Clinical response to azacitidine in MDS is associated with distinct DNA methylation changes in HSPCs.

Hypomethylating agents are frontline therapies for myelodysplastic neoplasms (MDS), yet clinical responses remain unpredictable. We conducted a phase 2 trial comparing injectable and oral azacitidine (AZA) administered over one or three weeks per four-week cycle, with the primary objective of investigating whether response is linked to in vivo drug incorporation or DNA hypomethylation. Our findings show that injection results in higher drug incorporation, but lower DNA demethylation per cycle, while global DNA methylation levels in mononuclear cells are comparable between responders and non-responders.

Inorganic nanoparticle-based advanced cancer therapies: Promising combination strategies.

Inorganic nanoparticles for drug delivery in cancer treatment offer many potential advantages because they can maximize therapeutic effect through targeting ligands while minimizing off-target side-effects through drug adsorption and infiltration. Although inorganic nanoparticles were introduced as drug carriers, they have emerged as having the capacity for combined therapeutic capabilities, including anticancer effects through cytotoxicity, suppression of oncogenes and cancer cell signaling pathway inhibition. The most promising advanced strategies for cancer therapy are as synergistic platforms for RNA interference (siRNA, miRNA, shRNA) and as synergistic drug delivery agents for the inhibition of cancer cell signaling pathways.

Mesoderm-derived PDGFRA cells regulate the emergence of hematopoietic stem cells in the dorsal aorta.

Mouse haematopoietic stem cells (HSCs) first emerge at embryonic day 10.5 (E10.5), on the ventral surface of the dorsal aorta, by endothelial-to-haematopoietic transition.

The splicing factor RBM17 drives leukemic stem cell maintenance by evading nonsense-mediated decay of pro-leukemic factors.

Chemo-resistance in acute myeloid leukemia (AML) patients is driven by leukemic stem cells (LSCs) resulting in high rates of relapse and low overall survival. Here, we demonstrate that upregulation of the splicing factor, RBM17 preferentially marks and sustains LSCs and directly correlates with shorten patient survival. RBM17 knockdown in primary AML cells leads to myeloid differentiation and impaired colony formation and in vivo engraftment.

Anticancer therapeutic effect of cerium-based nanoparticles: known and unknown molecular mechanisms.

Cerium-based nanoparticles (CeNPs), particularly cerium oxide (CeO), have been studied extensively for their antioxidant and prooxidant properties. However, their complete redox and enzyme-mimetic mechanisms of therapeutic action at the molecular level remain elusive, constraining their potential for clinical translation. Although the therapeutic effects of both antioxidant and prooxidant mechanisms generally are attributed to Ce ↔ Ce redox switching mediation, some studies have hinted at the involvement of unknown pathways in therapeutic effects.

initiates myeloid bias and myelodysplastic/myeloproliferative syndrome from hemopoietic stem cells.

Mutations in occur in myelodysplastic syndromes (MDS) and MDS/myeloproliferative neoplasms (MPN). mutations cluster at proline 95, with the most frequent mutation being a histidine (P95H) substitution. They undergo positive selection, arise early in the course of disease, and have been identified in age-related clonal hemopoiesis.

Identification of novel regulators of developmental hematopoiesis using Endoglin regulatory elements as molecular probes.

Enhancers are the primary determinants of cell identity, and specific promoter/enhancer combinations of Endoglin (ENG) have been shown to target blood and endothelium in the embryo. Here, we generated a series of embryonic stem cell lines, each targeted with reporter constructs driven by specific promoter/enhancer combinations of ENG, to evaluate their discriminative potential and value as molecular probes of the corresponding transcriptome. The Eng promoter (P) in combination with the -8/+7/+9-kb enhancers, targeted cells in FLK1 mesoderm that were enriched for blast colony forming potential, whereas the P/-8-kb enhancer targeted TIE2+/c-KIT+/CD41- endothelial cells that were enriched for hematopoietic potential.

GFI1(36N) as a therapeutic and prognostic marker for myelodysplastic syndrome.

Inherited gene variants play an important role in malignant diseases. The transcriptional repressor growth factor independence 1 (GFI1) regulates hematopoietic stem cell (HSC) self-renewal and differentiation. A single-nucleotide polymorphism of GFI1 (rs34631763) generates a protein with an asparagine (N) instead of a serine (S) at position 36 (GFI1(36N)) and has a prevalence of 3%-5% among Caucasians.

PDGF-AB and 5-Azacytidine induce conversion of somatic cells into tissue-regenerative multipotent stem cells.

Current approaches in tissue engineering are geared toward generating tissue-specific stem cells. Given the complexity and heterogeneity of tissues, this approach has its limitations. An alternate approach is to induce terminally differentiated cells to dedifferentiate into multipotent proliferative cells with the capacity to regenerate all components of a damaged tissue, a phenomenon used by salamanders to regenerate limbs.

Origins and functional consequences of somatic mitochondrial DNA mutations in human cancer.

Recent sequencing studies have extensively explored the somatic alterations present in the nuclear genomes of cancers. Although mitochondria control energy metabolism and apoptosis, the origins and impact of cancer-associated mutations in mtDNA are unclear. In this study, we analyzed somatic alterations in mtDNA from 1675 tumors.