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Promising applications of human-derived saliva biomarker testing in clinical diagnostics

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International Journal of Oral Science 2023年第1期15卷 16-32页

作者： Mengyuan Song Hao Bai Ping Zhang Xuedong Zhou binwu ying Department of Laboratory Medicine West China HospitalSichuan UniversityChengduChina State Key Laboratory of Oral Diseases&Human Saliva Laboratory&National Clinical Research Center for Oral Diseases&West China Hospital of Stomatology Sichuan UniversityChengduChina

Saliva testing is a vital method for clinical applications,for its noninvasive features,richness in substances,and the huge amount.Due to its direct anatomical connection with oral,digestive,and endocrine systems,clinical usage of saliva testing for these diseases is promising.Furthermore,for other diseases that seeming to have no correlations with saliva,such as neurodegenerative diseases and psychological diseases,researchers also reckon saliva informative.Tremendous papers are being produced in this field.Updated summaries of recent literature give newcomers a shortcut to have a grasp of this topic.Here,we focused on recent research about saliva biomarkers that are derived from humans,not from other organisms.The review mostly addresses the proceedings from 2016 to 2022,to shed light on the promising usage of saliva testing in clinical diagnostics.We recap the recent advances following the category of different types of biomarkers,such as intracellular DNA,RNA,proteins and intercellular exosomes,cell-free DNA,to give a comprehensive impression of saliva biomarker testing.

关键词： clinical testing mostly

Mutation-associated transcripts reconstruct the prognostic features of oral tongue squamous cell carcinoma

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International Journal of Oral Science 2023年第1期15卷 76-86页

作者： Libo Liang Yi Li binwu ying Xinyan Huang Shenling Liao Jiajin Yang Ga Liao General Practice Medical Center West China HospitalSichuan UniversityChengduChina State Key Laboratory of Oral Diseases&National Clinical Research Center for Oral Diseases&West China Hospital of Stomatology Sichuan UniversityChengduChina Department of Laboratory Medicine West China HospitalSichuan UniversityChengduChina West China School/Hospital of Stomatology Sichuan UniversityChengduChina Department of Information Management Department of Stomatology InformaticsWest China Hospital of StomatologySichuan UniversityChengduChina

Tongue squamous cell carcinoma is highly malignant and has a poor prognosis.In this study,we aimed to combine whole-genome sequencing,whole-genome methylation,and whole-transcriptome analyses to understand the molecular mechanisms of tongue squamous cell carcinoma better.Oral tongue squamous cell carcinoma and adjacent normal tissues from five patients with tongue squamous cell carcinoma were included as five paired samples.After multi-omics sequencing,differentially methylated intervals,methylated loop sites,methylated promoters,and transcripts were screened for variation in all paired samples.Correlations were analyzed to determine biological processes in tongue squamous cell carcinoma.We found five mutated methylation promoters that were significantly associated with mRNA and lncRNA expression levels.Functional annotation of these transcripts revealed their involvement in triggering the mitogen-activated protein kinase cascade,which is associated with cancer progression and the development of drug resistance during treatment.The prognostic signature models constructed based on WDR81 and HNRNPH1 and combined clinical phenotype-gene prognostic signature models showed high predictive efficacy and can be applied to predict patient prognostic risk in clinical settings.We identified biological processes in tongue squamous cell carcinoma that are initiated by mutations in the methylation promoter and are associated with the expression levels of specific mRNAs and lncRNAs.Collectively,changes in transcript levels affect the prognosis of tongue squamous cell carcinoma patients.

关键词： squamous involvement signature

Roles of alternative splicing in infectious diseases: from hosts, pathogens to their interactions

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Chinese Medical Journal 2023年第7期136卷 767-779页

作者： Mengyuan Lyu Hongli Lai Yili Wang Yanbing Zhou Yi Chen Dongsheng Wu Jie Chen binwu ying Department of Laboratory Medicine West China HospitalSichuan UniversityChengduSichuan 610041China Department of Thoracic Surgery and Institute of Thoracic Oncology West China HospitalSichuan UniversityChengduSichuan 610041China

Alternative splicing(AS)is an evolutionarily conserved mechanism that removes introns and ligates exons to generate mature messenger RNAs(mRNAs),extremely improving the richness of transcriptome and proteome.Both mammal hosts and pathogens require AS to maintain their life activities,and inherent physiological heterogeneity between mammals and pathogens makes them adopt different ways to perform AS.Mammals and fungi conduct a two-step transesterification reaction by spliceosomes to splice each individual mRNA(named cis-splicing).Parasites also use spliceosomes to splice,but this splicing can occur among different mRNAs(named trans-splicing).Bacteria and viruses directly hijack the host’s splicing machinery to accomplish this process.Infection-related changes are reflected in the spliceosome behaviors and the characteristics of various splicing regulators(abundance,modification,distribution,movement speed,and conformation),which further radiate to alterations in the global splicing profiles.Genes with splicing changes are enriched in immune-,growth-,or metabolism-related pathways,highlighting approaches through which hosts crosstalk with pathogens.Based on these infection-specific regulators or AS events,several targeted agents have been developed to fight against pathogens.Here,we summarized recent findings in the field of infection-related splicing,including splicing mechanisms of pathogens and hosts,splicing regulation and aberrant AS events,as well as emerging targeted drugs.We aimed to systemically decode host–pathogen interactions from a perspective of splicing.We further discussed the current strategies of drug development,detection methods,analysis algorithms,and database construction,facilitating the annotation of infection-related splicing and the integration of AS with disease phenotype.

关键词： Alternative splicing Infectious diseases Spliceosome Regulation mechanism Targeted drug

Multi-responsive nanotheranostics with enhanced tumor penetration and oxygen self-producing capacities for multimodal synergistic cancer therapy

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Acta Pharmaceutica Sinica B 2022年第1期12卷 406-423页

作者： Shuangquan Gou Nanxi Chen Xiaoai Wu Menghang Zu Shixiong Yi binwu ying Fangyin Dai Bowen Ke Bo Xiao Laboratory of Anesthesiology&Critical Care Medicine Department of AnesthesiologyWest China HospitalSichuan UniversityChengdu 610041China State Key Laboratory of Silkworm Genome Biology College of SericultureTextile and Biomass SciencesSouthwest UniversityChongqing 400715China Chongqing Key Laboratory of Soft-Matter Material Chemistry and Function Manufacturing School of Materials and EnergySouthwest UniversityChongqing 400715China Department of Nuclear Medicine West China HospitalSichuan UniversityChengdu 610041China Department of Laboratory Medicine West China HospitalSichuan UniversityChengdu 610041China

Incorporation of multiple functions into one nanoplatform can improve cancer diagnostic efficacy and enhance anti-cancer outcomes. Here, we constructed doxorubicin(DOX)-loaded silk fibroinbased nanoparticles(NPs) with surface functionalization by photosensitizer(N770). The obtained nanotheranostics(N770-DOX@NPs) had desirable particle size(157 nm) and negative surface charge(-25 m V). These NPs presented excellent oxygen-generating capacity and responded to a quadruple of stimuli(acidic solution, reactive oxygen species, glutathione, and hyperthermia). Surface functionalization of DOX@NPs with N770 could endow them with active internalization by cancerous cell lines, but not by normal cells. Furthermore, the intracellular NPs were found to be preferentially retained in mitochondria, which were also efficient for near-infrared(NIR) fluorescence imaging, photothermal imaging,and photoacoustic imaging. Meanwhile, DOX could spontaneously accumulate in the nucleus. Importantly, a mouse test group treated with N770-DOX@NPs plus NIR irradiation achieved the best tumorretardation effect among all treatment groups based on tumor-bearing mouse models and a patientderived xenograft model, demonstrating the unprecedented therapeutic effects of trimodal imagingguided mitochondrial phototherapy(photothermal therapy and photodynamic therapy) and chemotherapy.Therefore, the present study brings new insight into the exploitation of an easy-to-use, versatile, and robust nanoplatform for programmable targeting, imaging, and applying synergistic therapy to tumors.

关键词： Quadruple responsibility Silk fiborin Nanotheranostic Oxygen self-generation Mitochondrial targeting Phototherapy Chemotherapy Cancer

Novel directions of precision oncology:circulating microbial DNA emerging in cancer-microbiome areas

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Precision Clinical Medicine 2022年第1期5卷 46-62页

作者： Liting You Juan Zhou Zhaodan Xin J.Spencer Hauck Feifei Na Jie Tang Xiaohan Zhou Zichen Lei binwu ying Department of Laboratory Medicine West China HospitalSichuan UniversityChengdu 610041China Department of Pathology Duke University School of MedicineDurhamNC 27710USA Department of Thoracic Cancer West China HospitalSichuan UniversityChengdu 610041China Department of Clinical Laboratory Mianyang Central HospitalSchool of MedicineUniversity of Electronic Science and Technology of ChinaMianyang 621000China

Microbiome research has extended into the cancer area in the past decades.Microbes can affect oncogenesis,progression,and treatment response through various mechanisms,including direct regulation and indirect impacts.Microbiota-associated detectionmethods and agents have been developed to facilitate cancer diagnosis and therapy.Additionally,the cancermicrobiome has recently been redefined.The identification of intra-tumoral microbes and cancer-related circulating microbial DNA(cmDNA)has promoted novel research in the cancer–microbiome area.In this review,we define the human system of commensal microbes and the cancer microbiome from a brand-new perspective and emphasize the potential value of cmDNA as a promising biomarker in cancer liquid biopsy.We outline all existing studies on the relationship between cmDNA and cancer and the outlook for potential preclinical and clinical applications of cmDNA in cancer precision medicine,as well as critical problems to be overcome in this burgeoning field.

关键词： circulating microbial DNA liquid biopsy cancer-microbiome-immunity intra-tumor microbiome cancer precision diagnosis and therapy

Applications of laboratory findings in the prevention,diagnosis,treatment,and monitoring of COVID-19

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Signal Transduction and Targeted Therapy 2021年第9期6卷 2697-2722页

作者： Zirui Meng Shuo Guo Yanbing Zhou Mengjiao Li Minjin Wang binwu ying Department of Laboratory Medicine West China HospitalSichuan UniversityChengduSichuan ProvinceChina

The worldwide pandemic of coronavirus disease 2019(COVID-19)presents us with a serious public health crisis.To combat the virus and slow its spread,wider testing is essential.There is a need for more sensitive,specific,and convenient detection methods of the severe acute respiratory syndrome coronavirus 2(SARS-CoV-2).Advanced detection can greatly improve the ability and accuracy of the clinical diagnosis of COVID-19,which is conducive to the early suitable treatment and supports precise prophylaxis.In this article,we combine and present the latest laboratory diagnostic technologies and methods for SARS-CoV-2 to identify the technical characteristics,considerations,biosafety requirements,common problems with testing and interpretation of results,and coping strategies of commonly used testing methods.We highlight the gaps in current diagnostic capacity and propose potential solutions to provide cutting-edge technical support to achieve a more precise diagnosis,treatment,and prevention of COVID-19 and to overcome the difficulties with the normalization of epidemic prevention and control.

关键词： prevention diagnosis treatment

From tuberculosis bedside to bench:UBE2B splicing as a potential biomarker and its regulatory mechanism

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Signal Transduction and Targeted Therapy 2023年第3期8卷 1282-1295页

作者： Mengyuan Lyu Jian Zhou Yanbing Zhou Weelic Chong Wei Xu Hongli Lai Lu Niu Yang Hai Xiaojun Yao Sheng Gong Qinglan Wang Yi Chen Yili Wang Liyu Chen Zengwanggema Jiongjiong Zeng Chengdi Wang binwu ying Department of Laboratory Medicine West China HospitalSichuan UniversityChengduSichuan 610041China Department of Thoracic Surgery West China HospitalSichuan UniversityChengduSichuan 610041China Sidney Kimmel Medical College Thomas Jefferson UniversityPhiladelphiaPA 19107USA Department of Biostatistics Princess Margaret Cancer CentreUniversity Health NetworkTorontoOntario M5G 1L7Canada Dalla Lana School of Public Health University of TorontoTorontoON M5T 3M7Canada Institute of Thoracic Oncology West China HospitalSichuan UniversityChengduSichuan 610041China Department of Radiology Thomas Jefferson University HospitalPhiladelphiaPA 19107USA Department of Thoracic Surgery The Public and Health Clinic Centre of ChengduChengduSichuan 610066China Department of Respiratory and Critical Care Medicine Frontiers Science Center for Disease-related Molecular NetworkWest China HospitalSichuan UniversityChengduSichuan 610213China Department of Infectious Diseases West China HospitalSichuan UniversityChengduSichuan 610041China Zhaojue People’s Hospital of Liangshan Prefecture Liangshan PrefectureSichuan 616150China Department of Laboratory Medicine Ganzi People’s HospitalGanzi PrefectureSichuan 626099China

Alternative splicing(AS)is an important approach for pathogens and hosts to remodel transcriptome.However,tuberculosis(TB)-related AS has not been sufficiently explored.Here we presented the first landscape of TB-related AS by long-read sequencing,and screened four AS events(S100A8-intron1-retention intron,RPS20-exon1-alternaitve promoter,KIF13B-exon4-skipping exon(SE)and UBE2B-exon7-SE)as potential biomarkers in an in-house cohort-1.The validations in an in-house cohort-2(2274 samples)and public datasets(1557 samples)indicated that the latter three AS events are potential promising biomarkers for TB diagnosis,but not for TB progression and prognosis.The excellent performance of classifiers further underscored the diagnostic value of these three biomarkers.Subgroup analyses indicated that UBE2B-exon7-SE splicing was not affected by confounding factors and thus had relatively stable performance.The splicing of UBE2B-exon7-SE can be changed by heat-killed mycobacterium tuberculosis through inhibiting SRSF1 expression.After heat-killed mycobacterium tuberculosis stimulation,231 ubiquitination proteins in macrophages were differentially expressed,and most of them are apoptosis-related proteins.Taken together,we depicted a global TB-associated splicing profile,developed TB-related AS biomarkers,demonstrated an optimal application scope of target biomarkers and preliminarily elucidated mycobacterium tuberculosis-host interaction from the perspective of splicing,offering a novel insight into the pathophysiology of TB.

关键词： tuberculosis stimulation diagnosis

Identification of Abnormal 51 CTA/CTG Expansion as Probably the Shortest Pathogenic Allele for Spinocerebellar Ataxia-8 in China

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Neuroscience Bulletin 2018年第5期34卷 859-862页

作者： Minjin Wang Shuo Guo Wencong Yao Jun Wang Jianxia Tao Yanbing Zhou binwu ying Department of Laboratory Medicine West China HospitalSichuan University

Spinocerebellar ataxias （SCAs） are a group of genetic disorders characterized by slowly progressive incoordina- tion of gait and are often associated with poor coordination of the hands, speech, and eye movements. Frequently, atrophy of the cerebellum occurs. The genetic forms of ataxia are diagnosed by family history, physical examina- tion, neuroimaging, and molecular genetic testing. At present, 36 SCA subtypes including 27 pathogenic genes have been identified [1]. Different subtypes of SCAs have clear distribution differences among ethnic populations, and SCA8 is an infrequent entity worldwide, which has mostly been reported in Japanese, but has never been reported in Chinese [2]. SCAB involves bidirectional expression based on the total number of both the （CTA）n and （CTG）n expansion transcripts in ATXN8OS. The pathogenesis of this disorder is complex and the spectrum of clinical presentations is broad. It is predominantly characterized by drawn-out slowness of speech and gait instability, followed by slowly progressive ataxia, with disease onset typically occurring in adulthood [3]. How- ever, the lowest full-penetrance allele for SCA8 onset remains elusive and the current understanding of the phenotypic and genotypic features of SCA8 is limited. Since SCA8 has not yet been reported in the Chinese population and is scantily reported in a small proportion of pedigrees so far, clinical knowledge is still developing. Moreover, the boundary between the normal and patho- genic alleles of SCA8 is uncertain. Here we report the clinical and molecular genetic characteristics of 3 Chinese SCA8 families and have identified 51 CTA/CTG repeats within ATXN8OS, probably the shortest pathogenic allele for SCA8.

关键词： CTG OS CTA Identification of Abnormal 51 CTA/CTG Expansion as Probably the Shortest Pathogenic Allele for Spinocerebellar Ataxia-8 in China

Expression and prognosis analyses of Dectin-1 cluster genes in patients with lung adenocarcinoma (LUAD) and the association with immune checkpoint molecules

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BIOCELL 2021年第3期45卷 649-663页

作者： LITING YOU FEIFEI NA JUAN ZHOU LIN JIAO YI ZHOU binwu ying West China School of Medicine West China HospitalSichuan UniversityChengdu610041China Department of Thoracic Cancer West China HospitalSichuan UniversityChengdu610041China Department of Laboratory Medicine West China HospitalSichuan UniversityChengdu610041China

Reviews The Dectin-1 cluster comprises seven members:CLEC-12A,CLEC-12B,CLEC-1A,CLEC-7A,CLEC-2,CLEC-9A and OLR1.These members have been demonstrated to be involved in the tumorigenesis,progression,and metastasis of several cancers.However,little is known about their roles in human lung adenocarcinoma(LUAD).The expression patterns of the Dectin-1 cluster were analyzed via the ONCOMINE and GEPIA databases.We evaluated the prognostic value of the Dectin-1 cluster in patients with LUAD using the Kaplan-Meier plotter and GEPIA.Differential expression was validated with the EMBL-EBI database,and protein expression was analyzed with the HPA database.In addition,protein-protein interaction network,GO,and KEGG analyses were conducted.Finally,the correlations between CLEC-12A and immune molecules(immune inhibitors and MHC molecules)were investigated via TISIDB and GEPIA.The expression levels of Dectin-1 cluster genes were downregulated in LUAD tissues compared to those in normal lung tissues.The expression levels of CLEC-12A,CLEC-12B,CLEC-2,and CLEC-9A correlated with tumor stage,and CLEC-12A and CLEC-12B were significantly associated with survival in patients with LUAD.The seven genes mostly participated in immune regulation processes and were involved in autoimmune disorders and hematological malignancies.Finally,correlation analyses revealed CLEC-12A expression was associated with most immune inhibitors and MHCs.CLEC-12A was positively related to PD-1,PD-L1,PD-L2,CTLA4,TIM3,and LAG3.In conclusion,our findings suggest that CLEC-12A and CLEC-12B can be used as prognostic biomarkers in LUAD.CLEC-12A expression was associated with immune checkpoint molecules,and CLEC-12A may be a potential assistant target to improve the efficacy of immune checkpoint inhibitors immunotherapy.

关键词： CLEC-12A CLEC-12B Lung cancer Prognosis Immune regulation