A Ottolenghi

University of Pavia, Ticinum, Lombardy, Italy

Are you A Ottolenghi?

Claim your profile

Publications (126)150.32 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: The ultimate response of a cell or tissue to radiation is dependent in part on intercellular signalling. This becomes increasingly important at low doses, or at low dose rates, associated with typical human exposures. In order to help characterise the underlying mechanism of intercellular signalling, and how they are perturbed following exposure to ionising radiation, a previously well-defined model system of intercellular induction of apoptosis (IIA) (Portess et al. 2007, Cancer Res. 67, 1246-1253) was adopted. The aim of the present work is to evaluate the signalling mechanisms underpinning this process through exploring the variables that can affect the IIA, i.e. dose, time and space. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
    Radiation Protection Dosimetry 04/2015; DOI:10.1093/rpd/ncv176 · 0.86 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Ionising radiation exposure of cells might induce the perturbation of cell functions and, in particular, the activation or inhibition of several important pathways. This perturbation can cause the deregulation of both intra- and extra-cellular signalling cascades (such as the inflammatory pathway) and alter not only the behaviour of directly exposed cells but also the neighbouring non-irradiated ones, through the so-called bystander effect. The aim of the present work was to investigate the complex nonlinear interactions between the inflammatory pathway and other strictly interlaced signalling pathways, such as Erk1/2 and Akt/PKB, focusing on the radiation-induced perturbation of such pathways in the dose range of 0-2 Gy. The results show how radiation affects these interconnected pathways and how confounding factors, such as the change of culture medium, can hide radiation-induced perturbations. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
    Radiation Protection Dosimetry 04/2015; DOI:10.1093/rpd/ncv132 · 0.86 Impact Factor
  • A Ottolenghi, G Baiocco, V Smyth, K Trott
    [Show abstract] [Hide abstract]
    ABSTRACT: The usual method for estimating the risk from exposure to neutrons uses the concept of relative biological effectiveness (RBE) compared with the risk from photons, which is better known. RBE has been evaluated using cellular and animal models. But this causes difficulties in applying the concept to humans. The ANDANTE project takes a new approach using three different disciplines in parallel: Physics: a track structure model is used to contrast the patterns of damage to cellular macro-molecules from neutrons compared with photons. The simulations reproduce the same energy spectra as are used in the other two approaches. Stem cell radiobiology: stem cells from thyroid, salivary gland and breast tissue are given well characterised exposures to neutrons and photons. A number of endpoints are used to estimate the relative risk of damage from neutrons compared with photons. Irradiated cells will also be transplanted into mice to investigate the progression of the initial radiation effects in stem cells into tumours in a physiological environment. the relative incidence rates of second cancers of the thyroid, salivary gland and breast following paediatric radiotherapy (conventional radiotherapy for photons and proton therapy for neutrons) are investigated in a pilot single-institution study, exploring the possible design of a multi-institution prospective study comparing the long-term out-of-field and in-field effects of scanned and scattered protons. The results will be used to validate an RBE-based risk model developed by the project, and validate the corresponding RBE values. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
    Radiation Protection Dosimetry 04/2015; DOI:10.1093/rpd/ncv158 · 0.86 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Shwachman–Diamond syndrome is an autosomal-recessive disorder characterised by bone marrow failure and a cumulative risk of progression to acute myeloid leukaemia. The Shwachman–Bodian–Diamond syndrome (SBDS) gene, the only gene known to be causative of the pathology, is involved in ribosomal biogenesis, stress responses and DNA repair, and the lack of SBDS sensitises cells to many stressors and leads to mitotic spindle destabilisation. The effect of ionising radiation on SBDS-deficient cells was investigated using immortalised lymphocytes from SDS patients in comparison with positive and negative controls in order to test whether, in response to ionising radiation exposure, any impairment in the DNA repair machinery could be observed. After irradiating cells with different doses of X-rays or gamma-rays, DNA repair kinetics and the residual damages using the alkaline COMET assay and the γ-H2AX assay were assessed, respectively. In this work, preliminary data about the comparison between ionising radiation effects in different patients-derived cells and healthy control cells are presented.
    Radiation Protection Dosimetry 04/2015; · 0.86 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The aim of the present work was to investigate the mechanisms of radiation-induced bystander signalling leading to apoptosis in non-irradiated co-cultured cells. Cultured non-transformed cells were irradiated, and the effect on the apoptosis rate on co-cultured non-irradiated malignant cells was determined. For this, two different levels of the investigation are presented, i.e. release of signalling proteins and transcriptomic profiling of the irradiated and non-irradiated co-cultured cells. Concerning the signalling proteins, in this study, the attention was focussed on the release of the active and latent forms of the transforming growth factor-β1 protein. Moreover, global gene expression profiles of non-transformed and transformed cells in untreated co-cultures were compared with those of 0.5-Gy-irradiated non-transformed cells co-cultured with the transformed cells. The results show an effect of radiation on the release of signalling proteins in the medium, although no significant differences in release rates were detectable when varying the doses in the range from 0.25 to 1 Gy. Moreover, gene expression results suggest an effect of radiation on both cell populations, pointing out specific signalling pathways that might be involved in the enhanced induction of apoptosis. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
    Radiation Protection Dosimetry 04/2015; DOI:10.1093/rpd/ncv133 · 0.86 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Neutron relative biological effectiveness (RBE) is found to be energy dependent, being maximal for energies ∼1 MeV. This is reflected in the choice of radiation weighting factors wR for radiation protection purposes. In order to trace back the physical origin of this behaviour, a detailed study of energy deposition processes with their full dependences is necessary. In this work, the Monte Carlo transport code PHITS was used to characterise main secondary products responsible for energy deposition in a 'human-sized' soft tissue spherical phantom, irradiated by monoenergetic neutrons with energies around the maximal RBE/wR. Thereafter, results on the microdosimetric characterisation of secondary protons were used as an input to track structure calculations performed with PARTRAC, thus evaluating the corresponding DNA damage induction. Within the proposed simplified approach, evidence is suggested for a relevant role of secondary protons in inducing the maximal biological effectiveness for 1 MeV neutrons. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
    Radiation Protection Dosimetry 04/2015; DOI:10.1093/rpd/ncv134 · 0.86 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The inflammatory pathway has a pivotal role in regulating the fate and functions of cells after a wide range of stimuli, including ionizing radiation. However, the molecular mechanisms governing such responses have not been completely elucidated yet. In particular, the complex activation dynamics of the Nuclear transcription Factor kB (NF-kB), the key molecule governing the inflammatory pathway, still lacks a complete characterization. In this work we focused on the activation dynamics of the NF-kB (subunit p65) pathway following different stimuli. Quantitative measurements of NF-kB were performed and results interpreted within a systems theory approach, based on the negative feedback loop feature of this pathway. Time-series data of nuclear NF-kB concentration showed no evidence of γ-ray induced activation of the pathway for doses up to 5Gy but highlighted important transient effects of common environmental stress (e.g. CO2, temperature) and laboratory procedures, e.g. replacing the culture medium, which dominate the in vitro inflammatory response.
    Scientific Reports 03/2015; 5:9343. DOI:10.1038/srep09343 · 5.08 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: In 2009, the European High Level and Expert Group identified key policy and scientific questions to be addressed through a strategic research agenda for low-dose radiation risk. This initiated the establishment of a European Research Platform, called MELODI (Multidisciplinary European Low Dose Research Initiative). In 2010, the DoReMi Network of Excellence was launched in the Euratom 7th Framework Programme. DoReMi has acted as an operational tool for the sustained development of the MELODI platform during its early years. A long-term Strategic Research Agenda for European low-dose radiation risk research has been developed by MELODI. Strategic planning of DoReMi research activities is carried out in close collaboration with MELODI. The research priorities for DoReMi are designed to focus on objectives that are achievable within the 6-y lifetime of the project and that are in areas where stimulus and support can help progress towards the longer-term strategic objectives. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
    Radiation Protection Dosimetry 12/2014; DOI:10.1093/rpd/ncu350 · 0.86 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: In press (2014) - One of the main issues of low-energy internal emitters concerns the very short ranges of beta particles, comparable to the dimensions of the biological targets. Depending on the chemical form, the radionuclide may be more concentrated either in the cytoplasm or in the nucleus of the target cell. Consequently, the conventional dosimetry - neglecting this issue - may overestimate or underestimate the dose to the nucleus and hence the biological effects. To assess the magnitude of these deviations and to provide a realistic evaluation of the localized energy deposition by low-energy internal emitters, the biophysical track-structure code PARTRAC was used to calculate nuclear doses, DNA damage yields and fragmentation patterns for different localizations of radionuclides in human interphase fibroblasts. The nuclides considered in the simulations were tritium and nickel-63, emitting electrons with average energies of 5.7 keV (range in water of 0.42 µm) and 17 keV (range of 5 µm), respectively, covering both very short and medium ranges of beta-decay products. The simulations results show that the largest deviations from the conventional dosimetry occur for inhomogeneously distributed short-range emitters. For uniformly distributed radionuclides selectively in the cytoplasm but excluded from the cell nucleus, the dose in the nucleus is 15% of the average dose in the cell in the case of tritium but 64% for nickel-63. Also the numbers of double-strand breaks (DSB) and the distributions of DNA fragments depend on sub-cellular localization of the radionuclides; in the investigated low- and medium-dose regions, DSB numbers are proportional to the nuclear dose, with about 50 DSB/Gy for both studied nuclides. DSB numbers on specific chromosomes depend on the radionuclide localization in the cell too, with chromosomes located more peripherally in cell nucleus being more damaged by short-ranged emitters in cytoplasm as compared with chromosomes located more centrally. These results illustrate the potential overestimation or underestimation of the risk associated with low-energy emitters, particularly for tritium intake, when their distribution at sub-cellular levels is not considered appropriately.
    Radiation Research 06/2014; 182(3). DOI:10.1667/RR13664.1 · 2.45 Impact Factor
  • Source
  • Source
    Dataset: RadRes2013
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Radiation therapy is one of the most common and effective strategies used to treat cancer. The irradiation is usually performed with a fractionated scheme, where the dose required to kill tumour cells is given in several sessions, spaced by specific time intervals, to allow healthy tissue recovery. In this work, we examined the DNA repair dynamics of cells exposed to radiation delivered in fractions, by assessing the response of histone-2AX (H2AX) phosphorylation (γ-H2AX), a marker of DNA double strand breaks. γ-H2AX foci induction and disappearance were monitored following split dose irradiation experiments in which time interval between exposure and dose were varied. Experimental data have been coupled to an analytical theoretical model, in order to quantify key parameters involved in the foci induction process. Induction of γ-H2AX foci was found to be affected by the initial radiation exposure with a smaller number of foci induced by subsequent exposures. This was compared to chromatin relaxation and cell survival. The time needed for full recovery of γ-H2AX foci induction was quantified (12 hours) and the 1:1 relationship between radiation induced DNA double strand breaks and foci numbers was critically assessed in the multiple irradiation scenarios.
    PLoS ONE 11/2013; 8(11):e79541. DOI:10.1371/journal.pone.0079541 · 3.53 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Nowadays the Pavia TRIGA reactor is available for national and international collaboration in various research field. The TRIGA Mark II nuclear research reactor of the Pavia University offers different in- and out-core neutron irradiation channels, each characterized by different integral and differential (in energy) neutron spectra. In the last two years a campaign of measurements and simulations have been performed in order to guarantee a better characterization of these different fluxes to meet the demands of irradiations that required precise information on these spectra, as radiobiological and microdosimetric studies. Experimental data on neutron fluxes have been collected analyzing and measuring the induced gamma activity in thin target foils of different materials irradiated in different TRIGA experimental channels. The data on the induced gamma activities have been processed with the SAND II deconvolution code and finally compared with the spectra obtained with Monte Carlo simulation. The comparison between simulated and measured spectra showed good agreement allowing a more precise characterization of neutron spectra and a validation of the method adopted.
    Radiation Protection Dosimetry 10/2013; · 0.86 Impact Factor
  • A. Ottolenghi, V. Smyth, K. R. Trott
    [Show abstract] [Hide abstract]
    ABSTRACT: The ANDANTE project began in January 2012 as a spin-off of results of an earlier Euratom project, ALLEGRO, designed to address the problems of medium- and long-term risks following radiotherapy. ANDANTE will investigate the relative risk of induction of cancer from exposure to neutrons compared to photons. The project will focus on three specific cancers that may be detected as second malignant neoplasms following paediatric radiotherapy: salivary gland, thyroid gland, and breast tissue. Stem cells from each of the types of tissue will be exposed to well characterised beams of both neutrons and photons. Biological markers of possible tumorigenesis will be used to develop RBE models for neutrons. The experimental beams will be measured in terms of fluence and energy spectra in order to provide date for a track structure model, which will be developed to simulate the exact experimental conditions and to explore the relationships between exposure parameters and response. The RBE model will be utilized in the assessment of follow-up data from paediatric photon radiotherapy patients. The out-of-beam mixed photon-neutron fields generated during proton therapy will be measured in phantoms, and an analytic algorithm will be developed for reconstructing the fields distant from the treatment site using data available from clinical records. One of the aims of the project is a critical analysis of the potential power of a multi-centre cohort of paediatric patients to give confidence in the neutron risk estimates in radiotherapy patients.This paper focuses on the challenges in the ANDANTE project posed by the need to know detailed neutron, photon, and charged particle fluences and energy spectra in order to determine the neutron RBE as a function of dose and energy.
    Radiation Measurements 10/2013; 57:68-73. DOI:10.1016/j.radmeas.2012.10.017 · 1.14 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The number of small radiation-induced DNA fragments can be heavily underestimated when determined from measurements of DNA mass fractions by gel electrophoresis, leading to a consequent underestimation of the initial DNA damage induction. In this study we reanalyzed the experimental results for DNA fragmentation and DNA double-strand break (DSB) yields in human fibroblasts irradiated with γ rays and nitrogen ion beams with linear energy transfer (LET) equal to 80, 125, 175 and 225 keV/μm, originally measured by Höglund et al. (Radiat Res 155, 818-825, 2001 and Int J Radiat Biol 76, 539-547, 2000). In that study the authors converted the measured distributions of fragment masses into DNA fragment distributions using mid-range values of the measured fragment length intervals, in particular they assumed fragments with lengths in the interval of 0-48 kbp had the mid-range value of 24 kbp. However, our recent detailed simulations with the Monte Carlo code PARTRAC, while reasonably in agreement with the mass distributions, indicate significantly increased yields of very short fragments by high-LET radiation, so that the actual average fragment lengths, in the interval 0-48 kbp, 2.4 kbp for 225 keV/μm nitrogen ions were much shorter than the assumed mid-range value of 24 kbp. When the measured distributions of fragment masses are converted into fragment distributions using the average fragment lengths calculated by PARTRAC, significantly higher yields of DSB related to short fragments were obtained and resulted in a constant relative biological effectiveness (RBE) for DSB induction yield of 2.3 for nitrogen ions at 125-225 keV/μm LET. The previously reported downward trend of the RBE values over this LET range for DSB induction appears to be an artifact of an inadequate average fragment length in the smallest interval.
    Radiation Research 05/2013; DOI:10.1667/R3043.1 · 2.45 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Aims and background. To calculate peripheral radiation dose to the second primary site in patients who have developed a second malignancy after breast cancer radiotherapy (index cases) and to compare it with dose in the analogous anatomical site in radiotherapy-treated breast cancer patients who did not experience a second malignancy (controls). To evaluate the feasibility of Peridose-software peripheral dose calculation in retrospective case-control studies. Material and study design. A case-control study on 12,630 patients who underwent adjuvant breast radiotherapy was performed. Minimum 5-year follow-up was required. Each index case was matched with 5 controls by 1) year of birth, 2) year of radiotherapy and 3) follow-up duration. Peridose-software was used to calculate peripheral dose. Results. 195 second cancers were registered (0.019% of all patients treated with adjuvant irradiation). Several methodological limitations of the Peridose calculation were encountered including impossibility to calculate the peripheral dose in the patients treated with intraoperative or external electron beam radiotherapy, in case of second tumors located at <15 cm from the radiotherapy field etc. Moreover, Peridose requires full radiotherapy data and the distance between radiotherapy field and second primary site. Due to these intrinsic limitations, only 6 index cases were eligible for dose calculation. Calculated doses at the second cancer site in index cases and in an analogous site in controls ranged between 7.5 and 145 cGy. The mean index-control dose difference was -3.15 cGy (range, -15.8 cGy and +2.7 cGy).Conclusions. The calculated peripheral doses were low and the index-control differences were small. However, the small number of eligible patients precludes a reliable analysis of a potential dose-response relationship. Large patient series followed for a long period and further improvement in the methodology of the peripheral dose calculation are necessary in order to overcome the methodological challenges of the study.
    11/2012; 98(6):715-21. DOI:10.1700/1217.13494
  • PLoS ONE 07/2012; · 3.53 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The normal tissue complication probability (NTCP) models that are currently being proposed for estimation of risk of harm following radiotherapy are mainly based on simplified empirical models, consisting of dose distribution parameters, possibly combined with clinical or other treatment-related factors. These are fitted to data from retrospective or prospective clinical studies. Although these models sometimes provide useful guidance for clinical practice, their predictive power on individuals seems to be limited.
    Radiotherapy and Oncology 06/2012; 105(1). DOI:10.1016/j.radonc.2012.05.008 · 4.86 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Abstract Purpose: To investigate the mechanisms regulating the pathways of the bystander transmission in vitro, focusing on the radiation-perturbed signalling (via Interleukine 6, IL-6) of the irradiated cells after exposure to low doses of different radiation types. Materials and methods: An integrated 'systems radiation biology' approach was adopted. Experimentally the level of the secreted cytokine from human fibroblasts was detected with ELISA (Enzyme-Linked ImmunoSorbent Assay) method and subsequently the data were analyzed and coupled with a phenomenological model based on differential equations to evaluate the single-cell release mechanisms. Results: The data confirmed the important effect of radiation on the IL-6 pathway, clearly showing a crucial role of the ROS (Reactive Oxygen Species) in transducing the effect of initial radiation exposure and the subsequent long-term release of IL-6. Furthermore, a systematic investigation of radiation dose/radiation quality dependence seems to indicate an increasing efficiency of high LET (Linear Energy Transfer) irradiation in the release of the cytokine. Basic hypotheses were tested, on the correlation between direct radiobiological damage and signal release and on the radiation target for this endpoint (secretion of IL-6) Conclusions: The results demonstrate the role of reactive oxygen and nitrogen species in the signaling pathways of IL-6. Furthermore the systems radiation biology approach here adopted, allowed us to test and verify hypotheses on the behavior of the single cell in the release of cytokine, after the exposure to different doses and different qualities of ionizing radiation.
    International Journal of Radiation Biology 06/2012; 88(10):751-62. DOI:10.3109/09553002.2012.703365 · 1.84 Impact Factor

Publication Stats

2k Citations
150.32 Total Impact Points


  • 2002–2015
    • University of Pavia
      • Department of Physics
      Ticinum, Lombardy, Italy
  • 1989–2015
    • INFN - Istituto Nazionale di Fisica Nucleare
      • National Institute of Nuclear Physics (CNAF)
      Frascati, Latium, Italy
  • 2006
    • CERN
      Genève, Geneva, Switzerland
  • 1990–2006
    • University of Milan
      • Department of Physics
      Milano, Lombardy, Italy
  • 2003
    • University of Houston
      • Department of Physics
      Houston, TX, United States
  • 1996
    • Karolinska University Hospital
      • Department of Oncology
      Tukholma, Stockholm, Sweden