Project description:By performing single-cell RNA sequencing (scRNA-seq) analysis on the T cells which stimulated by phageome from normal or severe acute pancreatitis mice, we seek to understand which T cells contribute to the inflammation in pancreatitis. t-distributed stochastic neighbor embedding (tSNE) identified 5 distinct T cell cluster, including effector CD8, naïve CD8, CD4, proliferating CD8 and stem like CD8. Stimulation by different phages did not change the T cell heterogeneity. Comparison of genes revealed a significant enrichment in the cell proliferation after SAP derived phages treatment. Differential gene expression analysis confirmed that SAP derived phages treatment skewed the cell pattern toward more IL-7r expression, while control derived phages treatment induce the IL-22 expression.
Project description:The aggressive MLL-rearranged leukemias are well-known for their unique gene-expression profiles. The goal of this study was to characterize the MLL-specific DNA methylation profiles in infant acute lymphoblastic leukemia (ALL). Genome-wide DNA methylation profiling was performed on primary infant ALL samples. The majority of infant ALL samples demonstrated severe DNA hypermethylation compared with normal pediatric bone marrows, which implies that targeting of DNA methylation may be an interesting option for future therapeutic strategies in MLL-rearranged infant ALL. Using ALL cell lines carrying the MLL translocation t(4;11) (SEMK2 and RS4;11) as a model for the patient cells, we demonstrated that the hypermethylated genes are sensitive to demethylation.
Project description:Extensive molecular and prognostic characterization of wild-type MLL infant ALL. Background: Approximately 20% of all infant ALL cases carry wild-type (or germline) MLL genes. To date, wild-type MLL infant ALL patients are generally regarded as young pediatric precursor B-ALL patients, but extensive characterization of this specific patient group largely remains unacknowledged. Methods: We here studied a relatively large cohort of 78 wild-type MLL infant ALL samples, using clinical parameters, array-comparative genomic hybridization analysis, gene expression profiling, multiplex ligation-dependent probe amplification, and conventional sequencing. Findings: Wild-type MLL infant ALL patients are generally characterized by a lower incidence of favourable prognostic factors than pediatric (non-infant) B-ALL patients, and patients at high risk of therapy failure typically display an immature pro-B immunophenotype or respond poorly to prednisone. Using gene expression profiling, we found MEIS1 expression to additionally be highly predictive for clinical outcome in wild-type MLL infant ALL with a favourable prognosis in the wild-type MLL infants with low MEIS1 expression (DFS 88%% versus 50%, p=0•01). Overall the incidence of DNA copy number variations and genetic abnormalities in genes involved in B-cell differentiation is lower in wild-type MLL infant ALL patients as compared with pediatric precursor B-ALL patients. Interpretation: Wild-type MLL infant ALL represents a highly heterogeneous patient group, which cannot be unified by one or a few known recurrent genomic aberrations. High-level MEIS1 expression and an immature pro-B immunophenotype in high-risk wild-type MLL infant ALL patients shows parallel with the unfavourable prognosis of MLL-rearranged infant ALL patients. In contrast, wild-type MLL infant ALL patients expressing lower levels of MEIS1 and displaying more differentiated (pre-B or common) phenotypes may well be more related to pediatric precursor B-ALL patients older than 1 year of age. We advocate that a treatment strategy in wild-type MLL infant ALL based on MEIS1 expression could be beneficial for improving survival. Gene expression profiling of wild-type MLL infant ALL. Additional wild-type MLL infant ALL patient samples (n=17) to the earlier samples published under GSE19475 (GSM485309 to GSM485322).
Project description:Infants suffer disproportionately from respiratory infections and generate reduced vaccine responses compared to adults, although underlying mechanisms remain unclear. In adult mice, lung-localized, tissue-resident memory T cells (TRM) mediate optimal protection to respiratory pathogens. We hypothesized that reduced protection in infancy was due to impaired T effector localization and/or lung TRM establishment. Using an infant mouse model we demonstrate generation of lung-homing, virus-specific T effectors following influenza infection or live-attenuated vaccination, similar to adults. However, infection during infancy generated markedly fewer lung TRM and heterosubtypic protection was reduced compared to adults. Impaired TRM establishment was infant-T cell-intrinsic and infant effectors displayed distinct transcriptional profiles enriched for T-bet-regulated genes. Notably, mouse and human infant T cells exhibited increased T-bet expression following activation and reducing T-bet levels in infant mice enhanced lung TRM establishment. Our findings reveal that infant T cells are intrinsically programmed for short-term responses and targeting key regulators could promote long-term, tissue-targeted protection at this critical life stage.
Project description:Extensive molecular and prognostic characterization of wild-type MLL infant ALL. Background: Approximately 20% of all infant ALL cases carry wild-type (or germline) MLL genes. To date, wild-type MLL infant ALL patients are generally regarded as young pediatric precursor B-ALL patients, but extensive characterization of this specific patient group largely remains unacknowledged. Methods: We here studied a relatively large cohort of 78 wild-type MLL infant ALL samples, using clinical parameters, array-comparative genomic hybridization analysis, gene expression profiling, multiplex ligation-dependent probe amplification, and conventional sequencing. Findings: Wild-type MLL infant ALL patients are generally characterized by a lower incidence of favourable prognostic factors than pediatric (non-infant) B-ALL patients, and patients at high risk of therapy failure typically display an immature pro-B immunophenotype or respond poorly to prednisone. Using gene expression profiling, we found MEIS1 expression to additionally be highly predictive for clinical outcome in wild-type MLL infant ALL with a favourable prognosis in the wild-type MLL infants with low MEIS1 expression (DFS 88%% versus 50%, p=0•01). Overall the incidence of DNA copy number variations and genetic abnormalities in genes involved in B-cell differentiation is lower in wild-type MLL infant ALL patients as compared with pediatric precursor B-ALL patients. Interpretation: Wild-type MLL infant ALL represents a highly heterogeneous patient group, which cannot be unified by one or a few known recurrent genomic aberrations. High-level MEIS1 expression and an immature pro-B immunophenotype in high-risk wild-type MLL infant ALL patients shows parallel with the unfavourable prognosis of MLL-rearranged infant ALL patients. In contrast, wild-type MLL infant ALL patients expressing lower levels of MEIS1 and displaying more differentiated (pre-B or common) phenotypes may well be more related to pediatric precursor B-ALL patients older than 1 year of age. We advocate that a treatment strategy in wild-type MLL infant ALL based on MEIS1 expression could be beneficial for improving survival.
Project description:At birth, human infants are poised to survive in harsh, hostile conditions. An understanding of the state of newborn skin development and maturation is key to the maintenance of health, optimum response to injury, healing and disease. The observational study collected full-thickness newborn skin samples from 27 infants at surgery and compared them to skin samples from 43 adult sites protected from ultraviolet radiation exposure, as the standard for stable, mature skin. Transcriptomics profiling and gene set enrichment analysis were performed. Statistical analysis established over 25,000 differentially regulated probe sets, representing 10,647 distinct genes, in infant skin compared to adult skin. Gene set enrichment analysis showed a significant increase in 143 biological processes (adjusted p < 0.01) in infant skin, versus adult skin samples, including extracellular matrix (ECM) organization, cell adhesion, collagen fibril organization and fatty acid metabolic process. The top two biological processes were ECM organization and ECM structure organization. Genes involving epidermis development, immune function, cell differentiation, and hair cycle were overexpressed in adults, representing 101 significantly enriched biological processes (adjusted p < 0.01). The top processes involved skin and epidermal development, e.g., keratinocyte differentiation, keratinization and cornification intermediate filament cytoskeleton organization and hair cycle. Over half of the enriched biological processes also involved immune function, including antigen processing and presentation. The results provide essential insight regarding newborn infant skin and its ability to support the newborn’s preparedness to survive and flourish, despite the infant’s new environment laden with microbes, high oxygen tension and potential irritants. To our knowledge, this is the first report on newborn infant skin transcriptomics analysis. When compared to ultraviolet radiation protected adult skin, it highlights the substantial differences between them. This fundamental knowledge is expected to guide strategies to protect and preserve the features of unperturbed, young skin.