The nuclear factor kappa B (NF-κB) regulates genes that function in diverse cellular processes like inflammation, immunity and cell survival. The activation of NF-κB is tightly controlled and the deubiquitinase CYLD has emerged as a key negative regulator of NF-κB signalling. Optineurin, mutated in certain glaucomas and amyotrophic lateral sclerosis, is also a negative regulator of NF-κB activation. It competes with NEMO (NF-κB essential modulator) for binding to ubiquitinated RIP (receptor interacting protein) to prevent NF-κB activation. Recently we identified CYLD as optineurin-interacting protein. Here we have analysed the functional significance of interaction of optineurin with CYLD. Our results show that a glaucoma-associated mutant of optineurin, H486R, is altered in its interaction with CYLD. Unlike wild-type optineurin, the H486R mutant did not inhibit tumour necrosis factor α (TNFα)-induced NF-κB activation. CYLD mediated inhibition of TNFα-induced NF-κB activation was abrogated by expression of the H486R mutant. Upon knockdown of optineurin, CYLD was unable to inhibit TNFα-induced NF-κB activation and showed drastically reduced interaction with ubiquitinated RIP. The level of ubiquitinated RIP was increased in optineurin knockdown cells. Deubiquitination of RIP by over-expressed CYLD was abrogated in optineurin knockdown cells. These results suggest that optineurin regulates NF-κB activation by mediating interaction of CYLD with ubiquitinated RIP thus facilitating deubiquitination of RIP.

Prophylaxis has been established as the treatment of choice in children with haemophilia and its continuation into the adult years has been shown to decrease morbidity throughout life. The cost of factor therapy has made the option questionable in cost-effectiveness studies. The role of prophylaxis in pharmacokinetic dosage and tolerization against inhibitor formation were used to model the cost utility of prophylaxis vs. on-demand (OD) therapy over a lifetime horizon in severe haemophilia A. The model was applied to a single provider national health system exemplified by the United Kingdom's National Health Service and a third party provider in the United States. The incremental cost-effectiveness ratio (ICER) was estimated and compared to threshold values used by payer agencies to guide reimbursement decisions. A cost per quality-adjusted life year (QALY) was also estimated for Sweden. Prophylaxis was dominant over OD treatment in the UK. The model resulted in an ICER - $68 000 - within the range of treatments reimbursed in the USA. In Sweden, a cost/QALY of SEK 1.1 million was also within the range of reimbursed treatments in that country. Dosage- and treatment-induced inhibitor incidence were the most important variables in the model. Subject to continuing clinical evidence of the effectiveness of pharmacokinetic dosage and the role of prophylaxis in decreasing inhibitor incidence, treatment for life with prophylaxis is a cost-effective therapy, using current criteria for the reimbursement of health care technologies in a number of countries.

Autophagy is a quality-control mechanism that helps to maintain cellular homeostasis by removing damaged proteins and organelles through lysosomal degradation. During autophagy, signaling events lead to the formation of a cup-shaped structure called the phagophore that matures into the autophagosome. Recruitment of the autophagy-associated Atg12-5-16L1 complex to Wipi2-positive phagophores is crucial for producing microtubule-associated protein 1 light chain 3-II (LC3-II), which is required for autophagosome formation. Here, we explored the role of the autophagy receptor optineurin (Optn) in autophagosome formation. Fibroblasts from Optn knock-out mouse showed reduced LC3-II formation and a lower number of autophagosomes and autolysosomes during both basal and starvation-induced autophagy. However, the number of Wipi2-positive phagophores was not decreased in Optn-deficient cells. We also found that the number of Atg12/16L1-positive puncta and recruitment of the Atg12-5-16L1 complex to Wipi2-positive puncta are reduced in Optn-deficient cells. Of note, Optn was recruited to Atg12-5-16L1-positive puncta, and interacted with Atg5 and also with Atg12-5 conjugate. A disease-associated Optn mutant, E478G, defective in ubiquitin binding, was also defective in autophagosome formation and recruitment to the Atg12-5-16L1-positive puncta. Moreover, we noted that Optn phosphorylation at Ser-177 was required for autophagosome formation but not for Optn recruitment to the phagophore. These results suggest that Optn potentiates LC3-II production and maturation of the phagophore into the autophagosome, by facilitating the recruitment of the Atg12-5-16L1 complex to Wipi2-positive phagophores.

Duloxetine appears to be a cost-effective post-first-line treatment for CLBP compared with all but generic NSAIDs. In subpopulations at risk of NSAID-related AEs, it is particularly cost-effective.

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Optineurin is a multifunctional protein involved in a variety of cellular functions such as protein trafficking by vesicles, autophagy, and signal transduction. Certain mutations in optineurin (gene OPTN) are associated with neurodegenerative diseases like glaucoma and amyotrophic lateral sclerosis (ALS). Optineurin is also seen in pathological structures present in several other neurodegenerative diseases. In glaucoma, loss of vision occurs due to progressive degeneration of retinal ganglion cells, and perhaps loss of photoreceptor cone cells as well. Most of the glaucoma-associated mutations of optineurin are heterozygous missense mutations, whereas the ALS-associated mutations include deletion, truncation, and missense mutations. Optineurin mediates its functions by interacting with various proteins, often acting as an adaptor to provide a link between two or more proteins. Disease-causing mutations alter these interactions leading to functional defects in membrane vesicle trafficking, autophagy, signaling, aggregate formation, and other processes. Some of these functional defects, caused by glaucomaassociated mutants of optineurin, led to retinal cell death mediated by apoptosis and therefore may contribute to pathogenesis directly. Other mutations are likely to cause glaucoma by indirect mechanisms involving other cell types. Mechanisms of ALS pathogenesis by optineurin mutations are yet to be investigated in detail; however, some ALSassociated mutants cause defects in signaling, autophagy, and ubiquitin binding, which might contribute to pathogenesis. V C 2015 IUBMB Life, 67(2): [120][121][122][123][124][125][126][127][128] 2015

The model estimated that duloxetine was potentially cost effective in the base-case population and more cost effective for subgroups over 65 years or at high risk of NSAID-related AEs. In sensitivity analysis, duloxetine dominated all strong opioids in nearly all scenarios.