KMT2A promotes melanoma cell growth by targeting hTERT signaling pathway.

Melanoma is an aggressive cutaneous malignancy, illuminating the exact mechanisms and finding novel therapeutic targets are urgently needed. In this study, we identified KMT2A as a potential target, which promoted the growth of human melanoma cells. KMT2A knockdown significantly inhibited cell viability and cell migration and induced apoptosis, whereas KMT2A overexpression effectively promoted cell proliferation in various melanoma cell lines. Further study showed that KMT2A regulated melanoma cell growth by targeting the hTERT-dependent signal pathway. Knockdown of KMT2A markedly inhibited the promoter activity and expression of hTERT, and hTERT overexpression rescued the viability inhibition caused by KMT2A knockdown. Moreover, KMT2A knockdown suppressed tumorsphere formation and the expression of cancer stem cell markers, which was also reversed by hTERT overexpression. In addition, the results from a xenograft mouse model confirmed that KMT2A promoted melanoma growth via hTERT signaling. Finally, analyses of clinical samples demonstrated that the expression of KMT2A and hTERT were positively correlated in melanoma tumor tissues, and KMT2A high expression predicted poor prognosis in melanoma patients. Collectively, our results indicate that KMT2A promotes melanoma growth by activating the hTERT signaling, suggesting that the KMT2A/hTERT signaling pathway may be a potential therapeutic target for melanoma

Quercetin Suppresses Cyclooxygenase-2 Expression and Angiogenesis through Inactivation of P300 Signaling

Quercetin, a polyphenolic bioflavonoid, possesses multiple pharmacological actions including anti-inflammatory and antitumor properties. However, the precise action mechanisms of quercetin remain unclear. Here, we reported the regulatory actions of quercetin on cyclooxygenase-2 (COX-2), an important mediator in inflammation and tumor promotion, and revealed the underlying mechanisms. Quercetin significantly suppressed COX-2 mRNA and protein expression and prostaglandin (PG) E(2) production, as well as COX-2 promoter activation in breast cancer cells. Quercetin also significantly inhibited COX-2-mediated angiogenesis in human endothelial cells in a dose-dependent manner. The in vitro streptavidin-agarose pulldown assay and in vivo chromatin immunoprecipitation assay showed that quercetin considerably inhibited the binding of the transactivators CREB2, C-Jun, C/EBPβ and NF-κB and blocked the recruitment of the coactivator p300 to COX-2 promoter. Moreover, quercetin effectively inhibited p300 histone acetyltransferase (HAT) activity, thereby attenuating the p300-mediated acetylation of NF-κB. Treatment of cells with p300 HAT inhibitor roscovitine was as effective as quercetin at inhibiting p300 HAT activity. Addition of quercetin to roscovitine-treated cells did not change the roscovitine-induced inhibition of p300 HAT activity. Conversely, gene delivery of constitutively active p300 significantly reversed the quercetin-mediated inhibition of endogenous HAT activity. These results indicate that quercetin suppresses COX-2 expression by inhibiting the p300 signaling and blocking the binding of multiple transactivators to COX-2 promoter. Our findings therefore reveal a novel mechanism of action of quercetin and suggest a potential use for quercetin in the treatment of COX-2-mediated diseases such as breast cancers

High Power Waveguide Photodiodes - Analysis, Design and Demonstration

Large optical power at the photodiode is especially beneficial to the high speed fiber optic link that is demanded by the exponential internet traffic growth. The power handling capability of waveguide photodiode (WGPD) has been limited by one of its intrinsic feature, which is the lack of uniform absorption distribution in the absorber in the longitudinal direction. As the required bandwidth kept increasing, an increasing photocurrent is needed in a reduced absorber length, which challenges the traditional WGPD designs for high power fiber optic link. In order to study absorption uniformity in a high speed high power WGPD, supermode analysis is developed to replace the traditional WGPD analysis, which optimizes the absorption profile via adjusting the waveguide confinement factor. It is point out that the waveguide confinement factor has opposite effects on the bandwidth and power handling of a WGPD, and makes the traditional WGPD analysis ineffective for the high speed high power WGPD design. the supermode analysis focuses on finding out the features of supermodes that improve the absorption uniformity. The designs of the waveguide structure and the layer structure are guided by the supermode analysis to improve the absorption uniformity in a WGPD. The supermode analysis is applied to improve the absorption uniformity in a traditional WGPD. Traditional WGPD with the optimized structure experimentally demonstrates power handling capability higher than most of the reported WGPD with similar bandwidth. A layer structure with diluting layer is proposed to increases the power handling capability by 30% in the demonstrated WGPD. The supermode analysis also points out that the traditional WGPD has a trade-off of absorption uniformity and bandwidth-efficiency product. The supermode analysis is applied to re-design the directional coupler photodiode (DCPD), which is pre-studied in our group. With the optimization of absorption uniformity in a DCPD that has RC time limited bandwidth being close to 50 GHz, the re-designed DCPD shows better power handling capability than that of any other traditional WGPDs with similar bandwidth. Finally, we have proposed and demonstrated the incorporation of cascaded optical bandpass filters in a fiber optic link can significantly improve the link performance

IGF-1 mediates exercise-induced phospholipid alteration in the murine skin tissues

We previously demonstrated that exercise with an iso-caloric diet significantly reduced body weight and skin carcinogenesis in correspondence with lower plasma IGF-1 levels and IGF-1-dependent phospholipid signaling. This study was thus designed to test the hypothesis that IGF-1 reduction plays a causal role in exercise-induced phospholipid changes. SENCAR mice were randomly assigned to one of the following three groups for 12 weeks: ad libitum-fed sedentary control, exercise but pair-fed the amount of the control (PE), and PE with IGF-1 injection (PE+IGF-1). Treadmill exercise was conducted at 13.4 m/min for 90 min/d, 5 d/week. In the last two weeks IGF1 was i.p. injected (10 μg/g B.W.) twice per week. Both body weight and plasma IGF-1 levels were significantly reduced in PE mice when compared with the control. IGF-1 injection did not affect body weight, or the plasma levels of IGF-1 at the end of the experiment due to a rapid degradation with a half-life of 3.4 hrs. Of the 338 phospholipid species detected in the skin tissues by electron spray ionization tandem mass spectrometry, 21 were significantly changed in PE mice compared to control. Fourteen of the altered 21 species in PE mice were reversed by IGF-1 injection, including the most abundant phosphatidylinositol (PI) 38:4, a substrate for lipid PI3K signaling. Western Blot Analysis further showed the reduced PI3K, but not IGF-1R, in PE mice was also reversed by IGF-1 restoration. Overall, these data provided evidence that exercise-induced reduction of IGF-1 is required in mediating the alteration of phospholipid profile and PI-related PI3K signaling