Plasma secretome analyses identify IL-8 and nitrites as predictors of poor prognosis in nasopharyngeal carcinoma patients.

Predicting tumor recurrence and death in patients with nasopharyngeal carcinoma (NPC) remains to date challenging. We here analyzed the plasmatic secretomes of NPC untreated and relapsing patients, and explored possible correlations with the clinical and pathological features and survival characteristics of the corresponding patient cohorts, with the aim of identifying novel prognostic biomarkers. This study included 27 controls, 45 untreated NPC and 11 relapsed patients. A set of 14 plasma cytokines were analyzed using Millipore multiplex assay. Nitrites were assessed by Griess method. A comparative analysis of each groups' secretome showed upregulation of IL-8, IL-12p70, IL-10 and IP-10 in untreated patients, and of IL-6, IL-10, MCP-1 and IP-10 in relapsing patients. Nitrites significantly correlated with IL-8 during relapse. Secretomes' network analyses revealed prevalence of high correlations between IL8/IL-17A and IFN-γ/IL12p70 in the control group, between TNF-α/IL-8/IL-6, TNF-α/VEGF/IFN-γ and IL-10/MCP-1 in the untreated group, and between IL-8/IL-6/IL-10, TNF-α/IL-8/IL-6, IL12-p70/VEGF/IL-10/IFN-γ, IL-6/IL-10/IFN-γ and IL-8/IP-10 in the relapse group. IL-12p70, IP-10 and MCP-1 levels respectively associated with gender, age and node metastasis respectively. Recurrence-free survival (RFS) analysis showed that patients presenting High IL-8/Low NO immunological scores presented a combined 80% probability of relapse/death after 53 months (combined log-rank test p = 0.0034; individual p = 0.012 and p = 0.016). Multivariate Cox hazard regression analysis revealed that IL-8 (HR = 7.451; 95% CI [2.398-23.152]; p = 0.001) and treatment type (HR = 0.232; 95% CI 0.072-0.749; p = 0.015) were independent prognostic factors. C&RT decision tree analysis showed that High IL-8/Low NO immunological scores predicted treatment failure in 50% cases starting the 36th month of follow-up (AUC = 1) for all of the studied cases and in 57% cases for patients receiving chemotherapy alone (AUC = 1). Altogether, our results showed that NPC development is accompanied with cytokines deregulation to form specific interaction networks at time of diagnosis and relapse, and demonstrate that High IL-8/Low NO signature may constitute a predictor of poor prognosis which may be useful to improve risk stratification and therapy failure management.

Murine immunodeficiency virus-induced peripheral neuropathy and the associated cytokine responses.

Distal symmetrical polyneuropathy is the most common form of HIV infection-associated peripheral neuropathy and is often associated with pain. C57BL/6 (B6) mice infected with LP-BM5, a murine retroviral isolate, develop a severe immunodeficiency syndrome similar to that in humans infected with HIV-1, hence the term murine AIDS. We investigated the induction of peripheral neuropathy after LP-BM5 infection in B6 mice. Infected B6 mice, like HIV-infected humans, exhibited behavioral (increased sensitivity to mechanical and heat stimuli) and pathological (transient loss of intraepidermal nerve fibers) signs of peripheral neuropathy. The levels of viral gag RNA were significantly increased in all tissues tested, including spleen, paw skin, lumbar dorsal root ganglia, and lumbar spinal cord, postinfection (p.i.). Correlated with the development of peripheral neuropathy, the tissue levels of several cytokines, including IFN-γ, IL-1ß, IL-6, and IL-12, were significantly elevated p.i. These increases had cytokine-specific and tissue-specific profiles and kinetics. Further, treatment with the antiretroviral agent zidovudine either significantly reduced or completely reversed the aforementioned behavioral, pathologic, and cytokine changes p.i. These data suggest that LP-BM5 infection is a potential mouse model of HIV-associated distal symmetrical polyneuropathy that can be used for investigating the roles of various cytokines in infection-induced neuropathic pain. Further investigation of this model could give a better understanding of, and lead to more effective treatments for, HIV infection-associated painful peripheral neuropathy.