Homologous and heterologous desensitization of guanylyl cyclase-B signaling in GH3 somatolactotropes

The guanylyl cyclases, GC-A and GC-B, are selective receptors for atrial and C-type natriuretic peptides (ANP and CNP, respectively). In the anterior pituitary, CNP and GC-B are major regulators of cGMP production in gonadotropes and yet mouse models of disrupted CNP and GC-B indicate a potential role in growth hormone secretion. In the current study, we investigate the molecular and pharmacological properties of the CNP/GC-B system in somatotrope lineage cells. Primary rat pituitary and GH3 somatolactotropes expressed functional GC-A and GC-B receptors that had similar EC50 properties in terms of cGMP production. Interestingly, GC-B signaling underwent rapid homologous desensitization in a protein phosphatase 2A (PP2A)-dependent manner. Chronic exposure to either CNP or ANP caused a significant down-regulation of both GC-A- and GC-B-dependent cGMP accumulation in a ligand-specific manner. However, this down-regulation was not accompanied by alterations in the sub-cellular localization of these receptors. Heterologous desensitization of GC-B signaling occurred in GH3 cells following exposure to either sphingosine-1-phosphate or thyrotrophin-releasing hormone (TRH). This heterologous desensitization was protein kinase C (PKC)-dependent, as pre-treatment with GF109203X prevented the effect of TRH on CNP/GC-B signaling. Collectively, these data indicate common and distinct properties of particulate guanylyl cyclase receptors in somatotropes and reveal that independent mechanisms of homologous and heterologous desensitization occur involving either PP2A or PKC. Guanylyl cyclase receptors thus represent potential novel therapeutic targets for treating growth-hormone-associated disorders

Curcumin Prevents Palmitoylation of Integrin β4 in Breast Cancer Cells

We thank Dr. Tak yee Aw for technical assistance and critical discussion of the manuscript. This study is supported by American Cancer Society (RSG-09-091-01-CSM: JC) and NIH-NCI (R01CA163657-01A1: JC).Curcumin has been shown to mitigate cancer phenotypes such as invasive migration, proliferation, and survival by disrupting numerous signaling pathways. Our previous studies showed that curcumin inhibits integrin β4 (ITG β4)-dependent migration by blocking interaction of this integrin with growth factor receptors in lipid rafts. In the current study, we investigated the possibility that curcumin inhibits ITG β4 palmitoylation, a post-translational modification required for its lipid raft localization and signaling activity. We found that the levels of ITG β4 palmitoylation correlated with the invasive potential of breast cancer cells, and that curcumin effectively reduced the levels of ITG β4 palmitoylation in invasive breast cancer cells. Through studies of ITG β4 palmitoylation kinetics, we concluded curcumin suppressed palmitoylation independent of growth factor-induced phosphorylation of key ITG β4 Ser and Tyr residues. Rather, curcumin blocked autoacylation of the palmitoyl acyltransferase DHHC3 that is responsible for ITG β4 palmitoylation. Moreover, these data reveal that curcumin is able to prevent the palmitoylation of a subset of proteins, but not indiscriminately bind to and block all cysteines from modifications. Our studies reveal a novel paradigm for curcumin to account for much of its biological activity, and specifically, how it is able to suppress the signaling function of ITG β4 in breast cancer cells.Yeshttp://www.plosone.org/static/editorial#pee

Dealing with Time in Health Economic Evaluation: Methodological Issues and Recommendations for Practice

Time is an important aspect of health economic evaluation, as the timing and duration of clinical events, healthcare interventions and their consequences all affect estimated costs and effects. These issues should be reflected in the design of health economic models. This article considers three important aspects of time in modelling: (1) which cohorts to simulate and how far into the future to extend the analysis; (2) the simulation of time, including the difference between discrete-time and continuous-time models, cycle lengths, and converting rates and probabilities; and (3) discounting future costs and effects to their present values. We provide a methodological overview of these issues and make recommendations to help inform both the conduct of cost-effectiveness analyses and the interpretation of their results. For choosing which cohorts to simulate and how many, we suggest analysts carefully assess potential reasons for variation in cost effectiveness between cohorts and the feasibility of subgroup-specific recommendations. For the simulation of time, we recommend using short cycles or continuous-time models to avoid biases and the need for half-cycle corrections, and provide advice on the correct conversion of transition probabilities in state transition models. Finally, for discounting, analysts should not only follow current guidance and report how discounting was conducted, especially in the case of differential discounting, but also seek to develop an understanding of its rationale. Our overall recommendations are that analysts explicitly state and justify their modelling choices regarding time and consider how alternative choices may impact on results

Pediatric anterior cruciate ligament reconstruction

An increasing number of anterior cruciate ligament (ACL) injuries are seen in children now than in the past due to increased sports participation. The natural history of ACL deficient knees in active individuals, particularly in children is poor. Surgical management of ACL deficiency in children is complex due to the potential risk of injury to the physis and growth disturbance. Delaying ACL reconstruction until maturity is possible but risks instability episodes and intra-articular damage. Surgical options include physeal-sparing, partial transphyseal and complete transphyseal procedures. This article reviews the management of ACL injured skeletally immature patients including the functional outcome and complications of contemporary surgical techniques