Downregulation of Fzd6 and Cthrc1 and upregulation of olfactory receptors and protocadherins by dietary beta-carotene in lungs of Bcmo1-/- mice.

An ongoing controversy exists on beneficial versus harmful effects of high beta-carotene (BC) intake, especially for the lung. To elucidate potential mechanisms, we studied effects of BC on lung gene expression. We used a beta-carotene 15,15'-monooxygenase 1 (Bcmo1) knockout mouse (Bcmo1-/-) model, unable to convert BC to retinoids, and wild-type mice (Bcmo1+/+) mice to dissect the effects of intact BC from effects of BC metabolites. As expected, BC supplementation resulted in a higher BC accumulation in lungs of Bcmo1-/- mice than in lungs of Bcmo1+/+ mice. Whole mouse genome transcriptome analysis on lung tissue revealed that more genes were regulated in Bcmo1-/- mice than Bcmo1+/+ mice upon BC supplementation. Frizzled homolog 6 (Fzd6) and collagen triple helix repeat containing 1 (Cthrc1) were significantly downregulated (fold changes -2.99 and -2.60, respectively, false discovery rate <0.05) by BC in Bcmo1-/-. Moreover, many olfactory receptors and many members of the protocadherin family were upregulated. Since both olfactory receptors and protocadherins have an important function in sensory nerves and Fzd6 and Cthrc1 are important in stem cell development, we hypothesize that BC might have an effect on the highly innervated pulmonary neuroendocrine cell (PNEC) cluster. PNECs are highly associated with sensory nerves and are important cells in the control of stem cells. A role for BC in the innervated PNEC cluster might be of particular importance in smoke-induced carcinogenesis since PNEC-derived lung cancer is highly associated with tobacco smoke

Advanced data fusion: Random forest proximities and pseudo-sample principle towards increased prediction accuracy and variable interpretation

Data fusion has gained much attention in the field of life sciences, and this is because analysis of biological samples may require the use of data coming from multiple complementary sources to express the samples fully. Data fusion lies in the idea that different data platforms detect different biological entities. Therefore, if these different biological compounds are then combined, they can provide comprehensive profiling and understanding of the research question in hand. Data fusion can be performed in three different traditional ways: low-level, mid-level, and high-level data fusion. However, the increasing complexity and amount of generated data require the development of more sophisticated fusion approaches. In that regard, the current study presents an advanced data fusion approach (i.e. proximities stacking) based on random forest proximities coupled with the pseudo-sample principle. Four different data platforms of 130 samples each (faecal microbiome, blood, blood headspace, and exhaled breath samples of patients who have Crohn's disease) were used to demonstrate the classification performance of this new approach. More specifically, 104 samples were used to train and validate the models, whereas the remaining 26 samples were used to validate the models externally. Mid-level, high-level, as well as individual platform classification predictions, were made and compared against the proximities stacking approach. The performance of each approach was assessed by calculating the sensitivity and specificity of each model for the external test set, and visualized by performing principal component analysis on the proximity matrices of the training samples to then, subsequently, project the test samples onto that space. The implementation of pseudo-samples allowed for the identification of the most important variables per platform, finding relations among variables of the different data platforms, and the ex-amination of how variables behave in the samples. The proximities stacking approach outperforms both mid-level and high-level fusion approaches, as well as all individual platform predictions. Concurrently, it tackles significant bottlenecks of the traditional ways of fusion and of another advanced fusion way discussed in the paper, and finally, it contradicts the general belief that the more data, the merrier the result, and therefore, considerations have to be taken into account before any data fusion analysis is conducted. (c) 2021 Published by Elsevier B.V

Downregulation of Fzd6 and Cthrc1 and upregulation of olfactory receptors and protocadherins by dietary beta-carotene in lungs of Bcmo1-/- mice.

An ongoing controversy exists on beneficial versus harmful effects of high beta-carotene (BC) intake, especially for the lung. To elucidate potential mechanisms, we studied effects of BC on lung gene expression. We used a beta-carotene 15,15'-monooxygenase 1 (Bcmo1) knockout mouse (Bcmo1-/-) model, unable to convert BC to retinoids, and wild-type mice (Bcmo1+/+) mice to dissect the effects of intact BC from effects of BC metabolites. As expected, BC supplementation resulted in a higher BC accumulation in lungs of Bcmo1-/- mice than in lungs of Bcmo1+/+ mice. Whole mouse genome transcriptome analysis on lung tissue revealed that more genes were regulated in Bcmo1-/- mice than Bcmo1+/+ mice upon BC supplementation. Frizzled homolog 6 (Fzd6) and collagen triple helix repeat containing 1 (Cthrc1) were significantly downregulated (fold changes -2.99 and -2.60, respectively, false discovery rate <0.05) by BC in Bcmo1-/-. Moreover, many olfactory receptors and many members of the protocadherin family were upregulated. Since both olfactory receptors and protocadherins have an important function in sensory nerves and Fzd6 and Cthrc1 are important in stem cell development, we hypothesize that BC might have an effect on the highly innervated pulmonary neuroendocrine cell (PNEC) cluster. PNECs are highly associated with sensory nerves and are important cells in the control of stem cells. A role for BC in the innervated PNEC cluster might be of particular importance in smoke-induced carcinogenesis since PNEC-derived lung cancer is highly associated with tobacco smoke

DNA from Nails for Genetic Analyses in Large-Scale Epidemiologic Studies

BACKGROUND: Nails contain genomic DNA that can be used for genetic analyses, which is attractive for large epidemiologic studies that have collected or are planning to collect nail clippings. Study participants will more readily participate in a study when asked to provide nail samples than when asked to provide a blood sample. In addition, nails are easy and cheap to obtain and store compared with other tissues. METHODS: We describe our findings on toenail DNA in terms of yield, quality, genotyping a limited set of SNPs with the Sequenom MassARRAY iPLEX platform and high-density genotyping with the Illumina HumanCytoSNP_FFPE-12 DNA array (>262,000 markers). We discuss our findings together with other studies on nail DNA and we compare nails and other frequently used tissue samples as DNA sources. RESULTS: Although nail DNA is considerably degraded, genotyping a limited set of SNPs with the Sequenom MassARRAY iPLEX platform (average sample call rate, 97.1%) and high-density genotyping with the Illumina HumanCytoSNP_FFPE chip (average sample call rate, 93.8%) were successful. CONCLUSIONS: Nails are a suitable source of DNA for genotyping in large-scale epidemiologic studies, provided that methods are used that are suitable or optimized for degraded DNA. For genotyping through (next generation) sequencing where DNA degradation is less of an issue, nails may be an even more attractive DNA source, because it surpasses other sources in terms of ease and costs of obtaining and storing the samples. IMPACT: It is worthwhile to consider nails as a source of DNA for genotyping in large-scale epidemiologic studies. See all the articles in this CEBP Focus section, "Biomarkers, Biospecimens, and New Technologies in Molecular Epidemiology." Cancer Epidemiol Biomarkers Prev; 23(12); 2703-12. (c)2014 AACR

Antioxidant therapeutic advances in COPD

Chronic obstructive pulmonary disease (COPD) is associated with a high incidence of morbidity and mortality. Cigarette smoke-induced oxidative stress is intimately associated with the progression and exacerbation of COPD and therefore targeting oxidative stress with antioxidants or boosting the endogenous levels of antioxidants is likely to have beneficial outcome in the treatment of COPD. Among the various antioxidants tried so far, thiol antioxidants and mucolytic agents, such as glutathione, N-acetyl-L-cysteine, N-acystelyn, erdosteine, fudosteine and carbocysteine; Nrf2 activators; and dietary polyphenols (curcumin, resveratrol, and green tea catechins/quercetin) have been reported to increase intracellular thiol status along with induction of GSH biosynthesis. Such an elevation in the thiol status in turn leads to detoxification of free radicals and oxidants as well as inhibition of ongoing inflammatory responses. In addition, specific spin traps, such as α-phenyl-N-tert-butyl nitrone, a catalytic antioxidant (ECSOD mimetic), porphyrins (AEOL 10150 and AEOL 10113), and a SOD mimetic M40419 have also been reported to inhibit cigarette smoke-induced inflammatory responses in vivo in the lung. Since a variety of oxidants, free radicals and aldehydes are implicated in the pathogenesis of COPD, it is possible that therapeutic administration of multiple antioxidants and mucolytics will be effective in management of COPD. However, a successful outcome will critically depend upon the choice of antioxidant therapy for a particular clinical phenotype of COPD, whose pathophysiology should be first properly understood. This article will review the various approaches adopted to enhance lung antioxidant levels, antioxidant therapeutic advances and recent past clinical trials of antioxidant compounds in COPD

Coal tar therapy. Is it carcinogenic?

Coal tar therapy. Is it carcinogenic? van Schooten FJ, Godschalk R. Department of Health Risk Analysis and Toxicology, University of Maastricht, The Netherlands. [email protected] Epidemiological studies indicate that occupational exposure to coal tar may lead to an increased risk of lung, scrotum and skin cancer. Furthermore, studies with laboratory rodents show carcinogenicity of coal tar after dermal application. This effect may be attributable to polycyclic aromatic hydrocarbons (PAH), which are ubiquitous coal tar constituents. Absorbed PAH can be metabolised to reactive derivatives that bind to DNA. These PAH-DNA binding products are thought to be involved in PAH-induced carcinogenesis. However, no clearly increased skin cancer incidences have been reported in psoriasis patients who have been exposed to therapeutically high doses of coal tar. To determine whether patients treated with coal tar actually have an altered risk of cutaneous malignancies, we suggest that further controlled studies and experiments are necessary. Future research should also focus on the possibility of increased risks of developing internal malignancie

Ecogenotoxicology: the evolving field

The occurrence of chemical contaminants with DNA-damaging capacity in the environment represents a threat to human health as well as to the health of the ecosystem. This mini-review describes studies that were aimed to monitor at field conditions, the presence of such environmental toxicants and their DNA-damaging effects in aquatic and terrestrial species, as well as in birds. It is obvious that these studies, in particular are abundantly performed in fish and aquatic invertebrates, have brought forward new information on the levels and genotoxic effects of these compounds which complements data coming from monitoring the abiotic fractions of the ecosystem, thereby demonstrating that the ecogenotoxicological approach is fruitful. However, in order to assess the genotoxic impact on the health of the ecosystem, a second generation type of field studies is required focusing on adverse effects on biodiversity and on survival potency. For this, the application of DNA microarray-based technologies provides new opportunities