The adipose tissue-derived hormone, leptin, acts via its receptor (LepRb) in the brain to regulate energy balance and neuroendocrine function. Parsing the biology of leptin requires understanding LepRb signaling and the roles for specific signaling pathways in neural and physiological leptin action. Since the leptin acts via a broadly distributed network of LepRb-expressing neurons, understanding the function of each of these LepRb neural populations will also be crucial. Here, we review the status of knowledge regarding the molecular mediators of leptin action and the neural substrate via which leptin acts to regulate physiologic processes. LeptinAdipose tissue produces the hormone leptin in approximate proportion to fat stores. Circulating leptin communicates the level of energy reserves in the periphery to the central nervous system (CNS) in order to suppress food intake and permit energy expenditure (1-4). Adequate leptin levels permit energy expenditure on the processes of reproduction and growth, and similarly regulate other elements of the endocrine and immune systems (4-6). Conversely, lack of leptin signaling due to mutation of leptin (e.g. ob/ob mice) or the leptin receptor (LepR) (e.g. db/db mice) in rodents and humans results in increased food intake in combination with reduced energy expenditure (and thus obesity), plus neuroendocrine dysfunction (including hypothyroidism, decreased growth, infertility and decreased immune function) (1;7-9). Many of the effects of leptin are attributable to effects in the CNS, particularly in the hypothalamus, a site of high LepRb mRNA expression (2;3).

Previously published online as a Cell Cycle E-publication: http://www.landesbioscience.com/journals/cc/abstract.php?id=3699 KeY WORDSCHK1, CHK2, EXEL-9844, XL844, S-phase checkpoint, gemcitabine ABBReviATiONS ATRATM and Rad3-related kinase TGI tumor growth inhibition MBP myelin basic protein ABSTRACTChk1 and Chk2 kinases are critically involved in modulating DNA damage checkpoints. In particular, Chk1, a key activator of the S-phase DNA damage response, may be involved in resistance to genotoxic therapies that target DNA synthesis. We studied the in vitro and in vivo effects of EXEL-9844 (XL844), a potent, orally available, and specific inhibitor of Chk1 and Chk2, in combination with gemcitabine. In clonogenic assays using multiple cell lines in vitro, EXEL-9844 had only minor effects as a single agent but substantially enhanced gemcitabine-induced cell killing. Correspondingly, in PANC-1 cells, EXEL-9844 increased gemcitabine-induced H2AX phosphorylation, blocked Cdc25A phosphorylation, and induced premature mitotic entry. In a PANC-1 xenograft model, EXEL-9844 significantly enhanced gemcitabine antitumor activity but had limited effect as a single agent. Together, these data show that cell cycle checkpoint inhibitors may have significant clinical utility in potentiating the activity of gemcitabine.

The incidence of intrahepatic cholangiocarcinoma (ICC) is increasing worldwide. The prognosis of ICC is poor and a better understanding of ICC tumor biology is needed to more accurately predict clinical outcome and to suggest potential targets for more effective therapies. v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) and BRAF are frequently mutated oncogenes that promote carcinogenesis in a variety of tumor types. In this study, we analyze a large set of ICC tumors (N = 54) for mutations in these genes and compare the clinical outcomes of wild type versus KRAS and BRAF mutant cases. Out of 54 cases, 7.4% were mutant for KRAS, 7.4% were mutant for BRAF and these were mutually exclusive. These mutant cases were associated with a higher tumor stage at time of resection and a greater likelihood of lymph node involvement. These cases were also associated with a worse long-term overall survival. Therefore, testing for KRAS and BRAF mutations could be a valuable adjunct in improving both prognosis and outcome stratification among patients with ICC.

No abstract