FoxM1B transcriptionally regulates vascular endothelial growth factor expression and promotes the angiogenesis and growth of glioma cells.

We previously found that FoxM1B is overexpressed in human glioblastomas and that forced FoxM1B expression in anaplastic astrocytoma cells leads to the formation of highly angiogenic glioblastoma in nude mice. However, the molecular mechanisms by which FoxM1B enhances glioma angiogenesis are currently unknown. In this study, we found that vascular endothelial growth factor (VEGF) is a direct transcriptional target of FoxM1B. FoxM1B overexpression increased VEGF expression, whereas blockade of FoxM1 expression suppressed VEGF expression in glioma cells. Transfection of FoxM1 into glioma cells directly activated the VEGF promoter, and inhibition of FoxM1 expression by FoxM1 siRNA suppressed VEGF promoter activation. We identified two FoxM1-binding sites in the VEGF promoter that specifically bound to the FoxM1 protein. Mutation of these FoxM1-binding sites significantly attenuated VEGF promoter activity. Furthermore, FoxM1 overexpression increased and inhibition of FoxM1 expression suppressed the angiogenic ability of glioma cells. Finally, an immunohistochemical analysis of 59 human glioblastoma specimens also showed a significant correlation between FoxM1 overexpression and elevated VEGF expression. Our findings provide both clinical and mechanistic evidence that FoxM1 contributes to glioma progression by enhancing VEGF gene transcription and thus tumor angiogenesis

Association of antioxidants use with the risk of dementia among community-dwelling adults in the United Kingdom biobank

BackgroundData regarding the association between antioxidant supplementation and incident dementia are limited.MethodsWe included 494,632 adults (54.5% females) aged 40–71 years at baseline from the United Kingdom Biobank in the final analysis. Incident dementia was ascertained using hospital inpatient and death records up to January 2021.ResultsOver a median follow-up of 11.9 years, 7,128 new cases of all-cause dementia, 2,772 cases of Alzheimer’s disease, and 1,397 cases of vascular dementia were recorded. The hazard ratio (95% CI) for incident dementia associated with zinc supplementation was 0.84 (0.74–0.96), and the association remained significant after adjusting for all confounders (0.84 (0.74–0.96)). In the full model, zinc supplementation was associated with a reduced risk of Alzheimer’s disease [HR (95% CI): 0.71 (0.57–0.88)]. There was no significant association between zinc supplementation and the risk of vascular dementia. No significant associations with incident dementia were observed for other antioxidant supplementation. The association between zinc supplementation and incident dementia was significant among individuals with [HR (95% CI): 0.34 (0.15–0.77)] and without cataract [0.87 (0.77–0.99)] but it was stronger among those with cataract (p value for interaction = 0.0271).ConclusionOur findings suggest that zinc supplementation may help reduce the risk of all-cause dementia and Alzheimer’s disease in middle-aged or older adults, especially among those with cataracts

Safety of Spectacles for Children's Vision: A Cluster-Randomized Controlled Trial.

PURPOSE: To study safety of children's glasses in rural China, where fear that glasses harm vision is an important barrier for families and policy makers. DESIGN: Exploratory analysis from a cluster-randomized, investigator-masked, controlled trial. METHODS: Among primary schools (n = 252) in western China, children were randomized by school to 1 of 3 interventions: free glasses provided in class, vouchers for free glasses at a local facility, or glasses prescriptions only (Control group). The main outcome of this analysis is uncorrected visual acuity after 8 months, adjusted for baseline acuity. RESULTS: Among 19 934 children randomly selected for screening, 5852 myopic (spherical equivalent refractive error <=-0.5 diopters) eyes cif 3001 children (14.7%, mean age 10.5 years) had VA <= 6/12 without glasses correctable to >6/12 with glasses, and were eligible. Among these, 1903 (32.5%), 1798 (30.7%), and 2151 (36.8%) were randomized to Control, Voucher, and Free Glasses, respectively. Intention-to-treat analyses were performed on all 1831 (96.2%), 1699 (94.5%), and 2007 (93.3%) eyes of children with follow-up in Control, Voucher, and Free Glasses groups. Final visual acuity for eyes of children in the treatment groups (Free Glasses and Voucher) was significantly better than for Control children, adjusting only for baseline visual acuity (difference of 0.023 logMAR units [0.23 vision chart lines, 95% CI: 0.03, 0.43]) or for other baseline factors as well (0.025 logMAR units [0.25 lines, 95% CI 0.04, 0.45]). CONCLUSION: We found no evidence that spectacles promote decline in uncorrected vision with aging among children. (C) 2015 by Elsevier Inc. All rights reserved.ONESIGHT (MASON, OHIO); LUXOTTICA-CHINA (SHANGHAI); ESSILOR-CHINA (SHANGHAI); CREDIT LYONAIS Securities Asia (Asia Pacific Markets; Hong Kong); Charity Aid Foundation (Sydney); Chinese government; Ulverscroft Foundation; OneSight, Luxottica-China; Essilor-ChinaSCI(E)[email protected]

FoxM1B regulates NEDD4-1 expression, leading to cellular transformation and full malignant phenotype in immortalized human astrocytes.

Our recent studies have shown that the FoxM1B transcription factor is overexpressed in human glioma tissues and that the level of its expression correlates directly with glioma grade. However, whether FoxM1B plays a role in the early development of glioma (i.e., in transformation) is unknown. In this study, we found that the FoxM1B molecule causes cellular transformation and tumor formation in normal human astrocytes (NHA) immortalized by p53 and pRB inhibition. Moreover, brain tumors that arose from intracranial injection of FoxM1B-expressing immortalized NHAs displayed glioblastoma multiforme (GBM) phenotypes, suggesting that FoxM1B overexpression in immortalized NHAs not only transforms the cells but also leads to GBM formation. Mechanistically, our results showed that overexpression of FoxM1B upregulated NEDD4-1, an E3 ligase that mediates the degradation and downregulation of phosphatase and tensin homologue (PTEN) in multiple cell lines. Decreased PTEN in turn resulted in the hyperactivation of Akt, which led to phosphorylation and cytoplasmic retention of FoxO3a. Blocking Akt activation with phosphoinositide 3-kinase/Akt inhibitors inhibited the FoxM1B-induced transformation of immortalized NHAs. Furthermore, overexpression of FoxM1B in immortalized NHAs increased the expression of survivin, cyclin D1, and cyclin E, which are important molecules for tumor growth. Collectively, these results indicate that overexpression of FoxM1B, in cooperation with p53 and pRB inhibition in NHA cells, promotes astrocyte transformation and GBM formation through multiple mechanisms

Regional Geological Survey of Hanggai, Xianxia and Chuancun, Zhejiang Province in China

This Open Access book introduces readers to the regional geology of Hanggai, Xianxia and Chuancun, the area between China's northern Zhejiang Province and southern Anhui Province and explores the strata, magmatic rocks and tectonic structures in 1:50,000 scale geological maps. Based on studies of multiple stratigraphic divisions, the standard stratigraphic section of the upper Ordovician Hirnantian in the lower Yangtze region is established, revealing for the first time numerous “Burgess Shale-type” sponge fossils in Hirnantian strata and identifying 10 grapholite fossil belts and various fossil categories, including chitin, trilobites, gastropods, brachiopods, and cephalopods. Moreover, the book identifies for the first time Late Ordovician volcanic events in northern Zhejiang province. The work represents a major contribution to research on Paleozoic strata in the Lower Yangtze region, and sheds new light on understanding the Hirnantian glacial event and biological extinction event in South China by providing a high-precision time scale. In addition, the book opens an important avenue for future research on sponge evolution after the Cambrian life explosion. As such, it offers a unique and valuable asset for researchers and graduate students alike

DiVA -Digitala Vetenskapliga Arkivet

IR spectra, TG analysis and x-ray diffraction showed a solvated structure for the as-grown C 60 microtubes. Through a gentle heat-treatment in vacuum, pure C 60 microtubes with single crystalline fcc structure were obtained after the elimination of solvents. It is suggested that the C 60 microtubes form through self-assembly from several individual C 60 nanorods

Оценка помехоустойчивости метода диагностики роторных узлов машин в зависимости от условий предварительной фильтрации вибрационного сигнала

Произведено сравнение двух способов предварительной фильтрации при оценке технического состояния роторных узлов машин по методу анализа спектра огибающей вибрационного сигнала. Определена помехоустойчивость метода при воздействии широкополосных шумов.ditions of Prefiltration of the Vibration Signal The comparison of the two methods of prefiltration during evaluation of technical condition of the machine rotor units is performed in the paper using the method of the analysis of the spectrum of the vibration waveform envelope. Noise stability of the method under the action of broadband noise is determined

A preexisting rare PIK3CA e545k subpopulation confers clinical resistance to MEK plus CDK4/6 inhibition in NRAS melanoma and is dependent on S6K1 signaling

Combined MEK and CDK4/6 inhibition (MEKi + CDK4i) has shown promising clinical outcomes in patients with NRAS- mutant melanoma. Here, we interrogated longitudinal biopsies from a patient who initially responded to MEKi + CDK4i therapy but subsequently developed resistance. Whole-exome sequencing and functional validation identified an acquired PIK3CA E545K mutation as conferring drug resistance. We demonstrate that PIK3CA E545K preexisted in a rare subpopulation that was missed by both clinical and research testing, but was revealed upon multiregion sampling due to PIK3CA E545K being nonuniformly distributed. This resistant population rapidly expanded after the initiation of MEKi + CDK4i therapy and persisted in all successive samples even after immune checkpoint therapy and distant metastasis. Functional studies identified activated S6K1 as both a key marker and specific therapeutic vulnerability downstream of PIK3CA E545K -induced resistance. These results demonstrate that difficult-to-detect preexisting resistance mutations may exist more often than previously appreciated and also posit S6K1 as a common downstream therapeutic nexus for the MAPK, CDK4/6, and PI3K pathways. SIGNIFICANCE: We report the first characterization of clinical acquired resistance to MEKi + CDK4i, identifying a rare preexisting PIK3CA E545K subpopulation that expands upon therapy and exhibits drug resistance. We suggest that single-region pretreatment biopsy is insufficient to detect rare, spatially segregated drug-resistant subclones. Inhibition of S6K1 is able to resensitize PIK3CA E545K -expressing NRAS-mutant melanoma cells to MEKi + CDK4i. © 2018 AAC

Расчет распределения примеси и потоков ее миграции у клиновидного двойника на основании макроскопической дислокационной модели

High pressure Raman, IR and X-ray diffraction (XRD) studies have been carried out on C-70(Fe(C5H5)(2))(2) (hereafter, "C-70(Fc)(2)") sheets. Theoretical calculation is further used to analyze the Electron Localization Function (ELF) and charge transfer in the crystal and thus to understand the transformation of C-70(Fc)(2) under pressure. Our results show that even at room temperature dimeric phase and one dimensional (1D) polymer phase of C-70 molecules can be formed at about 3 and 8 GPa, respectively. The polymerization is found to be reversible Upon decompression and the reversibility is related to the pressure-tuned charge transfer, as well as the overridden steric repulsion of counter ions. According to the layered structure of the intercalated ferrocene molecules formed in the crystal, we suggest that ferrocene acts as not only a spacer to restrict the polymerization of C-70 molecules within a layer, but also as charge reservoir to tune the polymerization process. This supplies a possible way for us to design the polymerization of fullerenes at suitable conditions