The transcription factor signal transducer and activator of transcription 3 (STAT3) has two important phosphorylation sites, Tyr705 and Ser727, for its activation. Ser727 phosphorylation has been considered to be a secondary event after Tyr705 phosphorylation. In this study, the role and regulation of Ser727 phosphorylation in STAT3 in melanocytic cells were examined. STAT3 was phosphorylated on Ser727 in the absence of Tyr705 phosphorylation in melanocytes. 12-O-tetradecanoylphorbol-13-acetate-induced increase in cell survival activity and nuclear translocation of STAT3 was associated with Ser727 phosphorylation. Ser727 was constitutively phosphorylated in all melanoma cell lines examined irrespective of Tyr705 phosphorylation. The possible involvement of Ser727 phosphorylation in STAT3 in cell survival activity and nuclear translocation of STAT3 in melanocytes was demonstrated also in melanoma cells. The constitutive Ser727 phosphorylation in melanoma cells was partially mediated by the B-Raf-MEK-ERK1/2 pathway. Immunohistochemical studies on specimens of primary lesions of acral lentiginous melanoma revealed that Ser727 phosphorylation precedes Tyr705 phosphorylation in the early stages of melanoma progression. Our results indicate that Ser727 phosphorylation on STAT3 is not necessarily a secondary event after Tyr705 phosphorylation and suggest that it has a role in the regulation of cell survival activity and nuclear translocation of STAT3 in melanocytic cells.

Our studies revealed that the 3 LAGBD cases showed prominent IgG and IgA reactivity with laminin-332, which was only rarely reported. In addition, all cases showed IgG and IgA reactivity with other multiple antigens, indicating the role of epitope-spreading mechanisms initiated from laminin-332. The significance of IgA antibodies to laminin-332 should be studied in larger cohorts of both LAGBD and linear IgA bullous dermatosis.

The effect of smoking for postoperative pulmonary complications (PPCs) in minor surgical patients who have an early recovery has not been evaluated. Smoking may also affect intraoperative sputum volume. We thus evaluated whether smoking had a relation to intraoperative sputum volume or PPCs in minor surgical patients. Smoking status was determined through the interviewer-assisted questionnaires. Intraoperative sputum volume was judged using the number of trials to suck up sputum from the trachea. Current and Ex-smokers were significantly more likely to have an increased intraoperative sputum volume when compared with Non-smokers (18.3% and 17.9% vs. 9.4%) although the relationship between smoking and PPCs was not demonstrated. In the multivariate models, Current and Ex-Smokers was identified as an independent risk factor of an increased intraoperative sputum volume (odds ratio, 2.7; 95% confidence interval, 1.6-4.6). The patients with < 2 months smoking cessation were more likely to have an increased intraoperative sputum volume. In conclusion, smoking is the risk factor of an increased intraoperative sputum volume, and preoperative smoking cessation > or = 2 months is recommended to reduce the risk of an increased intraoperative sputum volume, although the relationship between smoking and PPCs was not elucidated in minor surgical patients.

Preoperative small-dose ketamine, IV, significantly prevented a systemic arterial pressure increase during prolonged tourniquet inflation in patients under general anesthesia.

e89-2 was suppressed by TO901317. Expression of microphthalmiaassociated transcription factor(MiTF), a master transcriptional regulator of melanogenesis, and upstream event, cAMP responsive element-binding activation were not affected. Of note, the degradation of MiTF was substantially accelerated by TO901317. Extracellular signal-regulated kinase(ERK) contributed to TO901317-induced anti-melanogenesis, which was supported by recovery of melanogenesis with an ERK inhibitor. Other LXR ligands like 22(R)-hydroxycholesterol and GW3965 also activated ERK and suppressed melanogenesis. Anti-melanogenic effects of TO901317 were confirmed in vivo in UVB-tanning model in brownish guinea pigs where topical application of TO901317 significantly reduced UVB-induced hyper-pigmentation, providing the first line of evidence that LXRs may be a novel target for anti-melanogenesis.http://dx.The transcription factor signal transducer and activator of transcription 3 (STAT3) is constitutively activated through Tyr705 phosphorylation in most melanoma cells. In this study, the role and regulation of Ser727 phosphorylation in STAT3, another critical phosphorylation event, in melanoma cells and melanocytes were examined. Ser727 was constitutively phosphorylated in all of seven melanoma cell lines examined. Constitutive Ser727 phosphorylation was partially attenuated by U0126, an inhibitor of extracellular-regulated kinase (ERK) kinase (MEK). In WM39 cells containing STAT3 phosphorylated on Ser727 (pS-STAT3) but not STAT3 phosphorylated on Tyr705 (pY-STAT3), pS-STAT3 was localized mainly in the nucleus and U0126 treatment resulted in a decrease in nuclear pS-STAT3 and total nuclear STAT3 concomitant with an increase in total cytosolic STAT3. Blockade of STAT3 activity in WM39 cells by small interfering RNAs suppressed the growth of the cells. Melanocytes did not express pY-STAT3 but expressed low levels of pS-STAT3 in the nucleus. Upon treatment with 12-O-tetradecanoylphorbol-ester (TPA), a growth stimulator for melanocytes, nuclear pS-STAT3 and total nuclear STAT3 were increased, without affecting Tyr705 phosphorylation, concomitant with enhanced proliferative activity. These results indicate that Ser727 phosphorylation in melanoma cells is mediated in part by the MEK-ERK1/2 pathway and that it plays a crucial role in the nuclear translocation of STAT3 and growth in melanoma cells and melanocytes. Furthermore, immunohistochemical studies on specimens of primary lesions of acral lentiginous melanoma (ALM) revealed that Ser727 phosphorylation frequently precedes Tyr705 phosphorylation in the early stages of ALM progression.Many chemokines show antitumor activity by stimulating immune cells, however, other chemokines promote tumor growth and metastasis by direct growth stimulation, enhancing cell motility, or angiogenesis. We found that some isolated tumor cells from advanced melanoma patients strongly express CCR5. Immunohistochemically, patients of melanoma expressing CCR5 in primary tumor have poorer survival rate than CCR5 negative cas...