Nanomedicine and epigenetics: New alliances to increase the odds in pancreatic cancer survival.

Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest cancers worldwide, primarily due to its robust desmoplastic stroma and immunosuppressive tumor microenvironment (TME), which facilitate tumor progression and metastasis. In addition, fibrous tissue leads to sparse vasculature, high interstitial fluid pressure, and hypoxia, thereby hindering effective systemic drug delivery and immune cell infiltration. Thus, remodeling the TME to enhance tumor perfusion, increase drug retention, and reverse immunosuppression has become a key therapeutic strategy. In recent years, targeting epigenetic pathways has emerged as a promising approach to overcome tumor immunosuppression and cancer progression. Moreover, the progress in nanotechnology has provided new opportunities for enhancing the efficacy of conventional and epigenetic drugs. Nano-based drug delivery systems (NDDSs) offer several advantages, including improved drug pharmacokinetics, enhanced tumor penetration, and reduced systemic toxicity. Smart NDDSs enable precise targeting of stromal components and augment the effectiveness of immunotherapy through multiple drug delivery options. This review offers an overview of the latest nano-based approaches developed to achieve superior therapeutic efficacy and overcome drug resistance. We specifically focus on the TME and epigenetic-targeted therapies in the context of PDAC, discussing the advantages and limitations of current strategies while highlighting promising new developments. By emphasizing the immense potential of NDDSs in improving therapeutic outcomes in PDAC, our review paves the way for future research in this rapidly evolving field.

Establishment of Pancreatic Cancer-Derived Tumor Organoids and Fibroblasts From Fresh Tissue.

Tumor organoids are three-dimensional (3D) ex vivo tumor models that recapitulate the biological key features of the original primary tumor tissues. Patient-derived tumor organoids have been used in translational cancer research and can be applied to assess treatment sensitivity and resistance, cell-cell interactions, and tumor cell interactions with the tumor microenvironment. Tumor organoids are complex culture systems that require advanced cell culture techniques and culture media with specific growth factor cocktails and a biological basement membrane that mimics the extracellular environment. The ability to establish primary tumor cultures highly depends on the tissue of origin, the cellularity, and the clinical features of the tumor, such as the tumor grade. Furthermore, tissue sample collection, material quality and quantity, as well as correct biobanking and storage are crucial elements of this procedure. The technical capabilities of the laboratory are also crucial factors to consider. Here, we report a validated SOP/protocol that is technically and economically feasible for the culture of ex vivo tumor organoids from fresh tissue samples of pancreatic adenocarcinoma origin, either from fresh primary resected patient donor tissue or patient-derived xenografts (PDX). The technique described herein can be performed in laboratories with basic tissue culture and mouse facilities and is tailored for wide application in the translational oncology field.

Intrathoracic liver herniation after pericardial fenestration - a case report.

BACKGROUND: Pericardial effusions with its potential life threatening progression towards cardiac tamponade have to be often managed with surgical intervention. In our case study we describe a complication after a common surgical procedure which has only scarce literature mentions. CASE PRESENTATION: We present a case of a 22-year-old male patient who underwent subxiphoidal pericardial fenestration, due to symptomatic pericardial effusion with the Chamberlain procedure and biopsy of enlarged mediastinal lymph nodes. The histology report confirmed classical Hodgkin lymphoma and subsequently the patient underwent oncological treatment. Later on he was admitted to the hospital with dyspnoea and chest pain. The initial examinations stated a suspicion for intrathoracic tumour arising from the pericardium or liver. Further investigation revealed symptomatic intrathoracic liver herniation for which the patient underwent laparoscopic surgery with the mobilisation of liver and placement of a perforated Parietene™ composite mesh. CONCLUSION: The purpose of this case report is to describe a rare complication after pericardial fenestration with its potential clinical implications.

Superior mesenteric vein absence with intestinal malrotation: a case report.

BACKGROUND: Congenital abnormalities are not very common and are even rarer when two or more are combined. Congenital malformation of the superior mesenteric vein may not affect normal development, or it may lead to moderate or even severe symptoms. In combination with intestinal malrotation, however, it may lead to the need for surgical intervention in the early years of life. CASE PRESENTATION: We present the case of a 22-year-old patient who had been diagnosed with iron deficiency anaemia at the age of two months. As a result of the absence of the proximal section of the superior mesenteric vein, the patient has always needed iron supplements and an occasional erythrocyte transfusion. This has resulted from the formation of collaterals throughout the small bowel, causing chronic blood loss with its clinical manifestation. Although, there are some congenital abnormalities of the superior mesenteric vein, the absence of the superior mesenteric vein is rare, and in this case the clinical course was quite severe. Therefore, we planned bypass surgery for this patient to reduce the duodenal collaterals and resolve the persistent anaemia caused by chronic blood loss from the duodenum. We successfully performed the surgery consisting of the formation of anastomosis between the large collateral vein from the distal end of the superior mesenteric vein and the anterior inferior pancreaticoduodenal vein. CONCLUSION: The purpose of this case report is to describe the rare anatomical malformation of the superior mesenteric vein accompanied by intestinal malrotation, with its potential clinical implications regarding symptoms, clinical presentation, and the impact on potential surgery planning.

DNA Methylation Mediates EMT Gene Expression in Human Pancreatic Ductal Adenocarcinoma Cell Lines.

Due to abundant stroma and extracellular matrix, accompanied by lack of vascularization, pancreatic ductal adenocarcinoma (PDAC) is characterized by severe hypoxia. Epigenetic regulation is likely one of the mechanisms driving hypoxia-induced epithelial-to-mesenchymal transition (EMT), responsible for PDAC aggressiveness and dismal prognosis. To verify the role of DNA methylation in this process, we assessed gene expression and DNA methylation changes in four PDAC cell lines. BxPC-3, MIA PaCa-2, PANC-1, and SU.86.86 cells were exposed to conditioned media containing cytokines and inflammatory molecules in normoxic and hypoxic (1% O2) conditions for 2 and 6 days. Cancer Inflammation and Immunity Crosstalk and Human Epithelial to Mesenchymal Transition RT² Profiler PCR Arrays were used to identify top deregulated inflammatory and EMT-related genes. Their mRNA expression and DNA methylation were quantified by qRT-PCR and pyrosequencing. BxPC-3 and SU.86.86 cell lines were the most sensitive to hypoxia and inflammation. Although the methylation of gene promoters correlated with gene expression negatively, it was not significantly influenced by experimental conditions. However, DNA methyltransferase inhibitor decitabine efficiently decreased DNA methylation up to 53% and reactivated all silenced genes. These results confirm the role of DNA methylation in EMT-related gene regulation and uncover possible new targets involved in PDAC progression.

Senescence in HBV-, HCV- and NAFLD- Mediated Hepatocellular Carcinoma and Senotherapeutics: Current Evidence and Future Perspective.

Cell senescence constitutes a physiological process that serves as protection from malignant transformation of cells. However, recent scientific discoveries also identify cell senescence as pivotal in hepatocellular cancer (HCC) biology. The review herein aimed to accumulate evidence on senescence as a mediator of HCC occurrence in hepatitis B (HBV), C (HCV) virus infections, and non-alcoholic fatty liver disease (NAFLD). In HBV infection, the carcinogenic HBV X protein frequently mutates during chronic infection, and subsequently exhibits different effects on senescence. In HCV infection, senescent non-functional T-cells do not effectively clear pre-malignant hepatocytes. Furthermore, the HCV Core protein inhibits the occurrence of normal stress-induced hepatocyte senescence, allowing damaged cells to maintain their proliferative potential. In NAFLD-mediated HCC, current data point towards the gut microbiome and hepatic stellate cell senescence. Additionally, senescence contributes in the development of resistance in targeted therapies, such as sorafenib. Finally, the promising role of senotherapeutics in HCC was also explored. Overall, although we may still be at a primitive stage in fully unraveling the role of senescence in cancer, it seems that understanding and harnessing senescence may have the potential to revolutionize the way we treat hepatocellular cancer.

The association of rs703842 variants in CYP27B1 with multiple sclerosis susceptibility is influenced by the HLA-DRB1*15:01 allele in Slovaks.

In this study, we analysed the association of rs703842 in CYP27B1 gene with multiple sclerosis (MS) risk and disability progression in a group of 496 MS patients and 521 controls. For the first time in Central European Slovak population, we found the rs703842 allele C to be protective factor against MS development (p = 1.09 × 10-5). Moreover, the risky genotypes TT and TC were showed to be associated with an increased MS risk, and this was aggravated by the homozygous carriage of the HLA-DRB1*15:01 allele (OR = 2.82 vs. 4.86, p < .0001). No association of rs703842 with MS disability progression or calcidiol serum level was found.