Effectiveness of denosumab for fracture prevention in real-world postmenopausal women with osteoporosis: a retrospective cohort study

Summary: To determine denosumab’s effectiveness for fracture prevention among postmenopausal women with osteoporosis in East Asia, the risk of fracture was compared between patients continuing denosumab therapy versus patients discontinuing denosumab after one dose. The real-world effectiveness was observed to be consistent with the efficacy demonstrated in the phase III trial. Introduction: After therapeutic efficacy is demonstrated for subjects in global clinical trials, real-world evidence may provide complementary knowledge of therapeutic effectiveness in a heterogeneous mix of patients seen in clinical practice. This retrospective cohort study was conducted to compare the fracture risk in real-world clinical care received in Taiwan and Hong Kong between a treatment cohort (patients receiving denosumab 60 mg subcutaneously every 6 months) versus an off-treatment cohort (patients discontinuing after 1 dose of denosumab, which has no known clinical benefit) among real-world postmenopausal women. Methods: This study included 38,906 and 2,835 postmenopausal women receiving denosumab in Taiwan and Hong Kong, respectively. The primary endpoint was hip fracture, and secondary endpoints were clinical vertebral and nonvertebral fractures. Propensity-score-matched analysis, adjusting for known covariates, was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). The robustness of findings was evaluated with a series of sensitivity and quantitative bias analyses. Results: In this study, 554 hip fractures were included in the primary Taiwan population analysis. The crude incidence rate was 0.9 per 100 person-years in the treatment cohort (n = 25,059) and 1.7 per 100 person-years in the off-treatment cohort (n = 13,847). After adjusting for prognostic differences between cohorts, denosumab reduced the risk of hip fractures by 38% (HR = 0.62, CI:0.52–0.75). Risk reductions of similar magnitude were observed for the secondary endpoints and for the analysis of the smaller Hong Kong population. Conclusion: The effectiveness of denosumab for fracture reduction among real-world postmenopausal women with osteoporosis was consistent with the efficacy demonstrated in a global clinical trial

Activation of p38MAPK Contributes to Expanded Polyglutamine-Induced Cytotoxicity

The signaling pathways that may modulate the pathogenesis of diseases induced by expanded polyglutamine proteins are not well understood.Herein we demonstrate that expanded polyglutamine protein cytotoxicity is mediated primarily through activation of p38MAPK and that the atypical PKC iota (PKCiota) enzyme antagonizes polyglutamine-induced cell death through induction of the ERK signaling pathway. We show that pharmacological blockade of p38MAPK rescues cells from polyglutamine-induced cell death whereas inhibition of ERK recapitulates the sensitivity observed in cells depleted of PKCiota by RNA interference. We provide evidence that two unrelated proteins with expanded polyglutamine repeats induce p38MAPK in cultured cells, and demonstrate induction of p38MAPK in an in vivo model of neurodegeneration (spinocerebellar ataxia 1, or SCA-1).Taken together, our data implicate activated p38MAPK in disease progression and suggest that its inhibition may represent a rational strategy for therapeutic intervention in the polyglutamine disorders

A novel high-nuclearity luminescent gold(I)-sulfido complex

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Syntheses and luminescence studies of mixed-metal gold(I)-copper(I) and -silver(I) alkynyl complexes. the "turning-on" of emission upon d 10 metal ion encapsulation

Reaction of the gold(I) alkynyl precursor complexes, [(R 3P)Au{CξCC(=CH2)Me}] (R = Ph 1,p-Tol 2) and [(μ-dppf)-Au2{CξCC(=CH2)Me}2] 3, with copper(I) or silver(I) ions led to the formation of a series of luminescent η2-alkynyl mixed-metal complexes, [{η2- (R 3P)Au{CξCC(=CH2)Me}}2Cu]PF6 (R = Ph 4, p-Tol 5) and [(μ-dppf)Au2{η2-CξCC-(= CH2)Me}2M]X (M = Cu, X = PF66; M = Ag, X = OTf 7). The X-ray crystal structures of 1 and 3 have been determined. The photophysical properties of the complexes have been investigated. Coordination of 1-3 as metalloligands to copper(I) and silver(I) ions to afford the respective complexes 4-7 has been demonstrated to be a versatile means to perturb the emission properties. The luminescence behaviour of 3 has been "turned on" upon copper(I) or silver(I) encapsulation in 6 and 7. © The Royal Society of Chemistry 2003.link_to_subscribed_fulltex

Synthesis, photoluminescent and electroluminescent behaviour of four- coordinate tetrahedral gold(I) complexes. X-ray crystal structure of [Au(dppn)2]Cl

Two tetrahedral four-coordinate Au(I) complexes, [Au(4-R-dppn)2]PF6 (R = H or Me), have been synthesized and the crystal structure of [Au(dppn)2]Cl has been determined by X-ray crystallography; the complexes have been found to exhibit both photoluminescent and electroluminescent behaviour.link_to_subscribed_fulltex