In vivo evaluation of a cancer therapy strategy combining HSV1716-mediated oncolysis with gene transfer and targeted radiotherapy

Oncolytic herpes viruses show promise for cancer treatment. However, it is unlikely that they will fulfill their therapeutic potential when used as monotherapies. An alternative strategy is to use these viruses not only as oncolytic agents but also as a delivery mechanism of therapeutic transgenes to enhance tumor cell killing. The herpes simplex virus 1 deletion mutant HSV1716 is a conditionally replicating oncolytic virus that selectively replicates in and lyses dividing tumor cells. It has a proven safety profile in clinical trials and has demonstrated efficacy as a gene-delivery vehicle. To enhance its therapeutic potential, we have engineered HSV1716 to convey the noradrenaline transporter (NAT) gene (HSV1716/NAT), whose expression endows infected cells with the capacity to accumulate the noradrenaline analog metaiodobenzylguanidine (MIBG). Thus, the NAT gene-infected cells are susceptible to targeted radiotherapy using radiolabeled I-131-MIBG, a strategy that has already shown promise for combined targeted radiotherapy-gene therapy in cancer cells after plasmid-mediated transfection. Methods: We used HSV1716/NAT as a dual cell lysis-gene delivery vehicle for targeting the NAT transgene to human tumor xenografts in vivo. Results: In tumor xenografts that did not express NAT, intratumoral or intravenous injection of HSV1716/NAT induced the capacity for active uptake of I-131-MIBG. Administration of HSV1716/NAT and I-131-MIBG resulted in decreased tumor growth and enhanced survival relative to injection of either agent alone. Efficacy was dependent on the scheduling of delivery of the 2 agents. Conclusion: These findings support a role for combination radiotherapy-gene therapy for cancer using HSV1716 expressing the NAT transgene and targeted radionuclide therapy

Domestication of the Triticeae in the Fertile Crescent

WOS: 000268721700003About 12,000 years ago, humans began the transition from hunter-gathering to a sedentary, agriculture-based society. From its origins ill the Fertile Crescent, farming expanded throughout Europe, Asia and Africa, together with various domesticated plants and animals. Where, how and why agriculture originated is still debated. Progress has been made in Understanding plant domestication in the last few years. New insights were obtained mainly due to (I) the use of comprehensive germplasm collections covering the whole distribution area for each species; (II) the comparison of many wild and domesticated accessions for each species; (III) the identification of the wild progenitor in the wild gene pool and its comparison with domesticate descendants (IV) the use of molecular fingerprinting techniques at many loci and the access to new generation high-throughput sequencing technologies; (V) the identification and cloning of genes involved in domestication, and (VI) excavation campaigns. This chapter reviews the recent knowledge on wheat, barley and rye domestication in the Fertile Crescent and covers several issues concerning the molecular knowledge of the effects induced by domestication and breeding of these crops