Developing a Phosphospecific IHC Assay as a Predictive Biomarker for Topoisomerase I Inhibitors.

Phosphorylation is the most extensively studied posttranslational modification of proteins. There are approximately 500 kinases known in the human genome. The kinase-activated pathways regulate almost every aspect of cell function and a deregulated kinase cascade leads to impaired cellular function. Impaired regulation of several kinase cascades, including the epidermal growth factor receptor (EGFR) pathway, leading to tumor pathogenesis, is well documented. Thus, a phosphospecific test with prognostic or predictive value was expected in oncology. However, no phosphospecific IHC test is used in oncology clinics. Human topoisomerase I (topoI) inhibitors, camptothecin and its analogues (CPT), are used extensively to treat various solid tumors. Depending on tumor type, the response rate is only 13-32%. We have demonstrated that the deregulated kinase cascade is at the core of CPT resistance. DNA-PKcs, a kinase central to the DNA-double-strand break (DSB) response pathway, phosphorylates topoI at serine 10 (topoI-pS10), and cells with higher basal levels of topoI-pS10 degrade topoI rapidly and are resistant to this class of drug. The higher basal level of topoI phosphorylation is due to continual activation of DNA-PKcs, and one potential mechanism of this pathway activation is failure of upstream effector phosphatases such as phosphatase and tensin homolog (PTEN). Based on this understanding, we have developed an IHC-based test (P-topoIDx) that can stratify the responder and non-responder patient population.

Do we produce enough fruits and vegetables to meet global health need?

BACKGROUND: Low fruit and vegetable (FV) intake is a leading risk factor for chronic disease globally, but much of the world's population does not consume the recommended servings of FV daily. It remains unknown whether global supply of FV is sufficient to meet current and growing population needs. We sought to determine whether supply of FV is sufficient to meet current and growing population needs, globally and in individual countries. METHODS AND FINDINGS: We used global data on agricultural production and population size to compare supply of FV in 2009 with population need, globally and in individual countries. We found that the global supply of FV falls, on average, 22% short of population need according to nutrition recommendations (supply:need ratio: 0.78 [Range: 0.05-2.01]). This ratio varies widely by country income level, with a median supply:need ratio of 0.42 and 1.02 in low-income and high-income countries, respectively. A sensitivity analysis accounting for need-side food wastage showed similar insufficiency, to a slightly greater extent (global supply:need ratio: 0.66, varying from 0.37 [low-income countries] to 0.77 [high-income countries]). Using agricultural production and population projections, we also estimated supply and need for FV for 2025 and 2050. Assuming medium fertility and projected growth in agricultural production, the global supply:need ratio for FV increases slightly to 0.81 by 2025 and to 0.88 by 2050, with similar patterns seen across country income levels. In a sensitivity analysis assuming no change from current levels of FV production, the global supply:need ratio for FV decreases to 0.66 by 2025 and to 0.57 by 2050. CONCLUSION: The global nutrition and agricultural communities need to find innovative ways to increase FV production and consumption to meet population health needs, particularly in low-income countries.