1,721,129 research outputs found
Il Pathway di NOTCH nei mielomi multipli : razionale per una possibile terapia inibitoria
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Myeloid derived-suppressor cells as a potential target of immunotherapy in notch dependent T-cell acute lymphoblastic leukemia
No full textNotch receptors play crucial roles in T-cell development, and their dysregulation leads to the development of T-cell Acute Lymphoblastic Leukemia (T-ALL), a condition that, as of now, lacks a definitive cure. Notch3 transgenic mice (N3-tg) represent a well- established model for T-ALL, where the constitutive activation of the receptor in immature thymocytes initiates an aggressive disease characterized by the expansion of tumoral T cells in the periphery. These tumor cells can trigger a Notch/IL-6-dependent accumulation of Myeloid-Derived Suppressor Cells (MDSCs), which, in turn, support tumor progression. MDSCs are an immature cell subset that inhibits immune responses, creating a conductive environment for tumor growth. Programmed cell death 1 (PD-1) is an inhibitory receptor of immune responses, recognized for its role as a suppressor of T-cell activation and proliferation when interacting with the PD-L1 ligand. MDSCs contribute to tumor progression through various mechanisms, including the expression of PD-L1, resulting in the inhibition of PD-1 expressing cells within the tumor microenvironment, such as T- and NK-cells.
The main aim of my thesis was to identify MDSC targets and mechanisms of action in the tumor microenvironment of our Notch-dependent murine model of T-ALL, with regard to their potential role in inhibiting NK activity, possibly through the PD-1/PD-L1 axis. Thus, this research ultimately aims to develop an innovative combined therapy for T-ALL, targeting tumor T cells, enhancing NK activity, and modulating MDSC function.
My data demonstrated that in N3-tg mice, number and function of NK cells decline significantly, while the percentage of them expressing PD-1 increases, during disease progression. This coincided with an expansion of functional MDSCs and in particular of the PD-L1+ fraction. This inverse correlation suggests us that NK impairment could be driven by MDSCs. Indeed, through in vitro cytotoxicity assay based on co-culture of NK cells with MDSCs, both from spleen of N3-tg mice, we confirmed that MDSCs can significantly hinder NK cell function.
Finally, treating N3-tg mice with anti-PD-L1 blocking antibodies markedly inhibits T- ALL progression, by significantly reductions in splenomegaly and absolute count of tumor cells. Moreover, the treatment led to a substantial decrease in overall MDSC numbers, particularly within the PD-L1-expressing subset. Concurrently, there was a noticeable expansion of PD-1+ NK cells, exhibiting a significantly heightened cytotoxic activity compared to the control group.
In conclusion, my results suggest that in Notch-dependent T-ALL, MDSCs may hinder the anti-tumor activity of NK cells via the PD-1/PD-L1 axis, thus favoring disease progression. Then, molecules and cells of this network could potentially serve as prognostic markers and/or targets for innovative therapies
Senescence-dependent regulation of type 1 plasminogen activator inhibitor in human vascular endothelial cells
No full textType 1 plasminogen activator inhibitor (PAI-1) is the primary inhibitor plasminogen activator and has been found to be increased in a number of clinical conditions generally defined as prothrombotic. Since in aging and in atherosclerosis the changes observed in the endothelium resemble those of in vitro aged endothelial cells, we have examined the expression of PAI-1 in cells at different population doublings. In senescent endothelial cells, PAI-1 mRNA and protein are constitutively high, but uninducible by exogenous interleukin 1 alpha as well as by the phorbol ester TPA. Interestingly the increase of PAI-1 levels correlates with the upregulation of interleukin 1 alpha, which characterizes endothelial cell senescence. Since PAI-1 expression is not increased in young cells made nondividing by contact inhibition, we anticipate that PAI-1 expression can be used as an appropriate marker of endothelial senescence. Moreover, PAI-1 was not upregulated in senescent or in progeric human fibroblasts, which do not overexpress interleukin 1 alpha, thus suggesting that multiple pathways may exist to regulate aging of human fibroblasts and endothelial cells
Allele frequency of two intragenic microsatellite loci of SEL1L gene in Northern Italy population
Full text linkTwo cytosine-adenine (CA) repeats CAR/CAL and RepIN20 occur in the human SEL1L gene, which is regarded as a candidate gene for insulin-dependent diabetes mellitus (IDDM) and Grave's disease. We have characterized these repeats to determine if they might serve as effective microsatellite markers for linkage analysis to clarify whether SEL1L gene plays a role in the pathogenesis of these autoimmune diseases. The allele frequencies and average heterozygosity of the microsatellite repeats were analysed in 94 DNA samples from peripheral blood mononuclear (PBMC) cells from adults of Northern Italy. The average heterozygosity was 0.68 for CAR/CAL polymorphism and 0.85 for RepIN20. The size of PCR fragments of CAR/CAL ranged from 207–225 bp and the most frequent allele was 207 bp (40.4%). The size of the fragments of RepIN20 ranged from 237–255 bp and the most frequent allele was 249 bp (30.8%). In the light of the highly polymorphic nature of both microsatellites and their intragenic location in SEL1L gene, we suggest that they could provide a means for linkage analysis to clarify the potential role of SEL1L in conferring susceptibility to IDDM or Grave's disease
T-ALL leukemogenesis : which targets are modulated by Notch pathway to regulate apoptosis and cell cycle?
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Computer sequence analysis of highly conserved zinc fingers modules
No full textWe defined a sub-family of zinc finger proteins by computer analyses and comparisons of five new finger domains against protein databases. This subclass of the cysteine-cysteine/histidine-histidine motif shows additional well conserved amino acid patterns and belongs to the human kox and gli-Kruppel gene family, sharing also the same stretches of regulatory zinc finger-containing proteins of mouse and Xenopus. We particularly describe ZF6 cDNA which contains the most interesting sequence, encoding a putative multi-domain regulatory protein
Regulation of the human glut4 gene expression in tumor RD18 cell line
No full textWe tested if glut4, the gene for muscle-specific glucose transporter, underwent some variations of expression in neoplastic cells. Our model was a rhabdomyosarcoma cell line (RD18) which retains the ability to differentiate along the myogenic pathway. Any definable changes of expression of glut4 in normal and RD18 cells were revealed by Northern blot analysis. In order to identify the transcriptional regulatory regions of the glut4 gene we performed a deletion analysis of the 5' flanking region. The downregulation which we found in the expression of this gene in RD18 cells could be related with the activity of a negative regulatory element
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