Primary human cytomegalovirus (HCMV) infection usually goes unnoticed, causing mild or no symptoms in immunocompetent individuals. Some rare severe clinical cases have however been reported without investigation of host immune responses or viral virulence. In this present study, we investigate, for the first time, phenotypic and functional features together with gene expression profiles in immunocompetent adults experiencing a severe primary HCMV infection. Twenty PHIP were enrolled as well as 26 HCMV-seronegative and 39 HCMV-seropositive healthy controls. PHIP had a huge lymphocytosis marked by massive expansion of NK and T cell compartments. Interestingly, PHIP mounted efficient innate and adaptive immune responses with a deep HCMV imprint, revealed mainly by the expansion of NKG2C+ NK cells, CD16+ V2- T cells and conventional HCMV-specific CD8+ T cells. The main effector lymphocytes were activated and displayed an early immune phenotype that developed toward a more mature differentiated status. We suggest that both huge lymphocytosis and excessive lymphocyte activation could contribute to a massive cytokine production known to mediate tissue damage observed in PHIP. Taken together, these findings bring new insights into the comprehensive understanding of immune mechanisms involved during primary HCMV-infection in immunocompetent individuals.
Severe Symptomatic Primary Human Cytomegalovirus Infection despite Effective Innate and Adaptive Immune Responses.
Disease
View SamplesTo systemically explore how RNA quality affects microarray assay results, a set of rat liver RNA samples with a progressive change in RNA quality was generated either by thawing frozen tissue or by ex vivo incubation of fresh tissue.
Characterization of the effect of sample quality on high density oligonucleotide microarray data using progressively degraded rat liver RNA.
Sex, Age, Specimen part, Time
View SamplesExtracellular matrix interactions play essential roles in normal physiology and many pathological processes. Here, we report a novel screening platform capable of measuring phenotypic responses to combinations of ECM molecules. While the importance of ECM interactions in metastasis is well documented, systematic approaches to identify their roles in distinct stages of tumorigenesis have not been described. Using a genetic mouse model of lung adenocarcinoma, we measured the ECM-dependent adhesion of tumor-derived cells. Hierarchical clustering of adhesion profiles generated using this platform differentially segregated metastatic cell lines from primary tumor lines. Furthermore, we uncovered that metastatic cells selectively associate with fibronectin when in combination with galectin-3, galectin-8, or laminin. These interactions appear to be mediated in part by 31 integrin both in vitro and in vivo. We show that these galectins also correlate with human disease at both a transcriptional and histological level. Thus, our in vitro platform allowed us to interrogate the interactions of metastatic cells with their surrounding environment, and identified ECM and integrin interactions that could lead to therapeutic targets for metastasis prevention.
A combinatorial extracellular matrix platform identifies cell-extracellular matrix interactions that correlate with metastasis.
Specimen part
View SamplesUsually starch is nearly depleted at the end of the night. To induce a gradual depletion of carbon, we have analysed the global response of transcripts during an extension of the night, where carbon becomes severely limiting from about four hours onwards.
Global transcript levels respond to small changes of the carbon status during progressive exhaustion of carbohydrates in Arabidopsis rosettes.
Specimen part
View SamplesAbstract: Colonic cancers with a serrated morphology have been proposed to comprise a molecularly distinct tumor entity following an alternative pathway of genetic alterations independently of APC mutations. Here we demonstrate that intestinal cell specific expression of oncogenic K-rasG12D in mice induces serrated hyperplasia, which is characterized by p16ink4a overexpression and induction of senescence. Deletion of Ink4a/Arf in K-rasG12D expressing mice prevents senescence and leads to invasive, metastasizing carcinomas with morphological and molecular alterations comparable to human KRAS mutated serrated tumors. Thus, we suggest that oncogenic K-ras is sufficient to initiate an alternative, serrated pathway to colorectal cancer and hence propose RAS-RAF-MEK signaling apart from APC as an additional gatekeeper in colorectal tumor development.
Ink4a/Arf and oncogene-induced senescence prevent tumor progression during alternative colorectal tumorigenesis.
Specimen part
View SamplesFoxp1 is expressed throughout B cell development, but the physiological functions in mature B lymphocytes are unknown. We therefore evaluated differential gene expression in Foxp1-deficient B cells, with or
Foxp1 controls mature B cell survival and the development of follicular and B-1 B cells.
Specimen part
View SamplesCurrent preclinical models in tumor biology are limited in their ability to recapitulate relevant (patho-) physiological processes, including autophagy. Three-dimensional (3D) growth cultures have frequently been proposed to overcome the lack of correlation between two-dimensional (2D) monolayer cell cultures and human tumors in preclinical drug testing. Besides 3D growth, it is also advantageous to simulate shear stress, compound flux and removal of metabolites, e.g. via bioreactor systems, through which culture medium is constantly pumped at a flow rate reflecting physiological conditions. Here, we show that both Staticic 3D growth and 3D growth within a bioreactor system modulate key hallmarks of cancer cells, including proliferation and cell death as well as macroautophagy, a recycling pathway often activated by highly proliferative tumors to cope with metabolic stress. The autophagy-related gene expression profiles of 2D- and 3D-grown cells are substantially different, with the 3D-grown cells exhibiting an expression profile closely resembling the (patho-) physiological Statice of a tumor. Underscoring the importance of this pathway, autophagy-controlling transcription factors, such as TFEB and FOXO3, are upregulated in tumors, and 3D-grown cells have increased expression compared with cells grown in 2D conditions. Three-dimensional cultures depleted of the autophagy mediators BECN1, ATG5 or ATG7 or the transcription factor FOXO3, are more sensitive to cytotoxic treatment. Accordingly, combining cytotoxic treatment with compounds affecting late autophagic flux, such as chloroquine, renders the 3D-grown cells more susceptible to therapy and increases intracellular doxorubicin concentration to the level of 2D-grown cells. Altogether, 3D cultures are a valuable tool to study drug response of tumor cells, as these models recapitulate (patho-) physiologically relevant pathways, such as autophagy.
Three-dimensional tumor cell growth stimulates autophagic flux and recapitulates chemotherapy resistance.
Specimen part, Cell line
View SamplesCMPF is elevated in diabetes and is associated with impaired insulin secretion. We used microarrays to determine the effect of CMPF on gene expression in isolated islets.
The furan fatty acid metabolite CMPF is elevated in diabetes and induces β cell dysfunction.
Sex, Age, Specimen part, Treatment
View SamplesTransplanting renal allografts represents the major curative treatment of chronic renal failure. Despite recent advances in immunosuppressive therapy, long-term survival of allografts remains a major clinical problem. Kidney function depends in part on transport proteins such as MRP2 (ABCC2) which facilitates renal secretion of amphiphilic exogenous and endogenous compounds. Inherited variants of genes not related to the immune system have been shown to modify the outcome after renal transplantation. We investigated whether ABCC2 gene variants in the donor kidney affect renal graft function.
Multidrug resistance-related protein 2 genotype of the donor affects kidney graft function.
Sex
View SamplesThe human prostate epithelium is predominantly comprised of two cell-types: basal and luminal. While basal cells exhibit significant progenitor activity in a variety of functional assays, luminal cells are depleted of this activity. Recent studies indicate that approximately 1% of luminal cells exhibit progenitor activity. We have discovered that differential expression of the glycoprotein CD38 can fractionate the luminal population into two subsets: CD38+ and CD38-low. In functional assays, the CD38-low luminal cells exhibit roughly 5-fold increased progenitor activity compared to the remaining CD38+ population. Therefore, we propose that CD38-low luminal cells represent an enriched luminal progenitor population while the CD38+ subset is predominantly comprised of mature non-progenitor luminal cells.
Low CD38 Identifies Progenitor-like Inflammation-Associated Luminal Cells that Can Initiate Human Prostate Cancer and Predict Poor Outcome.
Specimen part, Subject
View Samples