Hypoxia plays a critical role during the evolution of malignant cells and tumour microenvironment (TME).Tumour-derived exosomes contain informative microRNAs involved in the interaction of cancer and ...stromal cells, thus contributing to tissue remodelling of tumour microenvironment. This study aims to clarify how hypoxia affects tumour angiogenesis through exosomes shed from lung cancer cells. Lung cancer cells produce more exosomes under hypoxic conditions than do parental cells under normoxic conditions. miR-23a was significantly upregulated in exosomes from lung cancer under hypoxic conditions. Exosomal miR-23a directly suppressed its target prolyl hydroxylase 1 and 2 (PHD1 and 2), leading to the accumulation of hypoxia-inducible factor-1 α (HIF-1 α) in endothelial cells. Consequently, hypoxic lung cancer cells enhanced angiogenesis by exosomes derived from hypoxic cancer under both normoxic and hypoxic conditions. In addition, exosomal miR-23a also inhibits tight junction protein ZO-1, thereby increasing vascular permeability and cancer transendothelial migration. Inhibition of miR-23a by inhibitor administration decreased angiogenesis and tumour growth in a mouse model. Furthermore, elevated levels of circulating miR-23a are found in the sera of lung cancer patients, and miR-23a levels are positively correlated with proangiogenic activities. Taken together, our study reveals the clinical relevance and prognostic value of cancer-derived exosomal miR-23a under hypoxic conditions, and investigates a unique intercellular communication, mediated by cancer-derived exosomes, which modulates tumour vasculature.
Abstract
In this first paper in the SUPER GOODS series on powerfully star-forming galaxies in the two GOODS fields, we present a deep SCUBA-2 survey of the GOODS-N at both 850 and 450
μ
m (central ...rms noise of 0.28 mJy and 2.6 mJy, respectively). In the central region, the 850
μ
m observations cover the GOODS-N to near the confusion limit of ∼1.65 mJy, while over a wider 450 arcmin
2
region—well complemented by
Herschel
far-infrared imaging—they have a median
limit of 3.5 mJy. We present
catalogs of 186 850
μ
m and 31 450
μ
m selected sources. We use interferometric observations from the Submillimeter Array (SMA) and the Karl G. Jansky Very Large Array (VLA) to obtain precise positions for 114 SCUBA-2 sources (28 from the SMA, all of which are also VLA sources). We present new spectroscopic redshifts and include all existing spectroscopic or photometric redshifts. We also compare redshifts estimated using the 20 cm/850
μ
m and the 250 cm/850
μ
m flux ratios. We show that the redshift distribution increases with increasing flux, and we parameterize the dependence. We compute the star formation history and the star formation rate (SFR) density distribution functions in various redshift intervals, finding that they reach a peak at
before dropping to higher redshifts. We show that the number density per unit volume of
galaxies measured from the SCUBA-2 sample does not change much relative to that of lower SFR galaxies from UV selected samples over
, suggesting that, apart from changes in the normalization, the shape in the number density as a function of SFR is invariant over this redshift interval.
Lung cancer is the leading cause of cancer death worldwide, with metastasis underlying majority of related deaths. Angiomotin (AMOT), a scaffold protein, has been shown to interact with oncogenic ...Yes-associated protein/transcriptional co-activator with a PDZ-binding motif (YAP/TAZ) proteins, suggesting a potential role in tumor progression. However, the functional role of AMOT in lung cancer remains unknown. This study aimed to identify the patho-physiological characteristics of AMOT in lung cancer progression. Results revealed that AMOT expression was significantly decreased in clinical lung cancer specimens. Knockdown of AMOT in a low metastatic CL1-0 lung cancer cell line initiated cancer proliferation, migration, invasion and epithelial-mesenchymal transition. The trigger of cancer progression caused by AMOT loss was transduced by decreased cytoplasmic sequestration and increased nuclear translocation of oncogenic co-activators YAP/TAZ, leading to increased expression of the growth factor, Cyr61. Tumor promotion by AMOT knockdown was reversed when YAP/TAZ or Cyr61 was absent. Further, AMOT knockdown increased the growth and spread of Lewis lung carcinoma in vivo. These findings suggest that AMOT is a crucial suppressor of lung cancer metastasis and highlight its critical role as a tumor suppressor and its potential as a prognostic biomarker and therapeutic target for lung cancer.
Complex topological configurations are fertile ground for exploring emergent phenomena and exotic phases in condensed-matter physics. For example, the recent discovery of polarization vortices and ...their associated complex-phase coexistence and response under applied electric fields in superlattices of (PbTiO
)
/(SrTiO
)
suggests the presence of a complex, multi-dimensional system capable of interesting physical responses, such as chirality, negative capacitance and large piezo-electric responses
. Here, by varying epitaxial constraints, we discover room-temperature polar-skyrmion bubbles in a lead titanate layer confined by strontium titanate layers, which are imaged by atomic-resolution scanning transmission electron microscopy. Phase-field modelling and second-principles calculations reveal that the polar-skyrmion bubbles have a skyrmion number of +1, and resonant soft-X-ray diffraction experiments show circular dichroism, confirming chirality. Such nanometre-scale polar-skyrmion bubbles are the electric analogues of magnetic skyrmions, and could contribute to the advancement of ferroelectrics towards functionalities incorporating emergent chirality and electrically controllable negative capacitance.
Aim
To investigate whether the timing of root canal treatment (primary aim) or other endodontic parameters (secondary aim) is associated with the survival probability of autotransplanted third ...molars, using a nationwide population‐based database.
Methodology
A total of 1811 third molars autotransplanted between 2000 and 2013 met the inclusion criteria and were followed until the end of 2016. The teeth were classified into three groups on the basis of timing between root canal treatment and the autotransplantation: preoperative, extraoral and postoperative treatment groups. Univariate and multivariate Cox proportional hazards models were used to estimate the association between the timing of root canal treatment and the risk of tooth extraction after autotransplantation.
Results
Of the 1811 autotransplanted third molars, 462 were extracted, yielding a 17‐year survival probability of 0.578. The survival probability of autotransplanted teeth that received postoperative root fillings after 17 years was 0.583, which was significantly higher than the 0.434 and 0.566 for teeth that received preoperative and extraoral root fillings, respectively (P = 0.0013). After adjustment for potential confounding factors, teeth that received postoperative root fillings were associated with a significantly lower tooth extraction hazard ratio (HR) compared with those that received extraoral root fillings (adjusted HR, 1.43; 95% confidence interval CI, 1.14–1.78) and those that received preoperative root fillings (adjusted HR, 2.13; 95% CI, 1.19–3.82). Furthermore, the use of a rubber dam during postoperative root filling was associated with a significantly lower extraction rate after autotransplantation (adjusted HR, 0.54; 95% CI, 0.43–0.69).
Conclusions
Postoperative root canal treatment resulted in a significantly lower extraction rate than did preoperative or extraoral root canal treatment amongst autotransplanted third molars during a mean follow‐up period of 8.33 years. Rubber dam use is recommended during postoperative root canal treatment to improve the outcomes of autotransplantation.
The skeleton is the most common metastatic site for breast cancer, with bone metastasis causing pain as well as risk of pathological fractures. Interaction between tumors and the bone ...microenvironment creates a vicious cycle that accelerates both bone destruction and cancer progression. This study is the first to analyze the soluble factors secreted by breast tumor-associated osteoblasts (TAOBs), which are responsible for promoting cancer progression. The addition of CXCL5 (chemokine (C-X-C motif) ligand 5), present in large amounts in TAOB-condition medium (TAOB-CM), mimicked the inductive effect of TAOB-CM on breast cancer epithelial-mesenchymal transition, migration and invasion. In contrast, inhibition of CXCL5 in OBs decreased TAOB-mediated cancer progression. Inducement of MCF-7 and MDA-MB-231 cancer progression by TAOB-derived CXCL5 is associated with increased Raf/MEK/ERK activation, and mitogen- and stress-activated protein kinase 1 (MSK1) and Elk-1 phosphorylation, as well as Snail upregulation. Activation of Elk-1 facilitates recruitment of phosphorylated MSK1, which in turn enhances histone H3 acetylation and phosphorylation (serine 10) of Snail promoter, resulting in Snail enhancement and E-cadherin downregulation. Moreover, mice treated with anti-CXCL5 antibodies showed decreased metastasis of 4T1 breast cancer cells. Our study suggests that inhibition of CXCL5-mediated ERK/Snail signaling is an attractive therapeutic target for treating metastases in breast cancer patients.
We analyze the >4 sources in the most sensitive 100 arcmin2 area (rms < 0.56 mJy) of a SCUBA-2 850 m survey of the GOODS-S and present the 75 band-7 ALMA sources (>4.5 ) obtained from high-resolution ...interferometric follow-up observations. The raw SCUBA-2 >4 limit is fainter than 2.25 mJy throughout this region, and deboosting corrections would lower this further. Of the 53 SCUBA-2 sources in this sample, only five have no ALMA detections, while 13% (68% confidence range 7%-19%) have multiple ALMA counterparts. Color-based high-redshift dusty galaxy selection techniques find at most 55% of the total ALMA sample. In addition to using literature spectroscopic and optical/near-infrared photometric redshifts, we estimate far infrared photometric redshifts based on an Arp 220 template. We identify seven z 4 candidates. We see the expected decline with redshift of the 4.5 and 24 m to 850 m flux ratios, confirming these as good diagnostics of z 4 candidates. We visually classify 52 ALMA sources, finding 44% (68% confidence range 35%-53%) to be apparent mergers. We calculate rest-frame 2-8 keV and 8-28 keV luminosities using the 7 Ms Chandra X-ray image. Nearly all of the ALMA sources detected at 0.5-2 keV are consistent with a known X-ray luminosity to 850 m flux relation for star-forming galaxies, while most of those detected at 2-7 keV are moderate-luminosity AGNs that lie just above the 2-7 keV detection threshold. The latter largely have substantial obscurations of cm−2, but two of the high-redshift candidates may even be Compton thick.
Background: Mutations of the epidermal growth factor receptor (EGFR) gene in non-small-cell lung cancer (NSCLC) patients predict the patients who will respond to EGFR tyrosine kinase inhibitor (TKI) ...treatment. A recent study has suggested that 33% of NSCLC showed primary tumor/metastasis discordance of EGFR expression by immunohistochemistry analysis. We intended to find out whether the EGFR mutations of primary lung cancers are concordant to that of corresponding metastatic tumors. Materials and methods: We analyzed EGFR exons 18–21 from paired primary and metastatic tumors in 67 lung cancer patients who had not received TKI before tissues were sampled. Results: Using the direct sequencing method, 9 of 18 (50%) patients with EGFR mutation-positive primary lung tumors had lost the mutations in metastases. For 26 patients who were EGFR mutation positive in the metastatic tumors, 17 (65%) were negative in the primary tumors. We analyzed these paired tissues with discrepant EGFR mutations by the Scorpion Amplified Refractory Mutation System assay. Finally, the discordant rate reached 27% (18 of 67 cases). Conclusion: EGFR mutations in primary lung tumors do not always reflect the same situation in metastases. Analysis of EGFR mutations in the primary lung tumor would be inadequate for planning the use of TKI for advanced NSCLC.
The detection of CTCs prior to and during therapy is an independent and strong prognostic marker, and it is predictive of poor treatment outcome. A major challenge is that different technologies are ...available for isolation and characterization of CTCs in peripheral blood (PB). We compare the CellSearch system and AdnaTest BreastCancer Select/Detect, to evaluate the extent that these assays differ in their ability to detect CTCs in the PB of MBC patients. CTCs in 7.5 ml of PB were isolated and enumerated using the CellSearch, before new treatment. Two cutoff values of ≥2 and ≥5 CTCs/7.5 ml were used. AdnaTest requires 5 ml of PB to detect gene transcripts of tumor markers (GA733‐2, MUC‐1, and HER2) by RT‐PCR. AdnaTest was scored positive if ≥1 of the transcript PCR products for the 3 markers were detected at a concentration ≥0.15 ng/μl. A total of 55 MBC patients were enrolled. 26 (47%) patients were positive for CTCs by the CellSearch (≥2 cutoff), while 20 (36%) were positive (≥5 cutoff). AdnaTest was positive in 29 (53%) with the individual markers being positive in 18% (GA733‐2), 44% (MUC‐1), and 35% (HER2). Overall positive agreement was 73% for CTC≥2 and 69% for CTC≥5. These preliminary data suggest that the AdnaTest has equivalent sensitivity to that of the CellSearch system in detecting 2 or more CTCs. While there is concordance between these 2 methods, the AdnaTest complements the CellSearch system by improving the overall CTC detection rate and permitting the assessment of genomic markers in CTCs.
Directly Placed Restorative Materials Schwendicke, F.; Göstemeyer, G.; Blunck, U. ...
Journal of Dental Research,
06/2016, Letnik:
95, Številka:
6
Book Review, Journal Article
Recenzirano
For restoring cavitated dental lesions, whether carious or not, a large number of material combinations are available. We aimed to systematically review and synthesize data of comparative dental ...restorative trials. A systematic review was performed. Randomized controlled trials published between 2005 and 2015 were included that compared the survival of ≥2 restorative and/or adhesive materials (i.e., no need for restorative reintervention). Pairwise and Bayesian network meta-analyses were performed, with separate evaluations for cervical cavitated lesions and load-bearing posterior cavitated lesions in permanent and primary teeth. A total of 11,070 restorations (5,330 cervical, 5,740 load bearing) had been placed in 3,633 patients in the included trials. Thirty-six trials investigated restoration of cervical lesions (all in permanent teeth) and 36 of load-bearing lesions (8 in primary and 28 in permanent teeth). Resin-modified glass ionomer cements had the highest chance of survival in cervical cavitated lesions; composites or compomers placed via 2-step self-etch and 3-step etch-and-rinse adhesives were ranked next. Restorations placed with 2-step etch-and-rinse or 1-step self-etch adhesives performed worst. For load-bearing restorations, conventional composites had the highest probability of survival, while siloranes were found least suitable. Ambiguity remains regarding which adhesive strategy to use in load-bearing cavitated lesions. Most studies showed high risk of bias, and several comparisons were prone for publication bias. If prioritized for survival, resin-modified glass ionomer cements might be recommended to restore cervical lesions. For load-bearing ones, conventional or bulk fill composites seem most suitable. The available evidence is quantitatively and qualitatively insufficient for further recommendations, especially with regard to adhesive strategies in posterior load-bearing situations. Moreover, different material classifications might yield different findings on the same materials. Future trials should aim for sufficient power, longer follow-up times, and high internal validity to prove or refute differences between certain material combinations. An agreed material classification for future syntheses is desirable.
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