Gastric cancer can be divided in two major histological subtypes: diffuse and intestinal-type adenocarcinomas. Since both types diverge in many clinical and molecular characteristics, is widely accepted that both represent distinct disease entities that may benefit from different therapeutic approaches. The diffuse type is explicitly more invasive and affected patients possess extremely poor prognosis. Gene expression profiling studies identified numerous genes with differences in mRNA expression between the two types. However, little overlap of published gene lists exists forcing the need for further and more comprehensive analyses.
THBS4, a novel stromal molecule of diffuse-type gastric adenocarcinomas, identified by transcriptome-wide expression profiling.
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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 PPARγ in mouse macrophage populations reveals marked diversity in expression with critical roles in resolution of inflammation and airway immunity.
Sex, Treatment
View SamplesDendritic cells (DCs) in tissues and lymphoid organs comprise distinct functional subsets that differentiate in situ from circulating progenitors. Tissue-specific signals that regulate DC subset differentiation are poorly understood. We report that DC-specific deletion of the Notch2 receptor caused a reduction of DC populations in the spleen. Within the splenic CD11b+ DCs, Notch signaling blockade ablated a distinct population marked by high expression of adhesion molecule Esam. The Notch-dependent Esamhi DC subset also required lymphotoxin beta receptor signaling, proliferated in situ and facilitated efficient CD4+ T cell priming. The Notch-independent Esamlo DCs expressed monocyte-related genes and showed superior cytokine responses. In addition, Notch2 deletion led to the loss of CD11b+ CD103+ DCs in the intestinal lamina propria and to the corresponding decrease of IL-17-producing CD4+ T cells in the intestine. Thus,Notch2 is a common differentiation signal for T cell-priming CD11b+ DC subsets in the spleen and intestine.
Notch2 receptor signaling controls functional differentiation of dendritic cells in the spleen and intestine.
Specimen part
View SamplesIn Multiple Sclerosis, the pathological interaction of autoreactive helper T (TH) cells with mononuclear phagocytes in the central nervous system (CNS) drives initiation and maintenance of chronic neuroinflammation. Herein, we found that intrathecal transplantation of neural stem cells (NPCs) in mice with experimental autoimmune encephalomyelitis (EAE) impairs the accumulation of inflammatory monocyte-derived dendritic cells (moDCs) in the CNS leading to improved clinical outcome. NPCs treatment reduced in the CNS IL-23, IL-1 and TNF-a, cytokines required for terminal differentiation of TH cells and accordingly GM-CSF-producing pathogenic TH cells. In vivo and in vitro transcriptome analyses disclosed that NPC secreted factors induce an inhibition of DC differentiation and maturation, favoring a fate switch towards an anti-inflammatory phenotype. We identified TGF-ß2 as the crucial mediator of NPC immunomodulation: TGFß2 knockout NPCs transplanted in EAE are ineffective in impairing moDC accumulation within the CNS and fail to drive clinical improvement. This study provides evidence that intrathecally injected NPCs interfere with CNS-compartmentalized inflammation of the effector phase of EAE, reprogramming, through the secretion of TGF-ß2, inflammatory monocyte-derived DCs towards anti-inflammatory myeloid cells. Overall design: mRNA profiles of monocyte derived-dendritic cells (moDCs) isolated by FACS sorting at 7 days post-treatment from the CNS (hindbrain and spinal cord) of quadruplicate pool of 4–7 MOG35-55-immunized C57Bl/6 mice either intrathecally injected with PBS or 1 million neural precursor cells (NPCs) at the peak of the disease (2-4 days after clinical onset).
Neural precursor cell-secreted TGF-β2 redirects inflammatory monocyte-derived cells in CNS autoimmunity.
Specimen part, Disease, Disease stage, Cell line, Subject
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 SamplesObjective: to identify the early molecular processes involved in osseointegration associated with a micro roughened and nanosurface featured implants.
Comparative molecular assessment of early osseointegration in implant-adherent cells.
Sex, Specimen part
View SamplesIschemia exists in many diseased tissues including arthritic joints, atherosclerotic plaques and malignant tumors. Macrophages accumulate in these sites and upregulate genes in response to the hypoxia present.
Hypoxia-inducible factors 1 and 2 are important transcriptional effectors in primary macrophages experiencing hypoxia.
Specimen part
View SamplesAbsent in Melanoma 2 (AIM2) is a member of the HIN-200 family of hematopoietic, IFN-inducible nuclear proteins associated with infection defense and tumor pathology. Recently, AIM2 was found to act as a DNA sensor in innate immunity. In addition, a high frequency of AIM2-alterations was observed in microsatellite unstable tumors. To elucidate AIM2 function in colorectal tumors, we here addressed AIM2-responsive genes by microarray. Among genes up-regulated by AIM2, there were a number of interferon-stimulated genes (ISGs: IFIT1, IFIT2, IFIT3, IFI6, IRF7, ISG15, HLA-DRA, HLA-DRB, TLR3 and CIITA) as well as genes involved in intercellular adhesion and matrix remodeling. Expression of ISGs correlated with expression of AIM2 in ten different IFN- treated colorectal cancer cell lines. Moreover, knock-down of AIM2 resulted in reduced expression of HLA-DRA, HLA-DRB, and CIITA in IFN- treated cells. IFN- independent induction of HLA-DR genes and their encoded proteins was also demonstrated upon transient induction of AIM2. STAT-signaling was not involved in IFN- independent induction of ISGs, arguing against participation of cytokines released in an autocrine manner. Our data indicate that AIM2 mediates IFN- dependent and independent induction of several Interferon stimulated genes (ISGs) including genes encoding the MHC II antigens HLA-DR and .
Absent in Melanoma 2 (AIM2) is an important mediator of interferon-dependent and -independent HLA-DRA and HLA-DRB gene expression in colorectal cancers.
Cell line
View SamplesCombined transcriptomic and functional analyses of HCC cells at single-cell level were performed to assess CSC heterogeneity. Overall design: Single-cell transcriptome analyses of two HCC cell lines (HuH-1 and HuH-7) and one patient-derived circulating tumor cells by using SMART-Seq protocol ***Due to patient privacy concerns, the submitter declares that patient data will be submitted to dbGaP.***
Single-cell analysis reveals cancer stem cell heterogeneity in hepatocellular carcinoma.
Specimen part, Cell line, Subject
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Basonuclin-1 modulates epithelial plasticity and TGF-β1-induced loss of epithelial cell integrity.
Specimen part, Cell line
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