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Biomedical subjects

M Euler

Publications and source records attributed to M Euler.

10 recordsLinked to original sources
PubMed2005

Synergistic apoptosis induction by proteasome and histone deacetylase inhibitors is dependent on protein synthesis.

Proteasome inhibitors are able to efficiently induce apoptosis in many tumor cells while leaving quiescent, untransformed cells largely unharmed. Here we investigated the further enhancement of proteasome inhibitor-mediated apoptosis induction in Bcr-Abl positive K562 CML cells by simultaneous treatment with different histone deacetylase inhibitors (HDIs). Combining proteasome and HDIs resulted in rapid hyperacetylation of histone H3 and accumulation of polyubiquitinated proteins and the synergistic induction of apoptosis. Apoptosis induction was associated with caspase 8, 3 and 9 activation, Bid processing, destruction of the mitochondrial membrane potential, cleavage of PARP and lamin B and extensive DNA fragmentation. The pan-caspase inhibitor Z-VAD-FMK and the caspase-8 inhibitor Z-IETD-FMK could inhibit K562 cell apoptosis. Apoptosis was also delayed by overexpression of Bcl-xL, as well as by crmA, a known inhibitor of caspases 1 and 8. Caspase 8 activity could still be detected in the presence of ectopic Bcl-xL, but not in crmA transfected cells. The most striking anti-apoptotic effect though was obtained by the translational inhibitor cycloheximide, which abolished caspase 8 processing, blocked Bid cleavage and maintained the mitochondrial transmembrane potential. Apoptosis by the combination treatment occurred independently from CD95/Fas receptor stimulation. These results demonstrated that transcriptional activation by HDIs combined with proteasome inhibitor mediated posttranslational stabilization of protein(s) results in significantly enhanced CML apoptosis which was striktly dependent on uninterrupted protein synthesis.

Animals↗
PubMed2001

Characterization of the distribution of matter in hybrid liver support devices where cells are cultured in a 3-D membrane network or on flat substrata.

Bioreactors for liver assist tested on small animal models are generally scaled-up to treat humans by increasing their size to host a given liver cell mass. In this process, liver cell function in different culture devices is often established based on the metabolite concentration difference between the bioreactor inlet and outlet irrespective of how matter distributes in the bioreactor. In this paper, we report our investigation aimed at establishing whether bioreactor design and operating conditions influence the distribution of matter in two bioreactors proposed for liver assist. We investigated a clinical-scale bioreactor where liver cells are cultured around a three-dimensional network of hollow fiber membranes and a laboratory-scale bioreactor with cells adherent on collagen-coated flat substrata. The distribution of matter was characterized under different operating modes and conditions in terms of the bioreactor residence time distribution evaluated by means of tracer experiments and modeled as a cascade of N stirred tanks with the same volume. Under conditions recommended by the manufacturers, matter distributed uniformly in the clinical-scale bioreactor as a result of the intense backmixing (N=1) whereas axial mixing was negligible in the laboratory-scale bioreactor (N=8). Switching from recycle to single-pass operation definitely reduced axial mixing in the clinical-scale bioreactor (N=2). Increasing feed flow rate significantly enhanced axial mixing in the laboratory-scale bioreactor (N=4). The effects of design, operating mode and conditions on matter distribution in bioreactors for liver cell culture suggest that characterization of the distribution of matter is a necessary step in the scale-up of bioreactors for liver assist and when function of liver cells cultured in different bioreactors is evaluated and compared.

Bioreactors↗
PubMed2000

Hypoxia-induced vascular endothelial growth factor expression precedes neovascularization after cerebral ischemia.

We investigated the hypothesis that hypoxia induces angiogenesis and thereby may counteract the detrimental neurological effects associated with stroke. Forty-eight to seventy-two hours after permanent middle cerebral artery occlusion we found a strong increase in the number of newly formed vessels at the border of the infarction. Using the hypoxia marker nitroimidazole EF5, we detected hypoxic cells in the ischemic border of the neocortex. Expression of vascular endothelial growth factor (VEGF), which is the main regulator of angiogenesis and is inducible by hypoxia, was strongly up-regulated in the ischemic border, at times between 6 and 24 hours after occlusion. In addition, both VEGF receptors (VEGFRs) were up-regulated at the border after 48 hours and later in the ischemic core. Finally, the two transcription factors, hypoxia-inducible factor-1 (HIF-1) and HIF-2, known to be involved in the regulation of VEGF and VEGFR gene expression, were increased in the ischemic border after 72 hours, suggesting a regulatory function for these factors. These results strongly suggest that the VEGF/VEGFR system, induced by hypoxia, leads to the growth of new vessels after cerebral ischemia. Exogenous support of this natural protective mechanism might lead to enhanced survival after stroke.

Animals↗
PubMed1999

Classification of cutaneous malignant melanoma: a reassessment of histopathologic criteria for the distinction of different types.

BACKGROUND: Human cutaneous malignant melanoma currently is classified into four principle types: nodular, superficial spreading, lentigo maligna, and acral lentiginous. The criteria for the histopathologic diagnosis of these types are not applied consistently. Nevertheless, the classification has become the foundation of many clinical, histopathologic, epidemiologic, and molecular studies. The results of those studies can have validity only if the classification itself is valid. For this reason, the authors reassessed histopathologic criteria advocated for the distinction of the different types of melanoma and searched for other repeatable constellations of findings that may serve to define distinct subsets of the neoplasm. METHODS: Nine hundred fifteen melanomas were examined with regard to 72 parameters that are considered to be important for histopathologic diagnosis. The results were analyzed statistically with special attention to findings that have been reported to be characteristic of the four principle types of melanoma. RESULTS: The histopathologic criteria advocated for the distinction of different types of melanoma were found not to correlate with one another. A logistic regression analysis did not detect any other repeatable constellation of morphologic findings that may reflect a distinct biologic subgroup. CONCLUSIONS: The validity of the current classification of cutaneous malignant melanoma into four principle types could not be substantiated. Malignant melanoma may present with many different forms, but these forms appear to be part of a continuous spectrum rather than examples of distinct biologic entities.

Adult↗
PubMed1998

Capture of anti-(Galalpha1-3Gal) antibodies by immobilized Galalpha1-3Gal oligomers derived from carrageenan.

An immobilized Galalpha1-3Gal-bearing affinity ligand was prepared as a possible prophylactic binding site of human anti-(Galalpha1-3Gal) antibodies for the prevention of hyperacute rejection of pig xenografts. lambda-Carrageenan, a natural polysaccharide known to possess alternately alpha1-3 and beta1-4-linked D-galactopyranose sulphate residues, was selectively degraded by acetolysis and subsequently deacetylated to obtain lambda-carrageenan oligosaccharides. The resulting syrup was ultrafiltered to remove higher polymers and chromatographed on Sephadex G-15 to produce a series of sized oligosaccharide fractions. An immuno-dot-blot method was established on the basis of the competition between the lambda-carrageenan oligosaccharides in solution and bovine thyroglobulin (BTG), a glycoprotein known to express the Galalpha1-3Gal marker, as the solid-phase antigen. Increasing amounts of lambda-carrageenan fractions added to normal human plasma resulted in a progressive decrease in Galalpha1-3Gal-specific human IgM and IgG binding to BTG. Complete inhibition of Galalpha1-3Gal-specific human immunoglobulin was attained at concentrations less than 0.6 mg of carbohydrate/ml of human plasma with the more active fractions. These bioactive lambda-carrageenan oligosaccharides were immobilized on hydrazide-modified microporous nylon membranes, yielding capacities between 2.18 and 2.86 mg/ml of membrane. A subsequent decrease in the human anti-(Galalpha1-3Gal) antibody level in normal human plasma was demonstrated and proved with the established immuno-dot-blot procedure.

Animals↗
PubMed1987

Cytoskeletal immunohistochemistry of Alzheimer's disease.

The first half of this paper is devoted to a review on the cytoskeletal immunocytochemistry of the various morphological changes in Alzheimer's disease (AD), i.e. neurofibrillary tangles (NFT), senile plaques (SP), granulovacuolar degeneration (GV) and Hirano bodies (HB). In the second half it is demonstrated that sera raised against the paired helical filaments (PHF) in NFT, and monoclonal antibodies to phosphorylated epitopes on neurofilament proteins, also stain structures within neuronal perikarya without PHFs in some diseases. These include Pick bodies and swollen cells in Pick's disease, neurons in old dogs without NFTs, and occasional neurons without NFT in AD. We conclude that PHF constituent proteins can be accumulated in neuronal perikarya of cases with these diseases without being actually assembled to PHFs. In AD and in the old dogs, such accumulations occurring without the formation of PHFs might represent a precursor state of the latter.

Alzheimer Disease↗
PubMed1983

Far-field cochlear microphonics in man and their relation to cochlear integrity.

Far-field cochlear microphonics (CM) in man have been measured as a function of frequency by phase-sensitive detection. CM amplitude, dispersion and input-output functions vary periodically with frequency and exhibit certain frequency windows, where responses are approximately frequency specific, in contrast to the commonly accepted model of basal turn CM generators as main sources. Pathological cochleae show abnormal amplitude and phase functions. The results offer new diagnostic possibilities, because haircell function can be evaluated by a routine non-invasive procedure down to the low frequency speech range.

Audiometry, Evoked Response↗
PubMed1981

Frequency-following potentials in man by lock-in technique.

Frequency-following responses (FFR) from continuous tone stimulation were investigated by lock-in analysis. The technique is superior to conventional tone-burst stimulation, because it allows continuous registration of the response parameters with sweeping frequency. The scalp recorded FFR consists of at least two components separable from each other by their phase/frequency relationship. The microphonic component that dominates in ipsilateral records shows latencies of about 0.5 msec with negligible dispersion and must therefore originate in the basal cochlear turn. The neural component exhibits considerable dispersion, reflecting the travelling wave delay up to the region of best frequency. These long cochlear time delays are consistent with an apical FFR origin, and brain stem sources of the continuous tone response appear to be questionable. The present FFR analysis technique opens up a very direct and comprehensive way to assess the integrity of the entire inner ear for high frequency basal and low frequency apical cochlear regions as well.

Acoustic Stimulation↗