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Publications and source records attributed to R Müller.
[(S,S)-1,2-Bis(4-hydroxyphenyl)ethylenediamine]dichloroplatinum(II) shows a strong and dose-dependent effect on the hormone-dependent MXT mammary carcinoma of the mouse. The R,R/S,S-configurated compound is markedly less active.
Experiments on the P 388 D1 cell line (48 h exposure) demonstrate that [1,2-bis-(fluorophenyl)ethylenediamine]platinum(II) complexes are comparably active on the cell number and 3H-thymidine incorporation, irrespective of the position of the fluorine atom (ortho, meta, or para) and the nature of the "leaving group" (Cl- or H2O). However, the compounds of the R,R/S,S series are more active than those of the R,S series and comparable to cisplatin. In the "tumor colony forming assay" the R,R/S,S configurated compounds are about ten times as active as cisplatin. The R,R/S,S configurated diaqua[1,2-bis(4-fluorophenyl)ethylenediamine]platinum(II) salts reach their half maximum effect more readily (t1/2 approximately equal to 1.6 h) than their R,S configurated analogues (t1/2 approximately equal to 20 h). A time limited contact of the cells with R,R/S,S configurated diaqua[1,2-bis(4-fluorophenyl)ethylenediamine]platinum(II) salts (-1h) leads to a similar inhibition like a permanent drug exposure indicating a fast uptake of the complex by the tumor cell. In experiments on the Ehrlich ascites tumor of the mouse and on the L 1210 leukemia cell line R,R/S,S-[1,2-bis(4-fluorophenyl)ethylenediamine]dichloroplatinum(II) turns out to be equipotent with cisplatin.
Diastereomeric diaqua[1,2-bis(4-fluorophenyl)ethylenediamine]platinum(II) sulfates and nitrates produce a strong inhibition of the hormone-dependent MXT-M 3.2 mammary carcinoma of the B6D2F1 mouse. Besides an interference in the DNA synthesis in analogy to cisplatin a lowering of the estrogen level due to an interference in steroid biosynthesis is suggested as the mode of action. In contrast to the R,R/S,S configurated diaqua[1,2-bis(4-fluorophenyl)ethylenediamine]platinum(II) salts the corresponding R,S configurated compounds are also markedly active on the hormone-independent MXT-Ovex mammary carcinoma of the B6D2F1 mouse.
In this study, we show that Fos protein can repress transactivation by the glucocorticoid receptor (GR). In addition, we demonstrate that GR is capable of inhibiting, in a hormone-dependent fashion, Fos-mediated transactivation of AP-1 dependent transcription. Moreover, repression of the serum response element by Fos is abolished by the GR in the presence of hormone. Transrepression of glucocorticoid mediated induction involves a region of Fos, located between amino acids 40 and 111, to which no function has been previously assigned, and which is poorly conserved among Fos, FosB and Fra-1. In agreement with this finding, FosB is not capable of transrepressing GR activation of transcription, representing the first functional difference between Fos and FosB. We have mapped the domain of the GR which is required for repression of AP-1 dependent transcription, to the region of central DNA binding domain. Our results suggest that Fos and the GR may form transcriptionally inactive complexes and point to a regulatory interrelationship between different signal transduction pathways.
A 'motion onset VEP' was elicited by the onset of a pattern drift. The amplitude of the most distinct wave (AN200) was determined on the following stimulation conditions: eccentricity, 0 to 23 deg; velocity. 1.5 to 16 deg/s; spatial frequency, 0.19 to 2.1 c/deg; and stimulation field size, 0.2 to 160 deg2, AN200 remained constant at any degree of eccentricity if stimulation field size, velocity, and spatial frequency were M-scaled according to Rovamo-Virsu's M-equations. AN200 decreased as a function of eccentricity if field size and velocity were kept constant (spatial frequency had minimal effect). The size of the cortical representation field (Sc) in this case varied with change in eccentricity (stimulation field size constant). In another experiment, it varied by change in stimulation field size (eccentricity constant). For both conditions, AN200 was proportional to log Sc.
We studied amplitude of the wave N200 of the motion-onset VEP by varying the side length of a square stimulation field between 0.5 and 7 degrees. A significant increase in amplitude was obtained between 0.5 and 1 degree of side length in central stimulation and between 0.5 and 5 degrees in 10-degree peripheral stimulation. Variations of spatial frequency between 0.34 and 6.8c/deg did not modify the amplitude size, ie, no tuning effect could be found. The results of simultaneous and separate stimulation of foveal and parafoveal regions support the observation that the stimulation field size is a minor influence. Features of motion-sensitive cortical neurons, such as those found in monkeys, could account for this behavior.
The synthesis of diastereoisomeric [1,2-bis(2-hydroxyphenyl)ethylenediamine]dichloroplatinum(II) complexes, DL-3-PtCl2 and meso-3-PtCl2, and their evaluation on the hormone-independent, human MDA-MB231 breast cancer cell line, on the cisplatin-sensitive and -resistant L1210 leukemia cell line, on the cisplatin-resistant human NIH:OVCAR 3 ovarian cancer cell line, on the P-388 leukemia of the mouse and on the cisplatin-sensitive and -resistant Ehrlich ascites tumor of the mouse are described. On all tumor models DL-3-PtCl2 produces a marked inhibitory effect. The diastereoisomer meso-3-PtCl2 is less active and more toxic. It is striking that DL-3-PtCl2 leads to a pronounced inhibition of all cisplatin-resistant tumors. At non-toxic concentrations DL-3-PtCl2 produces cytocidal effects on the NIH:OV-CAR 3 cell line. Therefore DL-3-PtCl2 is of interest for further evaluation for the therapy of ovarian cancer.
The enantiomeric [1,2-bis(4-fluorophenyl)ethylenediamine]dichloroplatinum(II) complexes were synthesized and tested on the hormone-sensitive human MCF7 breast cancer cell line and on the P388 leukemia of the mouse. They showed a strong and comparable activity on both tumor models.
In vivo 3H-Thymidine autoradiographic investigations of DNA synthesis in acinar, islet and duct cells in the pancreas of normal rats showed that activity was dependent on age. The proliferation of acinar and islet cells, which was high in young animals, decreased exponentially with age; proliferation of the ductal cells on the other hand, increased until the animals became mature. These findings suggest that the physiological regeneration of acinar and islet cells, as well as their replacement after injury in adult animals commences from pancreatic ducts.
Two lambda gt11 clones containing overlapping DNA inserts encoding portions of a structural protein gene from Orgyia pseudotsugata multicapsid nuclear polyhedrosis virus (OpMNPV) were identified by their immunoreactivity with polyclonal antisera produced against purified polyhedra-derived virus. Sequence analysis of a 3.6-kb region of the baculovirus genome (map units 69.1-71.6) from which the lambda gt11 inserts originated revealed an open reading frame of 1872 nt (624 amino acids) encoding a predicted protein of 70.6 kDa. Northern blot, primer extension, and 3' S1 analysis of this ORF indicated that an mRNA of approximately 2100 nt was transcribed from this gene. The mRNA appears to initiate from a late promoter/mRNA start site consensus sequence GTAAG and is expressed at late times postinfection. A gene fusion containing the C-terminal 368 amino acids of the gene was constructed using a bacterial trpE expression vector. Rabbit antiserum made against the purified fusion protein reacted with a protein of 87 kDa on Western blots of infected cell extracts at 24 hr p.i. and thereafter. The p87 protein was shown to be a component of both budded and polyhedra-derived virus and purified capsids. Immunofluorescence analysis indicated that p87 is expressed late in infection and concentrated in infected cell nuclei.
A total of 58 patients with histologically confirmed chronic viral hepatitis B and presence of hepatitis B surface antigen and hepatitis B virus DNA (HBV DNA) in the serum were randomized in a prospectively controlled trial. Thirty patients were treated with 3 megaunits of recombinant interferon alfa-2b (INTRON A, R Schering-Plough, Essex Corporation) subcutaneously thrice weekly for 4 months. Twenty-eight controls received no treatment. The post-treatment follow-up period consisted of 6 months. Twenty-eight treated patients and 27 controls completed the protocol. One female patient of the treatment group showed a complete response, and eight other treated patients (32%) showed a partial response to therapy. Three patients in the control group (11%) lost hepatitis B e antigen and HBV DNA spontaneously. This finding is statistically significant (p less than 0.05). The elimination of hepatitis B virus markers from the serum was associated with a normalization of aminotransferase activities in the serum. Reactivation of hepatitis was not observed after seroconversion.
Two members of the Shaker K+ channel family designated ShA2 and ShD2 were characterized in the Xenopus oocyte expression system. The predicted amino acid sequences of ShA2 and ShD2 differ only in the amino terminus, which is located intracellularly according to the present topological model of K+ channels. The differing amino termini have profound effects on the electrophysiological and pharmacological properties of the K+ channel. Most markedly, the nature of the amino terminus determines whether the K+ channel mediates rapidly inactivating or noninactivating K+ currents. It also affects the 4-aminopyridine, tetraethylammonium, and charybdotoxin sensitivities of the K+ channels. These results suggest that the amino terminus of Shaker proteins affects K+ channel structures on both sides of the membrane.
Pentachlorophenol (PCP) dehalogenase from Arthrobacter sp. strain ATCC 33790 converts PCP to tetrachlorohydroquinone. In labeling experiments with H(2)18O or 18O2, only with H(2)18O was labeled product found. However, unlabeled tetrachlorohydroquinone became labeled after incubation with the enzyme in H(2)18O. Therefore, distinction between an oxygenolytic or a hydrolytic dehalogenation mechanism for the PCP dehalogenase is not possible.
In 19 asthmatic children aged 6-16 years, the degree of bronchial hyperreactivity was determined in relationship to the concentration of inhaled histamine which caused a fall of the specific conductance (sGaw) to 60% of the baseline value PC60sGaw. At the time of lung function testing, a sample of heparinized blood was obtained from each patient. Eosinophils were purified and separated into a normodense and hypodense fraction by Percoll gradient centrifugation. After in vitro stimulation by ionophore A 23187, the leukotriene C4 (LTC4) content was determined in the culture supernatants. Hypodense eosinophils of the 13 children with a histamine threshold lower than 1 mg/ml generated significantly (p less than 0.01) larger amounts of LTC4 (0.8-36.3 ng/10(6) cells) when compared to 6 children with a histamine threshold higher than 1 mg/ml (0.7-12.1 ng/10(6) cells) and 12 healthy controls (0.4-8.2 ng/10(6) cells). Preincubation of eosinophils with platelet activating factor (PAF) induced an enhanced LTC4 production, not only in hypodense cells from both asthmatic groups but also in normodense cells from patients with severe hyperresponsiveness. These results are consistent with other results which suggest an important role of eosinophils, their activation by PAF and enhanced release of spasmogenic LTC4 in the pathogenesis of asthma.
The products of the proto-oncogenes c-fos and c-jun form a tight protein complex that is a major component of the transcription factor AP1. To analyze the role of fos in the binding of this complex to the AP1 DNA recognition sequence and the mechanism of interaction in further detail, we have expressed a fos protein in E. coli using an expression vector containing the temperature-inducible lambda PL promoter and a synthetic translational start codon. The fos protein encoded by this construct (termed Baf) was enriched by biochemical purification techniques and was found to form a specific complex with c-jun obtained by in vitro transcription/translation. As shown in gel retardation assays, the baf/jun complex binds to the AP1 DNA recognition sequence with high affinity, while no significant binding was observed with either of the individual protein components, indicating cooperative DNA binding of the two proteins. The fact that the bacterial baf protein does not undergo glycosylation indicates that the post-translational modification of eukaryotic c-fos with N-acetylglucosamine is not required for the formation of a stable fos/jun/DNA complex.
A panel of epitope-specific antibodies, directed against c-Fos, c-Jun, and FosB derived oligopeptide sequences, was generated and used to study the interaction of Fos and Jun proteins and the binding of the Fos/Jun complex to the AP1-binding site (TRE). Our results strongly support results previously obtained by site-directed mutagenesis experiments. The leucine zipper is the major site of interaction between Fos and Jun. Antibodies directed against this domain of Fos bound free Fos protein efficiently, but were unable to recognize Fos within the Fos/Jun complex. In contrast, all other Fos epitope-specific antibodies showed similar reactivity with both free and complexed Fos. Antibodies directed against sequences adjacent to the leucine zipper inhibited formation of the complex. This may suggest that amino acids in the vicinity of the leucine zipper may also play some role in the formation of the protein complex. Binding of Fos/Jun to the TRE was inhibited only by antibodies directed against the basic regions in Fos or Jun previously suggested to represent the DNA binding sites. The fact that very similar results were obtained by two totally different strategies, i.e., mutagenesis experiments and domain mapping using epitope-specific antibodies, lends strong support to the proposed domain structure of Fos and Jun family members.
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Platelet concentrates of the cell separator AS 104 (Fresenius) are compared with those of the cell separator CS 3000 (Fenwal). At each cell separator two platelet preparation protocols and at CS 3000 additionally a WBC preparation protocol was analysed. Platelet counts before and after cellapheresis as well as separation efficiencies show no significant differences between the separation protocols (A, B) and the two cell separators. Platelets of varying volumes show different separation efficiencies. While in WBC concentrates the separation efficiencies of platelets continuously increase from small (2fl) to large (20 fl) platelets, the efficiencies in platelet concentrates decrease in volume range 2 fl-8 fl, and increase in range 8 fl-20 fl. There are no differences between the cell separators. The efficiencies of platelets with 2 fl and 4 fl volumes differ significantly (p less than 0.001) between the protocols A and B of AS 104. After WBC-donation, platelet loss of donors corresponds with platelet yields of the concentrates for the platelet volume range 2 fl-20 fl. Compared with the calculated platelet loss of donors after platelet donation more small platelets with 2 fl-8 fl volumes are found in platelet concentrates. The yields of platelets with 10 fl-20 fl volumes are in accordance with donor's platelet loss.