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.
Background and aims:Infliximab is an effective treatment for ulcerative colitis with over 60% of patients responding to treatment and up to 30% reaching remission. The mechanism of resistance to ...anti-tumour necrosis factor α (anti-TNFα) is unknown. This study used colonic mucosal gene expression to provide a predictive response signature for infliximab treatment in ulcerative colitis.Methods:Two cohorts of patients who received their first treatment with infliximab for refractory ulcerative colitis were studied. Response to infliximab was defined as endoscopic and histological healing. Total RNA from pre-treatment colonic mucosal biopsies was analysed with Affymetrix Human Genome U133 Plus 2.0 Arrays. Quantitative RT-PCR was used to confirm microarray data.Results:For predicting response to infliximab treatment, pre-treatment colonic mucosal expression profiles were compared for responders and non-responders. Comparative analysis identified 179 differentially expressed probe sets in cohort A and 361 in cohort B with an overlap of 74 probe sets, representing 53 known genes, between both analyses. Comparative analysis of both cohorts combined, yielded 212 differentially expressed probe sets. The top five differentially expressed genes in a combined analysis of both cohorts were osteoprotegerin, stanniocalcin-1, prostaglandin-endoperoxide synthase 2, interleukin 13 receptor alpha 2 and interleukin 11. All proteins encoded by these genes are involved in the adaptive immune response. These markers separated responders from non-responders with 95% sensitivity and 85% specificity.Conclusion:Gene array studies of ulcerative colitis mucosal biopsies identified predictive panels of genes for (non-)response to infliximab. Further study of the pathways involved should allow a better understanding of the mechanisms of resistance to infliximab therapy in ulcerative colitis.ClinicalTrials.gov number, NCT00639821.
Abstract
We present a spectral study of the black hole candidate MAXI J1348−630 during its 2019 outburst, based on monitoring observations with Insight-HXMT and Swift. Throughout the outburst, the ...spectra are well fitted with power-law plus disk-blackbody components. In the soft-intermediate and soft states, we observed the canonical relation
L
∝
T
in
4
between disk luminosity
L
and peak color temperature
T
in
, with a constant inner radius
R
in
(traditionally identified with the innermost stable circular orbit). At other stages of the outburst cycle, the behavior is more unusual, inconsistent with the canonical outburst evolution of black hole transients. In particular, during the hard rise, the apparent inner radius is smaller than in the soft state (and increasing), and the peak color temperature is higher (and decreasing). This anomalous behavior is found even when we model the spectra with self-consistent Comptonization models, which take into account the upscattering of photons from the disk component into the power-law component. To explain both anomalous trends at the same time, we suggest that the hardening factor for the inner-disk emission was larger than the canonical value of ≈1.7 at the beginning of the outburst. A more physical trend of radii and temperature evolution requires a hardening factor evolving from ≈3.5 at the beginning of the hard state to ≈1.7 in the hard-intermediate state. This could be evidence that the inner disk was in the process of condensing from the hot, optically thin medium and had not yet reached a sufficiently high optical depth for its emission spectrum to be described by the standard optically thick disk solution.
Autism spectrum disorder (ASD) has a high incidence of intestinal comorbidity, indicating a strong association with gut microbiota. The purpose of this study was to characterize gut microbiota ...profiles in children with ASD. Seventy-seven children with ASD 33 with mild ASD and 44 with severe ASD according to the Childhood Autism Rating Scale score and 50 age-matched healthy children were enrolled. Compared with children in the healthy control (HC) group, those in the ASD group showed higher biomass, richness, and biodiversity of gut microbiota, and an altered microbial community structure. At the genus level, there was a significant increase in the relative abundance of unidentified Lachnospiraceae, Clostridiales, Erysipelotrichaceae, Dorea, Collinsella, and Lachnoclostridium, whereas Bacteroides, Faecalibacterium, Parasutterella, and Paraprevotella were significantly lower in the ASD group than in the control group. The presence of unidentified Erysipelotrichaceae, Faecalibacterium, and Lachnospiraceae was positively correlated with ASD severity. Notably, three microbial markers (Faecalitalea, Caproiciproducens and Collinsella) were identified in a random forest model with an area under the curve (AUC) of 0.94 for differentiation between HCs and ASD patients. Furthermore, the validation model was consistent with the discovery set (AUC = 0.98, 95% CI: 97.9%–100%). The training and testing sets were more effective when the number of bacteria was increased. In addition, the functional properties (such as galactose metabolism, glycosyltransferase activity, and glutathione metabolism) displayed significant differences between the ASD and HC groups. The current study provides evidence for the relationship between gut microbiota and ASD, with the findings suggesting that gut microbiota could contribute to symptomology. Thus, modulation of gut microbiota may be a new therapeutic strategy for ASD.
Graves’ disease (GD) is a complex autoimmune disorder in which genetic and environmental factors are both involved in the pathogenesis. Early‐onset patients have a shorter exposure time to ...environmental factors and are, therefore, good models to help understand the genetic architecture of GD. Based on previous studies of early‐onset GD, 11 single nucleotide polymorphisms (SNPs) and their related SNPs (R2 > .6), SNPs located within a ±1‐Mb region of the FOXP3 gene, and 20 validated GD‐risk SNPs were selected and screened for genotyping in 3735 GD and 4893 control patients to investigate whether early‐onset GD is a subtype of GD with distinct susceptibility genes. Ultimately, we did not confirm the reported genetic markers of early‐onset GD in our Chinese Han population but found that a GD‐risk SNP located in the human leukocyte antigen class I region—rs4947296—was more strongly correlated with early‐onset GD than non‐early‐onset GD. In addition, heterogeneity analysis of GD patients suggests that it may be more reasonable to define early‐onset GD as an onset age ≤20 years.
Hematopoietic cell transplantation (HCT) activity in China was surveyed to assess its current status. A record number of HCTs (21 884: 16 631 allogeneic (76%) and 5253 autologous (24%)) were reported ...by 76 centers in China between 1 January 2008 and 30 June 2016. HCT trends included continued growth in transplant activity, a continued rapid increase in haploidentical donors (HID), and slower growth for unrelated donors, matched-related donors (MRD) and cord blood transplantation (CBT). The proportion of HID HCT among allogeneic HCTs increased from 29.6% (313/1062) in 2008 to 48.8% (1939/3975) in 2015, even 51.7% (1157/2237) in the first half of 2016. During this time frame, the proportion of MRD HCTs among allogeneic HCTs decreased from 48.1% (511/1062) to 33.0% (332/3975). The proportion of unrelated donor HCTs among allogeneic HCTs decreased from 20.4 (216/1062) to 13.6% (540/3975). The proportion of CBTs among allogeneic HCTs was increased from 2.1% (22/1062) to 4.2% (184/3975). HCTs have been increasing continuously for all indications except chronic myelogenous leukemia. Severe aplastic anemia is a common HCT indication among non-malignant diseases in China. The number of cases of allogeneic HCT for this disorder has increased annually, from 59 (5.6%) in 2008 to 569 (14.3%) in 2015, even 334 (14.9%) in the first half year in 2016. This survey clearly shows recent trends for HCTs in China.
Phase-change memory takes advantage of the fast phase transition between amorphous and crystalline phases of phase-change materials (
e.g.
, Ge
2
Sb
2
Te
5
or GST). To date, while the "SET" process ...(crystallization of GST glass) has been intensively studied, studies on the "RESET" process (melt-quenching amorphization of GST) are still limited. In this work, we explored the structural changes of GST upon rapid cooling by
ab initio
molecular dynamics simulations and atomistic cluster alignment (ACA) analysis. Different from other methods which only focus on the nearest bonding atoms, the ACA method can study both the short- and medium-range order clusters containing atoms beyond the first-neighboring shell and enables us to explore the changes of cluster structures in a larger scale. The results reveal that low-coordinated octahedral clusters tend to become high-coordinated ones, and Ge-centered octahedral structures change to tetrahedrons whereas Sb-centered tetrahedrons transform to octahedral structures during the amorphization process. Interestingly, tetrahedrons show aggregation in liquid and supercooled liquid in contrast to 6-fold octahedrons which present notable aggregation in amorphous GST. Moreover, our study showed that wrong bonds (Ge-Ge, Sb-Sb, Ge-Sb and Te-Te bonds) can promote the formation of large rings, and irreducible rings tend to separate into smaller and larger rings as the temperature is decreased. Our findings provide useful insights into the formation process and the structure of amorphous GST, which is valuable for facilitating the application of phase change materials.
Five structures (a tetrahedron and 3-, 4-, 5- and 6-fold octahedrons) are shown in the upper panel of the figure. Figures in the lower panel show the fractions of the five structures in Ge- and Sb-centered clusters with temperature.
Bimetallic based metal organic frameworks (MOFs) are one of the prominent candidates for technological important energy storage and conversion devices owing to their enhanced conductivity and ...stability. In this work, nickel-based bimetallic metal–organic frameworks were efficiently synthesized by a facile hydrothermal method, and cobalt metal ions were incorporated in different molar ratios into the frameworks. Influence of cobalt metal ion incorporation on the electrochemical performance was investigated. Significantly, partial substitution of cobalt metal ion into the framework favorably enhances the supercapacitor performance of the nickel-based bimetallic MOFs. The optimized nickel-based bimetallic MOFs with nickel and cobalt molar ratio of 1:1 exhibit a large specific capacitance of 3305 F/g at a current density of 2 A/g, with the lowest electrochemical internal resistance. Further studies disclose that the supercapacitor performance enhancement can be ascribed to the combined effect of synergistic interactions between two metal ions and the hierarchical microsphere structure in MOFs. This investigation result affords a better understanding in the fabrication of homogeneous bimetallic based MOFs electrode material for next-generation energy conversion and storage devices.
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