The molecular network of the proteasome machinery inhibition response is orchestrated by HSP70, revealing vulnerabilities in cancer cells.

Proteasome machinery is a major proteostasis control system in human cells, actively compensated upon its inhibition. To understand this compensation, we compared global protein landscapes upon the proteasome inhibition with carfilzomib, in normal fibroblasts, cells of multiple myeloma, and cancers of lung, colon, and pancreas. Molecular chaperones, autophagy, and endocytosis-related proteins are the most prominent vulnerabilities in combination with carfilzomib, while targeting of the HSP70 family chaperones HSPA1A/B most specifically sensitizes cancer cells to the proteasome inhibition. This suggests a central role of HSP70 in the suppression of the proteasome downregulation, allowing to identify pathways impinging on HSP70 upon the proteasome inhibition. HSPA1A/B indeed controls proteasome-inhibition-induced autophagy, unfolded protein response, and endocytic flux, and directly chaperones the proteasome machinery. However, it does not control the NRF1/2-driven proteasome subunit transcriptional bounce-back. Consequently, targeting of NRF1 proves effective in decreasing the viability of cancer cells with the inhibited proteasome and HSP70.

A Driver Never Works Alone-Interplay Networks of Mutant p53, MYC, RAS, and Other Universal Oncogenic Drivers in Human Cancer.

The knowledge accumulating on the occurrence and mechanisms of the activation of oncogenes in human neoplasia necessitates an increasingly detailed understanding of their systemic interactions. None of the known oncogenic drivers work in isolation from the other oncogenic pathways. The cooperation between these pathways is an indispensable element of a multistep carcinogenesis, which apart from inactivation of tumor suppressors, always includes the activation of two or more proto-oncogenes. In this review we focus on representative examples of the interaction of major oncogenic drivers with one another. The drivers are selected according to the following criteria: (1) the highest frequency of known activation in human neoplasia (by mutations or otherwise), (2) activation in a wide range of neoplasia types (universality) and (3) as a part of a distinguishable pathway, (4) being a known cause of phenotypic addiction of neoplastic cells and thus a promising therapeutic target. Each of these universal oncogenic factors-mutant p53, KRAS and CMYC proteins, telomerase ribonucleoprotein, proteasome machinery, HSP molecular chaperones, NF-κB and WNT pathways, AP-1 and YAP/TAZ transcription factors and non-coding RNAs-has a vast network of molecular interrelations and common partners. Understanding this network allows for the hunt for novel therapeutic targets and protocols to counteract drug resistance in a clinical neoplasia treatment.

Correlation of TNF-α and TGF-ß polymorphisms with protein levels in pancreatic ductal adenocarcinoma and colorectal cancer.

AIM OF THE STUDY: To determine the correlation of protein serum levels of two cytokines and their polymorphisms, which have an influence on their expression. MATERIAL AND METHODS: The study group consisted of 65 patients (33 men, 31 women) who met the criteria for inclusion and exclusion of pancreatic cancer, and 41 patients (25 men, 16 women) with colorectal cancer. The control group consisted of 100 healthy volunteers (63 men, 37 women). Detection of polymorphisms was performed using TaqMan probes, and concentration of proteins by ELISA method. RESULTS: The mean TNF-α concentration in patients with colorectal cancer was significantly higher compared to the control group, p< 0.0001. A statistically significant difference was noted when comparing both study groups, p = 0.0009. The analyses show that the occurrence of the polymorphic genotype -308AA of the TNF-α gene was not correlated with the increased concentration of the examined protein in patients with both pancreatic and colorectal cancer. It was also noted that the concentration of TGF-ß protein was significantly higher in patients with colorectal cancer than in patients with pancreatic cancer. These results also proved to be statistically significant, p = 0.0353. CONCLUSIONS: The only statistically significant effects were the correlations between patients belonging to a specific group (pancreatic cancer/colorectal cancer/control) and average protein levels. There was no effect of sex or genotype on the occurrence of elevated levels of TNF-α and TGF-ß protein control, despite their variability in particular types of cancer.

Management of acute pancreatitis (AP) - Polish Pancreatic Club recommendations.

The presented recommendations concern the current management of acute pancreatitis. The recommendations relate to the diagnostics and treatment of early and late phases of acute pancreatitis and complications of the disease taking into consideration surgical and endoscopic methods. All the recommendations were subjected to voting by the members of the Working Group of the Polish Pancreatic Club, who evaluated them every single time on a five-point scale, where A means full acceptance, B means acceptance with a certain reservation, C means acceptance with a serious reservation, D means rejection with a certain reservation and E means full rejection. The results of the vote, together with commentary, are provided for each recommendation.