Population risk factors for late-stage presentation of cervical cancer in sub-Saharan Africa.

BACKGROUND: Cervical cancer is the most prevalent malignancy in sub-Saharan Africa (SSA) with many women only seeking professional help when they are experiencing symptoms, implying late-stage malignancy and higher mortality rates. This ecological study assesses population-level exposures of SSA women to the numerous risk factors for HPV infection and cervical cancer, against late-stage presentation of cervical cancer. MATERIALS AND METHOD: A literature review revealed the relevant risk factors in SSA. Open-access databases were mined for variables closely representing each risk factor. A proxy for late-stage presentation was used (ratio of incidence-to-mortality, IMR), and gathered from IARC's GLOBOCAN 2012 database. Variables showing significant correlation to the IMR were used in stepwise multiple regression to quantify their effect on the IMR. RESULTS: Countries with high cervical cancer mortality rates relative to their incidence have an IMR nearer one, suggesting a larger proportion of late-stage presentation. Western Africa had the lowest median IMR (1.463), followed by Eastern Africa (IMR = 1.595) and Central Africa (IMR = 1.675), whereas Southern Africa had the highest median IMR (1.761). Variables selected for the final model explain 65.2% of changes seen in the IMR. Significant predictors of IMR were GDP (coefficient = 2.189 × 10-6, p = 0.064), HIV infection (-1.936 × 10-3, p = 0.095), not using a condom (-1.347 × 10-3, p = 0.013), high parity (-1.744 × 10-2, p = 0.008), and no formal education (-1.311 × 10-3, p < 0.001). CONCLUSION: Using an IMR enables identification of factors predicting late-stage cervical cancer in SSA including: GDP, HIV infection, not using a condom, high parity and no formal education.

Selective superoxide generation within mitochondria by the targeted redox cycler MitoParaquat.

Superoxide is the proximal reactive oxygen species (ROS) produced by the mitochondrial respiratory chain and plays a major role in pathological oxidative stress and redox signaling. While there are tools to detect or decrease mitochondrial superoxide, none can rapidly and specifically increase superoxide production within the mitochondrial matrix. This lack impedes progress, making it challenging to assess accurately the roles of mitochondrial superoxide in cells and in vivo. To address this unmet need, we synthesized and characterized a mitochondria-targeted redox cycler, MitoParaquat (MitoPQ) that comprises a triphenylphosphonium lipophilic cation conjugated to the redox cycler paraquat. MitoPQ accumulates selectively in the mitochondrial matrix driven by the membrane potential. Within the matrix, MitoPQ produces superoxide by redox cycling at the flavin site of complex I, selectively increasing superoxide production within mitochondria. MitoPQ increased mitochondrial superoxide in isolated mitochondria and cells in culture ~a thousand-fold more effectively than untargeted paraquat. MitoPQ was also more toxic than paraquat in the isolated perfused heart and in Drosophila in vivo. MitoPQ enables the selective generation of superoxide within mitochondria and is a useful tool to investigate the many roles of mitochondrial superoxide in pathology and redox signaling in cells and in vivo.