ESE3-positive PSCs drive pancreatic cancer fibrosis, chemoresistance and poor prognosis via tumour-stromal IL-1ß/NF-κB/ESE3 signalling axis.

BACKGROUND: Desmoplastic stroma, a feature of pancreatic ductal adenocarcinoma (PDAC), contains abundant activated pancreatic stellate cells (PSCs). How PSCs promote PDAC progression remains incompletely understood. METHODS: Effect of epithelium-specific E-twenty six factor 3 (ESE3)-positive PSCs on PDAC fibrosis and chemoresistance was examined by western blot, RT-PCR, immunofluorescence, flow cytometry assay, chromatin immunoprecipitation, luciferase assay, immunohistochemistry and subcutaneous pancreatic cancer mouse model. RESULTS: ESE3 expression increased in PSCs in PDAC tissues compared with those in normal PSCs. Clinical data showed that ESE3 upregulation in PSCs was positively correlated with tumour size, pTNM stage, CA19-9, carcinoembryonic antigen and serum CA242 level. ESE3 overexpression in PSCs was an independent negative prognostic factor for disease-free survival and overall survival amongst patients with PDAC. Mechanistically, the conditional medium from the loss and gain of ESE3-expressing PSCs influenced PDAC chemoresistance and tumour growth. ESE3 directly induced the transcription of α-SMA, collagen-I and IL-1ß by binding to ESE3-binding sites on their promoters to activate PSCs. IL-1ß upregulated ESE3 in PSCs through NF-κB activation, and ESE3 was required for PSC activation by tumour cell-derived IL-1ß. CONCLUSION: Inhibiting the IL-1ß/ESE3 (PSCs)/IL-1ß-positive feedback loop is a promising therapeutic strategy to reduce tumour fibrosis and increase chemotherapeutic efficacy in PDAC.

Screening diverse soybean genotypes for drought tolerance by membership function value based on multiple traits and drought-tolerant coefficient of yield.

BACKGROUND: Drought is a major limiting factor seriously influencing worldwide soybean production and its impact on yield, morphological and physiological traits depend on the timing it occurs and the intensity of water shortage. Only limited research has however been conducted on identifying the drought-tolerant genotypes at different growth stages (vegetative growth phase, reproductive growth phase and the whole growth phase) as well as evaluate the effectiveness and reliability of multiple phenotypic and yield-related characteristics in soybean. RESULTS: Two pot experiments and a 2-year field experiment were conducted to evaluate soybean drought tolerance at different growth stages. The membership function value of drought tolerance (MFVD) was used to identify drought-resistant cultivars during vegetative growth phase and reproductive growth stage; the relative drought index (RDI) of yield was used to assess drought-resistant cultivars during the whole growing period. In this study, regression models built based on MFVD indicated that the variation of drought tolerant coefficient (DC) of R/S, TRL, LAI and RSR could explain 73.70% of the total variation at vegetative growth phase. However, higher heritability only found in LAI and RSR, indicating the two traits could serve as reliable criteria for drought evaluation. Similarly, the DC of SPP, YPP, PH, PB, MSNN and STB could explain 94.30% of the total variation in MFVD according to stepwise multiple linear regression analyses at reproductive growth phase. Thus, these six traits were identified as indicators for screening drought resistance genotypes in soybean. In addition, correlation analysis revealed that the MFVD was significantly positively correlated with the DCRB, DCR/S, DCRSA, DCRSR and DCRBR at vegetative growth phase and DCYPP, DCSPP, DCRB, and DCPB at reproductive growth phase. This indicated that these traits were closely related to the drought resistance of plants. CONCLUSIONS: LD24, JD36 and TF31 of vegetative growth phase, and TD37 and LD26 of reproductive growth phase were identified with drought tolerant and highly drought tolerant, respectively. Moreover, 30 accessions with drought tolerance were screened in the field trial and could be applied for the drought resistance of other genotypes by cross-breeding.

Antiapoptosis effect of ZiShen prescription to increase learning and memory abilities of compound Alzheimer's disease model rats.

Alzheimer's disease (AD) is a neurodegenerative disease characterized progressive memory loss and cognitive impairment. In previous studies, the activities of extracts of Chinese medicinal herbs to treat brain function disorders caused by AD have already been reported. ZiShen prescription was a traditional Chinese medicine (TCM) compound prescription reformed for AD disease based on the basic theory of TCM. To explore the effect of ZiShen (kidney-reinforcing) prescription on the learning and memory abilities, we made compound AD model rats by injecting d-galactose and ibotenic acid into the abdominal cavity to damage both sides of the nucleus basalis of Meynert with ibotenic acid. The trisected Y-maze was used to test the learning and memory abilities of AD model rats before and after treatment by ZiShen prescription and Piracetam. To investigate the mechanism of ZiShen prescription, the expressions of apoptosis-related genes (Bcl-2/Bax) in the cortex and hippocampus of compound AD model rats were detected in the cortex and hippocampus. The results show that, comparing with Piracetam, a clinical medicine to promote the thinking and memory for AD patients, ZiShen prescription significantly increased the learning and memory abilities of the compound AD model rats. After the treatment of ZiShen prescription, the expression of Bcl-2 was upregulated, along with a downregulation of Bax in the cortex and hippocampus of compound AD model rats. And the results indicated that the clinical benefits of ZiShen prescription were slightly better than Piracetam. Still, further well-designed studies are required to ensure the clinical effect of ZiShen.

Genome-wide association mapping for yield-related traits in soybean (Glycine max) under well-watered and drought-stressed conditions.

Soybean (Glycine max) productivity is significantly reduced by drought stress. Breeders are aiming to improve soybean grain yields both under well-watered (WW) and drought-stressed (DS) conditions, however, little is known about the genetic architecture of yield-related traits. Here, a panel of 188 soybean germplasm was used in a genome wide association study (GWAS) to identify single nucleotide polymorphism (SNP) markers linked to yield-related traits including pod number per plant (PN), biomass per plant (BM) and seed weight per plant (SW). The SLAF-seq genotyping was conducted on the population and three phenotype traits were examined in WW and DS conditions in four environments. Based on best linear unbiased prediction (BLUP) data and individual environmental analyses, 39 SNPs were significantly associated with three soybean traits under two conditions, which were tagged to 26 genomic regions by linkage disequilibrium (LD) analysis. Of these, six QTLs qPN-WW19.1, qPN-DS8.8, qBM-WW1, qBM-DS17.4, qSW-WW4 and qSW-DS8 were identified controlling PN, BM and SW of soybean. There were larger proportions of favorable haplotypes for locus qPN-WW19.1 and qSW-WW4 rather than qBM-WW1, qBM-DS17.4, qPN-DS8.8 and qSW-DS8 in both landraces and improved cultivars. In addition, several putative candidate genes such as Glyma.19G211300, Glyma.17G057100 and Glyma.04G124800, encoding E3 ubiquitin-protein ligase BAH1, WRKY transcription factor 11 and protein zinc induced facilitator-like 1, respectively, were predicted. We propose that the further exploration of these locus will facilitate accelerating breeding for high-yield soybean cultivars.

Comparison of adjuvant nab-paclitaxel plus gemcitabine, S-1 and gemcitabine chemotherapy for resectable pancreatic cancer: a real-world study.

Background: A survival benefit has been seen for both adjuvant nab-paclitaxel plus gemcitabine (AG) and S-1 chemotherapy compared to gemcitabine (GEM) for resectable pancreatic cancer in the APACT (2019) and JASPAC01 trials (2016), respectively. However, supporting evidence regarding the effectiveness of AG or S-1 compared to gemcitabine in real-world clinical practice remains lacking. Methods: Our study included all 246 pancreatic cancer patients who underwent surgical treatment and received postoperative adjuvant chemotherapy with AG, S-1, or GEM except for those meeting exclusion criteria (R2 resection, neoadjuvant therapy, or synchronous malignancy) at Tianjin Medical University Cancer Institute and Hospital from June 2015 to July 2021. The primary outcome was overall survival (OS) and recurrence-free survival (RFS). Results: In total, 246 patients were included, of whom 54(22%) received adjuvant AG, 103(41%) received adjuvant S-1, and 89(37%) received adjuvant GEM. Adjuvant S-1 was associated with a prolonged OS compared to GEM (median OS S-1 vs GEM: 27.0 vs 20.0 months; HR: 0.65, P = .016) and a significantly prolonged RFS compared to GEM (median RFS S-1 vs GEM: 20.0 vs 8.2 months; HR: 0.58, P = .002). After adjusting for known prognostic factors in multivariate Cox regression analysis, this survival benefit persists and is consistent in most subgroups in our subgroup analysis. However, no statistically significant differences in OS or RFS were seen between patients treated with AG and patients treated with GEM. Conclusions: In this retrospective real-world study, adjuvant S-1 chemotherapy was associated with improved survival compared to GEM while no differences in OS or RFS were observed for AG compared to GEM.

PERK-eIF2α-ERK1/2 axis drives mesenchymal-endothelial transition of cancer-associated fibroblasts in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by remarkable desmoplasia, usually driven by cancer-associated fibroblasts (CAFs), influencing patient prognosis. CAFs are a group of plastic cells responsible for tumor growth and metastasis. Fibroblasts have been reported to directly contribute to angiogenesis by undergoing mesenchymal-endothelial transition (MEndoT) after ischemic injury in the heart, brain, and hindlimbs. However, whether CAFs can undergo similar transdifferentiation in the hostile tumor microenvironment and directly contribute to tumor angiogenesis remains unclear. Herein, we provide evidence that CAFs can adopt an endothelial cell-like phenotype and directly contribute to tumor angiogenesis in vitro and in vivo. Furthermore, this program is regulated by the PERK-eIF2α-ERK1/2 axis. Pharmacological inhibition of PERK with GSK2606414 limited the phenotypic transition of CAFs. In conclusion, our results suggest that CAFs contribute to tumor angiogenesis by undergoing the MEndoT, thus representing therapeutic targets for improving PDAC prognosis.

Down-regulation of SORL1 is associated with Alzheimer's disease through activating ABC transporter pathway.

Alzheimer's disease (AD) is a common neurodegenerative disease with high morbidity among elderly people. A genetic attribution has been extensively proved. Here, we propose to further prioritize genes that harbor single nucleotide variation (SNV) or structural variation (SV) for AD and explore the underlying potential mechanisms through exploiting their expression and methylation spectra. A high-confidence AD-associated candidate gene list was obtained from the ClinVar and Human Gene Mutation Database (HGMD). Genome-wide methylation and expression profiles of AD and normal subjects were downloaded from the Gene Expression Omnibus (GEO). Through comprehensive comparison of expression and methylation levels between AD and normal samples, as well as different stages of AD samples, SORL1 was identified as the most plausible gene for AD incidence and progression. Gene Set Enrichment Analysis (GSEA) revealed significant activation of the ABC (ATP binding cassette) transporter with the aberrant up-regulation of SORL1 within AD samples. This study unfolds the expression and methylation spectra of previously probed genes with SNV or SV in AD for the first time, and reports an aberrant activation of the ABC transporter pathway that might contribute to AD progression. This should shed some light on AD diagnosis and precision treatment.

Bioinformatics method combined with logistic regression analysis reveal potentially important miRNAs in ischemic stroke.

PURPOSE: The present study aimed to investigate the comprehensive differential expression profile of microRNAs (miRNAs) by screening for miRNA expression in ischemic stroke and normal samples. METHODS: Differentially expressed miRNA (DEM) analysis was conducted using limma R Bioconductor package. Target genes of DEMs were identified from TargetScanHuman and miRTarBase databases. Functional enrichment analysis of the target genes was performed using clusterProfiler R Bioconductor package. The miRNA-based ischemic stroke diagnostic signature was constructed via logistic regression analysis. RESULTS: Compared with the normal cohort, a total of 14 DEMs, including 5 up-regulated miRNAs and 9 down-regulated miRNAs, were identified in ischemic stroke patients. These DEMs have 1600 regulatory targets. Using a logistic regression model, the top five miRNAs were screened for constructing an miRNA-based ischemic stroke diagnostic signature. Using the miRNA-mRNA interaction pairs, two target genes (specificity protein 1 (SP1) and Argonaute 1 (AGO1)) were speculated to be the primary genes of ischemic stroke. DISCUSSION AND CONCLUSION: Here, several potential miRNAs biomarkers were identified and an miRNA-based diagnostic signature for ischemic stroke was established, which can be a valuable reference for future clinical researches.