Background:This study aims to identify distinct cellular subtypes within brain tissue using single-cell transcriptomic analysis,focusing on specific biomarkers that differentiate cell types and the effects of traditio...Background:This study aims to identify distinct cellular subtypes within brain tissue using single-cell transcriptomic analysis,focusing on specific biomarkers that differentiate cell types and the effects of traditional and exercise therapy.Methods:Four samples were analyzed:older control(OC),older exercise(OE),younger control(YC),and younger exercise(YE).Single-cell RNA sequencing was used to distinguish cellular subtypes through their biomarker profiles.Data visualization included violin and t-SNE plots to illustrate biomarker expression across cell clusters such as oligodendrocytes,microglia,and astrocytes.Additionally,BV2 cells were exposed to amyloid-beta fragments to simulate Alzheimer’s disease,assessing the impact of exercise-induced cellular responses.Results:Distinct cellular subtypes were identified:oligodendrocytes(MBP,St18),microglia(Dock8),and astrocytes(Aqp4,Gpc5).Sample OE was predominantly oligodendrocytes,while YE had more astrocytes,inhibitory neurons,and Canal-Retzius cells.YC showed a significant presence of Olfm3+ganglion neurons.ZEB1 gene knockout revealed changes in SMAD family gene expression,which regulate ferroptosis.Oxidative stress levels were also evaluated.Conclusion:This profiling enhances our understanding of brain cellular functions and interactions,potentially informing targeted therapies in neurological research.Exercise may influence brain cell immune responses and cell death pathways by regulating specific gene expressions,offering new insights for treating neuroinflammation and degeneration.展开更多
Background:Bladder cancer prognosis remains suboptimal despite advancements in research.Current molecular subtyping methods are resource-intensive,highlighting the need for efficient,cost-effective approaches to predi...Background:Bladder cancer prognosis remains suboptimal despite advancements in research.Current molecular subtyping methods are resource-intensive,highlighting the need for efficient,cost-effective approaches to predict BCa molecular subtypes.Method:We developed a predictive model for BCa molecular subtypes using machine learning(ML)and pathomics derived from Hematoxylin-Eosin stained pathological slides.A cohort of 353 patients from TCGA was employed,and image features were extracted for analysis.Pathomic signatures were constructed using the LASSO Cox regression algorithm,and a pathomic-clinical nomogram was developed and validated in training and testing cohorts.Results:Seventy distinct image features were identified from 150 pathomic signatures.The model demonstrated robust predictive ability,with AUCs of 0.833 and 0.822 in the training and validation cohorts,respectively.The addition of pathomic score,N stage,and M stage improved the model’s discrimination,achieving AUCs of 0.877 and 0.794 in the training and validation cohorts.Limitations include the lack of an external validation cohort.Conclusion:Our ML-based pathomics model shows promise in predicting BCa molecular subtypes and has the potential to enhance prognosis prediction and inform treatment strategies,marking a significant step towards precision medicine for BCa.展开更多
Objective:Circadian rhythm disruption(CRD)is a risk factor that correlates with poor prognosis across multiple tumor types,including hepatocellular carcinoma(HCC).However,its mechanism remains unclear.This study aimed...Objective:Circadian rhythm disruption(CRD)is a risk factor that correlates with poor prognosis across multiple tumor types,including hepatocellular carcinoma(HCC).However,its mechanism remains unclear.This study aimed to define HCC subtypes based on CRD and explore their individual heterogeneity.Methods:To quantify CRD,the HCC CRD score(HCCcrds)was developed.Using machine learning algorithms,we identified CRD module genes and defined CRD-related HCC subtypes in The Cancer Genome Atlas liver HCC cohort(n=369),and the robustness of this method was validated.Furthermore,we used bioinformatics tools to investigate the cellular heterogeneity across these CRD subtypes.Results:We defined three distinct HCC subtypes that exhibit significant heterogeneity in prognosis.The CRD-related subtype with high HCCcrds was significantly correlated with worse prognosis,higher pathological grade,and advanced clinical stages,while the CRD-related subtype with low HCCcrds had better clinical outcomes.We also identified novel biomarkers for each subtype,such as nicotinamide nmethyltransferase and myristoylated alanine-rich protein kinase C substrate-like 1.Conclusion:We classify the HCC patients into three distinct groups based on circadian rhythm and identify their specific biomarkers.Within these groups greater HCCcrds was associated with worse prognosis.This approach has the potential to improve prediction of an individual’s prognosis,guide precision treatments,and assist clinical decision making for HCC patients.展开更多
Objectives:Triple-negative breast cancer(TNBC)presents a major treatment challenge due to its aggressive behavior.The dysfunction of the Golgi apparatus(GA)contributes to the development of various cancers.This study ...Objectives:Triple-negative breast cancer(TNBC)presents a major treatment challenge due to its aggressive behavior.The dysfunction of the Golgi apparatus(GA)contributes to the development of various cancers.This study aimed to utilize GA-related genes(GARGs)to forecast the prognosis and immune profile of TNBC.Methods:The data were downloaded from The Cancer Genome Atlas(TCGA)database,including 175 TNBC and 99 healthy samples.The differentially expressed GARGs(DEGARGs)were analyzed using the TCGA biolinks package.The patients with TNBC were classified into two clusters utilizing the ConsensusClusterPlus package according to prognosis-related DEGARGs,followed by comparing the differences in prognosis and immune infiltration between the two clusters.Next,LASSO and stepwise Cox regression were applied to establish a GARGs signature to forecast the TNBC prognosis.The association of the GARGs signature with immune infiltrates and drug sensitivity was further explored.Results:In total,430 DEGARGs were identified between TNBC and healthy samples,among which 20 were related to TNBC prognosis.Two GARG-related molecular clusters associated with different survival times and immune heterogeneity were identified.A risk model for TNBC was established based on six GARGs,and the high-risk(HR)group exhibited a poor prognosis.The HR group demonstrated a distinctly high M2 macrophage infiltration and low M1 macrophage infiltration,which contributed to an immunosuppressive tumor microenvironment and thus led to poor prognosis of the HR group.Immune dysfunction scores and programmed cell death ligand 1(PD-L1)expression were substantially elevated in the HR group.The HR group showed increased sensitivity to anticancer drugs,such as cisplatin.Conclusion:Our findings suggest that GARGs are involved in the pathogenesis of TNBC and provide new insights into prognostic prediction.The identified clusters and GARGs signatures have the potential to guide individualized therapy.展开更多
Sonic Hedgehog Medulloblastoma(SHH-MB)is one of the four primary molecular subgroups of Medulloblastoma.It is estimated to be responsible for nearly one-third of allMB cases.Using transcriptomic and DNA methylation pr...Sonic Hedgehog Medulloblastoma(SHH-MB)is one of the four primary molecular subgroups of Medulloblastoma.It is estimated to be responsible for nearly one-third of allMB cases.Using transcriptomic and DNA methylation profiling techniques,new developments in this field determined four molecular subtypes for SHH-MB.SHH-MB subtypes show distinct DNAmethylation patterns that allow their discrimination fromoverlapping subtypes and predict clinical outcomes.Class overlapping occurs when two or more classes share common features,making it difficult to distinguish them as separate.Using the DNA methylation dataset,a novel classification technique is presented to address the issue of overlapping SHH-MBsubtypes.Penalizedmultinomial regression(PMR),Tomek links(TL),and singular value decomposition(SVD)were all smoothly integrated into a single framework.SVD and group lasso improve computational efficiency,address the problem of high-dimensional datasets,and clarify class distinctions by removing redundant or irrelevant features that might lead to class overlap.As a method to eliminate the issues of decision boundary overlap and class imbalance in the classification task,TL enhances dataset balance and increases the clarity of decision boundaries through the elimination of overlapping samples.Using fivefold cross-validation,our proposed method(TL-SVDPMR)achieved a remarkable overall accuracy of almost 95%in the classification of SHH-MB molecular subtypes.The results demonstrate the strong performance of the proposed classification model among the various SHH-MB subtypes given a high average of the area under the curve(AUC)values.Additionally,the statistical significance test indicates that TL-SVDPMR is more accurate than both SVM and random forest algorithms in classifying the overlapping SHH-MB subtypes,highlighting its importance for precision medicine applications.Our findings emphasized the success of combining SVD,TL,and PMRtechniques to improve the classification performance for biomedical applications with many features and overlapping subtypes.展开更多
The recent concurrent emergence of H5N1,H5N6,and H5N8 avian influenza viruses(AIVs)has led to significant avian mortality globally.Since 2020,frequent human-animal interactions have been documented.To gain insight int...The recent concurrent emergence of H5N1,H5N6,and H5N8 avian influenza viruses(AIVs)has led to significant avian mortality globally.Since 2020,frequent human-animal interactions have been documented.To gain insight into the novel H5 subtype AIVs(i.e.,H5N1,H5N6 and H5N8),we collected 6102 samples from various regions of China between January 2021 and September 2022,and identified 41 H5Nx strains.Comparative analyses on the evolution and biological properties of these isolates were conducted.Phylogenetic analysis revealed that the 41 H5Nx strains belonged to clade 2.3.4.4b,with 13 related to H5N1,19 to H5N6,and 9 to H5N8.Analysis based on global 2.3.4.4b viruses showed that all the viruses described in this study were likely originated from H5N8,exhibiting a heterogeneous evolutionary history between H5N1 and H5N6 during 2015–2022 worldwide.H5N1 showed a higher rate of evolution in 2021–2022 and more sites under positive selection pressure in 2015–2022.The antigenic profiles of the novel H5N1 and H5N6 exhibited notable variations.Further hemagglutination inhibition assay suggested that some A(H5N1)viruses may be antigenically distinct from the circulating H5N6 and H5N8 strains.Mammalian challenge assays demonstrated that the H5N8 virus(21GD001_H5N8)displayed the highest pathogenicity in mice,followed by the H5N1 virus(B1557_H5N1)and then the H5N6 virus(220086_H5N6),suggesting a heterogeneous virulence profile of H5 AIVs in the mammalian hosts.Based on the above results,we speculate that A(H5N1)viruses have a higher risk of emergence in the future.Collectively,these findings unveil a new landscape of different evolutionary history and biological characteristics of novel H5 AIVs in clade 2.3.4.4b,contributing to a better understanding of designing more effective strategies for the prevention and control of novel H5 AIVs.展开更多
Objective:Triple-negative breast cancer(TNBC)is a heterogeneous and aggressive cancer.Although our previous study classified primary TNBC into four subtypes,comprehensive longitudinal investigations are lacking.Method...Objective:Triple-negative breast cancer(TNBC)is a heterogeneous and aggressive cancer.Although our previous study classified primary TNBC into four subtypes,comprehensive longitudinal investigations are lacking.Methods:We assembled a large-scale,real-world cohort comprised of 880 TNBC patients[465 early-stage TNBC(eTNBC)and 415 metastatic TNBC(mTNBC)patients]who were treated at Fudan University Shanghai Cancer Center.The longitudinal dynamics of TNBC subtypes during disease progression were elucidated in this patient cohort.Comprehensive analysis was performed to compare primary and metastatic lesions within specific TNBC subtypes.Results:The recurrence and metastasis rates within 3 years after initial diagnosis in the eTNBC cohort were 10.1%(47/465).The median overall survival(OS)in the mTNBC cohort was 27.2 months[95%confidence interval(CI),24.4–30.2 months],which indicated a poor prognosis.The prognostic significance of the original molecular subtypes in both eTNBC and mTNBC patients was confirmed.Consistent molecular subtypes were maintained in 77.5%of the patients throughout disease progression with the mesenchymal-like(MES)subtype demonstrating a tendency for subtype transition and brain metastasis.Additionally,a precision treatment strategy based on the metastatic MES subtype of target lesions resulted in improved progression-free survival in the FUTURE trial.Conclusions:Our longitudinal study comprehensively revealed the clinical characteristics and survival of patients with the original TNBC subtypes and validated the consistency of most molecular subtypes throughout disease progression.However,we emphasize the major importance of repeat pathologic confirmation of the MES subtype.展开更多
Background:Pancreatic cancer is a common malignancy with poor prognosis and limited treatment.Here we aimed to investigate the role of host chromosomal instability(CIN)and tumor microbiome in the prognosis of pancreat...Background:Pancreatic cancer is a common malignancy with poor prognosis and limited treatment.Here we aimed to investigate the role of host chromosomal instability(CIN)and tumor microbiome in the prognosis of pancreatic cancer patients.Methods:One hundred formalin-fixed paraffin-embedded(FFPE)pancreatic cancer samples were collected.DNA extracted from FFPE samples were analyzed by low-coverage whole-genome sequencing(WGS)via a customized bioinformatics workflow named ultrasensitive chromosomal aneuploidy detector.Results:Samples were tested according to the procedure of ultrasensitive chromosomal aneuploidy detector(UCAD).We excluded 2 samples with failed quality control,1 patient lost to follow-up and 6 dead in the perioperative period.The final 91 patients were admitted for the following analyses.Thirteen(14.3%)patients with higher CIN score had worse overall survival(OS)than those with lower CIN score.The top 20 microbes in pancreatic cancer samples included 15 species of bacteria and 5 species of viruses.Patients with high human herpesvirus(HHV)-7 and HHV-5 DNA reads exhibited worse OS.Furthermore,we classified 91 patients into 3 subtypes.Patients with higher CIN score(n=13)had the worst prognosis(median OS 6.9 mon);patients with lower CIN score but with HHV-7/5 DNA load(n=24)had worse prognosis(median OS 10.6 mon);while patients with lower CIN score and HHV-7/5 DNA negative(n=54)had the best prognosis(median OS 21.1 mon).Conclusions:High CIN and HHV-7/5 DNA load were associated with worse survival of pancreatic cancer.The novel molecular subtypes of pancreatic cancer based on CIN and microbiome had prognostic value.展开更多
Investigating correlations between radiomic and genomic profiling in breast cancer(BC)molecular subtypes is crucial for understanding disease mechanisms and providing personalized treatment.We present a well-designed ...Investigating correlations between radiomic and genomic profiling in breast cancer(BC)molecular subtypes is crucial for understanding disease mechanisms and providing personalized treatment.We present a well-designed radiogenomic framework image–gene–gene set(IMAGGS),which detects multi-way associations in BC subtypes by integrating radiomic and genomic features.Our dataset consists of 721 patients,each of whom has 12 ultrasound(US)images captured from different angles and gene mutation data.To better characterize tumor traits,12 multi-angle US images are fused using two distinct strategies.Then,we analyze complex many-to-many associations between phenotypic and genotypic features using a machine learning algorithm,deviating from the prevalent one-to-one relationship pattern observed in previous studies.Key radiomic and genomic features are screened using these associations.In addition,gene set enrichment analysis is performed to investigate the joint effects of gene sets and delve deeper into the biological functions of BC subtypes.We further validate the feasibility of IMAGGS in a glioblastoma multiforme dataset to demonstrate the scalability of IMAGGS across different modalities and diseases.Taken together,IMAGGS provides a comprehensive characterization for diseases by associating imaging,genes,and gene sets,paving the way for biological interpretation of radiomics and development of targeted therapy.展开更多
Background:Cytotoxic T lymphocytes(CD8+T)cells function critically in mediating anti-tumor immune response in cancer patients.Characterizing the specific functions of CD8+T cells in lung adenocarcinoma(LUAD)could help ...Background:Cytotoxic T lymphocytes(CD8+T)cells function critically in mediating anti-tumor immune response in cancer patients.Characterizing the specific functions of CD8+T cells in lung adenocarcinoma(LUAD)could help better understand local anti-tumor immune responses and estimate the effect of immunotherapy.Methods:Gens related to CD8+T cells were identified by cluster analysis based on the single-cell sequencing data of three LUAD tissues and their paired normal tissues.Weighted gene co-expression network analysis(WGCNA),consensus clustering,differential expression analysis,least absolute shrinkage and selection operator(LASSO)and Cox regression analysis were conducted to classify molecular subtypes for LUAD and to develop a risk model using prognostic genes related to CD8+T cells.Expression of the genes in the prognostic model,their effects on tumor cell invasion,and interactions with CD8+T cells were verified by cell experiments.Results:This study defined two LUAD clusters(CD8+0 and CD8+1)based on CD8+T cells,with cluster CD8+0 being significantly associated with the prognosis of LUAD.Three heterogeneous subtypes(clusters 1,2,and 3)differing in prognosis,genome mutation events,and immune status were categorized using 42 prognostic genes.A prognostic model created based on 11 significant genes(including CD200R1,CLEC17A,ZC3H12D,GNG7,SNX30,CDCP1,NEIL3,IGF2BP1,RHOV,ABCC2,and KRT81)was able to independently estimate the death risk for patients in different LUAD cohorts.Moreover,the model also showed general applicability in external validation cohorts.Low-risk patients could benefit more from taking immunotherapy and were significantly related to the resistance to anticancer drugs.The results from cell experiments demonstrated that the expression of CD200R1,CLEC17A,ZC3H12D,GNG7,and SNX30 was significantly downregulated,while that of CDCP1,NEIL3,IGF2BP1,RHOV,ABCC2 and KRT81 was upregulated in LUAD cells.Inhibition of CD200R1 greatly increased the invasiveness of the LUAD cells,but inhibiting CDCP1 expression weakened the invasion ability of LUAD cells.Conclusion:This study defined two prognostic CD8+T cell clusters and classified three heterogeneous molecular subtypes for LUAD.A prognostic model predictive of the potential effects of immunotherapy on LUAD patients was developed.展开更多
BACKGROUND Cardioneuroablation(CNA)has shown encouraging results in patients with vasovagal syncope(VVS).However,data on different subtypes was scarce.METHODS This observational study retrospectively enrolled 141 pati...BACKGROUND Cardioneuroablation(CNA)has shown encouraging results in patients with vasovagal syncope(VVS).However,data on different subtypes was scarce.METHODS This observational study retrospectively enrolled 141 patients[mean age:40±18 years,51 males(36.2%)]with the diagnosis of VVS.The characteristics among different types of VVS and the outcomes after CNA were analyzed.RESULTS After a mean follow-up of 4.3±1.5 years,41 patients(29.1%)experienced syncope/pre-syncope events after CNA.Syncope/pre-syncope recurrence significantly differed in each subtype(P=0.04).The cardioinhibitory type of VVS had the lowest recurrence rate after the procedure(n=6,16.7%),followed by mixed(n=26,30.6%)and vasodepressive(n=9,45.0%).Additionally,a significant difference was observed in the analyses of the Kaplan-Meier survival curve(P=0.02).Syncope/pre-syncope burden was significantly reduced after CNA in the vasodepressive type(P<0.01).Vasodepressive types with recurrent syncope/pre-syncope after CNA have a lower baseline deceleration capacity(DC)level than those without(7.4±1.0 ms vs.9.0±1.6 ms,P=0.01).Patients with DC<8.4 ms had an 8.1(HR=8.1,95%CI:2.2-30.0,P=0.02)times risk of syncope/pre-syncope recurrence after CNA compared to patients with DC≥8.4 ms,and this association still existed after adjusting for age and sex(HR=8.1,95%CI:2.2-30.1,P=0.02).CONCLUSIONS Different subtypes exhibit different event-free rates.The vasodepressive type exhibited the lowest event-free rate,but those patients with DC≥8.4 ms might benefit from CNA.展开更多
Microglia are immune-competent cells involved in maintaining brain homeostasis through their capacity to prune synapses and continuously survey the brain environment.The activation of microglia is one of the most prom...Microglia are immune-competent cells involved in maintaining brain homeostasis through their capacity to prune synapses and continuously survey the brain environment.The activation of microglia is one of the most prominent characteristics of Alzheimer’s disease(AD),a severe neurodegenerative disease featuring extra-cellular deposits of amyloid-βplaques(Aβplaques)and intracellular neurofibrillary tangles(NFTs)as the result of tau hyperphosphorylation.Whether microglia activation is beneficial or detrimental for brains with AD is still con-troversial.In this article,we review recent studies focus-ing on microglia phenotypes in AD by single-cell omics,to understand the signature genes,functions,and regula-tory factors of each phenotype.A profound understanding of the heterogeneity of microglial phenotypes will sug-gest new avenues for treatments for AD.展开更多
The majority of bladder cancers(BCs)are non-muscle invasive BCs(NMIBCs)and show the morphology of a conventional urothelial carcinoma(UC).Aberrant morphology is rare but can be observed.The classification and characte...The majority of bladder cancers(BCs)are non-muscle invasive BCs(NMIBCs)and show the morphology of a conventional urothelial carcinoma(UC).Aberrant morphology is rare but can be observed.The classification and characterization of histologic subtypes(HS)in UC in BC have mainly been described in muscle in-vasive bladder cancer(MIBC).However,the currently used classification is ap-plied for invasive urothelial neoplasm and therefore,also valid for a subset of NMIBC.The standard transurethral diagnostic work-up misses the presence of HS in NMIBC in a considerable percentage of patients and the real prevalence is not known.HS in NMIBC are associated with an aggressive phenotype.Conse-quently,clinical guidelines categorize HS of NMIBC as“(very)high-risk”tumors and recommend offering radical cystectomy to these patients.Alternative strategies for bladder preservation can only be offered to highly selected patients and ideally within clinical trials.Novel treatment strategies and biomarkers have been established MIBC and NMIBC but have not been comprehensively invest-igated in the context of HS in NMIBC.Further evaluation prior to implementation into clinical practice is needed.展开更多
Objective:Circulating tumor DNA(ctDNA)is increasingly being used as a potential prognostic biomarker in cancer patients.We aimed to assess the prognostic value of ctDNA in different subtypes of breast cancer patients ...Objective:Circulating tumor DNA(ctDNA)is increasingly being used as a potential prognostic biomarker in cancer patients.We aimed to assess the prognostic value of ctDNA in different subtypes of breast cancer patients throughout the whole treatment cycle.Materials and methods:PubMed,Web of Science,Embase,Cochrane Library,Scopus,and clinical trials.gov databases were searched from January 2016 to May 2022.The following search terms were used:ctDNA OR circulating tumor DNA AND breast cancer OR breast carcinoma.Only studies written in English were included.The following pre-specified criteria should be met for inclusion:(i)original articles,conference abstracts,etc.;(ii)patients with breast cancer;(iii)ctDNA measurement;and(iv)clinical outcome data such as recurrence-free survival(RFS)and overall survival(OS).The random-effects model was preferred considering the potential het-erogeneity across studies.The main outcomes are ctDNA detection rate and postoperative long-term outcomes(RFS and OS).Results:A total of 24 studies were screened.At every measurement time,the ctDNA detection rate of the HR+subgroup was similar to that of the HR-subgroup(P=0.075;P=0.458;P=0.744;and P=0.578),and the ctDNA detection rate of the HER2+subgroup was similar to that of the HER2-subgroup(P=0.805;P=0.271;P=0.807;and P=0.703).In the HR+subgroup,RFS and OS of ctDNA positive patients were similar to those of ctDNA negative patients(P=0.589 and P=0.110),while RFS and OS of the ctDNA positive group was significantly shorter than those of the ctDNA negative patients in the HR-subgroup(HR=4.03,P<0.001;HR=3.21,P<0.001).According to HER grouping,the results were the same as above.In the triple negative breast cancer(TNBC)subgroup,the RFS and OS of ctDNA-positive patients was significantly shorter than of the ctDNA negative patients before and after surgery.Conclusions:ctDNA was more predictive of recurrence-free survival and overall survival in the HR-subgroup than in the HR+subgroup,and the same result was showed in the HER2-subgroup vs.HER2+subgroup.The prognosis of the TNBC subtype is closely related to ctDNA before and after surgery.展开更多
[Objective] The study aimed to investigate the genetic variation characters of entire sequences between two H9N2 subtype avian influenza virus strains and other reference strains.[Method] The entire sequences of 8 gen...[Objective] The study aimed to investigate the genetic variation characters of entire sequences between two H9N2 subtype avian influenza virus strains and other reference strains.[Method] The entire sequences of 8 genes were obtained by using RT-PCR,and these sequences were analyzed with that of six H9N2 subtype avian influenza isolates in homology comparison and genetic evolution relation.[Result] The results showed that the nucleotide sequence of entire gene of the strain shared 91.1%-95.4% homology with other seven reference strains,and PG08 shared the highest homology 91.3% with C/BJ/1/94;ZD06 shared the highest homology 92.3% with D/HK/Y280/97.HA cleavage sites of two H9N2 subtype avian influenza virus isolated strains were PARSSR/GLF,typical of mildly pathogenic avian influenza virus.[Conclusion] Phylogenetic tree for entire gene of eight strains showed that the genetic relationship was the closest between ZD06 and C/Pak/2/99 strains,which belonged to the Eurasian lineage;PG08 shared the highest homology 91.3% with ZD06,it may be the product of gene rearrangements of other sub-lines.展开更多
In order to compare the potential selectivity of R-（-）-DM-phencynonate hydrochloride with its racemate （±）-DM- phencynonate hydrochloride on acetylcholine muscarinic receptor subtypes, the five human acetylch...In order to compare the potential selectivity of R-（-）-DM-phencynonate hydrochloride with its racemate （±）-DM- phencynonate hydrochloride on acetylcholine muscarinic receptor subtypes, the five human acetylcholine muscarinic receptor subtypes （M1- M5） （CHO-hml-5R） were cloned and expressed in Chinese hamster ovary （CHO-K1） cell line. The specific mRNAs of the five acetylcholine muscarinic receptor subtypes were detected by the reverse transcription-polymerase chain reaction （RT-PCR） method, demonstrating the definite expression of muscarinic receptor subtype genes （CHO-hml-5R）. The affinity and saturability of different muscarinic receptor subtypes to [^3H] N-methylscopolamine （[^3H]-NMS） were obtained by radioligand binding assay. Equilibrium binding assay revealed that the maximum binding capacity of [^3H]-NMS （Bmax value） to CHO-hml-5R were 40.22±3.23, 24.53±4.11, 29.65±2.65, 25.41±2.46, 32.78±4.81 pmol/mg·protein, respectively. Kd values of [^3H]-NMS to muscarinic receptors M1 to M5 were 0.97±0.22, 1.16±0.14, 0.99±0.06, 0.56±0.08, 1.12±0.06 nM, respectively. R-（-）-DM- phencynonate hydrochloride was found to block the M4 receptor with a much higher potency （pD2 = 7.48） than those displayed on M1 （pD2 = 6.20）, M2 （pD2 = 5.99）, M3 （pD2 = 5.99） and M5 （pD2 = 6.70） subtypes. However, for （±）-DM-phencynonate hydrochloride, no significant subtype receptor selectivity was found. Both （±）-DM- and R-（-）-DM-phencynonate hydrochloride showed allosteric effects on muscarinic receptors, the Hill coefficient （nH） of five receptor subtypes was less than 1, respectively. The results revealed that R-（-）-DM-phencynonate hydrochloride showed selectivity torwards M4 subtype, and there were allosteric effects for both R-（-）-DM-phencynonate hydrochloride and （±）-DM-phencynonate hydrochloride on muscarinic receptors.展开更多
[ Objective] The study aimed to lay a foundation for the further studies on function mechanism of NS1 protein in the interspecies transmission of waterfowl influenza virus. [Method] Using the serologic assay and the s...[ Objective] The study aimed to lay a foundation for the further studies on function mechanism of NS1 protein in the interspecies transmission of waterfowl influenza virus. [Method] Using the serologic assay and the specific RT-PCR method, some strains of H9 subtype waterfowl influenza virus were isolated from the 12 to 20 day-old muscovy duck flocks without any clinical symptoms in different areas of Guangdong Province. Four of these strains, including A/duck/ZQ/303/2007（H9N2） （A3 for short）, A/Duck/FJ/301/2007 （H9N2） （C1 for short）, A/Duck/NH/306/2007（H9N2） （ D6 for short）, A/duck/SS/402/2007（H9N2） （ E2 for short）, and a strain named A/duck/ZC/2007（H9N2） （L1 for short） from a muscovy duck died of avian influenza virus （AIV）, were used for NSl gene cloning and sequencing. Subsequently, the obtained NSl gene sequences were compared with other NS1 sequences registered in GenBank, and the phylogenetic analysis was also conducted. [Result] When compared with the H9N2 AIV NS1 sequences in GenBank, the NSl genes of the four AIV strains A3, C1, 136 and E2 displayed homologies ranging from 99% to 100% at nucleotide level, and 95% to 100% at amino acid level; while the NSl gene of L1 strain displayed homology ranging from 94% to 97% at nucleotide level, and 93% to 98% at amino acid level. The phylogenetic tree demonstrated that A3, C1, D6 and E2 were highly resemblant, and L1 was closest to AY66473 （chicken, 2003）. By comparison with the NS1 gene sequences of L1, AF523514 （duck）, AY664743 （chicken） and EF155262.1 （quail） using DNAstar, A3, C1, D6 and E.2 presented nucleotide variations at site 21 （ R→Q）, 70, 71 （ KE→EG）, 86 （ A→S）, 124 （V→M） and 225 （ S→N）, and amino acid variations at site 21,70, 71 and 86 in dsRNA- dependent protein kinase （PKR） binding domain of NSl gene, which induced the evident variations of antigenic determinant and surface proba- bility plot of NS1 protein. [ Conclusion] This study suggested that the amino acid sequence variation in PKR binding domain of NS1 protein had something to do with the virus pathogenicity.展开更多
BACKGROUND Cardiac metastatic tumors(CMTs)are rare yet pose significant medical concerns.Clinical studies on CMT are limited,particularly those involving multicenter data analysis.AIM To systematically analyze the eti...BACKGROUND Cardiac metastatic tumors(CMTs)are rare yet pose significant medical concerns.Clinical studies on CMT are limited,particularly those involving multicenter data analysis.AIM To systematically analyze the etiology,sources,classification,treatment,and prognosis of CMT.METHODS A total of 226 CMT patients from two centers(2013 to 2023)were reviewed,and 153 tumor patients from China Health and Retirement Longitudinal Study were used as controls.The survival rates of 96 CMT patients were tracked through medical records and telephone follow-ups.Logistic regression and survival analyses were conducted to characterize CMT.RESULTS CMTs were predominantly male(67.26%vs 39.47%,P<0.001).Intracardiac metastasis patients had worse heart and coagulation function than pericardial metastasis patients(prothrombin time:13.90 vs 13.30,P=0.002),D-dimer levels(2.16 vs 0.85,P=0.001),B-type natriuretic peptide(BNP)levels(324.00 vs 136.50,P=0.004),and troponin levels(5.35 vs 0.03,P<0.001)).Lung and liver cancers were the predominant primary tumor types in CMT.Patients with lung cancer(76.40%vs 30.77%)and thymoma(7.45%vs 1.54%)exhibited a higher prevalence of pericardial metastasis,while those with liver cancer(35.38%vs 0.62%)showed a higher prevalence of intracardiac metastasis.Overall survival was better for pericardial metastasis than for intracardiac metastasis patients(median survival:419 days vs 129 days,log-rank test P=0.0029).Cox proportional hazards model revealed that advanced age[hazard ratio(HR)=1.034,95%confidence interval(95%CI):1.011-1.057]and higher BNP and troponin levels(HR=1.011,95%CI:1.004-1.018)were associated with worse survival.Surgery significantly improved the survival rate of patients.The median survival time was 275 days for patients who did not undergo surgery and 708 days for those who had surgery(log-rank test P=0.0128)CONCLUSION Clinicians should consider CMT in the male lung or liver cancer patients with cardiac symptoms.Abnormal coagulation,impaired heart function,tumor location,and age are key prognostic factors for CMT.Surgical intervention is the preferred treatment option,as it significantly prolongs median survival.展开更多
Diarrhea predominant irritable bowel syndrome(IBS-D)have a serious impact on the patient’s quality life due to the lack of safe and effective drugs.The transient receptor potential vanilloid subtype 1(TRPV1)is an ion...Diarrhea predominant irritable bowel syndrome(IBS-D)have a serious impact on the patient’s quality life due to the lack of safe and effective drugs.The transient receptor potential vanilloid subtype 1(TRPV1)is an ion channel receptor implicated in the perception of visceral injury.Recent studies indicated that TRPV1 mediates visceral hypersensitivity in IBS-D patients by enhancing the excitability of intestinal sensory neurons.Consequently,inhibiting the TRPV1 may be a promising option for the treatment of IBS-D.Current research demonstrates that various traditional Chinese medicine(TCM)methods,such as herbal prescriptions,acupuncture,and moxibustion,can reduce visceral sensitivity by regulating TRPV1 expression and its activation sensitization.This suggests that TCM methods may serve as safe and effective options for alleviating IBS-D.Therefore,this article summarizes potential therapeutic strategies of TCM as a regulator of TRPV1 for managing IBS-D.It also provides insights into potential TCM methods and natural phytochemical molecular nuclei for future drug research targeting TRPV1 in IBS-D.展开更多
Objective This study aimed to investigate the prevalence of HIV pretreatment drug resistance(PDR)and the transmission clusters associated with PDR-related mutations in newly diagnosed,treatmentnaive patients between 2...Objective This study aimed to investigate the prevalence of HIV pretreatment drug resistance(PDR)and the transmission clusters associated with PDR-related mutations in newly diagnosed,treatmentnaive patients between 2020 and 2023 in Dehong prefecture,Yunnan province,China.Methods Demographic information and plasma samples were collected from study participants.PDR was assessed using the Stanford HIV Drug Resistance Database.The Tamura-Nei 93 model within HIVTRACE was employed to compute pairwise matches with a genetic distance of 0.015 substitutions per site.Results Among 948 treatment-naive individuals with eligible sequences,36 HIV subtypes were identified,with unique recombinant forms(URFs)being the most prevalent(18.8%,178/948).The overall prevalence of PDR was 12.4%(118/948),and resistance to non-nucleotide reverse transcriptase inhibitors(NNRTIs),nucleotide reverse transcriptase inhibitors(NRTIs),and protease inhibitors(PIs)was10.7%,1.3%,and 1.6%,respectively.A total of 91 clusters were identified,among which eight showed evidence of PDR strain transmission.The largest PDR-associated cluster consisted of six CRF01_AE drugresistant strains carrying K103N and V179T mutations;five of these individuals had initial CD4^(+)cell counts<200 cells/μL.Conclusion The distribution of HIV subtypes in Dehong is diverse and complex.PDR was moderately prevalent(12.4%)between 2020 and 2023.Evidence of transmission of CRF01_AE strains carrying K103N and V179T mutations was found.Routine surveillance of PDR and the strengthening of control measures are essential to limit the spread of drug-resistance HIV strains.展开更多
文摘Background:This study aims to identify distinct cellular subtypes within brain tissue using single-cell transcriptomic analysis,focusing on specific biomarkers that differentiate cell types and the effects of traditional and exercise therapy.Methods:Four samples were analyzed:older control(OC),older exercise(OE),younger control(YC),and younger exercise(YE).Single-cell RNA sequencing was used to distinguish cellular subtypes through their biomarker profiles.Data visualization included violin and t-SNE plots to illustrate biomarker expression across cell clusters such as oligodendrocytes,microglia,and astrocytes.Additionally,BV2 cells were exposed to amyloid-beta fragments to simulate Alzheimer’s disease,assessing the impact of exercise-induced cellular responses.Results:Distinct cellular subtypes were identified:oligodendrocytes(MBP,St18),microglia(Dock8),and astrocytes(Aqp4,Gpc5).Sample OE was predominantly oligodendrocytes,while YE had more astrocytes,inhibitory neurons,and Canal-Retzius cells.YC showed a significant presence of Olfm3+ganglion neurons.ZEB1 gene knockout revealed changes in SMAD family gene expression,which regulate ferroptosis.Oxidative stress levels were also evaluated.Conclusion:This profiling enhances our understanding of brain cellular functions and interactions,potentially informing targeted therapies in neurological research.Exercise may influence brain cell immune responses and cell death pathways by regulating specific gene expressions,offering new insights for treating neuroinflammation and degeneration.
基金supported by the Guangzhou Municipal Basic Research Program Jointly Funded by City,University,and Enterprise Special Project(2024A03J0907)the Natural Science Foundation of Guangdong Province(2024A1515013201)+1 种基金the National Natural Science Foundation of China(82203720,82203188,82002682,81972731,81773026,81972383)the Science and Technology Project of Zhongshan Municipality(No.2024B1032).
文摘Background:Bladder cancer prognosis remains suboptimal despite advancements in research.Current molecular subtyping methods are resource-intensive,highlighting the need for efficient,cost-effective approaches to predict BCa molecular subtypes.Method:We developed a predictive model for BCa molecular subtypes using machine learning(ML)and pathomics derived from Hematoxylin-Eosin stained pathological slides.A cohort of 353 patients from TCGA was employed,and image features were extracted for analysis.Pathomic signatures were constructed using the LASSO Cox regression algorithm,and a pathomic-clinical nomogram was developed and validated in training and testing cohorts.Results:Seventy distinct image features were identified from 150 pathomic signatures.The model demonstrated robust predictive ability,with AUCs of 0.833 and 0.822 in the training and validation cohorts,respectively.The addition of pathomic score,N stage,and M stage improved the model’s discrimination,achieving AUCs of 0.877 and 0.794 in the training and validation cohorts.Limitations include the lack of an external validation cohort.Conclusion:Our ML-based pathomics model shows promise in predicting BCa molecular subtypes and has the potential to enhance prognosis prediction and inform treatment strategies,marking a significant step towards precision medicine for BCa.
基金supported by Tianjian advanced biomedical laboratory key research and development projectHenan Province Natural Science Foundation(grant number:242300421283)+1 种基金Henan Province Science and Technology Research and Development(grant number:242102311176)Henan Province medical science and technology research project(grant number:SBGJ202403038)。
文摘Objective:Circadian rhythm disruption(CRD)is a risk factor that correlates with poor prognosis across multiple tumor types,including hepatocellular carcinoma(HCC).However,its mechanism remains unclear.This study aimed to define HCC subtypes based on CRD and explore their individual heterogeneity.Methods:To quantify CRD,the HCC CRD score(HCCcrds)was developed.Using machine learning algorithms,we identified CRD module genes and defined CRD-related HCC subtypes in The Cancer Genome Atlas liver HCC cohort(n=369),and the robustness of this method was validated.Furthermore,we used bioinformatics tools to investigate the cellular heterogeneity across these CRD subtypes.Results:We defined three distinct HCC subtypes that exhibit significant heterogeneity in prognosis.The CRD-related subtype with high HCCcrds was significantly correlated with worse prognosis,higher pathological grade,and advanced clinical stages,while the CRD-related subtype with low HCCcrds had better clinical outcomes.We also identified novel biomarkers for each subtype,such as nicotinamide nmethyltransferase and myristoylated alanine-rich protein kinase C substrate-like 1.Conclusion:We classify the HCC patients into three distinct groups based on circadian rhythm and identify their specific biomarkers.Within these groups greater HCCcrds was associated with worse prognosis.This approach has the potential to improve prediction of an individual’s prognosis,guide precision treatments,and assist clinical decision making for HCC patients.
文摘Objectives:Triple-negative breast cancer(TNBC)presents a major treatment challenge due to its aggressive behavior.The dysfunction of the Golgi apparatus(GA)contributes to the development of various cancers.This study aimed to utilize GA-related genes(GARGs)to forecast the prognosis and immune profile of TNBC.Methods:The data were downloaded from The Cancer Genome Atlas(TCGA)database,including 175 TNBC and 99 healthy samples.The differentially expressed GARGs(DEGARGs)were analyzed using the TCGA biolinks package.The patients with TNBC were classified into two clusters utilizing the ConsensusClusterPlus package according to prognosis-related DEGARGs,followed by comparing the differences in prognosis and immune infiltration between the two clusters.Next,LASSO and stepwise Cox regression were applied to establish a GARGs signature to forecast the TNBC prognosis.The association of the GARGs signature with immune infiltrates and drug sensitivity was further explored.Results:In total,430 DEGARGs were identified between TNBC and healthy samples,among which 20 were related to TNBC prognosis.Two GARG-related molecular clusters associated with different survival times and immune heterogeneity were identified.A risk model for TNBC was established based on six GARGs,and the high-risk(HR)group exhibited a poor prognosis.The HR group demonstrated a distinctly high M2 macrophage infiltration and low M1 macrophage infiltration,which contributed to an immunosuppressive tumor microenvironment and thus led to poor prognosis of the HR group.Immune dysfunction scores and programmed cell death ligand 1(PD-L1)expression were substantially elevated in the HR group.The HR group showed increased sensitivity to anticancer drugs,such as cisplatin.Conclusion:Our findings suggest that GARGs are involved in the pathogenesis of TNBC and provide new insights into prognostic prediction.The identified clusters and GARGs signatures have the potential to guide individualized therapy.
基金funded by the Deanship of Graduate Studies and Scientific Research at Jouf University under grant No.(DGSSR-2024-02-01137).
文摘Sonic Hedgehog Medulloblastoma(SHH-MB)is one of the four primary molecular subgroups of Medulloblastoma.It is estimated to be responsible for nearly one-third of allMB cases.Using transcriptomic and DNA methylation profiling techniques,new developments in this field determined four molecular subtypes for SHH-MB.SHH-MB subtypes show distinct DNAmethylation patterns that allow their discrimination fromoverlapping subtypes and predict clinical outcomes.Class overlapping occurs when two or more classes share common features,making it difficult to distinguish them as separate.Using the DNA methylation dataset,a novel classification technique is presented to address the issue of overlapping SHH-MBsubtypes.Penalizedmultinomial regression(PMR),Tomek links(TL),and singular value decomposition(SVD)were all smoothly integrated into a single framework.SVD and group lasso improve computational efficiency,address the problem of high-dimensional datasets,and clarify class distinctions by removing redundant or irrelevant features that might lead to class overlap.As a method to eliminate the issues of decision boundary overlap and class imbalance in the classification task,TL enhances dataset balance and increases the clarity of decision boundaries through the elimination of overlapping samples.Using fivefold cross-validation,our proposed method(TL-SVDPMR)achieved a remarkable overall accuracy of almost 95%in the classification of SHH-MB molecular subtypes.The results demonstrate the strong performance of the proposed classification model among the various SHH-MB subtypes given a high average of the area under the curve(AUC)values.Additionally,the statistical significance test indicates that TL-SVDPMR is more accurate than both SVM and random forest algorithms in classifying the overlapping SHH-MB subtypes,highlighting its importance for precision medicine applications.Our findings emphasized the success of combining SVD,TL,and PMRtechniques to improve the classification performance for biomedical applications with many features and overlapping subtypes.
基金supported by the Science and Technology Program of Guangdong Province(2022B1111010004,2021B1212030015)China Agriculture Research System of MOF and MARA(CARS-41)China National Animal Disease Surveillance and Epidemiological Survey Program(2021–2025)(No.202111).
文摘The recent concurrent emergence of H5N1,H5N6,and H5N8 avian influenza viruses(AIVs)has led to significant avian mortality globally.Since 2020,frequent human-animal interactions have been documented.To gain insight into the novel H5 subtype AIVs(i.e.,H5N1,H5N6 and H5N8),we collected 6102 samples from various regions of China between January 2021 and September 2022,and identified 41 H5Nx strains.Comparative analyses on the evolution and biological properties of these isolates were conducted.Phylogenetic analysis revealed that the 41 H5Nx strains belonged to clade 2.3.4.4b,with 13 related to H5N1,19 to H5N6,and 9 to H5N8.Analysis based on global 2.3.4.4b viruses showed that all the viruses described in this study were likely originated from H5N8,exhibiting a heterogeneous evolutionary history between H5N1 and H5N6 during 2015–2022 worldwide.H5N1 showed a higher rate of evolution in 2021–2022 and more sites under positive selection pressure in 2015–2022.The antigenic profiles of the novel H5N1 and H5N6 exhibited notable variations.Further hemagglutination inhibition assay suggested that some A(H5N1)viruses may be antigenically distinct from the circulating H5N6 and H5N8 strains.Mammalian challenge assays demonstrated that the H5N8 virus(21GD001_H5N8)displayed the highest pathogenicity in mice,followed by the H5N1 virus(B1557_H5N1)and then the H5N6 virus(220086_H5N6),suggesting a heterogeneous virulence profile of H5 AIVs in the mammalian hosts.Based on the above results,we speculate that A(H5N1)viruses have a higher risk of emergence in the future.Collectively,these findings unveil a new landscape of different evolutionary history and biological characteristics of novel H5 AIVs in clade 2.3.4.4b,contributing to a better understanding of designing more effective strategies for the prevention and control of novel H5 AIVs.
基金This work was supported by grants from the National Natural Science Foundation of China(Grant No.82103039)the Program of Shanghai Academic/Technology Research Leader(Grant No.20XD1421100)the Wu Jieping Medical Foundation(Grant No.320.6750.2021-10-64).
文摘Objective:Triple-negative breast cancer(TNBC)is a heterogeneous and aggressive cancer.Although our previous study classified primary TNBC into four subtypes,comprehensive longitudinal investigations are lacking.Methods:We assembled a large-scale,real-world cohort comprised of 880 TNBC patients[465 early-stage TNBC(eTNBC)and 415 metastatic TNBC(mTNBC)patients]who were treated at Fudan University Shanghai Cancer Center.The longitudinal dynamics of TNBC subtypes during disease progression were elucidated in this patient cohort.Comprehensive analysis was performed to compare primary and metastatic lesions within specific TNBC subtypes.Results:The recurrence and metastasis rates within 3 years after initial diagnosis in the eTNBC cohort were 10.1%(47/465).The median overall survival(OS)in the mTNBC cohort was 27.2 months[95%confidence interval(CI),24.4–30.2 months],which indicated a poor prognosis.The prognostic significance of the original molecular subtypes in both eTNBC and mTNBC patients was confirmed.Consistent molecular subtypes were maintained in 77.5%of the patients throughout disease progression with the mesenchymal-like(MES)subtype demonstrating a tendency for subtype transition and brain metastasis.Additionally,a precision treatment strategy based on the metastatic MES subtype of target lesions resulted in improved progression-free survival in the FUTURE trial.Conclusions:Our longitudinal study comprehensively revealed the clinical characteristics and survival of patients with the original TNBC subtypes and validated the consistency of most molecular subtypes throughout disease progression.However,we emphasize the major importance of repeat pathologic confirmation of the MES subtype.
基金supported by grants from the National Natural Science Foundation of China(82171757)the Zhejiang Provincial Natural Science Foundation of China(LZ22H030004 and LQ20H160048).
文摘Background:Pancreatic cancer is a common malignancy with poor prognosis and limited treatment.Here we aimed to investigate the role of host chromosomal instability(CIN)and tumor microbiome in the prognosis of pancreatic cancer patients.Methods:One hundred formalin-fixed paraffin-embedded(FFPE)pancreatic cancer samples were collected.DNA extracted from FFPE samples were analyzed by low-coverage whole-genome sequencing(WGS)via a customized bioinformatics workflow named ultrasensitive chromosomal aneuploidy detector.Results:Samples were tested according to the procedure of ultrasensitive chromosomal aneuploidy detector(UCAD).We excluded 2 samples with failed quality control,1 patient lost to follow-up and 6 dead in the perioperative period.The final 91 patients were admitted for the following analyses.Thirteen(14.3%)patients with higher CIN score had worse overall survival(OS)than those with lower CIN score.The top 20 microbes in pancreatic cancer samples included 15 species of bacteria and 5 species of viruses.Patients with high human herpesvirus(HHV)-7 and HHV-5 DNA reads exhibited worse OS.Furthermore,we classified 91 patients into 3 subtypes.Patients with higher CIN score(n=13)had the worst prognosis(median OS 6.9 mon);patients with lower CIN score but with HHV-7/5 DNA load(n=24)had worse prognosis(median OS 10.6 mon);while patients with lower CIN score and HHV-7/5 DNA negative(n=54)had the best prognosis(median OS 21.1 mon).Conclusions:High CIN and HHV-7/5 DNA load were associated with worse survival of pancreatic cancer.The novel molecular subtypes of pancreatic cancer based on CIN and microbiome had prognostic value.
基金supported by the National Natural Science Foundation of China(81830058,82071945,91959207,92159301,and 82302212)the Science and Technology Commission of Shanghai Municipality(22ZR1404800)。
文摘Investigating correlations between radiomic and genomic profiling in breast cancer(BC)molecular subtypes is crucial for understanding disease mechanisms and providing personalized treatment.We present a well-designed radiogenomic framework image–gene–gene set(IMAGGS),which detects multi-way associations in BC subtypes by integrating radiomic and genomic features.Our dataset consists of 721 patients,each of whom has 12 ultrasound(US)images captured from different angles and gene mutation data.To better characterize tumor traits,12 multi-angle US images are fused using two distinct strategies.Then,we analyze complex many-to-many associations between phenotypic and genotypic features using a machine learning algorithm,deviating from the prevalent one-to-one relationship pattern observed in previous studies.Key radiomic and genomic features are screened using these associations.In addition,gene set enrichment analysis is performed to investigate the joint effects of gene sets and delve deeper into the biological functions of BC subtypes.We further validate the feasibility of IMAGGS in a glioblastoma multiforme dataset to demonstrate the scalability of IMAGGS across different modalities and diseases.Taken together,IMAGGS provides a comprehensive characterization for diseases by associating imaging,genes,and gene sets,paving the way for biological interpretation of radiomics and development of targeted therapy.
文摘Background:Cytotoxic T lymphocytes(CD8+T)cells function critically in mediating anti-tumor immune response in cancer patients.Characterizing the specific functions of CD8+T cells in lung adenocarcinoma(LUAD)could help better understand local anti-tumor immune responses and estimate the effect of immunotherapy.Methods:Gens related to CD8+T cells were identified by cluster analysis based on the single-cell sequencing data of three LUAD tissues and their paired normal tissues.Weighted gene co-expression network analysis(WGCNA),consensus clustering,differential expression analysis,least absolute shrinkage and selection operator(LASSO)and Cox regression analysis were conducted to classify molecular subtypes for LUAD and to develop a risk model using prognostic genes related to CD8+T cells.Expression of the genes in the prognostic model,their effects on tumor cell invasion,and interactions with CD8+T cells were verified by cell experiments.Results:This study defined two LUAD clusters(CD8+0 and CD8+1)based on CD8+T cells,with cluster CD8+0 being significantly associated with the prognosis of LUAD.Three heterogeneous subtypes(clusters 1,2,and 3)differing in prognosis,genome mutation events,and immune status were categorized using 42 prognostic genes.A prognostic model created based on 11 significant genes(including CD200R1,CLEC17A,ZC3H12D,GNG7,SNX30,CDCP1,NEIL3,IGF2BP1,RHOV,ABCC2,and KRT81)was able to independently estimate the death risk for patients in different LUAD cohorts.Moreover,the model also showed general applicability in external validation cohorts.Low-risk patients could benefit more from taking immunotherapy and were significantly related to the resistance to anticancer drugs.The results from cell experiments demonstrated that the expression of CD200R1,CLEC17A,ZC3H12D,GNG7,and SNX30 was significantly downregulated,while that of CDCP1,NEIL3,IGF2BP1,RHOV,ABCC2 and KRT81 was upregulated in LUAD cells.Inhibition of CD200R1 greatly increased the invasiveness of the LUAD cells,but inhibiting CDCP1 expression weakened the invasion ability of LUAD cells.Conclusion:This study defined two prognostic CD8+T cell clusters and classified three heterogeneous molecular subtypes for LUAD.A prognostic model predictive of the potential effects of immunotherapy on LUAD patients was developed.
基金supported by the CAMS Central Public Welfare Scientific Research Institute Basal Research Expenses (No.2021-XCGC09-1&No.2022-I2M-C&T-B-045)the Beijing Municipal Science&Technology Commission (Z191100006619019)the High-level Hospital Clinical Scientific Research Business Fees (No.2022-GSP-QZ-4)
文摘BACKGROUND Cardioneuroablation(CNA)has shown encouraging results in patients with vasovagal syncope(VVS).However,data on different subtypes was scarce.METHODS This observational study retrospectively enrolled 141 patients[mean age:40±18 years,51 males(36.2%)]with the diagnosis of VVS.The characteristics among different types of VVS and the outcomes after CNA were analyzed.RESULTS After a mean follow-up of 4.3±1.5 years,41 patients(29.1%)experienced syncope/pre-syncope events after CNA.Syncope/pre-syncope recurrence significantly differed in each subtype(P=0.04).The cardioinhibitory type of VVS had the lowest recurrence rate after the procedure(n=6,16.7%),followed by mixed(n=26,30.6%)and vasodepressive(n=9,45.0%).Additionally,a significant difference was observed in the analyses of the Kaplan-Meier survival curve(P=0.02).Syncope/pre-syncope burden was significantly reduced after CNA in the vasodepressive type(P<0.01).Vasodepressive types with recurrent syncope/pre-syncope after CNA have a lower baseline deceleration capacity(DC)level than those without(7.4±1.0 ms vs.9.0±1.6 ms,P=0.01).Patients with DC<8.4 ms had an 8.1(HR=8.1,95%CI:2.2-30.0,P=0.02)times risk of syncope/pre-syncope recurrence after CNA compared to patients with DC≥8.4 ms,and this association still existed after adjusting for age and sex(HR=8.1,95%CI:2.2-30.1,P=0.02).CONCLUSIONS Different subtypes exhibit different event-free rates.The vasodepressive type exhibited the lowest event-free rate,but those patients with DC≥8.4 ms might benefit from CNA.
文摘Microglia are immune-competent cells involved in maintaining brain homeostasis through their capacity to prune synapses and continuously survey the brain environment.The activation of microglia is one of the most prominent characteristics of Alzheimer’s disease(AD),a severe neurodegenerative disease featuring extra-cellular deposits of amyloid-βplaques(Aβplaques)and intracellular neurofibrillary tangles(NFTs)as the result of tau hyperphosphorylation.Whether microglia activation is beneficial or detrimental for brains with AD is still con-troversial.In this article,we review recent studies focus-ing on microglia phenotypes in AD by single-cell omics,to understand the signature genes,functions,and regula-tory factors of each phenotype.A profound understanding of the heterogeneity of microglial phenotypes will sug-gest new avenues for treatments for AD.
文摘The majority of bladder cancers(BCs)are non-muscle invasive BCs(NMIBCs)and show the morphology of a conventional urothelial carcinoma(UC).Aberrant morphology is rare but can be observed.The classification and characterization of histologic subtypes(HS)in UC in BC have mainly been described in muscle in-vasive bladder cancer(MIBC).However,the currently used classification is ap-plied for invasive urothelial neoplasm and therefore,also valid for a subset of NMIBC.The standard transurethral diagnostic work-up misses the presence of HS in NMIBC in a considerable percentage of patients and the real prevalence is not known.HS in NMIBC are associated with an aggressive phenotype.Conse-quently,clinical guidelines categorize HS of NMIBC as“(very)high-risk”tumors and recommend offering radical cystectomy to these patients.Alternative strategies for bladder preservation can only be offered to highly selected patients and ideally within clinical trials.Novel treatment strategies and biomarkers have been established MIBC and NMIBC but have not been comprehensively invest-igated in the context of HS in NMIBC.Further evaluation prior to implementation into clinical practice is needed.
基金funded by the Capital’s Funds for Health Improve-ment and Research(grant number:2024-1G-4023)the Special Project for Director,China Center for Evidence Based Traditional Chinese Medicine(grant number:2020YJSZX-2)the National Natural Sci-ence Foundation of China(grant number:72074011)。
文摘Objective:Circulating tumor DNA(ctDNA)is increasingly being used as a potential prognostic biomarker in cancer patients.We aimed to assess the prognostic value of ctDNA in different subtypes of breast cancer patients throughout the whole treatment cycle.Materials and methods:PubMed,Web of Science,Embase,Cochrane Library,Scopus,and clinical trials.gov databases were searched from January 2016 to May 2022.The following search terms were used:ctDNA OR circulating tumor DNA AND breast cancer OR breast carcinoma.Only studies written in English were included.The following pre-specified criteria should be met for inclusion:(i)original articles,conference abstracts,etc.;(ii)patients with breast cancer;(iii)ctDNA measurement;and(iv)clinical outcome data such as recurrence-free survival(RFS)and overall survival(OS).The random-effects model was preferred considering the potential het-erogeneity across studies.The main outcomes are ctDNA detection rate and postoperative long-term outcomes(RFS and OS).Results:A total of 24 studies were screened.At every measurement time,the ctDNA detection rate of the HR+subgroup was similar to that of the HR-subgroup(P=0.075;P=0.458;P=0.744;and P=0.578),and the ctDNA detection rate of the HER2+subgroup was similar to that of the HER2-subgroup(P=0.805;P=0.271;P=0.807;and P=0.703).In the HR+subgroup,RFS and OS of ctDNA positive patients were similar to those of ctDNA negative patients(P=0.589 and P=0.110),while RFS and OS of the ctDNA positive group was significantly shorter than those of the ctDNA negative patients in the HR-subgroup(HR=4.03,P<0.001;HR=3.21,P<0.001).According to HER grouping,the results were the same as above.In the triple negative breast cancer(TNBC)subgroup,the RFS and OS of ctDNA-positive patients was significantly shorter than of the ctDNA negative patients before and after surgery.Conclusions:ctDNA was more predictive of recurrence-free survival and overall survival in the HR-subgroup than in the HR+subgroup,and the same result was showed in the HER2-subgroup vs.HER2+subgroup.The prognosis of the TNBC subtype is closely related to ctDNA before and after surgery.
基金Supported by a Sub-project of 973 Program of China(2005CB523001)~~
文摘[Objective] The study aimed to investigate the genetic variation characters of entire sequences between two H9N2 subtype avian influenza virus strains and other reference strains.[Method] The entire sequences of 8 genes were obtained by using RT-PCR,and these sequences were analyzed with that of six H9N2 subtype avian influenza isolates in homology comparison and genetic evolution relation.[Result] The results showed that the nucleotide sequence of entire gene of the strain shared 91.1%-95.4% homology with other seven reference strains,and PG08 shared the highest homology 91.3% with C/BJ/1/94;ZD06 shared the highest homology 92.3% with D/HK/Y280/97.HA cleavage sites of two H9N2 subtype avian influenza virus isolated strains were PARSSR/GLF,typical of mildly pathogenic avian influenza virus.[Conclusion] Phylogenetic tree for entire gene of eight strains showed that the genetic relationship was the closest between ZD06 and C/Pak/2/99 strains,which belonged to the Eurasian lineage;PG08 shared the highest homology 91.3% with ZD06,it may be the product of gene rearrangements of other sub-lines.
基金National Natural Science Foundation of China (Grant No. 30672445)
文摘In order to compare the potential selectivity of R-（-）-DM-phencynonate hydrochloride with its racemate （±）-DM- phencynonate hydrochloride on acetylcholine muscarinic receptor subtypes, the five human acetylcholine muscarinic receptor subtypes （M1- M5） （CHO-hml-5R） were cloned and expressed in Chinese hamster ovary （CHO-K1） cell line. The specific mRNAs of the five acetylcholine muscarinic receptor subtypes were detected by the reverse transcription-polymerase chain reaction （RT-PCR） method, demonstrating the definite expression of muscarinic receptor subtype genes （CHO-hml-5R）. The affinity and saturability of different muscarinic receptor subtypes to [^3H] N-methylscopolamine （[^3H]-NMS） were obtained by radioligand binding assay. Equilibrium binding assay revealed that the maximum binding capacity of [^3H]-NMS （Bmax value） to CHO-hml-5R were 40.22±3.23, 24.53±4.11, 29.65±2.65, 25.41±2.46, 32.78±4.81 pmol/mg·protein, respectively. Kd values of [^3H]-NMS to muscarinic receptors M1 to M5 were 0.97±0.22, 1.16±0.14, 0.99±0.06, 0.56±0.08, 1.12±0.06 nM, respectively. R-（-）-DM- phencynonate hydrochloride was found to block the M4 receptor with a much higher potency （pD2 = 7.48） than those displayed on M1 （pD2 = 6.20）, M2 （pD2 = 5.99）, M3 （pD2 = 5.99） and M5 （pD2 = 6.70） subtypes. However, for （±）-DM-phencynonate hydrochloride, no significant subtype receptor selectivity was found. Both （±）-DM- and R-（-）-DM-phencynonate hydrochloride showed allosteric effects on muscarinic receptors, the Hill coefficient （nH） of five receptor subtypes was less than 1, respectively. The results revealed that R-（-）-DM-phencynonate hydrochloride showed selectivity torwards M4 subtype, and there were allosteric effects for both R-（-）-DM-phencynonate hydrochloride and （±）-DM-phencynonate hydrochloride on muscarinic receptors.
基金Supported by Key Specific Program for Science and Technology of Guangdong Province (2008B020700003 A2007A020400006)~~
文摘[ Objective] The study aimed to lay a foundation for the further studies on function mechanism of NS1 protein in the interspecies transmission of waterfowl influenza virus. [Method] Using the serologic assay and the specific RT-PCR method, some strains of H9 subtype waterfowl influenza virus were isolated from the 12 to 20 day-old muscovy duck flocks without any clinical symptoms in different areas of Guangdong Province. Four of these strains, including A/duck/ZQ/303/2007（H9N2） （A3 for short）, A/Duck/FJ/301/2007 （H9N2） （C1 for short）, A/Duck/NH/306/2007（H9N2） （ D6 for short）, A/duck/SS/402/2007（H9N2） （ E2 for short）, and a strain named A/duck/ZC/2007（H9N2） （L1 for short） from a muscovy duck died of avian influenza virus （AIV）, were used for NSl gene cloning and sequencing. Subsequently, the obtained NSl gene sequences were compared with other NS1 sequences registered in GenBank, and the phylogenetic analysis was also conducted. [Result] When compared with the H9N2 AIV NS1 sequences in GenBank, the NSl genes of the four AIV strains A3, C1, 136 and E2 displayed homologies ranging from 99% to 100% at nucleotide level, and 95% to 100% at amino acid level; while the NSl gene of L1 strain displayed homology ranging from 94% to 97% at nucleotide level, and 93% to 98% at amino acid level. The phylogenetic tree demonstrated that A3, C1, D6 and E2 were highly resemblant, and L1 was closest to AY66473 （chicken, 2003）. By comparison with the NS1 gene sequences of L1, AF523514 （duck）, AY664743 （chicken） and EF155262.1 （quail） using DNAstar, A3, C1, D6 and E.2 presented nucleotide variations at site 21 （ R→Q）, 70, 71 （ KE→EG）, 86 （ A→S）, 124 （V→M） and 225 （ S→N）, and amino acid variations at site 21,70, 71 and 86 in dsRNA- dependent protein kinase （PKR） binding domain of NSl gene, which induced the evident variations of antigenic determinant and surface proba- bility plot of NS1 protein. [ Conclusion] This study suggested that the amino acid sequence variation in PKR binding domain of NS1 protein had something to do with the virus pathogenicity.
文摘BACKGROUND Cardiac metastatic tumors(CMTs)are rare yet pose significant medical concerns.Clinical studies on CMT are limited,particularly those involving multicenter data analysis.AIM To systematically analyze the etiology,sources,classification,treatment,and prognosis of CMT.METHODS A total of 226 CMT patients from two centers(2013 to 2023)were reviewed,and 153 tumor patients from China Health and Retirement Longitudinal Study were used as controls.The survival rates of 96 CMT patients were tracked through medical records and telephone follow-ups.Logistic regression and survival analyses were conducted to characterize CMT.RESULTS CMTs were predominantly male(67.26%vs 39.47%,P<0.001).Intracardiac metastasis patients had worse heart and coagulation function than pericardial metastasis patients(prothrombin time:13.90 vs 13.30,P=0.002),D-dimer levels(2.16 vs 0.85,P=0.001),B-type natriuretic peptide(BNP)levels(324.00 vs 136.50,P=0.004),and troponin levels(5.35 vs 0.03,P<0.001)).Lung and liver cancers were the predominant primary tumor types in CMT.Patients with lung cancer(76.40%vs 30.77%)and thymoma(7.45%vs 1.54%)exhibited a higher prevalence of pericardial metastasis,while those with liver cancer(35.38%vs 0.62%)showed a higher prevalence of intracardiac metastasis.Overall survival was better for pericardial metastasis than for intracardiac metastasis patients(median survival:419 days vs 129 days,log-rank test P=0.0029).Cox proportional hazards model revealed that advanced age[hazard ratio(HR)=1.034,95%confidence interval(95%CI):1.011-1.057]and higher BNP and troponin levels(HR=1.011,95%CI:1.004-1.018)were associated with worse survival.Surgery significantly improved the survival rate of patients.The median survival time was 275 days for patients who did not undergo surgery and 708 days for those who had surgery(log-rank test P=0.0128)CONCLUSION Clinicians should consider CMT in the male lung or liver cancer patients with cardiac symptoms.Abnormal coagulation,impaired heart function,tumor location,and age are key prognostic factors for CMT.Surgical intervention is the preferred treatment option,as it significantly prolongs median survival.
基金supported by the Science and Technology Department of Sichuan Province(2023NSFSC1757)the"Xinglin Scholar"Talent Research Promotion Plan of Chengdu University of Traditional Chinese Medicine(grant number MPRC2021020).
文摘Diarrhea predominant irritable bowel syndrome(IBS-D)have a serious impact on the patient’s quality life due to the lack of safe and effective drugs.The transient receptor potential vanilloid subtype 1(TRPV1)is an ion channel receptor implicated in the perception of visceral injury.Recent studies indicated that TRPV1 mediates visceral hypersensitivity in IBS-D patients by enhancing the excitability of intestinal sensory neurons.Consequently,inhibiting the TRPV1 may be a promising option for the treatment of IBS-D.Current research demonstrates that various traditional Chinese medicine(TCM)methods,such as herbal prescriptions,acupuncture,and moxibustion,can reduce visceral sensitivity by regulating TRPV1 expression and its activation sensitization.This suggests that TCM methods may serve as safe and effective options for alleviating IBS-D.Therefore,this article summarizes potential therapeutic strategies of TCM as a regulator of TRPV1 for managing IBS-D.It also provides insights into potential TCM methods and natural phytochemical molecular nuclei for future drug research targeting TRPV1 in IBS-D.
基金supported by the National Key Research and Development Program of China(2022YFC2305201)National Natural Science Foundation of China(71874168)。
文摘Objective This study aimed to investigate the prevalence of HIV pretreatment drug resistance(PDR)and the transmission clusters associated with PDR-related mutations in newly diagnosed,treatmentnaive patients between 2020 and 2023 in Dehong prefecture,Yunnan province,China.Methods Demographic information and plasma samples were collected from study participants.PDR was assessed using the Stanford HIV Drug Resistance Database.The Tamura-Nei 93 model within HIVTRACE was employed to compute pairwise matches with a genetic distance of 0.015 substitutions per site.Results Among 948 treatment-naive individuals with eligible sequences,36 HIV subtypes were identified,with unique recombinant forms(URFs)being the most prevalent(18.8%,178/948).The overall prevalence of PDR was 12.4%(118/948),and resistance to non-nucleotide reverse transcriptase inhibitors(NNRTIs),nucleotide reverse transcriptase inhibitors(NRTIs),and protease inhibitors(PIs)was10.7%,1.3%,and 1.6%,respectively.A total of 91 clusters were identified,among which eight showed evidence of PDR strain transmission.The largest PDR-associated cluster consisted of six CRF01_AE drugresistant strains carrying K103N and V179T mutations;five of these individuals had initial CD4^(+)cell counts<200 cells/μL.Conclusion The distribution of HIV subtypes in Dehong is diverse and complex.PDR was moderately prevalent(12.4%)between 2020 and 2023.Evidence of transmission of CRF01_AE strains carrying K103N and V179T mutations was found.Routine surveillance of PDR and the strengthening of control measures are essential to limit the spread of drug-resistance HIV strains.
