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"Facoetti, A"
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In-vitro effects of the tyrosine kinase inhibitor imatinib on glioblastoma cell proliferation
Glioblastoma (GBL) is the most malignant brain tumour in adults, causing the death of most patients within 9–12 months of diagnosis. Treatment is based on a combination of surgery, radiation therapy, and chemotherapy. With these treatment modalities, however, responses are extremely poor, so identification of novel treatment strategies is highly warranted. Platelet-derived growth factors (PDGF) and their receptors are commonly coexpressed in GBL, suggesting that stimulation of autocrine PDGF receptors may contribute to their growth. Interest in these receptors as drug target for glioblastoma treatment has increased with the clinical availability of the PDGFR kinase inhibitor antagonist imatinib mesylate (STI571). In this study, T98G and A172 human GBL cell lines were analysed for their sensitivity to treatment with imatinib. In particular, we focussed our attention on analysis of DNA distribution by flow cytometry at different times of incubation with different imatinib concentrations (1–30 μ
M
). Our results show that imatinib induces growth arrest in T98G and A172 cells in the G
0
/G
1
phase of the cell cycle, at all the concentrations tested, as early as 24 h after treatment. However we have also seen, by means of annexin V staining, that at 20 and 30 μ
M
concentrations, in concomitance with a significant growth arrest in the G
0
/G
1
phase, there is an increase of apoptotic cells 48 h after treatment, suggesting that imatinib at low concentrations (1–10 μ
M
) could act as a cytostatic agent whereas at high concentrations (20, 30 μ
M
) it mainly behaves as a cytotoxic agent.
Journal Article
A Monte Carlo Study of the Radiation Quality Dependence of DNA Fragmentation Spectra
We simulated the irradiation of human fibroblasts with γ rays, protons and helium, carbon and iron ions at a fixed dose of 5 Gy. The simulations were performed with the biophysical Monte Carlo code PARTRAC. From the output of the code, containing in particular the genomic positions of the radiation-induced DNA double-strand breaks (DSBs), we obtained the DNA fragmentation spectra. Very small fragments, in particular those related to “complex lesions” (few tens of base pairs), are probably very important for the late cellular consequences, but their detection is not possible with the common experimental techniques. We paid special attention to the differences among the various ions in the production of these very small fragments; in particular, we compared the fragmentation spectra for ions of the same specific energy and for ions of the same LET (linear energy transfer). As found previously for iron ions, we found that the RBE (relative biological effectiveness) for DSB production was considerably higher than 1 for all high-LET radiations considered. This is at variance with the results obtainable from experimental data, and it is due to the ability to count the contribution of small fragments. It should be noted that for a given LET this RBE decreases with increasing ion charge, due mainly to the increasing mean energy of secondary electrons. A precise quantification of the DNA initial damage can be of great importance for both radiation protection, particularly in open-space long-term manned missions, and hadrontherapy.
Journal Article
EP696 Inoperable pelvic sidewall recurrence of gynecological cancer treated with proton and carbon ion radiotherapy: CNAO preliminary experience
Introduction/BackgroundRe-irradiation of local recurrences of gynaecological cancer pose a difficult challenge to Oncologist. For their biological and physical characteristics particle therapy (PT) could be an interesting treatment.MethodologyThe aim of the study was to evaluate the feasibility and early clinical outcome in patients (pts) with gynaecological pelvic sidewall recurrence (PSWr). Between May 2014 to December 2018, 10 patients (median age 56) with PSWr within or at the edge of the previously irradiated field were treated using PT. They had recurrence of: cervical (5), endometrial (3), uterine (1) and ovarian (1) cancer. Previous radiotherapy prescription dose ranged from 46 to 59.4 Gy and 5 patients underwent brachytherapy (range: 7–28 Gy).Two patients, with marginal lymph node recurrence, were irradiated with protons with up to a total dose of 25 GyRBE and 51 GyRBE, respectively. The remaining women underwent carbon-ion radiotherapy (median total dose 50.4 GyRBE; range: 36–57) administered in a median number of 12 fractions. Six patients with PSWr received surgical spacer placement by open surgery to keep intestinal tracts apart from the tumour as the distance between tumour and nearest intestinal tracts was not sufficient. No pts received concurrent chemotherapy. Preliminary local control (LC) and toxicity profile (according to CTCAE V4.03 scale) were evaluated.ResultsAll patients completed the planned treatment and no acute toxicities G>2 were observed. For the evaluable patients, 1 case of intermediate G≥3 toxicity was reported in women received sequential Bevacizumab (BV). For pts with a follow-up ≥3 months, median LC was 7 months (range: 3–14), median MFS was 4.5 months (range: 3–14,5) and median OS was 7 months (range: 3–14,5). 1 pt experienced local progression and 4 pts died for systemic progression. Data are still ongoing.ConclusionFor pts with PSWr a PT approach seems to be feasible and our results showed a promising short-term outcome and limited radiation-related side effects. Longer follow-up and large patient accrual are required.DisclosureNothing to disclose.
Journal Article
P178 Carbon-Ion radiotherapy for malignant gynecological melanoma
Introduction/BackgroundWe analyzed early clinical outcomes of carbon ion radiotherapy (CIRT) in the first patients with gynecological malignant mucosal melanoma(g-MMM) treated at CNAO.MethodologyBetween 2016 and 2018, 9 patients(pts) with g-MMM were treated with CIRT after surgery or in exclusive settings (table 1) . They had 7 vaginal(VaM),1 cervical(CM) and 1 vulvar(VuM)MMM. One pt with VaM had been previously irradiated with photons;8 pts are considered inoperable and 1 pt underwent adjuvant CIRT on the small pelvic space after radical surgery without lymphadenectomy. Two pts underwent neoadjuvant and sequential anti-PD-1 immunotherapy. Because of the large volume of macroscopic disease,CM and VuM patients were irradiated with up to a total dose of 28 GyRBE(3 fractions) and 68.8 GyRBE(16 fractions), respectively, to the Clinical Target Volume (CTV) defined as the Gross Tumor Volume (GTV)+uterine cervix and corpus for the CM and GTV+vulva for the VuM. For inoperable VaM, small pelvic space including GTV was irradiated with up to a total dose of 38.7-43 GyRBE followed by a GTV boost of up to a total dose of 68.8 GyRBE in 16 fractions (figure 1). All patients were treated with synchrotron-based scanning carbon ion beams. Early clinical and toxicity profile(according to CTCAE V4.03) were evaluated.ResultsTreatment was well tolerated and no interruption was needed. For the evaluable pts, toxicity profile was favorable and no G≥2 acute/late toxicities were observed. Overall,for pts with a follow-up≥3 months,median LC ranged from 3 to 13 months(
Journal Article
Orienting of visual attention in dyslexia: evidence for asymmetric hemispheric control of attention
The control of attentional orienting was studied in children with specific reading disorder (SRD) or dyslexia, and it was compared with that of normal readers. We used the covert orienting paradigm to measure subjects' reaction times for target detection both in valid and invalid cue conditions, either in the left or in the right visual fields. In experiment 1, we investigated exogenous orienting. The cue consisted of a peripheral abrupt onset and the cue-target delay was 350 ms. As compared with normal readers, in dyslexics the cue effect was absent in the right visual field, whereas in the left visual field a greater cue effect was observed. No visual field asymmetry was found in normal readers. In experiment 2, we investigated endogenous orienting. The cue was shown centrally and the cue-target delay was 750 ms. In dyslexics and normal readers, orienting of attention was present in both visual fields. However, in the invalid condition, dyslexic children showed significantly slower reaction times in the left visual field than in the right visual field. These results were interpreted as being due to an asymmetric control of visual spatial attention, possibly related with a posterior attention mechanism deficit in the right parietal cortex and/or an interhemispheric dysfunction and/or an impairment of cerebellar functions.
Journal Article
DNA Fragmentation Induced in Human Fibroblasts by 56Fe Ions: Experimental Data and Monte Carlo Simulations
Campa, A., Alloni, D., Antonelli, F., Ballarini, F., Belli, M., Dini, V., Esposito, G., Facoetti, A., Friedland, W., Furusawa, Y., Liotta, M., Ottolenghi, A., Paretzke, H. G., Simone, G., Sorrentino, E. and Tabocchini, M. A. DNA Fragmentation Induced in Human Fibroblasts by 56Fe Ions: Experimental Data and Monte Carlo Simulations. Radiat. Res. 171, 438–445 (2009). We studied the DNA fragmentation induced in human fibroblasts by iron-ion beams of two different energies: 115 MeV/nucleon and 414 MeV/nucleon. Experimental data were obtained in the fragment size range 1–5700 kbp; Monte Carlo simulations were performed with the PARTRAC code; data analysis was also performed through the Generalized Broken Stick (GBS) model. The comparison between experimental and simulated data for the number of fragments produced in two different size ranges, 1–23 kbp and 23–5700 kbp, gives a satisfactory agreement for both radiation qualities. The Monte Carlo simulations also allow the counting of fragments outside the experimental range: The number of fragments smaller than 1 kbp is large for both beams, although with a strong difference between the two cases. As a consequence, we can compute different RBEs depending on the size range considered for the fragment counting. The PARTRAC evaluation takes into account fragments of all sizes, while the evaluation from the experimental data considers only the fragments in the range of 1–5700 kbp. When the PARTRAC evaluation is restricted to this range, the agreement between experimental and computed RBE values is again good. When fragments smaller than 1 kbp are also considered, the RBE increases considerably, since γ rays produce a small number of such fragments. The analysis performed with the GBS model proved to be quite sensitive to showing, with a phenomenological single parameter, variations in double-strand break (DSB) correlation.
Journal Article
Action Video Games Enhance Attentional Control and Phonological Decoding in Children with Developmental Dyslexia
Reading acquisition is extremely difficult for about 5% of children because they are affected by a heritable neurobiological disorder called developmental dyslexia (DD). Intervention studies can be used to investigate the causal role of neurocognitive deficits in DD. Recently, it has been proposed that action video games (AVGs)—enhancing attentional control—could improve perception and working memory as well as reading skills. In a partial crossover intervention study, we investigated the effect of AVG and non-AVG training on attentional control using a conjunction visual search task in children with DD. We also measured the non-alphanumeric rapid automatized naming (RAN), phonological decoding and word reading before and after AVG and non-AVG training. After both video game training sessions no effect was found in non-alphanumeric RAN and in word reading performance. However, after only 12 h of AVG training the attentional control was improved (i.e., the set-size slopes were flatter in visual search) and phonological decoding speed was accelerated. Crucially, attentional control and phonological decoding speed were increased only in DD children whose video game score was highly efficient after the AVG training. We demonstrated that only an efficient AVG training induces a plasticity of the fronto-parietal attentional control linked to a selective phonological decoding improvement in children with DD.
Journal Article
Microbiota dysbiosis influences immune system and muscle pathophysiology of dystrophin‐deficient mice
Duchenne muscular dystrophy (DMD) is a progressive severe muscle‐wasting disease caused by mutations in
DMD
, encoding dystrophin, that leads to loss of muscle function with cardiac/respiratory failure and premature death. Since dystrophic muscles are sensed by infiltrating inflammatory cells and gut microbial communities can cause immune dysregulation and metabolic syndrome, we sought to investigate whether intestinal bacteria support the muscle immune response in mdx dystrophic murine model. We highlighted a strong correlation between DMD disease features and the relative abundance of
Prevotella
. Furthermore, the absence of gut microbes through the generation of mdx germ‐free animal model, as well as modulation of the microbial community structure by antibiotic treatment, influenced muscle immunity and fibrosis. Intestinal colonization of mdx mice with eubiotic microbiota was sufficient to reduce inflammation and improve muscle pathology and function. This work identifies a potential role for the gut microbiota in the pathogenesis of DMD.
Synopsis
The susceptibility of DMD patients to inflammatory events cannot solely be explained by skeletal muscle genetic defects but rather favors a new paradigm linking development of chronic inflammation with a strict regulation between epigenetics factors and degenerative environment.
Gut microbiota–specific alterations (dysbiosis) correlate with the dystrophic pathology in mdx mice, influencing muscle immunity and fibrosis.
Dysbiotic mdx microbiota induces a decreased innate immune response and altered muscle metabolism.
The study of the dysregulated immune system‐microbiota axis in mdx mice highlights the importance of microbiota as a potential target for therapeutic interventions.
Graphical Abstract
The susceptibility of DMD patients to inflammatory events cannot solely be explained by skeletal muscle genetic defects but rather favors a new paradigm linking the development of chronic inflammation with a strict regulation between epigenetics factors and degenerative environment.
Journal Article
Boron absorption imaging in rat lung colon adenocarcinoma metastases
Given the encouraging results from our previous work on the clinical application of BNCT on non-resectable, chemotherapy resistant liver metastases, we explore the possibility to extend our technique to lung metastases. A fundamental requirement for BNCT is achieving higher 10B concentrations in the metastases compared to those in healthy tissue. For this reason we developed a rat model with lung metastases in order to study the temporal distribution of 10B concentration in tissues and tumoral cells. Rats with induced lung metastases from colon adenocarcinoma were sacrificed two hours after intraperitoneal Boronphenylalanine infusion. The lungs were harvested, frozen in liquid nitrogen and subsequently histological sections underwent neutron autoradiography in the nuclear reactor Triga Mark II, University of Pavia. Our findings demonstrate higher Boron uptake in tumoral nodules compared to healthy lung parenchyma 2 hours after Boronphenylalanine infusion.
Journal Article