Field emission current from surfaces under vacuum and at high field strengths can be reduced by the injection of gas into the evacuated volume. In this paper, the effects of H2 , He, N2 , and Ar on ...this “dark” current emitted from a tungsten carbide point cathode for 2 cm gap distance is studied. Exposure to any of these gases at pressures on the order of 10−3–10−2Pa was found to reduce the emission current by up to 90% with a time constant on the order of ∼1minute as compared to the current at 10−6Pa . The effect was strongly dependent on the gas nature, with Ar and N2 having larger effects at lower pressures than He and H2 . The reduction was reversible, with the current increasing to near its original value with a time constant on the order of ∼1–10minutes after pumping down. The effect of the gas remained in the absence of electric field, whatever the gas pressure. Mechanisms for these and related phenomena are discussed.
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CMK, CTK, FMFMET, IJS, NUK, PNG, UL, UM, UPUK
Being recalled for further diagnostic procedures after an abnormal screening mammogram (ASM) can evoke a high state anxiety with lowered quality of life (QoL). We examined whether these adverse ...psychological consequences are found in all women with benign breast disease (BBD) or are particular to women referred after ASM. In addition, the influence of the anxiety as a personality characteristic (trait anxiety) was studied. Between September 2002 and February 2010 we performed a prospective longitudinal study in six Dutch hospitals. Women referred after ASM or with a palpable lump in the breast (PL), who were subsequently diagnosed with BBD, were included. Before diagnosis (at referral) and during follow-up, questionnaires were completed examining trait anxiety (at referral), state anxiety
,
depressive symptoms (at referral, one, three and 6 months after diagnosis), and QoL (at referral and 12 months). Women referred after ASM (
N
= 363) were compared with women with PL (
N
= 401). A similar state anxiety score was found in both groups, but a lower psychological QoL score at 12 months was seen in the ASM group. In women with not-high trait anxiety those in the ASM group were more anxious with more depressive symptoms at referral, and reported impaired psychological QoL at referral and at 12 months compared with the PL group. No differences were found between ASM and PL in women with high trait anxiety, but this group scored unfavorably on anxiety, depressive symptoms and QoL compared with women with not-high trait anxiety. ASM evokes more anxiety and depressive symptoms and lowered QoL compared with women referred with PL, especially in women who are not prone to anxiety. Women should be fully informed properly about the risks and benefits of breast cancer screening programs. We recommend identifying women at risk of reduced QoL using a psychometric test.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The α,β-unsaturated carbonyl group is recognized as alert for mutagenicity, attributed to (1) its direct reaction with DNA, counteractable by glutathione (GSH), and (2) oxidative stress caused ...indirectly by GSH depletion. Accordingly, the α,β,γ,δ-unsaturated lactone patulin (PAT), a mycotoxin detected in fruits and products derived thereof, is known to induce gene, chromosome, and genome mutations in vitro, its mutagenicity correlating inversely with intracellular GSH levels. Thus, the reactivity of PAT against DNA bases and nucleosides in the absence and presence of GSH and glutathione
S
-transferases (GSTs) was investigated under cell-free conditions using HPLC mass spectrometry techniques for identification of reaction products. Adduct formation with all four nucleobases as well as with purine base nucleosides occurred even in the presence of GSH, revealing several adducts of PAT, mono- and disubstituted with nucleobases/nucleosides as well as novel GSH–PAT adducts. In addition, novel mixed GSH–PAT–nucleobase adducts were observed. These adducts exhibited a ketohexanoic acid-type structure of the PAT molecule, C6 substituted with GSH and linking C1 of PAT with nitrogens of nucleobases/nucleosides via an amide bond. Formation of GSH–PAT–adenine adducts was not prevented by GSTs, and excess of GSH needed to reduce their formation was higher than for PAT–adenine adducts. The formation of mixed GSH–DNA base adducts has not been described for PAT or any other α,β-unsaturated carbonyl before, although the reaction mechanism seems to be applicable to a variety of α,β-unsaturated carbonyls occurring in food and in the environment.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The isoflavone irilone is found in human plasma after ingestion of red clover-based dietary supplements, but information allowing safety assessment is rare. Here, data in support of the mutagenic ...potential of irilone in cultured V79 cells 1 are presented. These data include (i) a quantitative assessment of irilone in the culture medium during the cell culture experiments, (ii) changes in the mutation spectrum in cDNA of the hypoxanthine-guanine phosphoribosyltransferase locus of irilone-treated V79 cells, (iii) occurrence of karyorrhexis and apoptosis as well as (iv) number of micronucleated cells containing whole chromosomes or chromosomal fragments. Also exemplary micrographs, used for the fluorescence microscopic assessment of (iii) and (iv) are presented.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Breast cancer etiology is associated with both proliferation and DNA damage induced by estrogens. Breast cancer risk factors (BCRF) such as body mass index (BMI), smoking, and intake of ...estrogen-active drugs were recently shown to influence intratissue estrogen levels. Thus, the aim of the present study was to investigate the influence of BCRF on estrogen-induced proliferation and DNA damage in 41 well-characterized breast glandular tissues derived from women without breast cancer. Influence of intramammary estrogen levels and BCRF on estrogen receptor (ESR) activation, ESR-related proliferation (indicated by levels of marker transcripts), oxidative stress (indicated by levels of
GCLC
transcript and oxidative derivatives of cholesterol), and levels of transcripts encoding enzymes involved in estrogen biotransformation was identified by multiple linear regression models. Metabolic fluxes to adducts of estrogens with DNA (E-DNA) were assessed by a metabolic network model (MNM) which was validated by comparison of calculated fluxes with data on methoxylated and glucuronidated estrogens determined by GC– and UHPLC–MS/MS. Intratissue estrogen levels significantly influenced ESR activation and fluxes to E-DNA within the MNM. Likewise, all BCRF directly and/or indirectly influenced ESR activation, proliferation, and key flux constraints influencing E-DNA (i.e., levels of estrogens,
CYP1B1
,
SULT1A1, SULT1A2
, and
GSTP1
). However, no unambiguous total effect of BCRF on proliferation became apparent. Furthermore, BMI was the only BCRF to indeed influence fluxes to E-DNA (via congruent adverse influence on levels of estrogens,
CYP1B1
and
SULT1A2
).
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Because of its assumed role in breast cancer etiology, estrogen biotransformation (and interaction of compounds therewith) has been investigated in human biospecimens for decades. However, little ...attention has been paid to the well-known fact that large inter-individual variations exist in the proportion of breast glandular (GLT) and adipose (ADT) tissues and less to adequate tissue characterization. To assess the relevance of this, the present study compares estrogen biotransformation in GLT and ADT. GLT and ADT were isolated from 47 reduction mammoplasty specimens derived from women without breast cancer and were characterized histologically and by their percentages of oil. Levels of 12 unconjugated and five conjugated estrogens were analyzed by GC- and UHPLC–MS/MS, respectively, and levels of 27 transcripts encoding proteins involved in estrogen biotransformation by Taqman
®
probe-based PCR. Unexpectedly, one-third of specimens provided neat GLT only after cryosection. Whereas 17β-estradiol, estrone, and estrone-3-sulfate were detected in both tissues, estrone-3-glucuronide and 2-methoxy-estrone were detected predominately in GLT and ADT, respectively. Estrogen levels as well as ratios 17β-estradiol/estrone and estrone-3-sulfate/estrone differed significantly between GLT and ADT, yet less than between individuals. Furthermore, estrogen levels in GLT and ADT correlated significantly with each other. In contrast, levels of most transcripts encoding enzymes involved in biotransformation differed more than between individuals and did not correlate between ADT and GLT. Thus, mixed breast tissues (and plasma) will not provide meaningful information on local estrogen biotransformation (and interaction of compounds therewith) whereas relative changes in 17β-estradiol levels may be investigated in the more abundant ADT.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
•The isoflavone irilone was tested in cultured Chinese hamster lung fibroblast V79, and…•Inhibited proliferation and did not increase the mutant frequency in the HPRT assay.•Altered significantly the ...mutation spectrum.•Significantly increased micronuclei with chromosomal fragments.•Disrupted mitosis and significantly increased micronuclei with whole chromosomes.
After consumption of red clover-based dietary supplements, plasma concentrations of the isoflavone irilone (IRI) equal that of the well-investigated daidzein. Since some isoflavones are genotoxic, the potential of IRI to induce mutations was investigated.
Gene mutations were determined by hypoxanthine-guanine phosphoribosyltransferase (HPRT) assay and sequencing of mutant cDNA, chromosome and genome mutations by micronucleus assay complemented by immunochemical staining of centromere proteins and microtubules in cultured V79 cells. Cell proliferation was monitored by electronic cell counting, flow cytometry and fluorescence microscopy.
IRI did not affect the mutant frequency in the Hprt locus but altered the mutation spectrum by increasing the proportion of deletions and decreasing that of base pair substitutions. Induction of chromosome mutations was supported by a slight but significant increase in the number of micronucleated cells containing chromosomal fragments despite activation of three cell cycle checkpoints possibly interfering with micronuclei formation. Moreover, IRI exhibited a strong aneugenic potential characterized by disrupted mitotic spindles, mitotic arrest, and asymmetrical cell divisions leading to chromosome loss, nuclear fragmentation as well as mitotic catastrophe. Thus, IRI might be another isoflavone to be taken into account in safety assessment of dietary supplements.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Understanding intramammary estrogen homeostasis constitutes the basis of understanding the role of lifestyle factors in breast cancer etiology. Thus, the aim of the present study was to identify ...variables influencing levels of the estrogens present in normal breast glandular and adipose tissues (GLT and ADT, i.e., 17β-estradiol, estrone, estrone-3-sulfate, and 2-methoxy-estrone) by multiple linear regression models. Explanatory variables (exVARs) considered were (a) levels of metabolic precursors as well as levels of transcripts encoding proteins involved in estrogen (biotrans)formation, (b) data on breast cancer risk factors (i.e., body mass index, BMI, intake of estrogen-active drugs, and smoking) collected by questionnaire, and (c) tissue characteristics (i.e., mass percentage of oil, oil%, and lobule type of the GLT). Levels of estrogens in GLT and ADT were influenced by both extramammary production (menopausal status, intake of estrogen-active drugs, and BMI) thus showing that variables known to affect levels of circulating estrogens influence estrogen levels in breast tissues as well for the first time. Moreover, intratissue (biotrans)formation (by aromatase, hydroxysteroid-17beta-dehydrogenase 2, and beta-glucuronidase) influenced intratissue estrogen levels, as well. Distinct differences were observed between the exVARs exhibiting significant influence on (a) levels of specific estrogens and (b) the same dependent variables in GLT and ADT. Since oil% and lobule type of GLT influenced levels of some estrogens, these variables may be included in tissue characterization to prevent sample bias. In conclusion, evidence for the intracrine activity of the human breast supports biotransformation-based strategies for breast cancer prevention. The susceptibility of estrogen homeostasis to systemic and tissue-specific modulation renders both beneficial and adverse effects of further variables associated with lifestyle and the environment possible.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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