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

Keloids are abnormal skin growths occurring in a significant portion of the global population. Despite their pervasiveness, the underlying pathophysiology of this scarring process is yet to be fully understood. In this review article, we delve into the current literature on the pathophysiological mechanisms of keloids. We take a top-down approach, first looking at host factors such as genetics and endocrine factors and then taking a more granular approach describing specific control factors such as germline keloid predisposition variants, epigenetics and transcriptomics, inflammatory and immune dysregulation, and the role of profibrotic and angiogenic cell signaling pathways. We then discuss current knowledge gaps, propose further research avenues, and explore potential future treatment options considering our increased understanding of keloid pathogenesis.

Early cutaneous squamous cell carcinoma (cSCC) diagnosis is essential to initiate adequate targeted treatment. Noninvasive diagnostic technologies could overcome the need of multiple biopsies and reduce tumor recurrence. To assess performance of noninvasive technologies for cSCC diagnostics, 947 relevant records were identified through a systematic literature search. Among the 15 selected studies within this systematic review, 7 were included in the meta-analysis, comprising of 1144 patients, 224 cSCC lesions, and 1729 clinical diagnoses. Overall, the sensitivity values are 92% (95% confidence interval [CI] = 86.6–96.4%) for high-frequency ultrasound, 75% (95% CI = 65.7–86.2%) for optical coherence tomography, and 63% (95% CI = 51.3–69.1%) for reflectance confocal microscopy. The overall specificity values are 88% (95% CI = 82.7–92.5%), 95% (95% CI = 92.7–97.3%), and 96% (95% CI = 94.8–97.4%), respectively. Physician’s expertise is key for high diagnostic performance of investigated devices. This can be justified by the provision of additional tissue information, which requires physician interpretation, despite insufficient standardized diagnostic criteria. Furthermore, few deep learning studies were identified. Thus, integration of deep learning into the investigated devices is a potential investigating field in cSCC diagnosis.

Psoriasis is an inflammatory skin disease characterized by epidermal and immune dysfunctions. Although efficient, current topical treatments display adverse effects, including skin atrophy and burning sensation, leading to poor patient adherence. To overcome these downsides, pickering emulsions were formulated in which the calcitriol-containing dispersed phase was stabilized with either cyclosporin A– or tacrolimus-loaded poly(lactic-co-glycolic) acid nanoparticles. This study aimed to investigate their biological effects on lymphocytes and epidermal cells and their effectiveness in an imiquimod-induced psoriasis-like mouse model. Results showed that both emulsions significantly inhibited nuclear factor of activated T cell translocation in T lymphocytes as well as their IL-2 production, cell activation, and proliferation. In keratinocytes, inhibition of nuclear factor of activated T cell translocation decreased the production of IL-8 and TNF-α. Topical application of emulsions over skin biopsies ex vivo showed accumulation of rhodamin B–coupled poly(lactic-co-glycolic) acid nanoparticles throughout the epidermis by immunofluorescence and significantly decreased the antigen-presenting capacity of Langerhans cells in relation to a reduced expression of activation markers CD40, CD86, and HLA-DR. Using an imiquimod-induced psoriasis model in vivo, pickering emulsions significantly alleviated psoriasiform lesions potentially attributed to the decreased cutaneous expression of T-cell markers, proinflammatory cytokines, chemokines, and specific epidermal cell genes. Altogether, pickering emulsion might be a very efficient formulation for treating inflammatory dermatoses.

The image quality received for clinical evaluation is often suboptimal. The goal is to develop an image quality analysis tool to assess patient- and primary care physician–derived images using deep learning model. Dataset included patient- and primary care physician–derived images from August 21, 2018 to June 30, 2022 with 4 unique quality labels. VGG16 model was fine tuned with input data, and optimal threshold was determined by Youden’s index. Ordinal labels were transformed to binary labels using a majority vote because model distinguishes between 2 categories (good vs bad). At a threshold of 0.587, area under the curve for the test set was 0.885 (95% confidence interval = 0.838–0.933); sensitivity, specificity, positive predictive value, and negative predictive value were 0.829, 0.784, 0.906, and 0.645, respectively. Independent validation of 300 additional images (from patients and primary care physicians) demonstrated area under the curve of 0.864 (95% confidence interval = 0.818–0.909) and area under the curve of 0.902 (95% confidence interval = 0.85–0.95), respectively. The sensitivity, specificity, positive predictive value, and negative predictive value for the 300 images were 0.827, 0.800, 0.959, and 0.450, respectively. We demonstrate a practical approach improving the image quality for clinical workflow. Although users may have to capture additional images, this is offset by the improved workload and efficiency for clinical teams.

The Reconstructed Human Epidermis (RHE) model derived from epidermal keratinocytes offers an ethical and scientific alternative to animal experimentation, particularly in cutaneous toxicology and dermatological research, where the elimination of animal cruelty is of paramount importance. Thus, we compared commercially available chemically defined animal origin-free (cdAOF) supplements, designed for regenerative medicine, to the widely utilized supplement (human keratinocyte growth supplement), which contains growth factors and bovine pituitary extract. Herein we present the extended characterization of RHE derived from newborn, adult, and immortalized N/telomerase reverse transcriptase keratinocytes under cdAOF conditions. Culture of RHE in the cdAOF media produced histological features that were similar to that produced using human keratinocyte growth supplement, with the exception that the basal keratinocytes were less cylindrical. Additionally, immunolocalization of involucrin in the basal layer and increased mRNA expression of several inflammatory-proliferative markers were observed under cdAOF conditions. In RHEs cultured in cdAOF media, expression and immunolocalization of other expected markers of keratinization were similar, while monitoring of barrier function (transepithelial electrical resistance) revealed results that were statistically equal to, or lower than those observed in RHE cultured in human keratinocyte growth supplement. Our study indicates that reconstruction of RHE was accomplished under cdAOF culture conditions and that further refinement could promote an expanded use beyond regenerative medicine, for in vitro toxicology applications.

IL-23 is a cytokine produced by myeloid cells that drives the T helper 17 pathway and plays an essential role in the pathophysiology of plaque psoriasis. IL-23 activation initiates a cascade of cytokines subsequently inducing the expression of many psoriasis-related proteins. This study aimed to better understand the underlying mechanisms driving the differences between IL-23 and IL-17A blockade in patients with psoriasis and their implications for durability of clinical responses. Serum and/or skin biopsies were isolated from patients treated with guselkumab or secukinumab for evaluation of potential biomarkers of pharmacodynamic response to treatment. Guselkumab treatment led to significantly greater reductions of IL-17F and IL-22 serum levels than treatment with secukinumab at weeks 24 and 48, demonstrating sustained regulation of the IL-23/T helper 17 pathway. Analyses of proteomic and transcriptomic profiles of patient sera and skin biopsies demonstrated differential regulation of proteins involved in chemokine, TNF, and relevant immune signaling pathways to a greater degree with guselkumab than with secukinumab treatment. These data provide insights into the differences between the mechanisms and impact of IL-23 and IL-17A blockade in psoriasis, with implications for efficacy observations and treatment paradigms. Trial Registration: The original study was registered at ClinicalTrials.gov (NCT03090100).

The National Psoriasis Foundation surveyed a random, stratified sample of individuals with psoriatic disease in the United States to determine the prevalence of an unacceptable psoriatic arthritis (PsA) symptom state and its effect on depression and social participation. Acceptable and unacceptable levels of PsA were defined using established cutoff points (acceptable ≤4 vs unacceptable >4) on the Psoriatic Arthritis Impact of Disease 9. Psoriasis severity was defined by body surface area: mild < 3%, moderate–severe ≥ 3%. Depression was assessed utilizing the Patient Health Questionnaire 2. Social participation was assessed by the Patient Reported Outcome Information Measurement System Ability to Participate in Social Role and Activities-SF4a. The analysis cohort comprised 801 patients with PsA. Unacceptable disease activity level (Psoriatic Arthritis Impact of Disease >4) was reported by 59.6% of participants. After adjusting for age, sex, and psoriasis severity, individuals with likely depression (OR = 0.014, P < .001) and those with limited ability to participate in social roles and activities (OR = 0.05, P < .001) were less likely to experience acceptable levels of PsA activity. Ultimately, the results demonstrated that most United States patients with PsA have unacceptable levels of disease activity, which is associated with increased prevalence of depression and limitations in social participation.

Smoothened inhibitors, such as vismodegib, exhibit remarkable success in treating patients with locally advanced basal cell carcinoma (LaBCC). Yet, vismodegib efficacy is hindered by notable side effects, which often lead to treatment discontinuation and subsequent relapse in patients with LaBCC. Prolonged remission was previously reported in patients with LaBCCs who underwent surgical debulking before starting vismodegib. In this study, we enrolled 4 patients with LaBCC who underwent debulking followed by vismodegib therapy to assess their clinical outcomes and analyze the cutaneous molecular changes occurring as a result of surgical intervention. After LaBCC debulking, patients underwent a punch biopsy of residual basal cell carcinoma tissue 1 week later. RT-qPCR analysis of 24 Notch and Wnt signaling–associated genes revealed elevated PTCH1, HEY2, LGR6, FZD2, LEF1, ALCAM, and RUNX1 expressions in follow-up biopsies compared with those in patient-matched debulked tissue. Immunoblot and immunostaining further confirmed elevated Notch signaling in follow-up biopsy tissue compared with that in patient-matched debulked tumor tissue. Patients 1, 3, and 4 displayed a clinical response to debulking followed by vismodegib, whereas patient 2 was lost to follow-up after debulking. These findings suggest that surgical manipulation of LaBCCs is correlated with molecular alterations in signaling pathways associated with cellular reprogramming.