Most FDA approved drugs are not equally effective in all patients, suggesting that identification of biomarkers to predict responders to a chemoprevention agent will be needed to stratify patients and achieve maximum benefit. The goal of this study was to investigate both patient specific and cell-context specific heterogeneity of metformin response, using cancer cell lines fibroblast cell lines and induced pluripotent stem cells differentiated into lung epithelial lineages.
Patient- and Cell Type-Specific Heterogeneity of Metformin Response.
Specimen part, Cell line
View SamplesThe aim of this study was to investigate correlations between early subclinical findings (10 and 90 day histology and gene expression data) and late outcomes (transplant glomerulopathy and graft loss) in positive crossmatch kidney transplants (+XMKTx).
Early subclinical inflammation correlates with outcomes in positive crossmatch kidney allografts.
Specimen part
View SamplesWe previously observed reduced graft survival for kidney transplants having interstitial fibrosis with subclinical inflammation, but not fibrosis alone, on 1-year protocol biopsy. The current study aimed to determine whether fibrosis with inflammation at 1 year is associated with renal functional decline in a low-risk transplant cohort and to characterize the nature of the inflammation. Subjects were living-donor, tacrolimus/mycophenolate-treated transplant recipients without overt risk factors for reduced graft survival (n=151). Transplants with normal histology (n=86) or fibrosis alone (n=45) on 1-year protocol biopsy had stable renal function between 1 and 5 years, while those having fibrosis with inflammation (n=20) had declining glomerular filtration rate and reduced graft survival. Immunohistochemistry confirmed increased interstitial T-cells and macrophages/dendritic cells in the fibrosis with inflammation group. Gene expression was performed on a subset of biopsies in each group and demonstrated increased expression of transcripts related to innate and cognate immunity in transplants having fibrosis with inflammation. Pathway- and pathological process-specific analyses of microarray profiles revealed that, in fibrosis with inflammation, over-expressed transcripts were enriched for potentially damaging immunological activities including Toll-like receptor signaling, antigen presentation/dendritic cell maturation, interferon gamma-inducible response, cytotoxic T lymphocyte-associated and acute rejection-associated genes. Thus, fibrosis with inflammation in 1-year protocol biopsies is associated with reduced graft survival and function and with a rejection-like gene expression signature even in recipients with no clinical risk for inferior outcome. Early interventions aimed at altering rejection-like inflammation may favor improved long-term KTx survival.
Fibrosis with inflammation at one year predicts transplant functional decline.
No sample metadata fields
View SamplesWe studied intragraft gene expression profiles of positive crossmatch (+XM) kidney transplant recipients who develop transplant glomerulopathy (TG) and those who do not. Whole genome microarray analysis and quantitative rt-PCR for 30 transcripts were performed on RNA from protocol renal allograft biopsies in 3 groups: 1) +XM/TG+ biopsies before and after TG; 2) +XM/NoTG; and 3) negative crossmatch kidney transplants (control). Microarray comparisons showed few differentially expressed genes between paired biopsies from +XM/TG+ recipients before and after the diagnosis of TG. Comparing +XM/TG+ and control groups, significantly altered expression was seen for 2,447 genes (18%) and 3,200 genes (24%) at early and late time points, respectively. Canonical pathway analyses of differentially expressed genes showed inflammatory genes associated with innate and adaptive immune responses. Comparing +XM/TG+ and +XM/NoTG groups, 3,718 probe sets were differentially expressed but these were over-represented in only 4 pathways. A classic accommodation phenotype was not identified. Using rt-PCR, the expression of inflammatory genes was significantly increased in +XM/TG+ recipients compared to control biopsies and to +XM/NoTG biopsies. In conclusion, pre-transplant DSA results in a gene expression profile characterized by inflammation and cellular infiltration and the majority of XM+ grafts are exposed to chronic injury.
Intragraft gene expression in positive crossmatch kidney allografts: ongoing inflammation mediates chronic antibody-mediated injury.
Specimen part, Time
View SamplesThe aim of this study was to investigate correlations between early subclinical findings (10 and 90 day histology and gene expression data) and late outcomes (transplant glomerulopathy and graft loss) in positive crossmatch kidney transplants (+XMKTx).
Unique molecular changes in kidney allografts after simultaneous liver-kidney compared with solitary kidney transplantation.
Specimen part, Subject
View SamplesIntroduction. Factors contributing to kidney transplant fibrosis remain incompletely understoodparticularly in the absence of acute complications.
A meta-analysis of kidney microarray datasets: investigation of cytokine gene detection and correlation with rt-PCR and detection thresholds.
No sample metadata fields
View SamplesThe combination of defined factors with small molecules targeting epigenetic factors is a strategy that has been shown to enhance optimal derivation of human iPSCs and could be used for therapeutic and regenerative medicine applications. In this study, we showed that a new first-in-class dual G9a/DNMT inhibitor CM272 compound improves the standard four-factor reprogramming efficiency of human fibroblast. The use of CM272 facilitates the generation of iPSC with only two factors, OCT4 and SOX2, allowing the removal of potentially oncogenic factors such as cMYC or KLF4. Taking a closer look at the early events occurring during cell reprogramming we demonstrated that treatment with our G9a/DNMT dual inhibitor induces heterochromatin relaxation, facilitates the engagement of OCT4 and SOX2 transcription factors to the genome and promotes mesenchymal to epithelial transition during cell reprogramming. Thus, the use of this new G9a/DNMT dual inhibitor compound may represent an interesting alternative for improving cell reprogramming.
Reversible dual inhibitor against G9a and DNMT1 improves human iPSC derivation enhancing MET and facilitating transcription factor engagement to the genome.
Sex, Specimen part, Disease, Cell line
View SamplesMyelodysplastic syndromes (MDS) are a heterogeneous group of hematopoietic stem cell diseases characterized by dysplasia of one or more hematologic lineages and a high-risk of developing acute myeloid leukemia (AML). MDS patients have recurrent bacterial infections and abnormal expression of CD56 by monocytes. We investigated MDS patients’ bone marrow CD56+/CD56- monocytes and their in vitro derived dendritic cell (DCs) populations in comparison to cells obtained from disease-free subjects. We found that monocytes from MDS patients, irrespective of CD56 expression, have reduced phagocytosis activity and low expression of genes involved in triggering immune responses, regulation of immune and inflammatory response signaling pathways, and in the response to lipopolysaccharide. Dendritic cells (DCs) derived in vitro from MDS monocytes failed to develop dendritic projections and had reduced expression of HLA-DR and CD86 suggesting that antigen processing and T cell activation capabilities are impaired. In conclusion, we identified in both CD56+ and CD56- monocytes from MDS-patients several abnormalities that may be related to the increased susceptibility to infections observed in these patients.
Bone Marrow Monocytes and Derived Dendritic Cells from Myelodysplastic Patients Have Functional Abnormalities Associated with Defective Response to Bacterial Infection.
Specimen part, Disease
View SamplesTranscriptional profiling of Human primary colon cancer cells under spheroid culture. Goal was to determine the effects of spheroid culture on global primary colon cancer cells gene expression.
No associated publication
Specimen part
View SamplesTo identify targets of PDGFRb signaling and potentially new markers for pericyte activation, we used microarray analysis to compare gene expression in control and mutant pericytes expressing a constitutively active PDGFRb.
PDGFRβ signaling regulates mural cell plasticity and inhibits fat development.
Specimen part
View Samples