The primary structure of human insulin-like growth factor II receptor, predicted from the complementary DNA sequence, reveals a transmembrane receptor molecule with a large extracellular domain made up of fifteen repeat sequences and a small region homologous to the collagen-binding domain of fibronectin. The structural and biochemical features of the IGF-II receptor appear identical to those of the cation-independent mannose-6-phosphate receptor.

Background: NAMPT catalyzes the rate-limiting reaction in converting nicotinamide to NAD ϩ in cancers.

Multiple risk behaviour is prevalent in both genders during adolescence but the pattern of individual risk behaviour varies between boys and girls. Effective interventions at the individual, family, school, community or population level are needed to address gender-specific patterns of risk behaviour during adolescence.

Background. Patterns of risk behaviour during teenage years may vary by socio-economic status (SES). We aimed to examine possible associations between individual and multiple risk behaviours and three measures of SES in mid-adolescence. Methods. The sample (n = 6406) comprised participants from the Avon Longitudinal Study of Parents and Children, a UK birth cohort. Thirteen risk behaviours spanning sexual health, substance use, self-harm, vehicle-related injury, criminality and physical inactivity were assessed in mid-adolescence (age 15–16 years). Associations between three measures of SES (maternal education, household income and parental social class) and (i) individual risk behaviours and (ii) the total number of risk behaviours were examined. Results. For a one-category reduction in social class, maternal education or income, the odds of having a greater number of multiple risk behaviours increased by 22, 15 and 12%, respectively. At the individual level, there was evidence of a strong relationship with decreasing SES across all three measures of SES and criminality, car passenger risk, TV viewing, scooter risk, early sexual behaviour and weekly tobacco use but insufficient evidence of a relationship for physical inactivity, cycling without a helmet and illicit substance use. There was weak evidence of association between SES and hazardous drinking, self-harm, cannabis use and unprotected sex, but this was not consistent across the SES measures. Conclusion. The association between multiple risk behaviours and SES suggests that prevention strategies should apply the principal of proportionate universalism with a focus on more deprived populations, within a population-wide strategy, to prevent widening of social inequalities.

The limitations of the study include incomplete data capture, analysis of only PF requiring revision and that observation does not imply causality. Nevertheless, this study demonstrates that the choice of a cemented stem may influence the risk of revision for PF. Cite this article: Bone Joint J 2016;98-B:1347-54.

The first potent inhibitors of glutamate racemase (MurI) enzyme that show whole cell antibacterial activity are described. Optically pure 4-substituted D-glutamic acid analogues with (2R,4S) stereochemistry and bearing aryl-, heteroaryl-, cinnamyl-, or biaryl-methyl substituents represent a novel class of glutamate racemase inhibitors. Exploration of the D-Glu core led to the identification of lead compounds (-)-8 and 10. 2-Naphthylmethyl derivative 10 was found to be a potent competitive inhibitor of glutamate racemase activity (K(i) = 16 nM, circular dichroism assay; IC(50) = 0.1 microg/mL high-performance liquid chromatography (HPLC) assay). Thorough structure-activity relationship (SAR) studies led to benzothienyl derivatives such as 69 and 74 with increased potency (IC(50) = 0.036 and 0.01 microg/mL, respectively, HPLC assay). These compounds showed potent whole cell antibacterial activity against S. pneumoniae PN-R6, and good correlation with the enzyme assay. Compounds 69, 74 and biaryl derivative 52 showed efficacy in an in vivo murine thigh infection model against Streptococcus pneumoniae. Data described herein suggest that glutamate racemase may be a viable target for developing new antibacterial agents.

The PI3K/AKT/mTOR pathway is among the most frequently altered pathways in cancer cell growth and survival.

Owing to the prevalence of the JAK2V617F mutation in myeloproliferative neoplasms (MPNs), its constitutive activity, and ability to recapitulate the MPN phenotype in mouse models, JAK2V617F kinase is an attractive therapeutic target. We report the discovery and initial characterization of the orally bioavailable imidazopyridazine, LY2784544, a potent, selective and ATP-competitive inhibitor of janus kinase 2 (JAK2) tyrosine kinase. LY2784544 was discovered and characterized using a JAK2-inhibition screening assay in tandem with biochemical and cell-based assays. LY2784544 in vitro selectivity for JAK2 was found to be equal or superior to known JAK2 inhibitors. Further studies showed that LY2784544 effectively inhibited JAK2V617F-driven signaling and cell proliferation in Ba/F3 cells (IC50=20 and 55 nM, respectively). In comparison, LY2784544 was much less potent at inhibiting interleukin-3-stimulated wild-type JAK2-mediated signaling and cell proliferation (IC50=1183 and 1309 nM, respectively). In vivo, LY2784544 effectively inhibited STAT5 phosphorylation in Ba/F3-JAK2V617F-GFP (green fluorescent protein) ascitic tumor cells (TED50=12.7 mg/kg) and significantly reduced (P<0.05) Ba/F3-JAK2V617F-GFP tumor burden in the JAK2V617F-induced MPN model (TED50=13.7 mg/kg, twice daily). In contrast, LY2784544 showed no effect on erythroid progenitors, reticulocytes or platelets. These data suggest that LY2784544 has potential for development as a targeted agent against JAK2V617F and may have properties that allow suppression of JAK2V617F-induced MPN pathogenesis while minimizing effects on hematopoietic progenitor cells.