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Colorectal cancer (CRC) is one of the most frequent malignant tumors. Signaling by the PI3K/AKTpathway is crucial for CRC development and progression, including proliferation and migration. Celastrol has an anticancer effect, but its mechanism needs to be determined. Here, we showed that celastrol suppressed CRC cell proliferation and migration. Celastrol treatment also decreased the PI3K/AKTpathway components, and MMP3and MMP7expression levels. In addition, knockdown of AKT, not mTOR, inhibited MMP3and MMP7expression levels and AKTsilencing promoted the celastrol-induced effects on CRC cell proliferation and migration. Taken together, these findings indicated that the celastrol-induced antitumor effects were mediated through MMP3and MMP7by the PI3K/AKTsignaling pathway.

Ecology—the place, environment, nature and the rich cultures over time—has powerful interaction and interplay with humanity, one species of zillions of organisms on mother earth. It is no exception to educational philosophy, which forms and develops in the specific place, time, and culture in the history. This paper will focus on Chinese educational philosophy and its interplay with Dunhuang, a famous and fascinating World Heritage site on the Silk Road in the desolated Gobi Dessert northwest of China. This paper will examine the roots, contents, process, and implementation of Chinese educational philosophy in the rich and diverse landscape of Dunhuang throughout the history. The collision and fusion of multiculturalism promoted the formation of Dunhuang civilization and its unique culture and thoughts such as Hinduism, Taoism, and Confucianism. The discussion will examine the successful interaction and convergence of multicultures in Dunhuang and their manifestations in Dunhuang Grottos. It will highlight the synergy and transformation of educational philosophy and practices in Dunhuang and China over the course of history and discuss their meaning for contemporary education today.

The response of human osteoblast-like osteosarcoma cells (MG63) to surface modification of Ti-6Al-4V implant alloy was investigated by Laser Interference Lithography (LIL). In this work, laser interference lithography was employed to fabricate the microstructures of grooves, dots and dimples onto the surfaces of Ti-6Al-4V samples. Two and three beam LIL systems were developed to carry out the experiments. The laser treatment resulted in the increases of the roughness and the contact angle of water on the implant alloy surfaces. The proliferation of osteoblasts was analyzed by MTT (3-(4,5-dimethyl- 2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide) assay for the time periods of 4 hours, 2 days, 3 days, and 6 days. The MTT test results demonstrated that the laser treatment surfaces had a positive impact on the proliferation of osteoblast cells after 24 hours. The alloy surface morphology and the morphological changes of MG63 cells cultured on the laser textured Ti-6Al-4V surface were observed by Scanning Electron Microscope (SEM). The SEM results indicated that the osteoblast cells were aligned on grooved surfaces and they were prolonged with the structures. Enzymatic detachment results showed that the 20 µm grooved structures provided the better cell adhesion to the textured Ti-6Al-4V surfaces.

The standard of care for unresectable lung cancer is chemoradiation. However, therapeutic options are limited and patients are rarely cured. We have previously shown that vitamin D and vitamin D analogs such as EB 1089 can enhance the response to radiation in breast cancer through the promotion of a cytotoxic form of autophagy. In A549 and H460 non-small cell lung cancer (NSCLC) cells, 1,25-D3(the hormonally active form of vitamin D) and EB 1089 prolonged the growth arrest induced by radiation alone and suppressed proliferative recovery, which translated to a significant reduction in clonogenic survival. In H838 or H358 NSCLC cells, which lack VDR/vitamin D receptor or functional TP53, respectively, 1,25-D3failed to modify the extent of radiation-induced growth arrest or suppress proliferative recovery post-irradiation. Sensitization to radiation in H1299 NSCLC cells was evident only when TP53 was induced in otherwise tp53-null H1299 NSCLC cells. Sensitization was not associated with increased DNA damage, decreased DNA repair or an increase in apoptosis, necrosis, or senescence. Instead sensitization appeared to be a consequence of the conversion of the cytoprotective autophagy induced by radiation alone to a novel cytostatic form of autophagy by the combination of 1,25-D3or EB 1089 with radiation. While both pharmacological and genetic suppression of autophagy or inhibition of AMPK phosphorylation sensitized the NSCLC cells to radiation alone, inhibition of the cytostatic autophagy induced by the combination treatment reversed sensitization. Evidence for selectivity was provided by lack of radiosensitization in normal human bronchial cells and cardiomyocytes. Taken together, these studies have identified a unique cytostatic function of autophagy that appears to be mediated by VDR, TP53, and possibly AMPK in the promotion of an enhanced response to radiation by 1,25-D3and EB 1089 in NSCLC.

This paper discusses the effects of azimuthal angles on two-, three-, and four-beam laser interference. In two- or three-beam laser interference, periodic surface structures of lines or dots were obtained. In four-beam laser interference with the polarization mode of TE–TM–TE–TM, the modulation in a particular direction was formed and calculated. In the work, a He–Ne laser system was used to simulate two-, three-, and four-beam laser interference, and the interference pattern was detected by a CCD. A high-power Nd:YAG laser interference lithography system was set up to pattern silicon wafers. In the experiments, one azimuthal angle was changed every time to form interference patterns when polarization states were fixed and incident angles were equal. The experimental results have shown that the azimuthal angle affects the periods and feature sizes of the interference patterns and the fabricated surface structures, which are in accordance with the theoretical and computer simulation results.

Exposure of MCF-7 breast tumor cells or HCT-116 colon carcinoma cells to clinically relevant concentrations of doxorubicin (Adriamycin; Farmitalia Research Laboratories, Milan, Italy) or camptothecin results in both autophagy and senescence. To determine whether autophagy is required for chemotherapy-induced senescence, reactive oxygen generation induced by Adriamycin was suppressed by N-acetyl cysteine and glutathione, and the induction of ataxia telangiectasia mutated, p53, and p21 was modulated pharmacologically and/or genetically. In all cases, autophagy and senescence were collaterally suppressed. The close association between autophagy and senescence indicated by these experiments reflects their collateral regulation via common signaling pathways. The potential relationship between autophagy and senescence was further examined through pharmacologic inhibition of autophagy with chloroquine and 3-methyl-adenine and genetic ablation of the autophagy-related genes ATG5 and ATG7. However, inhibition of autophagy by pharmacological and genetic approaches could not entirely abrogate the senescence response, which was only reduced and/or delayed. Taken together, our findings suggest that autophagy and senescence tend to occur in parallel, and furthermore that autophagy accelerates the development of the senescent phenotype. However, these responses are not inexorably linked or interdependent, as senescence can occur when autophagy is abrogated.

In MCF-7 breast tumor cells, ionizing radiation promoted autophagy that was cytoprotective; pharmacological or genetic interference with autophagy induced by radiation resulted in growth suppression and/or cell killing (primarily by apoptosis). The hormonally active form of vitamin D, 1,25D3, also promoted autophagy in irradiated MCF-7 cells, sensitized the cells to radiation and suppressed the proliferative recovery that occurs after radiation alone. 1,25D3enhanced radiosensitivity and promoted autophagy in MCF-7 cells that overexpress Her-2/neu as well as in p53 mutant Hs578t breast tumor cells. In contrast, 1,25D3failed to alter radiosensitivity or promote autophagy in the BT474 breast tumor cell line with low-level expression of the vitamin D receptor. Enhancement of MCF-7 cell sensitivity to radiation by 1,25D3was not attenuated by a genetic block to autophagy due largely to the promotion of apoptosis via the collateral suppression of protective autophagy. However, MCF-7 cells were protected from the combination of 1,25D3with radiation using a concentration of chloroquine that produced minimal sensitization to radiation alone. The current studies are consistent with the premise that while autophagy mediates a cytoprotective function in irradiated breast tumor cells, promotion of autophagy can also confer radiosensitivity by vitamin D (1,25D3). As both cytoprotective and cytotoxic autophagy can apparently be expressed in the same experimental system in response to radiation, this type of model could be utilized to distinguish biochemical, molecular and/or functional differences in these dual functions of autophagy.

Abstract: Calcitriol or 1,25-dihydroxyvitamin D3, the hormonally active form of vitamin D, as well as vitamin D analogs, has been shown to increase sensitivity to ionizing radiation in breast tumor cells. The current studies indicate that the combination of 1,25-dihydroxyvitamin D3 with radiation appears to kill p53 wild-type, estrogen receptor-positive ZR-75-1 breast tumor cells through autophagy. Minimal apoptosis was observed based on cell morphology by DAPI and TUNEL staining, annexin/PI analysis, caspase-3, and PARP cleavage as well as cell cycle analysis. Induction of autophagy was indicated by increased acridine orange staining, RFP-LC3 redistribution, and detection of autophagic vesicles by electron microscopy, while autophagic flux was monitored based on p62 degradation. The autophagy inhibitors, chloroquine and bafilomycin A1, as well as genetic suppression of the autophagic signaling proteins Atg5 or Atg 7 attenuated the impact of the combination treatment of 1,25 D3 with radiation. In contrast to autophagy mediating the effects of the combination treatment, the autophagy induced by radiation alone was apparently cytoprotective in that either pharmacological or genetic inhibition increased sensitivity to radiation. These studies support the potential utility of vitamin D for improving the impact of radiation for breast cancer therapy, support the feasibility of combining chloroquine with radiation for the treatment of breast cancer, and demonstrate the existence of an “autophagic switch” from cytoprotective autophagy with radiation alone to cytotoxic autophagy with the 1,25 D3–radiation combination.

Abstract: Our previous study suggests that cytochrome P-450 carbon 17α-hydroxylase/17,20-lyase (P450c17α) correlated with the overproduction of aldosterone in aldosterone-producing adenoma (APA) and idiopathic hyperaldosteronism (IHA) in patients with primary aldosteronism. To further investigate if cytochrome P-450 cholesterol side-chain cleavage enzyme (P450scc) contributes to the overproduction of aldosterone in APA and IHA and if its mRNA expression differs in APA and IHA in patients with primary aldosteronism, we studied the expression of P450scc mRNA in APA and idiopathic hyperplastic nodules. Total RNA was extracted from APA of eight patients diagnosed as APA, idiopathic hyperplastic nodules of four patients diagnosed as IHA, seven normal adrenal glands and one normal muscle tissue. P450scc mRNA was examined by Northern blot analysis. No significant difference in P450scc mRNA was found among normal adrenal gland, APA or idiopathic hyperplastic nodules (P > 0.05). These results suggest that P450scc contributes little to the overproduction of aldosterone in APA and IHA and cannot be considered as a marker to differentiate between them in patients with primary aldosteronism.

It is believed that the growth of local massive black holes was dominated by accretion during quasar phases, while a fraction of the local black hole mass was accumulated through accreting gases at very low rates. We derive the black hole mass density as a function of redshift with the bolometric luminosity function of active galactic nuclei (AGNs) assuming that massive black holes grew via accreting the circumnuclear gases, in which the derived black hole mass density is required to match the measured local black hole mass density at z = 0. Advection-dominated accretion flows (ADAFs) are supposed to be present in low-luminosity AGNs/normal galaxies, which are very hot and radiate mostly in the hard X-ray band. Most of the X-ray background (XRB) is contributed by bright AGNs, and a variety of AGN population synthesis models were developed to model the observed XRB in the last two decades. Based on our derived black hole mass density, we calculate the contribution to the XRB from the ADAFs in faint AGNs/normal galaxies with a given Eddington ratio distribution, which is mostly in the hard X-ray energy band with an energy peak at [?]200 keV. The growth of massive black holes during the ADAF phase can therefore be constrained with the observed XRB. Combining an AGN population synthesis model with our results, we find that the fitting on the observed XRB, especially at the hard X-ray energy band with [?]100 keV, is improved provided the contribution of the ADAFs in low-luminosity AGNs/normal galaxies is properly included. It is found that less than [?]15% of local massive black hole mass density was accreted during ADAF phases. We suggest that more accurate measurements of the XRB in the energy band with [?]100 keV in the future may help constrain the growth of massive black holes at their late stage. We also calculate their contribution to the extragalactic g-ray background (EGRB), and find that less than [?]1% of the observed EGRB is contributed by the ADAFs in these faint sources.

A bystander effect typically refers to the death, altered growth, or damage of cells that have not directly received chemotherapy or irradiation. Cancer cells derived from solid tumors readily undergo senescence in response to chemotherapeutic agents, prompting us to test for the existence of a senescence bystander effect. MCF-7 breast cancer cells were acutely exposed to Adriamycin to trigger senescence. Naïve MCF-7 cells, when cultured in conditioned media from senescent breast cancer cells, growth arrested despite mitogenic stimulation and exhibited SA -β-galactosidase activity, an enlarged cell size, and stable upregulation of p21WAF1 protein, collectively indicating a senescent state. In contrast, HCT-116 colon cancer cells, which also undergo p53-mediated senescence in response to acute AdR, did not undergo growth inhibition or senescence when cultured with conditioned media from senescent HCT-116 cells. Reciprocal experiments indicated that naïve HCT-116 cells are susceptible to the growth inhibitory effects of a breast cancer-derived mediator, which is independent of residual drug in conditioned media. Our study reveals a novel action of Adriamycin, which may contribute to its potent anti-breast cancer activity and lead to the discovery of additional therapeutic targets for the exploitation of a senescence bystander effect.

Direct experimental evidence implicates telomere erosion as a primary cause of cellular senescence. Using a well characterized model system for breast cancer, we define here the molecular and cellular consequences of adriamycin treatment in breast tumor cells. Cells acutely exposed to adriamycin exhibited an increase in p53 activity, a decline in telomerase activity, and a dramatic increase in beta-galactosidase, a marker of senescence. Inactivation of wild-type p53 resulted in a transition of the cellular response to adriamycin treatment from replicative senescence to delayed apoptosis, demonstrating that p53 plays an integral role in the fate of breast tumor cells treated with DNA-damaging agents. Stable introduction of hTERT, the catalytic protein component of telomerase, into MCF-7 cells caused an increase in telomerase activity and telomere length. Treatment of MCF-7-hTERT cells with adriamycin produced an identical senescence response as controls without signs of telomere shortening, indicating that the senescence after treatment is telomere length-independent. However, we found that exposure to adriamycin resulted in an overrepresentation of cytogenetic changes involving telomeres, showing an altered telomere state induced by adriamycin is probably a causal factor leading to the senescence phenotype. To our knowledge, these data are the first to demonstrate that the mechanism of adriamycin-induced senescence is dependent on both functional p53 and telomere dysfunction rather than overall shortening.

AbstractThis study introduced the use of instructional technology (primarily Internet) into educational foundation courses and examined the impact upon students' perception of instructional technology, their research skills, and their learning in each course. The overall findings yielded positive and statistically significant results for an integrated approach to instructional technology in educational foundations courses. While utilizing the Internet as a research tool, students were able to improve their perception of instructional technology in terms of their confidence and comfort levels, the frequency of their use of computers, and their views on instructional technology as a teaching tool.

AbstractThis research studies the effectiveness and impact of the use of an alternative evaluation tool for group work in teacher education courses. It shows that as a newly developed alternative evaluation for group work, the tool has displayed positive results and effectiveness in promoting students' learning in the social foundation courses and in their professional and personal development. The merits of this alternative evaluation reside in facilitating higher motivation, participation, critical thinking, and application. More importantly, it fosters a democratic and constructive environment and allows students to develop their professional thinking, knowledge, and skills through direct experience. The results of this study also point out the issues and concerns for further study.

If the QCD axion is a significant component of dark matter, and if the Universe was once hotter than a few hundred MeV, the axion relic abundance depends on the function χ(T), the temperature-dependent topological susceptibility. Uncertainties in this quantity induce uncertainties in the axion mass as a function of the relic density, or vice versa. At high temperatures, theoretical uncertainties enter through the dilute instanton gas computation, while in the intermediate and strong coupling regime, only lattice QCD can determine χ(T) precisely. We reassess the uncertainty on the instanton contribution, arguing that it amounts to less than 20% in the effective action, or a factor of 20 in χ at T = 1.5 GeV. We then combine the instanton uncertainty with a range of models for χ(T) at intermediate temperatures and determine the impact on the axion relic density. We find that for a given relic density and initial misalignment angle, the combined uncertainty amounts to a factor of 2-3 in the zero-temperature axion mass. [ABSTRACT FROM AUTHOR]