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Biomedical subjects

T Herrmann

Publications and source records attributed to T Herrmann.

At least 55 records · Page 3Linked to original sources
PubMed1999

Usage of Vbeta3.3 T-cell receptor by myelin basic protein-specific encephalitogenic T-cell lines in the Lewis rat.

T-cell receptor (TCR) beta-chain usage in experimental autoimmune encephalomyelitis (EAE) seems to be much more heterogeneous than previously assumed even for a single autoantigen in an inbred animal strain. Owing to the lack of suitable antibodies, this has been demonstrated only at the RNA level so far. To characterize further the TCR elements used in the Lewis rat for the recognition of the main encephalitogenic region of myelin basic protein (MBP), BALB/c mice were immunized with T-cell hybridomas expressing non-Vbeta8.2 TCR specific for guinea pig MBP peptide aa 68-88. Two B-cell hybridomas (clones C-A11 and F-D6) producing TCR Vbeta3.3-specific monoclonal antibodies were selected. Specificity was demonstrated by RT-PCR and cloning of PCR products obtained from sorted T-cell lines and naive T cells. MBP-specific Vbeta3.3 T cells used the L-S motif in the VDJ region, were associated with Valpha2 or Valpha8 chains, and specifically recognized MBP peptide aa 68-88. Vbeta3.3 TCR-positive T cells were detected in all of a panel of six MBP-specific T-cell lines, although to a lesser degree than Vbeta8.2 TCR-positive T cells. After intravenous injection of sorted Vbeta3.3 T cells, animals developed EAE, and Vbeta3.3-positive cells were found by immunocytochemical analyses in the spinal cord. Furthermore, treatment of EAE induced by immunization with MBP was more effective when a combination of anti-Vbeta3.3 and anti-Vbeta8.2 mAbs was used. These results confirm the functional role of TCR Vbeta3.3 and thus underscore the heterogeneity of TCR usage in MBP-associated autoimmunity.

Animals↗
PubMed1999

NMR structure and metal interactions of the CopZ copper chaperone.

A recently discovered family of proteins that function as copper chaperones route copper to proteins that either require it for their function or are involved in its transport. In Enterococcus hirae the copper chaperone function is performed by the 8-kDa protein CopZ. This paper describes the NMR structure of apo-CopZ, obtained using uniformly (15)N-labeled CopZ overexpressed in Escherichia coli and NMR studies of the impact of Cu(I) binding on the CopZ structure. The protein has a betaalphabetabetaalphabeta fold, where the four beta-strands form an antiparallel twisted beta-sheet, and the two helices are located on the same side of the beta-sheet. A sequence motif GMXCXXC in the loop between the first beta-strand and the first alpha-helix contains the primary ligands, which bind copper(I). Binding of copper(I) caused major structural changes in this molecular region, as manifested by the fact that most NMR signals of the loop and the N-terminal part of the first helix were broadened beyond detection. This effect was strictly localized, because the remainder of the apo-CopZ structure was maintained after addition of Cu(I). NMR relaxation data showed a decreased correlation time of overall molecular tumbling for Cu(I)-CopZ when compared with apo-CopZ, indicating aggregation of Cu(I)-CopZ. The structure of CopZ is the first three-dimensional structure of a cupro-protein for which the metal ion is an exchangeable substrate rather than an integral part of the structure. Implications of the present structural work for the in vivo function of CopZ are discussed, whereby it is of special interest that the distribution of charged residues on the CopZ surface is highly uneven and suggests preferred recognition sites for other proteins that might be involved in copper transfer.

Amino Acid Sequence↗
PubMed1999

[Results of irradiation of inoperable stage III non-small cell lung cancer with 25Gy in five fractions].

BACKGROUND: Patients with advanced Stage III inoperable non-small cell lung cancer who were not suitable for irradiation with curative doses, were treated at the Department of Radiotherapy of the University Hospital of Dresden with 25 Gy in 5 fractions over 1 to 2 weeks. Survival of these patients was compared in this retrospective study to the survival of patients treated during the same period with 60 Gy in 30 fractions. PATIENTS AND METHOD: Between 1985 and 1994 298 patients were treated for a histologically or cytologically proven non-small cell lung carcinoma with 60 Gy in 30 fractions (n = 80), with 40 Gy in 20 fractions (n = 26) or with 25 Gy in 5 fractions (n = 192). Overall survival was determined using actuarial methods. Prognostic parameters were analyzed using uni- and multivariate tests. RESULTS: Median overall survival for all patients was 6 months (95% confidence interval 5; 7). In univariate analysis, survival of the patients treated with 60 Gy was significantly better than survival in the other groups. Median survival was 11 months (9; 13) after 60 Gy, 6 months (4; 8) after 40 Gy and 5 months (4; 6) after 25 Gy. In multivariate analysis the treatment schedule lost its significant influence on outcome of the therapy. The most important prognostic parameter was the performance status of the patients. CONCLUSIONS: When stratified for performance status as the most important prognostic parameter the survival time after hypofractionated irradiation to 25 Gy given in 5 fractions in 1 to 2 weeks was not significantly different from the results after conventional fractionation to 60 Gy. Hypofractionated radiation schedules are often more convenient for the patient, economical, and have been shown to be effective in symptom control. Thus, in clear palliative situations hypofractionated treatment with 25 Gy in 5 fractions or a comparable schedule appears to be a reasonable therapeutic option.

Actuarial Analysis↗
PubMed1999

[Delayed toxicity of brief preoperative irradiation and risk-adjusted postoperative radiotherapy of operative rectal carcinoma. Results of a randomized prospective study].

AIM: Analysis of a randomized study of preoperative radiation therapy for operable carcinoma of the rectum with regard to late sequelae. Results of tumor control and survival, which have already been published in detail are summarized for comparison and for confirmation of the conclusions. PATIENTS AND METHODS: Between January 1988 and October 1993 94 patients with operable carcinoma of the rectum were included in a randomized trial. Fourty-seven patients were treated with 5 x 3.3 Gy (field size 16 x 16 cm, 9 MeV photons) 24 to 48 hours prior to surgery; 46 patients did not receive preoperative irradiation. If risk factors (T4-stage, R1/R2 resection, intraoperative tumor perforation) were present, postoperative irradiation was performed after CT-planning. Total postoperative doses of 41.4 Gy (preoperative irradiation) or 59.8 Gy (surgery only) were applied with doses per fraction of 1.8 to 2.0 Gy. Local control, survival, and pattern of side effects were analyzed at 5 years after conclusion of the trial. RESULTS: The frequency of local recurrence was markedly reduced by preoperative irradiation of R0-resected patients (24% vs 13%, p = 0.08). The time to recurrence was delayed (1.9 vs 3 years). The 5-year actuarial survival rate was significantly higher in the preoperatively irradiated group compared to the not pre-irradiated group (40% vs 28%, p = 0.027). Multivariate analysis revealed UICC-grading as the only independent parameter for local control (p = 0.0003), while preoperative irradiation (p = 0.07) and T-stage (p = 0.08) only displayed a trend. For patient survival, age (p = 0.0003). R-status (p = 0.01) and UICC-score (p = 0.001) were significant prognostic factors. Preoperative irradiation had a non-significant effect only (p = 0.078). Radiation-induced side effects with a LENT-SOMA score > 2 were observed neither during frequent follow-up nor at an additional examination of those patients still alive in 1998 (n = 25). Of 4 pre- and postoperatively irradiated patients with risk factors, 3 had side effects grade 1 or 2, predominantly rectal changes, at 5 to 11 years after treatment. CONCLUSIONS: A positive effect on tumor control and survival is achieved with preoperative irradiation with the doses used in this study, with moderate side effects.

Actuarial Analysis↗
PubMed1999

Response of pig lung to irradiation with accelerated 12C-ions.

The response of pig lungs to irradiation with 12C-ions was assessed in two experiments to validate the procedures for heavy ion therapy planning at the Gesellschaft für Schwerionenforschung (GSI) and to explore their range of applicability. In both experiments, the target volume (spread-out Bragg peak, SOBP) was planned to be a 4 cm long cylinder with a diameter of 4 cm. Doses in the SOBP were prescribed to be equivalent to 5x4 Gy, 5x5.5 Gy and 5x7 Gy of x-rays in the first experiment, and to 5 fractions of 7 Gy and 9 Gy in the second experiment. The lung response in the first experiment was less than expected on the basis of earlier experiments with photons. Pneumonitis reaction and chronic fibrotic changes were observed outside the prescribed high-dose region. In the second experiment, the effects were more pronounced than had been expected on the basis of the first experiment. Changes were most intense in the high-dose region, but were also seen throughout the lung along the beam channel. Moreover, significant skin reactions were observed at the beam entrance site in all animals and - less pronounced - at the beam exit site in 3 of the 6 animals. In conclusion, the complex irradiation geometry of the pig lung, the changes of body weight between the two experiments, and insufficient accounting for a change in the relative biological effectiveness (RBE) computation led to substantial deviations of the observed reactions from expectations, the reasons for which could be identified in a subsequent analysis. The less pronounced lung reaction in the first experiment was due to an overestimation of RBE in a preliminary version of the algorithm for its determination. The extension of the fibrotic reaction resulted from the smear-out of the high-dose region due to density variations in tissue structures, respiratory movement, and limited positioning accuracy. The skin reactions at the entrance port reflect the different treatment geometry in the two experiments. The one unexplained observation is the mild skin reaction that was observed in the second experiment at the beam exit site.

Animals↗
PubMed1999

Different manifestations of Toxoplasma gondii infection in F344 and LEW rats.

There is evidence that not only the immune status, but also the genetic predisposition of certain hosts influence the clinical outcome of Toxoplasma gondii infection. By far the majority of our knowledge on genetic and immunological mechanisms involved in control of T. gondii infection has been obtained by studying mouse models, which in terms of clinical outcome of infection differ considerably from humans. Rats which show a rather similar course of infection in comparison to humans have not so far been investigated for effects of genetic differences on course of the infection. In this study we show that, like mice, different strains of rats exhibit a remarkable variation in the number of brain cysts arising from chronic infection. LEW rats seem to be highly resistant to cyst formation, in contrast to F344 rats that are susceptible. In addition, F344 rats express high numbers of gammadelta T cells during the acute phase of infection, whereas LEW rats express elevated but comparably low numbers of gammadelta T cells. The RT1 (rat MHC) haplotypes of both strains are identical in the RT1A and RT1B/D regions, which encode the restriction elements for conventional peptide antigens. Consequently, rat strain-specific differences may be useful to define MHC-independent mechanisms of resistance against T. gondii, which may also act in humans.

Animals↗
PubMed1999

Late complications after a combined pre and postoperative (sandwich) radiotherapy for rectal cancer.

BACKGROUND AND PURPOSE: The purpose of this study was to analyse the treatment related side effects, the outcome and the prognostic significance of clinical parameters in two groups of patients with rectal cancer receiving either preoperative or pre and postoperative radiotherapy after radical resection. The authors of this study were not involved in the radiation treatments. PATIENTS AND METHODS: From 1986 to 1990, 63 patients received a combined pre and postoperative (sandwich) radiotherapy. Preoperative irradiation was given in four fractions of 5 Gy each applied within 2 or 3 days. Postoperative irradiation consisted mostly of 15 x 2 Gy (31 patients) but the range was 20-40 Gy. The results were compared with those on 73 patients who only received preoperative radiotherapy in the same time period. The distribution of prognostic factors was not very different between treatment groups. Out of 63 patients in the sandwich group, 22 received concurrent chemotherapy and 18 also received radiotherapy to the liver. Radical surgery usually followed on the day after the last preoperative radiotherapy session. Median follow-up of survivors was 6 years. RESULTS: Local tumour control was 88% after 5 years and 84% after 8 years in the sandwich group, and 90 and 85%, respectively, in the preoperative radiotherapy group. Thus, tumour control was similar for the two radiotherapy regimens applied. However, the percentage of patients suffering from one or more complications after 5 years was 84% in the sandwich and 17% in the preoperative radiotherapy group. The incidence of severe late complications (grade > or = 3) was recorded as a function of time after start of treatment. In the sandwich group the actuarial rates of late complications at 5 years (and the median time to diagnosis) were 53% (27 months) for anorectum, 43% (37 months) for bladder, 28% (51 months) for bone, 19% (36 months) for dermis, 47% (48 months) for ileum, 41% (32 months) for lymphatic and soft tissue, and 44% (53 months) for ureters. CONCLUSIONS: Severe late reactions did not occur within a certain period of time, but continued to appear for at least 10 years after radiotherapy. Sandwich therapy, as given in this series, did not appear to give a greater tumour control than preoperative radiotherapy alone, whereas the rate of complications was drastically enhanced. Thus, the rationale of a sandwich therapy with a long time interval between surgery and postoperative irradiation appears questionable.

Actuarial Analysis↗
PubMed1999

Heterogeneity of T-cell receptor usage in experimental autoimmune neuritis in the Lewis rat.

In experimental autoimmune neuritis (EAN), T-cell receptor (TCR) variable (V)-region gene usage by neuritogenic T cells has been reported to be clonally restricted at the RNA level. This study was designed to verify TCR usage by neuritogenic T cells at the protein level. We generated two monoclonal antibodies (mAbs) 7H4 and 8G8 specific for a Vbeta4/Valpha11 associated idiotype expressed by the majority of neuritogenic cells of P2-specific T-cell lines. The remaining neuritogenic P2-specific T cells either exhibited a dominant usage of the TCR Vbeta13 chain recognized by the recently generated mAbs 17D5 and 18B1 or showed diverse Vbeta usage. Treatment of adoptive-transfer (AT)-EAN or of EAN actively induced with the neuritogenic P2 peptide by mAbs 7H4 and 8G8 led to a partial, but significant, reduction of clinical disease. Treatment with Vbeta13-specific mAb 17D5 had no clear effect on active EAN. Our data show that at least three different TCR are used by P2-specific pathogenic T cells in EAN, an animal model for human inflammatory neuropathies.

Adoptive Transfer↗
PubMed1999

Differential CD4/CD8 subset-specific expression of highly homologous rat Tcrb-V8 family members suggests a role of CDR2 and/or CDR4 (HV4) in MHC class-specific thymic selection.

Different rat Tcrb haplotypes express either TCR beta variable segment (Tcrb-V) 8.2l or 8.4a. Both V segments bind the mAb R78 but differ by one conservative substitution (L14V) and clusters of two and four substitutions in the complementarity-determining region (CDR) 2 and CDR4 [hypervariable loop 4 (HV4)]. Independently of MHC alleles numbers of R78+ CD4+ cells are lower in Tcrb-V8.2l-expressing than in Tcrb-V8.4a-expressing strains. Expression of R78+ TCR during T cell development, analysis of backcross populations and generation of a Tcrb congenic strain [LEW.TCRB(AS)] define two mechanisms how Tcrb haplotypes affect the frequency of R78+ cells, one acting prior to thymic selection leading to up to 2-fold higher frequency of Tcrb-V8.4a versus Tcrb-V8.2l in unselected thymocytes and another occurring between the TCRlow and the CD4/CD8 single-positive stage. The latter leads to a 50% reduction of frequency of Tcrb-V8.4a CD8+ cells but not CD4+ cells and does not affect either subset of Tcrb-V8.2l cells. A comparison of rat classical class I MHC (RT1.A) sequences and current models of TCR-MHC-peptide interaction suggests that this reduction in frequency of Tcrb-V8.4a CD8 cells may be a consequence of differential selection of Tcrb-V8.2l versus Tcrb-V8.4a TCR by differential binding of CDR2beta to highly conserved areas of C-terminal parts of the alpha helices of class I MHC molecules.

Alleles↗
PubMed1998

Molecular cloning, structural organization, sequence, chromosomal assignment, and expression of the mouse alpha-N-acetylgalactosaminidase gene.

Alpha-N-acetylgalactosaminidase (2-acetamido-2-deoxy-alpha-d-galactoside acetamidodeoxy-galactohydrolase, NAGA; EC 3.2.1.49) deficiency is a recently recognized autosomal recessive lysosomal disease. As a prerequisite for the generation of an animal model, the mouse NAGA gene was cloned and characterized. The NAGA gene was assigned to mouse chromosome 15 band E3, syntenic to the region encompassing the human gene, and NAGA-deficient mutant human cells transfected with the cosmid clone containing the mouse NAGA gene expressed NAGA activity. Comparison of the mouse NAGA nucleotide sequence with the human NAGA sequence predicted that the mouse NAGA gene contains an open reading frame of 1245bp, comprising nine coding exons and spanning a genomic region of 8258bp, and a 3' untranslated region of 0.5kb. The 5' untranslated region was determined in primer extension studies to be 235bp in length. Nucleotide identity between the human and mouse NAGA exons ranged from 67.4 to 89.5%, with better matches for exons 1-7 than for 8 and 9. The overall amino acid identity between the mouse and human deduced NAGA polypeptides was 82.0%, between those of mouse and chicken 72.9%. Homology was found to only one other mouse gene, i.e. the alpha-galactosidase A (GALA; EC 3.2.1. 22) gene. The amino acid identity ranged from 51.6 to 62.1% in the polypeptide regions corresponding to NAGA exons 2-7 and GALA exons 1-6, but little, if any, in the remainder. These analyses gave emphasis to the strong conservation of the NAGA gene and its origin from an ancestor common with the GALA gene, with NAGA exons 8 and 9 and GALA exon 7 being the most divergent regions in the evolution of the two genes.

Amino Acid Sequence↗
PubMed1998

[Brief preoperative radiotherapy in surgical therapy of rectal carcinoma. Long-term results of a prospective randomized study].

To ascertain whether preoperative short-term radiotherapy can improve local tumor control and the long-term survival of patients with operable rectal cancer, a prospective randomised trial was performed from 1988 to 1993. Ninety-three patients with rectal cancer were either directly treated with surgery (n = 46) or underwent preoperative radiotherapy with 5 x 3.3 Gy irradiation and operation within 48 h (n = 47). If indicated (T4, UICC stage III) patients also received postoperative irradiation. Comparison of the methods of operation (abdominoperineal amputation versus anterior resection) revealed no significant difference in 5-year survival rate (P = 0.393). Local control of R0-resected tumors was improved after preoperative irradiation (P = 0.08). The 5-year survival rate was significantly higher after preoperative short-term radiotherapy (P = 0.027). Preoperative radiotherapy is not an independent factor according to overall survival (P = 0.078) and local recurrence (P = 0.07). In agreement with the results of other authors the present study indicates improved local tumor control of rectal cancer after preoperative radiation therapy. The 5-year survival rate was significantly better after preoperative radiotherapy than after surgery alone.

Adult↗