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- Beral, V, et al.
(författare)
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Alcohol, tobacco and breast cancer - collaborative reanalysis of individual data from 53 epidemiological studies, including 58515 women with breast cancer and 95067 women without the disease
- 2002
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Ingår i: British Journal of Cancer. - : Springer Science and Business Media LLC. - 1532-1827 .- 0007-0920. ; 87, s. 1234-45
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Tidskriftsartikel (refereegranskat)abstract
- Alcohol and tobacco consumption are closely correlated and published results on their association with breast cancer have not always allowed adequately for confounding between these exposures. Over 80% of the relevant information worldwide on alcohol and tobacco consumption and breast cancer were collated, checked and analysed centrally. Analyses included 58515 women with invasive breast cancer and 95067 controls from 53 studies. Relative risks of breast cancer were estimated, after stratifying by study, age, parity and, where appropriate, women's age when their first child was born and consumption of alcohol and tobacco. The average consumption of alcohol reported by controls from developed countries was 6.0 g per day, i.e. about half a unit/drink of alcohol per day, and was greater in ever-smokers than never-smokers, (8.4 g per day and 5.0 g per day, respectively). Compared with women who reported drinking no alcohol, the relative risk of breast cancer was 1.32 (1.19 - 1.45, P < 0.00001) for an intake of 35 - 44 g per day alcohol, and 1.46 (1.33 - 1.61, P < 0.00001) for greater than or equal to 45 g per day alcohol. The relative risk of breast cancer increased by 7.1% (95% CI 5.5-8.7%; P<0.00001) for each additional 10 g per day intake of alcohol, i.e. for each extra unit or drink of alcohol consumed on a daily basis. This increase was the same in ever-smokers and never-smokers (7.1 % per 10 g per day, P < 0.00001, in each group). By contrast, the relationship between smoking and breast cancer was substantially confounded by the effect of alcohol. When analyses were restricted to 22 255 women with breast cancer and 40 832 controls who reported drinking no alcohol, smoking was not associated with breast cancer (compared to never-smokers, relative risk for ever-smokers= 1.03, 95% CI 0.98 - 1.07, and for current smokers=0.99, 0.92 - 1.05). The results for alcohol and for tobacco did not vary substantially across studies, study designs, or according to 15 personal characteristics of the women; nor were the findings materially confounded by any of these factors. If the observed relationship for alcohol is causal, these results suggest that about 4% of the breast cancers in developed countries are attributable to alcohol. In developing countries, where alcohol consumption among controls averaged only 0.4 g per day, alcohol would have a negligible effect on the incidence of breast cancer. In conclusion, smoking has little or no independent effect on the risk of developing breast cancer; the effect of alcohol on breast cancer needs to be interpreted in the context of its beneficial effects, in moderation, on cardiovascular disease and its harmful effects on cirrhosis and cancers of the mouth, larynx, oesophagus and liver. (C) 2002 Cancer Research UK.
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| 3. |
- Cao, Han, et al.
(författare)
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Fabrication of 10 nm enclosed nanofluidic channels
- 2002
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Ingår i: Applied Physics Letters. - : AIP Publishing. - 0003-6951 .- 1077-3118. ; 81:1, s. 174-176
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Tidskriftsartikel (refereegranskat)abstract
- We made uniform arrays of nanometer scale structures using nanoimprint lithography over large areas (100 mm wafers). The nanofluidic channels were further narrowed and sealed by techniques that are based on nonuniform deposition. The resulting sealed channels have a cross section as small as 10 nm by 50 nm, of great importance for confining biological molecules into ultrasmall spaces. These techniques can be valuable fabrication tools for Nanoelectromechanical Systems and Micro/Nano Total Analysis Systems.
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| 5. |
- Wei, Yu-Dan, 1963-
(författare)
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Tryptophan photoproducts : regulation of CYP1A1 transcription and modulation of cell growth
- 2001
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor involved in the regulation of many drug-metabolizing enzymes. The regulation of cytochrome P4501A1 (CYP1A1) has been most intensively studied. A large number of highly toxic environmental compounds, such as dioxins and PAHs are ligands for the AhR and give rise to CYP1A1 induction. Also, UV-light induces CYP1A1. Accumulating data indicate the existence of endogenous ligands for the AhR which, however, remain to be identified. UV-irradiation of the amino acid tryptophan produces photoproducts that possess very high binding affinities for the AhR. These photoproducts have therefore been suggested as possible endogenous ligands for the AhR. The biologically most active compound has been identified as 6-formylindolo[3,2-b]carbazole (FICZ).The aim of the present study was to further investigate these compounds, focusing on FICZ , with respect to the regulation of CYP1A1 transcription and the modulation of cell growth, as well as their possible formation in biological systems. The study was carried out using different cultured mammalian cells, including two types of human cells (a keratinocyte cell line and peripheral blood mononuclear cells) as well as mouse hepatoma Hepa-1 cell lines.Experiments with dose- and time-dependent induction and comparison with other inducers showed that FICZ is a potent inducer of CYP1A1 mRNA and that the induction appears very rapidly and is transient in nature. Metabolism studies using Aroclor-induced rat liver S9 and S9 from mouse Hepa-1 cells with HPLC analysis revealed that the transient induction of CYP1A1 mRNA by FICZ was due to its metabolism by the CYP1A1 enzyme. These results, together with gene expression studies, indicated that the level of CYP1A1 mRNA induced by FICZ is auto-negatively controlled by the induced CYP1A1 enzyme and that FICZ thus behaves as an endogenous substrate involved in the autoregulation mechanism. Additionally, the studies in human cells showed that tryptophan facilitates UV-induced CYP1A1 gene expression, indicating that the tryptophan photoproducts may be formed in the cells upon UV-irradiation.The role of CYP1A1 in the regulation of cell growth was characterized. Observations of a slower cell proliferation in wild-type Hepa-1 cells compared to cells lacking CYP1A1 activity indicated that CYP1A1 could reduce cell growth most likely by metabolizing an endogenous substrate that stimulates growth. The results were confirmed by restoring the CYP1A1 activity in the deficient cells by transfection. FICZ was shown to enhance cell proliferation and modulate the expression of genes involved in signal transduction.In conclusion, the results provide evidence for tryptophan-derived substances as being endogenous AhR ligands which autoregulate CYP1A1 transcription and activate cell growth. These findings will form a basis for a better understanding of the physiological processes that are regulated by the AhR and CYP1A1 and thereby also a better understanding of the mechanisms by which xenobiotics disrupt these processes.
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- Yu, Zhengquan, 1965-, et al.
(författare)
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3-Aminopropanal is a lysosomotropic aldehyde that causes oxidative stress and apoptosis by rupturing lysosomes
- 2003
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Ingår i: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS). - : Wiley-Blackwell. - 0903-4641 .- 1600-0463. ; 111:6, s. 643-652
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Tidskriftsartikel (refereegranskat)abstract
- During cerebral ischemia and following trauma, potent cytotoxic polyamine-derived aminoaldehydes form, diffuse, and damage adjacent tissues not directly subjected to the initial insult. One such aldehyde is 3-aminopropanal (3-AP). The mechanisms by which such a small aldehydic compound is excessively cytotoxic have been unclear until recently when we showed that 3-AP, having the structure of a weak lysosomotropic base, concentrates within the acidic vacuolar compartment and causes lysosomal rupture that, in turn, induces caspase activation and apoptotic cell death. Here, using cultured J774 cells and 3-AP as a way to selectively burst lysosomes, we show that moderate lysosomal rupture induces a transient wave of oxidative stress. The start of this oxidative stress period is concomitant with a short period of enhanced mitochondrial membrane potential that later fades and is replaced by a decreased potential before the oxidative stress diminishes. The result of the study suggests that oxidative stress, which has often been described during apoptosis induced by agonists other than oxidative stress per se, may be a consequence of lysosomal rupture with direct and/or indirect effects on mitochondrial respiration and electron transport causing a period of passing enhanced formation of reactive oxygen species.
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| 7. |
- Zhengquan, Yu, 1965-, et al.
(författare)
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Human neuroblastoma (SH-SY5Y) cells are highly sensitive to the lysosomotropic aldehyde 3-aminopropanal
- 2004
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Ingår i: Brain Research. - : Elsevier BV. - 0006-8993 .- 1872-6240. ; 1016:2, s. 163-169
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Tidskriftsartikel (refereegranskat)abstract
- 3-Aminopropanal (3-AP), a degradation product of polyamines such as spermine, spermidine and putrescine, is a lysosomotropic small aldehyde that causes apoptosis or necrosis of most cells in culture, apparently by inducing moderate or extensive lysosomal rupture, respectively, and secondary mitochondrial changes. Here, using the human neuroblastoma SH-SY5Y cell line, we found simultaneous occurrence of apoptotic and necrotic cell death when cultures were exposed to 3-AP in concentrations that usually are either nontoxic, or only cause apoptosis. At 30 mM, but not at 10 mM, the lysosomotropic base and proton acceptor NH3 completely blocked the toxic effect of 3-AP, proving that 3-AP is lysosomotropic and suggesting that the lysosomal membrane proton pump of neuroblastoma cells is highly effective, creating a lower than normal lysosomal pH and, thus, extensive intralysosomal accumulation of lysosomotropic drugs. A wave of internal oxidative stress, secondary to changes in mitochondrial membrane potential, followed and gave rise to further lysosomal rupture. The preincubation of cells for 24 h with a chain-breaking free radical-scavenger, α-tocopherol, before exposure to 3-AP, significantly delayed both the wave of oxidative stress and the secondary lysosomal rupture, while it did not interfere with the early 3-AP-mediated phase of lysosomal break. Obviously, the reported oxidative stress and apoptosis/necrosis are consequences of lysosomal rupture with ensuing release of lysosomal enzymes resulting in direct/indirect effects on mitochondrial permeability, membrane potential, and electron transport. The induced oxidative stress seems to act as an amplifying loop causing further lysosomal break that can be partially prevented by α-tocopherol. Perhaps secondary brain damage during a critical post injury period can be prevented by the use of drugs that temporarily raise lysosomal pH, inactivate intralysosomal 3-AP, or stabilize lysosomal membranes against oxidative stress.
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