The exon 19 deletion (19 Del) and the exon 21 L858R point mutation (21 L858R) are two main subtypes of EGFR-mutant lung adenocarcinoma (LUAD) with distinct response to targeted treatment and immunotherapy. Understanding the intratumor heterogeneity (ITH) of EGFR-mutant LUAD may explain the reason. 157 multi-region tumor samples and matched distant normal lung tissues from 29 treatment-naïve operable EGFR-mutant LUAD patients were collected to perform whole genome sequencing, panel sequencing and whole transcriptome sequencing. We aimed to comprehensively assess genomic and transcriptomic ITH between 19 Del and 21 L858R. The 21 L858R LUAD exhibited significantly higher copy number variation (CNV) ITH index (ITHi) compared to the 19 Del LUAD, but there was no significant difference in somatic single-nucleotide variant (SNV) ITHi between them. Meanwhile, 19 Del LUAD owned more clonal genetic alterations, while 21 L858R LUAD had more subclonal events. Both linear and branch evolution models existed in 19 Del and 21 L858R LUAD. Besides, 19 Del seemed to be more dominant for driving tumor development, while other driver mutations participated jointly with 21 L858R in tumor evolution. Moreover, 19 Del LUAD exhibited significantly higher immune score and checkpoint inhibition signature than 21 L858R. Additionally, it indicated that high-level TMB might be a favorable prognostic factor for EGFR-mutant LUAD. Our study demonstrated diverse genomic heterogeneity and tumor immune microenvironment in EGFR-mutant LUAD, which might elaborate on potential explanations for different efficacy between 19 Del and 21 L858R and provide valuable hints to treatment strategy.

Programmed cell death (PCD) patterns play important roles in lung adenocarcinoma (LUAD) development as well as treatment resistance, and in-depth study of PCD is beneficial for improving the therapeutic paradigm for LUAD. Fourteen PCD-related patterns were integrated and multiple datasets from TCGA and GEO were collected to develop a PCD signature using 101 machine learning algorithm combinations. Prognosis, immune cell infiltration, and sensitivity to chemotherapy and immunotherapy were compared between different risk groups and validated by multiple bulk RNA-seq and scRNA-seq datasets of patients receiving immunotherapy. CellChat was used to analyze the cellular interactions between patients with different PCD groups. Immune cell infiltration in the tumor tissues of 38 LUAD patients treated with anti-PD-1 therapy was validated by multiplex immunohistochemistry (mIHC). A PCD signature containing 7 genes was constructed using 101 machine learning algorithm combinations and validated across multiple datasets. High PCD scores in patients are associated with poorer prognosis, lower immune cell infiltration, and reduced responsiveness to immunotherapy. In addition, the PCD signature were comprehensively analyzed by scRNA-seq, and the results showed that the high PCD signature was concentrated mainly in advanced LUAD. Moreover, pathways associated with tumor progression and immune resistance were more strongly promoted in the high PCD signature group. The expression of the key gene NAPSA correlated with immune cell infiltration and immunotherapy response, as confirmed by IHC and mIHC. The PCD signature confers significant potential to predict prognosis of LUAD in patients, and NAPSA is promising as a new marker for predicting the efficacy of immunotherapy. 1. A novel 7-gene programmed cell death signature for lung adenocarcinoma was constructed. 2. A high PCD score predicts poor prognosis and reduced response to immunotherapy. 3. Single-cell analysis reveals the PCD-high tumor microenvironment exhibits an immunosuppressive phenotype 4. The key gene NAPSA is a potential biomarker for immune infiltration and therapy efficacy.

Platinum-based chemotherapy resistance, particularly to carboplatin, is a major challenge in the treatment of non-small cell lung cancer (NSCLC). N6-methyladenosine (m6A) methylation, which regulates gene and protein expression by influencing numerous aspects of mRNA metabolism, has been implicated in NSCLC pathogenesis, but its role in treatment resistance remains unclear. We performed an innovative integrated analysis by combining genome-wide association study (GWAS) summary statistics, methylation quantitative trait loci (mQTL) data, and single-cell RNA sequencing (scRNA-seq) data from NSCLC patients. First, a transcriptome-wide association study (TWAS) using FUSION analysis was conducted to identify associations between m6A methylation sites, genes, and NSCLC by integrating m6A methylation profiles with GWAS summary statistics. Subsequently, scRNA-seq data were used to characterize NSCLC epithelial cell subpopulations and dynamically delineate the transition from treatment-sensitive to treatment-resistant states. Finally, a cross-omics correlation network was constructed by integrating the m6A and scRNA-seq datasets to identify associations between dynamic m6A modifications and carboplatin resistance. Our integrated analysis identified 6 m6A sites and 9 genes significantly associated with NSCLC. ScRNA-seq analysis revealed a significant increase in the proportion of epithelial cells in the carboplatin-resistant group. Marker genes of these carboplatin-resistant epithelial cells were enriched in pathways related to glutathione metabolism, ferroptosis, and endoplasmic reticulum protein processing. The RAS oncogene family member RAB7A was identified as a critical driver of treatment resistance. MeRIP-qPCR confirmed that RAB7A mRNA carries m6A modifications, and RIP-qPCR demonstrated direct binding of the m6A reader IGF2BP2 to RAB7A transcripts. Functional assays showed that RAB7A overexpression significantly increased intracellular glutathione levels and reduced lipid ROS, indicating enhanced antioxidant capacity and ferroptosis suppression. RAB7A expression was significantly upregulated in NSCLC patients with a poor response to neoadjuvant chemotherapy. Functional validation in vitro confirmed that overexpression of RAB7A conferred carboplatin resistance in NSCLC cells. This study establishes a novel paradigm in which m6A-mediated gene regulation is a key contributor to chemoresistance. Furthermore, we identify RAB7A as a functionally relevant gene associated with carboplatin resistance, warranting further investigation as a candidate therapeutic target.

OBJECTIVES:This study aimed to evaluate the prognostic value of quantitative N1 nodal burden metrics-including positive node count, positive station count, lymph node ratio (LNR), and lymph node station ratio (LNsR)-in patients with non-skip pN2 non-small cell lung cancer (NSCLC). METHODS:This retrospective study included 477 non-skip pN2 NSCLC patients who underwent complete surgical resection at our center from December 2008 to December 2020. N1 metrics were dichotomized based on optimal cutoffs determined by overall survival (OS). Kaplan-Meier analysis and Cox regression models were utilized to assess disease-free survival (DFS) and OS and to identify independent prognostic factors. RESULTS:In multivariable analysis, a high N1 LNR emerged as the sole N1 metric that independently predicted worse DFS (HR = 1.47, 95 % CI: 1.05-2.04, p = 0.023). In contrast, its prognostic significance for OS was attenuated (p = 0.162). However, an advanced pT4 stage (p = 0.044) was an independent predictor of worse OS, while adjuvant therapy (p = 0.016) was associated with improved OS. Notably, subgroup analysis revealed that an elevated N1 LNR independently predicted worse DFS in the pN2a subgroup (p = 0.009). Building on this, we developed a novel three-tiered stratification (pN2a-low LNR, pN2a-high LNR, and pN2b) that effectively discriminated patient outcomes for both DFS (p < 0.001) and OS (p < 0.01). CONCLUSIONS:N1 LNR is a powerful and independent predictor of disease recurrence in non-skip pN2 NSCLC, outperforming other N1 metrics for predicting DFS. Incorporating N1 LNR into clinical assessments, particularly for pN2a patients, can enhance prognostic accuracy and potentially guidemore personalized surveillance and treatment strategies.

Background:Transient receptor potential channel subfamily M member 4 (TRPM4) is a non-selective Na+ permeable ion channel that regulates disease processes by enhancing sodium entry and membrane depolarization, but its role in tumors remains underexplored. The purpose of this study is to investigate the role of TRPM4 in pan-cancer progression and immune regulation. Methods:The pan-cancer mRNA expression information of TRPM4 was obtained from TCGA and GTEx, and the protein expression information of TRPM4 was obtained from HPA database. STRING database was utilized to construct the protein-protein interaction network of TRPM4. Gene characterization of TRMP4 was analyzed by GSCA database. The relationship between TRPM4 and immune infiltration characteristics in pan-cancer was analyzed using TCGAplot. Multiple bulk RNA-seq and scRNA-seq datasets treated with PD-(L)1 were used to analyze the relationship between TRPM4 and immunotherapy response. Immunohistochemistry (IHC) and multiplex immunofluorescence (mIHC) were used to validate the expression of TRPM4 in tumor tissue from 19 lung adenocarcinoma patients in relation to the characteristics of immune cell infiltration. In vitro experiments were performed to validate the role of TRPM4 in human breast, lung adenocarcinoma, and esophageal cancer. Results:TRMP4 expression is higher in most tumors than in normal tissues, and the association with prognosis varies with cancer type. TRPM4 correlates with multiple immune checkpoints as well as the degree of immune cell infiltration. Multiple datasets of anti-PD-(L)1 treatment suggested that high expression of TRPM4 was associated with worse treatment prognosis. The IHC and mIHC found that TRPM4 expression was negatively correlated with the level of M1 macrophage and T cell infiltration. In vitro experiments confirmed that knockdown of TRPM4 inhibited proliferation, invasion and migration of human breast, lung and esophageal cancer cells. Conclusion:TRPM4 plays a complex role in tumor progression and immunotherapeutic response, and targeting TRPM4 may offer promising strategies for inhibiting tumor progression and improving immunotherapy resistance.

BackgroundThe lysosome plays a vitally crucial role in tumor development and is a major participant in the cell death process, involving aberrant functional and structural changes. However, there are few studies on lysosome-associated genes (LAGs) in lung adenocarcinoma (LUAD).MethodsBulk RNA-seq of LUAD was downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). The lysosome risk signature was constructed after univariate and least absolute shrinkage and selection operator (Lasso) cox regression analysis of the TCGA training set, and its capability was validated by additional validation sets from GEO. Single cell sequencing (scRNA) was obtained from GEO to analyze the differences of lysosome risk signature at the single-cell level and the differences in the function and pathway. In vitro experiments have validated the function of CTSH in LUAD.ResultsThe risk signature contained seven key LAGs, and patients were categorized into high- and low-risk groups based on a specific calculation formula. The LAG risk signature, which accurately predicted the prognostic status of LUAD patients, was still regarded as an independent prognostic indicator in multifactorial cox regression analysis. Subsequently, the combination of the signature and key clinical information was used to construct a column-line diagram for clinical assessment, which had a high discriminatory power. Immune infiltration analysis from bulk RNA-seq and scRNA-seq indicated that the low-risk group was immune-activated and had a better benefit in the prediction of immunotherapy. Finally, we validated its role in inhibiting tumor proliferation and metastasis in LUAD cells by knockdown of CTSH.ConclusionWe defined a new biomarker that provided unique insights for individualized survival prediction and immunotherapy recommendations for LUAD patients.

Lung adenocarcinoma (LUAD) is the most prevalent subtype of lung cancer, with poor prognosis due to rapid tumor growth and resistance to current treatments. Thus, the identification of novel biomarkers and therapeutic strategies has become increasingly important in the management of LUAD. A novel integrin α6-targeting peptide-drug conjugate, RWYD-MMAE, was designed to increase therapeutic precision and minimize off-target effects. Integrin α6 expression was examined in LUAD tissues and cell lines. The antitumor activity and safety of RWYD-MMAE for LUAD treatment were assessed in vitro and in vivo. Moreover, the combination of RWYD-MMAE with an anti-PD-1 monoclonal antibody was further investigated to elucidate the synergistic therapeutic effects. Integrin α6 was overexpressed in LUAD cells and tissues, suggesting that integrin α6 is a promising target of drug action for LUAD patients. RWYD-MMAE exhibited targeted antitumor activity in LUAD cell lines via G2 phase arrest and apoptosis. Notably, the antitumor efficacy of RWYD-MMAE was positively correlated with ITGA6 expression levels. In vivo experiments indicated that RWYD-MMAE significantly suppresses tumor growth with no detectable systemic toxicity. In addition, RWYD-MMAE was able to ameliorate the tumor immunosuppressive microenvironment and sensitized tumors to immunotherapy, thereby achieving a more pronounced therapeutic response when combined with anti-PD-1 immunotherapy. The integrin α6-targeting conjugate RWYD-MMAE demonstrates promising therapeutic efficacy and safety in treating LUAD. The synergistic therapeutic effect of combining RWYD-MMAE with anti-PD-1 immunotherapy provides a new perspective on the potential of combination therapy for LUAD treatment.

Small-cell lung cancer (SCLC), an aggressive neuroendocrine tumor strongly associated with exposure to tobacco carcinogens, is characterized by early dissemination and dismal prognosis with a five-year overall survival of less than 7%. High-frequency gain-of-function mutations in oncogenes are rarely reported, and intratumor heterogeneity (ITH) remains to be determined in SCLC. Here, via multiomics analyses of 314 SCLCs, we found that the ASCL1+/MKI67+ and ASCL1+/CRIP2+ clusters accounted for 74.38% of the 190,313 SCLC cancer cells from 39 patients, with the ASCL1+SOX1+ stem-like cell cluster across SCLC subtypes. The major histocompatibility complex (MHC) class I molecules were expressed at low levels in six and high levels in five cancer cell clusters and were inversely associated with the KI67 expression level. Abnormal splicing of mRNAs was a feature of SCLC, with focal adhesion kinase (FAK) splicing variants identified in 119 (77.3%) of 154 patients. FAK variants exhibited elevated kinase activity, were associated with the worst prognosis, and were sensitive to FAK inhibitors in patient-derived organoids and xenograft models. Eleven high-frequency mutations were identified in addition to TP53 and RB1, and smoking status and tumor stage did not affect microbiota variance in SCLC. Taken together, our data further revealed the complicated ITH and discovered that FAK splicing variants represent high-frequency gain-of-function alterations in oncogene in SCLC and potential therapeutic targets for this recalcitrant cancer.

Background:The prognostic significance of skip metastasis remains controversial in the context of the recently revised N2a (single-station) and N2b (multi-station) of non-small cell lung cancer (NSCLC). This study aims to investigate the survival impact of skip metastasis in these subgroups. Methods:We retrospectively analyzed 1,873 NSCLC patients who underwent surgery with systematic lymph node dissection at a single institution. Patients were categorized into pN1, skip pN2a, non-skip pN2a, skip pN2b, and non-skip pN2b groups. Overall survival (OS) and disease-free survival (DFS) were assessed using Kaplan-Meier analysis and Cox proportional hazards regression, with propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) applied to minimize confounding. Results:Skip metastasis was identified in 34.1% of pN2 cases, with a higher incidence in pN2a (41.3%) than in pN2b (24.3%). Skip pN2a showed significantly better 5-year OS and DFS rates compared to non-skip pN2a (72% vs. 67%, P=0.02; 57% vs. 48%, P=0.002). Similarly, skip pN2b had superior outcomes compared to non-skip pN2b (5-year OS: 65% vs. 58%, P=0.008; DFS: 42% vs. 37%, P=0.03). Notably, no significant survival difference was observed between skip pN2a and pN1, or between non-skip pN2a and skip pN2b, even after PSM and IPTW adjustments. Conclusions:Skip metastasis confers a survival advantage in both pN2a and pN2b NSCLC subgroups with comparable survival between skip pN2a and pN1, as well as between non-skip pN2a and skip pN2b.

This research aimed to examine the relationships between clinicopathological characteristics and the occurrence of Spread Through Air Spaces (STAS) in patients with stage IA lung adenocarcinoma (LUAD) and to develop a preoperative prediction model. Data from 1,375 patients with stage IA LUAD at Sun Yat-sen University Cancer Center were analyzed. Propensity score matching (PSM) was employed to match 141 STAS-positive patients with 282 STAS-negative patients. Both univariate and multivariate logistic regression analyses were performed to determine independent variables among 16 clinicopathological and 13 CT imaging characteristics. A nomogram prediction model was developed and evaluated via receiver operating characteristic (ROC) and decision curve analyses (DCAs). Multivariate analysis identified several independent risk factors. Irregular nodule shape (OR = 1.817, 95

Background Disulfidptosis is a recently proposed novel cell death mode in which cells with high SLC7A11 expression induce disulfide stress and cell death in response to glucose deficiency. The purpose of the research was to explore the function of disufidptosis and disulfide metabolism in the progression of lung adenocarcinoma (LUAD). Methods The RNA-seq data from TCGA were divided into high/low expression group on the base of the median expression of SLC7A11 , and the characteristic of differentially expressed disulfide metabolism-related genes. Least absolute shrinkage and selection operator (LASSO) algorithm was conducted the disulfidptosis and disulfide metabolism risk index. The tumor mutation burden (TMB), mechanism, pathways, tumor microenvironment (TME), and immunotherapy response were assessed between different risk groups. The role of TXNRD1 in LUAD was investigated by cytological experiments. Results We established the risk index containing 5 genes. There are significant differences between different risk groups in terms of prognosis, TMB and tumor microenvironment. Additionally, the low-risk group demonstrated a higher rate of response immunotherapy in the prediction of immunotherapy response. Experimental validation suggested that the knockdown of TXNRD1 suppressed cell proliferation, migration, and invasion of LUAD. Conclusion Our research highlights the enormous potential of disulfidptosis and disulfide metabolism risk index in predicting the prognosis of LUAD. And TXNRD1 has great clinical translational ability.

BACKGROUND:The incidence and mortality rates of esophageal squamous cell carcinoma (ESCC) are conspicuously augmented in men in contrast to women. The androgen receptor (AR), prevalently associated with the manifestation of male characteristics, is regarded as a pivotal determinant in tumor progression. Nevertheless, its exact role in ESCC remains insufficiently delineated. METHODS:In this study, we probed the expression levels of AR and glucose metabolism enzymes in ESCC tissues by means of immunohistochemistry. We exploited chromatin immunoprecipitation and dual luciferase reporter assays to delve into the transcriptional regulatory interrelationships between AR and these enzymes. A gamut of molecular techniques-including multi-omics sequencing, colony formation assays, cell counting kit 8 (CCK8), 5-Ethynyl-2'-deoxyuridine (EdU) incorporation assays, wound-healing assays, transwell migration assays, extracellular acidification rate (ECAR) measurements, lipid droplet fluorescence imaging, and xenograft models-were enlisted to illuminate the functions of these enzymes within ESCC cells. RESULTS:Our discoveries manifested that AR expression was strikingly higher in male ESCC tissues than in their female counterparts. Significantly, we discerned that glycogen phosphorylase B (PYGB), a cardinal enzyme implicated in glucose metabolism, demonstrated not only a positive correlation with AR expression but also an association with adverse prognostic outcomes for ESCC patients. Moreover, AR directly binds to the promoter region of the PYGB gene, thereby potentiating its transcriptional activity. This upregulation of PYGB was ascertained to facilitate proliferation, invasion, and metastasis among ESCC cells while intensifying glycolysis and modifying lipid metabolism pathways within these cells. In animal models employing nude mice, elevated PYGB levels were witnessed to expedite subcutaneous tumor growth as well as lung metastasis. CONCLUSIONS:Collectively, our study establishes PYGB as a direct target of AR that assumes an indispensable role in both tumor progression and metabolic reprogramming affiliated with ESCC, thus paving novel avenues for therapeutic strategies centered on metabolic intercessions.

Esophageal squamous cell carcinoma (ESCC) is a common malignant tumor in East Asia. Hypoxia, a hallmark of solid tumors, significantly alters redox homeostasis inside tumor microenvironment. This alteration drives tumor proliferation, invasion, and metastasis, leading to poor prognostic outcomes. However, the role of hypoxia-related genes in ESCC remains poorly understood. We employed RNA sequencing to identify differentially expressed genes in ESCC. Clinical data, transcriptome profiles, and a hypoxia-related gene set were extracted from open-source databases. A prognostic model was constructed using least absolute shrinkage and selection operator (LASSO) regression, which was then validated through Cox regression analysis. Within this prognostic model, we pinpointed and investigated a key hypoxia-related gene affecting prognosis. The gene's expression was validated using real-time PCR and immunohistochemistry in both esophageal carcinoma and normal tissues. Tumor proliferation was examined through in vitro and in vivo assays, including the Cell Counting Kit-8, EdU, colony formation, and subcutaneous tumor models. A robust four-gene prognostic model (VBP1, BGN, CDKN1A, and PPFIA1) was successfully constructed and validated. Among these, VBP1 emerged as a key gene, exhibiting high expression levels that correlated with poor prognosis in ESCC. Functional experiments confirmed that VBP1 significantly accelerated tumor proliferation both in vitro and in vivo. VBP1 is identified as a pivotal gene within the hypoxia-related prognostic signature, and it significantly promotes tumor proliferation in ESCC.

BACKGROUND:Bladder cancer (BLCA) is one of the most diagnosed cancers in humans worldwide. Recently, immunotherapy has become a main treatment option for BC. However, most BLCA patients do not respond to immune checkpoint inhibitors or relapse after immunotherapy. Therefore, it is very important to identify novel biomarkers for the prediction of immunotherapy response in B patients.METHODS:Pancancer single-cell RNA sequencing (scRNA-seq) data were used to identify the clusters of CD4+ T cells in the tumour microenvironment (TME). The clinical significance of key CD4+ T-cell clusters was evaluated based on the survival data of two independent immunotherapy bladder cancer (BLCA) cohorts. We also investigated the function of key clusters of CD4+ T cell in the TME of BC cells in vitro.RESULTS:This study identified two novel exhausted CD4+ T-cell subpopulations with the expression of PD1hi CD200hi or PD1hi CD200low in BC patients. Moreover, BLCA patients with a high level of PD1hi CD200hi CD4+ exhausted T cell showed immunotherapy resistance. Cell function analysis demonstrated that PD1hi CD200hi CD4+ exhausted T cell can promote epithelial-mesenchymal transition (EMT) and angiogenesis in BLCA cells. In addition, PD1hi CD200hi CD4+ exhausted T cells were shown to communicate with malignant BLCA cells through the GAS6-AXL axis. Finally, we also found that GAS6 expression is upregulated in B cells by METTL3-mediated m6A modification.CONCLUSIONS:PD1hi CD200hi CD4+ exhausted T cell may serve as a novel biomarker for poor prognosis and immunotherapy resistance in B. Targeted inhibitors of PD1hi CD200hi CD4+ exhausted T cells may help improve the efficacy of immunotherapy.

Purpose: Current evidence suggests that phosphoserine aminotransferase 1 (PSAT1) is overexpressed in various tumors. Herein, we investigate the significance of PSAT1 in non-small cell lung cancer (NSCLC) and its correlation with immune infiltration. Methods: The expression profile of PSAT1 in NSCLC patients and related clinical information was obtained from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA-NSCLC) databases. In silico and experimental validation were conducted to assess the role of PSAT1 in NSCLC. Gene set enrichment analysis (GSEA) was performed to investigate the disparities in biological functions between groups with high and low PSAT1 expression. Additionally, the biological characteristics and immune cell infiltration were compared between these two groups. We also assessed whether PSAT1 expression could predict the sensitivity of NSCLC patients to immunotherapy using the immunophenotype score (IPS) and an anti-PD-L1 immunotherapy cohort (IMvig-or210). Furthermore, the difference in drug sensitivity between PSAT1-high and PSAT1-low expression cell lines was investigated. Results: Analysis of transcriptional expression profiles using TCGA data revealed overexpression of PSAT1 in NSCLC tissues correlated with poor overall survival (OS). GSEA results showed enrichment of DNA recombination and repair, nucleotide biosynthesis, and the P53 signaling pathway in the PSAT1-high group. Experimental validation demonstrated that the knockdown of PSAT1 suppressed cell proliferation, migration, and invasion of NSCLC. Immune cell infiltration analysis revealed an immune-activated tumor microenvironment in the PSAT1-low group. It was also observed that PSAT1-low cell lines were more likely to benefit from immunotherapy and several chemotherapy drugs. Conclusions: PSAT1 has enormous potential for applications in the prediction of NSCLC patient outcomes and provides the foothold for more precise individualized treatment of this patient population.

INTRODUCTION:S-ketamine plays an important role in reducing postoperative pain, but its impact on the quality of recovery in breast cancer has not been clarified. We designed this trial to explore the effects of s-ketamine on the quality of postoperative recovery and inflammatory response in modified radical mastectomy. METHODS:A total of 138 patients were randomly assigned to group C (group control), group K1 (group of s-ketamine dose 1) and group K2 (group of s-ketamine dose 2). Groups K1 and K2 were given 0.1 mg/kg, 0.2 mg/kg s-ketamine intravenous (IV) after induction, followed by 0.1 mg/kg/h or 0.2 mg/kg/h continuous intravenous infusion, respectively. Group C received the same volume of saline. A 40-item Quality of Recovery Questionnaire (QoR-40) was used to assess the quality of recovery at 24 h postoperatively. Changes in inflammatory markers, nociceptive thresholds, and the occurrence of adverse events were recorded at 24 h postoperatively. RESULTS:The QoR-40 scores at 24 h postoperatively were higher in group K2 [182.00 (179.00-185.00)] compared to group K1 [174.00 (169.50-180.50)] and group C [169.00 (163.75-174.25)] (group K2 vs. group K1, P < 0.001; group K2 vs. group C, P < 0.001). At 24 h postoperatively, the neutrophil count, NLR (neutrophil-lymphocyte ratio), and CRP (C-creative protein) were all significantly lower in group K2 than group C(P < 0.05), no differences were observed between group K1 and C(P > 0.05), group K1 and K2(P > 0.05), respectively. There was no significant difference in the incidence of adverse effects among the three groups (P > 0.05). CONCLUSIONS:A high dose of s-ketamine improved the quality of recovery at 24 h after surgery, as well as alleviated the inflammatory response without increasing the incidence of adverse effects.

BackgroundIt is now understood that the effectiveness of checkpoint immunotherapy can be impaired by immunosuppressive tumor-associated macrophages (TAMs). Nonetheless, the impact of different TAM subpopulations on the antitumor immune response remains unclear, mainly due to their heterogeneity. Herein, we identified a novel TAM subpopulation in esophageal squamous cell carcinoma (ESCC) that might contribute to poor clinical outcomes and immunotherapy modulation. Methods and resultsWe analyzed two single-cell RNA sequencing (scRNA-seq) datasets (GSE145370 and GSE160269) of esophageal squamous cell carcinoma to identify a novel TREM2-positive TAM subpopulation characterized by upregulation of TREM2, C1QC, C1QB, C1QA, SPP1, and APOE. Quantitative real-time PCR (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA) demonstrated that these genes were significantly overexpressed in ESCC. Multiplex immunofluorescence validated the infiltration of TREM2(+) TAMs in ESCC tissues, which correlated with poorer overall survival (OS). The scRNA-seq analysis in dataset GSE120575 indicated significant enrichment of TREM2(+) TAMs in melanoma patients (n=48) with poor immunotherapy response, which had an identical gene signature with TREM2(+) TAMs from ESCC. Analysis of 29 bulk-RNA melanoma samples from dataset GSE78220 revealed that a gene signature of 40 genes associated with TREM2(+) TAMs was upregulated in the transcriptome of melanomas that did not respond to anti-PD1 therapy. Validation in the TCGA ESCC cohort (n=80) showed that a high enrichment score of the TREM2(+) TAM was associated with poor prognosis. In addition, 10 ESCC patients treated with anti-PD1 therapy suggested that patients who are not sensitive to immunotherapy have higher density of TREM2+TAMs infiltration. ConclusionOverall, TREM2(+) TAM infiltration in ESCC is associated with poor prognosis and may serve as a biomarker for predicting outcomes and immunotherapy modulation in this patient population. modulation; single-cell RNA sequencing

The occurrence and development of esophageal cancer involve multiple genetic abnormalities that contribute to the malignant transformation of esophageal epithelial cells, followed by invasion and metastasis, leading to a poor outcome. Esophageal squamous cell carcinoma (ESCC) is the predominant histological subtype of esophageal malignancy in East Asia, with approximately half of newly diagnosed ESCC cases occurring in China. The TP53 tumor suppressor gene mutation is one of the most common mutations in ESCC. TP53 mutations are observed even in the early phases of esophageal carcinogenesis. Normal functions of the p53 network are lost in cells of ESCC patients who harbor the mutant TP53 gene, inducing tumor development, radiation resistance, chemotherapy resistance, and immune suppression, promoting progression and metastasis, thereby resulting in an overall poor prognosis. Although clinical trials of several pharmacological compounds targeting mutational TP53 have been explored, novel approaches are still urgently required to improve the observed dismal survival. A better understanding of the role of the mutant TP53 gene in human ESCC might lead to the discovery of innovative targeted therapies to treat this malignancy.