Background: Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal cancers. Given the currently limited therapeutic options, the definition of molecular subgroups with the development of tailored therapies remains the most promising strategy. Patients with high-level gene amplification of urokinase plasminogen activator receptor (uPAR/PLAUR) have an inferior prognosis. We analyzed the uPAR function in PDAC to understand this understudied PDAC subgroup’s biology better. Methods: A total of 67 PDAC samples with clinical follow-up and TCGA gene expression data from 316 patients were used for prognostic correlations. Gene silencing by CRISPR/Cas9, as well as transfection of uPAR and mutated KRAS, were used in PDAC cell lines (AsPC-1, PANC-1, BxPC3) treated with gemcitabine to study the impact of these two molecules on cellular function and chemoresponse. HNF1A and KRT81 were surrogate markers for the exocrine-like and quasi-mesenchymal subgroup of PDAC, respectively. Results: High levels of uPAR were correlated with significantly shorter survival in PDAC, especially in the subgroup of HNF1A-positive exocrine-like tumors. uPAR knockout by CRISPR/Cas9 resulted in activation of FAK, CDC42, and p38, upregulation of epithelial makers, decreased cell growth and motility, and resistance against gemcitabine that could be reversed by re-expression of uPAR. Silencing of KRAS in AsPC1 using siRNAs reduced uPAR levels significantly, and transfection of mutated KRAS in BxPC-3 cells rendered the cell more mesenchymal and increased sensitivity towards gemcitabine. Conclusions: Activation of uPAR is a potent negative prognostic factor in PDAC. uPAR and KRAS cooperate in switching the tumor from a dormant epithelial to an active mesenchymal state, which likely explains the poor prognosis of PDAC with high uPAR. At the same time, the active mesenchymal state is more vulnerable to gemcitabine. Strategies targeting either KRAS or uPAR should consider this potential tumor-escape mechanism.

Developing high-performance biocathodes remain one of the most challenging aspects of the microbial electrosynthesis (MES) system and the primary factor limiting its output. Herein, a hollow porous carbon (PC) fabricated with MXenes coated over an electrode was developed for MES systems to facilitate the direct delivery of CO₂ to microorganisms colonized. The result highlighted that MXene@PC (Ti₃C₂T_x@PC) has a surface area of 434 m²/g. The Ti₃C₂T_x@PC MES cycle shows that in cycle 4 and cycle 5, the values are -309.2 and -352.3. Cyclic voltammetry showed that the coated electrode current response (mA) increased from -4.5 to -20.2. The substantial redox peaks of Ti₃C₂T_x@PC biofilms are displayed at -741, -516, and -427 mV vs Ag/AgCl, suggesting an enhanced electron transfer owing to the Ti₃C₂T_x@PC complex coating. Additionally, more active sites enhanced mass transfer and microbial development, resulting in a 46% rise in butyrate compared to the uncoated control. These findings demonstrate the value of PC modification as a method for MES-based product selection.

Purpose Lung cancer is the leading cause of cancer-related deaths worldwide. Patients with an amplification of the MTHFD2 gene have a particularly poor prognosis. MTHFD2 signaling has been associated with migration, metastasis, and proliferation of lung cancer cells mediated through ERK signaling. Although the enzymatic activity of the MTHFD2 protein is well understood, little is known about its larger role in chemoresistance. Methods Seventy-nine of non-small cell lung cancer (NSCLC) samples with clinical follow-up were subjected to immunohistochemical staining for MTHFD2 and sequenced using next generation sequencing (NGS) to determine EGFR status. MTHFD2 gene was knocked down in two NSCLC cell lines with wild type EGFR gene (HCC44 and H1993) where MTHFD2 signaling and chemotherapy resistance against pemetrexed were evaluated. Results MTHFD2 expression data revealed a strong prognosis relevance in adenocarcinoma (LUAD). Immunoblotting of cell lines showed a MTHFD2 dependent and cell type specific ERK signaling in EGFR wild type cells. MTHFD2 expression induced proliferation of NSCLC cells and their resistance against pemetrexed. Knocking down the MTHFD2 gene induced cycle arrest, however, it did not activate apoptosis signaling within HCC44 cell line. Conclusions MTHFD2 expression is strongly associated with prognosis in LUAD patients, as well as with increased cellular proliferation and resistance to pemetrexed in LUAD patients with wild-type EGFR. These findings suggest that MTHFD2 could serve as a valuable biomarker for predicting treatment outcomes in LUAD. Further studies are needed to fully explore the clinical implications and potential combination therapies targeting MTHFD2 in LUAD.