Interferon-γ Decreases Ceramides with Long-Chain Fatty Acids: Possible Involvement in Atopic Dermatitis and Psoriasis

Ceramide (CER) with long-chain fatty acids (FAs) in the human stratum corneum (SC) is important for the skin barrier functions. Changes in the CER profile have been associated with abnormal permeability of dermatoses such as atopic dermatitis (AD) and psoriasis. In addition, interferon-γ (IFN-γ) has been known to be abundant in both AD and psoriatic skin lesions. In this study, we aimed to identify the mechanism underlying the alteration of FA chain length of CERs in these diseases. Mass spectrometry analysis of CERs in the SC showed that the proportion of CERs with long-chain FAs was significantly lower in AD and psoriasis patients than in healthy controls, and this reduction was more pronounced in psoriasis than in AD. Using cultured human keratinocytes and epidermal sheets, we found that only IFN-γ among various cytokines decreased the mRNA expression of elongase of long-chain fatty acids (ELOVL) and ceramide synthase (CerS), enzymes involved in FA chain elongation. Furthermore, quantitative analysis showed that IFN-γ decreased the levels of CERs with long-chain FAs. These results suggest that IFN-γ decreases CERs with long-chain FAs through the downregulation of ELOVL and CerS and that this mechanism may be involved in the CER profile alteration observed in psoriasis and AD

Development, validation, and comparison of gene analysis methods for detecting EGFR mutation from non-small cell lung cancer patients-derived circulating free DNA

The feasibility and required sensitivity of circulating free DNA (cfDNA)-based detection methods in second-line epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) treatment are not well elucidated. We examined T790M and other activating mutations of EGFR by cfDNA to assess the clinical usability. In 45 non-small cell lung cancer (NSCLC) patients harboring activating EGFR mutations, cfDNAs were prepared from the plasma samples. EGFR mutations in cfDNA were detected using highly sensitive methods and originally developed assays and these results were compared to tissue-based definitive diagnoses. The specificity of each cfDNA-based method ranged 96–100% whereas the sensitivity ranged 56–67%, indicating its low pseudo-positive rate. In EGFR-TKI failure cohort, 41–46% samples were positive for T790M by each cfDNA-based method, which was comparable to re-biopsy tissue-based T790M positive rates in literature. The concordance of the results for each EGFR mutation ranged from 83–95%. In eight patients, the results of the cfDNA-based assays and re-biopsy-derived tissue-based test were compared. The observed overall agreement ranged in 50–63% in T790M, and in 63–100% in activating EGFR mutations. In this study, we have newly developed three types of assay which have enough sensitivity to detect cfDNA. We also detected T790M in 44% of patients who failed prior EGFR-TKI treatment, indicating that cfDNA-based assay has clinical relevance for detecting acquired mutations of EGFR

Structure-Activity Relationships of the Antitumor C5-Curcuminoid GO-Y030

1,5-Bis(4-hydroxy-3-methoxyphenyl)-1,4-pentadiene-3-one (2) was isolated from Curcuma domestica as a curcumin (1)-related compound, which we named C5-curcumin. Intrigued by the potent antitumor activity of C5-curcumin (2)-related 1,5-bisaryl-1,4-pentadiene-3-ones [bis(arylmethylidene)acetones, termed C5-curcuminoids], we previously conducted a structure–activity relationship study of C5-curcuminoids and showed that highly active GO-Y030 [1,5-bis(3,5-bis(methoxymethoxy)phenyl)-1,4-pentadiene-3-one (4)] is the most promising antitumor compound. In this study, a panel of C5-curcuminoids based on GO-Y030, consisting of 30 new and 10 known compounds, was synthesized to elucidate in detail which moiety of GO-Y030 is significant for antitumor activity. The results confirmed that both the cross-conjugated dienone moiety and the 3,5-bis(methoxymethoxy) substituent are important for the antitumor activity

Expression of Drebrin, an actin binding protein, in basal cell carcinoma, trichoblastoma and trichoepithelioma

Drebrin, an F-actin binding protein, is known to play important roles in cell migration, synaptogenesis and neural plasticity. Although drebrin was long thought to be specific for neuronal cells, its expression has recently been reported in non-neuronal cells. As for skin-derived cells, drebrin was shown to be enriched at adhering junctions (AJs) in cultured primary keratinocytes and also be highly expressed in basal cell carcinoma (BCC) cells. Since BCC and two types of benign neoplasm, trichoblastoma and trichoepithelioma, are considered to derive from the same origin, follicular germinative cells, it is sometimes difficult to morphologically distinguish BCC from trichoblastoma and trichoepithelioma. In this study, we performed immunohistochemical staining of drebrin in BCC, trichoblastoma and trichoepithelioma, to examine whether drebrin could serve as a biomarker for BCC diagnosis. In western blotting, drebrin was detected highly and moderately in the lysates from a squamous cell carcinoma cell line, DJM-1, and normal human epidermis, respectively. In immunofluorescence analyses, drebrin was colocalized with markers of AJs and tight junctions in DJM-1 cells and detected at cellcell junction areas of human normal epidermis tissue. We then examined the distribution patterns of drebrin in BCC, trichoblastoma and trichoepithelioma. In BCC tissues, intense and homogeneous drebrin expression was observed mainly at tumor cell-cell boundaries. In contrast, drebrin was stained only weakly and nonhomogeneously in trichoblastoma and trichoepthelioma tissue samples. For differential diagnosis of BCC, drebrin may be a novel and useful marker

Anti-MDA5 Antibody-Positive Dermatomyositis Presenting with Cellulitis-Like Erythema on the Mandible as an Initial Symptom

Panniculitis is an uncommon skin eruption observed in patients with dermatomyositis (DM)/clinically amyopathic dermatomyositis (CADM), especially in anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive DM. We present here a 51-year-old Japanese woman with an anti-MDA5 antibody-positive DM who initially had cellulitis-like erythema on her right mandible. Histopathological findings showed a subcutaneous lobular infiltration of lymphocytes. The patient developed typical skin eruptions of DM/CADM, rapidly progressive interstitial lung disease, and severe muscle weakness 2 weeks after the first visit. After the diagnosis of anti-MDA5 antibody-positive DM, she was treated with intravenous steroid pulse therapy (methylprednisolone, 1,000 mg/day for 3 days), oral prednisolone at 1.0 mg/kg/day, and tacrolimus at 4.0 mg/day. The lesions of panniculitis associated with DM/CADM typically present on the buttocks, thighs, arms, and abdomen. This is the first DM/CADM case with localized panniculitis on the face. Panniculitis and myositis usually show simultaneous improvement during treatment. Although panniculitis disappeared with steroid and tacrolimus treatment and did not recur, muscle weakness was intractable and recurred in this case. This indicates that the clinical courses of panniculitis and myositis of DM/CADM do not always change in parallel

Eosinophilic Fasciitis Associated with Myositis

Eosinophilic fasciitis is clinically characterized by symmetrical scleroderma-like indurations of the skin with pain. The histological features are fascial inflammation with lymphocytes and eosinophils as well as thickened and fibrotic fascia. Lymphocytic infiltration and degeneration of the underlying muscle are rarely observed. We report a 69-year-old Japanese woman who presented with multiple areas of glossy induration and painful peau d'orange-like lesions on the chest and four extremities. T2-weighted magnetic resonance imaging showed significant hyperintense thickening of the fascia of the lower extremities. Histopathological examination of a biopsy specimen from the induration showed marked fibrinoid degeneration of the fascia and the neighboring muscle with mixed cellular infiltration of lymphocytes and eosinophils. The predominant CD8+ lymphocytic infiltrates were observed by immunohistological study. A diagnosis of eosinophilic fasciitis with myositis was made. Oral administration of prednisolone and discontinuation of exercise significantly improved the lesions and pain

Drug-Induced Hypersensitivity Syndrome Followed by Subacute Thyroiditis

Drug-induced hypersensitivity syndrome (DIHS) is a severe multiorgan system adverse drug reaction with reactivation of human herpesviruses (HHVs) such as HHV-6, HHV-7, cytomegalovirus (CMV) and Epstein-Barr virus. Various complications, including autoimmune diseases, sometimes appear during the course of DIHS. We report a case of salazosulfapyridine-induced DIHS associated with HHV-6 reactivation. Two and a half months after the onset of DIHS, subacute thyroiditis occurred, possibly associated with CMV reactivation. Prednisolone (20 mg/day) was effective for subacute thyroiditis. Long-term follow-up is needed in patients with DIHS because of the possible onset of autoimmune diseases