Expression of V1A and GRP receptors leads to cellular transformation and increased sensitivity to substance-P analogue-induced growth inhibition.

Small-cell lung cancer (SCLC) is a particularly aggressive cancer, which metastasises early. Despite initial sensitivity to radio- and chemo-therapy, it invariably relapses, so that the 2-year survival remains less than 5%. Neuropeptides particularly arginine vasopressin (AVP) and gastrin-releasing peptide (GRP) act as autocrine and paracrine growth factors and the expression of these and their receptors are a hallmark of the disease. Substance-P analogues including [D-Arg1,D-Phe5,D-Trp7,9,Leu11]-substance-P (SP-D) and [Arg6,D-Trp7,9,NmePhe8]-substance-P (6-11) (SP-G) inhibit the growth of SCLC cells by modulating neuropeptide signalling. We show that GRP and V1A receptors expression leads to the development of a transformed phenotype. Addition of neuropeptide provides some protection from etoposide-induced cytotoxicity. Receptor expression also leads to an increased sensitivity to substance-P analogue-induced growth inhibition. We show that SP-D and SP-G act as biased agonists at GRP and V1A receptors causing blockade of Gq-mediated Ca2+ release while directing signalling to activate ERK via a pertussis toxin-sensitive pathway. This is the first description of biased agonism at V1A receptors. This unique pharmacology governs the antiproliferative properties of these agents and highlights their potential therapeutic potential for the treatment of SCLC and particularly in tumours, which have developed resistance to chemotherapy

B cell depletion in autoimmune diabetes:insights from murine models

INTRODUCTION: The incidence of type 1 diabetes (T1D) is rising for reasons that largely elude us. New strategies aimed at halting the disease process are needed. One type of immune cell thought to contribute to T1D is the B lymphocyte. The first Phase II trial of B cell depletion in new onset T1D patients indicated that this slowed the destruction of insulin-producing pancreatic beta cells. The mechanistic basis of the beneficial effects remains unclear. AREAS COVERED: Studies of B cell depletion and deficiency in animal models of T1D. How B cells can influence T cell-dependent autoimmune diabetes in animal models. The heterogeneity of B cell populations and current evidence for the potential contribution of specific B cell subsets to diabetes, with emphasis on marginal zone B cells and B1 B cells. EXPERT OPINION: B cells can influence the T cell response to islet antigens and B cell depletion or genetic deficiency is associated with decreased insulitis in animal models. New evidence suggests that B1 cells may contribute to diabetes pathogenesis. A better understanding of the roles of individual B cell subsets in disease will permit fine-tuning of therapeutic strategies to modify these populations

The LLNL configurable seismic monitoring system

Lawrence Livermore National Laboratory (LLNL) developed and tested a portable, high-quality seismic recording system for monitoring underground nuclear explosions. The configurable seismic monitoring system (CSMS) was designed to satisfy the designated seismic station (DSS) requirements for instrumentation to be deployed in a vault as set forth in the protocol of the Threshold Test Ban Treaty (TTBT). As a proof-of-concept test under treaty monitoring conditions, two configurations of this system were built, and each was deployed at a different seismic station to record the Nevada Test Site (NTS) event Bexar. Both configurations successfully recorded this event, demonstrating the flexibility and the operation of the basis design. 3 refs., 8 figs

Bradykinin antagonist dimer, CU201, inhibits the growth of human lung cancer cell lines by a “biased agonist” mechanism

All small cell (SCLCs) and many non-small cell lung cancers (NSCLCs) have neuroendocrine features including production of neuropeptides and cell surface receptors creating autocrine and paracrine growth loops. Neuropeptides bind to a family of 7-transmembrane receptors and activate heterotrimeric G proteins consisting of G(αq) and G(α12,13). Substance P derivatives (SPDs) induced apoptosis and inhibited growth of lung cancer cells by discoordinately inhibiting G(αq) and stimulating G(α12,13). However, these SPDs had low potency and short half-lives. In this report we show that a bradykinin antagonist dimer, CU201, inhibited the growth of SCLC and NSCLC cell lines with or without multidrug-resistant proteins and was 10-fold more potent with a longer plasma half-life than SPDs. Bradykinin agonists in either monomeric or dimeric form and monomeric bradykinin antagonist have no effect on lung cancer cell growth. The dimeric linking moiety of the two molecules was created, requiring a sufficient number of carbon chains to provide critical spacing between the two antagonists. CU201 inhibited intracellular Ca(2+) release in response to bradykinin, indicating blockage of the G(αq) signal, and stimulated c-Jun kinases, indicating stimulation of the G(α12,13) pathway. CU201-induced apoptosis was preceded by unique changes in apparent nuclear DNA binding and by c-Jun kinase and caspase-3 activation. At the concentration at which CU201 inhibited the growth of the cancer cells, it had no effect on the growth of normal lung cells in vitro. CU201 and similar compounds offer hope of becoming a new form of targeted therapy for tumors with neuroendocrine properties