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Environmental Factor, July 2015

Intramural papers of the month

By Tara Ann Cartwright, Monica Frazier, Gabriel Knudsen, Simone Otto, and Qing Xu

NTP develops tool to analyze and characterize Tox21 data

Researchers at the National Toxicology Program (NTP) recently described a new data analysis pipeline protocol to better characterize high throughput screening data generated in the Tox21 initiative. Tox21 is a collaboration between NIEHS/NTP, the U.S. Environmental Protection Agency National Center for Computational Toxicology, the U.S. Food and Drug Administration, and the National Center for Advancing Translational Sciences. Tox21 seeks to derive a quantitative response for 10,000 pharmaceutical and environmental chemicals for a panel of stress- and nuclear receptor signaling pathway assays using a quantitative high throughput screening approach.

Ideally, active chemicals are both reproducible across experimental runs and relevant to the pathway of interest. However, several challenges to data interpretation exist, from assay artifacts, such as non-reproducible signals, to interfering signals, like autofluorescence. To clarify the signals, a series of noise filtering and data curation protocols were developed in conjunction with a system to identify and flag assay interference. Concentration data were quantified using a weighted area under the curve, resulting in a highly reproducible signal profile, although cytotoxicity was a common confounding factor. In addition, a graphical user interface was introduced that allowed quick evaluation of the Tox21 screenings. (GK)

Citation Hsieh JH, Sedykh A, Huang R, Xia M, Tice RR. 2015. A data analysis pipeline accounting for artifacts in Tox21 quantitative high-throughput screening assays. J Biomol Screen; doi:10.1177/1087057115581317 [Online 22 April 2015].

What’s luck got to do with cancer?

Two scientists from the NIEHS Biostatistics and Computational Biology Branch, Clarice Weinberg, Ph.D., and Dmitri Zaykin, Ph.D., wrote a commentary that discussed three inferential pitfalls in a recent article published in the journal Science. Their critique considered an analysis by Christian Tomasetti, Ph.D., and Bert Vogelstein, M.D., which documented that on a logarithmic scale, the lifetime risk of cancer in a particular tissue type strongly correlates with the estimated lifetime number of stem cell divisions. These results were widely interpreted as suggesting that most cancers unpreventably occur as a result of bad luck, or errors in DNA replication, with each stem cell division bringing another roll of the dice.

Weinberg and Zaykin illustrated their points using the example of traffic fatalities. They showed how drawing conclusions from correlations based on aggregates of data can lead scientists astray, and offered a compelling argument that the correlation Tomasetti and Vogelstein found did not have implications for the role of genetic or preventable environmental factors. One cannot assign percentages to causative factors, in part because multiple factors often work together. Just as there is much more to traffic safety than the number of miles driven, such as drunk driving or vehicle safety, much of cancer may turn out to be preventable, despite the undeniable role of bad luck. (MF)

Citation Weinberg CR, Zaykin D. 2015. Is bad luck the main cause of cancer? J Natl Cancer Inst 107(7):djv125. ( Story)

Calcium sensor protein necessary for the development of psoriasis

NIEHS researchers have revealed that the calcium sensor protein, stromal interaction molecule 1 (STIM1), plays an important role in the development of psoriasis, a chronic inflammatory skin disorder characterized by plaque-like lesions on the skin. The condition occurs because a large influx of neutrophils enters the epidermis. Mice that lack STIM1 fail to elicit this response, and have less neutrophil infiltration than controls. The study opens a new avenue to treat psoriasis and other immune diseases.  

As one of the body’s first responders, neutrophils travel toward chemoattractants induced by inflamed skin, using a process known as chemotaxis. In psoriasis, STIM1 facilitates store-operated calcium entry (SOCE) into the cells.

The researchers found that silencing STIM1 in a human neutrophil-like cell line, and removing STIM1 in mouse neutrophils, inhibited chemotaxis, while overexpression of STIM1 enhanced calcium and chemotaxis response to chemoattractants. They also used imiquimod, a topical immune activator, to induce psoriasis-like damage in a mouse model. Compared to control mice, STIM1 knockout mice not only had reduced neutrophil infiltration in the skin, but also had hastened recovery from psoriasis plaques. These results suggest that STIM1 and other SOCE proteins may be potential therapeutic targets for neutrophil-involved disorders. (QX)

Citation Steinckwich N, Myers P, Janardhan KS, Flagler ND, King D, Petranka JG, Putney JW. 2015. Role of the store-operated calcium entry protein, STIM1, in neutrophil chemotaxis and infiltration into a murine model of psoriasis-inflamed skin. FASEB J; doi:10.1096/fj.14-265215 [Online 2 April 2015].

Heart rate variability in relation to Parkinson disease risk

NIEHS scientists have determined that decreased heart rate variability (HRV) is associated with an increased risk of neurodegeneration in Parkinson’s disease (PD), years prior to the manifestation of detectable motor symptoms. In addition to cardinal motor dysfunctions, such as tremor, patients often suffer from a range of nonmotor symptoms. These symptoms may include sleep disturbances, smell and taste dysfunction, constipation, and changes in HRV.

Using data from the 20-year Atherosclerosis Risk in Communities (ARIC) study, the researchers provided the first epidemiological evidence that decreased HRV, a marker of alterations in the cardiac autonomic system, predicts future risk of PD as predicted by the Braak hypothesis. This hypothesis indicates that the Lewy pathology, one of the pathological hallmarks of PD, may start in the olfactory bulb and lower brain stem, and even in periphery nerves, such as the enteric nerve in the gut and cardiac sympathetic or parasympathetic innervations. Research on this pathology and other nonmotor symptoms in the prodromal stage of PD may lead to methods for identifying individuals with higher risk of PD and to a better understanding of disease etiology. ( TAC)

Citation Alonso A, Huang X, Mosley TH, Heiss G, Chen H. 2015. Heart rate variability and the risk of Parkinson disease: The Atherosclerosis Risk in Communities study. Ann Neurol 77(5):877-883.

Lack of cross-reactivity between GST allergens could lead to new diagnostic tools

NIEHS scientists and their collaborators determined that glutathione S-transferase (GST) allergens from cockroach, roundworm, and 2 dust mite species did not contain cross-reactive sites. The discovery was the result of IgE reactivity assays and crystal structure data of allergen GSTs generated by the NIEHS members of the team. The finding is novel because it demonstrates that the allergic response to GST allergens is species-specific, contradicting previous studies that suggested these GST allergens were cross-reactive. Allergists can use the information to offer a more accurate diagnosis of the sensitizing organism and suggest the appropriate treatment. 

The research team investigated the IgE reactivity of U.S. patients allergic to cockroach and mite GSTs from 4 species, by comparing the common solvent-accessible areas in the crystal structures that could be responsible for cross-reactivity. The scientists also tested the IgE antibodies from U.S. patients, who are normally exposed to the cockroach and mite allergens, but not the roundworm allergen or the tropical species of mite. These patients allowed the researchers to differentiate the response. IgE antibodies from North American patients were also tested, and they contained antibodies to all 4 GSTs. The scientists concluded the South American patients were cosensitized to all 4 species in their environment, and that specific antibodies to these GST allergens can be used to diagnose the source of an allergy. (SO)

Citation Mueller GA, Pedersen LC, Glesner J, Edwards LL, Zakzuk J, London RE, Arruda LK, Chapman MD, Caraballo L, Pomes A. 2015. Analysis of glutathione S-transferase allergen cross-reactivity in a North American population: Relevance for molecular diagnosis. J Allergy Clin Immunol; doi:10.1016/j.jaci.2015.03.015 [Online 27 April 2015].

(Tara Ann Cartwright, Ph.D., is a former postdoctoral fellow in the NIEHS Intracellular Regulation Group. Monica Frazier, Ph.D., is a former Intramural Research Training Award [IRTA] fellow in the NIEHS Mechanisms of Mutation Group. Gabriel Knudsen, Ph.D., is a research fellow in the National Cancer Institute, Center for Cancer Research, Laboratory of Toxicology and Toxicokinetics. Simone Otto, Ph.D., is an IRTA fellow in the NIEHS Ion Channel Physiology Group. Qing Xu is a biologist in the NIEHS Metabolism, Genes, and Environment Group.)

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