Intratumoral injection of hemagglutinating virus of Japan-envelope vector yielded an antitumor effect for advanced melanoma: a phase I/IIa clinical study.

Hemagglutinating virus of Japan (HVJ; Sendai virus) is an RNA virus that has cell fusion activity. HVJ-envelope (HVJ-E) is a UV-irradiated HVJ particle that loses viral replication and protein synthesis activity but retains cell fusion activity. We recently reported that HVJ-E has antitumor effects on several types of tumors. Here, we describe the results of a first-in-human phase I/IIa study in patients with advanced melanoma, receiving intratumoral administration of HVJ-E. The primary aim was to evaluate the safety and tolerability of HVJ-E, and the secondary aim was to examine the objective tumor response and antitumor immunity. Six patients with stage IIIC or IV progressive malignant melanoma with skin or lymph metastasis were enrolled. Patients were separated into two groups (n = 3 each) and received low and high doses of HVJ-E. Five of the six patients completed 4 weeks of follow-up evaluation; one patient discontinued treatment owing to progressive disease. Complete or partial responses were observed in 3 of 6 (50%) injected target lesions, 7 of 15 (47%) noninjected target lesions, and 10 of 21 (48%) target lesions. Induction of antitumor immunity was observed: activation of natural killer cells, a marked increase in interferon-γ levels in the peripheral blood, and infiltration of cytotoxic T cells into both injected and noninjected tumor lesions. Thus, intratumoral injection of HVJ-E in advanced melanoma patients showed safety and tolerability with local regression of the tumor mediated by antitumor immunity. The results suggest that HVJ-E might be a new treatment approach in patients with advanced melanoma.

Jiadifenolide induces the expression of cellular communication network factor (CCN) genes, and CCN2 exhibits neurotrophic activity in neuronal precursor cells derived from human induced pluripotent stem cells.

Jiadifenolide has been reported to have neurotrophin-like activity in primary rat cortical neurons, and also possesses neurotrophic effects in neuronal precursor cells derived from human induced pluripotent stem cells (hiPSCs), as we have previously reported. However, the molecular mechanisms by which jiadifenolide exerts its neurotrophic effects in rat and human neurons are unknown. Thus, we aimed to investigate the molecular mechanisms and pathways by which jiadifenolide promotes neurotrophic effects. Here, we found that jiadifenolide activated cellular communication network factor (CCN) signaling pathways by up-regulating mRNA level expression of CCN genes in human neuronal cells. We also found that CCN2 (also known as connective tissue growth factor, CTGF) protein promotes neurotrophic effects through activation of the p44/42 mitogen-activated protein kinase signaling pathway. This is the first discovery which links neurotrophic activity with CCN signaling.

Neurotrophic activity of jiadifenolide on neuronal precursor cells derived from human induced pluripotent stem cells.

Although jiadifenolide has been reported to neurotrophin-like activity in primary cultured rat cortical neurons, it is unknown on that of activity in human neurons. Thus, we aimed to assess neurotrophin-like activity by jiadifenolide in human neuronal cells. We analyzed neuronal precursor cells derived from human induced pluripotent stem cells for microtuble-associated-protein-2 expression by immunofluorescence and western blot, following jiadifenolide treatment. Jiadifenolide promoted dendrite outgrowth, facilitated growth, and prevented death in neuronal cells derived from human induced pluripotent stem cells. Interestingly, jiadifenolide also increased postsynaptic density-95 protein expression suggesting that jiadifenolide promotes neuronal maturation and post-synaptic formation. We demonstrate for the first time that jiadifenolide exhibits neurotrophic effects on human neuronal precursor cells.

Anti-CCR4 mAb selectively depletes effector-type FoxP3+CD4+ regulatory T cells, evoking antitumor immune responses in humans.

CD4(+) Treg cells expressing the transcription factor FOXP3 (forkhead box P3) are abundant in tumor tissues and appear to hinder the induction of effective antitumor immunity. A substantial number of T cells, including Treg cells, in tumor tissues and peripheral blood express C-C chemokine receptor 4 (CCR4). Here we show that CCR4 was specifically expressed by a subset of terminally differentiated and most suppressive CD45RA(-)FOXP3(hi)CD4(+) Treg cells [designated effector Treg (eTreg) cells], but not by CD45RA(+)FOXP3(lo)CD4(+) naive Treg cells, in peripheral blood of healthy individuals and cancer patients. In melanoma tissues, CCR4(+) eTreg cells were predominant among tumor-infiltrating FOXP3(+) T cells and much higher in frequency compared with those in peripheral blood. With peripheral blood lymphocytes from healthy individuals and melanoma patients, ex vivo depletion of CCR4(+) T cells and subsequent in vitro stimulation of the depleted cell population with the cancer/testis antigen NY-ESO-1 efficiently induced NY-ESO-1-specific CD4(+) T cells. Nondepletion failed in the induction. The magnitude of the responses was comparable with total removal of FOXP3(+) Treg cells by CD25(+) T-cell depletion. CCR4(+) T-cell depletion also augmented in vitro induction of NY-ESO-1-specific CD8(+) T cells in melanoma patients. Furthermore, in vivo administration of anti-CCR4 mAb markedly reduced the eTreg-cell fraction and augmented NY-ESO-1-specific CD8(+) T-cell responses in an adult T-cell leukemia-lymphoma patient whose leukemic cells expressed NY-ESO-1. Collectively, these findings indicate that anti-CCR4 mAb treatment is instrumental for evoking and augmenting antitumor immunity in cancer patients by selectively depleting eTreg cells.

T helper 2 polarization in senile erythroderma with elevated levels of TARC and IgE.

BACKGROUND: Some cases of senile erythroderma tend to be diagnosed as senile atopic dermatitis (AD) based on elevated levels of immunoglobulin E (IgE) and thymus and activation-regulated chemokine (TARC). However, there are few studies that describe the detailed characteristics of senile erythroderma and senile AD. OBJECTIVE: We examined the association of erythroderma with AD. METHODS: In this retrospective observational study, 68 patients over 65 years of age who presented with erythroderma at Osaka University Hospital were enrolled. Patient data were collected through medical records and descriptive statistics. RESULTS: 47% of the patients were classified as having idiopathic erythroderma and 53% as having secondary erythroderma. In both idiopathic and secondary senile erythroderma patients, serum IgE and TARC levels were elevated. 84% of idiopathic erythroderma patients fulfilled the Japanese Dermatological Associations criteria for AD; however, only 4 patients were finally definitely diagnosed with senile AD. CONCLUSION: Many senile erythroderma patients showed AD-like symptoms due to T helper 2 polarization.

Artemin causes hypersensitivity to warm sensation, mimicking warmth-provoked pruritus in atopic dermatitis.

BACKGROUND: Itch impairs the quality of life for many patients with dermatoses, especially atopic dermatitis (AD), and is frequently induced by a warm environment. OBJECTIVE: To determine the mechanism underlying itch induction by warmth, we focused on artemin, a member of glial cell line-derived neurotrophic factors (GDNFs). METHODS: A gene array assay revealed that artemin was expressed in substance P-treated dermal fibroblasts. The expression of artemin in healthy and AD-lesional skin was evaluated with immunohistochemistry and in situ hybridization. The impact of fibroblast-derived artemin on the proliferation and morphology of neural cell was investigated in vitro. To confirm the involvement of artemin in skin sensibility, wild-type and GDNF family receptor α3 knockout mice were employed for sensory examination. RESULTS: Artemin-expressing fibroblasts accumulated in skin lesions of patients with AD. Artemin induced cell proliferation of a neuroblastoma cell line in vitro, and intradermal injection of artemin in mice resulted in peripheral nerve sprouting and thermal hyperalgesia. Artemin-treated mice demonstrated scratching behavior in a warm environment, but mice deficient for GDNF family receptor α3, a potent artemin receptor, did not show this behavior. Furthermore, the escaping response to heat stimulus was attenuated in GDNF family receptor α3 knockout mice, suggesting that artemin may contribute to sensitivity to heat. CONCLUSION: These data suggest that dermal fibroblasts secrete artemin in response to substance P, leading to abnormal peripheral innvervation and thermal hyperalgesia. We hypothesize that artemin lowers the threshold of temperature-dependent itch sensation and might therefore be a novel therapeutic target for treating pruritic skin disorders, including AD.

Prevalence and Impact of Past History of Food Allergy in Atopic Dermatitis.

BACKGROUND: Increases in allergic diseases have been reported from various epidemiological surveys. However, a few reports demonstrate the comorbidity of food allergy (FA) and allergic march. The aim of this study was to assess the prevalence and comorbidity of allergic diseases in Japanese students. METHODS: First-year students (n = 3,321; 2,209 male and 1,112 female) at Osaka University were asked about allergic diseases using postal interview sheets. Personal and family histories of doctor-diagnosed allergic diseases, clinical courses, and aggravating factors were included in the questionnaires. RESULTS: The lifetime prevalence of allergic rhinitis (AR), atopic dermatitis (AD), bronchial asthma (BA), and FA was 35.7%, 16.5%, 9.9%, and 7.0%, respectively. Disease-specific family histories existed for AR, AD, and BA. There was a positive correlation between the number of family histories of allergic disease and comorbidity (R = 0.370, P <0.001). Comorbidity with AD significantly lowered the onset age of both BA (P = 0.010) and AR (P <0.001). In addition, the onset age of AD was remarkably lowered by comorbidity with FA (P <0.001). Comorbidity with FA was the highest risk factor for the progression of allergic march. Although most students showed improvement in AD, BA, and AR over time, the peak recurrence period was observed in adolescence. CONCLUSIONS: These findings indicate that AD associated with FA accelerates the subsequent progression of allergic march. Early appropriate management for genetically high-risk groups is important for the prevention of allergic march.

Prevalence and impact of past history of food allergy in atopic dermatitis.

BACKGROUND: Increases in allergic diseases have been reported from various epidemiological surveys. However, a few reports demonstrate the comorbidity of food allergy (FA) and allergic march. The aim of this study was to assess the prevalence and comorbidity of allergic diseases in Japanese students. METHODS: First-year students (n = 3,321; 2,209 male and 1,112 female) at Osaka University were asked about allergic diseases using postal interview sheets. Personal and family histories of doctor-diagnosed allergic diseases, clinical courses, and aggravating factors were included in the questionnaires. RESULTS: The lifetime prevalence of allergic rhinitis (AR), atopic dermatitis (AD), bronchial asthma (BA), and FA was 35.7%, 16.5%, 9.9%, and 7.0%, respectively. Disease-specific family histories existed for AR, AD, and BA. There was a positive correlation between the number of family histories of allergic disease and comorbidity (R = 0.370, P < 0.001). Comorbidity with AD significantly lowered the onset age of both BA (P = 0.010) and AR (P < 0.001). In addition, the onset age of AD was remarkably lowered by comorbidity with FA (P < 0.001). Comorbidity with FA was the highest risk factor for the progression of allergic march. Although most students showed improvement in AD, BA, and AR over time, the peak recurrence period was observed in adolescence. CONCLUSIONS: These findings indicate that AD associated with FA accelerates the subsequent progression of allergic march. Early appropriate management for genetically high-risk groups is important for the prevention of allergic march.

Four cases of atopic dermatitis complicated by Sjögren's syndrome: link between dry skin and autoimmune anhidrosis.

We report four adult cases of atopic dermatitis (AD) complicated by Sjögren's syndrome (SS). The patients fulfilled diagnostic criteria for AD and SS. All cases showed persistent itchy dry skin and eczematous lesions complicated by sicca symptoms including dry eyes and dry mouth with moderate joint pain. One case manifested annular erythema and another manifested widespread discoid erythema. To investigate the underlying cause of dry skin in these cases, sweating function was evaluated using a quantitative sudomotor axon reflex test (QSART) in which the axon reflex is stimulated by acetylcholine iontophoresis. The sweating latency time was significantly prolonged in eczematous skin of AD and AD/SS compared to normal controls. Axon reflex (AXR) sweat volume was also significantly reduced in AD (normal and eczematous skin) and AD/SS (normal and eczema) compared to normal control. In contrast, the direct sweat volume of lesional or non-lesional AD skin induced by direct stimulation with acetylcholine was only slightly reduced compared to that in normal controls, but not in SS and lesional skin of AD/SS patients. These results suggest that the impaired sweat response in AD is attributable to an abnormal sudomotor axon reflex, which is accelerated and modulated when complicated by SS resulting in dry skin in the present cases.

Systemic sclerosis with sarcoidosis: case report and review of the published work.

Sarcoidosis and systemic sclerosis (SSc) rarely coexist. Here, we report a Japanese female SSc patient who developed systemic sarcoidosis. Her SSc was a limited type negative for anti-Scl-70 antibody and positive for anticentromere antibody (ACA). Moreover, we performed a review of the English-language published work that described cases of concurrent SSc and sarcoidosis. Then, we found that most SSc and sarcoidosis concurrent patients positive for anti-Scl-70 antibody were male (77.8%). On the other hand, most patients positive for ACA were female (87.5%). These results suggest some relationships between autoantibody profiles and sex in SSc and sarcoidosis concurrence.

Detection of self-reactive CD8⁺ T cells with an anergic phenotype in healthy individuals.

Immunological tolerance to self requires naturally occurring regulatory T (Treg) cells. Yet how they stably control autoimmune T cells remains obscure. Here, we show that Treg cells can render self-reactive human CD8(+) T cells anergic (i.e., hypoproliferative and cytokine hypoproducing upon antigen restimulation) in vitro, likely by controlling the costimulatory function of antigen-presenting cells. Anergic T cells were naïve in phenotype, lower than activated T cells in T cell receptor affinity for cognate antigen, and expressed several coinhibitory molecules, including cytotoxic T lymphocyte-associated antigen-4 (CTLA-4). Using these criteria, we detected in healthy individuals anergic T cells reactive with a skin antigen targeted in the autoimmune disease vitiligo. Collectively, our results suggest that Treg cell-mediated induction of anergy in autoimmune T cells is important for maintaining self-tolerance.

A case of giant squamous cell carcinoma of the buttock possibly arose from syringocystadenoma and invaded to the rectum.

We report a rare case of giant squamous cell carcinoma of the buttock infiltrated to the rectum. The tumor may have arisen from syringocystadenoma papilliferum. Since there was no sign of metastasis, radical operation including rectal amputation was performed after successful neoadjuvant therapies. Afterwards, the patient has been alive free from disease for 15 months with no lymph node and distant organ metastasis.

Pilomatrix carcinoma arising from pilomatricoma after 10-year senescent period: Immunohistochemical analysis.

Pilomatrix carcinoma is a rare malignant counterpart of pilomatricoma. To our knowledge, only approximately 90 cases have been published in English literature. Pilomatrix carcinoma is locally aggressive and occasionally shows rapid progression infiltrating to the muscle, bone and vessels. We report a case of pilomatrix carcinoma that developed in a 38-year-old man and started to grow after a long stable period, relapsed for a short time and infiltrated into the muscle underneath. While the initial skin biopsy showed histopathological findings consistent with pilomatricoma, the recurrent tumor contained marked cellular atypia and an aggressive growth pattern. Although it is still controversial whether pilomatrix carcinoma arises de novo or through malignant transformation of a pilomatricoma, the present case might be caused by the latter process considering the patient's clinical course. beta-catenin is a downstream effecter in the canonical pathway of Wnt, acting as a signal for cell differentiation and proliferation. The characteristic nuclear staining pattern of beta-catenin in the basaloid tumor cells, which is usually observed in pilomatrix carcinoma, supported the diagnosis of pilomatrix carcinoma in the present case.