Elevation of SHARPIN Protein Levels in Prostate Adenocarcinomas Promotes Metastasis and Impairs Patient Survivals.

BACKGROUND: SHARPIN, SHANK-associated RH domain interacting protein, associates with a linear ubiquitin chain assembly complex (LUBAC) to regulate inflammation and immunity. It has been reported that SHARPIN is highly expressed in several human tumors including ovarian cancer and liver cancer. We found that SHARPIN is also highly expressed in prostate cancer cell lines of DU145, LNCAP, and PC-3. Suppression of SHARPIN caused an inhibition of NF-κB signal and decreases in tumorigenesis of cultured cells in NOD/SCID mouse model. Overexpression of SHARPIN in prostate cancer cells promoted cell growth and reduced apoptosis through NF-kB/ERK/Akt pathway and apoptosis-associated proteins. METHODS: We analyzed the expression of SHARPIN in prostate cancer tissues from 95 patients and its relationship with other clinical characteristics associated with PCA malignancies and patient survivals, and examined the impacts of SHARPIN suppression with siRNA on proliferation, angiogenesis, invasion, and expression levels of MMP-9 of prostate cancer cells and metastasis to lung by these cells in nude mice. RESULTS: High levels of SHARPIN were associated with high malignancies of PCA and predicted shorter survivals of PCA patients. Suppression of SHARPIN impaired cell proliferation, angiogenesis, and invasion and reduced levels of MMP-9 in prostate cancer cells and reduced the size of metastatic lung tumors induced by these cells in mice. CONCLUSIONS: SHARPIN enhances the metastasis of prostate cancer and impair patient survivals. Prostate 77:718-728, 2017. © 2017 Wiley Periodicals, Inc.

Safety and immunogenicity of inactivated COVID-19 vaccine CoronaVac and the RBD-dimer-based COVID-19 vaccine ZF2001 in chronic hepatitis B patients.

Background and aims: Although COVID-19 vaccination is recommended for the patients with chronic liver disease, the clinical outcomes of COVID-19 vaccinated in patients with chronic hepatitis B (CHB) has not been well characterized. The study aimed to explore the safety and specific antibody responses following COVID-19 vaccination among CHB patients. Methods: Patients with CHB were included. All patients were vaccinated with two doses of inactivated vaccine (CoronaVac) or three doses of adjuvanted protein subunit vaccine (ZF2001). The adverse events were recorded and neutralizing antibody (NAb) were determined 14 days following the whole-course vaccination. Results: A total of 200 patients with CHB were included. Specific NAb against SARS-CoV-2 were positive in 170 (84.6%) patients. The median (IQR) concentrations of NAb were 16.32 (8.44-34.10) AU/ml. Comparison of immune responses between CoronaVac and ZF2001 vaccines showed no significant differences in neither the concentrations of NAb nor the seropositive rates (84.4 vs. 85.7%). Moreover, we observed lower immunogenicity in older patients and in patients with cirrhosis or underlying comorbidities. The incidences of adverse events were 37 (18.5%) with the most common adverse event as injection side pain [25 (12.5%)], followed by fatigue [15 (7.5%)]. There were no differences in the frequencies of adverse between CoronaVac and ZF2001 (19.3% vs. 17.6%). Almost all of the adverse reactions were mild and self-resolved within a few days after vaccination. Severe adverse events were not observed. Conclusions: COVID-19 vaccines, CoronaVac and ZF2001 had a favorable safety profile and induced efficient immune response in patients with CHB.

[Risk factors analysis on wound complications after closed calcaneal frature operation using lateral extensive L-shaped incision].

OBJECTIVE: To investigate the risk factors of wound complications after closed calcaneal fracture operation using a lateral extensive L-shaped incision and to explore the effective interventions to reduce the complications after incision. METHODS: Retrospective analysis of clinical data of 285 patients(315 calcaneal fractures) who underwent open reduction and internal fixation by using the lateral extensive L-shaped incision from January 2011 to January 2015. Eighteen factors which might cause the complications of calcaneal incision were compared by univariate analysis, and multiple Logistic regression analysis was performed for factors with statistically significances. RESULTS: Twenty-nine patients(30 calcaneus) had wound complications among all the 285 patients(315 calcaneus) after surgery, including 9 patients with incision redness, swelling, oozing or nonunion;16 patients with skin necrosis or incision rupture, 3 patients with soft tissue superficial infection, and 2 patients with osteomyelitis. Univariate analysis showed that fall height(P=0.017), diabetes (P=0.026), smoking(P=0.001), and operative time(P=0.003) were correlated with incision complications after surgery. Multivariate analysis showed that diabetes(P=0.029), smoking(P<0.001), and operative time(P=0.018) were risk factors for incision complications after operation. CONCLUSIONS: Preoperative smoking cessation, actively control of blood glucose and shortening the operation time by practicing can effectively reduce the incision complication after fracture surgery with the lateral extensive L-shaped incision.

Matrine suppresses invasion of castration-resistant prostate cancer cells by downregulating MMP-2/9 via NF-κB signaling pathway.

Matrine is an alkaloid from Sophora flavescens that exhibits multiple protective effects on cancers. However, the molecular mechanisms of anti-metastatic effects of matrine on castration-resistant prostate cancer (CRPC) remain unknown. This study investigated the anti-metastatic effects of matrine on CRPC to identify the underlying mechanisms. The effects of matrine on the cell viability of DU145 and PC-3 cells were measured using MTS assay. The impact of matrine on expression levels of matrix metalloproteinase (MMP)-9, MMP-2, nuclear factor-κB (NF-κB) subunit p65 and phosphorylated p65 in cells untreated or treated with matrine were analyzed by western blotting. The inhibitory effects of matrine on cell migration and invasion were examined by Transwell assay. The impact of matrine on tumorigenesis in male Balb/c nude mice inoculated subcutaneously with cells were investigated in vivo. We found that matrine inhibited the growth of DU145 and PC3 cells time- and dose-dependently both in vitro and in vivo. Migration and invasion capabilities of cells were also suppressed by matrine. At the same time, matrine markedly reduced the expression levels of MMP-9, MMP-2 and p-p65 in both cell lines. Further experiments revealed that matrine exhibited inhibitory effects of migration and invasion of CRPC by downregulating MMP-2/9 through NF-κB pathway. Matrine inhibits invasion of CRPC by reducing levels of MMP-9 and MMP-2 through NF-κB pathway. Therefore, it may be a potential anti-metastatic therapeutic agent for CRPC.

[The synthesis, characterization and in situ intestinal absorption of different molecular weight scutellarin-PEG conjugates].

In this report, highly water soluble esters of scutellarin with different molecular weight polyethylene glycol (PEG) were synthesized in order to improve the bioavailability of scutellarin. The physicochemical properties, the stabilities under different conditions and the in situ intestinal absorption in rats of the conjugates were investigated. By PEG modification, the greatly increased water solubility and desirable partition coefficient of scutellarin were obtained. These compounds function as prodrugs i. e. breakdown occurred in a predictable fashion: the t1/2 of them in PBS buffer at pH7.4 was above 12 h (37 degrees C) in vitro, while in plasma a rapid breakdown was observed, with a t1/2 of about 1. 5-3 h. The stabilities of the prodrugs were improved according to the increase of the molecular weight of PEG, thus, PEGylated prodrugs with desirable rates of hydrolysis could be obtained by the use of variable molecular weight PEGs. The PEGylation could enhance the absorption of scutellarin in rat intestine, and the absorption of scutellarin and its PEG conjugates by intestine was mainly via passive transport, for when the concentration was raised, the uptake did not appear saturable, and the permeability coefficient kept at an equilibrium level. When the molecular weight of PEG increased from 200 to 1000 Da, the absorption of the conjugates decreased. In conclusion, by overall consideration of the yield, stability and absorption, the present authors estimate that the PEG molecular weight used for the PEGylation of scutellarin should be within the range of 400-1 000 Da.