N-Acetylcysteine Prevents Post-embolization Syndrome in Patients with Hepatocellular Carcinoma Following Transarterial Chemoembolization.

BACKGROUND: Post-embolization syndrome is a common complication after transarterial chemoembolization (TACE) for hepatocellular carcinoma (HCC). N-acetylcysteine (NAC) is known to ameliorate liver damage from several causes. AIM: To determine the efficacy of intravenous NAC in the prevention of post-embolization syndrome in HCC patients following TACE. METHODS: In this study, patients with HCC admitted for TACE were prospectively enrolled. All patients were randomized stratified by Child A or B to receive NAC or placebo. The NAC group received intravenous NAC 24 h prior to TACE (150 mg/kg/h for 1 h followed by 12.5 mg/kg/h for 4 h, then continuous infusion 6.25 mg/h for 48 h after the procedure). The placebo group received an infusion of 5% glucose solution until 48 h after procedure. The post-embolization syndrome was defined as: T ≥ 38.5 c and serum ALT > 3 times of pretreatment value. RESULTS: In total, 111 HCC patients were enrolled; 57 were randomly assigned to NAC group and 54 to placebo group. The incidence of post-embolization syndrome was lower in NAC group (24.6%) compared to placebo group (48.2%); P = 0.01. On multivariate analysis, receiving IV NAC (P = 0.03) and HCC diameter (P < 0.01) were associated with developing post-embolization syndrome. Post-TACE liver decompensation was documented in 26/111 (23.4%) patients. There was no difference in the incidence of post-TACE liver decompensation between NAC and placebo group. CONCLUSIONS: In this study, intravenous NAC administration reduces the incidence of post-embolization syndrome after TACE in patients with HCC. However, it does not prevent post-TACE liver decompensation. TRIAL REGISTRATION NUMBER: This study was registered with Thai Clinical Trial Registry (TCTR20150313002).

Associations of DC-SIGN (CD209) promoter -336G/A polymorphism (rs4804803) with dengue infection: A systematic review and meta-analysis.

BACKGROUND AND AIM: Dengue virus entry into a host is associated with a cell surface protein, DC-SIGN (dendritic cell-specific intercellular adhesion molecule-3 grabbing non-integrin). A common CD209-336G/A (rs4804803) polymorphism in DC-SIGN may affect severity of dengue virus infection (DEN) and incidence of dengue fever (DF) or the more severe dengue hemorrhagic fever (DHF). However, the reported associations of these two outcomes and CD-209 have been inconsistent, which prompted a meta-analysis to obtain more precise estimates. METHODS: A literature search yielded seven case-control studies. We calculated pooled odds ratios (OR) and 95% confidence intervals using standard genetic models. Outlier treatment examined sources of potential heterogeneity. Subgroup analysis was performed for ethnicity and age. RESULTS: All significant outcomes for association indicating reduced risk were pegged at P=0.007-0.05. In the homozygous and recessive models, these were observed in the overall analysis (OR 0.52-0.55), and subgroups of South/Central Americans (OR 0.30-0.32) and school-age children (OR 0.44) in the DHF analysis as well as the codominant model among Asians in DF (OR 0.59). These significant outcomes are strengthened by their non-heterogeneity (P>0.10) and robustness of the effects. Most pooled effects in DF and DEN were variable. CONCLUSIONS: The DC-SIGN -336G/A polymorphism significantly affects DHF and DF incidence with the effect more pronounced in certain analyzed patient subgroups.

Doxorubicin-conjugated bacteriophages carrying anti-MHC class I chain-related A for targeted cancer therapy in vitro.

BACKGROUND: Cancer therapy by systemic administration of anticancer drugs, besides the effectiveness shown on cancer cells, demonstrated the side effects and cytotoxicity on normal cells. The targeted drug-carrying nanoparticles may decrease the required drug concentration at the site and the distribution of drugs to normal tissues. Overexpression of major histocompatibility complex class I chain-related A (MICA) in cancer is useful as a targeted molecule for the delivery of doxorubicin to MICA-expressing cell lines. METHODS: The application of 1-ethyl-3-[3-dimethylaminopropyl] carbodiimide (EDC) chemistry was employed to conjugate the major coat protein of bacteriophages carrying anti-MICA and doxorubicin in a mildly acid condition. Doxorubicin (Dox) on phages was determined by double fluorescence of phage particles stained by M13-fluorescein isothiocyanate (FITC) and drug autofluorescence by flow cytometry. The ability of anti-MICA on phages to bind MICA after doxorubicin conjugation was evaluated by indirect enzyme-linked immunosorbent assay. One cervical cancer and four cholangiocarcinoma cell lines expressing MICA were used as models to evaluate targeting activity by cell cytotoxicity test. RESULTS: Flow cytometry and indirect enzyme-linked immunosorbent assay demonstrated that most of the phages (82%) could be conjugated with doxorubicin, and the Dox-carrying phage-displaying anti-MICA (Dox-phage) remained the binding activity against MICA. Dox-phage was more efficient than free drugs in killing all the cell lines tested. The half maximal inhibitory concentration (IC50) values of Dox-phage were lower than those of free drugs at approximately 1.6-6 times depending on MICA expressions and the cell lines tested. CONCLUSION: Evidently, the application of 1-ethyl-3-[3-dimethylaminopropyl] carbodiimide chemistry is effective to conjugate doxorubicin and major coat protein of bacteriophages without destroying binding activity of MICA antibodies. Dox-carrying bacteriophages targeting MICA have been successfully developed and may enable a broad range of applications in cancer-targeting chemotherapy.

Improved binding activity of antibodies against major histocompatibility complex class I chain-related gene A by phage display technology for cancer-targeted therapy.

Major histocompatibility complex class I chain-related gene A (MICA) is an NKG2D ligand that is over-expressed under cellular stress including cancer transformation and viral infection. High expression of MICA in cancer tissues or patients' sera is useful for prognostic or follow-up markers in cancer patients. In this study, phage display technology was employed to improve antigen-binding activities of anti-MICA monoclonal antibodies (WW2G8, WW6B7, and WW9B8). The 12 amino acid residues in the complementarity determining regions (CDRs) on the V domain of the heavy chain CDR3 (HCDR3) of these anti-MICA antibodies were modified by PCR-random mutagenesis, and phages displaying mutated anti-MICA Fab were constructed. After seven rounds of panning, five clones of phages displaying mutant anti-MICA Fab which exhibited 3-7-folds higher antigen-binding activities were isolated. Two clones of the mutants (phage-displayed mutant Fab WW9B8.1 and phage-displayed mutant Fab WW9B8.21) were confirmed to have antigen-binding specificity for cell surface MICA proteins by flow cytometry. These phage clones are able to recognize MICA in a native form according to positive results obtained by indirect ELISA and flow cytometry. Thus, these phage particles could be potentially used for further development of nanomedicine specifically targeting cancer cells expressing MICA proteins.