Engineered Biomimetic Copper Sulfide Nanozyme Mediates "Don't Eat Me" Signaling for Photothermal and Chemodynamic Precision Therapies of Breast Cancer.

The rapid development of nanomedicine has brought hope and confidence to the precise treatment of tumors. However, the efficacy of nanoparticle-mediated therapy is severely limited due to phagocytosis and clearance by macrophages. CD47 is a well-documented ″don't eat me″ signaling molecule that binds to the SIRPα receptor on the macrophage surface, inhibiting the phagocytic behavior of the macrophages. In this study, CD47-overexpressing cancer cell membranes were used to coat hollow copper sulfide nanoparticles. The nanoparticles were shown to have an extended circulatory half-life and to actively target breast cancer, leading to increased accumulation in the tumor tissue. An excellent photothermal therapeutic effect was produced by near-infrared laser irradiation. At the same time, ß-lapachone within the nanoparticles generated large amounts of hydrogen peroxide in the tumor environment, which was then catalyzed by the copper sulfide nanozyme to cytotoxic hydroxyl radicals, exerting a chemodynamic therapeutic effect. This engineered biomimetic nanozyme, through the mediation of the ″don't eat me″ signal, achieved both photothermal and chemodynamic precision treatments of breast cancer, creating a new mode of safe and effective tumor treatment.

Urine α-fetoprotein and orosomucoid 1 as biomarkers of hepatitis B virus-associated hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the sixth common malignant tumor worldwide, but current efficient and convenient screening methods remain lacking. This study aimed to discover a diagnostic or a screening biomarker from the urine of hepatitis B virus (HBV)-related HCC patients. We used iTRAQ coupled with mass spectrometry to identify candidate urinary proteins in a discovery cohort (n = 40). The selected proteins were confirmed using ELISA in a validation cohort (n = 140). Diagnostic performance of the selected proteins was assessed using receiver operating characteristic (ROC) and qualitative diagnostic analysis. A total of 96 differentially expressed proteins were identified. Urinary α-fetoprotein (u-AFP) and orosomucoid 1 (u-ORM1) were selected as target proteins by bioinformatics analysis and were significantly higher in HCC than in non-HCC patients, as validated by Western blot analysis and ELISA. u-AFP had a strong correlation with serum AFP-L3 (Pearson's r = 0.944, P < 0.0001), indicating that u-AFP may be derived from circulating blood. The area under the curve (AUC) of u-AFP was 0.795 with a sensitivity of 62.5% and a specificity of 95.4%, which showed no significantly difference with serum AFP (se-AFP). The AUC was 0.864 as u-AFP and u-ORM1 were combined, and they performed much better than u-AFP or u-ORM1 alone. Qualitative diagnostic analysis showed that the positive predictive value of u-AFP was 90.1% and the diagnostic sensitivity of parallel combination of u-AFP and u-ORM1 was 85.1%. Taken together, AFP and ORM1 in the urine may be used as a diagnostic or screening biomarker of HCC, and studies on large samples are needed to validate the result.NEW & NOTEWORTHY This study provides a novel way to find biomarkers of hepatocellular carcinoma (HCC) and a new perspective of α-fetoprotein clinical application. The urine reagent strips may be helpful in high epidemic areas of HCC and in low-resource settings.

Relationship between nephrotoxicity and long-term adefovir dipivoxil therapy for chronic hepatitis B: A meta-analysis.

BACKGROUND: To assess the relationship between adefovir dipivoxil and renal function after anti-hepatitis B virus therapy and elucidate the risk factors involved. METHODS: Based on the requirements of the Cochrane systematic review methodology, 21 observational articles on adefovir dipivoxil-associated renal dysfunction were obtained by searching various databases, between January 1, 1995 and July 1, 2016. The Newcastle Ottawa Scale was used to evaluate risk bias. Parameters for 4276 chronic hepatitis B patients were analyzed by Review Manager and R software, and glomerular filtration rate, creatinine clearance, and serum creatinine values were extracted to evaluate renal function. RESULTS: Renal dysfunction was more likely to occur in patients receiving the adefovir dipivoxil therapy (odds ratio [OR] 1.98, 95% confidence interval [CI] 1.40-2.80) than the none-adefovir dipivoxil group. Subgroup analysis showed that renal function predictive value is higher for glomerular filtration rate (OR 2.42, 95% CI 1.34-3.14), compared with serum creatinine levels (OR 1.51, 95% CI 0.75-3.04). The rate of adefovir dipivoxil-associated renal dysfunction was 12% (95% CI 0.08-0.16). Older patients and patients with renal insufficiency, hypertension, and diabetes mellitus were more prone to developing adefovir dipivoxil-associated renal dysfunction; however, integrated raw data were insufficient for further detailed analysis. CONCLUSION: Long-term adefovir dipivoxil therapy is connected to renal dysfunction in chronic hepatitis B, necessitating the monitoring of kidney function.

[The safety of telbivudine in preventing mother-to-infant transmission of hepatitis B virus in pregnant women after discontinuation].

OBJECTIVE: To determine the efficacy and safety of telbivudine for blocking intrauterine transmission of hepatitis B virus (HBV) in pregnant women with high-load HBV DNA. METHODS: Women in general good health and pragnant were enrolled for study between the ages of 20 to 40 year-old, with a diagnosis of HBV infection with high-load HBV DNA level (≥1*10(6) IU/ml). According to each participant's willingness, the women were divided into a telbivudine treatment group (82 women) and an untreated control group (75 women). The telbivudine treatment was initiated at gestation week 26 as oral dosing of 600 mg/d and continued until 1 month after the birth.Women in the control group had not gotten any antiviral drug treatment. All of the women delivered by cesarean section, and all of the neonates were administered the standard passive immunization therapy, which consisted of a hepatitis B immunoglobulin (200 IU) injection given within 12 hours of birth and an injection of hepatitis B vaccine (20 µg) at birth and at postnatal month 1 and 6. None of the mother's performed breastfeeding. RESULTS: The telbivudine-treated women showed a significant decrease in HBV DNA levels prior to delivery, as well as significantly decreased prenatal HBV DNA levels (>2 logl0). Efficiency of the telbivudine treatment was 100%. Immediately prior to delivery, 16 (19.5%) of the women in the telbivudine treatment group showed negative HBV DNA status, as opposed to the untreated control group in which no women showed negative status. The telbivudine treatment group had no case of maternal or fetal adverse reaction or of congenital malformation. CONCLUSION: Use of telbivudine antiviral therapy during late pregnancy in women with high-load HBV DNA can significantly reduce level of HBV DNA in maternal peripheral blood, block HBV intrauterine transmission, and provide good short-term efficacy, with good tolerability and safety.

[Serum procalcitonin in cirrhotic patients with sepsis].

OBJECTIVE: To assess the clinical value ofprocalcitonin in cirrhotic patients with severe infection by comparing the serum procalcitonin levels in those patients with and without liver cirrhosis when suffering from sepsis. METHODS: A total of 225 septic patients were included in the study,including 91 patients without hepatopathy, 80 patients with cirrhosis, and 54 patients with chronic liver disease. The serum procalcitonin level was measured in all patients and statistically assessed for correlation with relevant clinical biochemistry indicators. The t-test, ANOVA test, Mann-Whitney U test, chi-square test and Spearman's correlation analysis were used for statistical analyses. RESULTS: The patients with cirrhosis showed significantly lower serum procalcitonin levels (0.84 (0.32-3.44) ng/ml) than the patients with no hepatopathy (2.17 (0.70-9.18) ng/ml) or the patients with chronic liver disease (2.12 (0.33-13.61) ng/ml) (both P less than 0.05); the patients in the no hepatopathy group and the chronic liver disease group showed statistically similar levels of serum procalcitonin (P=0.616). The patients with cirrhosis of Child-Pugh grade C showed significantly higher level of serum procalcitonin (1.25 (0.54-4.61) ng/ml) than those patients with Child-Pugh grade B (0.33 (0.14-1.31) ng/ml; P=0.026), suggesting that patients with Child-Pugh C stage cirrhosis may be more susceptible to gram-negative bacterial infection. In the cirrhosis group,serum procalcitonin level was positively correlated with white blood cell (WBC) count (r=0.312) and percentage of neutrophils (N%) (r=0.228) (both P less than 0.05). Correlation analysis of the no hepatopathy group and the chronic liver disease group showed no correlation between serum procalcitonin level and either WBC or N%. CONCLUSION: Under the sepsis condition, cirrhotic patients have lower serum procalcitonin level than patients without cirrhosis, and the serum procalcitonin level is positively correlated with WBC count and N%.

[Assessment of the factors associated with insulin resistance in patients with chronic hepatitis B infection].

OBJECTIVE: To investigate the factors associated with insulin resistance (IR) in patients with chronic hepatitis B virus (HBV) infection. METHODS: Sixty-eight patients with mild chronic hepatitis B (MCHB) caused by HBV were recruited for study. Sixty-seven healthy individuals with no hepatitis virus infections and normal liver function were enrolled as controls. Demographic, anthropometric, clinical, and blood biochemical parameters were compared between the two groups. IR was determined by the homeostasis model assessment (HOMA-IR). The MCHB group was further divided into patients with IR (HOMA-IR: > 2.7) and patients without IR (HOMA-IR: less than 2.7). Demographic, anthropometric, clinical, and blood biochemical parameters were compared between the two sub-groups. Finally, the potential factors associated with IR were evaluated. RESULTS: Compared to the healthy controls, the MCHB patients had significantly higher serum insulin (Z = -5.451, P less than 0.01), alanine aminotransferase (ALT) (Z = -8.211, P less than 0.01) and HOMA-IR (Z = -5.631, P less than 0.01). IR was detected in 44.12% (30/68) of the MCHB patients. The levels of ALT and body mass index (BMI) were significantly different between the MCHB patients with IR and without IR (t = -2.358, and t = -3.566, P less than 0.05). There was a significant correlation between BMI, ALT, and HOMA-IR in the MCHB patients (r = 0.374, r = 0.282, P less than 0.05), but not with the HBV DNA loads (r = 0.015, P = 0.904). Binary logistic regression analysis indicated that BMI [Exp(B): 1.859, P less than 0.01] and ALT [Exp(B): 1.022, P less than 0.05] were independent risk factors of IR in MCHB. CONCLUSION: There is a high prevalence of insulin resistance in patients with mild hepatitis caused by chronic HBV infection. In these patients, IR is correlated with abnormal liver function and BMI, and not HBV load.

[Effect of HBV on the expression of SREBP in the hepatocyte of chronic hepatitis B patients combined with hepatic fatty change].

To investigate the effect of HBV on the expression of Sterol regulatory element binding proteins( SREBP ) in the hepatocyte of patients with chronic hepatitis B (CHB) combined with hepatic fatty change. 55 cases diagnosed as CHB combined with hepatic fatty change in our department were selected and liver biopsies were carried out. The patients were dividied into 3 groups, group A: HBV DNA is less than or equal to 1000 copies/ml(15 cases), group B: 1000 copies/ml less than HBV DNA less than 100000 copies/ml (18 cases) and group C: HBV DNA is more than or equal to 100000 copies/ml (22 cases). 10 patients with HBV DNA in less than or equal to 1000 copies/ml after antiviral therapy with Nucleoside analogues were seen as group C1 (before treatment) and group C2 (after treatment) respectively; 12 patients with HBV DNA is more than or equal to 100000 copies/ml after antiviral therapy were classified as group C3 (before treatment) and group C4 (after treatment). Lipid droplets in the hepatic tissue were observed with oil red staining. Real time PCR were performed to detect the expressions of SREBP-1c and SREBP-2 mRNA in the liver. The protein expressions of SREBP-1c and SREBP-2 were detected with immunohistochemistry staining. Statistic data were analysed with SPSS11.5 software. (1) Red integrated optical densities (IOD) reflected by lipid drops in group A, B and C are 1004.27+/-218.63, 1937.01+/-401.47 and 4133.79+/-389.28 respectively, the degree of oil red O in each group was different (F = 385.69, P is less than to 0.01), which is increased as HBV DNA load increasing; Red IOD in group C1, C2 and C3, C4 are 4020.84+/-326.64, 1012.02+/-244.89, 4189.18+/-329.21 and 4121.76+/-304.09 respectively. Compared with group C1, the degree of oil red O in group C2 is decreased and the difference is statistically significant (t = 22.55, P is less than to 0.01); However, the difference of the degree of oil red O between group C4 and C3 is not statistically significant. (2) Compared with group A, the expressions of SREBP-1c mRNA in group B and C are raised by 1.218+/-0.130 and 1.798+/-0.118 times respectively, among group A, B, C, the expressions of SREBP-1c mRNA are statistically significant different ( F = 297.47, P is less than to 0.01). The expressions of SREBP-2 mRNA in group B and C are decreased by 0.956+/-0.118 and 0.972+/-0.153 times as compared to group A. However, the difference of SREBP-2 mRNA expression among the 3 groups is not statistically significant ( F = 0.568, P is more than to 0.05). Compared with group C1, SREBP-1c mRNA in group C2 is decreased by 0.714+/-0.081 folds (t=11.224, P is less than to 0.01), while SREBP-2 mRNA in group C2 is raised by1.034+/-0.155 times(t=0.692, P is more than to 0.05). SREBP-1c mRNA and SREBP-2 mRNA in group C4 are raised by 1.012+/-0.206 times and decreased by 0.998+/-0.183 times as compared to group C3 without difference found (t=0.196 or 0.031, P is more than to 0.05). (3) the expressions of SREBP-1c protein in group A, B and C are 36257.21+/-5709.79, 50413.47+/-4989.28 and 71025.83+/-6047.13 respectively, and the difference is statistically significant among the 3 groups (F = 178.26, P is less than to 0.01); the expressions of SREBP-2 protein in group A, B and C are 32913.52+/-3951.21, 32625.91+/-4025.06 and 34173.44+/-5316.25 respectively, but the difference is not statistically significant among the 3 groups ( F = 0.562, P is more than to 0.05), SREBP-1c protein levels in group C1, C2, C3, C4 are 69832.16+/-4941.36, 48735.47+/-5471.41, 70871.69+/-5083.14 and 68913.32+/-5343.22 respectively, the difference of SREBP-1c protein levels between group C1 and C2 is statistically significant (t=10.260, P is less than to 0.01); while the difference between group C3 and group C4 is not statistically significant(t=1.558, P is more than to 0.05). The expressions of SREBP-2 protein in group C1, C2, C3 and C4 are 33 980.21+/-4081.80, 34011.50+/-3859.27, 33610.12+/-4761.10 and 32915.66+/-5023.61 respectively, the difference of SREBP-2 protein levels in group C1 and group C2 is not statistically significant (t=0.038, P is more than to 0.05) and same result exists between group C3 and group C4 (t=0.459, P is more than to 0.05). HBV DNA may participate in the hepatic steatosis formation through interfering with the SREBP-1c expression.