Exosomes are secreted membrane vesicles that have been proposed as an effective means to detect a variety of disease states, including cancer. The properties of exosomes, including stability in biological fluids, allow for their efficient isolation and make them an ideal vehicle for studies on early disease detection and evaluation. Much data has been collected over recent years regarding the messenger RNA, microRNA, and protein contents of exosomes. In addition, many studies have described the functional role that exosomes play in disease initiation and progression. Tumor cells have been shown to secrete exosomes, often in increased amounts compared to normal cells, and these exosomes can carry the genomic and proteomic signatures characteristic of the tumor cells from which they were derived. While these unique signatures make exosomes ideal for cancer detection, exosomes derived from cancer cells have also been shown to play a functional role in cancer progression. Here, we review the unique genomic and proteomic contents of exosomes originating from cancer cells as well as their functional effects to promote tumor progression.

ClinicalTrials.gov; No.: NCT01752114; URL: www.clinicaltrials.gov).

Background: Pancreatic cancer retains a poor prognosis among the gastrointestinal cancers. It affects 230,000 individuals worldwide, has a very high mortality rate, and remains one of the most challenging malignancies to treat successfully. Treatment with gemcitabine, the most widely used chemotherapeutic against pancreatic cancer, is not curative and resistance may occur. Combinations of gemcitabine with other chemotherapeutic drugs or biological agents have resulted in limited improvement.

There is some evidence that bilateral therapy improves function in adults with chronic stroke, however more quality RCTs are required to strengthen this evidence.

A series of diaryl-and fluorenone-based analogs of the lead compound UA-62784 [4-(5-(4-methoxyphenyl)oxazol-2-yl)-9H-fluoren-9-one] was synthesized with the intention of improving upon the selective cytotoxicity of UA-62784 against human pancreatic cancer cell lines with a deletion of the tumor suppressor gene deleted in pancreas cancer locus 4 (DPC-4, SMAD-4). Over 80 analogs were synthesized and tested for antitumor activity against pancreatic cancer (PC) cell lines (the PC series). Despite a structural relationship to UA-62784, which inhibits the mitotic kinesin centromere protein E (CENP-E), none of the analogs was selective for DPC-4-deleted pancreatic cancer cell lines. Furthermore, none of the analogs was a potent or selective inhibitor of four different mitotic kinesins (mitotic kinesin-5, CENP-E, mitotic kinesin-like protein-1, and mitotic centromere-associated kinesin). Therefore, other potential mechanisms of action were evaluated. A diaryl oxazole lead analog from this series, PC-046 [5-(4-methoxyphenyl)-2-(3-(3-methoxyphenyl)pyridin-4-yl) oxazole], was shown to potently inhibit several protein kinases that are overexpressed in human pancreatic cancers, including tyrosine receptor kinase B, interleukin-1 receptor-associated kinase-4, and proto-oncogene Pim-1. Cells exposed to PC-046 exhibit a cell cycle block in the S-phase followed by apoptotic death and necrosis. PC-046 effectively reduced MiaPaca-2 tumor growth in severe combined immunodeficiency mice by 80% compared with untreated controls. The plasma half-life was 7.5 h, and cytotoxic drug concentrations of Ͼ3 M were achieved in vivo in mice. The diaryl oxazole series of compounds represent a new chemical class of anticancer agents that inhibit several types of cancer-relevant protein kinases.Pancreatic cancer is the fourth leading cause of death from cancer in North America (Jemal et al., 2008). There are two agents approved in the United States for the treatment of metastatic pancreas cancer: 1) the cytidine analog gemcitabine and 2) the epidermal growth factor receptor inhibitor erlotinib (Tarceva) (Burris and Rocha-Lima, 2008). Neither drug alone or in combination is curative, and only incremental improvements in survival are produced by these agents (Burris and Rocha-Lima, 2008). Whereas many other anticancer agents have been explored in the treatment of metastatic pancreatic cancer, none has yet proven to be effective. Thus, new agents with novel mechanisms of action are needed to treat metastatic pancreatic adenocarcinoma, which is the most commonly diagnosed stage of this disease.The original intent of the chemistry campaign in this project was to develop analogs of a lead molecule UA-62784 that had showed modest selectivity for human pancreatic cancer cells with the deleted in pancreas cancer locus 4 (DPC-4) gene deletion (Henderson et al., 2009). The DPC-4 deletion interrupts tumor suppression mediated by transforming growth factor-␤ signaling (Jones et al., 2008), and more than half of pancreatic cancers have DPC-4 deletions (...