Analysis of clinicopathologic and imaging features of dual-phenotype hepatocellular carcinoma.

Dual-phenotype hepatocellular carcinoma (DPHCC) is a new subtype of hepatocellular carcinoma (HCC). This study aimed to investigate the relationship between the computerized tomography scan (CT) imaging and clinicopathologic features of DPHCC. The CT imaging and clinicopathologic data of 97 HCC cases who underwent radical resection were collected retrospectively. The CT imaging feature was evaluated by the ratio of the average CT value of tumor to liver (TLR) in the plain scan, arterial, portal vein and delayed phases. The association between CT imaging and clinicopathologic features was analyzed using the t-test or chi-square test. Univariate and multivariate recurrence-free survival (RFS) analysis and overall survival (OS) were performed. The positive rates of cytokeratin 7 (CK7) and CK19 were 35.1% and 20.6% respectively. The positive rate of CK19 was significantly higher in cases with age < 47 years (P = 0.005), tumor diameter > 4 cm (P = 0.016) or AFP ≥ 400 ng/ml (P = 0.007). The TLR in the portal vein phase was significantly lower in CK19 positive group (P = 0.024). The recurrence risk was significantly higher in cases with CK19 positive (HR: 2.17, 95% CI 1.16 to 4.04, P = 0.013), tumor diameter > 4 cm (HR: 2.05, 95% CI 1.11 to 3.78, P = 0.019), AFP ≥ 400 ng/ml (HR: 2.50, 95% CI 1.37 to 4.54, P = 0.002) or CA199 ≥ 37 U/ml (HR: 2.23, 95% CI 1.12 to 4.42, P = 0.020). However, imaging features, pathological subtype, CK7 or CK19 expression were not significantly related to HCC OS in the univariate and multivariate analysis (all P > 0.05). The expression of CK19 may be associated with the enhancement feature of the portal vein phase CT image, and CK19 positive may suggest a worse RFS.

Sarcosine dehydrogenase as an immune infiltration-associated biomarker for the prognosis of hepatocellular carcinoma.

This study was aimed to investigate the prognostic value and clinical significance of sarcosine dehydrogenase (SARDH) in hepatocellular carcinoma (HCC) and to explore the underlying mechanisms. The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), HPA and CPTAC databases were adopted to analyze the expression of SARDH mRNA and protein between normal liver tissue and HCC, and examine their relationship with clinicopathological features. Kaplan-Meier analysis, Cox regression, as well as nomogram were adopted to explore the prognostic value of SARDH in HCC. Gene Ontology (GO), Kyoto Gene and Genome Encyclopedia (KEGG) together with Gene Set Enrichment Analysis (GSEA) were adopted to analyze the molecular mechanisms and biological functions of SARDH in HCC; while MethSurv, STRING, GeneMANIA, TIMER database data and single-sample gene set enrichment analysis (ssGSEA) algorithm were used for other bioinformatic analysis. Furthermore, immunohistochemistry was used to verify the expression of SARDH. Compared to normal liver tissue, SARDH expression was markedly lower in HCC. A lower SARDH expression was linked with Pathologic T stage (T3&T4), pathologic stage (Stage III&IV), and histologic grade (G3&4), which further indicates worse prognosis. Besides, results of bioinformatic analysis proved that SARDH expression was correlated with immune infiltration. In addition, SARDH hypermethylation was related to a poorer prognosis. SARDH expression was related to several key genes in the Ferroptosis pathway.

Silencing of KIF2C enhances the sensitivity of hepatocellular carcinoma cells to cisplatin through regulating the PI3K/AKT/MAPK signaling pathway.

In the treatment of unresectable advanced hepatocellular carcinoma (HCC), cisplatin is administered transhepatic arterially for local treatment, but the clinical application of cisplatin drugs is frequently hindered by the emergence of drug resistance. Kinesin family member 2C( KIF2C ) has been shown as oncogene in a variety of tumors. Nevertheless, its effect on cisplatin sensitivity has yet to be ascertained. Herein, we aim to investigate the impact of the KIF2C gene on cisplatin sensitivity within HCC and the plausible underlying molecular mechanism. We examined the expression level of the KIF2C gene in HCC cells by real-time quantitative reverse transcription PCR and Western blot analysis, and analyzed bioinformatically by The Gene Expression Omnibus database and The Cancer Genome Atlas database. The KIF2C gene was silenced using the small interfering RNA technology, and its effect on cisplatin drug sensitivity in HCC cells was evaluated by flow cytometry, cell proliferation, cell migration, and invasion assays. Our results indicated that KIF2C was highly expressed in HCC cells. KIF2C silencing inhibits HCC cell proliferation, migration and invasion, promotes apoptosis, and keeps the cell cycle in G2 phase. In addition, KIF2C silencing enhanced the sensitivity of HCC cells to cisplatin. KIF2C silencing down-regulates the expression levels of phosphatidylinositol 3-kinase (PI3K), protein kinase B (AKT) and mitogen-activated protein kinase 3 (MAPK3) proteins. In conclusion, KIF2C silencing amplifies the sensitivity of HCC cells to cisplatin by regulating the PI3K/AKT/MAPK signaling pathway. Consequently, targeting KIF2C shows great application potential as a strategy for enhancing the effectiveness of HCC treatment.

Dual transformation therapy for giant hepatocellular carcinoma: Two case reports and review of literature.

BACKGROUND: In the translational therapy of giant hepatocellular carcinoma (HCC), hepatic arterial infusion chemotherapy (HAIC) combined with anti-PD-1 immunotherapy and tyrosine kinase inhibitors (TKI) after laparoscopic portal vein ligation (PVL) is extremely rare. This is a dual conversion therapy that combines surgery and oncology. Here, we report two cases of successful surgical completion after dual conversion therapy. CASE SUMMARY: We report that a 54-year-old man and a 69-year-old woman were diagnosed with primary HCC combined with hepatitis B cirrhosis (case 2 also combined with fatty liver) on physical examination. Due to the insufficient residual liver volume assessed before surgery, laparoscopic right PVL was performed, followed by HAIC combined with anti-PD-1 immunotherapy and TKI. Finally, surgical resection was successfully completed, and pathology confirmed that the tumor was mostly necrotic (90%) in one case, and no live tumor tissue was found in the other case. CONCLUSION: In the process of surgical transformation, our treatment plan takes into account the control and transformation of oncology at the same time, which is expected to provide more opportunities for radical hepatectomy and improve the prognosis of patients with large liver cancer.

Outer dynein arm docking complex subunit 2 polymorphism rs7893462 modulates hepatocellular carcinoma susceptibility and can serve as an overall survival biomarker for hepatitis B virus-related hepatocellular carcinoma after hepatectomy: a cohort study with a long-term follow-up.

BACKGROUND: Genetic variants of outer dynein arm docking complex subunit 2 (ODAD2) have been reported to be closely associated with primary ciliary dyskinesia and colorectal cancer in previous studies, but the association of genetic variants of ODAD2 with hepatocellular carcinoma (HCC) has not been reported. METHODS: We enrolled 80 healthy subjects and 468 Guangxi hepatitis B virus (HBV)-related HCC patients in this study. A case-control study method was used to explore the association of different ODAD2-rs7893462 genotypes with hepatocarcinogenesis. A comprehensive survival analysis was used to explore the association of rs7893462 with the prognosis of HBV-related HCC in Guangxi. RESULTS: Through a case-control study, we observed that patients carrying the G allele of rs7893462 had a markedly increased susceptibility to hepatocarcinogenesis (odds ratio = 1.712, 95% confidence interval = 1.032-2.839, P = 0.037). We found that there were significant prognosis differences among three different genotypes of rs7893462. Nomogram analysis suggested that the contribution of rs7893462 polymorphisms to the prognosis of HBV-related HCC was second only to the BCLC stage. Stratified survival analysis suggested that the AG genotype of rs7893462 was an independent prognostic risk factor for HBV-related HCC. Joint effect survival analysis also observed that the AG genotype of rs7893462 combined with clinical parameters could significantly identify HBV-related HCC patients with different prognostic outcomes more accurately, and the AG genotype was also observed to be independent of clinical factors in HBV-related HCC survival. CONCLUSION: The ODAD2-rs7893462 polymorphisms can be used as an independent prognostic indicator of HBV-related HCC overall survival and are significantly associated with susceptibility to hepatocarcinogenesis.

Case Report: A case of hepatocellular carcinoma with aberrant right hepatic artery treated with transarterial chemoembolization and infusion chemotherapy separately to bilobar lesion combining with systemic therapies and sequential hepatectomy.

Background: Hepatocellular carcinoma (HCC) with a dismal prognosis is the second most deadly malignancy globally. Surgery is believed to be a curative approach. Nevertheless, there is still a considerable probability of postoperative recurrence. Most patients present in advanced stages with a surgically and oncologically unresectable disease. Systemic medicines are increasingly important to downstage the disease and further improve survival. Case summary: A 67-year-old Chinese man with uncontrolled hepatitis B was discovered to have liver masses with abnormal serum vitamin K absence or antagonist-II (PIVKA-II) level during checkup for upper abdominal discomfort. Abdominal multiphase computerized tomography (CT) and gadoxetate disodium-enhanced magnetic resonance imaging (MRI) showed the bulky bilobar HCCs of Barcelona Clinic Liver Cancer stage B and China Liver Cancer Staging stage IIa. Furthermore, the aberrant right hepatic artery (RHA) originates from the superior mesenteric artery. Due to the location being adjacent to important vasculatures and massive size of the right-sided lesion, curative resection appears to be challenging. To achieve a favorable surgical margin, repeated hepatic arterial infusion chemotherapy (HAIC) was adopted through the variant RHA, while transarterial chemoembolization (TACE) was delivered to the left lobe to arrest tumor growth. Furthermore, sintilimab plus lenvatinib served as the sequential systemic therapy. After 5 months of conversion treatment, the partial response with a decreased serum PIVKA-II level was attained. The R0 hepatectomy was then performed without postoperative complications. The immunohistochemistry and next-generation sequencing results suggested that the two-side HCCs existing tumor heterogeneity were not completely consistent. The patient continues to be without evidence of disease. Conclusion: Our case highlights a favorable outcome in a man with bilobar bulky HCC after undergoing the comprehensive therapeutic schedule that includes personalized intervention and systemic drug therapy. In terms of conversion therapy, our case provides a secure and practical reference for managing unresectable bilobar HCC coexisting with the aberrant hepatic artery.

Correlation between ABO blood group and prognosis of hepatectomy for hepatitis B virus-associated hepatocellular carcinoma.

BACKGROUND: The relationship between ABO blood group and prognosis of patients with hepatocellular carcinoma (HCC) remains unclear. We investigated the relationship between prognosis and ABO blood group in patients with hepatitis B-associated HCC after radical hepatectomy. METHODS: The medical records of 874 patients with hepatitis B-associated HCC who underwent radical liver tumor resection were retrospectively collected. Cox proportional risk models were constructed for analysis, and the patient data were further balanced using propensity score matching (PSM) analysis to assess the impact of ABO blood group on the prognosis of patients with hepatitis B-associated HCC. RESULTS: In univariate Cox regression analysis, the overall survival (OS) of non-A blood type group vs. A blood type group [hazard ratio (HR) (95% confidence interval [CI]) = 1.504 (1.003-2.255), P = 0.048], in multivariate Cox regression analysis the OS of non-A blood type group versus A blood type group [HR (95% CI) = 1.596 (1.054-2.417), P = 0.027]. After PSM, the baseline information was more balanced between the two groups, yielding the same results as above [HR (95% CI) = 1.550 (1.012-2.373), P = 0.044]. CONCLUSION: The difference in OS after radical hepatectomy in patients with hepatitis B-associated HCC was statistically significant in terms of ABO blood group, OS was lower in patients with non-A blood group than in patients with A blood group.

Tumor Targeting with Apatinib-loaded Nanoparticles and Sonodynamic Combined Therapy

INTRODUCTION: This study implies the enhancement of apatinib killing effect in 4T1 tumor cells through constructing drug-loaded nanoparticles apatinib/Ce6@ZIF-8@Membranes (aCZM) to enhance tumor therapeutic targeting and reduce toxic side following sonodynamic therapy (SDT). METHODS: apatinib/Ce6@ZIF-8 (aCZ) were synthesized by in situ encapsulation, and aCZM were constructed by encapsulating the nanoparticles with extracted breast cancer 4T1 cell membranes. aCZM were characterized and tested for the stability by electron microscopy, and the membrane proteins on the nanoparticles' surface were assessed using SDS-PAGE gel electrophoresis. The cell viability of 4T1 cells following treatment with aCZM was tested using cell counting kit-8 (CCK-8). The uptake of nanoparticles was detected by laser confocal microscopy and flow cytometry, and the SDT-mediated production of reactive oxygen species (ROS) was verified by singlet oxygen sensor green (SOSG), electron spin resonance (ESR), and DCFH-DA fluorescent probes. The CCK-8 assay and flow cytometry using Calcein/PI were used to assess the antitumoral effect of aCZM nanoparticles under SDT. The biosafety of aCZM was further verified in vitro and in vivo using the hemolysis assay, routine blood test and H&E staining of vital organs in Balb/c mice. RESULTS: aCZM with an average particle size of about 210.26 nm were successfully synthesized. The results of the SDS-PAGE gel electrophoresis experiment showed that aCZM have a band similar to that of pure cell membrane proteins. The CCK-8 assay demonstrated the absence of effects on cell viability at a low concentration range, and the relative cell survival rate reached more than 95%. Laser confocal microscopy and flow cytometry analysis showed that aCZM treated group has the strongest fluorescence and the highest cellular uptake of nanoparticles. SOSG, ESR, and DCFH-DA fluorescent probes all indicated that the aCZM + SDT treated group has the highest ROS production. The CCK-8 assay also showed that when the ultrasound intensity was fixed at 0.5 W/cm2, the relative cell survival rates in the medium concentration group (10 µg/ml) (5.54 ± 1.26%) and the high concentration group (20 µg/ml) (2.14 ± 1.63%) were significantly lower than those in the low concentration group (5 µg/ml) (53.40 ± 4.25%). Moreover, there was a concentration and intensity dependence associated with the cell-killing effect. The mortality rate of the aCZM in the ultrasound group (44.95±3.03%) was significantly higher than that of the non-ultrasound (17.00±2.26%) group and aCZ + SDT group (24.85 ± 3.08%) (P<0.0001). The live and dead cells' staining (Calcein/PI) also supported this result. Finally, in vitro hemolysis test at 4 and 24 hours showed that the hemolysis rate of the highest concentration group was less than 1%. The blood routine, biochemistry, and H&E staining results of major organs in Balb/c mice undergoing nano-treatments showed no obvious functional abnormalities and tissue damage in 30 days. CONCLUSION: In this study, a multifunctional bionic drug delivery nanoparticles (aCZM) system with good biosafety and compatibility in response to acoustic dynamics was successfully constructed and characterized. This system enhanced apatinib killing effect on tumor cells and reduced toxic side effects under SDT.

PUS1 May Be a Potential Prognostic Biomarker and Therapeutic Target for Hepatocellular Carcinoma.

Objective: The mechanisms of pseudouridine synthase (PUS) are not definite in hepatocellular carcinoma (HCC), the objective of this study is to investigate the effect of PUS genes in HCC. Materials and Methods: Differentially expressed and prognostic gene of PUS enzymes was identified based on The Cancer Genome Atlas (TCGA), International Cancer Genome Consortium (ICGC) and Gene Expression Profiling Interactive Analysis (GEPIA) databases. For the identified gene, pseudouridine synthase 1 (PUS1), was used for further research. The clinicopathological feature of PUS1 was analyzed by Student's t-test. Prognostic significance was explored by Kaplan-Meier (KM) analysis and Cox proportional hazards regression model. Receiver operating characteristic (ROC) curve was applied to appraise diagnostic and prognostic value. The Database for Annotation, Visualization, and Integrated Discovery (DAVID) and Gene Set Enrichment Analysis (GSEA) were implemented to explore mechanism of PUS1. A Guangxi cohort was applied to verify differential expression. In vitro cell experiments were implemented to investigate the influence for proliferation, reactive oxygen species (ROS) level, migration, and invasion of HCC cells after a knockdown of PUS1. Results: PUS1 was significantly overexpressed in HCC tissues, and patients with high PUS1 were related to unpromising clinicopathological features. Survival analysis revealed high PUS1 expression was associated with a poor overall survival (OS) and 1 year-recurrence free survival (RFS), was an independent risk factor. Meanwhile, ROC curve showed that PUS1 had a diagnostic and prognostic significance to HCC. Functional enrichment analysis implied that PUS1 may be involved in metabolic pathways, mitochondrial function, non-alcoholic fatty liver disease (NAFLD), and some important carcinogenic pathways. Cell assays revealed that knockdown of PUS1 significantly constrained the migration, proliferation, invasion and improved the ROS level of HCC cells. Conclusion: PUS1 may be a prognostic biomarker and a underlying treatment target for HCC.

Massive Hepatocellular Carcinoma with Situs Inversus Totalis Achieved a Complete Response Following Camrelizumab Plus Apatinib and Combined with Two-Stage Hepatectomy: A Case Report.

Situs inversus totalis (SIT) is a rare congenital condition in which abdominal and thoracic organs are transposed from normal positions. Two-stage hepatectomy (TSH) combined with translational therapy for hepatocellular carcinoma (HCC) with SIT has been rarely reported. We report a 41-year-old man with giant hepatocellular carcinoma (71 mm × 55 mm × 51 mm) whose future residual liver (FLR) and standard liver volume (SLV) ratio at first diagnosis was 37.4%. Preoperative volume assessment of portal vein ligation (PVL) revealed inadequate hypertrophy of FLR. After a multidisciplinary group discussion (MDT), the patient decided to follow conversion therapy. Three months later, ratio of the FLR/SLV increased from 37.4% to 71% after operation, which met the surgical requirements. Second hepatectomy, right lobectomy was successful. There was no recurrence after six months of follow-up. In our case, conversion therapy appears to be effective in maintaining residual liver hyperplasia, reducing tumor load, and preventing tumor progression in patients with large HCC during TSH.

Comprehensive analysis of LILR family genes expression and tumour-infiltrating immune cells in early-stage pancreatic ductal adenocarcinoma.

Leucocyte immunoglobulin-like receptors (LILRs) are closely related to tumourigenesis, but their clinical value in early-stage pancreatic ductal adenocarcinoma (PDAC) after pancreaticoduodenectomy remains unknown. Kaplan-Meier and Cox proportional hazards regression models is used to investigate the association between LILR expression and prognosis in tumour biopsies and peripheral blood mononuclear cells. Risk score was calculated for each patient based on the prognostic model. DAVID, STRING, GeneMANIA, and GSEA were used to conduct pathway and functional analyses. The CIBERSORT algorithm is used to analyse tumour-infiltrating immune cells. Survival analysis showed that high levels of LILRA4 (p = 0.006) and LILRB4 (p = 0.04) were significantly associated with better overall survival. High levels of LILRA2 (p = 0.008) and LILRB4 (p = 0.038) were significantly associated with better relapse-free survival. JAK-STAT signalling pathway, regulation of T cell activation, regulation of the immune effector process, and tumour necrosis factor superfamily cytokine production were involved in molecular mechanisms that affected poor prognoses in the high-risk group in GSEA. CIBERSORT demonstrated that the high-risk group had significantly higher infiltrating fraction of memory-activated CD4 T cells and activated NK cells and lower fraction of resting dendritic cells and neutrophils. LILRB4 plays crucial roles in affecting the clinical outcomes of early-stage PDAC.

Recurrence of Early Hepatocellular Carcinoma after Surgery May Be Related to Intestinal Oxidative Stress and the Development of a Predictive Model.

Background: Early stage hepatocellular carcinoma (HCC) has a high recurrence rate after surgery and lacks reliable predictive tools. We explored the potential of combining enhanced CT with gut microbiome to develop a predictive model for recurrence after early HCC surgery. Methods: A total of 112 patients with early HCC who underwent hepatectomy from September 2018 to December 2020 were included in this study, and the machine learning method was divided into a training group (N = 71) and a test group (N = 41) with the observed endpoint of recurrence-free survival (RFS). Features were extracted from the arterial and portal phases of enhanced computed tomography (CT) images and gut microbiome, and features with minimum absolute contraction and selection operator regression were created, and the extracted features were scored to create a preoperative prediction model by using the multivariate Cox regression analysis with risk stratification analysis. Results: In the study cohort, the model constructed by combining radiological and gut flora features provided good predictive performance (C index, 0.811 (0.650-0.972)). The combined radiology and gut flora-based model constructed risk strata with high, intermediate, or low risk of recurrence and different characteristics of recurrent tumor imaging and gut flora. Recurrence of early stage hepatocellular carcinoma may be associated with oxidative stress in the intestinal flora. Conclusions: This study successfully constructs a risk model integrating enhanced CT and gut microbiome characteristics that can be used for the risk of postoperative recurrence in patients with early HCC. In addition, intestinal flora associated with HCC recurrence may be involved in oxidative stress.

Biomimetic cytomembrane-coated ZIF-8-loaded DMDD nanoparticle and sonodynamic co-therapy for cancer.

Background: Breast cancer (BC) is the most common type of cancer affecting females. It is also a leading cause of cancer-related death in women worldwide. Methods: Sonodynamic therapy (SDT) is an emerging therapeutic strategy for cancer treatment. SDT ensures non-invasive penetration of deep tumors and results in activation of non-toxic sonosensitizers administered in deep tumor sites to become cytotoxic. It has been reported that 2-dodecyl-6-methoxycyclohexa-2,5-diene-1,4-dione (DMDD) has a significant anti-tumor effect against various cancer types including BC. However, DMDD is hydrophobic. Therefore, a one-step encapsulation method was used in the current study to construct zeolitic imidazole frameworks-8 (ZIF-8) loaded with DMDD and sonosensitizer chlorin e6 (Ce6). ZIF-8 was further modified by coating it with a biomimetic cell membrane to improve targeted delivery. Results: In vitro and in vivo results indicated that the nanomedicines had great biocompatibility properties and targeting ability. The nanocomposite exhibited a higher release rate under an acidic tumor microenvironment. The tumor killing effect of reactive oxygen species (ROS) generated from Ce6 and inhibition of tumor growth was enhanced after ultrasound (US) treatment, which might be caused by the increase in apoptosis rate. Conclusions: These findings show that the combination of nanomedicine and SDT provides a potential therapeutic method for BC.

A novel Peng's test in reducing bile leakage after partial hepatectomy for hepatocellular carcinoma: From an animal study to a clinical cohort Propensity score matching comparative study.

BACKGROUND: Bile leakage (BL) is a common complication of partial hepatectomy for hepatocellular carcinoma (HCC). However, various intraoperative approaches to detect BL have not been widely accepted owing to uncertainty in their treatment effectiveness and complexity of use. MATERIALS AND METHODS: A novel BL-detection approach (Peng's test) was developed in a swine model to determine the pressures generated in the gallbladder and common bile duct (CBD) during the test. A comparative study was then conducted on a prospective cohort of patients using Peng's test versus a retrospective historical cohort patient group using the White Gauze test in partial hepatectomy for HCC. Propensity score matching (PSM) was performed in a 1:1 ratio to balance confounding factors. RESULTS: The maximum pressures with methylene blue injection in the gallbladder and CBD without Pringle's maneuver in the four swines were 103.8 ± 11.8 and 42.3 ± 6.1, respectively. After Pringle's maneuver, 32.0 ± 6.8 mL methylene blue injection led to a maximum pressure in the CBD of 85.3 ± 9.5 cmH2O. The pressures in CBD were 25.8 ± 3.3 and 86.0 ± 9.9 cmH2O when BL appeared at small bile ducts and around the ligation sites, respectively. Of the 206 patients enrolled in the historical control group, 31 (15.0%) developed BL, while of the 54 patients in the study group, only 1 developed grade A BL. The number of BL detected by the routine white gauze test in the control group was significantly lower than that in the study group (Z = -3.002, P = 0.003). After PSM, the incidence of BL in the control group and grade B/C BL was 20.4% and 11.1%, respectively. The corresponding incidences in the study group were 1.9% (χ2 = 7.594, P = 0.006) and 0% (P = 0.027), respectively. The length of hospital stay in the study group was significantly reduced (Z = -6.048, P < 0.001). CONCLUSION: Peng's test for intraoperative BL detection is safe and effective in reducing BL after hepatectomy.

Effects of 2-dodecyl-6-methoxycyclohexa-2,5-diene-1,4-dione on autophagy and the PI3K/AKT/mTOR signaling pathway in human cholangiocarcinoma QBC939 cells.

Background: 2-dodecyl-6-methoxycyclohexa-2,5-diene-1,4-dione (DMDD) has been reported to have good antitumor effects. The aim of this study was to investigate whether DMDD induces apoptosis and autophagy in human cholangiocarcinoma (CCA) QBC939 cells and determine its effect on the PI3K/AKT/mTOR signaling pathway. Methods: QBC939 cells were cultured in vitro and changes in cell viability were detected by the Cell Counting Kit (CCK8) assay after treatment with different concentrations of DMDD for 24, 48, and 72 h. The cells were divided into control and DMDD-treated groups (treated concentrations were 10, 15, and 20 µM/L), and the cell cycle, apoptosis, and autophagic vesicles were assessed. The expression levels of PI3K, AKT, mTOR, microtubule-associated protein 1 light chain 3 beta (LC3-II)/I, Beclin-1, and P62 were detected by Western blot. A xenograft mouse model was constructed to detect the effect of DMDD on CCA. Results: The experimental results showed that DMDD was able to inhibit proliferation, migration, and invasion and induce cell cycle arrest and autophagy of QBC939 cells. In addition, DMDD decreased the protein expression of PI3K, AKT, and mTOR and increased the expression of LC3-II/I, Beclin-1, and P62. In mice, DMDD was able to inhibit the growth of tumors. Conclusions: DMDD inhibits CCA cell viability and induces cell cycle arrest and autophagy by a mechanism that may be related to the downregulation of the PI3K/AKT/mTOR signaling pathway.

Graft versus host disease after liver transplantation following radiotherapy for the treatment of hepatocellular carcinoma: A case report and literature review.

Graft versus host disease after solid organ transplantation is very rare. This article reports a case of graft versus host disease after liver transplantation following targeted therapy and radiotherapy for the treatment of hepatocellular carcinoma. The patient developed a symptomatic skin rash and pancytopenia 13 days after surgery, which was confirmed as graft versus host disease after liver transplantation by histopathology and fluorescence in situ hybridization. Early diagnosis of graft versus host disease after solid organ transplantation is difficult and often delayed due to nonspecific manifestations that overlap with other diseases. Currently, the treatment of graft versus host disease after liver transplantation occurs by either strengthening the immune suppression or weakening the immune suppression; however, there is no unified standard treatment strategy. We found that in addition to age, gender, and human leukocyte antigen type, preoperative radiotherapy is a likely risk factor for graft versus host disease after liver transplantation.

Acyl-CoA Binding Domain Containing 4 Polymorphism rs4986172 and Expression Can Serve as Overall Survival Biomarkers for Hepatitis B Virus-Related Hepatocellular Carcinoma Patients After Hepatectomy.

Background: The aim of our study was to evaluate the potential of expression and single nucleotide polymorphism of Acyl-CoA binding domain containing 4 (ACBD4) gene as prognosis biomarkers in patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) after hepatectomy. Methods: HBV-related HCC patients from the First Affiliated Hospital of Guangxi Medical University and GSE14520 were included in the current study, as well as The Cancer Genome Atlas (TCGA) HCC verification cohort. Prognostic analysis and multiple functional enrichment analysis methods were used to evaluate the prognostic value and potential biological functions of the ACBD4 gene in HBV-related HCC. Results: We found that ACBD4 gene is highly expressed in normal liver tissues and markedly down-regulated in HBV-related HCC tissues. ACBD4 gene was significantly related to overall survival (OS) of HCC in TCGA and GSE14520 cohorts, and patients with low ACBD4 expression were markedly related to poor OS. Rs4986172 was observed as an OS biomarker after hepatectomy in the Guangxi HBV-related HCC cohort. The OS of rs4986172 GG genotype was worse than that of HCC patients with A allele (AA and AG genotypes). Multifunctional enrichment analysis suggested that ACBD4 gene is closely related to the metabolic, peroxisome proliferator-activated receptor and cytochrome P450 pathway. Through connectivity map, we also identified eight compounds that may be used as targeted therapeutic agents for ACBD4 gene in HBV-related HCC; these compounds were scopoletin, alfaxalone, bephenium hydroxynaphthoate, apramycin, 4,5-dianilinophthalimide, DL-thiorphan, aminohippuric acid and quinidine. Immune microenvironment analysis revealed that there were significant differences in immune scores of HBV-related HCC tumor tissues with different ACBD4 expression levels. Conclusion: Our study reveals that ACBD4 expression and rs4986172 can be serve as biomarkers of OS in HBV-related HCC patients after hepatectomy.

Down regulated oncogene KIF2C inhibits growth, invasion, and metastasis of hepatocellular carcinoma through the Ras/MAPK signaling pathway and epithelial-to-mesenchymal transition.

Background: Hepatocellular carcinoma (HCC) is the leading cause of cancer death. Kinesin family member 2C (KIF2C) has been shown as oncogene in a variety of tumors. However, its role in HCC remains unclear. Methods: In this study, the expression level of KIF2C in HCC was detected by immunohistochemical staining and RT-PCR, and verified by Gene Expression Omnibus (GEO), The Cancer Genome Atlas (TCGA) and Oncomine database. A curve was established to evaluate the diagnostic efficiency of KIF2C. The effect of KIF2C on HCC was investigated by flow cytometry, Cell Counting Kit-8, Transwell, and the wound-healing assay. We explored the underlying mechanism through epithelial-to-mesenchymal transition (EMT) and transcriptome sequences analysis. Results: KIF2C was overexpression in HCC tissue and related to neoplasm histologic grade (P<0.001), pathology stage (P=0.001), and a dismal prognosis (overall, recurrence-free, and disease-free survival). The diagnostic efficacy of KIF2C was >90% in diagnosing HCC. The HCC cell function experiments showed that KIF2C promoted HCC cell proliferation, migration, invasion, and an accelerated cell cycle, and inhibited apoptosis. Based on western blot analysis and RT-PCR, we found that KIF2C promoted HCC invasion and metastasis through activation of the EMT. Based on transcriptome sequences, we showed that KIF2C promoted HCC through the Ras/MAPK and PI3K/Akt signaling pathway. Conclusions: KIF2C was found to promote the progression of HCC and is anticipated to serve as a biomarker for HCC diagnosis, prognosis, and targeted therapy.

Biomimetic Metal-Organic Framework Nanoparticles for Synergistic Combining of SDT-Chemotherapy Induce Pyroptosis in Gastric Cancer.

In recent years, sonodynamic therapy (SDT) has been widely developed for cancer research as a promising non-invasive therapeutic strategy. Here, we synthesized zeolitic imidazole frameworks-8 (ZIF-8) and utilized its properties to encapsulate hydrophobic Chlorin e6 (Ce6) and hydrophilic tirapazamine (TPZ) for a synergistic sonodynamic chemotherapy, which was also accompanied by the modification of cytomembrane of gastric cancer (GC) cells. Thus, we enabled the biomimetic property to achieve targeted delivery. Ce6-mediated SDT, in combination with ultrasound irradiation, could target the release of reactive oxygen species (ROS) to aggravate further hypoxia and activate TPZ. Combining these effects could induce the pyroptosis of GC cells and play the anti-tumor function, which could provide a potential therapeutic method for cancer therapy.

Gender disparity in hepatocellular carcinoma recurrence after curative hepatectomy.

INTRODUCTION AND OBJECTIVES: Whether there is gender disparity in the recurrence of hepatocellular carcinoma (HCC) has been not fully addressed. This study aimed to investigate the impact of gender on HCC recurrence following curative hepatectomy. PATIENTS AND METHODS: This retrospective cohort study included 1087 patients with HCC (917 males, 170 females) who underwent curative hepatectomy. Cox regression models were constructed to estimate the hazard ratio (HR) and 95% confidence interval (CI) of the risk parameters associated with HCC recurrence. In the sensitivity analysis, subgroup analysis, and propensity score matching (PSM) analysis were used. Logistic regression models were used to assess the odds ratio (OR) and 95% CI of the risk parameters related to early and late recurrence. RESULTS: Male patients showed significantly higher risk for HCC recurrence than females, in both multivariate Cox regression analysis (HR [95% CI] = 1.480 [1.084-2.020], P = 0.014) and PSM analysis (HR [95% CI] = 1.589 [1.093-2.312], P = 0.015). Higher risk of HCC recurrence was again found in males in the subgroup analysis, but the effect of male versus female gender on HCC recurrence did not depend on any selected subgroups (all P for interaction > 0.05). Gender was an independent risk factor for early recurrence (OR [95% CI] = 1.864 [1.215-2.936], P = 0.006), but not for late recurrence. CONCLUSIONS: There is gender disparity in the recurrence of patients with HCC after curative hepatectomy: males had a higher risk for HCC recurrence than females.