Chemo-Senolytic Therapeutic Potential against Angiosarcoma.

Angiosarcoma is an aggressive soft-tissue sarcoma with a poor prognosis. Chemotherapy for this cancer typically employs paclitaxel, a taxane (genotoxic drug), although it has a limited effect owing to chemoresistance to prolonged treatment. In this study, we examine an alternative angiosarcoma treatment approach that combines chemotherapeutic and senolytic agents. We find that the chemotherapeutic drugs cisplatin and paclitaxel efficiently induce senescence in angiosarcoma cells. Subsequent treatment with the senolytic agent ABT-263 eliminates senescent cells by activating the apoptotic pathway. In addition, expression analysis indicates that senescence-associated secretory phenotype genes are activated in senescent angiosarcoma cells and that ABT-263 treatment downregulates IFN-I pathway genes in senescent cells. Moreover, we show that cisplatin treatment alone requires high doses to remove angiosarcoma cells. In contrast, lower doses of cisplatin are sufficient to induce senescence, followed by the elimination of senescent cells by the senolytic treatment. This study sheds light on a potential therapeutic strategy against angiosarcoma by combining a relatively low dose of cisplatin with the ABT-263 senolytic agent, which can help ease the deleterious side effects of chemotherapy.

Treatment of dermal ulcer with autologous fibrin glue: Two case reports of an exploratory prospective pilot study.

INTRODUCTION: The healing of recurrent and refractory skin ulcers requires a long time, during which there is risk of infection, and hospital admission is occasionally required for surgical or daily conservative treatment. Therefore, the development of promising treatments that promote faster, uneventful healing is a must. Composed of cryoprecipitate and thrombin, fibrin glue has a history of surgical use for preventing bleeding and spinal fluid leakage. Moreover, in-house cryoprecipitates contain higher concentrations of coagulation factors and cytokines that may enhance wound healing than commercially available products. However, the efficacy of completely autologous fibrin glue (AFG) in tissue repair has not yet been fully demonstrated. PATIENT CONCERNS: This study aimed to evaluate the efficacy of AFG in the treatment of refractory skin ulcers in comparison with the conventional treatment. DIAGNOSIS: Two patients with skin ulcer on their lower extremities due to trauma or scleroderma who showed resistance to conventional treatment were included in the study. Both study participants were diagnosed with refractory skin ulcer and were ineligible for autologous skin transplantation. INTERVENTIONS: AFG was prepared following autologous blood donation using a Cryoseal® system. Subsequently, AFG was administered to 50% of the area of each ulcer and observed for 4 weeks in comparison with recombinant basic fibroblast growth factor with bucladesine sodium treatment that was administered to the rest of the ulcer. OUTCOMES: The skin ulcer after trauma in participant 1 showed better improvement in the AFG-treated area. Although AFG did not show superiority regarding the ulcer area of a patient with scleroderma, it guarded the continuous exudation from the edge of the swollen skin surrounding the ulcer. CONCLUSION: AFG showed effective and beneficial results for wound healing of refractory skin ulcer and prevented exudation without any severe adverse events.

Severe and delayed-onset acneiform eruptions as an adverse reaction to regorafenib.

Regorafenib is an oral multikinase inhibitor targeting several tyrosine kinase receptors including BRAF and epidermal growth factor receptor (EGFR) and is approved as a third-line treatment for metastatic gastrointestinal stromal tumor (GIST). While acneiform eruptions have been observed in patients receiving other BRAF and EGFR inhibitors, the commonly reported adverse reactions to regorafenib are fatigue and palmar-plantar erythrodysesthesia. Herein, we report, to the best of our knowledge, the first case who presented with a severe acneiform eruption 24 months after beginning regorafenib for the treatment of GIST. A 61-year-old woman developed GIST with multiple liver metastases, and she was treated with imatinib and sunitinib. However, these therapies were discontinued, and regorafenib was administered. Twenty-four months after beginning regorafenib, she developed an acneiform eruption on her back. Histopathologic analysis of a skin biopsy from the back revealed neutrophilic suppurative folliculitis. Therefore, she postponed regorafenib administration for 2 months and was treated with topical application of clindamycin phosphate hydrate, which was effective. Consistent with reported evidence that the presence of acneiform eruption and the efficacy of EGFR inhibitors are positively associated, regorafenib had good anticancer activity in our patient. Ultimately, we found that although regorafenib- associated skin toxicities usually appear within 1 month of treatment, patients potentially can present with delayed-onset acneiform eruptions even 24 months later.

NUMB as a Therapeutic Target for Melanoma.

The upregulation of the adaptor protein NUMB triggers melanocytic differentiation from multipotent skin stem cells, which share many properties with aggressive melanoma cells. Although NUMB acts as a tumor suppressor in various human cancer types, little is known about its role in melanoma. In this study, we investigated the role of NUMB in melanoma progression and its regulatory mechanism. Analysis of The Cancer Genome Atlas melanoma datasets revealed that high NUMB expression in melanoma tissues correlates with improved patient survival. Moreover, NUMB expression is downregulated in metastatic melanoma cells. NUMB knockdown significantly increased the invasion potential of melanoma cells in a three-dimensional collagen matrix in vitro and in the lungs of a mouse model in vivo; it also significantly upregulated the expression of the NOTCH target gene CCNE. Previous studies suggested that Wnt signaling increases NUMB expression. By mimicking Wnt stimulation through glycogen synthase kinase-3 inhibition, we increased NUMB expression in melanoma cells. Furthermore, a glycogen synthase kinase-3 inhibitor reduced the invasion of melanoma cells in a NUMB-dependent manner. Together, our results suggest that NUMB suppresses invasion and metastasis in melanoma, potentially through its regulation of the NOTCH‒CCNE axis and that the inhibitors that upregulate NUMB can exert therapeutic effects in melanoma.

Intravenous immunoglobulin-induced severe vesicular eczematous eruption successfully treated with narrow band-ultraviolet B therapy.

Intravenous immunoglobulins (IVIg) are increasingly being used to treat a wide spectrum of dermatological and neurological autoimmune diseases. Although the administration of IVIg does not usually result in severe adverse reactions, side effects of IVIg reportedly occur in 6-13% of patients. Most reported cases were not severe, and IVIg is considered a relatively safe drug. Some reports described a vesicular eczematous eruption caused by IVIg that was cured by applying topical steroid ointments or systemic steroids. Herein, we present, to the best of our knowledge, the first case of severe vesicular eczematous eruption all over the body induced by IVIg that was unresponsive to topical steroid ointment and was subsequently treated with narrow band-ultraviolet B (NB-UVB) therapy successfully. NB-UVB was started at a dose of 400 mJ/cm2 once a week, and swift improvement was observed. The skin rash disappeared in the first 2 months, and the pathogenesis of IVIg-induced eczematous eruption remains unelucidated. No change in eosinophils and complement levels were observed in our case. Given the increase in the widespread use of IVIg, we have shown that NB-UVB therapy is a candidate choice for the treatment of IVIg-induced severe vesicular eczematous eruption.

Fas-FasL interaction in cytotoxic T cell-mediated vitiligo: The role of lesional expression of tumor necrosis factor-α and interferon-γ in Fas-mediated melanocyte apoptosis.

Vitiligo is an acquired skin depigmentation disorder resulting from the selective loss of epidermal melanocytes, and previous studies have suggested that a T lymphocyte-mediated mechanism has a role in melanocyte loss. Although Fas-Fas ligand (FasL) interactions are important for T lymphocytes to mediate cytotoxicity, there are only few reports examining the involvement of the Fas-FasL pathway in vitiligo using in vivo mouse models. In addition, there have been no reports concerning Fas-mediated apoptosis in human melanocytes in vitro. In this study, we found that the Fas-mediated pathway is involved in cytotoxic T lymphocyte (CTL)-dependent vitiligo in a mouse model and FasL-induced apoptosis of human melanocytes. Tumor necrosis factor (TNF)-α and interferon (IFN)-γ, the expression levels of which have been reported to be elevated in lesional skin of patients with vitiligo, synergistically upregulated Fas expression on human melanocytes but inhibited the Fas-mediated apoptosis. Treatment with TNF-α and IFN-γ synergistically upregulated the expression of the anti-apoptotic genes, c-IAP2, c-FLIP and MCL1. A siRNA knock-down study showed that c-FLIP and MCL1, but not c-IAP2, were involved in inducing synergistic inhibitory effects on Fas-mediated apoptosis. Furthermore, we found that FasL and TNF-related apoptosis-inducing ligand (TRAIL) synergistically induced apoptosis on human melanocytes. In conclusion, our results suggest that the Fas-FasL pathway is involved in CTL-dependent vitiligo and the elevated expression levels of TNF-α and IFN-γ in lesional skin may act synergistically on melanocytes to suppress Fas-mediated apoptosis.

Exacerbation and Prolongation of Psoriasiform Inflammation in Diabetic Obese Mice: A Synergistic Role of CXCL5 and Endoplasmic Reticulum Stress.

Accumulating evidence suggests that psoriasis is frequently accompanied by metabolic disorders, such as obesity and diabetes. However, the mechanisms underlying the association between increased psoriasis severity and concomitant metabolic syndrome have not been fully clarified. Herein, we show that imiquimod-induced psoriasiform inflammation was exacerbated and prolonged in diabetic obese mice compared to that in control mice, accompanied by remarkably increased lesional expressions of Cxcl5 and Il-1b. Notably, a large number of CXCL5+ Ly6G+ cells infiltrated the dermis and subcutaneous fat tissue of the diabetic obese mice. Most macrophages in the subcutaneous fat tissues of the diabetic obese mice were positive for expression of IL-1ß and GRP78/Bip, an endoplasmic reticulum stress marker. Depletion of Ly6G+ cells and macrophages diminished the imiquimod-induced psoriasiform inflammation. Further, CXCL5 potentiated the secretion of IL-1ß from macrophages and palmitic acid, a fatty acid released from subcutaneous adipocytes, further enhanced IL-1ß secretion via endoplasmic reticulum stress induction. Combined with the fact that the serum levels of both CXCL5 and palmitic acid are significantly elevated in patients with metabolic syndrome, our results suggest a role for CXCL5 and endoplasmic reticulum stress in the increase of psoriasis severity of patients with concomitant metabolic syndrome.

Gene Expression and Methylation Analysis in Melanomas and Melanocytes From the Same Patient: Loss of NPM2 Expression Is a Potential Immunohistochemical Marker for Melanoma.

DNA methylation is considered the primary epigenetic mechanism underlying the development of malignant melanoma. Since DNA methylation can be influenced by environmental factors, it is preferable to compare cancer and normal cells from the same patient. In order to compare the methylation status in melanoma tissues and melanocytes from the same individuals, we employed a novel epidermal sheet cultivation technique to isolate normal melanocytes from unaffected sites of melanoma patients. We also analyzed primary and metastatic melanoma samples, three commercially available melanocytes, and four melanoma cell lines. Cluster analysis of DNA methylation data classified freshly isolated melanomas and melanocytes into the same group, whereas the four melanoma cell lines were clustered together in a distant clade. Moreover, our analysis discovered methylation at several novel loci (KRTCAP3, AGAP2, ZNF490), in addition to those identified in previous studies (COL1A2, GPX3); however, the latter two were not observed in fresh melanoma samples. Subsequent studies revealed that NPM2 was hypermethylated and downregulated in melanomas, which was consistent with previous reports. In many normal melanocytes, NPM2 showed distinct immunohistochemical staining, while its expression was lost in malignant melanoma cells. In particular, intraepithelial lesions of malignant melanoma, an important challenge in clinical practice, could be distinguished from benign nevi. The present findings indicate the importance of using fresh melanoma samples, not melanoma cell lines and melanocytes in epigenetic studies. In addition, NPM2 immunoreactivity could be used to differentiate melanomas from normal melanocytes or benign disease.

Interleukin (IL)-18, cooperatively with IL-23, induces prominent inflammation and enhances psoriasis-like epidermal hyperplasia.

The interleukin (IL)-23/IL-17 axis is strongly implicated in the pathogenesis of psoriasis. Previous studies showed that IL-18 was elevated in early active and progressive plaque-type psoriatic lesions and that serum or plasma levels of IL-18 correlated with the Psoriasis Area and Severity Index. However, the mechanism whereby IL-18 affects disease severity remains unknown. In this study, we investigated the effects of IL-18 on a psoriasis-like skin inflammation model induced by recombinant mouse IL-23. We found that IL-18, cooperatively with IL-23, induced prominent inflammation and enhanced psoriasis-like epidermal hyperplasia. In the skin of mice treated with IL-23 plus IL-18, the expression of interferon-γ was significantly upregulated and that of chemokine (C-X-C motif) ligand 9 (CXCL9) was synergistically increased. Histologically, strong positive signals of CXCL9 were observed around the infiltrating inflammatory cells. The current results suggest that IL-18 might synergize with IL-23 to induce a T helper 1 immune reaction, without inhibiting the IL-23/IL-17 axis, and thus may aggravate psoriatic inflammation.