OpenNAU:An open-source platform for normalizing,analyzing,and visualizing cancer untargeted metabolomics data

Objective:As an important part of metabolomics analysis,untargeted metabolomics has become a powerful tool in the study of tumor mechanisms and the discovery of metabolic markers with high-throughput spectrometric data which also poses great challenges to data analysis,from the extraction of raw data to the identification of differential metabolites.To date,a large number of analytical tools and processes have been developed and constructed to serve untargeted metabolomics research.The different selection of analytical tools and parameter settings lead to varied results of untargeted metabolomics data.Our goal is to establish an easily operated platform and obtain a repeatable analysis result.Methods:We used the R language basic environment to construct the preprocessing system of the original data and the LAMP(Linux+Apache+MySQL+PHP)architecture to build a cloud mass spectrum data analysis system.Results:An open-source analysis software for untargeted metabolomics data(openNAU)was constructed.It includes the extraction of raw mass data and quality control for the identification of differential metabolic ion peaks.A reference metabolomics database based on public databases was also constructed.Conclusions:A complete analysis system platform for untargeted metabolomics was established.This platform provides a complete template interface for the addition and updating of the analysis process,so we can finish complex analyses of untargeted metabolomics with simple human-computer interactions.The source code can be downloaded from https://github.com/zjuRong/openNAU.

Adrenal pheochromocytoma impacts three main pathways: cysteine-methionine, pyrimidine, and tyrosine metabolism

Pheochromocytomas and paragangliomas(PPGLs)cause symptoms by altering the circulation levels of catecholamines and peptide hormones.Currently,the diagnosis of PPGLs relies on diagnostic imaging and the detection of catecholamines.In this study,we used ultra-performance liquid chromatography(UPLC)/quadrupole time-of-flight mass spectrometry(Q-TOF MS)analysis to identify and measure the perioperative differential metabolites in the plasma of adrenal pheochromocytoma patients.We identified differentially expressed genes by comparing the transcriptomic data of pheochromocytoma with the normal adrenal medulla.Through conducting two steps of metabolomics analysis,we identified 111 differential metabolites between the healthy group and the patient group,among which 53 metabolites were validated.By integrating the information of differential metabolites and differentially expressed genes,we inferred that the cysteine-methionine,pyrimidine,and tyrosine metabolism pathways were the three main metabolic pathways altered by the neoplasm.The analysis of transcription levels revealed that the tyrosine and cysteine-methionine metabolism pathways were downregulated in pheochromocytoma,whereas the pyrimidine pathway showed no significant difference.Finally,we developed an optimized diagnostic model of two metabolites,L-dihydroorotic acid and vanylglycol.Our results for these metabolites suggest that they may serve as potential clinical biomarkers and can be used to supplement and improve the diagnosis of pheochromocytoma.

Towards understandings of serine/arginine-rich splicing factors

Serine/arginine-rich splicing factors(SRSFs)refer to twelve RNA-binding proteins which regulate splice site recognition and spliceosome assembly during precursor messenger RNA splicing.SRSFs also participate in other RNA metabolic events,such as transcription,translation and nonsensemediated decay,during their shuttling between nucleus and cytoplasm,making them indispensable for genome diversity and cellular activity.Of note,aberrant SRSF expression and/or mutations elicit fallacies in gene splicing,leading to the generation of pathogenic gene and protein isoforms,which highlights the therapeutic potential of targeting SRSF to treat diseases.In this review,we updated current understanding of SRSF structures and functions in RNA metabolism.Next,we analyzed SRSF-induced aberrant gene expression and their pathogenic outcomes in cancers and non-tumor diseases.The development of some well-characterized SRSF inhibitors was discussed in detail.We hope this review will contribute to future studies of SRSF functions and drug development targeting SRSFs.

S100A8 promotes epithelial-mesenchymal transition and metastasis under TGF-β/USF2 axis in colorectal cancer

Background:The transforming growth factor-β(TGF-β)pathway plays a pivotal role in inducing epithelial-mesenchymal transition(EMT),which is a key step in cancer invasion and metastasis.However,the regulatory mechanism of TGF-βin inducing EMT in colorectal cancer(CRC)has not been fully elucidated.In previous studies,it was found that S100A8 may regulate EMT.This study aimed to clarify the role of S100A8 in TGF-β-induced EMT and explore the underlying mechanism in CRC.Methods:S100A8 and upstream transcription factor 2(USF2)expression was detected by immunohistochemistry in 412 CRC tissues.Kaplan-Meier survival analysis was performed.In vitro,Western blot,and migration and invasion assays were performed to investigate the effects of S100A8 and USF2 on TGF-β-induced EMT.Mouse metastasis models were used to determine in vivo metastasis ability.Luciferase reporter and chromatin immunoprecipitation assay were used to explore the role of USF2 on S100A8 transcription.Results:During TGF-β-induced EMT in CRC cells,S100A8 and the transcription factor USF2 were upregulated.S100A8 promoted cell migration and invasion and EMT.USF2 transcriptionally regulated S100A8 expression by directly binding to its promoter region.Furthermore,TGF-βenhanced the USF2/S100A8 signaling axis of CRC cells whereas extracellular S100A8 inhibited the USF2/S100A8 axis of CRC cells.S100A8 expression in tumor cells was associated with poor overall survival in CRC.USF2 expression was positively related to S100A8 expression in tumor cells but negatively related to S100A8-positive stromal cells.Conclusions:TGF-βwas found to promote EMT and metastasis through the USF2/S100A8 axis in CRC while extracellular S100A8 suppressed the USF2/S100A8 axis.USF2 was identified as an important switch on the intracellular and extracellular S100A8 feedback loop.

Deep learning in digital pathology image analysis:a survey

deep learning(DL)has achieved state-of-the-art performance in many digital pathology analysis tasks.Traditional methods usually require hand-crafted domain-specific features,and DL methods can learn representations without manually designed features.In terms of feature extraction,DL approaches are less labor intensive compared with conventional machine learning methods.In this paper,we comprehensively summarize recent DL-based image analysis studies in histopathology,including different tasks(e.g.,classification,semantic segmentation,detection,and instance segmentation)and various applications(e.g.,stain normalization,cell/gland/region structure analysis).DL methods can provide consistent and accurate outcomes.DL is a promising tool to assist pathologists in clinical diagnosis.

GLTSCR1 coordinates alternative splicing and transcription elongation of ZO1 to regulate colorectal cancer progression

Alternative splicing(AS)and transcription elongation are vital biological processes,and their dysregulation causes multiple diseases,including tumors.However,the coregulatory mechanism of AS and transcription elongation in tumors remains unclear.This study demonstrates a novel AS pattern of tight junction protein 1(ZO1)regulated by the RNA polymerase II elongation rate in colorectal cancer(CRC).Glioma tumor suppressor candidate region gene 1(GLTSCR1)decreases the transcription elongation rate of ZO1 to provide a time window for binding of the splicing factor HuR to the specific motif in intron 22 of ZO1 and spliceosome recognition of the weak 3 and 5 splice sites in exon 23 to promote exon 23 inclusion.Since exon 23 inclusion in ZO1 suppresses migration and invasion of CRC cells,our findings suggest a novel potential therapeutic target for CRC.