Endothelial YAP/TEAD1-CXCL17 signaling recruits myeloid-derived suppressor cells against liver ischemia-reperfusion injury.

BACKGROUND AND AIMS: Liver ischemia-reperfusion injury (IRI) is a common complication of liver transplantation and hepatectomy and causes acute liver dysfunction and even organ failure. Myeloid-derived suppressor cells (MDSCs) accumulate and play immunosuppressive function in cancers and inflammation. However, the role of MDSCs in liver IRI has not been defined. APPROACH AND RESULTS: We enrolled recipients receiving OLT and obtained the pre-OLT/post-OLT blood and liver samples. The proportions of MDSCs were significantly elevated after OLT and negatively associated with liver damage. In single-cell RNA-sequencing analysis of liver samples during OLT, 2 cell clusters with MDSC-like phenotypes were identified and showed maturation and infiltration in post-OLT livers. In the mouse model, liver IRI mobilized MDSCs and promoted their infiltration in the damaged liver, and intrahepatic MDSCs were possessed with enhanced immunosuppressive function by upregulation of STAT3 signaling. Under treatment with αGr-1 antibody or adoptive transfer MDSCs to change the proportion of MDSCs in vivo, we found that intrahepatic MDSCs alleviated liver IRI-induced inflammation and damage by inhibiting M1 macrophage polarization. Mechanistically, bulk RNA-sequencing analysis and in vivo experiments verified that C-X-C motif chemokine ligand 17 (CXCL17) was upregulated by YAP/TEAD1 signaling and subsequently recruited MDSCs through binding with GPR35 during liver IRI. Moreover, hepatic endothelial cells were the major cells responsible for CXCL17 expression in injured livers, among which hypoxia-reoxygenation stimulation activated the YAP/TEAD1 complex to promote CXCL17 transcription. CONCLUSIONS: Endothelial YAP/TEAD1-CXCL17 signaling recruited MDSCs to attenuate liver IRI, providing evidence of therapeutic potential for managing IRI in liver surgery.

Delivery of Synthetic Interleukin-22 mRNA to Hepatocytes via Lipid Nanoparticles Alleviates Liver Injury.

Hepatocellular injury, a pivotal contributor to liver diseases, particularly hepatitis, lacks effective pharmacological treatments. Interleukin-22 (IL-22), crucial for liver cell survival, shows potential in treating liver diseases by regulating repair and regeneration through signal transducer and activator of transcription 3 (STAT3) activation. However, the short half-life and off-target effects limit its clinical applications. To address these issues, lipid nanoparticles are employed to deliver synthetic IL-22 mRNA (IL-22/NP) for in situ IL-22 expression in hepatocytes. The study reveals that IL-22/NP exhibits liver-targeted IL-22 expression, with increased IL-22 levels detected in the liver as early as 3 h postintravenous injection, lasting up to 96 h. Furthermore, IL-22/NP activates STAT3 signaling in an autocrine or paracrine manner to upregulate downstream factors Bcl-xL and CyclinD1, inhibiting hepatocyte apoptosis and promoting cell proliferation. The therapeutic efficacy of IL-22/NP is demonstrated in both chronic and acute liver injury models, suggesting IL-22 mRNA delivery as a promising treatment strategy for hepatitis and liver diseases involving hepatocellular injury.

RNA N6-Methyladenosine Patterns in Hepatocellular Carcinoma Reveal a Distinct Immune Infiltration Landscape and Clinical Significance.

BACKGROUND RNA N6-methyladenosine (m6A) methylation, the most abundant and prominent form of epigenetic modification, is involved in hepatocellular carcinoma (HCC) initiation and progression. However, the role of m6A methylation in HCC tumor microenvironment (TME) formation is unexplored. This study aimed to reveal the TME features of HCC patients with distinct m6A expression patterns and establish a prognostic model based on m6A signatures for HCC cohorts. MATERIAL AND METHODS We classified the m6A methylation patterns in 365 HCC samples based on 21 m6A modulators using a consensus clustering algorithm. Single-sample gene set enrichment analysis algorithm was used to quantify the abundance of immune cell infiltration. Gene set variation analysis revealed the biological characteristics between the m6A modification patterns. The m6A-based prognostic model was constructed using a training set with least absolute shrinkage and selection operator regression and validated in internal and external datasets. RESULTS Two distinct m6A modification patterns exhibiting different TME immune-infiltrating characteristics, heterogeneity, and prognostic variations were identified in the HCC cohort. After depicting the immune landscape of TME in HCC, we found patients with high LRPPRC m6A modulator expression had depletion of T cells, cytotoxic cells, dendritic cells, and cytolytic activity response. A high m6A score, characterized by suppression of immunity, indicated an immune-excluded TME phenotype, with poor survival. A nomogram was developed to facilitate HCC clinical decision making. CONCLUSIONS Our results highlight the nonnegligible role of m6A methylation in TME formation and reveal a potential clinical application of the m6A-associated prognostic model for patients with HCC.

Overexpression of B7H5/CD28H is associated with worse survival in human gastric cancer.

Gastric cancer (GC) is a common malignancy with low 5-year overall survival (OS). Recently, immune therapy has been used to treat cancer. B7H5 and CD28H are novel immune checkpoint molecules. However, the prognostic value of B7H5/CD28H expression in patients with GC remains unclear. In this study, seventy-one patients diagnosed with GC were included in this study. Patients' GC tissues and matched adjacent tissue constructed a tissue microarray. The expression levels of B7H5 and CD28H were examined using immunohistochemistry. Correlations between the expression of B7H5 and CD28H and the clinical data were evaluated. We found that the expression of B7H5 and CD28H (both P = .001) were higher in GC tumour tissues than in adjacent noncancerous tissues. B7H5/CD28H expression acted as an independent predictive factor in the OS of patients with GC. High expression of B7H5 and CD28H predicted poor outcome. Patients in the B7H5+CD28H+ group had a lower 5-year OS compared with patients in the B7H5-CD28- group (4.5% vs 55.6%, P = .001). A significant difference was found in the 5-year OS between patients in the B7H5+CD28H- and B7H5+CD28H+ groups (33.5% vs 4.5%, P = .006). However, there was no correlation between B7H5 and CD28H expression (P = .844). Therefore, B7H5 and CD28H expression are up-regulated in GC and are independent prognostic factors for overall survival in patients with GC. Although there was no correlation between B7H5 and CD28H expression, high expression of B7H5 and CD28H predicts poor prognosis, especially when both are highly expressed.

Systematic Analysis of Alternative Splicing Landscape in Pancreatic Adenocarcinoma Reveals Regulatory Network Associated with Tumorigenesis and Immune Response.

BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive gastrointestinal tumors and has an extremely high mortality rate. Recent studies indicate that alternative splicing (AS), a common post-transcriptional process, has important roles in tumor biological behaviors and may provide novel immunotherapeutic targets. This study systematically analyzes AS profiles in PDAC and reveals their potential regulatory effects on cancer immune response. MATERIAL AND METHODS AS event, RNA sequencing, and splicing factor (SF) data were extracted from SpliceSeq, The Cancer Genome Atlas, and SpliceAid2, respectively. Overall survival (OS)-associated AS events and SFs were identified with univariate analysis. The LASSO method and multivariate Cox regression analysis were used to construct predictive signatures for the prediction of patient prognosis. The proportions of immune cells within PDAC samples were evaluated using the CIBERSORT algorithm. The correlations among AS events, SFs, and immune cell proportions were calculated using Spearman correlation analysis. Consensus clustering and immune classification were performed on the PDAC cohort. RESULTS A total of 4812 OS-related AS events from 3341 parent genes were identified, and 8 AS-based predictive models were constructed for PDAC. An OS-related SF-AS regulatory network was constructed. The AS events regulated by ELAVL4 exhibited strong correlations with CD8 T cells and regulatory T cells. In addition, AS-based clusters demonstrated distinct OS outcomes and immune features. CONCLUSIONS AS-based predictive models with high accuracy were constructed to facilitate prognosis prediction and treatment of PDAC. An SF-AS regulatory network was constructed, revealing the potential relationships among SF, AS, and immune response.

An On-Demand Collaborative Innate-Adaptive Immune Response to Infection Treatment.

Deep tissue infection is a common clinical issue and therapeutic difficulty caused by the disruption of the host antibacterial immune function, resulting in treatment failure and infection relapse. Intracellular pathogens are refractory to elimination and can manipulate host cell biology even after appropriate treatment, resulting in a locoregional immunosuppressive state that leads to an inadequate response to conventional anti-infective therapies. Here, a novel antibacterial strategy involving autogenous immunity using a biomimetic nanoparticle (NP)-based regulating system is reported to induce in situ collaborative innate-adaptive immune responses. It is observed that a macrophage membrane coating facilitates NP enrichment at the infection site, followed by active NP accumulation in macrophages in a mannose-dependent manner. These NP-armed macrophages exhibit considerably improved innate capabilities, including more efficient intracellular ROS generation and pro-inflammatory factor secretion, M1 phenotype promotion, and effective eradication of invasive bacteria. Furthermore, the reprogrammed macrophages direct T cell activation at infectious sites, resulting in a robust adaptive antimicrobial immune response to ultimately achieve bacterial clearance and prevent infection relapse. Overall, these results provide a conceptual framework for a novel macrophage-based strategy for infection treatment via the regulation of autogenous immunity.

T cell-derived exosomes in tumor immune modulation and immunotherapy.

Exosomes are nanoscale vesicles secreted by most cells and have a phospholipid bilayer structure. Exosomes contain DNA, small RNA, proteins, and other substances that can carry proteins and nucleic acids and participate in communication between cells. T cells are an indispensable part of adaptive immunity, and the functions of T cell-derived exosomes have been widely studied. In the more than three decades since the discovery of exosomes, several studies have revealed that T cell-derived exosomes play a novel role in cell-to-cell signaling, especially in the tumor immune response. In this review, we discuss the function of exosomes derived from different T cell subsets, explore applications in tumor immunotherapy, and consider the associated challenges.

Macrophages in melanoma: A double­edged sword and targeted therapy strategies (Review).

Melanoma, which evolves from melanocytes, is the most malignant skin cancer and is highly fatal, although it only accounts for 4% of all skin cancers. Numerous studies have demonstrated that melanoma has a large tumor mutational burden, which means that melanoma has great potential to achieve immune evasion. Tumor-associated macrophages (TAMs) are an important component of both the immune system and tumor microenvironment. Several studies have demonstrated their double-edged sword effects on melanoma. The present review focuses on the role of TAMs in melanoma development, including regulation of proliferation, invasion, metastasis, angiogenesis and chemical resistance of melanoma. Furthermore, the existing mechanisms of action of the TAM-targeting treatments for melanoma are reviewed. More broadly, the weak points of existing research and the direction of future research are finally identified and described.

Efficacy and safety of percutaneous endoscopic cervical discectomy for cervical disc herniation: a systematic review and meta-analysis.

BACKGROUND: Since there are currently no systematic evidence-based medical data on the efficacy and safety of PECD, this meta-analysis pooled data from studies that reported the efficacy or safety of PECD for cervical disc herniation to examine the efficacy, recurrence and safety of using PECD to treat cervical disc herniation. METHODS: We searched the PubMed, EMBASE and Cochrane Library databases for studies published from inception to July 2022. Nine nonrandomized controlled trials (non-RCTs) that reported the efficacy or safety of percutaneous endoscopic cervical discectomy for cervical disc herniation were included. We excluded duplicate publications, studies without full text, studies with incomplete information, studies that did not enable us to conduct data extraction, animal experiments and reviews. STATA 15.1 software was used to analyse the data. RESULTS: The proportions of excellent and good treatment results after PECD for CDH were 39% (95% CI: 31-48%) and 47% (95% CI: 34-59%), respectively. The pooled results showed that the VAS scores at 1 week post-operatively (SMD = -2.55, 95% CI: - 3.25 to - 1.85) and at the last follow-up (SMD = - 4.30, 95% CI: - 5.61 to - 3.00) after PECD for cervical disc herniation were significantly lower than the pre-operative scores. The recurrence rate of neck pain and the incidence of adverse events after PECD for cervical disc herniation were 3% (95% CI: 1-6%) and 5% (95% CI: 2-9%), respectively. Additionally, pooled results show that the operative time (SMD = - 3.22, 95% CI: - 5.21 to - 1.43) and hospital stay (SMD = - 1.75, 95% CI: - 2.67to - 0.84) were all significantly lower for PECD than for ACDF. The pooled results also showed that the proportion of excellent treatment results was significantly higher for PECD than for ACDF (OR = 2.29, 95% CI: 1.06-4.96). CONCLUSION: PECD has a high success rate in the treatment of CHD and can relieve neck pain, and the recurrence rate and the incidence of adverse events are low. In addition, compared with ACDF, PECD has a higher rate of excellent outcomes and a lower operative time and hospital stay. PECD may be a better option for treating CHD.

Tumor-derived extracellular vesicles in melanoma immune response and immunotherapy.

Tumor-derived extracellular vesicles (EVs) are key immune regulators of the tumor microenvironment. They reshape the immune microenvironment and prevent antitumor immune responses via their immunosuppressive cargo, thereby determining cancer responsiveness to treatment. In the immune microenvironment of melanoma, tumor-derived EVs influence tumor progression by regulating innate and adaptive immune responses. Tumor-derived EV-based therapy is a cutting-edge and promising strategy for inhibiting melanoma progression and enhancing antitumor immunity. This review aimed to summarize the regulatory roles of EVs in the immune responses and immunotherapy of patients with melanoma. This paper provided insights into future exploration directions and potential clinical strategies targeting EVs for melanoma treatment.

Acupuncture and moxibustion combined with cupping for the treatment of post-herpetic neuralgia: A meta-analysis.

BACKGROUND: There are still controversies between the curative effect of acupuncture combined with cupping therapy and western medicine for post-herpetic neuralgia (PHN). Our meta-analysis fully incorporates the research of acupuncture combined with cupping therapy versus Western medicine for PHN, aiming to explore the difference in the efficacy of the 2 therapies, so as to provide guidance for clinical treatment. METHODS: We searched PubMed, Embase, Cochrane Library, CNKI, Wanfang, CQVIP, CBM, from establishment of the database to September, 2020. Include studies that are clearly defined as PHN or herpes zoster, and exclude duplicate publications; studies with no full text, incomplete information, or inability to extract data; the definition of exposure is quite different from most literature; animal experiments. RESULTS: The total effective rate (relative ratio [RR] = 1.21, 95% confidence interval [CI]: 1.12-1.31) and the rate of remarkable effect (RR = 1.46, 95% CI: 1.30-1.63) of acupuncture and moxibustion combined with cupping in the treatment of PHN were significantly higher than that of conventional western medicine. The visual analogue scale score of acupuncture and moxibustion combined with cupping for PHN was significantly lower than that of conventional western medicine treatment (WMD = -1.77, 95% CI [-2.79, -0.75]). In addition, acupuncture and moxibustion combined with cupping therapy significantly reduced the occurrence of PHN compared with conventional western medicine treatment after treatment of acute herpes zoster (RR = 0.30, 95% CI: 0.20-0.45). In order to explore the differences in the efficacy and preventive effects of different types of acupuncture and cupping therapy, we have further conducted a subgroup analysis. CONCLUSION: The effect of acupuncture and moxibustion combined with cupping in the treatment of PHN is significantly higher than that of conventional western medicine, and it can significantly prevent the occurrence of PHN. Chinese medicine should be used more widely in the treatment of PHN.

Gastric Cancer Tumor Microenvironment Characterization Reveals Stromal-Related Gene Signatures Associated With Macrophage Infiltration.

The tumor microenvironment (TME) has attracted attention owing to its essential role in tumor initiation, progression, and metastasis. With the emergence of immunotherapies for various cancers, and their high efficacy, an understanding of the TME in gastric cancer (GC) is critical. The aim of this study was to investigate the effect of various components within the GC TME, and to identify mechanisms that exhibit potential as therapeutic targets. The ESTIMATE algorithm was used to quantify immune and stromal components in GC samples, whose clinicopathological significance and relationship with predicted outcomes were explored. Low tumor mutational burden and high M2 macrophage infiltration, which are considered immune suppressive characteristics and may be responsible for unfavorable prognoses in GC, were observed in the high stromal group (HR = 1.585; 95% CI, 1.112-2.259; P = 0.009). Furthermore, weighted correlation network, differential expression, and univariate Cox analyses were used, along with machine learning methods (LASSO and SVM-RFE), to reveal genome-wide immune phenotypic correlations. Eight stromal-relevant genes cluster (FSTL1, RAB31, FBN1, ANTXR1, LRRC32, CTSK, COL5A2, and ENG) were identified as adverse prognostic factors in GC. Finally, using a combination of TIMER database and single-sample gene set enrichment analyses, we found that the identified genes potentially contribute to macrophage recruitment and polarization of tumor-associated macrophages. These findings provide a different perspective into the immune microenvironment and indicate potential prognostic and therapeutic targets for GC immunotherapies.

IRF1-mediated immune cell infiltration is associated with metastasis in colon adenocarcinoma.

BACKGROUND: Evidence suggests that metastasis is chiefly responsible for the poor prognosis of colon adenocarcinoma (COAD). The tumor microenvironment plays a vital role in regulating this biological process. However, the mechanisms involved remain unclear. The aim of this study was to identify crucial metastasis-related biomarkers in the tumor microenvironment and investigate its association with tumor-infiltrating immune cells. METHODS: We obtained gene expression profiles and clinical information from The Cancer Genome Atlas database. According to the "Estimation of STromal and Immune cells in MAlignant Tumor tissue using Expression data" algorithm, each sample generated the immune and stromal scores. Following correlation analysis, the metastasis-related gene was identified in The Cancer Genome Atlas database and validated in the GSE40967 dataset from Gene Expression Omnibus. The correlation between metastasis-related gene and infiltrating immune cells was assessed using the Tumor IMmune Estimation Resource database. RESULTS: The analysis included 332 patients; the metastatic COAD samples showed a low immune score. Correlation analysis results showed that interferon regulatory factor 1 (IRF1) was associated with tumor stage, lymph node metastasis, and distant metastasis. Furthermore, significant associations between IRF1 and CD8+ T cells, T cell (general), dendritic cells, T-helper 1 cells, and T cell exhaustion were demonstrated by Spearmans correlation coefficients and P values. CONCLUSIONS: The present findings suggest that IRF1 is associated with metastasis and the degree of immune infiltration of CD8+ T cells (general), dendritic cells, T-helper 1 cells, and T cell exhaustion in COAD. These results may provide information for immunotherapy in colon cancer.

V9302-loaded copper-polyphenol hydrogel for enhancing the anti-tumor effect of disulfiram.

Disulfiram (DSF) is a safe drug with negligible toxicity and Cu-dependent anti-tumor efficacy. However, the accumulation and combination of DSF and Cu in non-tumor tissues leads to systemic toxicity owing to the formation of highly poisonous diethyldithiocarbamate (CuET). In addition, CuET-mediated tumor-killing reactive oxygen species may be weakened by intra-tumoral glutathione (GSH). Herein, a synergistic treatment was developed that utilized the oral delivery of DSF and an injectable polyphenol-copper (PA-Cu) hydrogel loaded with the glutamine uptake inhibitor 2-amino-4-bis(phenoxymethyl)aminobutane (V9302). The injectable hydrogels were synthesized by the Schiff base reaction of hydroxypropyl chitosan (HPCS) with a PA-Cu reversible cross-linking agent. Because of the dynamic coordination between PA and Cu, the PA-Cu/HPCS hydrogel gradually releases Cu2+, forming CuET with DSF. The released V9302 inhibits glutamine uptake, thereby suppressing GSH synthesis and enhancing the therapeutic efficacy of the in situ formed CuET. The synergistic effect of PA-Cu/HPCS/V9302 and DSF in eliminating intracellular GSH and killing tumor cells was validated by in vitro cell experiments. Animal experiments further confirmed that PA-Cu/HPCS/V9302 and DSF have an inhibitory effect on tumor growth while maintaining the biosafety of main organs.