Adiponectin is not altered with exercise training despite enhanced insulin action

Adiponectin is an adipocytokine that is hypothesized to be involved in the regulation of insulin action. The purpose of the present investigation was to determine whether plasma adiponectin is altered in conjunction with enhanced insulin action with exercise training. An insulin sensitivity index (S(I)) and fasting levels of glucose, insulin, and adiponectin were assessed before and after 6 mo of exercise training (4 days/wk for approximately 45 min at 65-80% peak O(2) consumption) with no loss of body mass (PRE, 91.9 +/- 3.8 kg vs. POST, 91.6 +/- 3.9 kg) or fat mass (PRE, 26.5 +/- 1.8 kg vs. POST, 26.7 +/- 2.2 kg). Insulin action significantly (P < 0.05) improved with exercise training (S(I) +98%); however, plasma adiponectin concentration did not change (PRE, 6.3 +/- 1.5 microg/ml vs. POST, 6.6 +/- 1.8 microg/ml). In contrast, in a separate group of subjects examined before and after weight loss, there was a substantial increase in adiponectin (+281%), which was accompanied by enhanced insulin action (S(I), +432%). These data suggest that adiponectin is not a contributory factor to the exercise-related improvements in insulin sensitivity.     

Tumour class prediction and discovery by microarray-based DNA methylation analysis

Aberrant DNA methylation of CpG sites is among the earliest and most frequent alterations in cancer. Several studies suggest that aberrant methylation occurs in a tumour type-specific manner. However, large-scale analysis of candidate genes has so far been hampered by the lack of high throughput assays for methylation detection. We have developed the first microarray-based technique which allows genome-wide assessment of selected CpG dinucleotides as well as quantification of methylation at each site. Several hundred CpG sites were screened in 76 samples from four different human tumour types and corresponding healthy controls. Discriminative CpG dinucleotides were identified for different tissue type distinctions and used to predict the tumour class of as yet unknown samples with high accuracy using machine learning techniques. Some CpG dinucleotides correlate with progression to malignancy, whereas others are methylated in a tissue-specific manner independent of malignancy. Our results demonstrate that genome-wide analysis of methylation patterns combined with supervised and unsupervised machine learning techniques constitute a powerful novel tool to classify human cancers.     

Combined p53/Bax mutation results in extremely poor prognosis in gastric carcinoma with low microsatellite instability

Gastric cancer is highly refractory to DNA-damaging therapies. We therefore studied both gene mutation and protein expression of p53 and Bax in a cohort of 116 patients with gastric cancer who underwent R0-resection with a curative intent. Bax mutation was independent from severe microsatellite instability (MSI), that is, global mismatch repair deficiency as determined by analysis of BAT-25/BAT-26 microsatellite markers. Thus, Bax-frameshift mutation is a feature of tumors with low MSI. In contrast and as expected, no p53 mutations were observed in the microsatellite instable tumors. p53 Mutation or p53 overexpression did not have an impact on disease prognosis. p53-Inactivation was, however, associated with an extremely poor prognosis in the subgroup of patients with Bax-mutated tumors. Thus, we show for the first time that the combined mutation of p53 and Bax, two key regulators of the mitochondrial apoptosis pathway, results in an extremely aggressive tumor biology and poor clinical prognosis.     

Structural modeling of ataxin-3 reveals distant homology to adaptins

Spinocerebellar ataxia type 3 (SCA3) is a polyglutamine disorder caused by a CAG repeat expansion in the coding region of a gene encoding ataxin-3, a protein of yet unknown function. Based on a comprehensive computational analysis, we propose a structural model and structure-based functions for ataxin-3. Our predictive strategy comprises the compilation of multiple sequence and structure alignments of carefully selected proteins related to ataxin-3. These alignments are consistent with additional information on sequence motifs, secondary structure, and domain architectures. The application of complementary methods revealed the homology of ataxin-3 to ENTH and VHS domain proteins involved in membrane trafficking and regulatory adaptor functions. We modeled the structure of ataxin-3 using the adaptin AP180 as a template and assessed the reliability of the model by comparison with known sequence and structural features. We could further infer potential functions of ataxin-3 in agreement with known experimental data. Our database searches also identified an as yet uncharacterized family of proteins, which we named josephins because of their pronounced homology to the Josephin domain of ataxin-3.     

Benzoquinone derivatives of Myrsine africana and Maesa lanceolata

The fruits of Myrsine africana afforded two new benzoquinone derivatives, methylvilangin and methylanhydrovilangin. On the other hand, from the fruits of Maesa lanceolata two more novel compounds; 2,5-dihydroxy-3-(nonadec-14-enyl)-benzoquinone and lanciaquinone were isolated. Their structural elucidation was achieved by spectroscopic measurements including 2D NMR experiments.     

Scaphopetalone and scaphopetalumate,a lignan and a triterpene ester from Scaphopetalum thonneri

From the methanol extract of the stem bark of Scaphopetalum thonneri, two new compounds, including one lignan, named scaphopetalone, one new ester of ferulic acid, named scaphopetalumate were isolated together with three known compounds including: two coumarins (scopoletin and scopolin), and one pentacyclic triterpene (oleanolic acid). The structure of the new compounds were elucidated by means of spectroscopic analyses.     

Association between 8-hydroxy-2'-deoxyguanosine levels in DNA of workers highly exposed to asbestos and their clinical data, occupational and non-occupational confounding factors, and cancer

In the preceding paper [B. Marczynski, P. Rozynek, T. Kraus, St. Schl?sser, H.J. Raithel, X. Baur, Levels of 8-hydroxy-2'-deoxyguanosine in DNA of white blood cells from workers highly exposed to asbestos in Germany, Mutat. Res. (2000) submitted] we described significant increases (p<0.001) in the levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG) adducts in the DNA of white blood cells (WBC) of workers highly exposed to asbestos fibers at the workplace relative to those found in the control group in all three study years (period between 1994 and 1997). The results show that the oxidative DNA damage in exposed individuals is between 1.7 times and twice that found in control samples for all 3 years of the study (p<0.001). The aim of this study was to examine the association between the 8-OHdG levels in WBC DNA of workers highly exposed to asbestos fibers at the workplace and clinical data, occupational and non-occupational confounding factors, and cancer. There is no obvious correlation between the steady-state levels of 8-OHdG in the circulating WBC DNA of asbestos workers and possible confounding factors, such as the presence of benign asbestos-associated diseases, the duration of asbestos exposure, the latency period, the fixed cumulative fibrous dust dose ("fiber years"), age, smoking status, acute febrile infections, medicines, aspirin, calcium (Ca(2+)), magnesium (Mg(2+)), and the hormone and vitamin intake. This indicates that previous inhalation of asbestos fibers is the major factor responsible for the difference observed in oxidative DNA damage between asbestos workers and controls. For patients suffering from respiratory cancer, cancer of the gastrointestinal tract, mouth/pharynx/larynx, and urogenital tract the mean DNA-adduct level was significantly higher (p<0.01) than that found in controls, but not significantly higher (p>0.05) than that for asbestos-exposed patients without tumours. The formation of 8-OHdG adduct levels in WBC DNA of patients with hematopoietic cancer, chondrosarcomas and multiform glioblastomas was not significantly higher than that found in the control group (p>0.05). Our results support the hypothesis that oxidative DNA damage in man caused by asbestos fibers plays a role in the formation of malignant tumours.