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
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
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
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
Recent studies demonstrated that bladder cancers can be grouped into basal and luminal molecular subtypes that possess distinct biological and clinical characteristics.Basal bladder cancers express biomarkers characte...Recent studies demonstrated that bladder cancers can be grouped into basal and luminal molecular subtypes that possess distinct biological and clinical characteristics.Basal bladder cancers express biomarkers characteristic of cancer stem cells and epithelial-tomesenchymal transition(EMT).Patients with basal cancers tend have more advanced stage and metastatic disease at presentation.In preclinical models basal human orthotopic xenografts are also more metastatic than luminal xenografts are,and they metastasize via an EMT-dependent mechanism.However,preclinical and clinical data suggest that basal cancers are also more sensitive to neoadjuvant chemotherapy(NAC),such that most patients with basal cancers who are aggressively managed with NAC have excellent outcomes.Importantly,luminal bladder cancers can also progress to become invasive and metastatic,but they appear to do so via mechanisms that are much less dependent on EMT and may involve help from stromal cells,particularly cancer-associated fibroblasts(CAFs).Although patients with luminal cancers do not appear to derive much clinical benefit from NAC,the luminal tumors that are infiltrated with stromal cells appear to be sensitive to anti-PDL1 antibodies and possibly other immune checkpoint inhibitors.Therefore,neoadjuvant and/or adjuvant immunotherapy may be the most effective approach in treating patients with advanced or metastatic infiltrated luminal bladder cancers.展开更多
It is unanimously accepted that stroke is a highly heterogeneous disorder. Different subtypes of ischemic stroke may have different risk factors, clinical features, and prognoses. The aim of this study was to evaluate...It is unanimously accepted that stroke is a highly heterogeneous disorder. Different subtypes of ischemic stroke may have different risk factors, clinical features, and prognoses. The aim of this study was to evaluate the risk factors, clinical characteristics, and prognoses of different subtypes of ischemic stroke defined by the Trial of ORG10172 in Acute Stroke Treatment （TOAST） criteria. We prospectively analyzed the data from 530 consecutive patients who were admitted to our hospital with acute ischemic stroke within 7 days of stroke onset during the study period. Standardized data assessment was used and the cause of ischemic stroke was classified according to the TOAST criteria. Patients were followed up till 30 and 90 days after stroke onset. It was found that large-artery atherosclerosis was the most frequent etiology of stroke （37.4%）, and showed the highest male preponderance, the highest prevalence of previous transient ischemic attack, and the longest hospital stay among all subtypes. Small artery disease （36.4%） was associated with higher body mass index, higher plasma triglycerides, and lower plasma high-density lipoprotein cholesterol than cardioembolism. Cardioembolism （7.7%）, which was particularly common in the elderly （i.e., individuals aged 65 years and older）, showed the highest female preponderance, the highest prevalence of atrial fibrillation, the earliest presentation to hospital after stroke onset, the most severe symptoms on admission, the maximum complications associated with an adverse outcome, and the highest rate of stroke recurrence and mortality. Our results suggest that ischemic stroke should be regarded as a highly heterogeneous disorder. Studies involving risk factors, clinical features, and prognoses of ischemic stroke should differentiate between etiologic stroke subtypes.展开更多
Breast cancer is a heterogeneous complex of diseases, a spectrum of many subtypes with distinct biological features that lead to differences in response patterns to various treatment modalities and clinical outcomes. ...Breast cancer is a heterogeneous complex of diseases, a spectrum of many subtypes with distinct biological features that lead to differences in response patterns to various treatment modalities and clinical outcomes. Traditional classification systems regarding biological characteristics may have limitations for patient-tailored treatment strategies. Tumors with similar clinical and pathological presentations may have different behaviors. Analyses of breast cancer with new molecular techniques now hold promise for the development of more accurate tests for the prediction of recurrence. Gene signatures have been developed as predictors of response to therapy and protein gene products that have direct roles in driving the biology and clinical behavior of cancer cells are potential targets for the development of novel therapeutics. The present review summarizes current knowledge in breast cancer molecular biology, focusing on novel prognostic and predictive factors.展开更多
AIM: To elucidate the differences in somatic, psycho-logical and biochemical pattern between the subtypes of irritable bowel syndrome (IBS). METHODS: Eighty IBS patients, 30 diarrhoea pre-dominant (D-IBS), 16 constipa...AIM: To elucidate the differences in somatic, psycho-logical and biochemical pattern between the subtypes of irritable bowel syndrome (IBS). METHODS: Eighty IBS patients, 30 diarrhoea pre-dominant (D-IBS), 16 constipation predominant (C-IBS) and 34 alternating IBS (A-IBS) underwent physi-otherapeutic examinations for dysfunctions in body movements and awareness and were compared to an apparently healthy control group (AHC). All groups an-swered questionnaires for gastrointestinal and psycho-logical symptoms. Biochemical variables were analysed in blood. RESULTS: The D-IBS group showed less body aware-ness, less psychological symptoms, a more normal sense of coherence and psychosocial rating as well as higher C-peptide values. C-IBS had a higher degree of body dysfunction and psychological symptoms, as well as the lowest sense of coherence compared to controls and D-IBS. They also demonstrated the most elevated prolactin levels. A-IBS had the lowest degree of body disturbance, deteriorated quality of life and affected bi-ochemical pattern. All subtypes had higher pain scores compared to controls. In addition they all had signifi -cantly increased triglycerides and elevated morning cortisol levels, however, without statistical signifi cance compared with the controls.CONCLUSION: IBS subtypes showed different pro-files in body awareness, somatic and psychological symptoms and in biochemical variables. D-IBS differed compared to the other groups by lowered body aware-ness, less psychological symptoms and a higher sense of coherence and elevated C-peptide values. C-IBS and A-IBS subtypes suffered more from depression and anxiety, associated with a lower quality of life. These differences may be important and will be taken into account in our treatment of these patients.展开更多
Objective： To investigate the associations between the different breast cancer subtypes and survival in Chinese women with operable primary breast cancer. Methods： A total of 1538 Chinese women with operable primary...Objective： To investigate the associations between the different breast cancer subtypes and survival in Chinese women with operable primary breast cancer. Methods： A total of 1538 Chinese women with operable primary breast cancer were analyzed in this study, the median follow-up was 77 months. Estrogen receptor （ER）, progesterone receptor （PR）, and HER2 status were available for these patients. Results： Luminal A （ER＋ and/or PR＋, HER2-） had a favorable disease-free survival （DFS） and overall survival （OS） compared with other subtypes in the entire cohort. Using the luminal A as a reference, among the patients with lymph node positive disease, HER2＋ （ER-, PR-, HER2＋） had the worst DFS （hazard ratio, HR=1.80, 95% CI 1.11 to 2.91, P=0.017） and luminal B （ER＋ and/or PR＋, HER2＋） had the worst OS （HR=2.27, 95% CI 1.50 to 3.45, P0.001）; among the patients with lymph node negative disease, triple-negative （ER-, PR-, HER2-） had the worst DFS （HR=2.21, 95% CI 1.43 to 3.41, P0.001）, whereas no significant difference in DFS between HER2＋ and luminal B or luminal A was observed. Conclusion： As compared with luminal A, luminal B and HER2＋ have the worst survival in patients with lymph node positive disease, but this is not the case in patients with lymph node negative disease; triple-negative subtype has a worse survival in both lymph node positive and lymph node negative patients.展开更多
AIM： To explore the propriety of providing hepatitis B virus （HBV） genotypes F and H with two distinct genotypes. METHODS： Eleven HBV isolates of genotype F （HBV/F） were recovered from patients living in San Fra...AIM： To explore the propriety of providing hepatitis B virus （HBV） genotypes F and H with two distinct genotypes. METHODS： Eleven HBV isolates of genotype F （HBV/F） were recovered from patients living in San Francisco, Japan, Panama, and Venezuela, and their full-length sequences were determined. Phylogenetic analysis was carded out among them along with HBV isolates previously reported. RESULTS： Seven of them clustered with reported HBV/F Isolates in the phylogenetic tree constructed on the entire genomic sequence. The remaining four flocked on another branch along with three HBV isolates formerly reported as genotype H. These seven HBV isolates, including the four in this study and the three reported, had a sequence divergence of 7.3-9.5% from the other HBV/F isolates, and differed by 〉13.7% from HBV isolates of the other six genotypes （A-E and G）. Based on a marked genomic divergence, falling just short of 〉8% separating the seven genotypes, these seven HBV/F isolates were classified into F2 subtype and the former seven into F1 subtype provisionally. In a pairwise comparison of the S-gene sequences among the 7 HBV/F2 isolates and against 47 HBV/F1 isolates as well as 136 representing the other six genotypes （A-E and G）, two clusters separated by distinct genetic distances emerged.CONCLUSION： Based on these analyses, dassifying HBV/ F isolates into two subtypes （F1 and F2） would be more appropriate than providing them with two distinct genotypes （F and H）.展开更多
Summary： Based on the recently proposed Chinese ischemic stroke subclassification （CISS） system, intracranial branch atheromatous disease （BAD） is divided into large artery atherosclerosis （LAA） and penetrating...Summary： Based on the recently proposed Chinese ischemic stroke subclassification （CISS） system, intracranial branch atheromatous disease （BAD） is divided into large artery atherosclerosis （LAA） and penetrating artery disease （PAD）. In the current retrospective analysis, we compared the general charac- teristics of BAD-LAA with BAD-PAD, BAD-LAA with non-BAD-LAA and BAD-PAD with non-BAD-PAD. The study included a total of 80 cases, including 45 cases of BAD and 35 cases of non-BAD. Subjects were classified using CISS system： BAD-LAA, BAD-PAD, non-BAD-LAA and non-BAD-PAD. In addition to analysis of general characteristics, the correlation between the factors and the two subtypes of BAD was evaluated. The number of cases included in the analysis was： 32 cases of BAD-LAA, 13 cases of BAD-PAD, 21 cases of non-BAD-LAA, and 14 cases of non-BAD-PAD. Dia- betes mellitus affected more non-BAD-LAA patients than BAD-LAA patients （P=0.035）. In comparison with non-BAD-PAD, patients with BAD-PAD were younger （P=-0.040）, had higher initial NIHSS score （P〈0.001） and morbidity of ischemic heart disease （P=0.033）. Within patients with BAD, the PAD sub- type was associated with smoking （OR=0.043; P=0.011）, higher low-density lipoprotein （OR=5.339; P=0.029）, ischemic heart disease （OR=9.383; P=0.047） and diabetes mellitus （OR=12.59;P=-0.020）. It was concluded that large artery atherosclerosis was the primary mechanism of BAD. The general char- acteristics showed no significant differences between the CISS subtypes of LAA and PAD within BAD, as well as between the BAD and non-BAD within LAA subtype. Several differences between PAD sub- types of BAD and non-BAD were revealed.展开更多
AIM To detect human papilloma virus(HPV) presence and to characterize cellular immune response in breast cancer patients. METHODS A total of 74 women were included, of which 48 samples were from patients diagnosed wit...AIM To detect human papilloma virus(HPV) presence and to characterize cellular immune response in breast cancer patients. METHODS A total of 74 women were included, of which 48 samples were from patients diagnosed with breast cancer and 26 patients with benign pathology of the breast. Molecular subtype classification was performed based on the immunohistochemical reports of the tumor piece. HPV genome detection and genotyping from fresh breast biopsies was performed using the INNO-LIPA HPV Genotyping Extra test(Innogenetics, Ghent, Belgium). CD3+, CD4+, CD8+ and natural killer(NK)+ cells levels from peripheral blood samples from patients with breast cancer and benign pathology were measured by flow cytometry. RESULTS Luminal A was the most frequent breast cancer molecular subtype(33.33%). HPV was detected in 25% of the breast cancer patients, and genotype 18 was the most frequent in the studied population. The mean of CD3+, CD4+ and CD8+ subpopulations were decreased in patients with breast cancer, in relation to those with benign pathology, with a statistically significant difference in CD8+ values(P = 0.048). The mean of NK+ cells was increased in the benign pathology group. The average level of CD3+, CD4+, CD8+ and NK+ cells decreased as the disease progressed. HER2+ and Luminal B HER2+ tumors had the lowest counts of cell subsets. HPV breast cancer patients had elevated counts of cellular subsets. CONCLUSION Determining level changes in cellular subsets in breast cancer patients is a useful tool to evaluate treatment response.展开更多
A retrospective study was performed to explore the relationship between molecular subtypes and clinicopathological features of breast cancer in Chinese women. Six hundred and twenty-eight Chi- nese women with breast c...A retrospective study was performed to explore the relationship between molecular subtypes and clinicopathological features of breast cancer in Chinese women. Six hundred and twenty-eight Chi- nese women with breast cancer were classified into four molecular subtypes according to their estrogen receptor （ER）, progesterone receptor （PR） and Her-2 status. The prevalence rate of each molecular sub- type was analyzed. Relationship between the subtypes and clinicopathologic features was determined. The distribution of molecular subtypes was as follows： luminal A 46.5%, luminal B 17.0%, basal 21.5%, HER2/neu 15.0%. The subtypes had no significant difference under different menopausal status. How- ever, in the age-specific groups, the age group of〈35 years was more likely to get basal cell-like cancer （36.9%）. Statistically significant differences were found among molecular subtypes by age, nuclear grade, tumor size, lymph node （LN） metastasis, tumor stage by American Joint Committee on Cancer （AJCC）, radiotherapy but not by chemotherapy, types of surgery. After adjusting for several relative confounding factors, the basal subtype more likely had lower nodal involvement in both the incidence of LN metastasis （〉1 positive LN） and incidence of high-volume LN metastasis （〉4 positive LN）. The HER2/neu subtype had higher nodal involvement in the incidence of high-volume LN metastases. After adjusting for relative confounding factors, the HER2/neu subtype more likely had higher AJCC tumor stages. It was suggested that there existed close relationship between molecular subtypes and clinicopa- thological features of breast cancer. In addition, the breast cancer subtypes have been proven to be an independent predictor of LN involvement and AJCC tumor stage. These findings are very important for understanding the occurrence, development, prognosis and treatment of breast cancer in Chinese popu-lation.展开更多
The limited molecular classifications and disease signatures of osteoarthritis(OA)impede the development of prediagnosis and targeted therapeutics for OA patients.To classify and understand the subtypes of OA,we colle...The limited molecular classifications and disease signatures of osteoarthritis(OA)impede the development of prediagnosis and targeted therapeutics for OA patients.To classify and understand the subtypes of OA,we collected three types of tissue including cartilage,subchondral bone,and synovium from multiple clinical centers and constructed an extensive transcriptome atlas of OA patients.By applying unsupervised clustering analysis to the cartilage transcriptome,OA patients were classified into four subtypes with distinct molecular signatures:a glycosaminoglycan metabolic disorder subtype(C1),a collagen metabolic disorder subtype(C2),an activated sensory neuron subtype(C3),and an inflammation subtype(C4).Through ligand-receptor crosstalk analysis of the three knee tissue types,we linked molecular functions with the clinical symptoms of different OA subtypes.For example,the Gene Ontology functional term of vasculature development was enriched in the subchondral bone-cartilage crosstalk of C2 and the cartilage-subchondral bone crosstalk of C4,which might lead to severe osteophytes in C2 patients and apparent joint space narrowing in C4 patients.Based on the marker genes of the four OA subtypes identified in this study,we modeled OA subtypes with two independent published RNA-seq datasets through random forest classification.The findings of this work contradicted traditional OA diagnosis by medical imaging and revealed distinct molecular subtypes in knee OA patients,which may allow for precise diagnosis and treatment of OA.展开更多
Our knowledge of renal cell carcinoma(RCC) is rapidly expanding. For those who diagnose and treat RCC, it is important to understand the new developments. In recent years, many new renal tumors have been described and...Our knowledge of renal cell carcinoma(RCC) is rapidly expanding. For those who diagnose and treat RCC, it is important to understand the new developments. In recent years, many new renal tumors have been described and defined, and our understanding of the biology and clinical correlates of these tumors is changing. Evolving concepts in Xp11 translocation carcinoma, mucinous tubular and spindle cell carcinoma, multilocular cystic clear cell RCC, and carcinoma associated with neuroblastoma are addressed within this review. Tubulocystic carcinoma, thyroid-like follicular carcinoma of kidney, acquired cystic disease-associated RCC, and clear cell papillary RCC are also described. Finally, candidate entities, including RCC with t(6;11) translocation, hybrid oncocytoma/chromophobe RCC, hereditary leiomyomatosis and RCC syndrome, and renal angiomyoadenomatous tumor are reviewed. Knowledge of these new entities is important for diagnosis, treatment and subsequent prognosis. This review provides a targeted summary of new developments in RCC.展开更多
Objective：Menage a trois 1（MAT1）is a targeting subunit of cyclin-dependent kinase-activating kinase and general transcription factor IIH kinase,which modulates cell cycle,transcription and DNA repair.Its dysregulat...Objective：Menage a trois 1（MAT1）is a targeting subunit of cyclin-dependent kinase-activating kinase and general transcription factor IIH kinase,which modulates cell cycle,transcription and DNA repair.Its dysregulation is responsible for diseases including cancers.To further explore the role of MAT1 in breast cancer,we investigated the pathways in which MAT1 might be involved,the association between MAT1 and molecular subtypes,and the role of MAT1 in clinical outcomes of breast cancer patients.Methods：We conducted immunohistochemistry staining on tissue microarray and immunofluorescence staining on sections of MAT1 stable breast cancer cells.Also,we performed Kyoto Encyclopedia of Genes and Genomes pathway analysis,correlation analysis and prognosis analysis on public databases.Results：MAT1 was involved in multiple pathways including normal physiology signaling and disease-related signaling.Furthermore,MAT1 positively correlated with the protein status of estrogen receptor and progesterone receptor,and was enriched in luminal-type and human epidermal growth factor receptor 2-enriched breast cancer in comparison with basal-like subtype at both m RNA and protein levels.Correlation analysis revealed significant association between MAT1 m RNA amount and epithelial markers,mesenchymal markers,cancer stem cell markers,apoptosis markers,transcription markers and oncogenes.Consistently,the results of immunofluorescence stain indicated that MAT1 overexpression enhanced the protein abundance of epidermal growth factor receptor,vimentin,sex determining region Y-box 2 and sine oculis homeobox homolog 1.Importantly,Kaplan-Meier Plotter analysis reflected that MAT1 could serve as a prognostic biomarker predicting worse relapse-free survival and metastasis-free survival.Conclusions：MAT1 is correlated with molecular subtypes and is associated with unfavorable prognosis for breast cancer patients.展开更多
Microvesicles （MVs） are the heterogeneous mixtures of vesicles. MVs released by leukemia cells constitute an important part of the leukemia microenvironment. MVs might act as important reser- voirs of microRNAs （mi...Microvesicles （MVs） are the heterogeneous mixtures of vesicles. MVs released by leukemia cells constitute an important part of the leukemia microenvironment. MVs might act as important reser- voirs of microRNAs （miRNAs）. It is worth evaluating whether MVs possess some unique miRNA con- tents that are valuable in understanding the pathogenesis. In this study, we investigated the miRNA ex- pression patterns of Nalm-6-derived MVs, Jurkat-derived MVs and normal cell-derived MVs using miRNA microarrays. The potential target genes regulated by differentially expressed miRNAs were also predicted and analyzed. Results demonstrated that 182 miRNAs and 166 miRNAs were differentially expressed in Nalm-6-MVs and Jurkat-MVs, respectively. Many oncogenes, tumor suppressors and sig- nal pathway genes were targeted by these aberrantly expressed miRNAs, which might contribute to the development of B-ALL or T-ALL. Our findings expanded the potential diagnostic markers of ALL and provided useful information for ALL pathogenesis.展开更多
BACKGROUND mRNA vaccines have been investigated in multiple tumors,but limited studies have been conducted on their use for hepatocellular carcinoma(HCC).AIM To identify candidate mRNA vaccine antigens for HCC and sui...BACKGROUND mRNA vaccines have been investigated in multiple tumors,but limited studies have been conducted on their use for hepatocellular carcinoma(HCC).AIM To identify candidate mRNA vaccine antigens for HCC and suitable subpopu-lations for mRNA vaccination.METHODS Gene expression profiles and clinical information of HCC datasets were obtained from International Cancer Genome Consortium and The Cancer Genome Atlas.Genes with somatic mutations and copy number variations were identified by cBioPortal analysis.The differentially expressed genes with significant prognostic value were identified by Gene Expression Profiling Interactive Analysis 2 website analysis.The Tumor Immune Estimation Resource database was used to assess the correlation between candidate antigens and the abundance of antigen-presenting cells(APCs).Tumor-associated antigens were overexpressed in tumors and associated with prognosis,genomic alterations,and APC infiltration.A consensus cluster analysis was performed with the Consensus Cluster Plus package to identify the immune subtypes.The weighted gene coexpression network analysis(WGCNA)was used to determine the candidate biomarker molecules for appropriate populations for mRNA vaccines.immune subtypes showed distinct cellular and clinical characteristics.The IS1 and IS3 immune subtypes were immunologically“cold”.The IS2 and IS4 immune subtypes were immunologically“hot”,and the immune checkpoint genes and immunogenic cell death genes were upregulated in these subtypes.IS1-related modules were identified with the WGCNA algorithm.Ultimately,five hub genes(RBP4,KNG1,METTL7A,F12,and ABAT)were identified,and they might be potential biomarkers for mRNA vaccines.CONCLUSION AURKA,CCNB1,CDC25C,CDK1,TRIP13,PES1,MCM3,PPM1G,NEK2,KIF2C,PTTG1,KPNA2,and PRC1 have been identified as candidate HCC antigens for mRNA vaccine development.The IS1 and IS3 immune subtypes are suitable populations for mRNA vaccination.RBP4,KNG1,METTL7A,F12,and ABAT are potential biomarkers for mRNA vaccines.展开更多
The brain tumor perivascular niche(PVN),the region in the vicinity of microvessels is a prime location for brain tumor stem-like cells(BTSCs)[1].Tumor microvasculature creates a complex microenvironment consisting of ...The brain tumor perivascular niche(PVN),the region in the vicinity of microvessels is a prime location for brain tumor stem-like cells(BTSCs)[1].Tumor microvasculature creates a complex microenvironment consisting of various cell types,the extracellular matrix,and soluble factors that mediate cell-cell interaction.The brain tumor PVN controls maintenance,expansion,and differentiation of BTSCs via direct cell contact or paracrine signaling cues.BTSCs often receive bidirectional crosstalk from endothelial cells and other cell types in the niche[2].In addition,the perivascular zone may serve as a path for tumor cells to migrate over long distances(3,4)Unlike other solid tumors,glioblastoma multiforme(GBM)cells rarely metastasize to other organs,but they can invade the entire brain by migrating along specific brain tissue structures,such as blood vessels or white matter tracts,leading to high rates of relapse.Despite the success in modeling diffuse brain tumors in both genetically-modified and patient-derived xenograft(PDX)animals,there is an unmet need for an in vitro system that can bridge conventional cell culture and animal models by mimicking not only the anatomy but also the function of the PVN to study the dynamics of BTSCs.In this presentation,I will describe the use of a microvasculature-on-a-chip system as a PVN model to evaluate the dynamics of BTSCs ex vivo from 10 glioblastoma patients [5].We observed that BTSCs preferentially localize in the perivascular zone.Live cell tracking showed that the cells residing in the vicinity of microvessels had the lowest motility,while a fraction of cells on the microvessels unexpectedly possessed the highest motility and migrated over the longest distance.These results indicate that the perivascular zone is a niche for BTSCs,while the microvascular tracks are also a path for long-distance tumor cell migration and invasion.Additionally,the degree of co-localization between tumor cells and microvessels varied significantly across patients.To validate the results from our microvasculature-on-a-chip system,we used single-cell transcriptome sequencing(10 patients and 21,750 single cells in total)to identify the subtype of each tumor cell.The co-localization coefficient was found to correlate positively with proneural(stem-like)or mesenchymal(invasive)but not classical(proliferative)tumor cells.Furthermore,we found that a gene signature profile including PDGFRA correlated strongly with the'homing'of brain tumor cells to the PVN.Our findings demonstrated that ex vivo dynamics of human brain tumor cells in a microvasculature-on-a-chip model can recapitulate in vivo tumor cell dynamics,heterogeneity,and subtypes,representing a new route to the study of human tumor cell biology and uncover patient-specific tumor cell functions.Acknowledgments:We thank Drs.Laura Niklason,Eric Holland,Franziska Michor,and Frank Szulzewsky for scientific discussion.We thank Misha Guy,Vladimir Polejaev,Zhenting Jiang,and Alice Yun for suggestions and help on the simulation computing and SEM/confocal imaging process.This research was supported by the Packard Fellowship for Science and Engineering(R.F.),National Science Foundation CAREER Award CBET-1351443(R.F.),U54 CA193461(R.F.),U54CA209992(Sub-Project ID:7297 to R.F.),R01 NS095817(J.Z.),Yale Cancer Center Co-Pilot Grant(to R.F.).The molds for microfluidic devices were fabricated in the Yale School of Engineering and Applied Science cleanroom.Sequencing was performed at the Yale Center for Genome Analysis(YCGA)facility.Data was analyzed at Yale High Performance Computing(HPC)center.Super resolution confocal imaging was performed at Yale Center for Cellular and Molecular Imaging(CCMI).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 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.
文摘Recent studies demonstrated that bladder cancers can be grouped into basal and luminal molecular subtypes that possess distinct biological and clinical characteristics.Basal bladder cancers express biomarkers characteristic of cancer stem cells and epithelial-tomesenchymal transition(EMT).Patients with basal cancers tend have more advanced stage and metastatic disease at presentation.In preclinical models basal human orthotopic xenografts are also more metastatic than luminal xenografts are,and they metastasize via an EMT-dependent mechanism.However,preclinical and clinical data suggest that basal cancers are also more sensitive to neoadjuvant chemotherapy(NAC),such that most patients with basal cancers who are aggressively managed with NAC have excellent outcomes.Importantly,luminal bladder cancers can also progress to become invasive and metastatic,but they appear to do so via mechanisms that are much less dependent on EMT and may involve help from stromal cells,particularly cancer-associated fibroblasts(CAFs).Although patients with luminal cancers do not appear to derive much clinical benefit from NAC,the luminal tumors that are infiltrated with stromal cells appear to be sensitive to anti-PDL1 antibodies and possibly other immune checkpoint inhibitors.Therefore,neoadjuvant and/or adjuvant immunotherapy may be the most effective approach in treating patients with advanced or metastatic infiltrated luminal bladder cancers.
文摘It is unanimously accepted that stroke is a highly heterogeneous disorder. Different subtypes of ischemic stroke may have different risk factors, clinical features, and prognoses. The aim of this study was to evaluate the risk factors, clinical characteristics, and prognoses of different subtypes of ischemic stroke defined by the Trial of ORG10172 in Acute Stroke Treatment （TOAST） criteria. We prospectively analyzed the data from 530 consecutive patients who were admitted to our hospital with acute ischemic stroke within 7 days of stroke onset during the study period. Standardized data assessment was used and the cause of ischemic stroke was classified according to the TOAST criteria. Patients were followed up till 30 and 90 days after stroke onset. It was found that large-artery atherosclerosis was the most frequent etiology of stroke （37.4%）, and showed the highest male preponderance, the highest prevalence of previous transient ischemic attack, and the longest hospital stay among all subtypes. Small artery disease （36.4%） was associated with higher body mass index, higher plasma triglycerides, and lower plasma high-density lipoprotein cholesterol than cardioembolism. Cardioembolism （7.7%）, which was particularly common in the elderly （i.e., individuals aged 65 years and older）, showed the highest female preponderance, the highest prevalence of atrial fibrillation, the earliest presentation to hospital after stroke onset, the most severe symptoms on admission, the maximum complications associated with an adverse outcome, and the highest rate of stroke recurrence and mortality. Our results suggest that ischemic stroke should be regarded as a highly heterogeneous disorder. Studies involving risk factors, clinical features, and prognoses of ischemic stroke should differentiate between etiologic stroke subtypes.
文摘Breast cancer is a heterogeneous complex of diseases, a spectrum of many subtypes with distinct biological features that lead to differences in response patterns to various treatment modalities and clinical outcomes. Traditional classification systems regarding biological characteristics may have limitations for patient-tailored treatment strategies. Tumors with similar clinical and pathological presentations may have different behaviors. Analyses of breast cancer with new molecular techniques now hold promise for the development of more accurate tests for the prediction of recurrence. Gene signatures have been developed as predictors of response to therapy and protein gene products that have direct roles in driving the biology and clinical behavior of cancer cells are potential targets for the development of novel therapeutics. The present review summarizes current knowledge in breast cancer molecular biology, focusing on novel prognostic and predictive factors.
基金Grants from the University of Gothenburg, Sweden
文摘AIM: To elucidate the differences in somatic, psycho-logical and biochemical pattern between the subtypes of irritable bowel syndrome (IBS). METHODS: Eighty IBS patients, 30 diarrhoea pre-dominant (D-IBS), 16 constipation predominant (C-IBS) and 34 alternating IBS (A-IBS) underwent physi-otherapeutic examinations for dysfunctions in body movements and awareness and were compared to an apparently healthy control group (AHC). All groups an-swered questionnaires for gastrointestinal and psycho-logical symptoms. Biochemical variables were analysed in blood. RESULTS: The D-IBS group showed less body aware-ness, less psychological symptoms, a more normal sense of coherence and psychosocial rating as well as higher C-peptide values. C-IBS had a higher degree of body dysfunction and psychological symptoms, as well as the lowest sense of coherence compared to controls and D-IBS. They also demonstrated the most elevated prolactin levels. A-IBS had the lowest degree of body disturbance, deteriorated quality of life and affected bi-ochemical pattern. All subtypes had higher pain scores compared to controls. In addition they all had signifi -cantly increased triglycerides and elevated morning cortisol levels, however, without statistical signifi cance compared with the controls.CONCLUSION: IBS subtypes showed different pro-files in body awareness, somatic and psychological symptoms and in biochemical variables. D-IBS differed compared to the other groups by lowered body aware-ness, less psychological symptoms and a higher sense of coherence and elevated C-peptide values. C-IBS and A-IBS subtypes suffered more from depression and anxiety, associated with a lower quality of life. These differences may be important and will be taken into account in our treatment of these patients.
基金supported by grants from the Program fro Breast Cancer Tissue Bank of Beijingthe National Natural Science Foundation of China (No.30973436)
文摘Objective： To investigate the associations between the different breast cancer subtypes and survival in Chinese women with operable primary breast cancer. Methods： A total of 1538 Chinese women with operable primary breast cancer were analyzed in this study, the median follow-up was 77 months. Estrogen receptor （ER）, progesterone receptor （PR）, and HER2 status were available for these patients. Results： Luminal A （ER＋ and/or PR＋, HER2-） had a favorable disease-free survival （DFS） and overall survival （OS） compared with other subtypes in the entire cohort. Using the luminal A as a reference, among the patients with lymph node positive disease, HER2＋ （ER-, PR-, HER2＋） had the worst DFS （hazard ratio, HR=1.80, 95% CI 1.11 to 2.91, P=0.017） and luminal B （ER＋ and/or PR＋, HER2＋） had the worst OS （HR=2.27, 95% CI 1.50 to 3.45, P0.001）; among the patients with lymph node negative disease, triple-negative （ER-, PR-, HER2-） had the worst DFS （HR=2.21, 95% CI 1.43 to 3.41, P0.001）, whereas no significant difference in DFS between HER2＋ and luminal B or luminal A was observed. Conclusion： As compared with luminal A, luminal B and HER2＋ have the worst survival in patients with lymph node positive disease, but this is not the case in patients with lymph node negative disease; triple-negative subtype has a worse survival in both lymph node positive and lymph node negative patients.
文摘AIM： To explore the propriety of providing hepatitis B virus （HBV） genotypes F and H with two distinct genotypes. METHODS： Eleven HBV isolates of genotype F （HBV/F） were recovered from patients living in San Francisco, Japan, Panama, and Venezuela, and their full-length sequences were determined. Phylogenetic analysis was carded out among them along with HBV isolates previously reported. RESULTS： Seven of them clustered with reported HBV/F Isolates in the phylogenetic tree constructed on the entire genomic sequence. The remaining four flocked on another branch along with three HBV isolates formerly reported as genotype H. These seven HBV isolates, including the four in this study and the three reported, had a sequence divergence of 7.3-9.5% from the other HBV/F isolates, and differed by 〉13.7% from HBV isolates of the other six genotypes （A-E and G）. Based on a marked genomic divergence, falling just short of 〉8% separating the seven genotypes, these seven HBV/F isolates were classified into F2 subtype and the former seven into F1 subtype provisionally. In a pairwise comparison of the S-gene sequences among the 7 HBV/F2 isolates and against 47 HBV/F1 isolates as well as 136 representing the other six genotypes （A-E and G）, two clusters separated by distinct genetic distances emerged.CONCLUSION： Based on these analyses, dassifying HBV/ F isolates into two subtypes （F1 and F2） would be more appropriate than providing them with two distinct genotypes （F and H）.
文摘Summary： Based on the recently proposed Chinese ischemic stroke subclassification （CISS） system, intracranial branch atheromatous disease （BAD） is divided into large artery atherosclerosis （LAA） and penetrating artery disease （PAD）. In the current retrospective analysis, we compared the general charac- teristics of BAD-LAA with BAD-PAD, BAD-LAA with non-BAD-LAA and BAD-PAD with non-BAD-PAD. The study included a total of 80 cases, including 45 cases of BAD and 35 cases of non-BAD. Subjects were classified using CISS system： BAD-LAA, BAD-PAD, non-BAD-LAA and non-BAD-PAD. In addition to analysis of general characteristics, the correlation between the factors and the two subtypes of BAD was evaluated. The number of cases included in the analysis was： 32 cases of BAD-LAA, 13 cases of BAD-PAD, 21 cases of non-BAD-LAA, and 14 cases of non-BAD-PAD. Dia- betes mellitus affected more non-BAD-LAA patients than BAD-LAA patients （P=0.035）. In comparison with non-BAD-PAD, patients with BAD-PAD were younger （P=-0.040）, had higher initial NIHSS score （P〈0.001） and morbidity of ischemic heart disease （P=0.033）. Within patients with BAD, the PAD sub- type was associated with smoking （OR=0.043; P=0.011）, higher low-density lipoprotein （OR=5.339; P=0.029）, ischemic heart disease （OR=9.383; P=0.047） and diabetes mellitus （OR=12.59;P=-0.020）. It was concluded that large artery atherosclerosis was the primary mechanism of BAD. The general char- acteristics showed no significant differences between the CISS subtypes of LAA and PAD within BAD, as well as between the BAD and non-BAD within LAA subtype. Several differences between PAD sub- types of BAD and non-BAD were revealed.
基金Supported by FONACIT Project,No.G2005000408PEII Project,No.2012001201
文摘AIM To detect human papilloma virus(HPV) presence and to characterize cellular immune response in breast cancer patients. METHODS A total of 74 women were included, of which 48 samples were from patients diagnosed with breast cancer and 26 patients with benign pathology of the breast. Molecular subtype classification was performed based on the immunohistochemical reports of the tumor piece. HPV genome detection and genotyping from fresh breast biopsies was performed using the INNO-LIPA HPV Genotyping Extra test(Innogenetics, Ghent, Belgium). CD3+, CD4+, CD8+ and natural killer(NK)+ cells levels from peripheral blood samples from patients with breast cancer and benign pathology were measured by flow cytometry. RESULTS Luminal A was the most frequent breast cancer molecular subtype(33.33%). HPV was detected in 25% of the breast cancer patients, and genotype 18 was the most frequent in the studied population. The mean of CD3+, CD4+ and CD8+ subpopulations were decreased in patients with breast cancer, in relation to those with benign pathology, with a statistically significant difference in CD8+ values(P = 0.048). The mean of NK+ cells was increased in the benign pathology group. The average level of CD3+, CD4+, CD8+ and NK+ cells decreased as the disease progressed. HER2+ and Luminal B HER2+ tumors had the lowest counts of cell subsets. HPV breast cancer patients had elevated counts of cellular subsets. CONCLUSION Determining level changes in cellular subsets in breast cancer patients is a useful tool to evaluate treatment response.
文摘A retrospective study was performed to explore the relationship between molecular subtypes and clinicopathological features of breast cancer in Chinese women. Six hundred and twenty-eight Chi- nese women with breast cancer were classified into four molecular subtypes according to their estrogen receptor （ER）, progesterone receptor （PR） and Her-2 status. The prevalence rate of each molecular sub- type was analyzed. Relationship between the subtypes and clinicopathologic features was determined. The distribution of molecular subtypes was as follows： luminal A 46.5%, luminal B 17.0%, basal 21.5%, HER2/neu 15.0%. The subtypes had no significant difference under different menopausal status. How- ever, in the age-specific groups, the age group of〈35 years was more likely to get basal cell-like cancer （36.9%）. Statistically significant differences were found among molecular subtypes by age, nuclear grade, tumor size, lymph node （LN） metastasis, tumor stage by American Joint Committee on Cancer （AJCC）, radiotherapy but not by chemotherapy, types of surgery. After adjusting for several relative confounding factors, the basal subtype more likely had lower nodal involvement in both the incidence of LN metastasis （〉1 positive LN） and incidence of high-volume LN metastasis （〉4 positive LN）. The HER2/neu subtype had higher nodal involvement in the incidence of high-volume LN metastases. After adjusting for relative confounding factors, the HER2/neu subtype more likely had higher AJCC tumor stages. It was suggested that there existed close relationship between molecular subtypes and clinicopa- thological features of breast cancer. In addition, the breast cancer subtypes have been proven to be an independent predictor of LN involvement and AJCC tumor stage. These findings are very important for understanding the occurrence, development, prognosis and treatment of breast cancer in Chinese popu-lation.
基金the National Key R&D Program of China(2017YFA0104900)the National Natural Science Foundation of China(81630065,31830029,and 81802195)the China Postdoctoral Science Foundation(2017M621913).
文摘The limited molecular classifications and disease signatures of osteoarthritis(OA)impede the development of prediagnosis and targeted therapeutics for OA patients.To classify and understand the subtypes of OA,we collected three types of tissue including cartilage,subchondral bone,and synovium from multiple clinical centers and constructed an extensive transcriptome atlas of OA patients.By applying unsupervised clustering analysis to the cartilage transcriptome,OA patients were classified into four subtypes with distinct molecular signatures:a glycosaminoglycan metabolic disorder subtype(C1),a collagen metabolic disorder subtype(C2),an activated sensory neuron subtype(C3),and an inflammation subtype(C4).Through ligand-receptor crosstalk analysis of the three knee tissue types,we linked molecular functions with the clinical symptoms of different OA subtypes.For example,the Gene Ontology functional term of vasculature development was enriched in the subchondral bone-cartilage crosstalk of C2 and the cartilage-subchondral bone crosstalk of C4,which might lead to severe osteophytes in C2 patients and apparent joint space narrowing in C4 patients.Based on the marker genes of the four OA subtypes identified in this study,we modeled OA subtypes with two independent published RNA-seq datasets through random forest classification.The findings of this work contradicted traditional OA diagnosis by medical imaging and revealed distinct molecular subtypes in knee OA patients,which may allow for precise diagnosis and treatment of OA.
文摘Our knowledge of renal cell carcinoma(RCC) is rapidly expanding. For those who diagnose and treat RCC, it is important to understand the new developments. In recent years, many new renal tumors have been described and defined, and our understanding of the biology and clinical correlates of these tumors is changing. Evolving concepts in Xp11 translocation carcinoma, mucinous tubular and spindle cell carcinoma, multilocular cystic clear cell RCC, and carcinoma associated with neuroblastoma are addressed within this review. Tubulocystic carcinoma, thyroid-like follicular carcinoma of kidney, acquired cystic disease-associated RCC, and clear cell papillary RCC are also described. Finally, candidate entities, including RCC with t(6;11) translocation, hybrid oncocytoma/chromophobe RCC, hereditary leiomyomatosis and RCC syndrome, and renal angiomyoadenomatous tumor are reviewed. Knowledge of these new entities is important for diagnosis, treatment and subsequent prognosis. This review provides a targeted summary of new developments in RCC.
基金supported by the National Natural Science Foundation of China (Grant No.81572608 and 81172422)the Wuhan Science and Technology Bureau (Grant No.2017060201010170)
文摘Objective：Menage a trois 1（MAT1）is a targeting subunit of cyclin-dependent kinase-activating kinase and general transcription factor IIH kinase,which modulates cell cycle,transcription and DNA repair.Its dysregulation is responsible for diseases including cancers.To further explore the role of MAT1 in breast cancer,we investigated the pathways in which MAT1 might be involved,the association between MAT1 and molecular subtypes,and the role of MAT1 in clinical outcomes of breast cancer patients.Methods：We conducted immunohistochemistry staining on tissue microarray and immunofluorescence staining on sections of MAT1 stable breast cancer cells.Also,we performed Kyoto Encyclopedia of Genes and Genomes pathway analysis,correlation analysis and prognosis analysis on public databases.Results：MAT1 was involved in multiple pathways including normal physiology signaling and disease-related signaling.Furthermore,MAT1 positively correlated with the protein status of estrogen receptor and progesterone receptor,and was enriched in luminal-type and human epidermal growth factor receptor 2-enriched breast cancer in comparison with basal-like subtype at both m RNA and protein levels.Correlation analysis revealed significant association between MAT1 m RNA amount and epithelial markers,mesenchymal markers,cancer stem cell markers,apoptosis markers,transcription markers and oncogenes.Consistently,the results of immunofluorescence stain indicated that MAT1 overexpression enhanced the protein abundance of epidermal growth factor receptor,vimentin,sex determining region Y-box 2 and sine oculis homeobox homolog 1.Importantly,Kaplan-Meier Plotter analysis reflected that MAT1 could serve as a prognostic biomarker predicting worse relapse-free survival and metastasis-free survival.Conclusions：MAT1 is correlated with molecular subtypes and is associated with unfavorable prognosis for breast cancer patients.
基金supported by the National Natural Science Foundation of China(No.81170462)
文摘Microvesicles （MVs） are the heterogeneous mixtures of vesicles. MVs released by leukemia cells constitute an important part of the leukemia microenvironment. MVs might act as important reser- voirs of microRNAs （miRNAs）. It is worth evaluating whether MVs possess some unique miRNA con- tents that are valuable in understanding the pathogenesis. In this study, we investigated the miRNA ex- pression patterns of Nalm-6-derived MVs, Jurkat-derived MVs and normal cell-derived MVs using miRNA microarrays. The potential target genes regulated by differentially expressed miRNAs were also predicted and analyzed. Results demonstrated that 182 miRNAs and 166 miRNAs were differentially expressed in Nalm-6-MVs and Jurkat-MVs, respectively. Many oncogenes, tumor suppressors and sig- nal pathway genes were targeted by these aberrantly expressed miRNAs, which might contribute to the development of B-ALL or T-ALL. Our findings expanded the potential diagnostic markers of ALL and provided useful information for ALL pathogenesis.
文摘BACKGROUND mRNA vaccines have been investigated in multiple tumors,but limited studies have been conducted on their use for hepatocellular carcinoma(HCC).AIM To identify candidate mRNA vaccine antigens for HCC and suitable subpopu-lations for mRNA vaccination.METHODS Gene expression profiles and clinical information of HCC datasets were obtained from International Cancer Genome Consortium and The Cancer Genome Atlas.Genes with somatic mutations and copy number variations were identified by cBioPortal analysis.The differentially expressed genes with significant prognostic value were identified by Gene Expression Profiling Interactive Analysis 2 website analysis.The Tumor Immune Estimation Resource database was used to assess the correlation between candidate antigens and the abundance of antigen-presenting cells(APCs).Tumor-associated antigens were overexpressed in tumors and associated with prognosis,genomic alterations,and APC infiltration.A consensus cluster analysis was performed with the Consensus Cluster Plus package to identify the immune subtypes.The weighted gene coexpression network analysis(WGCNA)was used to determine the candidate biomarker molecules for appropriate populations for mRNA vaccines.immune subtypes showed distinct cellular and clinical characteristics.The IS1 and IS3 immune subtypes were immunologically“cold”.The IS2 and IS4 immune subtypes were immunologically“hot”,and the immune checkpoint genes and immunogenic cell death genes were upregulated in these subtypes.IS1-related modules were identified with the WGCNA algorithm.Ultimately,five hub genes(RBP4,KNG1,METTL7A,F12,and ABAT)were identified,and they might be potential biomarkers for mRNA vaccines.CONCLUSION AURKA,CCNB1,CDC25C,CDK1,TRIP13,PES1,MCM3,PPM1G,NEK2,KIF2C,PTTG1,KPNA2,and PRC1 have been identified as candidate HCC antigens for mRNA vaccine development.The IS1 and IS3 immune subtypes are suitable populations for mRNA vaccination.RBP4,KNG1,METTL7A,F12,and ABAT are potential biomarkers for mRNA vaccines.
文摘The brain tumor perivascular niche(PVN),the region in the vicinity of microvessels is a prime location for brain tumor stem-like cells(BTSCs)[1].Tumor microvasculature creates a complex microenvironment consisting of various cell types,the extracellular matrix,and soluble factors that mediate cell-cell interaction.The brain tumor PVN controls maintenance,expansion,and differentiation of BTSCs via direct cell contact or paracrine signaling cues.BTSCs often receive bidirectional crosstalk from endothelial cells and other cell types in the niche[2].In addition,the perivascular zone may serve as a path for tumor cells to migrate over long distances(3,4)Unlike other solid tumors,glioblastoma multiforme(GBM)cells rarely metastasize to other organs,but they can invade the entire brain by migrating along specific brain tissue structures,such as blood vessels or white matter tracts,leading to high rates of relapse.Despite the success in modeling diffuse brain tumors in both genetically-modified and patient-derived xenograft(PDX)animals,there is an unmet need for an in vitro system that can bridge conventional cell culture and animal models by mimicking not only the anatomy but also the function of the PVN to study the dynamics of BTSCs.In this presentation,I will describe the use of a microvasculature-on-a-chip system as a PVN model to evaluate the dynamics of BTSCs ex vivo from 10 glioblastoma patients [5].We observed that BTSCs preferentially localize in the perivascular zone.Live cell tracking showed that the cells residing in the vicinity of microvessels had the lowest motility,while a fraction of cells on the microvessels unexpectedly possessed the highest motility and migrated over the longest distance.These results indicate that the perivascular zone is a niche for BTSCs,while the microvascular tracks are also a path for long-distance tumor cell migration and invasion.Additionally,the degree of co-localization between tumor cells and microvessels varied significantly across patients.To validate the results from our microvasculature-on-a-chip system,we used single-cell transcriptome sequencing(10 patients and 21,750 single cells in total)to identify the subtype of each tumor cell.The co-localization coefficient was found to correlate positively with proneural(stem-like)or mesenchymal(invasive)but not classical(proliferative)tumor cells.Furthermore,we found that a gene signature profile including PDGFRA correlated strongly with the'homing'of brain tumor cells to the PVN.Our findings demonstrated that ex vivo dynamics of human brain tumor cells in a microvasculature-on-a-chip model can recapitulate in vivo tumor cell dynamics,heterogeneity,and subtypes,representing a new route to the study of human tumor cell biology and uncover patient-specific tumor cell functions.Acknowledgments:We thank Drs.Laura Niklason,Eric Holland,Franziska Michor,and Frank Szulzewsky for scientific discussion.We thank Misha Guy,Vladimir Polejaev,Zhenting Jiang,and Alice Yun for suggestions and help on the simulation computing and SEM/confocal imaging process.This research was supported by the Packard Fellowship for Science and Engineering(R.F.),National Science Foundation CAREER Award CBET-1351443(R.F.),U54 CA193461(R.F.),U54CA209992(Sub-Project ID:7297 to R.F.),R01 NS095817(J.Z.),Yale Cancer Center Co-Pilot Grant(to R.F.).The molds for microfluidic devices were fabricated in the Yale School of Engineering and Applied Science cleanroom.Sequencing was performed at the Yale Center for Genome Analysis(YCGA)facility.Data was analyzed at Yale High Performance Computing(HPC)center.Super resolution confocal imaging was performed at Yale Center for Cellular and Molecular Imaging(CCMI).
