Capecitabine or Capecitabine Plus Oxaliplatin Versus Fluorouracil Plus Cisplatin in Definitive Concurrent Chemoradiotherapy for Locally Advanced Esophageal Squamous Cell Carcinoma (CRTCOESC): A Multicenter, Randomized, Open-Label, Phase 3 Trial.

PURPOSE: This phase 3 trial aimed to compare the efficacy and safety of capecitabine or capecitabine plus oxaliplatin (XELOX) with those of fluorouracil plus cisplatin (PF) in definitive concurrent chemoradiotherapy (DCRT) for inoperable locally advanced esophageal squamous cell carcinoma (ESCC). METHODS: Patients were randomly assigned to receive two cycles of capecitabine, XELOX, or PF along with concurrent intensity-modulated radiation therapy. Patients in each arm were again randomly assigned to receive two cycles of consolidation chemotherapy or not. The primary end points were 2-year overall survival (OS) rate and incidence of grade ≥3 adverse events (AEs). RESULTS: A total of 246 patients were randomly assigned into the capecitabine (n = 80), XELOX (n = 85), and PF (n = 81) arms. In capecitabine, XELOX, and PF arms, the 2-year OS rate was 75%, 66.7%, and 70.9% (capecitabine v PF: hazard ratio [HR], 0.91 [95% CI, 0.61 to 1.35]; nominal P = .637; XELOX v PF: 0.86 [95% CI, 0.58 to 1.27]; P = .444); the median OS was 40.9 (95% CI, 34.4 to 49.9), 41.9 (95% CI, 28.6 to 52.1), and 35.4 (95% CI, 30.4 to 45.4) months. The incidence of grade ≥3 AEs during the entire treatment was 28.8%, 36.5%, and 45.7%, respectively. Comparing the consolidation chemotherapy with the nonconsolidation chemotherapy groups, the median OS was 41.9 (95% CI, 34.6 to 52.8) versus 36.9 (95% CI, 28.5 to 44) months (HR, 0.71 [95% CI, 0.52 to 0.99]; nominal P = .0403). CONCLUSION: Capecitabine or XELOX did not significantly improve the 2-year OS rate over PF in DCRT for inoperable locally advanced ESCC. Capecitabine showed a lower incidence of grade ≥3 AEs than PF did.

RUNX1-induced upregulation of PTGS2 enhances cell growth, migration and invasion in colorectal cancer cells.

Colorectal cancer (CRC) arises via the progressive accumulation of dysregulation in key genes including oncogenes and tumor-suppressor genes. Prostaglandin-endoperoxide synthase 2 (PTGS2, also called COX2) acts as an oncogenic driver in CRC. Here, we explored the upstream transcription factors (TFs) responsible for elevating PTGS2 expression in CRC cells. The results showed that PTGS2 silencing repressed cell growth, migration and invasion in HCT116 and SW480 CRC cells. The two fragments (499-981 bp) and (1053-1434 bp) were confirmed as the core TF binding profiles of the PTGS2 promoter. PTGS2 expression positively correlated with RUNX1 level in colon adenocarcinoma (COAD) samples using the TCGA-COAD dataset. Furthermore, RUNX1 acted as a positive regulator of PTGS2 expression by promoting transcriptional activation of the PTGS2 promoter via the 1086-1096 bp binding motif. In conclusion, our study demonstrates that PTGS2 upregulation induced by the TF RUNX1 promotes CRC cell growth, migration and invasion, providing an increased rationale for the use of PTGS2 inhibitors in CRC prevention and treatment.

Functional analysis of CYP71AV1 reveals the evolutionary landscape of artemisinin biosynthesis.

Artemisinin biosynthesis, unique to Artemisia annua, is suggested to have evolved from the ancestral costunolide biosynthetic pathway commonly found in the Asteraceae family. However, the evolutionary landscape of this process is not fully understood. The first oxidase in artemisinin biosynthesis, CYP71AV1, also known as amorpha-4,11-diene oxidase (AMO), has specialized from ancestral germacrene A oxidases (GAOs). Unlike GAO, which exhibits catalytic promiscuity toward amorpha-4,11-diene, the natural substrate of AMO, AMO has lost its ancestral activity on germacrene A. Previous studies have suggested that the loss of the GAO copy in A. annua is responsible for the abolishment of the costunolide pathway. In the genome of A. annua, there are two copies of AMO, each of which has been reported to be responsible for the different product profiles of high- and low-artemisinin production chemotypes. Through analysis of their tissue-specific expression and comparison of their sequences with those of other GAOs, it was discovered that one copy of AMO (AMOHAP) exhibits a different transcript compared to the reported artemisinin biosynthetic genes and shows more sequence similarity to other GAOs in the catalytic regions. Furthermore, in a subsequent in vitro enzymatic assay, the recombinant protein of AMOHAP unequivocally demonstrated GAO activity. This result clearly indicates that AMOHAP is a GAO rather than an AMO and that its promiscuous activity on amorpha-4,11-diene has led to its misidentification as an AMO in previous studies. In addition, the divergent expression pattern of AMOHAP compared to that of the upstream germacrene A synthase may have contributed to the abolishment of costunolide biosynthesis in A. annua. Our findings reveal a complex evolutionary landscape in which the emergence of a new metabolic pathway replaces an ancestral one.

Componential usage patterns in dengue 4 viruses reveal their better evolutionary adaptation to humans.

There have been at least four types of dengue outbreaks in the past few years. The evolutionary characteristics of dengue viruses have aroused great concerns. The evolutionary characteristics of dengue 4 viruses are studied in the present study based on their base usage patterns and codon usage patterns. The effective number of codons and relative synonymous codon usage (RSCU) values of four types of dengue viruses were counted or calculated. The Kullback-Leibler (K-L) divergences of relative synonymous codon usage from dengue viruses to humans and the Kullback-Leibler divergences of amino acid usage patterns from dengue viruses to humans were calculated to explore the adaptation levels of dengue viruses. The results suggested that: (1) codon adaptation in dengue 4 viruses occurred through an evolutionary process from 1956 to 2021, (2) overall relative synonymous codon usage values of dengue 4 viruses showed more similarities to humans than those of other subtypes of dengue viruses, and (3) the smaller Kullback-Leibler divergence of amino acid usage and relative synonymous codon usage from dengue viruses to humans indicated that the dengue 4 viruses adapted to human hosts better. All results indicated that both mutation pressure and natural selection pressure contributed to the codon usage pattern of dengue 4 viruses more obvious than to other subtypes of dengue viruses and that the dengue 4 viruses adapted to human hosts better than other types of dengue viruses during their evolutionary process.

CircUSP36 attenuates ischemic stroke injury through the miR-139-3p/SMAD3/Bcl2 signal axis.

Circular RNAs (circRNAs) play important roles in a variety of physiological and pathological processes. Researches demonstrated that circRNAs provided novel strategies for the prevention and treatment of IS. However, the biological function of hsa_circ_0045932 (circUSP36) has not been revealed yet. Here, we explored the effect of circUSP36 on IS and its mechanism. In the present study, we found that circUSP36 expression was significantly decreased in the peripheral blood of IS patients and was negatively correlated with the severity, infarct volume and poor prognosis of IS. Functionally, circUSP36 silencing inhibited cellular activity and proliferation and promoted apoptosis after oxygen-glucose deprivation/reperfusion (OGD/R) treatment, while circUSP36 overexpression reversed these cellular phenotypes in vitro. Adeno-associated virus (AAV)-mediated overexpression of circUSP36 attenuates brain injury and neurological deficit and promotes motor function recovery of transient middle cerebral artery occlusion (tMCAO) mice. Subsequently, the RNA antisense purification (RAP) and luciferase reporter assay confirmed that circUSP36 acts as a sponge to adsorb miR-139-3p, and miR-139-3p could bind and inhibit SMAD3 expression. Further rescue experiments showed that both miR-139-3p overexpression and SMAD3 silencing could abolish the antiapoptotic effect of circUSP36. In summary, we reveal for the first time that circUSP36 attenuates ischemic stroke injury through the miR-139-3p/SMAD3/Bcl2 signal axis, which make circUSP36 a potential therapeutic target for IS.

Whole Transcriptome Sequencing Identified CircRNA Profiles and the Related Networks in Schizophrenia.

Schizophrenia (SCZ) is a complex psychiatric syndrome with uncertain etiology. This study aimed to uncover the expression profiles and related regulatory networks of circular RNA (circRNA) in SCZ. Whole transcriptome sequencing was performed to assess the expression profiles of circRNAs and microRNAs (miRNAs) in the peripheral blood of three patients with SCZ and three healthy controls. Five circRNAs were validated by quantitative real-time PCR (RT-qPCR). TargetScan, RNAhybrid, and miRanda were performed to predict the target miRNAs of the top 10 dysregulated circRNAs. MiRTarBase was applied to predict the target mRNAs of miRNAs to construct circRNA-miRNA-mRNA (ceRNA) networks. CatRAPID and StarBase were used to predict the target RNA-binding proteins (RBPs) of circRNAs to construct circRNA-RBP networks. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to predict the potential functions of the maternal genes of circRNAs and target mRNAs. In total, 450 circRNAs and 160 miRNAs were found to be significantly differentially expressed, with hsa_circ_0003999 and hsa_circ_0030042 being significantly different between patients with SCZ and healthy controls (P < 0.05). The PI3K-AKT, MAPK, and cell cycle pathways were predicted to be associated with SCZ. GO analysis showed that focal adhesion was related to SCZ. The ceRNA networks, especially hsa_circ_0006151/hsa-miR-4685-3p/ZBTB16, hsa_circ_0000008/hsa-miR-1976/ZBTB16, and the hsa_circ_0007963/hsa-miR-3127-3p/UBE2K axes have the greatest probability of being involved in the pathophysiology of SCZ. The RBP networks, FXR1, FXR2, DGCR8, XRN2, FMR1, and QKI were the RBPs associated with SCZ. In conclusion, the circRNAs, ceRNAs, and RBP network expression patterns and related pathways indicate the potential role of circRNAs in the pathogenesis and development of SCZ.

Genome-wide association studies-supported rs12966547 variant of the long noncoding RNA LOC105372125 is significantly associated with susceptibility to schizophrenia and bipolar disorder in Han Chinese women.

OBJECTIVE: Genome-wide association studies have found that rs12966547 polymorphism was associated with susceptibility to schizophrenia in European populations. Recent studies showed that a genetic overlap may exist in schizophrenia and bipolar disorder. Here, we analyzed the associations between LOC105372125 rs12966547 polymorphism and schizophrenia and bipolar disorder in the Han Chinese population. METHODS: Our study recruited 548 schizophrenia patients, 512 bipolar disorder patients, and 598 healthy controls. Genotyping of rs12966547 were performed using the Sequenom MassARRAY platform. RESULTS: A significant association between rs12966547 polymorphism and susceptibility to bipolar disorder was observed after adjusting for sex and age (additive model: Padj = 0.040, recessive model: Padj = 0.044). However, no significant association was found between rs12966547 polymorphism and schizophrenia risk (all P > 0.05). In the analysis of gender, rs12966547 polymorphism was significantly associated with bipolar disorder (additive model: Padj = 0.027) and schizophrenia (dominant model: Padj = 0.039) in women. However, no significant association was found between rs12966547 polymorphism and the risk of bipolar disorder or schizophrenia in men (all Padj > 0.05). CONCLUSIONS: Polymorphism of rs12966547 on the long noncoding RNA LOC10537215 are a shared genetic variant of schizophrenia and bipolar disorder in Han Chinese women.

Analysis of expression profiles and bioinformatics suggests that plasma exosomal circular RNAs may be involved in ischemic stroke in the Chinese Han population.

Circular RNAs (circRNAs) have been confirmed to be associated with ischemic stroke(IS), but the involvement of exosomal circRNAs in plasma still needs to be extensively discussed. Therefore, we aimed to investigate the expression profile of exosomal circRNAs in plasma and the potential roles and mechanisms of exosomal circRNAs in the pathogenesis of ischemic stroke in the Chinese Han population. In this study, the plasma exosomal circRNA expression profiles of three IS patients and three healthy controls were analyzed using circRNA sequencing. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis and circRNA-miRNA-mRNA regulatory network analysis were performed for the aberrantly expressed genes. Protein-protein interaction (PPI) networks and molecular complex detection algorithms (MCODEs) were analyzed by STRING and Cystoscope for functional annotation and construction, respectively. RNA-Seq analysis revealed that a total of 3540 circRNAs were aberrantly expressed in exosomes, 1177 circRNAs were significantly upregulated, and 2363 circRNAs were downregulated in IS patients compared to healthy controls. Bioinformatics analysis revealed that the parental genes of differentially expressed circRNAs as well as the mRNAs predicted in the circRNA-miRNA-mRNA regulatory network are enriched for signaling pathways associated with IS pathology, such as the MAPK signaling pathway, lipid and atherosclerosis, neurotrophic factor signaling pathways, mTOR signaling pathway, the p53 signaling pathway etc. Then, 10 hub genes were identified from the PPI and module networks, including FBXW11, FBXW7, UBE2V2, ANAPC7, CDC27, UBC, CDC5L, POLR2H, POLR2F and RBX1. Overall, the present study provides evidence of an altered plasma exosomal circRNA expression profile and its potential function in IS. Our findings may contribute to the study of the pathogenesis of circRNAs in IS and provide ideas for studying potential diagnostic biomarkers and therapeutic targets for IS.

Application of machine learning in diagnostic value of mRNAs for bipolar disorder.

PURPOSE: Bipolar disorder (BD) is a type of severe mental illness with symptoms of mania or depression, it is necessary to find out effective diagnostic biomarkers for BD due to diagnosing BD is based on clinical interviews without objective indicators. MATERIALS AND METHODS: The mRNA expression levels of genes included PIK3R1, FYN, TP53, PRKCZ, PRKCB, and YWHAB in the peripheral blood of 43 patients with bipolar disorder and 47 healthy controls were detected. Machine learning methods included Artificial Neural Networks, Extreme Gradient Boosting, Random Forest, and Support Vector Machine were adopted to fit different gene combinations to evaluate diagnostic value for bipolar disorder. RESULTS: The combination 'PIK3R1 + FYN' in the SVM model showed the best diagnostic value, with AUC, sensitivity, and specificity values of 0.951, 0.928, and 0.937, respectively. CONCLUSIONS: The diagnostic efficiency for bipolar disorder was significantly improved by fitting PIK3R1 and FYN through the Support Vector Machine model.

A colorimetric and fluorescence dual-signal determination for iron (II) and H2O2 in food based on sulfur quantum dots.

A colorimetric and fluorescence dual-signal method based on sulfur quantum dots (SQDs) was established for determination of iron (II) (Fe2+) and H2O2 in foods. Due to the complexation of Fe2+ with SQD, Fe2+ can cause fluorescence quenching of SQDs, and the color of the mixed solution changed from light yellow to deep green. By use of Fenton reaction, H2O2 can restore the quenched fluorescence of SQDs, and the color of the mixture changed from green to colorless. The concentration of Fe2+ and H2O2 has a good linear relationship with the fluorescence intensity and absorbance in the range of 2.5-55 µM and 1.25-500 µM, and the detection limits were 1.41 µM and 0.54 µM, respectively. For determination of H2O2, the linear ranges were 1.17-1.97 mM and 0.867-1.50 mM, and the detection limits were 0.03 µM and 0.06 µM, respectively.

LncRNA SERPINB9P1 expression and polymorphisms are associated with ischemic stroke in a Chinese Han population.

Long noncoding RNAs (lncRNAs) were reported to play important roles in the pathogenesis of ischemic stroke (IS). Our study aimed to investigate the role of lncRNA SERPINB9P1 expression in ischemic stroke and the association between SERPINB9P1 polymorphisms and IS risk, as well as examine the correlation of SERPINB9P1 expression and variants with clinical parameters of IS. The SERPINB9P1 levels in human participants and oxygen-glucose deprivation (OGD)-treated human A172 cells were measured by qRT-PCR. The SERPINB9P1 polymorphisms (rs375556 and rs318429) were genotyped by the MassARRAY platform. We found that the SERPINB9P1 expression was significantly downregulated in patients with IS compared with that in healthy controls. On the 14th day in the hospital, the SERPINB9P1 level in patients with moderate and severe stroke was significantly downregulated compared with the normal group. After stratification by gender, the rs375556 polymorphism was significantly associated with susceptibility to female IS in the recessive model, and the significant association remained after adjusting for age. After adjusting for gender and age, rs318429 was significantly associated with FPG and D-D levels, and rs375556 was significantly associated with INR and PTA levels in IS cases. Besides, the lncRNA SERPINB9P1 expressed downregulated in OGD/reoxygenation-treated human A172 cells. In conclusion, the lncRNA SERPINB9P1 may protect against cerebral ischemia-reperfusion injury and neurological impairment after IS. The SERPINB9P1 rs375556 polymorphism was associated with susceptibility to female IS, and SERPINB9P1 polymorphisms may influence the metabolism of blood glucose and regulation of coagulation function in patients with IS.

The machine learning algorithm for the diagnosis of schizophrenia on the basis of gene expression in peripheral blood.

BACKGROUND: Schizophrenia (SCZ) is a highly heritable mental disorder with a substantial disease burden. Machine learning (ML) method can be used to identify individuals with SCZ on the basis of blood gene expression data with high accuracy. METHODS: This study aimed to differentiate patients with SCZ from healthy individuals by using the messenger RNA expression level in peripheral blood of 48 patients with SCZ and 50 controls via ML algorithms, namely, artificial neural networks, extreme gradient boosting, support vector machine (SVM), decision tree, and random forest. The expression of six mRNAs was detected using quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS: The relative expression levels of GNAI1 (P < 0.001), PRKCA (P < 0.001), and PRKCB (P = 0.021) increased in the SCZ group, whereas those of FYN (P < 0.001), LYN (P = 0.022), and YWHAZ (P < 0.001) decreased in the SCZ group. We generated models with various combinations of genes based on five ML algorithms. The SVM model with six factors (GNAI1, FYN, PRKCA, YWHAZ, PRKCB, and LYN genes) was the best model for distinguishing patients with SCZ from healthy individuals (AUC = 0.993, sensitivity = 1.000, specificity = 0.895, and Youden index = 0.895). CONCLUSIONS: This study suggested that the combination of genes using the ML method is better than the use of a single gene to discriminate patients with SCZ from healthy individuals. The combination of GNAI1, FYN, PRKCA, YWHAZ, PRKCB, and LYN under the SVM model can be used as a diagnostic biomarker for SCZ.