Exploration of nucleos(t)ide analogs cessation in chronic hepatitis B patients with hepatitis B e antigen loss.

BACKGROUND: Nucleos(t)ide analogs (NAs) cessation in chronic hepatitis B (CHB) patients remains a matter of debate in clinical practice. Current guidelines recommend that patients with hepatitis B e antigen (HBeAg) seroconversion discontinue NAs after relatively long-term consolidation therapy. However, many patients fail to achieve HBeAg seroconversion after the long-term loss of HBeAg, even if hepatitis B surface antigen (HBsAg) loss occurs. It remains unclear whether NAs can be discontinued in this subset of patients. AIM: To investigate the outcomes and factors associated with HBeAg-positive CHB patients with HBeAg loss (without hepatitis B e antibody) after cessation of NAs. METHODS: We studied patients who discontinued NAs after achieving HBeAg loss. The Cox proportional hazards model was used to identify predictors for virological relapse after cessation of NAs. The cut-off value of the consolidation period was confirmed using receiver operating characteristic curves; we confirmed the cut-off value of HBsAg according to a previous study. The log-rank test was used to compare cumulative relapse rates among groups. We also studied patients with CHB who achieved HBeAg seroconversion and compared their cumulative relapse rates. Propensity score matching analysis (PSM) was used to balance baseline characteristics between the groups. RESULTS: We included 83 patients with HBeAg loss. The mean age of these patients was 32.1 ± 9.5 years, and the majority was male (67.5%). Thirty-eight patients relapsed, and the cumulative relapse rate at months 3, 6, 12, 24, 36, 60, 120, and 180 were 22.9%, 36.1%, 41.0%, 43.5%, 45.0%, 45.0%, 45.0%, and 52.8%, respectively. Twenty-six (68.4%) patients relapsed in the first 3 mo after NAs cessation, and 35 patients (92.1%) relapsed in the first year after NAs cessation. Consolidation period (≥ 24 mo vs < 24 mo) (HR 0.506, P = 0.043) and HBsAg at cessation (≥ 100 IU/mL vs < 100 IU/mL) (HR 14.869, P = 0.008) were significant predictors in multivariate Cox regression. In the PSM cohort, which included 144 patients, there were lower cumulative relapse rates in patients with HBeAg seroconversion (P = 0.036). CONCLUSION: HBeAg-positive CHB patients with HBeAg loss may be able to discontinue NAs therapy after long-term consolidation, especially in patients with HBsAg at cessation < 100 IU/mL. Careful monitoring, especially in the early stages after cessation, may ensure a favorable outcome.

The Value of DNA Quantitative Cytology Test for the Screening of Endometrial Cancer.

OBJECTIVE: To evaluate the accuracy, sensitivity, and specificity of DNA quantitative cytology test for the diagnosis of endometrial cancer or precancerous lesions and then discuss the value of DNA quantitative cytology as a screening tool for endometrial cancer. METHODS: The study enrolled 575 patients from September 2013 to January 2017 in Shanghai Minhang Central Hospital. Endometrial hysteroscopy plus dilation and curettage and DNA quantitative cytology tests were conducted as a method for the diagnosis of endometrial cancer. The accuracy, sensitivity, and specificity of this method were calculated according to histopathologic diagnoses which were used as the gold standard for diagnosis confirmation. RESULTS: For the DNA quantitative cytology diagnosis of endometrial cancer, accuracy was estimated at 85.57%, sensitivity at 87.01%, specificity at 85.34%, positive predictive value (PPV) at 47.86%, and negative predictive value (NPV) at 97.07%. For the DNA quantitative cytology diagnosis of endometrial cancer in menopausal patients: accuracy was estimated at 89.95%, sensitivity at 97.73%, specificity at 87.59%, positive predictive value (PPV) at 70.49%, negative predictive value (NPV) at 99.22%. For the DNA quantitative cytology diagnosis of endometrial cancer in non-menopausal patients, accuracy was estimated at 83.42%, sensitivity at 72.73%, specificity at 84.42%, positive predictive value (PPV) at 30.38%, and negative predictive value (NPV) at 97.07%. CONCLUSION: DNA heteroploidy can be tested for the occurrence and the development of endometrial cancer. A small number of non-endometrial cancer cases may also appear DNA heteroploidy, but the number of >5c cells is less than 3. DNA quantitative analysis is a useful tool for the screening of endometrial cancer, worthy of being popularized and applied in endometrial cancer diagnosis.

Metabolic-induced cytotoxicity of diosbulbin B in CYP3A4-expressing cells.

As a candidate antitumor agent, diosbulbin B (DB) can induce serious liver toxicity and other adverse reactions. DB is mainly metabolized by CYP3A4 in vitro and in vivo, but the cytotoxicity and anti-tumor mechanisms of DB have yet to be clarified. This study aimed to determine whether the cytotoxicity and anti-tumor effects of DB are related to the metabolism-induced activation of CYP3A4 in various cell models, including CYP-free NIH3T3 cells, primary rat hepatocytes, HepG2 and L02 cells of high CYP3A4 expression and wild-type. Results showed that DB did not markedly decrease the viability of NIH3T3 cells. DB metabolites, obtained from the metabolism by mouse liver microsomes, did not elicit cytotoxicity on NIH3T3 cells either. By contrast, DB could induce significant cytotoxicity on primary rat hepatocytes. The DB induced cytotoxicity on HepG2 or L02 cells with high CYP3A4 expression were stronger than those on wild-type cells. As a metabolic biomarker, the metabolite conjugate (M31) of DB with GSH was detected in the incubation system. A higher amount of M31 was generated in the transfected HepG2 and L02 cells than in the wild-type cells at different time points. Ketoconazole, however, could restrain DB induced cytotoxicity on primary rat hepatocytes and in CYP3A4 transfected HepG2 and L02 cells. Therefore, the cytotoxicity of DB was closely related to CYP3A4-metabolized reactive DB metabolites.

[Clinical characteristics and effect of secondary individualized therapy in chronic hepatitis B patients infected with the rtA181 mutation hepatitis B virus].

OBJECTIVE: To investigate chronic hepatitis B (CHB) patients infected with the antiviral-resistant rtA181 mutation hepatitis B virus (HBV) who have been unresponsive to general therapy to determine the effects of individualized therapy. METHODS: Fifty-four patients with confirmed rtA181 mutation and who experienced virological breakthrough during nucleus(t)ide analogue (NUC) treatment were enrolled in this prospective cohort study. Their serum levels of HBV DNA, hepatitis B surface antigen (HBsAg), and alanine transaminase (ALT) were tested. Each patient was genotyped by pyrosequencing for 10 mutation sites in the HBV P gene that have been previously correlated to NUC efficacy. Each patient's antiviral therapy and response history was analyzed in regard to their particular mutation pattern. The serological index was determined for carriers of the rtA181T/V mutation. The secondary individualized treatment included adding/switching to entecavir (ETV; group A) or adding telbivudine (LdT; group B) upon confirmation of drug resistance. Effect of individualized treatment was analyzed by T test and Mann-Whitney U test for continuous variables with normal or skewed distributions, respectively. Categorical variables were analyzed by the Chi-squared ( x² ) or Fisher's exact tests. RESULTS: The rtA181T mutation was found in 64.8% (35/54) of patients with rtA181 mutation HBV. The most frequent previously administered medications were adefovir dipivoxil (ADV) and lamivudine (LAM). Multi-site rtA181 mutations occurred more frequently in the patients with multi-NUCs history (57.6%) than in those with single NUCs history (28.6%) (x²=4.342, P less than 0.05). Serum HBV DNA level at virological breakthrough was lower than that at baseline of the first antiviral treatment (5.66+/-1.01 vs. 6.75+/-0.81 log10 copies/ml; t=-4.210, P less than 0.01). The serum HBsAg level was higher in carriers of the rtA181T mutation than in carriers of the rtA181V mutation (3.80+/-0.45 vs. 3.46+/-0.60 log10 IU/ml; t=2.109, P less than 0.05). In patients with serum HBV DNA more than or equal to 6 log10 copies/ml at viral breakthrough, 100% (8/8) of patients in the secondary treatment group A and 75% (3/4) patients in the secondary treatment group B exhibited virological response at week 24 after intervention. Undetectable HBV DNA was achieved in three patients of group A and one patient of group B. In patients with serum HBV DNA less than 6 log10 copies/ml at viral breakthrough, 100% (14/14) of patients in group A and 71.4% (5/7) of patients in group B exhibited biological response at week 24 after intervention. The serum HBV DNA level decreased to undetectable levels in 12 patients of group A and four patients of group B. CONCLUSION: The rtA181 mutation pattern correlates with previous antiviral therapy response. In addition, multi-site rtA181 mutations occur more frequently in patients with a history of multi-NUCs therapy. Adding or switching rtA181 carriers to ETV produces a more robust virological suppression than adding LdT.

Bis{µ-2,2'-[ethane-1,2-diylbis(nitrilo-methyl-idyne)]diphenolato}bis-[(thio-cyanato)manganese(III)].

The reported structure is a monoclinic polymorph of the title compound, [Mn(2)(C(16)H(14)N(2)O(2))(2)(NCS)(2)], which has been characterized previously in an ortho-rhom-bic form. Each Mn(III) atom is chelated by a tetra-dentate 2,2'-[ethane-1,2-diylbis(nitrilo-methyl-idyne)]diphenolate ligand and by the N atom of a thio-cyanate anion, in a square-pyramidal arrangement. The complexes form centrosymmetric dimers, with an Mn-O contact of 2.557 (3) Štrans to each thio-cyanate anion, completing a distorted octa-hedral coordination geometry.

Lignans from bark of Larix olgensis var. koreana.

Six new lignans (2-7) were isolated from the bark of Larix olgensis var. koreana, and their structures were determined on the basis of their spectroscopic data. Seven known lignans were also obtained and identified as (+)-lariciresinol 9'-p-coumarate (1), (+)-lariciresinol, (-)-secoisolariciresinol, (+)-isolariciresinol, vladinol D, sesquipinsapol B, and ehletianol C. Compound 1 showed weak inhibition against K562, SHG44, HCT-8, A549, and PC-3M tumor cells with IC50 values of 2.9, 21.4, 32.9, 33.8, and 28.0 microg/mL, respectively.

[Studies on chemical constituents in bark of Larix olgensis var. koreana].

OBJECTIVE: To study the chemical constituents in bark of Larix olgensis var. koreana. METHOD: The compounds were isolated with silica gel column chromatography and their structures were elucidated on the basis of spectral analysis (IR, EI-MS, 1H-NMR, 13C-NMR). RESULT: Eight compounds were isolated and identified as isopimaric acid (I), beta-sitosterol (II), 24R,5alpha-stigmast-3,6-dione (III), larixol (IV), ferulic acid (V), lariciresinol (VI), secroisolariciresinol (VII) and isolariciresinol (VIII). CONCLUSION: All the compounds were isolated from this plant for the first time.