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Biomedical subjects

M Hofmann

Publications and source records attributed to M Hofmann.

At least 163 records · Page 9Linked to original sources
PubMed1994

The role of the cAMP pathway in mediating the effect of head activator on nerve-cell determination and differentiation in hydra.

In hydra, head activator (HA) acts as positive signal for nerve-cell determination and differentiation. For both events, HA uses cAMP as the second messenger. Evidence is presented that the cAMP agonist, Sp-cAMPS, is able to mimick the effect of HA on nerve-cell determination and differentiation and that it is blocked by the antagonist Rp-cAMP. An adenylyl cyclase associated protein, CAP, appears to be involved as mediator for transducing the signal from the transmembrane HA receptor to the cAMP system. A cDNA coding for hydra CAP was isolated from the multiheaded mutant of Chlorohydra viridissima. The hydra CAP shows extensive homology with the yeast and, more so, mammalian CAPs. In hydra, CAP mRNA is expressed abundantly in interstitial and epithelial cells. The effect of HA, but not of cAMP, on nerve-cell differentiation was inhibited by pretreatment of hydra with a cap antisense oligonucleotide, suggesting a role for CAP as mediator in the signal transduction cascade between HA and cAMP.

Amino Acid Sequence↗
PubMed1994

Randomized trial comparing two devices: the Palmaz-Schatz stent and the Strecker stent in bail-out situations.

UNLABELLED: To assess whether differences in design (geometry, flexibility) and material (electrostatic behavior) may influence the acute and late outcome following intracoronary stent implantation in the treatment of acute or threatened closure after prolonged balloon inflations, 50 patients were randomized to receive either a Palmaz-Schatz stent (n = 25) or a Strecker stent (n = 25). RESULTS: [table: see text] CONCLUSION: Both Palmaz-Schatz and Strecker stents are equally effective in restoring vessel patency in bail-out situations. The incidence of complications is high and similar for both stents if they were used after failed prolonged balloon inflations. Differences in design and material do not seem to influence the results.

Angioplasty, Balloon, Coronary↗
PubMed1993

The structures of native phosphorylated chicken cystatin and of a recombinant unphosphorylated variant in solution.

The solution structures of the phosphorylated form of native chicken cystatin and the recombinant variant AEF-S1M-M29I-M89L were determined by 2D, 3D and 4D-NMR. The structures turn out to be very similar, despite the substitutions and the phosphorylation of the wild-type. Their dominant feature is a five-stranded beta-sheet, which is wrapped around a five-turn alpha-helix, as shown by X-ray crystallographic studies of wild-type chicken cystatin. However, the NMR analysis shows that the second helix observed in the crystal is not present in solution. The phosphorylation occurs at S80, which is located in a flexible region. For this reason, very few effects on the structure are observed. Comparison of structures of the unphosphorylated variant and the wild-type shows small effects on H84 which is located in the supposed recognition site of the serine kinase. This recognition site appears to be well structured as a large loop-containing bulge of the beta-sheet. The N termini of both mutants, which contribute to a large extent to the binding to the proteinase, are very flexible. A loop structure involving the residues L7 to A10 as found in related inhibitors, such as in the kininogen domains 2 and 3, is not sufficiently populated to be observed.

Amino Acid Sequence↗
PubMed1993

Variant CD44 adhesion molecules are expressed in human brain metastases but not in glioblastomas.

Although human glioblastomas are highly invasive tumors intracerebrally, only rarely do they metastasize outside the central nervous system. In contrast, the brain is a major target for metastatic spread of many systemic tumors. Recently, it was demonstrated that expression of splice variants of CD44 (CD44v), but not standard CD44 (CD44s), was sufficient to confer metastatic potential to low- or nonmetastatic rat tumor cells. Because CD44 is expressed in brain tumors, we examined whether differential expression of CD44 isoforms was correlated with the metastatic behavior of these tumors. We compared CD44s and CD44v expression in 17 human glioblastomas, 18 glioma cell lines, and metastases of 15 other tumors to the brain by reverse transcription/polymerase chain reaction, Northern blotting, and immunocytochemistry. These experiments showed that 0 of 17 glioblastomas and 0 of 18 glioma cell lines expressed CD44v as compared to 12 of 15 brain metastases. These data show a correlation between CD44v expression and the metastatic ability of the tumors analyzed (P < 0.01). This suggests (a) that the biological significance of the lack of CD44v expression in human glioblastomas warrants further examination with regard to their inability to metastasize extraneurally and (b) that CD44v expression may play a role in the intracerebral spread of about 80% [corrected] of the brain metastases. Therefore, CD44v expression should be further considered as a potential marker for differential diagnosis and prognosis of patients with brain metastases.

Base Sequence↗
PubMed1993

Investigation of the human metabolism of antipyrine using coupled liquid chromatography and nuclear magnetic resonance spectroscopy of urine.

The potential of coupled high-performance liquid chromatography-nuclear magnetic resonance spectroscopy for the detection and identification of drug metabolites has been investigated by direct analysis of human urine collected following administration of antipyrine. This approach provided a rapid method of characterizing the major human urinary metabolites of this drug and promises to be of widespread value in structural studies of xenobiotic metabolites.

Antipyrine↗
PubMed1993

[The long-term success after coronary angioplasty in old age].

Long-term results of coronary angioplasty (CAP) were compared between two age-groups of patients. Group 1 had 227 patients (158 men, 69 women) with a mean age of 70 (65-88) years, group 2 had 717 patients (611 men, 106 women), mean age 54 (20-64) years. Unstable angina was more common in group 1 than group 2 (48.9 vs 37.7%, P < 0.05). Multi-vessel disease was present in 50.7% of those in group 1 and 41.9% in group 2. Primary success of CAP was similar in the two groups (group 1: 88.1%, group 2: 90.5%). The long-term effect at the first follow-up angiography 3-4 months after CAP was slightly less favourable in group 1 than 2 (54.9 vs 58.3%; difference not significant). However, there were more patients with unstable angina in group 1. Thus the angiographic long-term results were worse in the older patients (44.6 vs 60.1%; P < 0.05), while there was no difference between the two groups as regards stable angina (64.7 vs 57.2%). After a second CAP (because of recurrence), the long-term angiographic effect was, if anything, slightly better in the older patients (87.0 vs 77.1%). The death-rate (cardiac causes of death) up to one year after CAP was comparable in the two groups (1.7 vs 0.8%), as was the rate of non-fatal myocardial infarction (2.2 vs 1.3%). These data indicate that clinical and angiographic long-term success after CAP is comparable in older and younger patient groups and age alone does not present a higher risk.

Adult↗
PubMed1993

A link between ras and metastatic behavior of tumor cells: ras induces CD44 promoter activity and leads to low-level expression of metastasis-specific variants of CD44 in CREF cells.

The activated oncogene c-Ha-ras induces expression of the surface glycoprotein CD44 in cloned rat embryonic fibroblasts (CREF). Induction is transcriptional as shown by transient cotransfections of c-Ha-ras expression constructs and CD44 promoter reporter gene constructs and depends on the presence of an AP-1 binding site at position -110. Increased transcript levels for the standard isoform of CD44 (CD44s) are accompanied by the appearance of alternatively spliced RNAs and the synthesis of variants of CD44 (CD44v). These CD44v molecules differ from the standard type by the addition of sequences in the extracellular portion of the molecules. The occurrence of CD44v molecules in CREF cells upon induction of the CD44 promoter is probably due to leakiness of the splice control in these cells since stable transfection with c-Ha-ras does not alter the CD44v/total CD44 ratio. Upon ras overexpression, however, using an inducible mouse mammary tumor virus-ras construct, a transient increase of CD44v/total CD44 ratio of 3-4 has been determined suggesting that a burst of ras expression, in the genetic background of CREF cells, influences both promoter activity and splice control or accuracy. The expression of CD44v proteins is responsible for the metastatic potential in a variety of tumors (U. Günthert et al., Cell, 65: 13-24, 1991). Also in CREF cells expression of CD44v correlates with metastatic behavior, ras-transfected CREF cells are not only fully transformed but also give rise to metastatic spread as measured in the spontaneous metastasis assay. The adenoviral oncogene E1A counteracts ras-induced promoter function and, consequently, inhibits metastatic behavior without extinguishing transformation.

Animals↗
PubMed1993

The two major CD44 proteins expressed on a metastatic rat tumor cell line are derived from different splice variants: each one individually suffices to confer metastatic behavior.

The metastatic pancreas carcinoma cell line BSp73ASML produces a variety of different splice variants of the transmembrane glycoprotein CD44. The NH2-terminal portions are identical and heavily glycosylated. The variant sequences are inserted just outside the transmembrane region of the molecules. The two most abundant variants have 162 and 85 extra amino acids, respectively. When individually expressed, these suffice to establish metastatic properties in the nonmetastatic tumor cell line BSp73AS, as assayed by the spontaneous metastasis protocol.

Adenocarcinoma↗
PubMed1993

Splicing choice from ten variant exons establishes CD44 variability.

The enormous heterogeneity of the surface protein designated CD44 is in part due to posttranslational modification, and in part due to differential splicing. Alternative splicing occurs within one particular region encoding the extracellular portion of the protein. Comparison of various cDNA clones with different 'inserts' in this variable region with sequences of genomic clones from the mouse has revealed the existence of at least ten exons from which sequences are chosen by alternative splicing. Various combinations of these exons account for the tremendous heterogeneity of CD44 molecules expressed in different tissues, and in progressing tumor cells. The existence of different isoforms of CD44 suggests a broad spectrum of yet unknown physiologic functions.

Amino Acid Sequence↗
PubMed1993

High-performance liquid chromatography coupled to high-field proton nuclear magnetic resonance spectroscopy: application to the urinary metabolites of ibuprofen.

The use of coupled reversed-phase high-performance liquid chromatography and high-field proton nuclear magnetic resonance spectroscopy (HPLC-NMR) for the detection and identification of the urinary metabolites of ibuprofen is described. Urine was obtained from a healthy human volunteer following a normal therapeutic dose of 400 mg of ibuprofen. Analysis was performed on both a freeze-dried urine concentrate and partially purified extracts obtained by solid-phase extraction onto C-18 bonded silica gel. Both continuous and stop-flow methods were used to obtain spectra enabling the major urinary metabolites of ibuprofen to be detected and identified.

Chromatography, High Pressure Liquid↗
PubMed1993

Prevention of tumor metastasis formation by anti-variant CD44.

A splice variant of CD44 (CD44v) originally discovered on metastases of a rat pancreatic adenocarcinoma (BSp73ASML) has been shown by transfection to confer metastatic behavior to nonmetastatic tumor cells (Günthert U., M. Hofmann, W. Rudy, S. Reber, M. Zöller, I. Haussmann, S. Matzku, A. Wenzel, H. Ponta, and P. Herrlich. 1991. Cell. 65:13). A monoclonal antibody (mAb), 1.1ASML, to the metastasis-specific domain of the CD44v molecule retards growth of lymph node and lung metastases of the metastatic tumor line BSp73ASML, and can efficiently prevent formation of metastases by the transfected line. The antibody is only effective when given before lymph node colonization. Anti-CD44v does not downregulate the expression of CD44v, and prevention of metastatic growth by anti-CD44v is not due to activation of any kind of immune defense. We suggest that the mAb interferes with proliferation of metastasizing tumor cells in the draining lymph node, most probably by blocking a ligand interaction. The interference with metastatic spread will greatly facilitate the exploration of the function of CD44v and, in particular, may also open new strategies for the therapy of human metastases.

Animals↗
PubMed1993

Coupling of HPLC with 19F- and 1H-NMR spectroscopy to investigate the human urinary excretion of flurbiprofen metabolites.

Results of an on-line HPLC-NMR analysis of human urine from a volunteer administered the anti-inflammatory drug flurbiprofen are reported. The two major human urinary metabolites, namely the glucuronides of flurbiprofen and of 4'-hydroxyflurbiprofen, have been identified using 1H- and 19F-NMR spectroscopy. In vivo conjugation of the racemic drug and its metabolites with D-glucuronic acid results in diastereomeric molecules which give resolved NMR spectra thereby permitting the diastereomeric proportions to be evaluated. The cause of the observed deviation from equal proportions is discussed. This study represents the first use of both 19F- and 600 MHz 1H-NMR spectroscopy coupled to HPLC.

Chromatography, High Pressure Liquid↗
PubMed1993

Expression of CD44 isoforms carrying metastasis-associated sequences in newborn and adult rats.

Expression of a splice variant of CD44, recognised by the monoclonal antibody (Mab) 1.1ASML, confers metastatic potential to non-metastasising tumour cells (Cell 1991, 65, 13-24). To explore whether the metastasis-associated variant of CD44 (CD44v) is expressed under physiological conditions, tissues of newborn and adult rats were stained with the Mab 1.1ASML. The 1.1ASML epitope is, indeed, expressed on the basal layer of the epidermis and the hair follicles as well as on cryptic epithelia in the gut. In addition, ductal epithelia of the pancreatic gland of newborn rats express CD44v. This pattern of expression differs from that of standard lymphocyte CD44 (CD44s). The anti-CD44s mAB Ox50 predominantly stains connective tissue. Although different variants of CD44 may express the epitope recognised by 1.1ASML, cells expressing CD44v share properties with metastasising tumour cells: the stage of proliferation and a restricted degree of mobility. Thus, during metastatic progression tumour cells may reactivate the expression of gene segments which serve highly specialised functions in embryonic and adult tissues.

Aging↗
PubMed1993

A human homologue of the rat metastasis-associated variant of CD44 is expressed in colorectal carcinomas and adenomatous polyps.

A recently described splice variant of CD44 expressed in metastasizing cell lines of rat tumors has been shown to confer metastatic potential to a non-metastasizing rat pancreatic carcinoma cell line and to non-metastasizing sarcoma cells. Homologues of this variant as well as several other CD44 splice variants are also expressed at the RNA level in human carcinoma cell lines from lung, breast, and colon, and in immortalized keratinocytes. Using antibodies raised against a bacterial fusion protein encoded by variant CD44 sequences, we studied the expression of variant CD44 glycoproteins in normal human tissues and in colorectal neoplasia. Expression of CD44 variant proteins in normal human tissues was readily found on several epithelial tissues including the squamous epithelia of the epidermis, tonsils, and pharynx, and the glandular epithelium of the pancreatic ducts, but was largely absent from other epithelia and from most non-epithelial cells and tissues. In human colorectal neoplasia CD44 variant proteins, including homologues of those which confer metastatic ability to rat tumors, were found on all invasive carcinomas and carcinoma metastases. Interestingly, focal expression was also observed in adenomatous polyps, expression being related to areas of dysplasia. The distribution of the CD44 variants in human tissues suggests that they play a role in a few restricted differentiation pathways and that in colorectal tumors one of these pathways has been reactivated. The finding that metastasis-related variants are already expressed at a relatively early stage in colorectal carcinogenesis and tumor progression, i.e., in adenomatous polyps, suggests the existence of a yet unknown selective advantage linked to CD44 variant expression. The continued expression in metastases would be compatible with a role in the metastatic process.

Antibodies, Monoclonal↗
PubMed1993

Activated mouse astrocytes and T cells express similar CD44 variants. Role of CD44 in astrocyte/T cell binding.

The CD44 adhesion molecule is expressed by astrocytes, glial-type cells which exhibit features of accessory cells for immune responses in the central nervous system. In primary cultures of mouse astrocytes, we have observed that surface expression and mRNA levels of CD44 are induced following stimulation with either PMA, or tumor necrosis factor alpha plus gamma interferon. Comparison of CD44 splice variants expressed by astrocytes and a T cell hybridoma shows that upon activation, both cell types express a similar pattern of CD44 transcripts. Thus, in both cell types, CD44 transcripts are produced which contain additional exons, including the exon v6 (known to be expressed by in vivo activated lymphocytes and by metastatic variants of tumor cells) as well as variants of larger size. In the autoimmune disease multiple sclerosis, activated T cells cross the blood-brain barrier and lead to inflammation in the central nervous system. Analysis of mice with experimental allergic encephalomyelitis, frequently used as an animal model of multiple sclerosis, shows that CD44 is induced in vivo on glial cells surrounding inflammatory lesions. Using an in vitro model for adhesion between T cells and astrocytes, we have found a correlation between the activation state of these cells and their adhesion potential. Dose-dependent inhibition of adhesion by hyaluronate and by anti-CD44 monoclonal antibody KM81 shows that CD44 is involved in the adhesive interactions between T cells and astrocytes.

Animals↗
PubMed1993

[Plasma concentrations of non-esterified fatty acids and lipids in high-dose medroxyprogesterone therapy of metastatic breast cancer].

The objective of this study was to investigate the influence of high dose MPA on serum cholesterol, triglyceride, phospholipids as well as free fatty acids given to 17 patients with metastatic breast cancer. Before the therapy, the patients with cancer revealed higher level in serum cholesterol, triglyceride, phospholipids and C 12:0, C 18:0 as we found it in the control (13 patients without cancer). There was no significant change in lipid parameters by treatment with MPA whereas cortisol decreases and insulin increases under therapy. The results are discussed under biochemical aspects.

Blood Glucose↗