53 results on '"Valentina Bravatà"'
Search Results
2. Glut-3 Gene Knockdown as a Potential Strategy to Overcome Glioblastoma Radioresistance
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Gaia Pucci, Luigi Minafra, Valentina Bravatà, Marco Calvaruso, Giuseppina Turturici, Francesco P. Cammarata, Gaetano Savoca, Boris Abbate, Giorgio Russo, Vincenzo Cavalieri, and Giusi I. Forte
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glioblastoma ,radioresistance ,chemical hypoxia ,gene knockdown ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
The hypoxic pattern of glioblastoma (GBM) is known to be a primary cause of radioresistance. Our study explored the possibility of using gene knockdown of key factors involved in the molecular response to hypoxia, to overcome GBM radioresistance. We used the U87 cell line subjected to chemical hypoxia generated by CoCl2 and exposed to 2 Gy of X-rays, as single or combined treatments, and evaluated gene expression changes of biomarkers involved in the Warburg effect, cell cycle control, and survival to identify the best molecular targets to be knocked-down, among those directly activated by the HIF-1α transcription factor. By this approach, glut-3 and pdk-1 genes were chosen, and the effects of their morpholino-induced gene silencing were evaluated by exploring the proliferative rates and the molecular modifications of the above-mentioned biomarkers. We found that, after combined treatments, glut-3 gene knockdown induced a greater decrease in cell proliferation, compared to pdk-1 gene knockdown and strong upregulation of glut-1 and ldha, as a sign of cell response to restore the anaerobic glycolysis pathway. Overall, glut-3 gene knockdown offered a better chance of controlling the anaerobic use of pyruvate and a better proliferation rate reduction, suggesting it is a suitable silencing target to overcome radioresistance.
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- 2024
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3. A preliminary PET radiomics study of brain metastases using a fully automatic segmentation method
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Alessandro Stefano, Albert Comelli, Valentina Bravatà, Stefano Barone, Igor Daskalovski, Gaetano Savoca, Maria Gabriella Sabini, Massimo Ippolito, and Giorgio Russo
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Cancer ,Active contour ,Positron emission tomography ,Biological target volume ,Radiomics ,Computer applications to medicine. Medical informatics ,R858-859.7 ,Biology (General) ,QH301-705.5 - Abstract
Abstract Background Positron Emission Tomography (PET) is increasingly utilized in radiomics studies for treatment evaluation purposes. Nevertheless, lesion volume identification in PET images is a critical and still challenging step in the process of radiomics, due to the low spatial resolution and high noise level of PET images. Currently, the biological target volume (BTV) is manually contoured by nuclear physicians, with a time expensive and operator-dependent procedure. This study aims to obtain BTVs from cerebral metastases in patients who underwent L-[11C]methionine (11C-MET) PET, using a fully automatic procedure and to use these BTVs to extract radiomics features to stratify between patients who respond to treatment or not. For these purposes, 31 brain metastases, for predictive evaluation, and 25 ones, for follow-up evaluation after treatment, were delineated using the proposed method. Successively, 11C-MET PET studies and related volumetric segmentations were used to extract 108 features to investigate the potential application of radiomics analysis in patients with brain metastases. A novel statistical system has been implemented for feature reduction and selection, while discriminant analysis was used as a method for feature classification. Results For predictive evaluation, 3 features (asphericity, low-intensity run emphasis, and complexity) were able to discriminate between responder and non-responder patients, after feature reduction and selection. Best performance in patient discrimination was obtained using the combination of the three selected features (sensitivity 81.23%, specificity 73.97%, and accuracy 78.27%) compared to the use of all features. Secondly, for follow-up evaluation, 8 features (SUVmean, SULpeak, SUVmin, SULpeak prod-surface-area, SUVmean prod-sphericity, surface mean SUV 3, SULpeak prod-sphericity, and second angular moment) were selected with optimal performance in discriminant analysis classification (sensitivity 86.28%, specificity 87.75%, and accuracy 86.57%) outperforming the use of all features. Conclusions The proposed system is able i) to extract 108 features for each automatically segmented lesion and ii) to select a sub-panel of 11C-MET PET features (3 and 8 in the case of predictive and follow-up evaluation), with valuable association with patient outcome. We believe that our model can be useful to improve treatment response and prognosis evaluation, potentially allowing the personalization of cancer treatment plans.
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- 2020
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4. Evaluation of proton beam radiation-induced skin injury in a murine model using a clinical SOBP.
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Pietro Pisciotta, Angelita Costantino, Francesco Paolo Cammarata, Filippo Torrisi, Giovanna Calabrese, Valentina Marchese, Giuseppe Antonio Pablo Cirrone, Giada Petringa, Giusi Irma Forte, Luigi Minafra, Valentina Bravatà, Massimo Gulisano, Fabrizio Scopelliti, Francesco Tommasino, Emanuele Scifoni, Giacomo Cuttone, Massimo Ippolito, Rosalba Parenti, and Giorgio Russo
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Medicine ,Science - Abstract
The purpose of this paper is to characterize the skin deterministic damage due to the effect of proton beam irradiation in mice occurred during a long-term observational experiment. This study was initially defined to evaluate the insurgence of myelopathy irradiating spinal cords with the distal part of a Spread-out Bragg peak (SOBP). To the best of our knowledge, no study has been conducted highlighting high grades of skin injury at the dose used in this paper. Nevertheless these effects occurred. In this regard, the experimental evidence of significant insurgence of skin injury induced by protons using a SOBP configuration will be shown. Skin damages were classified into six scores (from 0 to 5) according to the severity of the injuries and correlated to ED50 (i.e. the radiation dose at which 50% of animals show a specific score) at 40 days post-irradiation (d.p.i.). The effects of radiation on the overall animal wellbeing have been also monitored and the severity of radiation-induced skin injuries was observed and quantified up to 40 d.p.i.
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- 2020
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5. Biological and Mechanical Characterization of the Random Positioning Machine (RPM) for Microgravity Simulations
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Marco Calvaruso, Carmelo Militello, Luigi Minafra, Veronica La Regina, Filippo Torrisi, Gaia Pucci, Francesco P. Cammarata, Valentina Bravatà, Giusi I. Forte, and Giorgio Russo
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space biology ,cancer biology ,TNBC ,simulated microgravity ,random positioning machine ,Science - Abstract
The rapid improvement of space technologies is leading to the continuous increase of space missions that will soon bring humans back to the Moon and, in the coming future, toward longer interplanetary missions such as the one to Mars. The idea of living in space is charming and fascinating; however, the space environment is a harsh place to host human life and exposes the crew to many physical challenges. The absence of gravity experienced in space affects many aspects of human biology and can be reproduced in vitro with the help of microgravity simulators. Simulated microgravity (s-μg) is applied in many fields of research, ranging from cell biology to physics, including cancer biology. In our study, we aimed to characterize, at the biological and mechanical level, a Random Positioning Machine in order to simulate microgravity in an in vitro model of Triple-Negative Breast Cancer (TNBC). We investigated the effects played by s-μg by analyzing the change of expression of some genes that drive proliferation, survival, cell death, cancer stemness, and metastasis in the human MDA-MB-231 cell line. Besides the mechanical verification of the RPM used in our studies, our biological findings highlighted the impact of s-μg and its putative involvement in cancer progression.
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- 2021
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6. Radiobiological Outcomes, Microdosimetric Evaluations and Monte Carlo Predictions in Eye Proton Therapy
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Giada Petringa, Marco Calvaruso, Valeria Conte, Pavel Bláha, Valentina Bravatà, Francesco Paolo Cammarata, Giacomo Cuttone, Giusi Irma Forte, Otilija Keta, Lorenzo Manti, Luigi Minafra, Vladana Petković, Ivan Petrović, Selene Richiusa, Aleksandra Ristić Fira, Giorgio Russo, and Giuseppe Antonio Pablo Cirrone
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protontherapy ,proton ,RBE ,radiobiology ,microdosimetry ,Geant4 ,Technology ,Engineering (General). Civil engineering (General) ,TA1-2040 ,Biology (General) ,QH301-705.5 ,Physics ,QC1-999 ,Chemistry ,QD1-999 - Abstract
CATANA (Centro di AdroTerapia ed Applicazioni Nucleari Avanzate) was the first Italian protontherapy facility dedicated to the treatment of ocular neoplastic pathologies. It is in operation at the LNS Laboratories of the Italian Institute for Nuclear Physics (INFN-LNS) and to date, 500 patients have been successfully treated. Even though proton therapy has demonstrated success in clinical settings, there is still a need for more accurate models because they are crucial for the estimation of clinically relevant RBE values. Since RBE can vary depending on several physical and biological parameters, there is a clear need for more experimental data to generate predictions. Establishing a database of cell survival experiments is therefore useful to accurately predict the effects of irradiations on both cancerous and normal tissue. The main aim of this work was to compare RBE values obtained from in-vitro experimental data with predictions made by the LEM II (Local Effect Model), Monte Carlo approaches, and semi-empirical models based on LET experimental measurements. For this purpose, the 92.1 uveal melanoma and ARPE-19 cells derived from normal retinal pigmented epithelium were selected and irradiated in the middle of clinical SOBP of the CATANA proton therapy facility. The remarkable results show the potentiality of using microdosimetric spectrum, Monte Carlo simulations and LEM model to predict not only the RBE but also the survival curves.
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- 2021
- Full Text
- View/download PDF
7. Molecular Investigation on a Triple Negative Breast Cancer Xenograft Model Exposed to Proton Beams
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Francesco P. Cammarata, Giusi I. Forte, Giuseppe Broggi, Valentina Bravatà, Luigi Minafra, Pietro Pisciotta, Marco Calvaruso, Roberta Tringali, Barbara Tomasello, Filippo Torrisi, Giada Petringa, Giuseppe A. P. Cirrone, Giacomo Cuttone, Rosaria Acquaviva, Rosario Caltabiano, and Giorgio Russo
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triple-negative breast cancer (TNBC) ,proton therapy ,xenograft mice ,microarray ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Specific breast cancer (BC) subtypes are associated with bad prognoses due to the absence of successful treatment plans. The triple-negative breast cancer (TNBC) subtype, with estrogen (ER), progesterone (PR) and human epidermal growth factor-2 (HER2) negative receptor status, is a clinical challenge for oncologists, because of its aggressiveness and the absence of effective therapies. In addition, proton therapy (PT) represents an effective treatment against both inaccessible area located or conventional radiotherapy (RT)-resistant cancers, becoming a promising therapeutic choice for TNBC. Our study aimed to analyze the in vivo molecular response to PT and its efficacy in a MDA-MB-231 TNBC xenograft model. TNBC xenograft models were irradiated with 2, 6 and 9 Gy of PT. Gene expression profile (GEP) analyses and immunohistochemical assay (IHC) were performed to highlight specific pathways and key molecules involved in cell response to the radiation. GEP analysis revealed in depth the molecular response to PT, showing a considerable immune response, cell cycle and stem cell process regulation. Only the dose of 9 Gy shifted the balance toward pro-death signaling as a dose escalation which can be easily performed using proton beams, which permit targeting tumors while avoiding damage to the surrounding healthy tissue.
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- 2020
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8. Nutraceutical Compounds as Sensitizers for Cancer Treatment in Radiation Therapy
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Marco Calvaruso, Gaia Pucci, Rosa Musso, Valentina Bravatà, Francesco P. Cammarata, Giorgio Russo, Giusi I. Forte, and Luigi Minafra
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nutraceuticals ,radiotherapy ,cancer ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
The improvement of diagnostic techniques and the efficacy of new therapies in clinical practice have allowed cancer patients to reach a higher chance to be cured together with a better quality of life. However, tumors still represent the second leading cause of death worldwide. On the contrary, chemotherapy and radiotherapy (RT) still lack treatment plans which take into account the biological features of tumors and depend on this for their response to treatment. Tumor cells’ response to RT is strictly-connected to their radiosensitivity, namely, their ability to resist and to overcome cell damage induced by ionizing radiation (IR). For this reason, radiobiological research is focusing on the ability of chemical compounds to radiosensitize cancer cells so to make them more responsive to IR. In recent years, the interests of researchers have been focused on natural compounds that show antitumoral effects with limited collateral issues. Moreover, nutraceuticals are easy to recover and are thus less expensive. On these bases, several scientific projects have aimed to test also their ability to induce tumor radiosensitization both in vitro and in vivo. The goal of this review is to describe what is known about the role of nutraceuticals in radiotherapy, their use and their potential application.
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- 2019
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9. Proton Therapy and Src Family Kinase Inhibitor Combined Treatments on U87 Human Glioblastoma Multiforme Cell Line
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Francesco P Cammarata, Filippo Torrisi, Giusi I Forte, Luigi Minafra, Valentina Bravatà, Pietro Pisciotta, Gaetano Savoca, Marco Calvaruso, Giada Petringa, Giuseppe A. P. Cirrone, Anna L Fallacara, Laura Maccari, Maurizio Botta, Silvia Schenone, Rosalba Parenti, Giacomo Cuttone, and Giorgio Russo
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glioblastoma multiforme ,proton therapy ,combined treatments ,gene signatures ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Glioblastoma Multiforme (GBM) is the most common of malignant gliomas in adults with an exiguous life expectancy. Standard treatments are not curative and the resistance to both chemotherapy and conventional radiotherapy (RT) plans is the main cause of GBM care failures. Proton therapy (PT) shows a ballistic precision and a higher dose conformity than conventional RT. In this study we investigated the radiosensitive effects of a new targeted compound, SRC inhibitor, named Si306, in combination with PT on the U87 glioblastoma cell line. Clonogenic survival assay, dose modifying factor calculation and linear-quadratic model were performed to evaluate radiosensitizing effects mediated by combination of the Si306 with PT. Gene expression profiling by microarray was also conducted after PT treatments alone or combined, to identify gene signatures as biomarkers of response to treatments. Our results indicate that the Si306 compound exhibits a radiosensitizing action on the U87 cells causing a synergic cytotoxic effect with PT. In addition, microarray data confirm the SRC role as the main Si306 target and highlights new genes modulated by the combined action of Si306 and PT. We suggest, the Si306 as a new candidate to treat GBM in combination with PT, overcoming resistance to conventional treatments.
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- 2019
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10. Radiation-Induced Gene Expression Changes in High and Low Grade Breast Cancer Cell Types
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Valentina Bravatà, Claudia Cava, Luigi Minafra, Francesco Paolo Cammarata, Giorgio Russo, Maria Carla Gilardi, Isabella Castiglioni, and Giusi Irma Forte
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ionizing radiation ,breast cancer ,gene expression profile ,pathway analysis ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Background: There is extensive scientific evidence that radiation therapy (RT) is a crucial treatment, either alone or in combination with other treatment modalities, for many types of cancer, including breast cancer (BC). BC is a heterogeneous disease at both clinical and molecular levels, presenting distinct subtypes linked to the hormone receptor (HR) status and associated with different clinical outcomes. The aim of this study was to assess the molecular changes induced by high doses of ionizing radiation (IR) on immortalized and primary BC cell lines grouped according to Human epidermal growth factor receptor (HER2), estrogen, and progesterone receptors, to study how HR status influences the radiation response. Our genomic approach using in vitro and ex-vivo models (e.g., primary cells) is a necessary first step for a translational study to describe the common driven radio-resistance features associated with HR status. This information will eventually allow clinicians to prescribe more personalized total doses or associated targeted therapies for specific tumor subtypes, thus enhancing cancer radio-sensitivity. Methods: Nontumorigenic (MCF10A) and BC (MCF7 and MDA-MB-231) immortalized cell lines, as well as healthy (HMEC) and BC (BCpc7 and BCpcEMT) primary cultures, were divided into low grade, high grade, and healthy groups according to their HR status. At 24 h post-treatment, the gene expression profiles induced by two doses of IR treatment with 9 and 23 Gy were analyzed by cDNA microarray technology to select and compare the differential gene and pathway expressions among the experimental groups. Results: We present a descriptive report of the substantial alterations in gene expression levels and pathways after IR treatment in both immortalized and primary cell cultures. Overall, the IR-induced gene expression profiles and pathways appear to be cell-line dependent. The data suggest that some specific gene and pathway signatures seem to be linked to HR status. Conclusions: Genomic biomarkers and gene-signatures of specific tumor subtypes, selected according to their HR status and molecular features, could facilitate personalized biological-driven RT treatment planning alone and in combination with targeted therapies.
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- 2018
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11. Biological and Mechanical Characterization of the Random Positioning Machine (RPM) for Microgravity Simulations
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Valentina Bravatà, Veronica La Regina, Marco Calvaruso, Carmelo Militello, Luigi Minafra, Gaia Pucci, Giusi Irma Forte, Giorgio Ivan Russo, Filippo Torrisi, and Francesco Paolo Cammarata
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random positioning machine ,Space technology ,Random positioning machine ,Science ,Human life ,Paleontology ,space biology ,cancer biology ,TNBC ,simulated microgravity ,General Biochemistry, Genetics and Molecular Biology ,Space exploration ,Article ,simulatedmicrogravity ,randompositioningmachine ,Simulated microgravity ,Space and Planetary Science ,Systems engineering ,Cancer biology ,Interplanetary spaceflight ,Ecology, Evolution, Behavior and Systematics ,Space environment - Abstract
The rapid improvement of space technologies is leading to the continuous increase of space missions that will soon bring humans back to the Moon and, in the coming future, toward longer interplanetary missions such as the one to Mars. The idea of living in space is charming and fascinating; however, the space environment is a harsh place to host human life and exposes the crew to many physical challenges. The absence of gravity experienced in space affects many aspects of human biology and can be reproduced in vitro with the help of microgravity simulators. Simulated microgravity (s-μg) is applied in many fields of research, ranging from cell biology to physics, including cancer biology. In our study, we aimed to characterize, at the biological and mechanical level, a Random Positioning Machine in order to simulate microgravity in an in vitro model of Triple-Negative Breast Cancer (TNBC). We investigated the effects played by s-μg by analyzing the change of expression of some genes that drive proliferation, survival, cell death, cancer stemness, and metastasis in the human MDA-MB-231 cell line. Besides the mechanical verification of the RPM used in our studies, our biological findings highlighted the impact of s-μg and its putative involvement in cancer progression.
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- 2021
12. Radiosensitizing effect of curcumin-loaded lipid nanoparticles in breast cancer cells
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Giorgio Ivan Russo, Francesco Paolo Cammarata, Marcella Bonanomi, Daniela Gaglio, Carmelo Militello, Maria Carla Gilardi, Nunziatina Porcino, Margherita Baglio, G. Evangelista, Gaetano Savoca, B. Abbate, G. Iacoviello, Erika Amore, Giusi Irma Forte, Luigi Minafra, Valentina Bravatà, Maria Luisa Bondì, Minafra, L, Porcino, N, Bravatà, V, Gaglio, D, Bonanomi, M, Amore, E, Cammarata, F, Russo, G, Militello, C, Savoca, G, Baglio, M, Abbate, B, Iacoviello, G, Evangelista, G, Gilardi, M, Bondì, M, and Forte, G
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0301 basic medicine ,Radiation-Sensitizing Agents ,Radiosensitizer ,Curcumin ,Cell Survival ,medicine.medical_treatment ,lcsh:Medicine ,Antineoplastic Agents ,Apoptosis ,Breast Neoplasms ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,Drug Delivery Systems ,0302 clinical medicine ,Cell Line, Tumor ,medicine ,Humans ,Radiosensitivity ,Particle Size ,Clonogenic assay ,lcsh:Science ,IC50 ,Drug Carriers ,Multidisciplinary ,Radiotherapy ,Chemistry ,lcsh:R ,Radiotherapy, Systems biology ,Lipids ,In vitro ,Radiation therapy ,030104 developmental biology ,Cancer cell ,MCF-7 Cells ,Cancer research ,Nanoparticles ,Female ,lcsh:Q ,Systems biology ,030217 neurology & neurosurgery - Abstract
In breast cancer (BC) care, radiotherapy is considered an efficient treatment, prescribed both for controlling localized tumors or as a therapeutic option in case of inoperable, incompletely resected or recurrent tumors. However, approximately 90% of BC-related deaths are due to the metastatic tumor progression. Then, it is strongly desirable to improve tumor radiosensitivity using molecules with synergistic action. The main aim of this study is to develop curcumin-loaded solid nanoparticles (Cur-SLN) in order to increase curcumin bioavailability and to evaluate their radiosensitizing ability in comparison to free curcumin (free-Cur), by using an in vitro approach on BC cell lines. In addition, transcriptomic and metabolomic profiles, induced by Cur-SLN treatments, highlighted networks involved in this radiosensitization ability. The non tumorigenic MCF10A and the tumorigenic MCF7 and MDA-MB-231 BC cell lines were used. Curcumin-loaded solid nanoparticles were prepared using ethanolic precipitation and the loading capacity was evaluated by UV spectrophotometer analysis. Cell survival after treatments was evaluated by clonogenic assay. Dose–response curves were generated testing three concentrations of free-Cur and Cur-SLN in combination with increasing doses of IR (2–9 Gy). IC50 value and Dose Modifying Factor (DMF) was measured to quantify the sensitivity to curcumin and to combined treatments. A multi-“omic” approach was used to explain the Cur-SLN radiosensitizer effect by microarray and metobolomic analysis. We have shown the efficacy of the Cur-SLN formulation as radiosensitizer on three BC cell lines. The DMFs values, calculated at the isoeffect of SF = 50%, showed that the Luminal A MCF7 resulted sensitive to the combined treatments using increasing concentration of vehicled curcumin Cur-SLN (DMF: 1,78 with 10 µM Cur-SLN.) Instead, triple negative MDA-MB-231 cells were more sensitive to free-Cur, although these cells also receive a radiosensitization effect by combination with Cur-SLN (DMF: 1.38 with 10 µM Cur-SLN). The Cur-SLN radiosensitizing function, evaluated by transcriptomic and metabolomic approach, revealed anti-oxidant and anti-tumor effects. Curcumin loaded- SLN can be suggested in future preclinical and clinical studies to test its concomitant use during radiotherapy treatments with the double implications of being a radiosensitizing molecule against cancer cells, with a protective role against IR side effects.
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- 2019
13. Hypoxia Transcriptomic Modifications Induced by Proton Irradiation in U87 Glioblastoma Multiforme Cell Line
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Giusi Irma Forte, Francesco Paolo Cammarata, Olga Sokol, Walter Tinganelli, Giorgio Ivan Russo, Marco Calvaruso, Giada Petringa, G.A.P. Cirrone, Valentina Bravatà, Emanuele Scifoni, and Luigi Minafra
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0301 basic medicine ,Programmed cell death ,medicine.medical_treatment ,Medicine (miscellaneous) ,omic science ,Article ,Transcriptome ,03 medical and health sciences ,0302 clinical medicine ,Radioresistance ,medicine ,proton therapy ,transcriptome ,hypoxia ,glioblastoma ,ddc:610 ,U87 ,Chemistry ,Hypoxia (medical) ,Biomarker (cell) ,Radiation therapy ,030104 developmental biology ,Cell culture ,030220 oncology & carcinogenesis ,Cancer research ,Medicine ,medicine.symptom - Abstract
Journal of Personalized Medicine 11(4), 308 (2021). doi:10.3390/jpm11040308, Published by MDPI, Basel
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- 2021
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14. Transcriptomics and Metabolomics Integration Reveals Redox-Dependent Metabolic Rewiring in Breast Cancer Cells
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Paola Paci, Marco Vanoni, Tatiana Volpari, Fabrizia Mastroianni, Stefano D'Errico, Valentina Bravatà, Anna Maria Colangelo, Marcella Bonanomi, Daniela Gaglio, Lilia Alberghina, Manuela Scorza, Federica Conte, Giulia Fiscon, Noemi Salmistraro, Elenio Avolio, Gennaro Piccialli, Giusi Irma Forte, Bonanomi, M., Salmistraro, N., Fiscon, G., Conte, F., Paci, P., Bravata, V., Forte, G. I., Volpari, T., Scorza, M., Mastroianni, F., D'Errico, S., Avolio, E., Piccialli, G., Colangelo, A. M., Vanoni, M., Gaglio, D., Alberghina, L., Bonanomi, M, Salmistraro, N, Fiscon, G, Conte, F, Paci, P, Bravata, V, Forte, G, Volpari, T, Scorza, M, Mastroianni, F, D'Errico, S, Avolio, E, Piccialli, G, Colangelo, A, Vanoni, M, Gaglio, D, and Alberghina, L
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Pyruvate decarboxylation ,Cancer metabolic rewiring ,CtBP2 ,Epigenetics ,Metabolomics integration ,Transcriptomics ,Cancer Research ,epigenetics ,Chemistry ,cancer metabolic rewiring ,transcriptomics ,metabolomics integration ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Epigenetic ,Metabolism ,Article ,Cell biology ,Oncology ,Transcriptomic ,Anaerobic glycolysis ,Cancer cell ,Glycolysis ,NAD+ kinase ,Reprogramming ,RC254-282 - Abstract
Simple Summary Metabolic rewiring fuels cancer proliferation by enhanced glycolysis and the increased NADH/NAD+ ratio. In this study, we highlight the critical role of NADH in the epigenetic landscape mediated by CtBP2 (C-terminal binding protein 2) activation, linking metabolism to epigenetic transcriptional reprogramming. Moreover, using metabolomics and transcriptomics integration, we show that genetic and pharmacological down-regulation of CtBP2 strongly reduces cell proliferation by modulating the redox balance, nucleotide synthesis, reactive oxygen species (ROS) generation, and scavenging. Therefore, we provide evidence that metabolic rewiring plasticity regulates the crosstalk between metabolism and the transcriptional program that sustains energetic and anabolic demands in cancer cells. Abstract Rewiring glucose metabolism toward aerobic glycolysis provides cancer cells with a rapid generation of pyruvate, ATP, and NADH, while pyruvate oxidation to lactate guarantees refueling of oxidized NAD+ to sustain glycolysis. CtPB2, an NADH-dependent transcriptional co-regulator, has been proposed to work as an NADH sensor, linking metabolism to epigenetic transcriptional reprogramming. By integrating metabolomics and transcriptomics in a triple-negative human breast cancer cell line, we show that genetic and pharmacological down-regulation of CtBP2 strongly reduces cell proliferation by modulating the redox balance, nucleotide synthesis, ROS generation, and scavenging. Our data highlight the critical role of NADH in controlling the oncogene-dependent crosstalk between metabolism and the epigenetically mediated transcriptional program that sustains energetic and anabolic demands in cancer cells.
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- 2021
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15. Radiobiological outcomes, microdosimetric evaluations and monte carlo predictions in eye proton therapy
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Vladana Petković, Ivan Petrović, Valentina Bravatà, Marco Calvaruso, Giada Petringa, G.A.P. Cirrone, Francesco Paolo Cammarata, Lorenzo Manti, V. Conte, Luigi Minafra, Otilija Keta, Aleksandra M Ristić Fira, Selene Richiusa, Giacomo Cuttone, Giusi Irma Forte, Pavel Bláha, Giorgio Ivan Russo, Petringa, G., Calvaruso, M., Conte, V., Blaha, P., Bravata, V., Cammarata, F. P., Cuttone, G., Forte, G. I., Keta, O., Manti, L., Minafra, L., Petkovic, V., Petrovic, I., Richiusa, S., Fira, A. R., Russo, G., and Cirrone, G. A. P.
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Technology ,medicine.medical_specialty ,Radiobiology ,QH301-705.5 ,QC1-999 ,Monte Carlo method ,Sobp ,Normal tissue ,Geant4 ,RBE ,Microdosimetry ,030218 nuclear medicine & medical imaging ,03 medical and health sciences ,0302 clinical medicine ,medicine ,General Materials Science ,Medical physics ,Biology (General) ,protontherapy ,proton ,radiobiology ,microdosimetry ,QD1-999 ,Instrumentation ,Proton therapy ,Cell survival ,Fluid Flow and Transfer Processes ,Physics ,Protontherapy ,Process Chemistry and Technology ,General Engineering ,Experimental data ,Engineering (General). Civil engineering (General) ,3. Good health ,Computer Science Applications ,Chemistry ,030220 oncology & carcinogenesis ,Pigmented Epithelium ,Proton ,TA1-2040 - Abstract
CATANA (Centro di AdroTerapia ed Applicazioni Nucleari Avanzate) was the first Italian protontherapy facility dedicated to the treatment of ocular neoplastic pathologies. It is in operation at the LNS Laboratories of the Italian Institute for Nuclear Physics (INFN-LNS) and to date, 500 patients have been successfully treated. Even though proton therapy has demonstrated success in clinical settings, there is still a need for more accurate models because they are crucial for the estimation of clinically relevant RBE values. Since RBE can vary depending on several physical and biological parameters, there is a clear need for more experimental data to generate predictions. Establishing a database of cell survival experiments is therefore useful to accurately predict the effects of irradiations on both cancerous and normal tissue. The main aim of this work was to compare RBE values obtained from in-vitro experimental data with predictions made by the LEM II (Local Effect Model), Monte Carlo approaches, and semi-empirical models based on LET experimental measurements. For this purpose, the 92.1 uveal melanoma and ARPE-19 cells derived from normal retinal pigmented epithelium were selected and irradiated in the middle of clinical SOBP of the CATANA proton therapy facility. The remarkable results show the potentiality of using microdosimetric spectrum, Monte Carlo simulations and LEM model to predict not only the RBE but also the survival curves.
- Published
- 2021
16. A preliminary PET radiomics study of brain metastases using a fully automatic segmentation method
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Massimo Ippolito, Albert Comelli, Igor Daskalovski, Valentina Bravatà, Gaetano Savoca, Alessandro Stefano, Giorgio Ivan Russo, Stefano Barone, Maria Gabriella Sabini, Stefano A., Comelli A., Bravata V., Barone S., Daskalovski I., Savoca G., Sabini M.G., Ippolito M., and Russo G.
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Male ,Positron emission tomography ,Computer science ,Lesion volume ,lcsh:Computer applications to medicine. Medical informatics ,Biochemistry ,030218 nuclear medicine & medical imaging ,Lesion ,03 medical and health sciences ,0302 clinical medicine ,Radiomics ,Structural Biology ,Artificial Intelligence ,medicine ,Humans ,Segmentation ,Neoplasm Metastasis ,lcsh:QH301-705.5 ,Molecular Biology ,Cancer ,Active contour model ,medicine.diagnostic_test ,Brain Neoplasms ,business.industry ,Applied Mathematics ,Research ,Pattern recognition ,Middle Aged ,Prognosis ,medicine.disease ,Computer Science Applications ,Cancer treatment ,Biological target volume ,lcsh:Biology (General) ,Feature (computer vision) ,030220 oncology & carcinogenesis ,Positron-Emission Tomography ,Fully automatic ,lcsh:R858-859.7 ,Female ,Active contour ,Artificial intelligence ,medicine.symptom ,Radiomic ,business - Abstract
BackgroundPositron Emission Tomography (PET) is increasingly utilized in radiomics studies for treatment evaluation purposes. Nevertheless, lesion volume identification in PET images is a critical and still challenging step in the process of radiomics, due to the low spatial resolution and high noise level of PET images. Currently, the biological target volume (BTV) is manually contoured by nuclear physicians, with a time expensive and operator-dependent procedure.This study aims to obtain BTVs from cerebral metastases in patients who underwent L-[11C]methionine (11C-MET) PET, using a fully automatic procedure and to use these BTVs to extract radiomics features to stratify between patients who respond to treatment or not. For these purposes, 31 brain metastases, for predictive evaluation, and 25 ones, for follow-up evaluation after treatment, were delineated using the proposed method. Successively, 11C-MET PET studies and related volumetric segmentations were used to extract 108 features to investigate the potential application of radiomics analysis in patients with brain metastases. A novel statistical system has been implemented for feature reduction and selection, while discriminant analysis was used as a method for feature classification.ResultsFor predictive evaluation, 3 features (asphericity, low-intensity run emphasis, and complexity) were able to discriminate between responder and non-responder patients, after feature reduction and selection. Best performance in patient discrimination was obtained using the combination of the three selected features (sensitivity 81.23%, specificity 73.97%, and accuracy 78.27%) compared to the use of all features. Secondly, for follow-up evaluation, 8 features (SUVmean, SULpeak, SUVmin, SULpeakprod-surface-area, SUVmeanprod-sphericity, surface mean SUV 3, SULpeakprod-sphericity, and second angular moment) were selected with optimal performance in discriminant analysis classification (sensitivity 86.28%, specificity 87.75%, and accuracy 86.57%) outperforming the use of all features.ConclusionsThe proposed system is able i) to extract 108 features for each automatically segmented lesion and ii) to select a sub-panel of 11C-MET PET features (3 and 8 in the case of predictive and follow-up evaluation), with valuable association with patient outcome. We believe that our model can be useful to improve treatment response and prognosis evaluation, potentially allowing the personalization of cancer treatment plans.
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- 2020
17. Molecular Investigation on a Triple Negative Breast Cancer Xenograft Model Exposed to Proton Beams
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Giuseppe Broggi, Giacomo Cuttone, Marco Calvaruso, Giusi Irma Forte, Rosario Caltabiano, Giorgio Ivan Russo, Rosaria Acquaviva, Francesco Paolo Cammarata, Luigi Minafra, Giada Petringa, G.A.P. Cirrone, Valentina Bravatà, Filippo Torrisi, Roberta Tringali, Barbara Tomasello, and Pietro Pisciotta
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0301 basic medicine ,xenograft mice ,Apoptosis ,Triple Negative Breast Neoplasms ,THERAPY ,triple-negative breast cancer (TNBC) ,lcsh:Chemistry ,Mice ,0302 clinical medicine ,Cell Movement ,proton therapy ,Tumor Cells, Cultured ,Medicine ,lcsh:QH301-705.5 ,Spectroscopy ,Triple-negative breast cancer ,RISK ,Mice, Inbred BALB C ,General Medicine ,Cell cycle ,DOSE IONIZING-RADIATION ,Computer Science Applications ,Gene Expression Regulation, Neoplastic ,030220 oncology & carcinogenesis ,Immunohistochemistry ,Female ,Triple-negative breast cancer (TNBC) ,microarray ,Stem cell ,Protons ,medicine.drug_class ,Mice, Nude ,Article ,Catalysis ,Inorganic Chemistry ,03 medical and health sciences ,Breast cancer ,In vivo ,MASTECTOMY ,Biomarkers, Tumor ,Animals ,Humans ,CELL ,Physical and Theoretical Chemistry ,Molecular Biology ,Cell Proliferation ,business.industry ,Gene Expression Profiling ,Organic Chemistry ,medicine.disease ,Xenograft Model Antitumor Assays ,030104 developmental biology ,lcsh:Biology (General) ,lcsh:QD1-999 ,Estrogen ,Molecular Response ,Cancer research ,business ,RESISTANCE - Abstract
Specific breast cancer (BC) subtypes are associated with bad prognoses due to the absence of successful treatment plans. The triple-negative breast cancer (TNBC) subtype, with estrogen (ER), progesterone (PR) and human epidermal growth factor-2 (HER2) negative receptor status, is a clinical challenge for oncologists, because of its aggressiveness and the absence of effective therapies. In addition, proton therapy (PT) represents an effective treatment against both inaccessible area located or conventional radiotherapy (RT)-resistant cancers, becoming a promising therapeutic choice for TNBC. Our study aimed to analyze the in vivo molecular response to PT and its efficacy in a MDA-MB-231 TNBC xenograft model. TNBC xenograft models were irradiated with 2, 6 and 9 Gy of PT. Gene expression profile (GEP) analyses and immunohistochemical assay (IHC) were performed to highlight specific pathways and key molecules involved in cell response to the radiation. GEP analysis revealed in depth the molecular response to PT, showing a considerable immune response, cell cycle and stem cell process regulation. Only the dose of 9 Gy shifted the balance toward pro-death signaling as a dose escalation which can be easily performed using proton beams, which permit targeting tumors while avoiding damage to the surrounding healthy tissue.
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- 2020
18. Nutraceutical Compounds as Sensitizers for Cancer Treatment in Radiation Therapy
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Giorgio Ivan Russo, Francesco Paolo Cammarata, Valentina Bravatà, Gaia Pucci, Marco Calvaruso, Luigi Minafra, Giusi Irma Forte, and Rosa Musso
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Oncology ,medicine.medical_specialty ,Radiation-Sensitizing Agents ,medicine.medical_treatment ,Review ,Catalysis ,Inorganic Chemistry ,lcsh:Chemistry ,Nutraceutical ,Internal medicine ,Neoplasms ,medicine ,cancer ,Animals ,Humans ,Radiosensitivity ,Physical and Theoretical Chemistry ,Molecular Biology ,Cell damage ,lcsh:QH301-705.5 ,Spectroscopy ,nutraceuticals ,Chemotherapy ,Radiotherapy ,business.industry ,Organic Chemistry ,Cancer ,General Medicine ,medicine.disease ,radiotherapy ,Computer Science Applications ,Cancer treatment ,Radiation therapy ,lcsh:Biology (General) ,lcsh:QD1-999 ,Cancer cell ,Dietary Supplements ,business - Abstract
The improvement of diagnostic techniques and the efficacy of new therapies in clinical practice have allowed cancer patients to reach a higher chance to be cured together with a better quality of life. However, tumors still represent the second leading cause of death worldwide. On the contrary, chemotherapy and radiotherapy (RT) still lack treatment plans which take into account the biological features of tumors and depend on this for their response to treatment. Tumor cells’ response to RT is strictly-connected to their radiosensitivity, namely, their ability to resist and to overcome cell damage induced by ionizing radiation (IR). For this reason, radiobiological research is focusing on the ability of chemical compounds to radiosensitize cancer cells so to make them more responsive to IR. In recent years, the interests of researchers have been focused on natural compounds that show antitumoral effects with limited collateral issues. Moreover, nutraceuticals are easy to recover and are thus less expensive. On these bases, several scientific projects have aimed to test also their ability to induce tumor radiosensitization both in vitro and in vivo. The goal of this review is to describe what is known about the role of nutraceuticals in radiotherapy, their use and their potential application.
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- 2019
19. Gene Expression Profiles Induced by High-dose Ionizing Radiation in MDA-MB-231 Triple-negative Breast Cancer Cell Line
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Valentina Bravatà, Giorgio Ivan Russo, Ivan Fazio, Gaia Pucci, Giusi Irma Forte, Luigi Minafra, Rosa Musso, Massimiliano Spada, and Francesco Paolo Cammarata
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Cancer Research ,medicine.medical_treatment ,Triple Negative Breast Neoplasms ,Biology ,Biochemistry ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,Ionizing radiation (IR) ,MDA-MB-231 cells ,gene expression profile (GEP) ,Radioresistance ,Cell Line, Tumor ,Radiation, Ionizing ,Gene expression ,Genetics ,medicine ,Humans ,Clonogenic assay ,Molecular Biology ,Triple-negative breast cancer ,Microarray analysis techniques ,medicine.disease ,Radiation therapy ,Cell culture ,030220 oncology & carcinogenesis ,Cancer research ,Female ,Transcriptome ,Research Article - Abstract
Background/aim Radiation therapy (RT) represents a therapeutic option in breast cancer (BC). Even if a great number of BC patients receive RT, not all of them report benefits, due to radioresistance that gets activated through several factors, such as the hormone receptor status. Herein, we analyzed the gene expression profiles (GEP) induced by RT in triple-negative BC (TNBC) MDA-MB-231, to study signalling networks involved in radioresistance. Materials and methods GEP of MDA-MB-231 BC cells treated with a high dose of radiation, went through cDNA microarray analysis. In addition, to examine the cellular effects induced by RT, analyses of morphology and clonogenic evaluation were also conducted. Results A descriptive report of GEP and pathways induced by IR is reported from our microarray data. Moreover, the MDA-MB-231 Radioresistent Cell Fraction (RCF) selected, included specific molecules able to drive radioresistance. Conclusion In summary, our data highlight, the RT response of TNBC MDA-MB-231 cell line at a transcriptional level, in terms of activating radioresistance in these cells, as a model of late-stage BC.
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- 2019
20. Proton-irradiated breast cells: molecular points of view
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Valentina Bravatà 1, Francesco P. Cammarata 1, Luigi Minafra 1, Pietro Pisciotta 1, 2, Concetta Scazzone 3, Lorenzo Manti 4, Gaetano Savoca 1, Giada Petringa 1, Giuseppe A.P. Cirrone 2, Giacomo Cuttone 2, Maria C. Gilardi 1, 5, Giusi I. Forte 1, Giorgio Russo 1, Bravata, V, Cammarata, F, Minafra, L, Pisciotta, P, Scazzone, C, Manti, L, Savoca, G, Petringa, G, Cirrone, G, Cuttone, G, Gilardi, M, Forte, G, Russo, G, Bravata, V., Cammarata, F. P., Minafra, L., Pisciotta, P., Scazzone, C., Manti, L., Savoca, G., Petringa, G., Cirrone, G. A. P., Cuttone, G., Gilardi, M. C., Forte, G. I., Russo, G., Bravatà, Valentina, Cammarata, Francesco P, Minafra, Luigi, Pisciotta, Pietro, Scazzone, Concetta, Manti, Lorenzo, Savoca, Gaetano, Petringa, Giada, Cirrone, Giuseppe A P, Cuttone, Giacomo, Gilardi, Maria C, Forte, Giusi I, and Russo, Giorgio
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breast cancer, cDNA microarray, gene signature, proton therapy, radiation, Breast, Breast Neoplasms, Cell Line, Tumor, DNA, Complementary, Dose-Response Relationship, Radiation, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Inflammation, MCF-7 Cells, Oligonucleotide Array Sequence Analysis, Phenotype, Proton Therapy, Radiation Tolerance, Radiotherapy, Protons ,DNA, Complementary ,Health, Toxicology and Mutagenesis ,medicine.medical_treatment ,Breast Neoplasms ,Cell fate determination ,Radiation Tolerance ,gene signature ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,breast cancer ,Cell Line, Tumor ,Regular Paper ,medicine ,proton therapy ,Humans ,Radiology, Nuclear Medicine and imaging ,Breast ,Clonogenic assay ,Biology ,Proton therapy ,Oligonucleotide Array Sequence Analysis ,030304 developmental biology ,Inflammation ,cDNA microarray ,0303 health sciences ,Radiotherapy ,Chemistry ,Gene Expression Profiling ,radiation ,Cancer ,Dose-Response Relationship, Radiation ,Gene signature ,medicine.disease ,Gene Expression Regulation, Neoplastic ,Gene expression profiling ,Radiation therapy ,Phenotype ,030220 oncology & carcinogenesis ,MCF-7 Cells ,Cancer research ,Female ,Protons - Abstract
Breast cancer (BC) is the most common cancer in women, highly heterogeneous at both the clinical and molecular level. Radiation therapy (RT) represents an efficient modality to treat localized tumor in BC care, although the choice of a unique treatment plan for all BC patients, including RT, may not be the best option. Technological advances in RT are evolving with the use of charged particle beams (i.e. protons) which, due to a more localized delivery of the radiation dose, reduce the dose administered to the heart compared with conventional RT. However, few data regarding proton-induced molecular changes are currently available. The aim of this study was to investigate and describe the production of immunological molecules and gene expression profiles induced by proton irradiation. We performed Luminex assay and cDNA microarray analyses to study the biological processes activated following irradiation with proton beams, both in the non-tumorigenic MCF10A cell line and in two tumorigenic BC cell lines, MCF7 and MDA-MB-231. The immunological signatures were dose dependent in MCF10A and MCF7 cell lines, whereas MDA-MB-231 cells show a strong pro-inflammatory profile regardless of the dose delivered. Clonogenic assay revealed different surviving fractions according to the breast cell lines analyzed. We found the involvement of genes related to cell response to proton irradiation and reported specific cell line- and dose-dependent gene signatures, able to drive cell fate after radiation exposure. Our data could represent a useful tool to better understand the molecular mechanisms elicited by proton irradiation and to predict treatment outcome
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- 2019
21. STUDY OF THE DISCREPANCY BETWEEN ANALYTICAL CALCULATIONS AND THE OBSERVED BIOLOGICAL EFFECTIVENESS IN PROTON BORON CAPTURE THERAPY (PBCT)
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G. A. P. Cirrone, Lorenzo Manti, G. Petringa, A. Attili, D. Chiappara, Daniele Margarone, Giacomo Cuttone, Valentina Bravatà, M. Mazzocco, Cirrone, G. A. P., Petringa, G., Attili, A., Chiappara, D., Manti, L., Bravatà, V., Margarone, D., Mazzocco, M., and Cuttone, G.
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Materials science ,Proton ,chemistry ,Media Technology ,Physical chemistry ,chemistry.chemical_element ,Boron - Published
- 2019
22. Proton therapy and src family kinase inhibitor combined treatments on U87 human glioblastoma multiforme cell line
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Francesco P Cammarata 1, 2, Filippo Torrisi 2, 3, Giusi I Forte 1, Luigi Minafra 1, Valentina Bravatà 1, Pietro Pisciotta 2, 4, Gaetano Savoca 1, Marco Calvaruso 1, Giada Petringa 2, Giuseppe AP Cirrone 2, Anna L Fallacara 5, 6, Laura Maccari 5, Maurizio Botta 5, Silvia Schenone 7, Rosalba Parenti 3, Giacomo Cuttone 2, and Giorgio Russo 1
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Microarray ,Combined treatments, Gene signatures, Glioblastoma multiforme, Proton therapy ,medicine.medical_treatment ,Antineoplastic Agents ,Glioblastoma multiforme ,Radiation Tolerance ,Catalysis ,Article ,Inorganic Chemistry ,lcsh:Chemistry ,combined treatments ,gene signatures ,glioblastoma multiforme ,proton therapy ,Inhibitory Concentration 50 ,Mice ,Cell Line, Tumor ,medicine ,Cytotoxic T cell ,Animals ,Humans ,Src family kinase ,Physical and Theoretical Chemistry ,U87 ,Molecular Biology ,lcsh:QH301-705.5 ,Protein Kinase Inhibitors ,Spectroscopy ,Chemotherapy ,Dose-Response Relationship, Drug ,Microarray analysis techniques ,business.industry ,Brain Neoplasms ,Gene Expression Profiling ,Organic Chemistry ,Gene signatures ,Dose-Response Relationship, Radiation ,General Medicine ,Xenograft Model Antitumor Assays ,Proton therapy ,Computer Science Applications ,Gene expression profiling ,Disease Models, Animal ,src-Family Kinases ,lcsh:Biology (General) ,lcsh:QD1-999 ,Cancer research ,business ,Glioblastoma ,Combined treatments ,Proto-oncogene tyrosine-protein kinase Src - Abstract
Glioblastoma Multiforme (GBM) is the most common of malignant gliomas in adults with an exiguous life expectancy. Standard treatments are not curative and the resistance to both chemotherapy and conventional radiotherapy (RT) plans is the main cause of GBM care failures. Proton therapy (PT) shows a ballistic precision and a higher dose conformity than conventional RT. In this study we investigated the radiosensitive effects of a new targeted compound, SRC inhibitor, named Si306, in combination with PT on the U87 glioblastoma cell line. Clonogenic survival assay, dose modifying factor calculation and linear-quadratic model were performed to evaluate radiosensitizing effects mediated by combination of the Si306 with PT. Gene expression profiling by microarray was also conducted after PT treatments alone or combined, to identify gene signatures as biomarkers of response to treatments. Our results indicate that the Si306 compound exhibits a radiosensitizing action on the U87 cells causing a synergic cytotoxic effect with PT. In addition, microarray data confirm the SRC role as the main Si306 target and highlights new genes modulated by the combined action of Si306 and PT. We suggest, the Si306 as a new candidate to treat GBM in combination with PT, overcoming resistance to conventional treatments.
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- 2019
23. Radiation-Induced Gene Expression Changes in High and Low Grade Breast Cancer Cell Types
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Isabella Castiglioni, Claudia Cava, Francesco Paolo Cammarata, Giorgio Ivan Russo, Maria Carla Gilardi, Giusi Irma Forte, Luigi Minafra, Valentina Bravatà, Bravata, V, Cava, C, Minafra, L, Cammarata, F, Russo, G, Gilardi, M, Castiglioni, I, and Forte, G
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0301 basic medicine ,medicine.medical_treatment ,ionizing radiation ,breast cancer ,gene expression profile ,pathway analysis ,Radiation Tolerance ,lcsh:Chemistry ,0302 clinical medicine ,Radiation, Ionizing ,Gene expression ,Medicine ,Gene Regulatory Networks ,Receptor ,lcsh:QH301-705.5 ,Spectroscopy ,Cell Line, Transformed ,General Medicine ,3. Good health ,Computer Science Applications ,Gene Expression Regulation, Neoplastic ,Hormone receptor ,030220 oncology & carcinogenesis ,Female ,Breast cancer, Gene expression profile, Ionizing radiation, Pathway analysis ,Signal Transduction ,Breast Neoplasms ,Radiation Dosage ,Article ,Catalysis ,Inorganic Chemistry ,03 medical and health sciences ,Breast cancer ,Cell Line, Tumor ,Humans ,Physical and Theoretical Chemistry ,Molecular Biology ,business.industry ,Gene Expression Profiling ,Organic Chemistry ,Computational Biology ,Cancer ,Dose-Response Relationship, Radiation ,Radiation-Induced Gene Expression ,medicine.disease ,Radiation therapy ,030104 developmental biology ,lcsh:Biology (General) ,lcsh:QD1-999 ,Cancer research ,Gene chip analysis ,Neoplasm Grading ,Transcriptome ,business - Abstract
Background: There is extensive scientific evidence that radiation therapy (RT) is a crucial treatment, either alone or in combination with other treatment modalities, for many types of cancer, including breast cancer (BC). BC is a heterogeneous disease at both clinical and molecular levels, presenting distinct subtypes linked to the hormone receptor (HR) status and associated with different clinical outcomes. The aim of this study was to assess the molecular changes induced by high doses of ionizing radiation (IR) on immortalized and primary BC cell lines grouped according to Human epidermal growth factor receptor (HER2), estrogen, and progesterone receptors, to study how HR status influences the radiation response. Our genomic approach using in vitro and ex-vivo models (e.g., primary cells) is a necessary first step for a translational study to describe the common driven radio-resistance features associated with HR status. This information will eventually allow clinicians to prescribe more personalized total doses or associated targeted therapies for specific tumor subtypes, thus enhancing cancer radio-sensitivity. Methods: Nontumorigenic (MCF10A) and BC (MCF7 and MDA-MB-231) immortalized cell lines, as well as healthy (HMEC) and BC (BCpc7 and BCpcEMT) primary cultures, were divided into low grade, high grade, and healthy groups according to their HR status. At 24 h post-treatment, the gene expression profiles induced by two doses of IR treatment with 9 and 23 Gy were analyzed by cDNA microarray technology to select and compare the differential gene and pathway expressions among the experimental groups. Results: We present a descriptive report of the substantial alterations in gene expression levels and pathways after IR treatment in both immortalized and primary cell cultures. Overall, the IR-induced gene expression profiles and pathways appear to be cell-line dependent. The data suggest that some specific gene and pathway signatures seem to be linked to HR status. Conclusions: Genomic biomarkers and gene-signatures of specific tumor subtypes, selected according to their HR status and molecular features, could facilitate personalized biological-driven RT treatment planning alone and in combination with targeted therapies.
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- 2018
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24. Radiogenomics: the utility in patient selection
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Pietro Pisciotta, Giusi Irma Forte, Valentina Bravatà, Maria Carla Gilardi, Luigi Minafra, G.A.P. Cirrone, Giorgio Ivan Russo, Debora Lamia, Francesco Paolo Cammarata, Giacomo Cuttone, Forte, G, Minafra, L, Bravata, V, Cammarata, F, Lamia, D, Pisciotta, P, Cirrone, G, Cuttone, G, Gilardi, M, and Russo, G
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0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,medicine.medical_treatment ,Radiogenomics ,Tumor heterogeneity ,03 medical and health sciences ,0302 clinical medicine ,Therapeutic index ,Cancer stem cell ,Internal medicine ,Omics, Radiation therapy (RT), Radiation toxicity ,medicine ,Radiology, Nuclear Medicine and imaging ,In patient ,Medical physics ,Radiation treatment planning ,business.industry ,Radiation therapy ,030104 developmental biology ,030220 oncology & carcinogenesis ,State of art ,business ,Radiation therapy (RT) ,radiation toxicity ,omics - Abstract
The goal of radiation therapy (RT) is to deliver the therapeutic dose to target tissues minimizing the risks of normal tissue complication. Nowadays, technological advances in radiation delivery and the introduction of particle therapies have strongly limited the amount of dose distributed to normal tissues and enhanced the tumor killing capacity. Here, we discuss about the state of art in RT treatment modalities, tumor sensitivity and radiation toxicity. A special insight is dedicated to the role of tumor heterogeneity, cancer stem cells (CSCs) and hypoxia. In addition, in this review we provide an overview of the most recently studies evaluating the potential role of “omic” biomarkers for a personalized biological-driven treatment planning, useful to maximize the radiotherapy success without normal tissues complications.
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- 2017
25. High-Intensity Focused Ultrasound- and Radiation Therapy-Induced Immuno-modulation: Comparison and Potential Opportunities
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Roberta Cirincione 1, Federica Maria Di Maggio 1, 2, Giusi Irma Forte 1, Luigi Minafra 1, Valentina Bravatà 1, Laura Castiglia 1, Vincenzo Cavalieri 4, Giovanni Borasi 1, Giorgio Russo 1, Domenico Lio 2, Cristina Messa 1, 4, 5, Maria Carla Gilardi 1, Francesco Paolo Cammarata 1, Cirincione, R, Di Maggio, F, Forte, G, Minafra, L, Bravatà, V, Castiglia, L, Cavalieri, V, Borasi, G, Russo, G, Lio, D, Messa, C, Gilardi, M, Cammarata, F, and Messa, M
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0301 basic medicine ,Pathology ,medicine.medical_specialty ,Radiology, Nuclear Medicine and Imaging ,Acoustics and Ultrasonics ,medicine.medical_treatment ,Biophysics ,Immunomodulation ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Neoplasms ,medicine ,Bystander effect ,Humans ,Cancer ,Chemotherapy ,Radiological and Ultrasound Technology ,business.industry ,medicine.disease ,Primary tumor ,Thermal ablation ,High-intensity focused ultrasound ,Radiation therapy ,Immuno-therapy ,Tumor vaccine ,030104 developmental biology ,Biophysic ,030220 oncology & carcinogenesis ,Cancer cell ,Cancer research ,High-Intensity Focused Ultrasound Ablation ,Anti-tumor immunity ,business - Abstract
In recent years, high-intensity focused ultrasound (HIFU) has emerged as a new and promising non-invasive and non-ionizing ablative technique for the treatment of localized solid tumors. Extensive pre-clinical and clinical studies have evidenced that, in addition to direct destruction of the primary tumor, HIFU-thermoablation may elicit long-term systemic host anti-tumor immunity. In particular, an important consequence of HIFU treatment includes the release of tumor-associated antigens (TAAs), the secretion of immuno-suppressing factors by cancer cells and the induction of cytotoxic T lymphocyte (CTL) activity. Radiation therapy (RT) is the main treatment modality used for many types of tumors and about 50% of all cancer patients receive RT, often used in combination with surgery and chemotherapy. It is well known that RT can modulate anti-tumor immune responses, modifying micro-environment and stimulating inflammatory factors that can greatly affect cell invasion, bystander effects, radiation tissue complications (such as fibrosis), genomic instability and thus, intrinsic cellular radio-sensitivity. To date, various combined therapeutic strategies (such as immuno-therapy) have been performed in order to enhance RT success in treating locally advanced and recurrent tumors. Recent works suggested the combined use of HIFU and RT treatments to increase the tumor cell radio-sensitivity, in order to synergize the effects reaching the maximum results with minimal doses of ionizing radiation (IR). Here, we highlight the opposite immuno-modulation roles of RT and HIFU, providing scientific reasons to test, by experimental approaches, the use of HIFU immune-stimulatory capacity to improve tumor radio-sensitivity, to reduce the RT induced inflammatory response and to decrease the dose-correlated side effects in normal tissues.
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- 2017
26. Preliminary study for small animal preclinical hadrontherapy facility
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Valentina Bravatà, Giusi Irma Forte, G.A.P. Cirrone, V. Marchese, Luigi Minafra, Francesco Paolo Cammarata, Pietro Pisciotta, Rosaria Acquaviva, Debora Lamia, Giacomo Cuttone, Fabrizio Romano, G. V. Russo, Maria Carla Gilardi, Russo, G, Pisciotta, P, Cirrone, G, Romano, F, Cammarata, F, Marchese, V, Forte, G, Lamia, D, Minafra, L, Bravata, V, Acquaviva, R, Gilardi, M, and Cuttone, G
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Physics ,Nuclear and High Energy Physics ,medicine.medical_specialty ,Monte Carlo method ,Detector ,Preclinical studies ,Geant4 ,Imaging phantom ,030218 nuclear medicine & medical imaging ,Gamma index ,03 medical and health sciences ,DICOM ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Small animal ,Hadrontherapy ,Dosimetry ,Small animal irradiation protocol ,medicine ,Medical physics ,Tumour configuration ,Dosimetry, Geant4, Hadrontherapy, Preclinical studies, Small animal irradiation protocol ,Instrumentation ,Simulation - Abstract
Aim of this work is the study of the preliminary steps to perform a particle treatment of cancer cells inoculated in small animals and to realize a preclinical hadrontherapy facility. A well-defined dosimetric protocol was developed to explicate the steps needed in order to perform a precise proton irradiation in small animals and achieve a highly conformal dose into the target. A precise homemade positioning and holding system for small animals was designed and developed at INFN-LNS in Catania (Italy), where an accurate Monte Carlo simulation was developed, using Geant4 code to simulate the treatment in order to choose the best animal position and perform accurately all the necessary dosimetric evaluations. The Geant4 application can also be used to realize dosimetric studies and its peculiarity consists in the possibility to introduce the real target composition in the simulation using the DICOM micro-CT image. This application was fully validated comparing the results with the experimental measurements. The latter ones were performed at the CATANA (Centro di AdroTerapia e Applicazioni Nucleari Avanzate) facility at INFN-LNS by irradiating both PMMA and water solid phantom. Dosimetric measurements were performed using previously calibrated EBT3 Gafchromic films as a detector and the results were compared with the Geant4 simulation ones. In particular, two different types of dosimetric studies were performed: the first one involved irradiation of a phantom made up of water solid slabs where a layer of EBT3 was alternated with two different slabs in a sandwich configuration, in order to validate the dosimetric distribution. The second one involved irradiation of a PMMA phantom made up of a half hemisphere and some PMMA slabs in order to simulate a subcutaneous tumour configuration, normally used in preclinical studies. In order to evaluate the accordance between experimental and simulation results, two different statistical tests were made: Kolmogorov test and gamma index test. This work represents the first step towards the realization of a preclinical hadrontherapy facility at INFN-LNS in Catania for the future in vivo studies.
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- 2017
27. Cytokine profile of breast cell lines after different radiation doses
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Francesco Paolo Cammarata, Maria Carla Gilardi, Valentina Bravatà, Federica Maria Di Maggio, Giusi Irma Forte, Domenico Lio, Luigi Minafra, Giorgio Ivan Russo, Giuseppa Augello, Bravatà, Valentina, Minafra, Luigi, Forte, Giusi Irma, Cammarata, Francesco Paolo, Russo, Giorgio, Di Maggio, Federica Maria, Augello, Giuseppa, Lio, Domenico, Gilardi, Maria Carla, Bravata, V, Minafra, L, Forte, G, Cammarata, F, Russo, G, Di Maggio, F, Augello, G, Lio, D, and Gilardi, M
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0301 basic medicine ,Ionizing radiation ,Radiology, Nuclear Medicine and Imaging ,Cell Survival ,Cytokine profile ,Breast Neoplasms ,Inflammation ,Radiation ,Radiation Tolerance ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,breast cancer ,Cell Line, Tumor ,medicine ,cytokine ,Humans ,skin and connective tissue diseases ,Cell survival ,Radiological and Ultrasound Technology ,Chemistry ,breast cancer, cytokines, inflammation, Ionizing radiation, Breast Neoplasms, Cell Line, Tumor, Cell Survival, Culture Media, Conditioned, Dose-Response Relationship, Radiation, Humans, Phenotype, Radiation Tolerance ,Dose-Response Relationship, Radiation ,medicine.disease ,cytokines ,Dose–response relationship ,030104 developmental biology ,Phenotype ,Cell culture ,inflammation ,030220 oncology & carcinogenesis ,Culture Media, Conditioned ,Immunology ,Cancer research ,medicine.symptom ,Breast Neoplasm ,Human - Abstract
Purpose: Ionizing radiation (IR) treatment activates inflammatory processes causing the release of a great amount of molecules able to affect the cell survival. The aim of this study was to analyze the cytokine signature of conditioned medium produced by non-tumorigenic mammary epithelial cell line MCF10A, as well as MCF7 and MDA-MB-231 breast cancer cell lines, after single high doses of IR in order to understand their role in high radiation response. Materials and methods: We performed a cytokine profile of irradiated conditioned media of MCF10A, MCF7 and MDA-MB-231 cell lines treated with 9 or 23 Gy, by Luminex and ELISA analyses. Results: Overall, our results show that both 9 Gy and 23 Gy of IR induce the release within the first 72 h of cytokines and growth factors potentially able to influence the tumor outcome, with a dose-independent and cell-line dependent signature. Moreover, our results show that the cell-senescence phenomenon does not correlate with the amount of ‘senescence-associated secretory phenotype’ (SASP) molecules released in media. Thus, additional mechanisms are probably involved in this process. Conclusions: These data open the possibility to evaluate cytokine profile as useful marker in modulating the personalized radiotherapy in breast cancer care.
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- 2017
28. 49. Combined treatments with Hadrontherapy – in vitro tests and preclinical approach
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Giorgio Ivan Russo, Luigi Minafra, Valentina Bravatà, Pietro Pisciotta, Filippo Torrisi, Giovanna Calabrese, Francesco Paolo Cammarata, Laura Maccari, Giusi Irma Forte, Anna Lucia Fallacara, V. Marchese, Maurizio Botta, Rosalba Parenti, Giacomo Cuttone, and G.A.P. Cirrone
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Oncology ,medicine.medical_specialty ,business.industry ,Biophysics ,General Physics and Astronomy ,General Medicine ,medicine.disease ,In vitro ,Hadron therapy ,Therapy response ,Internal medicine ,medicine ,Radiology, Nuclear Medicine and imaging ,Molecular imaging ,U87 ,business ,Dose rate ,Proton therapy ,Glioblastoma - Abstract
Purpose Glioblastoma multiforme (GBM) is the most aggressive types of central nervous system tumors. The aim of the project is to validate an innovative molecule developed by Lead Discovery Siena [LDS] showing inhibitory activity against Src kinases to be associated with proton therapy treatments. Materials Human glioblastoma cells (U87) were treated at INFN-LNS in Catania with 2 and 10 Gy of proton beams at dose rate of 10 Gy/min in the middle of the extended modulated Bragg peak and in combination with different concentrations of the LDS molecule (10 and 20 μM). The fraction of surviving cells (SF) was evaluated with the clonogenicity test 15 days after irradiation. Results The data in the figure show the synergistic effect of the combined treatment with LDS. Conclusions In vitro studies confirmed the efficacy of the hadron therapy treatment in combination with the molecule. The next step is to translate these studies on the mouse model thanks to the existence of an Animal Facility created by the synergy between the following institution: the LNS-INFN, the University of Catania – Capir Center, IBFM-CNR and H. Cannizzaro, with the departments of Nuclear Medicine and Medical Physics. The facility will be able to provide unique research activities in the European panorama: hadron therapy treatments, dose distribution studies using the Monte Carlo GEANT4 method, molecular imaging using microPET/ CT tomography with different radiotracers and image processing implementation for therapy response quantification.
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- 2018
29. Radiation Therapy Towards Laser-Driven Particle Beams: An 'OMICS' Approach in Radiobiology
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Francesco Paolo Cammarata, Giusi Irma Forte, Luigi Minafra, and Valentina Bravatà
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0301 basic medicine ,Physics ,medicine.medical_specialty ,Radiobiology ,medicine.medical_treatment ,Nanotechnology ,Proteomics ,Laser ,Tumor control ,law.invention ,Ionizing radiation ,Radiation therapy ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,law ,030220 oncology & carcinogenesis ,Molecular Response ,Relative biological effectiveness ,medicine ,Medical physics - Abstract
The main goal of radiation therapy (RT) treatments is to achieve local tumor control, to selectively kill cancer cells without causing significant damage to the surrounding normal tissues. RT uses ionizing radiation (IR) generated with conventional accelerators, such as X-rays, γ-rays, electrons, protons and ions. It is now well recognized by the entire scientific community that to evaluate the biological effects of IR it is essential an “OMIC” approach to take into account both the different cell types involved and the different IR’s used. The latest advances on cell and molecular response to IR, the most relevant data emerging from recent studies (genomics, epigenetics, proteomics and immunology) about different cell types, will be reported. We will discuss mainly biological effects of IR generated by conventional accelerators but we will also consider the few and preliminary radiobiological studies performed so far with laser-driven electron and proton beams. This will allow us in particular to speculate on cell and molecular effects of the laser-driven electron beams, a topic that can be now carefully investigated thanks to the impressive progress of “table-top” laser-driven accelerators.
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- 2016
30. Protein modulation in mouse heart under acute and chronic hypoxia
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Agnese Viganò, Cecilia Gelfi, Daniele Capitanio, Michele Vasso, Michele Samaja, Chiara Fania, Laura Terraneo, Anna Caretti, Valentina Bravatà, Viganò, A, Vasso, M, Caretti, A, Bravatà, V, Terraneo, L, Fania, C, Capitanio, D, Samaja, M, and Gelfi, C
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Proteomics ,Cell signaling ,Proteome ,Immunoblotting ,Apoptosis ,Biology ,Protein degradation ,Biochemistry ,Two-Dimensional Difference Gel Electrophoresis ,Mice ,Contractile Proteins ,Heat shock protein ,medicine ,Animals ,Hypoxia ,Molecular Biology ,Heat-Shock Proteins ,Animal ,Myocardium ,Autophagy ,AMPK / Animal proteomics / Apoptosis / Autophagy / Heart / Hypoxia ,Apoptosi ,Proteomic ,AMPK ,Heat-Shock Protein ,Hypoxia (medical) ,Hypoxia-Inducible Factor 1, alpha Subunit ,Cell biology ,Gene Expression Regulation ,Mitochondrial biogenesis ,Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization ,Adenosylhomocysteinase ,Contractile Protein ,medicine.symptom ,Energy Metabolism - Abstract
Exploring cellular mechanisms underlying beneficial and detrimental responses to hypoxia represents the object of the present study. Signaling molecules controlling adaptation to hypoxia (HIF-1α), energy balance (AMPK), mitochondrial biogenesis (PGC-1α), autophagic/apoptotic processes regulation and proteomic dysregulation were assessed. Responses to acute hypoxia (AH) and chronic hypoxia (CH) in mouse heart proteome were detected by 2-D DIGE, mass spectrometry and antigen-antibody reactions. Both in AH and CH, the results indicated a deregulation of proteins related to sarcomere stabilization and muscle contraction. Neither in AH nor in CH the HIF-1α stabilization was observed. In AH, the metabolic adaptation to lack of oxygen was controlled by AMPK activation and sustained by an up-regulation of adenosylhomocysteinase and acetyl-CoA synthetase. AH was characterized by the mitophagic protein Bnip 3 increment. PGC-1α, a master regulator of mitochondrial biogenesis, was down-regulated. CH was characterized by the up-regulation of enzymes involved in antioxidant defense, in aldehyde bio-product detoxification and in misfolded protein degradation. In addition, a general down-regulation of enzymes controlling anaerobic metabolism was observed. After 10 days of hypoxia, cardioprotective molecules were substantially decreased whereas pro-apoptotic molecules increased accompained by down-regulation of specific target proteins.
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- 2011
31. Gene expression profiling of breast cancer cell lines treated with proton and electron radiations
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Francesco Paolo Cammarata, Maria Carla Gilardi, Giada Petringa, Debora Lamia, Valentina Bravatà, G.A.P. Cirrone, V. Marchese, Luigi Minafra, Giacomo Cuttone, Lorenzo Manti, Pietro Pisciotta, Giorgio Ivan Russo, Giusi Irma Forte, Bravata, V., Minafra, L., Cammarata, F. P., Pisciotta, P., Lamia, D., Marchese, V., Petringa, G., Manti, L., Cirrone, G. A. P., Gilardi, M. C., Cuttone, G., Forte, G. I., Russo, G., Bravata, V, Minafra, L, Cammarata, F, Pisciotta, P, Lamia, D, Marchese, V, Petringa, G, Manti, L, Cirrone, G, Gilardi, M, Cuttone, G, Forte, G, and Russo, G
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0301 basic medicine ,Proton ,Quantitative Biology::Tissues and Organs ,medicine.medical_treatment ,Nuclear Theory ,Physics::Medical Physics ,Gene Expression ,Breast Neoplasms ,Electrons ,Electron ,Adenocarcinoma ,Radiation Tolerance ,Cell Line ,03 medical and health sciences ,0302 clinical medicine ,Conventional radiotherapy ,Breast cancer cell line ,Adenocarcinoma, Breast Neoplasms, Carcinoma, Ductal, Breast, Cell Line, Cell Line, Tumor, Electrons, Gene Expression, Humans, Linear Energy Transfer, Oligonucleotide Array Sequence Analysis, Precision Medicine, Radiation Tolerance, Gene Expression Profiling, Proton Therapy ,Cell Line, Tumor ,Proton Therapy ,medicine ,Humans ,Linear Energy Transfer ,Radiology, Nuclear Medicine and imaging ,Precision Medicine ,Nuclear Experiment ,Oligonucleotide Array Sequence Analysis ,FACTOR-KAPPA-B ,TRANSCRIPTION FACTOR ,INDUCED APOPTOSIS ,ENERGY-TRANSFER ,MONTE-CARLO ,THERAPY ,RADIOTHERAPY ,SIMULATION ,INHIBITION ,PATHWAY ,Full Paper ,Chemistry ,Gene Expression Profiling ,Carcinoma, Ductal, Breast ,General Medicine ,Gene expression profiling ,Radiation therapy ,030104 developmental biology ,030220 oncology & carcinogenesis ,Cancer research - Abstract
OBJECTIVE: Technological advances in radiation therapy are evolving with the use of hadrons, such as protons, indicated for tumors where conventional radiotherapy does not give significant advantages or for tumors located in sensitive regions, which need the maximum of dose-saving of the surrounding healthy tissues. The genomic response to conventional and non conventional Linear Energy Transfer exposure is a poor investigated topic and became an issue of radiobiological interest. The aim of this work was to analyze and compare molecular responses in term of gene expression profiles, induced by electron and proton irradiation in breast cancer cell lines. METHODS: We studied the gene expression profiling differences by cDNA microarray activated in response to electron and proton irradiation with different Linear Energy Transfer values, among three breast cell lines (the tumorigenic MCF7 and MDA-MB-231 and the non tumorigenic MCF10A), exposed to the same sub-lethal dose of 9 Gy. RESULTS: Gene expression profiling pathway analyses showed the activation of different signaling and molecular networks in a cell line and radiation type-dependent manner. MCF10A and MDA-MB-231 cell lines were found to induce factors and pathways involved in the immunological process control. CONCLUSIONS: Here we describe in a detailed way the gene expression profiling and pathways activated after electron and proton irradiation in breast cancer cells. Summarizing, although specific pathways are activated in a radiation type-dependent manner, each cell line activates overall similar molecular networks in response to both these two types of ionizing radiation. Advances in knowledge: In the era of personalized medicine and breast cancer target-directed intervention, we trust that this study could drive radiation therapy towards personalized treatments, evaluating possible combined treatments, based on the molecular characterization.
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- 2018
32. Teaching NeuroImages: Subacute encephalopathy in a young woman with THTR2 gene mutation
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Luigi Minafra, Valentina Bravatà, GianPietro Sechi, Alberto Addis, Elia Sechi, and Giulia Fadda
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Pathology ,medicine.medical_specialty ,Encephalopathy ,THTR2 gene mutation ,Gene mutation ,Young Adult ,Medicine ,Humans ,Thiamine ,Young adult ,Coma ,Brain Diseases ,business.industry ,Brain ,Membrane Transport Proteins ,medicine.disease ,Treatment Outcome ,Mutation ,Gait Ataxia ,Hyperlactatemia ,Female ,Neurology (clinical) ,medicine.symptom ,business ,young woman ,human activities ,Somnolence ,Subacute encephalopathy - Abstract
A 21-year-old woman presented with coma after 5 days of fever, gait ataxia, and somnolence. Brain MRI showed lesions in medial thalami, caudate heads, and periaqueductal region (figure). Hyperlactatemia was present; serum thiamine levels were normal.
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- 2015
33. DVWA gene polymorphisms and osteoarthritis
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Valentina Bravatà 1, Luigi Minafra 1, Giusi I Forte 1, Francesco P Cammarata 1, Michele Saporito 2, Filippo Boniforti 3, Domenico Lio 4, Maria C Gilardi 1, 5, 6, Cristina Messa 1, 7, BRAVATA', V, Minafra, L, Forte, GI, Cammarata, FP, Saporito, M, Boniforti, F, Lio, D, Gilardi, MC, Messa, C, Bravatà, V, Forte, G, Cammarata, F, Gilardi, M, and Messa, M
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Male ,Linkage disequilibrium ,Short Report ,Single-nucleotide polymorphism ,Osteoarthritis ,Collagen Type VI ,Bioinformatics ,Polymorphism, Single Nucleotide ,General Biochemistry, Genetics and Molecular Biology ,Linkage Disequilibrium ,White People ,Gene Frequency ,Haplotype ,Genetic predisposition ,DVWA ,Medicine ,SNP ,Humans ,Genetic Predisposition to Disease ,Allele ,Osteoarthritis, DVWA, Single nucleotide polymorphisms, Haplotypes, KL ,Allele frequency ,Sicily ,Alleles ,Aged ,Medicine(all) ,Aged, 80 and over ,Biochemistry, Genetics and Molecular Biology(all) ,business.industry ,Homozygote ,General Medicine ,Single nucleotide polymorphisms ,Middle Aged ,Osteoarthritis, Knee ,medicine.disease ,Single nucleotide polymorphism ,KL ,Haplotypes ,Osteoarthriti ,Female ,business ,Pseudogenes - Abstract
Background: Osteoarthritis (OA) is a degenerative joints disorder influenced by genetic predisposition. We reported that rs11718863 DVWA SNP was represented in Sicilian with a more severe Kellgren and Lawrence (KL) radiographic grade, displaying its predictive role as OA marker progression. Here, we describe the DVWA SNPs: rs11718863, rs7639618, rs7651842, rs7639807 and rs17040821 probably able to induce protein functional changes. Findings: Sixty-one Sicilian patients with knee OA and 100 healthy subjects were enrolled. Clinical and radiographic evaluation was performed using AKSS scores and KL. Linkage Disequilibrium (LD) analyses were performed in order to verify whether the SNPs segregate as haplotype. All DVWA SNPs'MinorAllele Frequencies (MAF) were greater than in the European. The rs7639618 SNP showed a statistical association with KL. Our analyses show that a LD exists among rs11718863 and rs7639618, as well as between rs7651842, rs7639807 and rs17040821 SNPs. We also observed that three out of the 161 individuals investigated were simultaneously homozygous carriers of the rs7651842, rs7639807 and rs17040821 MAF alleles. Conclusions: In summary, the purpose of this preliminary research was to highlight possible associations between DVWA SNPs and OA clinical and radiographic data. This work represents a multidisciplinary medicine approach to study OA where clinical, radiological and genetic evaluation could contribute to better define OA grading.
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- 2015
34. High-dose Ionizing Radiation Regulates Gene Expression Changes in the MCF7 Breast Cancer Cell Line
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Valentina Bravatà 1, Luigi Minafra 1, Giorgio Russo 1, Giusi Irma Forte 1, Francesco Paolo Cammarata 1, Marilena Ripamonti 1, Carlo Casarino 1, Giuseppa Augello 2, Francesca Costantini 2, Giovanna Barbieri 2, Cristina Messa 1, 3, 5, Maria Carla Gilardi 1, and 4
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MCF7 breast cancer cells ,Intraoperative electron radiation therapy ,IR ,microarray ,ionizing radiation ,IOERT - Abstract
BACKGROUND: Intraoperative electron radiation therapy (IOERT) is a therapeutic technique which administers a single high dose of ionizing radiation immediately after surgical tumor removal. IOERT induces a strong stress response: both tumor and normal cells activating pro- and antiproliferative cell signaling pathways. Following treatment, several genes and factors are differently modulated, producing an imbalance in cell fate decision. However, the contribution of these genes and pathways in conferring different cell radiosensitivity and radioresistance needs to be further investigated, in particular after high-dose treatments. Despite the documented and great impact of IOERT in breast cancer care, and the trend for dose escalation, very limited data are available regarding gene-expression profiles and cell networks activated by IOERT or high-dose treatment. The aim of the study was to analyze the main pathways activated following high radiation doses in order to select for potential new biomarkers of radiosensitivity or radioresistance, as well as to identify therapeutic targets useful in cancer care. MATERIALS AND METHODS: We performed gene-expression profiling of the MCF7 human breast carcinoma cell line after treatment with 9- and 23-Gy doses (conventionally used during IOERT boost and exclusive treatments, respectively) by cDNA microarrays. Real-Time Quantitative Reverse Transcription PCR (qRT-PCR), immunofluorescence and immunoblot experiments were performed to validate candidate IOERT biomarkers. We also conducted clonogenic tests and cellular senescence assays to monitor for radiation-induced effects. RESULTS: The analyses highlighted a transcriptome dependent on the dose delivered and a number of specific key genes that may be proposed as new markers of radiosensitivity. Cell and molecular traits observed in MCF7 cells revealed a typical senescent phenotype associated with cell proliferation arrest after treatments with 9- and 23-Gy doses. CONCLUSION: In this study, we report genes and cellular networks activated following high-dose IOERT. The selected validated genes were used to design two descriptive models for each dose delivered. We believe that this study could contribute to the understanding over the complex mechanisms which regulate cell radiosensitivity and radioresistance in order to improve personalized radiotherapeutic treatment.
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- 2015
35. Gene expression profiling of epithelial-mesenchymal transition in primary breast cancer cell culture
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Luigi, Minafra, Valentina, Bravatà, Giusi Irma, Forte, Francesco Paolo, Cammarata, Maria Carla, Gilardi, and Cristina, Messa
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Epithelial-Mesenchymal Transition ,Cell Movement ,Reverse Transcriptase Polymerase Chain Reaction ,Gene Expression Profiling ,Carcinoma, Ductal, Breast ,Humans ,Breast Neoplasms ,Female ,Real-Time Polymerase Chain Reaction ,Transcriptome ,Cells, Cultured ,Oligonucleotide Array Sequence Analysis - Abstract
Epithelial-mesenchymal transition (EMT) is a process co-opted by cancer cells to invade and form metastases. In the present study we analyzed gene expression profiles of primary breast cancer cells in culture in order to highlight genes related to EMT.Microarray expression analysis of primary cells isolated from a specimen of a patient with an infiltrating ductal carcinoma of the breast was performed. Real-Time Quantitative Reverse Transcription PCR (qRT-PCR) analyses validated microarray gene expression trends.Thirty-six candidate genes were selected and used to generate a molecular network displaying the tight relationship among them. The most significant Gene Ontology biological processes characterizing this network were involved in cell migration and motility.Our data revealed the involvement of new genes which displayed tight relationships among them, suggesting a molecular network in which they could contribute to control of EMT in breast cancer. This study may offer a basis for understanding complex mechanisms which regulate breast cancer progression and for designing individualized anticancer therapies.
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- 2014
36. Controversial roles of methylenetetrahydrofolate reductase polymorphisms and folate in breast cancer disease
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Valentina Bravatà and Bravatà, V
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Oncology ,medicine.medical_specialty ,Breast Neoplasms ,Single-nucleotide polymorphism ,Disease ,Polymorphism, Single Nucleotide ,Folic Acid ,Breast cancer ,Risk Factors ,Internal medicine ,medicine ,Humans ,Mthfr c677t ,Folate intake ,MTHFR ,MTHFR A1298C ,MTHFR C677T ,Methylenetetrahydrofolate Reductase (NADPH2) ,Genetic association ,Genetics ,Breast cancer, MTHFR, MTHFR A1298C, MTHFR C677T ,biology ,business.industry ,medicine.disease ,Methylenetetrahydrofolate reductase ,Mutation ,biology.protein ,Female ,business ,Food Science - Abstract
Breast cancer (BC) represents a highly heterogeneous tumour at both the clinical and molecular levels. Single-nucleotide polymorphisms (SNPs) of the folate-metabolising enzyme methylenetetrahydrofolate-reductase (MTHFR) may modify the association between folate intake and BC and influence plasma folate concentration. The role of folate in BC is equivocal, association studies between the common MTHFR SNPs C677T and A1298C and BC risk are controversial. In this study, I have reviewed observed associations between folate intake, as well as its blood levels, and BC. The purpose of this review is to analyse the role of folate and the two SNPs associated with reduced enzyme activity in BC. I explored the most relevant and updated work that emphasises positive and negative associations among these variables. My findings indicate that no definitive conclusions can be drawn from the studies on this topic. However, this manuscript highlights variables that could be useful to explore in further association analyses.
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- 2014
37. Cell and molecular response to IORT treatment
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Luigi Minafra, Valentina Bravatà, Minafra, L, and Bravatà, V
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ionizing radiations (IRs) ,cell death ,Intraoperative radiotherapy (IORT) ,gene expression profile - Abstract
Ionizing radiations (IRs) generated by intraoperative radiotherapy (IORT) treatment activates both pro- and antiproliferative signal pathways producing an imbalance in cell fate decision regulated by several genes and factors involved in cell cycle progression, survival and/or cell death, DNA repair and inflammation. This paper describes the latest advances on cellular and molecular response to IR, highlighting the most relevant research data from cell biology, gene expression profiling and epigenetic studies on different tumor cell types. Understanding the cell molecular strategies to choose between death and survival, after an irradiation-induced damage, opens new avenues for the selection of a proper therapy schedule, to counteract cancer growth and preserve healthy surrounding tissue by radiation effects.
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- 2014
38. Analysis of thiamine transporter genes in sporadic beriberi
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Valentina Bravatà, Cecilia Gelfi, Luigi M.E. Grimaldi, Graziella Callari, Luigi Minafra, Bravat a, V, Minafra, L, Callari, G, Gelfi, C, and Grimaldi, LME.
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Adult ,Male ,medicine.medical_specialty ,SLC19 A- SLC25 A19 ,SLC19 A ,Endocrinology, Diabetes and Metabolism ,Gene mutation ,Beriberi ,medicine.disease_cause ,Mitochondrial Membrane Transport Proteins ,law.invention ,law ,Internal medicine ,Genotype ,medicine ,Thiamine transporter ,Objective: Thiamine or vitamin B1 deficiency diminishes thiamine-dependent enzymatic activity, alters mitochondrial function, impairs oxidative metabolism, and causes selective neuronal death. We analyzed for the first time, the role of all known mutations within three specific thiamine carrier genes, SLC19 A2, SLC19 A3, and SLC25 A19, in a patient with atrophic beriberi, a multiorgan nutritional disease caused by thiamine deficiency. Methods: A 44-year-old male alcoholic patient from Morocco developed massive bilateral leg edema, a subacute sensorimotor neuropathy, and incontinence. Despite normal vitamin B1 serum levels, his clinical picture was rapidly reverted by high-dose intramuscular thiamine treatment, suggesting a possible genetic resistance. We used polymerase chain reaction followed by amplicon sequencing to study all the known thiamine-related gene mutations identified within the Human Gene Mutation Database. Results: Thirty-seven mutations were tested: 29 in SLC19 A2, 6 in SLC19 A3, and 2 in SLC25 A19. Mutational analyses showed a wild-type genotype for all sequences investigated. Conclusion: This is the first genetic study in beriberi disease. We did not detect any known mutation in any of the three genes in a sporadic dry beriberi patient. We cannot exclude a role for other known or unknown mutations, in the same genes or in other thiamine-associated genes, in the occurrence of this nutritional neuropathy ,Humans ,Thiamine ,Gene ,Polymerase chain reaction ,Genetics ,Mutation ,Nutrition and Dietetics ,biology ,Membrane Transport Proteins ,Thiamine Deficiency ,medicine.disease ,Alcoholism ,Endocrinology ,biology.protein ,Mutations - Abstract
Objective Thiamine or vitamin B 1 deficiency diminishes thiamine-dependent enzymatic activity, alters mitochondrial function, impairs oxidative metabolism, and causes selective neuronal death. We analyzed for the first time, the role of all known mutations within three specific thiamine carrier genes, SLC19 A2, SLC19 A3 , and SLC25 A19 , in a patient with atrophic beriberi, a multiorgan nutritional disease caused by thiamine deficiency. Methods A 44-year-old male alcoholic patient from Morocco developed massive bilateral leg edema, a subacute sensorimotor neuropathy, and incontinence. Despite normal vitamin B 1 serum levels, his clinical picture was rapidly reverted by high-dose intramuscular thiamine treatment, suggesting a possible genetic resistance. We used polymerase chain reaction followed by amplicon sequencing to study all the known thiamine-related gene mutations identified within the Human Gene Mutation Database. Results Thirty-seven mutations were tested: 29 in SLC19 A2, 6 in SLC19 A3, and 2 in SLC25 A19 . Mutational analyses showed a wild-type genotype for all sequences investigated. Conclusion This is the first genetic study in beriberi disease. We did not detect any known mutation in any of the three genes in a sporadic dry beriberi patient. We cannot exclude a role for other known or unknown mutations, in the same genes or in other thiamine-associated genes, in the occurrence of this nutritional neuropathy.
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- 2014
39. Theoretical and experimental study of the kinetics of particle chains near electrodes in dielectrophoretic devices
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A. La Magna, M. Camarda, Valentina Bravatà, Gi Forte, Silvia Scalese, Luigi Minafra, Gianluca Giustolisi, Mc Gilardi, Bravata, F. Di Raimondo, Fabrizio Vicari, Marzia Pucci, Alessandra Romano, S. Baldo, Fp Cammarata, Andrea Ballo, Giuseppe Russo, Camarda, M, Baldo, S, Scalese, S, Ballo, A, Giustolisi, G, Romano, A, Di Raimondo, F, Pucci, M, Vicari, F, Minafra, L, Cammarata, FP, Bravata, V, Forte, GI, Russo, G, Gilardi, MC, and La Magna, A
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Materials science ,kinetics of particle chains, dielectrophoretic devices ,particle chains ,Kinetics ,Electrode ,Dielectrophoresis ,Analytical chemistry ,cells ,Particle chains ,Nanotechnology - Abstract
Using a three dimensional coupled Monte Carlo-Poisson algorithm and experimental results we studied the role of the particle-particle dipole interaction on the kinetics of a system of human cells suspended in a static liquid medium under the action of an oscillating non-uniform electric field generated by polynomial electrodes. We found that the kinetics of the cells during negative/repulsive dielectrophoresis depends on the local distribution of particles. If the cells have generated long chains during positive/attractive dielectrophoresis, such chains can hinder subsequent detachment resulting in a reduction of the separation/manipulation efficiency of dielectrophoretic device. This effect can be avoided by proper design of the electrodes schema.
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- 2014
40. 'Omics' of HER2-positive breast cancer
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Francesco Paolo Cammarata, Valentina Bravatà, Luigi Minafra, Giusi Irma Forte, Bravatà, V, Cammarata, FP, Forte, GI, and Minafra, L
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Proteomics ,Receptor, ErbB-2 ,Breast Neoplasms ,Biology ,Bioinformatics ,Antibodies, Monoclonal, Humanized ,Biochemistry ,Epigenesis, Genetic ,HER2/Neu Positive ,Germline mutation ,Breast cancer ,breast cancer ,Trastuzumab ,Genetics ,medicine ,Biomarkers, Tumor ,Humans ,OMICS ,Epigenetics ,skin and connective tissue diseases ,neoplasms ,Molecular Biology ,Genomics ,Genes, erbB-2 ,Omics ,medicine.disease ,Tumor progression ,Molecular Medicine ,HER2/neu-positive ,Female ,Transcriptome ,Biotechnology ,medicine.drug - Abstract
HER2/neu amplification/overexpression is the only somatic mutation widely considered to be a marker of disease outcome and response to treatment in breast cancer. Pathologists have made large efforts to achieve accuracy in characterizing HER2/neu status. The introduction of transtuzumab contributed to development of additional measures to identify sensitive and resistant subclasses of HER2/neu-positive tumors. In this article, we describe the latest advances in HER2/neu status diagnostic assessment and the most relevant research emerging from ‘‘Omics’’ (genomics, epigenetics, transcriptomics, and proteomics) studies on HER2/neu-positive breast cancer. A large quantity of biomarkers from different studies highlighted HER2/neu-positive specific proliferation, cell cycle arrest, and apoptosis mechanisms, as well as immunological and metabolic behavior. Major driver genes of tumor progression have had a candidate status (GRB7, MYC, CCND1, EGFR, etc.), even though the main role for HER2/neu is largely recognized. Nonetheless, existing omics data and HER2/neupositive molecular profiles seem to suggest that few proteogenomic alterations in HER2, EGFR, and PI3K networks could significantly affect the effectiveness of transtuzumab. The systematic search of molecular alterations in and across these pathways can help to select the most appropriate drug for a given patient based on in-depth understanding of complexity in tumor biology.
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- 2013
41. Single-nucleotide polymorphisms and FDG-PET in breast cancer
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Valentina Bravatà, Alessandro Stefano, Francesco Paolo Cammarata, Luigi Minafra, Giorgio Russo, S. Nicolosi, Sabina Pulizzi, V. Tripoli, Isabella Castiglioni, Cecilia Gelfi, Maria Carla Gilardi, and Messa Cristina.
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- 2013
42. Genotyping analysis and 18FDG uptake in breast cancer patients: a preliminary research
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Giorgio Ivan Russo, Francesco Paolo Cammarata, Alessandro Stefano, Cristina Messa, Maria Carla Gilardi, Cecilia Gelfi, Valentina Bravatà, Luigi Minafra, Sabina Pulizzi, Stefania Nicolosi, Bravatà, V, Stefano, A, Cammarata, F, Minafra, L, Russo, G, Nicolosi, S, Pulizzi, S, Gelfi, C, Gilardi, M, Messa, M, and Messa, C
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Oncology ,Cancer Research ,medicine.medical_specialty ,Pathology ,dbSNP ,Genotype ,PET-CT ,Single-nucleotide polymorphism ,Standardized uptake value ,Breast Neoplasms ,Gene mutation ,Multimodal Imaging ,Polymorphism, Single Nucleotide ,Breast cancer ,Fluorodeoxyglucose F18 ,Internal medicine ,medicine ,Humans ,SUVpvc ,biology ,business.industry ,Research ,Glucose analog ,SUVmax ,Single nucleotide polymorphisms ,medicine.disease ,Single nucleotide polymorphism ,Breast cancer, Single nucleotide polymorphisms, PET-CT, SUVmax, SUVpvc ,Methylenetetrahydrofolate reductase ,Positron-Emission Tomography ,biology.protein ,Female ,Radiopharmaceuticals ,business ,Tomography, X-Ray Computed - Abstract
Background: Diagnostic imaging plays a relevant role in the care of patients with breast cancer (BC). Positron Emission Tomography (PET) with 18F-fluoro-2-deoxy-D-glucose (FDG) has been widely proven to be a clinical tool suitable for BC detection and staging in which the glucose analog supplies metabolic information about the tumor. A limited number of studies, sometimes controversial, describe possible associations between FDG uptake and single nucleotide polymorphisms (SNPs). For this reason this field has to be explored and clarified. We investigated the association of SNPs in GLUT1, HIF-1a, EPAS1, APEX1, VEGFA and MTHFR genes with the FDG uptake in BC. Methods: In 26 caucasian individuals with primary BC, whole-body PET-CT scans were obtained and quantitative analysis was performed by calculating the maximum Standardized Uptake Value normalized to body-weight (SUVmax) and the mean SUV normalized to body-weight corrected for partial volume effect (SUVpvc). Human Gene Mutation Database and dbSNP Short Genetic Variations database were used to analyze gene regions containing the selected SNPs. Patient genotypes were obtained using Sanger DNA sequencing analysis performed by Capillary Electrophoresis. Results: BC patients were genotyped for the following nine SNPs: GLUT1: rs841853 and rs710218; HIF-1a: rs11549465 and rs11549467; EPAS1: rs137853037 and rs137853036; APEX1: rs1130409; VEGFA: rs3025039 and MTHFR: rs1801133. In this work correlations between the nine potentially useful polymorphisms selected and previously suggested with tracer uptake (using both SUVmax and SUVpvc) were not found. Conclusions: The possible functional influence of specific SNPs on FDG uptake needs further studies in human cancer. In summary, this is the first pilot study, to our knowledge, which investigates the association between a large panel of SNPs and FDG uptake specifically in BC patients. This work represents a multidisciplinary and translational medicine approach to study BC where, the possible correlation between SNPs and tracer uptake, may be considered to improve personalized cancer treatment and care.
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- 2013
43. Gene expression profiles in irradiated cancer cells
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Marilena Ripamonti, Luigi Minafra, Giorgio Ivan Russo, Maria Carla Gilardi, Valentina Bravatà, Minafra, L, BRAVATA', V, Russo, G, Ripamonti, M, and Gilardi, MC
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Candidate gene ,radiation, gene expression profile ,Cancer ,Computational biology ,Biology ,medicine.disease ,Bioinformatics ,Complementary DNA ,Cancer cell ,Gene expression ,Gene chip analysis ,medicine ,DNA microarray ,Gene - Abstract
Knowledge of the molecular and genetic mechanisms underlying cellular response to radiation may provide new avenues to develop innovative predictive tests of radiosensitivity of tumours and normal tissues and to improve individual therapy. Nowadays very few studies describe molecular changes induced by hadrontherapy treatments, therefore this field has to be explored and clarified. High-throughput methodologies, such as DNA microarray, allow us to analyse mRNA expression of thousands of genes simultaneously in order to discover new genes and pathways as targets of response to hadrontherapy. Our aim is to elucidate the molecular networks involved in the sensitivity/resistance of cancer cell lines subjected to hadrontherapy treatments with a genomewide approach by using cDNA microarray technology to identify gene expression profiles and candidate genes responsible of differential cellular responses.
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- 2013
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44. Brain-derived neurotrophic factor (Val66Met) polymorphism does not influence recovery from a post-traumatic vegetative state: a blinded retrospective multi-centric study
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Antonio De Tanti, Valentina Bravatà, Lucia Francesca Lucca, Caterina Pistarini, Cristina Boccagni, Rita Formisano, Giuliano Dolce, Alberto Castiglione, Giuseppe Galardi, Maria Andriolo, Luigi Minafra, Cecilia Gelfi, Sergio Bagnato, Antonino Sant'Angelo, Bagnato, S, Minafra, L, Bravata', V, Boccagni, C, Sant’Angelo, A, Castiglione, A, Andriolo, M, Lucca, LF, De Tanti, A, Pistarini, C, Formisano, R, Dolce, G, Gelfi, C, and Galardi, G
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Oncology ,Adult ,Male ,medicine.medical_specialty ,disorders of consciousne ,Adolescent ,Genotype ,Traumatic brain injury ,Polymorphism, Single Nucleotide ,vegetative state ,Young Adult ,Neurotrophic factors ,Internal medicine ,Neuroplasticity ,medicine ,Humans ,Young adult ,Psychiatry ,Retrospective Studies ,Brain-derived neurotrophic factor ,biology ,traumatic brain injury ,Brain-Derived Neurotrophic Factor ,Persistent Vegetative State ,levels of cognitive functioning ,genetic factor ,Retrospective cohort study ,Cognition ,Recovery of Function ,Middle Aged ,medicine.disease ,nervous system ,Brain Injuries ,biology.protein ,Female ,Neurology (clinical) ,Psychology ,Polymorphism, Restriction Fragment Length ,Neurotrophin - Abstract
Brain-derived neurotrophic factor (BDNF) is a neurotrophin that influences neuronal plasticity throughout life. Emergence from a vegetative state (VS) after a traumatic brain injury (TBI) implies that the brain undergoes plastic changes. A common polymorphism in the BDNF gene—BDNF Val66Met (referred to herein as BDNFMet)—impairs cognitive function in healthy subjects. The aim of this study was to determine whether the BDNFMet polymorphism plays a role in the recovery of consciousness and cognitive functions in patients in a VS after a TBI. Fifty-three patients in a VS 1 month after a TBI were included in the study and genotyped for the BDNFMet polymorphism. Scores of levels of cognitive functioning (LCF) at 1, 3, 6, and 12 months post-TBI were retrospectively compared in patients without (Val group), and with (Met group), the BDNFMet polymorphism. The BDNFMet polymorphism was detected in 20 out of the 53 patients. The mean LCF scores in the Val and Met groups were 1.6 – 0.5 and 1.4 – 0.5 at 1 month, 2.3 – 0.7 and 2.5 – 1.2 at 3 months, 3.3 – 1.7 and 3.5 – 1.7 at 6 months, and 4 – 1.9 and 3.9 – 1.8 at 12 months, respectively ( p > 0.05). The percentages of patients in the Val and Met groups who emerged from the VS were 36.4% and 30% at 3 months, 66.3% and 70% at 6 months, and 70% and 87.5% at 12 months ( p > 0.05), respectively. These findings provide evidence that the BDNFMet polymorphism is not involved in cognitive improvement in patients with a VS following TBI. Future studies should focus on the role of other BDNF polymorphisms in the recovery from a VS.
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- 2012
45. Unmasking epithelial-mesenchymal transition in a breast cancer primary culture: a study report
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Cecilia Gelfi, Luigi Minafra, Valentina Bravatà, Rossana Norata, Carmelo Lupo, Massimo Viola, Cristina Messa, Minafra, L, Norata, R, Bravatà, V, Viola, M, Lupo, C, Gelfi, C, Messa, M, Bravatà, V, and Messa, C
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Pathology ,medicine.medical_specialty ,Epithelial-Mesenchymal Transition ,Immunocytochemistry ,Short Report ,lcsh:Medicine ,Breast Neoplasms ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Cell Line ,Breast cancer ,Carcinoma ,medicine ,Biomarkers, Tumor ,Tumor Cells, Cultured ,Humans ,Vimentin ,Microscopy, Phase-Contrast ,Epithelial–mesenchymal transition ,Primary cell culture ,lcsh:Science (General) ,lcsh:QH301-705.5 ,Medicine(all) ,Biochemistry, Genetics and Molecular Biology(all) ,Reverse Transcriptase Polymerase Chain Reaction ,lcsh:R ,Mesenchymal stem cell ,Carcinoma, Ductal, Breast ,Cancer ,Muscle, Smooth ,Breast cancer, Primary cell culture, Epithelial-mesenchymal transition (EMT) ,General Medicine ,medicine.disease ,Cadherins ,Immunohistochemistry ,Actins ,Gene Expression Regulation, Neoplastic ,Epithelial-mesenchymal transition (EMT) ,lcsh:Biology (General) ,Cell culture ,Cancer cell ,Keratins ,Female ,lcsh:Q1-390 - Abstract
Background Immortalized cancer cell lines are now well-established procedures in biomedicine for a more complete understanding of cellular processes in cancer. However, they are more useful in preparation of fresh tumour tissue, in order to obtain cancer cells with highly preserved individual tumour properties. In the present study we report an analytical investigation on a breast cancer primary cell culture isolated from a surgical specimen obtained from a patient with an infiltrating ductal carcinoma. The objective of the research was to reveal unrecognized aspects of neoplastic cells, typical of the tumour from where the cells were derived, but masked in fixed tissue sections, in order to better predict the aggressive potentiality of the tumour. Findings Using a combination of mechanical and enzymatic treatment, the tumour tissue was dissociated immediately after surgical removal. The primary cells were isolated by differential cell centrifugation and grown in selective media. Immunocytochemistry and quantitative RT-PCR analysis were performed to detect the presence of specific biomarkers at protein and transcript level. The isolated primary breast cancer cells displayed phenotypic behaviour, characteristic of malignant cells and expression of several mesenchymal markers, revealing a strong signature for the epithelial-to-mesenchymal transition associated to a stellate morphology with a number of cellular protrusions and the attitude to overgrow as multilayered overlapping cellular foci. Conclusions Our data are a further meaningful indication that primary cell cultures represent a powerful system that could be applied to those cases deserving a deeper investigation at molecular level in order to design individualized anticancer therapies in the future.
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- 2012
46. A genetic study on the role of thiamine transporters in a case of atrophic beri-beri
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G. Callari 1, Valentina Bravatà 2, Luigi Minafra L. 2, and P. Morana 1, G. Vitello 1, Cecilia Gelfi 3, L. Grimaldi L.
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- 2011
47. BDNF polymorphisms and outcome of post-traumatic vegetative state: results from an italian multicentric study
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S. Bagnato 1, Luigi Minafra 2, L. Lucca 3, A. De Tanti 4, C. Pistarini 5, R. Formisano 6, C. Boccagni 7, Valentina Bravatà 2, M. Amdriolo 8, A. Sant'Angelo 7, A. Castiglione 1, G. Dolce 3, Cecilia Gelfi 9,10, G. Galardi, and 7
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- 2011
48. Genetic, clinical and radiographic signs in knee osteoarthritis susceptibility
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Valentina Bravatà, Michele Saporito, Luigi Minafra, Cristina Messa, Giusi Irma Forte, Francesco Paolo Cammarata, Salvatore Caldarella, Filippo Boniforti, Michele D'Arienzo, Maria Carla Gilardi, Minafra, L, Bravatà, V, Saporito, M, Cammarata, FP, Forte, GI, Caldarella, S, D'Arienzo, M, Gilardi, MC, Messa, C, Boniforti, F, Cammarata, F, Forte, G, D. Arienzo, M, Gilardi, M, and Messa, M
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Male ,medicine.medical_specialty ,Pathology ,dbSNP ,Genotype ,Single Nucleotide Polymorphisms ,Immunology ,Single-nucleotide polymorphism ,Osteoarthritis ,Polymorphism, Single Nucleotide ,Radiographic ,Rheumatology ,Internal medicine ,Settore MED/33 - Malattie Apparato Locomotore ,OMIM : Online Mendelian Inheritance in Man ,Humans ,Immunology and Allergy ,Medicine ,Genetic Predisposition to Disease ,Grading (tumors) ,Aged ,Aged, 80 and over ,Reverse Transcriptase Polymerase Chain Reaction ,business.industry ,Middle Aged ,Osteoarthritis, Knee ,medicine.disease ,Radiography ,Orthopedic surgery ,Cohort ,Female ,Osteoarthriti ,business ,Research Article - Abstract
INTRODUCTION: Osteoarthritis (OA) is considered to be a multifactorial and polygenic disease and diagnosis is mainly clinical and radiological. Correlation between radiographic data and clinical status has been reported. However, very few studies, especially in Caucasian people, describe the association between the Kellgren and Lawrence OA grading scale (KL) and genetic alterations to better understand OA etiopathogenesis and susceptibility. In order to update the knee OA grading, in this study we assessed the associations between KL grade, clinical features such as American Knee Society Score (AKSS), age, and polymorphisms in the principal osteoarthritis susceptibility (OS) genes in Sicilian individuals. METHODS: In 66 Sicilian individuals affected by primary knee OA, the clinical and radiographic evaluation was performed using 2 sub-scores of AKSS (knee score (KS) and function score (FS)) and KL. The patients were also classified according to age. Online Mendelian Inheritance in Man (OMIM) and Database of Single Nucleotide Polymorphisms (dbSNP) Short Genetic Variations databases were used to select gene regions containing the following polymorphisms to analyze: FRZB rs288326 and rs7775, MATN3 rs77245812, ASPN D14 repeats, PTHR2 rs76758470, GDF5 rs143383 and DVWA rs11718863. Patient genotypes were obtained using Sanger DNA sequencing analysis. RESULTS: In our cohort of patients a statistical association between the variables analyzed was reported in all associations tested (KL versus KS, FS and age). We observed that a mild to severe OA radiographic grade is related to severe clinical conditions and loss of articular function and that the severity of symptoms increases with age. Concerning the genotyping analysis, our results revealed a significant statistical association between KL grading and GDF5 rs143383 and DVWA rs11718863 genetic alterations. The latter was also associated with a more severe radiographic grade, displaying its predictive role as OA marker progression. Statistically significant association between clinical, radiographic and genetic signs observed, suggests extending the actual grading of knee OA based mainly on X-ray features. CONCLUSIONS: This work represents a multidisciplinary and translational medicine approach to study OA where clinical, radiological, and OS5 and OS6 SNPs evaluation could contribute to better define grading and progression of OA and to the development of new therapies.
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- 2014
49. Correlation between clinical and radiographic classification of osteoarthritis and SNPs linked to osteoarthritis susceptibility
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Michele Saporito, Luigi Minafra, Francesco Paolo Cammarata, Filippo Boniforti, Valentina Bravatà, Saporito, M, Minafra, L, Bravatà, V, Cammarata, FP, and Boniforti, F
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medicine.medical_specialty ,business.industry ,Radiography ,Biomedical Engineering ,Single-nucleotide polymorphism ,Osteoarthritis ,medicine.disease ,Correlation ,SNP, Osteoarthritis ,Rheumatology ,Internal medicine ,Medicine ,Orthopedics and Sports Medicine ,business - Full Text
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50. Portrait of inflammatory response to ionizing radiation treatment
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Giusi Irma Forte, Valentina Bravatà, Federica Maria Di Maggio, Luigi Minafra, Maria Carla Gilardi, Cristina Messa, Domenico Lio, Francesco Paolo Cammarata, Di Maggio, F, Minafra, L, Forte, G, Cammarata, F, Lio, D, Messa, M, Gilardi, M, Bravatà, V, Di Maggio, FM, Forte, GI, Cammarata, FP, Messa, C, and Gilardi, MC
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Ionizing radiation ,DNA repair ,Fibrosi ,medicine.medical_treatment ,Clinical Biochemistry ,Inflammation ,Review ,Cell fate determination ,Bioinformatics ,Immune system ,Medicine ,Cytokine ,Regulation of gene expression ,Invasivene ,business.industry ,Cancer ,Ionizing radiation, Inflammation, Cytokine, Fibrosis, Invasiveness ,Cell Biology ,medicine.disease ,Fibrosis ,Invasiveness ,Radiation therapy ,Cancer research ,medicine.symptom ,business - Abstract
Ionizing radiation (IR) activates both pro-and anti-proliferative signal pathways producing an imbalance in cell fate decision. IR is able to regulate several genes and factors involved in cell-cycle progression, survival and/or cell death, DNA repair and inflammation modulating an intracellular radiation-dependent response. Radiation therapy can modulate anti-tumour immune responses, modifying tumour and its microenvironment. In this review, we report how IR could stimulate inflammatory factors to affect cell fate via multiple pathways, describing their roles on gene expression regulation, fibrosis and invasive processes. Understanding the complex relationship between IR, inflammation and immune responses in cancer, opens up new avenues for radiation research and therapy in order to optimize and personalize radiation therapy treatment for each patient.
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