Efficacy and safety of ixekizumab through 52 weeks in two phase 3, randomised, controlled clinical trials in patients with active radiographic axial spondyloarthritis (COAST-V and COAST-W).

OBJECTIVES: To investigate the efficacy and safety of ixekizumab for up to 52 weeks in two phase 3 studies of patients with active radiographic axial spondyloarthritis (r-axSpA) who were biological disease-modifying antirheumatic drug (bDMARD)-naive (COAST-V) or tumour necrosis factor inhibitor (TNFi)-experienced (COAST-W). METHODS: Adults with active r-axSpA were randomised 1:1:1:1 (n=341) to 80 mg ixekizumab every 2 (IXE Q2W) or 4 weeks (IXE Q4W), placebo (PBO) or 40 mg adalimumab Q2W (ADA) in COAST-V and 1:1:1 (n=316) to IXE Q2W, IXE Q4W or PBO in COAST-W. At week 16, patients receiving ixekizumab continued their assigned treatment; patients receiving PBO or ADA were rerandomised 1:1 to IXE Q2W or IXE Q4W (PBO/IXE, ADA/IXE) through week 52. RESULTS: In COAST-V, Assessment of SpondyloArthritis international Society 40 (ASAS40) responses rates (intent-to-treat population, non-responder imputation) at weeks 16 and 52 were 48% and 53% (IXE Q4W); 52% and 51% (IXE Q2W); 36% and 51% (ADA/IXE); 19% and 47% (PBO/IXE). Corresponding ASAS40 response rates in COAST-W were 25% and 34% (IXE Q4W); 31% and 31% (IXE Q2W); 14% and 39% (PBO/IXE). Both ixekizumab regimens sustained improvements in disease activity, physical function, objective markers of inflammation, QoL, health status and overall function up to 52 weeks. Safety through 52 weeks of ixekizumab was consistent with safety through 16 weeks. CONCLUSION: The significant efficacy demonstrated with ixekizumab at week 16 was sustained for up to 52 weeks in bDMARD-naive and TNFi-experienced patients. bDMARD-naive patients initially treated with ADA demonstrated further numerical improvements after switching to ixekizumab. Safety findings were consistent with the known safety profile of ixekizumab. TRIAL REGISTRATION NUMBER: NCT02696785/NCT02696798

Analysis of western lowland gorilla (Gorilla gorilla gorilla) specific Alu repeats

Background: Research into great ape genomes has revealed widely divergent activity levels over time for Alu elements. However, the diversity of this mobile element family in the genome of the western lowland gorilla has previously been uncharacterized. Alu elements are primate-specific short interspersed elements that have been used as phylogenetic and population genetic markers for more than two decades. Alu elements are present at high copy number in the genomes of all primates surveyed thus far. The AluY subfamily and its derivatives have been recognized as the evolutionarily youngest Alu subfamily in the Old World primate lineage. Results: Here we use a combination of computational and wet-bench laboratory methods to assess and catalog AluY subfamily activity level and composition in the western lowland gorilla genome (gorGor3.1). A total of 1,075 independent AluY insertions were identified and computationally divided into 10 subfamilies, with the largest number of gorilla-specific elements assigned to the canonical AluY subfamily. Conclusions: The retrotransposition activity level appears to be significantly lower than that seen in the human and chimpanzee lineages, while higher than that seen in orangutan genomes, indicative of differential Alu amplification in the western lowland gorilla lineage as compared to other Homininae. © 2013 McLain et al.; licensee BioMed Central Ltd

Analysis of western lowland gorilla (Gorilla gorilla gorilla) specific Alu repeats

Abstract Background Research into great ape genomes has revealed widely divergent activity levels over time for Alu elements. However, the diversity of this mobile element family in the genome of the western lowland gorilla has previously been uncharacterized. Alu elements are primate-specific short interspersed elements that have been used as phylogenetic and population genetic markers for more than two decades. Alu elements are present at high copy number in the genomes of all primates surveyed thus far. The AluY subfamily and its derivatives have been recognized as the evolutionarily youngest Alu subfamily in the Old World primate lineage. Results Here we use a combination of computational and wet-bench laboratory methods to assess and catalog AluY subfamily activity level and composition in the western lowland gorilla genome (gorGor3.1). A total of 1,075 independent AluY insertions were identified and computationally divided into 10 subfamilies, with the largest number of gorilla-specific elements assigned to the canonical AluY subfamily. Conclusions The retrotransposition activity level appears to be significantly lower than that seen in the human and chimpanzee lineages, while higher than that seen in orangutan genomes, indicative of differential Alu amplification in the western lowland gorilla lineage as compared to other Homininae.http://deepblue.lib.umich.edu/bitstream/2027.42/112762/1/13100_2013_Article_86.pd

An invasive adenocarcinoma of the accessory parotid gland: a rare example developing from a low-grade cribriform cystadenocarcinoma?

Low-grade cribriform cystadenocarcinoma (LGCCA) is a rare tumor of the salivary gland that exhibits clinically indolent behavior. In this paper, we present a case of invasive adenocarcinoma of the accessory parotid gland in a young male that exhibited histology suggestive of an association of LGCCA. A 27-year-old man presented with a subcutaneous tumor in his left cheek. The tumor was separated from the parotid gland and located on the masseter muscle. The tumor was resected, and the postoperative histological diagnosis was adenocarcinoma, not otherwise specified (ANOS). The tumor exhibited papillary-cystic and cribriform proliferation of the duct epithelium and obvious stromal infiltration. Some tumor nests were rimmed by myoepithelium positive for smooth muscle actin, p63, and cytokeratin 14, indicating the presence of intraductal components of the tumor. Tumor cells exhibited mild nuclear atypia, and some of them presented an apocrine-like appearance and had cytoplasmic PAS-positive/diastase-resistant granules and hemosiderin. Other cells had foamy cytoplasm with microvacuoles. Immunohistochemistry revealed that the almost all of the tumor cells were strongly positive for S-100. These histological findings suggest the possibility that ANOS might arise secondarily from LGCCA. This is an interesting case regarding the association between ANOS and LGCCA in oncogenesis

Overexpression of sphingosine kinase 1 is associated with salivary gland carcinoma progression and might be a novel predictive marker for adjuvant therapy

<p>Abstract</p> <p>Background</p> <p>Overexpression of sphingosine kinase-1 (SPHK1) has been demonstrated to be associated with the development and progression in various types of human cancers. The current study was to characterize the expression of SPHK1 in salivary gland carcinomas (SGC) and to investigate the association between SPHK1 expression and progression of SGC.</p> <p>Methods</p> <p>The expression of SPHK1 was examined in 2 normal salivary gland tissues, 8 SGC tissues of various clinical stages, and 5 pairs of primary SGC and adjacent salivary gland tissues from the same patient, using real-time PCR and western blot analysis. Furthermore, the SPHK1 protein expression was analyzed in 159 clinicopathologically characterized SGC cases by immunohistochemistry. Statistical analyses were performed to determine the prognostic and diagnostic associations.</p> <p>Results</p> <p>SPHK1 expression was found to be markedly upregulated in SGC tissues than that in the normal salivary gland tissues and paired adjacent salivary gland tissues, at both mRNA and protein levels. Statistical analysis revealed a significant correlation of SPHK1 expression with the clinical stage (<it>P </it>= 0.005), T classification (<it>P </it>= 0.017), N classification (<it>P </it>= 0.009), M classification (<it>P </it>= 0.002), and pathological differentiation (<it>P </it>= 0.013). Patients with higher SPHK1 expression had shorter overall survival time, whereas patients with lower SPHK1 expression had better survival. Importantly, patients in the group without adjuvant therapy who exhibited high SPHK1 expression had significantly lower overall survival rates compared with those with low SPHK1 expression. Moreover, multivariate analysis suggested that SPHK1 expression might be an independent prognostic indicator for the survival of SGC patients.</p> <p>Conclusions</p> <p>Our results suggest that SPHK1 expression is associated with SGC progression, and might represent as a novel and valuable predictor for adjuvant therapy to SGC patients.</p

A cross dialectal view of the Arabic dative alternation

This paper is concerned with the syntax of ditransitive verbs in Arabic.We concentrate on the vernaculars, focussing in particular on three geographically spread dialects: Egyptian Cairene Arabic, the dominant vernacular in Egypt, Hijazi Arabic, spoken in Western Saudi Arabia and Maltese, a mixed language with a Magrebi/Siculo-Arabic stratum. We show that all three exhibit an alternation (the dative alternation) between a ditransitive ('double object') construction and a corresponding prepositional dative construction, and outline a number of differences between these constructions in the different varieties of Arabic. We consider the distribution of verbs exhibiting the dative alternation in the light of Ryding's (2011) observations concerning Modern Standard Arabic

Novel Mouse Model Reveals Distinct Activity-Dependent and –Independent Contributions to Synapse Development

The balanced action of both pre- and postsynaptic organizers regulates the formation of neuromuscular junctions (NMJ). The precise mechanisms that control the regional specialization of acetylcholine receptor (AChR) aggregation, guide ingrowing axons and contribute to correct synaptic patterning are unknown. Synaptic activity is of central importance and to understand synaptogenesis, it is necessary to distinguish between activity-dependent and activity-independent processes. By engineering a mutated fetal AChR subunit, we used homologous recombination to develop a mouse line that expresses AChR with massively reduced open probability during embryonic development. Through histological and immunochemical methods as well as electrophysiological techniques, we observed that endplate anatomy and distribution are severely aberrant and innervation patterns are completely disrupted. Nonetheless, in the absence of activity AChRs form postsynaptic specializations attracting motor axons and permitting generation of multiple nerve/muscle contacts on individual fibers. This process is not restricted to a specialized central zone of the diaphragm and proceeds throughout embryonic development. Phenotypes can be attributed to separate activity-dependent and -independent pathways. The correct patterning of synaptic connections, prevention of multiple contacts and control of nerve growth require AChR-mediated activity. In contrast, myotube survival and acetylcholine-mediated dispersal of AChRs are maintained even in the absence of AChR-mediated activity. Because mouse models in which acetylcholine is entirely absent do not display similar effects, we conclude that acetylcholine binding to the AChR initiates activity-dependent and activity-independent pathways whereby the AChR modulates formation of the NMJ