Use of data from the Vascular Quality Initiative registry to support regulatory decisions yielded a high return on investment.

BACKGROUND: Real-world data (RWD) from the Society for Vascular Surgery Vascular Quality Initiative (VQI) registry has been used to support US Food and Drug Administration (FDA) regulatory decisions regarding vascular devices. The variables of cost and time needed for these registry-based studies have not been previously compared to traditional, independent, industry studies that would otherwise have been conducted to support regulatory decisions. OBJECTIVES: To determine the potential value (cost and time saving and return on investment) created by device evaluation studies using the VQI registry infrastructure. METHODS: We compared studies that used data from the VQI registry with estimated costs of independent industry studies (counterfactual studies) using an established model using design specifications determined by FDA reviewers. RESULTS: We analyzed the initial six studies evaluating vascular devices for regulatory decisions using data from the VQI registry that generated evidence for four device manufacturers. Return on investment for these studies was estimated to be 143% and cost saving as 59% based on an actual per patient (with 5-year follow-up) cost of US$11K using VQI data versus US$26K from the counterfactual when averaged across all studies. Significant enrollment time savings (45%-71%) were also realized compared with industry-based estimates. CONCLUSIONS: The use of RWD from the VQI registry in this study and the transcatheter valve treatment coordinated registry network in a prior study indicates that substantial value was added to device evaluation projects by the reuse of registry data, with additional potential savings if linked claims data can be used instead of costly long-term in-person follow-up.

Streptolysin O enhances keratinocyte migration and proliferation and promotes skin organ culture wound healing in vitro.

ML-05, a modified form of the hemolytic and cytotoxic bacterial toxin, streptolysin O, is currently being investigated as a treatment for collagen-related disorders such as scleroderma and fibrosis. Furthermore, ML-05 may be effective in promoting wound healing and alleviating the formation of hypertrophic scars and keloids. To investigate the effects of ML-05 on wound-healing processes, in vitro wound-healing scratch assays (using human primary epidermal keratinocytes and dermal fibroblasts) and a human skin organ culture wound model were utilized. ML-05 markedly enhanced keratinocyte migration and proliferation in wound scratch assays. ML-05 did not affect either proliferation or migration of dermal fibroblasts, indicating that ML-05's effects on cell migration/proliferation may be keratinocyte-specific. ML-05 was tested in a dose-dependent manner in a skin organ culture wound model using two different application methods: Through the culture media (dermal exposure) or direct topical treatment of the wound surface. ML-05 was found to accelerate wound healing as measured by reepithelialization, particularly after topical application. Therefore, ML-05 may have potential as a wound-healing agent that promotes reepithelialization through stimulation of keratinocyte migration and proliferation.

Homeobox gene Dlx3 is regulated by p63 during ectoderm development: relevance in the pathogenesis of ectodermal dysplasias.

Ectodermal dysplasias (EDs) are a group of human pathological conditions characterized by anomalies in organs derived from epithelial-mesenchymal interactions during development. Dlx3 and p63 act as part of the transcriptional regulatory pathways relevant in ectoderm derivatives, and autosomal mutations in either of these genes are associated with human EDs. However, the functional relationship between both proteins is unknown. Here, we demonstrate that Dlx3 is a downstream target of p63. Moreover, we show that transcription of Dlx3 is abrogated by mutations in the sterile alpha-motif (SAM) domain of p63 that are associated with ankyloblepharon-ectodermal dysplasia-clefting (AEC) dysplasias, but not by mutations found in ectrodactylyectodermal dysplasia-cleft lip/palate (EEC), Limb-mammary syndrome (LMS) and split hand-foot malformation (SHFM) dysplasias. Our results unravel aspects of the transcriptional cascade of events that contribute to ectoderm development and pathogenesis associated with p63 mutations.

Protein kinase Cdelta regulates antigen receptor-induced lytic granule polarization in mouse CD8+ CTL.

Lytic granule exocytosis is the major pathway used by CD8+ CTL to kill virally infected and tumor cells. Despite the obvious importance of this pathway in adaptive T cell immunity, the molecular identity of enzymes involved in the regulation of this process is poorly characterized. One signal known to be critical for the regulation of granule exocytosis-mediated cytotoxicity in CD8+ T cells is Ag receptor-induced activation of protein kinase C (PKC). However, it is not known which step of the process is regulated by PKC. In addition, it has not been determined to date which of the PKC family members is required for the regulation of lytic granule exocytosis. By combination of pharmacological inhibitors and use of mice with targeted gene deletions, we show that PKCdelta is required for granule exocytosis-mediated lytic function in mouse CD8+ T cells. Our studies demonstrate that PKCdelta is required for lytic granule exocytosis, but is dispensable for activation, cytokine production, and expression of cytolytic molecules in response to TCR stimulation. Importantly, defective lytic function in PKCdelta-deficient cytotoxic lymphocytes is reversed by ectopic expression of PKCdelta. Finally, we show that PKCdelta is not involved in target cell-induced reorientation of the microtubule-organizing center, but is required for the subsequent exocytosis step, i.e., lytic granule polarization. Thus, our studies identify PKCdelta as a novel and selective regulator of Ag receptor-induced lytic granule polarization in mouse CD8+ T cells.

Dlx genes, p63, and ectodermal dysplasias.

Many events in vertebrate morphogenesis and organogenesis develop from epithelial/mesenchymal interactions. These processes involve a series of sequential and reciprocal interactions between the thickened epithelial sheets and underlying mesenchymal cells. Much has been learned from in vitro assays and knockout experiments in mice on the early signaling molecules that regulate the initial stages of the epithelial/mesenchymal interactions. In this review, we discuss effectors of these initial signals, specifically the p63 and Dlx families of transcription factors, that play central roles in embryonic patterning and regulation of different developmental processes, and provide a review of some of the mutations in these genes that have been associated with ectodermal dysplasias (EDs).