13 research outputs found
Human predecidual stromal cells are mesenchymal stromal/stem cells and have a therapeutic effect in an immune-based mouse model of recurrent spontaneous abortion
Human decidual stromal cells (DSCs) are involved in the maintenance and development of
pregnancy, in which they play a key role in the induction of immunological maternal–fetal tolerance. Precursors of
DSCs (preDSCs) are located around the vessels, and based on their antigen phenotype, previous studies suggested
a relationship between preDSCs and mesenchymal stromal/stem cells (MSCs). This work aimed to further elucidate
the MSC characteristics of preDSCs. Under the effect of P4 and cAMP, the preDSC lines and clones decidualized in vitro: the cells became rounder
and secreted PRL, a marker of physiological decidualization. PreDSC lines and clones also exhibited MSC characteristics.
They differentiated into adipocytes, osteoblasts, and chondrocytes, and preDSC lines expressed stem cell markers OCT-
4, NANOG, and ABCG2; exhibited a cloning efficiency of 4 to 15%; significantly reduced the embryo resorption rate
(P < 0.001) in the mouse model of abortion; and survived for prolonged periods in immunocompetent mice. The fact
that 3 preDSC clones underwent both decidualization and mesenchymal differentiation shows that the same type of
cell exhibited both DSC and MSC characteristics. Together, our results confirm that preDSCs are decidual MSCs and suggest that these cells are involved
in the mechanisms of maternal–fetal immune toleranceThis work was supported by the Plan Estatal de Investigación Científica y
Técnica y de Innovación 2013–2016, ISCIII-Subdirección General de Evaluación y
Fomento de la Investigación, the Ministerio de Economía y Competitividad,
Spain (Grant PI16/01642) and European Regional Development Fund (ERDF/
FEDER funding), the European Community, and the Cátedra de Investigación
Anto nio Chamorro–Alejandro Otero, Universidad de Granada (CACH2017-1)
A Prospective Randomized Study Comparing Reduced-Intensity Conditioning and Myeloablative Conditioning in Patients with Myeloid Leukemia Undergoing Allogeneic Hematopoietic Stem Cell Transplantation
A Proinflammatory Invariant Natural Killer T Cells Phenotypic State Associates with Human Graft-Versus-Host Disease Onset and Response
A Proinflammatory Invariant Natural Killer T Cell Phenotypic State Associates with Human Graft-Versus-Host Disease Onset
MTH1 inhibitor TH1579 induces oxidative DNA damage and mitotic arrest in acute myeloid leukemia
Acute myeloid leukemia (AML) is an aggressive hematological malignancy, exhibiting high levels of reactive oxygen species (ROS). ROS levels have been suggested to drive leukemogenesis and is thus a potential novel target for treating AML. MTH1 prevents incorporation of oxidized nucleotides into the DNA to maintain genome integrity and is upregulated in many cancers. Here we demonstrate that hematological cancers are highly sensitive to MTH1 inhibitor TH1579 (karonudib). A functional precision medicine ex vivo screen in primary AML bone marrow samples demonstrated a broad response profile of TH1579, independent of the genomic alteration of AML, resembling the response profile of the standard-of-care treatments cytarabine and doxorubicin. Furthermore, TH1579 killed primary human AML blast cells (CD45+) as well as chemotherapy resistance leukemic stem cells (CD45+Lin-CD34+CD38-),which are often responsible for AML progression. TH1579 killed AML cells by causing mitotic arrest, elevating intracellular ROS levels, and enhancing oxidative DNA damage. TH1579 showed a significant therapeutic window, was well tolerated in animals, and could be combined with standard-of-care treatments to further improve efficacy. TH1579 significantly improved survival in two different AML disease models in vivo. In conclusion, the pre-clinical data presented here support that TH1579 is a promising novel anticancer agent for AML, providing a rational to investigate the clinical usefulness of TH1579 in AML in an on-going clinical phase 1 trial