Nimbolide is a tetranortriterpenoid isolated from the leaves and flowers of Azadirachta indica which has been shown to exhibit anticancer, antioxidant, anti-inflammatory, and anti-invasive properties in a variety of cancer cells. However, the anti-tumor effect on human renal cell carcinoma (RCC) cells is unknown. In this study, we found that nimbolide treatment had a cytotoxic effect on 786-O and A-498 RCC cells in a dose-dependent manner. According to flow cytometric analysis, nimbolide treatment resulted in G2/M arrest in 786-O and A-498 cells accompanied with an increase in the phosphorylation status of p53, cdc2, cdc25c, and decreased expressions of cyclin A, cyclin B, cdc2, and cdc25c. Nimbolide also caused DNA damage in a dose-dependent manner as determined by comet assay and measurement of γ-H2AX. In addition, apoptotic cells were observed in an Annexin V-FITC/propidium iodide double-stained assay. The activities of caspase-3, -9, and poly ADP-ribose polymerase (PARP) were increased, and the expression of pro-caspase-8 was decreased in nimbolide-treated 786-O and A-498 cells. Western blot analysis revealed that the levels of intrinsic-related apoptotic proteins Bax and extrinsic-related proteins (DR5, CHOP) were significantly increased in nimbolide-treated 786-O and A-498 cells. In addition, the expressions of Bcl-2 and Mcl-1 were decreased in 786-O and A-498 cells after nimbolide treatment. We conclude that nimbolide can inhibit the growth of human RCC cells by inducing G2/M phase arrest by modulating cell cycle-related proteins and cell apoptosis by regulating intrinsic and extrinsic caspase signaling pathways. Nimbolide may be a promising therapeutic strategy for the treatment of RCC.

Oncostatin M (OSM) is linked with multiple biological responses including growth and differentiation. Previous reports showed inhibitory effects of OSM in tumor progression while others showed promoting effects. The dual role of OSM in the development of various cancers is still unclear. We previously described OSM-mediated SLUG suppression, leading to repressed metastasis of lung adenocarcinoma (LAC) cells. However, the underlying mechanism remains elusive. Here, we showed that OSM suppresses SLUG express in LAC cells through a STAT1-dependent transcriptional inhibition. Knockdown of STAT1 reversed the OSM-suppressed SLUG expression and rescued the OSM-mediated inhibition of cell proliferation, migration, and invasion in vitro, as well as pulmonary metastasis in vivo. STAT1 suppressed SLUG transcription through binding to its promoter region in response to OSM. Furthermore, PIAS4, a co-repressor of STAT, and HDAC1 were able to bind to STAT1 on SLUG promoter region, resulting in reduced H3K9 acetylation and suppressed SLUG expression upon OSM treatment. In contrast, PIAS3 bound to activated STAT3, another effector of OSM, in response to OSM and blocked the binding of STAT3 to SLUG promoter region, preventing STAT3-dependent activation of SLUG transcription. Our findings suggested that OSM suppresses SLUG expression and tumor metastasis of LAC through inducing the inhibitory effect of the STAT1-dependent pathway and suppressing the activating effect of STAT3-dependent signaling. These results can serve as a scientific basis for the potential therapeutic intervention of OSM in cancer cells.

Background: To evaluate dosimetric differences of salvage irradiations using two commercially available volumetric modulated arc therapy (VMAT) stereotactic body radiation therapy (SBRT) techniques: RapidArc (RA) and HyperArc (HA), for recurrent nasopharyngeal carcinoma (NPC) after initial radiation therapy. Methods: Ten patients with recurrent NPC status previously treated with radiation therapy were considered suitable candidates for salvage SBRT using VMAT approach. Two separate treatment plans were created with HA and RA techniques for each case, with dosimetric outcomes compared with respect to tumor target coverage and organs-atrisk (OARs) sparing. Furthermore, the cumulative radiobiological effects to the relevant OARs from the original radiotherapy to the respective salvage SBRT plans were analyzed in terms of biologically effective dose (BED). Results: Treatment with HA exhibited similar target dose coverage as with RA, while delivering a higher mean dose to the targets. Using RA technique, the mean maximal doses to optic apparatus and the mean brain dose were reduced by 1 to 1.5 Gy, comparing to HA technique. The conformity index, gradient radius, and intermediate dose spillage in HA plans were significantly better than those in RA. With HA technique, the volume of brain receiving 12 Gy or more was reduced by 44%, comparing to RA technique. The cumulative BEDs to spinal cord and optic apparatus with RA technique were 1 to 2 Gy 3 less than those with HA. HA technique significantly reduced the volume within body that received more than 100 Gy. Conclusions: With better dose distribution than RA while maintaining sufficient target dose coverage, HA represents an attractive salvage SBRT technique for recurrent NPC.

Stem cell products and its clinical applications have been widely discussed in recent years, particularly when the Japanese "induced pluripotent stem cells" founder Dr. Yamanaka was awarded as Nobel Prize laureate in 2013. For decades, major progresses have been achieved in the stem cell biology field, and more and more evidence showed that skin stem cells are involved in the process of skin repair. Stem/progenitor cells of the epidermis are recognized to play the most essential role in the tissue regeneration of skin. In this review, we first illustrated basic stem cell characteristics and various stem cell subtypes resided in the skin. Second, we provided several literatures to elucidate how stem/progenitor cells collaborate in the process of skin repair with the evidence from animal model studies and in vitro experiments. Third, we also introduced several examples of skin cell products on the pharmaceutic market and the ongoing clinical trials aiming for unmet medical difficulties of skin. Last but not least, we summarized general reviewing concerns and some disputatious issues on dermatological cell products. With this concise review, we hope to provide further beneficial suggestions for the development of more effective and safer dermatological stem/progenitor cell products in the future.

The effect of under-bump-metallization (UBM) on electromigration was investigated at temperatures ranging from 135 o C to 165 o C. The UBM structures were examined: 5-µm-Cu/3-µm-Ni and 5 µm Cu. Experimental results show that the solder joint with the Cu/Ni UBM has a longer electromigration lifetime than the solder joint with the Cu UBM. Three important parameters were analyzed to explain the difference in failure time, including maximum current density, hot-spot temperature, and electromigration activation energy. The simulation and experimental results illustrate that the addition 3-µm-Ni layer is able to reduce the maximum current density and hot-spot temperature in solder, resulting in a longer electromigration lifetime. In addition, the Ni layer changes the electromigration failure mode. With the 5 µm Cu UBM, dissolution of Cu layer and formation of Cu 6 Sn 5 intermetallic compounds are responsible for the electromigration failure in the joint. Yet, the failure mode changes to void formation in the interface of Ni 3 Sn 4 and the solder for the joint with the Cu/Ni UBM. The measured activation energy is 0.85 eV and 1.06 eV for the joint with the Cu/Ni and the Cu UBM, respectively.