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T Herrmann

Publications and source records attributed to T Herrmann.

At least 37 records · Page 2Linked to original sources
PubMed2001

A new concept of cellular uptake and intracellular trafficking of long-chain fatty acids.

Fatty acids are the main structural and energy sources of the human body. Within the organism, they are presented to cells as fatty acid:albumin complexes. Dissociation from albumin represents the first step of the cellular uptake process, involving membrane proteins with high affinity for fatty acids, e.g., fatty acid translocase (FAT/CD 36) or the membrane fatty acid-binding protein (FABPpm). According to the thus created transmembrane concentration gradient, uncharged fatty acids can flip-flop from the outer leaflet across the phospholipid bilayer. At the cytosolic surface of the plasma membrane, fatty acids can associate with the cytosolic FABP (FABP(c)) or with caveolin-1. Caveolins are constituents of caveolae, which are proposed to serve as lipid delivery vehicles for subcellular organelles. It is not known whether protein (FABP(c))- and lipid (caveolae)-mediated intracellular trafficking of fatty acids operates in conjunction or in parallel. Channeling fatty acids to the different metabolic pathways requires activation to acyl-CoA. For this process, the family of fatty acid transport proteins (FATP 1-5/6) might be relevant because they have been shown to possess acyl-CoA synthetase activity. Their variable N-terminal signaling sequences suggest that they might be targeted to specific organelles by anchoring in the phospholipid bilayer of the different subcellular membranes. At the highly conserved cytosolic AMP-binding site of FATP, fatty acids are activated to acyl-CoA for subsequent metabolic disposition by specific organelles. Overall, fatty acid uptake represents a continuous flow involving the following: dissociation from albumin by membrane proteins with high affinity for fatty acids; passive flip-flop across the phospholipid bilayer; binding to FABP(C) and caveolin-1 at the cytosolic plasma membrane; and intracellular trafficking via FABP(c) and/or caveolae to sites of metabolic disposition. The uptake process is terminated after activation to acyl-CoA by the members of the FATP family targeted intracellularly to different organelles.

Animals↗
PubMed2001

Quantification of late complications after radiation therapy.

BACKGROUND: An increasing number of patients survive cancer after having received radiation therapy. Therefore, the occurrence of late normal tissue complications among long-term survivors is of particular concern. METHODS: Sixty-three patients treated by radical surgery and irradiation for rectal carcinoma were subjected to an unconventional sandwich therapy. 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 (range, 20-40 Gy). A considerable proportion of these patients developed severe late complications (Radiother Oncol 53 (1999) 177). The data allowed a detailed analysis of complication kinetics, leading to a new model which was tested using data from the literature. RESULTS: Data on late complications were obtained for eight different organs with a follow-up of up to 10 years. For the various organs, the percentage of patients being free from late complications, plotted as a function of time after start of radiation therapy, was adequately described by exponential regression. From the fit, the parameter p(a) was obtained, which is the percentage of patients at risk in a given year of developing a complication in a given organ during that year. The rate p(a) remained about constant with time. Following sandwich therapy, the annual incidence of complications in the bladder, ileum, lymphatic and soft tissue, and ureters was about the same (p(a)=10-14%/year), whereas complications in bone or dermis occurred at lower rates (4.7 or 7.5%/year, respectively). DISCUSSION: Numerous data sets collected from published reports were analyzed in the same way. Many of the data sets studied were from patients in a series where there was a high incidence of late effects. Three types of kinetics for the occurrence of late effects after radiotherapy were identified: Type 1, purely exponential kinetics; Type 2, exponential kinetics, the slope of which decreased exponentially with time; Type 3, curves composed of two components, a fast initial decline followed by an exponential decrease. For each kind of kinetics, provided that the dose distribution is not too heterogeneous, the incidence of late effects appears to occur at exponential or approximately exponential kinetics, even many years after treatment. This implies that a random process might be involved in the occurrence of late radiation sequelae. CONCLUSIONS: There might be a lifelong risk of developing late complications, of which patients and clinicians should be aware. It appears worthwhile to try to identify, in follow-up examinations of patients after radiation therapy, what kind of processes might be involved in triggering subclinical residual injury to develop into a clinically manifest late effect.

Adenocarcinoma↗
PubMed2001

Dose and fractionation concepts in the primary radiotherapy of non-small cell lung cancer.

At present, radiotherapy alone or in combination with chemotherapy offers the only chance of cure of medically inoperable or locally advanced unresectable non-small cell lung cancer. The radiobiological basis and clinical results of current dose and fractionation concepts in the primary radiotherapy of NSCLC are briefly reviewed. Whenever possible, focus is given to the results of randomized phase III trials. With the exception of early disease treated to doses higher than 60 Gy, the prognosis of inoperable localized NSCLC is very poor. Local recurrence is the major cause of failure after radiation therapy calling for intensified local treatment. Dose-escalation using conventional fractionation or moderate hypofractionation is promising but randomized trials are presently not available. Dose-escalated hyperfractionation theoretically offers advantages, however, there appears currently no strong evidence from randomized trials supporting this approach in NSCLC. The highly accelerated CHART regimen significantly improved survival by 9% compared to standard radiotherapy. Nevertheless, even when treated with CHART, about 80% of all patients will eventually develop local recurrence and 60% distant metastases. Many trials on combined radiochemotherapy have used radiotherapy regimens that are not optimal from a current perspective. Because of the high rate of both, local recurrence and distant metastases, future research should be directed to further intensify radiotherapy as well as to integrate such protocols with systemic treatment in carefully selected patients. Since toxicity is expected to increase, state-of-the-art 3D conformal radiation techniques need to be part of clinical trials testing such strategies.

Carcinoma, Non-Small-Cell Lung↗
PubMed2001

Thymic development and repertoire selection: the rat perspective.

This review summarizes our current knowledge of T-cell maturation and repertoire selection in the rat thymus. Some unique features of early thymocyte development and of CD4/CD8 lineage decision are described. A detailed analysis of lineage progression through the CD4, CD8 "double positive" compartment and T-cell receptor-induced CD8 T-cell maturation in cell culture is provided. A second emphasis is placed on interactions between germline-encoded T-cell receptor elements with MHC molecules in thymic repertoire selection and alloreactivity

Animals↗
PubMed2001

Differential modulation of CD8beta by rat gammadelta and alphabeta T cells after activation.

Major histocompatibility complex (MHC) class I-restricted alphabeta T cells express the CD8alphabeta heterodimer, which acts as a MHC class I-specific co-receptor. Rats are so far the only species with frequent expression of the CD8alphabeta by MHC-unrestricted gammadelta T cells. This study compares CD8alphabeta expression by splenic rat alphabeta and gammadelta T cells and reveals a lineage-specific difference in the control of CD8beta expression. After activation in vitro, many gammadelta T cells, but not alphabeta T cells, persistently down-modulate the expression of CD8beta, but not CD8alpha, at the RNA level. Down-regulation occurred after stimulation with T-cell receptor (TCR)-specific monoclonal antibody (mAb) and interleukin-2 (IL-2) or CD28-mediated costimulation, and after activation with phorbol 12-myristate 13-acetate (PMA) and ionomycin. Functional differences between modulating and non-modulating cells were not found with respect to interferon-gamma (IFN-gamma) production and cytolytic activity. The modulation could be indicative for a fundamental difference between alphabeta and gammadelta T cells and also limits the use of CD8beta as a stable marker of gammadelta T-cell subsets. Possibly, CD8beta modulation provides a mechanism to escape over-stimulation by (auto-)antigens by increasing the threshold of TCR-mediated activation in gammadelta T cells.

Animals↗
PubMed2000

Functional and histochemical analysis of MDR3 P-glycoprotein in a tetracycline-controlled gene expression system.

Aim of the present study was to establish a cell system to study the physiological function of human MDR3 P-glycoprotein in cellular phosphatidylcholine (PC) secretion. MDR3 cDNA was expressed in HeLa cells using the tet-off system together with a luciferase reporter gene. MDR3 Pgp expression was turned on upon removal of doxycycline as shown by Western blot analysis. Immunohistochemistry using a specific anti human MDR3 Pgp antibody revealed a prominent staining of MDR3 Pgp covering the cytoplasm and the area of the plasma membrane. In presence of doxycycline MDR3 Pgp expression was turned off. For analysis of PC secretory activity, MDR3 Pgp expressing and non-expressing cells as well as control HeLa cells with low endogenous MDR3 were preincubated with [(3)H]choline for synthesis of cellular [(3)H]PC. Cells were then incubated for 2 h in media with 0-4 mM taurocholate (TC) and release of cellular [(3)H]PC was recorded. [(3)H]PC secretion was observed in presence of TC without impairing cell viability. There was a significant increase in [(3)H]PC excretion in MDR3 Pgp expressing cells compared to non-expressing controls (e.g. 4.5 fold at 4 mM TC), revealing a high efficiency of transport activity (turnover). From the data it is concluded that the MDR3 Pgp expressing cell system under control of a doxycycline responsive promotor is functionally active and provides a tool to further study MDR3 Pgp mediated transport.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed2000

Expression of functional CD8alpha Beta heterodimer on rat gamma delta T cells does not correlate with the CDR3 length of the TCR delta chain predicted for MHC class I-restricted antigen recognition.

In accordance with their lack of MHC restriction, most mouse and human gamma delta T cells express neither the CD4 nor CD8(alpha beta) coreceptor. In striking contrast, up to 80% of splenic rat gamma delta T cells express the CD8alpha beta isoform of CD8, which for the alpha beta T cell subset serves as a marker for MHC class I-restricted cells. We compared CD8 on alpha beta and gamma delta T cells with regard to co-stimulatory function and correlation of CD8 expression with TCRDV usage and CDR3delta length. In both subsets, CD8 acted as a co-stimulatory molecule in vitro and was found to bind the kinase lck efficiently. No differences between the CDR3delta length spectra of CD8+ and CD8- gamma delta T cells or between unselected thymic and peripheral gamma delta T cells were found. As seen in man and mice, CDR3delta were rather long, a structural feature which can be expected to interfere with an alpha beta TCR-like mode of MHC class I binding. In summary, CD8 expressed by rat gamma delta T cells is a molecule with the potential to act as a coreceptor, but its expression gives no indication for antigen recognition analogous to that of MHC class I-restricted alpha beta T cells.

Animals↗
PubMed2000

Analysis of single-nucleotide polymorphisms in the interleukin-4 receptor gene for association with inflammatory bowel disease.

Genetic linkage analysis in families with multiple cases of inflammatory bowel disease (IBD) has mapped a gene which confers susceptibility to IBD to the pericentromeric region of chromosome 16 (IBD1). The linked region includes the interleukin(IL)-4 receptor gene (IL4R). Since IL-4 regulation and expression are abnormal in IBD, the IL4R gene is thus both a positional and functional candidate for IBD1. We screened the gene for single-nucleotide polymorphisms (SNPs) by fluorescent chemical cleavage analysis, and tested a subset of known and novel SNPs for allelic association with IBD in 355 families, which included 435 cases of Crohn's disease and 329 cases of ulcerative colitis. No association was observed between a haplotype of four SNPs (val50ile, gln576arg, A3044G, G3289A) and either the Crohn's disease or ulcerative colitis phenotypes using the transmission disequilibrium test. There was also no evidence for association when the four markers were analyzed individually. The results indicate that these variants are not significant genetic determinants of IBD, and that the IL4R gene is unlikely to be IBD1. Linkage disequilibrium analyses showed that the val50ile and gln576arg variants are in complete equilibrium with each other, although they are separated by only about 21 kilobases of genomic DNA. This suggests that a very dense SNP map may be required to exclude or detect disease associations with some candidate genes.

Alleles↗
PubMed2000

A polymorphism of the rat T-cell receptor beta-chain variable gene 13 (BV13S1) correlates with the frequency of BV13S1-positive CD4 cells.

Three rat BV13S1 alleles (T-cell receptor beta-chain variable gene 13) were characterized by new BV13S1-allele specific monoclonal antibodies (18B1 and 17D5) and sequence analysis of expressed and genomic BV13S1. Two alleles were functional and designated BV13S1A1 present in strains LEW, BUF, PVG, and BV13S1A2 present in BN and WF. Their products differed by six amino acids, two of them in complementarity-determing region (CDR)1 and one in CDR2. A third nonfunctional allele, BV13S1A3P, was found in strains F344 and DA. Apart from a single nucleotide insertion, it was identical to BV13S1A2. All 12 rat strains tested showed association of TCRBC1 with BV8S2/4 alleles but not with the BV13S1 alleles, which may reflect a different gene order of the rat BV compared to mouse. BV13S1A1-encoded T-cell receptors (TCRs) which bind both monoclonal antibody (mAb) 18B1 and mAb 17D5 are over-represented in the CD4 lymphocyte subset. BV13S1A2-encoded TCRs which are stained by mAb 18B1 but not by mAb 17D5 show a slight CD8-biased expression. Preferential usage of BV13S1A1-positive TCRs by CD4 but not by CD8 cells in (LEW x WF)F1 hybrids and cosegregation of BV13SA1 and increased frequency of BV13S1 TCR-positive CD4 cells in a (LEW x BN)x BN backcross suggest structural differences of the two allelic products as the reason for their contrasting CD4/CD8 subset bias.

Alleles↗
PubMed2000

Lack of effect of small high-dose volumes on the dose-response relationship for the development of fibrosis in distant parts of the ipsilateral lung in mini-pigs.

PURPOSE: Multi-field radiation therapy for intrathoracic tumours results in a heterogeneous dose distribution in lung tissue. This study investigated whether irradiation of small lung volumes with high fibrogenic doses affects the dose-response relationship for development of fibrosis in distant parts of the ipsilateral lung of mini-pigs. MATERIALS AND METHODS: The whole right lung of 26 'Mini-Lewe' pigs was irradiated with homogeneous doses of between 25 Gy and 40 Gy given in five equal fractions using opposing anterior-posterior portals and a linear accelerator. Another 32 animals were irradiated with a constant dose of 35 Gy to a small house-shaped high-dose field (base 3.0 cm, height 4 cm) located 3 cm caudolateral to the right hilus, while the surrounding right lung received either no irradiation or homogeneous doses of between 20 Gy and 30 Gy. The radiation fields were simulated and port films were obtained for each of the 10 fields in all pigs. Fibrosis was quantified 9 months after irradiation by determination of the hydroxyproline (HP) content of the 32 high-dose volumes and in the lung apex and the basolateral lung of all 58 pigs. Based on the reference value for the HP-ratio, i.e. the HP-concentration of the right lung over the left lung, obtained in 12 unirradiated control animals, the experimental results were converted into quantal data for probit analysis, a responder being an animal with an HP-ratio > 1.33. RESULTS: A dose-response relationship for the HP-ratio was obtained in the different lung sites and irradiation groups. For a given dose level the mean HP-ratios and response rates did not differ systematically between the lung apex and the basolateral lung. Probit analysis of the pooled data produced ED50 values of 21.8 Gy (95% CI 12-37) for irradiation without a high-dose volume and 25.9 Gy (24-28) for irradiation with a high-dose volume. These values are not significantly different. The results from both irradiation groups could be well fitted by a common dose-response curve with an ED50 value of 26.1 Gy. Unexpectedly, the response rates in the high-dose volume increased with increasing dose to the surrounding right lung. Analysis of the port films provided an explanation for this finding: inaccuracies in daily field positioning. When this error was corrected for by use of the mean dose to the high-dose volume, a dose-response curve with an ED50 of 25.2 Gy (22-29) was determined for the high-dose volume. CONCLUSIONS: The results of the study indicate that the irradiation of a small lung volume with high fibrogenic doses does not affect the dose-response relationship for development of fibrosis in distant parts of the ipsilateral lung.

Animals↗
PubMed2000

[Effects of knowledge acquisition on verbal linearization about spatial orientation].

This paper deals with determinants of linearization in spatial communication. The well-known linearization principles, such as the principle of natural order, primarily emphasize features of the given information. We assume that verbal linearization is in addition influenced by the speakers' knowledge acquisition. Six experiments with a total of 272 participants are reported here. A particular spatial constellation was presented to the participants, who were asked to talk about it afterwards. The linearizations then produced were defined as dependent variables. The results show that the linearizations were influenced by the speaker's experience with the configuration (according-to-experience effect) and also demonstrate the importance of the first encounter (anchor effect). Further characteristics of the effects mentioned above are described and discussed regarding memory research and psycho-linguistics.

Adult↗
PubMed1999

HFE downregulates iron uptake from transferrin and induces iron-regulatory protein activity in stably transfected cells.

Hereditary hemochromatosis (HH) is a common autosomal-recessive disorder of iron metabolism. More than 80% of HH patients are homozygous for a point mutation in a major histocompatibility complex (MHC) class I type protein (HFE), which results in a lack of HFE expression on the cell surface. A previously identified interaction of HFE and the transferrin receptor suggests a possible regulatory role of HFE in cellular iron absorption. Using an HeLa cell line stably transfected with HFE under the control of a tetracycline-sensitive promoter, we investigated the effect of HFE expression on cellular iron uptake. We demonstrate that the overproduction of HFE results in decreased iron uptake from diferric transferrin. Moreover, HFE expression activates the key regulators of intracellular iron homeostasis, the iron-regulatory proteins (IRPs), implying that HFE can affect the intracellular "labile iron pool." The increase in IRP activity is accompanied by the downregulation of the iron-storage protein, ferritin, and an upregulation of transferrin receptor levels. These findings are discussed in the context of the pathophysiology of HH and a possible role of iron-responsive element (IRE)-containing mRNAs.

Down-Regulation↗