Immunomodulatory Precision: A Narrative Review Exploring the Critical Role of Immune Checkpoint Inhibitors in Cancer Treatment.

An immune checkpoint is a signaling pathway that regulates the recognition of antigens by T-cell receptors (TCRs) during an immune response. These checkpoints play a pivotal role in suppressing excessive immune responses and maintaining immune homeostasis against viral or microbial infections. There are several FDA-approved immune checkpoint inhibitors (ICIs), including ipilimumab, pembrolizumab, and avelumab. These ICIs target cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), and programmed death ligand 1 (PD-L1). Furthermore, ongoing efforts are focused on developing new ICIs with emerging potential. In comparison to conventional treatments, ICIs offer the advantages of reduced side effects and durable responses. There is growing interest in the potential of combining different ICIs with chemotherapy, radiation therapy, or targeted therapies. This article comprehensively reviews the classification, mechanism of action, application, and combination strategies of ICIs in various cancers and discusses their current limitations. Our objective is to contribute to the future development of more effective anticancer drugs targeting immune checkpoints.

A protein-based prognostic model for pancreatic ductal adenocarcinoma: Construction and validation.

BACKGROUND: Probing relevant proteomic biomarkers may facilitate effective pancreatic adenocarcinoma (PDAC) diagnosis, treatment and prevention. Here, we developed a protein-based prognostic model for PDAC by using relevant proteomic biomarkers data from The Cancer Genome Atlas (TCGA). METHODS: We obtained PDAC's proteomic and clinical data from TCGA and used various analytical tools to identify differentially expressed proteins between normal and cancer tissues. We constructed our protein-based prognostic model and confirmed its accuracy using receiver operating characteristic curve and Kaplan-Meier survival analyses. We elucidated clinical factor-signature protein correlations by clinical correlation assessments and protein coexpression networks. We also used immunohistochemistry (protein expression assessment), Gene Set Enrichment Analysis (protein role identification) and CIBERSORT (infiltrating immune cell distribution assessment). RESULTS: CIITA, BRAF_pS445, AR, YTHDF2, IGFBP2 and CDK1_pT14 were identified as PDAC-associated prognostic proteins. All risk scores calculated using our model provided 1-, 3-, 5-year survival probability at 70 % accuracy. The reliability of our model was validated by the GEO as well. In high- and low-risk groups, age, sex, T- and N- stage disparities were significant, and prognostic and coexpressed proteins correlated. PDAC tissues demonstrated significant CDK1_pT14 overexpression but significant BRAF_pS445, YTHDF2, and IGFBP2 underexpression. Downstream proteins of BRAF were validated by IHC. Low-risk tissues demonstrated more naïve B cells, eosinophils, activated NK cells and regulatory T cells, whereas high-risk tissues demonstrated more activated memory T cells, monocytes, neutrophils, dendritic cells and resting NK cells. CONCLUSIONS: Our protein-based prognostic model for PDAC, along with six signature proteins, might aid in predicting PDAC prognosis and therapeutic targets.

Risk Factors of Gastrointestinal Perforation with a Poor Prognosis.

Background: Despite medical progress, mortality from gastrointestinal perforation was relatively high. Our study's objective was to identify risk factors associated with a poor prognosis for gastrointestinal perforation. Methods: Patients diagnosed with gastrointestinal perforation at the Longchuan County People's Hospital between January 2019 and February 2022 were the subject of a retrospective analysis of their laboratory data. Patients were grouped based on length of hospital stay, septic shock, and mortality. Results: A total of 240 patients participated in our study. Using univariate and multivariate analysis, we identified several risk factors for gastrointestinal perforation associated with a dismal prognosis. Lower digestive tract perforation (OR=2.418, 95% CI 1.119-5.227, P=0.025), low total protein (OR=0.934, 95% CI 0.879-0.992, P=0.026) and low hemoglobin (OR=0.985, 95% CI 0.971-0.999, P=0.039) were linked to a longer length of stay, especially hemoglobin (OR=0.978, 95% CI 0.966-0.991, P=0.001) in upper digestive tract. High ratio of neutrophils to lymphocytes (NLR) (OR=1.043, 95% CI 1.012-1.076, P=0.007), high lymphocyte-to-monocyte ratio (LMR) (OR=2.158, 95% CI 1.495-3.115, P<0.001) and low prognostic nutrition index (PNI) (OR=0.814, 95% CI 0.751-0.833, P<0.001) predicted septic shock. In upper digestive tract, PLR (OR=1.001, 95% CI 1.000-1.002, P=0.067), LMR (OR=2.160, 95% CI 1.440-3.240, P<0.001) and PNI (OR=0.843, 95% CI 0.767-0.926, P<0.001) were risk factors for septic shock, and total protein (OR=0.796, 95% CI 0.686-0.923, P=0.003) was a risk factor for septic shock in lower digestive tract. High NLR (OR=1.056, 95% CI 1.019-1.093, P=0.003), high LMR (OR=1.760, 95% CI 1.177-2.632, P=0.006) and low PNI (OR=0.832, 95% CI 0.754-0.918, P<0.001) were the risk factors of mortality. In subgroup analysis of perforation site, albumin (OR=0.820, 95% CI 0.719-0.934, P=0.003) and LMR (OR=1.506, 95% CI 1.069-2.123, P=0.019) were risk factors for mortality in upper digestive tract and PNI (OR=0.636, 95% CI 0.445-0.908, P=0.013) was a risk factor for mortality in lower digestive tract. Conclusion: Our research found that the perforation site, total protein, albumin, hemoglobin, NLR, LMR, PLR and PNI were risk factors for gastrointestinal perforation with a poor prognosis.

Role of TLR5 in the Translocation and Dissemination of Commensal Bacteria in the Intestine after Traumatic Hemorrhagic Shock.

Enterogenous infection is a major cause of death during traumatic hemorrhagic shock (THS). It has been reported that Toll-like receptor 5 (TLR5) plays an integral role in regulating mucosal immunity and intestinal homeostasis of the microbiota. However, the roles played by TLR5 on intestinal barrier maintenance and commensal bacterial translocation post-THS are poorly understood. In this research, we established THS models in wild-type (WT) and Tlr5-/- (genetically deficient in TLR5 expression) mice. We found that THS promoted bacterial translocation, while TLR5 deficiency played a protective role in preventing commensal bacteria dissemination after THS. Furthermore, intestinal microbiota analysis uncovered that TLR5 deficiency enhanced the mucosal biological barrier by decreasing RegIIIγ-mediated bactericidal activity against G+ anaerobic bacteria. We then sorted small intestinal TLR5+ lamina propria dendritic cells (LPDCs) and analyzed TH1 differentiation in the intestinal lamina propria and a coculture system consisting of LPDCs and naïve T cells. Although TLR5 deficiency attenuated the regulation of TH1 polarization by LPDCs, it conferred stability to the cells during THS. Moreover, retinoic acid (RA) released from TLR5+ LPDCs could play a key role in modulating TH1 polarization. We also found that gavage administration of RA alleviated bacterial translocation in THS-treated WT mice. In summary, we documented that TLR5 signaling plays a pivotal role in regulating RegIIIγ-induced killing of G+ anaerobic bacteria, and LPDCs mediated TH1 differentiation via RA. These processes prevent intestinal bacterial translocation and enterogenous infection after THS, suggesting that therapeutically targeting LPDCs or gut microbiota can interfere with bacterial translocation after THS.

Regulator of calcineurin 1 gene isoform 4 in pancreatic ductal adenocarcinoma regulates the progression of tumor cells.

Therapeutic strategies to treat pancreatic ductal adenocarcinoma (PDAC) remain unsatisfying and limited. Therefore, it is imperative to fully determine the mechanisms underlying PDAC progression. In the present study, we report a novel role of regulator of calcineurin 1, isoform 4 (RCAN1.4) in regulating PDAC progression. We demonstrated that RCAN1.4 expression was decreased significantly in PDAC tissues compared with that in para-cancerous tissues, and correlated with poor prognosis of patients with pancreatic cancer. In vitro, stable high expression of RCAN1.4 could suppress the metastasis and proliferation and angiogenesis of pancreatic tumor cells. In addition, interferon alpha inducible protein 27 (IFI27) was identified as having a functional role in RCAN1.4-mediated PDAC migration and invasion, while VEGFA play a vital role in RCAN1.4-mediated PDAC angiogenesis. Analysis of mice with subcutaneously/orthotopic implanted xenograft tumors and liver metastasis model confirmed that RCAN1.4 could modulate the growth, metastasis, and angiogenesis of tumors via IFI27/VEGFA in vivo. In conclusion, our results suggested that RCAN1.4 suppresses the growth, metastasis, and angiogenesis of PDAC, functioning partly via IFI27 and VEGFA. Importantly, our results provided possible diagnostic criteria and therapeutic targets for PDAC.

Characterization of Placental Microvascular Architecture by MV-Flow Imaging in Normal and Fetal Growth-Restricted Pregnancies.

OBJECTIVES: To observe the microvascular architecture in the placental bed and explore the feasibility and clinical utility of MV-Flow imaging (Samsung Medison Co, Ltd, Seoul, Korea) during normal pregnancy and fetal growth restriction (FGR). METHODS: Placental microvascular structure ultrasound imaging by MV-Flow was performed on 227 unaffected and 17 FGR fetuses between 11 and 41 weeks' gestation. A placental vascular index (VIMV ) was acquired by application of various MV-Flow regions of interest (ellipse, rectangle, and manual trace). Unaffected control and FGR groups were assessed for umbilical artery, middle cerebral artery, and uterine artery pulsatility indices and the cerebroplacental ratio calculated by ultrasound. RESULTS: No significant difference in the VIMV by varying regions of interest or placental regions was observed in the control group. The VIMV in the first trimester was lower than that in the second and third trimesters, with 5th through 95th percentile normal VIMV reference values of 18.39 to 63.79 for 13.6 weeks and earlier, 28.53 to 66.64 for 14 weeks to 27 weeks 6 days, and 21.95 to 67.45 for 28 weeks and later. The VIMV values in the FGR group were lower than those in the control group in the upper, middle, and lower parts of the placenta (mean ± SD, 24.9 ± 13.9 versus 45.0 ± 13.4; P < .01; 30.5 ± 16.1 versus 44.7 ± 14.3; P < .01; and 29.9 ± 17.4 versus 47.6 ± 12.2; P < .01, respectively). Higher umbilical artery and uterine artery pulsatility indices and a lower cerebroplacental ratio were found in the FGR group compared with the control group (P < .01). CONCLUSIONS: MV-Flow technology can display and quantify placental microvascular architecture at the level of the stem villi and villous leaves, and the VIMV provides for quantification of tissue vascularity. MV-Flow is a potentially powerful and promising tool to explore placental microvascular perfusion and provide new information on a host of pregnancy-related conditions.

Effects of Short-Peptide-Based Enteral Nutrition on the Intestinal Microcirculation and Mucosal Barrier in Mice with Severe Acute Pancreatitis.

SCOPE: Short-peptide-based enteral nutrition (SPEN) is absorbed more efficiently in patients with severe acute pancreatitis (SAP). More importantly, SPEN decreases SAP-induced enterogenous infection risk. This study aims to investigate whether SPEN alleviates intestinal bacterial translocation in mice with SAP, and the underlying mechanisms. METHODS AND RESULTS: The SAP model is established after pre-treatment with SPEN or intact-protein-based enteral nutrition. Although there is no improvement in pancreas injury, as evaluated through Hematoxylin-Eosin staining or serum amylase, SPEN obviously attenuates intestinal bacterial translocation after SAP. To unveil the mechanisms, it is found that the intestinal mechanical barrier destroyed by SAP is significantly relieved by SPEN, which presents with recovered ZO-1 expression, mucus layer, and goblet cell function. Additionally, SPEN alleviates local CCR6/CCL20 induced CD11c+ dendritic cell infiltration, systemic immunosuppression, and inhibits the secretion of luminal secretory immunoglobulin A. Possibly responsible for SAP-induced mucosal dysfunctions, destroyed intestinal mucosal microcirculation and local hypoxia are largely improved in SAP+SPEN group. CONCLUSION: SPEN can improve downregulated intestinal mucosal microcirculation secondary to SAP, which may be responsible for mucosal inflammation relief, maintenance of the mechanical barrier and mucosal immunity, the correction of systemic immunosuppression, and play a protective role in defending commensal bacterial translocation after SAP.

Severe traumatic hemorrhagic shock induces compromised immune barrier function of the mesenteric lymph node leading to an increase in intestinal bacterial translocation.

Critically ill patients have increased susceptibility to translocation of gut bacteria. However, the mechanisms are complicated and remain unclear, and the aim of this study was to explore these mechanisms. Rats exposed to different levels of shock were orally administrated with bioluminescent Citrobacter. We found that severe shock caused an increase in bacterial translocation to the visceral organs, such as liver, spleen and blood, compared with mild shock. Surprisingly, bacterial translocation to mesenteric lymph node (MLN) was unchanged between the two shock groups. Various methods, including flow cytometry, a co-culture model and western blots, were used to evaluate MLN-associated immune function. Specifically, we focused on mesenteric lymph node dendritic cells (MLN-DCs), the critical antigen presenting cells involved in the construction of the immune barrier in MLN. We also found that severe shock impaired the phenotypic maturation of MLN-DCs and induced a tolerogenic phenotype. Furthermore, co-culture assays of DCs with naive CD4+ T cells showed that DCs subject to severe shock were more inclined to polarize native CD4+ T cells into Th2 and Treg cells. This study successfully reproduced the clinical phenomenon of severe shock resulting in increased bacterial translocation to extraintestinal tissues, and this may be related to the compromised immune barrier function of MLN, as maturation and function of MLN-DC's were badly impaired.

ARK5 promotes doxorubicin resistance in hepatocellular carcinoma via epithelial-mesenchymal transition.

AMP-activated protein kinase family member 5 (ARK5) overexpression has been reported in many human cancers, and ARK5 is associated with poor prognosis in hepatocellular carcinoma (HCC). However, whether ARK5 is involved in HCC chemoresistance is unclear. The present study aimed to investigate the role of ARK5 in HCC chemoresistance and the underlying mechanism. In this study, we found that SNU387 and SNU449 HCC cell lines overexpressing ARK5 displayed low doxorubicin sensitivity compared to Huh7 and Hep3B HCC cell lines with ARK5 low-expression. And knockdown of ARK5 increased the doxorubicin sensitivity in all HCC cell lines in the manner of inhibiting cell proliferation. Western blotting and immunofluorescence both showed that ARK5 knockdown upregulated E-cadherin and downregulated vimentin, which was consistent with the knockdown of TWIST, indicating ARK5 was involved in epithelial-mesenchymal transition (EMT). Moreover, suppressing ARK5 by siRNA restored E-cadherin and vimentin expression induced by doxorubicin treatment or hypoxia culture. Our results indicated ARK5 confers doxorubicin resistance in HCC via inducing EMT.