Anaplastic lymphoma kinase inhibitor NVP­TAE684 suppresses the proliferation of human pancreatic adenocarcinoma cells.

Anaplastic lymphoma kinase (ALK) is known to be an important therapeutic target in various types of cancer. NVP­TAE684, a well­known inhibitor of ALK, was revealed to exert antitumor effects in several different malignancies. However, the molecular mechanisms responsible for these antitumor effects in cancer cells, including pancreatic adenocarcinoma cells, remain unknown. In the present study, NVP­TAE684 was investigated for its antitumor effects towards pancreatic adenocarcinoma cells. MTT assay, western blot analysis, flow cytometry, caspase­3/7 activity assay and Trypan blue exclusion assay were used and it was revealed that NVP­TAE684 suppressed the proliferation of seven human pancreatic adenocarcinoma cell lines (AsPC­1, Panc­1, MIA PaCa­2, Capan­1, CFPAC­1, Colo­357 and BxPC­3), and significantly increased G2/M arrest and apoptotic cell death. Furthermore, NVP­TAE684 inhibited the phosphorylation of ALK at Y1604, as well as that of downstream mediators such as AKT (S473) and ERK1/2 (Y202/T204). Notably, knocking down ALK with siRNAs also decreased proliferation and promoted G2/M arrest and apoptosis. Furthermore, inhibition of ALK with NVP­TAE684 or siRNA synergistically enhanced gemcitabine­induced cell death by inducing apoptosis. In conclusion, the findings of the present study indicated that NVP­TAE684 exerted its antitumor effects by inducing G2/M arrest and apoptosis via the inhibition of the ALK signaling pathway, and suggests its potential use as an antitumor agent against pancreatic adenocarcinoma.

Growth in children infected with HIV receiving anti-retroviral therapy in Vietnam.

BACKGROUND: There are currently two markers used to monitor treatment response to anti-retroviral therapy (ART) in HIV-infected children: CD4 T-cell count and HIV viral load; but analysis of these could be challenging in resource-poor countries. The aim of this study was therefore to determine whether change in growth parameters such as weight-for-age Z score (WAZ), height-for-age Z score (HAZ) and body mass index-for-age Z score (BMIZ) is associated with treatment response in HIV-infected children. METHODS: This was a nested case-control study, in which the data were collected at enrolment and then periodically every 6 months for a total 36 month follow up of 107 HIV-infected children enrolled and treated at National Hospital of Pediatrics, Vietnam. RESULTS: At treatment initiation, WAZ, HAZ and BMIZ were not significantly higher in the treatment success (TS) group compared with the treatment failure (TF) group. After ART initiation, WAZ and HAZ increased, and this was significant in the TS group (from -1.5 to -0.54, P < 0.01 and from -2.06 to -0.84, P < 0.01, respectively). Low HAZ was significantly associated with TF (HR, 0.71; 95% CI: 0.54-0.92). CONCLUSION: Height-for-age Z score was the most sensitive growth parameter in prediction of the treatment response. In order to use growth parameters, particularly HAZ as a prognosis marker for TF in clinical practice, further research should be conducted to evaluate the role of growth parameters and their effects on treatment response.

Clinical characteristics of pediatric HIV-1 patients treated with first-line antiretroviral therapy in Vietnam: a nested case-control study.

OBJECTIVES: Over the past decades, Vietnam has made great strides in reducing the rate of mortality in HIV-related deaths, due to increased access of antiretroviral therapy (ART); however, given the significantly high level of treatment failure (TF), it is essential to identify markers that describe the failure of ART in HIV-1 infected children. METHODS: A nested case-control study was conducted with clinical data collected from 101 HIV-infected children [26 TF and 75 treatment success (TS)] at National Hospital of Pediatrics, Vietnam (2008-2012). RESULTS: The results showed that certain factors including height, weight, vaccination with Hepatitis B, and platelet were significantly different between TF and TS before starting the treatment. In addition, age to start the treatment, CD4 percentage, and opportunistic infection were found to significantly predict treatment outcome most frequently, implying the importance of clinical markers in the treatment response by Cox regression analysis. CONCLUSIONS: There is an inherent complexity within clinical markers that is challenging to determine HIV-pediatric failure and further research is needed to build a complete picture to guide clinical, evidence-based practice.

IL-7 promotes CD95-induced apoptosis in B cells via the IFN-γ/STAT1 pathway.

Interleukin-7 (IL-7) concentrations are increased in the blood of CD4+ T cell depleted individuals, including HIV-1 infected patients. High IL-7 levels might stimulate T cell activation and, as we have shown earlier, IL-7 can prime resting T cell to CD95 induced apoptosis as well. HIV-1 infection leads to B cell abnormalities including increased apoptosis via the CD95 (Fas) death receptor pathway and loss of memory B cells. Peripheral B cells are not sensitive for IL-7, due to the lack of IL-7Ra expression on their surface; however, here we demonstrate that high IL-7 concentration can prime resting B cells to CD95-mediated apoptosis via an indirect mechanism. T cells cultured with IL-7 induced high CD95 expression on resting B cells together with an increased sensitivity to CD95 mediated apoptosis. As the mediator molecule responsible for B cell priming to CD95 mediated apoptosis we identified the cytokine IFN-γ that T cells secreted in high amounts in response to IL-7. These results suggest that the lymphopenia induced cytokine IL-7 can contribute to the increased B cell apoptosis observed in HIV-1 infected individuals.