Dickkopf-1 (DKK1) promotes tumor growth via Akt-phosphorylation and independently of Wnt-axis in Barrett’s associated esophageal adenocarcinoma

Esophageal adenocarcinoma (EAC) is still associated with poor prognosis, despite modern multi-modal therapies. New molecular markers, which control cell cycle and promote lymph node metastases or tumor growth, may introduce novel target therapies. Dickkopf-1 (DKK1) is a secreted glycoprotein that blocks the oncogenic Wnt/β-catenin signaling and its aberrant expression has been observed in many malignancies, including EAC. In this study, we investigated the biological role of DKK1 in EAC. Analysis of DKK1 and active β-catenin expression in human esophageal tissues confirmed a simultaneous DKK1-overexpression together with aberrant activation of β-catenin signaling in EAC in comparison with Barrett’s and healthy mucosa. To elucidate the molecular role of DKK1, the OE33 adenocarcinoma cells, which were found to overexpress DKK1, were subjected to functional and molecular assays following siRNA-mediated DKK1-knockdown. At the functional level, OE33 cell viability, proliferation, migration and invasion were significantly attenuated by the absence of DKK1. At the molecular level, neither DKK1-knockdown nor application of exogenous recombinant DKK1 were found to alter the baseline β-catenin signaling in OE33 cells. However, DKK1-knockdown significantly abrogated downstream Akt-phosphorylation. On the other hand, the Wnt-agonist, Wnt3a, restored the Akt-phorphorylation in the absence of DKK1, without, however, being able to further stimulate β-catenin transcription. These findings suggest that the β-catenin transcriptional activity in EAC is independent of Wnt3a/DKK1 site-of-action and define an oncogenic function for DKK1 in this type of malignancy via distinct activation of Akt-mediated intracellular pathways and independently of Wnt-axis inhibition. Taken together, DKK1 may present a novel therapeutic target in EAC

Non-invasive Amide Proton Transfer Imaging and ZOOM Diffusion-Weighted Imaging in Differentiating Benign and Malignant Thyroid Micronodules

Background: Pre-operative non-invasive differentiation of benign and malignant thyroid nodules is difficult for doctors. This study aims to determine whether amide proton transfer (APT) imaging and zonally oblique multi-slice (ZOOM) diffusion-weighted imaging (DWI) can provide increased accuracy in differentiating benign and malignant thyroid nodules.Methods: This retrospective study was approved by the institutional review board and included 60 thyroid nodules in 50 patients. All of the nodules were classified as malignant (n = 21) or benign (n = 39) based on pathology. It was meaningful to analyze the APT and apparent diffusion coefficient (ADC) values of the two groups by independent t-test to identify the benign and malignant thyroid nodules. The relationship between APT and ZOOM DWI was explored through Pearson correlation analysis. The diagnostic efficacy of APT and ZOOM DWI in determining if thyroid nodules were benign or malignant was compared using receiver operating characteristic (ROC) curve analysis.Results: The mean APTw value of the benign nodules was 2.99 ± 0.79, while that of the malignant nodules was 2.14 ± 0.73. Additionally, there was a significant difference in the APTw values of the two groups (P < 0.05). The mean ADC value of the benign nodules was 1.84 ± 0.41, and was significantly different from that of the malignant nodules, which was 1.21 ± 0.19 (P < 0.05). Scatter point and Pearson test showed a moderate positive correlation between the APT and ADC values (P < 0.05). The ROC curve showed that the area under the curve (AUC) value of ZOOM DWI (AUC = 0.937) was greater than that of APT (AUC = 0.783) (P = 0.028).Conclusion: APT and ZOOM DWI imaging improved the accuracy of distinguishing between benign and malignant thyroid nodules. ZOOM DWI is superior to APTw imaging (Z = 2.198, P < 0.05)

Meteorological Influences on Spatiotemporal Variation of PM2.5 Concentrations in Atmospheric Pollution Transmission Channel Cities of the Beijing–Tianjin–Hebei Region, China

Understanding the spatiotemporal characteristics of PM2.5 concentrations and identifying their associated meteorological factors can provide useful insight for implementing air pollution interventions. In this study, we used daily air quality monitoring data for 28 air pollution transmission channel cities in the Beijing–Tianjin–Hebei region during 2014–2019 to quantify the relative contributions of meteorological factors on spatiotemporal variation in PM2.5 concentration by combining time series and spatial perspectives. The results show that annual mean PM2.5 concentration significantly decreased in 24 of the channel cities from 2014 to 2019, but they all still exceeded the Grade II Chinese Ambient Air Quality Standards (35 μg m−3) in 2019. PM2.5 concentrations exhibited clear spatial agglomeration in the most polluted season, and their spatial pattern changed slightly over time. Meteorological variables accounted for 31.96% of the temporal variation in PM2.5 concentration among the 28 cities during the study period, with minimum temperature and average relative humidity as the most critical factors. Spatially, atmospheric pressure and maximum temperature played a key role in the distribution of PM2.5 concentration in spring and summer, whereas the effect of sunshine hours increased greatly in autumn and winter. These findings highlight the importance of future clean air policy making, but also provide a theoretical support for precise forecasting and prevention of PM2.5 pollution

Correlation between symptoms and cognitive function changes in patients with primary insomnia and pathways in gut microbiota

Background: Primary insomnia (PI) refers to syndromes of difficulty falling asleep, poor sleep quality, early awakening, and difficulty falling asleep after waking up. Although there have been numerous studies, the specific etiology and pathogenesis of PI are still misunderstanding. In recent years, the gut microbiota has been proved to be involved in the metabolism of many mental disorders. But the specific mechanisms of its involvement in PI have not been fully elucidated. This study aims to explore the relationship between the gut microbiota and the symptoms, cognitive function changes in PI. Methods: In this study, the gut microbiota of PI patients and healthy controls was profiled by performing stool 16s rRNA gene sequencing. The co-occurrence network was constructed by using Weight Gene Co-expression Network Analysis (WGCNA) algorithm. The correlation between gut microbiota associated pathways and traits in PI were predicted. Results: WGCNA results demonstrated several Operational Taxonomic Units (OTU) modules are correlated to symptoms. By using PICRUSt2 software, we predicted the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways of microbiota in modules. For instance, sleep efficiency may be correlated with the presence of Insulin signaling pathway, Flavonoid biosynthesis, Ascorbate and aldarate metabolism, Nitrotoluene degradation, Biotin metabolism, RNA polymerase and Chlorocyclohexane and chlorobenzene degradation. Total sleep time may be correlated with the presence of Tyrosine metabolism, Propanoate metabolism, Carbon fixation pathways in prokaryotes, Carotenoid biosynthesis, Systemic lupus erythematosus, Nitrotoluene degradation and Biosynthesis of unsaturated fatty acids. The severity of insomnia may be correlated with Insulin signaling pathway, Flavonoid biosynthesis, Ascorbate and aldarate metabolism, Nitrotoluene degradation, Biotin metabolism and RNA polymerase. Change of name score in Montreal Cognitive Assessment (MoCA) may be correlated with Tyrosine metabolism, Propanoate metabolism, Carbon fixation pathways in prokaryotes, Carotenoid biosynthesis, Systemic lupus erythematosus, Nitrotoluene degradation, Biosynthesis of unsaturated fatty acids, Apoptosis, Steroid hormone biosynthesis, Geraniol degradation, Protein digestion and absorption and Bisphenol degradation in Gut Microbiota (GM). Conclusion: This study revealed the potential relationships between gut microbiota and PI. By using pathway prediction and enrichment analysis, we concluded many metabolic pathways may associated with some important traits of insomnia patients, including sleep efficiency, severe insomnia, total sleep time and change of name score in MoCA. The metabolic pathways include Insulin signaling pathway, Flavonoid biosynthesis, Ascorbate and aldarate metabolism, Nitrotoluene degradation, Biotin metabolism, RNA polymerase and Chlorocyclohexane, chlorobenzene degradation, Tyrosine metabolism, Propanoate metabolism, Carbon fixation pathways in prokaryotes, Carotenoid biosynthesis, Systemic lupus erythematosus, Biosynthesis of unsaturated fatty acids, Apoptosis, Steroid hormone biosynthesis, Geraniol degradation, Protein digestion and absorption and Bisphenol degradation.Our study demonstrated that PI patients demonstrate significant changes in gut microbiota, which will help delineate the relationship between gut microbiota and syndromes of PI

Dickkopf-1 (DKK1) promotes tumor growth via Akt-phosphorylation and independently of Wnt-axis in Barrett’s associated esophageal adenocarcinoma

Esophageal adenocarcinoma (EAC) is still associated with poor prognosis, despite modern multi-modal therapies. New molecular markers, which control cell cycle and promote lymph node metastases or tumor growth, may introduce novel target therapies. Dickkopf-1 (DKK1) is a secreted glycoprotein that blocks the oncogenic Wnt/β-catenin signaling and its aberrant expression has been observed in many malignancies, including EAC. In this study, we investigated the biological role of DKK1 in EAC. Analysis of DKK1 and active β-catenin expression in human esophageal tissues confirmed a simultaneous DKK1-overexpression together with aberrant activation of β-catenin signaling in EAC in comparison with Barrett’s and healthy mucosa. To elucidate the molecular role of DKK1, the OE33 adenocarcinoma cells, which were found to overexpress DKK1, were subjected to functional and molecular assays following siRNA-mediated DKK1-knockdown. At the functional level, OE33 cell viability, proliferation, migration and invasion were significantly attenuated by the absence of DKK1. At the molecular level, neither DKK1-knockdown nor application of exogenous recombinant DKK1 were found to alter the baseline β-catenin signaling in OE33 cells. However, DKK1-knockdown significantly abrogated downstream Akt-phosphorylation. On the other hand, the Wnt-agonist, Wnt3a, restored the Akt-phorphorylation in the absence of DKK1, without, however, being able to further stimulate β-catenin transcription. These findings suggest that the β-catenin transcriptional activity in EAC is independent of Wnt3a/DKK1 site-of-action and define an oncogenic function for DKK1 in this type of malignancy via distinct activation of Akt-mediated intracellular pathways and independently of Wnt-axis inhibition. Taken together, DKK1 may present a novel therapeutic target in EAC