundamental human rights according to the Alma Ata Declaration of 1978. Although 45 years have passed since then, health inequalities still exist, not only among countries but also within populations of the same country. For example, several small Greek islands have only a small Primary Healthcare Center in order to provide healthcare services to the insular population. In the current study, we investigated the level of self-reported overall, dental and mental health status and the level of satisfaction regarding the access to and the quality of the healthcare services provided by the Primary Healthcare center of Alonissos, along with registering the requirements for transportation to the mainland in order to receive such services. In this questionnaire-based cross-sectional study, 235 inhabitants of the remote Greek island of Alonissos that accounts for nearly 9% of the population participated (115 males and 120 females). The self-reported overall health status was reported to be moderate to very poor at a percentage of 31.49%, and the results were similar for dental and self-reported mental health status. Although nearly 60% of the participants reported very good/good quality of the healthcare provision, only 37.45% reported that the access to healthcare was very good/good, while around 94% had at least one visit to the mainland in order to receive proper healthcare services. Strategies for improving access to healthcare services need to be placed in remote Greek islands like Alonissos.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest malignancies, largely due to intrinsic or acquired resistance to systemic therapy. In addition to dysregulated glucose metabolism, emerging evidence implicates amino acid metabolism as a key determinant of tumor growth and treatment adaptation. To identify biomarkers associated with chemoresistance, we performed SILAC-based mass spectrometry secretome profiling of gemcitabine-resistant and chemosensitive PDAC cell models, followed by qRT-PCR and immunoblot validation. Functional relevance was assessed by stable shRNA-mediated KYNU knockdown, proliferation assays, and Transwell migration assays. Clinical significance was evaluated by immunohistochemical analysis of KYNU expression in a PDAC tissue microarray (n = 368) and correlation with overall survival. Transcriptomic and pathway enrichment analyses were used to characterize resistance-associated programs. Kynureninase (KYNU), a tryptophan-catabolic enzyme, was upregulated and preferentially secreted by gemcitabine-resistant cells and induced by gemcitabine, interferon-γ, and hypoxia. KYNU knockdown significantly reduced proliferation without affecting migration. Resistant cells displayed higher KYNU expression and a broader therapy-adapted cellular state. In patient samples, high KYNU expression was associated with significantly shorter overall survival (p = 0.0198). These findings identify KYNU as a marker of a therapy-adapted PDAC phenotype and support its potential as a prognostic and treatment-response biomarker.