Biomedical subjects

Francesca Ballarini

Publications and source records attributed to Francesca Ballarini.

9 recordsLinked to original sources

PubMed2006

Simulation of light ion induced DNA damage patterns.

The biophysical simulation code PARTRAC was extended by a module to handle ions heavier than alpha particles. Cross sections for ion-electron interactions were taken from He(++) ions of the same velocity and scaled by Z(eff(2))/4. Calculated linear energy transfer values, radial dose distributions and secondary electron spectra were found in agreement with experimental results. DNA damage due to irradiation of human fibroblast cells by several light ions from H to S was calculated for various energies complemented by 220 kV(p) X rays as reference radiation. With increasing linear energy transfer, the calculated total yield of double-strand breaks per dose showed saturation behaviour at about twice the value for reference radiation. When data analysis methods for experimental double-strand break yield determination were applied to the simulated DNA damage patterns, the two data sets were found in accord. The calculated patterns of DNA damage clusters were analysed on local and regional scale finding regional clusters in closer correlation to experimental cell inactivation data.

Chromatin↗

PubMed2005

A model of chromosome aberration induction: applications to space research.

A mechanistic model and Monte Carlo code simulating chromosome aberration induction in human lymphocytes is presented. The model is based on the assumption that aberrations arise from clustered DNA lesions and that only the free ends of clustered lesions created in neighboring chromosome territories or in the same territory can join and produce exchanges. The lesions are distributed in the cell nucleus according to the radiation track structure. Interphase chromosome territories are modeled as compact intranuclear regions with volumes proportional to the chromosome DNA contents. Both Giemsa staining and FISH painting can be simulated, and background aberrations can be taken into account. The good agreement with in vitro data provides validation of the model in terms of both the assumptions adopted and the simulation techniques. As an application in the field of space research, the model predictions were compared with aberration yields measured among crew members of long-term missions on board Mir and ISS, assuming an average radiation quality factor of 2.4. The agreement obtained also validated the model for in vivo exposure scenarios and suggested possible applications to the prediction of other relevant aberrations, typically translocations.

Chromosome Aberrations↗

PubMed2004

A model of chromosome aberration induction and chronic myeloid leukaemia incidence at low doses.

Some chromosome aberration types, generally translocations, are correlated with specific cancers. An example is provided by chronic myeloid leukemia (CML) cells, most of which carry a translocation involving the ABL gene on chromosome 9 and the BCR gene on chromosome 22. The hypothesis of a causal relationship between CML and the chimeric protein product of the BCR-ABL translocation has recently received strong support. In this framework, a mechanistic model and Monte-Carlo code simulating radiation-induced chromosome aberrations in human lymphocytes will be presented. The current version of the model can predict dose-response curves for the main aberration types following acute irradiation with gamma rays and light ions of different energies. The model is based on the assumption that only clustered DNA lesions can lead to aberrations and that only lesion free ends in neighbouring chromosome territories can join and form exchanges. Such lesions are distributed within the cell nucleus according to the radiation track structure, i.e. randomly for low-LET radiation and along straight lines for high-LET light ions. Interphase chromosome territories are explicitly simulated and background aberrations are taken into account. Very good agreement was found with experimental data taken from the literature that provided a further validation of the model. As an application, yields of BCR-ABL translocations were calculated. Preliminary results led to a CML induction dose-response that is approximately quadratic below 0.1 Gy and essentially linear at higher doses up to 1 Gy. The numerical values obtained for the probability of CML induction are consistent with values obtained by other groups with different approaches.

Animals↗

PubMed2004

Role of DNA organisation and environmental scavenging capacity in the evolution of radiobiological damage: models and simulations.

BACKGROUND AND PURPOSE: Theoretical models and Monte Carlo simulations were developed, aimed to investigate the role played by the organisation of interphase DNA and the environmental scavenging capacity conditions in the induction of radiobiological damage. METHODS: The induction of single- and double-strand breaks by gamma rays impinging on different DNA structures (e.g. linear DNA, SV40 minichromosome and cellular DNA) was simulated as a function of the environment scavenging capacity. Furthermore, yields of chromosome aberrations (CA) induced by gamma rays and light ions were simulated with a purposely developed MC code that explicitly takes into account the DNA higher-order organisation as chromosome territories. RESULTS AND CONCLUSIONS: Simulations performed with the PARTRAC code allowed quantification of the dependence of dsb and ssb both on the target structure, and on the scavenging capacity. The results relative to CA showed the importance of DNA damage complexity (nanometre scale) and interphase chromosome domains (micrometre scale) in the process of aberration formation. Very good agreement was found between the model predictions on ssb, dsb and CA and available experimental data.

Animals↗

PubMed2003

Papillary carcinoma of the thyroid: evidence for a role for hepatocyte growth factor (HGF) in promoting tumour angiogenesis.

The pattern of vascularization of papillary carcinoma was investigated in tumour sections from 31 cases and in primary cultures from 12 cases. Tumour sections were immunostained for von Willebrand Factor (vWF) to visualize blood vessels; for endothelial-specific nitric-oxide-synthase (EC-NOS), as a marker of endothelial cell activation; and for Ki-67 to evaluate endothelial cell proliferation. It was found that endothelial cells lining venous vessels located in peritumoural fibrous tissue were intensely EC-NOS-positive and occasionally Ki-67-positive. Capillary vessels of tumour papillae were not stained for Ki-67 and were weakly EC-NOS-positive. Primary cultures of papillary carcinoma cells were used as a potential source of factors active on endothelial cells. It was found that thyroid tumour cells contain RNAs for angiopoietin, vascular endothelial growth factor (VEGF), and VEGF-C; moreover, they release large amounts of VEGF into culture supernatants and exert chemotactic activity in vitro for the endothelial cell line SIEC. The ability of papillary carcinoma cells to release angiogenic factors could be stimulated in vitro. Hepatocyte growth factor (HGF; 25 ng/ml) induced a 1.2- to 5-fold increase in the amount of VEGF released by tumour cells and a 1.2- to 4.2-fold increase in the amount of chemotactic activity present in culture supernatants. Met protein, the high affinity HGF-receptor, is overexpressed in a large proportion of cases of papillary carcinoma. These findings are consistent with the possibility that HGF-Met protein interaction is one of the molecular mechanisms promoting the vascularization of papillary carcinoma of the thyroid.

Adult↗

PubMed2003

In situ study of chemokine and chemokine-receptor expression in Kaposi sarcoma.

Tissue expression of CC and CXC chemokines and chemokine receptors was investigated in 6 cases of classic non-AIDS Kaposi sarcoma (KS) using immunohistochemistry and RNase protection assay (RPA). Immunostaining of frozen sections of KS skin biopsies revealed that KS spindle cells express several chemokine receptors. In KS nodules, almost all KS spindle cells were intensely stained for CXCR4 and CCR5. Other chemokine receptors as CCR1, CXCR3, and CCR2 were also detected in the large majority of KS spindle cells. A minority of KS spindle cells also expressed the fractalkine receptor (FK-R) CX3CR1. The immunohistochemical findings were confirmed at RNA level. In fact, the RNase protection assay (RPA) revealed in 6 of 6 cases the presence of consistent amounts of mRNAs for CXCR4 and CCR1 and in 5 of 6 cases also for CCR5 and CXCR3. Expression of chemokine receptors by KS cells was associated with chemokine production within the lesions. In the same cases, RPA demonstrated the presence of mRNAs for MCP-1, RANTES, IP-10, MIP-1alpha, and MIP-1beta. Chemokine-producing cells, as detected by immunohistochemistry, were mainly spindle-shaped cells resembling tissue macrophages outside KS lesions and some scattered cells (<5%) present within KS nodules. The demonstration of chemokine receptors in KS cells raises the possibility that recruitment of KS cells in response to locally produced chemotactic stimuli may be one of the events involved in the pathogenesis of Kaposi sarcoma.

Chemokines↗

PubMed2002

Cellular communication and bystander effects: a critical review for modelling low-dose radiation action.

Available data suggesting the occurrence of "bystander effects" (i.e. damage induction in cells not traversed by radiation) were collected and critically evaluated, in view of the development of low-dose risk models. Although the underlying mechanisms are largely unknown, cellular communication seems to play a key role. In this context, the main features of cellular communication were summarised and a few representative studies on bystander effects were reported and discussed. Three main approaches were identified: (1) conventional irradiation of cell cultures with very low doses of light ions; (2) irradiation of single cells with microbeam probes; (3) treatment with irradiated conditioned medium (ICM), i.e. feeding of unexposed cells with medium taken from irradiated cultures. Indication of different types of bystander damage (e.g. cell killing, gene mutations and modifications in gene expression) has been found in each of the three cases. The interpretations proposed by the investigators were discussed and possible biases introduced by specific experimental conditions were outlined. New arguments and experiments were suggested, with the main purpose of obtaining quantitative information to be included in models of low-dose radiation action. Implications in interpreting low-dose data and modelling low-dose effects at cellular and supra-cellular level, including cancer induction, were analysed. Possible synergism with other low-dose specific phenomena such as adaptive response (AR) (i.e. low-dose induced resistance to subsequent irradiation) was discussed.

Animals↗

PubMed2002

Low-dose radiation action: possible implications of bystander effects and adaptive response.

Several experimental studies performed in the last decade have suggested the occurrence of low-dose-specific phenomena such as the bystander effect (BE, damage induction in cells not directly hit by radiation) and adaptive response (AR, induction of resistance to subsequent irradiation with higher doses). Although the underlying mechanisms are still not known in detail, cellular communication is widely regarded as a key factor. BE and AR may have a non-negligible role in modulating low-dose radiation effects not only in cells, but also in tissues and organs. Whether these phenomena would imply an increase or a decrease of low-dose cancer risk is still an open question. In this context a few representative findings are discussed, focusing on their possible implications for low-dose risk.

Animals↗

PubMed2002

Modelling the influence of shielding on physical and biological organ doses.

Distributions of "physical" and "biological" dose in different organs were calculated by coupling the FLUKA MC transport code with a geometrical human phantom inserted into a shielding box of variable shape, thickness and material. While the expression "physical dose" refers to the amount of deposited energy per unit mass (in Gy), "biological dose" was modelled with "Complex Lesions" (CL), clustered DNA strand breaks calculated in a previous work based on "event-by-event" track-structure simulations. The yields of complex lesions per cell and per unit dose were calculated for different radiation types and energies, and integrated into a version of FLUKA modified for this purpose, allowing us to estimate the effects of mixed fields. As an initial test simulation, the phantom was inserted into an aluminium parallelepiped and was isotropically irradiated with 500 MeV protons. Dose distributions were calculated for different values of the shielding thickness. The results were found to be organ-dependent. In most organs, with increasing shielding thickness the contribution of primary protons showed an initial flat region followed by a gradual decrease, whereas secondary particles showed an initial increase followed by a decrease at large thickness values. Secondary particles were found to provide a substantial contribution, especially to the biological dose. In particular, the decrease of their contribution occurred at larger depths than for primary protons. In addition, their contribution to biological dose was generally greater than that of primary protons.

Cosmic Radiation↗