Spotlight pubs.acs.org/crt
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HOUSING TEMPERATURE INFLUENCES TUMOR GROWTH IN LAB MICE Mouse models are indispensable for investigating cancer development, progression, antitumor immune response, and therapies. Current National Research Council guidelines stipulate that mice be housed at room temperatures between 20 and 26 °C; however, this temperature range is much lower than that which healthy mice normally prefer (30−31 °C). At the latter “thermoneutral” temperature range (TT), mouse basal metabolism suffices to maintain normal body temperature, while at subthermoneutral temperatures (ST), mice undergo adaptive thermogenesis induced by cold stress in order to maintain normal body temperature. Previous studies on fever, obesity, and macrophage activation in mice have demonstrated that housing temperature impacts biological outcome; thus, a research team led by Elizabeth A. Repasky decided to investigate the influence of housing temperature on mouse tumor models as well ((2013) PNAS, 110, 20176−20181). The researchers found that several model mouse strains injected with tumor cells or treated with a carcinogen developed tumors at a higher frequency and faster rate when they were housed at ST rather than TT conditions. However, tumor growth in immunodeficient mice was no different at ST than at TT, indicating that the temperature sensitivity observed in the other mouse strains was mediated through an antitumor immune response. Specifically, CD8+ T cell levels were elevated, and suppressor/ regulatory immune cells were depleted in immunosufficient mice housed at TT relative to those housed at ST. The authors hypothesize that cold stress at ST causes systemic immunosuppression that enables a more rapid tumor growth. Heidi A. Dahlmann
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NANOTOXOIDS ENABLE SAFE, EFFECTIVE VACCINATION In July 2013, the Chemical Research in Toxicology Spotlight highlighted the research of Liangfang Zhang and co-workers, who developed biomimetic nanosponges that could absorb and detoxify various pore-forming toxins (PFTs) circulating in vivo ((2013) Chem. Res. Toxicol., 26, 1029−1030). PFTs, which are proteins that damage host cell membranes, are involved in the virulence of nasty pathogens like Escherichia coli, Helicobacter pylori, and Staphylococcus aureus. Zhang and co-workers demonstrated that the biomimetic sponges, which consisted of natural red blood cell (RBC) bilayers wrapped around biodegradable poly(lacto-co-glycolic acid) (PLGA) cores, could be used as a universal antidote for PFT exposure. According to new research by the same group, the nanosponges could also be applied in vaccinations against PFTs ((2013) Nat. Nanotechnol., 8, 933−938). PFT vaccine production typically involves chemical or heatmediated denaturation of toxin proteins, which typically alters their antigen presentation. To produce a more effective vaccine, Zhang and co-workers prepared “nanotoxoids” by absorbing the PFT α-hemolysin into the previously described nanosponges. The resulting nanotoxoids were able to trigger the production of a large amount of anti-α-hemolysin antibodies in mice; the antibodies had high binding affinity for the target toxin. Ultimately, mice vaccinated with nanotoxoids showed better survival upon exposure to α-hemolysin than did mice vaccinated with heat-denatured α-hemolysin. These results highlight the advantage of presenting nondisrupted antigens to produce vaccines with improved immunogenicity and efficacy. Heidi A. Dahlmann
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During the onset of type 1 diabetes, an autoimmune response toward insulin-producing beta cells in pancreatic islets impairs the function of beta cells and induces beta cell death. Beta cell damage is mediated by exposure to cytokines (particularly IL1β and IFNγ) produced by various cells of the immune system. IL-1β and IFNγ induce elevated expression of inducible nitric oxide synthase (iNOS) in beta cells, resulting in the production of micromolar concentrations of nitric oxide. Nitric oxide plays an important role in beta cell death since iNOS inhibitors prevent cell death, while exogenous nitric oxide induces cell death. However, nitric oxide can also react with superoxide to produce peroxynitrite, a powerful oxidant. Thus, it was debated whether beta cell death is due to nitric oxide or peroxynitriteinduced damage. Recently, a research team led by John A. Corbett used a peroxynitrite-specific chemically reactive probe, coumarin-7boronate (see above), to demonstrate that cytokines failed to stimulate peroxynitrite generation in model beta cell lines, even when the cells were also exposed to an agent that induces enzyme-mediated superoxide production ((2013) J. Biol. Chem., 288, 36567−36578). Cells treated with exogenous sources of superoxide and nitric oxide did produce peroxyntitrite, but surprisingly, they seemed to be protected from the cytotoxic effects observed upon exposure to cytokines or endogenous nitric oxide alone. These findings allowed the research team to conclude that nitric oxide, as opposed to peroxynitrite, likely mediates the toxic effects of cytokines. Heidi A. Dahlmann
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COPY NUMBER VARIATION DETECTED IN SINGLE CIRCULATING TUMOR CELLS When normal cells undergo mutations such as single-nucleotide variations (SNVs), insertions, or deletions (INDELs), or copy number variations (CNVs), they may eventually form cancerous tumors. Cancer progression from the primary tumor to secondary metastases is known to occur due to the migration and proliferation of circulating tumor cells (CTCs); however,
PEROXYNITRITE NOT RESPONSIBLE FOR CYTOKINE-MEDIATED BETA CELL DEATH
Published: February 17, 2014 © 2014 American Chemical Society
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Spotlight
genomic alterations driving metastasis are largely uncharacterized. Thanks to the recent advancements in whole-genome amplification methods, a research team led by Fan Bai, X. Sunney Xie, and Jie Wang were able to investigate genomic alterations in individual CTCs from 11 lung cancer patients ((2013) PNAS, 110, 21083−21088). The researchers found that CTCs derived from adenocarcinoma (ADC) patients had very similar SNV and INDELs as their corresponding metastases but not their primary tumors. Overall, largely reproducible CNVs occurred in each CTC derived from an individual patient, with nearly identical global CNV patterns occurring between each ADC patient. Less correlation was found in CNV patterns derived from small-cell lung cancer (SCLC) patients, but notably, a gain in copy number for the human leukocyte antigen gene (associated with tumor progression) was found in all ADC and SCLC patients. Interestingly, the researchers also found that while SNVs and INDELs increased during one patient’s chemotherapy and cancer progression, the patient’s CNV patterns did not change over the same time period. The authors note that tracking reproducible CNV patterns in CTCs from individual patients may facilitate noninvasive cancer diagnosis. Heidi A. Dahlmann
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NEUROSTEROID PREGNENOLONE MITIGATES CANNABIS INTOXICATION
The infamous effects of Cannabis sativa (marijuana) consumption are primarily mediated by the interaction of Δ9tetrahydrocannabinol (THC) with type-1 cannabinoid (CB1) receptors in the brain. Many agonists and antagonists of the well-studied CB1 receptor have been identified, and now due to research led by Monique Vallée and Pier Vincenzo Piazza, a new CB1 receptor inhibitor can be added to the list: the neurosteroid pregnenolone ((2014) Science, 343, 94−98). This result was surprising since pregnenolone, the precursor to all steroid hormones, was previously considered to be inactive. The research team discovered that mice and rats treated with THC show remarkably large increases in pregnenolone production in the brain; the binding of THC to CB1 receptors appeared to induce a signaling cascade that significantly upregulated levels of enzymes involved in pregnenolone biosynthesis. Subsequent binding of pregnenolone to CB1 receptors mediated a negative feedback response that prevented CB1 receptor overactivation. Mice pretreated with pregnenolone displayed reduced symptoms of intoxication upon exposure to THC and were less likely to indulge in selfadministration of a model cannabinoid drug. On the basis of these results, the authors suggest that selective allosteric inhibitors of CB1 receptors, such as pregnenolone, would be potentially useful for treating cannabis intoxication and addiction. Heidi A. Dahlmann
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