Flexor tendon injury, repair and rehabilitation.

Injuries to the flexor tendons remain among the most difficult problems in hand surgery. Historically, lacerations to the intrasynovial portion of the flexor tendons were thought to be unsuitable for primary repair. Despite continuing advances in our knowledge of flexor tendon biology, repair, and rehabilitation, good results following primary repair of flexor tendons remain challenging to achieve.

Hepatitis B virus HBx protein impairs liver regeneration through enhanced expression of IL-6 in transgenic mice.

BACKGROUND & AIMS: Conflicting results have been reported regarding the impact of hepatitis B virus X protein (HBx) expression on liver regeneration triggered by partial hepatectomy (PH). In the present report we investigated the mechanisms by which HBx protein alters hepatocyte proliferation after PH. METHODS: PH was performed on a transgenic mouse model in which HBx expression is under the control of viral regulatory elements and liver regeneration was monitored. LPS, IL-6 neutralizing antibody, and SB203580 were injected after PH to evaluate IL-6 participation during liver regeneration. RESULTS: Cell cycle progression of hepatocytes was delayed in HBx transgenic mice compared to WT animals. Moreover, HBx induced higher secretion of IL-6 soon after PH. Upregulation of IL-6 was associated with an elevation of STAT3 phosphorylation, SOCS3 transcript accumulation and a decrease in ERK1/2 phosphorylation in the livers of HBx transgenic mice. The involvement of IL-6 overexpression in cell cycle deregulation was confirmed by the inhibition of liver regeneration in control mice after the upregulation of IL-6 expression using LPS. In addition, IL-6 neutralization with antibodies was able to restore liver regeneration in HBx mice. Finally, the direct role of p38 in IL-6 secretion after PH was demonstrated using SB203580, a pharmacological inhibitor. CONCLUSIONS: HBx is able to induce delayed hepatocyte proliferation after PH, and HBx-induced IL-6 overexpression is involved in delayed liver regeneration. By modulating IL-6 expression during liver proliferation induced by stimulation of the cellular microenvironment, HBx may participate in cell cycle deregulation and progression of liver disease.

Radiosensitization of prostate cancer cells by the dual PI3K/mTOR inhibitor BEZ235 under normoxic and hypoxic conditions.

BACKGROUND AND PURPOSE: Despite appropriate radiotherapy, high-risk prostate cancer patients often experience local relapse and progression to metastatic disease. Radioresistance may be due to tumor-hypoxia but also due to the PTEN mutation/deletion present in 70% prostate cancers. We investigated whether the novel PI3K/mTOR inhibitor BEZ235 might sensitize prostate cancer cells to radiation and reduce hypoxia-induced radioresistance. MATERIALS AND METHODS: The potential radiosensitizing properties of BEZ235 were investigated in vitro and in vivo using two prostate cancer cell lines, PC3 (PTEN(-/-)) and DU145 (PTEN(+/+)), under normoxic (21% O(2)) and hypoxic (0.5% O(2)) conditions. RESULTS: BEZ235 rapidly inhibited PI3K and mTOR signaling in a dose dependent manner and limited tumor cell proliferation and clonogenic survival in both cell lines independently of PTEN status. In vivo, BEZ235 pretreatment enhanced the efficacy of radiation therapy on PC3 xenograft tumors in mice without inducing intestinal radiotoxicity. In culture, BEZ235 radiosensitized both cell lines in a comparable manner. Moreover, BEZ235 inhibited PI3K/mTOR activation and radiosensitized both cell lines under normoxia and hypoxia. BEZ235 radiosensitizing effects correlated with a decrease in γH2AX foci repair and increased G2/M cell cycle arrest. CONCLUSIONS: BEZ235 is a potent radiosensitizer of normoxic and hypoxic prostate cancer cells.

Production of hepatitis B defective particles is dependent on liver status.

Defective hepatitis B virus (dHBV) generated from spliced RNA is detected in the sera of HBV-chronic carriers. Our study was designed to determine whether the proportion of dHBV changed during the course of infection, and to investigate whether dHBV might interfere with HBV replication. To achieve this, HBV wild-type and dHBV levels were determined by Q-PCR in sera from 56 untreated chronic patients and 23 acute patients, in sequential samples from 4 treated-patients and from liver-humanized mice after HBV infection. The proportion of dHBV was higher in patients with severe compared to null/moderate liver disease or with acute infection. Follow-up showed that the proportion of dHBV increased during disease progression. By contrast, a low and stable proportion of dHBV was observed in the humanized-mouse model of HBV infection. Our results highlight a regulation of the proportion of dHBV during liver disease progression that is independent of interference with viral replication.

Antiviral activity of Bay 41-4109 on hepatitis B virus in humanized Alb-uPA/SCID mice.

Current treatments for HBV chronic carriers using interferon alpha or nucleoside analogues are not effective in all patients and may induce the emergence of HBV resistant strains. Bay 41-4109, a member of the heteroaryldihydropyrimidine family, inhibits HBV replication by destabilizing capsid assembly. The aim of this study was to determine the antiviral effect of Bay 41-4109 in a mouse model with humanized liver and the spread of active HBV. Antiviral assays of Bay 41-4109 on HepG2.2.15 cells constitutively expressing HBV, displayed an IC(50) of about 202 nM with no cell toxicity. Alb-uPA/SCID mice were transplanted with human hepatocytes and infected with HBV. Ten days post-infection, the mice were treated with Bay 41-4109 for five days. During the 30 days of follow-up, the HBV load was evaluated by quantitative PCR. At the end of treatment, decreased HBV viremia of about 1 log(10) copies/ml was observed. By contrast, increased HBV viremia of about 0.5 log(10) copies/ml was measured in the control group. Five days after the end of treatment, a rebound of HBV viremia occurred in the treated group. Furthermore, 15 days after treatment discontinuation, a similar expression of the viral capsid was evidenced in liver biopsies. Our findings demonstrate that Bay 41-4109 displayed antiviral properties against HBV in humanized Alb-uPA/SCID mice and confirm the usefulness of Alb-uPA/SCID mice for the evaluation of pharmaceutical compounds. The administration of Bay 41-4109 may constitute a new strategy for the treatment of patients in escape from standard antiviral therapy.