RSS 1.0Barth, Brian
Recent Submissions
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Influences on the Hematopoietic Stem Cell NicheHematopoietic Stem Cells (HSCs) are supported by the bone marrow microenvironment to maintain normal production of blood cells. The niche may be considered an “ecosystem” that support the function of HSCs and other supportive cells. Alterations in the bone marrow niche are commonly observed in hematologic malignancies. Here, we review recent insights into the location and the molecular and cellular components of the bone marrow niche. Moreover, we discuss how the niche interacts with HSCs to drive the pathogenesis of hematopoietic malignancies. Overall, a better understanding of the influences on the HSC niche may drive therapeutic development targeting defective and aberrant hematopoiesis.
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Therapeutic Potential of Ceramide in Cancer TreatmentCeramides are a family of wax-like lipids that fall under the broader category of sphingolipids. A ceramide is composed of a sphingosine side chain coupled to a fatty acid via an amide linkage. Distinct from complex sphingolipids, the head of ceramide is a simple alcohol rather than a phosphate, phosphocholine, sugar, or more. The fatty acid chains of ceramide can also vary in chain length and degree of saturation. The degree of saturation may determine the biological activity of the ceramide species. Ceramides are highly abundant within the cell membrane of eukaryotic cells and are appreciated for their structural roles in these cells. Moreover, ceramides are well known for their biological activity including as regulators of apoptosis, senescence, the cell cycle, and differentiation. This review discusses pathways of ceramide, roles of ceramide in various diseases, targeting ceramide metabolism in the treatment of cancer, as well as ceramide-delivering nanotechnologies.
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Obesity Promotes the Ceramide-Mediated NADPH Oxidase in Acute Myeloid LeukemiaAcute myeloid leukemia (AML) is a type of blood cancer of the myeloid cell lineage. Obesity is characterized by an increase in body weight that results in excessive fat accumulation. Obesity has been associated with an increased incidence of many cancers, including blood cancers. This study evaluated the role obesity in AML progression in a novel transgenic mouse model developed by crossing Flt3ITD mice with Lepob/ob mice. Leukemia burden was augmented in obese AML mice. In addition, it was determined that obesity upregulated the ceramide-mediated and ceramide-1-phosphate-mediated NADPH oxidase 2 (NOX2). Notably, increased oxidative pathways has been attributed to disease progression in AML. Taken together, this study demonstrates a direct link between obesity and the progression of AML in part by augmenting the ceramide mediated NOX2.
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Acute myeloid leukemia stratifies as 2 clinically relevant sphingolipidomic subtypesAcute myeloid leukemia (AML) is an aggressive, heterogeneous disease with genomic subtypes that are increasingly treated differently. There is a growing interest in going beyond mutations and cytogenetics to stratify AML. Recent work has combined proteomics,1 signaling,2,3 or immunophenotypes4 with integrated genomic-transcriptomic measurements to improve AML risk classifications.5 Although invaluable as resources, such approaches can neither extend retroactively to existing repositories nor prospectively to new AML cases lacking these data types. We sought to develop a more extensible approach involving sphingolipids (Figure 1A), a family of bioactive molecules implicated in AML pathogenesis and therapeutic resistance6,7 that differentially regulate cell proliferation,8 differentiation,9 autophagy,10 apoptosis,11 and immune cell activation.12 Sphingolipid abundances in AML vary heterogeneously and ratiometrically,13 prompting us to ask whether systematic sphingolipidomic profiling could meaningfully stratify patients with AML and common AML cell lines.
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Alaska’s Flora as a Treatment for CancerCancer is an extraordinarily complex illness, with many tumors ultimately developing resistance to the currently available therapeutics. This highlights a need for the discovery of new anticancer medicines. Natural products have been utilized for centuries by the indigenous people of Alaska for both spiritual and medicinal purposes and have traditionally been administered as medicine for a wide range of ailments from the common cold to cancer. These plants, including Devil’s club, Labrador tea, Western skunk cabbage, and various species of wild berries such as blueberries, lingonberries, salmonberries, and high-bush cranberries, contain a wide variety of natural compounds with therapeutic potential. Various anthocyanins and polyphenols, including quercetin, as well as the pentacyclic triterpenoid ursolic acid, have been identified in these medicinal plants and have demonstrated antioxidant, anti-inflammatory, and anticancer activity. These ethnobotanicals and the unique compounds found within may be integral to the development of novel therapeutics for the treatment of cancer and other conditions.
