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Biomedical subjects

W Hofmann

Publications and source records attributed to W Hofmann.

At least 37 records · Page 2Linked to original sources
PubMed2003

Mechanistic interpretation of the slow bronchial clearance phase.

A slow bronchial clearance phase, describing the removal of insoluble particles from the sol layer, has recently been incorporated into the ICRP human respiratory tract model. A striking feature of that clearance phase is the size dependence of the slowly cleared fraction. In the theoretical approach presented here, it is suggested that the slow bronchial clearance phase includes three main mechanisms: (1) re-transfer of particles onto the gel layer after a certain time delay, (2) intra- or intercellular transfer of particles through the airway epithelium and subsequent transport to the blood or lymph nodes, and (3) uptake of particles by airway macrophages. The experimentally observed inverse relationship between the slow clearance fraction and geometric particle size is interpreted as an increasing capture probability in the sol layer and transepithelial transport with decreasing particle diameter.

Absorption↗
PubMed2003

Simulation of deposition and clearance of inhaled particles in central human airways.

In this study local distributions of deposited inhaled particles such as radon progenies in realistic human airway bifurcation models of bronchial generations one to six are computed for different geometries, inlet flow profiles, flow rates and particle sizes with computational fluid particle dynamics methods. The movement of the mucus layer in the large central human airways is also simulated by computational fluid dynamic techniques. There is experimental evidence that bronchogenic carcinomas mainly originate at the central zone of the large airway bifurcations, where primary hot-spots of deposition have been found. However, current lung deposition models do not take into consideration the inhomogeneity of deposition within the airways. The inhomogeneous movement of the mucus layer may strongly influence the effect of primary deposition. On the basis of our results, both the deposition and the clearance patterns are highly non-uniform, especially in the vicinity of the carinal ridge of the bifurcations.

Absorption↗
PubMed2003

Stochastic model of ultrafine particle deposition and clearance in the human respiratory tract.

Deposition and clearance of insoluble ultrafine particles, ranging from 1 to 100 nm, were simulated by stochastic models using Monte Carlo methods. Brownian motion is the dominant mode of deposition in human airways. The additional effects of convective diffusion in bifurcations and axial diffusion (convective mixing) primarily affect particle transport and deposition of particles in the 1-10 nm range. Regarding total deposition, the effects of both convective mechanisms are practically compensated by the concomitant effect of molecular radial diffusion (Brownian motion). During the first hours following inhalation, 1 nm particles are predicted to be cleared much faster than particles in the size range from 10 to 100 nm, with a retained fraction of about 80% after 24 h. For 1-10 nm particles, extracellular transfer to blood is the most likely mode of clearance, while uptake and subsequent accumulation in epithelial cells are assumed to be the preferential mechanisms for 10-100 nm particles.

Adsorption↗
PubMed2002

Testing extrapolation of a biologically based exposure-response model from in vitro to in vivo conditions.

Models of carcinogenesis may become so flexible as to preclude the possibility of being falsified by data. This problem is removed in part by stronger biophysical specification of processes and parameters within the model prior to fitting to in vivo data on the relationship between exposure and cancer incidence. This paper explores the use of a biophysical model of chromosomal damage, cellular transformation, repair, mitosis, initiation, promotion, progression, and cytotoxicity in developing exposure-response models for radiation-induced cancer. Many of the aspects of model form and parameter values are developed from in vitro data, and the model then is extrapolated to the in vivo setting using a dosimetric model to account for dose inhomogeneity within the lung tissue of rats exposed to radon progeny in air. The ability of the model to predict cancer incidence in the rats is assessed and is shown to be problematic at higher doses. This calls into question whether a full claim may be made about the ability of first-principle models to fully constrain models applied to in vivo data at present. Possible explanations for the discrepancy, and implications for extrapolation, are provided.

Animals↗
PubMed2002

Explanation of protective effects of low doses of gamma-radiation with a mechanistic radiobiological model.

PURPOSE: To test whether data that show protective effects of low doses against spontaneous neoplastic transformation of C3H 10T1/2 cells can be explained with a biomathematical model that includes radioprotective mechanisms. To link important features of the model to known biological processes. MATERIALS AND METHODS: The model simulates double-strand break formation in transcriptionally active and in bulk DNA, translocation of DNA segments, and the fixation of damage at mitosis; promotion is also included. The model equations were solved numerically using a stiff solver. RESULTS: The data were successfully simulated by the model: cell transformation-reducing effects of low doses of gamma-radiation delivered at low dose-rates are explained by radiation-inducible DNA repair and enzymatic scavenging. CONCLUSIONS: The model successfully simulates experimental data. The highly nonlinear features of the data point to a nonlinear dose-effect relationship at low doses and indicate that linear extrapolation from moderate (or high) to low doses and dose-rates may not be justified for in vitro studies of the cell line under consideration.

Animals↗
PubMed2002

Modelling carcinogenic effects of low doses of inhaled radon progenies.

In this study, cellular hit probabilities of alpha particles emitted by inhaled radon progenies in sensitive epithelial cell nuclei were simulated at low exposure levels to obtain useful data for the rejection or in support of the linear no-threshold dose-effect hypothesis. In this work, local distributions of deposited inhaled radon progenies in airway bifurcation models were computed at exposure conditions which are characteristic of homes and uranium mines. Then, maximum local deposition enhancement factors, that is, local per average deposition densities, were simulated, and the effects of the inhomogeneity of deposition on hit probabilities were characterised. Our results suggest that in the vicinity of the carinal regions of the central airways the probability of multiple hits can be quite high even at low doses.

Administration, Inhalation↗
PubMed2002

Energy deposition, cellular radiation effects and lung cancer risk by radon progeny alpha particles.

Slowing down spectra, LET spectra, hit probabilities, and radiation doses were simulated for the interaction of single 218Po and 214Po alpha particles with sensitive basal and secretory cell nuclei in the bronchial epithelium of human and rat lungs for defined exposure conditions. Probabilities per unit track length for transformation, derived from in vitro experiments with C3H 10T1/2 cells, were used to estimate transformation probabilities for randon progeny alpha particles in basal and secretory cells. Different weighting schemes were assumed to relate cellular hit probabilities, doses and transformation probabilities, obtained for different cell depths and airway generations, to lung cancer risk per unit exposure. In vitro transformation and in vivo lung cancer incidence were simulated by a state-vector model which provides a stochastic formulation of dose-rate dependent cellular transitions related to formation of double strand breaks, repair, inactivation, stimulated mitosis and promotion through loss of intercellular communication.

Alpha Particles↗
PubMed2002

Monte Carlo code for microdosimetry of inhaled alpha emitters.

A Monte Carlo code has been developed to calculate the local energy deposited by alpha emitters deposited on the inner surface in the lung airway. Developed to deal further with airway bifurcations, this code has been as a first step validated in a cylindrical airway configuration by comparison with well-established analytical codes in the case of contamination of bronchiolar airways with actinides. The code has then been applied to the study of uniform and non-uniform contamination of cylindrical bronchial airways by radon progeny in indoor and mine exposure conditions. In addition to the microdosimetric spectra, the average microdosimetric parameters (zp, n, z) have been evaluated. The work currently in progress consists in adapting this developed Monte Carlo code to the configuration of an airway bifurcation with realistic particles deposition.

Alpha Particles↗
PubMed2002

Local deposition distributions of inhaled radionuclides in the human tracheobronchial tree.

There is experimental evidence that bronchogenic carcinomas originate mainly at the carinal ridges of the large central airways, where primary hot spots of deposition have been found. However, current lung dosimetry models do not take into consideration the inhomogeneity of deposition within the airways. In this study, computed local distributions of deposited inhaled radionuclides such as radon progenies in morphologically realistic human airway bifurcation models are analysed for different flow rates and particle sizes. Then, local deposition enhancement factors, defined as the ratio of local to average deposition densities, are computed by scanning along the surface of the bifurcation with pre-specified surface area elements. Computed enhancement factors indicate that cells located at carinal ridges or at the inner sides of the progeny branches may receive localised doses which are two orders of magnitude higher than the average values.

Administration, Inhalation↗
PubMed2001

Constitutional genomic instability with inversions, duplications, and amplifications in 9p23-24 in BRCA2 mutation carriers.

Germ-line mutations of the BRCA2 gene (13q12-13) account for a large proportion of familial breast cancer cases in females and the majority of familial breast cancers in males. Recent studies provide evidence for a role of the BRCA2 protein in the maintenance of genomic integrity by involvement in DNA repair and recombination. In pursuit of identifying in humans genetic damage resulting from mutated BRCA2, we have analyzed constitutional karyotypes of BRCA2 mutation carriers. The present study establishes that constitutional distal 9p rearrangements without obvious additional gross chromosomal alterations are a recurrent feature of independently ascertained families. From our cytogenetic analyses we have no indication of additional gross rearrangements, but we cannot exclude more subtle recombinations in other genomic regions. We also show that the topography of the 9p rearrangements can differ among family members, even within an individual that can have cell populations with different 9p rearrangements. Collectively these results raise point to an association of mutant BRCA2 with genomic instability and gene alteration in 9p23-24 in at least a subset of BRCA2 mutation carriers.

Adult↗
PubMed2001

Mutational analysis of the peroxisome proliferator-activated receptor gamma gene in human malignancies.

Peroxisome proliferator-activated receptor gamma (PPARgamma) plays an important role in adipocyte differentiation and is expressed in many human malignancies, including those from prostate, breast, as well as colon. It regulates differentiation and/or cell growth of these cells. However, expression of this nuclear hormone receptor in other types of cancer, especially in hematological malignancies, remains to be fully elucidated. The PPARgamma gene has been mapped to chromosome band 3p25, where chromosomal abnormalities are observed in a variety of human malignancies. Furthermore, a recent study revealed that the PPARgamma gene is functionally mutated in sporadic colon cancer cells. Therefore, PPARgamma could be an important tumor suppressor gene. This prompted us to investigate the expression and mutational status of the PPARgamma gene in cancers of a variety of tissues. A total of 159 samples were interrogated for their expression of PPARgamma as measured by reverse transcription-polymerase chain reaction and/or Western blot analysis. In each of the samples, expression of PPARgamma was detectable. In addition, a total of 397 clinical samples and cell lines including colon, prostate, breast and lung cancers, and leukemias were analyzed for mutations of the PPARgamma gene by either reverse transcription-polymerase chain reaction-single-strand conformation polymorphism or polymerase chain reaction-single-strand conformation polymorphism analysis. No abnormalities were detectable in any of the human malignancies. On the other hand, shifted bands were easily detectable when using positive controls, which harbored the same sequence alterations reported previously in colon cancer cells. Taken together, PPARgamma is expressed in a variety of cancers, and mutation of the PPARgamma gene is a very rare event in human malignancies.

Blotting, Western↗
PubMed2001

alpha1 Integrin cytoplasmic domain is involved in focal adhesion formation via association with intracellular proteins.

Integrins are heterodimeric adhesion receptors consisting of alpha- and beta-subunits capable of binding extracellular matrix molecules as well as other adhesion receptors on neighbouring cells. These interactions induce various signal transduction pathways in many cell types, leading to cytoskeletal reorganization, phosphorylation and induction of gene expression. Integrin ligation leads to cytoplasmic protein-protein interactions requiring both integrin cytoplasmic domains, and these domains are initiation points for focal adhesion formation and subsequent signal transduction cascades. In previous studies we have shown that the very short cytoplasmic alpha1 tail is required for post-ligand events, such as cell spreading as well as actin stress-fibre formation. In the present paper we report that cells lacking the cytoplasmic domain of the alpha1 integrin subunit are unable to form proper focal adhesions and that phosphorylation on tyrosine residues of focal adhesion components is reduced on alpha1beta1-specific substrates. The alpha1 cytoplasmic sequence is a specific recognition site for focal adhesion components like paxillin, talin, alpha-actinin and pp125FAK. It seems to account for alpha1-specific signalling, since when peptides that mimic the cytoplasmic domain of alpha1 are transferred into cells, they influence alpha1beta1-specific adhesion, presumably by competing for binding partners. For alpha1 integrin/protein binding, the conserved Lys-Ile-Gly-Phe-Phe-Lys-Arg motif and, in particular, the two lysine residues, are important.

Actinin↗
PubMed2001

Cofactor requirements for nuclear export of Rev response element (RRE)- and constitutive transport element (CTE)-containing retroviral RNAs. An unexpected role for actin.

Nuclear export of proteins containing leucine-rich nuclear export signals (NESs) is mediated by the export receptor CRM1/exportin1. However, additional protein factors interacting with leucine-rich NESs have been described. Here, we investigate human immunodeficiency virus type 1 (HIV-1) Rev-mediated nuclear export and Mason-Pfizer monkey virus (MPMV) constitutive transport element (CTE)-mediated nuclear export in microinjected Xenopus laevis oocytes. We show that eukaryotic initiation factor 5A (eIF-5A) is essential for Rev and Rev-mediated viral RNA export, but not for nuclear export of CTE RNA. In vitro binding studies demonstrate that eIF-5A is required for efficient interaction of Rev-NES with CRM1/exportin1 and that eIF-5A interacts with the nucleoporins CAN/nup214, nup153, nup98, and nup62. Quite unexpectedly, nuclear actin was also identified as an eIF-5A binding protein. We show that actin is associated with the nucleoplasmic filaments of nuclear pore complexes and is critically involved in export processes. Finally, actin- and energy-dependent nuclear export of HIV-1 Rev is reconstituted by using a novel in vitro egg extract system. In summary, our data provide evidence that actin plays an important functional role in nuclear export not only of retroviral RNAs but also of host proteins such as protein kinase inhibitor (PKI).

Actins↗
PubMed2001

Correlated hit probability and cell transformation in an effect-specific track length model applied to in vitro alpha irradiation.

In estimating the risk from low doses of alpha particles such as those emitted by radon progeny, it is important to consider the correlation between cellular inactivation and transformation that can exist at the cellular level. A phenomenological model of radiation-induced cellular inactivation and transformation at this level is presented here which incorporates aspects of a state vector model of radiation carcinogenesis and of correlated hit probabilities for inactivation and transformation. The general form of the model assumes that both inactivation and initial initiation damage are produced through the interaction of sublesions induced by radiation passing through cell nuclei, with the production of sublesions governed by hit probabilities and a characteristic probability-per-unit track length. The inactivation and initiation events are partially correlated through the use of hit probabilities. In addition, promotional events are incorporated for the case of cellular transformation based on a previously published state vector model. The model provides good fits to available data on the relationship between inactivation, transformation and LET for doses of alpha above 0.1 Gy in the range of LETs commonly produced by radon and progeny; by "good fits" we mean here the ability to yield the correct shapes of dose-response data using parameter values that vary smoothly with LET and using inactivation parameters that are applied consistently between inactivation and transformation assays. The resulting model correctly predicts recent findings indicating an increased transformation frequency per surviving cell when a population receives a distribution of hits compared to irradiation where all cells receive the same number of hits.

Animals↗
PubMed2001

Identification of a recurrent BRCA1 mutation in German breast-cancer and/or ovarian-cancer families.

Specific BRCA1 mutations have been reported to be common within particular populations. We have investigated German breast- and/or ovarian-cancer families and detected a recurrent carboxy-terminal BRCA1 mutation, 5622C > T, using PCR-based restriction assay and haplotype analysis. Unrelated families carrying this BRCA1 mutation shared two different disease-associated haplotypes, indicating two independent mutation events.

Breast Neoplasms↗
PubMed2001

Comparison of clearance of particles inhaled with bolus and extremely slow inhalation techniques.

Ten healthy nonsmokers inhaled 6-microm (aerodynamic diameter) Teflon particles labelled with 111In twice, once with the shallow bolus technique (volumetic lung depth 76+/-20 mL ([+/- SD]) and once with the extremely slow inhalation technique (0.05 L/s). The radioactivity in the lungs was measured at 1 and 24 hours as well as at 1, 2, and 3 weeks after both inhalations. The 24-hour lung retention a percentage of lung deposition was significantly lower for the bolus inhalation, 46%+/-9% (+/- SD) than for the extremely slow inhalation, 56%+/-11%. The retention after 21 days as a percentage of the 24-hour retention was 55%+/-9% for the shallow bolus inhalation and 56%+/-10% for the extremely slow inhalation. Also within the subjects, clearance was similar for the 2 modes of inhalation. Deposition of particles inhaled with the 2 modes of inhalation was calculated with 2 model, one being based on Monte (Carlo particle transport together with an asymmetric lung model. Deposition predicted with this model agreed well with the experimental data under the assumption that there are large retained fractions only in small ciliated airways (bronchioli) and not in large ones. For the bolus inhalation, the model predicted 43% to 50% deposition in the bronchial (BB) region of initial lung deposition, 33% to 38% in the bronchiolar (bb) region, and 16% to 22% in the alveolar region. For the extremely slow inhalation, the model predicted 31% to 34% deposition in the BB region, 45% to 47% in the bb region, and 21% to 22% in the alveolar region. In addition, it predicted about the same ratio between bb and alveolar depositions for the 2 modes of inhalation. Thus, both the experimental and theoretical data indicate that the shallow bolus particles to a considerable extent reach both the bb and the alveolar regions and that they do that at about the same extent as the particles inhaled extremely slow. This conclusion is concerning the experimental data based on the assumption that there are no large retained fractions in the BB region. Another interpretation of the similar clearance for the two modes of inhalation is that there are large retained fractions in both the BB and the bb regions and that individual charactristics of clearance of these fractions are of importance rather than the site of deposition.

Administration, Inhalation↗