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H Schreiber

Publications and source records attributed to H Schreiber.

At least 37 records · Page 2Linked to original sources
PubMed1999

X-ray structure and conformational dynamics of the HIV-1 protease in complex with the inhibitor SDZ283-910: agreement of time-resolved spectroscopy and molecular dynamics simulations.

Based on the X-ray structure of the human immunodeficiency virus type-1 (HIV-1) protease in complex with the statine-derived inhibitor SDZ283-910, a 542 ps molecular dynamics trajectory was computed. For comparison with the 805 ps trajectory obtained for the uncomplexed enzyme, the theoretical fluorescence anisotropy decay of the unliganded protease and the inhibitor complex was calculated from the trajectories of the Trp6A/Trp6B and Trp42A/Trp42B transition dipole moments. This enabled us to directly compare the simulated data with the experimental picosecond time-resolved fluorescence data. Fitting both experimental and simulated data to the Kohlrausch-Williams-Watts (KWW) function exp(-t/tauk)beta revealed a very good agreement for the uncomplexed protease as well as for the SDZ283-910 complex. Binding of the inhibitor induced a faster decay of both the experimental and the computed protease fluorescence anisotropy decay. By this integrative approach, the atomic detail of inhibitor-induced changes in the conformational dynamics of the HIV-1 protease was experimentally verified and will be used for further inhibitor optimisation.

Anti-HIV Agents↗
PubMed1999

Central nervous system effects of intranasally administered insulin during euglycemia in men.

Insulin receptors have been detected in several structures of the brain, yet the biological significance of insulin acting on the brain remains rather unclear. In humans, direct central nervous effects of insulin are difficult to distinguish from alterations in neuronal functions because of insulin-induced decrease in blood glucose levels. Since several intranasally administered viruses, peptides, and hormones have been shown to penetrate directly from the nose to the brain, we tested whether insulin after intranasal administration likewise has access to the brain. After a 60-min baseline period, insulin (20 IU H-Insulin 100 Hoechst) or vehicle (2.7 mg/ml m-Cresol) was intranasally administered every 15 min to 18 healthy subjects according to a double-blind within-subject crossover design. Auditory-evoked potentials (AEP) indexing cortical sensory processing were recorded while the subjects performed a vigilance task (oddball paradigm) during the baseline phase and after 60 min of intranasal treatment with insulin or placebo. Blood glucose and serum insulin levels were not affected by intranasal insulin. Compared with placebo, intranasal administration of insulin reduced amplitudes of the N1 (P < 0.005) and P3 (P < 0.02) components of the AEP and increased P3 latency (P < 0.05). The reduction in P3 amplitude was most pronounced over the frontal recording site (2.42 +/- 1.00 vs. 4.92 +/- 0.79 microV, P < 0.0005). At this site, after insulin administration, a broad negative shift developed in the AEP between 280 and 500 ms poststimulus (area under the curve -166.0 +/- 183.8 vs. 270.8 +/- 138.7 microV x ms after placebo, P < 0.01). The results suggest that after intranasal administration, insulin directly enters the brain and exerts distinct influences on central nervous functions in humans.

Administration, Intranasal↗
PubMed1999

Enhanced eradication of local and distant tumors by genetically produced interleukin-12 and radiation.

Ionizing radiation (IR) is frequently unsuccessful in the treatment of cancer because of local failure or distant metastases. The efficacy of systemically administered cytokines for cancer therapy is often limited by toxicity. We report that intratumoral injection of an adenoviral vector with interleukin-12 (IL-12) enhances local anti-tumor effects of irradiation (IR). We demonstrate that microscopic tumor growth at a distant site is suppressed following treatment of the primary tumor with adeno-murine IL-12 (Adm.IL-12). The results support a model in which the anti-angiogenic effects of IL-12 contribute to the local anti-tumor effects of radiation, while IL-12 induced immunity suppresses growth of microscopic tumors distant from the primary irradiated site. These data suggest that combining radiotherapy with IL-12 improves both local and distant tumor control compared to either treatment alone. Immunoradiotherapy may be employed in addition to or in place of current conventional therapies to increase local control and decrease distant tumor growth.

Animals↗
PubMed1998

Tumor cells induce cytolytic T cells to a single immunodominant mutant peptide.

Two different approaches have shown that cancers express mutant proteins that may be recognized as tumor-specific antigens. On the one hand, DNA sequences known to be mutant in tumor cells have been used to select for mutant peptides that induce tumor-specific T cells (the so-called "reverse immunologic" approach). On the other, T cells induced by vaccination with whole tumor cells have been used to identify tumor-specific mutations in proteins ("direct immunologic approach"). While both approaches generate tumor-specific T cells that can lyse cancer cells expressing the relevant mutant protein, the present study suggests that there may be crucial differences. Mutant epitopes originally defined from DNA sequences have so far been immunorecessive, and tumor cells themselves generally appear unable to induce specific CD8+ T cells that recognize the encoded mutant gene product. In contrast, we find that mutant epitopes identified by CD8+ T cells stimulated by immunization with whole tumor cells induce cytolytic T cells to such mutant peptides. In fact, much or all of the response appears to be to a single mutant octapeptide that seems to be immunodominant. One possible reason for the failure of immunorecessive antigens to induce a response may be the presence of lower amounts of the antigen in the cancer cell, but other mechanisms are possible as well. For example, in the host bearing a growing tumor, neither purified proteins nor peptides might be known; thus, only immunodominant unique antigens may be able to restimulate and activate tumor-specific memory T cells that localize in the tumor following active immunization.

Animals↗
PubMed1998

Loss of resistance to a highly immunogenic tumor with age corresponds to the decline of CD8 T cell activity.

A number of ultraviolet light-induced tumors that do not grow progressively in 3- or 9-month-old animals grow progressively in animals starting at approximately 15 months of age. We investigated the immune response to one such tumor, 6130, in young and old mice to determine in nature of this breakdown in immune protection with age. The 6130 tumor cells that grow progressively in 22-month-old animals still retain sensitivity of cytotoxic T lymphocytes (CTLs) generated against the highly immunogenic "6130-A" antigen and consequently are still immunologically rejected when transplanted into 3- and 9-month-old animals, but not in mice older than 15 months. Investigation of the CD8+ CTL response found that in animals 3-12 months old, primary and secondary tumor-specific CTL responses to 6130 can be generated in vivo and in vitro. On the other hand, the CD8+ CTL responses to 6130 seen in animals 15 months of age or older were significantly depressed or absent. These results indicate that a decline in antigen-specific CD8+ CTL is the major cause of increased susceptibility to 6130 tumor growth in older animals.

Aging↗
PubMed1998

Active immunization against cancer cells: impediments and advances.

Immunotherapy of cancer is still mainly an experimental treatment. Some monoclonal antibodies have been approved for adjuvant therapy of cancer in patients, but active immunization strategies have not yet matured to this stage. The fact that vaccination against viral diseases is effective has primed high expectations for successful vaccination against cancer as well. Indeed, in some animal models, therapeutic results could be obtained against short-term established tumors, which paved the way for clinical trials. However, the first results with active immunization in cancer patients were disappointing and this led to a careful examination of current protocols and the search for more effective approaches. Evaluation of the available data suggests that cancer patients may not be comparable in their immune response to cancer vaccines with healthy persons. Furthermore, the tumor seems to be able to develop several immune-escape mechanisms, which either inactivate the specific immune cells or prevent activation of potential effector mechanisms against the tumor. Here, we review the impediments that have been identified in murine models and clinical trials for immunotherapy of cancer. It will be important to study the hurdles to come to a better understanding of the immune evasion of tumors and to achieve efficient activation of the immune system in cancer patients against the tumor. This knowledge will open new possibilities for active immunization against cancer.

Animals↗
PubMed1997

Antigenic cancer cells grow progressively in immune hosts without evidence for T cell exhaustion or systemic anergy.

One enigma in tumor immunology is why animals bearing malignant grafts can reject normal grafts that express the same nonself-antigen. An explanation for this phenomenon could be that different T cell clones react to the normal graft and the malignant cells, respectively, and only the tumor-reactive clonotypes may be affected by the growing tumor. To test this hypothesis, we used a T cell receptor transgenic mouse in which essentially all CD8(+) T cells are specific for a closely related set of self-peptides presented on the MHC class I molecule Ld. We find that the tumor expressed Ld in the T cell receptor transgenic mice but grew, while the Ld-positive skin was rejected. Thus, despite an abundance of antigen-specific T cells, the malignant tissue grew while normal tissue expressing the same epitopes was rejected. Therefore, systemic T cell exhaustion or anergy was not responsible for the growth of the antigenic cancer cells. Expression of costimulatory molecules on the tumor cells after transfection and preimmunization by full-thickness skin grafts was required for rejection of a subsequent tumor challenge, but there was no detectable effect of active immunization once the tumor was established. Thus, the failure of established tumors to attract and activate tumor-specific T cells at the tumor site may be a major obstacle for preventive or therapeutic vaccination against antigenic cancer.

Animals↗
PubMed1997

Calculation of the dielectric properties of a protein and its solvent: theory and a case study.

This paper presents a rigorous derivation of a theory for the calculation of the frequency-dependent dielectric properties of each component of the system protein/water/ions with the aim of enabling comparison to experimentally determined dielectric properties. We apply this theory to a very long (13.1 ns) molecular dynamics simulation of an HIV1 zinc finger peptide, its co-ordinated zinc ion, and two chloride ions in a box of SPC/E water molecules. We find the dielectric relaxation of the water molecules restricted compared to pure water, giving rise to a static dielectric constant for the water-component of only 47. The peptide is found to have a complicated dielectric relaxation behaviour, with a static dielectric constant of 15. We also calculate the frequency-dependent conductivity of the ions in this system. We analyze all contributions to the calculation of these dielectric properties and find that the coupling between the dielectric relaxation of the peptide and that of the water-component is particularly important for correctly describing the dielectric constant of the peptide.

Chlorides↗
PubMed1997

Visually-guided saccadic eye movements in adolescents at genetic risk for schizophrenia.

Visually-guided saccades of 21 offspring of schizophrenic parents and 21 individually matched controls were compared with regard to the frequency of occurrence of saccadic hypometria and hypermetria, non-fixations, and omissions of target jumps. Target steps ranged from 10 to 60 degrees, and interstimulus intervals averaged 2.5 s; subjects were promised financial reward depending on performance. Recordings were carried out at the subjects' homes. To screen for cognitive abilities and psychopathological behavior, subjects were tested by means of an intelligence scale and a behavioral checklist. With large target steps (40-60 degrees), the high-risk group made significantly more grossly hypometric saccades (gain < or = 0.8) than the control group; responses to small target steps (10-30 degrees) exhibited a similar, albeit statistically not significant, trend. There were no significant differences with regard to the occurrence of hypermetria. Non-fixations scored marginally higher in the high-risks as compared to controls, but this was again not a significant difference. The incidence of omissions of saccades was very low in both groups. The results of the study suggest that subjects at genetic risk for schizophrenia may differ from controls by an increased incidence of conspicuously hypometric saccades. Clearly, this difference is not caused by a deficit of the saccadic motor circuitry proper; comparison to control data obtained with a similar experimental protocol suggests that it probably reflects an impaired internal control of saccades in the presence of distraction and stress. The relevance of saccades as indicators of a possible schizophrenic vulnerability is discussed.

Adolescent↗
PubMed1997

The immunodominant antigen of an ultraviolet-induced regressor tumor is generated by a somatic point mutation in the DEAD box helicase p68.

The genetic origins of CD8+ T cell-recognized unique antigens to which mice respond when immunized with syngeneic tumor cells are unknown. The ultraviolet light-induced murine tumor 8101 expresses an H-2Kb-restricted immunodominant antigen, A, that induces cytolytic CD8+ T cells in vivo A+ 8101 cells are rejected by naive mice while A- 8101 tumor cells grow. To identify the antigen H-2Kb molecules were immunoprecipitated from A+ 8101 cells and peptides were eluted by acid. The sensitizing peptide was isolated by sequential reverse-phase HPLC and sequenced using microcapillary HPLC-triple quadruple mass spectrometry. The peptide, SNFVFAGI, matched the sequence of the DEAD box protein p68 RNA helicase except for a single amino acid substitution, caused by a single nucleotide change. This mutation was somatic since fibroblasts from the mouse of tumor origin expressed the wild-type sequence. The amino acid substitution created an anchor for binding of the mutant peptide to H-2Kb. Our results are consistent with mutant p68 being responsible for rejection of the tumor. Several functions of p68, which include nucleolar assembly and inhibition of DNA unwinding, may be mediated through its IQ domain, which was altered by the mutation. This is the first description of a somatic tumor-specific mutation in the coding region of a nucleic acid helicase.

Amino Acid Sequence↗
PubMed1997

Cerebellopontine angle lipoma: a rare differential diagnosis.

Intracranial lipomas in an infratentorial and extra-axial location are extremely rare. The presented case of an extensive lipoma of the cerebellopontine angle (CPA) represents 0.05% of all CPA tumors operated on in our department from 1978 to 1996. The lipoma constitutes an important differential diagnosis because the clinical management differs significantly from other CPA lesions. The clinical presentation and management of the presented case are analyzed in comparison to all previously described cases of CPA lipomas. The etiology and the radiological features of CPA lipomas are reviewed and discussed. CPA lipomas are maldevelopmental lesions that may cause slowly progressive symptoms. Neuroradiology enables a reliable preoperative diagnosis. Attempts of complete lipoma resection usually result in severe neurological deficits. Therefore, we recommend a conservative approach in managing these patients. Limited surgery is indicated if the patient has an associated vascular compression syndrome or suffers from disabling vertigo.

Case Reports↗
PubMed1997

An approach to the treatment of recurring polyarthralgia after jejunoileal bypass.

Polyarthralgia after jejunoileal bypass (JI) is a well-documented complication. In the past, this was treated by antibiotic therapy, but definitive therapy uncommonly necessitated surgical reversal of the JI bypass. This case report discusses the etiology of arthralgias and presents a technique for its treatment without bypass reversal.

Adult↗
PubMed1996

Preattentive information processing as measured by backward masking and texton detection tasks in adolescents at high genetic risk for schizophrenia.

Schizophrenic patients have consistently been reported to show deficits in preattentive information processing as demonstrated by impairments in visual backward masking and texton detection tasks. Texton detection refers to Julesz's texton theory, which defines a certain limited number of texton elements (e.g., one 'L' among many '+') that can be detected readily and simultaneously without attentional effort irrespective of the size of the rest of the visual field. The present study investigated whether deficits of preattentive information processing are more prevalent in a group of adolescents of high genetic risk for schizophrenia compared to matched control subjects. Although differences in the performance in visual backward masking tasks could not be detected with our experimental approach, preattentive texton detection was to a certain extent disturbed in subjects at risk. Moreover, subjects at risk did not show the advantage of the right hemisphere in processing texton elements which was found in the control group. This may point to a subtle dysfunction of the right hemisphere in the risk group. It is concluded from the present study that deficits in preattentive texton detection may represent an indicator for a schizophrenic disposition. However, further studies including other high risk groups, schizophrenics in remission and individuals with a schizotypal personality disorder are needed to confirm this hypothesis.

Adolescent↗
PubMed1996

The influence of a protein on water dynamics in its vicinity investigated by molecular dynamics simulation.

A system containing the globular protein ubiquitin and 4,197 water molecules has been used for the analysis of the influence exerted by a protein on solvent dynamics in its vicinity. Using Voronoi polyhedra, the solvent has been divided into three subsets, i.e., the first and second hydration shell, and the remaining bulk, which is hardly affected by the protein. Translational motion in the first shell is retarded by a factor of 3 in comparison to bulk. Several molecules in the first shell do not reach the diffusive regime within 100 ps. Shell-averaged orientational autocorrelation functions, which are also subject to a retardation effect, cannot be modeled by a single exponential time law, but are instead well-described by a Kohlrausch-Williams-Watts (KWW) function. The underlying distribution of single-molecule rotational correlation times is both obtained directly from the simulation and derived theoretically. The temperature dependence of reorientation is characterized by a strongly varying correlation time, but a virtually temperature-independent KWW exponent. Thus, the coupling of water structure relaxation with the respective environment, which is characteristic of each solvation shell, is hardly affected by temperature. In other words, the functional form of the distributions of single-molecule rotational correlation times is not subject to a temperature effect. On average, a correlation between reorientation and lifetimes of neighborhood relations is observed.

Proteins↗
PubMed1996

Unique tumor antigens redefined as mutant tumor-specific antigens.

The extraordinary specificity of immune responses mediated by T cells against individual syngeneic tumors has led to the concept that many tumor antigens are 'unique'. The recent isolation of several T-cell-recognized unique antigens from various murine and human tumors has shown that the antigenic peptides are caused by somatic mutations and, thus, are truly tumor-specific. The following review summarizes current knowledge about these mutant tumor-specific antigens and their possible role in the development and progression of cancer. It also discusses some functional differences between mutant tumor-specific and shared tumor antigens, which generally represent unaltered peptides, also present on some normal cells.

Animals↗