Constitutive MET signaling promotes invasiveness in primary and recurrent GBM; however, current MET-targeting strategies lack of effective biomarkers for selecting suitable patients for treatment. Here, we identified a predictive signature potentially valuable for indicating vulnerability to MET-targeted therapy in GBM. The use of both human and mouse gene expression microarrays showed that MET inhibitors regulate tumor (human) and host (mouse) cells within the tumor via distinct molecular processes, but overall they impede tumor growth by inhibiting cell cycle progression. Notably, GBM tumors with EGFRamp that showed resistance to erlotinib treatment also showed activation of the MET pathway, suggesting that a combination of EGFR and MET inhibitors may overcome or prevent such resistance in patients with EGFRamp GBM.
No associated publication
Specimen part, Disease, Disease stage, Cell line
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Large-scale hypomethylated blocks associated with Epstein-Barr virus-induced B-cell immortalization.
Specimen part, Time
View SamplesHuman mucosal surfaces contain a wide range of microorganisms. The biological effects of these organisms are largely unknown. Large-scale metagenomic sequencing is emerging as a method to identify novel microbes. Unexpectedly, we identified DNA sequences homologous to virus ATCV-1, an algal virus not previously known to infect humans, in oropharyngeal samples obtained from healthy adults. The presence of ATCV-1 was associated with a modest but measurable decrease in cognitive functioning. A relationship between ATCV-1 and cognitive functioning was confirmed in a mouse model, which also indicated that exposure to ATCV-1 resulted in changes in gene expression within the brain. Our study indicates that viruses in the environment not thought to infect humans can have biological effects.
Chlorovirus ATCV-1 is part of the human oropharyngeal virome and is associated with changes in cognitive functions in humans and mice.
Treatment
View SamplesMania is a serious neuropsychiatric condition associated with significant morbidity and mortality. Previous studies have suggested that environmental exposures can contribute to mania pathogenesis. We measured dietary exposures in a cohort of individuals with mania and other psychiatric disorders as well as in control individual without a psychiatric disorder. We found that a history of eating nitrated dry cured meat, but not other meat or fish products, was strongly and independently associated with current mania (adjusted odds ratio 3.49, 95% confidence interval (CI) 2.24-5.45, p<8.97x 10-8). Lower odds of association were found between eating nitrated dry cured meat and other psychiatric disorders. We further found that the feeding of meat preparations with added nitrate to rats resulted in alterations in behavior and changes in intestinal microbiota. Rats fed diets with added nitrate also showed alterations of brain pathways dysregulated in mania. These findings may lead to new methods for preventing mania and for developing novel therapeutic interventions
Nitrated meat products are associated with mania in humans and altered behavior and brain gene expression in rats.
Sex, Specimen part
View SamplesThe size of lentiviral DNA reservoirs reflects effectiveness of immune responses against lentiviruses. So far, abundant information has been gathered on the control of HIV-1 replication. Understanding of innate mechanisms contributing to containment of HIV-DNA reservoir, however, are only partly clarified and are relevant to guide interventions for reservoir containment or eradication. We studied the contribution of Natural Killer (NK) cell functional features in HIV patients either controlling replication either spontaneously (HIC) or after progression and antiretroviral treatment (PP). An inverse correlation between HIV-DNA copy numbers (either total or integrated) in circulating CD4+ cells and NK cell function were observed. Induced IFN-gamma production and NKp46/NKp30 activating receptor-induced expression correlated inversely with reservoir size. The correlation was present not only when considering a homogeneous cohort of HIC patients, but also when PP patients were included in the analysis. Adaptive (NKG2C + CD57 + ) NK cell features were not associated with reservoir size. However a distinct set of 370 differentially expressed transcripts was found to underlie functional differences in NK cells controlling HIV-DNA reservoir size. In proof-of-principle in vitro experiments of CD4+ cell infection with HIV-1, purified NK cells with the above functional/transcriptional features displayed a 10- and 30-fold higher ability to control HIV replication and DNA burden in vitro, respectively, compared to other NK cells. Thus, NK cells with a specific functional and transcriptional signature contribute to control of HIV reservoir in CD4+ cells. Their selection, expansion and/or adoptive transfer may support strategies to eradicate HIV-1 infection or to safely deescalate antiretroviral treatment.
No associated publication
Specimen part, Disease, Disease stage
View SamplesKabuki syndrome is a Mendelian intellectual disability syndrome caused by mutations in either of two genes (KMT2D and KDM6A) involved in chromatin accessibility. We previously showed that an agent that promotes chromatin opening, the histone deacetylase inhibitor (HDACi) AR-42, ameliorates the deficiency of adult neurogenesis in the granule cell layer of the dentate gyrus, and rescues hippocampal memory defects in a mouse model of Kabuki syndrome (Kmt2d+/Geo). Unlike a drug, a dietary intervention could be quickly transitioned to the clinic. Therefore, we have explored whether treatment with a ketogenic diet could lead to a similar rescue through increased amounts of beta-hydroxybutyrate, an endogenous HDACi. Here, we report that a ketogenic diet in Kmt2d+/Geo mice modulates H3ac and H3K4me3 in the granular cell layer, with concomitant rescue of both the neurogenesis defect and hippocampal memory abnormalities seen in Kmt2d+/Geo mice; similar effects on neurogenesis were observed upon exogenous administration of beta-hydroxybutyrate. These data suggests that dietary modulation of epigenetic modifications through elevation of beta-hydroxybutyrate may provide a feasible strategy to treat the intellectual disability seen in Kabuki syndrome and related disorders.
No associated publication
Sex, Specimen part
View SamplesWe hypothesize that gene expression in the cigarette smoke (CS) exposed neonatal lung and age-matched controls will be divergent. CS exposed lung will have divergence of immune response genes and structural genes. The lungs of (6) 2 week old neonatal mice exposed to 2 weeks of CS were compared to the lung of (4) 2 week old age-matched control mice. We utilized microarray analysis to examine transcriptional differences between smoke exposed neonatal lung and age-matched controls.
Impaired lung homeostasis in neonatal mice exposed to cigarette smoke.
No sample metadata fields
View SamplesTo determine what DNA methylation and gene expression changes occur following EBV transformation. B-cells were isolated from 3 donors. Resting, CD40 activated and EBV transfromed cells from each donor was analyzed. Each sample was assayed using Affymetrix expression arrays and whole genome bisulfite sequenicng. Additional time points during transformation and activation were sequenced as well, but not assayed for expression.
Large-scale hypomethylated blocks associated with Epstein-Barr virus-induced B-cell immortalization.
Specimen part
View SamplesWolbachia, an endosymbiotic bacterium, is being investigated as a vector control agent in several insect species. Along with the well known classical reproductive parasitism Wolbachia employs against its host to spread within the population, it is emerging that the bacteria can protect the host against pathogens and reduced pathogen transmission. Anopheles mosquitoes, which transmit malaria, have never been found to harbour Wolbachia in nature, and despite numerous transinfection attempts, no stable line has been developed.
Wolbachia infections in Anopheles gambiae cells: transcriptomic characterization of a novel host-symbiont interaction.
No sample metadata fields
View SamplesDuring the course of many chronic inflammatory disorders, a persistent Natural Killer (NK) cell derangement and activation is observed. While increased cell turnover is expected in these cases, little is known about whether and how NK cell homeostatic balance and numbers are maintained by CD34+ progenitor cells. Accordingly, we studied peripheral blood progenitor cells in patients with chronic inflammatory disorders including HIV-1, HCV, TB, COPD and PAPA. Cytometric analysis revealed the presence of a so far unidentified CD34+CD226(DNAM-1)brightCXCR4+ cell population in all these conditions. Further, microarray and PCR analysis showed transcriptional signatures typical of common lymphocyte precursors. Culture of CD34+CD226brightCXCR4+ cells gave rise to NK cell progenies characterized by high expression of activating receptors and mature function. Importantly, in healthy donors CD34+CD226brightCXCR4+ cells reside in bone marrow but do not circulate in peripheral blood and are absent in umbilical cord blood. The proportion of CD34+CD226brightCXCR4+ PBMC were found to correlate with the degree of inflammation, and represent an indicator of lymphoid cell turnover/reconstitution during chronic inflammation. Identification of CD34+CD226brightCXCR4+ circulation offers a novel view of emergency recruitment of cell-precursors upgrade our understanding and monitoring of chronic inflammatory conditions, and provide new insight of intermediate stages of NK cell development.
No associated publication
Specimen part, Disease, Disease stage
View Samples