editorial focus for F-00640-2011.R2.

Treatment of lupus nephritis (LN) with cyclophosphamide (CYC) is effective but retains a certain severe adverse effect. Tacrolimus (TAC) may be a suitable treatment for LN. Forty patients with diffuse proliferative or membranous LN were recruited for this non-randomized open-label study - 67.5%(27/40) had nephrotic proteinuria (>3.5 g/day) and 50.0%(20/40) had low estimated glomerular filtration rate (eGFR)(<60 mL/min/1.73m(2)). We compared the efficacy and adverse effects of TAC (0.04-0.08 mg/kg/d)/prednisone for 12 months (TAC group, n = 20) with intravenous CYC (750 mg/m(2) per month)/prednisone for six months followed by azathioprine (Aza)(100 mg/day)/prednisone for six months (CYC group, n = 20). The TAC target concentration was 6-8 ng/mL or 4-6 ng/mL, respectively, when induction or maintenance therapy was required and 4.0 ng/mL for patient with renal insufficiency. In the TAC group, mean urinary protein excretion decreased significantly from 5.00 ± 1.91 g/day at baseline to 2.54 ± 1.68 g/day after two weeks of therapy (P < 0.001), compared with the CYC group (4.9 ± 19.4 g/day), P = 0.001, and 65.0%(13/20) achieved partial remission at one month, compared with the CYC group (0/20), P < 0.001. The incidence of complete remission (CR) was significantly higher in the TAC group than in the CYC group (55.0% vs.15.0% by five months, P = 0.008, and 75.0% vs.40.0% by 12 months, P = 0.025, respectively). The significant improvement in serum anti-dsDNA and systemic lupus erythematosus (SLE) disease activity index (DAI) was in the TAC group relative to the CYC group at 12 months (P = 0.031, P = 0.003, respectively). The eGFR improved in the TAC group from 59.90 ± 23.64 mL/min/1.73m(2) at baseline to 93.75 ± 28.52 mL/min/1.73m(2) after 12 months, P = 0.001. In the CYC group, two patients developed end-stage renal disease (ESRD), three patients experienced serious pneumonia, and one patient died. Our preliminary study showed TAC is a safe and effective treatment for LN with severe renal disease, and with less-severe adverse events compared with CYC followed Aza therapy. Further larger sample studies are needed to confirm our conclusion.

The long asymptomatic stage of HIV infection poses a great challenge in identifying recent HIV infections. This is a bottleneck for monitoring HIV epidemic trends and evaluating the effectiveness of national AIDS control programs. Several serological methods were used to address this issue with some success. Because of high false-positive rates in patients with advanced infection or in ART treatment, UNAIDS still hesitates to recommend their use in routine surveillance. We developed a new pattern-based method for measuring intra-patient viral genetic diversity for determination of recent infections and estimation of population incidence. This method is verified by using several datasets (424 subtype B and 77 CRF07_BC samples) with clearly identified HIV-1 infection times. Pattern-based diversities of recent infections are significantly lower than that of chronic ones. With larger window periods varying from 200 to 350 days, a higher accuracy (90%-95%) not affected by advanced disease nor ART treatment could be obtained. The pattern-based genetic method is supplementary to the existing serology-based assays, both of which could be suitable for use in low and high epidemic regions, respectively.

BACKGROUND: Previous studies suggest center volume is associated with outcome after the Norwood operation; however, the impact of surgeon volume is less clear. We evaluated the relative impact of surgeon and center volume on mortality in a large Norwood cohort. METHODS: Patients in the Society of Thoracic Surgeons Congenital Heart Surgery Database undergoing the Norwood operation (2000 to 2009) were included. Using multivariable logistic regression, we evaluated the relationship between in-hospital mortality and annual center and surgeon volume, adjusting for patient factors. RESULTS: A total of 2,555 patients were operated on at 53 centers by 111 surgeons. Overall unadjusted mortality was 22.1%. When analyzed individually, both lower center and surgeon volume were associated with higher mortality (odds ratio for centers with 0 to 10 vs >20 cases per year 1.56 [95% confidence interval 1.05 to 2.31]; odds ratio for surgeons with 0 to 5 vs >10 cases per year 1.60 [95% confidence interval 1.12 to 2.27]). When analyzed together, the addition of surgeon volume to the center volume models attenuated but did not completely mitigate the association of center volume with outcome (relative attenuation of odds ratio = 34%). Adjusted mortality rates in low, medium, and high volume centers were 25.6%, 22.3%, and 17.7%, respectively. Across all center volume strata, lower volume surgeons had higher adjusted mortality rates. CONCLUSIONS: Both center and surgeon volumes appear to influence Norwood outcomes. These data suggest outcomes may potentially be improved through strategies that take advantage of the positive influence of both of these variables. This could include further investigation into the feasibility of regional collaborations, and the development of quality improvement initiatives within and across centers.

Adenomyosis is a common estrogen-dependent disorder of females characterized by a downward extension of the endometrium into the uterine myometrium and neovascularization in ectopic lesions. It accounts for chronic pelvic pain, dysmenorrhea, menorrhagia and infertility in 8.8-61.5% women worldwide. However, the molecular mechanisms for adenomyosis development remain poorly elucidated. Here, we utilized a 2-DE/MS-based proteomics analysis to compare and identify differentially expressed proteins in matched ectopic and eutopic endometrium of adenomyosis patients. A total of 93 significantly altered proteins were identified by tandem MS analysis. Further cluster analysis revealed a group of estrogen-responsive proteins as dysregulated in adenomyosis, among which annexin A2, a member of annexin family proteins, was found up-regulated most significantly in the ectopic endometrium of adenomyosis compared with its eutopic counterpart. Overexpression of ANXA2 was validated in ectopic lesions of human adenomyosis and was found to be tightly correlated with markers of epithelial-to-mesenchymal transition and dysmenorrhea severity of adenomyosis patients. Functional analysis demonstrated that estrogen could remarkably up-regulate ANXA2 and induce epithelial-to-mesenchymal transition in an in vitro adenomyosis model. Enforced expression of ANXA2 could mediate phenotypic mesenchymal-like cellular changes, with structural and functional alterations in a β-catenin/Tcf signaling-associated manner, which could be reversed by inhibition of ANXA2 expression. We also proved that enforced expression of ANXA2 enhanced the proangiogenic capacity of adenomyotic endometrial cells through HIF-1α/VEGF-A pathway. In vivo, we demonstrated that ANXA2 inhibition abrogated endometrial tissue growth, metastasis and angiogenesis in an adenomyosis nude mice model and significantly alleviated hyperalgesia. Taken together, our data unraveled a dual role for ANXA2 in the pathogenesis of human adenomyosis through conferring endometrial cells both metastatic potential and proangiogenic capacity, which could serve as a potential therapeutic target for the treatment of adenomyosis patients.

Canonical Wnt signalling requires caveolin-dependent internalization of low-density lipoprotein receptor-related protein 6 (LRP6). Here we report that the tumour suppressor and endocytic adaptor disabled-2 (Dab2), previously described as an inhibitor of Wnt/β-catenin signalling, selectively recruits LRP6 to the clathrin-dependent endocytic route, thereby sequestering it from caveolin-mediated endocytosis. Wnt stimulation induces the casein kinase 2 (CK2)-dependent phosphorylation of LRP6 at S1579, promoting its binding to Dab2 and internalization with clathrin. LRP6 receptor mutant (S1579A), deficient in CK2-mediated phosphorylation and Dab2 binding, fails to associate with clathrin, and thus escapes the inhibitory effects of Dab2 on Wnt/β-catenin signalling. Our data suggest that the S1579 site of LRP6 is a negative regulatory point during LRP6-mediated dorsoventral patterning in zebrafish and in allograft mouse tumour models. We conclude that the tumour suppressor functions of Dab2 involve modulation of canonical Wnt signalling by regulating the endocytic fate of the LRP6 receptor.

The goal of this study was to investigate whether glycosylphosphatidylinositol (GPI)-anchored 6 kDa early secreted antigenic target (ESAT-6) and IL-21-producing B16F10/ESAT-6-GPI-IL-21 viable vaccine would induce antitumor efficacy. Mice were immunized with B16F10/ESAT-6-GPI-IL-21 vaccine and challenged by B16F10 cells 2 weeks later. Antitumor efficacy and mechanisms of the vaccine were analyzed. Vaccination with the viable B16F10/ESAT-6-GPI-IL-21 vaccine resulted in an increase of IFN-γ level and the CD8(+)CTL cytotoxicity, a decrease in TGF-β generation and increase in the expression of miR-200c that serves as melanoma suppressor by directly targeting zinc-finger E-box binding homeobox 1 to inhibit epithelial-mesenchymal transition and block tumor metastasis. The vaccine significantly inhibited the melanoma growth, reduced the lung melanoma nodules, and prolonged the mouse survival compared with the controls. These findings highlighted IL-21 as an immune adjuvant in an engineered viable tumor vaccine to reinforce heterogenetic antigen ESAT-6 immune tolerance break to induce powerful antitumor efficacy in mice.

ABSTRACT:: Study Design. A retrospective study of magnetic resonance imaging of the lower lumbar spine.Objective. To describe the characteristics of the concave angle of the vertebral endplate (CAVE) and study the association between CAVE and lumbar intervertebral disc degeneration (IVDD).Summary of Background Data. The vertebral endplate is responsible for transferring stress between disc and vertebral body, and its concavity is important in dispersing compression stress. However, the characteristics of CAVE and the relationship between CAVE and IVDD have not been investigated.Methods. MRI films of the lower lumbar spine in 511 patients with low back pain were examined by two experienced spine surgeons. The grades of IVDD and lumbar disc herniation (LDH) were evaluated, several parameters including CAVE, height and the sagittal diameter of vertebral body were measured, and the association between IVDD or LDH and CAVE was analyzed.Results. At L3/4, L4/5 and L5/S1, CAVE was smaller in the upper endplate (that is, the inferior endplate of the superior vertebra) than the lower endplate (that is, the superior endplate of the inferior vertebra). There was no male/female difference in the size of CAVE in any of the segments. According to partial correlation analysis, CAVE was moderately related to IVDD, but no association between CAVE and LDH was found.Conclusion. When lumbar intervertebral disc degeneration occurs, the concave angle of the vertebral endplate increases and the endplate tends to flatten. The degree of flattening is related to the severity of the degeneration.

A cDNA library from white alpaca (Vicugna pacos) skin was constructed using SMART technology to investigate the global gene expression profile in alpaca skin and identify genes associated with physiology of alpaca skin and pigmentation. A total of 5359 high-quality EST (expressed sequence tag) sequences were generated by sequencing random cDNA clones from the library. Clustering analysis of sequences revealed a total of 3504 unique sequences including 739 contigs (assembled from 2594 ESTs) and 2765 singletons. BLAST analysis against GenBank nr database resulted in 1287 significant hits (E-value < 10-10), of which 863 were annotated through gene ontology analysis. Transcripts for genes related to fleece quality, growth and coat color (e.g. collagen types I and III, troponin C2 and secreted protein acidic and rich in cysteine) were abundantly present in the library. Other genes, such as keratin family genes known to be involved in melanosome protein production, were also identified in the library. Members (KRT10, 14 and 15) of this gene family are evolutionarily conserved as revealed by a cross-species comparative analysis. This collection of ESTs provides a valuable resource for future research to understand the network of gene expression linked to physiology of alpaca skin and development of pigmentation.