Parmacek, Michael S
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PublicationImpaired Notch Signaling Promotes De novo Squamous Cell Carcinoma Formation(2006-08-01) Lepore, John J.; Cheng, Lan; Seykora, John J; Proweller, Aaron; Millar, Sarah E; Tu, Lili; Pear, Warren S; Parmacek, Michael S; Lu, Min MinSignaling through Notch receptors in the skin has been implicated in the differentiation, proliferation, and survival of keratinocytes, as well as in the pathogenesis of basal cell carcinoma (BCC). To determine the composite function of Notch receptor–mediated signaling in the skin and overcome potential redundancies between receptors, conditional transgenic mice were generated that express the pan-Notch inhibitor, dominant-negative Mastermind Like 1 (DNMAML1), to repress all canonical [CBF-1/Suppressor of hairless/LAG-1 (CSL)–dependent] Notch signaling exclusively in the epidermis. Here, we report that DNMAML1 mice display hyperplastic epidermis and spontaneously develop cutaneous squamous cell carcinoma (SCC) as well as dysplastic precursor lesions, actinic keratoses. Mice expressing epidermal DNMAML1 display enhanced accumulation of nuclear ß-catenin and cyclin D1 in suprabasilar keratinocytes and in lesional cells from SCCs, which was also observed in human cutaneous SCC. These results suggest a model wherein CSL-dependent Notch signaling confers protection against cutaneous SCC. The demonstration that inhibition of canonical Notch signaling in mice leads to spontaneous formation of SCC and recapitulates the disease in humans yields fundamental insights into the pathogenesis of SCC and provides a unique in vivo animal model to examine the pathobiology of cutaneous SCC and for evaluating novel therapies. PublicationPrior Authorization Requirements for Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors Across US Private and Public Payers(2018-03-28) Doshi, Jalpa A; Parmacek, Michael S; Puckett, John; Rader, Daniel JA comprehensive review of prior authorization (PA) requirements for a new class of expensive cholesterol-lowering drugs known as proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors has found unusually complex and burdensome demands across public and private insurance plans in the United States. These findings raise concerns that current policies may create undue barriers to care even in medically appropriate patients, particularly since requirements were just as stringent for patients with a genetic condition that creates more clear-cut eligibility for PCSK9 inhibitor treatment.