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Wound healing and tissue regeneration is an intricate biological process that involves repair of cellular damage and maintenance of tissue integrity. Cascades involved in wound healing and tissue regeneration highly overlap with cancer causing pathways. Usually, subsequent tissue damage events include release of a number of cytokines to accomplish post-trauma restoration. IL-22 is one of the cytokines that are immediately produced to initiate immune response against several tissue impairments. IL-22 is a fundamental mediator in inflammation, mucous production, protective role against pathogens, wound healing, and tissue regeneration. However, accumulating evidence suggests pivotal role of IL-22 in instigation of various cancers due to its pro-inflammatory and tissue repairing activity. In this review, we summarize how healing effects of IL-22, when executed in an uncontrollable fashion can lead to carcinogenesis.

To evaluate a novel anticoagulation strategy in an extracorporeal circuit, we introduce a device that induces local hypothermia as blood flows through the circuit. Using a pig model, we assessed its technical feasibility, biocompatibility, and safety. Sixteen pigs were randomly assigned to either the cooled group or the control group and underwent midline laparotomy to establish extracorporeal circulation (blood flow 500 ml/min) via the caudal vena cava for up to four hours. Blood samples were collected at baseline and at 15, 60, and 240 min during the experiment. In the cooled group, blood was cooled to 20 °C and then rewarmed to 37 °C, while in the control group, blood was maintained at 37 °C. A total of 6 cooled and 4 control pigs completed 4 h of the experiment. Our findings confirm the technical feasibility of the proposed device, which effectively maintained the required temperature differentials while keeping the pressure differentials in the circuit within 150 mmHg. No issues with circuit patency were observed. Additionally, no adverse effects were detected on erythrocyte stability. Within the limitation of the short observation period, no adverse effects were observed on renal, liver, or cardiac function. Our data suggest that local hypothermia in the extracorporeal circuit may mitigate surgery-induced inflammation.

ATP-binding cassette (ABC) and solute carrier (SLC) transporters translocate diverse substances across cellular membranes and their deregulation may cause drug resistance of cancers. This study investigated significance of protein expression and cellular localization of the previously suggested putative prognostic markers ABCC2 and SLC22A3 in pancreatic cancer patients. Protein localization and brush border staining intensity of ABCC2 and SLC22A3 was assessed in tumor tissue blocks of 65 pancreatic cancer patients and associated with clinical data and survival of patients with regard to therapy. Negative SLC22A3 brush border staining in pancreatic tumors significantly increased the risk of both disease progression and patient´s death in univariate analyses. Multivariate analyses confirmed the association of SLC22A3 expression with progression-free survival of patients. A subgroup analysis of patients treated with regimens based on nucleoside analogs suggested that patients with negative brush border staining or apical localization of SLC22A3 in tumor cells have worse overall survival. The combination of positive ABCC2 and negative SLC22A3 brush border staining predicted worst overall survival and patients with positive brush border staining of both proteins had best overall and progression-free survival. The present study shows for the first time that the protein presence and to some extent also localization of SLC22A3 significantly associate with prognosis of pancreatic cancer in both unstratified and chemotherapy-treated patients. The combination of ABCC2 and SLC22A3 brush border staining also needs further attention in this regard.

Background Hepatocellular carcinoma (HCC) is a fatal disease characterized by early genetic alterations in telomerase reverse transcriptase promoter (TERTp) and β-catenin (CTNNB1) genes and immune cell activation in the tumor microenvironment. As a novel approach, we wanted to assess patient survival influenced by combined presence of mutations and densities of CD8+ cytotoxic T cells. Methods Tissue samples were obtained from 67 HCC patients who had undergone resection. We analysed CD8+ T cells density, TERTp mutations, rs2853669 polymorphism, and CTNNB1 mutations. These variables were evaluated for time to recurrence (TTR) and disease free survival (DFS). Results TERTp mutations were found in 75.8% and CTNNB1 mutations in 35.6% of the patients. TERTp mutations were not associated with survival but polymorphism rs2853669 in TERTp was associated with improved TTR and DFS. CTNNB1 mutations were associated with improving TTR. High density of CD8+ T-lymphocytes in tumor center and invasive margin correlated with longer TTR and DFS. Combined genetic and immune factors further improved survival showing higher predictive values. E.g., combining CTNNB1 mutations and high density of CD8+ T-lymphocytes in tumor center yielded HRs of 0.12 (0.03–0.52), p  = 0.005 for TTR and 0.25 (0.09–0.74), p  = 0.01 for DFS. Conclusion The results outline a novel integrative approach for prognostication through combining independent predictive factors from genetic and immune cell profiles. However, larger studies are needed to explore multiple cell types in the tumor microenvironment.

Background While nuclear DNA (nDNA) damage and alterations in nDNA repair are known to play a role in colon cancer (CC), there is insufficient research investigating these processes in mitochondrial DNA (mtDNA). Methods This study investigates mtDNA changes in CC, focusing on mitochondrial DNA copy number (mtDNA-CN) variations, mtDNA damage, and the expression and mutation status of DNA repair genes. Three cohorts were analyzed: healthy controls, colon adenoma patients, and CC patients, divided into a pilot and a validation set. Results Our findings revealed that mtDNA-CN was elevated in colon adenomas compared to adenoma-adjacent mucosa (FDR = 0.04), healthy mucosa (FDR = 0.005), and tumor-adjacent mucosa (FDR = 0.005). Moreover, mtDNA-CN was elevated in adenoma-adjacent mucosa compared to healthy mucosa (FDR = 0.04). MtDNA damage was greater in tumor-adjacent mucosa compared to tumor tissue in both the pilot and validation sets (FDR = 0.031 and FDR = 2.06e-05, respectively). Additionally, we identified novel DNA repair genes associated with mtDNA damage, predominantly upregulated in adenoma and tumor tissues compared to healthy colon tissues. Conclusions To conclude, this study highlights the importance of mtDNA alterations in CC development and identifies potential mtDNA biomarkers.

Genotoxic stress triggers a combined action of DNA repair and cell cycle checkpoint pathways. Protein phosphatase 2C delta (referred to as WIP1) is involved in timely inactivation of DNA damage response by suppressing function of p53 and other targets at chromatin. Here we show that WIP1 promotes DNA repair through homologous recombination. Loss or inhibition of WIP1 delayed disappearance of the ionizing radiation-induced 53BP1 foci in S/G2 cells and promoted cell death. We identify breast cancer associated protein 1 (BRCA1) as interactor and substrate of WIP1 and demonstrate that WIP1 activity is needed for correct dynamics of BRCA1 recruitment to chromatin flanking the DNA lesion. In addition, WIP1 dephosphorylates 53BP1 at Threonine 543 that was previously implicated in mediating interaction with RIF1. Finally, we report that inhibition of WIP1 allowed accumulation of DNA damage in S/G2 cells and increased sensitivity of cancer cells to a poly-(ADP-ribose) polymerase inhibitor olaparib. We propose that inhibition of WIP1 may increase sensitivity of BRCA1-proficient cancer cells to olaparib.

There is a lack of systematic research exploring cross-species variation in liver lobular geometry and zonation patterns of critical drug-metabolizing enzymes, a knowledge gap essential for translational studies. This study investigated the critical interplay between lobular geometry and key cytochrome P450 (CYP) zonation in four species: mouse, rat, pig, and human. We developed an automated pipeline based on whole slide images (WSI) of hematoxylin-eosin-stained liver sections and immunohistochemistry. This pipeline allows accurate quantification of both lobular geometry and zonation patterns of essential CYP proteins. Our analysis of CYP zonal expression shows that all CYP enzymes (besides CYP2D6 with panlobular expression) were observed in the pericentral region in all species, but with distinct differences. Comparison of normalized gradient intensity shows a high similarity between mice and humans, followed by rats. Specifically, CYP1A2 was expressed throughout the pericentral region in mice and humans, whereas it was restricted to a narrow pericentral rim in rats and showed a panlobular pattern in pigs. Similarly, CYP3A4 is present in the pericentral region, but its extent varies considerably in rats and appears panlobular in pigs. CYP2D6 zonal expression consistently shows a panlobular pattern in all species, although the intensity varies. CYP2E1 zonal expression covered the entire pericentral region with extension into the midzone in all four species, suggesting its potential for further cross-species analysis. Analysis of lobular geometry revealed an increase in lobular size with increasing species size, whereas lobular compactness was similar. Based on our results, zonated CYP expression in mice is most similar to humans. Therefore, mice appear to be the most appropriate species for drug metabolism studies unless larger species are required for other purposes, e.g., surgical reasons. CYP selection should be based on species, with CYP2E1 and CYP2D6 being the most preferable to compare four species. CYP1A2 could be considered as an additional CYP for rodent versus human comparisons, and CYP3A4 for mouse/human comparisons. In conclusion, our image analysis pipeline together with suggestions for species and CYP selection can serve to improve future cross-species and translational drug metabolism studies.

We study the impact of the media negativity bias on tax compliance. Through a framed laboratory experiment, we assess how the exposure to biased news about government action affects compliance in a repeated taxation game. Subjects treated with positive news are significantly more compliant than the control group. Instead, the exposure to negative news does not prompt any significant reaction compared to the neutral condition, suggesting that participants may perceive the media negativity bias in the selection and tonality of news as the norm rather than the exception. Overall, our results suggest that biased news provision is a constant source of psychological priming and plays a vital role in taxpayers’ compliance decisions.

[...]I realised that the vocabulary book was insufficient. Some history teachers have, sometimes as a reaction against and sometimes as a consequence of the above-mentioned developments, tried to foster students' understanding of the distinctive characteristics that mark history as a discipline and not an ordinary subject that is purely based on content or 'skills'.10 The ability, for example, to link substantive knowledge and historical thinking by enshrining a historical topic within an enquiry or lesson sequence driven conceptually by an 'enquiry question' has been used to foster students' efforts to construct informed, historical claims and to critique those of others.\\n I did not observe this in my data, but my students were much younger than Hammonds and had only studied history at secondary level for two years.

The relationship between knowledge and literacy is a central concern for all teachers. In his teaching, Palek noted that his students were struggling to understand complex substantive concepts such as \"parliament\" and decided to explore the relationship between students' understanding of a concept and their wider substantive knowledge that rendered the concept meaningful. Through a careful analysis of students work, Palek concluded that there is a close relationship between a student's ability to construct a causal argument and his or her \"security\" in understanding relevant substantive concepts. Such a conclusion further supports a renewed emphasis by history teachers on the role played by substantive knowledge in the process of learning history as a discipline, and raises questions about the means by which pupils' progression in history might be assessed.