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Generalized pustular psoriasis (GPP) is a rare inflammatory skin disease that can be life-threatening. Recently, it has been reported that familial GPP is caused by homozygous or compound heterozygous mutations of IL36RN. However, the majority of GPP cases are sporadic and it is controversial whether IL36RN mutations are a causative/predisposing factor for sporadic GPP. We searched for IL36RN mutations in two groups of GPP patients in the Japanese population in this study: GPP without psoriasis vulgaris (PV), and GPP with PV. Eleven cases of GPP without PV (GPP alone) and 20 cases of GPP accompanied by PV (GPP with PV) were analyzed. Surprisingly, 9 out of 11 cases of GPP alone had homozygous or compound heterozygous mutations in IL36RN. In contrast, only 2 of 20 cases of GPP with PV had compound heterozygous mutations in IL36RN. The two cases of GPP with PV who had compound heterozygous mutations in IL36RN are siblings, and both cases had PV-susceptible HLA-A*0206. We determined that GPP alone is a distinct subtype of GPP and is etiologically distinguished from GPP with PV, and that the majority of GPP alone is caused by deficiency of the interleukin-36 receptor antagonist due to IL36RN mutations.

Promising antitumor activities of nivolumab, a fully humanized IgG4 inhibitor antibody against the programmed death‐1 protein, were suggested in previous phase 1 studies. The present phase 2, single‐arm study (JAPIC‐CTI #111681) evaluated the antitumor activities of nivolumab and explored its predictive correlates in advanced melanoma patients at 11 sites in Japan. Intravenous nivolumab 2 mg/kg was given repeatedly at 3‐week intervals to 35 of 37 patients enrolled from December 2011 to May 2012 until they experienced unacceptable toxicity, disease progression, or complete response. Primary endpoint was objective response rate. Serum levels of immune modulators were assessed at multiple time points. As of 21 October 2014, median response duration, median progression‐free survival, and median overall survival were 463 days, 169 days, and 18.0 months, respectively. The overall response rate and 1‐ and 2‐year survival rates were 28.6%, 54.3%, and 42.9%, respectively. Thirteen patients remained alive at the end of the observation period and no deaths were drug related. Grade 3–4 drug‐related adverse events were observed in 31.4% of patients. Pretreatment serum interferon‐γ, and interleukin‐6 and ‐10 levels were significantly higher in the patients with objective tumor responses than in those with tumor progression. In conclusion, giving repeated i.v. nivolumab had potent and durable antitumor effects and a manageable safety profile in advanced melanoma patients, strongly suggesting the usefulness of nivolumab for advanced melanoma and the usefulness of pretreatment serum cytokine profiles as correlates for predicting treatment efficacy. Repeated intravenous administration of nivolumab had potent and durable anti‐tumor effects and a manageable safety profile in advanced melanoma patients in Japan. Pre‐treatment serum cytokine profiles were suggested as correlates for predicting treatment efficacy.

Pustulosis palmaris et plantaris or palmoplantar pustulosis (PPP) is a refractory pustular eruption on the palms and soles with unknown etiology. Numerous eccrine sweat pores exist on the palms and soles, suggesting the involvement of eccrine sweating in the pathogenesis of PPP. To the best of our knowledge, however, no definite abnormality in sweating has been documented in PPP. Accordingly, we analyzed the eccrine sweat duct involvement in the mechanism of vesicle formation in PPP. Dermatoscopy showed that PPP vesicles are located on the top of the ridges but not in the furrows. The sweat secretion in the lesional area was much lower than that in the nonlesional area, with or without pain stimulation to induce sweating. Immunostaining of horizontal sections of the lesions using antibodies against gross cystic disease fluid protein-15 (GCDFP-15) and epithelial membrane antigen (EMA) showed that these markers were localized in the cells lining the intraepidermal vesicles. Although the sweat antimicrobial peptides, dermcidin and human cathelicidin antimicrobial peptide 18 (hCAP-18)/LL-37, were detected in the fluid of the vesicles/pustules, neither dermcidin nor hCAP-18/LL-37 were overexpressed by neighboring keratinocytes. These findings suggest that the acrosyringium may be involved as the main site of the vesicle formation in the pathomechanism of PPP.

Citrulline-containing proteins, mainly originating from keratin K1 and formed by enzymatic deimination of arginine residues, have been identified in the cornified layers of human epidermis. We analyzed the localization and nature of the deiminated proteins in psoriatic epidermis. Immunostaining based on chemical modification of citrulline residues showed that the normal and psoriatic uninvolved epidermis contained deiminated proteins diffusely in the cornified cell layer, whereas the involved epidermis had no detectable or markedly reduced levels of deiminated proteins. Immunolabeling with polyclonal antibodies against a synthetic citrulline-containing peptide corresponding to a deiminated sequence of mouse K1 also suggested markedly decreased deiminated K1 in psoriatic involved lesions. Keratin analyses indicated that deiminated K1 present in normal and psoriatic uninvolved epidermis was not detected in the psoriatic involved epidermis. Double staining with a monoclonal antibody, 34βB4, and the polyclonal antibodies demonstrated that epidermis with low suprabasal keratin expression was negative for deiminated K1. In contrast, intralesional acrosyringia showing decreased suprabasal keratin immunoreactivity like that of the surrounding psoriatic epidermis showed strong deiminated K1 staining. This suggests that abnormal keratin deimination is restricted to the psoriatic hyperproliferative epidermis, without affecting sweat ductal epithelia.

Cystatin M/E is a cysteine protease inhibitor with two distinct binding sites for papain-like cysteine proteases (family C1) and the asparaginyl endopeptidase (AEP) legumain of family C13. We have previously demonstrated that deficiency of cystatin M/E in mice causes ichthyosiform skin changes and barrier disruption, which could be caused by unrestrained AEP activity. Recently, we provided biochemical evidence that human cathepsin V (CTSV) and cathepsin L (CTSL) are additional biological targets for human cystatin M/E. To address the possible role of these three proteases and their inhibitor in epidermal differentiation, we investigated the localization of these proteins in normal human skin. Whereas CTSL and AEP were broadly expressed in epithelial cells of the skin, we found a specific colocalization of cystatin M/E and CTSV in the stratum granulosum and in the root sheets of the hair follicle, using immunofluorescence microscopy. Immunoelectron microscopy revealed that cystatin M/E and CTSV are separately transported within the lamellar granules. Cystatin M/E was also found in the extracellular space in the stratum corneum associated with corneodesmosomes, where it was closely associated with CTSV. Based on the striking stratum-specific colocalization of cystatin M/E and CTSV, we propose that these molecules could have an important role in epidermal differentiation and desquamation.

The final step of keratinocyte differentiation, transition from the granular cells to the cornified cells, involves various post-translational modifications that include deimination of arginine residues. Major deiminated epidermal proteins are derived from K1. Two preferred deimination sites were identified in mouse K1, one in the V1 and the other in the V2 subdomains. An antibody against the deiminated peptide sequence in the V2 subdomain recognized not only deiminated mouse K1 but also deiminated human K1. In this study we analyzed distribution of deiminated K1 in normal human skin and in bullous congenital ichthyosiform erythroderma at light and electron microscopic levels. In normal skin the first few (1–3) cornified cell layers were positive for filaggrin and negative for the antibody against deiminated mouse K1 peptide, whereas the more superficial cells were negative for filaggrin and strongly positive for the antibody against deiminated mouse K1 peptide, indicating slightly delayed onset of K1 deimination at the initial stage of cornification. The clumped keratin in bullous congenital ichthyosiform erythroderma that was not properly compacted with filaggrin was poorly positive to the antibody against deiminated mouse K1 peptide. In addition, K1 derivatives in bullous congenital ichthyosiform erythroderma reacted poorly with the antibody against deiminated mouse K1 peptide compared with the normal control in immunoblot analyses. Our results suggest sequential reorganization of cornified cell keratin filaments involving filaggrin-mediated compaction and K1 deimination. Abnormal keratin aggregation in bullous congenital ichthyosiform erythroderma is likely to disturb the normal deimination of K1.

Cutaneous adverse events associated with the use of epidermal growth factor receptor inhibitors, such as cetuximab are relatively common. Although there are reports about possible treatments for acne or acneiform lesions induced by cetuximab, there are only few reports of prospective studies. The aim of the study was to analyze the efficacy of varius treatment modalities and their combinations in patients with acneiform eruptions caused by cetuximab. We studied 14 patients treated with an epidermal growth factor receptor inhibitors, including 7 patients cetuximab, who developed acneiform eruptions in the course of therapy. All patients were diagnosed as grade II according to the Common Terminology Criteria for Adverse Events (CTCAE) v4.0. A corticosteroid ointment, tacrolimus ointment, and ketoconazole ointment were used in a randomized manner. Oral therapy included administration of antihistaminic drugs, tetracycline, a cyclooxygenase inhibitor, or a macrolide. We measured the numer of days required to achieve improvement from grade II to grade I during cetuximab treatment. Our results showed that tetracycline treatment may shorten the period needed to achieve improvement. Ketoconazole cream and a combination of oral tetracycline and topical ketoconazole also significantly shortened this period. The results of our short case study may indicate that a combitation therapy of oral tetracyclin and topical ketokonazole is most effective in the therapy of patients with acneiform eruptions caused by cetuximab.

Background Focal adhesion kinase (FAK) is a ubiquitously expressed non-receptor tyrosine kinase involved in cancer progression and metastasis that is found overexpressed in a large number of tumors such as breast, colon, prostate, melanoma, head and neck, lung and ovary. Thus, FAK could be an attractive tumor associated antigen (TAA) for developing immunotherapy against a broad type of malignancies. In this study, we determined whether predicted T cell epitopes from FAK would be able to induce anti-tumor immune cellular responses. Methods To validate FAK as a TAA recognized by CD4 helper T lymphocytes (HTL), we have combined the use of predictive peptide/MHC class II binding algorithms with in vitro vaccination of CD4 T lymphocytes from healthy individuals and melanoma patients. Results Two synthetic peptides, FAK₁₄₃₋₁₅₇ and FAK₁,₀₀₀₋₁,₀₁₄, induced HTL responses that directly recognized FAK-expressing tumor cells and autologous dendritic cells pulsed with FAK-expressing tumor cell lysates in an HLA class II-restricted manner. Moreover, since the FAK peptides were recognized by melanoma patient's CD4 T cells, this is indicative that T cell precursors reactive with FAK already exist in peripheral blood of these patients. Conclusions Our results provide evidence that FAK functions as a TAA and describe peptide epitopes that may be used for designing T cell-based immunotherapy for FAK-expressing cancers, which could be used in combination with newly developed FAK inhibitors.

Intracellular cyclic AMP (cAMP) increased by extracellular stimuli induces various biological effects, such as cell proliferation, differentiation, and migration. Previous reports regarding the effect of cAMP on keratinocyte proliferation are contradictory and indicate that the effect apparently depends on cellular density. Recent studies have revealed that cAMP signaling regulates cell proliferation by modulating mitogen-activated protein kinase (MAPK) activity. The precise mechanism by which cAMP affects keratinocyte proliferation and/or the crosstalk between the cAMP and MAPK signaling pathways, however, remain to be determined. Using normal human keratinocytes (NHK), we investigated the effect of cAMP on keratinocyte proliferation and its molecular mechanism in terms of cellular density. In confluent NHK, cyclic AMP decreased extracellular regulated kinase (ERK) phosphorylation and cell proliferation in a Ras-independent and Rap1-dependent manner. The decreased cell proliferation by cAMP was blocked by the MEK-1 inhibitor, PD98059. In contrast, in subconfluent NHK, cAMP increased ERK phosphorylation and cell proliferation. Western blot analysis revealed that NHK expressed B-Raf and Rap-1. Although both 95 kDa and 62 kDa B-Raf isoforms were expressed in subconfluent NHK, only 62 kDa B-Raf was detected in confluent NHK. Transfection of 95 kDa B-Raf into confluent NHK resulted in a cAMP-dependent increase in ERK phosphorylation and cell proliferation. These findings indicate that differential expression of B-Raf isoforms is critical for cAMP-dependent regulation of NHK proliferation that depends on phosphorylation of ERK.