Cancer cells maintain chronically elevated levels of reactive oxygen species (ROS) while relying on robust antioxidant programs to preserve redox homeostasis and viability. Although therapeutic strategies that disrupt this balance to induce lethal oxidative stress and ferroptosis have emerged as promising anticancer approaches, the upstream signaling mechanisms that constrain ROS accumulation under physiologically relevant stress conditions remain incompletely understood. Here, we identify the stress-responsive kinases SMG1 and DNA-dependent protein kinase (DNA-PK) as functionally redundant regulators of redox homeostasis and ferroptosis resistance. Genetic or pharmacological inhibition of either kinase triggers ferroptotic cell death, accompanied by marked accumulation of total ROS, ferrous iron, and lipid hydroperoxides. Mechanistically, under mild oxidative stress, SMG1 and DNA-PK cooperatively phosphorylate the central antioxidant transcription factor NRF2 at serine 13 and serine 40, weakening its interaction with the negative regulator KEAP1 and promoting NRF2 accumulation and transcriptional activation. Transcriptomic profiling of de novo mRNAs revealed that inhibition of either kinase is sufficient to suppress NRF2-driven antioxidant gene expression. In contrast, excessive oxidative stress overrides this pro-survival pathway and redirects signaling toward anti-survival responses mediated by ATF4, ATM-CHK2, and JNK/p38 pathways. Collectively, these findings uncover a previously unrecognized SMG1/DNA-PK-NRF2 signaling axis that functions as a redox stress-intensity-dependent switch governing cell fate decisions between antioxidant adaptation and ferroptotic death. Targeting this axis may represent a promising therapeutic strategy for cancer treatment.

ABSTRACTAngiosarcoma (AS) is a rare, aggressive malignancy originating from vascular or lymphatic endothelial cells. Despite its severity, little is known about its epidemiology, and no geographical regions have previously been identified as having an exceptionally high incidence. We retrospectively analyzed medical records spanning 37 years (1987–2023) in Okinawa, Japan, identifying 135 cases of AS that were used to calculate its incidence. This incidence was compared to global data to highlight significant regional differences. Factors related to patients' survival were also assessed. The age‐adjusted incidence of AS of the scalp in Okinawa was 4.1 per million per year (mpy; 2015 Japanese model population) or 2.0 per mpy (2000 US standard population), significantly higher than the global data, including in the United States (about eightfold higher) and mainland Japan (about fourfold higher). The estimated five‐year survival for patients with AS of the scalp in Okinawa was 9.2%. Multivariate analysis identified surgery, chemotherapy, and radiotherapy as significant factors associated with patient survival. This study provides the first evidence of a significantly higher incidence rate of AS of the scalp in Okinawa. Given its rarity, further research is crucial to uncover the epidemiological, genetic, and environmental factors driving this cancer.

Injuries, which affect survival and biological functioning, are common in the animal kingdom. This study systematically investigated whether the slow wound healing observed in humans is a unique characteristic within the primate order. First, we found no significant difference in wound-healing rates between baboons under experimental conditions and those in their natural environment (0.613 mm d-1). Second, comparisons among four non-human primates (velvet monkeys, Sykes' monkeys, baboons and chimpanzees) revealed no significant differences in wound-healing rates. Furthermore, these rates showed no significant differences compared to those observed in rodents, suggesting a potential commonality in wound-healing rates across diverse animal species. In contrast, human wound-healing rates were found to be markedly slower (0.25 mm d-1), approximately three times slower than those observed in non-human primates. This finding indicates that the slow wound healing observed in humans is not a common characteristic among primate order and highlights the possibility of evolutionary adaptations in humans. Understanding these inter-species differences in wound-healing rates may provide valuable insights into the evolutionary implications of wound healing. This study also underscores the need for further research into the biological processes underlying wound healing in various species.

Severe recessive dystrophic epidermolysis bullosa (RDEB) is usually caused by biallelic loss-of-function mutations in COL7A1. While the c.5756delG variant has been previously reported in heterozygous form, its clinical impact in homozygosity has not been described. We report a Japanese male infant born to non-consanguineous parents who presented at birth with generalized blistering and erosions. Skin biopsy revealed sub-lamina densa blistering with absence of anchoring fibrils, and immunofluorescence showed complete loss of type VII collagen. Whole-exome sequencing identified a homozygous COL7A1 c.5756delG deletion, confirmed by carrier status in both parents. RNA analysis demonstrated no exon skipping, confirming a frameshift and premature termination codon. This is the first report of homozygous COL7A1 c.5756delG causing RDEB. This case not only adds a novel homozygous COL7A1 mutation to the mutational spectrum of RDEB but also emphasizes the importance of zygosity and functional validation in interpreting the clinical impact of COL7A1 variants.

Aeromonas dhakensis is highly virulent but often misidentified in clinical settings. The entire genome sequence of a metallo-β-lactamase-producing A. dhakensis strain from a clinical specimen has been presented in this study. The genome comprised a single chromosome of 4.89 Mbp with 61.6% G + C content.

Regulation of gene expression in response to various biological processes, including extracellular stimulation and environmental adaptation requires nascent RNA synthesis and translation. Analysis of the coordinated regulation of dynamic RNA synthesis and translation is required to determine functional protein production. However, reliable methods for the simultaneous measurement of nascent RNA synthesis and translation at the gene level are limited. Here, we developed a novel method for the simultaneous assessment of nascent RNA synthesis and translation by combining 4-thiouridine (4sU) metabolic RNA labeling and translating ribosome affinity purification (TRAP) using a monoclonal antibody against evolutionarily conserved ribosomal P-stalk proteins. The P-stalk-mediated TRAP (P-TRAP) technique recovered endogenous translating ribosomes, allowing easy translatome analysis of various eukaryotes. We validated this method in mammalian cells by demonstrating that acute unfolded protein response (UPR) in the endoplasmic reticulum (ER) induces dynamic reprogramming of nascent RNA synthesis and translation. Our nascent P-TRAP (nP-TRAP) method may serve as a simple and powerful tool for analyzing the coordinated regulation of transcription and translation of individual genes in various eukaryotes.

The Journal of DermatologyEarly View LETTER TO THE EDITOR Chronic mucocutaneous candidiasis due to STAT1 gene mutation Mami Kudou, Mami Kudou Department of Dermatology, University of the Ryukyus Graduate School of Medicine, Okinawa, JapanSearch for more papers by this authorKyoko Fukai, Kyoko Fukai Department of Dermatology, University of the Ryukyus Graduate School of Medicine, Okinawa, JapanSearch for more papers by this authorSayaka Yamaguchi, Corresponding Author Sayaka Yamaguchi [email protected] orcid.org/0000-0001-7556-7210 Department of Dermatology, University of the Ryukyus Graduate School of Medicine, Okinawa, Japan Correspondence Sayaka Yamaguchi, Department of Dermatology, Graduate School and Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Okinawa 903-0125, Japan. Email: [email protected]Search for more papers by this authorTakuya Omine, Takuya Omine Department of Dermatology, University of the Ryukyus Graduate School of Medicine, Okinawa, JapanSearch for more papers by this authorTakuya Miyagi, Takuya Miyagi Department of Dermatology, University of the Ryukyus Graduate School of Medicine, Okinawa, JapanSearch for more papers by this authorDaisuke Utsumi, Daisuke Utsumi Department of Dermatology, University of the Ryukyus Graduate School of Medicine, Okinawa, JapanSearch for more papers by this authorKenzo Takahashi, Kenzo Takahashi Department of Dermatology, University of the Ryukyus Graduate School of Medicine, Okinawa, JapanSearch for more papers by this author Mami Kudou, Mami Kudou Department of Dermatology, University of the Ryukyus Graduate School of Medicine, Okinawa, JapanSearch for more papers by this authorKyoko Fukai, Kyoko Fukai Department of Dermatology, University of the Ryukyus Graduate School of Medicine, Okinawa, JapanSearch for more papers by this authorSayaka Yamaguchi, Corresponding Author Sayaka Yamaguchi [email protected] orcid.org/0000-0001-7556-7210 Department of Dermatology, University of the Ryukyus Graduate School of Medicine, Okinawa, Japan Correspondence Sayaka Yamaguchi, Department of Dermatology, Graduate School and Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Okinawa 903-0125, Japan. Email: [email protected]Search for more papers by this authorTakuya Omine, Takuya Omine Department of Dermatology, University of the Ryukyus Graduate School of Medicine, Okinawa, JapanSearch for more papers by this authorTakuya Miyagi, Takuya Miyagi Department of Dermatology, University of the Ryukyus Graduate School of Medicine, Okinawa, JapanSearch for more papers by this authorDaisuke Utsumi, Daisuke Utsumi Department of Dermatology, University of the Ryukyus Graduate School of Medicine, Okinawa, JapanSearch for more papers by this authorKenzo Takahashi, Kenzo Takahashi Department of Dermatology, University of the Ryukyus Graduate School of Medicine, Okinawa, JapanSearch for more papers by this author First published: 06 July 2023 https://doi.org/10.1111/1346-8138.16890Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat No abstract is available for this article. REFERENCES 1Okada S, Puel A, Casanova JL, Kobayashi M. Chronic mucocutaneous candidiasis disease associated with inborn errors of IL-17 immunity. Clin Transl Immunology. 2016; 5:e114. 2Zhang W, Chen X, Gao G, Xing S, Zhou L, Tang X, et al. Clinical relevance of gain- and loss-of-function germline mutations in STAT1: a systematic review. Front Immunol. 2021; 11:654406. 3Toubiana J, Okada S, Hiller J, Oleastro M, Lagos Gomez M, Aldave Becerra JC, et al. International STAT1 Gain-of-Function Study Group. Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype. Blood. 2016; 127: 3154–64. Early ViewOnline Version of Record before inclusion in an issue ReferencesRelatedInformation

Abstract Background Hypervirulent Klebsiella pneumoniae (hvKp) is associated with severe clinical outcomes, including liver abscesses and disseminated infections (Fig 1). The hypermucoviscosity phenotype (HMV), confirmed by the String test, has been linked to hvKP. This study aimed to investigate the prevalence and genomic characteristics of HMV-Kp isolates in patients with K. pneumoniae bacteremia in a single medical center in Japan.Figure 1.The case of endophthalmitis and multiple abscesses by hypermucovisucosity phenotype K. pneumoniae Methods We conducted a retrospective study at University of the Ryukyus Hospital between January 2021 and November 2022, extracting patients with HMV-Kp bacteremia. K. pneumoniae isolates were subjected to String test (Fig 2), antimicrobial susceptibility testing, and genomic analysis. Whole-genome sequencing and genomic analysis were conducted to identify multilocus sequence type (MLST), K capsule serotype, virulence genes, and antimicrobial resistance genes.Figure 2.String test Results During the study period, 29 cases of K. pneumoniae bacteremia were identified, with six cases of HMV-Kp bacteremia. Five of these cases were male patients and had organ abscess formation (Table 1). The results of the genomic analysis are shown in Table 2. All six HMV-Kp strains were positive for rmpA/rmpA2. MLST and K serotyping revealed that two isolates belong to ST23-K1 and ST86-K2, a known hypervirulent clone. All strains contained virulence genes, with the two ST23-K1 strains carrying all the typical hvKp virulence genes. No strains harbored ESBL or carbapenemase genes.Table 1.Clinical backgrounds of the cases.Table 2.Sequence typing and Virulence genes of the isolates. Conclusion All HMV-Kp strains isolated in this study carried virulent genes, including the hvKP clones ST23-K1 and ST86-K2. The String test for HMV phenotype confirmation appears useful to estimate the presence of hvKp. Our findings provide insights into the virulence and potential clinical implications of HMV-Kp isolates in Japan, highlighting the need for further investigation and monitoring. Disclosures Kazuko Yamamoto, MD, PhD, Fisher & Paykel Healthcare: Grant/Research Support|Kirin Holdings Co.: Grant/Research Support

Evidence has accumulated that higher consumption of high-fat diets (HFDs) during the juvenile/adolescent period induces altered hippocampal function and morphology; however, the mechanism behind this phenomenon remains elusive. Using high-resolution structural imaging combined with molecular and functional interrogation, a murine model of obesity treated with HFDs for 12 weeks after weaning mice was shown to change in the glutamate-mediated intracellular calcium signaling and activity, including further selective reduction of gray matter volume in the hippocampus associated with memory recall disturbance. Dysregulation of intracellular calcium concentrations was restored by a non-competitive α-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) antagonist, followed by normalization of hippocampal volume and memory recall ability, indicating that AMPARs may serve as an attractive therapeutic target for obesity-associated cognitive decline.

壊死性軟部組織感染症は比較的まれな疾患である。我々は 6 カ月間で 4 例を経験し，3 例を救命できた。4 例の初診時主訴は多彩であり，明らかな感染徴候がない例，発熱・嘔吐・下痢など急性胃腸炎様症状を呈した例など，発症初期には軟部組織感染症を疑うことができなかった症例が存在した。1 例は搬送時に全身状態が悪くデブリードマンを行えず死亡，3 例は緊急デブリードマンを行い救命できた。診断には A 群 β 溶血性連鎖球菌抗原キット検査が全例陽性であり非常に有用であった。血液検査では好酸球数の著明な低下と CRP 高値が 4 例に共通していた。A 群 β 溶血性連鎖球菌による壊死性軟部組織症は，初期診断が困難な症例があるが，治療が遅れると致死率が高く，早期診断が重要である。

The Journal of DermatologyVolume 47, Issue 4 p. e122-e124 Letter to the Editor Carney complex 1 with PRKAR1A mutations manifesting as multiple repeated skin myxomas: A case report Hiroyuki Sakugawa, Hiroyuki Sakugawa Department of Dermatology, Graduate School of Medicine, University of the Ryukyus, Nishihara, JapanSearch for more papers by this authorKentaro Hayashi, Kentaro Hayashi Department of Dermatology, Graduate School of Medicine, University of the Ryukyus, Nishihara, JapanSearch for more papers by this authorMichihito Uema, Michihito Uema Faculty of Medicine, University of the Ryukyus, Nishihara, JapanSearch for more papers by this authorTakuya Miyagi, Takuya Miyagi Department of Dermatology, Graduate School of Medicine, University of the Ryukyus, Nishihara, JapanSearch for more papers by this authorDaisuke Utsumi, Daisuke Utsumi Department of Dermatology, Graduate School of Medicine, University of the Ryukyus, Nishihara, JapanSearch for more papers by this authorSayaka Yamaguchi, Corresponding Author Sayaka Yamaguchi sayaka-y@med.u-ryukyu.ac.jp orcid.org/0000-0002-3761-444X Department of Dermatology, Graduate School of Medicine, University of the Ryukyus, Nishihara, Japan Correspondence: Sayaka Yamaguchi, M.D., Ph.D., Department of Dermatology, Graduate School of Medicine, University of the Ryukyus, 207 Uehara, Nakagami, Nishihara, Okinawa 903-0125, Japan. Email: sayaka-y@med.u-ryukyu.ac.jpSearch for more papers by this authorKenzo Takahashi, Kenzo Takahashi Department of Dermatology, Graduate School of Medicine, University of the Ryukyus, Nishihara, JapanSearch for more papers by this author Hiroyuki Sakugawa, Hiroyuki Sakugawa Department of Dermatology, Graduate School of Medicine, University of the Ryukyus, Nishihara, JapanSearch for more papers by this authorKentaro Hayashi, Kentaro Hayashi Department of Dermatology, Graduate School of Medicine, University of the Ryukyus, Nishihara, JapanSearch for more papers by this authorMichihito Uema, Michihito Uema Faculty of Medicine, University of the Ryukyus, Nishihara, JapanSearch for more papers by this authorTakuya Miyagi, Takuya Miyagi Department of Dermatology, Graduate School of Medicine, University of the Ryukyus, Nishihara, JapanSearch for more papers by this authorDaisuke Utsumi, Daisuke Utsumi Department of Dermatology, Graduate School of Medicine, University of the Ryukyus, Nishihara, JapanSearch for more papers by this authorSayaka Yamaguchi, Corresponding Author Sayaka Yamaguchi sayaka-y@med.u-ryukyu.ac.jp orcid.org/0000-0002-3761-444X Department of Dermatology, Graduate School of Medicine, University of the Ryukyus, Nishihara, Japan Correspondence: Sayaka Yamaguchi, M.D., Ph.D., Department of Dermatology, Graduate School of Medicine, University of the Ryukyus, 207 Uehara, Nakagami, Nishihara, Okinawa 903-0125, Japan. Email: sayaka-y@med.u-ryukyu.ac.jpSearch for more papers by this authorKenzo Takahashi, Kenzo Takahashi Department of Dermatology, Graduate School of Medicine, University of the Ryukyus, Nishihara, JapanSearch for more papers by this author First published: 03 February 2020 https://doi.org/10.1111/1346-8138.15254Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume47, Issue4April 2020Pages e122-e124 RelatedInformation

Background: Trichorrhexis invaginata, the main diagnostic feature of Netherton syndrome, is often difficult to detect, especially in adult patients. Objective: We sought to describe a characteristic feature of hairs in Netherton syndrome using a polarized light microscope and the underlying histopathologic changes. Methods: Hairs obtained from 8 patients with Netherton syndrome were observed under polarized light, and we evaluated the correlation between number of band-like patterns and disease severity. Results: Under polarized microscopy, the hair shafts of 8 patients showed a characteristic band-like pattern under polarized light that was not observed in healthy control individuals or patients with atopic dermatitis. This discontinuity of polarized light shows a band-like pattern in which the bands mostly ranged from 0.1 to 1.0 mm in width. The observed ratio of this finding was significantly higher than that of trichorrhexis invaginata observed under light microscopy, and patients with severe dermatitis tended to have a higher ratio than those with less severe dermatitis. Limitations: Comparative examination among other congenital ichthyoses was not performed. Conclusions: A band-like pattern in hairs with polarized light microscopy can be seen in Netherton syndrome and may have potential utility as a diagnostic marker.

Dear Editor, Dystrophic epidermolysis bullosa (DEB) is a subepidermal bulla, characterized by severe itching, lichenoid or nodular prurigo-like lesions, skin erosion, scars, milia, and nail dystrophy, resulting from COL7A1 mutation. Herein, we report a case of dominant DEB with a G2043R mutation in COL7A1. A-25-year-old Japanese woman was referred to our clinic for recurrent intense pruritis and hypertrophic scars on the abdomen (Figure 1, a). She presented with paper-like scars on her forehead, breast, back, buttock, and extremities (Figure 1, b) with mild toenail hypoplasia (Figure 1, c), but no symptoms on the fingernails, hair, teeth, or esophagus. She had developed erosions at the ankle joint a few days after birth. Her parents and four siblings had no related symptoms. She had been diagnosed with DEB at 11 months based on clinical and histopathological findings. Erythema, bullae, and skin ulcers had healed with scarring on the extensor surface of the lower legs at 7 years (Figure 1, d). Histopathological findings revealed subepidermal bulla with lymphocyte and eosinophil infiltration in the upper dermis (Figure 1, e). Immunofluorescence staining with type VII collagen antibody showed uneven faint localization at the basement membrane zone (Figure 1, f). Electron microscopy showed scanty and hypoplastic anchoring fibrils (Figure 1, g). Following ethical approval, informed consent was obtained in compliance with the Declaration of Helsinki guidelines, DNA was extracted from peripheral blood lymphocytes of the patient, and exome sequence analysis was performed. A heterozygous single nucleotide substitution c.6127G>A in exon 73 of COL7A1 was found, which converts glycine to arginine residue, designated p. G2043R. Since COL7A1 is a giant gene with 118 exons and 9276 base pairs, exome sequencing is convenient to determine the mutated gene. In dominant DEB, pathogenic mutations usually occur in glycine substitutions within the type VII collagen triple helix (1). The mutation impedes the trimer formation of collagen and disrupts the normal location of anchoring fibril. The particular localization of mutated collagen VII protein could vary based on the position of mutated glycine residue. In our patient, the mutated collagens were observed sparsely and unevenly at the basement membrane, but can accumulate granularly within the basal keratinocytes (2,3). G2043R mutation such as in the present case has been previously described with dominant DEB in Italian, Hungarian, Norwegian, Mexican, Scottish, Finnish, American, Chinese, and Japanese cases (1). Given the widespread geographical distribution of this mutation and its occurrence as a de novo event like in our case, G2043R can be one of the mutational hotspots in dominant DEB (1). Symptom severity in dominant DEB varies in the same mutation or intra-familial cases, and symptoms regress with age (4). The patient had severe blisters on her legs in early childhood; however, as her age increased, the hypertrophic or atrophic scars on the lower abdomen and extensor surface of her lower legs became the primary skin symptoms. It is presumed that some factor will compensate for the vulnerabilities.

Kaposi’s sarcoma-associated herpesvirus (KSHV) causes both AIDS-related Kaposi’s sarcoma (KS) and classic KS, but their clinical presentations are different, and respective mechanisms remain to be elucidated. The KSHV K1 gene is reportedly involved in tumorigenesis through the immunoreceptor tyrosine-based activation motif (ITAM). Since we found the sequence variations in the K1 gene of KSHV isolated from AIDS-related KS and classic KS, we hypothesized that the transformation activity of the K1 gene contributes to the different clinical presentations. To evaluate our hypothesis, we compared the transformation activities of the K1 gene between AIDS-related KS and classic KS. We also analyzed ITAM activities and the downstream AKT and NF-κB. We found that the transformation activity of AIDS-related K1 was greater than that of classic K1, and that AIDS-related K1 induced higher ITAM activity than classic K1, causing more potent Akt and NF-κB activities. K1 downregulation by siRNA in AIDS-related K1 expressing cells induced a loss of transformation properties and decreased both Akt and NF-κB activities, suggesting a correlation between the transformation activity of K1 and ITAM signaling. Our study indicates that the increased transformation activity of AIDS-related K1 is associated with its clinical aggressiveness, whereas the weak transformation activity of classic type K1 is associated with a mild clinical presentation and spontaneous regression. The mechanism of spontaneous regression of classic KS may provide new therapeutic strategy to cancer.

Human skin is morphologically and physiologically different from the skin of other primates. However, the genetic causes underlying human-specific skin characteristics remain unclear. Here, we quantitatively demonstrate that the epidermis and dermis of human skin are significantly thicker than those of three Old World monkey species. In addition, we indicate that the topography of the epidermal basement membrane zone shows a rete ridge in humans but is flat in the Old World monkey species examined. Subsequently, we comprehensively compared gene expression levels between human and nonhuman great ape skin using next-generation cDNA sequencing (RNA-Seq). We identified four structural protein genes associated with the epidermal basement membrane zone or elastic fibers in the dermis (COL18A1, LAMB2, CD151, and BGN) that were expressed significantly greater in humans than in nonhuman great apes, suggesting that these differences may be related to the rete ridge and rich elastic fibers present in human skin. The rete ridge may enhance the strength of adhesion between the epidermis and dermis in skin. This ridge, along with a thick epidermis and rich elastic fibers might contribute to the physical strength of human skin with a low amount of hair. To estimate transcriptional regulatory regions for COL18A1, LAMB2, CD151, and BGN, we examined conserved noncoding regions with histone modifications that can activate transcription in skin cells. Human-specific substitutions in these regions, especially those located in binding sites of transcription factors which function in skin, may alter the gene expression patterns and give rise to the human-specific adaptive skin characteristics.

Skin wound healing of wild and laboratory animals including mice and rats have been classically known to be very rapid compared to that of human. However, there are few reports measuring the exact wound healing rates of over multiple mammalian species including human, primates, rodents and others. Three different primate species, baboons (Papio anubis), Sykes’ monkeys (Cercopithecus albogularis) and Vervet monkeys (Chlorocebus pygerythrus), were recruited as representatives of primates to this study in the collaboration with Institute of Primate Research in Kenya. For comparison, mice, hairless mice and pigs (Agubuta, endemic species of the Ryukyus) were also engaged. Full thickness skin defects of 3–4 cm in diameter were made on the back skin of these animals, and the sizes of the ulcers were measured periodically. To analyze the healing speed of human skin, we measured the skin defects of hospitalized adult patients who were resected of their skin cancer and waited for two-stage skin grafts. The three primates showed similar wound closure speeds; the average reduction in size of wounds was of 66.2 mm2 per day. Of the most interesting, the equivalent healing rates were obtained in wounds of multiple mice and pigs regardless of the presence of body hair. In contrast, the average healing rate of human skin defects was of 11.8 mm2 per day, more than five times slower than those of all examined primates and experimental animals. From our data, the human should be the evolutionary exceptional mutant animal in the aspect of wound healing even compared with the closely related primates. During the evolutional process to obtain the human specific skin phenotype, homo sapience must have lost some key gene or cellular function to contract the skin wounds.