Publications by authors named "Akiharu Kubo"

86 Publications

Neonatal Linear IgA Bullous Dermatosis Mediated by Breast Milk-Borne Maternal IgA.

JAMA Dermatol 2021 Jul 14. Epub 2021 Jul 14.

Department of Dermatology, Keio University School of Medicine, Tokyo, Japan.

Importance: Neonatal linear immunoglobulin A (IgA) bullous dermatosis (LABD) is a rare disease that can be fatal when associated with respiratory failure. All previously reported cases of neonatal LABD have been in newborns with healthy asymptomatic mothers, and the pathogenic IgA was of unknown origin.

Objective: To clarify the origin of IgA associated with LABD in neonates born of healthy asymptomatic mothers.

Design, Setting, And Participants: This case study analyzed the laboratory findings of a single breast-fed newborn male with neonatal LABD admitted to the Keio University Hospital in Tokyo and his healthy asymptomatic mother. The healthy newborn developed life-threatening blisters and erosions of the skin and mucous membranes on day 4 after birth. Blood serum, skin, and maternal breast milk were examined for IgA autoantibodies.

Main Outcomes And Measures: Histopathologic and immunofluorescence analyses of specimens (serum, skin, and breast milk) from the patient and his mother.

Results: Histopathologic evaluation of the newborn's skin revealed subepidermal blisters with neutrophil infiltrates, and immunofluorescence testing showed linear IgA deposition along the basement membrane zone (BMZ), which lead to the diagnosis of neonatal LABD. Indirect immunofluorescence using normal human skin after treatment with 1-mol/L sodium chloride showed the patient to have circulating IgA binding to the dermal side of BMZ. Immunohistochemical staining proved the deposition of secretory IgA in the neonatal skin by demonstrating the presence of J chain-not been seen in other LABD cases-indicating that the autoantibodies producing the blisters were derived from the maternal breast milk. Although no circulating IgA against the skin was detected in mother's sera, the breast milk contained IgA that reacted with the dermal side of the BMZ. No new blister formation was observed after cessation of breastfeeding.

Conclusions And Relevance: The results of this case study suggest a passive transfer of pathogenic IgA to a newborn from an asymptomatic mother via breast milk. In prior reports, no serum from asymptomatic mothers of newborns with LABD had IgA autoantibodies binding to skin components; however, in this case, we found that the maternal breast milk contained IgA autoantibodies associated with neonatal LABD. In neonatal LABD, maternal breast milk should be examined for IgA autoantibodies and breast milk feeding should be discontinued as soon as neonatal LABD is suspected.
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http://dx.doi.org/10.1001/jamadermatol.2021.2392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8280969PMC
July 2021

Japanese guidelines for the management of palmoplantar keratoderma.

J Dermatol 2021 Aug 13;48(8):e353-e367. Epub 2021 Jun 13.

Department of Dermatology, Osaka City University Graduate School of Medicine, Osaka, Japan.

Palmoplantar keratoderma (PPK) is a collective term for keratinizing disorders in which the main clinical symptom is hyperkeratosis on the palms and soles. To establish the first Japanese guidelines approved by the Japanese Dermatological Association for the management of PPKs, the Committee for the Management of PPKs was founded as part of the Study Group for Rare Intractable Diseases. These guidelines aim to provide current information for the management of PPKs in Japan. Based on evidence, they summarize the clinical manifestations, pathophysiologies, diagnostic criteria, disease severity determination criteria, treatment, and treatment recommendations. Because of the rarity of PPKs, there are only few clinical studies with a high degree of evidence. Therefore, several parts of these guidelines were established based on the opinions of the committee. To further optimize the guidelines, periodic revision in line with new evidence is necessary.
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http://dx.doi.org/10.1111/1346-8138.15850DOI Listing
August 2021

Frequent FGFR3 and Ras Gene Mutations in Skin Tags/Acrochordons.

J Invest Dermatol 2021 Apr 30. Epub 2021 Apr 30.

Department of Dermatology, Keio University School of Medicine, Tokyo 160-8582, Japan; Keio-Maruho Laboratory of Skin Barriology, Keio University School of Medicine, Tokyo 160-8582, Japan. Electronic address:

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http://dx.doi.org/10.1016/j.jid.2021.03.028DOI Listing
April 2021

Autosomal dominant familial acanthosis nigricans caused by a C-terminal nonsense mutation of FGFR3.

J Hum Genet 2021 Aug 12;66(8):831-834. Epub 2021 Feb 12.

Department of Dermatology, Keio University School of Medicine, Tokyo, Japan.

FGFR3 encodes a transmembrane receptor tyrosine kinase that has six autophosphorylation sites of tyrosine. Among them, Y770 is a negative regulatory site for the downstream signaling of FGFR3. Constitutive active mutations in FGFR3 are involved in human developmental disorders including familial acanthosis nigricans, an autosomal dominant disorder characterized by general hyperpigmentation with mild acanthosis of the epidermis. Here, we report two unrelated cases of familial acanthosis nigricans with a heterozygous c.2302G>T (p.E768*) mutation in FGFR3 (NM_000142.5). FGFR3 mRNA purified from the skin lesion neither showed aberrant splicing nor nonsense-mediated mRNA decay, indicating that the FGFR3 mutant simply lacked the C-terminal 768-806 amino acids including Y770. While all of the known pathogenic mutations were missense mutations in FGFR3 showing autosomal dominant trait, the c.2302G>T mutation of FGFR3 is a unique autosomal dominant nonsense mutation that causes familial acanthosis nigricans probably via loss of negative regulatory autophosphorylation site of FGFR3.
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http://dx.doi.org/10.1038/s10038-021-00905-1DOI Listing
August 2021

Single nucleotide variations in genes associated with innate immunity are enriched in Japanese adult cases of face and neck type atopic dermatitis.

J Dermatol Sci 2021 Feb 19;101(2):93-100. Epub 2020 Nov 19.

Center for Supercentenarian Medical Research, Keio University School of Medicine, Tokyo, Japan. Electronic address:

Background: Atopic dermatitis (AD) is heterogenous in terms of phenotype as well as genetic and environmental factors, while its associated genetic factors and pathophysiology are not fully understood.

Objective: We identify novel genetic factors enriched in a subgroup of AD patients with characteristic clinical features.

Methods: We clinically subgrouped 18 AD patients who exhibited distinctive characteristic of persistent skin eruption areas on the face and neck from 92 Japanese adult AD patients and identified disease-associated genetic factors enriched within the subgroup. Targeted resequencing and subsequent genetic association analyses were used to identify novel enriched genetic variations in the subgroup compared with the other AD patients.

Results: Targeted resequencing of 648 skin associated genes revealed an enrichment of 12 single nucleotide variations (SNVs) in patients with face and neck AD (n = 18) compared with the general Japanese population in the database. Subsequent allele frequency comparison between the face and neck AD and non - face and neck AD subgroups revealed enrichment of five SNVs. Multivariate analysis using genotype data revealed that three SNVs in theTLR1, TIRAP, and PSAPL1 genes, two of the three genes are involved in the Toll-like receptor pathway, were significantly enriched in patients with face and neck AD.

Conclusion: These findings revealed that the SNVs in genes associated with the innate immune pathway are enriched in a subgroup of AD. The combinational approach of clinical subgrouping and genotyping is valuable for detecting novel disease-associated genetic factors.
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http://dx.doi.org/10.1016/j.jdermsci.2020.11.005DOI Listing
February 2021

Premature aging syndrome showing random chromosome number instabilities with CDC20 mutation.

Aging Cell 2020 11 23;19(11):e13251. Epub 2020 Oct 23.

Department of Dermatology, Keio University School of Medicine, Tokyo, Japan.

Damage to the genome can accelerate aging. The percentage of aneuploid cells, that is, cells with an abnormal number of chromosomes, increases during aging; however, it is not clear whether increased aneuploidy accelerates aging. Here, we report an individual showing premature aging phenotypes of various organs including early hair loss, atrophic skin, and loss of hematopoietic stem cells; instability of chromosome numbers known as mosaic variegated aneuploidy (MVA); and spindle assembly checkpoint (SAC) failure. Exome sequencing identified a de novo heterozygous germline missense mutation of c.856C>A (p.R286S) in the mitotic activator CDC20. The mutant CDC20 showed lower binding affinity to BUBR1 during the formation of the mitotic checkpoint complex (MCC), but not during the interaction between MCC and the anaphase-promoting complex/cyclosome (APC/C)-CDC20 complex. While heterozygous knockout of CDC20 did not induce SAC failure, knock-in of the mutant CDC20 induced SAC failure and random aneuploidy in cultured cells, indicating that the particular missense mutation is pathogenic probably via the resultant imbalance between MCC and APC/C-CDC20 complex. We postulate that accelerated chromosome number instability induces premature aging in humans, which may be associated with early loss of stem cells. These findings could form the basis of a novel disease model of the aging of the body and organs.
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http://dx.doi.org/10.1111/acel.13251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7681047PMC
November 2020

Eosinophilic pustular folliculitis with palmoplantar lesions and nail deformity.

J Dermatol 2020 Oct 16;47(10):e357-e359. Epub 2020 Jul 16.

Department of Dermatology, Keio University School of Medicine, Tokyo, Japan.

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http://dx.doi.org/10.1111/1346-8138.15503DOI Listing
October 2020

Case of intermediate recessive dystrophic epidermolysis bullosa with negative LH7.2 staining.

J Dermatol 2020 Oct 12;47(10):e370-e372. Epub 2020 Jul 12.

Department of Dermatology, Toho University School of Medicine, Tokyo, Japan.

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http://dx.doi.org/10.1111/1346-8138.15498DOI Listing
October 2020

Successful treatment with secukinumab of three psoriatic patients undergoing dialysis.

J Dermatol 2020 Jan 27;47(1):e26-e28. Epub 2019 Oct 27.

Department of Dermatology, School of Medicine, Keio University, Tokyo, Japan.

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http://dx.doi.org/10.1111/1346-8138.15132DOI Listing
January 2020

Subclinical hypopigmentation of the skin and hair in a Japanese patient with Hermansky-Pudlak syndrome type 3.

J Dermatol 2020 Jan 16;47(1):e18-e20. Epub 2019 Oct 16.

Department of Dermatology, Keio University School of Medicine, Tokyo, Japan.

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http://dx.doi.org/10.1111/1346-8138.15118DOI Listing
January 2020

Phakomatosis Pigmentokeratotica.

N Engl J Med 2019 10;381(15):1458

University of Tokyo Graduate School of Medicine, Tokyo, Japan.

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http://dx.doi.org/10.1056/NEJMicm1817155DOI Listing
October 2019

Filaggrin Expression and Processing Deficiencies Impair Corneocyte Surface Texture and Stiffness in Mice.

J Invest Dermatol 2020 03 31;140(3):615-623.e5. Epub 2019 Aug 31.

Amsterdam UMC, University of Amsterdam, Coronel Institute of Occupational Health, Amsterdam Public Health research institute, Amsterdam, Netherlands. Electronic address:

Abundant corneocyte surface protrusions, observed in patients with atopic dermatitis with filaggrin loss-of-function mutations, are inversely associated with levels of natural moisturizing factors (NMFs) in the stratum corneum. To dissect the etiological role of NMFs and filaggrin deficiency in surface texture alterations, we examined mouse models with genetic deficiencies in the synthesis or degradation of filaggrin monomers for NMFs, cell stiffness (elastic modulus) and corneocyte surface protrusion density (dermal texture index). Five neonatal and adult mouse models carrying inactivating mutations of SASPase (Sasp), filaggrin (Flg and Flg), filaggrin-hornerin (FlgHrnr), and bleomycin hydrolase (Blmh) were investigated. Sasp and Flg were on the hairless mouse background. Atomic force microscopy was used to determine elastic modulus and dermal texture index. Corneocytes of each neonatal as well as hairless adult knockout mouse exhibited an increased number of protrusions and decreased elastic modulus. In these mice, NMFs were reduced except for Sasp. Dermal texture index was inversely correlated with NMFs and elastic modulus. Our findings demonstrate that any filaggrin-NMF axis deficiency can affect corneocyte mechanical properties in mice and likely in humans. Differences in NMFs and corneocyte surface texture between neonatal and adult as well as hairless and hairy mice emphasize the need for carefully selecting the most appropriate animal models for studies.
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http://dx.doi.org/10.1016/j.jid.2019.07.716DOI Listing
March 2020

Holocrine Secretion Occurs outside the Tight Junction Barrier in Multicellular Glands: Lessons from Claudin-1-Deficient Mice.

J Invest Dermatol 2020 02 22;140(2):298-308.e5. Epub 2019 Aug 22.

Department of Dermatology, Keio University School of Medicine, Tokyo, Japan; Keio-Maruho Laboratory of Skin Barriology, Keio University School of Medicine, Tokyo, Japan. Electronic address:

Holocrine secretion is a specific mode of secretion involving secretion of entire cytoplasmic materials with remnants of dead cells, as observed in multicellular exocrine glands of reptiles, birds, and mammals. Here, we found that sebaceous glands in mice, representative of multicellular exocrine glands of mammals, exhibit a form of polarized stratified epithelium equipped with tight junctions (TJs), and found that holocrine secretion occurred outside the TJ barriers. Sebaceous glands share characteristics of stratified epithelia with interfollicular epidermis, including basal-layer-restricted cell proliferation, TJ barrier formation at a specific single layer of cells with apico-basolateral plasma membrane polarity, and cell death outside the TJ barrier. Knockout of claudin-1, a transmembrane adhesive protein in TJs, in mice caused leakage of the TJ barrier in sebaceous glands and incomplete degradation of the plasma membrane and nuclei during holocrine secretion. Claudin-1 knockout resulted in the accumulation of incompletely degenerated sebocytes in sebaceous ducts, suggesting that the TJ barrier was necessary for differentiation of holocrine secretion. The redefinition of sebaceous glands as TJ-forming stratified epithelia provides an important framework to understand the molecular mechanism of holocrine secretion.
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http://dx.doi.org/10.1016/j.jid.2019.06.150DOI Listing
February 2020

Novel gene mutations in Chédiak-Higashi syndrome with hyperpigmentation.

J Dermatol 2019 Nov 27;46(11):e416-e418. Epub 2019 Jun 27.

Department of Dermatology, Hamamatsu University School of Medicine, Hamamatsu, Japan.

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http://dx.doi.org/10.1111/1346-8138.14987DOI Listing
November 2019

Clonal Expansion of Second-Hit Cells with Somatic Recombinations or C>T Transitions Form Porokeratosis in MVD or MVK Mutant Heterozygotes.

J Invest Dermatol 2019 12 15;139(12):2458-2466.e9. Epub 2019 Jun 15.

Department of Dermatology, Keio University School of Medicine, Tokyo, Japan; Keio-Maruho Laboratory of Skin Barriology, Keio University School of Medicine, Tokyo, Japan.

Patients with disseminated superficial actinic porokeratosis (DSAP) and linear porokeratosis (LP) exhibit monoallelic germline mutations in genes encoding mevalonate pathway enzymes, such as MVD or MVK. Here, we showed that each skin lesion of DSAP exhibited an individual second hit genetic change in the wild-type allele of the corresponding gene specifically in the epidermis, indicating that a postnatal second hit triggering biallelic deficiency of the gene is required for porokeratosis to develop. Most skin lesions exhibited one of two principal second hits, either somatic homologous recombinations rendering the monoallelic mutation biallelic or C>T transition mutations in the wild-type allele. The second hits differed among DSAP lesions but were identical in those of congenital LP, suggesting that DSAP is attributable to sporadic postnatal second hits and congenital LP to a single second hit in the embryonic period. In the characteristic annular skin lesions of DSAP, the central epidermis featured mostly second hit keratinocytes, and that of the annular ring featured a mixture of such cells and naïve keratinocytes, implying that each lesion reflects the clonal expansion of single second hit keratinocytes. DSAP is therefore a benign intraepidermal neoplasia, which can be included in the genetic tumor disorders explicable by Knudson's two-hit hypothesis.
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http://dx.doi.org/10.1016/j.jid.2019.05.020DOI Listing
December 2019

Homeostatic pruning and activity of epidermal nerves are dysregulated in barrier-impaired skin during chronic itch development.

Sci Rep 2019 06 13;9(1):8625. Epub 2019 Jun 13.

Laboratory for Tissue Dynamics, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, 230-0045, Japan.

The epidermal barrier is thought to protect sensory nerves from overexposure to environmental stimuli, and barrier impairment leads to pathological conditions associated with itch, such as atopic dermatitis (AD). However, it is not known how the epidermal barrier continuously protects nerves for the sensory homeostasis during turnover of the epidermis. Here we show that epidermal nerves are contained underneath keratinocyte tight junctions (TJs) in normal human and mouse skin, but not in human AD samples or mouse models of chronic itch caused by epidermal barrier impairment. By intravital imaging of the mouse skin, we found that epidermal nerve endings were frequently extended and retracted, and occasionally underwent local pruning. Importantly, the epidermal nerve pruning took place rapidly at intersections with newly forming TJs in the normal skin, whereas this process was disturbed during chronic itch development. Furthermore, aberrant Ca increases in epidermal nerves were induced in association with the disturbed pruning. Finally, TRPA1 inhibition suppressed aberrant Ca increases in epidermal nerves and itch. These results suggest that epidermal nerve endings are pruned through interactions with keratinocytes to stay below the TJ barrier, and that disruption of this mechanism may lead to aberrant activation of epidermal nerves and pathological itch.
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http://dx.doi.org/10.1038/s41598-019-44866-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6565750PMC
June 2019

The desmosome is a mesoscale lipid raft-like membrane domain.

Mol Biol Cell 2019 06 3;30(12):1390-1405. Epub 2019 Apr 3.

Department of Cell Biology, Emory University School of Medicine, Atlanta, GA 30322.

Desmogleins (Dsgs) are cadherin family adhesion molecules essential for epidermal integrity. Previous studies have shown that desmogleins associate with lipid rafts, but the significance of this association was not clear. Here, we report that the desmoglein transmembrane domain (TMD) is the primary determinant of raft association. Further, we identify a novel mutation in the DSG1 TMD (G562R) that causes severe dermatitis, multiple allergies, and metabolic wasting syndrome. Molecular modeling predicts that this G-to-R mutation shortens the DSG1 TMD, and experiments directly demonstrate that this mutation compromises both lipid raft association and desmosome incorporation. Finally, cryo-electron tomography indicates that the lipid bilayer within the desmosome is ∼10% thicker than adjacent regions of the plasma membrane. These findings suggest that differences in bilayer thickness influence the organization of adhesion molecules within the epithelial plasma membrane, with cadherin TMDs recruited to the desmosome via the establishment of a specialized mesoscale lipid raft-like membrane domain.
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http://dx.doi.org/10.1091/mbc.E18-10-0649DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6724694PMC
June 2019

A case of woolly hair nevus, multiple linear pigmentation, and epidermal nevi with somatic HRAS p.G12S mutation.

Pediatr Dermatol 2019 May 12;36(3):368-371. Epub 2019 Mar 12.

Department of Biochemistry, Keio University School of Medicine, Tokyo, Japan.

Woolly hair nevus is a rare syndrome that presents as woolly hair in restricted areas of the scalp and may be associated with pigmented macules or epidermal nevus on the body. Here, we report a case of woolly hair nevus, linear pigmentation, and multiple epidermal nevi with a somatic HRAS c.34G>A(p.G12S) mutation.
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http://dx.doi.org/10.1111/pde.13783DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6593414PMC
May 2019

Case of Conradi-Hünermann-Happle syndrome due to a nonsense mutation of c.245G>A (p.W82*).

J Dermatol 2019 08 27;46(8):e296-e298. Epub 2019 Feb 27.

Department of Dermatology, Keio University School of Medicine, Tokyo, Japan.

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http://dx.doi.org/10.1111/1346-8138.14836DOI Listing
August 2019

Cross-sectional survey on disease severity in Japanese patients with harlequin ichthyosis/ichthyosis: Syndromic forms and quality-of-life analysis in a subgroup.

J Dermatol Sci 2018 Nov 11;92(2):127-133. Epub 2018 Sep 11.

Department of Dermatology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8560, Japan. Electronic address:

Background: Congenital ichthyoses (CIs) adversely affect quality of life (QOL) in patients. However, the effects of CIs on patient QOL have not been studied sufficiently.

Objective: To investigate the association between disease severity and QOL in patients with harlequin ichthyosis (HI) and ichthyosis: syndromic forms (ISFs) METHODS: Clinical information of patients with HI and ISFs from 2010 to 2015 were obtained from 100 dermatology departments/divisions of principal institutes/hospitals throughout Japan. We examined the relationship between disease severity and QOL in patients with HI and ISFs. Patients who were aged 8 years or older and participated in a multicenter retrospective questionnaire survey in Japan were assessed by dermatology life quality index (DLQI, range of 0-30) and clinical ichthyosis score (range of 0-100).

Results: Netherton syndrome patients had a significantly higher risk of allergy to food or environmental allergens than patients with other phenotypes. Keratitis-ichthyosis-deafness (KID) syndrome patients showed a significantly higher risk of skin infections than patients with other phenotypes. Complete data on DLQI were obtained from 13 patients, whose median age was 21 (8-71) years. Nine patients were male, and 4 were female. Systemic retinoids were administrated to 2 of the 3 HI patients. The Spearman's correlation coefficient between the clinical ichthyosis score and DLQI was 0.611 (P < 0.05).

Conclusion: We confirmed that Netherton syndrome and KID syndrome patients have a higher risk of allergy to food or environmental allergens and of skin infections, respectively. QOL impairment correlates with disease severity in HI and ISFs patients.
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http://dx.doi.org/10.1016/j.jdermsci.2018.08.008DOI Listing
November 2018

Junctional epidermolysis bullosa without pyloric atresia due to a homozygous missense mutation in ITGB4.

J Dermatol 2019 Feb 6;46(2):e61-e63. Epub 2018 Aug 6.

Dermatology, Toho University School of Medicine, Tokyo, Japan.

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http://dx.doi.org/10.1111/1346-8138.14591DOI Listing
February 2019

Identification of a human papillomavirus type 58 lineage in multiple Bowen's disease on the fingers: Case report and published work review.

J Dermatol 2018 Oct 23;45(10):1195-1198. Epub 2018 Jul 23.

Department of Dermatology, Keio University School of Medicine, Tokyo, Japan.

Human papillomavirus (HPV) has been detected in some cases of Bowen's disease, particularly on the fingers and genitalia. HPV-58 is classified as a high-risk mucosal type and accounts for a high percentage of cervical cancer in Asia. Moreover, several HPV-58 lineages, including sublineage A1, have a high prevalence in Asia. However, the nature of HPV-58-associated skin cancer is still unknown. Here, we report a case of a Japanese patient with multiple Bowen's disease on the fingers. A 33-year-old man presented with multiple reddish-brown scaly plaques on his left middle finger and right ring finger. All lesions were surgically excised, and the diagnosis of Bowen's disease was made. We performed Sanger sequencing using DNA extracted from paraffin-embedded samples and identified HPV-58 sublineage A1. Additionally, we review previous reports on HPV-58-associated skin cancers, including our case, showing a high regional prevalence in Asia. Further studies would be needed to reveal the relationship between HPV-58 lineages and carcinogenesis in the skin.
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http://dx.doi.org/10.1111/1346-8138.14574DOI Listing
October 2018

Maintenance of tight junction barrier integrity in cell turnover and skin diseases.

Exp Dermatol 2018 08;27(8):876-883

Department of Dermatology, Keio University School of Medicine, Tokyo, Japan.

The skin forms a life-sustaining barrier between the organism and the physical environment. The physical barrier of the skin is mainly comprised of the stratum corneum (SC) and tight junctions (TJs). In recent years, there have been significant advances in our understanding of the epidermal TJ function, composition and regulation. In contrast to the SC, TJs are highly dynamic structures. It was discovered that spatiotemporal regulation of dynamic TJ replacement from cell to cell maintains the TJ barrier homeostasis of the skin, despite continuous cellular turnover. This review summarizes current knowledge about how TJ barrier homeostasis is maintained in simple and stratified epithelia, and how diseases and other conditions affect the TJ barrier in the skin.
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http://dx.doi.org/10.1111/exd.13742DOI Listing
August 2018

Linear keratinocytic epidermal nevi on trunk skin caused by a somatic FGFR2 p.C382R mutation.

J Dermatol 2018 Nov 27;45(11):e302-e303. Epub 2018 Apr 27.

Department of Dermatology, Keio University School of Medicine, Tokyo, Japan.

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http://dx.doi.org/10.1111/1346-8138.14344DOI Listing
November 2018

Characterization of centriole duplication in human epidermis, Bowen's disease, and squamous cell carcinoma.

J Dermatol Sci 2018 Jul 16;91(1):9-18. Epub 2018 Mar 16.

Department of Dermatology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan. Electronic address:

Background: Centrosomes contain two centrioles: a pre-existing mature centriole and a newly formed immature centriole. Each centriole is duplicated once within a cell cycle, which is crucial for proper centrosome duplication and cell division.

Objective: To describe the centrosome duplication cycle in human epidermis, Bowen's disease (BD), and squamous cell carcinoma (SCC).

Methods: Immunofluorescent staining of centriolar proteins and Ki-67 was used to evaluate cell cycles and the number of centrioles. Centrobin and Outer dense fiber of sperm tails 2 (ODF2) were used as markers for immature and mature centrioles, respectively.

Results: Normal human primary epidermal keratinocytes in a monolayered culture have one centrobin centriole (CTRB cells) supposed in G0/G1 phases or have two centrobin centrioles (CTRB cells) supposed in S-G2 phase. In a three-dimensional culture and in vivo human epidermis, the majority of suprabasal cells were CTRB cells, in spite of their non-proliferative Ki-67 nature. The tumor mass of BD and SCC contained CTRB cells and Ki-67 proliferating and Ki-67 non-proliferative CTRB cells. Clumping cells in BD had increased numbers of centrioles, with an approximate 1:1 to 2:1 ratio of centrobin to ODF2 centrioles.

Conclusions: The cell cycle arrest of suprabasal cells is distinct from the G0 arrest of monolayered epithelial cells. Tumor mass of BD and SCC contained non-proliferative cells with the characteristics of the suprabasal cells of normal epidermis. A constant ratio of the number of centrobin to ODF2 centrioles indicates that multiple centrioles were induced by cell division failure rather than centriole overduplication in clumping cells.
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http://dx.doi.org/10.1016/j.jdermsci.2018.03.008DOI Listing
July 2018
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