Emerging evidence suggests that epithelial‐mesenchymal transitions (EMTs) play important roles in tumor metastasis and recurrence. Understanding molecular mechanisms that regulate the EMT process is ...crucial for improving treatment of hepatocellular carcinoma (HCC). MicroRNAs (miRNAs) play important roles in HCC; however, the mechanisms by which miRNAs target the EMT and their therapeutic potential remains largely unknown. To better explore the roles of miRNAs in the EMT process, we established an EMT model in HCC cells by transforming growth factor beta 1 treatment and found that several tumor‐related miRNAs were significantly decreased. Among these miRNAs, miR‐125b expression was most strongly suppressed. We also found down‐regulation of miR‐125b in most HCC cells and clinical specimens, which correlated with cellular differentiation in HCC patients. We then demonstrated that miR‐125b overexpression attenuated EMT phenotype in HCC cancer cells, whereas knockdown of miR‐125b promoted the EMT phenotype in vitro and in vivo. Moreover, we found that miR‐125b attenuated EMT‐associated traits, including chemoresistance, migration, and stemness in HCC cells, and negatively correlated with EMT and cancer stem cell (CSC) marker expressions in HCC specimens. miR‐125b overexpression could inhibit CSC generation and decrease tumor incidence in the mouse xenograft model. Mechanistically, our data revealed that miR‐125b suppressed EMT and EMT‐associated traits of HCC cells by targeting small mothers against decapentaplegic (SMAD)2 and 4. Most important, the therapeutic delivery of synthetic miR‐125b mimics decreased the target molecule of CSC and inhibited metastasis in the mice model. These findings suggest a potential therapeutic treatment of miR‐125b for liver cancer. Conclusion: miR‐125b exerts inhibitory effects on EMT and EMT‐associated traits in HCC by SMAD2 and 4. Ectopic expression of miR‐125b provides a promising strategy to treat HCC. (Hepatology 2015;62:801–815)
Cancer‐associated mesenchymal stem cells (MSCs) play a pivotal role in modulating tumor progression. However, the interactions between liver cancer‐associated MSCs (LC‐MSCs) and hepatocellular ...carcinoma (HCC) remain unreported. Here, we identified the presence of MSCs in HCC tissues. We also showed that LC‐MSCs significantly enhanced tumor growth in vivo and promoted tumor sphere formation in vitro. LC‐MSCs also promoted HCC metastasis in an orthotopic liver transplantation model. Complementary DNA (cDNA) microarray analysis showed that S100A4 expression was significantly higher in LC‐MSCs compared with liver normal MSCs (LN‐MSCs) from adjacent cancer‐free tissues. Importantly, the inhibition of S100A4 led to a reduction of proliferation and invasion of HCC cells, while exogenous S100A4 expression in HCC cells resulted in heavier tumors and more metastasis sites. Our results indicate that S100A4 secreted from LC‐MSCs can promote HCC cell proliferation and invasion. We then found the expression of oncogenic microRNA (miR)‐155 in HCC cells was significantly up‐regulated by coculture with LC‐MSCs and by S100A4 ectopic overexpression. The invasion‐promoting effects of S100A4 were significantly attenuated by a miR‐155 inhibitor. These results suggest that S100A4 exerts its effects through the regulation of miR‐155 expression in HCC cells. We demonstrate that S100A4 secreted from LC‐MSCs promotes the expression of miR‐155, which mediates the down‐regulation of suppressor of cytokine signaling 1, leading to the subsequent activation of STAT3 signaling. This promotes the expression of matrix metalloproteinases 9, which results in increased tumor invasiveness. Conclusion: S100A4 secreted from LC‐MSCs is involved in the modulation of HCC progression, and may be a potential therapeutic target. (HEPATOLOGY 2013)
Kernel and ear traits are key components of grain yield in maize (
L.). Investigation of these traits would help to develop high-yield varieties in maize. Genome-wide association study (GWAS) uses ...the linkage disequilibrium (LD) in the whole genome to determine the genes affecting certain phenotype. In this study, five ear traits (kernel length and width, ear length and diameter, cob diameter) were investigated across multi-environments for 2 years. Combining with the genotype obtained from Maize SNP50 chip, genetic diversity and association mapping in a set of 292 inbred lines were performed. Results showed that maize lines were clustered into seven subgroups and a total of 20 SNPs were found to be associated with ear traits significantly (
< 3.95E-05). The candidate genes identified by GWAS mainly encoded ubiquitin-activation enzymes (GRMZM2G015287), carotenoid cleavage dioxygenase (GRMZM2G446858), MYB-CC type transfactor, and phosphate starvation response protein 3, and they were associated with kernel length (KL) and ear diameter (ED), respectively. Moreover, two novel genes corresponding to RNA processing and fructose metabolism were found. Further, the SNPs detected by GWAS were confirmed by meta-QTL analysis. These genes and SNPs identified in the study would offer essential information for yield-related genes clone and breeding program in maize.
Diabetic retinopathy (DR) has become a leading cause of global blindness as a microvascular complication of diabetes. Regular screening of diabetic retinopathy is strongly recommended for people with ...diabetes so that timely treatment can be provided to reduce the incidence of visual impairment. However, DR screening is not well carried out due to lack of eye care facilities, especially in the rural areas of China. Artificial intelligence (AI) based DR screening has emerged as a novel strategy and show promising diagnostic performance in sensitivity and specificity, relieving the pressure of the shortage of facilities and ophthalmologists because of its quick and accurate diagnosis. In this study, we estimated the cost-effectiveness of AI screening for DR in rural China based on Markov model, providing evidence for extending use of AI screening for DR.
We estimated the cost-effectiveness of AI screening and compared it with ophthalmologist screening in which fundus images are evaluated by ophthalmologists. We developed a Markov model-based hybrid decision tree to analyze the costs, effectiveness and incremental cost-effectiveness ratio (ICER) of AI screening strategies relative to no screening strategies and ophthalmologist screening strategies (dominated) over 35 years (mean life expectancy of diabetes patients in rural China). The analysis was conducted from the health system perspective (included direct medical costs) and societal perspective (included medical and nonmedical costs). Effectiveness was analyzed with quality-adjusted life years (QALYs). The robustness of results was estimated by performing one-way sensitivity analysis and probabilistic analysis.
From the health system perspective, AI screening and ophthalmologist screening had incremental costs of $180.19 and $215.05 but more quality-adjusted life years (QALYs) compared with no screening. AI screening had an ICER of $1,107.63. From the societal perspective which considers all direct and indirect costs, AI screening had an ICER of $10,347.12 compared with no screening, below the cost-effective threshold (1-3 times per capita GDP of Chinese in 2019).
Our analysis demonstrates that AI-based screening is more cost-effective compared with conventional ophthalmologist screening and holds great promise to be an alternative approach for DR screening in the rural area of China.
Celotno besedilo
Dostopno za:
CEKLJ, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The first enantioselective organocatalytic two- and three-component reactions via a domino Knoevenagel/Michael/cyclization sequence with cupreine as catalyst have been developed. A wide range of ...optically active spiro4H-pyran-3,3′-oxindoles were obtained in excellent yields (up to 99%) with good to excellent enantioselectivities (up to 97%) from simple and readily available starting materials under mild reaction conditions. These heterocyclic spirooxindoles will provide promising candidates for chemical biology and drug discovery.
Indole-3-acetic acid (IAA) plays an important role in the growth and development of plants. In this study, a series of predominant strains were isolated and identified as
sp. with remarkable ...IAA-producing capabilities. The IAA-producing strains are mainly tryptophan-dependent and have significantly high yields of IAA (3477 μg mL
and 3378 μg mL
). The
gene encoding indole-3-pyruvate decarboxylase was identified by genomic analysis and RT-qPCR analysis, indicating the involvement of the indole-3-pyruvic acid (IPyA) pathway of IAA biosynthesis. The IPyA pathway was also confirmed by the intermediate assay. The IAA product of microbial metabolites was isolated, purified and characterized. These microbes exhibiting IAA production significantly promoted the growth of maize, increasing root length, plant height, fresh weight and dry weight. Thus,
sp. with high IAA production has great prospects in agricultural and industrial applications.
Immunoassays and liquid chromatography tandem mass spectrometry (LC-MS/MS) are two major methods for therapeutic drug monitoring (TDM) of immunosuppressant drugs. Compared to the relatively limited ...analytical performance and cross reactivities of immunoassays, the LC-MS/MS method is considered as a gold standard; however, the lack of systematic evaluation and standardization needs to be addressed.
A LC-MS/MS method for the determination of cyclosporine A, sirolimus, tacrolimus, and everolimus was developed. One-step protein precipitation was used to prepare blood samples. The newly developed method was systematically evaluated and validated according to the standard guidelines.
The quantitative method for four immunosuppressant drugs in human whole blood was validated according to the guidelines. The lower limits of the measuring interval (LLMI) for cyclosporine A, sirolimus, tacrolimus, and everolimus were 5, 0.5, 0.5, and 0.5 ng/mL, respectively. Linear correlation coefficients were all >0.999. Internal standard-normalized (IS-normalized) matrix correction factor was within the range 0.88–1.17. The average spiked recoveries of five replicates for the four immunosuppressant drugs were in the range 87.4–109.6%.
An LC-MS/MS method combined with one-step protein precipitation was developed, providing short sample preparation and chromatographic run time, thus allowing easy clinical diagnosis.
•A straightforward LC-MS/MS method was developed for determination of four immunosuppressant drugs.•One-step protein precipitation was used to deal with the blood samples, which was easy and high throughput.•Systematic evaluation were validated to access the method strictly according to the guidelines
Machilus pauhoi Kanehira is an important timber species in China. A provenance trial was recently set up to evaluate the growth performance of trees from different localities, with the aim of ...designing seed transfer guidelines. Here, we tested twelve nuclear microsatellite markers derived from other species of the Lauraceae family and investigated population genetic structure in M. pauhoi. Both the number of observed alleles per locus (Na) and the polymorphic information content (PIC) significantly decreased against the latitude, but showed an insignificant decrease against the longitude. Heterozygosity (Ho) and gene diversity (h) exhibited a weak correlation with geographic location. Private alleles were present in multiple populations, and a moderate level of population genetic differentiation was detected (Gst = 0.1691). The joint pattern of genetic diversity (Na, PIC, Ho, and h) suggests that general northeastward dispersal led to the current distribution of M. pauhoi. Significant but weak effects of isolation-by-distance (IBD) occurred, implicating the mountain ranges as the major barrier to gene flow. Both STRUCTURE and hierarchical clustering analyses showed three distinct groups of populations related to the physical connectivity among mountain ranges. A priority in designing genetic conservation should be given to the populations at the southwest side of the species' distribution. This conservation strategy can also be combined with the pattern of adaptive genetic variation from the provenance trial for comprehensive genetic resource management of native M. pauhoi.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract Long noncoding RNA (lncRNA), with size larger than 200 nucleotides, is a new class of noncoding RNA. Emerging evidence has revealed that lncRNAs play a key role in the regulation of ...immunological functions and autoimmunity. Herein, we review the recent findings of lncRNA regulation in immune functions and in the development of autoimmunity and autoimmune disease. In addition, we focus on the involvement of lncRNA regulation in innate and adaptive immune responses, immune cell development, and differential expression of lncRNAs in autoimmune diseases, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), type 1 diabetes mellitus (T1DM), multiple sclerosis (MS), autoimmune thyroid disease (AITD), psoriasis, polymyositis/dermatomyositis (PM/DM) and Crohn's disease (CD).
Background
Atrial esophageal fistula (AEF) is a lethal complication that can occur post atrial fibrillation (AF) ablation. Esophageal injury (EI) is likely to be the initial lesion leading to AEF. ...Endoscopic examination is the gold standard for a diagnosis of EI but extensive endoscopic screening is invasive and costly. This study was conducted to determine whether fecal calprotectin (Fcal), a marker of inflammation throughout the intestinal tract, may be associated with the existence of esophageal injury.
Methods
This diagnostic study was conducted in a cohort of 166 patients with symptomatic AF undergoing radiofrequency catheter ablation from May 2020 to June 2021. Fcal tests were performed 1–7 days after ablation. All patients underwent endoscopic ultrasonography 1 or 2 days after ablation.
Results
The levels of Fcal were significantly different between the EI and non‐EI groups (404.9 µg/g (IQR 129.6–723.6) vs. 40.4 µg/g (IQR 15.0–246.2), p < .001). Analysis of ROC curves revealed that a Fcal level of 125 µg/g might be the optimal cut‐off value for a diagnosis of EI, giving a 78.8% sensitivity and a 65.4% specificity. The negative predictive value of Fcal was 100% for ulcerated EI.
Conclusions
The level of Fcal is associated with EI post AF catheter ablation. 125 µg/g might be the optimal cut‐off value for a diagnosis of EI. Negative Fcal could predict the absence of ulcerated EI, which could be considered a precursor to AEF.
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