SYK inhibition targets acute myeloid leukemia stem cells by blocking their oxidative metabolism

Spleen tyrosine kinase (SYK) is an important oncogene and signaling mediator activated by cell surface receptors crucial for acute myeloid leukemia (AML) maintenance and progression. Genetic or pharmacologic inhibition of SYK in AML cells leads to increased differentiation, reduced proliferation, and cellular apoptosis. Herein, we addressed the consequences of SYK inhibition to leukemia stem-cell (LSC) function and assessed SYK-associated pathways in AML cell biology. Using gain-of-function MEK kinase mutant and constitutively active STAT5A, we demonstrate that R406, the active metabolite of a small-molecule SYK inhibitor fostamatinib, induces differentiation and blocks clonogenic potential of AML cells through the MEK/ERK1/2 pathway and STAT5A transcription factor, respectively. Pharmacological inhibition of SYK with R406 reduced LSC compartment defined as CD34+CD38-CD123+ and CD34+CD38-CD25+ in vitro, and decreased viability of LSCs identified by a low abundance of reactive oxygen species. Primary leukemic blasts treated ex vivo with R406 exhibited lower engraftment potential when xenotransplanted to immunodeficient NSG/J mice. Mechanistically, these effects are mediated by disturbed mitochondrial biogenesis and suppression of oxidative metabolism (OXPHOS) in LSCs. These mechanisms appear to be partially dependent on inhibition of STAT5 and its target gene MYC, a well-defined inducer of mitochondrial biogenesis. In addition, inhibition of SYK increases the sensitivity of LSCs to cytarabine (AraC), a standard of AML induction therapy. Taken together, our findings indicate that SYK fosters OXPHOS and participates in metabolic reprogramming of AML LSCs in a mechanism that at least partially involves STAT5, and that SYK inhibition targets LSCs in AML. Since active SYK is expressed in a majority of AML patients and confers inferior prognosis, the combination of SYK inhibitors with standard chemotherapeutics such as AraC constitutes a new therapeutic modality that should be evaluated in future clinical trials

Applicator Exposure to Glycol Derivatives and Total Volatile Organic Compounds during the Application of Spray Polyurethane Foam Insulation

There is currently high demand for new building materials which are considered environmentally friendly or green for both new construction and renovations. Spray polyurethane foam (SPUF) insulation has gained significant acceptance by both consumers and the construction industry due to its high R-value, which results into significant energy savings among other things. Despite its acceptance by consumers and the construction industry, consideration must be given to potential chemical exposures to applicators installing these products. This study sought to determine, through quantitative experimentation, if there was a release of glycol derivatives including, diethylene glycol (DEG), ethylene glycol (EG), and propylene glycol (PEG), during the application of SPUF. In addition, total volatile organic Compounds (tVOCs) and various environmental parameters were also collected during this research. This study utilized a two-component small-scale SPUF kit manufactured by the Dow Chemical Company, known as the FROTH-PAK™ kit. This specific kit is typically used by the construction industry to fill cavities, cracks, floor and wall penetrations, and expansion joints of buildings. In order to determine the presence of these glycol derivatives, personal breathing zone samples were collected during the application of the SPUF during three application trials. Glycols derivatives were measured using active sampling techniques. Supplementary parameters including tVOCs, ambient and wet-bulb temperature, relative humidity, carbon monoxide, and carbon dioxide, were measured using direct-reading techniques. During this study several modifications were made to the work area and the air sampling methodology to assist in verifying the presence of the glycols and the conditions in which they may be present in the air during the application of SPUF insulation. All samples were sent to an accredited laboratory and were analyzed by the Nation Institute of Occupational Safety and Health Method 5523. During this study, measurable amounts of diethylene glycol and propylene glycol were detected in two of the trials in which no ventilation in the work area was utilized. During one trial in which a work area ventilation system was utilized, none of the glycols were detected in the laboratory analysis above the limit of detection given the analytical method. Ethylene glycol was not detected in any of the samples submitted for analysis. The results for the tVOC measurements were inconclusive. Based on the results of the air sampling, it is likely that exposure to diethylene glycol and propylene glycol may occur under certain conditions. However, due to the limited number of samples and the variation between the samples collected in this study, a generation rate or concentration buildup estimate for comparison of the OELs was not conducted. These conditions include the quantity of ventilation used during application, the application duration, and proper operation of the SPUF application equipment. Based on the results, there is evidence that additional research may be needed in this area

Federal Legislative Proposals for the Protection of Privacy

Previously, privacy rights had to be litigated under one of the four recognized tort claim of actions. With the advent of the computer age, it was argued that new causes of actions should be created to supplement the individually recognized privacy rights of the people. At the time this article was written, several privacy related bills were before congress. The note examines the benefits of the bills proposed, and the (justified) failure of the proposals to consider a single federal information data bank due to its inability to safeguard privacy. It also synopsizes the Subcommittee on Constitutional Rights\u27 findings on these issues as well as the privacy rights afforded by the Freedom of Information Act and the Privacy Act of 1974