Nanoformulation of Paclitaxel: Exploring the Cyclodextrin / PLGA Nano Delivery Carrier to Slow Down Paclitaxel Release, Enhance Accumulation .

Improving the aggregation and penetration in tumor sites increases the anti-tumor efficacy of nanomedicine. In the current study, we designed cyclodextrin modified PLGA nanoparticles loaded with paclitaxel to elevate the accumulation and prolong circulation of chemotherapy drugs . The PLGA nanoparticles loaded with paclitaxel (PTX PLGA NPs) and cyclodextrin (CD) modified PLGA nanoparticles loaded with paclitaxel (PTX PLGA/CD NPs) were prepared using the emulsification solvent evaporation method.

Rapid Preparation of Antifreezing Conductive Hydrogels for Flexible Strain Sensors and Supercapacitors.

Conductive hydrogels have shown great promise in flexible electronics, but their practical applications may be impeded by the time-consuming and energy-consuming polymerization process. We proposed a sodium lignosulfonate-Fe (SLS-Fe) strategy to address this challenge and took advantage of carboxymethyl cellulose (CMC) and poly(acrylic acid) to prepare the CMC/PAA/Fe/LiCl interpenetrating conductive hydrogels with good self-healing properties, antifreezing properties, and a 6-fold increase in conductivity in this study. The hydrogel-based flexible strain sensors demonstrated a broad detection range (400%), high sensitivity (GF = 6.

HoxA9 binds and represses the Cebpa +8 kb enhancer.

C/EBPα plays a key role in specifying myeloid lineage development. HoxA9 is expressed in myeloid progenitors, with its level diminishing during myeloid maturation, and HOXA9 is over-expressed in a majority of acute myeloid leukemia cases, including those expressing NUP98-HOXD13. The objective of this study was to determine whether HoxA9 directly represses Cebpa gene expression.

Patient-Driven Discovery, Therapeutic Targeting, and Post-Clinical Validation of a Novel Fusion-Driven Cancer.

Despite the important role of the PI3K/AKT/mTOR axis in the pathogenesis of cancer, to date there have been few functional oncogenic fusions identified involving the genes. A 12-year-old female with a histopathologically indeterminate epithelioid neoplasm was found to harbor a novel fusion between the and genes. Through expanded use access, she became the first pediatric patient to be treated with the oral ATP-competitive pan-AKT inhibitor ipatasertib.

The protective role of DOT1L in UV-induced melanomagenesis.

The DOT1L histone H3 lysine 79 (H3K79) methyltransferase plays an oncogenic role in MLL-rearranged leukemogenesis. Here, we demonstrate that, in contrast to MLL-rearranged leukemia, DOT1L plays a protective role in ultraviolet radiation (UVR)-induced melanoma development. Specifically, the DOT1L gene is located in a frequently deleted region and undergoes somatic mutation in human melanoma.

A new target for differentiation therapy in AML.

Despite major advances in understanding the genetics and epigenetics of acute myelogenous leukemia, there is still a great need to develop more specific and effective therapies. High throughput approaches involving either genetic approaches or small molecule inhibitor screens are beginning to identify promising new therapeutic targets.

S6K1 regulates hematopoietic stem cell self-renewal and leukemia maintenance.

Hyperactivation of the mTOR pathway impairs hematopoietic stem cell (HSC) functions and promotes leukemogenesis. mTORC1 and mTORC2 differentially control normal and leukemic stem cell functions. mTORC1 regulates p70 ribosomal protein S6 kinase 1 (S6K1) and eukaryotic initiation factor 4E-binding (eIF4E-binding) protein 1 (4E-BP1), and mTORC2 modulates AKT activation.

PRDM16 Suppresses MLL1r Leukemia via Intrinsic Histone Methyltransferase Activity.

PRDM16 is a transcription co-factor that plays critical roles in development of brown adipose tissue, as well as maintenance of adult hematopoietic and neural stem cells. Here we report that PRDM16 is a histone H3K4 methyltransferase on chromatin. Mutation in the N-terminal PR domain of PRDM16 abolishes the intrinsic enzymatic activity of PRDM16.

Role of p85α in neutrophil extra- and intracellular reactive oxygen species generation.

Drug resistance is a growing problem that necessitates new strategies to combat pathogens. Neutrophil phagocytosis and production of intracellular ROS, in particular, has been shown to cooperate with antibiotics in the killing of microbes. This study tested the hypothesis that p85α, the regulatory subunit of PI3K, regulates production of intracellular ROS.

Pak and Rac GTPases promote oncogenic KIT-induced neoplasms.

An acquired somatic mutation at codon 816 in the KIT receptor tyrosine kinase is associated with poor prognosis in patients with systemic mastocytosis and acute myeloid leukemia (AML). Treatment of leukemic cells bearing this mutation with an allosteric inhibitor of p21-activated kinase (Pak) or its genetic inactivation results in growth repression due to enhanced apoptosis. Inhibition of the upstream effector Rac abrogates the oncogene-induced growth and activity of Pak.

ROCK1 functions as a critical regulator of stress erythropoiesis and survival by regulating p53.

Erythropoiesis is a dynamic, multistep process whereby hematopoietic stem cells differentiate toward a progressively committed erythroid lineage through intermediate progenitors. Although several downstream signaling molecules have been identified that regulate steady-state erythropoiesis, the major regulators under conditions of stress remain poorly defined. Rho kinases (ROCKs) belong to a family of serine/threonine kinases.

The human Nav1.5 F1486 deletion associated with long QT syndrome leads to impaired sodium channel inactivation and reduced lidocaine sensitivity.

The deletion of phenylalanine 1486 (F1486del) in the human cardiac voltage-gated sodium channel (hNav1.5) is associated with fatal long QT (LQT) syndrome. In this study we determined how F1486del impairs the functional properties of hNav1.

Role of SHP2 phosphatase in KIT-induced transformation: identification of SHP2 as a druggable target in diseases involving oncogenic KIT.

Intracellular mechanism(s) that contribute to promiscuous signaling via oncogenic KIT in systemic mastocytosis and acute myelogenous leukemia are poorly understood. We show that SHP2 phosphatase is essential for oncogenic KIT-induced growth and survival in vitro and myeloproliferative disease (MPD) in vivo. Genetic disruption of SHP2 or treatment of oncogene-bearing cells with a novel SHP2 inhibitor alone or in combination with the PI3K inhibitor corrects MPD by disrupting a protein complex involving p85α, SHP2, and Gab2.

p85β regulatory subunit of class IA PI3 kinase negatively regulates mast cell growth, maturation, and leukemogenesis.

We show that loss of p85α inhibits the growth and maturation of mast cells, whereas loss of p85β enhances this process. Whereas restoring the expression of p85α in P85α(-/-) cells restores these functions, overexpression of p85β has the opposite effect. Consistently, overexpression of p85β in WT mast cells represses KIT-induced proliferation and IL-3-mediated maturation by inhibiting the expression of Microphthalmia transcription factor.

Role of intracellular tyrosines in activating KIT-induced myeloproliferative disease.

Gain-of-function mutations in KIT receptor in humans are associated with gastrointestinal stromal tumors, systemic mastocytosis and acute myelogenous leukemia. The intracellular signals that contribute to oncogenic KIT-induced myeloproliferative disease (MPD) are poorly understood. Here, we show that oncogenic KITD814V-induced MPD occurs in the absence of ligand stimulation.

Class I(A) PI3Kinase regulatory subunit, p85α, mediates mast cell development through regulation of growth and survival related genes.

Stem cell factor (SCF) mediated KIT receptor activation plays a pivotal role in mast cell growth, maturation and survival. However, the signaling events downstream from KIT are poorly understood. Mast cells express multiple regulatory subunits of class 1(A) PI3Kinase (PI3K) including p85α, p85β, p50α, and p55α.

Rho kinase regulates the survival and transformation of cells bearing oncogenic forms of KIT, FLT3, and BCR-ABL.

We show constitutive activation of Rho kinase (ROCK) in cells bearing oncogenic forms of KIT, FLT3, and BCR-ABL, which is dependent on PI3K and Rho GTPase. Genetic or pharmacologic inhibition of ROCK in oncogene-bearing cells impaired their growth as well as the growth of acute myeloid leukemia patient-derived blasts and prolonged the life span of mice bearing myeloproliferative disease. Downstream from ROCK, rapid dephosphorylation or loss of expression of myosin light chain resulted in enhanced apoptosis, reduced growth, and loss of actin polymerization in oncogene-bearing cells leading to significantly prolonged life span of leukemic mice.

Balanced interactions between Lyn, the p85alpha regulatory subunit of class I(A) phosphatidylinositol-3-kinase, and SHIP are essential for mast cell growth and maturation.

The growth and maturation of bone marrow-derived mast cells (BMMCs) from precursors are regulated by coordinated signals from multiple cytokine receptors, including KIT. While studies conducted using mutant forms of these receptors lacking the binding sites for Src family kinases (SFKs) and phosphatidylinositol-3-kinase (PI3K) suggest a role for these signaling molecules in regulating growth and survival, how complete loss of these molecules in early BMMC progenitors (MCps) impacts maturation and growth during all phases of mast cell development is not fully understood. We show that the Lyn SFK and the p85α subunit of class I(A) PI3K play opposing roles in regulating the growth and maturation of BMMCs in part by regulating the level of PI3K.

The PI3K pathway drives the maturation of mast cells via microphthalmia transcription factor.

Mast cell maturation is poorly understood. We show that enhanced PI3K activation results in accelerated maturation of mast cells by inducing the expression of microphthalmia transcription factor (Mitf). Conversely, loss of PI3K activation reduces the maturation of mast cells by inhibiting the activation of AKT, leading to reduced Mitf but enhanced Gata-2 expression and accumulation of Gr1(+)Mac1(+) myeloid cells as opposed to mast cells.

Deficiency of Src family kinases compromises the repopulating ability of hematopoietic stem cells.

Objective: Src family kinases (SFK) have been implicated in regulating growth factor and integrin-induced proliferation, migration, and gene expression in multiple cell types. However, little is known about the role of these kinases in the growth, homing, and engraftment potential of hematopoietic stem and progenitor cells.

Results: Here we show that loss of hematopoietic-specific SFKs Hck, Fgr, and Lyn results in increased number of Sca-1(+)Lin(-) cells in the bone marrow, which respond differentially to cytokine-induced growth in vitro and manifest a significant defect in the long-term repopulating potential in vivo.

[Detection of Borna disease virus-p24 specific antibody in the sera of schizophrenic patients of China by means of Western-blot].

Background: To investigate whether Borna disease virus (BDV) infection is related to the schizophrenic patients from China.

Methods: A reliable Western-blot method for detection of BDV-p24 antibody was established by adjusting the reaction conditions of BDV-p24 recombinant protein and specific antibodies. The sera of schizophrenic patients and normal controls from Heilongjiang Province were screened for specific BDV-p24 antibody by this method, and the BDV-p24 antibody positive sera were confirmed by the Western-blot method with sera-GST protein absorption.