Glucagon-like peptide-1 (GLP-1) is a gut hormone synthesized by post-translational processing in intestinal L-cells, and it is released in response to food ingestion. GLP-1 stimulates insulin secretion during hyperglycemia, suppresses glucagon secretion, stimulates (pro)-insulin biosynthesis and decreases the rate of gastric emptying and acid secretion. GLP-1 has also been shown to have a prosatiety effect. In addition, it has been demonstrated that a long-term infusion with GLP-1, or exendin-4, a long-acting analog of human GLP-1, increases b-cell mass in rats. In conclusion, GLP-1 appears to regulate plasma glucose levels via various and independent mechanisms. GLP-1 is an excellent candidate option for the treatment of patients with type 2 diabetes mellitus.

Natural killer (NK) cells produce interferon (IFN)-γ and thus have been suggested to promote type I immunity during bacterial infections. Yet, Listeria monocytogenes (Lm) and some other pathogens encode proteins that cause increased NK cell activation. Here, we show that stimulation of NK cell activation increases susceptibility during Lm infection despite and independent from robust NK cell production of IFNγ. The increased susceptibility correlated with IL-10 production by responding NK cells. NK cells produced IL-10 as their IFNγ production waned and the Lm virulence protein p60 promoted induction of IL-10 production by mouse and human NK cells. NK cells consequently exerted regulatory effects to suppress accumulation and activation of inflammatory myeloid cells. Our results reveal new dimensions of the role played by NK cells during Lm infection and demonstrate the ability of this bacterial pathogen to exploit the induction of regulatory NK cell activity to increase host susceptibility.

The incretin hormone glucagon-like peptide-1 (GLP-1) is capable of ameliorating glucose-dependent insulin secretion in subjects with diabetes. However, its very short half-life (1.5 -5 min) in plasma represents a major limitation for its use in the clinical setting. The present study was designed to characterize the duration of the effect of GLP-1 in the Zucker diabetic fatty (ZDF) rat. ZDF rats were subjected to a 48 h infusion of human GLP-1 (30 pmol/kg per min), followed by an i.p. glucose tolerance test (IPGTT) (1 g/kg body weight), 2 h after removing the infusion pump. At 15 min from the beginning of the test, GLP-1-treated animals had lower plasma glucose levels (442^38 mg/dl) than salineinfused controls ð583^63 mg=dl; P , 0:01Þ: This was reflected in the higher insulin levels attained in the GLP-1-treated animals ð1999^163 vs 1250^51 pmol=l; GLP-1 vs saline respectively, P , 0:01Þ: Repetition of the IPGTT on day 3, 9 and 16 from the removal of the infusion pump revealed a surprising lasting 'memory' of the exposure to GLP-1. Indeed, the best insulin secretory response was observed approximately 1 week after discontinuation of the GLP-1 infusion, and lasted up to 3 weeks from the early exposure to GLP-1. Detection of fasting plasma levels of GLP-1 during the 3 weeks of the experiment showed a very rapid decline, consistent with the data reported by others. Our findings provide evidence for a long-lasting beneficial effect of GLP-1 that persists for weeks even when the circulating levels of GLP-1 are back to normal.

An acquired immune deficiency due to interferon gamma (IFN-γ) autoantibodies was diagnosed in a 78-year-old Japanese man with treatment-refractory disseminated nontuberculous mycobacterial infection. In addition to standard antimycobacterial therapy, he was successfully treated with rituximab to eliminate B cells and thereby the autoantibody. Subsequently, he obtained a sustained remission from infection.

A class of 2-acyliminobenzimidazoles has been developed as potent and selective inhibitors of anaplastic lymphoma kinase (ALK). Structure based design facilitated the rapid development of structure-activity relationships (SAR) and the optimization of kinase selectivity. Introduction of an optimally placed polar substituent was key to solving issues of metabolic stability and led to the development of potent, selective, orally bioavailable ALK inhibitors. Compound 49 achieved substantial tumor regression in an NPM-ALK driven murine tumor xenograft model when dosed qd. Compounds 36 and 49 show favorable potency and PK characteristics in preclinical species indicative of suitability for further development.