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Supporting Figures S1â S16. (DOCX 8.22 kb)

Figure S1. Sample size by recruitment centers. (PDF 10 kb)

Figure S3. Correlation heatmap of methylation levels inside the two most significant DMR of folate and alcohol. (PDF 43 kb)

Figure S4. DMRs and FL regions of folate in each chromosome. Dark blue rectangles represent DMRs and light blue FL regions. Overlaps between the two methods are represented by red points. Positive coefficients of the two methods are represented on the top part of each graphic, and negative coefficients are on the bottom part. Positive (negative) coefficients of DMRs were set to 0.5 (− 0.5) and positive (negative) coefficients of FL regions were set to 1 (− 1) to clearly differentiate DMRs from FL regions. The x-axis represents the rank of CpG sites according to their position on the chromosome. (PDF 12 kb)

Figure S2. Graphical representation of the most 2 significant DMR of dietary folate and alcohol intake. The x-axis represents the position (hg 19 coordinates) of the CpGs included in the plotted DMR. Each tertile of dietary folate, alcohol intake, or their interaction is represented by different colors: green for T1, blue for T2, and red for T3. For all the CpGs included in the plotted DMR, the dashed lines are their 1st and 3rd quartiles of methylation levels and the points represent their median values. (PDF 33 kb)

Table S2. DMRs associated with alcohol intake. (DOCX 34 kb)

Figure S5. DMRs and FL regions of alcohol in each chromosome. Dark blue rectangles represent DMRs and light blue FL regions. Overlaps between the two methods are represented by red points. Positive coefficients of the two methods are represented on the top part of each graphic and negative coefficients are on the bottom part. Positive (negative) coefficients of DMRs were set to 0.5 (− 0.5), and positive (negative) coefficients of FL regions were set to 1 (− 1) to clearly differentiate DMRs from FL regions. The x-axis represents the rank of CpG sites according to their position on the chromosome. (PDF 58 kb)

It has proved difficult to develop suitable models to study radiation-induced carcinogenesis by using human epithelial cells. However, immortalised human epithelial cell lines have proved useful. Unirradiated cells from the human keratinocyte cell line (HPV-G) and the human embryonic lung cell line (L132) were found to be tumourigenic in T-cell-deficient mice; thus, they are not suitable for transformation studies. Human urothelial cell lines (SV-HUC-1, NT11, BC16) and the human thyroid epithelial cell line (HTori-3) were nontumourigenic. The urothelial cell lines were refractory to radiation-induced carcinogenesis, and only one small tumour was observed in 57 mice that received irradiated cells. Whereas tumours were not produced following irradiation of these urothelial cells, changes in anchorage-independent growth were observed after a single dose of 8 Gy gamma-irradiation but not after 2 or 4 Gy. Irradiation of the human thyroid epithelial cell line (HTori-3) in vitro resulted in tumour formation. Passaging of the cells in vitro before injection did not seem to be critical. Some of the cell lines derived from the primary thyroid tumours exhibited p53 mutations in exons 5, 6, 7, and 8, as detected by single-stranded conformational polymorphism (SSCP) analysis. Thus, the human thyroid epithelial cell line (HTori-3) looks promising as a model for investigating the molecular events in radiation-induced carcinogenesis.

The term ‘epigenetic’ refers to all heritable changes in gene expression and associated phenotypic traits that are not coded in the DNA sequence itself. Epigenetic inheritance includes DNA methylation, histone modifications, and micro-RNAs, all of which are essential mechanisms that allow the stable propagation of gene activity states from one generation of cells to the next. Many epidemiological and laboratory-based studies either confirm or implicate epigenetic changes induced by environmental, nutritional, and lifestyle factors in a variety of human cancer. Environmental factors known to play important roles in the etiology of human cancer include chemical carcinogens, such as those found in cigarette smoke; dietary contaminants, such as the aflatoxin B1; and physical carcinogen, such as UV radiation. Lifestyles such as smoking, alcohol consumption, excess exposure to sunlight, and fat consumption are environmental factors that contribute to human malignancies. Epigenetic mechanisms play a critical role in normal physiological responses to environmental stimuli that establish an appropriate gene expression pattern by altering the epigenetic state of the genome. Exposure to environmental, physical, and chemical carcinogens, infectious agents, and lifestyle may induce epigenetic changes that alter critical cellular processes including silencing of tumor suppressor genes, activation of oncogenes, aberrant cell cycle, defects in DNA repair, and deregulation of cell death, all of which may promote the development of cancer.

Mouse embryo fibroblasts lacking poly(ADP-ribose) polymerase (PARP)-1 express a barely detectable level of wild-type (wt) p53 protein. Doxorubicin at concentrations activating wt p53 in normal mouse embryo fibroblasts failed to induce it in mutant cells. wt p53 was only activated in response to a 10-fold higher doxorubicin dose. Treatment with higher doxorubicin concentrations was cytotoxic for normal but not for PARP-1 -/- cells. The latter was also resistant to other anticancer agents. The increased resistance of mutant cells to drugs resembled a unique phenomenon known as multidrug resistance (MDR). Interestingly, the MDR gene product P-glycoprotein was clearly up-regulated in PARP-1-deficient cells as compared with normal counterparts. Pretreatment with verapamil reversed the MDR phenotype.

Human thyroid carcinomas have been induced following exposure of SV40-immortalized human thyroid epithelial cells in vitro to single doses (0.14 Gy to 1.57 Gy) of 3.26 MeV alpha-particles from a plutonium 238 source. Tumours were detected between 50 and 160 days following subcutaneous transplantation of the irradiated cells in athymic mice. No tumours were observed following transplantation of unirradiated cells. The relative biological effectiveness (RBE) of the alpha-particles, estimated from cell survival curves, was 4.8 at 50% survival and 3.3 at 5% survival. A first estimate of the RBE at peak tumour induction was 3.8. This system provides a means of studying the mechanisms of tumourigenesis in human thyroid epithelial cells induced by ionizing radiations, including tumours induced by single alpha particles such as from environmental natural radon and polonium and artificial plutonium and americium, and those induced by beta- or Auger-emissions from particular iodine isotopes.

It has proved difficult to develop suitable models to study radiation-induced carcinogenesis by using human epithelial cells. However, immortalised human epithelial cell lines have proved useful. Unirradiated cells from the human keratinocyte cell line (HPV-G) and the human embryonic lung cell line (L132) were found to be tumourigenic in T-cell-deficient mice; thus, they are not suitable for transformation studies. Human urothelial cell lines (SV-HUC-1, NT11, BC16) and the human thyroid epithelial cell line (HTori-3) were nontumourigenic. The urothelial cell lines were refractory to radiation-induced carcinogenesis, and only one small tumour was observed in 57 mice that received irradiated cells. Whereas tumours were not produced following irradiation of these urothelial cells, changes in anchorage-independent growth were observed after a single dose of 8 Gy gamma-irradiation but not after 2 or 4 Gy. Irradiation of the human thyroid epithelial cell line (HTori-3) in vitro resulted in tumour formation. Passaging of the cells in vitro before injection did not seem to be critical. Some of the cell lines derived from the primary thyroid tumours exhibited p53 mutations in exons 5, 6, 7, and 8, as detected by single-stranded conformational polymorphism (SSCP) analysis. Thus, the human thyroid epithelial cell line (HTori-3) looks promising as a model for investigating the molecular events in radiation-induced carcinogenesis.

A case report is presented of a man with pronounced tracheobronchomegaly who has had respiratory symptoms since childhood. In spite of numerous medical examinations a disease remains undetected for many years. Authors bring up different standpoints about etiology and the most often accepted hypothesis about the autosomal recessive inheritance. They also point their attention to a small number of diagnosed cases despite high prevalence (0,4-1%) and typical symptoms.

An analytical expression is derived for the electrical transparency of a corona triode with a biased parallel wire grid. This analysis is extended to a square grid by modelling it with an equivalent parallel grid having the same optical transparency. The experimental results obtained with a small corona triode, agree with the theoretical model for the parallel wire grids and the square grid with a large optical transparency. For a square grid with transparency less than 60%, good agreement is obtained by allowing one of the terms in the mathematical model to become an experimentally adjusted constant.

Table S1. DMRs associated with dietary folate (log). (DOCX 19 kb)

Herceg Z., Juraga E., Sobota-Salamon B., Režek-Jambrak A. (2012): Inactivation of mesophilic bacteria in milk by means of high intensity ultrasound using response surface methodology. Czech J. Food Sci., 30: 108–117. High-intensity ultrasound was used to investigate the inactivation of microorganisms in raw bovine milk. Raw bovine milk with 4% of milk fat was treated with ultrasonic probe that was 12 mm in diameter and with 20 kHz frequency immerged in milk directly. In the ultrasound treatment, three parameters were varied according to the statistical ex perimental design. The centre composite design was used to design and optimise the experimental parameters: tem perature (20, 40, and 60°C), amplitude (120, 90, and 60 µm), and time (6, 9, and 12 min). All analyses were performed immediately after sonication and after 3 days and 5 days of storage under refrigeration at 4°C. The factors that seem to affect substantially the inactivation of microorganisms in using ultrasound are the amplitude of the ultrasonic waves, the exposure/contact time with the microorganisms, and the temperature of the treatment. The results achieved indicate a significant inactivation of microorganisms under longer periods of the treatment with ultrasonic probe, particularly in combination of higher temperature and amplitude. The output optimal value of total bacteria count was defined by Statgraphics where the lowest bacteria count was 3.688 log CFU/ml for the following specific ultrasound parameters: amplitude 120 μm, treatment time 9.84 min, and temperature 45.34°C.

A corona device with point-to-plane electrode geometry is used to simulate electrical operating conditions in industrial electrostatic precipitators. The particular aspect investigated is the effect of electrode coating by precipitated particulates of high resistivity, and as simulated by layers of porous insulating materials. The typical measured d.c.characteristics and square-wave response of the device are presented and discussed. The corona modes are identified from measurements, and the device performance is represented by a lumped-element circuit model based on a spatial systematisation of corona phenomena into four regions described as the primary-ionisation, accumulation, transport, and secondary-ionisation regions. The lumped parameters of the circuit model are used for a semiquantitative formulation of criteria for typical corona modes and corresponding electrical characteristics. Further, the circuit model is implemented in the design of a simple solid-state analogue, which can simulate the negative-corona characteristics of the device under different operating conditions.