Akiko Arakawa

Generation of neural crest-derived peripheral neurons and floor plate cells from mouse and primate embryonic stem cells

To understand the range of competence of embryonic stem (ES) cell-derived neural precursors, we have examined in vitro differentiation of mouse and primate ES cells into the dorsal- (neural crest) and ventralmost (floor plate) cells of the neural axis. Stromal cell-derived inducing activity (SDIA; accumulated on PA6 stromal cells) induces cocultured ES cells to differentiate into rostral CNS tissues containing both ventral and dorsal cells. Although early exposure of SDIA-treated ES cells to bone morphogenetic protein (BMP)4 suppresses neural differentiation and promotes epidermogenesis, late BMP4 exposure after the fourth day of coculture causes differentiation of neural crest cells and dorsalmost CNS cells, with autonomic system and sensory lineages induced preferentially by high and low BMP4 concentrations, respectively. In contrast, Sonic hedgehog (Shh) suppresses differentiation of neural crest lineages and promotes that of ventral CNS tissues such as motor neurons. Notably, high concentrations of Shh efficiently promote differentiation of HNF3β+ floor plate cells with axonal guidance activities. Thus, SDIA-treated ES cells generate naïve precursors that have the competence of differentiating into the “full” dorsal–ventral range of neuroectodermal derivatives in response to patterning signals.

CD8+tumor-infiltrating lymphocytes at primary sites as a possible prognostic factor of cutaneous angiosarcoma

Tumor‐infiltrating lymphocytes (TILs) have been reported as a prognostic factor in various cancers and are a promising target for immunotherapy. To investigate whether TILs have any impact on the prognosis of angiosarcoma patients, 55 non‐treated patients (40 patients at stage 1 with cutaneous localized tumors, 4 patients at stage 2 with lymph node metastases and 11 patients at stage 3 with distant metastases) with angiosarcoma were evaluated retrospectively by immunohistochemistry stained CD4, CD8, FOXP3 and Ki67. The Kaplan–Meier method was used to estimate overall survival with patients at stage 1. Survival differences were analyzed by the log‐rank test. Patients with higher numbers of CD8+ TILs in their primary tumors survived significantly longer compared with patients with lower values. Moreover, the number of CD8 in TILs was positively correlated with a distant metastasis‐free period. The total number of primary TILs (CD4 plus CD8) and CD8+ primary TILs of stage 3 patients with distant metastases was positively correlated with their overall survival. To evaluate whether CD8+ effector T cells are activated or differentiated, flow cytometric analysis of peripheral blood mononuclear cells (PBMC) was performed. The percentages of CD8+ T cells producing IFN‐γ in PBMC were significantly higher in patients with angiosarcoma (n = 10) compared not only with that of healthy controls (n = 20) but also patients with advanced melanoma (n = 11). These results suggest that anti‐tumor immunity is clinically relevant in angiosarcoma.

Anterior neural development requires Del1, a matrix-associated protein that attenuates canonical Wnt signaling via the Ror2 pathway

During early embryogenesis, the neural plate is specified along the anterior-posterior (AP) axis by the action of graded patterning signals. In particular, the attenuation of canonical Wnt signals plays a central role in the determination of the anterior brain region. Here, we show that the extracellular matrix (ECM) protein Del1, expressed in the anterior neural plate, is essential for forebrain development in the Xenopus embryo. Overexpression of Del1 expands the forebrain domain and promotes the formation of head structures, such as the eye, in a Chordin-induced secondary axis. Conversely, the inhibition of Del1 function by a morpholino oligonucleotide (MO) represses forebrain development. Del1 also augments the expression of forebrain markers in neuralized animal cap cells, whereas Del1-MO suppresses them. We previously reported that Del1 interferes with BMP signaling in the dorsal-ventral patterning of the gastrula marginal zone. By contrast, we demonstrate here that Del1 function in AP neural patterning is mediated mainly by the inhibition of canonical Wnt signaling. Wnt-induced posteriorization of the neural plate is counteracted by Del1, and the Del1-MO phenotype (posteriorization) is reversed by Dkk1. Topflash reporter assays show that Del1 suppresses luciferase activities induced by Wnt1 and β-catenin. This inhibitory effect of Del1 on canonical Wnt signaling, but not on BMP signaling, requires the Ror2 pathway, which is implicated in non-canonical Wnt signaling. These findings indicate that the ECM protein Del1 promotes forebrain development by creating a local environment that attenuates the cellular response to posteriorizing Wnt signals via a unique pathway.

Perturbations of both nonregulatory and regulatory FOXP3+ T cells in patients with malignant melanoma

Background  ‘FOXP3+ regulatory T cells’ (Tregs) are reported to be increased in tumour‐bearing hosts including patients with melanoma, leading to tumour immune suppression. However, this idea is challenged by recent evidence that the ‘FOXP3+ Treg’ fraction in fact contains activated ‘nonregulatory’ T cells. Also, FOXP3+ T cells are reported to have functionally and kinetically distinct subsets.

Case of Conradi–Hünermann–Happle syndrome with alopecia: Histological examination of affected follicles

Dear Editor, Conradi–Hünermann–Happle (CHH) syndrome (Online Mendelian Inheritance in Man no. 302960) is a rare genetic disorder characterized by short stature, stippled epiphyses, cataracts, transient ichthyosis, alopecia and atrophic residua in a mosaic pattern. Among the symptoms, hair loss impairs the quality of life. However, only limited information has been reported thus far. Here, we present a case of CHH syndrome with alopecia and provide histological observation. The female infant was born spontaneously after an uneventful pregnancy, presenting thickened and diffusely reddened skin with large adherent scales (Fig. 1a). When she visited our clinic at 1 month of age, the erythroderma and scaling had become unremarkable. Instead, hyperpigmentation had become remarkable in a Blaschko-linear arrangement on the arms, trunk and shoulders (especially the M-shaped line on the shoulders) (Fig. 1b). At 2 years of age, she presented with short stature and persistent incomplete alopecia. The alopecia accompanied atrophic and slightly reddish skin without folliculitis. At the age of 3 years, she had a congenital cataract in the right eye and a slightly shorter right thighbone. At the age of 4 years, the skin exhibited a mixture of mild hyperand hypopigmentation with atrophic streaks in a Blaschko-linear arrangement on her extremities. Mental development was normal. Notably, her mother had showed similar cutaneous symptoms at birth followed by mild hypopigmentation in a linear arrangement on her arms without hair loss. A biopsied sample of alopecia (Fig. 1c) revealed orthohyperkeratosis, partly thinned and partly thickened epidermis, hypogranulosis, perivascular and perifollicular infiltration of lymphocytes, and granulation tissue with some destroyed hair follicles and orphaned hair muscles without interface change or mucinosis (Fig. 1d,e). These were consistent with pseudopelade. In addition, in some hair units, only sebaceous glands were infiltrated with lymphocytes, sparing hair follicles (Fig. 1f). In summary, the patient exhibited symptoms of transient ichthyosis, short stature, alopecia, cataracts, hyperpigmentation and hypopigmentation with atrophic streaks of the skin, and minor asymmetrical shortening of the right thighbone. These were consistent with CHH syndrome. We did not analyze mutations because her mother refused further examination after being informed. Skin disorders in a Blaschko-linear arrangement are explained by functional X-chromosomal mosaicism which is observed in various X-linked skin diseases. In congenital and syndromic ichthyosis, skin disorders in a Blaschko-linear arrangement suggest CHH syndrome and ichthyosis hystrix. However, we excluded the latter because of its non-syndromic character. Although Goltz syndrome and hypomelanosis of Ito also show Blaschko-linear arrangement of dermal lesion, they are not accompanied by ichthyosis at birth. Ichthyosis syndrome with alopecia and bone abnormalities reminded us of

Hair regrowth following TNF-Α blockade in coexisting psoriasis vulgaris and alopecia areata

Tumor necrosis factor (TNF)-Α can modulate hair cycles [1], as well as mediate immunological diseases [2]. TNF-Α blockade is thought to be effective for psoriasis vulgaris (PV) [2] but not for alopecia areata (AA) [3]. We herein report a case with co-existing PV and AA universalis, which allowed two observations, terminal hair growth limited to psoriatic lesions before treatment, and clearance of psoriasis plaques with transient hair regrowth under anti-TNF-Α therapy.A 28-year-old woman presented [...]

Simultaneous occurrence of distantly located multiple sebaceous carcinomas with elevated serum TGF-β in Muir-Torre syndrome

ejd.2012.1705 Auteur(s) : Satoshi Nakamizo, Akiko Arakawa arakawa@kuhp.kyoto-u.ac.jp, Akihiko Kitoh, Satoshi Kore-Eda, Atsushi Utani, Yoshiki Miyachi Department of Dermatology, Kyoto School of Medicine, 54 Shogoin-Kawara, Sakyo, Kyoto 606-8507, Japan Muir-Torre syndrome (MTS) is a cancer susceptibility syndrome, defined as the association of sebaceous tumor and internal malignancy [1]. Tumors in MTS are characterized by the accumulation of microsatellite instability (MSI) in a repeated sequence [...]