The ligation between ERMAP, galectin-9 and dectin-2 promotes Kupffer cell phagocytosis and antitumor immunity.

Kupffer cells, the liver tissue resident macrophages, are critical in the detection and clearance of cancer cells. However, the molecular mechanisms underlying their detection and phagocytosis of cancer cells are still unclear. Using in vivo genome-wide CRISPR-Cas9 knockout screening, we found that the cell-surface transmembrane protein ERMAP expressed on various cancer cells signaled to activate phagocytosis in Kupffer cells and to control of liver metastasis. ERMAP interacted with ß-galactoside binding lectin galectin-9 expressed on the surface of Kupffer cells in a manner dependent on glycosylation. Galectin-9 formed a bridging complex with ERMAP and the transmembrane receptor dectin-2, expressed on Kupffer cells, to induce the detection and phagocytosis of cancer cells by Kupffer cells. Patients with low expression of ERMAP on tumors had more liver metastases. Thus, our study identified the ERMAP-galectin-9-dectin-2 axis as an 'eat me' signal for Kupffer cells.

SLC38A4 functions as a tumour suppressor in hepatocellular carcinoma through modulating Wnt/ß-catenin/MYC/HMGCS2 axis.

BACKGROUND: Many molecular alterations are shared by embryonic liver development and hepatocellular carcinoma (HCC). Identifying the common molecular events would provide a novel prognostic biomarker and therapeutic target for HCC. METHODS: Expression levels and clinical relevancies of SLC38A4 and HMGCS2 were investigated by qRT-PCR, western blot, TCGA and GEO datasets. The biological roles of SLC38A4 were investigated by functional assays. The downstream signalling pathway of SLC38A4 was investigated by qRT-PCR, western blot, immunofluorescence, luciferase reporter assay, TCGA and GEO datasets. RESULTS: SLC38A4 silencing was identified as an oncofetal molecular event. DNA hypermethylation contributed to the downregulations of Slc38a4/SLC38A4 in the foetal liver and HCC. Low expression of SLC38A4 was associated with poor prognosis of HCC patients. Functional assays demonstrated that SLC38A4 depletion promoted HCC cellular proliferation, stemness and migration, and inhibited HCC cellular apoptosis in vitro, and further repressed HCC tumorigenesis in vivo. HMGCS2 was identified as a critical downstream target of SLC38A4. SLC38A4 increased HMGCS2 expression via upregulating AXIN1 and repressing Wnt/ß-catenin/MYC axis. Functional rescue assays showed that HMGCS2 overexpression reversed the oncogenic roles of SLC38A4 depletion in HCC. CONCLUSIONS: SLC38A4 downregulation was identified as a novel oncofetal event, and SLC38A4 was identified as a novel tumour suppressor in HCC.

P21-activated kinase 5 plays essential roles in the proliferation and tumorigenicity of human hepatocellular carcinoma.

AIM: To investigate the roles of P21-activated kinase 5 (PAK5) in proliferation and tumorigenicity of human hepatocellular carcinoma (HCC). METHODS: HCC and matched paraneoplastictis tissue samples were obtained from 30 patients. Human HCC cell lines SMMC7721, HepG2, Hep3B, SK-HEP-1, Huh-7, and liver cell line HL-7702 were examined. The expression of PAK5 gene was studied using real-time qPCR and Western blotting. Cell proliferation was quantified with the MTT assay. Cell cycle was analyzed with flow cytometry. The tumorigenicity of Lv-shRNA-transfected HepG2 cells was evaluated in BALB/cA nude mice. RESULTS: The mRNA level of PAK5 was significantly higher in 25 out of 30 HCC samples compared to the matched paraneoplastic tissues. The HCC cell lines showed varying expression of PAK5 protein, and the highest level was found in the HepG2 cells. PAK5 gene silencing in HepG2 cells markedly reduced the cell proliferation and colony formation, and induced cell cycle arrest in the G1 phase. Furthermore, PAK5 gene silencing suppressed the tumor formation in nude mice, and significantly decreased the expression of HCC-related genes Cyclin D1 and beta-catenin. CONCLUSION: PAK5 may play essential roles in the initiation and progression of human HCC. Thus, it may be an effective therapeutic target or perhaps serve as a clinical diagnostic or prognostic marker in human HCC.

Survival benefit of surgical treatment for hepatocellular carcinoma with inferior vena cava/right atrium tumor thrombus: results of a retrospective cohort study.

BACKGROUND: The significance of surgery in the treatment of hepatocellular carcinoma (HCC) extending into the inferior vena cava (IVC)/right atrium (RA) is currently unclear. We sought to clarify whether surgical treatment can improve survival in such patients. METHODS: A retrospective review was undertaken of patients with HCC and IVC/RA tumor thrombus who were potential candidates for surgery but who were finally treated surgically and nonsurgically between September 2000 and October 2010. The patients were subdivided according to therapeutic modalities, and the results for each group were compared. RESULTS: A total of 56 patients were included in this study. They were divided into three groups. Twenty-five patients underwent hepatectomy plus thrombectomy (surgical group), with minor morbidity and no mortality; the patients in this group had 1-, 3-, and 5-year survival rates of 68.0, 22.5, and 13.5%, respectively, with a median survival of 19 months. Twenty patients were treated with transcatheter arterial chemoembolization, with 1- and 3-year survival rates of 15.0 and 5.0%, respectively (median survival 4.5 months). Eleven patients received symptomatic treatment only, and no one in this group survived longer than 1 year (median survival 5 months). The patients in surgical group survived significantly longer than the patients in the other two groups (p < 0.001). CONCLUSIONS: Although technically challenging, surgery for HCC with IVC/RA tumor thrombus can be safely performed and should be considered in patients with resectable primary tumor and sufficient hepatic reservoir because compared with transcatheter arterial chemoembolization or symptomatic treatment, it significantly improved patient survival.

Effects of exercise by type and duration on quality of life in patients with digestive system cancers: A systematic review and network meta-analysis.

BACKGROUND: There is scant evidence regarding the effects of exercise type and duration on quality of life (QoL) in digestive system cancer (DSC) survivors. We aim to investigate the optimal type and duration of exercise to improve QoL for DSC survivors through a systematic review and network meta-analysis. METHODS: A systematic literature search of PubMed, Embase, and Web of Science was performed. Eligibility for study inclusion was limited to studies that were randomized controlled trials involving all kinds of exercise in adult patients with DSCs, and the comparator was in standard care or other types of exercise. The primary outcome was QoL, including general health, physical health, mental health, and role function. Secondary outcomes included cancer-related symptoms such as fatigue, insomnia, depression, anxiety, and duration of hospital stay. The network meta-analyses were performed using a random-effect model. RESULTS: The analysis included 32 eligible articles and a total of 2558 participants. Our primary outcome indicated that short-term aerobic exercise significantly enhanced general health (standardized mean difference (SMD) = 0.66, 95% credible intervals (CrIs): 0.05 to 1.30), and also contributed to a better mental health (SMD = 0.38, 95%CrI: -0.05 to 0.81) and role function (SMD = 0.48, 95%CrI: -0.27 to 1.20). Although without significant changes, short-term resistance exercise tended to increase the physical health of patients with DSCs (SMD = 0.69, 95%CrI: -0.07 to 1.50) and effective in alleviating fatigue (SMD = -0.77, 95%CrI: -1.50 to 0.01). Short-term aerobic exercise was related to a lower score of insomnia (SMD = -1.20, 95%CrI: -2.40 to 0.06), depression (SMD = -0.51, 95%CrI: -1.50 to 0.45), and anxiety (SMD = -0.45, 95%CrI: -1.30 to 0.34). All types of exercise related to a trend of declined hospital stays (-0.87 to -5.00 day). Long-term resistance exercise, however, was negatively associated with general health (SMD = -0.33, 95%CrI: -1.70 to 1.00), physical health (SMD = -0.18, 95%CrI: -1.30 to 0.90), and role function (SMD = -1.20, 95%CrI: -2.50 to 0.11). CONCLUSION: This study suggests that short-term aerobic exercise, with or without resistance exercise programs, enhances QoL (especially for general health) as well as relieves cancer-related symptoms for DSC survivors, while long-term resistance exercise may have negative effects, and thus should be adopted cautiously. These results provide important evidence for the management of DSCs.

Electrospun fibers with blank surface and inner drug gradient for improving sustained release.

New engineering methods and advanced strategies are highly desired for creating novel drug sustained release nanomaterials. In this study, a trilayer concentric spinneret was explored to implement several multifluid electrospinning processes. A trilayer core-shell nanofiber was successfully fabricated, which comprise a drug-free polymeric coating and an inner drug gradient distribution, and then compared with bilayer core-shell and monolithic medicated nanofibers. All the electrospun nanofibers similarly consisted of two components (guest drug acetaminophen and host polymer cellulose acetate) and presented a linear morphology. Due to the secondary interactions within nanofibers, loaded drug with amorphous state was detected, as demonstrated by SEM, DSC, XRD, and FTIR determinations. In vitro and in vivo gavage treatments to rats tests were carried out, the trilayer nanofiber with an elaborate structure design were demonstrated to provide better drug sustained release profile than the bilayer core-shell nanofibers in term of initial burst release, later tail-off release and long sustained release time period. The synergistic mechanism for improving the drug sustained release behaviors is disclosed. By breaking the traditional concepts about the implementation of multifluid electrospinning and the strategy of combining surface properties and inner structural characteristics, the present protocols open a new way for developing material processing methods and generating novel functional nanomaterials.

Development and validation of a nomogram to predict overall survival in patients with incidental gallbladder cancer: A retrospective cohort study.

Objective: The aim of this study was to develop and validate a nomogram to predict the overall survival of incidental gallbladder cancer. Methods: A total of 383 eligible patients with incidental gallbladder cancer diagnosed in Shanghai Eastern Hepatobiliary Surgery Hospital from 2011 to 2021 were retrospectively included. They were randomly divided into a training cohort (70%) and a validation cohort (30%). Univariate and multivariate analyses and the Akaike information criterion were used to identify variables independently associated with overall survival. A Cox proportional hazards model was used to construct the nomogram. The C-index, area under time-dependent receiver operating characteristic curves and calibration curves were used to evaluate the discrimination and calibration of the nomogram. Results: T stage, N metastasis, peritoneal metastasis, reresection and histology were independent prognostic factors for overall survival. Based on these predictors, a nomogram was successfully established. The C-index of the nomogram in the training cohort and validation cohort was 0.76 and 0.814, respectively. The AUCs of the nomogram in the training cohort were 0.8, 0.819 and 0.815 for predicting OS at 1, 3 and 5 years, respectively, while the AUCs of the nomogram in the validation cohort were 0.846, 0.845 and 0.902 for predicting OS at 1, 3 and 5 years, respectively. Compared with the 8th AJCC staging system, the AUCs of the nomogram in the present study showed a better discriminative ability. Calibration curves for the training and validation cohorts showed excellent agreement between the predicted and observed outcomes at 1, 3 and 5 years. Conclusions: The nomogram in this study showed excellent discrimination and calibration in predicting overall survival in patients with incidental gallbladder cancer. It is useful for physicians to obtain accurate long-term survival information and to help them make optimal treatment and follow-up decisions.

Clinical parameters predicting survival duration after hepatectomy for intrahepatic cholangiocarcinoma.

BACKGROUND: Currently, the most effective treatment for intrahepatic cholangiocarcinoma (ICC) is complete hepatic tumour excision. OBJECTIVE: To identify the clinical parameters associated with survival duration for ICC patients following hepatectomy, and to construct a mathematical model for predicting survival duration. METHODS: Demographic data and clinical variables for 102 patients diagnosed with ICC, who underwent exploratory laparotomy at a single centre from July 1998 to December 2000 and were followed for an average of 24 months, were collected in 2011. Patients were randomly assigned into training (n=76) and validation (n=26) groups. Univariate and multivariate analyses were performed to identify factors associated with posthepatectomy survival duration. RESULTS: Univariate analysis revealed that more than three lymph node metastases, a serum carbohydrate antigen 19-9 level greater than 37 U/mL, stage IVa tumours, and intra- or perihepatic metastases were significantly associated with decreased survival duration. Curative resection was significantly associated with increased survival duration. A mathematical model incorporating parameters of age, sex, metastatic lymph node number, curative surgery, carbohydrate antigen 19-9 concentration, alpha-fetoprotein concentration, hepatitis B, TNM stage and tumour differentiation was constructed for predicting survival duration. For a survival duration of less than one year, the model exhibited 93.8% sensitivity, 92.3% total accuracy and a positive predictive value of 93.8%; for a survival duration of one to three years, the corresponding values were 80.0%, 69.2% and 57.1%, respectively. CONCLUSIONS: The mathematical model presented in the current report should prove to be useful in the clinical setting for predicting the extent to which curative resection affects the survival of ICC patients, and for selecting optimal postoperative treatment strategies.

The prognostic value of Niemann-Pick C1-like protein 1 and Niemann-Pick disease type C2 in hepatocellular carcinoma.

Niemann-Pick C1-like 1 (NPC1L1) and Niemann-Pick C2 (NPC2) is a critical mediator of cholesterol absorption. The aim of the present study was to investigate the prognostic value of NPC1L1 and NPC2 in human primary hepatocellular carcinoma (HCC). The expression level of NPC1L1 and NPC2 were evaluated by Immunohistochemistry, Westen blot and Real-time Quantitative PCR. Protein expression level in tissue was represented by integral optic density (IOD). For prognosis analyses, outcome-based cut-point was calculated by X-tile software. Kaplan-Meier analysis, Cox regression analysis were used evaluate prognostic value of NPC1L1 and NPC2 and NPC1L1/NPC2 combination. Both of NPC1L1 and NPC2 were significantly decreased in HCC tissues than peritumoral liver tissues (61 pairs of tissue for Immunohistochemistry and 10 pairs of tissues for Western blot and Real-time Quantitative PCR), respectively. (n=61: p=0.0005 for NPC1L1 and p=0.0001 for NPC2; n=10: p=0.0002 for NPC1L1 and p=0.0489 for NPC2). Kaplan-Meier analyses in 265 HCC cases were showed that the low expression level of NPC1L1 and NPC2 and NPC1L1/NPC2 combination were significantly correlated with poor overall survival (OS) and shorter time to recurrence (TTR). In addition, univariate and multivariate Cox analyses showed that the expression level of NPC1L1/NPC2 combination in HCC was an independent prognostic factor for OS and TTR. Conclusion: NPC1L1 and NPC2 were lowly expressed in HCC compared with peritumoral liver tissues, and low expression of NPC1L1 and NPC2 in HCC tissues may indicate poor outcome of HCC patients after surgery. NPC1L1/NPC2 combination is an independent prognostic factor for OS and TTR in postoperative HCC patients.