Non-steroidal anti-inflammatory drug (NSAID) use and levels of a lipid oxidation marker in plasma and nipple aspirate fluids

Non-steroidal anti-inflammatory drugs (NSAIDs) are thought to reduce cancer risk by inhibiting cyclo-oxygenases, resulting in deceased formation of inflammatory mediators and oxidative stress. We examined whether the level of one oxidative stress marker, 15-F 2t -isoprostane, was affected by NSAID use in plasma and breast nipple aspirate fluids (NAF) of pre-menopausal women who were participating in a dietary intervention trial ( n =121). Baseline levels of 15-F 2t -isoprostane were lower in NSAID users than non-users in both NAF and plasma, although the differences did not persist after intervention. Over the duration of the study, information on NSAID use was collected five times, and average 15-F 2t -isoprostane levels in both NAF and plasma exhibited a statistically significant trend for decreases with increased frequency of NSAID use. These results indicate that NSAID use can result in lower levels of 15-F 2t -isoprostane, which may have implications for the effects of NSAID use on breast cancer risk.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44237/1/10549_2005_Article_9102.pd

Intronic L1 Retrotransposons and Nested Genes Cause Transcriptional Interference by Inducing Intron Retention, Exonization and Cryptic Polyadenylation

Transcriptional interference has been recently recognized as an unexpectedly complex and mostly negative regulation of genes. Despite a relatively few studies that emerged in recent years, it has been demonstrated that a readthrough transcription derived from one gene can influence the transcription of another overlapping or nested gene. However, the molecular effects resulting from this interaction are largely unknown.Using in silico chromosome walking, we searched for prematurely terminated transcripts bearing signatures of intron retention or exonization of intronic sequence at their 3' ends upstream to human L1 retrotransposons, protein-coding and noncoding nested genes. We demonstrate that transcriptional interference induced by intronic L1s (or other repeated DNAs) and nested genes could be characterized by intron retention, forced exonization and cryptic polyadenylation. These molecular effects were revealed from the analysis of endogenous transcripts derived from different cell lines and tissues and confirmed by the expression of three minigenes in cell culture. While intron retention and exonization were comparably observed in introns upstream to L1s, forced exonization was preferentially detected in nested genes. Transcriptional interference induced by L1 or nested genes was dependent on the presence or absence of cryptic splice sites, affected the inclusion or exclusion of the upstream exon and the use of cryptic polyadenylation signals.Our results suggest that transcriptional interference induced by intronic L1s and nested genes could influence the transcription of the large number of genes in normal as well as in tumor tissues. Therefore, this type of interference could have a major impact on the regulation of the host gene expression

The Elongator Complex Interacts with PCNA and Modulates Transcriptional Silencing and Sensitivity to DNA Damage Agents

Histone chaperones CAF-1 and Asf1 function to deposit newly synthesized histones onto replicating DNA to promote nucleosome formation in a proliferating cell nuclear antigen (PCNA) dependent process. The DNA replication- or DNA repair-coupled nucleosome assembly pathways are important for maintenance of transcriptional gene silencing and genome stability. However, how these pathways are regulated is not well understood. Here we report an interaction between the Elongator histone acetyltransferase and the proliferating cell nuclear antigen. Cells lacking Elp3 (K-acetyltransferase Kat9), the catalytic subunit of the six-subunit Elongator complex, partially lose silencing of reporter genes at the chromosome VIIL telomere and at the HMR locus, and are sensitive to the DNA replication inhibitor hydroxyurea (HU) and the damaging agent methyl methanesulfonate (MMS). Like deletion of the ELP3, mutation of each of the four other subunits of the Elongator complex as well as mutations in Elp3 that compromise the formation of the Elongator complex also result in loss of silencing and increased HU sensitivity. Moreover, Elp3 is required for S-phase progression in the presence of HU. Epistasis analysis indicates that the elp3Δ mutant, which itself is sensitive to MMS, exacerbates the MMS sensitivity of cells lacking histone chaperones Asf1, CAF-1 and the H3 lysine 56 acetyltransferase Rtt109. The elp3Δ mutant has allele specific genetic interactions with mutations in POL30 that encodes PCNA and PCNA binds to the Elongator complex both in vivo and in vitro. Together, these results uncover a novel role for the intact Elongator complex in transcriptional silencing and maintenance of genome stability, and it does so in a pathway linked to the DNA replication and DNA repair protein PCNA

Relations between lipoprotein(a) concentrations, LPA genetic variants, and the risk of mortality in patients with established coronary heart disease: a molecular and genetic association study

BACKGROUND: Lipoprotein(a) concentrations in plasma are associated with cardiovascular risk in the general population. Whether lipoprotein(a) concentrations or LPA genetic variants predict long-term mortality in patients with established coronary heart disease remains less clear. METHODS: We obtained data from 3313 patients with established coronary heart disease in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. We tested associations of tertiles of lipoprotein(a) concentration in plasma and two LPA single-nucleotide polymorphisms ([SNPs] rs10455872 and rs3798220) with all-cause mortality and cardiovascular mortality by Cox regression analysis and with severity of disease by generalised linear modelling, with and without adjustment for age, sex, diabetes diagnosis, systolic blood pressure, BMI, smoking status, estimated glomerular filtration rate, LDL-cholesterol concentration, and use of lipid-lowering therapy. Results for plasma lipoprotein(a) concentrations were validated in five independent studies involving 10 195 patients with established coronary heart disease. Results for genetic associations were replicated through large-scale collaborative analysis in the GENIUS-CHD consortium, comprising 106 353 patients with established coronary heart disease and 19 332 deaths in 22 studies or cohorts. FINDINGS: The median follow-up was 9·9 years. Increased severity of coronary heart disease was associated with lipoprotein(a) concentrations in plasma in the highest tertile (adjusted hazard radio [HR] 1·44, 95% CI 1·14-1·83) and the presence of either LPA SNP (1·88, 1·40-2·53). No associations were found in LURIC with all-cause mortality (highest tertile of lipoprotein(a) concentration in plasma 0·95, 0·81-1·11 and either LPA SNP 1·10, 0·92-1·31) or cardiovascular mortality (0·99, 0·81-1·2 and 1·13, 0·90-1·40, respectively) or in the validation studies. INTERPRETATION: In patients with prevalent coronary heart disease, lipoprotein(a) concentrations and genetic variants showed no associations with mortality. We conclude that these variables are not useful risk factors to measure to predict progression to death after coronary heart disease is established. FUNDING: Seventh Framework Programme for Research and Technical Development (AtheroRemo and RiskyCAD), INTERREG IV Oberrhein Programme, Deutsche Nierenstiftung, Else-Kroener Fresenius Foundation, Deutsche Stiftung für Herzforschung, Deutsche Forschungsgemeinschaft, Saarland University, German Federal Ministry of Education and Research, Willy Robert Pitzer Foundation, and Waldburg-Zeil Clinics Isny

Riesgos y controversias en la construcción social del concepto de alimento saludable: el caso de la soja

Riscos e controvérsias na construção social do conceito de alimento saudável são discutidos, tendo a soja como objeto de estudo. Estudos dos impactos da soja sobre a saúde e da sojicultura sobre o meio socioambiental foram revisados para analisar as controvérsias científicas da pesquisa na área de soja e saúde humana, bem como seu contexto político e as repercussões socioambientais da sojicultura. Com base na Sociologia do Conhecimento Científico e na Sociologia Ambiental, argumenta-se que a fronteira entre o alimento saudável e o de risco é tênue e vulnerável a diferentes influências construídas reflexivamente. Destaca-se a importância de ampliar o conceito de alimento saudável para o de alimentação saudável, considerando sua dimensão cultural e socioambiental.Controversies and risks in the social construction of the concept of healthy food are discussed, using soybean as the object of study. Studies concerning the impacts of soy on human health and the effects of its cultivation on the social-environmental domain were reviewed to analyze the political context of the discussion surrounding soy and the socio-environmental repercussions of its cultivation. Based on the sociology of scientific knowledge and the environmental sociology, we identified a thin line between healthy and risky food, which is vulnerable to different reflexively constructed influences. It is important to broaden the concept of healthy food to healthy alimentation and to consider its cultural and social-environmental dimension.Riesgos y controversias en la construcción social del concepto de alimento saludable son discutidos, teniendo a la soja como objeto de estudio. Estudios de los impactos de la soja sobre la salud y de la sojicultura sobre el medio socioambiental fueron revisados para analizar las controversias científicas de la investigación en el área de soja y salud humana, así como su contexto político y las repercusiones socioambientales de la sojicultura. Con base en la Sociología del Conocimiento Científico y en la Sociología Ambiental, se argumenta que la frontera entre el alimento saludable y el de riesgo es tenue y vulnerable en diferentes influencias construidas reflexivamente. Se destaca la importancia de ampliar el concepto de alimento saludable para el de alimentación saludable, considerando su dimensión cultural y socioambiental.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP