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T Meyer

Publications and source records attributed to T Meyer.

At least 325 records · Page 18Linked to original sources
PubMed1994

Neuron-specific human glutamate transporter: molecular cloning, characterization and expression in human brain.

A cDNA encoding a neuron-specific glutamate/aspartate transporter was isolated from human brain cDNA libraries and characterized. The new cDNA, designated human glutamate transporter III, is structurally distinct from two previously described brain specific glutamate transporters. This human cDNA is 90% and 95% homologous at nucleotide and amino acid level, respectively, with a previously reported rabbit glutamate/aspartate transporter. Northern blot analysis of human tissues revealed that the mRNA of this transporter is expressed in brain, liver, muscle, ovary, testis and in retinoblastoma cell lines. In situ hybridization in human brain sections showed that the mRNA is densely expressed in substantia nigra, red nucleus, hippocampus, and in cerebral cortical layers. Southern blot analysis revealed that the gene encoding this mRNA exists as a single copy in the human genome.

Aged↗
PubMed1994

Dianilinophthalimides: potent and selective, ATP-competitive inhibitors of the EGF-receptor protein tyrosine kinase.

Dianilinophthalimides represent a novel class of inhibitors of the EGF-receptor protein tyrosine kinase with a high degree of selectivity versus other tyrosine and serine/threonine kinases. Steady-state kinetic analysis of compound 3, which showed potent inhibitory activity, revealed competitive type kinetics relative to ATP. Despite a highly symmetrical structure of compound 3, X-ray studies revealed an unsymmetrical propeller-shaped conformation of the molecule which differs clearly from that of the constitutionally related staurosporine aglycons. These conformational differences may explain the reversal of the selectivity profile of compound 3 relative to the staurosporine aglycons. In cellular assays compounds 3 and 4 have been shown to inhibit EGF-induced receptor autophosphorylation, c-fos induction and EGF-dependent proliferation of Balb/c MK cells. This inhibition was selective as compounds had no effect on PDGF-induced receptor autophosphorylation and c-fos induction. Furthermore, compound 3 showed potent antitumor activity in vivo at well-tolerated doses.

3T3 Cells↗
PubMed1994

4,5-Dianilinophthalimide: a protein-tyrosine kinase inhibitor with selectivity for the epidermal growth factor receptor signal transduction pathway and potent in vivo antitumor activity.

Deregulated signal transduction via the epidermal growth factor receptor (EGF-R) family of protein-tyrosine kinase growth factor receptors is associated with proliferative diseases. We describe a class of compounds (4,5-dianilinophthalimides) that inhibit the EGF-R protein-tyrosine kinase in vitro with high selectivity. In cells, 4,5-dianilinophthalmide selectively inhibited both ligand-induced EGF-R and p185c-erbB2 autophosphorylation and c-fos mRNA induction. Antitumor activity could be demonstrated in vivo against xenografts of the A431 and SK-OV-3 tumors, which overexpress the EGF-R and p185c-erbB2, respectively. In contrast, a platelet-derived growth factor-driven tumor was not inhibited by 4,5-dianilinophthalimide, which is compatible with its cellular selectivity and hypothesized mechanism of action. No overt cumulative toxicity was observed during treatment even though high efficacy was observed, indicating a good therapeutic window. 4,5-Dianilinophthalimides may offer therapeutic agents for the treatment of hyperproliferative diseases that overexpress EGF-R family protein-tyrosine kinases or their ligands.

3T3 Cells↗
PubMed1994

Design, synthesis and investigation of mechanisms of action of novel protein kinase C inhibitors: perylenequinonoid pigments.

A series of perylenequinonoid pigments (PQPs) and related compounds were synthesized and screened for the inhibition of protein kinase C (PKC), a key enzyme involved in cellular differentiation and proliferation, and a potential target for anticancer and antiviral chemotherapeutic drugs. This study has established PQPs as efficient PKC inhibitors, and elucidated aspects of the light-enhanced action mode of the PKC inhibitors. Comparative studies between natural and synthetic PQPs led to the recognition of the effect of certain structural features of PQPs on PKC inhibition, including the skeleton of the 3,10-dihydroxy-4,9-perylenequinonoid chromophore and the configuration of the two side chains at positions 1 and 12. Calphostin C was identified as a superior PKC inhibitor of the POP class, and with the latter as a representative structure, we investigated the mechanism of PKC inhibition by PQPs via electron paramagnetic resonance spectroscopy in conjunction with the spin-trapping technique, absorption and fluorescence spectroscopy, photochemical and photobiological studies, and enzyme methodology. Multiple modes of action are suggested for PKC inhibition, comprising the following steps: (1) the binding of PQPs to the PKC regulatory domain via complexation; (2) the photobonding between mercapto groups of PKC cysteine residues and the PQP quinonoid moiety; and (3) the PQP-sensitized photodamage of PKC via Type I and/or Type II photosensitization.

Antibiotics, Antineoplastic↗
PubMed1994

Identification of active cytomegalovirus infection by analysis of immediate-early, early and late transcripts in peripheral blood cells of immunodeficient patients.

Owing to the persistence of viral DNA in leukocytes after primary CMV infection, detection of CMV DNA in these cells does not necessarily represent active infection. To identify CMV replication more precisely we have analysed immediate-early, early and late CMV transcripts by RNA amplification. The assay seems to be specific for active infection since no RNA-derived PCR products were obtained from healthy seropositive persons. The late UL83 transcript was detected in 80% of the patients with active CMV infections. Diagnosis of CMV replication by amplification of early and immediate-early transcripts was considerably less sensitive. In the case of continual CMV DNA detection in blood leukocytes by PCR without pp65 antigenemia the analysis of defined CMV transcripts would allow differentiation of active and non-active infection. In two cases the RNA assay became negative prior to DNA PCR analysis and pp65 antigen detection upon antiviral treatment, indicating that RNA amplification could be a suitable assay for early detection of the end of viral replication. No strong correlation was found between RNA detection and appearance of clinical symptoms. The development of CMV disease probably depends more on the extent of the functional impairment of the immune system.

AIDS-Related Opportunistic Infections↗
PubMed1994

A rapid luciferase transfection assay for transcription activation effects and stability control of estrogenic drugs in cell cultures.

A rapid assay system for measuring the potential of estrogenic drugs is introduced. Luciferase induction could be measured in estrogen-receptor-positive human MCF-7 breast cancer cells, which had been transfected with a novel luciferase reporter plasmid ERE luc. The minimal requirement was 1 h exposure to the inducing drug and 3.5 h of incubation after removal of the drug. The assay system was used to measure the stability of the drug diaqua-[1,2-bis (2,6-dichloro-4-hydroxyphenyl) ethylenediamine] platinum(II) sulfate, containing an estrogenic ligand and reactive platinum. Luciferase activity was observed only when the drug was in the culture medium and cells for short times, whereas the estrogenic ligand alone remained active. It is assumed that binding of the platinum moiety to macromolecular constituents of the culture or cells renders the drug inaccessible for binding to the estrogen receptor.

Antineoplastic Agents↗
PubMed1994

Expression of meta-vinculin in human coronary arteriosclerosis is related to the histological grade of plaque formation.

In the present study we demonstrate that the quantitative reduction of meta-vinculin expression parallels histological changes during the course of coronary arteriosclerosis. Immunofluorescence stainings of coronary arteries revealed that vinculin distribution resembled that of other smooth muscle-specific cytoskeletal proteins like alpha-actin, caldesmon or myosin light chain kinase in labeling smooth muscle cells brightly. Although close to arteriosclerotic plaques, the cellularity as measured by the density of nuclei was often not significantly altered. Cells of this location expressed markedly reduced amounts of vinculin, suggesting that they are smooth muscle cells of a synthetic phenotype. To determine the fractional meta-vinculin content in arteriosclerotic lesions, we performed densitometric scanning of immunoblots incubated with anti-vinculin monoclonal antibodies reacting with both meta-vinculin (150 kDa) and vinculin (130 kDa). In parallel, each tissue sample was evaluated histologically for the degree of arteriosclerotic alterations according to the morphometric atheroma score of Stratford et al. (n = 13). In type 1 lesions covering slight intimal thickening, meta-vinculin represented 36% (mean, range 35%-39%) of the total vinculin immunoreactivity. In type 2 lesions consisting of fibrous plaques of up to twice the original artery wall thickness, meta-vinculin accounted for 28% (mean, range 22%-35%) of the total vinculin content. Meta-vinculin was substantially reduced in type 3 lesions (mean 13%, range 8%-18%) which are characterized by extensive atheromatous plaques. Thus, the meta-vinculin/vinculin ratio differed significantly between early, intermediate and advanced phases of coronary arteriosclerotic plaque formation.

Aged↗
PubMed1994

Dual role of calmodulin in autophosphorylation of multifunctional CaM kinase may underlie decoding of calcium signals.

Autophosphorylation of multifunctional Ca2+/calmodulin-dependent protein kinase makes it Ca2+ independent by trapping bound calmodulin and by enabling the kinase to remain partially active even after calmodulin dissociates. We show that autophosphorylation is an intersubunit reaction between neighbors in the multimeric kinase which requires two molecules of calmodulin. Ca2+/calmodulin acts not only to activate the "kinase" subunit but also to present effectively the "substrate" subunit for autophosphorylation. Conversion of the kinase to the potentiated or trapped state is a cooperative process that is inefficient at low occupancy of calmodulin. Simulations show that repetitive Ca2+ pulses at limiting calmodulin lead to the recruitment of calmodulin to the holoenzyme, which further stimulates autophosphorylation and trapping. This cooperative, positive feedback loop will potentiate the response of the kinase to sequential Ca2+ transients and establish a threshold frequency at which the enzyme becomes highly active.

Amino Acid Sequence↗
PubMed1994

[Involvement of the pericardium in Churg-Strauss syndrome].

In two patients (24 and 26 years old) with chronic bronchial asthma, allergic rhinitis, peripheral blood eosinophilia of 48% and 51%, respectively, mononeuritis multiplex and abnormal erythrocyte sedimentation rate, Churg-Strauss syndrome was diagnosed. Acute pericarditis with abnormal ECGs and compensatory sinus tachycardia was documented in both cases as a sign of systemic vasculitis. Echocardiography revealed hemodynamically relevant pericardial effusions of 1.3 cm and 2.7-3.2 cm leading in one case to slightly diastolic compression of the right ventricle. The pericardial lesions showed good response to diuretic therapy with furosemide and administration of immunosuppressive agents like cyclophosphamide and azathioprine in combination with corticosteroids. The two presented cases underline that pericardial effusions of hemodynamic significance can be prominent clinical features of Churg-Strauss syndrome.

Adrenal Cortex Hormones↗
PubMed1994

Protein kinase C and mammary cell differentiation: involvement of protein kinase C alpha in the induction of beta-casein expression.

Treatment of HC11 mouse mammary epithelial cells with the lactogenic hormones dexamethasone, insulin, and prolactin (DIP) leads to cellular differentiation and production of the milk protein beta-casein. The following experimental evidence suggests the involvement of protein kinase C (PKC) in DIP induced signal transduction. Down-regulation of PKC by 12-O-tetradecanoylphorbol-13-acetate or addition of CGP 41251, a selective inhibitor of PKC, inhibited beta-casein protein expression induced by DIP in HC11 cells. This inhibition occurs at the level of transcription, since the DIP mediated activation of a beta-casein promoter-luciferase reporter construct or of mammary gland specific factor (MGF), an essential transcription factor for beta-casein promoter activity, was also inhibited by CGP 41251. Inhibition or down-regulation of PKC reduced the activation of MGF by prolactin as well. PKC-alpha, the only conventional PKC isoform expressed in HC11 cells, is most likely involved in the DIP induced beta-casein expression. (a) Only PKC-alpha and PKC-epsilon are down-regulated by 12-O-tetradecanoylphorbol-13-acetate whereas PKC-delta and PKC-zeta are not. (b) Of the PKC isoforms expressed in HC11 cells, CGP 41251 inhibits PKC-alpha more potently than PKC-delta, PKC-epsilon, and PKC-zeta. The IC50 for the inhibition of beta-casein synthesis, MGF activation, and beta-casein promoter activity by CGP 41251 correlated well with the IC50 of PKC-alpha inhibition. (c) Finally, only PKC-alpha translocated to membrane fractions after DIP or prolactin treatment. Taken together, these data indicate that PKC-alpha plays an important role in the signaling pathway activated by prolactin during beta-casein induction.

Alkaloids↗
PubMed1994

[Extremity perfusion in malignant melanoma].

Isolation perfusion was introduced in 1957 by Creech and Krementz for treatment of in-transit metastases from malignant melanoma of the limbs. The isolation of the extremity from the body circulation allows a high concentration of cytostatics without systemic side effects. In combination with hyperthermic tissue temperatures around 41.5 degrees C an additional effect can be expected. Regional metastasizing malignant melanomas with satellites, in-transit or lymph node metastases are generally accepted indications for isolation perfusion. There is still controversy about elective adjuvant perfusion in stage I melanoma. In spite of performing this treatment modality over 40 years in practice there are still many factors under discussion and many problems to be solved. The surgical procedure and techniqual aspects are described in detail. Krementz demonstrated long term survival rates between 19% and 53%. The patients treated in the Surgical Department of the University Hospital in Erlangen since 1975 with satellites and in-transit metastases had a 10-year survival rate of 48%. Considering the historical data of our patients without perfusion with a 10-year survival of 11% there is a highly significant statistical difference. In conclusion isolation perfusion is the therapy of choice in patients with locally metastasized malignant melanoma of the limbs.

Antineoplastic Agents↗
PubMed1993

Atomic structure of a cytochrome c' with an unusual ligand-controlled dimer dissociation at 1.8 A resolution.

The crystallographic structure of cytochrome c' from the purple phototrophic bacterium Chromatium vinosum (CVCP) has been determined at 1.8 A resolution using multiple isomorphous replacement. The molecule is a dimer, with each 131-residue chain folding as a four-helical bundle incorporating a covalently bound heme group at the core. This structure is the third of the ubiquitous cytochromes c' to be solved and is similar to the known structures of cytochrome c' from R. molischianum (RMCP) and R. rubrum (RRCP). CVCP is unique in exhibiting ligand-controlled dimer dissociation while RMCP and RRCP do not. The Tyr16 side-chain, which replaced Met16 in RMCP and Leu14 in RRCP, is parallel to the heme plane and located directly above the sixth ligand site of the heme Fe. Any ligand binding to this site, such as CO or CN-, must move the Tyr16 side-chain, which would be expected to cause other conformational changes of helix A, which contributes to the dimer interface, and consequently disrupting the dimer. Thus, the crystallographic structure of CVCP suggests a mechanism for dimer dissociation upon ligand binding. The dimer interface specificity is due to a lock and key shape complementarity of hydrophobic residues and not to any charge complementarity or cross-interface hydrogen bonds as is common in other protein-protein interfaces. The co-ordinates have been deposited in the Brookhaven Data Bank (entry P1BBH).

Amino Acid Sequence↗
PubMed1993

[Pathology and clinical aspects of peripheral neuroectodermal tumors].

A 36-year-old man developed progressive pain in the left thorax radiating to the shoulder, associated with weight loss as well as axillary and supraclavicular lymph-node swellings, and a left Horner's syndrome. The radiological diagnosis was Pancoast tumour. Computed tomography of the thorax revealed that the tumour had almost completely infiltrated the left lung and hilus. Sonography demonstrated metastases in the liver and retroperitoneum. Histological examination of an excised axillary lymph-node metastasis showed an undifferentiated small-cell tumour. Immunohistochemical tests revealed expression of protein S 100 and neurofilamental proteins, i.e. evidence of a peripheral malignant neuroectodermal tumour. The tumour also expressed vimentin. Treatment consisted of two chemotherapy cycles according to the EVAIA scheme (daily three times 235 mg etoposide, 2 mg vincristine, three times 0.8 mg actinomycin D, three times 3.2 g ifosfamide, three times 30 mg doxorubicin, and three times 12 mg dexamethasone), without any effect on the rapid progression of the disease. He died 17 weeks after the diagnosis had been made.

Adult↗
PubMed1993

Use of intracellular Ca2+ stores from rat basophilic leukemia cells to study the molecular mechanism leading to quantal Ca2+ release by inositol 1,4,5-trisphosphate.

Quantal Ca2+ release is a novel motif for the mediation of signal transduction in which the amplitude of a biological response following multiple stepwise increases in agonist concentration is retained. The release of Ca2+ from permeabilized cells in response to the second messenger inositol 1,4,5-trisphosphate (InsP3) proceeds in this fashion. The mechanisms leading to quantal Ca2+ release are unknown. InsP3 releases 50-90% of the Ca2+ sequestered within the intracellular stores of mammalian cells permeabilized with saponin. However, preparation of microsomes results in the loss of this sensitivity. In this report, functionally intact intracellular Ca2+ stores were isolated from rat basophilic leukemia (RBL) cells by osmotic lysis followed by differential and sucrose density gradient centrifugation. From this preparation, 64% of the stored Ca2+ is released by InsP3. We demonstrate that quantal Ca2+ release is retained by isolated Ca2+ stores and is identical to that observed in permeabilized cells. Addition of a subsaturating (28 nM) concentration of InsP3 to permeabilized cells at 37 degrees C results in the release of only a small fraction of the sequestered Ca2+. When the cells are cooled to 11 degrees C, the remaining Ca2+ is rapidly released. Hence, the mechanism leading to the quantal nature of Ca2+ release is reversible and is thus not likely to be the result of a covalent modification of the channel protein or of the Ca2+ store.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Stent wire cutting during coronary directional atherectomy.

Directional atherectomy represents one potential approach for the treatment of restenosis in stented coronary arteries. In this case report we demonstrate an important pitfall of this angioplasty technique for stent restenosis--inadvertent entanglement of the stent wire in the device. While cutting and removal of part of the wire was achieved in the case presented, this potential adverse event limits the applicability of directional atherectomy for restenosis in coronary stents.

Angioplasty, Balloon, Coronary↗
PubMed1993

Immune thrombocytopenia associated with hemorrhagic diathesis due to ibuprofen administration.

Acute thrombocytopenic purpura temporally related to the oral administration of ibuprofen developed in a patient with ankylosing spondylitis. Clinical manifestations, with sudden onset occurring within 12 h of drug ingestion and rapid increase of platelet counts following discontinuation of the drug, were characteristic of an antibody-mediated immune pathomechanism. Immunological studies demonstrated IgM and IgG antibodies in the patient's serum that were capable of binding to allogenic platelets in the presence of a metabolite preparation. This finding suggested that an ibuprofen metabolite, rather then the drug itself, was the antigenic agent responsible for the immune reaction. Despite its widespread therapeutic use, ibuprofen has not been described previously as causing immune-mediated thrombocytopenia.

Aged↗