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Dobry, Allison S.

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Dobry

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Allison S.

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Dobry, Allison S.

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2015 - 20173

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Author's Publications: search.filters.isAuthorOfPublication.7f5a72ae-c4ff-4862-ac1b-38ca1c29f29c

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    A UV-Independent Topical Small-Molecule Approach for Melanin Production in Human Skin
    (2017) Mujahid, Nisma; Liang, Yanke; Murakami, Ryo; Choi, Hwan Geun; Dobry, Allison S.; Wang, Jinhua; Suita, Yusuke; Weng, Qing Yu; Allouche, Jennifer; Kemeny, Lajos; Hermann, Andrea L.; Roider, Elisabeth; Gray, Nathanael; Fisher, David
    SUMMARY The presence of dark melanin (eumelanin) within human epidermis represents one of the strongest predictors of low skin cancer risk. Topical rescue of eumelanin synthesis, previously achieved in “redhaired” Mc1r-deficient mice, demonstrated significant protection against UV damage. However, application of a topical strategy for human skin pigmentation has not been achieved, largely due to the greater barrier function of human epidermis. Salt-inducible kinase (SIK) has been demonstrated to regulate MITF, the master regulator of pigment gene expression, through its effects on CRTC and CREB activity. Here, we describe the development of small-molecule SIK inhibitors that were optimized for human skin penetration, resulting in MITF upregulation and induction of melanogenesis. When topically applied, pigment production was induced in Mc1r-deficient mice and normal human skin. These findings demonstrate a realistic pathway toward UV-independent topical modulation of human skin pigmentation, potentially impacting UV protection and skin cancer risk.
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    Utilizing a Novel Giant Congenital Melanocytic Nevus Murine Model to Investigate Therapeutic Strategies and Model Tumorigenesis
    (2017-05-12) Dobry, Allison S.
    Giant congenital melanocytic nevi (gCMN) are oncogene-driven proliferations of melanocytes present since birth that are greater than 20 cm in projected adult size, and have a melanoma conversion frequency of ranging from 5-15%. Patients with gCMN typically develop melanoma in early childhood that is extremely aggressive and almost universally fatal. Therefore, targeted therapies to induce nevus regression would be enormously beneficial. NRAS activating mutations are postulated to be the driver mutation gCMN. Described here are two novel gCMN preclinical murine models that harbor an NrasQ61R mutation. Evaluation of both the constitutive nevus model (Dct promoter-driven constitutive Cre with NrasQ61R mutation) and the inducible nevus model (Tyr promoter-driven tamoxifen-inducible CreERT2 with NrasQ61R mutation) demonstrate that both models recapitulate human gCMN histological architecture and model spontaneous tumorigenesis. Of the various drug candidates tested, topical administration of a combination of the MEK inhibitor binimetinib and the c-KIT inhibitor imatinib was superior in causing almost complete nevus regression, as measured by a reduction of melanin deposition and melanocytes in the dermal layer. This may represent a potential topical treatment strategy for the regression of gCMN that avoids both the more deleterious side effects of either systemic drug administration or large-scale surgical procedures. Ultimately, this preclinical murine model may help generate new information about the rare, but deadly gCMN that may aid in improving daily symptoms from these lesions as well as hopefully reduce overall melanoma risk.
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    Craniofacial Measurements of Donors and Recipients Correlate with Aesthetic Outcome in Virtual Face Transplantation
    (Wolters Kluwer Health, 2015) S. Wallins, Joseph; Chandawarkar, Akash A.; Dobry, Allison S.; Diaz-Siso, J. Rodrigo; Bueno, Ericka M.; Caterson, Edward; Jania, Camille; Hevelone, Nathanael D.; Lipsitz, Stuart; Mukundan, Srinivasan; Pomahac, Bohdan
    Background: Face transplantation is an increasingly feasible option for patients with severe disfigurement. Donors and recipients are currently matched based on immune compatibility, skin characteristics, age, and gender. Aesthetic outcomes of the match are not always optimal and not possible to study in actual cases due to ethical and logistical challenges. We have used a reproducible and inexpensive three-dimensional virtual face transplantation (VFT) model to study this issue. Methods: Sixty-one VFTs were performed using reconstructed high-resolution computed tomography angiographs of male and female subjects aged 20–69 years. Twenty independent reviewers evaluated the level of disfigurement of the posttransplant models. Absolute differences in 9 soft-tissue measurements and 16 bony cephalometric measurements from each of the VFT donor and recipient pretransplant model pairs were correlated to the reviewers’ evaluation of disfigurement after VFT through a multivariate logistic regression model. Results: Five soft-tissue measurements and 3 bony measurements were predictive of the rating of disfigurement after VFT (odds ratio; 95% confidence interval): trichion-to-nasion facial height (1.106; 1.066–1.148), endocanthal width (1.096; 1.051–1.142), exocanthal width (1.067; 1.036–1.099), mouth/chelion width (1.064; 1.019–1.110), subnasale-to-menton facial height (1.029; 1.003–1.056), inner orbit width (1.039; 1.009–1.069), palatal plane/occlusal plane angle (1.148; 1.047–1.258), and sella-nasion/mandibular plane angle (1.079; 1.013–1.150). Conclusions: This study provides early evidence for the importance of soft-tissue and bony measurements in planning of facial transplantation. With future improvements to immunosuppressive regimens and increased donor availability, these measurements may be used as an additional criterion to optimize posttransplant outcomes.