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M.-A. von Mach
J. G. Hengstler
Leibniz Research Centre for Working Environment and Human Factors
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L. S. Weilemann, Mainz, Germany
I. Ishibashi, Tokyo, Japan
P. Micke, Uppsala, Sweden
J. Timmer, Freiburg, Germany
A. Winterpacht, Erlangen, Germany
B. C. Behera, Pune, India

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A Role for Integrin avß3 in Invasion Activity of Highly Metastatic Syrian Hamster Fibroblasts
(2004-12-09) Berman, A. E.; Kozlova, N. E.; Morozevich, G. E.
The expression of extracellular matrix (ECM) specific receptors, integrins, was investigated in two closely related strains of oncogenically transformed fibroblasts drastically differing in spontaneous metastasizing. The highly metastatic cells (HM) were shown to express in their surface membranes much higher levels of collagen/vitronectin-specific integrin avß3, as compared to their lowly metastatic counterparts (LM). Inhibition of the avß3-mediated signal transduction strongly reduced the in vitro invasiveness of HM, whereas stimulation of avß3 signaling markedly augmented their invasive activity. The data obtained provide a direct evidence for implication of avß3 integrin in invasive phenotype of the oncotransformed fibroblasts.
Cellular Characterization of SARS Coronavirus Nucleocapsid
(2004-11-01) Choi, Yook-Wah; Fielding, Burtram; Goh, Phuay-Yee; Hong, Wanjin; Lim, Seng Gee; Ooi, Eng-Eong; Shuo, Shen; Tan, Timothy H. P.; Tan, Yee-Joo
The Severe and Acute Respiratory Syndrome coronavirus (SARS CoV) is a newly-emerged virus that caused an outbreak of atypical pneumonia in the winter of 2002-2003. Polyclonal antibodies raised against the nucleocapsid (N) of the SARS CoV showed the localization of N to the cytoplasm and the nucleolus in virus-infected and N-expressing Vero E6 cells. Like other coronavirus N proteins, the SARS N is probably a phosphoprotein. N protein expressed in mammalian cells is apparently able to "spread" to neighboring cells. For N to spread to neighboring cells, it must be exported out of the expressing cells. This is shown by the immunoprecipitation of N from the culture medium of a stable cell line expressing myc-N. Deletion studies showed that the 27 kD C-terminal domain of N (C1/2) is the minimal region of N that can spread to other cells. The nucleolar localization and spreading of N are artefacts of fixation, reminiscent of other protein-transduction domain (PTD)-containing proteins.
The Absence of Prion-Like Infectivity in Mice expressing Prion Protein-Like Protein
(2004-10-28) Atarashi, Ryuichiro; Katamine, Shigeru; Sakaguchi, Suehiro; Shigematsu, Kazuto
Cellular prion protein, PrP^C, undergoes pathogenic structural conversion into the proteinase K (PK)-resistant isoform, PrP^Sc, to constitute a nucleic acid-free infectious agent, so called a prion. To determine whether a recently identified PrP-like protein, named PrPLP/Dpl, could also be transformed to a prion-like protein, we intracerebrally inoculated a mouse-adapted Fukuoka-1 prion into Ngsk and Zrch I mice either homozygously (Prnp^0/0) or heterozygously (Prnp^0/+) devoid of PrP^C. Only the former expressed PrPLP/Dpl ectopically in the brains, particularly in neurons. Ngsk Prnp^0/+ and Zrch I Prnp^0/+ mice similarly developed the disease. The diseased Ngsk Prnp0/+ mice transmitted the disease to the mice expressing PrP^C but not to the mice expressing PrPLP/Dpl, showing abundant accumulation of PrP^Sc but not PK-resistant PrPLP/Dpl in the brains. Moreover, the inoculated Ngsk Prnp^0/0 mice neither developed the disease nor produced any infectivity transmissible to PrPLP/Dpl-expressing mice. These results indicate that PrPLP/Dpl have no potential to undergo pathogenic conversion to form a prion-like infectious particle.
Expression of Integrins, Anchorage Dependent Apoptosis and Invasiveness of Multidrug Resistant Human Breast Carcinoma Cells
(2004-10-11) Berman, A. E.; Chubukina, A. N.; Kozlova, N. I.; Morozevich, G. E.; Shtil, A. A.
The aim of the study was to investigate the role of integrins in anchorage dependent apoptosis (anoikis) and in vitro invasion of human breast cancer cell line MCF-7 and its multidrug resistant subline MCF-7Dox. Acquisition of MDR was associated with markedly decreased expression of collagen specific a2ß1 and avß3 integrins, laminin specific a3ß1 and a6ß1 receptors and dramatic up-regulation of fibronectin specific a5ß1 integrin. The MDR subline was substantially more resistant to anoikis than their wild type counterparts. Furthermore, MCF-7Dox cells secreted MMP-9 collagenase and invaded Matrigel. We demonstrate for the first time that stimulation of ß1 integrin signaling strongly sensitizes MCF-7 cells to anoikis.
Smoking, genetic polymorphisms of glutathione S-transferases and biological indices of inflammation and cellular adhesion in the STANISLAS study
(2004-09-13) Bolt, Hermann M.; Habdous, Mohammed; Haddy, Nadia; Herbeth, Bernard; Lambert, Daniel; Ponthieux, Anne; Siest, Gérard; Thier, Ricarda; Visvikis, Sophie
A recent clinical study has focused on: 1- the interaction between genetic variants of glutathione S-transferases M1 and T1 (GSTM1 and GSTT1) and smoking on the risk of cardiovascular diseases, 2- the potential capacity of GSTM1 and T1 genotypes in modifying the effect of smoking on inflammation and endothelial function. In this study, we investigated whether carriage of these 2 polymorphisms altered the smoking impact on biological indices of inflammation and cellular adhesion. White blood cell count (WBC), albumin, C-reactive protein (CRP), interleukine-6 (IL-6), tumor necrosis factor-alpha (TNF-a), L-selectin, E-selectin, P-selectin and intracellular adhesion molecule-1 (ICAM-1) were measured in 189 non-smokers and 76 smokers (aged 20-55 years) genotyped for the GSTM1 and T1 polymorphisms. Accounting for age and sex, smokers lacking GSTM1 had a higher WBC count, CRP and ICAM-1 levels as compared to the other groups; interaction term between smoking and genotype being significant (p=0.05). Conversely, non-smokers lacking GSTM1 had a higher levels of TNF-a; the test for interaction being significant (p=0.05). No significant interaction was found between smoking and GSTT1 genotypes, considering the 9 biological indices. However, significantly lower levels of IL-6 were noticed for non-smokers with GSTT1-0 null allele (p=0.05). Our study confirms previous results showing that GSTM1 polymorphism could modulate the interrelationships between smoking and biological markers of inflammation and endothelial function.
The first experience with a mini-rating scale for the assessment of sexual dysfunction and life-satisfaction in depressed patients in the practice
(2004-08-11) Antonioli, D.; Bischof, R.; Delini-Stula, A.; Fauchère, P.-A.; Mullor, R.
Even though many scales for the assessment of sexual dysfunction have been recently developed, most of them are suitable rather for the research purpose in clinical trials than to routine interviews in a daily, private practice. We report here the first experience with a simple, semi-quantitative scale for parallel assessment of sexual dysfunction and life-satisfaction (considered to globally reflect the quality of life), which was tested in depressed patients treated in the psychiatric, private practice setting. A combined Sexual Dysfunction(SD-S) and Life-Satisfaction Scale (LS-S), was constructed based on previous interviews with patients. Both consisted of 4-items, assumed to represent core elements of sexual function and individual well-being. The scales were applied to depressed patients treated with any of the SSRIs or with moclobemide, a reversible and selective MAO-A inhibitor. These two treatments were selected for testing the scales because it is known that SSRIs can induce or exacerbate them and moclobemide does not seem to affect them. The selection of treatment modality in this study was, however, entirely at the discretion of the physician. The assessments were done during 3 visits (at baseline, after 2 months and after 4 months). The results of this exploratory trial, testing the applicability, acceptance and utility of a combined mini- SD-S- and LS-S- scale, in 62 depressed patients, showed that the scale: a) was simple to use and well accepted by physicians and patients, b) was a suitable instrument for the practicing physician to control the success of the treatment and c) was sensitively assessing the presence and severity of sexual dysfunction.
Susceptible Amino Acid Pairs in Variants in Human Collagen alpha1(III) Chain Precursor
(2004-05-28) Wu, Guang; Yan, Shaomin
In a previous study we presented a technique to differentiate between randomly predictable and randomly unpredictable amino acid pairs. We have shown that all of 95 variants in human collagen alpha1(I) chain precursor (CA11) occurred at randomly unpredictable amino acid pairs. To study whether this is unique for the human collagen alpha1(I) chain precursor (CA11) or whether this is a more general principle we examined another human collagen precursor, the human collagen alpha1(III) chain precursor (CA13), in which 106 variants have been documented. Interestingly, all of 106 variants occurred at randomly unpredictable amino acid pairs in human CA13. In conclusion, the observation that randomly unpredictable amino acid pairs are more susceptible to variation seems to be a more general principle for human collagen chain precursor proteins.
Amino Acid Pairs Sensitive to Variants in Human Collagen alpha1(I) Chain Precursor
(2004-04-26) Wu, Guang; Yan, Shaomin
In this data-based theoretical analysis, we use our random approach to analyse amino acid pairs in human collagen a 1(I) chain precursor (CA11) in order to determine which amino acid pairs are more sensitive to 95 variants with missense mutant in human CA11 protein. The rationale of this study is based on our hypothesis and previous findings that harmful variance is more likely to occur at randomly unpredictable amino acid pair position rather than at randomly predictable positions. This is reasonable to argue that the randomly predictable amino acid pairs are less likely to be deliberately evolved, whereas the randomly unpredictable amino acid pairs are probably deliberately evolved in connection with protein function. The results show that all of 95 variants occurred at randomly unpredictable amino acid pairs and the chance of a variant occurring is markedly higher in randomly unpredictable amino acid pairs than in predictable ones. Thus, the randomly unpredictable amino acid pairs are more sensitive to variance in human CA11 protein. Also the results suggest that the human CA11 protein has a natural tendency towards variants.
Changes in Liver Function correlate with the Improvement of Lipid Profile after Restoration of Euthyroidism in Patients with Subclinical Hypothyroidism
(2004-01-12) Christ-Crain, Mirjam; Huber, Peter R.; Keller, Ulrich; Meier, Christian; Müller, Beat; Puder, Jardena; Staub, Jean-Jacques
Overt hypothyroidism frequently leads to liver dysfunction. Subclinical hypothyroidism (SCH) is linked to abnormalities of lipoprotein metabolism, however, data on liver function are lacking. We analyzed the effects of L-thyroxine (L-T4) therapy on liver function and their association with changes of serum lipoproteins in SCH as part of a prospective, double-blind study. 66 women with SCH were randomly assigned to receive either L-thyroxine or placebo for 48 weeks. Circulating liver and biliary enzymes as well as serum lipid levels were assessed at baseline and after 24 and 48 weeks. Alkaline phosphatase as parameter of hepato-biliary function increased after 48 weeks of L-T4 treatment (p=0.004). Circulating levels of alanine amino transferase (ALT) and serum aspartate transferase (AST) did not change during L-T4 treatment. However, there was a correlation between both, deltaAST and deltaALT with delta-total cholesterol (r=0.60, p<0.001 and r=0.52, p=0.002, respectively). Similarly, both, deltaAST and deltaALT, correlated with deltaLDL cholesterol (LDL-C), respectively. Consecutively, patients with marked decrease of serum lipids during L-T4 therapy had a significantly higher decrease in AST and ALT, respectively, as compared to patients without amelioration of the lipid profile. Thyroid hormone replacement in SCH affects biliary tract function, yet, has no overall effect on hepatocellular enzymes. The relatively strong correlation between changes of serum AST and ALT with changes of LDL-C levels suggests that the mechanism of decreased LDL-C observed in restoration of euthyroidism in patients with SCH might be caused in part by changes of hepatic lipoprotein catabolism and a restored hepato-cellular function.

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