The objectives of this study were to propose a clinical prognostic scoring system applicable for intrahepatic cholangiocarcinoma (ICC) and to evaluate the prognostic validity of the American Joint ...Committee on Cancer (AJCC) 7th edition staging system.
Retrospective univariate and multivariate survival analyses were conducted for 344 patients with ICC who underwent hepatectomy. A simple clinical prognostic scoring system (Fudan score) was developed based on the independent predictors. The prognostic validity was assessed in 74 patients with unresected tumors and compared with the AJCC 6th and 7th edition systems.
In the training set, serum alkaline phosphatase level, carbohydrate antigen 19-9 level, tumor boundary type, tumor size, and number of intrahepatic tumors were independent predictive factors of survival in ICC and were incorporated into the Fudan score. Three hundred forty-four patients were categorized into four subsets with 5-year overall survival rates of 48.6%, 25.6%, 10.3%, and 0.0% for low-, intermediate-, high-, and extremely high-risk groups, respectively. The discriminative ability of the Fudan score was better than that of the AJCC staging system and well applied in the unresected patient set.
A Fudan score based on clinical factors may provide a relatively accurate prognostic prediction for ICC patients regardless of resection status.
Cancer associated fibroblasts (CAFs) are key stroma cells that play dominant roles in tumor progression. However, the CAFs-derived molecular determinants that regulate colorectal cancer (CRC) ...metastasis and chemoresistance have not been fully characterized.
CAFs and NFs were obtained from fresh CRC and adjacent normal tissues. Exosomes were isolated from conditioned medium and serum of CRC patients using ultracentrifugation method and ExoQuick Exosome Precipitation Solution kit, and characterized by transmission electronic microscopy, nanosight and western blot. MicroRNA microarray was employed to identify differentially expressed miRNAs in exosomes secreted by CAFs or NFs. The internalization of exosomes, transfer of miR-92a-3p was observed by immunofluorescence. Boyden chamber migration and invasion, cell counting kit-8, flow cytometry, plate colony formation, sphere formation assays, tail vein injection and primary colon cancer liver metastasis assays were employed to explore the effect of NFs, CAFs and exosomes secreted by them on epithelial-mesenchymal transition, stemness, metastasis and chemotherapy resistance of CRC. Luciferase report assay, real-time qPCR, western blot, immunofluorescence, and immunohistochemistry staining were employed to explore the regulation of CRC metastasis and chemotherapy resistance by miR-92a-3p, FBXW7 and MOAP1.
CAFs promote the stemness, epithelial-mesenchymal transition (EMT), metastasis and chemotherapy resistance of CRC cells. Importantly, CAFs exert their roles by directly transferring exosomes to CRC cells, leading to a significant increase of miR-92a-3p level in CRC cells. Mechanically, increased expression of miR-92a-3p activates Wnt/β-catenin pathway and inhibits mitochondrial apoptosis by directly inhibiting FBXW7 and MOAP1, contributing to cell stemness, EMT, metastasis and 5-FU/L-OHP resistance in CRC. Clinically, miR-92a-3p expression is significantly increased in CRC tissues and negatively correlated with the levels of FBXW7 and MOAP1 in CRC specimens, and high expression of exosomal miR-92a-3p in serum was highly linked with metastasis and chemotherapy resistance in CRC patients.
CAFs secreted exosomes promote metastasis and chemotherapy resistance of CRC. Inhibiting exosomal miR-92a-3p provides an alternative modality for the prediction and treatment of metastasis and chemotherapy resistance in CRC.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
China has implemented a large number of major infrastructure projects (MIPs) over the last three decades. Social responsibility management is crucial for MIPs' sustainable development. What is social ...responsibility of major infrastructure (MIP-SR)? To answer this question, this article proposes the concept and key issues of major infrastructure projects' social responsibility (MIP-SR) and develops a comprehensive conceptual framework for MIP-SR, which covers three dimensions: (i) project life-cycle dynamics; (ii) stakeholder's heterogeneity and (iii) social responsibility interactivity. The three-dimensional framework provides a systematic framework for MIP-SR's academic research and practical implementation, which in turn promotes the sustainable development of MIPs.
•We propose a concept of major infrastructure projects' social responsibility (MIP-SR).•We describe major conflicts in MIP-SR and key issues of MIP-SR.•We develop a three-dimension conceptual framework for MIP-SR.•MIP-SR covers three dimensions: dynamics, heterogeneity, and interactivity.
Ferritic stainless steels have become the candidate materials for interconnects of intermediate temperature solid oxide fuel cell (SOFC). The present issues to be solved urgently for the application ...of ferritic stainless steel interconnects are their rapid increase in contact resistance and Cr poisoning. In the present study, a chloride electrolyte suspension has been developed to electro-deposit a Co–Mn alloy on a type 430 stainless steel, followed by heat treatment at 750 °C in argon and at 800 °C in air to obtain Co–Mn spinel coatings. The experimental results indicate that an adhesive and compact Co–Mn alloy layer can be deposited in the chloride solution. After heat treatment, a complex coating composed of an external MnCo2O4 layer and an inner Cr-rich oxide layer has been formed on 430SS. The coating improves the oxidation resistance of the steel at 800 °C in air, especially in wet air, and inhibits the outward diffusion of Cr from the Cr-rich scale. Moreover, a low contact resistance has been achieved with the application of the spinel coatings.
•Co–Mn alloys are deposited in chloride solutions to protect metallic interconnects.•The Co–Mn alloy is converted into adhesive spinel coatings by heat treatment in air.•Spinel coatings consist of an external MnCo2O4 layer and an inner Cr-rich layer.•spinel coatings inhibit the oxidation of the steel at 800 °C in air and air-10%H2O.•Spinel coatings decrease the area specific electrical resistance of the steel.
•EOLakeWatch is an Earth Observation tool for monitoring Canadian inland water HABs.•Derived indices document bloom spatial extent, intensity, duration and severity.•Blooms are characterized for ...three lakes (Erie, Winnipeg and Lake of the Woods)•Collectively, indices deliver a comprehensive assessment of bloom conditions.
Early detection and comprehensive monitoring of inland water algal blooms is fundamental to their effective management and mitigation of potential ecosystem and public health impacts. With the spatial and temporal limitations of in situ sampling, algal bloom monitoring capabilities have been enhanced greatly by advancements in satellite Earth Observation (EO). Three turbid, eutrophic Canadian lakes (Lake Winnipeg (LW); Lake Erie (LE); Lake of the Woods (LoW)) have been the focus of Environment and Climate Change Canada (ECCC) research and monitoring initiatives due to concerns over persistent degraded water quality from recurring algal blooms. ECCC’s EOLakeWatch was developed to deliver a suite of useful, easily interpretable, and accessible EO-derived products to support algal bloom monitoring on these three lakes. Algal bloom indices, describing bloom spatial extent, intensity, duration, and severity were derived using the European Space Agency’s OLCI (Ocean and Land Colour Instrument) sensor for observations from 2016 to present and its predecessor MERIS (Medium Resolution Imaging Spectrometer) for 2002 to 2011. Results document widespread blooms on each lake, with maximum spatial extent of 21,641 km2 (representing 88.1% of the lake area) on LW, 3070 km2 (79.5%) on LoW and 5257 km2 (19.7%) on LE. Bloom intensity showed seasonal and inter-annual variability on all three lakes, with a suggestion that LoW may be responding to reduced nutrient loads with a recent decrease in bloom intensity. Annual bloom duration on LW and LoW was on average 44 and 47 days respectively, while on LE blooms were significantly shorter in duration at an average of 24 days. Variance among the derived bloom indices was shown to be significant (i.e. the most extensive bloom was not necessarily the longest or most intensive), demonstrating the need for the indices to be used collectively, or for any single comprehensive bloom indicator to capture the variability of all individual metrics. Bloom indices are processed in a fully automated operational capacity, distributed in near-real-time through a web portal and collated into end-user-friendly annual algal bloom reports for each lake. These products go a long way to address existing monitoring gaps, delivering prompt, consistent measures of lake-wide algal bloom conditions required to provide stakeholders with early warning of bloom risks, identify areas of potential concern, quantify spatio-temporal trends, further understand bloom dynamics and drivers, as well as guide and determine the effectiveness of implemented management actions.
•Significantly higher active SOC fractions in the plots with straw incorporation.•Significant and positive correlations among SOC and active SOC fractions.•Active SOC fractions were positively ...correlated with soil water and total N content.•Straw incorporation increased CPMI in the early but not late paddy field.•Straw residues should be applied in the aerobic period during the early paddy field.
Understanding the dynamics of soil organic carbon (SOC) in response to changing environment and management practices is crucial for minimizing the climatic impacts of rice agriculture. This study examined the effects of rice straw incorporation on total SOC, active SOC fractions, and carbon pool management index (CPMI) in a subtropical paddy field in China. The straw collected after harvesting the early and late paddy was incorporated immediately into the top 10cm soil at a rate of 3.3Mgha−1 and the top 40cm soil samples in the triplicate treatment, control and reference plots were analyzed for the concentrations of total SOC and four other active SOC fractions at the end of the early and late seasons. The concentrations of total soil organic carbon (SOC), light fraction organic carbon (LFOC), dissolved organic carbon (DOC), and microbial biomass carbon (MBC) were significantly (P<0.05) higher in the straw application plots than in the controls by 7.1–128.6% for both the early and late paddy season. In general, significant and positive correlations were observed between SOC, DOC, LFOC, MBC and labile organic carbon (LOC) in the treatment and control plots for both early and late paddy (r=0.60–0.96, P<0.05). Moreover, there were significant and positive correlations of total SOC and active SOC fractions with both soil water content (r=0.69–0.94, P<0.01) as well as total soil nitrogen content (r=0.69–0.99, P<0.05). Straw incorporation significantly increased CPMI and other active soil organic carbon pools in the early paddy field (P<0.05), but had no significant effects on CPMI in the late paddy field. It is therefore better to incorporate straw residues in the aerobic condition during the early paddy season in order for rice to benefit from an increased CPMI.
P85α, which acts as a tumour suppressor, is frequently found to be downregulated in various human cancers. However, the role of p85α in the tumour microenvironment is unknown. Here, we report that ...aberrantly low expression of p85α in breast cancer stroma is clinically relevant to breast cancer disease progression. Stromal fibroblasts can acquire the hallmarks of cancer-associated fibroblasts (CAFs) as a result of the loss of p85α expression. Paracrine Wnt10b from p85α-deficient fibroblasts can promote cancer progression via epithelial-to-mesenchymal transition (EMT) induced by the canonical Wnt pathway. Moreover, exosomes have a key role in paracrine Wnt10b transport from fibroblasts to breast cancer epithelial cells. Our results reveal that p85α expression in stromal fibroblasts haves a crucial role in regulating breast cancer tumourigenesis and progression by modifying stromal-epithelial crosstalk and remodelling the tumour microenvironment. Therefore, p85α can function as a tumour suppressor and represent a new candidate for diagnosis, prognosis and targeted therapy.
Abstract
F
1
F
o
ATP synthase functions as a biological rotary generator that makes a major contribution to cellular energy production. It comprises two molecular motors coupled together by a central ...and a peripheral stalk. Proton flow through the F
o
motor generates rotation of the central stalk, inducing conformational changes in the F
1
motor that catalyzes ATP production. Here we present nine cryo-EM structures of
E. coli
ATP synthase to 3.1–3.4 Å resolution, in four discrete rotational sub-states, which provide a comprehensive structural model for this widely studied bacterial molecular machine. We observe torsional flexing of the entire complex and a rotational sub-step of F
o
associated with long-range conformational changes that indicates how this flexibility accommodates the mismatch between the 3- and 10-fold symmetries of the F
1
and F
o
motors. We also identify density likely corresponding to lipid molecules that may contribute to the rotor/stator interaction within the F
o
motor.
We studied the impacts of anthropogenic changes in land use on the stoichiometric imbalance of soil carbon (C), nitrogen (N), phosphorus (P) and potassium (K) in Phragmites australis wetlands in the ...Minjiang River estuary. We compared five areas with different land uses: P. australis wetland (control), grassland, a mudskipper breeding flat, pond aquaculture and rice cropland. Human activity has affected the elemental and stoichiometric compositions of soils through changes in land use. In general, soil C and N concentrations were lower and total soil K concentrations were higher at the sites under human land uses relative to the control site, and total soil P concentrations were generally not significantly different. The close relationship between total soil C and N concentrations in all cases, including fertilization with N, suggested that N was the most limiting nutrient in these wetlands. Lower soil N concentrations and similar soil P concentrations and higher soil K concentrations under human land-use activities suggest that human activity has increased the role of N limitation in these wetlands. Only grassland use increases soil N contents (only in the 0–10cm of soil). Despite N fertilization, lower soil N concentrations were also observed in the rice cropland, indicating the difficulty of avoiding N limitation in these wetlands. The observed lower soil N:P ratio, together with higher soil P and K availabilities in rice croplands, is consistent with the tendency of human activity to change the competitive relationships of plants, in this case favoring species adapted to high rates of growth (low N:P ratio) and/or favoring plants with high demands for P and K. Both, soil C storage and respiration were higher in grasslands, likely due to the introduction of grasses, which led to a high density of plants, increased grazing activity and soil compaction. Soil C storage and respiration were lower under human land uses, except in the rice cropland, with respect to natural wetland. Using overall data, soil C storage and respiration were correlated, indicating that soil respiration was correlated with plant productivity. In this wetland area the impacts of different human land-uses on soil stoichiometry and C-cycle can be very different depending on the activity. Further regeneration of natural communities can be determined by the previous type of land-use.
•Human activity increases total soil K and available-P concentrations.•Despite low soil N:P ratio, human activities decrease even more the soil N:P ratios.•These decreases of soil N:P are linked with the presence of high growth rate species.•Human activities decrease soil C and N concentrations affecting C storing capacity.•These soil stoichiometry changes can influence the regeneration of natural vegetation.
Metastasis is responsible for the rapid recurrence and poor survival of malignancies. Epithelial-mesenchymal transition (EMT) has a critical role in metastasis. Increasing evidence indicates that EMT ...can be regulated by microRNAs (miRNAs). miR-148a is a liver-abundant miRNA. However, the role of miR-148a in the development of liver cancer remains largely unknown. In this study, we found that, compared with normal livers, miR-148a was significantly decreased in hepatocellular carcinoma (HCC) tissues, especially in those with the portal vein tumor thrombus. An in vitro transwell assay and an in vivo orthotopic liver xenograft model showed that the restoration of miR-148a expression significantly repressed the migration and pulmonary metastasis of hepatoma cells. Linear regression analysis revealed a positive correlation between the expression of miR-148a and the mRNA level of E-cadherin gene in human HCC tissues. Both gain- and loss-of-function studies disclosed that miR-148a promoted the expression of epithelial marker (E-cadherin) and reduced the levels of mesenchymal markers (N-cadherin, fibronectin or vimentin) in hepatoma cells. These data suggest that miR-148a may suppress EMT and cancer metastasis. Further mechanistic investigations showed that miR-148a directly inhibited Met expression by binding to its 3'-UTR. Moreover, the reintroduction of miR-148a attenuated the downstream signaling of Met, like activated phosphorylation of AKT-Ser473 and inhibitory phosphorylation of GSK-3β-Ser9, and consequently reduced the nuclear accumulation of Snail, a transcription factor that promotes EMT. Taken together, miR-148a may negatively regulate Met/Snail signaling and therefore inhibit the EMT and metastasis of hepatoma cells. These findings highlight the significance of miR-148a downregulation in tumor progression and implicate miR-148a as an attractive candidate for cancer therapy.
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