RAS oncogene signal strength regulates matrisomal gene expression and tumorigenicity of mouse keratinocytes.

Environmental and molecular carcinogenesis are linked by the discovery that chemical carcinogen induced-mutations in the Hras or Kras genes drives tumor development in mouse skin. Importantly, enhanced expression or allele amplification of the mutant Ras gene contributes to selection of initiated cells, tumor persistence, and progression. To explore the consequences of Ras oncogene signal strength, primary keratinocytes were isolated and cultured from the LSL-HrasG12D and LSL-KrasG12D C57BL/6J mouse models and the mutant allele was activated by adeno-Cre recombinase. Keratinocytes expressing one (H) or two (HH) mutant alleles of HrasG12D, one KrasG12D allele (K), or one of each (HK) were studied. All combinations of activated Ras alleles stimulated proliferation and drove transformation marker expression, but only HH and HK formed tumors. HH, HK, and K sustained long-term keratinocyte growth in vitro, while H and WT could not. RNA-Seq yielded two distinct gene expression profiles; HH, HK, and K formed one cluster while H clustered with WT. Weak MAPK activation was seen in H keratinocytes but treatment with a BRAF inhibitor enhanced MAPK signaling and facilitated tumor formation. K keratinocytes became tumorigenic when they were isolated from mice where the LSL-KrasG12D allele was backcrossed from the C57BL/6 onto the FVB/N background. All tumorigenic keratinocytes but not the non-tumorigenic precursors shared a common remodeling of matrisomal gene expression that is associated with tumor formation. Thus, RAS oncogene signal strength determines cell-autonomous changes in initiated cells that are critical for their tumor-forming potential.

Combined carvedilol and gabapentin treatment induces a rapid response in red scrotum syndrome.

Red scrotum syndrome (RSS) is a rare dermatologic condition characterized by persistent erythema and analgesia of the male genitalia that cannot be attributed to contact or atopic dermatitis or acute or chronic infections. Treatment of RSS is challenging since it often fails to respond to corticosteroids, antifungals, antivirals, and antibiotics. Several reports described RSS patients who responded to gabapentin, pregabalin, and ?-adrenergic receptor blockers, suggesting a neuropathic etiology. Here we present a refractory RSS case with rapid clinical improvement on a combined carvedilol plus gabapentin therapy. We suggest that RSS manifestations are driven by neurogenic inflammation and that the efficacy of gabapentin/carvedilol relates to the suppression of the neuro-immuno-epidermal axis.

Sweet syndrome with pulmonary involvement in a patient with myelodysplastic syndrome.

We report a patient with Sweet syndrome involving the pulmonary system in the context of myelodysplastic syndrome. Although Sweet syndrome may involve a variety of organ systems, the pulmonary system is rarely affected and can result in poor clinical outcomes, including acute respiratory distress syndrome. Both cutaneous and pulmonary symptoms respond well to systemic corticosteroid therapy and early diagnosis and treatment can improve the prognosis. Our case highlights the importance of collaboration between hematologists, dermatologists, and pulmonologists to facilitate effective diagnosis, triage, and treatment of these patients.

Tunable heat shock protein-mediated NK cell responses are orchestrated by STAT1 in Antigen Presenting Cells.

The release of Heat Shock Proteins (HSPs) from aberrant cells can initiate immune responses following engagement of the HSPs with antigen presenting cells (APCs). This is an important mechanism for cancer immunosurveillance and can also be modeled by vaccination with HSPs through various routes, targeting specific APCs expressing the HSP receptor CD91. Immunological outcomes can be varied as a result of the broad expression of CD91 in different dendritic cell and macrophage populations. We investigated the cellular response of different APCs to the prototypical immunogenic HSP, gp96, in the context of Th1 immunity. Although APCs generally express similar levels of the HSP receptor CD91, we uncovered APC-distinct, downstream signaling pathways activating STAT1, and differential STAT1 induced genes. As a result of this differential and unique signaling we determined that gp96-activated macrophages, but not DCs are capable of activating NK cells to produce IFN-[Formula: see text]. These data demonstrate that different APC subsets elicit unique intracellular signaling responses to HSPs which result in different patterns of downstream cellular activation and immune responses. Collectively this provides a novel tunable and autochthonous immune response to extracellular HSPs which has important implications on the development of immunity to cancer and infectious disease, as well as homeostasis.

Access to consultative dermatologic care via physician-to-physician asynchronous outpatient teledermatology.

OBJECTIVES: To determine whether physician-to-physician outpatient asynchronous store-and-forward teledermatology can be a portal for patient access to consultative dermatologic care and decrease primary care physician referrals to dermatology. STUDY DESIGN: Retrospective study. METHODS: Reviewed outpatient teledermatology consults completed within a shared Epic electronic health record at the University of Pittsburgh Medical Center (UPMC) Health System between August 4, 2013, and December 19, 2019. Study data were reviewed for consult response time and triage percentage. Patient and physician experiences were collected by satisfaction surveys. RESULTS: This study reviewed 1581 teledermatology consults that originated from UPMC primary care provider (PCP) appointments. The average response time for a completed consult was 1 hour, 13 minutes for same-day consult submissions. The majority of consults, 63%, were completed online, whereas only 37% of patients were recommended for an in-person referral visit to the dermatology clinic. Surveyed patients (81%) and PCPs (90%) responded positively to their teledermatology experience. CONCLUSIONS: Physician-to-physician outpatient asynchronous teledermatology consults can provide a model for rapid consultation and decreased primary care referral to dermatology.

Keratinocyte death by ferroptosis initiates skin inflammation after UVB exposure.

The ultraviolet B radiation (UVB) causes skin inflammation, which contributes to the causality and the exacerbation of a number of cutaneous diseases. However, the mechanism of UVB-driven inflammation in the skin remains poorly understood. We show that ferroptosis, a non-apoptotic programmed cell death pathway that is promoted by an excessive phospholipid peroxidation, is activated in the epidermal keratinocytes after their exposure to UVB. The susceptibility of the keratinocytes to UVB-induced ferroptosis depends on the extent of pro-ferroptosis death signal generation and the dysregulation of the glutathione system. Inhibition of ferroptosis prevents the release of HMGB1 from the human epidermal keratinocytes, and blocks necroinflammation in the UVB-irradiated mouse skin. We show that while apoptosis and pyroptosis are also detectable in the keratinocytes after UVB exposure, ferroptosis plays a significant role in initiating UVB-induced inflammation in the skin. Our results have important implications for the prevention and the treatment of a broad range of skin diseases which are fostered by UVB-induced inflammation.