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Abstract Purpose This study aims to investigate whether adding fosaprepitant to palonosetron and dexamethasone is effective in preventing postoperative nausea and vomiting (PONV) in high-risk patients undergoing gynecologic surgery. Methods Eligible patients undergoing gynecological surgery were randomized into two groups (1:1). One group received fosaprepitant (150 mg) and the other (control) received a placebo infusion. Both groups received a single dose of palonosetron (0.25 mg) and dexamethasone (5 mg) together with therapeutic medication. The primary endpoint was the absence of vomiting and no use of rescue antiemetics during the first 24 h after surgery; complete response rate (CRR). Results CRR was significantly higher in the fosaprepitant group compared to the control group 0–24 h after surgery (P = 0.037; relative risk [RR], 1.116; 95% confidence interval [CI], 1.007 to 1.235). Moreover, CRR was also significantly higher during the 24–48 h (P = 0.004; RR, 1.148; 95% CI, 1.045 to 1.261) and 48–72 h (P = 0.039; RR, 1.083; 95% CI, 1.005 to 1.168) observation periods respectively. The complete control rate was higher in the fosaprepitant group than in the control group during the 0–24 h observation period (P = 0.012; RR, 1.367; 95% CI, 1.067 to 1.751). Nausea and rescue antiemetic use were comparable between the two groups. The severity of vomiting was significantly higher in the fosaprepitant group than in the control group on the second day (P = 0.016). Dynamic pain visual analog scale score was lower in the fosaprepitant group and quality of recovery-15 scores were significantly higher in the same group during 0–24 h observation period (P = 0.018 and 0.005, respectively). Conclusions The triple combination of fosaprepitant, palonosetron, and dexamethasone was superior in the prevention of PONV after gynecologic surgery in high-risk patients. We suggest that for high-risk patients, a triple combination therapy may be a better choice. Trial registration Registered at the Chinese Clinical Trial Registry ( https://www.chictr.org.cn/showproj.html?proj=171741 ) with No. ChiCTR2200060890 on June 13, 2022. Principal investigator: Jingdun Xie.

Abstract Glioblastoma (GBM) is a lethal disease with a poor prognosis due to its strong infiltration, which makes it difficult to remove completely. In this study, an implantable, modulus‐tunable, and ultrasound‐powered MXene/PVA hydrogel‐based tumor treatment device (UP‐MPH‐TTD), which generates specific electromagnetic alternating fields that disrupt the mitosis of cancer cells without adversely affecting normal neurons is developed. The MXene/PVA hydrogel is used to form a tumor treatment field due to its high biocompatibility, excellent flexibility, and high conductivity, which improves ultrasonic electrical conversion efficiency and significantly reduces the size of the equipment. The implantable UP‐MPH‐TTD is wirelessly ultrasound‐powered, small‐sized, lightweight, and simply structured, significantly boosting therapeutic efficiency and reducing restrictions on patient movement. In vitro and in vivo experiments confirmed the device's therapeutic effect, demonstrating a ≈92% inhibition rate in the growth of clinical tumor cells and a 73% reduction in tumor area in tumor‐bearing mice. The promising results indicate the broad application potential of the device in the treatment and prognostic improvement of GBM.

BackgroundOpioid anesthesia can modulate the impaired immune response and opioid-sparing anesthesia may preserve immune functions. This study was performed to assess the effects of opioid-free anesthesia (OFA) and opioid-based anesthesia (OA) on perioperative macrophages differentiation, cytokine changes, and perioperative complications in locally advanced GC (LAGC) patients.MethodsWe used quality of recovery-15 (QoR-15) questionnaire scores and visual analog scale (VAS) scores to compare postoperative quality of recovery and pain level. In addition, the adverse reactions of patients in the two groups were compared. The perioperative serum level of inflammatory cytokines and the ratio of macrophage subtypes were detected.ResultsThe OFA group had significantly longer extubation time and PACU stay, whereas the OA group had significantly higher rate of hypotension, higher doses of norepinephrine, higher PONV and dizziness rate, and delayed flatus passage time. The QoR-15 score on postoperative 24 h was significantly higher in OFA group than in OA group. At the end of or after the surgery, the OFA group had higher levels of interleukin (IL)-12, IL-1β, tumor necrosis factor (TNF)-α, CD68+CD163− macrophage rate, but lower levels of IL-10, transforming growth factor (TGF)-β, and CD68+CD163+ macrophage rate, indicating OFA attenuated perioperative immunosuppression by diminishing M2 and promoting M1 macrophage polarization. And the reversal tendency is more obvious in LAGC patients with neoadjuvant PD-1 inhibitor.ConclusionsThe OFA may attenuate perioperative immunosuppression by diminishing M2 and promoting M1 macrophage polarization in LAGC patients with neoadjuvant PD-1 inhibitor.Clinical trial registrationhttp://gcpgl.sysucc.org.cn, identifier 2022-FXY-001.

BackgroundStatic tumor features before initiating anti-tumor treatment were insufficient to distinguish responding from non-responding tumors under the selective pressure of immuno-therapy. Herein we investigated the longitudinal dynamics of peripheral blood inflammatory indexes (dPBI) and its value in predicting major pathological response (MPR) in non-small cell lung cancer (NSCLC).MethodsA total of 147 patients with NSCLC who underwent neoadjuvant immunochemotherapy were retrospectively reviewed as training cohort, and 26 NSCLC patients from a phase II trial were included as validation cohort. Peripheral blood inflammatory indexes were collected at baseline and as posttreatment status; their dynamics were calculated as their posttreatment values minus their baseline level. Least absolute shrinkage and selection operator algorithm was utilized to screen out predictors for MPR, and a MPR score was integrated. We constructed a model incorporating this MPR score and clinical predictors for predicting MPR and evaluated its predictive capacity via the area under the curve (AUC) of the receiver operating characteristic and calibration curves. Furthermore, we sought to interpret this MPR score in the context of micro-RNA transcriptomic analysis in plasma exosomes for 12 paired samples (baseline and posttreatment) obtained from the training cohort.ResultsLongitudinal dynamics of monocyte–lymphocyte ratio, platelet-to-lymphocyte ratio, platelet-to-albumin ratio, and prognostic nutritional index were screened out as significant indicators for MPR and a MPR score was integrated, which was further identified as an independent predictor of MPR. Then, we constructed a predictive model incorporating MPR score, histology, and differentiated degree, which discriminated MPR and non-MPR patients well in both the training and validation cohorts with an AUC value of 0.803 and 0.817, respectively. Furthermore, micro-RNA transcriptomic analysis revealed the association between our MPR score and immune regulation pathways. A significantly better event-free survival was seen in subpopulations with a high MPR score.ConclusionOur findings suggested that dPBI reflected responses to neoadjuvant immuno-chemotherapy for NSCLC. The MPR score, a non-invasive biomarker integrating their dynamics, captured the miRNA transcriptomic pattern in the tumor microenvironment and distinguished MPR from non-MPR for neoadjuvant immunochemotherapy, which could support the clinical decisions on the utilization of immune checkpoint inhibitor-based treatments in NSCLC patients.

Abstract Peripheral nerve block is performed for precise pain control and lesser side effects after surgery by reducing opioid consumption. Injectable hydrogel delivery systems with high biosafety and moisture content have good clinical application prospects for local anesthetic delivery. However, how to achieve high drug loading and long‐term controlled release of water‐soluble narcotic drugs remains a big challenge. In this study, heterogeneous microspheres and an injectable gel‐matrix composite drug delivery system are designed in two steps. First, heterogeneous hydrogel microspheres loaded with ropivacaine (HMS‐ROP) are prepared using a microfluidic chip and in situ alkalization. An injectable self‐healing hydrogel matrix (Gel) is then prepared from modified carboxymethylcellulose (CMC‐ADH) and oxidized hyaluronic acid (OHA). A local anesthetic delivery system, Gel/HMS‐ROP/dexmedetomidine (DEX), with long‐term retention and drug release in vivo is prepared by combining HMS‐ROP and Gel/DEX. The drug loading of HMS‐ROP reached 41.1%, with a drug release time of over 160 h in vitro, and sensory and motor blockade times in vivo of 48 and 36 h, respectively. In summary, the sequential release and synergistic analgesic effects of the two anesthetics are realized using core‐shell microspheres, DEX, and an injectable gel, providing a promising strategy for long‐acting postoperative pain management.

Abstract Acute lung injury (ALI) as well as its more severe form, acute respiratory distress syndrome (ARDS), frequently leads to an uncontrolled inflammatory response. N6-methyladenosine (m6A) modification was associated with the progression of several inflammatory diseases. However, the role of methyltransferase-like 14 (METTL14)-mediated m6A methylation in ALI/ARDS remains unclear. Here, we reported an increase in overall expression levels of m6A and METTL14 in circulating monocyte-derived macrophages recruited to the lung following ALI, which is correlated with the severity of lung injury. We further demonstrated the critical function of METTL14 in activating NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome in vitro and in mouse models of ALI/ARDS, and validated NLRP3 as the downstream target of METTL14 by the m6A RNA immunoprecipitation (MeRIP) and RIP assays. Mechanistically, METTL14-methylated NLRP3 transcripts were subsequently recognized by insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2), an m6A reader, which stabilized NLRP3 mRNA. Furthermore, we observed that IGF2BP2 knockdown diminished LPS-induced ALI in mice by downregulating NLRP3 expression. In summation, our study revealed that the molecular mechanism underlying the pathogenesis of ALI/ARDS involves METTL14-mediated activation of NLRP3 inflammasome in an IGF2BP2 dependent manner, thereby demonstrating the potential of METTL14 and IGF2BP2 as promising biomarkers and therapeutic targets for ALI/ARDS treatment.

Chemotherapy-induced peripheral neuropathy (CIPN) is a frequent and severe side effect of first-line chemotherapeutic agents. The association between circular RNAs (circRNAs) and CIPN remains unclear. In this study, CIPN models were constructed with Taxol, while 134 differentially expressed circRNAs, 353 differentially expressed long non-coding RNAs, and 86 differentially expressed messenger RNAs (mRNAs) were identified utilizing RNA sequencing. CircRNA-targeted microRNAs (miRNAs) were predicted using miRanda, and miRNA-targeted mRNAs were predicted using TargetScan and miRDB. The intersection of sequencing and mRNA prediction results was selected to establish the circRNA–miRNA–mRNA networks, which include 15 circRNAs, 18 miRNAs, and 11 mRNAs. Functional enrichment pathway analyses and immune infiltration analyses revealed that differentially expressed mRNAs were enriched in the immune system, especially in T cells, monocytes, and macrophages. Cdh1, Satb2, Fas, P2ry2, and Zfhx2 were further identified as hub genes and validated by RT-qPCR, correlating with macrophages, plasmacytoid dendritic cells, and central memory CD4 T cells in CIPN. Additionally, we predicted the associated diseases, 36 potential transcription factors (TFs), and 30 putative drugs for hub genes using the DisGeNET, TRRUST, and DGIdb databases, respectively. Our results indicated the crucial role of circRNAs, and the immune microenvironment played in CIPN, providing novel insights for further research.

The development of neural tissue engineering has brought new hope to the treatment of spinal cord injury (SCI). Up to date, various scaffolds have been developed to induce the oriented growth and arrangement of nerves to facilitate the repair after injury. In this work, a conductive and anisotropic inverse opal substrate was presented by modifying polystyrene (PS) inverse opal films with carbon nanotubes and then stretching them to varying degrees. The film had good biocompatibility, and neural stem cells (NSCs) grown on the film displayed good orientation along the stretching direction. In addition, benefiting from the conductivity and anisotropy of the film, NSCs differentiated into neurons significantly. These results suggest that the conductive and anisotropic PS inverse opal substrates possess value in nerve tissue engineering regeneration.

Abstract Background Dopamine receptors have been reported to play important roles in cancer progression. However, the role of dopamine receptor D3 (DRD3) in hepatocellular carcinoma (HCC) remains unclear. Methods The expression of DRD3 was detected by immunohistochemistry and real-time qPCR. The prognostic value of DRD3 in patients was investigated by analyzing selected databases, including cBioPortal and Kaplan–Meier plotter. Cell growth was tested by CCK8 assay, and Transwell assays were performed to assess cancer cell migration and invasion. The cAMP/ERK/CREB signaling pathway was evaluated by Western blot analysis and ELISA. An HCC xenograft model was established for in vivo experiments. Results DRD3 mRNA expression was significantly higher in nontumor tissues than in tumor tissues. Lower protein expression of DRD3 was related to poor recurrence-free survival (RFS) and overall survival (OS). Kaplan–Meier plotter analysis showed that higher expression of DRD3 mRNA was associated with better OS, RFS, disease-specific survival (DSS), and progression-free survival (PFS). cBioPortal analysis revealed that the alteration group, which harbored genetic mutations in DRD3, exhibited poor OS, RFS, DSS and PFS. According to CCK8 and Transwell assays, stable DRD3 overexpression cell line (ex-DRD3-SK-HEP-1) showed weaker proliferation, migration and invasion behaviors. PD128907, a DRD3 agonist, suppressed proliferation, migration and invasion in HCC cell lines, while U99194, a DRD3 antagonist, enhanced proliferation, migration and invasion in HCC cell lines. Western blot analysis and ELISA revealed that stable DRD3 knock-down cell line (sh-DRD3-PLC/PRF/5) and U99194 both increased the protein levels of cAMP, p-ERK and p-CREB; on the other hand, ex-DRD3-SK-HEP-1 and PD128907 decreased the protein levels of cAMP, p-ERK and p-CREB. SCH772984, an ERK antagonist, abolished the effect of U99194 on the malignant biological behaviors of HCC cells. In vivo, PD128907 suppressed tumor growth, and U99194 enhanced tumor growth. Conclusion Our results suggest that down-regulation of DRD3 is strongly involved in the progression of HCC, and DRD3 might be consider as an independent prognostic factor for HCC. Furthermore, DRD3 agonists may be a promising strategy for HCC therapy.

Abstract Background Liver cancer is one of the most deadly and prevalent cancers. A routine follow‐up plan for liver cancer is crucial but limited. In the present study, we aimed to disclose possible risk factors and critical survival time windows for primary liver cancer. Methods We enrolled 692 liver cancer patients from Sun Yat‐sen University Cancer Center (SYSUCC). Univariate and multivariate logistic regression analyses of cirrhosis and recurrence were conducted. A meta‐analysis was utilized to validate an indication of creatinine (CRE) in recurrence. Conditional survival analysis was performed using the Kaplan–Meier method. The results were further verified by the SYSUCC validation cohort and Surveillance, Epidemiology, and End Results (SEER) validation cohort. Results Our results indicated that A/G, history of hepatitis, history of alcohol consumption and platelet (PLT) might be potential prognostic factors for cirrhosis in liver cancer patients. CRE was significantly correlated with recurrence due to various therapies, especially after transarterial embolization. Moreover, 1.5 years to 2 years may be a critical time window for deterioration in survival rate based on the conditional survival analysis. Conclusion A/G, history of hepatitis, alcohol consumption and PLT may be potential prognostic factors for cirrhosis in liver cancer patients. More attention should be focused on the renal function when treating the patients due to the significant role of CRE. 1.5 years to 2 years is a critical time window for deterioration in survival rate for liver cancer patients that contributes to determining the optimal follow‐up plan in the future.

Abstract Repair of spinal cord injury (SCI) depends on microenvironment improvement and the reconnection between injured axons and regenerated neurons. Here, we fabricate a GelMA-MXene hydrogel nerve conduit with electrical conductivity and internal-facing longitudinal grooves and explore its function in SCI repair. It is found that the resultant grooved GelMA-MXene hydrogel could effectively promote the neural stem cells (NSCs) adhesion, directed proliferation and differentiation in vitro. Additionally, when the GelMA-MXene conduit loaded with NSCs (GMN) is implanted into the injured spinal cord site, effective repair capability for the complete transection of SCI was demonstrated. The GMN group shows remarkable nerve recovery and significantly higher BBB scores in comparison to the other groups. Therefore, GMN with the microgroove structure and loaded with NSCs is a promising strategy in treating SCI.

Abstract Opioids and their receptors are involved in cancer progression. However, the roles of the nociceptin receptor (NOP) and its antagonist (JTC801) in hepatocellular carcinoma (HCC) are poorly understood. The prognostic value of NOP expression was evaluated using tissue microarray and immunohistochemical staining analyses in a human HCC cohort. The biological role and mechanism of NOP in HCC tumor growth were determined in vitro and in vivo. We found that NOP was associated with the clinicopathological features and survival outcomes of HCC patients. NOP overexpression promoted HCC growth in vitro and in vivo. Mechanistically, NOP activated NF-kB signaling to promote autophagy, which inhibited apoptosis, in HCC cells. An inhibitor of autophagy, 3-MA, and an inhibitor of NF-kB, JSH-23, attenuated the function of NOP in HCC. E2F1 was identified as a transcription factor of NOP. The oncogenic role of NOP was positively regulated by E2F1. Furthermore, JTC801, a selective antagonist of NOP, abolished the function of NOP by inhibiting NF-kB signaling and autophagy. Our study demonstrates that NOP is an oncogene in HCC. We provide a potential therapeutic candidate and prognostic predictor for HCC. JTC801 could become a potential drug for HCC therapy.

Background: N6-Methyladenosine (m6A) RNA methylation of eukaryotic mRNA is involved in the progression of various tumors. We aimed to investigate m6A-related genes and m6A regulators in hepatocellular carcinoma (HCC) and their association with prognosis in HCC. Methods: We downloaded liver cancer sample data from The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium database. A total of 21 m6A regulators and 1258 m6A-related genes were then analyzed by consensus clustering, Spearman’s correlation, GO, KEGG, LASSO Cox regression, and univariate Cox regression analyses. Finally, we constructed a risk prognostic model. Results: We obtained 192 candidate m6A-related genes and 3 m6A regulators, including YTHDF1, YTHDF2, and YTHDC1. The expression of these genes and regulators differed significantly in different stages of HCC. Based on Cox regression analysis, 19 of 98 m6A-related prognostic genes were obtained to construct a risk score model. The 1- and 3-year area under the curves (AUCs) among HCC patients were greater than 0.7. Finally, based on analysis of mutation differences between high- and low-risk score groups, we determined that TP53 had the highest mutation frequency in the high-risk HCC patient group, whereas titin (TTN) had the highest mutation frequency in the low-risk HCC patient group. Conclusion: This study comprehensively analyzed m6A regulators and m6A-related genes through an integrated bioinformatic analysis, including expression, clustering, protein–protein interaction, and prognosis, thus providing novel insights into the roles of m6A regulators and m6A-related genes in HCC.

BackgroundMajor depressive disorder (MDD) is a heterogeneous and prevalent mental disorder associated with increased morbidity, disability, and mortality. However, its underlying mechanisms remain unclear.Materials and methodsAll analyses were conducted based on integrated samples from the GEO database. Differential expression analysis, unsupervised consensus clustering analysis, enrichment analysis, and regulation network analysis were performed.ResultsMitogen-activated protein kinase (MAPK) signaling pathway was identified as an associated pathway in the development of MDD. From transcriptional signatures, we classified the MDD patients into two subgroups using unsupervised clustering and revealed 13 differential expression genes between subgroups, which indicates the probably relative complications. We further illustrated potential molecular mechanisms of MDD, including dysregulation in the neurotrophin signaling pathway, peptidyl-serine phosphorylation, and endocrine resistance. Moreover, we identified hub genes, including MAPK8, TP53, and HRAS in the maintenance of MDD. Furthermore, we demonstrated that the axis of miRNAs-TFs-HRAS/TP53/MAPK8 may play a critical role in MDD.ConclusionTaken together, we demonstrated an overview of MAPK-related key genes in MDD, determined two molecular subtypes, and identified the key genes and core network that may contribute to the procession of MDD.

BackgroundNeuropathic pain is a debilitating disease caused by damage or diseases of the somatosensory nervous system. Previous research has indicated potential associations between neuropathic pain and aging. However, the mechanisms by which they are interconnected remain unclear. In this study, we aim to identify the common differentially expressed genes (co-DEGs) between neuropathic pain and aging through integrated bioinformatics methods and further explore the underlying molecular mechanisms.MethodsThe microarray datasets GSE24982, GSE63442, and GSE63651 were downloaded from Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) and co-DEGs were first identified. Functional enrichment analyses, protein-protein Interaction (PPI) network, module construction and hub genes identification were performed. Immune infiltration analysis was conducted. Targeted transcription factors (TFs), microRNAs (miRNAs) and potential effective drug compounds for hub genes were also predicted.ResultsA total of 563 and 1,250 DEGs of neuropathic pain and aging were screened, respectively. 16 genes were further identified as co-DEGs. The functional analysis emphasizes the vital roles of the humoral immune response and complement and coagulation cascades in these two diseases. Cxcl14, Fblim1, RT1-Da, Serping1, Cfd, and Fcgr2b were identified as hub genes. Activated B cell, mast cell, activated dendritic cell, CD56 bright natural killer cell, effector memory CD8 + T cell, and type 2 T helper cell were significantly up-regulated in the pain and aging condition. Importantly, hub genes were found to correlate with the activated B cell, activated dendritic cell, Gamma delta T cell, central memory CD4 + T cell and mast cell in pain and aging diseases. Finally, Spic, miR-883-5p, and miR-363-5p et al. were predicted as the potential vital regulators for hub genes. Aldesleukin, Valziflocept, MGD-010, Cinryze, and Rhucin were the potential effective drugs in neuropathic pain and aging.ConclusionThis study identified co-DEGs, revealed molecular mechanisms, demonstrated the immune microenvironment, and predicted the possible TFs, miRNAs regulation networks and new drug targets for neuropathic pain and aging, providing novel insights into further research.

The signature composed of immune-related long noncoding ribonucleic acids (irlncRNAs) with no requirement of specific expression level seems to be valuable in predicting the survival of patients with hepatocellular carcinoma (HCC). Here, we retrieved raw transcriptome data from The Cancer Genome Atlas (TCGA), identified irlncRNAs by co-expression analysis, and recognized differently expressed irlncRNA (DEirlncRNA) pairs using univariate analysis. In addition, we modified Lasso penalized regression. Then, we compared the areas under curve, counted the Akaike information criterion (AIC) values of 5-year receiver operating characteristic curve, and identified the cut-off point to set up an optimal model for distinguishing the high- or low-disease-risk groups among patients with HCC. We then reevaluated them from the viewpoints of survival, clinic-pathological characteristics, tumor-infiltrating immune cells, chemotherapeutics efficacy, and immunosuppressed biomarkers. 36 DEirlncRNA pairs were identified, 12 of which were included in a Cox regression model. After regrouping the patients by the cut-off point, we could more effectively differentiate between them based on unfavorable survival outcome, aggressive clinic-pathological characteristics, specific tumor immune infiltration status, low chemotherapeutics sensitivity, and highly expressed immunosuppressed biomarkers. The signature established by paring irlncRNA regardless of expression levels showed a promising clinical prediction value.

Glioblastoma multiform is a lethal primary brain tumor derived from astrocytic, with a poor prognosis in adults. Reticulocalbin-1 (RCN1) is a calcium-binding protein, dysregulation of which contributes to tumorigenesis and progression in various cancers. The present study aimed to identify the impact of RCN1 on the outcomes of patients with Glioblastoma multiforme (GBM). The study applied two public databases to require RNA sequencing data of Glioblastoma multiform samples with clinical data for the construction of a training set and a validation set, respectively. We used bioinformatic analyses to determine that RCN1 could be an independent factor for the overall survival of Glioblastoma multiform patients. In the training set, the study constructed a predictive prognostic model based on the combination of RCN1 with various clinical parameters for overall survival at 0.5-, 1.0-, and 1.5-years, as well as developed a nomogram, which was further validated by validation set. Pathways analyses indicated that RCN1 was involved in KEAS and MYC pathways and apoptosis. In vitro experiments indicated that RCN1 promoted cell invasion of Glioblastoma multiform cells. These results illustrated the prognostic role of RCN1 for overall survival in Glioblastoma multiform patients, indicated the promotion of RCN1 in cell invasion, and suggested the probability of RCN1 as a potential targeted molecule for treatment in Glioblastoma multiform.

Friend recommendations based on social relationships have attracted thousands of research under the rapid development of social networks. However, most of the existing friend recommendation methods use user attributes or a single social network, while rarely integrating multiple social relationships to enhance the representation. This paper focuses on integrating various social relationships to guide the representation learning, and further generating personalized friend recommendations. We design an end-to-end framework based on multiple social networks to learn the potential features of users and construct a friend recommendation model named Multi-Social Graph Convolutional Network (MSGCN). It learns the features of higher-order neighbors from multiple social networks to enrich the representation of the target user based on the improved graph convolution neural network. In particular, some graph fusion strategies by adjusting and fusing the Laplace matrix of the graph are designed to integrate social relationships. Finally, we use Bayesian theory to transform friend recommendation into a sorting problem for personalized recommendation. The experimental results show that the proposed model outperforms the state-of-the-art methods.

Background: Opioid anesthesia can modulate the impaired immune response and opioid-sparing anesthesia may preserve immune functions. This study was performed to assess the effects of opioid-free anesthesia (OFA) and opioid-based anesthesia (OA) on perioperative macrophages differentiation, cytokine changes, and perioperative complications in locally advanced GC (LAGC) patients. Methods: We used quality of recovery-15 (QoR-15) questionnaire scores and visual analog scale (VAS) scores to compare postoperative quality of recovery and pain level. In addition, the adverse reactions of patients in the two groups were compared. The perioperative serum level of inflammatory cytokines and the ratio of macrophage subtypes were detected. Results: The OFA group had significantly longer extubation time and PACU stay, whereas the OA group had significantly higher rate of hypotension, higher doses of norepinephrine, higher PONV and dizziness rate, and delayed flatus passage time. The QoR-15 score on postoperative 24 h was significantly higher in OFA group than in OA group. At the end of or after the surgery, the OFA group had higher levels of interleukin (IL)-12, IL-1b, tumor necrosis factor (TNF)-a, CD68 +CD163-macrophage rate, but lower levels of IL-10, transforming growth factor (TGF)-b, and CD68+CD163+ macrophage rate, indicating OFA attenuated perioperative immunosuppression by diminishing M2 and promoting M1 macrophage polarization. And the reversal tendency is more obvious in LAGC patients with neoadjuvant PD-1 inhibitor. Conclusions: The OFA may attenuate perioperative immunosuppression by diminishing M2 and promoting M1 macrophage polarization in LAGC patients with neoadjuvant PD-1 inhibitor. [ABSTRACT FROM AUTHOR]

The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway induces innate immunity by activating the production of inflammatory cytokines and type I interferons. Recently, studies revealed that self-DNA from by-products of chromosome instability and tumors could activate the cGAS-STING pathway, and subsequently promote or inhibit tumor development. However, the prognostic value and correlations with immune infiltrates of the cGAS-STING pathway in hepatocellular carcinoma (HCC) have not been clarified. In the present study, we used theMolecular Signatures Database, Oncomine, UALCAN, Human Protein Atlas, Kaplan-Meier plotter, LinkedOmics, and Tumor Immune Estimation Resource databases. Overexpression of XRCC5, IRF3, TRIM21, STAT6, DDX41, TBK1, XRCC6, TREX1, PRKDC, and TMEM173 was markedly correlated with clinical stages and pathological grades in HCC. Moreover, higher mRNA expression of XRCC5, XRCC6, and PRKDC was significantly related with shorter overall survival. However, higher mRNA expression of IFI16, STAT6, NLRC3, and TMEM173 was associated with favorable overall survival. Our results suggested that the kinase targets of the cGAS-STING pathway included the SRC family of tyrosine kinases (LCK and LYN), phosphoinositide 3-kinase-related protein kinase (PIKK) family kinases (ATM and ATR), and mitogen-activated protein kinase 1 (MAPK1). Furthermore, we identified significant correlations among the expression of cGAS-STING pathway and infiltration of B cells, CD4+T cells, CD8+ T cells, macrophages, neutrophils, and dendritic cells in HCC. The expression of the cGAS-STING pathway also exhibited strong relationships with diverse immune marker sets in HCC. These findings suggest that cGAS-STING pathway members may be used as prognostic biomarkers and immunotherapeutic targets HCC patients. [ABSTRACT FROM AUTHOR]

Epigenetics is a biological process that modifies and regulates gene expression, affects neuronal function, and contributes to pain. However, the mechanism by which epigenetics facilitates and maintains chronic pain is poorly understood. We aimed to determine whether N6-methyladenosine (m6A) specifically modified by methyltransferase-like 14 (METTL14) alters neuronal activity and governs pain by sensitizing the GluN2A subunit of the N-methyl-d-aspartate receptor (NMDAR) in the dorsal root ganglion (DRG) neurons in a model of chemotherapy-induced neuropathic pain (CINP). Using dot blotting, immunofluorescence, gain/loss-of-function, and behavioral assays, we found that m6A levels were upregulated in L4-L6 DRG neurons in CINP in a DBP/METTL14-dependent manner, which was also confirmed in human DRGs. Blocking METTL14 reduced m6A methylation and attenuated pain hypersensitivity. Mechanistically, METTL14-mediated m6A modification facilitated the synaptic plasticity of DRG neurons by enhancing the GluN2A subunit of NMDAR, and inhibiting METTL14 blocked this effect. In contrast, overexpression of METTL14 upregulated m6A modifications, enhanced presynaptic NMDAR activity in DRG neurons, and facilitated pain sensation. Our findings reveal a previously unrecognized mechanism of METTL14-mediated m6A modification in DRG neurons to maintain neuropathic pain. Targeting these molecules may provide a new strategy for pain treatment. [ABSTRACT FROM AUTHOR]