Coordinated effects of sequence variation on DNA binding, chromatin structure, and transcription.

DNA sequence variation has been associated with quantitative changes in molecular phenotypes such as gene expression, but its impact on chromatin states is poorly characterized. To understand the interplay between chromatin and genetic control of gene regulation, we quantified allelic variability in transcription factor binding, histone modifications, and gene expression within humans. We found abundant allelic specificity in chromatin and extensive local, short-range, and long-range allelic coordination among the studied molecular phenotypes. We observed genetic influence on most of these phenotypes, with histone modifications exhibiting strong context-dependent behavior. Our results implicate transcription factors as primary mediators of sequence-specific regulation of gene expression programs, with histone modifications frequently reflecting the primary regulatory event.

Circulating estrogens and progesterone during primiparous pregnancies and risk of maternal breast cancer.

Pregnancy reduces maternal risk of breast cancer in the long term, but the biological determinants of the protection are unknown. Animal experiments suggest that estrogens and progesterone could be involved, but direct human evidence is scant. A case-control study (536 cases and 1,049 controls) was nested within the Finnish Maternity Cohort. Eligible were primiparous women who delivered at term a singleton offspring before age 40. For each case, two individually matched controls by age (±6 months) and date of sampling (±3 months) were selected. Estradiol, estrone and progesterone in first-trimester serum were measured by high-performance liquid chromatography tandem mass spectrometry and sex-hormone binding globulin (SHBG) by immunoassay. Odds ratios (OR) and 95% confidence intervals (CI) were estimated through conditional logistic regression. In the whole study population there was no association of breast cancer with any of the studied hormones. In analyses stratified by age at diagnosis, however, estradiol concentrations were positively associated with risk of breast cancer before age 40 (upper quartile OR, 1.81; CI, 1.08-3.06), but inversely associated with risk in women who were diagnosed ≥age 40 (upper quartile OR, 0.64; CI, 0.40-1.04), p(interaction) 0.004. Risk estimates for estrone mirrored those for estradiol but were less pronounced. Progesterone was not associated with risk of subsequent breast cancer. Our results provide initial evidence that concentrations of estrogens during the early parts of a primiparous pregnancy are associated with maternal risk of breast cancer and suggest that the effect may differ for tumors diagnosed before and after age 40.

Insulin-like growth factor-I and C-reactive protein during pregnancy and maternal risk of non-epithelial ovarian cancer: a nested case-control study.

BACKGROUND: Insulin-like growth factor-I (IGF-I) and C-reactive protein (CRP) may be positively associated with the risk of epithelial ovarian cancer (EOC) but no previous studies have investigated their associations with non-epithelial ovarian cancers (NEOC). METHODS: A case-control study was nested within the Finnish Maternity Cohort. Case subjects were 58 women diagnosed with sex cord-stromal tumors (SCST) and 30 with germ cell tumors (GCT) after recruitment. Control subjects (144 for SCST and 74 for GCT) were matched for age, parity, and date of blood donation of the index case. RESULTS: Doubling of IGF-I concentration was not related to maternal risk of either SCST (OR 0.97, 95% CI 0.58-1.62) or GCT (OR 1.13, 95% CI 0.51-2.51). Similarly, doubling of CRP concentrations was not related to maternal risk of either SCST (OR 1.10, 95% CI 0.85-1.43) or GCT (OR 0.93, 95% CI 0.68-1.28). CONCLUSIONS: Pre-diagnostic IGF-I and CRP concentrations during the first trimester of pregnancy were not associated with increased risk of NEOC in the mother. Risk factors for NEOC may differ from those of EOC.

Circulating insulin-like growth factor-I in pregnancy and maternal risk of breast cancer.

BACKGROUND: Elevated serum concentrations of insulin-like growth factor (IGF)-1 have been associated with increased risk of breast cancer. Previously, we reported a similar association in samples obtained during pregnancy. The current study was conducted to further characterize the association of IGF-1 during pregnancy with maternal breast cancer risk. METHODS: A case-control study was nested within the Finnish Maternity Cohort. The study was limited to primiparous women less than 40 years of age, who donated blood samples during early (median, 12 weeks) pregnancy and delivered a single child at term. Seven hundred and nineteen women with invasive breast cancer were eligible. Two controls (n = 1,434) were matched to each case on age and date at blood donation. Serum IGF-1 concentration was measured using an Immulite 2000 analyzer. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI).RESULTS: No significant associations were observed between serum IGF-1 concentrations and breast cancer risk in both the overall analysis (OR 1.08 (95% CI 0.80-1.47) and in analyses stratified by histological subtype, lag-time to cancer diagnosis, age at pregnancy or age at diagnosis.CONCLUSIONS: There was no association between IGF-1 and maternal breast cancer risk during early pregnancy in this large nested case-control study.Impact:Serum IGF-1 concentrations during early pregnancy may not be related to maternal risk of breast cancer.

Lektüren im intermedialen Dialog

Die Studie geht davon aus, dass das Zusammenspiel von Text und Bild auf dem Prinzip der Dialogizität und Komplementarität zwischen zwei einander fremden Systemen gründet. Texte generieren Bilder, Bilder evozieren Narrationen. Im Zusammentreffen zwischen den beiden Medien werden Energien freigesetzt und ein Mehr an Bedeutung entsteht. Sprache und Bild können rivalisieren oder sich gegenseitig inspirieren, einander ergänzen oder ersetzen, ineinandergreifen oder kontrastieren. Abhängig von der jeweiligen Inszenierung, von der visuellen Anordnung, von inhaltlichen llbereinstimmungen oder formalen Annäherungen setzen die Medien divergierende oder kongruierende Systeme in Szene. Aus dem weiten Feld der intermedialen Verknüpfungen von Text und Bild wählt die Studie eine Reihe von Text-Bild-Kombinationen, in denen skripturale und piktoriale Elemente nebeneinander inszeniert werden und in ihrem prozesshaften Zusammenwirken den Rezipienten zur Lekture von unterschiedlichen narrativen Möglichkeiten herausfordern: Max Ernsts Collageroman Rêve d'une petite fille qui voulut entrer au CarmeI ; Peter Weiss' Text- Bild-Ensemble Der Schatten des Kòrpers des Kutschers, Le rêve de Paul Delvaux, ein Text- Bild-Projekt, für das der Nouveau Romancier Michel Butor eine Erzählung zu einer Reihe von Bildern des Surrealisten Paul Delvaux verfasst ; die Ballade Minotaurus von Friedrich Dürrenmatt , sowie Der Schachspieler, eine Reaktion des Illustrators Hannes Binder auf einen posthum erschienenen Text Durrenmatts . In fünf Einzellektüren und fünf Kapiteln wird der Frage nachgegangen wie sich Narration im Text-Bild-Spiegel generiert und welche Rolle der Lektüreakt dabei spielt. Dabei interessieren die Werke als vergleichbare, aber heterogene Kombinationsformen von Text und Bild. Im Zentrum der Analysen stehen die Darstellung von Raum- und Zeitelementen, die sprachlichen Erzählinstanzen, die das Zusammenspiel von Stimme und Körper konstituieren, sowie der Informationstrager Buch als medialer wie auch materieller Gegenstand.

Momentous

Hannes Schmid, photography, installation / new média, interactivity, cultural exchange, art in a global context, Momentous.

Identification and removal of low-complexity sites in allele-specific analysis of ChIP-seq data.

MOTIVATION: High-throughput sequencing technologies enable the genome-wide analysis of the impact of genetic variation on molecular phenotypes at unprecedented resolution. However, although powerful, these technologies can also introduce unexpected artifacts. Results: We investigated the impact of library amplification bias on the identification of allele-specific (AS) molecular events from high-throughput sequencing data derived from chromatin immunoprecipitation assays (ChIP-seq). Putative AS DNA binding activity for RNA polymerase II was determined using ChIP-seq data derived from lymphoblastoid cell lines of two parent-daughter trios. We found that, at high-sequencing depth, many significant AS binding sites suffered from an amplification bias, as evidenced by a larger number of clonal reads representing one of the two alleles. To alleviate this bias, we devised an amplification bias detection strategy, which filters out sites with low read complexity and sites featuring a significant excess of clonal reads. This method will be useful for AS analyses involving ChIP-seq and other functional sequencing assays.

Human chorionic gonadotropin in pregnancy and maternal risk of breast cancer.

Full-term pregnancies are associated with long-term reductions in maternal risk of breast cancer, but the biological determinants of the protection are unknown. Experimental observations suggest that human chorionic gonadotropin (hCG), a major hormone of pregnancy, could play a role in this association. A case-control study (242 cases and 450 controls) nested within the Northern Sweden Maternity Cohort included women who had donated a blood sample during the first trimester of a first full-term pregnancy. Total hCG was determined on Immulite 2000 analyzer. Odds ratios (OR) and 95% confidence intervals (CI) were estimated through conditional logistic regression. Maternal breast cancer risk decreased with increasing hCG (upper tertile OR, 0.67; CI, 0.46-0.99), especially for pregnancies before age 25 (upper tertile OR, 0.41; CI, 0.21-0.80). The association diverged according to age at diagnosis: risk was reduced after age 40 (upper tertile OR, 0.60; CI, 0.39-0.91) and seemed to increase before age 40 (upper tertile OR, 1.78; CI, 0.72-4.38). Risk was reduced among those diagnosed 10 years or longer after blood draw (upper tertile OR, 0.60; CI, 0.40-0.90), but not so among those diagnosed within 10 years (upper tertile OR, 4.33; CI, 0.86-21.7). These observations suggest that the association between pregnancy hCG and subsequent maternal risk of breast cancer is modified by age at diagnosis. Although the hormone seems to be a determinant of the reduced risk around or after age 50, it might not confer protection against, or it could even increase the risk of, cancers diagnosed in the years immediately following pregnancy.

Determinants of maternal sex steroids during the first half of pregnancy.

OBJECTIVE: To examine the associations of maternal and child characteristics with early pregnancy maternal concentrations of testosterone, androstenedione, progesterone, 17-hydroxyprogesterone, and estradiol (E2). METHODS: We analyzed these hormones among 1,343 women with singleton pregnancies who donated serum samples to the Finnish Maternity Cohort from 1986 to 2006 during the first half of pregnancy (median 11 weeks). The associations of maternal and child characteristics with hormone concentrations were investigated by correlation and multivariable regression. RESULTS: Women older than age 30 years had lower androgen and E2 but higher progesterone concentrations than women younger than that age. Multiparous women had 14% lower testosterone, 11% lower androstenedione and 17-hydroxyprogesterone, 9% lower progesterone, and 16% lower E2 concentrations compared with nulliparous women (all P<.05). Smoking mothers had 11%, 18%, and 8% higher testosterone, androstenedione, and 17-hydroxyprogesterone levels, respectively, but 10% lower progesterone compared with nonsmoking women (all P<.05). E2 concentrations were 9% higher (P<.05) among women with a female fetus compared with those with a male fetus. CONCLUSION: Parity, smoking, and, to a lesser extent, maternal age and child sex are associated with sex steroid levels during the first half of a singleton pregnancy. The effects of smoking on the maternal hormonal environment and the possible long-term deleterious consequences on the fetus deserve further evaluation. LEVEL OF EVIDENCE: II.

Elaborated Literary Violence: Genre and Ideology of the Two Stories I Sam 22,6-23 and II Sam 21,1-14

The present article focuses on two stories dealing with acts of big blood shed. I Sam 22,6-23 relates the massacre of the priests of Nob; II Sam 21,1-14 is about the execution of seven descendents of Saul, as atonement for Saul's attempt to exterminate the Gibeonites. Most researchers consider both stories or at least certain parts of them old.1 For both stories few verses are regarded as secondary. In this paper I try to reassess the analysis of these stories and will point to indices favoring a late date of origin for both of them. They concern the language in use, intertextual connections and particular motifs. A further indication consists in the fact that the reported events of the stories lack significant resonance in the corpus of the Hebrew Bible. There are only two texts, I Sam 2,33 and Ps 52,2, which allude or refer to I Sam 22,6-23.With regard to the importance of the related events and acts this silence in the Biblical context is astonishing. Interestingly, also in the Book of Chronicles one does not find any allusions to these stories. This raises the question whether the latter were composed after the formation of the book of Chronicles.