The effect of altered fractionation schedule on the spinal cord response: radiobiological considerations

Increased fractionation spares late reacting normal tissues more than acute reacting normal tissues. A linear quadratic model is valid from large dose per fraction down to dose per fraction of 2 Gy. Experimental studies on animals and clinical studies on the spinal cord tolerance have shown incidences of myelopathy at doses lower than 50 Gy. The α/β value of the linear quadratic model have been lower for low doses per fraction, indicating a sparing effect of altered fractionation for spinal cord myelitis. Animal data, clinical and radiobiological explanations suggest limitation of the radiobiological models. Further data suggest that one must not assume the spinal cord to have a greater tolerance at doses per fraction below the conventional dose per fraction of 2 Gy.     

Integrating mouse anatomy and pathology ontologies into a phenotyping database: Tools for data capture and training

The Mouse Disease Information System (MoDIS) is a data capture system for pathology data from laboratory mice designed to support phenotyping studies. The system integrates the mouse anatomy (MA) and mouse pathology (MPATH) ontologies into a Microsoft Access database facilitating the coding of organ, tissue, and disease process to recognized semantic standards. Grading of disease severity provides scores for all lesions that can then be used for quantitative trait locus (QTL) analyses and haplotype association gene mapping. Direct linkage to the Pathbase online database provides reference definitions for disease terms and access to photomicrographic images of similar diagnoses in other mutant mice. MoDIS is an open source and freely available program (). This provides a valuable tool for setting up a mouse pathology phenotyping program.     

Production and validation of CR-39-based dishes for alpha-particle radiobiological experiments

The study of radiobiological effects induced in vitro by low fluences of alpha particles would be significantly enhanced if the precise localization of each particle track in the cell monolayer was known. From this perspective, we developed a new method based on tailor-made UV-radiation-cured CR-39, the production of which is described. Its validation both as a petri dish and as solid-state nuclear track detectors is demonstrated. With respect to the demands on solid-state nuclear track detectors in such experiments, these biologically compatible detectors have a controlled micrometric thickness that allows them to be crossed by the alpha particles. In this study, we present a method for obtaining 10-mum-thick CR-39, its chemical characterization, and its properties as a solid-state nuclear track detector under the environmental conditions of radiobiological experiments. The experimental studies performed with 3.5 MeV alpha particles show that their transmitted energy is sufficient enough to cross the entire cellular volume. Under optimal conditions, etched tracks are clearly defined 2 h after etching. Moreover, the UV-radiation-cured CR-39 represents an essentially zero background that is due to the short time between the production and use of the polymer. Under a confocal microscope, this thin solid-state nuclear track detector allows the precise localization of the impact parameter at the subcellular level.     

Morphinome--a meta-analysis applied to proteomics studies in morphine dependence

This review is a meta-analysis of data describing proteins regulated by morphine influence studied worldwide across last years administration. Up to date (July 2010), 15 studies concerning this subject have been published. Animal models, examined brain structures, the route of morphine administration and proteomic platforms used for identification of differentially expressed proteins were described. Standardization of obtained results allowed for creation of database of proteins, whose expression was altered by morphine administration (www.addiction-proteomics.org). Their analysis by tools available in Celera Panther Database was possible too. Proteins, which seem to be the most promising candidates for further research, due to their consistent appearance in different studies, were indicated. Created database may facilitate further studies by providing a possibility to compare results obtained during different experiments. At the end, dynamic picture of proteome after morphine administration, which emerges from the obtained results, is discussed and need for standardization of proteomics experiments is stressed. As meta-analysis is a very powerful tool for evaluation and comparison of multiple data. We believe this approach will be useful in the nearest future to extract vital information from a vast number of similar publications. Morphinome database created already by our group is a comfortable tool for validation and verification of new data received after morphine influence on proteomes investigations. It gives a chance for fast comparison of results without hours spent on life science literature mining.     

A radiobiological model for the relative biological effectiveness of high-dose-rate 252Cf brachytherapy

While there is significant clinical experience using both low- and high-dose-rate 252Cf brachytherapy, there are minimal data regarding values for the neutron relative biological effectiveness (RBE) with both modalities. The aim of this research was to derive a radiobiological model for 252Cf neutron RBE and to compare these results with neutron RBE values used clinically in Russia. The linear-quadratic (LQ) model was used as the basis to characterize cell survival after irradiation, with identical cell killing rates (S(N) = S(gamma)) between 252Cf neutrons and photons used for derivation of RBE. Using this equality, a relationship among neutron dose and LQ radiobiological parameter (i.e., alpha(N), beta(N), alpha(gamma), beta(gamma)) was obtained without the need to specify the photon dose. These results were used to derive the 252Cf neutron RBE, which was then compared with Russian neutron RBE values. The 252Cf neutron RBE was determined after incorporating the LQ radiobiological parameters obtained from cell survival studies with fast neutrons and teletherapy photons. For single-fraction high-dose-rate neutron doses of 0.5, 1.0, 1.5 and 2.0 Gy, the total biologically equivalent doses were 1.8, 3.4, 4.7 and 6.0 RBE Gy with 252Cf neutron RBE values of 3.2, 2.9, 2.7 and 2.5, respectively. Using clinical data for late-responding reactions from 252Cf, Russian investigators created an empirical model that predicted high-dose-rate 252Cf neutron RBE values ranging from 3.6 to 2.9 for similar doses and fractionation schemes and observed that 252Cf neutron RBE increases with the number of treatment fractions. Using these relationships, our results were in general concordance with high-dose-rate 252Cf RBE values obtained from Russian clinical experience.     

Systems approach to modeling radiobiological effects

Basic principles of the systemic approach to modelling of the radiobiological effects at different levels of cell organization have been formulated. The methodology is proposed for theoretical modelling of the effects at these levels.     

A mathematical model of brain tumour response to radiotherapy and chemotherapy considering radiobiological aspects

Glioblastoma is the most frequent and malignant brain tumour. For many years, the conventional treatment has been maximal surgical resection followed by radiotherapy (RT), with a median survival time of less than 10 months. Previously, the use of adjuvant chemotherapy (given after RT) has failed to demonstrate a statistically significant survival advantage. Recently, a randomized phase III trial has confirmed the benefit of temozolomide (TMZ) and has defined a new standard of care for the treatment of patients with high-grade brain tumours. The results showed an increase of 2.5 months in median survival, and 16.1% in 2 year survival, for patients receiving RT with TMZ compared with RT alone. It is not clear whether the major benefit of TMZ comes from either concomitant administration of TMZ with RT, or from six cycles of adjuvant TMZ, or both.The objectives were to develop our original model, which addressed survival after RT, to construct a new module to assess the potential role of TMZ from clinical data, and to explore its synergistic contribution in addition to radiation. The model has been extended to include radiobiological parameters. The addition of the linear quadratic equation to describe cellular response to treatment has enabled us to quantify the effects of radiation and TMZ in radiobiological terms.The results indicate that the model achieves an excellent fit to the clinical data, with the assumption that TMZ given concomitantly with RT synergistically increases radiosensitivity. The alternative, that the effect of TMZ is due only to direct cell killing, does not fit the clinical data so well. The addition of concomitant TMZ appears to change the radiobiological parameters. This aspect of our results suggests possible treatment developments.Our observations need further evaluations in real clinical trials, may suggest treatment strategies for new trials, and inform their design.     

A Web-based classification system of DNA-binding protein families

Rational classification of proteins encoded in sequenced genomes is critical for making the genome sequences maximally useful for functional and evolutionary studies. The family of DNA-binding proteins is one of the most populated and studied amongst the various genomes of bacteria, archaea and eukaryotes and the Web-based system presented here is an approach to their classification. The DnaProt resource is an annotated and searchable collection of protein sequences for the families of DNA-binding proteins. The database contains 3238 full-length sequences (retrieved from the SWISS-PROT database, release 38) that include, at least, a DNA-binding domain. Sequence entries are organized into families defined by PROSITE patterns, PRINTS motifs and de novo excised signatures. Combining global similarities and functional motifs into a single classification scheme, DNA-binding proteins are classified into 33 unique classes, which helps to reveal comprehensive family relationships. To maximize family information retrieval, DnaProt contains a collection of multiple alignments for each DNA-binding family while the recognized motifs can be used as diagnostically functional fingerprints. All available structural class representatives have been referenced. The resource was developed as a Web-based management system for online free access of customized data sets. Entries are fully hyperlinked to facilitate easy retrieval of the original records from the source databases while functional and phylogenetic annotation will be applied to newly sequenced genomes. The database is freely available for online search of a library containing specific patterns of the identified DNA-binding protein classes and retrieval of individual entries from our WWW server (http://kronos.biol.uoa.gr/~mariak/dbDNA.html).     

Impact of microgravity on radiobiological processes and efficiency of DNA repair

To study the influence of microgravity on radiobiological processes in space, space experiments have been performed, using an on-board 1×g reference centrifuge as in-flight control. The trajectory of individual heavy ions was localized in relation to the biological systems by use of the Biostack concept, or an additional high dose of radiation was applied either before the mission or during the mission from an on-board radiation source. In embryonic systems, such as early developmental stages of Drosophila melanogaster and Carausius morosus, the occurrence of chromosomal translocations and larval malformations was dramatically increased in response to microgravity and radiation. It has been hypothesized that these synergistic effects might be caused by an interference of microgravity with DNA repair processes. However, recent studies on bacteria, yeast cells and human fibroblasts suggest that a disturbance of cellular repair processes in the microgravity environment might not be a complete explanation for the reported synergism of radiation and microgravity. As an alternative explanation, an impact of microgravity on signal transduction, on the metabolic/physiological state or on the chromatin structure at the cellular level, or modification of self-assembly, intercellular communication, cell migration, pattern formation or differentiation at the tissue and organ level should be considered.     

L2L: a simple tool for discovering the hidden significance in microarray expression data

L2L is a database consisting of lists of differentially expressed genes compiled from published mammalian microarray studies, along with an easy-to-use application for mining the database with the user's own microarray data. As illustrated by re-analysis of a recent study of diabetic nephropathy, L2L identifies novel biological patterns in microarray data, providing insights into the underlying nature of biological processes and disease. L2L is available online at the authors' website [].     

PEATmoss (Physcomitrella Expression Atlas Tool): a unified gene expression atlas for the model plant Physcomitrella patens

Physcomitrella patens is a bryophyte model plant that is often used to study plant evolution and development. Its resources are of great importance for comparative genomics and evo‐devo approaches. However, expression data from Physcomitrella patens were so far generated using different gene annotation versions and three different platforms: CombiMatrix and NimbleGen expression microarrays and RNA sequencing. The currently available P. patens expression data are distributed across three tools with different visualization methods to access the data. Here, we introduce an interactive expression atlas, Physcomitrella Expression Atlas Tool (PEATmoss), that unifies publicly available expression data for P. patens and provides multiple visualization methods to query the data in a single web‐based tool. Moreover, PEATmoss includes 35 expression experiments not previously available in any other expression atlas. To facilitate gene expression queries across different gene annotation versions, and to access P. patens annotations and related resources, a lookup database and web tool linked to PEATmoss was implemented. PEATmoss can be accessed at https://peatmoss.online.uni-marburg.de     

FlgM anti-sigma factors: identification of novel members of the family, evolutionary analysis, homology modeling, and analysis of sequence-structure-function relationships

FlgM proteins, also known as Anti-sigma-28 factor (sigma28), are negative regulators of flagellin synthesis. Recently, a three-dimensional structure of the Aquifex aeolicus sigma28/FlgM complex (PDB code: 1rp3) was determined by X-ray crystallography at 2.3 A resolution. Furthermore, experimental data on bacterial FlgM, including site-directed mutagenesis and structural characterization by NMR are also available. However, an interpretation of the sequence-structure-function relationships combining X-ray and NMR data with the evolutionary information extracted from the increasing number of FlgM-related sequences annotated in databases is not available. In the present study, we combined database sequence searches and sequence-analysis tools to update the multiple sequence alignment of a previously characterized cluster of orthologs (COG2747) and the PFAM classification of protein domains (PF04316) for the FlgM family. A phylogenetic analysis of 77 protein sequences revealed the presence of at least three major sequence clades within the FlgM family. Besides, we predicted functional residues using a SequenceSpace method. We also generated homology models for Bacillus subtilis and Salmonella typhimurium FlgM proteins, for which sequence-structure-function relationship data are available, and used the docking program ClusPro to hypothesize about the dimer association between FlgM proteins. In conclusion, the analysis presented in this work will be useful in designing new experiments to understand better protein-protein interactions between FglM, sigma factors, and putative molecules from the flagellar export apparatus. Electronic Supplementary Material is available in the online version of this article at http://link.springer.de/     

Methodologies for predicting the expected combined stochastic radiobiological effects of different ionizing radiations and some applications

A methodology for predicting the expected combined stochastic radiobiological effects of sequential exposure to different ionizing radiations is used to arrive at a methodology for predicting the radiobiological effects of simultaneous exposure. Both methodologies require developing additive-damage dose-effect models. Additive-damage dose-effect models are derived assuming (a) each radiation comprised by the combined exposure produces initial damage called critical damage that could lead to the radiobiological effect of interest; (b) doses of different radiations that lead to the same level of radiobiological effect (or risk) can be viewed as producing the same amount of critical damage and being indistinguishable as far as the effects of subsequently administered radiation. Derived dose-effect functions that describe the risk per individual, conditional on radiation dose, are called risk functions. The methodologies allow the use of known radiation-specific risk functions to derive risk functions for combined effects of different radiations. The risk functions for combined exposure to different radiations are called global risk functions. For sequential exposures to different ionizing radiations, the global risk functions derived depend on how individual radiation doses are ordered. Global risk functions can also differ for sequential and simultaneous exposure. The methodologies are used to account for some previously unexplained radiobiological effects of combined exposure to high and low linear-energy-transfer radiations.     

A radiobiological comparison of hypo-fractionation versus conventional fractionation for breast cancer 3D-conformal radiation therapy

BackgroundThe present research was aimed to compare the toxicity and effectiveness of conventional fractionated radiotherapy versus hypo-fractionated radiotherapy in breast cancer utilizing a radiobiological model.Materials and methodsThirty-five left-sided breast cancer patients without involvement of the supraclavicular and axillary lymph nodes (with the nodal stage of N0) that had been treated with conventional or hypo-fractionated were incorporated in this study. A radiobiological model was performed to foretell normal tissue complication probability (NTCP) and tumor control probability (TCP).ResultsThe data represented that TCP values for conventional and hypo-fractionated regimens were 99.16 ± 0.09 and 95.96 ± 0.48, respectively (p = 0.00). Moreover, the NTCP values of the lung for conventional and hypo-fractionated treatment were 0.024 versus 0.13 (p = 0.035), respectively. Also, NTCP values of the heart were equal to zero for both regimens.ConclusionIn summary, hypo-fractionated regimens had comparable efficacy to conventional fraction radiation therapy in the case of dosimetry parameters for patients who had left breast cancer. But, utilizing the radiobiological model, conventional fractionated regimens presented better results compared to hypo-fractionated regimens.     

Principal inferences from studies of radiobiological effects for radiation protection purposes

The most recent Recommendations (Publication 103) issued by the International Commission for Radiological Protection (ICRP) are based on the data that have been published since 1990 up to now. The basic task of the ICRP Committee 1 was to formulate the key implications of studies on radiobiological effects for the purposes of radiological protection. Presented in the paper are the new achievements in the field of biology, radiobiology and radiation epidemiology which were taken into account by the ICRP in the process of Publication 103 preparation. The Recommendations provide present-day values of weighting factors for radiation exposure and tissue weighting factors, as well as radiation detriment and radiogenic risk factors for cancer and genetic diseases. Also considered are tissue reactions to radiation exposure, consequences of in utero exposure and the risks of developing non-cancer diseases for exposed individuals. It should be noted that the key inferences and recommendations are to a considerable degree related to biological effects accounted for by acute and chronic exposure to ionizing radiation in the range of small doses (up to 100 mSv).     

WebACT--an online companion for the Artemis Comparison Tool

SUMMARY: WebACT is an online resource which enables the rapid provision of simultaneous BLAST comparisons between up to five genomic sequences in a format amenable for visualization with the well-known Artemis Comparison Tool (ACT). Comparisons can be generated on-the-fly using sequences directly retrieved via EMBL database queries, or by entering or uploading user sequences. Furthermore, pre-computed comparisons are available between all publicly available, completed prokaryotic genomes and plasmids currently contained within the Genome Reviews database (372 sequences, representing 175 different species). The system is designed to minimize the volume of downloaded data and maximize performance. Genome sequences, annotation and pre-computed comparisons are stored in a relational database allowing flexible querying based on user-defined sequence regions, from whole genome to a defined region flanking a specified gene. Comparison and sequence files, whether computed online or retrieved from the database of pre-computed genome comparisons, can be viewed online using ACT and are available for download. AVAILABILITY: Freely accessible at http://www.webact.org. SUPPLEMENTARY INFORMATION: User guide and worked examples are available at http://www.webact.org/WebACT/docs.     

Annotated reference compilation: Conducting qualitative and quantitative ecological risk assessments at hazardous waste sites

As the field of ecological risk assessment (ERA) broadens, scientists from various disciplines are called upon to become assessors at hazardous waste sites. Although a United States Environmental Protection Agency (USEPA) Framework for ERAs exists, the guidance is unlike the detailed USEPA guidance available for human risk assessments. Currently, the quality of an ERA is dependent upon the assessor's scientific acumen, professional experience, and recognized reference documents. This annotated reference compilation encompasses published documents which have provided useful and important information for qualitative and quantitative ERAs.