Collagen XVII deficiency alters epidermal patterning.

Vertebrates exhibit patterned epidermis, exemplified by scales/interscales in mice tails and grooves/ridges on the human skin surface (microtopography). Although the role of spatiotemporal regulation of stem cells (SCs) has been implicated in this process, the mechanism underlying the development of such epidermal patterns is poorly understood. Here, we show that collagen XVII (COL17), a niche for epidermal SCs, helps stabilize epidermal patterns. Gene knockout and rescue experiments revealed that COL17 maintains the width of the murine tail scale epidermis independently of epidermal cell polarity. Skin regeneration after wounding was associated with slender scale epidermis, which was alleviated by overexpression of human COL17. COL17-negative skin in human junctional epidermolysis bullosa showed a distinct epidermal pattern from COL17-positive skin that resulted from revertant mosaicism. These results demonstrate that COL17 contributes to defining mouse tail scale shapes and human skin microtopography. Our study sheds light on the role of the SC niche in tissue pattern formation.

Type XVII collagen interacts with the aPKC-PAR complex and maintains epidermal cell polarity.

Type XVII collagen (COL17) is a transmembrane protein expressed in the basal epidermis. COL17 serves as a niche for epidermal stem cells, and although its reduction has been implicated in altering cell polarity and ageing of the epidermis, it is unknown how COL17 affects epidermal cell polarity. Here, we uncovered COL17 as a binding partner of the aPKC-PAR complex, which is a key regulating factor of cell polarity. Immunoprecipitation-immunoblot assay and protein-protein binding assay revealed that COL17 interacts with aPKC and PAR3. COL17 deficiency or epidermis-specific aPKCλ deletion destabilized PAR3 distribution in the epidermis, while aPKCζ knockout did not. Asymmetrical cell division was pronounced in COL17-null neonatal paw epidermis. These results show that COL17 is pivotal for maintaining epidermal cell polarity. Our study highlights the previously unrecognized role of COL17 in the basal keratinocytes.

Sox13 is a novel early marker for hair follicle development.

Sox13, a group D member of the Sry-related high-mobility group box (Sox) transcription factor family, is expressed in various tissues including the hair follicle. However, its spatiotemporal expression patterns in the hair follicle and its role in hair development remain to be elucidated. To address these questions, we generated Sox13-LacZ-knock-in mice (Sox13LacZ/+), in which the LacZ reporter gene was inserted in-frame into exon 2, which contains the translation initiation codon. X-gal staining in Sox13LacZ/+ embryos revealed that Sox13 is initially expressed in the epithelial portion of the placode, and subsequently in the hair germ and the hair peg during early hair follicle development. In postnatal catagen and anagen, Sox13 was detected in the epithelial sheath, whereas in telogen, Sox13 was localized in the bulge region, where hair follicle stem cells reside. Immunohistochemistry with an anti-ß-galactosidase antibody and anti-hair keratin antibodies that specifically mark the different layers of the hair follicle revealed that Sox13 was predominantly expressed in the outer root sheath in anagen. However, the integumentary structures of Sox13LacZ/LacZ mice were grossly and histologically indistinguishable from those of wild type mice. These results suggest that although Sox13 is dispensable for epidermal and adnexal development, Sox13 is a useful marker for early hair follicle development.

Recurrence or de novo? Intradermal Basal Cell Carcinoma of the Scrotum: A Report of Two Cases.

Basal cell carcinoma (BCC) is the most common cutaneous malignancy, usually occurring in sun-exposed areas. Although BCC in the scrotal region is uncommon, it carries a higher risk of metastasis than BCC at other sites. Here, we report two cases of BCC that developed in the scrotal region: Case 1 presented as a superficial nodule and Case 2 as a subcutaneous nodule. Histopathologically, both tumors lacked continuity with the surface epidermis and formed an intradermal nodule. In Case 1, BCC occurred for the first time and presumably developed de novo. Case 2 underwent excision of a scrotal BCC 5 years previously, and the histopathological diagnosis at that time was nodular BCC. However, when the original specimen was re-examined, it was determined that, although the tumor had been completely resected, part of the lesion had moved away from the nodular area to represent a micronodular phenotype, an aggressive BCC subtype. We hypothesized that partial evolution from a nodular to a micronodular phenotype may have contributed to the recurrence of BCC in Case 2.

Barrier Factors of Adherence to Dupilumab Self-Injection for Severe Allergic Disease: A Non-Interventional Open-Label Study.

Purpose: The status of dupilumab self-injection at home is not well understood. We therefore aimed to identify the barriers to adherence to dupilumab self-injection. Patients and Methods: This non-interventional open-label study was conducted between March 2021 and July 2021. Patients with atopic dermatitis, bronchial asthma, and chronic rhinosinusitis with nasal polyps receiving dupilumab, from 15 sites, were requested to complete a self-administered questionnaire regarding the frequency and effectiveness of dosing as well as their use and satisfaction with dupilumab. Barriers to adherence were assessed using the Adherence Starts with Knowledge-12. Results: We included 331 patients who used dupilumab for atopic dermatitis (n = 164), chronic rhinosinusitis with nasal polyps (n = 102), and bronchial asthma (n = 65). The median efficacy of dupilumab scored 9.3 on the visual analog scale. Overall, 85.5% of the patients self-injected dupilumab, and 70.7% perfectly complied with the established injection dates. The pre-filled pen was significantly superior to the conventional syringe in terms of usability, operability, ease of pushing the plunger, and patient satisfaction. However, the pre-filled pen caused more pain during self-injection than did the syringe. Multivariate logistic regression analysis showed that adherence decreased with longer dupilumab treatment duration (p = 0.017) and was not associated with age, sex, underlying disease, or device type. There was a difference in responses related to "inconvenience/forgetfulness" between the good and poor adherence groups. Conclusion: The pre-filled dupilumab pen was superior to the syringe in terms of usability, operability, ease of pushing the plunger, and satisfaction. Repetitive instructions are recommended for preventing poor adherence to dupilumab self-injection.

Maculopapular Drug Eruption Caused by Apalutamide: Case Report and Review of the Literature.

Apalutamide, an oral androgen receptor signaling inhibitor, is approved for the treatment of non-metastatic castration-resistant prostate cancer and metastatic prostate cancer. In the international randomized placebo-controlled clinical trials, apalutamide was associated with a higher rate of rash than placebo. However, given that reports from a dermatological perspective are limited, the skin manifestations and histopathology of the skin lesions caused by apalutamide are largely unknown. Here, we report a case of apalutamide-induced drug eruption. A 66-year-old man developed itchy maculopapular erythema on the trunk and extremities 10 weeks after starting apalutamide for progressive prostate cancer. A biopsy specimen showed interface dermatitis with perivascular lymphocytic infiltration in the upper dermis. The lymphocyte transformation test was positive for apalutamide. The skin manifestations improved after discontinuation of apalutamide and treatment with topical corticosteroids and systemic prednisolone. A review of the dermatology literature on apalutamide-induced drug eruption yielded only six cases, including our case. Dermatologically, there were four cases of maculopapular rash and two of toxic epidermal necrolysis and histopathologically, there were three cases of interface dermatitis, two of epidermal necrosis, and one of spongiotic dermatitis. Four patients had peripheral eosinophilia. A lymphocyte transformation test was performed in three cases and was positive for apalutamide in all cases. Except for the two cases of toxic epidermal necrolysis, which were fatal, the skin eruptions appeared 10 weeks after starting apalutamide. Considering the increasing number of patients with prostate cancer being treated with apalutamide, cases of apalutamide-induced drug eruption need to be accumulated and analyzed.

Atypical protein kinase C isoforms differentially regulate directional keratinocyte migration during wound healing.

BACKGROUND: The epidermis possesses regenerative properties that become apparent only after wounding. Atypical protein kinase C (aPKC) isoforms aPKCζ and aPKCλ form a ternary complex with Par3 and Par6, and play crucial roles in establishing and maintaining epithelial cell polarity. The epidermal loss of aPKCλ results in progressive depletion of hair follicle stem cells. However, it is unclear whether aPKCs have equivalent activities in epidermal regeneration. OBJECTIVES: To clarify functional differences between aPKCζ and aPKCλ in cutaneous wound healing. METHODS: We compared cutaneous wound healing processes in vivo using mutant mice with genetic deletion of each aPKC isoform. We also analyzed functional differences between aPKCζ and aPKCλ in cell proliferation, directional cell migration, and formation of microtubules in vitro using primary keratinocytes established from each mutant mouse. RESULTS: Wound healing was significantly retarded in epidermis-specific aPKCλ knockout mice. In aPKCλ-deleted keratinocytes, the correct orientation of cell protrusions toward the wound was disrupted through the destabilization of Par6ß. The elongation of stabilized ß-tubulin was also deteriorated in aPKCλ-deleted keratinocytes, leading to defects in cell spreading. Conversely, wound healing and directional cell migration in aPKCζ-deleted mice were comparable to those in their control littermates. CONCLUSIONS: aPKCs are not functionally equivalent; aPKCλ, but not aPKCζ, plays a primary role in cutaneous wound healing.

Incidence rate of cutaneous squamous cell carcinoma is rapidly increasing in Akita Prefecture: Urgent alert for super-aged society.

Incidence rates of cutaneous squamous cell carcinoma (SCC) are increasing in many countries. To estimate detailed trends of SCC incidence rates in the population of Akita Prefecture as the forerunner of super-aged societies, we conducted a retrospective analysis of patients diagnosed with SCC between 2007 and 2016 in Akita University Hospital. The crude SCC incidence rate increased rapidly between 2007 and 2016 from 2.5 to 10.0/100 000 people. Remarkably, the age-specific incidence rate of people aged 80 years or over increased between 2007 and 2016 from 14.7 to 51.6/100 000 people, suggesting that SCC incidence rates increase possibly due to not only the increased number of aged people but also because of unidentified cancer-prone environments. When the findings of the present study are generalized to other regions entering the era of super-aging, it is clear that we need to prepare for the economic disease burden together with careful monitoring to confirm future trends for SCC.

Epidermoid Cyst Arising on the Body of the Tongue: Case Report and Literature Review.

BACKGROUND: Epidermoid cysts of the body of the tongue are rare. Only 12 cases of such lesions have been reported in the English literature. CASE: A 14-year-old boy had a 7×5-mm-sized cystic lesion with a yellowish-white surface on the ventral aspect of his tongue. The cystic wall was composed of squamous epithelium containing keratinous material. No skin appendages were attached to the wall. These findings were consistent with a diagnosis of an epidermoid cyst. LITERATURE REVIEW: For the thirteen cases, including ours, the average age was 18.0 years. The highest incidence was found in the first decade of life. Eight of the patients were male and five were female. The size varied from several millimeters to several centimeters. There may be a left side predilection of the occurrence. There is no evidence for malignant transformation of epidermoid cysts of the tongue, though two cases were reported as carcinoma arising from an epidermoid or dermoid cyst of another oral area. DISCUSSION: Epidermoid cysts of the body of the tongue are congenital or acquired. The congenital type can arise due to a failure of surface ectoderm separation or invagination of the surface ectoderm along the embryologic fusion sites. The acquired type is caused by trauma, with implanting of an epithelial element into the deeper tissue. In the present case, it was difficult to determine whether the pathogenesis was congenital or acquired because there are no clinical or histopathological differences between the two types.

Topical 3-bromopyruvate is a novel targeted therapy for melanoma in a preclinical model.

BACKGROUND: Targeting cancer metabolism is a promising strategy in improving cancer treatment. OBJECTIVE: To introduce a targeted therapy with topical 3-bromopyruvate (3BP), aglycolytic inhibitor, into the clinic in the near future. METHOD: We investigated the anti-tumor efficacy of 3BP on melanoma cells in vitro and in a preclinical model. RESULTS: Our cell-based study demonstrated that 3BP showed cytotoxicity for melanoma cells under anchorage-dependent or independent cell growth via a reactive oxygen species-mediated and caspase-independent cell death pathway. Moreover, 3BP inhibited both self-renewal potential and growth of slow-cycling phenotype in melanoma cells. Remarkably, the preclinical mouse xenograft model shed light on topical application of 3BP, showing significant anti-tumor effects with no apparent toxicity in surrounding normal tissues. CONCLUSION: We have now proposed that a targeted therapy with topical 3BP is an innovative strategy for adjuvant chemotherapy of technically or medically unresectable melanoma and possibly other skin cancers.

Guidelines for the diagnosis and treatment of male-pattern and female-pattern hair loss, 2017 version.

Male-pattern hair loss (MPHL, androgenetic alopecia) is a slowly progressive form of alopecia which begins after puberty. In 2010, we published the first Japanese edition of guidelines for the diagnosis and treatment of MPHL. It achieved the original goal of providing physicians and patients in Japan with evidence-based information for choosing efficacious and safe therapy for MPHL. Subsequently, new therapeutic drugs and treatment methods have been developed, and women's perception of MPHL has undergone change and the term "female-pattern hair loss (FPHL)" is becoming more common internationally. Thus, here we report a revised version of the 2010 guidelines aimed at both MPHL and FPHL. In these guidelines, finasteride 1 mg daily, dutasteride 0.5 mg daily and topical 5% minoxidil twice daily for MPHL, and topical 1% minoxidil twice daily for FPHL, are recommended as the first-line treatments. Self-hair transplantation, irradiation by light-emitting diodes and low-level lasers, and topical application of adenosine for MPHL are recommended, whereas prosthetic hair transplantation and oral administration of minoxidil should not be performed. Oral administration of finasteride or dutasteride are contraindicated for FPHL. In addition, we have evaluated the effectiveness of topical application of carpronium chloride, t-flavanone, cytopurine, pentadecane and ketoconazole, and wearing a wig. Unapproved topical application of bimatoprost and latanoprost, and emerging hair regeneration treatments have also been addressed. We believe that the revised guidelines will improve further the diagnostic and treatment standards for MPHL add FPHL in Japan.

Systematic screening for genes specifically expressed in the anterior neuroectoderm during early Xenopus development.

A cDNA library derived from the anterior neuroectoderm (ANE) of Xenopus late-gastrula embryos was systematically screened to isolate novel developmental regulatory genes involved in early brain development. We isolated 1,706 5 expressed sequence tags (ESTs), which were subdivided into 1,383 clusters and categorized into 19 classes based on predicted functions according to their similarities to other known genes. Of these, 757 clusters that were considered possible novel regulatory genes or unknown genes were subjected to expression pattern analysis using whole-mount in situ hybridization. Genes from 69 clusters (9%) were expressed in the ANE region. Based on their expression patterns and predicted amino acid sequences, 25 genes were selected for further analysis as novel Xenopus genes expressed broadly or region-specifically in the ANE. Eighteen genes were expressed in postulated patterning centers in the neuroectoderm, including the anterior (four genes) and lateral (nine genes) neural ridges, the midbrain-hindbrain boundary region (one gene) and the midline region of the neural plate (two genes), whereas 13 genes were expressed in the eye anlagen. Therefore, early regionalization of the neuroectoderm appears to occur mainly in those neural patterning centers and the eye anlagen. We determined the entire coding regions of p54nrb, Semaphorin 6D and a novel gene designated scribble-related protein 1 (SCRP1). Interestingly, Semaphorin 6D is expressed in the mesoderm with a dorsoventral gradient, as well as in the ectoderm at the gastrula stage, implying a new role for this protein in development other than in axon guidance.