Identification of germline alterations of the mad homology 2 domain of SMAD3 and SMAD4 from the Ontario site of the breast cancer family registry (CFR)

Abstract Introduction A common feature of neoplastic cells is that mutations in SMADs can contribute to the loss of sensitivity to the anti-tumor effects of transforming growth factor-β (TGF-β). However, germline mutation analysis of SMAD3 and SMAD4, the principle substrates of the TGF-β signaling pathway, has not yet been conducted in breast cancer. Thus, it is currently unknown whether germline SMAD3 and SMAD4 mutations are involved in breast cancer predisposition. Methods We performed mutation analysis of the highly conserved mad-homology 2 (MH2) domains for both genes in genomic DNA from 408 non-BRCA1/BRCA2 breast cancer cases and 710 population controls recruited by the Ontario site of the breast cancer family registry (CFR) using denaturing high-performance liquid chromatography (DHPLC) and direct DNA sequencing. The results were interpreted in several ways. First, we adapted nucleotide diversity analysis to quantitatively assess whether the frequency of alterations differ between the two genes. Next, in silico tools were used to predict variants' effect on domain function and mRNA splicing. Finally, 37 cases or controls harboring alterations were tested for aberrant splicing using reverse-transcription polymerase chain reaction (PCR) and real-time PCR statistical comparison of germline expressions by non-parametric Mann-Whitney test of independent samples. Results We identified 27 variants including 2 novel SMAD4 coding variants c.1350G > A (p.Gln450Gln), and c.1701A > G (p.Ile525Val). There were no inactivating mutations even though c.1350G > A was predicted to affect exonic splicing enhancers. However, several additional findings were of note: 1) nucleotide diversity estimate for SMAD3 but not SMAD4 indicated that coding variants of the MH2 domain were more infrequent than expected; 2) in breast cancer cases SMAD3 was significantly over-expressed relative to controls (P A was associated with elevated germline expression (> 5-fold); 3) separate analysis using tissue expression data showed statistically significant over-expression of SMAD3 and SMAD4 in breast carcinomas. Conclusions This study shows that inactivating germline alterations in SMAD3 and SMAD4 are rare, suggesting a limited role in driving tumorigenesis. Nevertheless, aberrant germline expressions of SMAD3 and SMAD4 may be more common in breast cancer than previously suspected and offer novel insight into their roles in predisposition and/or progression of breast cancer

Cancer effects of formaldehyde: a proposal for an indoor air guideline value

Formaldehyde is a ubiquitous indoor air pollutant that is classified as “Carcinogenic to humans (Group 1)” (IARC, Formaldehyde, 2-butoxyethanol and 1-tert-butoxypropanol-2-ol. IARC monographs on the evaluation of carcinogenic risks to humans, vol 88. World Health Organization, Lyon, pp 39–325, 2006). For nasal cancer in rats, the exposure–response relationship is highly non-linear, supporting a no-observed-adverse-effect level (NOAEL) that allows setting a guideline value. Epidemiological studies reported no increased incidence of nasopharyngeal cancer in humans below a mean level of 1 ppm and peak levels below 4 ppm, consistent with results from rat studies. Rat studies indicate that cytotoxicity-induced cell proliferation (NOAEL at 1 ppm) is a key mechanism in development of nasal cancer. However, the linear unit risk approach that is based on conservative (“worst-case”) considerations is also used for risk characterization of formaldehyde exposures. Lymphohematopoietic malignancies are not observed consistently in animal studies and if caused by formaldehyde in humans, they are high-dose phenomenons with non-linear exposure–response relationships. Apparently, these diseases are not reported in epidemiological studies at peak exposures below 2 ppm and average exposures below 0.5 ppm. At the similar airborne exposure levels in rodents, the nasal cancer effect is much more prominent than lymphohematopoietic malignancies. Thus, prevention of nasal cancer is considered to prevent lymphohematopoietic malignancies. Departing from the rat studies, the guideline value of the WHO (Air quality guidelines for Europe, 2nd edn. World Health Organization, Regional Office for Europe, Copenhagen, pp 87–91, 2000), 0.08 ppm (0.1 mg m−3) formaldehyde, is considered preventive of carcinogenic effects in compliance with epidemiological findings

THEORETICAL STUDY OF OPTICAL PROPERTIES. PHOTON ABSORPTION COEFFICIENTS, OPACITIES, AND EQUATIONS OF STATE OF LIGHT ELEMENTS INCLUDING THE EFFECT OF LINES. Final Report. APPENDIX A: THERMODYNAMIC PROPERTIES AND MEAN OPACITIES

Photon absorption coefficients and mean opacities were calculated for hydrogen, beryllium, carbon, nitrogen, aluminum, and silicon over a temperature range froni l.5 to 34 ev and a density range from about l0/sup -1/g/cm/sup 3/ downward. Contributions to the absorption coefficient from free-free (inverse- bremsstrahlung), bound-free (photoelectric), and bound-bound (line-absorption) processes are included, as is Compton scattering. Certain thermodynamic properties are also given. An improved recipe for pressure ionization was derived which is approximately valid at nondegencrate densities for any ratio of Debye length to ion-sphere radius. Line absorption was evaluated using recent results from pressure-broadening theory and a representation of line series which is computationally as simple as the statistical method. The results show that lines increase the Rosseland mean opacity by a factor which can be nearly ten and which is insensitive to moderate changes in line widths. The code employed generated ionic energy levels internally by isoelectronic interpolation, and is immediately applicable to any- mixture of elements in which no ion has more than 14 bound electrons. The results of the calculations of thermodynamic properties and mean opacities are given in the tables in Appendix A, and the graphs of the monochromatic absorption coefficients are given in Appendix B, which comprises Vols. II and III. (auth

THEORETICAL STUDY OF OPTICAL PROPERTIES. APPENDIX B: MONOCHROMATIC ABSORPTION COEFFICIENTS FOR HYDROGEN, BERYLLIUM, AND CARBON. Final Report

No abstract.<><DSN>16:004155<ABS>No abstract.<><DSN>16:004156<ABS>Nitrosylium hexafluoroniolybdate(V) and nitrosylium hexafluorouranate(V) were prepared and characterized. These compounds were prepared by the reaction of nitric oxide with the respective hexafluoride. Nitric oxide did not react with tungsten hexafliioride. Nitrous oxide was found to be unreactive toward molybdenum, tungsten, and uranium hexafluorides. (auth