Podcasts about nod scid

BUFFALO, NY- November 7, 2023 – A new #researchpaper was #published in Aging (listed by MEDLINE/PubMed as "Aging (Albany NY)" and "Aging-US" by Web of Science) Volume 15, Issue 20, entitled, “Deciphering reproductive aging in women using a NOD/SCID mouse model for distinct physiological ovarian phenotypes.” Female fertility is negatively correlated with age, with noticeable declines in oocyte quantity and quality until menopause. To understand this physiological process and evaluate human approaches for treating age-related infertility, preclinical studies in appropriate animal models are needed. In this new study, researchers María Marchante, Noelia Ramirez-Martin, Anna Buigues, Jessica Martinez, Nuria Pellicer, Antonio Pellicer, and Sonia Herraiz from IVIRMA, University of Valencia and Instituto Investigación Sanitaria La Fe aimed to characterize an immunodeficient physiological aging mouse model displaying ovarian characteristics of different stages during women's reproductive life. “The main purpose of our study was to establish a physiological ovarian aging mouse model that could be employed to evaluate potential therapeutic interventions derived from human origin.” NOD/SCID mice of different ages (8-, 28-, and 36–40-week-old) were employed to mimic ovarian phenotypes of young, Advanced Maternal Age (AMA), and old women (~18–20-, ~36–38-, and >45-years-old, respectively). Mice were stimulated, mated, and sacrificed to recover oocytes and embryos. Then, ovarian reserve, follicular growth, ovarian stroma, mitochondrial dysfunction, and proteomic profiles were assessed. Age-matched C57BL/6 mice were employed to cross-validate the reproductive outcomes. The quantity and quality of oocytes were decreased in AMA and Old mice. These age-related effects associated spindle and chromosome abnormalities, along with decreased developmental competence to blastocyst stage. Old mice had less follicles, impaired follicle activation and growth, an ovarian stroma inconducive to growth, and increased mitochondrial dysfunctions. Proteomic analysis corroborated these histological findings. Based on that, NOD/SCID mice can be used to model different ovarian aging phenotypes and potentially test human anti-aging treatments. “In summary, in this study we characterized the quality of the ovarian microenvironment and reproductive outcomes of an immunodeficient murine model of physiological ovarian aging by evaluating fertility outcomes, ovarian reserve and stroma, mitochondrial dysfunctions, and the ovarian proteome at different stages. This model adequately mimicked the characteristics of the reproductive stages in women, without external agents compromising folliculogenesis, or disrupting molecular mechanisms and ovarian function, which could mask the processes of physiological aging.” DOI - https://doi.org/10.18632/aging.205086 Corresponding author - Sonia Herraiz - sonia_herraiz@iislafe.es About Aging-US Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging-US go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways. Please visit our website at https://www.Aging-US.com​​ and connect with us: SoundCloud - https://soundcloud.com/Aging-Us Facebook - https://www.facebook.com/AgingUS/ X - https://twitter.com/AgingJrnl Instagram - https://www.instagram.com/agingjrnl/ YouTube - https://www.youtube.com/@AgingJournal LinkedIn - https://www.linkedin.com/company/aging/ Pinterest - https://www.pinterest.com/AgingUS/ Media Contact 18009220957 MEDIA@IMPACTJOURNALS.COM

We recently identified the AP4 transcription factor as a c-MYC-inducible mediator of epithelial-mesenchymal transition/EMT in colorectal cancer (CRC). Here we report that AP4 is down-regulated after DNA damage in a p53-dependent manner. p53 repressed AP4 via inducing the microRNAs miR-15a and miR-16-1, which are encoded by the DLEU2 gene and represent tumor suppressors in chronic lymphocytic leukemia. miR-15a/16-1 acted via a conserved seed-matching sequence in the AP4 3’-UTR. Ectopic miR-15a/16-1 also down-regulated AP4 expression and induced mesenchymal-epithelial transition (MET) of CRC cells. Induction of miR-15a/16-1 was necessary for p53-induced MET and mediated, at least in part, inhibition of migration by p53. Down-regulation of AP4 was necessary for miR-15a/16-1-induced MET and suppression of migration and cell cycle progression. Furthermore, constitutive ectopic expression of miR-15a/16-1 in xeno-transplanted CRC cells suppressed the formation of lung metastases in NOD/SCID mice. In addition, ectopic AP4 suppressed the expression of miR-15a/16-1 by direct occupancy of E-boxes in the vicinity of the two alternative DLEU2 promoters. Finally, expression of miR-15a and DLEU2 was significantly down-regulated in primary colon and colorectal cancer samples, which displayed elevated AP4 protein levels, a marker previously shown to correlate with distant metastasis and poor survival. In conclusion, miR-15a/16-1 and AP4 therefore constitute a double-negative feed-back loop, which may serve to stabilize epithelial and mesenchymal states, respectively. During CRC progression, and presumably in other tumor entities, the deregulation of this circuitry by inactivation of p53 or/and DLEU2, or activation of AP4 may contribute to metastasis.

Background: Animal models of human inflammatory diseases have limited predictive quality for human clinical trials for various reasons including species specific activation mechanisms and the immunological background of the animals which markedly differs from the genetically heterogeneous and often aged patient population. Objective: Development of an animal model allowing for testing therapeutics targeting pathways involved in the development of Atopic Dermatitis (AD) with better translatability to the patient. Methods: NOD-scid IL2R gamma(null) mice engrafted with human peripheral blood mononuclear cells (hPBMC) derived from patients suffering from AD and healthy volunteers were treated with IL-4 and the antagonistic IL-4 variant R121/Y124D (Pitrakinra). Levels of human (h) IgE, amount of B-, T- and plasma-cells and ratio of CD4 : CD8 positive cells served as read out for induction and inhibition of cell proliferation and hIgE secretion. Results were compared to in vitro analysis. Results: hIgE secretion was induced by IL-4 and inhibited by the IL-4 antagonist Pitrakinra in vivo when formulated with methylcellulose. B-cells proliferated in response to IL-4 in vivo; the effect was abrogated by Pitrakinra. IL-4 shifted CD4 : CD8 ratios in vitro and in vivo when hPBMC derived from healthy volunteers were used. Pitrakinra reversed the effect. Human PBMC derived from patients with AD remained inert and engrafted mice reflected the individual responses observed in vitro. Conclusion: NOD-scid IL2R gamma(null) mice engrafted with human PBMC reflect the immunological history of the donors and provide a complementary tool to in vitro studies. Thus, studies in this model might provide data with better translatability from bench to bedside.

ABCG2 is a transporter protein that has the ability to efflux many drugs and fluorescent dyes. Primitive haematopoietic stem cells highly express ABCG2 and the expression level decreases as these cells differentiate indicating a possible role of this transporter in HSC. In the present study, we have analyzed the role of ABCG2 in early haematopoietic stem cells by constitutively expressing ABCG2 in human CB derived CD133+ cells. This constitutive expression of ABCG2 demonstrated an enhancement of primary CFCs in vitro, including the most primitive clonogenic cells the CFU-GEMM (n=12, p

The hallmark of hematopoietic stem cells (HSC) is their ability of self-renewal and differentiation into multiple hematopoietic cell lineages. Although the molecular network controlling stem cell fate decisions is largely unknown, multiple studies have attributed a key role to transcription factors in this developmental process. In this context the family of homeobox genes was characterized as ‘master genes’ of this early hematopoietic development. The identification of new genes involved in normal and leukemic hematopoiesis and the development of therapies against deregulated processes in hematopoiesis are the major goals in experimental and clinical hematology. . The identification of new genes involved in normal and leukemic hematopoiesis and the development of therapies against deregulated processes in hematopoiesis are the major goals in experimental and clinical hematology. Therefore, the focus of this thesis was the characterization of two novel putative regulatory proteins of early human hematopoiesis, the hematopoietic PBX-interacting protein (HPIP) and the human Vent-like Homeobox gene (VENTX2) and to investigate to the activity of the FLT3 protein kinase inhibitor SU5614 on leukemic blast from AML patient samples. Using complex in vitro assays we analyzed the impact of constitutive expression of HPIP and VENTX2 on stem cell and early human hematopoietic development. To detect clonal progenitor cells primary and secondary colony-forming-unit (CFC) assays were performed. In addition the in vitro equivalent of HSC long-term culture initiating cells were detected with the (LTC-IC) assay. We were able to show that the constitutive expression of HPIP can rapidly lead to increased numbers of cells detected on the level of committed clonogenic progenitor cells and LTC-ICs. In addition, the production of CFC per LTC-IC is markedly enhanced when cord blood (CB) cells are transduced with HPIP as compared to the control. Notably, besides its effect on maintenance of primitive hematopoietic progenitor cells, constitutive expression of HPIP did not block terminal hematopoietic differentiation. Additional we could show that the constitutive expression of HPIP leads to an increase of myeloid cells in transplanted NOD/SCID mice. These data characterize HPIP as a novel regulator of the early human hematopoietic stem cell, demonstrating that its constitutive expression has a notable impact on self renewal and differentiation of human hematopoietic stem cells. In vitro and in vivo analyses shed light on the understanding to the function of the homeobox gene VENTX2. On the level of the most primitive hematopoietic progenitors we could not observe a significant increase in the frequency of HSCs. Furthermore, the number of colonies generated per LTC-IC did not significantly differ between the VENTX2 arm and the control arm. A strong effect was obtained on the level of clonogenic progenitor cells. VENTX2 increased the production of myeloid cells 1.7-fold in comparison to the control. Secondary replating assay confirmed the amplificatory effect of VENTX2 transduced cells in the number of secondary G-CFU indicating that VENTX2 promote myeloid lineage differentiation. Interestingly, on the level of clonogenic progenitors VENTX2 expression resulted in a significantly decreased growth of erythroid colonies by 4.2-fold compared to the control suggesting that constitutive expression of VENTX2 may inhibit early erythroid differentiation. This inhibition did not occur on the level of primitive hematopoietic cells detected by Limiting Dilution LTC-IC assay where VENTX2 increased within a 2.2 fold compared to the control. The observation that VENTX2 overexpression drives CD34+ to differentiate into myeloid lineage was additional proved by in vivo experiments. In NOD/SCID mice VENTX2 induced a 3-fold increase in the proportion of CD15+ mature myeloid cells within the GFP-positive compartment compared to the control. A 7-fold increase was observed in the total of CD38+ GFP+ cells in comparison to the MIG mice control (p

Two human stromal cell lines were established previously from bone marrow-derived primary long-term cultures by immortalization using the SV40 large T antigen and cellular cloning. After irradiation, the fibroblast-like cell lines L87/4 and L88/5 support hematopoietic differentiation of allogeneic cord blood cells in vitro. The stromal cells do not express CD34 and CD50, but some adhesion molecules and integrins, such as CD44, CD54 and CD58. Their expression profiles on RNA and protein levels are suggestive of their osteogenic potency. The quality and quantity of osteocalcin and osteopontin protein expression depended on the culture conditions. Expression of the osteogenic markers increased over time in culture, especially in cells growing in clusters. The stromal cells also expressed collagens I and V, but did not show any expression of collagens II and III. The potentially osteoblastic stromal cells were transplanted into NOD/SCID recipient mice by intravenous injection and were found in various mesenchymal organs up to 10 weeks after transplantation. Osteocalcin-positive human stromal cells could be detected in the bone marrow, thymus, liver, brain and gut of the recipient animals. In summary, there is evidence that human bone-marrow-derived stromal cells have to be considered mesenchymal progenitors, persistently expressing osteogenic markers in vitro and in vivo. Copyright (C) 2001 S, Karger AG, Basel.