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Recently, patients with advanced cancers have been benefited greatly from immune checkpoint blockade immunotherapy. However, immune checkpoint blockade is still suboptimal in HCC treatment and more immune modifications are needed to achieve an efficient therapeutic goal. Here, we investigated the combined administration of a Listeria-based HCC vaccine, Lmdd-MPFG, and the anti-PD-1 immune checkpoint blockade antibody. We found that Lmdd-MPFG promoted the expression of PD-L1 in HCC cells but resensitized the tumor local T cell to respond to the anti-PD-1 immunotherapy. Mechanistically, the Lmdd-MPFG vaccine activates the NF-κB pathway in the tumor-associated macrophages (TAMs) through the TLR2 and MyD88 pathway, and recruits p62 to activate the autophagy pathway. The overall effect is skewing the TAMs from M2-polarized TAMs into the M1-polarized TAMs. Most importantly, it skewed the cytokine profiles into antitumor one in the tumor microenvironment (TME). This change restores the T-cell reactivity to the anti-PD-1 blockade. Our results suggested that Lmdd-MPFG combined with PD-1 blockade exerted synergistic antitumor effects through modifying TAMs in the TME and removing T-cell inhibitory signals, thereby providing a new potential strategy for HCC treatment.

To address the problems of low identification accuracy, poor global search capability, and susceptibility to local optima in permanent magnet synchronous motor (PMSM) parameter identification, this paper proposes a hybrid niching clonal selection black widow optimization (NCS-BWO) algorithm. This algorithm combines the exploitation capability of black widow optimization (BWO) with the exploration capability of the clonal selection algorithm (CSA). First, a niching strategy called nearest-better clustering (NBC) is used to generate sub-populations, incorporating a cluster size optimization mechanism to ensure a balanced population distribution. Subsequently, adaptive Gaussian mutation and elite differential evolution (DE) mutation operators are introduced during the CSA hypermutation stage. Finally, the high-quality population resulting from the niching clonal selection algorithm (NCSA) serves as the initial population for the BWO. The effectiveness of the NCS-BWO algorithm was validated using six benchmark test functions, and its performance was compared with that of six other algorithms. Furthermore, a full-rank discrete model of the PMSM was established, and the NCS-BWO algorithm was applied for parameter identification. Both the simulation and experimental results demonstrate that the proposed NCS-BWO algorithm achieves superior accuracy in PMSM parameter identification.

Molecular variation between geographical populations and subtypes indicate potential genomic heterogeneity and novel genomic features within CCA. Here, we analyze exome-sequencing data of 87 perihilar cholangiocarcinoma (pCCA) and 261 intrahepatic cholangiocarcinoma (iCCA) cases from 3 Asian centers (including 43 pCCAs and 24 iCCAs from our center). iCCA tumours demonstrate a higher tumor mutation burden and copy number alteration burden (CNAB) than pCCA tumours, and high CNAB indicates a poorer pCCA prognosis. We identify 12 significantly mutated genes and 5 focal CNA regions, and demonstrate common mutations in post-transcriptional modification-related potential driver genes METTL14 and RBM10 in pCCA tumours. Finally we demonstrate the tumour-suppressive role of METTL14, a major RNA N6-adenosine methyltransferase (m6A), and illustrate that its loss-of-function mutation R298H may act through m6A modification on potential driver gene MACF1. Our results may be valuable for better understanding of how post-transcriptional modification can affect CCA development, and highlight both similarities and differences between pCCA and iCCA. Cholangiocarcinoma is a heterogenous group of cancers, with large genetic variation seen within subtypes. Here, the authors find 12 significantly mutated genes and 5 focal CNA regions were found in perihilar cholangiocarcinoma, and identified METTL14 to have a potential tumour suppressive role.

Background circular RNAs (circRNAs) have been reported to exert important effects in the progression of numerous cancers. However, the functions of circRNAs in intrahepatic cholangiocarcinoma (ICC) are still unclear. Methods circPCNXL2 (has_circ_0016956) were identified in paired ICC by circRNA microarray. Then, we assessed the biological functions of circPCNXL2 by CCK8, EdU, clone formation, transwell, wound healing assays, and xenograft models. RNA pull-down, mass spectrometry, and RNA immunoprecipitation (RIP) were applied to explore the interaction between cirrcPCNXL2 and serine-threonine kinase receptor-associated protein (STRAP). RNA pull-down, RIP and luciferase reporter assays were used to investigate the sponge functions of circPCNXL2. In the end, we explore the effects of circPCNXL2 and trametinib (a MEK1/2 inhibitor) in vivo. Results circPCNXL2 was upregulated in ICC tissues and cell lines, which promoted the proliferation and metastasis of ICC in vitro and in vivo. In terms of the mechanisms, circPCNXL2 could directly bind to STRAP and induce the interaction between STRAP and MEK1/2, resulting in the tumor promotion in ICC by activation of ERK/MAPK pathways. Besides, circPCNXL2 could regulate the expression of SRSF1 by sponging miR-766-3p and subsequently facilitated the growth of ICC. Finally, circPCNXL2 could partially inhibit the anti-tumor activity of trametinib in vivo. Conclusion circPCNXL2 played a crucial role in the progression of ICC by interacting with STRAP to activate the ERK signaling pathway, as well as by modulating the miR-766-3p/SRSF1 axis. These findings suggest that circPCNXL2 may be a promising biomarker and therapeutic target for ICC.

BackgroundImmune checkpoint inhibitors monotherapy has been studied in patients with advanced biliary tract cancer (BTC). The aim of this study was to assess the efficacy and safety of camrelizumab, plus gemcitabine and oxaliplatin (GEMOX) as first-line treatment in advanced BTC and explored the potential biomarkers associated with response.MethodsIn this single-arm, open-label, phase II study, we enrolled stage IV BTC patients. Participants received camrelizumab (3 mg/kg) plus gemcitabine (800 mg/m2) and oxaliplatin (85 mg/m2). Primary endpoints were 6-month progression-free survival (PFS) rate and safety. Secondary endpoints were objective response rate (ORR), PFS and overall survival (OS). Exploratory endpoints included association between response and tumor mutational burden (TMB), blood TMB, dynamic change of ctDNA and immune microenvironment.Results54 patients with advanced BTC were screened, of whom 38 eligible patients were enrolled. One patient withdrew informed consent before first dose treatment. Median follow-up was 11.8 months. The 6-month PFS rate was 50% (95% CI 33 to 65). Twenty (54%) out of 37 patients had an objective response. The median PFS was 6.1 months and median OS was 11.8 months. The most common treatment-related adverse events (TRAEs) were fatigue (27 (73%)) and fever (27 (73%)). The most frequent grade 3 or worse TRAEs were hypokalemia (7 (19%)) and fatigue (6 (16%)). The ORR was 80% in patients with programmed cell death ligand-1 (PD-L1) tumor proportion score (TPS) ≥1% versus 53.8% in PD-L1 TPS <1%. There was no association between response and TMB, blood TMB, immune proportion score or immune cells (p>0.05), except that PFS was associated with blood TMB. Patients with positive post-treatment ctDNA had shorter PFS (p=0.007; HR, 2.83; 95% CI 1.27 to 6.28).ConclusionCamrelizumab plus GEMOX showed a promising antitumor activity and acceptable safety profile as first-line treatment in advanced BTC patients. Potential biomarkers are needed to identify patients who might respond to camrelizumab plus GEMOX.Trial registration numberNCT03486678.

Background Spindle and kinetochore-associated complex subunit 3 (SKA3) plays an important role in cell proliferation by regulating the separation of chromosomes and their division into daughter cells. Previous studies demonstrated that SKA3 was strongly implicated in tumor development and progression. However, the roles of SKA3 in cholangiocarcinoma (CCA) and the underlying mechanisms remain unclear. Methods Next-generation sequencing (NGS) was performed with paired CCA tissues and normal adjacent tissues (NATs). SKA3 was chose to be the target gene because of its remarkably upregulation and unknown function in cholangiocarcinoma in TCGA datasets, GSE107943 datasets and our sequencing results. RT-PCR and immunohistochemistry staining were used to detect the expression of SKA3 in paired CCA tissues and normal adjacent tissues. The SKA3 knockdown and overexpression cell line were constructed by small interfering RNA and lentivirus vector transfection. The effect of SKA3 on the proliferation of cholangiocarcinoma under hypoxic conditions was detected by experiments in vitro and in vivo. RNA-seq was used to find out the differentially expressed pathways in cholangiocarcinoma proliferation under hypoxia regulated by SKA3. IP/MS analysis and Western blot assays were used to explore the specific mechanism of SKA3 in regulating the expression of HIF-1a under hypoxia. Results SKA3 was up-regulated in NGS, TCGA and GSE107943 databases and was associated with poor prognosis. Functional experiments in vitro and in vivo showed that hypoxia-induced SKA3 promoted cholangiocarcinoma cell proliferation. RNA-sequencing was performed and verified that SKA3 enhanced fatty acid synthesis by up-regulating the expression of key fatty acid synthase, thus promoting cholangiocarcinoma cell proliferation under hypoxic conditions. Further studies indicated that under hypoxic conditions, SKA3 recruited PARP1 to bind to HIF-1a, thus enhancing the poly ADP-ribosylation (PARylation) of HIF-1a. This PARylation enhanced the binding between HIF-1a and USP7, which triggered the deubiquitylation of HIF-1a under hypoxic conditions. Additionally, PARP1 and HIF-1a were upregulated in CCA and promoted CCA cell proliferation. SKA3 promoted CCA cell proliferation and fatty acid synthesis via the PARP1/HIF-1a axis under hypoxic conditions. High SKA3 and HIF-1a expression levels were associated with poor prognosis after surgery. Conclusion Hypoxia-induced SKA3 promoted CCA progression by enhancing fatty acid synthesis via the regulation of PARylation-dependent HIF-1a deubiquitylation. Furthermore, increased SKA3 level enhanced chemotherapy-resistance to gemcitabine-based regimen under hypoxic conditions. SKA3 and HIF-1a could be potential oncogenes and significant biomarkers for the analysis of CCA patient prognosis.

BackgroundThe significance of the relationship between the microbiota and diseases is increasingly being recognized. However, the characterization of tumor microbiome and their precise molecular mechanisms through which microbiota promotes hepatocellular carcinoma (HCC) development are still unclear.MethodsThe intrahepatic microbiota was investigated from tumor, normal adjacent tissues in 46 patients with HCC and normal hepatic tissues in 33 patients with hemangioma by 16S rRNA gene sequencing. Taxonomic composition differences in patients were evaluated using Linear discriminant analysis Effect Size (LefSe) and Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) to predict microbial functional pathways. Associations between the most relevant taxa and clinical characteristics of HCC patients were analyzed by Spearman rank correlations. The effects of microbe on hepatic stellate cells (HSCs) activation and HCC progression were examined.ResultsWe observed intrahepatic microbiota disturbances by reduced microbial diversity in HCC. The tumor microbiota of the HCC patients with cirrhosis showed higher abundance of Stenotrophomonas maltophilia (S. maltophilia). S. maltophilia provoked senescence-associated secretory phenotype (SASP) in HSCs by activating TLR-4-mediated NF-κB signaling pathway, which in turn induced NLRP3 inflammasome complex formation and secreted various inflammatory factors in the liver, thus facilitating HCC progression in mice. Moreover, signs of SASP were also observed in the HSCs in the area of HCC with higher S. maltophilia enrichment arising in patients with cirrhosis.ConclusionsOur analysis of the hepatic microbiota revealed for the first time that patients with HCC exhibited a dysbiotic microbial community with higher S. maltophilia abundance, which induced the expression SASP factors of HSCs and cirrhosis in the liver, concurring in the process of hepatocarcinogenesis.

Background Prehabilitation is a crucial component of tumor rehabilitation that attempts to improve patients’ preoperative health, although its efficacy in treating patients with cancers of the digestive system is still up for debate. Methods The records from PubMed (MEDLINE), Embase, Web of Science, Cochrane Library, EBSCO, Scopus, CNKI and Wan fang database up to November 2024 were systematically searched. The Cochrane Collaboration tool was employed for evaluating the risk of bias in each study, and the PRISMA 2020 checklist provided by the EQUATOR network was utilized. Results Through quality analysis, 20 articles were included, involving 1719 patients. Although its effect on severe complications is still unknown, the prehabilitation significantly decreased overall postoperative complications when compared to standard care, with a risk ratio (RR) of 0.74 (95% CI: 0.65 to 0.84). Despite not shortening the postoperative hospital stay (MD: -0.13, 95% CI: -0.29 to 0.03), prehabilitation demonstrated notable improvements in the 6-minute walk distance (6MWD), with preoperative gains (MD: 25.87, 95% CI: 14.49 to 37.25) and sustained benefits at 4 weeks postoperatively (MD: 22.48, 95% CI: 7.85 to 37.12). However, no significant differences in 6MWD were observed at 6 or 8 weeks postoperatively. The average improvement in 6MWD from baseline to preoperative was 28.99 (95% CI: 10.89 to 47.08, P  = 0.002), and from 4 weeks postoperative to baseline, it was 25.95 (95% CI: 6.84 to 45.07, P  = 0.008), with no significant change at 8 weeks. The acceptance and completion rates of prehabilitation were commendably high at 61% (95% CI: 47–75%) and 90% (95% CI: 87–93%), respectively, alongside a relatively low dropout rate of 10% (95% CI: 7% to13%). Conclusions Prehabilitation reduces postoperative complications and improves short-term physical function in digestive surgery patients, with good patient acceptance; however, the long-term effects are unknown due to a lack of follow-up data. Registration It was registered with the International Prospective Register of Systematic Reviews (PROSPERO) with the identification code CRD42022361100.

Background Cholangiocarcinoma (CHOL) is the second most common primary hepatic malignant tumor, following hepatocellular carcinoma (HCC). CHOL is highly aggressive and heterogeneous resulting in poor prognosis. The diagnosis and prognosis of CHOL has not improved in the past decade. Acyl-CoA synthetase long-chain family member 4 (ACSL4) is reported to be associated with tumors, however, its role in CHOL has not been revealed. This study is mainly for exploring the prognostic values and potential function of ACSL4 in CHOL. Methods We investigated the expression level and prognostic value of ACSL4 in CHOL based on The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets. TIMER2.0, TISIDB and CIBERSORT databases were utilized to assess the associations between ACSL4 and immune infiltration cells in CHOL. Single-cell sequencing data from GSE138709 was analyzed to study the expression of ACSL4 in different types of cells. ACSL4 co-expressed genes were analyzed by Linkedomics. Additionally, Western Blot, qPCR, EdU assay, CCK8 assay, transwell assay and wound healing assay were performed to further confirm the roles of ACSL4 in the pathogenesis of CHOL. Results We found that the level of ACSL4 was higher in CHOL and it was correlated with the diagnosis and prognosis of CHOL patients. Then, we observed that the infiltration level of immune cells was related to the level of ACSL4 in CHOL. Moreover, ACSL4 and its co-expressed genes were mainly enriched in metabolism-related pathway and ACSL4 is also a key pro-ferroptosis gene in CHOL. Finally, knockdown of ACSL4 could reverse the tumor-promoting effect of ACSL4 in CHOL. Conclusions The current findings demonstrated ACSL4 may as a novel biomarker for CHOL patients, which might regulate immune microenvironment and metabolism resulting in poor prognosis.

BackgroundThe impact of tumor size on account of the long-term survival results in gallbladder cancer (GBC) patients has been controversial. It is urgent necessary to identify the optimal cut-off value of tumor size in resected GBC, and we attempted to integrate tumor size with other prognostic factors into a prognostic nomogram to predict the cancer-specific survival (CSS) of GBC patients.Methods1639 patients with resected GBC were extracted from the Surveillance, Epidemiology and End Results (SEER) database. X-tile program was used to identify the optimal cut-off value of tumor size. A nomogram including tumor size was established to predict 1-, 3- and 5-year CSS based on the independent risk factors chosen by univariate and multivariable cox analyses. The precision of the nomogram for predicting survival was validated with Harrell’s concordance index (C-index), calibration curves, and receiver operating characteristic curve (ROC) internally and externally.ResultsPatients with GBC were classified into 1–13 mm, 14–63 mm and 64 mm subgroup based on the optimal cut-off for tumor size in terms of CSS. The nomogram according to the independent factors was well calibrated and displayed better discrimination power than 7th tumor–node–metastasis (TNM) stage systems.ConclusionsThe results demonstrated that increased tumor size is closely associated with the worse CSS. Our novel nomogram, which outperforms the conventional TNM staging system, showed satisfactory accuracy and clinically practicality for predicting the outcome of resected GBC patients.