Ko-ichi Tada

ER signaling is activated to protect human HaCaT keratinocytes from ER stress induced by environmental doses of UVB

Proteins are folded properly in the endoplasmic reticulum (ER). Various stress such as hypoxia, ischemia and starvation interfere with the ER function, causing ER stress, which is defined by the accumulation of unfolded protein (UP) in the ER. ER stress is prevented by the UP response (UPR) and ER-associated degradation (ERAD). These signaling pathways are activated by three major ER molecules, ATF6, IRE-1 and PERK. Using HaCaT cells, we investigated ER signaling in human keratinocytes irradiated by environmental doses of ultraviolet B (UVB). The expression of Ero1-L(alpha), an upstream signaling molecule of ER stress, decreased at 1-4h after 10 mJ/cm(2) irradiation, indicating that the environmental dose of UVB-induced ER stress in HaCaT cells, without growth retardation. Furthermore, expression of intact ATF6 was decreased and it was translocated to the nuclei. The expression of XBP-1, a downstream molecule of IRE-1, which is an ER chaperone whose expression is regulated by XBP-1, and UP ubiquitination were induced by 10 mJ/cm(2) UVB at 4h. PERK, which regulates apoptosis, was not phosphorylated. Our results demonstrate that UVB irradiation generates UP in HaCaT cells and that the UPR and ERAD systems are activated to protect cells from UVB-induced ER stress. This is the first report to show ER signaling in UVB-irradiated keratinocytes.

Edaravone: a new therapeutic approach for the treatment of acute stroke.

Acute stroke, including acute ischemic stroke (AIS) and acute hemorrhagic stroke, (AHS) is a common medical problem with particular relevance to the demographic changes in industrialized societies. In recent years, treatments for AIS have emerged, including thrombolysis with tissue plasminogen activator (t-PA). Although t-PA is the most effective currently available therapy, it is limited by a narrow therapeutic time window and side effects, and only 3% of all AIS patients receive thrombolysis. Edaravone was originally developed as a potent free radical scavenger and, since 2001, has been widely used to treat AIS in Japan. It was shown that edaravone extended the narrow therapeutic time window of t-PA in rats. The therapeutic time window is very important for the treatment of AIS, and early edaravone treatment is more effective. Thus, more AIS patients might be rescued by administering edaravone with t-PA. Meanwhile, edaravone attenuates AHS-induced brain edema, neurologic deficits and oxidative injury in rats. Although edaravone treatment is currently only indicated for AIS, it does offer neuroprotective effects against AHS in rats. Therefore, we hypothesize that early administration of edaravone can rescue AHS patients as well as AIS patients. Taken together, our findings suggest that edaravone should be immediately administered on suspicion of acute stroke, including AIS and AHS.

Evaluation of a newly‐developed immunochromatography strip test for diagnosing dermatophytosis

Background  Traditionally, dermatophytosis, a common disease affecting millions of people world‐wide, has been diagnosed by direct microscopy and fungal culture. The immunochromatography (ICG) strip test was recently developed.

MK615, a Prunus mume Steb. Et Zucc (‘Ume’) Extract, Attenuates the Growth of A375 Melanoma Cells by Inhibiting the ERK1/2‐Id‐1 Pathway

The Japanese apricot, a commonly consumed food called ‘Ume’ in Japan, has been used for a traditional Japanese medicine for centuries. MK615, an extract of compounds from ‘Ume’, has strong antitumorigenic and antiinflammatory effects including the induction of apoptosis and autophagy, and inhibition of cytokine production mediated via the inhibition of MAPKs signaling including ERK‐1/2, JNK and p38MAPK. The inhibitor of DNA binding 1 (Id‐1), a basic helix‐loop‐helix (bHLH) transcription factor family, is essential for DNA binding and the transcriptional regulation of various proteins that play important roles in the development, progression and invasion of tumors. In melanoma, Id‐1 is constitutively expressed in the late and early stages, suggesting it as a therapeutic target in patients with melanoma. This study reports that MK615 profoundly reduced both the mRNA‐ and protein expression levels of Id‐1 and inhibited cell growth in A375 melanoma cells. MK615 markedly inhibited the phosphorylation of ERK1/2, which is associated with Id‐1 protein expression in A375 cells. Id‐1‐specific RNAi induced the death of A375 cells. Moreover, the expression of Bcl‐2 was decreased by both MK615 and Id‐1‐specific RNAi in A375 cells. The results suggest that MK615 is a potential therapeutic agent for treating malignant melanoma. Copyright

Metastatic cutaneous squamous cell carcinoma treated successfully with surgery, radiotherapy and S-1/cisplatin chemotherapy

Primary cutaneous squamous cell carcinoma (SCC) is a malignant tumor that arises from keratinizing cells of the epidermis or its appendages. We present a patient with cutaneous SCC on the left instep with metastases to multiple lymph nodes in the para‐aortic, iliac and groin region. We chose a combination of surgery and concurrent chemoradiotherapy. The chemotherapeutic agent S‐1/cisplatin was selected based on results of the histoculture drug response assay. The patient responded dramatically to this multidisciplinary treatment and complete remission was achieved.

Elevation of serum KL-6 in patients with psoriasis treated with anti-tumour necrosis factor-α therapy

We report three patients with psoriasis whose serum level of Krebs Von Den Lungen (KL)‐6 increased during therapy with anti‐tumour necrosis factor (TNF)‐α. A diagnosis of early‐phase or subclinical interstitial pneumonia was made in two patients, and their KL‐6 level decreased after anti‐TNF‐α discontinuation. The rise in KL‐6 in the other patient was attributed to methotrexate. We propose that serum KL‐6 should be monitored routinely in patients treated with anti‐TNF agents.

Bilateral diffuse uveal melanocytic proliferation with mucocutaneous pigmentation.

Bilateral diffuse uveal melanocytic proliferation (BDUMP) is a rare paraneoplastic syndrome associated with extraocular malignancies. Extraocular pigmented lesions have been reported. We report that two patients with BDUMP presented with non‐ocular pigmented lesions.

Multifocal haemangioma with extracutaneous involvement associated with hypergalactosaemia

Neonatal haemangiomatosis, characterized by multiple haemangiomas, is a rare disease that develops during the neonatal period with or without visceral involvement. We report a 1‐month‐old Japanese boy with multifocal haemangiomas with extracutaneous involvement. A haemangioma on his left lower eyelid, present at birth, increased in size during the first postnatal month and more lesions developed during the same period. Neonatal mass screening showed hypergalactosaemia. Laboratory investigations found raised total bile acid and ammonia. Computed tomography and abdominal ultrasonography studies showed multiple hepatic haemangiomas and intrahepatic portovenous shunts. The child’s cutaneous and hepatic haemangiomas disappeared spontaneously with normalization of laboratory data, and galactose accumulation improved with the feeding of lactose‐free milk. There were no complications and the child has had no recurrence of the symptoms. Our case implies a possible association of multiple haemangioma and hypergalactosaemia, suggesting the necessity for visceral investigation.