Gold nanoparticles (AuNPs) can rapidly deliver artificial microRNA (AmiRNA)-ATG6 to silence ATG6 expression in Arabidopsis.

KEY MESSAGE: We establish a fast and efficient transient silencing system that facilitates functional studies of some genes, whose knockout leads to plant lethality. In plants, the generation of loss-of-function mutants is crucial for studying gene function. Artificial microRNA (AmiRNA) technology is a more targeted and effective tool for gene silencing. Gold nanoparticles (AuNPs) can bind nucleic acids and deliver them into animal cells. Here, AuNPs are used in combination with AmiRNA technology in plants. We found that AmiRNA-autophagy-related proteins (ATG6) can be delivered to cells by AuNPs to achieve the effect of ATG6 silencing. It is worth noting that on the 10th day there is still a silencing effect. Similar to the atg5 lines, silencing of ATG6 significantly reduced plant resistance to Pseudomonas syringae pv.maculicola (Psm) ES4326/AvrRpt2. Interestingly, ATG6 silencing and ATG5 mutation in NPR1-GFP (nonexpressor of pathogenesis-related genes) lines significantly reduced plant resistance to Psm ES4326/AvrRpt2, suggesting that autophagy is also involved in NPR1-regulated plant immune responses. In summary, we establish a fast and efficient transient silencing system that facilitates functional studies of some genes, whose knockout leads to plant lethality.

Evaluation of common genetic variants in vitamin E-related pathway genes and colorectal cancer susceptibility.

Vitamin E is effective for preventing the risk of cancer. However, few studies have elucidated the mechanism of vitamin E in cancer occurrence. Herein, we aimed to identify the genetic variants in vitamin E-related pathway genes associated with colorectal cancer risk. We applied logistic regression models to assess the association between single-nucleotide polymorphisms (SNPs) in vitamin E-related pathway genes and colorectal cancer risk in the Chinese and European population. The false discovery rate (FDR) method was used to correct multiple comparisons. The mRNA and protein expression analysis were evaluated in public database and in-house RNA-Seq data. SCARB1 rs73227586 was identified significantly increased risk of colorectal cancer in the Chinese population (odd ratio (OR) = 1.46, 95% confidence interval (CI) = 1.22-1.75, P = 2.99 × 10-5). This finding was further validated in the European population (OR = 1.11, 95% CI = 1.02-1.20, P = 1.44 × 10-2). Additionally, the mRNA and protein expression of SCARB1 were markedly up-regulated in colorectal tumor tissues. Moreover, rs73227586 T allele could increase the minimum free energy (MFE) and weaken binding ability to transcription factor ELL2. Our findings indicated that SCARB1 may play a carcinogenic role in colorectal cancer. Genetic variants in vitamin E-related pathway genes may concern to be predictors of colorectal cancer risk.

Genetic variants in Hippo signalling pathway-related genes affect the risk of colorectal cancer.

The Hippo signalling pathway plays a crucial role in carcinogenesis. Therefore, we hypothesized that genetic variants in genes related to this pathway are associated with the colorectal cancer risk. A case-control study including 1150 patients and 1342 controls was performed to assess the association of genetic variants of genes involved in the Hippo signalling pathway with the risk of colorectal cancer. The results were corrected for multiple comparisons using the false discovery rate (FDR). We used a regression model to determine the effects of single-nucleotide polymorphisms (SNPs) on the survival of patients with colorectal cancer in The Cancer Genome Atlas (TCGA) datasets. An expression quantitative trait loci (eQTL) analysis was performed using TCGA datasets and the Genotype-Tissue Expression (GTEx) project. Gene Expression Omnibus (GEO) datasets were used to provide additional data on the expression of genes in colorectal cancer. The SCRIB rs13251492 G allele was associated with a significantly decreased risk of colorectal cancer (odds ratio (OR) = 0.79, 95% confidence interval (CI) = 0.70-0.89, P = 7.76 × 10-5, P(FDR) = 6.98 × 10-4). Patients with the rs13251492 AG/GG allele experienced a longer recurrence-free survival (RFS) time (hazard ratio (HR) = 0.64, 95% CI = 0.42-0.99, P = 0.049) than patients with the rs13251492 A allele. The eQTL analysis revealed a significant association between rs13251492 and the expression of the SCRIB mRNA in colorectal tumors. Dual-luciferase reporter assays in DLD-1 and HCT116 cells revealed a lower enhancer activity of the rs13251492 G allele than the A allele. In addition, the SCRIB mRNA was expressed at markedly higher levels in colorectal cancer tissues than in normal tissues. Therefore, we identified the SCRIB rs13251492 variant as a novel colorectal cancer susceptibility locus and provided evidence of its functional relevance.

Genetic variants in m6A modification genes are associated with colorectal cancer risk.

The N6-methyladenosine (m6A) modification plays important regulatory roles in gene expression, cancer occurrence and metastasis. Herein, we aimed to explore the association between genetic variants in m6A modification genes and susceptibility to colorectal cancer. We used logistic regression models to investigate the associations between candidate single-nucleotide polymorphisms (SNPs) in 20 m6A modification genes and colorectal cancer risk. The false discovery rate (FDR) method was used for multiple comparisons. Dual luciferase assays and RNA m6A quantifications were applied to assess transcriptional activity and measure m6A levels, respectively. We found that SND1 rs118049207 was significantly associated with colorectal cancer risk in a Nanjing population (odds ratio (OR) = 1.69, 95% confidence interval (95% CI) = 1.31-2.18, P = 6.51 × 10-6). This finding was further replicated in an independent Beijing population (OR = 1.36, 95% CI = 1.04-1.79, P = 2.41 × 10-2) and in a combined analysis (OR = 1.52, 95% CI = 1.27-1.84, P = 8.75 × 10-6). Stratification and interaction analyses showed that SND1 rs118049207 multiplicatively interacted with the sex and drinking status of the patients to enhance their colorectal cancer risk (P = 1.56 × 10-3 and 1.41 × 10-2, respectively). Furthermore, rs118049207 served as an intronic enhancer on SND1 driven by DMRT3. SND1 mRNA expression was markedly increased in colorectal tumour tissues compared with adjacent normal tissues. The colorimetric m6A quantification strategy revealed that SND1 could alter m6A levels in colorectal cancer cell lines. Our findings indicated that genetic variants in m6A modification genes might be promising predictors of colorectal cancer risk.

Functional genetic variant of HSD17B12 in the fatty acid biosynthesis pathway predicts the outcome of colorectal cancer.

Fatty acids are involved in the development and progression of colorectal cancer (CRC). However, genetic effects of fatty acid biosynthesis pathway on CRC outcome are unclear. Cox regression model was used to evaluate genetic effects on CRC overall survival (OS) and progression-free survival (PFS), accompanied by calculating hazard ratios (HRs) and confidence intervals (CIs). Differential expression analysis, expression quantitative trait loci analysis, dual-luciferase reporter assay and chromatin immunoprecipitation assay were performed to explore the genetically biological mechanism. The rs10838164 C>T in HSD17B12 was significantly associated with an increased risk of death and progression of CRC (OS, HR = 2.12, 95% CI = 1.40-3.22, P = 4.03 × 10-4 ; PFS, HR = 1.64, 95% CI = 1.11-2.44, P = 1.35 × 10-2 ), of which T allele could increase HSD17B12 expression (P = 1.78 × 10-11 ). Subsequently, the functional experiments indicated that rs10838164 T allele could not only enhance the binding affinity of transcription factor YY1 to HSD17B12 region harbouring rs10838164 but also promote the transcriptional activity of HSD17B12, which was significantly up-regulated in colorectal tumour tissues. Our findings suggest that genetic variants in fatty acid biosynthesis pathway play an important role in CRC outcome.

Genetic variants in circTUBB interacting with smoking can enhance colorectal cancer risk.

Circular RNAs (circRNAs) are an intriguing class of regulatory RNAs involved in the tumorigenesis of many cancers, including colorectal cancer. Mechanistically, circRNAs sponge microRNAs (miRNAs) with specific miRNA response elements (MREs) and compete for regulatory target genes downstream. However, the genetic effects of MREs on colorectal cancer susceptibility remain unclear. The MREs of colorectal cancer-associated circRNAs (CRC-circRNAs) and corresponding single nucleotide polymorphisms (SNPs) were identified by the transcriptome of cancer cells and the 1000 Genomes Project. The association between candidate SNPs and colorectal cancer risk was evaluated in a Chinese population (1150 cases and 1342 controls) and two European populations (9023 cases and 386,896 controls) using logistic regression analysis. Among the 197 candidate SNPs within MREs of 186 CRC-circRNAs, rs25497 in circTUBB was significantly associated with colorectal cancer risk in a Chinese population after false discovery rate (FDR) correction [odds ratio (OR) = 1.78, 95% confidence interval (CI) = 1.44-2.21, P = 1.42 × 10-7, PFDR = 2.80 × 10-5] and even reached significance in a genome-wide association study (GWAS) under the dominant model (P = 1.28 × 10-8). Similar results were found in the European populations (ORmeta = 1.30, 95% CI = 1.10-1.53). Both stratification and interaction analyses revealed that rs25497 interacting with smoking affected the colorectal cancer risk (Pinteraction = 1.48 × 10-2). Here, we first comprehensively identified genetic variants in MREs of CRC-circRNAs and evaluated their effects on colorectal cancer risk in both Chinese and European populations. These findings provide basis for a comprehensive understanding of colorectal cancer etiology.

Combinations of single nucleotide polymorphisms identified in genome-wide association studies determine risk for colorectal cancer.

Genome-wide association studies (GWASs) have identified single nucleotide polymorphisms (SNPs) associated with colorectal cancer (CRC) risk, but whether these SNPs have additive effects on the risk of CRC remains unclear. We performed a systematic analysis of GWAS-identified SNPs using GWAS datasets from China (2,248 patients and 3,173 controls) and Europe (4,461 patients and 4,140 controls). We analyzed 58 independent variants from DNA samples from Chinese populations and found 19 SNPs that were significantly associated with CRC risk. We identified two genetic risk scores (GRSs) based on 58 and 19 SNPs, which were significantly associated with an increased risk of CRC. A decision curve analysis showed higher predictive power for the 58 SNPs. Using all the 58 SNPs to assess 5-year absolute risk (AR), we found that, at a cutoff of 0.4% (two times the median AR) and 0.6% (three times the median AR), approximately 32.76 and 16.45% of Chinese individuals were grouped as high risk for developing CRC, respectively. Risk stratification analysis further indicated that the population in the top 30% risk group accounted for 46.71% of the CRC cases. In addition, the 58 SNPs could explain approximately 1.13% of the phenotypic variance in Chinese populations. Similar findings were found in European populations. Combinations of SNPs identified in GWASs may therefore be useful for identifying individuals at high risk for CRC.

T1-weighted MRI of targeting atherosclerotic plaque based on CD40 expression on engulfed USPIO's cell surface.

Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of cholesterol within the arterial wall. Its progression can be monitored via magnetic resonance imaging (MRI). Ultrasmall Superparamagnetic Particles of Iron Oxide (USPIO) (<5 nm) have been employed as T1 contrast agents for MRI applications. In this study, we synthesized USPIO with an average surface carboxylation of approximately 5.28 nm and a zeta potential of -47.8 mV. These particles were phagocytosed by mouse aortic endothelial cells (USPIO-MAECs) and endothelial progenitor cells (USPIO-EPCs), suggesting that they can be utilized as potential contrast agent and delivery vehicle for the early detection of atherosclerosis. However, the mechanism by which this contrast agent is delivered to the plaque remains undetermined. Our results demonstrated that with increasing USPIO concentration during 10-100 µg ml-1, consistent change appeared in signal enhancement on T1-weighted MRI. Similarly, T1-weighted MRI of MAECs and EPCs treated with these concentrations exhibited a regular change in signal enhancement. Prussian blue staining of USPIO revealed substantial absorption into MAECs and EPCs after treatment with 50 µg ml-1USPIO for 24 h. The iron content in USPIO-EPCs was much higher (5 pg Fe/cell) than in USPIO-MAECs (0.8 pg Fe/cell). In order to substantiate our hypothesis that CD40 protein on the cell surface facilitates migration towards inflammatory cells, we utilized AuNPs-PEI (gold nanoparticles-polyethylenimine) carrying siRNACD40to knockout CD40 expression in MAECs. It has been documented that gold nanoparticle-oligonucleotide complexes could be employed as intracellular gene regulation agents for the control of protein level in cells. Our results confirmed that macrophages are more likely to bind to MAECs treated with AuNPs-PEI-siRNANC(control) for 72 h than to MAECs treated with AuNPs-PEI-siRNACD40(reduced CD40 expression), thus confirming CD40 targeting at the cellular level. When USPIO-MAECs and MAECs (control) were delivered to mice (high-fat-fed) via tail vein injection respectively, we observed a higher iron accumulation in plaques on blood vessels in high-fat-fed mice treated with USPIO-MAECs. We also demonstrated that USPIO-EPCs, when delivered to high-fat-fed mice via tail vein injection, could indeed label plaques by generating higher T1-weighted MRI signals 72 h post injection compared to controls (PBS, USPIO and EPCs alone). In conclusion, we synthesized a USPIO suitable for T1-weighted MRI. Our results have confirmed separately at the cellular and tissue andin vivolevel, that USPIO-MAECs or USPIO-EPCs are more accessible to atherosclerotic plaques in a mouse model. Furthermore, the high expression of CD40 on the cell surface is a key factor for targeting and USPIO-EPCs may have potential therapeutic effects.

Identification of common genetic variants in KCNQ family genes associated with gastric cancer survival in a Chinese population.

KCNQ family genes ( KCNQ1-5), encoding voltage-gated K + (Kv) channels, have been revealed to have potential pathophysiological roles in cancers. However, the associations between genetic variants located in KCNQ family genes and gastric cancer survival remain unclear. A large-scale cohort comprising 1,135 Chinese gastric cancer patients was enrolled to identify genetic variants in KCNQ family genes associated with overall survival (OS). Based on the survival evaluation of all five members, KCNQ1 was selected for subsequent genetic analysis. Cox regression models and stepwise Cox regression models were conducted to evaluate survival-related genetic variants. We found that KCNQ1 rs10832417 was associated with increased OS in gastric cancer patients (adjusted hazard ratio (HR) = 0.84, 95% confidence interval (CI): 0.72-0.98, P = 0.023). Subsequently, a nomogram was generated to support the prognostic capacity and clinical translation of rs10832417 variants. The rs10832417 T allele was predicted to increase the minimum free energy (MFE) of the secondary structure. Furthermore, we observed that gastric cancer patients with downregulation of KCNQ1 had poor survival in multiple public datasets. The present study found that KCNQ1 rs10832417 could serve as an independent prognostic predictor of gastric cancer, yielding novel insight into the progression and survival of gastric cancer.

Differential temporal utility of passively sensed smartphone features for depression and anxiety symptom prediction: a longitudinal cohort study.

While studies show links between smartphone data and affective symptoms, we lack clarity on the temporal scale, specificity (e.g., to depression vs. anxiety), and person-specific (vs. group-level) nature of these associations. We conducted a large-scale (n = 1013) smartphone-based passive sensing study to identify within- and between-person digital markers of depression and anxiety symptoms over time. Participants (74.6% female; M age = 40.9) downloaded the LifeSense app, which facilitated continuous passive data collection (e.g., GPS, app and device use, communication) across 16 weeks. Hierarchical linear regression models tested the within- and between-person associations of 2-week windows of passively sensed data with depression (PHQ-8) or generalized anxiety (GAD-7). We used a shifting window to understand the time scale at which sensed features relate to mental health symptoms, predicting symptoms 2 weeks in the future (distal prediction), 1 week in the future (medial prediction), and 0 weeks in the future (proximal prediction). Spending more time at home relative to one's average was an early signal of PHQ-8 severity (distal ß = 0.219, p = 0.012) and continued to relate to PHQ-8 at medial (ß = 0.198, p = 0.022) and proximal (ß = 0.183, p = 0.045) windows. In contrast, circadian movement was proximally related to (ß = -0.131, p = 0.035) but did not predict (distal ß = 0.034, p = 0.577; medial ß = -0.089, p = 0.138) PHQ-8. Distinct communication features (i.e., call/text or app-based messaging) related to PHQ-8 and GAD-7. Findings have implications for identifying novel treatment targets, personalizing digital mental health interventions, and enhancing traditional patient-provider interactions. Certain features (e.g., circadian movement) may represent correlates but not true prospective indicators of affective symptoms. Conversely, other features like home duration may be such early signals of intra-individual symptom change, indicating the potential utility of prophylactic intervention (e.g., behavioral activation) in response to person-specific increases in these signals.

Salicylic acid accelerates carbon starvation-induced leaf senescence in Arabidopsis thaliana by inhibiting autophagy through Nonexpressor of pathogenesis-related genes 1.

In plants, leaf senescence is regulated by several factors, including age and carbon starvation. The molecular mechanism of age-regulated developmental leaf senescence differs from that of carbon starvation-induced senescence. Salicylic acid (SA) and Nonexpressor of pathogenesis-related genes 1 (NPR1) play important roles in promoting developmental leaf senescence. However, the relationship between SA signaling and carbon starvation-induced leaf senescence is not currently well understood. Here, we used Arabidopsis thaliana as material and found that carbon starvation-induced leaf senescence was accelerated in the SA dihydroxylase mutants s3hs5h compared to the Columbia ecotype (Col). Exogenous SA treatment significantly promoted carbon starvation-induced leaf senescence, especially in NPR1-GFP. Increasing the endogenous SA and overexpression of NPR1 inhibited carbon starvation-induced autophagy. However, mutation of NPR1 delayed carbon starvation-induced leaf senescence, increased autophagosome production and accelerated autophagic degradation of the Neighbor of BRCA1 gene 1 (NBR1). In conclusion, SA promotes carbon starvation-induced leaf senescence by inhibiting autophagy via NPR1.

Specific associations of passively sensed smartphone data with future symptoms of avoidance, fear, and physiological distress in social anxiety.

Background: Prior literature links passively sensed information about a person's location, movement, and communication with social anxiety. These findings hold promise for identifying novel treatment targets, informing clinical care, and personalizing digital mental health interventions. However, social anxiety symptoms are heterogeneous; to identify more precise targets and tailor treatments, there is a need for personal sensing studies aimed at understanding differential predictors of the distinct subdomains of social anxiety. Our objective was to conduct a large-scale smartphone-based sensing study of fear, avoidance, and physiological symptoms in the context of trait social anxiety over time. Methods: Participants (n = 1013; 74.6 % female; M age = 40.9) downloaded the LifeSense app, which collected continuous passive data (e.g., GPS, communication, app and device use) over 16 weeks. We tested a series of multilevel linear regression models to understand within- and between-person associations of 2-week windows of passively sensed smartphone data with fear, avoidance, and physiological distress on the self-reported Social Phobia Inventory (SPIN). A shifting sensor lag was applied to examine how smartphone features related to SPIN subdomains 2 weeks in the future (distal prediction), 1 week in the future (medial prediction), and 0 weeks in the future (proximal prediction). Results: A decrease in time visiting novel places was a strong between-person predictor of social avoidance over time (distal ß = -0.886, p = .002; medial ß = -0.647, p = .029; proximal ß = -0.818, p = .007). Reductions in call- and text-based communications were associated with social avoidance at both the between- (distal ß = -0.882, p = .002; medial ß = -0.932, p = .001; proximal ß = -0.918, p = .001) and within- (distal ß = -0.191, p = .046; medial ß = -0.213, p = .028) person levels, as well as between-person fear of social situations (distal ß = -0.860, p < .001; medial ß = -0.892, p < .001; proximal ß = -0.886, p < .001) over time. There were fewer significant associations of sensed data with physiological distress. Across the three subscales, smartphone data explained 9-12 % of the variance in social anxiety. Conclusion: Findings have implications for understanding how social anxiety manifests in daily life, and for personalizing treatments. For example, a signal that someone is likely to begin avoiding social situations may suggest a need for alternative types of exposure-based interventions compared to a signal that someone is likely to begin experiencing increased physiological distress. Our results suggest that as a prophylactic means of targeting social avoidance, it may be helpful to deploy interventions involving social exposures in response to decreases in time spent visiting novel places.

Analyzing text message linguistic features: Do people with depression communicate differently with their close and non-close contacts?

BACKGROUND: Relatively little is known about how communication changes as a function of depression severity and interpersonal closeness. We examined the linguistic features of outgoing text messages among individuals with depression and their close- and non-close contacts. METHODS: 419 participants were included in this 16-week-long observational study. Participants regularly completed the PHQ-8 and rated subjective closeness to their contacts. Text messages were processed to count frequencies of word usage in the LIWC 2015 libraries. A linear mixed modeling approach was used to estimate linguistic feature scores of outgoing text messages. RESULTS: Regardless of closeness, people with higher PHQ-8 scores tended to use more differentiation words. When texting with close contacts, individuals with higher PHQ-8 scores used more first-person singular, filler, sexual, anger, and negative emotion words. When texting with non-close contacts these participants used more conjunctions, tentative, and sadness-related words and fewer first-person plural words. CONCLUSION: Word classes used in text messages, when combined with symptom severity and subjective social closeness data, may be indicative of underlying interpersonal processes. These data may hold promise as potential treatment targets to address interpersonal drivers of depression.

Integrated multi-omics approach to distinct molecular characterization and classification of early-onset colorectal cancer.

Incidence of early-onset colorectal cancer (EOCRC), defined by a diagnosed age under 50 years, is increasing, but its heterogeneous etiologies that differ from general CRC remain undetermined. We initially characterize the genome, epigenome, transcriptome, and proteome of tumors from 79 patients in a Chinese CRC cohort. Data for an additional 126 EOCRC subjects are obtained from the International Cancer Genome Consortium Chinese cohort and The Cancer Genome Atlas European cohort. We observe that early-onset tumors have a high tumor mutation burden; increased DNA repair features by mutational signature 3 and multi-layer pathway enrichments; strong perturbations at effects of DNA methylation and somatic copy-number alteration on gene expression; and upregulated immune infiltration as hot tumors underlying immunophenotypes. Notably, LMTK3 exhibits ancestral mutation disparity, potentially being a functional modulator and biomarker that drives molecular alterations in EOCRC development and immunotherapies. This integrative omics study provides valuable knowledge for precision oncology of CRC.

Association of genetic variants in autophagy-lysosome pathway genes with susceptibility and survival to prostate cancer.

BACKGROUND: Previous studies have indicated the connections between autophagy-lysosome pathway genes dysfunction and prostate cancer, but few studies have investigated whether single nucleotide polymorphisms (SNPs) in autophagy-lysosome pathway genes are implicated in prostate cancer risk and survival. MATERIALS AND METHODS: Logistic regression analysis and stepwise Cox regression analysis were conducted in 4,662 cases and 3,114 controls from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. The false positive rate probability (FPRP) method was applied to correct for multiple comparisons. Gene-based analysis was calculated by versatile gene-based association study approach. RESULTS: We found that SLC11A1 rs7573065 significantly increased the risk of prostate cancer [adjusted odds ratio (OR) = 1.24, 95% confidence interval (CI) = 1.06-1.46, P = 7.02 × 10-3, FPRP = 0.082]. Furthermore, rs7573065 was confirmed as the independent predicator of overall survival (OS) for prostate cancer patients [Hazard ratio (HR) = 1.30, 95% CI = 1.01-1.66, P = 0.041]. The significant association between SLC11A1 and prostate cancer risk was calculated by gene-based analysis (P = 0.030). We also observed that the mRNA of SLC11A1 in prostate tumor tissues was significantly over-expressed than that in normal tissues. CONCLUSION: This study suggested that rs7573065 in SLC11A1 was associated with an increased risk and poor OS of prostate cancer. Our findings may provide evidence for genetic variants in autophagy-lysosome pathway as the risk and prognostic biomarkers for prostate cancer.

Expression of PEI-coated gold nanoparticles carrying exogenous gene in periwinkle mesophyll cells and its practice in huanglongbing research.

Huanglongbing (HLB) is a devastating disease of citrus, which is mostly caused by Candidatus Liberibacter asiaticus (CLas). To realize the specific application of nano-transgenic technology in HLB, AuNPs-PEI (Gold Nanoparticles-Polyethylenimine) was used to carry foreign genes into the leaves of periwinkle (Catharanthus roseus) by infiltration. Here, we demonstrated that NPR1-GFP protein expression was observed from the 12th hour to the 10th day after infiltrating AuNPs-PEI-pNPR1 (Arabidopsis thaliana nonexpressor of pathogenesis-related gene 1)-GFP. Fluorescence of mCherry was observed 6 h after AuNPs-PEI-pNLS (nuclear localization signal sequence)-mCherry infiltration and fluorescence of FAM was observed in the nucleus 4 h after AuNPs-PEI-FAM-siRNA NPR1 infiltration. In addition, NPR1-GFP expression in CLas-infected periwinkle leaves was significantly higher than that in healthy periwinkle leaves after infiltration. Our work confirmed that the expression of exogenous NPR1-GFP could reduce the CLas titers by promoting the expression of PR (pathogenesis related) genes and ICS (isochorismate synthase) gene.

Genome-Wide Association Analyses Identify CATSPERE as a Mediator of Colorectal Cancer Susceptibility and Progression.

Genome-wide association studies (GWAS) have revealed numerous genetic loci associated with colorectal cancer risk, but the mechanisms underlying these loci have not been comprehensively elucidated. In this study, we performed a GWAS meta-analysis with a two-stage replication strategy by combining eight colorectal cancer cohorts encompassing 7,186 cases and 8,512 controls in Chinese populations, accompanied by an evaluation encompassing 29,832 cases and 406,694 controls in European populations. The genetic variant rs505706 A>G, located at chr1q44 in the upstream region of catsper channel auxiliary subunit epsilon (CATSPERE), was associated with colorectal cancer risk and exhibited genome-wide significance (OR, 0.73; 95% confidence interval, 0.67-0.80; P = 9.75 × 10-12). Cell line and animal models were applied to assess the biological function of the genetic risk variant and the corresponding susceptibility gene. Genetically, the G allele of rs505706 resulted in long-range regulatory effects, reducing the binding affinity of POU2F1 for the CATSPERE promoter and thus abolishing the inhibitory effect of POU2F1 on CATSPERE transcription. Phenotypically, CATSPERE upregulation attenuated tumor growth in both colorectal cancer cells and xenograft models. Mechanistically, CATSPERE promoted calcium ion influx and apoptotic pathway activity. In zebrafish models, CATSPERE exerted pleiotropic effects, enhancing the progression of colorectal cancer. Collectively, these findings highlight a colorectal cancer susceptibility locus that acts to remotely modulate the activity of CATSPERE, a gene that mediates multiple functions involved in colorectal tumorigenesis and progression. SIGNIFICANCE: A GWAS meta-analysis identifies a novel susceptibility locus harboring a genetic risk variant that mediates pleiotropic biological effects in colorectal tumorigenesis and progression.

Genetic variants in the cholesterol biosynthesis pathway genes and risk of prostate cancer.

Previous studies have found the relationship between cholesterol biosynthesis pathway genes and the risk or prognosis of prostate cancer (PCa), while there is no definite evidence that genetic variants in the cholesterol biosynthesis pathway gene is related to PCa risk. Consequently, we performed this study to explore the associations of single-nucleotide polymorphisms (SNPs) in the cholesterol biosynthesis pathway with PCa risk. We systematically evaluated the association of SNPs in 21 cholesterol biosynthesis pathway genes with the risk of PCa using the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial database using a logistic regression model. Gene expression data of PCa from Gene Expression Omnibus (GEO) datasets and the Cancer Genome Atlas (TCGA) database were applied for mRNA expression analysis. The TCGA database was used to perform expression quantitative trait loci (eQTL) analysis. The interaction between demographic factors and SNPs was analyzed using two-by-four tables. We found T allele of rs67415672 in HMGCS1 is a significant protective allele of PCa [adjusted odds ratio (OR) = 0.90, 95% confidence interval (CI) = 0.83-0.97, P = 4.16 × 10-3]. Moreover, rs67415672 was an eQTL for HMGCS1 (P = 2.23 × 10-6). The expression of HMGCS1 significantly decreased in PCa primary tumors than that in normal tissues. These findings indicated that the HMGCS1 rs67415672 might be possible functional susceptibility loci for PCa.

Association study between genetic variants in retinol metabolism pathway genes and prostate cancer risk.

BACKGROUND: Evidence suggests that serum retinol level is associated with prostate cancer risk, but the association between genetic variants in the retinol metabolism pathway genes and prostate cancer risk remains unclarified. METHODS: Single-nucleotide polymorphisms (SNPs) in 31 genes in the retinol metabolism pathway were genotyped to evaluate the association with prostate cancer risk in 4,662 cases and 3,114 controls from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. The gene expression analysis was evaluated using data from the Gene Expression Omnibus (GEO) datasets and the Cancer Genome Atlas (TCGA) database. Data from the Genotype-Tissue Expression (GTEx) project dataset were utilized to perform the expression quantitative trait loci (eQTL) analysis. RESULTS: Two SNPs were significantly associated with prostate cancer risk [rs1330286 in ALDH1A1: odds ratio (OR) = 0.88, 95% confidence interval (CI) = 0.83-0.94, p = 2.45 × 10-4 ; rs4646653 in ALDH1A3: OR = 1.17, 95% CI =1.07-1.27, p = 4.33 × 10-4 ]. Moreover, the mRNA level of ALDH1A3 was significantly higher in prostate cancer tissues than in normal tissues in both TCGA datasets and GEO datasets (p = 1.63 × 10-12 and p = 4.33 × 10-2 , respectively). rs1330286 was an eQTL of ALDH1A1 (P = 2.90 × 10-3 ). CONCLUSION: Our findings highlight that genetic variants in retinol metabolism pathway genes are associated with prostate cancer risk.

Sex hormones and genetic variants in hormone metabolic pathways associated with the risk of colorectal cancer.

OBJECTIVE: The different incidence of colorectal cancer between the sexes suggests that sex hormones may be involved in the susceptibility to colorectal cancer. The association between sex hormones and genetic variants in hormone metabolic pathways and the colorectal cancer risk remains unclear. METHODS: We detected sex hormone levels in plasma from colorectal cancer patients and controls in males by ultra-high-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). We evaluated the clinical significance of sex hormones on colorectal cancer diagnosis with the area under the receiver operating characteristic curve (AUC). The role of genetic variants in hormone metabolic pathways in the colorectal cancer risk was assessed by a logistic regression model. The biological functions were detected by luciferase reporter assays and cell behavior experiments. RESULTS: We found that 2-methoxyestrone (2-MeO-E1) was highly expressed in cases (PFDR = 3.48 × 10-19). The expression of 2-MeO-E1 in plasma showed improved accuracy for predicting colorectal cancer (AUC = 0.88). In the 2-MeO-E1 metabolic pathway, rs165599 in COMT was significantly associated with an increased risk of colorectal cancer (P = 0.009). Mechanistically, we found that the rs165599 G allele could decrease the binding ability of miR-22-3p to the COMT 3'-UTR. Furthermore, knockdown of COMT inhibited cell proliferation, induced cell apoptosis and arrested the cell cycle in the G1 phase. CONCLUSION: This is the first study to show that 2-MeO-E1 and a genetic variant in COMT contribute to the susceptibility to colorectal cancer. These results shed light on the different incidence of colorectal cancer between the sexes.