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1.
AJNR Am J Neuroradiol ; 42(12): 2245-2250, 2021 12.
Article in English | MEDLINE | ID: mdl-34674998

ABSTRACT

BACKGROUND AND PURPOSE: Posterior fossa type A (PFA) ependymomas have 2 molecular subgroups (PFA-1 and PFA-2) and 9 subtypes. Gene expression profiling suggests that PFA-1 and PFA-2 tumors have distinct developmental origins at different rostrocaudal levels of the brainstem. We, therefore, tested the hypothesis that PFA-1 and PFA-2 ependymomas have different anatomic MR imaging characteristics at presentation. MATERIALS AND METHODS: Two neuroradiologists reviewed the preoperative MR imaging examinations of 122 patients with PFA ependymomas and identified several anatomic characteristics, including extension through the fourth ventricular foramina and encasement of major arteries and tumor type (midfloor, roof, or lateral). Deoxyribonucleic acid methylation profiling assigned ependymomas to PFA-1 or PFA-2. Information on PFA subtype from an earlier study was also available for a subset of tumors. Associations between imaging variables and subgroup or subtype were evaluated. RESULTS: No anatomic imaging variable was significantly associated with the PFA subgroup, but 5 PFA-2c subtype ependymomas in the cohort had a more circumscribed appearance and showed less tendency to extend through the fourth ventricular foramina or encase blood vessels, compared with other PFA subtypes. CONCLUSIONS: PFA-1 and PFA-2 ependymomas did not have different anatomic MR imaging characteristics, and these results do not support the hypothesis that they have distinct anatomic origins. PFA-2c ependymomas appear to have a more anatomically circumscribed MR imaging appearance than the other PFA subtypes; however, this needs to be confirmed in a larger study.


Subject(s)
Ependymoma , Infratentorial Neoplasms , Cohort Studies , Ependymoma/diagnostic imaging , Ependymoma/genetics , Ependymoma/pathology , Humans , Infratentorial Neoplasms/diagnostic imaging , Magnetic Resonance Imaging , Neuroimaging
2.
Leukemia ; 29(8): 1684-94, 2015 Aug.
Article in English | MEDLINE | ID: mdl-25733167

ABSTRACT

Diffuse large B-cell lymphoma (DLBCL) is a biologically and clinically heterogeneous disease with marked genomic instability and variable response to conventional R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) chemotherapy. More clinically aggressive cases of DLBCLs have high level of circulating interleukin 10 (IL10) cytokine and evidence of activated intracellular STAT3 (signal transducer and activator of transcription 3) signaling. We investigated the role of IL10 and its surface receptor in supporting the neoplastic phenotype of DLBCLs. We determined that IL10RA gene is amplified in 21% and IL10RB gene in 10% of primary DLBCLs. Gene expression of IL10, IL10RA and IL10RB was markedly elevated in DLBCLs. We hypothesized that DLBCLs depend for their proliferation and survival on IL10-STAT3 signaling and that blocking the IL10 receptor (IL10R) would induce cell death. We used anti-IL10R blocking antibody, which resulted in a dose-dependent cell death in all tested activated B-cell-like subtype of DLBCL cell lines and primary DLBCLs. Response of germinal center B-cell-like subtype of DLBCL cell lines to anti-IL10R antibody varied from sensitive to resistant. Cells underwent cell cycle arrest, followed by induction of apoptosis. Cell death depended on inhibition of STAT3 and, to a lesser extent, STAT1 signaling. Anti-IL10R treatment resulted in interruption of IL10-IL10R autostimulatory loop. We thus propose that IL10R is a novel therapeutic target in DLBCLs.


Subject(s)
Biomarkers, Tumor/metabolism , Interleukin-10/metabolism , Lymphoma, Large B-Cell, Diffuse/metabolism , Lymphoma, Large B-Cell, Diffuse/pathology , Receptors, Interleukin-10/metabolism , Apoptosis , Biomarkers, Tumor/genetics , Blotting, Western , Cell Cycle , Cell Proliferation , High-Throughput Nucleotide Sequencing , Humans , Immunoenzyme Techniques , Interleukin-10/genetics , Lymphoma, Large B-Cell, Diffuse/mortality , Neoplasm Staging , Prognosis , RNA, Messenger/genetics , Real-Time Polymerase Chain Reaction , Receptors, Interleukin-10/genetics , Reverse Transcriptase Polymerase Chain Reaction , Survival Rate , Tissue Array Analysis , Tumor Cells, Cultured
3.
Transl Psychiatry ; 3: e218, 2013 Jan 22.
Article in English | MEDLINE | ID: mdl-23340501

ABSTRACT

Early life adversity, including adverse gestational and postpartum maternal environment, is a contributing factor in the development of autism, attention deficit hyperactivity disorder (ADHD), anxiety and depression but little is known about the underlying molecular mechanism. In a model of gestational maternal adversity that leads to innate anxiety, increased stress reactivity and impaired vocal communication in the offspring, we asked if a specific DNA methylation signature is associated with the emergence of the behavioral phenotype. Genome-wide DNA methylation analyses identified 2.3% of CpGs as differentially methylated (that is, differentially methylated sites, DMSs) by the adverse environment in ventral-hippocampal granule cells, neurons that can be linked to the anxiety phenotype. DMSs were typically clustered and these clusters were preferentially located at gene bodies. Although CpGs are typically either highly methylated or unmethylated, DMSs had an intermediate (20-80%) methylation level that may contribute to their sensitivity to environmental adversity. The adverse maternal environment resulted in either hyper or hypomethylation at DMSs. Clusters of DMSs were enriched in genes that encode cell adhesion molecules and neurotransmitter receptors; some of which were also downregulated, indicating multiple functional deficits at the synapse in adversity. Pharmacological and genetic evidence links many of these genes to anxiety.


Subject(s)
Anxiety/genetics , CpG Islands/genetics , DNA Methylation/genetics , Dentate Gyrus/metabolism , Receptor, Serotonin, 5-HT1A/genetics , Animals , Cell Adhesion/genetics , Disease Models, Animal , Epigenesis, Genetic , Female , Male , Mice , Mice, Transgenic , Pregnancy , Prenatal Exposure Delayed Effects/genetics , Vocalization, Animal/physiology
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