Interleukins 4 and 13 drive lipid abnormalities in skin cells through regulation of sex steroid hormone synthesis.

Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by skin dryness, inflammation, and itch. A major hallmark of AD is an elevation of the immune cytokines IL-4 and IL-13. These cytokines lead to skin barrier disruption and lipid abnormalities in AD, yet the underlying mechanisms are unclear. Sebaceous glands are specialized sebum-producing epithelial cells that promote skin barrier function by releasing lipids and antimicrobial proteins to the skin surface. Here, we show that in AD, IL-4 and IL-13 stimulate the expression of 3ß-hydroxysteroid dehydrogenase 1 (HSD3B1), a key rate-limiting enzyme in sex steroid hormone synthesis, predominantly expressed by sebaceous glands in human skin. HSD3B1 enhances androgen production in sebocytes, and IL-4 and IL-13 drive lipid abnormalities in human sebocytes and keratinocytes through HSD3B1. Consistent with our findings in cells, HSD3B1 expression is elevated in the skin of AD patients and can be restored by treatment with the IL-4Rα monoclonal antibody, Dupilumab. Androgens are also elevated in a mouse model of AD, though the mechanism in mice remains unclear. Our findings illuminate a connection between type 2 immunity and sex steroid hormone synthesis in the skin and suggest that abnormalities in sex steroid hormone synthesis may underlie the disrupted skin barrier in AD. Furthermore, targeting sex steroid hormone synthesis pathways may be a therapeutic avenue to restoring normal skin barrier function in AD patients.

Epidermolytic Hyperkeratosis in an Epidermoid (Infundibular) Cyst.

ABSTRACT: Epidermolytic hyperkeratosis (EHK) is an uncommon histopathologic reaction pattern that may represent a primary pathological process or a coincidental finding in a variety of neoplasms. We present a case of EHK in an epidermoid (infundibular) cyst. Histopathologically, EHK demonstrates vacuolar degeneration of keratinocytes in the spinous and granular cell layers, with disrupted cellular boundaries, enlarged basophilic keratohyalin-like granules and amorphous eosinophilic inclusions, along with massive hyperkeratosis. In addition to the morphologic description of EHK, we summarize the diagnoses in which EHK has been reported. Prior cases of EHK in an epidermoid (infundibular) cyst are summarized to compare findings. The significance of incidental EHK in skin lesions is unknown.

Unmet Needs and Receipt of Supportive Care Services in Head and Neck Cancer Patients Prior to Oncologic Treatment: A Prospective, Cross-Sectional Pilot Study.

OBJECTIVE: To characterize the supportive care (SC) needs and receipt of SC services among head and neck cancer (HNC) patients prior to oncologic treatment and to explore the influence of social determinants of health on these outcomes. MATERIALS AND METHODS: Newly diagnosed HNC patients were surveyed via telephone prior to oncologic treatment between 10/2019 and 1/2021 using a prospective, cross-sectional, bi-institutional, pilot study design. The primary study outcome was unmet SC needs (Supportive Care Needs Survey-Short Form34 [SCNS-SF34]). Hospital type (university- vs county safety-net) was explored as an exposure. Descriptive statistics were performed using STATA16 (College Station, TX). RESULTS: Among 158 potentially eligible patients, 129 were successfully contacted, 78 met the study criteria, and 50 completed the survey. The mean age was 61, 58% exhibited clinical stage III-IV disease, and 68% and 32% were treated at the university and county safety-net hospital, respectively. Patients were surveyed a median of 20 days after their first oncology visit and 17 days prior to initiation of oncology treatment. They had a median of 24 total needs (11 were met and 13 were unmet) and preferred to see a median of 4 SC services but received care from none. County safety-net patients had comparatively more unmet needs than university patients (14.5 vs 11.5, P = .04). CONCLUSION: Pretreatment HNC patients at a bi-institutional academic medical center report a high number of unmet SC needs with corollary poor receipt of available SC services. Novel interventions to address this significant gap in care are needed.

Supportive Care Needs Among Head and Neck Cancer Patients Prior to Oncologic Treatment: A Prospective, Nested Cross-Sectional Qualitative Analysis.

OBJECTIVES: To qualitatively characterize pretreatment head and neck cancer (HNC) patients' supportive care (SC) needs, attitudes toward SC, and barriers to SC utilization. MATERIALS AND METHODS: A prospective, nested, bi-institutional, cross-sectional pilot study design was employed. Participants were sub-selected from a representative sample of 50 patients newly diagnosed with mucosal or salivary gland HNC or sarcoma of the head and neck. Eligibility criteria included reporting ≥2 unmet needs (according to the Supportive Care Needs Survey-Short Form 34) or clinically-significant distress (National Comprehensive Cancer Network Distress Thermometer score ≥4). Semi-structured interviews were performed prior to initiation of oncologic treatment. Audio-recorded interviews were transcribed and thematically analyzed using NVivo 12.0 (QSR Australia). Thematic findings and representative quotes were interpreted by the entire research team. RESULTS: Twenty-seven patients were interviewed. One-third were treated at the county safety-net hospital and the remainder were treated at the university health system. An equal proportion of patients presented with oral cavity, oropharyngeal, and laryngeal or other tumors. Two significant findings were identified on semi-structured interviews. First, patients did not perceive the relevance of SC prior to treatment. Second, anxiety surrounding the HNC diagnosis and impending treatment dominated in the pretreatment phase. CONCLUSION: Improved HNC patient education about the relevance and importance of SC in the pretreatment setting is needed. Integration of social work or psychological services in HNC clinics is warranted to address patients' cancer-related worry-a discrete, dominant pretreatment SC need.

Single-Cell RNA Sequencing Reveals Cellular and Transcriptional Changes Associated With M1 Macrophage Polarization in Hidradenitis Suppurativa.

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease characterized by recurrent abscesses, nodules, and sinus tracts in areas of high hair follicle and sweat gland density. These sinus tracts can present with purulent drainage and scar formation. Dysregulation of multiple immune pathways drives the complexity of HS pathogenesis and may account for the heterogeneity of treatment response in HS patients. Using transcriptomic approaches, including single-cell sequencing and protein analysis, we here characterize the innate inflammatory landscape of HS lesions. We identified a shared upregulation of genes involved in interferon (IFN) and antimicrobial defense signaling through transcriptomic overlap analysis of differentially expressed genes (DEGs) in datasets from HS skin, diabetic foot ulcers (DFUs), and the inflammatory stage of normal healing wounds. Overlap analysis between HS- and DFU-specific DEGs revealed an enrichment of gene signatures associated with monocyte/macrophage functions. Single-cell RNA sequencing further revealed monocytes/macrophages with polarization toward a pro-inflammatory M1-like phenotype and increased effector function, including antiviral immunity, phagocytosis, respiratory burst, and antibody-dependent cellular cytotoxicity. Specifically, we identified the STAT1/IFN-signaling axis and the associated IFN-stimulated genes as central players in monocyte/macrophage dysregulation. Our data indicate that monocytes/macrophages are a potential pivotal player in HS pathogenesis and their pathways may serve as therapeutic targets and biomarkers in HS treatment.