Retrospective Analysis of Fever and Sepsis Patients from Cambodia Reveals Serological Evidence of Melioidosis.

Burkholderia pseudomallei, the etiologic agent of melioidosis, is predicted to be ubiquitous in tropical regions of the world with areas of highest endemicity throughout Southeast Asia (SEA). Nevertheless, the distribution of B. pseudomallei and the burden of melioidosis in many SEA countries remain unclear. In Cambodia, only two human endemic cases of melioidosis were reported through 2008 and since then only a few hundred cases have been described in the literature. This is in sharp contrast to the annual burden of thousands of cases in surrounding areas. To further investigate the prevalence of melioidosis in Cambodia, we used a recently developed O-polysaccharide-based rapid enzyme-linked immunosorbent assay to detect B. pseudomallei-specific antibodies in serum samples obtained from 1,316 febrile illness or sepsis patients from 10 different provinces. Based on a cutoff value derived through culture-confirmed melioidosis cases, the proportion of positive samples in our cohort was approximately 12%. Regression analysis indicated that the odds of obtaining a positive result were 2.2 times higher for males than females controlling for age and province (95% confidence interval: 1.6-3.2, P < 0.001). Consistent with this, 9.2% of females were positive versus 18.2% of males (P < 0.001). Notably, 22.5% of grain or rice farmers were positive versus 10.1% of subjects with occupations not involving regular contact with soil. Positive results varied significantly by province. Collectively, the results of this study suggest that the true burden of melioidosis in Cambodia is greater than has previously been reported.

MYC regulates the unfolded protein response and glucose and glutamine uptake in endocrine resistant breast cancer.

BACKGROUND: About 70% of all breast cancers are estrogen receptor alpha positive (ER+) and are treated with antiestrogens. However, 50% of ER + tumors develop resistance to these drugs (endocrine resistance). In endocrine resistant cells, an adaptive pathway called the unfolded protein response (UPR) is elevated that allows cells to tolerate stress more efficiently than in sensitive cells. While the precise mechanism remains unclear, the UPR can trigger both pro-survival and pro-death outcomes that depend on the nature and magnitude of the stress. In this study, we identified MYC, an oncoprotein that is upregulated in endocrine resistant breast cancer, as a regulator of the UPR in glucose-deprived conditions. METHODS: ER+ human breast cancer cell lines (LCC1, LCC1, LY2 and LCC9) and rat mammary tumors were used to confirm upregulation of MYC in endocrine resistance. To evaluate functional relevance of proteins, siRNA-mediated inhibition or small molecule inhibitors were used. Cell density/number was evaluated with crystal violet assay; cell cycle and apoptosis were measured by flow cytometry. Relative quantification of glutamine metabolites were determined by mass spectrometry. Signaling molecules of the UPR, apoptosis or autophagy pathways were investigated by western blotting. RESULTS: Increased MYC function in resistant cells correlated with increased dependency on glutamine and glucose for survival. Inhibition of MYC reduced cell growth and uptake of both glucose and glutamine in resistant cells. Interestingly, in glucose-deprived conditions, glutamine induced apoptosis and necrosis, arrested autophagy, and triggered the unfolded protein response (UPR) though GRP78-IRE1α with two possible outcomes: (i) inhibition of cell growth by JNK activation in most cells and, (ii) promotion of cell growth by spliced XBP1 in the minority of cells. These disparate effects are regulated, at different signaling junctions, by MYC more robustly in resistant cells. CONCLUSIONS: Endocrine resistant cells overexpress MYC and are better adapted to withstand periods of glucose deprivation and can use glutamine in the short term to maintain adequate metabolism to support cell survival. Our findings reveal a unique role for MYC in regulating cell fate through the UPR, and suggest that targeting glutamine metabolism may be a novel strategy in endocrine resistant breast cancer.