A chimeric strain of porcine reproductive and respiratory syndrome virus 2 derived from HP-PRRSV and NADC30-like PRRSV confers cross-protection against both strains.

Porcine reproductive and respiratory syndrome (PRRS) is one of the most significant swine viral infectious diseases worldwide. Vaccination is a key strategy for the control and prevention of PRRS. At present, the NADC30-like PRRSV strain has become the predominant epidemic strain in China, superseding the HP-PRRSV strain. The existing commercial vaccines offer substantial protection against HP-PRRSV, but their efficacy against NADC30-like PRRSV is limited. The development of a novel vaccine that can provide valuable cross-protection against both NADC30-like PRRSV and HP-PRRSV is highly important. In this study, an infectious clone of a commercial MLV vaccine strain, GD (HP-PRRSV), was first generated (named rGD). A recombinant chimeric PRRSV strain, rGD-SX-5U2, was subsequently constructed by using rGD as a backbone and embedding several dominant immune genes, including the NSP2, ORF5, ORF6, and ORF7 genes, from an NADC30-like PRRSV isolate. In vitro experiments demonstrated that chimeric PRRSV rGD-SX-5U2 exhibited high tropism for MARC-145 cells, which is of paramount importance in the production of PRRSV vaccines. Moreover, subsequent in vivo inoculation and challenge experiments demonstrated that rGD-SX-5U2 confers cross-protection against both HP-PRRSV and NADC30-like PRRSV, including an improvement in ADG levels and a reduction in viremia and lung tissue lesions. In conclusion, our research demonstrated that the chimeric PRRSV strain rGD-SX-5U2 is a novel approach that can provide broad-spectrum protection against both HP-PRRSV and NADC30-like PRRSV. This may be a significant improvement over previous MLV vaccinations.

Assessment of intercostal nerve block analgesia and local anesthetic infiltration for thoracoscopic pulmonary bullae resection: a comparative study.

OBJECTIVE: The purpose of this study was to compare the analgesic effects of intercostal nerve block (ICNB) and local anesthetic infiltration (LAI) on postoperative pain and recovery following thoracoscopic resection of pulmonary bullae. METHODS: A total of 160 patients undergoing thoracoscopic pulmonary bullae resection were randomly assigned to receive either ICNB (n = 80) or LAI (n = 80). An experienced anesthesiologist administered ultrasound guided ICNB at the T4 and T7 levels with 5 mL of 0.375% ropivacaine hydrochloride for the ICNB group. Instead, the LAI group received 10 mL of the same concentration of ropivacaine hydrochloride at the same concentration used for ICNB for infiltration anesthesia at the incision sites. Out of the initial cohort, 146 patients completed the study (ICNB group, n = 71; LAI group, n = 75). The collected data included preoperative clinical characteristics, visual analog scale (VAS) scores for pain at various time points post-surgery (6, 12, 24, 48, and 72 h). Additionally, the Quality of Recovery-15 (QoR-15) questionnaire was administered 24 h after surgery, and sleep quality was evaluated using the Pittsburgh Sleep Quality Index (PSQI). RESULTS: No significant differences were found in drainage volume, use of additional analgesics, duration of chest tube placement, or hospital stay between the two groups. However, the ICNB group had significantly lower VAS scores and QoR-15 scores 24 h postoperatively (p < 0.05), indicating better pain management and recovery. The ICNB group also reported better sleep quality, as reflected by lower PSQI scores. CONCLUSION: ICNB provides superior analgesia compared to LAI after thoracoscopic resection of pulmonary bullae, significantly improving postoperative recovery.

Integrated metabolomics and network pharmacology analysis to reveal the protective effect of Complanatoside A on nonalcoholic fatty liver disease.

INTRODUCTION: The rising prevalence and severe consequences of nonalcoholic fatty liver disease (NAFLD) have driven the quest for preventive medications. Complanatoside A (CA) is the marked flavonoid of Astragali complanati semen, a traditional Chinese herb that acts on the liver meridian and is widely used to treat liver problems. CA has been proven to have considerable lipid-lowering and liver-protective effects in vitro. However, the efficacy of CA in preventing NAFLD has yet to be shown in vivo. METHODS: First, the effectiveness of CA against NAFLD was assessed using a high-fat diet (HFD) mouse model. Second, the CA protective mechanism against NAFLD was investigated using a combined metabolomics and network pharmacology strategy. Differential metabolites were identified by metabolomics-based analyses, and metabolic pathway analysis was accomplished by MetaboAnalyst. Potential therapeutic targets were obtained through network pharmacology. Finally, key targets were identified via compound-target networks and validated by molecular docking and western blotting. RESULTS: CA prevented NAFLD mainly by reducing liver lipid accumulation in HFD mice. Metabolomics identified 22 potential biomarkers for CA treatment of NAFLD, primarily involving glycerophospholipid and arachidonic acid metabolism. Fifty-one potential targets were determined by network pharmacology. Co-analysis revealed that albumin, peroxisome proliferator-activated receptor-alpha, retinoid X receptor alpha, interleukin-6, and tumor necrosis factor alpha were key targets. CONCLUSION: This experiment revealed that CA has a preventive effect on NAFLD, primarily by regulating the peroxisome proliferator-activated receptor-alpha/retinoid X receptor alpha pathway. Furthermore, it provides evidence supporting the potential use of CA in the long-term prevention of NAFLD.

Melatonin Attenuates Diabetic Retinopathy by Regulating EndMT of Retinal Vascular Endothelial Cells via Inhibiting the HDAC7/FOXO1/ZEB1 Axis.

Diabetic retinopathy (DR) is characterized as a microvascular disease. Nonproliferative diabetic retinopathy (NPDR) presents with alterations in retinal blood flow and vascular permeability, thickening of the basement membrane, loss of pericytes, and formation of acellular capillaries. Endothelial-mesenchymal transition (EndMT) of retinal microvessels may play a critical role in advancing NPDR. Melatonin, a hormone primarily secreted by the pineal gland, is a promising therapeutic for DR. This study explored the EndMT in retinal microvessels of NPDR and its related mechanisms. The effect of melatonin on the retina of diabetic rats was evaluated by electroretinogram (ERG) and histopathologic slide staining. Furthermore, the effect of melatonin on human retinal microvascular endothelial cells (HRMECs) was detected by EdU incorporation assay, scratch assay, transwell assay, and tube formation test. Techniques such as RNA-sequencing, overexpression or knockdown of target genes, extraction of cytoplasmic and nuclear protein, co-immunoprecipitation (co-IP), and multiplex immunofluorescence facilitated the exploration of the mechanisms involved. Our findings reveal, for the first time, that melatonin attenuates diabetic retinopathy by regulating EndMT of retinal vascular endothelial cells via inhibiting the HDAC7/FOXO1/ZEB1 axis. Collectively, these results suggest that melatonin holds potential as a therapeutic strategy to reduce retinal vascular damage and protect vision in NPDR.

Host cells reprogram lipid droplet synthesis through YY1 to resist PRRSV infection.

Metabolism in host cells can be modulated after viral infection, favoring viral survival or clearance. Here, we report that lipid droplet (LD) synthesis in host cells can be modulated by yin yang 1 (YY1) after porcine reproductive and respiratory syndrome virus (PRRSV) infection, resulting in active antiviral activity. As a ubiquitously distributed transcription factor, there was increased expression of YY1 upon PRRSV infection both in vitro and in vivo. YY1 silencing promoted the replication of PRRSV, whereas YY1 overexpression inhibited PRRSV replication. PRRSV infection led to a marked increase in LDs, while YY1 knockout inhibited LD synthesis, and YY1 overexpression enhanced LD accumulation, indicating that YY1 reprograms PRRSV infection-induced intracellular LD synthesis. We also showed that the viral components do not colocalize with LDs during PRRSV infection, and the effect of exogenously induced LD synthesis on PRRSV replication is nearly lethal. Moreover, we demonstrated that YY1 affects the synthesis of LDs by regulating the expression of lipid metabolism genes. YY1 negatively regulates the expression of fatty acid synthase (FASN) to weaken the fatty acid synthesis pathway and positively regulates the expression of peroxisome proliferator-activated receptor gamma (PPARγ) to promote the synthesis of LDs, thus inhibiting PRRSV replication. These novel findings indicate that YY1 plays a crucial role in regulating PRRSV replication by reprogramming LD synthesis. Therefore, our study provides a novel mechanism of host resistance to PRRSV and suggests potential new antiviral strategies against PRRSV infection.IMPORTANCEPorcine reproductive and respiratory virus (PRRSV) has caused incalculable economic damage to the global pig industry since it was first discovered in the 1980s. However, conventional vaccines do not provide satisfactory protection. It is well known that viruses are parasitic pathogens, and the completion of their replication life cycle is highly dependent on host cells. A better understanding of host resistance to PRRSV infection is essential for developing safe and effective strategies to control PRRSV. Here, we report a crucial host antiviral molecule, yin yang 1 (YY1), which is induced to be expressed upon PRRSV infection and subsequently inhibits virus replication by reprogramming lipid droplet (LD) synthesis through transcriptional regulation. Our work provides a novel antiviral mechanism against PRRSV infection and suggests that targeting YY1 could be a new strategy for controlling PRRSV.

Deletion of a 7-amino-acid region in the porcine epidemic diarrhea virus envelope protein induces higher type I and III interferon responses and results in attenuation in vivo.

Porcine epidemic diarrhea virus (PEDV) leads to enormous economic losses for the pork industry. However, the commercial vaccines failed to fully protect against the epidemic strains. Previously, the rCH/SX/2016-SHNXP strain with the entire E protein and the rCH/SX/2015 strain with the deletion of 7-amino-acid (7-aa) at positions 23-29 in E protein were constructed and rescued. The pathogenicity assay indicated that rCH/SX/2015 is an attenuated strain, but rCH/SX/2016-SHNXP belongs to the virulent strains. Then, the recombination PEDV (rPEDV-EΔaa23-aa29)strain with a 7-aa deletion in the E protein was generated, using the highly virulent rCH/SX/2016-SHNXP strain (rPEDV-Ewt) as the backbone. Compared with the rPEDV-Ewt strain, the release and infectivity of the rPEDV-EΔaa23-aa29 strain were significantly reduced in vitro, but stronger interferon (IFN) responses were triggered both in vitro and in vivo. The pathogenicity assay showed that the parental strain resulted in severe diarrhea (100%) and death (100%) in all piglets. Compared with the parental strain group, rPEDV-EΔaa23-aa29 caused lower mortality (33%) and diminished fecal PEDV RNA shedding. At 21 days, all surviving pigs were challenged orally with rPEDV-Ewt. No pigs died in the two groups. Compared with the mock group, significantly delayed and milder diarrhea and reduced fecal PEDV RNA shedding were detected in the rPEDV-EΔaa23-aa29 group. In conclusion, the deletion of a 7-aa fragment in the E protein (EΔaa23-aa29) attenuated PEDV but retained its immunogenicity, which can offer new ideas for the design of live attenuated vaccines and provide new insights into the attenuated mechanism of PEDV. IMPORTANCE Porcine epidemic diarrhea virus (PEDV) causes high mortality in neonatal piglets and remains a large challenge to the pork industry. Unfortunately, no safe and effective vaccines are available yet. The pathogenesis and molecular basis of the attenuation of PEDV remain unclear, which seriously hinders the development of PEDV vaccines. This study found that the rPEDV carrying EΔaa23-aa29 mutation in the E protein induced significantly higher IFN responses than the parental virus, partially attenuated, and remained immunogenic in piglets. For the first time, PEDV E was verified as an IFN antagonist in the infection context and identified as a virulence factor of PEDV. Our data also suggested that EΔaa23-aa29 mutation can be a good target for the development of live attenuated vaccines for PEDV and also provide new perspectives for the attenuated mechanism of PEDV.

Genomic similarity and antibody-dependent enhancement of immune serum potentially affect the protective efficacy of commercial MLV vaccines against NADC30-like PRRSV.

Porcine reproductive and respiratory syndrome (PRRS) is one of the most significant diseases affecting the pig industry worldwide. The PRRSV mutation rate is the highest among the RNA viruses. To date, NADC30-like PRRSV and highly pathogenic PRRSV (HP-PRRSV) are the dominant epidemic strains in China; however, commercial vaccines do not always provide sufficient cross-protection, and the reasons for insufficient protection are unclear. This study isolated a wild-type NADC30-like PRRSV, SX-YL1806, from Shaanxi Province. Vaccination challenge experiments in piglets showed that commercial modified live virus (MLV) vaccines provided good protection against HP-PRRSV. However, it could not provide sufficient protection against the novel strain SX-YL1806. To explore the reasons for this phenomenon, we compared the genomic homology between the MLV strain and HP-PRRSV or NADC30-like PRRSV and found that the MLV strain had a lower genome similarity with NADC30-like PRRSV. Serum neutralization assay showed that MLV-immune serum slightly promoted the homologous HP-PRRSV replication and significantly promoted the heterologous NADC30-like PRRSV strain replication in vitro, suggesting that antibody-dependent enhancement (ADE) might also play a role in decreasing MLV protective efficacy. These findings expand our understanding of the potential factors affecting the protective effect of PRRSV MLV vaccines against the NADC30-like strains.

Emerging role of ubiquitination/deubiquitination modification of PD-1/PD-L1 in cancer immunotherapy.

As members of the immune checkpoint family, PD-1 and its ligand PD-L1 play critical roles in maintaining the balance between autoimmunity and tolerance. The interaction of PD-1/PD-L1 is also involved in tumor evasion inside the tumor microenvironment, caused by reduced T cell activation, proliferation, cytotoxic secretion, and survival. Previous research has shown that the expression level of PD-1/PD-L1 may be regulated by ubiquitin-mediated proteasome degradation, which is an important mode of post-translational modification (PTM). PD-1/PD-L1 ubiquitin modification research in tumor immunotherapy is the subject of the present review, which aims to assess the most recent developments in this area. We offer a short explanation of PD-1/PD-L1 as well as some basic background information on the UPS system and discuss many routes that target E3s and DUBs, respectively, in the regulation of PD-1/PD-L1 in tumor immunotherapy. In addition, we offer numerous innovative prospective research areas for the future, as well as novel immunotherapy concepts and ideas. Taken together, the information compiled herein should serve as a comprehensive repository of information about tumor immunotherapy that is currently available, and it should be useful in the design of future studies, as well as the development of potential targets and strategies for future tumor immunotherapy.

Coronavirus Porcine Epidemic Diarrhea Virus Utilizes Chemokine Interleukin-8 to Facilitate Viral Replication by Regulating Ca2+ Flux.

Chemokine production by epithelial cells is crucial for neutrophil recruitment to sites of inflammation during viral infection. However, the effect of chemokine on epithelia and how chemokine is involved in coronavirus infection remains to be fully understood. Here, we identified an inducible chemokine interleukin-8 (CXCL8/IL-8), which could promote coronavirus porcine epidemic diarrhea virus (PEDV) infection in African green monkey kidney epithelial cells (Vero) and Lilly Laboratories cell-porcine kidney 1 epithelial cells (LLC-PK1). IL-8 deletion restrained cytosolic calcium (Ca2+), whereas IL-8 stimulation improved cytosolic Ca2+. The consumption of Ca2+ restricted PEDV infection. PEDV internalization and budding were obvious reductions when cytosolic Ca2+ was abolished in the presence of Ca2+ chelators. Further study revealed that the upregulated cytosolic Ca2+ redistributes intracellular Ca2+. Finally, we identified that G protein-coupled receptor (GPCR)-phospholipase C (PLC)-inositol trisphosphate receptor (IP3R)-store-operated Ca2+ (SOC) signaling was crucial for enhancive cytosolic Ca2+ and PEDV infection. To our knowledge, this study is the first to uncover the function of chemokine IL-8 during coronavirus PEDV infection in epithelia. PEDV induces IL-8 expression to elevate cytosolic Ca2+, promoting its infection. Our findings reveal a novel role of IL-8 in PEDV infection and suggest that targeting IL-8 could be a new approach to controlling PEDV infection. IMPORTANCE Coronavirus porcine epidemic diarrhea virus (PEDV) is a highly contagious enteric coronavirus that caused severe economic losses worldwide, and more effort is needed to develop economical and efficient vaccines to control or eliminate this disease. The chemokine interleukin-8 (CXCL8/IL-8) is indispensable for the activation and trafficking of inflammatory mediators and tumor progression and metastasis. This study evaluated the effect of IL-8 on PEDV infection in epithelia. We found that IL-8 expression improved cytosolic Ca2+ in epithelia, facilitating PEDV rapid internalization and egress. G protein-coupled receptor (GPCR)-phospholipase C (PLC)-inositol trisphosphate receptor (IP3R)-SOC signaling was activated by IL-8, releasing the intracellular Ca2+ stores from endoplasmic reticulum (ER). These findings provide a better understanding of the role of IL-8 in PEDV-induced immune responses, which will help develop small-molecule drugs for coronavirus cure.

Identification of the pyroptosis-related gene signature and risk score model for esophageal squamous cell carcinoma.

Advanced esophageal squamous cell carcinoma (ESCC) still has a dismal prognostic outcome. However, the current approaches are unable to evaluate patient survival. Pyroptosis represents a novel programmed cell death type which widely investigated in various disorders and can influence tumor growth, migration, and invasion. Furthermore, few existing studies have used pyroptosis-related genes (PRGs) to construct a model for predicting ESCC survival. Therefore, the present study utilized bioinformatics approaches for analyzing ESCC patient data obtained from the TCGA database to construct the prognostic risk model and applied it to the GSE53625 dataset for validation. There were 12 differentially expressed PRGs in healthy and ESCC tissue samples, among which eight were selected through univariate and LASSO cox regression for constructing the prognostic risk model. According to K-M and ROC curve analyses, our eight-gene model might be useful in predicting ESCC prognostic outcomes. Based on the cell validation analysis, C2, CD14, RTP4, FCER3A, and SLC7A7 were expressed higher in KYSE410 and KYSE510 than in normal cells (HET-1A). Hence, ESCC patient prognostic outcomes can be assessed by our PRGs-based risk model. Further, these PRGs may also serve as therapeutic targets.

HDAC7/c-Myc signaling pathway promotes the proliferation and metastasis of choroidal melanoma cells.

Choroidal melanoma (CM) is the most common type of diagnosed uveal melanoma (UM), which is prone to metastasis and exhibits a poor prognosis. The molecular mechanisms underlying CM progression need further elucidation to research effective therapeutic strategies. Histone deacetylase 7 (HDAC7) is very important in regulating cancer progression, but the significance and effect of HDAC7 on CM progression are unclear. In the present study, we found that HDAC7 is overexpressed in CM tissues versus normal tissues. We built HDAC7 overexpressing CM cell lines to study the functions of HDAC7 in CM progression and verified that upregulation of HDAC7 promoted the proliferation and metastasis of CM cells, while pharmacological inhibition of HDAC7 suppressed both the proliferation and metastasis of CM cells. Furthermore, we found that the aforementioned cancer-promoting effect of HDAC7 was mediated by c-Myc. Targeted inhibition of c-Myc inhibited CM progression by interfering with the HDAC7/c-Myc signaling pathway. Our study highlighted the function of targeting the HDAC7/c-Myc signaling pathway to intervene in the pathological process of CM, which provides potential therapeutic strategies for CM treatment.

Melatonin inhibits ESCC tumor growth by mitigating the HDAC7/ß-catenin/c-Myc positive feedback loop and suppressing the USP10-maintained HDAC7 protein stability.

BACKGROUND: Melatonin, a natural hormone secreted by the pineal gland, has been reported to exhibit antitumor properties through diverse mechanisms of action. However, the oncostatic function of melatonin on esophageal squamous cell carcinoma (ESCC) remains elusive. This study was conducted to investigate the potential effect and underlying molecular mechanism of melatonin as single anticancer agent against ESCC cells. METHODS: ESCC cell lines treated with or without melatonin were used in this study. In vitro colony formation and EdU incorporation assays, and nude mice tumor xenograft model were used to confirm the proliferative capacities of ESCC cells. RNA-seq, qPCR, Western blotting, recombinant lentivirus-mediated target gene overexpression or knockdown, plasmids transfection and co-IP were applied to investigate the underlying molecular mechanism by which melatonin inhibited ESCC cell growth. IHC staining on ESCC tissue microarray and further survival analyses were performed to explore the relationship between target genes' expression and prognosis of ESCC. RESULTS: Melatonin treatment dose-dependently inhibited the proliferative ability and the expression of histone deacetylase 7 (HDAC7), c-Myc and ubiquitin-specific peptidase 10 (USP10) in ESCC cells (P < 0.05). The expressions of HDAC7, c-Myc and USP10 in tumors were detected significantly higher than the paired normal tissues from 148 ESCC patients (P < 0.001). Then, the Kaplan-Meier survival analyses suggested that ESCC patients with high HDAC7, c-Myc or USP10 levels predicted worse overall survival (Log-rank P < 0.001). Co-IP and Western blotting analyses further revealed that HDAC7 physically deacetylated and activated ß-catenin thus promoting downstream target c-Myc gene transcription. Notably, our mechanistic study validated that HDAC7/ß-catenin/c-Myc could form the positive feedback loop to enhance ESCC cell growth, and USP10 could deubiquitinate and stabilize HDAC7 protein in the ESCC cells. Additionally, we verified that inhibition of the HDAC7/ß-catenin/c-Myc axis and USP10/HDAC7 pathway mediated the anti-proliferative action of melatonin on ESCC cells. CONCLUSIONS: Our findings elucidate that melatonin mitigates the HDAC7/ß-catenin/c-Myc positive feedback loop and inhibits the USP10-maintained HDAC7 protein stability thus suppressing ESCC cell growth, and provides the reference for identifying biomarkers and therapeutic targets for ESCC.

Characterization and validation of a ferroptosis-related LncRNA signature as a novel prognostic model for lung adenocarcinoma in tumor microenvironment.

Ferroptosis is a more relatively recently identified type of programmed cell death, which is associated with tumor progression. However, the mechanism underlying the effect of ferroptosis-related long non-coding RNAs (lncRNAs) in lung adenocarcinoma (LUAD) remains elusive. Therefore, the current study aimed to investigate the role of ferroptosis-related lncRNAs in LUAD and to develop a prognostic model. The clinicopathological characteristics of patients and the gene sequencing data were obtained from The Cancer Genome Atlas, while the ferroptosis-associated mRNAs were downloaded from the FerrDb database. A ferroptosis-related lncRNA signature was established with Least Absolute Shrinkage and Selection Operator Cox regression analysis. Furthermore, the risk scores of ferroptosis-related lncRNAs were calculated and LUAD patients were then assigned to high- and low-risk groups based on the median risk score. The prognostic model was established by K-M plotters and nomograms. Gene set enrichment analysis (GSEA) was performed to evaluate the association between immune responses and ferroptosis-related lncRNAs. A total of 10 ferroptosis-related lncRNAs were identified as independent predictors of LUAD outcome, namely RP11-386M24.3, LINC00592, FENDRR, AC104699.1, AC091132.1, LANCL1-AS1, LINC-PINT, IFNG-AS1, LINC00968 and AC006129.2. The area under the curve verified that the established signatures could determine LUAD prognosis. The nomogram model was used to assess the predictive accuracy of the established signatures. Additionally, GSEA revealed that the 10 ferroptosis-related lncRNAs could be involved in immune responses in LUAD. Overall, the results of the current study may provide novel insights into the development of novel therapies or diagnostic strategies for LUAD.

Clinicopathological characteristics and prognostic significance of HDAC11 protein expression in non-small cell lung cancer: a retrospective study.

Background: Although the prognosis of non-small cell lung cancer (NSCLC) can be assessed based on pathological type, disease stage and inflammatory indicators, the prognostic scoring model of NSCLC still needs to improve. HDAC11 is associated with poor prognosis of partial tumors, but its prognostic relationship with NSCLC is poorly understood. In this study, the role of HDAC11 in NSCLC was studied to evaluate relationship with disease prognosis and potential therapeutic target. Methods: The clinicopathological and paracancerous tissues of patients with NSCLC primarily diagnosed in Tangdu Hospital from 2009 to 2013 were collected. Follow-up of patients were made every three months and the last follow-up period was December 2018. The expression of HDAC11 was assessed by immunohistochemistry (IHC). Then, weighted gene co-expression network analysis (WGCNA) was used to analyze the relationship between HDAC11 expression and the prognosis of lung adenocarcinoma (LUAD) patients. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Kaplan-Meier plotter database was used to verify the connection between hub genes and tumor stage and prognosis. We accessed the relationship between HDAC11 expression and clinicopathological features, and impact on the prognosis. Results: The study assessed 326 patients with NSCLC. Compared with adjacent tissues, HDAC11 expression was upregulated (HR =1.503, 95% CI: 1.172 to 1.927, P=0.001). Kaplan-Meier survival analyses showed that HDAC11 expression was closely related to OS of NSCLC patients (P=0.0011). Univariate and multivariate analyses showed that the independent risk factors of OS were clinical stage, HDAC11 expression, and HDAC11 differentiation (all P≤0.001). HDAC11 was significantly associated with prognosis in LUAD. A total of 1,174 differential genes and WGCNA were obtained to construct a co-expression network in LUAD. The GO and KEGG pathway enrichment analyses showed the relevance with staphylococcus aureus infection, NOD-like receptor signaling pathway, and others. The results of LUAD survival analysis showed that HDAC11-related genes NKX2-5 and FABP7 were significantly associated with LUAD prognosis. Conclusions: The high expression of HDAC11 is related to the poor prognosis of LUAD, and it is expected to become a therapeutic target and prognostic evaluation therapy for LUAD in the future. However, the relevant results need to be further studied and verified.

Neoadjuvant Pembrolizumab and Chemotherapy in Resectable Esophageal Cancer: An Open-Label, Single-Arm Study (PEN-ICE).

Background: In this single-arm study, the efficacy and safety of neoadjuvant pembrolizumab plus chemotherapy were evaluated in patients with resectable esophageal squamous cell carcinoma (ESCC). Methods: This study included patients with ESCC of clinical stages II-IVA who underwent surgery within 4 to 6 weeks after completing treatment with pembrolizumab (200 mg) combined with a conventional chemotherapy regimen (3 cycles). The safety and efficacy of this combination treatment were evaluated as primary endpoints of the study. Results: From April 2019 to August 2020, a total of 18 patients (including 14 men) were enrolled, of whom 13 patients progressed to surgery. Postoperative pathology revealed a major pathological response (MPR) in 9 cases (9/13, 69.2%) and a pathological complete response (pCR) in 6 cases (6/13, 46.2%). Five patients (5/18, 27.8%) experienced serious treatment-related adverse events (AEs) of grades 3-4. At the time of data cutoff (Mar 25, 2022), the shortest duration of follow-up was 17.8 months. Programmed death-ligand 1 (PD-L1) expression in pretreatment specimens was not significantly associated with the percentage of residual viable tumor (RVT) (r=-0.55, P=0.08). Changes in counts of CD68+ macrophage between pre- and post-treatment specimens were weakly correlated with RVT (r=0.71; P=0.07), while a positive correlation was observed between postoperative forkhead box P3-positive (Foxp3)+T cells/CD4+Tcells ratios and RVT (r=0.84, P=0.03). Conclusions: The combination of neoadjuvant immunotherapy and chemotherapy for ESCC is associated with a high pathological response and immunologic effects in the tumor microenvironment (TME). It has acceptable toxicity and great efficacy, suggesting a strong rationale for its further evaluation in randomized clinical trials (RCTs). Trial Registration: ChiCTR2100048917.

The value of WNT5A as prognostic and immunological biomarker in pan-cancer.

Background: Finding new immune-related biomarkers is one of the promising research directions for tumor immunotherapy. The WNT5A gene could stimulate the WNT pathway and regulate the progression of various tumors. Recent studies have partially revealed the relationship between WNT5A and tumor immunity, but the correlation and underlying mechanisms in pan-cancer remain obscure. Thus, we conducted this study aiming to characterize the prognostic value and immunological portrait of WNT5A in cancer. Methods: The data obtained from The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), and Cancer Cell Line Encyclopedia (CCLE) databases was utilized to analyze WNT5A expression levels by Kruskal-Wallis test and correlation to prognosis by Cox regression test and Kaplan-Meier test, while the data was also used to study the association between WNT5A expression and immune microenvironment, immune neoantigens, immune checkpoints, tumor mutational burden (TMB), and microsatellite instability (MSI) in pan-cancer. Gene set enrichment analysis (GSEA) was used to clarify the relevant signaling pathways. The R package was used for data analysis and to create the plots. Results: The pan-cancer analysis revealed that the expression level of WNT5A is generally elevated in most tumors (19/34, 55.88%), and high WNT5A expression was correlated with poor prognosis in esophageal carcinoma (ESCA, P<0.05), low-grade glioma (LGG, P<0.01), adrenocortical carcinoma (ACC, P<0.01), pancreatic adenocarcinoma (PAAD, P<0.01), and head and neck squamous cell carcinoma (HNSC, P<0.05). In addition, WNT5A expression was positively associated with immune infiltration, stromal score, and immune checkpoints in most cancers, and correlated to immune neoantigens, TMB, and MSI. Finally, GSEA indicated that WNT5A is implicated in the transforming growth factor ß (TGFß), Notch, and Hedgehog signaling pathways, which may be related to tumor immunity. Conclusions: The expression of WNT5A is elevated in most tumors and associated with tumor prognosis. Furthermore, WNT5A is associated with tumor immunity and may be an immunological biomarker in cancer.

Lysine Acetylation/Deacetylation Modification of Immune-Related Molecules in Cancer Immunotherapy.

As major post-translational modifications (PTMs), acetylation and deacetylation are significant factors in signal transmission and cellular metabolism, and are modulated by a dynamic process via two pivotal categories of enzymes, histone acetyltransferases (HATs) and histone deacetylases (HDACs). In previous studies, dysregulation of lysine acetylation and deacetylation has been reported to be associated with the genesis and development of malignancy. Scientists have recently explored acetylation/deacetylation patterns and prospective cancer therapy techniques, and the FDA has approved four HDAC inhibitors (HDACi) to be used in clinical treatment. In the present review, the most recent developments in the area of lysine acetylation/deacetylation alteration in cancer immunotherapy were investigated. Firstly, a brief explanation of the acetylation/deacetylation process and relevant indispensable enzymes that participate therein is provided. Subsequently, a multitude of specific immune-related molecules involved in the lysine acetylation/deacetylation process are listed in the context of cancer, in addition to several therapeutic strategies associated with lysine acetylation/deacetylation modification in cancer immunotherapy. Finally, a number of prospective research fields related to cancer immunotherapy concepts are offered with detailed analysis. Overall, the present review may provide a reference for researchers in the relevant field of study, with the aim of being instructive and meaningful to further research as well as the selection of potential targets and effective measures for future cancer immunotherapy strategies.

WNT5A promotes the metastasis of esophageal squamous cell carcinoma by activating the HDAC7/SNAIL signaling pathway.

Esophageal squamous cell carcinoma (ESCC) is one of the most common cancers worldwide, with high incidence and mortality rates and low survival rates. However, the detailed molecular mechanism of ESCC progression remains unclear. Here, we first showed significantly higher WNT5A and SNAIL expression in ESCC samples than in corresponding paracancerous samples. High WNT5A and SNAIL expression levels correlated positively with lymphatic metastasis and poor prognosis for patients with ESCC based on immunohistochemical (IHC) staining of 145 paired ESCC samples. Spearman's correlation analyses confirmed the strong positive correlation between WNT5A and SNAIL expression, and patients with ESCC presenting coexpression of WNT5A and SNAIL had the worst prognosis. Then, we verified that the upregulation of WNT5A promoted ESCC cell metastasis in vivo and in vitro, suggesting that WNT5A might be a promising therapeutic target for the prevention of ESCC. Furthermore, WNT5A overexpression induced the epithelial-mesenchymal transition via histone deacetylase 7 (HDAC7) upregulation, and HDAC7 silencing significantly reversed WNT5A-induced SNAIL upregulation and ESCC cell metastasis. In addition, we used HDAC7 inhibitors (SAHA and TMP269) to further confirm that HDAC7 participates in WNT5A-mediated carcinogenesis. Based on these results, HDAC7 is involved in WNT5A-mediated ESCC progression, and approaches targeting WNT5A and HDAC7 might be potential therapeutic strategies for ESCC.