Although hyperactivation of the Ras-Erk signaling pathway is known to underlie the pathogenesis of juvenile myelomonocytic leukemia (JMML), a fatal childhood disease, the PI3K-Akt signaling pathway is also dysregulated in this disease. Using genetic models, we demonstrate that inactivation of phosphatidylinositol-3-kinase (PI3K) catalytic subunit p110δ, but not PI3K p110α, corrects gain-of-function (GOF) Shp2-induced granulocyte macrophage-colony-stimulating factor (GM-CSF) hypersensitivity, Akt and Erk hyperactivation, and skewed hematopoietic progenitor distribution. Likewise, potent p110δ-specific inhibitors curtail the proliferation of GOF Shp2-expressing hematopoietic cells and cooperate with mitogen-activated or extracellular signal-regulated protein kinase kinase (MEK) inhibition to reduce proliferation further and maximally block Erk and Akt activation. Furthermore, the PI3K p110δ-specific inhibitor, idelalisib, also demonstrates activity against primary leukemia cells from individuals with JMML. These findings suggest that selective inhibition of the PI3K catalytic subunit p110δ could provide an innovative approach for treatment of JMML, with the potential for limiting toxicity resulting from the hematopoietic-restricted expression of p110δ.
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http://dx.doi.org/10.1182/blood-2013-10-535104 | DOI Listing |
J Agric Food Chem
December 2024
School of Food and Biological Engineering, Engineering Research Center of Bio-process of Ministry of Education, Key Laboratory for Agricultural Products Processing of Anhui Province, Hefei University of Technology, Hefei 230009, Anhui, P. R. China.
The ingestion of red kidney bean products is hindered by the persistent allergenicity of lectins, even after autoclaving. This study examined the modification of lectin allergenicity in red kidney beans by pH-shifting and autoclaving treatments, utilizing BALB/c mouse sensitization, recirculating perfusion, and a bone marrow-derived dendritic cell (BMDC) model for allergenicity evaluation. Compared to autoclaving alone, combined pH-shifting and autoclaving reduced allergic symptoms in BALB/c mice, as evidenced by lower serum IgE, mMCPT-1, GM-CSF, HIS, IL-2, IL-4, IL-9, IL-13, and IL-17 levels and higher IgG1, IgG2a, IL-10, IFN-γ, and IFN-α cytokine release.
View Article and Find Full Text PDFImmunol Med
November 2024
Department of Pediatrics, Hokkaido University Hospital, Sapporo, Japan.
X-linked NF-κB essential modulator (NEMO) deficiency is a primary immunodeficiency characterized by combined immunodeficiency and ectodermal dysplasia. Monocytes from the patients demonstrate a severely impaired response to tissue necrosis factor or lipopolysaccharide, whereas hyper-inflammation is found in some patients. Juvenile myelomonocytic leukemia (JMML) is a pediatric malignancy caused by hypersensitivity to granulocyte-macrophage colony-stimulating factor (GM-CSF) and aberrant RAS signaling activation.
View Article and Find Full Text PDFHum Vaccin Immunother
December 2024
Development, BriaCell Therapeutics Corp, Philadelphia, PA, USA.
This Phase I/IIa open-label, single-arm clinical trial addressing advanced, refractory, metastatic breast cancer was conducted at six medical centers in the United States. We repeated inoculations with irradiated SV-BR-1-GM, a breast cancer cell line with antigen-presenting activity engineered to release granulocyte-macrophage colony-stimulating factor (GM-CSF), with pre-dose low-dose cyclophosphamide and post-dose local interferon alpha. Twenty-six patients were enrolled; 23 (88.
View Article and Find Full Text PDFJ Allergy Clin Immunol Pract
November 2024
Rheumatology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
Background: Severe eosinophilic asthma (SEA) may be the prodromal phase of eosinophilic granulomatosis with polyangiitis (EGPA). Nevertheless, few studies have tried to recognize EGPA in the early stages of the disease.
Objective: To identify a panel of clinical and biological markers to detect which severe asthmatic patient might be considered in a prodromal phase of EGPA and crafting a strategy for diagnostic decision-making.
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