Computed tomography radiomic features and clinical factors predicting the response to first transarterial chemoembolization in intermediate-stage hepatocellular carcinoma.

BACKGROUND: According to clinical practice guidelines, transarterial chemoembolization (TACE) is the standard treatment modality for patients with intermediate-stage hepatocellular carcinoma (HCC). Early prediction of treatment response can help patients choose a reasonable treatment plan. This study aimed to investigate the value of the radiomic-clinical model in predicting the efficacy of the first TACE treatment for HCC to prolong patient survival. METHODS: A total of 164 patients with HCC who underwent the first TACE from January 2017 to September 2021 were analyzed. The tumor response was assessed by modified response evaluation criteria in solid tumors (mRECIST), and the response of the first TACE to each session and its correlation with overall survival were evaluated. The radiomic signatures associated with the treatment response were identified by the least absolute shrinkage and selection operator (LASSO), and four machine learning models were built with different types of regions of interest (ROIs) (tumor and corresponding tissues) and the model with the best performance was selected. The predictive performance was assessed with receiver operating characteristic (ROC) curves and calibration curves. RESULTS: Of all the models, the random forest (RF) model with peritumor (+10 mm) radiomic signatures had the best performance [area under ROC curve (AUC) = 0.964 in the training cohort, AUC = 0.949 in the validation cohort]. The RF model was used to calculate the radiomic score (Rad-score), and the optimal cutoff value (0.34) was calculated according to the Youden's index. Patients were then divided into a high-risk group (Rad-score > 0.34) and a low-risk group (Rad-score ≤ 0.34), and a nomogram model was successfully established to predict treatment response. The predicted treatment response also allowed for significant discrimination of Kaplan-Meier curves. Multivariate Cox regression identified six independent prognostic factors for overall survival, including male [hazard ratio (HR) = 0.500, 95% confidence interval (CI): 0.260-0.962, P = 0.038], alpha-fetoprotein (HR = 1.003, 95% CI: 1.002-1.004, P < 0.001), alanine aminotransferase (HR = 1.003, 95% CI: 1.001-1.005, P = 0.025), performance status (HR = 2.400, 95% CI: 1.200-4.800, P = 0.013), the number of TACE sessions (HR = 0.870, 95% CI: 0.780-0.970, P = 0.012) and Rad-score (HR = 3.480, 95% CI: 1.416-8.552, P = 0.007). CONCLUSIONS: The radiomic signatures and clinical factors can be well-used to predict the response of HCC patients to the first TACE and may help identify the patients most likely to benefit from TACE.

Comparison of CalliSpheres® microspheres drug-eluting beads and conventional transarterial chemoembolization in hepatocellular carcinoma patients: a randomized controlled trial.

BACKGROUND: This trial aimed to compare the outcomes of drug-eluting beads transarterial chemoembolization (DEB-TACE) with CalliSpheres® microspheres (CSM) and conventional transarterial chemoembolization cTACE in the treatment of patients with unresectable hepatocellular carcinoma (HCC). PATIENTS AND METHODS: A total of 90 patients were divided into DEB-TACE group (n = 45) and cTACE group (n = 45). The treatment response, overall survival (OS), progression-free survival (PFS), and the safety were compared between the two groups. RESULTS: The objective response rate (ORR) in the DEB-TACE group was significantly higher than that in cTACE group at 1, 3, and 6 months of follow-up (P = 0.031, P = 0.003, P = 0.002). The complete response (CR) in DEB-TACE group was significantly higher than that in cTACE group at 3 months (P = 0.036). Survival analysis revealed that, DEB-TACE group had better survival benefits than cTACE group (median OS: 534 days vs. 367 days, P = 0.027; median PFS: 352 days vs. 278 days P = 0.004). The degree of liver function injury was more serious in DEB-TACE group at 1 week, but was similar between the two groups at 1 month. DEB-TACE with CSM caused a high incidence of fever and a severe abdominal pain (P = 0.031, P = 0.037). CONCLUSIONS: DEB-TACE with CSM showed better treatment response and survival benefits than cTACE group. Although a transient more severe liver damage, high incidence of fever and a severe abdominal pain occurred in the DEB-TACE group, it could be resolved through symptomatic treatment.

Construction and validation of a novel prognostic model for thyroid cancer based on N7-methylguanosine modification-related lncRNAs.

BACKGROUND: To construct and verify a novel prognostic model for thyroid cancer (THCA) based on N7-methylguanosine modification-related lncRNAs (m7G-lncRNAs) and their association with immune cell infiltration. METHODS: In this study, we identified m7G-lncRNAs using co-expression analysis and performed differential expression analysis of m7G-lncRNAs between groups. We then constructed a THCA prognostic model, performed survival analysis and risk assessment for the THCA prognostic model, and performed independent prognostic analysis and receiver operating characteristic curve analyses to evaluate and validate the prognostic value of the model. Furthermore, analysis of the regulatory relationship between prognostic differentially expressed m7G-related lncRNAs (PDEm7G-lncRNAs) and mRNAs and correlation analysis of immune cells and risk scores in THCA patients were carried out. RESULTS: We identified 29 N7-methylguanosine modification-related mRNAs and 116 differentially expressed m7G-related lncRNAs, including 87 downregulated and 29 upregulated lncRNAs. Next, we obtained 8 PDEm7G-lncRNAs. A final optimized model was constructed consisting of 5 PDEm7G-lncRNAs (DOCK9-DT, DPP4-DT, TMEM105, SMG7-AS1 and HMGA2-AS1). Six PDEm7G-lncRNAs (DOCK9-DT, DPP4-DT, HMGA2-AS1, LINC01976, MID1IP1-AS1, and SMG7-AS1) had positive regulatory relationships with 10 PDEm7G-mRNAs, while 2 PDEm7G-lncRNAs (LINC02026 and TMEM105) had negative regulatory relationships with 2 PDEm7G-mRNAs. Survival curves and risk assessment predicted the prognostic risk in both groups of patients with THCA. Forest maps and receiver operating characteristic curves were used to evaluate and validate the prognostic value of the model. Finally, we demonstrated a correlation between different immune cells and risk scores. CONCLUSION: Our results will help identify high-risk or low-risk patients with THCA and facilitate early prediction and clinical intervention in patients with high risk and poor prognosis.

[One case of giant liposarcoma of hypopharynx].

The clinical manifestations of this patient with hypopharyngeal liposarcoma are dyspnea, dysphagia and aspiration. Fiberlaryngoscopic examination showed a grayish-yellow mass with a smooth surface and a broad base in the left hypopharynx, piriform fossa, and laryngeal entrance. CT examination revealed a solid mass with clear borders in the hypopharynx and a fibrous septum. Pathology revealed a highly differentiated liposarcoma of the hypopharynx.

EIF3D silencing suppresses renal cell carcinoma tumorigenesis via inducing G2/M arrest through downregulation of Cyclin B1/CDK1 signaling.

There are no effective therapies for advanced renal cell carcinoma (RCC), except for VEGFR inhibitors with only ~50% response rate. To identify novel targets and biomarkers for RCC is of great importance in treating RCC. In this study, we observed that eukaryotic initiation factor 3d (EIF3D) expression was significantly increased in RCC compared with paracarcinoma tissue using immunohistochemistry staining and western blot analysis. Furthermore, bioinformatics meta-analysis using ONCOMINE microarray datasets showed that EIF3D mRNA expressions in CCRCC tissue specimens were significantly higher than that in normal tissue specimens. In addition, RCC tissue microarray demonstrated that elevated EIF3D expression was positively correlated with TNM stage and tumor size. EIF3D silencing in human 786-O and ACHN CCRCC cell lines by RNA interference demonstrated that EIF3D knockdown obviously inhibited cell proliferation and colony formation, caused G2/M arrest through downregulation of Cyclin B1 and Cdk1 and upregulation of p21, and induced apoptosis shown by sub-G1 accumulation and RARP cleavage. Moreover, correlation analysis using ONCOMINE microarray datasets indicated that increased EIF3D mRNA expression was positively correlated to PCNA, Cyclin B1 and CDK1 mRNA expression in RCC. Collectively, these results provide reasonable evidences that EIF3D may function as a potential proto-oncogene that participates in the occurrence and progression of RCC.

Downregulation of B7-H4 in the MHCC97-H hepatocellular carcinoma cell line by arsenic trioxide.

Arsenic trioxide (As2O3; ATO), a compound which is characterized by its ability to function as a potent anticancer agent, has been investigated in a variety of carcinomas. B7­H4, a transmembrane protein, may inhibit the function of the T cell effector, and therefore, may be useful in investigating different types of tumor therapies. However, few studies have been published previously associated with the roles of ATO and B7­H4 in human hepatocellular carcinoma (HCC). The aim of the present study was to investigate the anti­invasive role of ATO in HCC, to determine the effect of ATO treatment on the expression of B7­H4 and to further assess the possible underlying mechanisms. Following treatment of the cells with 2, 4 and 8 µM ATO for 48 h, cell counting kit­8 (CCK­8), Transwell and western blot assays were used to determine the extent of human MHCC97­H HCC cell proliferation, apoptosis, invasion and B7­H4 expression, respectively. The results revealed that 1 µM ATO markedly decreased cellular proliferation, and ATO administered at concentrations of 0.1, 0.2 and 0.5 µM markedly inhibited the migration and invasion of the human MHCC97­H HCC cell line. The expression of B7­H4 in the treatment groups was markedly reduced. Signal transduction mediated via the Janus kinase 2/signal transducers and activators of transcription 3 pathway was inhibited upon treatment with 0.1, 0.2 and 0.5 µM ATO. Additionally, the protein expression levels of matrix metalloproteinase 2 and vascular endothelial growth factor were markedly reduced in HCC cells upon treatment with ATO. In conclusion, ATO may reduce the protein expression levels of B7­H4 in MHCC97­H HCC cells, and further affected HCC tumorigenesis and progression. ATO may be a putative agent for the development of therapeutic strategies against human liver cancer.

Serum miR-335 Level is Associated with the Treatment Response to Trans-Arterial Chemoembolization and Prognosis in Patients with Hepatocellular Carcinoma.

AIM: To identify the role of serum MicroRNA-335 (miR-335) in determining the treatment response to Trans-arterial chemoembolization (TACE) in patients with hepatocellular carcinoma (HCC) and their prognosis after TACE. METHODS: A total of 125 HCC patients were enrolled in this study. All these patients underwent TACE and the treatment response was evaluated. All patients were followed for prognosis analyses. Serum miR-335 levels immediate before and 30 days after TACE were determined. RESULTS: HCC patients had significantly lower miR-335 levels than hepatitis patients and healthy controls. Lower serum miR-335 levels were closely associated with more progressive clinical features, including a higher mean serum AFP level, more vascular invasion, cirrhosis and larger tumor size. Response rates were higher in patients with high miR-335 compared to those with low miR-335 level. Patients with lower serum miR-335 levels had significantly poorer prognosis than patients with higher serum miR-335 levels. CONCLUSION: Our data suggest that serum miR-335 can be used as a molecular marker to predict the treatment response and clinical outcome in HCC patients receiving TACE.

Role of SMC1A overexpression as a predictor of poor prognosis in late stage colorectal cancer.

BACKGROUND: Structural maintenance of chromosomes 1A (SMC1A) is a member of the cohesion family of proteins that plays crucial roles in cell cycle control. Recent studies have concluded that SMC1A is involved in the pathogenesis of cancer. This study aims to evaluate the functional role of SMC1A in colorectal cancer (CRC) both in vitro and in vivo, and the underlying molecular mechanisms. METHODS: We firstly investigated the expression levels of SMC1A in 427 CRC specimens. Antigen expression was determined by immunohistochemical analysis of SMC1A on tissue microarrays. Stable SMC1A knockdown CRC cell lines were employed. The effects of SMC1A depletion on cell growth in vitro were examined by MTT, colony formation and flow cytometry assays. Tumor forming was evaluated by nude mice model in vivo. To detect the activation of intracellular signaling, pathscan intracellular signaling array and western blotting were performed. RESULTS: The expression of SMC1A was much stronger in CRC tumor tissues than in adenomas and normal colorectal tissues. High SMC1A expression, indicated as an independent poor prognostic predictor for patients with stage III and stage IV CRC, was correlated with overall survival (OS) (p = 0.008). Functional analysis indicated that SMC1A knockdown by small interfering RNA (siRNA) mediated the significant inhibition of cell proliferation; induced cell cycle arrest and apoptosis via the suppression of CDK4, PCNA and PARP; and blocked the activation of the Erk1/2 and Akt cascades in CRC cells. In addition, SMC1A depletion significantly decreased the growth of subcutaneously inoculated tumors in nude mice. CONCLUSIONS: These results suggest that SMC1A plays an essential role in the development of CRC and may be a predictive factor in patients with CRC. The inhibition of SMC1A may serve as a promising therapeutic strategy for human CRC.

Seroprevalence of Toxoplasma gondii infection in female sterility patients in China.

Toxoplasmosis is an important parasitic disease worldwide and is related to certain psychiatric disorders and sterility. In the present study, serum samples from 882 female sterility patients and 107 pregnant-puerperant women were assayed for anti- T. gondii IgG antibodies using ELISA. The overall T. gondii seroprevalence was 14.8%. In the female sterility patients, 15.9% (140/882) were seropositive and, in the pregnant-puerperant women, 5.6% (6/107) were positive for anti- T. gondii IgG antibodies. There was a significant difference between the 2 groups ( P < 0.05). The samples were further divided into 5 groups based on age, but no significant difference was found among the 5 groups (P > 0.05). Results of the present study argue for more attention to prevention of T. gondii infection in the female population and, in particular, women of childbearing age.

Arsenic trioxide and promyelocytic leukemia protein-adenovirus synergistically inhibit in vitro and in vivo growth of a hepatoma cell line.

The present study investigated the in vitro and in vivo growth-inhibitory effects of combination therapy with arsenic trioxide (As2O3) and an adenovirus expressing promyelocytic leukemia protein (Ad-PML). Growth of HepG2 cells in culture was not inhibited by As2O3 at concentrations below 5 micromol/L (p > 0.05). However, growth was inhibited by Ad-PML alone and synergistic growth inhibition was observed following combined treatments (p < 0.05). Flow cytometry analyses demonstrated an increase in apoptosis following combined treatment with As2O3 and Ad-PML for 24 h, which was correlated with increased p53 and decreased Bcl-2 expression. To examine treatment effects on in vivo cell growth, control HepG2 cells and cells treated with As2O3, Ad-PML, or both therapies were subcutaneously injected in nude mice. After 6 weeks, tumor volumes were 0.097 +/- 0.031 and 0.083 +/- 0.005 cm3 in the control and As2O3 alone groups, respectively (p > 0.05), but were undetectable in the Ad-PML alone or Ad-PML plus As2O3 groups. Finally, established HepG2 tumors in nude mice were injected with PBS, Ad-PML, As2O3, or Ad-PML plus As2O3, the tumor volumes were measured by ultrasound, and the therapeutic effects were compared. As2O3 alone had no effect at concentrations below 5 micromol/L (p > 0.05), while Ad-PML alone at a multiplicity of infection of 20 or As2O3 plus Ad-PML significantly decreased tumor volumes (p < 0.05). Thus, the combination of As2O3 and Ad-PML has synergistic inhibitory effects on hepatocellular carcinoma (HCC), possibly resulting from regulation of apoptotic gene expression enhanced HCC apoptosis.

Drug permeability and mucoadhesion properties of thiolated trimethyl chitosan nanoparticles in oral insulin delivery.

Trimethyl chitosan-cysteine conjugate (TMC-Cys) was synthesized in an attempt to combine the mucoadhesion and the permeation enhancing effects of TMC and thiolated polymers related to different mechanisms for oral absorption. TMC-Cys with various molecular weights (30, 200, and 500 kDa) and quaternization degrees (15 and 30%) was allowed to form polyelectrolyte nanoparticles with insulin through self-assembly, which demonstrated particle size of 100-200 nm, zeta potential of +12 to +18 mV, and high encapsulation efficiency. TMC-Cys/insulin nanoparticles (TMC-Cys NP) showed a 2.1-4.7-fold increase in mucoadhesion compared to TMC/insulin nanoparticles (TMC NP), which might be partly attributed to disulfide formation between TMC-Cys and mucin as evidenced by DSC measurement. Compared to insulin solution and TMC NP, TMC-Cys NP induced increased insulin transport through rat intestine by 3.3-11.7 and 1.7-2.6 folds, promoted Caco-2 cell internalization by 7.5-12.7 and 1.7-3.0 folds, and augmented uptake in Peyer's patches by 14.7-20.9 and 1.7-5.0 folds, respectively. Such results were further confirmed by in vivo experiment with the optimal TMC-Cys NP. Biocompatibility assessment revealed lack of toxicity of TMC-Cys NP. Therefore, self-assembled nanoparticles between TMC-Cys and protein drugs could be an effective and safe oral delivery system.

Cytotoxicity and genotoxicity of superporous hydrogel containing interpenetrating polymer networks.

The superporous hydrogel containing poly(acrylic acid-co-acrylamide)/O-carboxymethyl chitosan (O-CMC) interpenetrating polymer networks (SPH-IPN) that had been developed as an oral delivery vehicle for protein drugs was subject to cytotoxicity and genotoxicity testing, thus evaluating its biological safety in use. In a battery of cytotoxicity assays on RBL-2H3 and Caco-2 cells, the SPH-IPN caused minimal damage towards cell viability, lysosomal activity, and metabolic activity following both direct and indirect treatment. The SPH-IPN did not induce cell apoptosis or DNA breakage in the above cell lines; it did not increase micronucleus (MN) incidence in mouse bone marrow, either. Therefore, the SPH-IPN was preliminarily considered to be biocompatible and might be a safe carrier for protein drugs. In addition, using the HPLC method, residual acrylic acid, acrylamide, and glutaraldehyde in the SPH-IPN were quantified to be 1.4, 2.0, and below 0.2 ppm, respectively. Lack of these low molecular monomers and crosslinker that were mainly responsible for the toxicity provided evidence for the good biocompatibility of the SPH-IPN.