EGFR and PDGFR differentially promote growth in malignant epithelioid mesothelioma of short and long term survivors.

BACKGROUND: Malignant pleural mesothelioma (MPM) is an asbestos related tumour difficult to detect early and treat effectively. Asbestos causes genetic modifications and cell signalling events that favour the resistance of MPM to apoptosis and chemotherapy. Only a small number of patients, approximately 10%, survive more than 3 years. The aim of our study was to assess possible differences within signalling pathways between short term survivors (survival <3 years; STS) and long term survivors (survival >3 years; LTS) of MPM. METHODS: 37 antibodies detecting proteins engaged in cell signalling pathways, enforcing proliferation, antiapoptosis, angiogenesis and other cellular activities were investigated by tissue microarray (TMA) technology. RESULTS: Epidermal growth factor receptor (EGFR) was expressed stronger in LTS whereas platelet derived growth factor receptor (PDGFR) signalling was more abundant in STS. Expression of TIE2/Tek, a receptor for tyrosine kinases involved in angiogenesis, was differentially regulated via PDGFR and thus is more important in STS. Antiapoptosis was upregulated in STS by signal transducer and activator of transcription 1 (STAT1)-survivin and related molecules, but not in LTS. Our study provides novel insights into the regulatory mechanisms of signalling pathways in MPM, which differentially promote tumour growth in LTS and STS. CONCLUSION: We have demonstrated that small scale proteomics can be carried out by powerful linkage of TMA, immunohistochemistry and statistical methods to identify proteins which might be relevant targets for therapeutic intervention.

Is high-grade adenomatous hyperplasia an early bronchioloalveolar adenocarcinoma?

Atypical adenomatous hyperplasia (AAH) is a probable forerunner of bronchioloalveolar carcinoma (BAC) and pulmonary adenocarcinoma (AC) of mixed type. The present study analysed four low-grade AAHs, 13 high-grade AAHs, two BACs, nine mixed ACs, and one squamous cell carcinoma derived from 13 patients using comparative genomic hybridization. The average number of chromosomal aberrations was 1.2 in low-grade AAH, 9.6 in high-grade AAH, and 12.5 in AC. A high degree of overlap of genetic changes was found in high-grade AAH, BAC, and AC within individual patients. The high number of aberrations and the degree of shared aberrations found in high-grade AAH and AC raises questions about the separation of these two entities. In addition, in view of the monoclonal origin of multiple foci within the same patient, AAH may not be a precursor of AC in some cases, but rather may represent intraepithelial spread.

[Central nervous system control of micturition in patients with bladder dysfunctions in comparison with healthy control probands. An electrophysiological study]. / Zentralnervöse Kontrolle der Miktion bei Patienten mit Blasenfunktionsstörung im Vergleich zu gesunden Kontrollpersonen. Eine elektrophysiologische Studie.

PURPOSE: The pontine micturition center plays a central role in regulating the micturition reflex, but the precise neural mechanisms are unclear. The cerebral cortex is involved in coordinating micturition but there is little knowledge on specific evolutionary higher brain regions. The present study aimed to investigate whether cortical activation during micturition can be demonstrated by EEG power spectra patterns and to explore whether specific cortical regions involved in the interaction of inhibition and release during the micturition reflex can be discerned. We also aimed to test whether intravesical electrostimulation (IVES) therapy in patients with micturition disorders has an effect on patterns of cortical activity. METHODS: The healthy control group was divided into those who were able to void when requested (6 women, 12 men) and those who were not (8 women, 10 men). These subgroups were compared separately with the 14 patients before and after IVES for voiding dysfunction. Following IVES all patients were able to void spontaneously. Mean age of the patients and healthy volunteers was 52 and 30 years, respectively. At the beginning of the study all subjects had a bladder volume of approximately 250 mL as measured by sonography. The EEG was obtained at rest and during the attempt to void. In the patients' group EEG was obtained before IVES treatment and at the day of the last stimulation. The measurement period lasted about 6 minutes. At the beginning of the recording the proband was asked to close his/her eyes. During the resting period after 1 minute the patient was asked to open his/her eyes. After 10 seconds he/she was asked to close his/her eyes again. Then, with eyes still closed, the patient was asked to void. During the entire EEG recording the patient was seated in a comfortable, electrically isolated chair in a darkened room and separated from the examiner by a partition. The subject was asked to relax and not move his/her eyes. The EEG was recorded from the 19 standard points (10-20 System) versus an averaged mastoid electrode with a gold-plated cup electrode (Glass). An EOG was recorded simultaneously to register eye artefacts. The amplification chain was calibrated with a 10-Hz 100-microVss sinus signal generated with a biosignal amplifier. The transitional resistances of all EEG channels were less than 5 kOhm and established as soon as possible. EEG and EOG signals were amplified and recorded with a B.E.S.T. Brain Mapping System. The recording frequency was 256 Hz and the resolution of the analog digital conversion was 12 bit. A high pass and a low pass filter were set to 0.53 Hz and 70 Hz, respectively. All recordings were inspected visually before computer analysis. Artefacts were marked and excluded from the further analysis. None of the EEG recordings showed clinical abnormalities. As expected, the EEGs during voiding attempts showed some muscle potentials and slow motion artefacts. For each subject two artefact-free resting segments of about 20 seconds, one from the resting phase and one from the voiding attempt, were defined by hand for automated analysis. Relative power spectra (microV2) were calculated for the defined segments. From the spectra the relative alpha band power (7.5-13.0 Hz) was calculated for each subject for rest and voiding. Group (patients vs. voiding probands vs. probands unable to void) and sex were independent variables. The alpha power of the 17 electrode positions of the 10-20 system (without Fp1 and Fp2) during rest and attempted voiding were repeated measurement variables. The frontopolar electrode was not used because of its susceptibility to artefacts. The number of dependent variables was due to the explorative nature of the study. With interactions of variables with more than two factor levels a Greenhouse-Geisser correction was performed. Interactions were subjected to contrast analysis and Newman-Keuls-Post tests. RESULTS: Significant effects were seen for BEDINGUNG (