MED: Dermatology Papers
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Item Characteristics of the Early Immune Response Following Transplantation of Mouse ES Cell Derived Insulin-Producing Cell Clusters(Public Library of Science, 2010-6-4) Boyd, Ashleigh S.; Wood, Kathryn J.BACKGROUND. The fully differentiated progeny of ES cells (ESC) may eventually be used for cell replacement therapy (CRT). However, elements of the innate immune system may contribute to damage or destruction of these tissues when transplanted. METHODOLOGY/PRINCIPAL FINDINGS. Herein, we assessed the hitherto ill-defined contribution of the early innate immune response in CRT after transplantation of either ESC derived insulin producing cell clusters (IPCCs) or adult pancreatic islets. Ingress of neutrophil or macrophage cells was noted immediately at the site of IPCC transplantation, but this infiltration was attenuated by day three. Gene profiling identified specific inflammatory cytokines and chemokines that were either absent or sharply reduced by three days after IPCC transplantation. Thus, IPCC transplantation provoked less of an early immune response than pancreatic islet transplantation. CONCLUSIONS/SIGNIFICANCE. Our study offers insights into the characteristics of the immune response of an ESC derived tissue in the incipient stages following transplantation and suggests potential strategies to inhibit cell damage to ensure their long-term perpetuation and functionality in CRT.Item Inhibition of Melanoma Angiogenesis by Telomere Homolog Oligonucleotides(Hindawi Publishing Corporation, 2010-6-28) Coleman, Christina; Levine, Danielle; Kishore, Raj; Qin, Gangjian; Thorne, Tina; Lambers, Erin; Sasi, Sharath P.; Yaar, Mina; Gilchrest, Barbara A.; Goukassian, David A.Telomere homolog oligonucleotides (T-oligos) activate an innate telomere-based program that leads to multiple anticancer effects. T-oligos act at telomeres to initiate signaling through the Werner protein and ATM kinase. We wanted to determine if T-oligos have antiangiogenic effects. We found that T-oligo-treated human melanoma (MM-AN) cells had decreased expression of vascular endothelial growth factor (VEGF), VEGF receptor 2, angiopoeitin-1 and -2 and decreased VEGF secretion. T-oligos activated the transcription factor E2F1 and inhibited the activity of the angiogenic transcription factor, HIF-1α. T-oligos inhibited EC tubulogenesis and total tumor microvascular density matrix invasion by MM-AN cells and ECs in vitro. In melanoma SCID xenografts, two systemic T-oligo injections decreased by 60% (P<.004) total tumor microvascular density and the functional vessels density by 80% (P <.002). These findings suggest that restriction of tumor angiogenesis is among the host's innate telomere-based anticancer responses and provide further evidence that T-oligos may offer a powerful new approach for melanoma treatment.Item Role of BMP-4 and Its Signaling Pathways in Cultured Human Melanocytes(Hindawi Publishing Corporation, 2009-12-30) Park, Hee-Young; Wu, Christina; Yaar, Mina; Stachur, Christina M.; Kosmadaki, Marita; Gilchrest, Barbara A.Bone Morphogenetic Protein (BMP-4) was shown to down-regulate melanogenesis, in part, by decreasing the level of tyrosinase [Yaar et al. (2006) JBC:281]. Results presented here show that BMP-4 down-regulated the protein levels of TRP-1, PKC-β, and MCI-R. When paired cultures of human melanocytes were treated with vehicle or BMP-4 (25ng/ml), MAPK/ERK were phosphorylated within one hour of BMP-4 treatment. Then the activated MAPK/ERK caused an acute phosphorylation of MITF, followed by proteosome-mediated degradation of MITF, the key transcription factor for melanogenic proteins [Wu et al. (2000) Gene & Development:14]. However, prolonged exposure of melanocytes to BMP-4 (up to 48 hours) caused a decrease in the level of MITF-M transcript. In addition, BMP-4 decreased the intracellular level of cAMP, the key regulator of MITF expression. These results demonstrate that BMP-4 activates MAPK/ERK signaling pathway to transiently activate MITF; however, chronic treatment of BMP-4 to melanocytes causes a down-regulation of the expression of MITF, possibly in a cAMP-dependent pathway.Item Nonlinear Modeling of Venous Leg Ulcer Healing Rates(BioMed Central, 2009-3-31) Cardinal, Matthew; Phillips, Tania; Eisenbud, David E.; Harding, Keith; Mansbridge, Jonathan; Armstrong, David G.BACKGROUND. The purpose of this manuscript was to determine whether the change in wound surface area over time could be described through nonlinear mathematics. METHODS. We studied 3,588 serial wound tracings of 338 venous leg ulcers (VLUs) that had been followed during a controlled, prospective, randomized trial of two topical wound treatments. RESULTS. A majority (72%) of VLUs exhibited surface area reduction via an exponential decay model, particularly during the early stages of healing. These results were consistent with the mechanics of wound contraction and epithelial cell proliferation, supported by the higher frequency at which exponential surface area reduction associated with full wound closure (35% of wounds that fit the exponential model healed vs. 21% of wounds that did not fit the exponential model completely healed during the study period, p = 0.018). Goodness-of-fit statistics suggested that much of the individual variation in healing could be described as nonlinear variation from the exponential model. CONCLUSION. We believe that parameter estimates from a mathematical model may provide a more accurate quantification of wound healing rates, and that similar models may someday reach routine use in comparing the efficacy of various treatments in routine practice and in product registration trials.Item Telomeric DNA Induces Apoptosis and Senescence of Human Breast Carcinoma Cells(BioMed Central, 2007-1-26) Yaar, Mina; Eller, Mark S.; Panova, Izabela; Kubera, John; Wee, Lee Hng; Cowan, Kenneth H.; Gilchrest, Barbara A.INTRODUCTION. Cancer is a leading cause of death in Americans. We have identified an inducible cancer avoidance mechanism in cells that reduces mutation rate, reduces and delays carcinogenesis after carcinogen exposure, and induces apoptosis and/or senescence of already transformed cells by simultaneously activating multiple overlapping and redundant DNA damage response pathways. METHODS. The human breast carcinoma cell line MCF-7, the adriamycin-resistant MCF-7 (Adr/MCF-7) cell line, as well as normal human mammary epithelial (NME) cells were treated with DNA oligonucleotides homologous to the telomere 3' overhang (T-oligos). SCID mice received intravenous injections of MCF-7 cells followed by intravenous administration of T-oligos. RESULTS. Acting through ataxia telangiectasia mutated (ATM) and its downstream effectors, T-oligos induced apoptosis and senescence of MCF-7 cells but not NME cells, in which these signaling pathways were induced to a far lesser extent. In MCF-7 cells, experimental telomere loop disruption caused identical responses, consistent with the hypothesis that T-oligos act by mimicking telomere overhang exposure. In vivo, T-oligos greatly prolonged survival of SCID mice following intravenous injection of human breast carcinoma cells. CONCLUSION. By inducing DNA damage-like responses in MCF-7 cells, T-oligos provide insight into innate cancer avoidance mechanisms and may offer a novel approach to treatment of breast cancer and other malignancies.Item Preventive strategies and research for ultraviolet-associated cancer(National Institute of Environmental Health Sciences, 1995-11) Koh, H.K.Ultraviolet (UV)-associated cancer is the most common cancer in the United States. Approximately 90% of nonmelanoma skin cancer and 65% of melanoma are attributable to UV exposure and theoretically could be eliminated by primary prevention measures. Safe sun strategy includes use of sunscreens, use of protective clothing, minimization of exposure from 10 A.M. to 3 P.M., and avoidance of tanning parlors. Although more definitive data in human populations on the effectiveness of sunscreens to prevent melanoma and skin cancer are needed, sunscreens are thought to reduce risk. Safe sun prevention must start in childhood and adolescence when people receive most of their UV exposure. Secondary prevention through professional and public education and early detection may further reduce melanoma mortality.Item Can an hour or two of sun protection education keep the sunburn away? Evaluation of the Environmental Protection Agency's SunWise School Program(BioMed Central, 2003-11-3) Geller, Alan C.; Rutsch, Linda; Kenausis, Kristin; Selzer, Paula; Zhang, ZiBACKGROUND: Melanoma incidence is rising at a rate faster than any other preventable cancer in the United States. Childhood exposure to ultraviolet (UV) light increases risk for skin cancer as an adult, thus starting positive sun protection habits early may be key to reducing the incidence of this disease. METHODS: The Environmental Protection Agency's SunWise School Program, a national environmental and health education program for sun safety of children in primary and secondary schools (grades K-8), was evaluated with surveys administered to participating students and faculty. RESULTS: Pretests (n = 5,625) and posttests (n = 5,028) were completed by students in 102 schools in 42 states. Significant improvement was noted for the three knowledge variables. Intentions to play in the shade increased from 68% to 75%(p < 0.001) with more modest changes in intentions to use sunscreen. Attitudes regarding healthiness of a tan also decreased significantly. CONCLUSIONS: Brief, standardized sun protection education can be efficiently interwoven into existing school curricula, and result in improvements in knowledge and positive intentions for sun protection.