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.
Abstract
Nickel-based complex oxides have served as a playground for decades in the quest for a copper-oxide analog of the high-temperature superconductivity. They may provide clues towards ...understanding the mechanism and an alternative route for high-temperature superconductors. The recent discovery of superconductivity in the infinite-layer nickelate thin films has fulfilled this pursuit. However, material synthesis remains challenging, direct demonstration of perfect diamagnetism is still missing, and understanding of the role of the interface and bulk to the superconducting properties is still lacking. Here, we show high-quality Nd
0.8
Sr
0.2
NiO
2
thin films with different thicknesses and demonstrate the interface and strain effects on the electrical, magnetic and optical properties. Perfect diamagnetism is achieved, confirming the occurrence of superconductivity in the films. Unlike the thick films in which the normal-state Hall-coefficient changes signs as the temperature decreases, the Hall-coefficient of films thinner than 5.5 nm remains negative, suggesting a thickness-driven band structure modification. Moreover, X-ray absorption spectroscopy reveals the Ni-O hybridization nature in doped infinite-layer nickelates, and the hybridization is enhanced as the thickness decreases. Consistent with band structure calculations on the nickelate/SrTiO
3
heterostructure, the interface and strain effect induce a dominating electron-like band in the ultrathin film, thus causing the sign-change of the Hall-coefficient.
Inverse modeling of regional CO2 fluxes using atmospheric CO2 data is sensitive to the observational coverage of the observing network. Here we use the GEOS‐Chem adjoint model to examine the ...sensitivity to CO2 fluxes of observations from the in situ surface network, the Total Carbon Column Observing Network (TCCON), the Greenhouse Gases Observing Satellite (GOSAT), and the Orbiting Carbon Observatory (OCO‐2). We find that OCO‐2 has high sensitivity to fluxes throughout the tropics and Southern Hemisphere, while surface observations have high sensitivity to fluxes in the northern extratropics throughout the year. For GOSAT viewing modes, ocean glint data provide the strongest constraints on fluxes in the tropics and Southern Hemisphere during Northern Hemisphere fall and winter relative to other viewing modes. In contrast, GOSAT nadir land data offer the greater sensitivity to fluxes in these regions during Northern Hemisphere spring and summer. For OCO‐2 viewing modes, ocean glint data provided the dominant sensitivity to the surface fluxes in the northern subtropics, tropics, and Southern Hemisphere. We performed a series of inversion analyses using pseudodata and found that the varying sensitivities can result in large differences in regional flux estimates. However, combining measurements from different observing systems to exploit their complementarity may lead to a posteriori flux estimates with improved accuracy.
Key Points
Large spatiotemporal differences in sensitivity to surface fluxes between observing systems
OCO‐2 has the highest sensitivity to surface fluxes throughout the tropics and Southern Hemisphere
Surface observations have the highest sensitivity to surface fluxes in the northern extratropics
Aim To evaluate the utility of T1 mapping on gadoxetic acid-enhanced magnetic resonance imaging (MRI) and diffusion-weighted imaging (DWI) for staging liver fibrosis. Materials and methods This ...retrospective study was approved by the institutional review board and included 145 patients (mean age: 54 years old; 115 men and 30 women). Necro-inflammatory activity grade (G) and liver fibrosis stage (S) were histopathologically determined. T1 relaxation time and apparent diffusion coefficient (ADC) of the liver were measured and the reduction rate of the T1 relaxation time (Δ%) was calculated. T1 relaxation time measurements were compared with ADC values according to S/G scores. Results Unenhanced hepatobiliary phase (HBP) and Δ% of T1 relaxation times showed significant correlations with S/G scores (rho: 0.28, 0.51, −0.35 for the S score, 0.26, 0.39, −0.26 for the G score, respectively, p< 0.05). ADC values showed significant correlation with the S score (rho: −0.17, p =0.04) and did not correlate significantly with the G score (rho: −0.07, p =0.39). The areas under receiver operator characteristics (AUC) curve of unenhanced HBP, Δ% T1 relaxation time, and the ADC value were 0.68, 0.82, 0.71, 0.61 for the identification of S≥3, and 0.63, 0.68, 0.62, 0.52 for the identification of G≥3, respectively. The HBP T1 relaxation time was better than that of ADC for identification of S≥3 ( p =0.0005) and G≥3 ( p =0.014). Conclusions The HBP T1 relaxation time measurement on gadoxetic acid-enhanced MRI images might be a potential biomarker in the staging of hepatic fibrosis, and was more accurate than the ADC measurement.
Background
Autophagy is a lysosomal degradation pathway that is essential for cell survival, differentiation, and homeostasis. This study aimed to investigate the contribution of autophagy to the ...pathogenesis of CRS with nasal polyps (CRSwNP).
Methods
The expression of autophagic proteins microtubule‐associated protein 1 light chain 3B (LC3B)‐II, autophagy‐related proteins (Atg), and Beclin 1, substrate proteins (p62 and ubiquitinated proteins), and apoptotic signaling molecules cysteine‐aspartic protease‐3 and cysteine‐aspartic protease‐8, and poly‐ADP‐ribose polymerase in the sinonasal mucosa and nasal epithelial cells (NECs) was detected by immunohistochemistry and Western blotting. Autophagic vacuoles were observed with transmission electron microscopy. BEAS‐2B cells and NECs were treated with rapamycin, bafilomycin A1, or various cytokines. In some experiments, cultured NECs were transfected with small interfering RNA targeting p62 (sip62) or Atg5 (siAtg5). Cultured cells were analyzed with Western blotting and flow cytometry.
Results
Although autophagic protein expression and autophagic vacuole formation were increased in both eosinophilic and noneosinophilic CRSwNP, particularly in NECs, there was also an up‐regulation of substrate proteins and apoptotic signaling molecules. IFN‐γ, but not IL‐4, IL‐13, or IL‐17A, simultaneously enhanced LC3B‐II and p62 levels as well as cell apoptosis in BEAS‐2B cells and/or normal NECs. Bafilomycin A1 up‐regulated the levels of LC3B‐II and p62 in polyp NECs and IFN‐γ‐treated normal NECs. IFN‐γ‐induced apoptosis of normal NECs was exaggerated by bafilomycin A1 and siAtg5. Sip62 suppressed apoptosis of polyp NECs and IFN‐γ‐treated NECs. IFN‐γ protein levels were increased in both eosinophilic and noneosinophilic CRSwNP.
Conclusions
IFN‐γ induces activated but insufficient autophagy and thus contributes to a degree to p62‐dependent apoptosis of NECs in CRSwNP.
Improvac has been tentatively used to immune-castrate roosters. The aim of this study was to investigate whether Improvac affected skeletal muscle development in chickens. The muscle fiber type and ...size and the expression levels of genes related to muscle development in pectoral and thigh muscles were examined at 5, 9, and 14 wk of age in the control, early, late, and early + late Improvac-treated groups. Immunocastration with Improvac affected the development of thigh muscles and the expression of MYH1B, MSTN, and SM. The cross-sectional area in the early group was significantly larger than in the control group at the 14th week (P < 0.01). At the fifth week, the expression levels of MYH1B, MYOD, and MSTN in the early group were significantly higher than those in the control group (P < 0.05), and at the ninth week, the expression level of SM1 in the control group was significantly lower than that in early and late groups (P < 0.05). Immunocastration did not affect pectoral muscle development or the expression of genes related to muscle development.
Nd-rich phase plays a critical role in wetting grain boundary and facilitating texture formation for hot deformed (HD) Nd-Fe-B magnets. In this study, a non-uniform distribution of Nd-rich phase with ...dimension up to a few micrometers was observed in nanocrystalline HD magnets. The aggregation of the Nd-rich phase is confirmed to result from the low density precursor prepared by spark plasma sintering (SPS). The large local demagnetizing fields induced by Nd-rich phase aggregation led to the open recoil loops and reduced coercivity. Upon reducing recoil loop openness by eliminating Nd-rich phase aggregation, the coercivity of the HD magnet was significantly improved from 226 kA/m to 995 kA/m, and a high maximum energy product of 293 kJ/m3 was obtained. The dependences of microstructure and coercivity on the recoil loop characteristics suggest an essential approach for improving the magnetic properties of nanocrystalline HD Nd-Fe-B magnets.
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Neoadjuvant therapy is recommended for locally advanced esophageal cancer, but the optimal strategy remains unclear. We aimed to evaluate the safety and efficacy of neoadjuvant chemoradiotherapy ...(nCRT) versus neoadjuvant chemotherapy (nCT) followed by minimally invasive esophagectomy (MIE) for locally advanced esophageal squamous cell carcinoma (ESCC).
Eligible patients staged as cT3-4aN0-1M0 ESCC were randomly assigned (1 : 1) to the nCRT or nCT group stratified by age, cN stage, and centers. The chemotherapy, based on paclitaxel and cisplatin, was administered to both groups, while concurrent radiotherapy was added for the nCRT group; then MIE was carried out. The primary endpoint was 3-year overall survival. This study is registered with ClinicalTrials.gov (NCT03001596).
A total of 264 patients were eligible for the intention-to-treat analysis. By 30 November 2021, 121 deaths had occurred. The median follow-up was 43.9 months (interquartile range 36.6-49.3 months). The overall survival in the intention-to-treat population was comparable between the nCRT and nCT strategies hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.58-1.18; P = 0.28, with a 3-year survival rate of 64.1% (95% CI 56.4% to 72.9%) versus 54.9% (95% CI 47.0% to 64.2%), respectively. There were also no differences in progression-free survival (HR 0.83, 95% CI 0.59-1.16; P = 0.27) and recurrence-free survival (HR 1.07, 95% CI 0.71-1.60; P = 0.75), although the pathological complete response in the nCRT group (31/112, 27.7%) was significantly higher than that in the nCT group (3/104, 2.9%; P < 0.001). Besides, a trend of lower risk of recurrence was observed in the nCRT group (P = 0.063), while the recurrence pattern was similar (P = 0.802).
NCRT followed by MIE was not associated with significantly better overall survival than nCT among patients with cT3-4aN0-1M0 ESCC. The results underscore the pending issue of the best strategy of neoadjuvant therapy for locally advanced bulky ESCC.
•The CMISG1701 trial assessed the safety and efficacy of nCRT versus nCT followed by MIE for locally advanced bulky ESCC.•The nCRT followed by MIE strategy could not improve survival significantly compared with the nCT strategy.•The best strategy of neoadjuvant therapy for locally advanced bulky ESCC remains a pending issue.
The dual-scale structured Al–Sn based alloys are potential alternative for journal bearings of automotive application due to their excellent tribological and mechanical properties. In this work, the ...authors attempted to further promote wear properties of dual-scale structured Al–12wt% Sn alloys by Mg addition. It has been found that appropriate Mg addition could increase wet-ability and reduce divorced Sn eutectics, resulting improved distribution of Sn phase, strength and ductility. Moreover, the mechanism for the improvement of the wear properties of Mg-containing Al–Sn alloy was revealed, and could be summarized as follows: (1) The improved transportation and distribution of the Sn nanophases, including nanoparticles and nanowires, towards the worn surface effectively reduced the friction coefficient; (2) enhanced Mg-oxide film and tribolayer formation on the mating surfaces and (3) increased stability of tribolayer owing to better combination of the strength and ductility. But excessive Mg addition led to too high amount of Mg2Sn and Mg17Al12 intermetallic phases, which worsen the wear properties. The dual-scale CG-30 Al–Sn with 1.2wt% Mg addition exhibits the best wear performance under the present experiment conditions.
•Wear properties are further enhanced by Mg addition in the dual-scale Al–Sn alloy.•Mg addition improves Sn dispersion and transportation and reduces friction coefficient.•A stable tribolayer formation by Mg addition further improves wear resistance.
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