JID innovations : skin science from molecules to population health最新文献

Patients who are immunosuppressed, such as solid organ transplant recipients (SOTRs), are at a higher risk of developing cutaneous squamous cell carcinoma (cSCC). This population is at a higher risk of metastasis and worse disease-specific survival. The objective of this review is to better characterize the immunosuppressed population with metastatic cSCC. A literature search was conducted to identify reports of lymphatic metastases in immunosuppressed patients with cSCC. Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines were followed during creation of a cohort with desired inclusion and exclusion criteria. One hundred and thirty-five articles met the inclusion/exclusion criteria, yielding 1020 total cases. We discovered that the most common forms of immunosuppression within the cohort were solid organ transplantation and hematologic malignancy. White males and cSCC tumors involving the head and neck comprised most cases. Using Brigham and Women’s Hospital and Eighth edition of American Joint Committee on Cancer tumor staging criteria, we observed a trend toward higher stage tumors in SOTR than in patients with hematologic malignancy. This review confirms that known clinical risk factors for metastatic cSCC appear to be similar among the immunosuppressed population and the cSCC population at large. Interestingly, our data suggest that current staging systems may not accurately reflect metastatic risk among patients with hematologic malignancy.

Cutaneous squamous cell carcinoma (cSCC) is the second most prevalent form of skin cancer. An increasing number of cSCCs are associated with dysregulation of key molecules that control skin homeostasis. These observations have increased interest in the role of neurotrophins and their receptors in the pathogenesis of cSCC. They have been demonstrated to have a considerable impact on the aggressiveness potential of skin cancer by both in vitro and in vivo models. In this context, mouse models are classically used to dissect proliferation versus differentiation balance, but they have some limitations in terms of time, space, and costs. Recently, zebrafish models have been implemented as a new tool to obtain information regarding the invasive capacity and metastasis of neoplastic cells. By xenotransplantation technique, cSCC cells from a patient’s biopsy or cell line can be successfully characterized, with or without the presence of genetic manipulation or treatments. In addition, the evaluation of the immune microenvironment contributes to potentially identifying connections and homologies with humans. In this review, we retrace the role of the neurotrophin network in healthy and pathological skin, particularly in cSCC. We review how zebrafish models can be important tools for studying cSCC development, growth, and potential treatments.

Background

Psoriasis is an immune-mediated inflammatory disease characterized by activation of IL-23–driven IL-17–producing T cell and other IL-23 receptor–positive IL-17–producing cell responses. Selective blockade of IL-23p19 with guselkumab was superior to blockade of TNF-α with adalimumab (ADA) in treating moderate-to-severe psoriasis. Objective: Pharmacodynamic responses of guselkumab versus ADA were compared in patients with psoriasis in VOYAGE 1.

Design

Inflammatory cytokine serum levels were assessed (n = 118), and lesional and nonlesional skin biopsies were collected (n = 38) in patient subsets at baseline and 4, 24, and 48 weeks after treatment to evaluate pharmacodynamic responses of guselkumab versus those of ADA.

Results

Guselkumab provided rapid reductions in serum IL-17A, IL-17F, and IL-22 levels by week 4 versus at baseline, which were maintained through weeks 24 and 48 (P < .001). The magnitude of reduction of IL-17A and IL-22 at week 48 and IL-17F at weeks 4, 24, and 48 were greater with guselkumab than with ADA (all P < .05). In the skin, guselkumab reduced the expression of IL-23/IL-17 pathway–associated and psoriasis-associated genes.

Conclusion

These data provide extensive characterization of pharmacodynamic anti-inflammatory responses to IL-23p19 and TNF-α inhibition in human blood and tissue over time with FDA-approved doses of guselkumab and ADA. Trial registration: ClinicalTrials.govClinicalTrials.gov (NCT02207231).

We aimed to explore the differences in immune checkpoint inhibitor (ICI) immunotherapy utilization for advanced melanoma by examining patient and neighborhood characteristics. We performed a retrospective cohort study using a deidentified, random sample of SEER-Medicare beneficiaries aged ≥65 years with stage III or stage IV melanoma (2011–2017). Our primary outcome was initiation of ICI immunotherapy (ipilimumab, pembrolizumab, nivolumab, or atezolizumab) after stage III or stage IV melanoma diagnosis. We analyzed ICI usage with multivariable logistic regression. After analyzing the entire 2011–2017 cohort, we conducted a secondary analysis in which we separately analyzed the 2011–2014 and 2015–2017 cohorts to assess possible differences over time. We included 3531 beneficiaries, with mean follow-up of 2.1 (SD = 2.0) years. Higher likelihood of ICI usage was associated with male sex (OR = 1.21, 95% confidence interval = 1.04–1.42) and higher density of medical oncologists (OR = 1.02, 95% confidence interval = 1.01–1.04). Lower likelihood of ICI usage was associated with older age group and Charlson comorbidity score (score ≥2; OR = 0.72, 95% confidence interval = 0.60–0.86). These associations were diminished in more recent years (no association with sex, medical oncologist density, Charlson comorbidity score, and association with only the oldest age group in years 2015–2017). We found significant sex- and age-related differences in initiation among SEER-Medicare beneficiaries with stage III or stage IV melanoma, which appear to be improving over time.

Basal cell carcinoma (BCC) is classified histologically into subtypes that determine treatment decisions. MicroRNAs (miRs) are short noncoding RNAs that may serve as diagnostic biomarkers. We investigated if particular miRs could distinguish BCC subtypes. We sequenced miRs from 55 archival BCC and 9 control skin specimens and then validated these miRs by qRT-PCR assay on a second BCC cohort (18 superficial, 16 nodular, 15 infiltrative) and control skin (n = 12). Expression values for individual miRs were normalized to miR-16-5p, which was the least variant among the control skin and BCC samples. We found that (i) miR-383-5p and miR-145-5p are downregulated in all BCC subtypes compared with control skin, (ii) miR-181c-5p is downregulated in superficial compared with invasive (nodular/infiltrative) BCC, and (iii) miR-22-5p and miR-708-5p are upregulated in infiltrative compared with superficial/nodular BCC and miR-30c-5p is downregulated in infiltrative compared with nodular BCC. Receiver operating characteristic analysis demonstrated excellent capacity of these miRs to discriminate between BCC and control skin (area under the curve, 0.94–0.98), whereas the capacity to discriminate between superficial and invasive subtypes was less robust (area under the curve, 0.7–0.8). Future prospective studies may determine the utility of these miRs as diagnostic biomarkers to guide biopsy and treatment of BCC.

NSG (NOD/Scid IL2Rγ^null) mice reconstituted with PBMCs donated by patients with ulcerative colitis or Crohn’s disease highly reflect the respective pathological phenotype. To determine whether these findings could be applicable to atopic dermatitis (AD) and psoriasis vulgaris (PV), PBMCs isolated from patients with AD and PV were first subjected to immunological profiling. Subsequently, NSG mice were reconstituted with these PBMCs. Hierarchical clustering and network analysis revealed a distinct profile of patients with AD and PV with activated CD4+ T cells (CD69, CD25) occupying a central position in the AD network and CD4+ CD134+ cells acting as the main hub in the PV network. After dermal application of DMSO, both NSG mice reconstituted with PBMCs from donors with AD (ie, NSG-AD mice) and NSG mice reconstituted with PBMCs from donors with PV (ie, NSG-PV mice) exhibited increased clinical, skin, and histological scores. Immunohistochemical analysis, frequencies of splenic human leukocytes, and cytokine expression levels indicated that CD4+ CD69+ cells, M1 and TSLP receptor–expressing monocytes, switched B cells, and monocyte chemoattractant protein 3 were the driving factors of inflammation in NSG-AD mice. In contrast, inflammation in NSG-PV mice was characterized by an increase in fibroblasts in the epidermis, frequencies of CD1a-expressing monocytes, and IL-17 levels. Therefore, the pathological phenotypes of NSG-AD mice and NSG-PV mice differ and partially reflect the respective human diseases.

Hand–foot skin reaction is the most common adverse event of multikinase inhibitors, such as sorafenib. Although hand–foot skin reaction is not life threatening, severe cases impair quality of life because of pain and reduced activities of daily living. However, the pathological mechanisms of hand–foot skin reaction have not yet been elucidated in detail, and there is currently no effective treatment. We aimed to identify keratinocyte cytoprotectants against sorafenib toxicity. The screening of cytoprotectants against sorafenib toxicity was performed using cultured normal human epidermal keratinocytes or a reconstructed human epidermis model and off-patent approved drugs in the Prestwick Chemical library. Among 1273 drugs in the chemical library, 8 dose-dependently increased cell viability by >200% in the presence of sorafenib. In the presence of sorafenib, the number of proliferating cell nuclear antigen–positive cells was significantly higher in clofazimine-, cyclosporin A–, and itraconazole-treated reconstructed human epidermis models than in sorafenib-treated models, and candidate drugs suppressed sorafenib-induced apoptosis in normal human epidermal keratinocytes. In addition, clofazimine, itraconazole, and pyrvinium pamoate significantly recovered the phosphorylation of extracellular signal–regulated kinase 1/2 in the presence of sorafenib. Collectively, hit drugs promoted cell viability and normalized keratinocyte proliferation in the presence of sorafenib. These candidate drugs have potential as treatments for multikinase inhibitor–induced hand–foot skin reaction.

Staphylococcus aureus (SA) colonizes and can damage skin in atopic dermatitis lesions, despite being commonly found with Staphylococcus epidermidis (SE), a commensal that can inhibit SA’s virulence and kill SA. In this study, we developed an in silico model, termed a virtual skin site, describing the dynamic interplay between SA, SE, and the skin barrier in atopic dermatitis lesions to investigate the mechanisms driving skin damage by SA and SE. We generated 10⁶ virtual skin sites by varying model parameters to represent different skin physiologies and bacterial properties. In silico analysis revealed that virtual skin sites with no skin damage in the model were characterized by parameters representing stronger SA and SE growth attenuation than those with skin damage. This inspired an in silico treatment strategy combining SA-killing with an enhanced SA–SE growth attenuation, which was found through simulations to recover many more damaged virtual skin sites to a non-damaged state, compared with SA-killing alone. This study demonstrates that in silico modelling can help elucidate the key factors driving skin damage caused by SA–SE colonization in atopic dermatitis lesions and help propose strategies to control it, which we envision will contribute to the design of promising treatments for clinical studies.

Inflammation is a hallmark of remitting-relapsing dermatological diseases. Although a large emphasis has been placed on adaptive immune cells as mediators of relapse, evidence in epithelial and innate immune biology suggests that disease memory is widespread. In this study, we bring to the fore the concept of inflammatory memory or nonspecific training of long-lived cells in the skin, highlighting the epigenetic and other mechanisms that propagate memory at the cellular level. We place these findings in the context of psoriasis, a prototypic flaring disease known to have localized memory, and underscore the importance of targeting memory to limit disease flares.