Background and Aims
Heparin‐binding epidermal growth factor (HB‐EGF), a member of the epidermal growth factor family, plays a pivotal role in the progression of several malignancies, but its role and ...regulatory mechanisms in hepatocellular carcinoma (HCC) remain obscure. Here, we report that transmembrane protease serine 4 (TMPRSS4) significantly enhanced the expression and proteolytic cleavage of HB‐EGF to promote angiogenesis and HCC progression.
Approach and Results
A mechanistic analysis revealed that TMPRSS4 not only increased the transcriptional and translational levels of HB‐EGF precursor, but also promoted its proteolytic cleavage by enhancing matrix metallopeptidase 9 expression through the EGF receptor/Akt/mammalian target of rapamycin/ hypoxia‐inducible factor 1 α signaling pathway. In addition, HB‐EGF promoted HCC proliferation and invasion by the EGF receptor/phosphoinositide 3‐kinase/Akt signaling pathway. The level of HB‐EGF in clinical samples of serum or HCC tissues from patients with HCC was positively correlated with the expression of TMPRSS4 and the microvessel density, and was identified as a prognostic factor for overall survival and recurrence‐free survival, which suggests that HB‐EGF can serve as a potential therapeutic target for HCC. More importantly, we provide a demonstration that treatment with the HB‐EGF inhibitor cross‐reacting material 197 alone or in combination with sorafenib can significantly suppress angiogenesis and HCC progression.
Conclusions
HB‐EGF can be regulated by TMPRSS4 to promote HCC proliferation, invasion, and angiogenesis, and the combination of the HB‐EGF inhibitor cross‐reacting material 197 with sorafenib might be used for individualized treatment of HCC.
Summary
Norway spruce is a boreal forest tree species of significant ecological and economic importance. Hence there is a strong imperative to dissect the genetics underlying important wood quality ...traits in the species. We performed a functional genome‐wide association study (GWAS) of 17 wood traits in Norway spruce using 178 101 single nucleotide polymorphisms (SNPs) generated from exome genotyping of 517 mother trees. The wood traits were defined using functional modelling of wood properties across annual growth rings. We applied a Least Absolute Shrinkage and Selection Operator (LASSO‐based) association mapping method using a functional multilocus mapping approach that utilizes latent traits, with a stability selection probability method as the hypothesis testing approach to determine a significant quantitative trait locus. The analysis provided 52 significant SNPs from 39 candidate genes, including genes previously implicated in wood formation and tree growth in spruce and other species. Our study represents a multilocus GWAS for complex wood traits in Norway spruce. The results advance our understanding of the genetics influencing wood traits and identifies candidate genes for future functional studies.
Significance Statement
Wood provides both structural support and a transport route for water and solutes in trees. Our work provides a framework to dissect the genetic nature of wood formation and adds to our understanding of tree growth and development. With the current research focus on wood cell wall biosynthesis in general, and lignocellulose feedstock for biorefineries, we believe that this contribution will be of wide interest for the plant science community.
Summary
Vast population movements induced by recurrent climatic cycles have shaped the genetic structure of plant species. During glacial periods species were confined to low‐latitude refugia from ...which they recolonized higher latitudes as the climate improved. This multipronged recolonization led to many lineages that later met and formed large contact zones.
We utilize genomic data from 5000 Picea abies trees to test for the presence of natural selection during recolonization and establishment of a contact zone in Scandinavia.
Scandinavian P. abies is today made up of a southern genetic cluster originating from the Baltics, and a northern one originating from Northern Russia. The contact zone delineating them closely matches the limit between two major climatic regions. We show that natural selection contributed to its establishment and maintenance. First, an isolation‐with‐migration model with genome‐wide linked selection fits the data better than a purely neutral one. Second, many loci show signatures of selection or are associated with environmental variables. These loci, regrouped in clusters on chromosomes, are often related to phenology.
Altogether, our results illustrate how climatic cycles, recolonization and selection can establish strong local adaptation along contact zones and affect the genetic architecture of adaptive traits.
Genomic selection (GS) can increase genetic gain by reducing the length of breeding cycle in forest trees. Here we genotyped 1370 control-pollinated progeny trees from 128 full-sib families in Norway ...spruce (Picea abies (L.) Karst.), using exome capture as genotyping platform. We used 116,765 high-quality SNPs to develop genomic prediction models for tree height and wood quality traits. We assessed the impact of different genomic prediction methods, genotype-by-environment interaction (G × E), genetic composition, size of the training and validation set, relatedness, and number of SNPs on accuracy and predictive ability (PA) of GS.
Using G matrix slightly altered heritability estimates relative to pedigree-based method. GS accuracies were about 11-14% lower than those based on pedigree-based selection. The efficiency of GS per year varied from 1.71 to 1.78, compared to that of the pedigree-based model if breeding cycle length was halved using GS. Height GS accuracy decreased to more than 30% while using one site as training for GS prediction and using this model to predict the second site, indicating that G × E for tree height should be accommodated in model fitting. Using a half-sib family structure instead of full-sib structure led to a significant reduction in GS accuracy and PA. The full-sib family structure needed only 750 markers to reach similar accuracy and PA, as compared to 100,000 markers required for the half-sib family, indicating that maintaining the high relatedness in the model improves accuracy and PA. Using 4000-8000 markers in full-sib family structure was sufficient to obtain GS model accuracy and PA for tree height and wood quality traits, almost equivalent to that obtained with all markers.
The study indicates that GS would be efficient in reducing generation time of breeding cycle in conifer tree breeding program that requires long-term progeny testing. The sufficient number of trees within-family (16 for growth and 12 for wood quality traits) and number of SNPs (8000) are required for GS with full-sib family relationship. GS methods had little impact on GS efficiency for growth and wood quality traits. GS model should incorporate G × E effect when a strong G × E is detected.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background and Aim
The purpose of the present study was to evaluate the effect of direct‐acting antivirals (DAAs) therapy on the clinical outcomes of hepatitis C virus (HCV) patients with ...hepatocellular carcinoma (HCC).
Methods
We searched multiple electronic databases from database inception to June 14, 2021. Meta‐analyses were performed separately for HCC recurrence and overall survival (OS).
Results
A total of 23 studies were identified for the primary analysis. Compared with no intervention, pooled data showed significant benefit from DAAs therapy in reducing recurrence (adjusted HR = 0.55, 95% CI 0.41–0.74, P < 0.001; I2 = 66.6%, P < 0.001) and improving OS (adjusted HR = 0.36, 95% CI 0.16–0.83, P = 0.017; I2 = 90.7%, P < 0.001) of HCV‐related HCC patients. Compared with non‐responders, patients with sustained virologic response (SVR) had greater benefit from DAAs therapy in reducing recurrence (HR = 0.37, 95% CI 0.16–0.84, P = 0.017; I2 = 58.8%, P = 0.088) and improving OS (HR = 0.17; 95% CI 0.06–0.50; P = 0.001; I2 = 56.4%, P = 0.130). Though DAAs did not show significant advantages over IFN in reducing recurrence (adjusted HR = 0.96, 95% CI 0.72–1.28, P = 0.784; I2 = 0.0%, P = 0.805), there seems to be a trend toward OS benefit from DAAs therapy (adjusted HR = 0.11, 95% CI 0.01–1.19, P = 0.059).
Conclusion
DAAs therapy can prevent recurrence and improve OS of HCV‐related HCC patients, especially for patients with SVR. Further prospective randomized controlled trial is warranted to validate these results.
Genome-wide association studies (GWAS) identify loci underlying the variation of complex traits. One of the main limitations of GWAS is the availability of reliable phenotypic data, particularly for ...long-lived tree species. Although an extensive amount of phenotypic data already exists in breeding programs, accounting for its high heterogeneity is a great challenge. We combine spatial and factor-analytics analyses to standardize the heterogeneous data from 120 field experiments of 483,424 progenies of Norway spruce to implement the largest reported GWAS for trees using 134 605 SNPs from exome sequencing of 5056 parental trees.
We identify 55 novel quantitative trait loci (QTLs) that are associated with phenotypic variation. The largest number of QTLs is associated with the budburst stage, followed by diameter at breast height, wood quality, and frost damage. Two QTLs with the largest effect have a pleiotropic effect for budburst stage, frost damage, and diameter and are associated with MAP3K genes. Genotype data called from exome capture, recently developed SNP array and gene expression data indirectly support this discovery.
Several important QTLs associated with growth and frost damage have been verified in several southern and northern progeny plantations, indicating that these loci can be used in QTL-assisted genomic selection. Our study also demonstrates that existing heterogeneous phenotypic data from breeding programs, collected over several decades, is an important source for GWAS and that such integration into GWAS should be a major area of inquiry in the future.
Aim
This study aimed to explore the effect of organisational innovation climate on nurse innovation behaviour and the mediating role of psychological empowerment.
Background
Encouraging nurses to ...generate more innovative behaviours has become an important development direction for improving the quality of nursing services.
Method
We employed a self‐report questionnaire to collect data in Jinan City, China. A total of 2018 valid surveys were obtained. Hierarchical multiple regression model analysis was conducted to test the study hypothesis.
Result
The mean values of innovation behaviour and organisational innovation climate were 35.29 and 83.30, respectively. Psychological empowerment was found to have partially mediating effect on the relationship between organisational innovation climate and innovation behaviour.
Conclusion
Organisational innovation climate has significant impact on innovation behaviour, and it can indirectly affect innovation behaviour via the mediating role of psychological empowerment.
Implications for nursing management
Nursing managers should enhance innovation climate through formal rules, procedures and training activities. They can establish resource guarantee system and information sharing platform, and strengthen work autonomy for nurses to improve their psychological empowerment.
Genomic prediction (GP) or genomic selection is a method to predict the accumulative effect of all quantitative trait loci (QTLs) in a population by estimating the realized genomic relationships ...between the individuals and by capturing the linkage disequilibrium between markers and QTLs. Thus, marker preselection is considered a promising method to capture Mendelian segregation effects. Using QTLs detected in a genome-wide association study (GWAS) may improve GP. Here, we performed GWAS and GP in a population with 904 clones from 32 full-sib families using a newly developed 50 k SNP Norway spruce array. Through GWAS we identified 41 SNPs associated with budburst stage (BB) and the largest effect association explained 5.1% of the phenotypic variation (PVE). For the other five traits such as growth and wood quality traits, only 2 - 13 associations were observed and the PVE of the strongest effects ranged from 1.2% to 2.0%. GP using approximately 100 preselected SNPs, based on the smallest p-values from GWAS showed the greatest predictive ability (PA) for the trait BB. For the other traits, a preselection of 2000-4000 SNPs, was found to offer the best model fit according to the Akaike information criterion being minimized. But PA-magnitudes from GP using such selections were still similar to that of GP using all markers. Analyses on both real-life and simulated data also showed that the inclusion of a large QTL SNP in the model as a fixed effect could improve PA and accuracy of GP provided that the PVE of the QTL was ≥ 2.5%.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Gastric cancer results in great cancer mortality worldwide, and inducing ferroptosis dramatically improves the malignant phenotypes of gastric cancer. DNA polymerase epsilon subunit 2 (POLE2) plays ...indispensable roles in tumorigenesis; however, its involvement and molecular basis in ferroptosis and gastric cancer are not clear. Human gastric cancer cells were infected with lentiviral vectors to knock down or overexpress POLE2, and cell ferroptosis was detected. To further validate the involvement of nuclear factor erythroid 2‐related factor 2 (NRF2) and glutathione peroxidase 4 (GPX4), lentiviral vectors were used. POLE2 expression was elevated in human gastric cancer cells and tissues and closely correlated with clinicopathological features in gastric cancer patients. POLE2 knockdown was induced, while POLE2 overexpression inhibited ferroptosis of human gastric cancer cells, thereby modulating the malignant phenotypes of gastric cancer. Mechanistic studies revealed that POLE2 overexpression elevated NRF2 expression and activity and subsequently activated GPX4, which then prevented lipid peroxidation and ferroptosis in human gastric cancer cells. In contrast, either NRF2 or GPX4 silence significantly prevented POLE2 overexpression‐mediated inductions of cell proliferation, migration, invasion and inhibition of ferroptosis. POLE2 overexpression inhibits ferroptosis in human gastric cancer cells through activating NRF2/GPX4 pathway, and inhibiting POLE2 may be a crucial strategy to treat gastric cancer.
Thickness reduction or loss of the calcareous eggshell is one of major phenotypic changes in the transition from oviparity to viviparity. Whether the reduction of eggshells in viviparous squamates is ...associated with specific gene losses is unknown. Taking advantage of a newly generated high‐quality genome of the viviparous Chinese crocodile lizard (Shinisaurus crocodilurus), we found that ovocleidin‐17 gene (OC‐17), which encodes an eggshell matrix protein that is essential for calcium deposition in eggshells, is not intact in the crocodile lizard genome. Only OC‐17 transcript fragments were found in the oviduct transcriptome, and no OC‐17 peptides were identified in the eggshell proteome of crocodile lizards. In contrast, OC‐17 was present in the eggshells of the oviparous Mongolia racerunner (Eremias argus). Although the loss of OC‐17 is not common in viviparous species, viviparous squamates show fewer intact eggshell‐specific proteins than oviparous squamates. Our study implies that functional loss of eggshell‐matrix protein genes may be involved in the reduction of eggshells during the transition from oviparity to viviparity in the crocodile lizard.
Could gene loss play a role in the evolution of eggshell reduction in viviparous squamates? The functional loss of OC‐17 in the Chinese crocodile lizard provides new clues.
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