Skin diseases following organ transplantation--risk factors and new therapeutic approaches.
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Basal Cell Carcinoma↗
Biomedical subjects
T Meyer
Publications and source records attributed to T Meyer.
Inhibitors of protein kinases: CGP 41251, a protein kinase inhibitor with potential as an anticancer agent.
CGP 41251 was originally identified as an inhibitor of protein kinase C (PKC), inhibiting mainly the conventional PKC subtypes, and subsequently shown to inhibit the vascular endothelial growth factor (VEGF) receptor kinase insert domain-containing receptor, which is involved in angiogenesis. CGP 41251 inhibits reversibly intracellular PKC activity, induction of c-fos and the corresponding activation of the mitogen-activated protein kinase induced by either tumor promoting phorbol esters, platelet-derived growth factor, or basic fibroblast growth factor, but not by the epidermal growth factor. CGP 41251 inhibited the ligand-induced autophosphorylation of the receptors for platelet-derived growth factor, stem cell factor, and VEGF (kinase insert domain-containing receptor) that correlated with the inhibition of the mitogen-activated protein kinase activation, but did not affect the ligand-induced autophosphorylation of the receptors for insulin, insulin-like growth factor-I, or epidermal growth factor. CGP 41251 showed broad antiproliferative activity against various tumor and normal cell lines in vitro, and is able to reverse the p-glycoprotein-mediated multidrug resistance of tumor cells in vitro. CGP 41251 showed in vivo antitumor activity as single agent and inhibited angiogenesis in vivo. Thus, CGP 41251 may suppress tumor growth by inhibiting tumor angiogenesis (via its effects on the VEGF receptor tyrosine kinases) in addition to directly inhibiting tumor cell proliferation (via its effects on PKCs).
Antineoplastic Agents↗
New scoring functions for virtual screening from molecular dynamics simulations with a quantum-refined force-field (QRFF-MD). Application to cyclin-dependent kinase 2.
A recently introduced new methodology based on ultrashort (50-100 ps) molecular dynamics simulations with a quantum-refined force-field (QRFF-MD) is here evaluated in its ability both to predict protein-ligand binding affinities and to discriminate active compounds from inactive ones. Physically based scoring functions are derived from this approach, and their performance is compared to that of several standard knowledge-based scoring functions. About 40 inhibitors of cyclin-dependent kinase 2 (CDK2) representing a broad chemical diversity were considered. The QRFF-MD method achieves a correlation coefficient, R(2), of 0.55, which is significantly better than that obtained by a number of traditional approaches in virtual screening but only slightly better than that obtained by consensus scoring (R(2) = 0.50). Compounds from the Available Chemical Directory, along with the known active compounds, were docked into the ATP binding site of CDK2 using the program Glide, and the 650 ligands from the top scored poses were considered for a QRFF-MD analysis. Combined with structural information extracted from the simulations, the QRFF-MD methodology results in similar enrichment of known actives compared to consensus scoring. Moreover, a new scoring function is introduced that combines a QRFF-MD based scoring function with consensus scoring, which results in substantial improvement on the enrichment profile.
Computer Simulation↗
Distribution of HPV 53, HPV 73 and CP8304 in genital epithelial lesions with different grades of dysplasia.
To characterize the risk of malignant progression of cervical epithelial lesions associated with human papillomavirus (HPV) types of yet unknown oncogenic potential the prevalences of these HPVs in different cervical epithelial lesions of 809 patients were determined. HPV types 53, 73, and CP8304 were detected in genital specimens of 16, 22, and 12 of the patients, respectively. The ratio of prevalence in high grade dysplastic lesions or cancers and low grade dysplastic lesions or normal specimens was calculated and compared to corresponding values of well known high-risk (HR) and low-risk (LR) HPVs. For HPV 6, 11, 16, 18, 35, and 73 a ratio of 0.1, 0.2, 5.9, 6.5, 2.5, and 2.4, respectively, was calculated. The ratios of HPV53 and CP8304 were less than 1. Moreover, in contrast to HPV73, these viruses have never been detected in cancer specimens. Thus, HPV53 and CP8304 infections are probably not associated with a high risk of carcinogenesis, while HPV73 could be another HR-HPV type.
Adult↗
Alveolar deposition of monodisperse aerosol particles in the lung of patients with chronic obstructive pulmonary disease.
Knowledge about the regional deposition of aerosol particles is essential in order to perform efficient inhalation therapy or to minimize health risks due to environmental or occupational aerosol particles. In this study, 2 techniques were used to measure thoracic deposition and to differentiate between bronchial and alveolar deposition. The first technique was the clearance-derived regional deposition (CRD) technique and the second the single-breath regional deposition (SBRD) technique. Deposition was measured in 12 patients with alpha1-antitrypsin deficiency and symptoms of moderate to severe chronic obstructive pulmonary disease (COPD) using monodisperse test particles with aerodynamic diameters of 2, 3, and 4 microm. In CRD, the kinetic of particle clearance within the first 24 hours after inhalation was used to determine bronchial and alveolar deposition. In SBRD, the longitudinal distribution of deposited inert test particles was used to calculate the particle fraction deposited within and distal to the dead space. Both techniques delivered very similar mean values for total and alveolar deposition. Due to controlled slow and deep inhalations, alveolar deposition was as much as 50%. Therefore, SBRD can be considered as an easy tool to study alveolar deposition in patients.
Aerosols↗
Pulmonary deposition of monodisperse aerosols in patients with chronic obstructive pulmonary disease.
In order to improve patient convenience and drug availability for patients with alpha 1-protease inhibitor deficiency, the administration via the inhalation route has been considered. This study investigated if it is possible to obtain high values of peripheral aerosol deposition by using optimized and controlled inhalation conditions. Therefore, peripheral deposition was studied in 10 patients with alpha 1-protease inhibitor deficiency (phenotype PiZ) and moderate to severe chronic obstructive pulmonary disease by measuring the 24-hour Clearance of radiolabeled inert iron oxide particles with diameters of 2 microns, 3 microns, and 4 microns. Patients inhaled a large volume of aerosol (1000 to 2000 cm3), which was normalized to the individual lung function, with a flow rate of 200 cm3/S. Due to this breathing pattern, peripheral deposition was for all particle sizes above 50% of the inhaled aerosol. The highest peripheral deposition (68%) was found for 3-microns particles.
Administration, Inhalation↗
Two populations of erythrocytes associated with XX-XY mosaicism.
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Blood Group Antigens↗
Differential distribution of serotonin and tryptophan hydroxylase in the human gastrointestinal tract.
The distribution of tryptophan hydroxylase, the rate-limiting enzyme in the biosynthesis of serotonin, was investigated immunohistochemically in various organs of the gastrointestinal tract and compared with that of neuroendocrine markers. While immunoreactivity for serotonin and chromogranin A was restricted to enterochromaffin cells, positive staining for tryptophan hydroxylase was detected in normal enterocytes lining the epithelium of the small intestine. Tryptophan hydroxylase was localized in the supranuclear cytoplasm of absorptive cells, and was absent from the terminal web. The enterocytes of the exfoliation zone at the tips of the villi demonstrated a strong immunoreactivity similar to those at the slope of the villi. Mucus-containing Goblet cells, Paneth cells and stromal cells of the lamina propria remained unlabelled. The duodenal glands of Brunner revealed only sporadically a weak immunostaining for tryptophan hydroxylase. The monooxygenase was also detected in numerous secretory tubules of the pyloric mucosa, where the proportion of positive cells decreased progressively from the crypts towards the upper parts of the gastric glands. No significant immunoreactivity was demonstrated in colon, adrenal cortex, liver, pancreas, and mesenteric lymph nodes. The demonstration of tryptophan hydroxylase in normal enterocytes suggested that epithelial cells of the small intestine are able to synthesize 5-hydroxytryptophan.
Digestive System↗
Depression but not anxiety is a significant predictor of physicians' assessments of medical status in physically ill patients.
BACKGROUND: In a cross-sectional study we investigated associations between self-ratings of anxiety and depression, physical factors and physicians' assessments of patients' medical status. METHODS: Hospital inpatients (n = 574) consecutively admitted to internal medical wards were evaluated for the presence of anxiety and depressive symptoms using the Hospital Anxiety and Depression Scale (HADS). Physicians were asked for their perception of psychiatric problems in their patients and for their assessments of patients' severity of illness, functional impairment and 1-year prognosis on 3-point ranking scales. Detailed somatic data including comorbidity and accepted risk factors were taken from the patients' records. RESULTS: Almost two thirds of all patients with abnormal HADS scores (65.2%) were not identified by their attending physicians as suffering from psychiatric problems. Using multiple-regression models, HADS scores for depression, but not for anxiety, proved to be an independent predictor for the clinicians' judgements of disease severity [exp(beta) = 1.08; 95% confidence interval (CI) 1. 03-1.13; p < 0.01] and functional impairment [exp(beta) = 1.11; 95% CI 1.05-1.17; p < 0.01]. The estimation of prognosis, however, was only related to physical predictors and showed no association with depressive symptoms or other psychosocial factors. CONCLUSIONS: Our data demonstrate that internists' ratings of severity of illness and functional impairment, but not prognosis, are associated with HADS depression scores, whereas there is no such association with self-rated anxiety.
Adult↗
Giant cell myocarditis due to coxsackie B2 virus infection.
Giant cell myocarditis is a rare disorder characterized by the histologic hallmark of diffuse inflammatory infiltrates with the appearance of multinucleated giant cells. We report on a 52-year-old man who died of rapidly progressive cardiogenic shock due to giant cell myocarditis. Serological and immunoblotting techniques revealed a myocardial infection with coxsackie B2 virus, suggesting a viral etiology of this disease. Here we present evidence for the involvement of autoimmune responses to the myocardium as numerous cardiomyocytes exhibited deposits of cell-adherent immunoglobulins. Although other causative factors may initiate giant cell myocarditis as well, our case suggests coxsackie B2 virus as one etiologic agent capable of triggering autoimmune reactions to altered heart tissue.
Antibodies, Viral↗
Tryptophan hydroxylase and 5-hydroxytryptamine in carcinoids of the gastrointestinal tract.
BACKGROUND: Tryptophan hydroxylase is the enzyme that catalyzes the formation of 5-hydroxy-L-tryptophan which is the initial and rate-limiting enzyme in the biosynthesis of 5-hydroxytryptamine (serotonin). The aim of this study was to analyze the differential expression of tryptophan hydroxylase and 5-hydroxytryptamine in human gastrointestinal carcinoids. MATERIAL AND METHODS: Primary carcinoids and hepatic carcinoid metastases (n = 8) were investigated for the presence of tryptophan hydroxylase, 5-hydroxytryptamine and chromogranin A. RESULTS: Only one of the tumors examined was immunoreactive for tryptophan hydroxylase, as determined by immunohistochemical techniques and Western blot analysis. All carcinoids expressed 5-hydroxytryptamine and chromogranin A. CONCLUSIONS: Carcinoids appear to be a heterogeneous group with respect to the expression of this monooxygenase. Based on these results it is proposed that other cells of the intestine are involved in the biosynthesis of 5-hydroxytryptamine precursors taken up by carcinoid tumor cells.
Carcinoid Tumor↗
[Endodontic treatment for the aged].
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Aged↗
Effects of cyclophosphamide and ifosfamide on neuroblastoma cells before and after activation by microsomes.
Cyclophosphamide (CP) and Ifosfamide (IF) are of great importance in the therapy of neuroblastoma (NB). They are prodrugs which have to be activated by microsomes in order to become active compounds. We established a test system which allowed the activation of CP and IF by liver microsomes in the presence of NB cells. The data from these experiments showed that neuroblastoma cells (SK-N-SH, SK-N-LO and IMR-5) were unable to activate CP and IF, but in the presence of rat liver microsomes considerable cytotoxicity was achieved, similar to those of the preactivated derivatives maphosphamide (MP) and 4-hydroxy-ifosfamide (4-OH-IF). Compared to other compounds the final metabolite acrolein contributes significantly to the cytotoxicity of CP and IF, obviously through significant lowering of the glutathione levels in the cells. The incubation system as described allows the rapid determination of the cytotoxicity of CP and IF in the simultaneous presence of microsomes. The results show great differences in the sensibility of NB cells toCP and IF.
Animals↗
Design and synthesis of novel tyrosine kinase inhibitors using a pharmacophore model of the ATP-binding site of the EGF-R.
One of the most promising targets for the rational design of anti-cancer drugs is the family of the EGF-receptor protein tyrosine kinases. Despite the high sequence homology within the ATP-binding region of protein tyrosine and/or serine threonine kinases, ATP-competitive compounds have the potential to be selective inhibitors of protein kinases. Dianilino-phthalimides CGP 52 411 and CGP 53,353 have been identified as potent and ATP-competitive inhibitors of the EGF-R tyrosine kinase with no or only minor activity against a panel of tyrosine and serine/threonine kinases. Using a calculated 3-D computer model of the catalytic domain of the EGF-R-tyrosine kinase together with CGP 52 411 as example of an ATP-competitive inhibitor, a pharmacophore model for ATP-competitive inhibitors in the active site of the EGF-R PTK was developed. With the help of this model, 4-phenylamino-7H-pyrrolo[2,3-d]pyrimidines were then identified as new potent EGF-R PTK inhibitors. In an interactive process, the class of the 4-phenylamino-pyrrolo-pyrimidines was optimized and structure-activity-relationship of a series of derivatives thereof are discussed. In vitro, the most active compounds (CGP 59 326, CGP 60 261, CGP 62 706) inhibited the EGF-R tyrosine kinase with IC50 value between 6-30 nM. High selectivity towards a panel of non-receptor tyrosine kinases (c-SRC, v-Abl) and serine/threonine kinases (PKC alpha, PKA) was observed. Kinetic analysis revealed competitive type kinetics relative to ATP. In cells, EGF-stimulated cellular tyrosine phosphorylation was inhibited by these compounds at IC50 values between 0.1-0.3 microM, whereas the ligand-induced receptor autophosphorylation of the PDGR-R was not effected by concentrations up to 100 microM. Furthermore, CGP 59 326, CGP 60 261, CGP 62 706 were able to selectively inhibit c-fos mRNA expression in EGF-dependent cell lines with (IC50) approx. 0.1-1 microM) but not in EGF-independent cell systems (IC50 > 100 microM). Proliferation of the EGF-dependent MK cell line was inhibited with similar IC50 values. In addition, CGP 59 326 and CGP 62 706 showed good in vivo efficacy at low doses after oral or subcutaneous administration in nude mice tumor models using xenografts of the EGF-dependent A431 cell lines. The ED50 values were between 1.5-2 mg/kg. Phenylamino-pyrrolo-pyrimidines therefore represent a new series of tyrosine kinase inhibitors which preferentially inhibit the EGF-mediated signal transduction pathway and have the characteristics for further evaluation as anticancer agents.
Adenosine Triphosphate↗
Tryptophan hydroxylase antibodies used in the diagnosis of carcinoid.
The expression of tryptophan hydroxylase, the rate-limiting enzyme in the biosynthesis of serotonin, is described in a case of a 35 year-old patient with metastatic jejunal carcinoid. Immunohistochemically, monoclonal anti-tryptophan hydroxylase antibodies positively identified liver metastases of a neuroendocrine tumor. The cellular distribution of tryptophan hydroxylase was restricted exclusively to the cytoplasm of carcinoid cells, where it was found in large amounts. By means of immunoblotting, anti-tryptophan hydroxylase antibodies detected in samples from carcinoid tissue two closely migrating polypeptide bands with molecular weights of 26 kDa and 29 kDa, respectively. These two protein bands appear to represent proteolytically degraded polypeptides, since tryptophan hydroxylase is known for its extreme unstability in vitro. In our case, the immunohistochemical and biochemical identification of tryptophan hydroxylase in liver lesions of a neuroendocrine tumor permitted the correct diagnosis of a metastatic carcinoid.
Adult↗