Vasquezgomez0324

Acute myeloid leukemia development occurs in a stepwise fashion whereby an original driver mutation is followed by additional mutations. this website The first type of mutations tends to be in genes encoding members of the epigenetic/transcription regulatory machinery (i.e., RUNX1, DNMT3A, TET2), while the secondary mutations often involve genes encoding members of signaling pathways that cause uncontrolled growth of such cells such as the growth factor receptors c-KIT of FLT3. Patients usually present with both types of mutations, but it is currently unclear how both mutational events shape the epigenome in developing AML cells. To this end we generated an in vitro model of t(8;21) AML by expressing its driver oncoprotein RUNX1-ETO with or without a mutated (N822K) KIT protein. Expression of N822K-c-KIT strongly increases the self-renewal capacity of RUNX1-ETO-expressing cells. Global analysis of gene expression changes and alterations in the epigenome revealed that N822K-c-KIT expression profoundly influences the open chromatin landscape and transcription factor binding. However, our experiments also revealed that double mutant cells still differ from their patient-derived counterparts, highlighting the importance of studying patient cells to obtain a true picture of how gene regulatory networks have been reprogrammed during tumorigenesis.Multiple sclerosis is an autoimmune disease that affects white matter in the central nervous system. It is one of the primary causes of neurological disability among young people. Its characteristic pathological lesion is called a plaque, a zone of inflammatory activity and tissue destruction that expands radially outward by destroying the myelin and oligodendrocytes of white matter. The present paper develops a mathematical model of the multiple sclerosis plaques. Although these plaques do not provide reliable information of the clinical disability in MS, they are nevertheless useful as a primary outcome measure of Phase II trials. The model consists of a system of partial differential equations in a simplified geometry of the lesion, consisting of three domains perivascular space, demyelinated plaque, and white matter. The model describes the activity of various pro- and anti-inflammatory cells and cytokines in the plaque, and quantifies their effect on plaque growth. We show that volume growth of plaques are in qualitative agreement with reported clinical studies of several currently used drugs. We then use the model to explore treatments with combinations of such drugs, and with experimental drugs. We finally consider the benefits of early vs. delayed treatment.A range of cationic delivery systems have been investigated as vaccine adjuvants, though few direct comparisons exist. To investigate the impact of the delivery platform, we prepared four cationic systems (emulsions, liposomes, polymeric nanoparticles and solid lipid nanoparticles) all containing equal concentrations of the cationic lipid dimethyldioctadecylammonium bromide in combination with the Neisseria adhesin A variant 3 subunit antigen. The formulations were physicochemically characterized and their ability to associate with cells and promote antigen processing (based on degradation of DQ-OVA, a substrate for proteases which upon hydrolysis is fluorescent) was compared in vitro and their vaccine efficacy (antigen-specific antibody responses and IFN-γ production) and biodistribution (antigen and adjuvant) were evaluated in vivo. Due to their cationic nature, all delivery systems gave high antigen loading (> 85%) with liposomes, lipid nanoparticles and emulsions being less then 200 nm, whilst polymeric nanoparticles were larger (~350 nm). In vitro, the particulate systems tended to promote cell uptake and antigen processing, whilst emulsions were less effective. Similarly, whilst the particulate delivery systems induced a depot (of both delivery system and antigen) at the injection site, the cationic emulsions did not. However, out of the systems tested the cationic emulsions induced the highest antibody responses. These results demonstrate that while cationic lipids can have strong adjuvant activity, their formulation platform influences their immunogenicity.Polyamidoamine dendrimer has been studied as an efficient gene carrier. Due to its anti-inflammatory properties, polyamidoamine is a useful gene carrier, especially for inflammatory diseases. However, the commonly used polyamidoamine generation 6 dendrimer (PG6) has higher cytotoxicity than low-molecular weight polyamidoamines, which limits its applications. Therefore, early-generation polyamidoamine dendrimers, such as generation 2 (PG2), have been investigated as an alternative to PG6, although PG2 has a lower transfection efficiency. In this study, to improve gene delivery efficiency, histidine and arginine were conjugated on the primary amines of PG2, synthesizing PG2HR. The gene delivery efficiency of PG2HR was higher than that of PG2 or of PG2 conjugated with only arginine (PG2R), which may be due to higher cellular uptake and endosomal escape of the plasmid DNA (pDNA)/PG2HR complex. In addition, PG2HR had lower cytotoxicity than polyethylenimine (25 kDa, PEI25k), PG2, and PG2R. Mechanism studies showed that PG2HR delivered pDNA into the cells mainly by clathrin-independent endocytosis and partly by macropinocytosis. The therapeutic potential of PG2HR-mediated gene delivery was evaluated in middle cerebral artery occlusion (MCAO)-reperfusion stroke animal models. Heme oxygenase-1 (HO-1) plasmid was delivered into the brain by local injection. The results showed that PG2HR had higher gene delivery efficiency in the brain than did PEI25k, PG2, or PG2R. Furthermore, compared to the pHO-1/PEI25k, pHO-1/PG2, and pHO-1/PG2R complexes, the pHO-1/PG2HR complex had reduced apoptosis levels and infarct sizes in ischemic brains. Therefore, because of its low cytotoxicity and high gene delivery efficiency, PG2HR may be useful for gene therapy of inflammatory diseases including ischemic stroke.We developed a pH-activatable cell-penetrating peptide dimer LH2 with histidine residues, which can penetrate cells, specifically in weak acidic conditions, even at few tens of nanomolar concentrations. LH2 effectively delivered paclitaxel into triple-negative breast cancer cells, MDA-MB-231, via formation of non-covalent complexes (PTX-LH2(M)) or covalent conjugates (PTX-LH2(C)). Moreover, LH2 showed prolonged circulation in the body and enhanced accumulation in tumors. Both PTX-LH2(M) and PTX-LH2(C) showed strong antitumor effects in a triple-negative breast cancer grafted mouse model at an extremely low dosage.