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Abstract Background Owing to the lack of evidence-based medical studies with large sample sizes, the surgical approach for the radical resection of rectal neuroendocrine tumors remains controversial. Methods We retrospectively collected the medical records of patients with rectal neuroendocrine tumors who underwent radical resection at 17 large tertiary care hospitals in China between January 1, 2010, and April 30, 2022. All patients were divided into laparoscopic and open surgery groups. After propensity score matching to reduce confounders, the postoperative and oncologic outcomes were compared between the groups. Results We enrolled 174 patients with rectal neuroendocrine tumors who underwent radical surgery. After random matching, 124 patients were included in the comparison (62, laparoscopic surgery group; 62, open surgery group). The laparoscopic surgery group had fewer complications (14.5% vs. 35.5%, P = 0.007) and superior relapse-free survival (P = 0.048). Subgroup analysis revealed that the laparoscopic surgery group had fewer complications (10.9% vs. 34.7%, P = 0.004), shorter postoperative hospital stays (9.56 ± 5.21 days vs. 12.31 ± 8.61 days, P = 0.049) and superior relapse-free survival (P = 0.025) in the rectal neuroendocrine tumors ≤ 4 cm subgroup. Conclusions Laparoscopic surgery was associated with improved postoperative outcomes and oncologic prognosis for patients with rectal neuroendocrine tumors ≤ 4 cm; it can serve as a safe and feasible option for radical surgery of rectal neuroendocrine tumors.

Abstract Primary gastric adenosquamous carcinoma (PGASC) is a rare type of gastric cancer with limited research and poorly understood clinicopathological features. This study investigated the clinicopathological features and outcomes of PGASC. Patients with PGASC from Union Hospital, Tongji Medical College, Huazhong University of Science and Technology and from the published literature were enrolled in this study. Survival curves were generated using the Kaplan–Meier method, and prognostic factors were identified through Cox proportional hazards regression models. This study identified 76 eligible cases of PGASC, with 45 cases from published literature and 31 from our center. The most prevalent symptoms were abdominal pain and dysphagia, with a median age of 62 years (range: 29–84 years). The primary lesions were predominantly in the proximal stomach, with a median tumor size of 6.5 cm (range: 1.5–16.0 cm). Tumor stages II, III, and IV were detected in 12 (16.7%), 43 (59.7%), and 17 (23.6%) patients, respectively. Most tumors were poorly differentiated in both the squamous cell carcinoma (SCC) component and adenocarcinoma (AC) component. The median survival time was 17 months (range: 2–122 months). The 1, 3, and 5-year overall survival (OS) was 60.7%, 31.1%, and 24.1%, respectively. Multivariate analysis revealed that OS was independently predicted by the proportion of SCC component, differentiation of AC component, and tumor stage. PGASC is a rare disease with a poor prognosis. A high proportion of SCC components, low differentiated AC components, and advanced tumor were associated with worse survival in patients with PGASC. Adjuvant therapy did not improve survival time.

Abstract The role of circDHX8 in the interplay between autophagy and gastric cancer (GC) progression remains unclear. In this study, we investigated the mechanism underlying the role of hsa_circ_003899 (circDHX8) in the malignancy of GC. Differential expression of circRNAs between GC and normal tissues was determined using circle-seq and microarray datasets (GSE83521). These circRNAs were validated using qPCR and Sanger sequencing. The function of circDHX8 was investigated through interference with circDHX8 expression experiments using in vitro and in vivo functional assays. Western blotting, immunofluorescence, and transmission electron microscopy were used to establish whether circDHX8 promoted autophagy in GC cells. To elucidate the mechanism underlying the circDHX8-mediated regulation of autophagy, we performed bioinformatics analysis, RNA pull-down, mass spectrometry (MS), RNA immunoprecipitation (RIP), and other western Blot related experiments. Hsa_circ_0003899 (circDHX8) was identified as upregulated and shown to enhance the malignant progression in GC cells by promoting cellular autophagy. Mechanistically, circDHX8 increased ATG2B protein levels by preventing ubiquitin-mediated degradation, thereby facilitating cell proliferation and invasion in GC. Additionally, circDHX8 directly interacts with the E3 ubiquitin-protein ligase RNF5, inhibiting the RNF5-mediated degradation of ATG2B. Concurrently, ATG2B, an acetylated protein, is subjected to SIRT1-mediated deacetylation, enhancing its binding to RNF5. Consequently, we established a novel mechanism for the role of circDHX8 in the malignant progression of GC.

Background: Although anti-HER2 therapies have been widely used against gastric carcinoma, the prognostic significance of HER2 overexpression remains unclear. Previous studies failed to provide convincible evidence due to inconsistent HER2 evaluation criteria and heterogeneous clinical characteristics. Objectives: To figure out the prognostic significance of HER2 expression in gastric cancer, we rigorously designed and conducted this study. Design: Meta-analysis. Data sources and methods: Record retrieval was performed by searching PubMed, Web of Science, Cochrane Library, Embase, ASCO, and ESMO meeting libraries from inception to November 2022. Cohort studies investigating overall survival comparison between HER2-positive and HER2-negative gastric cancer patients were included. Both resectable and advanced cases were separately collected while HER2 evaluation standards should be consistent across eligible studies. Newcastle–Ottawa Scale was used for quality assessment. Overall survival was the only endpoint and effect size was presented by hazard ratio (HR) with its 95% confidence interval. The pooled calculation was conducted on Review Manager 5.4. Results: Thirty studies were eligible, including 9945 patients. Eligible studies were mostly high quality ( n = 31). Regarding resectable cases ( n = 22), HER2-positive groups had significantly worse prognosis than HER2-negative counterparts (HR 1.56, 95%CI 1.32–1.85, p

Abstract Background To investigate the role of C-reactive protein (CRP), procalcitonin (PCT), and interleukin-6 (IL-6) as early predictors of infectious complications after laparoscopic gastric cancer surgery. Methods Patients who underwent laparoscopic gastric cancer surgery between January 2020 and June 2022 were retrospectively enrolled. IL-6, PCT, and CRP levels were assessed before surgery and on postoperative days (PODs) 3 and 5. Differences in serum IL-6, PCT, and CRP levels between the infected and non-infected groups were compared. The diagnostic accuracy was determined using the area under the receiver operating characteristic curve (AUC). Results A total of 206 patients were enrolled, and 21 patients (10.19%) developed postoperative infections. Serum IL-6, PCT, and CRP levels in the infected group were significantly higher than those in the non-infected group on PODs 3 and 5. IL-6 with an optimal cutoff value of 84.00 pg/mL (AUC 0.84), PCT with an optimal cutoff value of 1.39 ng/mL (AUC 0.80), CRP with an optimal cutoff value of 150.00 mg/L (AUC 0.76) on POD 3 had superior diagnostic accuracy in predicting postoperative infections. Multivariate analysis identified PCT and IL-6 levels on POD 3 as independent risk factors, the AUC of the combination of IL-6 and PCT was 0.89. The Delong test showed no difference between the AUC of IL-6 alone and IL-6 combined with PCT prediction (P = 0.07, Z = 1.81). Conclusions IL-6 level on POD 3 is an excellent predictor of infectious complications following laparoscopic gastric cancer surgery. Patients with IL-6 levels lower than 84.00 pg/mL on POD 3 can ensure safe early discharge with a low probability of infection.

Abstract Gastric cancer (GC) is one of the most common and deadliest cancers worldwide. Lipid homeostasis is essential for tumour development because lipid metabolism is one of the most important metabolic reprogramming pathways within tumours. Elucidating the mechanism of lipid homeostasis in GC might significantly improve treatment strategies and patient prognosis. GSE62254 was applied to construct a lipid homeostasis-related gene signature score (HGSscore) by multiple bioinformatic algorithms including weighted gene coexpression network analysis (WGCNA) and LASSO-Cox regression. A nomogram based on HGSscore and relevant clinical characteristics was constructed to predict the survival of patients with GC. TIMER and xCell were used to evaluate immune and stromal cell infiltration in the tumour microenvironment. Correlations between lipid homeostasis-related genes and chemotherapeutic efficacy were analysed in GSCAlite. RT‒qPCR and cell viability assays were applied to verify the findings in this study. HGSscore was constructed based on eighteen lipid homeostasis-related genes that were selected by WGCNA and LASSO-Cox regression. HGSscore was strongly associated with advanced TNM stage and showed satisfactory value in predicting GC prognosis in three independent cohorts. Furthermore, we found that HGSscore was associated with the tumour mutation burden (TMB) and immune/stromal cell infiltration, which are related to GC prognosis, indicating that lipid homeostasis impacts the formation of the tumour microenvironment (TME). With respect to the GSCAlite platform, PLOD2 and TGFB2 were shown to be positively related to chemotherapeutic resistance, while SLC10A7 was a favourable factor for chemotherapy efficacy. Cell viability assays showed that disrupted lipid homeostasis could attenuate GC cell viability. Moreover, RT‒qPCR revealed that lipid homeostasis could influence expression of specific genes. We identified a lipid homeostasis-related gene signature that correlated with survival, clinical characteristics, the TME, and chemotherapeutic efficacy in GC patients. This research provides a new perspective for improving prognosis and guiding individualized chemotherapy for patients with GC.

Abstract Metabolic states greatly influence functioning and differentiation of immune cells. Regulating the metabolism of immune cells can effectively modulate the host immune response. Itaconate, an intermediate metabolite derived from the tricarboxylic acid (TCA) cycle of immune cells, is produced through the decarboxylation of cis-aconitate by cis-aconitate decarboxylase in the mitochondria. The gene encoding cis-aconitate decarboxylase is known as immune response gene 1 (IRG1). In response to external proinflammatory stimulation, macrophages exhibit high IRG1 expression. IRG1/itaconate inhibits succinate dehydrogenase activity, thus influencing the metabolic status of macrophages. Therefore, itaconate serves as a link between macrophage metabolism, oxidative stress, and immune response, ultimately regulating macrophage function. Studies have demonstrated that itaconate acts on various signaling pathways, including Keap1-nuclear factor E2-related factor 2-ARE pathways, ATF3–IκBζ axis, and the stimulator of interferon genes (STING) pathway to exert antiinflammatory and antioxidant effects. Furthermore, several studies have reported that itaconate affects cancer occurrence and development through diverse signaling pathways. In this paper, we provide a comprehensive review of the role IRG1/itaconate and its derivatives in the regulation of macrophage metabolism and functions. By furthering our understanding of itaconate, we intend to shed light on its potential for treating inflammatory diseases and offer new insights in this field.

Abstract Tumor metastasis severely limits the prognosis of gastric cancer patients. RNA-binding proteins (RBPs) are crucial in tumor metastasis, yet there is limited research into their involvement in gastric cancer. Here, we found that ESRP1, a RBP specific in epithelial cells, is important in regulating the metastasis of gastric cancer cells. ESRP1 is negatively correlated with distant metastasis and lymph node metastasis in gastric cancer patients. And we demonstrated that ESRP1 inhibit migration and invasion of gastric cancer in vitro and in vivo. Mechanistically, ESRP1 promotes exon 11 alternative splicing of CLSTN1 pre-mRNA. The post-splicing short CLSTN1 stabilizes the Ecadherin/β-catenin binding structure, and promotes β-catenin protein ubiquitination and degradation, thereby inhibiting the migration and invasion of gastric cancer cells. Our study highlights the role of ESRP1 in regulating metastasis of gastric cancer and extends its mechanism. These results provide a possibility for ESRP1 and CLSTN1 to become therapeutic targets for metastasis of gastric cancer.

Abstract Background Laparoscopic gastrectomy (LG) is increasingly applied in locally advanced gastric cancer (LAGC) after neoadjuvant chemotherapy (NC). However, there is no study to comprehensively evaluate the clinicopathological, prognostic, and laboratory data such as nutrition, immune, inflammation-associated indexes, and tumor markers between LG and open gastrectomy (OG) for LAGC following NC. Methods The clinicopathological, prognostic, and laboratory data of LAGC patients with clinical stage of cT2-4aN1-3M0 who underwent gastrectomy after NC were retrospectively collected. The effects of LG and OG were compared after propensity score matching (PSM). Results This study enrolled 148 cases, of which 110 cases were included after PSM. The LG group had a shorter length of incision (P

Objectives: Studies on rectal neuroendocrine tumors (R-NETs) that are 1–2 cm in size are limited, and the optimal treatment for these tumors is not well established. Methods: Data from patients with primary localized R-NETs 1–2 cm in size were retrospectively collected from 17 large-scale referral medical centers in China. Long-term prognosis, quality of life (QOL), and fecal incontinence were evaluated, and the effects of local excision (LE) or radical resection (RR) were elucidated using propensity score matching (PSM). Results: A total of 272 patients were included in this study; 233 underwent LE, and the remaining 39 underwent RR. Patients in the LE group showed lower tumor location, fewer postoperative Clavien–Dindo III–V complications, more G1 tumors, and lower tumor stage. There were no significant differences in the relapse-free survival or overall survival (OS) between the LE and RR groups after PSM. Patients in the LE group reported superior physical, role, emotional, social, and cognitive functions, global QOL, and Wexner fecal incontinence scores compared with those in the RR group (all P 1.80 (OR = 4.50, 1.46–15.89, P = 0.012), and T3–T4 (OR = 36.31, 95% CI 7.85–208.62, P 1.8 or T3/T4 tumors, RR should be considered.

Abstract Background The prognostic nutritional index (PNI), alkaline phosphatase (ALP), and lymph node ratio (LNR) are reportedly related to prognosis. The aim of this study was to elucidate the clinical importance of the LNR and hematological parameters in patients with high grade rectal neuroendocrine neoplasms (HG-RNENs) who were undergoing radical resection. Methods We reviewed the medical records of patients with HG-RNENs from 17 large-scale medical centers in China (January 1, 2010–April 30, 2022). A nomogram was constructed by using a proportional hazard model. Bootstrap method was used to draw calibration plots to validate the reproducibility of the model. Concordance index (C-Index), decision curve analysis (DCA), and time-dependent area under the receiver operating characteristic curve (TD-AUC) analysis were used to compare the prognostic predictive power of the new model with American Joint Committee on Cancer (AJCC) TNM staging and European Neuroendocrine Tumor Society (ENETS) TNM staging. Results A total of 85 patients with HG-RNENs were enrolled in this study. In the 45 patients with HG-RNENs who underwent radical resection, PNI ≤ 49.13 (HR: 3.997, 95% CI: 1.379–11.581, P = 0.011), ALP > 100.0 U/L (HR: 3.051, 95% CI: 1.011–9.205, P = 0.048), and LNR > 0.40 (HR: 6.639, 95% CI: 2.224–19.817, P = 0.0007) were independent predictors of relapse-free survival. The calibration plots suggested that the nomogram constructed based on the three aforementioned factors had good reproducibility. The novel nomogram revealed a C-index superior to AJCC TNM staging (0.782 vs 0.712) and ENETS TNM staging (0.782 vs 0.657). Also, the new model performed better compared to AJCC TNM staging and ENETS TNM staging in DCA and TD-AUC analyses. Conclusions LNR, ALP, and PNI were independent prognostic factors in patients with HG-RNENs after radical resection, and the combined indicator had better predictive efficacy compared with AJCC TNM staging and ENETS TNM staging.

Abstract Oxaliplatin is widely used in chemotherapy for colorectal cancer (CRC), but its sensitivity has become a major obstacle to limiting efficacy. Many literatures reported that Nrf2 activation promoted tumor chemoresistance. In this study, we explored the role and mechanism of Nrf2 inhibition in oxaliplatin-based chemosensitivity of CRC. In vitro experiments, we applied 4-octyl itaconate (4-OI) to activate Nrf2, and used lentivirus to knock down Nrf2 in CRC cell lines. By measuring cell viability, colony formation, apoptosis, reactive oxygen species production, and western blot, we found that oxaliplatin and lobaplatin suppressed the growth of HCT-116 and LOVO cells in a dose-dependent manner, and promoted the expression of Nrf2. 4-OI, an Nrf2 activator, reduced the sensibility of CRC cells to oxaliplatin and lobaplatin, while the knockdown of Nrf2 promoted the sensibility of CRC cells to oxaliplatin and lobaplatin. Through the public databases, we found that the expression of GPX4 in normal tissues was lower compared with cancer tissues in CRC, and the high GPX4 expression predicted a poor prognosis. Meanwhile, we found that oxaliplatin reduced the expression of GPX4 in vitro. The knockdown of Nrf2 enhanced the effects of oxaliplatin to reduce the expression of GPX4 and GSH content, and increase the MDA content, which enhanced oxaliplatin-induced ferroptosis. Subsequently, we found that oxaliplatin promoted the expression of GSDME-N, and induced LDH, IL-1β, and TNF-a release, and the knockdown of Nrf2 aggravated the occurrence of GSMDE-mediated pyroptosis. Finally, we found that the knockdown of Nrf2 enhanced the inhibition of oxaliplatin on HCT116 xenograft tumor growth in vivo. Thus, our study showed that Nrf2 inhibition improved sensitivity to oxaliplatin of CRC cells by promoting ferroptosis and pyroptosis, which provided a new target for overcoming chemoresistance in CRC.

Background: The number of lymph nodes examined (LNe) is often insufficient in patients with rectal cancer (RC) treated with neoadjuvant therapy; however, its prognostic value remains controversial. Thus, we retrospectively explored whether LNe had an influence on staging and prognosis and investigated whether there was a cut-off value for better prognosis in patients with RC treated with neoadjuvant therapy. Methods: Data were collected from seven prospective hospital databases in China from July 2002 to May 2018. Binary logistic regression models were used to predict lymph node metastasis. The cut-off value for LNe was determined using X-tile 3.6.1. Survival outcomes and risk factors were analyzed using the log-rank test and Cox regression model. Results: A total of 482 patients were included, of whom 459 had complete overall survival (OS) information. Using the percentile method, the total number of lymph nodes examined (TLNe) was 14–16 (40th–60th percentile), and the proportion of patients with lymph node metastasis reached a maximum of 48.1%. Cox multivariate analysis showed that the odds ratio (OR) remained the highest when TLNe was 14–16 (OR = 3.379, P = 0.003). The 3-year and 5-year OS were 85.4% and 77.8%, respectively. Negative lymph nodes examined (NLNe) of ≤6 was an independent risk factor for 3-year and 5-year OS (3-year OS 71.1% vs. 85.9%, P = 0.004; 5-year OS 66.3% vs. 74.3%, P = 0.035). Subgroup analysis for patients with ypN + showed that higher 3-year and 5-year OS were achieved when the TLNe was >10, 78.8% vs. 54.0% (P = 0.005), and 60.8% vs. 36.0% (P = 0.012), respectively. Patients with ypN0M0 had a higher 5-year OS when the TLNe was >19 (P = 0.055). Conclusion: The TLNe and NLNe influenced the staging accuracy and demonstrated prognostic value in patients with RC treated with neoadjuvant therapy.

Inflammatory bowel disease (IBD) is a chronic relapsing gastrointestinal disorder, while the treatment effect is not satisfactory. Immune responsive gene 1 (IRG1) is a highly expressed gene in macrophage in response to inflammatory response and catalyzes the production of itaconate. Studies have reported that IRG1/itaconate has a significant antioxidant effect. This study aimed to investigate the effect and mechanism of IRG1/itaconate on dextran sulfate sodium (DSS)-induced colitis in vivo and in vitro. In vivo experiments, we found IRG1/itaconate exerted protective effects against acute colitis by increasing mice weight, the length of colon, reducing disease activity index and colonic inflammation. Meanwhile, IRG1 deletion aggravated the macrophages/CD4+/CD8+ T-cell accumulation, and increased the release of interleukin (IL)-1β, tumor necrosis factor-α (TNF-α), IL-6, the activation of nuclear factor-κB (NF-κB)/mitogen-activated protein kinase (MAPK) signaling pathway, and gasdermin D (GSDMD) mediated pyroptosis. Four-octyl itaconate (4-OI), a derivative of itaconate, attenuated these changes, therefore relieved DSS-induced colitis. In vitro experiment, we found 4-OI inhibited the reactive oxygen species production, thereby inhibiting the activation of MAPK/NF-κB signaling pathway in RAW264.7 and murine bone-marrow-derived macrophages. Simultaneously, we found 4-OI inhibited caspase1/GSDMD-mediated pyroptosis to reduce the release of cytokines. Finally, we found anti-TNF-α agent reduced the severity of DSS-induced colitis and inhibited gasdermin E (GSDME)-mediated pyroptosis in vivo. Meanwhile, our study revealed that 4-OI inhibited caspase3/GSDME-mediated pyroptosis induced by TNF-α in vitro. Taken together, IRG1/itaconate exerted a protective role in DSS-induced colitis by inhibiting inflammatory response and GSDMD/GSDME-mediated pyroptosis, which could be a promising candidate for IBD therapy.

Objectivegastrointestinal stromal tumors (GISTs) with KIT exon 11 deletions have more malignant clinical outcomes. A radiomics model was constructed for the preoperative prediction of KIT exon 11 deletion in GISTs.MethodsOverall, 126 patients with GISTs who underwent preoperative enhanced CT were included. GISTs were manually segmented using ITK-SNAP in the arterial phase (AP) and portal venous phase (PVP) images of enhanced CT. Features were extracted using Anaconda (version 4.2.0) with PyRadiomics. Radiomics models were constructed by LASSO. The clinical-radiomics model (combined model) was constructed by combining the clinical model with the best diagnostic effective radiomics model. ROC curves were used to compare the diagnostic effectiveness of radiomics model, clinical model, and combined model. Diagnostic effectiveness among radiomics model, clinical model and combine model were analyzed in external cohort (n=57). Statistics were carried out using R 3.6.1.ResultsThe Radscore showed favorable diagnostic efficacy. Among all radiomics models, the AP-PVP radiomics model exhibited excellent performance in the training cohort, with an AUC of 0.787 (95% CI: 0.687-0.866), which was verified in the test cohort (AUC=0.775, 95% CI: 0.608-0.895). Clinical features were also analyzed. Among the radiomics, clinical and combined models, the combined model showed favorable diagnostic efficacy in the training (AUC=0.863) and test cohorts (AUC=0.851). The combined model yielded the largest AUC of 0.829 (95% CI, 0.621–0.950) for the external validation of the combined model. GIST patients could be divided into high or low risk subgroups of recurrence and mortality by the Radscore.ConclusionThe radiomics models based on enhanced CT for predicting KIT exon 11 deletion mutations have good diagnostic performance.

The cGAS/STING signaling pathway plays a pivotal role in regulating innate immunity. Emerging novel drugs aim to regulate the anti-tumor immune response by activating innate immunity. The anti-diabetic drug metformin has been reported to exhibit anti-cancer effect against various types of cancer. However, the role of metformin in regulating the cGAS/STING signaling pathway in gastric cancer remains unknown. In our study, we first used bioinformatic analysis to detect that metformin is closely related to tumor immunity in multiple tumors. Next, we validated the function of metformin in activating the cGAS/STING signaling pathway in gastric cancer cell lines. In addition, KEGG pathway enrichment analysis showed that metformin is negatively correlated with the PI3K/AKT signaling pathway in gastric cancer. We further verified that metformin activates the cGAS/STING signaling pathway by blocking AKT phosphorylation. Moreover, we found that metformin regulates the AKT signaling pathway by mediating the transcription factor SOX2. Thus, our study indicates that metformin activates the cGAS/STING signaling pathway by suppressing SOX2/AKT and has promising potential in gastric cancer immunotherapy.

Background: The drug selection of radical surgery (RS), with hyperthermic intraperitoneal chemotherapy (HIPEC), in pT4 colorectal cancer (CRC) remains controversial. Methods: Adverse events after HIPEC were estimated by common terminology criteria for adverse events version 5.0. The efficacy was evaluated using overall survival (OS) and recurrence-free rate (RFR). Propensity score matching (PSM) was used to reduce the influence of confounders between Mitomycin and Lobaplatin groups. Results: Of the 146 patients, from April 2020 to March 2021, 47 were managed with mitomycin and 99 with lobaplatin. There was no significant difference in the incidence of all adverse events between the two groups after PSM. OS and RFR were not significantly different between the two groups at 22 months (p = 0.410; p = 0.310). OS and RFR of the two groups also showed no significant difference for patients with T4a or T4b stage, tumor size < or ≥ 5 cm. Among patients with colon cancer, RFR at 22 months of the two groups was significantly different (100.0% vs. 63.2%, p = 0.028). Conclusions: In summary, the safety of mitomycin and lobaplatin for HIPEC was not different. Compared with lobaplatin, mitomycin for HIPEC after RS could benefit patients with colon cancer in RFR.

Abstract Background The accuracy of lymph node ratio (LNR) as a prognostic index remains to be proven for gastric cancer patients after neoadjuvant chemotherapy (NACT). This study sought to investigate the prognostic value of LNR in locally advanced gastric cancer (LAGC) patients after NACT. Methods LAGC patients with clinical TNM stages 2–3, Her2(−), and Eastern Cooperative Oncology Group, scores 0–2 are routinely scheduled with NACT. Patients with LAGC after NACT and surgical operation between January 2012 and October 2020 were retrospectively reviewed. The correlation between LNR and survival was investigated. Results Overall, 148 patients were enrolled: 103 with low-LNR (LNR ≤ 30%) and 45 with high-LNR (LNR > 30%). Approximately, 50.5% and 24.4% patients responded to NACT at the primary site in the low-LNR and high-LNR groups, respectively. The overall survival (OS) and progression-free survival (PFS) of low-LNR group were considerably better than those of high-LNR group (3-year OS: 81.9% vs 18.5%, P < 0.001; 3-year PFS: 72.6% vs 13.5%, P < 0.001). In the low-LNR group, OS and PFS were superior in patients with tumor regression grade (TRG) 0–2 than in those with TRG 3 (3-year OS: 89.2% vs 73.2%, P = 0.086; 3-year PFS: 80.3% vs 66.5%, P = 0.036). In association with OS and PFS, the degree of tumor differentiation, TRG, and LNR were identified as predictive factors, and LNR was identified as the independent prognostic factor in univariate and multivariate analyses, respectively. Conclusions LNR is a prospective index of prognosis in patients with LAGC after NACT.

ObjectivesImmunotherapy plus chemotherapy has recently been applied in the neoadjuvant treatment for locally advanced gastric cancer (LAGC), while its superiority over neoadjuvant chemotherapy (NACT) alone remains to be explored. This study explored the safety and efficacy of NACT plus tislelizumab in patients with LAGC.MethodsThe data on patients with LAGC who received NACT combined with radical gastrectomy and NACT plus tislelizumab followed by radical gastrectomy was retrospectively collected. Clinicopathological characteristics of the two groups were compared.ResultsA total of 119 and 50 patients with gastric cancer treated with NACT and NACT plus tislelizumab, respectively, were enrolled. No significant difference was found between the baseline data of the two groups. The operative time (210.5 ± 70.4 min vs. 237.6 ± 68.4 min, P=0.732), intraoperative blood loss (157.8 ± 75.9 ml vs. 149.1 ± 92.5 ml, P=0.609), and number of dissected lymph nodes (24.7 ± 9.3 vs. 28.1 ± 10.3, P=0.195) was not statistically different between the two groups. In comparison to the NACT plus tislelizumab group, the R0 resection rate (100% vs. 89.9%, P=0.019) and pathologic complete response rate (26.0% vs. 3.4%, P

Cuproptosis, a novel copper-induced cell death pathway, is linked to mitochondrial respiration and mediated by protein lipoylation. The discovery of cuproptosis unfolds new areas of investigation, particularly in cancers. The present study aimed to explore the role of cuproptosis in colorectal cancer progression. The genetic alterations of cuproptosis in colon cancer were evaluated using a database. MTT assays, colony formation, and flow cytometry were used to examine the effect of elesclomol-Cu and 4-Octyl itaconate (4-OI) on colorectal cancer cell and oxaliplatin-resistant cell viability. The anti-tumor effect of elesclomol with 4-OI was verified in vivo assay. The results showed that FDX1, SDHB, DLAT, and DLST genes were more highly expressed in normal tissues than those in primary tumor tissues. Patients with high expressions of these genes in tumor tissues had a better prognosis. Using MTT assay and colony formation analysis, elesclomol-Cu pulse treatment showed significant inhibition of cell viability in HCT116, LoVo, and HCT116-R cells. In addition, flow cytometry revealed elesclomol-Cu significantly promoted apoptosis. Tetrathiomolybdate, a copper chelator, markedly inhibited cuproptosis. Subsequently, we found 2-deoxy-D-glucose, a glucose metabolism inhibitor, sensitized cuproptosis. Furthermore, galactose further promoted cuproptosis. Interestingly, 4-OI significantly enhanced cuproptosis which was irrelevant to ROS production, apoptosis, necroptosis, or pyroptosis pathways. Aerobic glycolysis was inhibited by 4-OI through GAPDH, one of the key enzymes of glycolysis, sensitizing cuproptosis. Meanwhile, FDX1 knockdown weakened the ability of 4-OI to promote cuproptosis. In vivo experiments, 4-OI with elesclomol-Cu showed better anti-tumor effects. These results indicated that elesclomol-Cu rapidly halted cell growth in colorectal cancer cells and oxaliplatin-resistant cell line. Importantly, we revealed that 4-OI inhibited aerobic glycolysis by targeting GAPDH to promote cuproptosis.

BackgroundColorectal cancer (CRC) is the second most common cause of cancer-related deaths worldwide. Tumor metastasis and CD8+ T cell infiltration play a crucial role in CRC patient survival. It is important to determine the etiology and mechanism of the malignant progression of CRC to develop more effective treatment strategies.MethodsWe conducted weighted gene co‐expression network analysis (WGCNA) to explore vital modules of tumor metastasis and CD8+ T cell infiltration, then with hub gene selection and survival analysis. Multi-omics analysis is used to explore the expression pattern, immunity, and prognostic effect of MXRA8. The molecular and immune characteristics of MXRA8 are analyzed in independent cohorts, clinical specimens, and in vitro.ResultsMXRA8 expression was strongly correlated with tumor malignancy, metastasis, recurrence, and immunosuppressive microenvironment. Furthermore, MXRA8 expression predicts poor prognosis and is an independent prognostic factor for OS in CRC.ConclusionMXRA8 may be a potential immunotherapeutic and prognostic biomarker for CRC.

BackgroundOpen hemorrhoidectomy is one of the standard procedures for grade IV hemorrhoids. Postsurgical pain is a common problem for patients. We aim to prospectively evaluate potential factors affecting postoperative pain among hemorrhoidectomy patients.MethodsAn observational study was conducted on 360 patients who had undergone Milligan-Morgan open hemorrhoidectomy. Details of the surgery and baseline information were recorded. Preoperative anxiety and depression were analyzed via the self-rating anxiety scale 20 (SAS-20) and self-rating depression scales 20 (SDS-20), respectively. Postoperative pain score was performed daily after surgery until the patient was discharged. The numerical pain score was evaluated by the visual analogue scale (VAS). The association between preoperative psychological states (anxiety or depression) and postoperative pain was analyzed using a generalized additive mixed model.ResultsA total of 340 patients eventually provided complete data and were included in our study. The average age was 43.3 ± 14.4 years, and 62.1% of patients were women. In total, 14.9% of patients had presurgical anxiety and 47.1% had presurgical depression. Postsurgical pain reached a peak point 1–2 days after surgery and went down to a very low level around 4–5 days after surgery. More excision of hemorrhoids could lead to more pain experience after surgery. Presurgical depression was associated with postsurgical pain. Patients who had presurgical depression had higher pain scores after surgery (2.3 ± 1.9 vs. 3.3 ± 1.9, p = 0.025).ConclusionPreoperative depression and the amount of excisional hemorrhoids are positively related to postsurgical pain.

BackgroundBariatric surgery is associated with a positive effect on the progress of non-alcoholic associated fatty liver disease (NAFLD). Although weight loss is the obvious mechanism, there are also weight-independent mechanisms.MethodsWe collected blood samples from 5 patients with obesity before and 3 months after surgery and performed an LC-MS-based untargeted metabolomics test to detect potential systemic changes. We also constructed sleeve gastrectomy (SG) mice models. The plasma, liver and intestine samples were collected and analyzed by qPCR, ELISA and HPLC. Cohousing experiments and feces transplantation experiments were performed on mice to study the effect of gut microbiota. Genistein administration experiments were used to study the in vivo function of the metabolites.ResultsPlasma genistein (GE) was identified to be elevated after surgery. Both clinical data and rodent models suggested that plasma GE is negatively related to the degree of NAFLD. We fed diet-induced obese (DIO) mice with GE, and we found that there was significant remission of NAFLD. Both in vivo and in vitro experiments showed that GE could restrict the inflammation state in the liver and thus relieve NAFLD. Finally, we used co-housing experiments to alter the gut microbiota in mice, and it was identified that sleeve gastrectomy (SG) mice had a special gut microbiota phenotype, which could result in higher plasma GE levels. By feces transplantation experiment (FMT), we found that only feces from the SG mice (and not from other lean mice) could induce higher plasma GE levels.ConclusionOur studies showed that SG but not calorie restriction could induce higher plasma GE levels by altering the gut microbiota. This change could promote NAFLD remission. Our study provides new insights into the systemic effects of bariatric surgery. Bariatric surgery could affect remote organs via altered metabolites from the gut microbiota. Our study also identified that additional supplement of GE after surgery could be a therapy for NAFLD.

Summary: Centrosomal protein 120 (CEP120) is a 120 kDa centrosome protein that plays an important role in centrosome replication. Overexpression of CEP120 can lead to centrosome duplicate abnormality, which is closely associated with tumorigenesis and development. However, there are no reports on the relationship between CEP120 and tumors. In our study, overexpression of CEP120 promoted centrosome amplification in gastric cancer (GC), and the role of CEP120 in promoting GC progression was demonstrated in vitro and in vivo. We demonstrated that CEP120 promotes centrosome amplification and GC progression by promoting the expression and centrosome aggregation of the deubiquitinating enzyme USP54, maintaining the stability of PLK4 and reducing its ubiquitination degradation. In conclusion, the CEP120-USP54-PLK4 axis may play an important role in promoting centrosome amplification and GC progression, thus providing a potential therapeutic target for GC.

Abstract Background Identification of genomic biomarkers to predict the anticancer effects of indicated drugs is considered a promising strategy for the development of precision medicine. DNA endonuclease MUS81 plays a pivotal role in various biological processes during malignant diseases, mainly in DNA damage repair and replication fork stability. Our previous study reported that MUS81 was highly expressed and linked to tumor metastasis in gastric cancer; however, its therapeutic value has not been fully elucidated. Methods Bioinformatics analysis was used to define MUS81-related differential genes, which were further validated in clinical tissue samples. Gain or loss of function MUS81 cell models were constructed to elucidate the effect and mechanism of MUS81 on WEE1 expression. Moreover, the antitumor effect of targeting MUS81 combined with WEE1 inhibitors was verified using in vivo and in vitro assays. Thereafter, the cGAS/STING pathway was evaluated, and the therapeutic value of MUS81 for immunotherapy of gastric cancer was determined. Results In this study, MUS81 negatively correlated with the expression of cell cycle checkpoint kinase WEE1. Furthermore, we identified that MUS81 regulated the ubiquitination of WEE1 via E-3 ligase β-TRCP in an enzymatic manner. In addition, MUS81 inhibition could sensitize the anticancer effect of the WEE1 inhibitor MK1775 in gastric cancer in vitro and in vivo. Interestingly, when MUS81 was targeted, it increased the accumulation of cytosolic DNA induced by MK1775 treatment and activated the DNA sensor STING-mediated innate immunity in the gastric cancer cells. Thus, the WEE1 inhibitor MK1775 specifically enhanced the anticancer effect of immune checkpoint blockade therapy in MUS81 deficient gastric cancer cells. Conclusions Our data provide rational evidence that targeting MUS81 could elevate the expression of WEE1 by regulating its ubiquitination and could activate the innate immune response, thereby enhancing the anticancer efficacy of WEE1 inhibitor and immune checkpoint blockade combination therapy in gastric cancer cells.

Abstract Background Circular RNAs (circRNAs) are a class of non-coding RNA that play critical roles in the development and pathogenesis of various cancers. The circRNA circGSK3B (hsa_circ_0003763) has been shown to enhance cell proliferation, migration, and invasion in hepatocellular carcinoma. However, the specific functions and underlying mechanistic involvement of circGSK3B in gastric cancer (GC) have not yet been explored. Our study aimed to investigate the effect of circGSK3B on the progression of GC and to identify any potential mechanisms underlying this process. Methods CircRNA datasets associated with GC were obtained from the PubMed, GEO, and ArrayExpress databases, and circRNAs were validated via RT-qPCR and Sanger sequencing. Biotin-labeled RNA pull-down, mass spectrometry, RNA immunoprecipitation, and in vitro binding assays were employed to determine proteins demonstrating interactions with circGSK3B. Gene expression regulation was assessed through RT-qPCR, chromatin immunoprecipitation, and western blot assays. Gain- and loss-of-function assays were used to analyze any effects of circGSK3B and its partner regulatory molecule (EZH2) on the proliferation, invasion, and migration abilities of GC cells both in vitro and in vivo. Results CircGSK3B was mainly identified in the nucleus. This circRNA was present at a reduced concentration in GC tissues and cell lines. Overexpression of circGSK3B was shown to inhibit the growth, invasion, and metastasis of GC cells both in vitro and in vivo. Mechanistically, circGSK3B directly interacted with EZH2, acting to suppress the binding of EZH2 and H3K27me3 to the RORA promoter, and leading to an elevation in RORA expression and ultimately the suppression of GC progression. Conclusions CircGSK3B acts as a tumor suppressor, reducing EZH2 trans-inhibition and GC progression. This demonstrates the potential use of this RNA as a therapeutic target for GC.

BackgroundRecently, the combination of immunotherapy with chemotherapy has been recommended as first-line treatment of metastatic gastric/gastroesophageal junction (G/GEJ) in the clinical guidelines of many countries; the therapeutic potential of this application needs to be further investigated for neoadjuvant therapy of advanced G/GEJ cancer patients.MethodsWe performed a prospective, single-arm, open-label, phase 2 trial of the PD-1 inhibitor tislelizumab combined with S-1 plus oxaliplatin (SOX) in patients with advanced LAG/GEJ cancer. All patients underwent the three-cycle (21 days/cycle) treatment except for one patient who underwent two cycles. The primary endpoints were tumor major pathology response (MPR) and other events of tumor response assessed by the RECIST 1.1 and Becker criteria. Moreover, we constructed a few-shot learning model to predict the probability of MPR, which could screen those patients who might benefit from the neoadjuvant immunotherapy–chemotherapy scheme. This study was registered at https://clinicaltrials.gov/ct2/show/NCT0-4890392.ResultsThirty-two patients were enrolled; 17 patients (53.1%) achieved MPR (≤10% viable tumor cells) after treatment, and among them, 8 (25.0%) had a pathological complete response (pCR). The 1-year overall survival (OS) rate was 91.4% and the 1-year recurrence-free survival (RFS) rate was 90.0%. Adverse events occurred in 24 patients (65.6%) and grade III–IV adverse events were observed in 4 patients (12.5%) during the neoadjuvant period. Furthermore, we found commonly used preoperative assessment tools such as CT and EUS, which presented limited accuracy of tumor therapeutic response in this study; thus, we developed a therapeutic response predictive model that consisted of TNFα, IFNγ, IL-10, CD4, and age of patient, and the AUC of this FSL model was 0.856 (95% CI: 0.823–0.884).DiscussionOur study showed that the neoadjuvant PD-1 inhibitor tislelizumab combined with SOX had promising application potential and presented no increasing treatment-related adverse events in patients with advanced G/GEJ cancer. Moreover, the predictive model could help therapists to evaluate the therapeutic response of this scheme accurately.Clinical Trial Registrationhttps://clinicaltrials.gov/ct2/show/NCT0-4890392, identifier [NCT04890392].

MUS81 is a critical endonuclease involved in heterodimer formation with Eme1/Mms4 and an important DNA damage repair regulatory molecule. Our previous study suggested that MUS81 was overexpressed and its high expression was positively correlated with gastric cancer metastasis. However, the therapeutic potential of targeting MUS81 in gastric cancer requires further exploration. Therefore, in this study, the Cancer Genome Atlas (TCGA) data were analyzed and showed that MUS81 is a key regulator of cell cycle distribution and DNA damage repair in gastric cancer. In vitro and in vivo, MUS81 knockdown significantly enhanced the anticancer effect of the PARP inhibitor talazoparib. Mechanistically, MUS81 inhibition impaired the activation of the ATR/CHK1 cell cycle signaling pathway and promoted gastric cancer cells with talazoparib-induced DNA damage to continue mitosis. Moreover, addition of the bromodomain-containing protein 4 inhibitor AZD5153 increased the anticancer effect of talazoparib via MUS81 inhibition in gastric cancer cells, and this combination effect was largely impaired when MUS81 was knocked down. In conclusion, these data suggested that MUS81 regulated ATR/CHK1 activation, a key signaling pathway in the G2M checkpoint, and targeting MUS81 enhanced the antitumor efficacy of talazoparib. Therefore, AZD5153 combined with talazoparib may represent a promising therapeutic strategy for patients with MUS81 proficient gastric cancer.

Drugs, viruses, and chemical poisons stimulating live in a short period of time can cause acute liver injury (ALI). ALI can further develop into serious liver diseases such as cirrhosis and liver cancer. Therefore, how to effectively prevent and treat ALI has become the focus of research. Numerous studies have reported Maresin1 (MaR1) has anti-inflammatory effect and protective functions on organs. In the present study, we used d-galactosamine/lipopolysaccharide (D-GalN/LPS) to establish an ALI model, explored the mechanism of liver cells death caused by D-GalN/LPS, and determined the effect of MaR1 on D-GalN/LPS-induced ALI. In vivo experiments, we found that MaR1 and ferrostatin-1 significantly alleviated D-GalN/LPS-induced ALI, reduced serum alanine transaminase and aspartate transaminase levels, and improved the survival rate of mice. Meanwhile, MaR1 inhibited hepatocyte death, inhibited tissue reactive oxygen species (ROS) expression, reduced malondialdehyde (MDA), reduced glutathione (GSH), GSH/oxidized glutathione (GSSG), and iron content induced by D-GalN/LPS in mice. In addition, MaR1 inhibited ferroptosis-induced liver injury through inhibiting the release of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and IL-6. Subsequently, western blot showed that MaR1 improved the expression of nuclear factor E2-related factor 2(Nrf2)/heme oxygenase-1 (HO-1)/glutathione peroxidase 4 (GPX4). In vitro experiments, we found that MaR1 inhibited LPS-induced and erastin-induced cell viability reduction. Meanwhile, we found that MaR1 increased the MDA and GSH levels in cells. Western blot showed that MaR1 increased the expression level of Nrf2/HO-1/GPX4. Next, the Nrf2 was knocked down in HepG2 cells, and the results showed that the protective effect of MaR1 significantly decreased. Finally, flow cytometry revealed that MaR1 inhibited ROS production and apoptosis. Overall, our study showed MaR1 inhibited ferroptosis-induced liver injury by inhibiting ROS production and Nrf2/HO-1/GPX4 activation.

RimK-like family member B (RIMKLB) is an enzyme that post-translationally modulates ribosomal protein S6, which can affect the development of immune cells. Some studies have suggested its role in tumor progression. However, the relationships among RIMKLB expression, survival outcomes, and tumor-infiltrating immune cells (TIICs) in colorectal cancer (CRC) are still unknown. Therefore, we analyzed RIMKLB expression levels in CRC and normal tissues and investigated the correlations between RIMKLB and TIICs as well as the impact of RIMKLB expression on clinical prognosis in CRC using multiple databases, including the Tumor Immune Estimation Resource (TIMER), Gene Expression Profiling Interactive Analysis (GEPIA), PrognoScan, and UALCAN databases. Enrichment analysis was conducted with the cluster Profiler package in R software to explore the RIMKLB-related biological processes involved in CRC. The RIMKLB expression was significantly decreased in CRC compared to normal tissues, and correlated with histology, stage, lymphatic metastasis, and tumor status (p < 0.05). Patients with CRC with high expression of RIMKLB showed poorer overall survival (OS) (HR = 2.5,p = 0.00,042), and inferior disease-free survival (DFS) (HR = 1.9,p = 0.19) than those with low expression of RIMKLB. TIMER analysis indicated that RIMKLB transcription was closely related with several TIICs, including CD4+ and CD8+ T cells, B cells, tumor-associated macrophages (TAMs), monocytes, neutrophils, natural killer cells, dendritic cells, and subsets of T cells. Moreover, the expression of RIMKLB showed significant positive correlations with infiltrating levels of PD1 (r = 0.223, p = 1.31e-06; r = 0.249, p = 1.25e-03), PDL1 (r = 0.223, p = 6.03e-07; r = 0.41, p = 5.45e-08), and CTLA4 (r = 0.325, p = 9.68e-13; r = 0.41, p = 5.45e-08) in colon and rectum cancer, respectively. Enrichment analysis showed that the RIMKLB expression was positively related to extracellular matrix and immune inflammation-related pathways. In conclusion, RIMKLB expression is associated with survival outcomes and TIICs levels in patients with CRC, and therefore, might be a potential novel prognostic biomarker that reflects the immune infiltration status.

4-Octyl itaconate (OI) is a novel anti-inflammatory metabolite that exerts protective effects in many various disease models. However, its function in autoimmune hepatitis- (AIH-) associated hepatic injury has not been investigated. In this study, we successfully used concanavalin A (Con A) to establish an AIH-associated liver injury model. Furthermore, we investigated the effect of OI in Con A-induced liver injury and found that OI mitigated Con A-induced histopathological damage. OI administration reduced serum levels of alanine transaminase and aspartate transaminase in Con A-treated mice and attenuated the infiltration of macrophages induced by Con A. Moreover, OI effectively inhibited the expression of proinflammatory cytokines including interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ), and IL-1β induced by Con A. Furthermore, OI decreased hepatocyte apoptosis and malondialdehyde levels and increased the reduced glutathione/oxidized glutathione ratio in the Con A-induced liver injury model. In addition, we found that OI inhibited Con A-induced hepatocyte apoptosis in vitro, while Nrf2 deletion eliminated this effect. Furthermore, we administrated the Nrf2 inhibitor ML385 in OI+Con A-treated mice and found that ML385 eliminated the protective effect of OI in vivo. In addition, OI inhibited Con A-induced activation of nuclear factor-kappa B (NF-𝜅B) and the expression of proinflammatory cytokines in macrophages. Therefore, OI protected mice from Con A-induced liver damage and may be associated with Nrf2 activation and NF-𝜅B inhibition. Finally, our study revealed that OI inhibited TNF-α, or supernatants from Con A-treated RAW264.7 cells induced hepatocyte apoptosis. In conclusion, our study indicated that OI alleviated Con A-induced hepatic damage by reducing inflammatory response, oxidative stress, and apoptosis.

Colorectal cancer (CRC) is critically related to aging and severely threatens human lives. To better explore the effects of aging on CRC progression and therapy outcome, a reliable aging subtypes identification of CRC is urgently desired. Here, 28 aging-related genes associated with the CRC prognosis were selected by univariate Cox analyses. Based on these 28 genes, CRC patients were divided into the aging subtype and young subtype by non-negative matrix factorization clustering. Aging subtype and young subtype of CRC were identified with distinct molecular features and clinical prognosis. The aging subtype was characterized by upregulation of senescence-associated secretory phenotype, higher frequencies of TP53 and immune checkpoint molecules, and high sensitivity to protein kinase and angiogenesis inhibitors. Furthermore, 14 genes were selected by LASSO penalized Cox regression analyses for aging-related risk signature construction. The constructed aging risk signature exhibited good prediction and the nomogram showed robust discrimination power over the traditional CRC staging system. In conclusion, this study successfully established aging subtype and young subtype of CRC, which is helpful to identify patients with aging characteristics to evaluate prognosis and treatment outcomes. Introducing aging-based subtypes into clinical concern and patient prognostication provides new opportunities for personalized CRC treatment.