CDKN1B (p27) was formally established as a tumor suppressor gene (tsg) following the identification of inactivating germline mutations in rats (MENX syndrome) and patients (MEN4 syndrome) developing multiple neuroendocrine tumors (NETs). MENX-affected rats are homozygous for the predisposing p27 mutation, suggesting a canonical tsg function. In contrast, mice heterozygous for a defective Cdkn1b allele are already predisposed to tumor formation (haploinsufficiency). We here report that heterozygous mutant rats (p27+/mut) develop the same NETs seen in the homozygous (p27mut/mut) animals but with slower progression. In the tumors of p27+/mut rats, the wild-type allele is neither lost nor silenced, implying that p27 is haploinsufficient for tumor suppression also in this model.
Characterization of neuroendocrine tumors in heterozygous mutant MENX rats: a novel model of invasive medullary thyroid carcinoma.
Age
View SamplesAs overwhelming evidence coming from transgenic mouse models but also from MEN4 patients seem to suggest that loss or inactivation of a single p27 allele plays an important role in neuroendocrine tumorigenesis, we decided to perform a detailed analysis of the phenotype of rats heterozygous for the MENX-associated germline Cdkn1b mutation. We here show that the reduction to a single functional p27 allele predisposes MENX heterozygous rats to the development of neuroendocrine malignancies.
Characterization of neuroendocrine tumors in heterozygous mutant MENX rats: a novel model of invasive medullary thyroid carcinoma.
Sex, Age, Specimen part
View SamplesAs overwhelming evidence coming from transgenic mouse models but also from MEN4 patients seem to suggest that loss or inactivation of a single p27 allele plays an important role in neuroendocrine tumorigenesis, we decided to perform a detailed analysis of the phenotype of rats heterozygous for the MENX-associated germline Cdkn1b mutation.
Characterization of neuroendocrine tumors in heterozygous mutant MENX rats: a novel model of invasive medullary thyroid carcinoma.
Sex, Age, Specimen part
View SamplesCD19-specific CARs that comprise CD28 and CD3z signaling domains program highly performing effector functions that mediate potent tumor elimination, but they impart a relatively limited T cell lifespan. Increasing functional T cell persistence without reducing effector potency is therefore likely to further enhance the therapeutic success of 1928z CAR T cells. We demonstrate that the number and position of ITAMs in 1928z CAR T cells influence functional, phenotypic and transcriptional programs, resulting in profound effects on antitumor efficacy. Improved therapeutic potency of CAR T cells can thus be achieved by calibrating activation strength, thereby retaining memory functions and preventing exhaustion, without compromising effector functions. Our transcriptional analysis underscores the potential of ITAM dosage and position to direct different T cell fates. We were able to identify a novel CAR design, termed 1XX, which programs a favorable balance of effector and memory signatures, inducing increased persistence of highly functional CARs with the replicative capacity of long-lived memory cells and potent effector functions. Overall design: In order to assess the different phenotypic and functional patterns of CARs encoding a single immunoreceptor tyrosine-based activation motif (ITAM), we compared the genome-wide transcriptional profiles of 1928z, 1XX and XX3 after CD19 antigen stimulation of TRAC-edited naïve T cells. Sorted naïve (TN), stem cell memory (TSCM) and effector (TEFF) CD8+ T cells served as controls.
Calibration of CAR activation potential directs alternative T cell fates and therapeutic potency.
Specimen part, Subject
View SamplesGlobal deficiency of catalytic subunit Ppp3cb, and tissue-specific ablation of regulatory subunit Ppp3r1 from skeletal muscle but not adipose tissue or liver led to protection from high-fat diet induced obesity and comorbid sequel.
Calcineurin Links Mitochondrial Elongation with Energy Metabolism.
Sex, Specimen part
View SamplesInsulin-dependent diabetes is a complex multifactorial disorder characterized by
Identification of proliferative and mature β-cells in the islets of Langerhans.
Sex, Specimen part
View SamplesAnthocyanin induction in plant is considered a general defense response against biotic and abiotic stresses. The infection by Ustilago maydis, the corn smut pathogen, is accompanied with anthocyanin induction in leaf tissue. We revealed that anthocyanin is intentionally induced by the virulence promoting secreted effector protein Tin2. Tin2 protein functions inside plant cells where it interacts with cytoplasmic maize protein kinase ZmTTK1. Tin2 masks an ubiquitin-proteasome degradation motif in ZmTTK1 leading to a more stable active kinase. Active ZmTTK1 controls transcriptional activation of genes in the anthocyanin biosynthesis pathway rerouting phenylalanine away from lignin biosynthesis.
A secreted Ustilago maydis effector promotes virulence by targeting anthocyanin biosynthesis in maize.
Specimen part
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Thymic negative selection is functional in NOD mice.
Sex, Age
View SamplesThe aim of this study was to quantify the impact of NOD genetic vatiation on thymic negative selection transcriptional programs.
Thymic negative selection is functional in NOD mice.
Sex, Age
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
View Samples