This SuperSeries is composed of the SubSeries listed below.
Post-transplant molecularly defined Burkitt lymphomas are frequently MYC-negative and characterized by the 11q-gain/loss pattern.
Sex, Age, Treatment
View SamplesWe performed genomic and transcriptomic analysis of seven cases of molecular Burkitt lymphoma (mBL) developed in immunosuppressed patients who underwent solid organ transplantation. Interestingly, three cases (43%) were MYC-translocation-negative and revealed the 11q-gain/loss aberration recently identified in 3% of mBL developed in immunocompetent hosts.1 Based on array CGH data, minimal gain and loss regions of 11q (MGR/~4Mb and MLR/~13.5Mb, respectively) were defined and integrative genomic and transcriptomic analysis identified 35 differentially expressed genes, when compared with classic BL. All 16 MGR-dysregulated genes were upregulated, including cancer related USP2, CBL and PAFAH1B2. As expected, all 19 MGL-dysregulated genes were downregulated and two of them, TBRG1 and EI24, are potential tumor suppressor genes. Interestingly, the vast majority of dysregulated 11q23-q25 genes are involved in the MYC and TP53 networks. We hypothesize that the 11q-gain/loss aberration represents a molecular variant of t(8q24/MYC) and affects the same pathological pathways as the MYC oncogene.
Post-transplant molecularly defined Burkitt lymphomas are frequently MYC-negative and characterized by the 11q-gain/loss pattern.
Sex, Age, Treatment
View SamplesThe biological effects of TTR proteins in the vasculature remain unknown.
Transthyretin proteins regulate angiogenesis by conferring different molecular identities to endothelial cells.
Specimen part
View SamplesPPAR is known for its anti-inflammatory actions in macrophages. However, which macrophage populations express PPAR in vivo and how it regulates tissue homeostasis in the steady state and during inflammation is not completely understood. We show that lung and spleen macrophages constitutively expressed PPAR, while other macrophage populations did not. Recruitment of monocytes to sites of inflammation was associated with induction of PPAR as they differentiated to macrophages. Its absence in these macrophages led to failed resolution of inflammation, characterized by persistent, low-level recruitment of leukocytes. Conversely, PPAR agonists supported an earlier cessation in leukocyte recruitment during resolution of acute inflammation and likewise suppressed monocyte recruitment to chronically inflamed atherosclerotic vessels. In the steady state, PPAR deficiency in macrophages had no obvious impact in the spleen but profoundly altered cellular lipid homeostasis in lung macrophages. Reminiscent of pulmonary alveolar proteinosis, LysM-Cre x PPARflox/flox mice displayed mild leukocytic inflammation in the steady-state lung and succumbed faster to mortality upon infection with S. pneumoniae. Surprisingly, this mortality was not due to overly exuberant inflammation, but instead to impaired bacterial clearance. Thus, in addition to its anti-inflammatory role in promoting resolution of inflammation, PPAR sustains functionality in lung macrophages and thereby has a pivotal role in supporting pulmonary host defense.
Systemic analysis of PPARĪ³ in mouse macrophage populations reveals marked diversity in expression with critical roles in resolution of inflammation and airway immunity.
Sex, Treatment
View SamplesMagnaporthe oryzae causes rice blast, the most devastating foliar fungal disease of cultivated rice. During disease development the fungus simultaneously maintains both biotrophic and necrotrophic growth corresponding to a hemi-biotrophic life style. The ability of M. oryzae to also colonize roots and subsequently develop blast symptoms on aerial tissue has been recognized. The fungal root infection strategy and the respective host responses are currently unknown. Global temporal expression analysis suggested a purely biotrophic infection process reflected by the rapid induction of defense response-associated genes at the early stage of root invasion and subsequent repression coinciding with the onset of intracellular fungal growth. The same group of down-regulated defense genes was increasingly induced upon leaf infection by M. oryzae where symptom development occurs shortly post tissue penetration. Our molecular analysis therefore demonstrates the existence of fundamentally different tissue-specific fungal infection strategies and provides the basis for enhancing our understanding of the pathogen life style.
Tissue-adapted invasion strategies of the rice blast fungus Magnaporthe oryzae.
Specimen part
View SamplesTransient expression of two factors, or from Oct4 alone, resulted in efficient generation of human iPSCs. The reprogramming strategy described revealed a potential transcriptional signature for human iPSCs yet retaining the gene expression of donor cells in human reprogrammed cells free of viral and transgene interference.
Transcriptional signature and memory retention of human-induced pluripotent stem cells.
Sex, Specimen part
View SamplesThe p53 tumor suppressor is a DNA damage responsive sequence-specific transcriptional activator. The sustained activation of the p53 response is incompatible with cell growth and viability. To circumvent this issue, a variety of negative feedback loops exist to limit the duration of p53 activation. Despite our understanding of p53-regulation, very little is known about the effect of transient p53 activation on the long term expression of p53 target genes. Here we used a temperature sensitive variant of p53 and oligonucleotide microarrays to monitor gene expression during and following reversible p53 activation. The expression of most p53-induced transcripts was rapidly reversible, consistent with active mRNA decay. Representative 3UTRs derived from short-lived transcripts (i.e. DDB2 and GDF15) conferred instability on a heterologous mRNA while 3UTRs derived from more stable transcripts (i.e. CRYAB and TP53I3) did not. The 3UTRs derived from unstable p53-induced mRNAs were significantly longer than those derived from stable mRNAs. These 3UTRs had high uridine and low cytosine content, leading to a higher density of U-, AU- and GU-rich sequences. Remarkably, short-lived p53 targets were induced faster reaching maximum transcript levels earlier than the stable p53-targets. Taken together, the p53 transcriptional response has evolved with primarily short-lived target mRNAs and that post-transcription processes play a prominent role in the p53 response.
The role of mRNA decay in p53-induced gene expression.
Specimen part, Cell line
View SamplesActivating Transcription Factor 4 (ATF4) is a transcription factor induced by the integrated stress response (ISR). This experiment is a genome-wide profiling of ATF4-dependent RNA expression in human HAP-1 cells. HAP-1 is a near-haploid human cell line that was derived from KBM-7 cells isolated from a patient with Chronic Myelogenous Leukemia. We analyzed WT and ATF4 KO cells. We induced ATF4 expression by mimicking amino acid starvation with the drug histidinol. Overall design: RNA expression profiles were generated for WT and ATF4 KO HAP1 cells. ATF4 genes were mutated using Cas9 genome editing technology. Amino acid starvation was mimicked by treating WT and ATF4 KO cells with 2 mM histidinol for 24 hours, which increases ATF4 expression.
A forward genetic screen reveals novel independent regulators of ULBP1, an activating ligand for natural killer cells.
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View SamplesABSTRACT Background: Viral myocarditis is a life-threatening illness that may lead to heart failure or cardiac arrhythmias. This study examined whether human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) could be used to model the pathogenic processes of coxsackievirus-induced viral myocarditis and to screen antiviral therapeutics for efficacy. Methods and Results: Human iPSC-CMs were infected with a luciferase-expressing mutant of the coxsackievirus B3 strain (CVB3-Luc). Brightfield microscopy, immunofluorescence, and calcium imaging were used to characterize virally infected hiPSC-CMs. Viral proliferation on hiPSC-CMs was subsequently quantified using bioluminescence imaging. For drug screening, select antiviral compounds including interferon beta 1 (IFN1), ribavirin, pyrrolidine dithiocarbamate (PDTC), and fluoxetine were tested for their capacity to abrogate CVB3-Luc proliferation in hiPSC-CMs in vitro. The ability of some of these compounds to reduce CVB3-Luc proliferation in hiPSC-CMs was consistent with the reported drug effects in previous studies. Finally, mechanistic analyses via gene expression profiling of hiPSC-CMs infected with CVB3-Luc revealed an activation of viral RNA and protein clearance pathways within these hiPSC-CMs after IFN1 treatment. Conclusions: This study demonstrates that hiPSC-CMs express the coxsackievirus and adenovirus receptor, are susceptible to coxsackievirus infection, and can be used to confirm antiviral drug efficacy. Our results suggest that the hiPSC-CM/CVB3-Luc assay is a sensitive platform that could be used to screen novel antiviral therapeutics for their effectiveness in a high-throughput fashion.
Human induced pluripotent stem cell-derived cardiomyocytes as an in vitro model for coxsackievirus B3-induced myocarditis and antiviral drug screening platform.
Specimen part, Treatment
View SamplesA rare complication of multiple myeloma is a secondary extramedullary involvement, and the skin is one of the possible sites, due to the physiological homing of plasma cells (PCs) into the skin. The article reports a case of a relapsed refractory MM patient, who developed a cutaneous localization after 16 months from the diagnosis under Bortezomib treatment without a leukemic phase. Patient was refractory to Bortezomib. We analyzed the gene expression profiles, the immunophenotypic and immunohistochemistry profiles of MM cells across the course of the disease at the bone marrow and skin localization. Data obtained were further expanded by an immunohistochemistry analysis on selected molecules in a large cohort of MM patients with cutaneous localization. In particular we focused on the expression of chemokines and chemokine receptors involved in the PC skin homing.
Cutaneous localization in multiple myeloma in the context of bortezomib-based treatment: how do myeloma cells escape from the bone marrow to the skin?
Sex, Age, Specimen part, Subject, Time
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