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Immunosuppressive factors within the tumor microenvironment (TME), such as Transforming growth factor beta (TGF-β), constitute a crucial hindrance to immunotherapeutic approaches in colorectal cancer (CRC). Furthermore, immune checkpoint factors (e.g., programmed death-ligand 1 [PD-L1]) inhibit T-cell proliferation and activation. To cope with the inhibitory effect of immune checkpoints, the therapeutic value of dual targeting PD-L1 and TGF-β pathways via M7824 plus 5-FU in CRC has been evaluated. Integrative-systems biology approaches and RNAseq were used to assess the differential level of genes associated with 88 metastatic-CRC patients. The level of PD-L1 and TGF-β was evaluated in a validation cohort. The anti-proliferative, migratory, and apoptotic effects of PD-L1/TGF-β inhibitor, M7824, were assessed by MTT, wound-healing assay, and flow cytometry. Anti-tumor activity was assessed in a xenograft model, followed by biochemical studies and histological staining, and gene/protein expression analyses by RT-PCR and ELISA/IHC. The result of differentially expressed genes (DEGs) analysis showed 1268 upregulated and 1074 downregulated genes in CRC patients. Among the highest scoring genes and dysregulated pathways associated with CRC, PD-L1, and TGF-β were identified and further validated in 92 CRC patients. Targeting of PD-L1-TGF-β inhibited cell growth and migration, associated with modulation of CyclinD1 and MMP9. Furthermore, M7824 inhibited tumor growth via targeting TGF-β and PD-L1 pathways, resulting in modulation of inflammatory response and fibrosis via TNF-α/IL6/CD4–8 and COL1A1/1A2, respectively. In conclusion, our data illustrated that co-targeting PD-L1 and TGF-β pathways increased the effect of Fluorouracil (5-FU) and reduced the tumor growth in PD-L1/TGF-β expressing tumors, providing a new therapeutic option in the treatment of CRC.

Background. Clinical guidelines are texts developed to assist both physicians and patients in deciding on the most appropriate health care. This study evaluated the compliance of emergency performance with clinical guidelines at Sina Medical Training Center in Tabriz. Methods. This descriptive-analytical study was conducted on a case study at Sina Hospital under the supervision of Tabriz University of Medical Sciences. In the first stage, as a research tool, a checklist, approved in terms of validity and reliability, was set up to evaluate clinical guidelines. The second phase of this study was cross-sectional, conducted in a period of one month. All medical records of people referring to level 1 and 2 triage were reviewed based on the checklist and the data were entered into SPSS software, and since the normality of the data was confirmed, descriptive statistics and parametric tests (t-test and ANOVA) were used to analyze the data. Results. Considering the mean (1.72 ± 0.097) in this study, the adherence to clinical guidelines seems to be higher than average. The results also showed that there was no significant relationship between any of the demographic variables and the mean score of total compliance with the guidelines (P-value> 0.05). However, among other variables, a significant relationship was found between the place of the patient's visit as well as the type and time of patient assignment on the one hand and the average score of total compliance with the guidelines (P-value

Additional file 1: Instrument and manual instrument guide.

OBJECTIVE: Thrombin is a proinflammatory and pro-coagulant agent which is upregulated in several human diseases. Thrombin has a critical role in promoting cell proliferation and microvascular leakage in malignant cells, resulting in cancer growth and progression. Here, we explored the potential therapeutic value of curcumin on permeability induced by thrombin in mice. MATERIALS AND METHODS: To assess the activity of curcumin on thrombin-induced vascular permeability mice model, C57BL / 6 mice were randomly divided into four groups: (1) control (2) Thrombin (3) Thrombin + Curcumin and (4) Thrombin + Metformin. Thirty minutes after treatment, Evans blue was injected intravenously through the tail vein to mice. Then, animals were sacrificed and the dye was extracted from the skin tissue by incubation with formamide. Heatmap and correlation map were generated and protein-protein interaction network of the hub genes was drawn by Cytoscape software. RESULTS: Hub DEG expression rate showed that Heat shock protein a1 (Hspa1) family (comprised of HSPa1a, b, and HSPa5), caspase 3, and minichromosome maintenance complex component 2 were overexpressed after treatment with curcumin. Functional modules of curcumin enriched through Enrich gene biological process and revealed positive association of gene expression of apoptosis process with the therapy. Curcumin was also found to reduce leucocyte migration in murine tissues. Additionally, treatment with curcumin resulted in downregulation of heat shock proteins and proinflammatory cytokines such as monocyte chemotactic protein 1, interleukin-6 and chemokine (C-X-C motif) ligand 3. CONCLUSION: Curcumin inhibited the proinflammatory cytokines and inflammatory HSPs in endothelial cells and reduced thrombin-induced barrier destabilization in vivo.