The Role of Calcineurin/NFAT in SFRP2 Induced Angiogenesis—A Rationale for Breast Cancer Treatment with the Calcineurin Inhibitor Tacrolimus

Tacrolimus (FK506) is an immunosuppressive drug that binds to the immunophilin FKBPB12. The FK506-FKBP12 complex associates with calcineurin and inhibits its phosphatase activity, resulting in inhibition of nuclear translocation of nuclear factor of activated T-cells (NFAT). There is increasing data supporting a critical role of NFAT in mediating angiogenic responses stimulated by both vascular endothelial growth factor (VEGF) and a novel angiogenesis factor, secreted frizzled-related protein 2 (SFRP2). Since both VEGF and SFRP2 are expressed in breast carcinomas, we hypothesized that tacrolimus would inhibit breast carcinoma growth. Using IHC (IHC) with antibodies to FKBP12 on breast carcinomas we found that FKBP12 localizes to breast tumor vasculature. Treatment of MMTV-neu transgenic mice with tacrolimus (3 mg/kg i.p. daily) (n = 19) resulted in a 73% reduction in the growth rate for tacrolimus treated mice compared to control (n = 15), p = 0.003; which was associated with an 82% reduction in tumor microvascular density (p<0.001) by IHC. Tacrolimus (1 µM) inhibited SFRP2 induced endothelial tube formation by 71% (p = 0.005) and inhibited VEGF induced endothelial tube formation by 67% (p = 0.004). To show that NFATc3 is required for SFRP2 stimulated angiogenesis, NFATc3 was silenced with shRNA in endothelial cells. Sham transfected cells responded to SFRP2 stimulation in a tube formation assay with an increase in the number of branch points (p<0.003), however, cells transfected with shRNA to NFATc3 showed no increase in tube formation in response to SFRP2. This demonstrates that NFATc3 is required for SFRP2 induced tube formation, and tacrolimus inhibits angiogenesis in vitro and breast carcinoma growth in vivo. This provides a rationale for examining the therapeutic potential of tacrolimus at inhibiting breast carcinoma growth in humans

Knee movement patterns of injured and uninjured adolescent basketball players when landing from a jump: A case-control study

BACKGROUND: A common knee injury mechanism sustained during basketball is landing badly from a jump. Landing is a complex task and requires good coordination, dynamic muscle control and flexibility. For adolescents whose coordination and motor control has not fully matured, landing badly from a jump can present a significant risk for injury. There is currently limited biomechanical information regarding the lower limb kinetics of adolescents when jumping, specifically regarding jump kinematics comparing injured with uninjured adolescents. This study reports on an investigation of biomechanical differences in landing patterns of uninjured and injured adolescent basketball players. METHODS: A matched case-control study design was employed. Twenty-two basketball players aged 14–16 years participated in the study: eleven previously knee-injured and eleven uninjured players matched with cases for age, gender, weight, height and years of play, and playing for the same club. Six high-speed, three-dimensional Vicon 370 cameras (120 Hz), Vicon biomechanical software and SAS Version 8 software were employed to analyse landing patterns when subjects performed a "jump shot". Linear correlations determined functional relationships between the biomechanical performance of lower limb joints, and paired t-tests determined differences between the normalised peak biomechanical parameters. RESULTS: The average peak vertical ground reaction forces between the cases and controls were similar. The average peak ground reaction forces between the cases and controls were moderately correlated (r = -0.47). The control (uninjured) players had significantly greater hip and knee flexion angles and significantly greater eccentric activity on landing than the uninjured cases (p < 0.01). CONCLUSION: The findings of the study indicate that players with a history of knee injuries had biomechanically compromised landing techniques when compared with uninjured players matched for gender, age and club. Descriptions (norms) of expected levels of knee control, proprioceptive acuity and eccentric strength relative to landing from a jump, at different ages and physical developmental stages, would assist clinicians and coaches to identify players with inappropriate knee performance comparable to their age or developmental stage

Genetic association analyses implicate aberrant regulation of innate and adaptive immunity genes in the pathogenesis of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a genetically complex autoimmune disease characterized by loss of immune tolerance to nuclear and cell surface antigens. Previous genome-wide association studies (GWAS) had modest sample sizes, reducing their scope and reliability. Our study comprised 7,219 cases and 15,991 controls of European ancestry, constituting a new GWAS, a meta-analysis with a published GWAS and a replication study. We have mapped 43 susceptibility loci, including ten new associations. Assisted by dense genome coverage, imputation provided evidence for missense variants underpinning associations in eight genes. Other likely causal genes were established by examining associated alleles for cis-acting eQTL effects in a range of ex vivo immune cells. We found an over-representation (n = 16) of transcription factors among SLE susceptibility genes. This finding supports the view that aberrantly regulated gene expression networks in multiple cell types in both the innate and adaptive immune response contribute to the risk of developing SLE

Moving from a continuum to a community: reconceptualising the provision of support

The notion of the continuum is applied to special education in diverse contexts across many nations. This paper explores its conceptual underpinnings, drawing upon a systematic search of the literature to review recurring ideas associated with the notion and to explicate both its uses and short-comings. Through a thematic analysis of the literature the research team derived twenty-nine continua, situated within six broad groupings (space, students, staffing, support, strategies and systems). This provides a clear structure for reconsidering the issues which the notion of the continuum is supposed to describe and enables a reconceptualisation of how the delivery of services is represented. We present the initial underpinnings for a community of provision, in which settings and services work together to provide learning and support for all children and young people in their locality

What is damaging the kidney in lupus nephritis?

Despite marked improvements in the survival of patients with severe lupus nephritis over the past 50 years, the rate of complete clinical remission after immune suppression therapy i

Early Devonian (Late Emsian) shark fin remains (Chondrichthyes) from the Paraná Basin, southern Brazil

This is an open-access article distributed under the terms of the Creative Commons Attribution License [Attribution-NonCommercial 4.0 International (CC BY-NC 4.0)]. The attached file is the published version of the article