Biomedical subjects

Michael Bachmann

Publications and source records attributed to Michael Bachmann.

At least 19 recordsLinked to original sources

PubMed2006

Microcanonical analyses of peptide aggregation processes.

We propose the use of microcanonical analyses for numerical studies of peptide aggregation transitions. Performing multicanonical Monte Carlo simulations of a simple hydrophobic-polar continuum model for interacting heteropolymers of finite length, we find that the microcanonical entropy behaves convex in the transition region, leading to a negative microcanonical specific heat. As this effect is also seen in first-order-like transitions of other finite systems, our results provide clear evidence for recent hints that the characterization of phase separation in first-order-like transitions of finite systems profits from this microcanonical view.

Chemical Phenomena↗

PubMed2006

Nuclear localization of Survivin renders HeLa tumor cells more sensitive to apoptosis by induction of p53 and Bax.

Clinical studies have shown that nuclear expression of the inhibitor of apoptosis protein Survivin in tumor cells predicted a favorable prognosis whereas cytosolic-localized protein caused a decreased overall survival. Therefore Survivin's subcellular localization may be important for its anti-apoptotic capacity. To address this question, we investigated localization and function of Survivin in normal human lung fibroblasts (NHLFs) and HeLa tumor cells. NHLFs of early passages expressed Survivin in the nucleus and were highly sensitive to C2 ceramide, which induces the mitochondrial apoptotic pathway. In contrast, NHLFs at higher passages relocated Survivin to the cytosol and became more resistant to C2 ceramide. Blocking nuclear export of Survivin by leptomycin B in HeLa cells increased susceptibility to C2 ceramide. In addition, transduction of HeLa cells with Survivin fused to a nuclear localization signal augmented basal expression levels of p53 and Bax and enhanced sensitivity for intrinsic apoptosis. Those findings suggest that a predominant nuclear localization of Survivin increases the sensitivity for pro-apoptotic stimuli, whereas nuclear export enables Survivin to fulfill its inhibitor of apoptosis function. A therapeutic intervention which holds Survivin in the nucleus of tumor cells might improve cancer therapy.

Apoptosis↗

PubMed2006

Structural properties of small semiconductor-binding synthetic peptides.

We have performed exhaustive multicanonical Monte Carlo simulations of three 12-residue synthetic peptides in order to investigate the thermodynamic and structural properties as well as the characteristic helix-coil transitions. In these studies, we employ a realistic model where the interactions between all atoms are taken into account. Effects of solvation are also simulated by using an implicit-solvent model.

Journal Article↗

PubMed2006

9-O-acetyl GD3 protects tumor cells from apoptosis.

The ganglioside GD3 (Neu5Ac alpha8Neu5Ac alpha3Gal beta4GlcCer) is an intracellular lipid messenger that induces apoptosis by targeting mitochondria in various cell types. GD3 can also promote apoptosis when externally added to cells. Previous studies showed that the proapoptotic effects of GD3 can be counteracted by 9-O-acetylation. To determine whether 9-O-acetyl GD3 (acGD3) has a general antiapoptotic potential, the apoptosis-sensitive Jurkat cell line and an apoptosis-sensitive variant of the cell line Molt-4 were preincubated with micromolar concentrations of acGD3 and then treated with inducers of apoptosis. A reduced apoptotic index and an increased cell viability were observed. On the other hand, when the Jurkat cells were treated with GD3 for extended periods of time, a population was selected that was resistant to apoptosis induction by N-acetyl sphingosine as well as by the anti-leukemic drug daunorubicin. Comparative analysis of gangliosides revealed the formation of acGD3 in the resistant Jurkat cells that was not found in the apoptosis-sensitive cells. Conversely, exposing the acGD3 positive and apoptosis-resistant cell line Molt-4 to the O-deacetylating activity of salicylate resulted in a complete disappearance of acGD3 and an enhanced sensitivity to N-acetyl sphingosine-mediated apoptosis. Formation of acGD3 might thus represent a new mechanism how tumor cells can escape apoptosis.

Acetylation↗

PubMed2006

Oxidatively modified autoantigens in autoimmune diseases.

Free radical-mediated oxidative damage and consequent protein modification by the end products of oxidative damage are important mediators of cell toxicity and disease pathogenesis. Aldehydic products, mainly the 4-hydroxy-2-alkenals, form adducts with proteins and make them highly immunogenic. Oxidative modification of proteins has been shown to elicit antibodies in a variety of diseases including systemic lupus erythematosus (SLE), alcoholic liver disease, diabetes mellitus (DM), and rheumatoid arthritis (RA). Oxidatively modified DNA (8-oxodeoxyguanine) and low-density lipoproteins (LDL) occur in SLE, a disease in which premature atherosclerosis is a serious problem. In addition, immunization with 4-hydroxy-2-nonenal (HNE)-modified 60-kDa Ro autoantigen elicits an accelerated epitope spreading in an animal model of SLE. Advanced glycation end product (AGE) pentosidine and AGE-modified IgG have been shown to correlate with RA disease activity. Oxidatively modified glutamic acid decarboxylase is important in type 1 DM, while autoantibodies against oxidized LDL are prevalent in Behcet's disease. The fragmentation of scleroderma-specific autoantigens occurs as a result of oxidative modification and is thought to be responsible for the production of autoantibodies through the release of cryptic epitopes. In the face of overwhelming evidence for the involvement of oxidative damage in autoimmunity the administration of antioxidants is a viable untried alternative for preventing or ameliorating autoimmune disease, although results in cardiovascular disease are disappointing.

Autoantigens↗

PubMed2006

Substrate adhesion of a nongrafted flexible polymer in a cavity.

In a contact-density chain-growth study we investigate the solubility-temperature pseudophase diagram of a lattice polymer in a cavity with an attractive surface. In addition to the main phases of adsorbed and desorbed conformations we find numerous subphases of collapsed and expanded structures.

Journal Article↗

PubMed2006

Identification of a naturally processed T cell epitope derived from the glioma-associated protein SOX11.

The development of T cell-based immunotherapies of cancer depends on the identification of tumor-associated antigens capable of eliciting tumor-directed cytotoxic T cell responses. In malignant glioma the number of well-defined target antigens for cytotoxic T lymphocytes (CTLs) is still very limited. Recently, we demonstrated the abundant and specific overexpression of the transcription factor SOX11 in malignant glioma. Here, we describe the SOX11-derived peptide LLRRYNVAKV which is capable of inducing human leukocyte antigen-A*0201-restricted and tumor-reactive CTLs. This novel CTL epitope may serve as an attractive candidate for a T cell-based immunotherapy of glioma.

Amino Acid Sequence↗

PubMed2006

Substrate specificity of peptide adsorption: a model study.

Applying the contact density chain-growth algorithm to lattice heteropolymers, we identify the conformational transitions of a nongrafted hydrophobic-polar heteropolymer with 103 residues in the vicinity of a polar, a hydrophobic, and a uniformly attractive substrate. Introducing only two system parameters, the numbers of surface contacts and intrinsic hydrophobic contacts, respectively, we obtain surprisingly complex temperature and solvent dependent, substrate-specific pseudophase diagrams.

Adsorption↗

PubMed2005

D-TMPP: a novel androgen-regulated gene preferentially expressed in prostate and prostate cancer that is the first characterized member of an eukaryotic gene family.

BACKGROUND: The understanding of the molecular biology of the prostate and the process of prostate carcinogenesis is brought forward by the identification and characterization of new genes specifically expressed in prostate tissue. The encoded proteins may, in addition, provide novel diagnostic and therapeutic tools in prostate carcinoma (PCa). Here, we identify the novel gene Dresden-transmembrane protein of the prostate (D-TMPP) that is overexpressed in human prostate and prostate cancer. METHODS: Proceeding from a prostate-specific expressed sequence tag identified with an Affymetrix chip-based expression database, the full-length cDNA of the novel gene was isolated from prostate tissue. The potential protein-coding function of the open reading frame (ORF) was tested by in vitro transcription-coupled translation and recombinant expression in transfected prostate cancer cells. The expression pattern of D-TMPP in malignant and nonmalignant tissues and tumor cell lines was analyzed by hybridization of a radioactively labeled cDNA probe with a multiple tissue expression array and by a quantitative real-time PCR assay. RESULTS: The D-TMPP-mRNA encodes a putative seven-span transmembrane protein of 883 amino acids and is selectively overexpressed in prostate tissue. D-TMPP represents the first cloned and characterized transcript of a family of eukaryotic genes. D-TMPP transcripts were detected in all analyzed pairs (n = 25) of malignant and nonmalignant prostate tissues. In the androgen-dependent PCa cell line LNCaP, D-TMPP was upregulated by methyltrienolone. CONCLUSIONS: We describe the novel prostate-restricted molecule D-TMPP widely expressed in prostate cancer tissues.

Aged↗

PubMed2005

Conformational transitions of nongrafted polymers near an absorbing substrate.

We have performed multi-canonical chain-growth simulations of a polymer interacting with an adsorbing surface. The polymer, which is not explicitly anchored at the surface, experiences a hierarchy of phase transitions between conformations binding and nonbinding with the substrate. We discuss the phase diagram in the temperature-solubility plane and highlight the transition path through the free-energy landscape.

Absorption↗

PubMed2005

Tissue-specificity of prostate specific antigens: comparative analysis of transcript levels in prostate and non-prostatic tissues.

Activation of immune defense mechanisms against tumor antigens appears to be a promising therapeutic option for advanced prostate cancer (PCa). Specific immunotherapy critically depends on target antigens that are selectively expressed in the tumorous and optional in the normal prostate tissue in sufficient amounts. Although several prostate antigens have been described and some have already been used in clinical trials, a detailed comparative evaluation of their tissue-specificity and expression levels is still lacking. We determined the transcript levels of eight prostate targets (PSA, PAP, PSCA, PSGR, Prostein, PSMA, AIbZIP, trp-p8) in 16 different tissues by quantitative PCR and calculated a tissue-specificity index (TSI) for each molecule. Besides a preferential expression in prostate for all targets, striking differences in the expression levels and TSI were revealed which may be important for the selection of appropriate antigens for immunotherapy of PCa.

Acid Phosphatase↗

PubMed2005

Transcript quantification of Dresden G protein-coupled receptor (D-GPCR) in primary prostate cancer tissue pairs.

Recently, we identified the novel protein D-GPCR (Dresden G protein-coupled receptor) which is selectively overexpressed in human prostate cancer (PCa) and belongs to the subfamily of odorant-like orphan GPCRs. Quantification of D-GPCR transcripts in paired malignant and non-malignant prostate tissues of 106 patients with primary PCa by real-time PCR demonstrated a significant up-regulation of this gene in tumor samples. Furthermore, its expression increases with higher tumor stages and grades. The evaluation of D-GPCR expression as a potential molecular tumor marker was performed by receiver-operating characteristic curve (ROC) analysis resulting in an area under the curve (AUC) value of 0.6452. Hence, the evaluation of D-GPCR as possible additive diagnostic tool and putative therapy target appears promising.

Aged↗

PubMed2005

Tumoricidal potential of native blood dendritic cells: direct tumor cell killing and activation of NK cell-mediated cytotoxicity.

Dendritic cells (DCs) are characterized by their unique capacity for primary T cell activation, providing the opportunity for DC-based cancer vaccination protocols. Novel findings reveal that besides their role as potent inducers of tumor-specific T cells, human DCs display additional antitumor effects. Most of these data were obtained with monocyte-derived DCs, whereas studies investigating native blood DCs are limited. In the present study, we analyze the tumoricidal capacity of M-DC8(+) DCs, which represent a major subpopulation of human blood DCs. We demonstrate that IFN-gamma-stimulated M-DC8(+) DCs lyse different tumor cell lines but not normal cells. In addition, we show that tumor cells markedly enhance the production of TNF-alpha by M-DC8(+) DCs via cell-to-cell contact and that this molecule essentially contributes to the killing activity of M-DC8(+) DCs. Furthermore, we illustrate the ability of M-DC8(+) DCs to promote proliferation, IFN-gamma production, and tumor-directed cytotoxicity of NK cells. The M-DC8(+) DC-mediated enhancement of the tumoricidal potential of NK cells is mainly dependent on cell-to-cell contact. These results reveal that, in addition to their crucial role in activating tumor-specific T cells, blood DCs exhibit direct tumor cell killing and enhance the tumoricidal activity of NK cells. These findings point to the pivotal role of DCs in triggering innate and adaptive immune responses against tumors.

Blood Cells↗

PubMed2005

Multicanonical study of coarse-grained off-lattice models for folding heteropolymers.

We have performed multicanonical simulations of hydrophobic-hydrophilic heteropolymers with two simple effective, coarse-grained off-lattice models to study the influence of specific interactions in the models on conformational transitions of selected sequences with 20 monomers. Another aspect of the investigation was the comparison with the purely hydrophobic homopolymer and the study of general conformational properties induced by the "disorder" in the sequence of a heteropolymer. Furthermore, we applied an optimization algorithm to sequences with up to 55 monomers and compared the global-energy minimum found with lowest-energy states identified within the multicanonical simulation. This was used to find out how reliable the multicanonical method samples the free-energy landscape, in particular for low temperatures.

Binding Sites↗

PubMed2005

Modification of lupus-associated 60-kDa Ro protein with the lipid oxidation product 4-hydroxy-2-nonenal increases antigenicity and facilitates epitope spreading.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with autoantibodies as a near universal feature of the disease. The Ro ribonucleoprotein particle, composed of a 60-kDa protein noncovalently associated with human cytoplasmic RNA, is the target of antibodies in 25-40% of lupus patients. Purified human 60-kDa Ro was found to be oxidatively modified. Earlier investigations from our laboratory revealed increased oxidative damage in SLE patients. Therefore we hypothesized that oxidation by-products, such as 4-hydroxy-2-nonenal (HNE), could lead to neoantigens like HNE-modified 60-kDa Ro, which could in turn initiate autoimmunity or drive epitope spreading. To test this hypothesis we immunized rabbits with either HNE-modified 60-kDa Ro or the unmodified Ro. Intramolecular epitope spreading within the Ro molecule and intermolecular epitope spreading to La, double-stranded DNA, nRNP, and Sm occurred preferentially in HNE-Ro-immunized animals. Nonspecific anti-HNE antibody, generated by immunization with HNE-keyhole limpet hemocyanin conjugate, did not significantly bind to these autoantigens. These data may suggest a hitherto unappreciated mechanism by which oxidative stress facilitates epitope spreading in SLE.

Aldehydes↗

PubMed2005

Exact sequence analysis for three-dimensional hydrophobic-polar lattice proteins.

We have exactly enumerated all sequences and conformations of hydrophobic-polar (HP) proteins with chains of up to 19 monomers on the simple cubic lattice. For two variants of the HP model, where only two types of monomers are distinguished, we determined and statistically analyzed designing sequences, i.e., sequences that have a nondegenerate ground state. Furthermore we were interested in characteristic thermodynamic properties of HP proteins with designing sequences. In order to be able to perform these exact studies, we applied an efficient enumeration method based on contact sets.

Amino Acid Sequence↗

PubMed2004

D-GPCR: a novel putative G protein-coupled receptor overexpressed in prostate cancer and prostate.

The use of molecular targets in novel strategies of tumor treatment largely depends on the identification of proteins with a tumor- or tissue-restricted expression. We identified the novel protein D-GPCR that is selectively overexpressed in human prostate cancer and prostate and belongs to the subfamily of odorant-like orphan G protein-coupled receptors. Quantification of D-GPCR transcripts in different human tissues by real-time PCR demonstrated 27-fold overexpression in prostate compared to skeletal muscle, the organ with second highest transcript numbers in males. Investigation of tumor/normal cDNA pairs obtained from 241 cancer patients including four prostate tumors confirmed the preferential expression in prostate. When comparing the mean transcript level of 15 prostate cancer tissues to their non-tumorous counterparts, D-GPCR was almost 6-fold upregulated. Coupled in vitro transcription and translation of D-GPCR cDNA produced a protein band of approximately 28 kDa. Recombinant, His-tagged protein was expressed in transfected HEK293 cells and gave rise to a 30 kDa band specifically detected by anti-His antibody. These data provide the basis for future studies evaluating the diagnostic potential of D-GPCR and its utility as a novel target in immunotherapy of prostate cancer.

Aged↗

PubMed2004

Thermodynamics of lattice heteropolymers.

We calculate thermodynamic quantities of hydrophobic-polar (HP) lattice proteins by means of a multicanonical chain-growth algorithm that connects the new variants of the Pruned-Enriched Rosenbluth Method and flat histogram sampling of the entire energy space. Since our method directly simulates the density of states, we obtain results for thermodynamic quantities of the system for all temperatures. In particular, this algorithm enables us to accurately simulate the usually difficult accessible low-temperature region. Therefore, it becomes possible to perform detailed analyses of the low-temperature transition between ground states and compact globules.

Algorithms↗