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Thousands of patients die each year from residual cancer that remains following cytoreductive surgery. Use of tumor-targeted fluorescent dyes (TTFDs) to illuminate undetected malignant tissue and thereby facilitate its surgical resection shows promise for reducing morbidity and mortality associated with unresected malignant disease. TTFDs can also improve i) detection of recurrent malignant lesions, ii) differentiation of normal from malignant lymph nodes, iii) accurate staging of cancer patients, iv) detection of tumors during robotic/endoscopic surgery (where tumor palpation is no longer possible), and v) preservation of healthy tissue during resection of cancer tissue. Although TTFDs that passively accumulate in a tumor mass provide some tumor contrast, the most encouraging TTFDs in human clinical trials are either enzyme-activated or ligand-targeted to tumor-specific receptors., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Ectopic expression of the Mycobacterium tuberculosis PE-family gene Rv1818c, triggers apoptosis in the mammalian Jurkat T cells, which is blocked by anti-apoptotic protein Bcl-2. Although complete overlap is not observed, a considerable proportion of cellular pools of ectopically expressed Rv1818c localizes to mitochondria. However, recombinant Rv1818c does not trigger release of cytochrome c from isolated mitochondria even though Rv1818c protein induced apoptosis of Jurkat T cells. Apoptosis induced by Rv1818c is blocked by the broad-spectrum caspase inhibitory peptide zVAD-FMK. Unexpectedly, Rv1818c-induced apoptosis is not blocked in a Jurkat sub-clone deficient for caspase-8 (JI 9.2) or in cells where caspase-9 function is inhibited or expression of caspase-9 reduced by siRNA, arguing against a central role for these caspases in Rv1818c-induced apoptotic signaling. Depleting cellular pools of the mitochondrial protein Smac/DIABLO substantially reduces apoptosis consistent with mitochondrial involvement in this death pathway. We present evidence that Rv1818c-induced apoptosis is blocked by the co-transfection of an endogenous inhibitor of caspase activation, XIAP in T cells. Additionally, Rv1818c is released into extracellular environment via exosomes secreted by M. tuberculosis infected BM-DC's and macrophages. Furthermore, the extracellular Rv1818c protein can be detected in T cells co-cultured with infected BM-DC's. Taken together, these data suggest that Rv1818c-induced apoptotic signaling is likely regulated in part by the Smac-dependent activation of caspases in T cells.