No abstract

To date, the molecular mechanism underlying constitutive signal transducer and activator of transcription 3 (STAT3) activation in gliomas is largely unclear. In this study, we report that Smad6 is overexpressed in nuclei of glioma cells, which correlates with poor patient survival and regulates STAT3 activity via negatively regulating the Protein Inhibitors of Activated STAT3 (PIAS3). Mechanically, Smad6 interacts directly with PIAS3, and this interaction is mediated through the Mad homology 2 (MH2) domain of Smad6 and the Ring domain of PIAS3. Smad6 recruits Smurf1 to facilitate PIAS3 ubiquitination and degradation, which also depends on the MH2 domain and the PY motif of Smad6. Consequently, Smad6 reduces PIAS3-mediated STAT3 inhibition and promotes glioma cell growth and stem-like cell initiation. Moreover, the Smad6 MH2 transducible protein restores PIAS3 expression and subsequently reduces gliomagenesis. Collectively, we conclude that nuclear-Smad6 enhances glioma development by inducing PIAS3 degradation and subsequent STAT3 activity upregulation.

3.

An electronic screening algorithm combined with an electronic health record review of flagged cases can be used as a valid source for TJR SSI surveillance. The algorithm successfully reduced the volume of chart review for surveillance by 90.5%.

No abstract

The defective gene responsible for the recessively inherited immunodeficiency X-linked agammaglobulinemia (XLA) has been shown to encode a cytoplasmic protein tyrosine kinase of the Src family designated Btk (Bruton's tyrosine kinase). To facilitate the search for germline mutations of the Btk gene, we have characterized its genomic structure. Eighteen introns were positioned within the approximately 37 kb gene. Each of the exon/intron boundaries were defined and sequenced, and all but two conform to consensus sequences. We have utilized the genomic organization of Btk and the intervening sequence data to design an assay for amplifying each of the 19 exons from XLA patient DNA for single strand conformation polymorphism (SSCP) analysis. By using this method we have identified mutations in 12 of 14 unrelated affected males: seven different base substitutions and two small deletions. Two of the mutations described in exon 15 of the kinase domain were found in more than one patient and may represent a mutation hot spot. Exon scanning has proven to be a valuable method for identifying the patient mutations in genomic DNA without the use of cDNA. The mutations are easily confirmed with direct sequencing of the amplified exons. This approach will greatly benefit XLA family studies involving carrier detection and prenatal diagnosis. In addition, the mutations identified may reveal residues involved in the specific protein interactions necessary in the B-cell developmental pathway, of which Btk is an integral component.

Implant selection can have a considerable effect on the risk for aseptic revision following a cemented unicompartmental knee arthroplasty, as can patient and surgeon factors. Therefore, the variation among risk estimates reported in the literature for unicompartmental knee arthroplasty revision may be explained by differences in patient characteristics and implant selection as well as the surgeons' yearly volume of unicompartmental knee arthroplasties.

No abstract