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Engineering the polyphenolic biosynthetic pathway stimulates metabolic and molecular changes during fruit ripening in "Bronze" tomato.
Scarano, A, Gerardi, C, Sommella, E, Campiglia, P, Chieppa, M, Butelli, E, Santino, A
Horticulture research. 2022;:uhac097
Abstract
The metabolic engineered Bronze tomato line is characterized by the constitutive over-expression of the VvStSy gene encoding a structural protein responsible for the stilbenoids biosynthesis and the fruit-specific over-expression of AmDel/Rosea1 and AtMYB12 genes encoding transcription factors that activate the polyphenol biosynthetic pathway. This tomato line is known for the increased levels of polyphenols in ripe fruits and for beneficial health promoting antioxidant and anti-inflammatory effects. In this study we analyzed the transcriptional and metabolic profiling in mature green, breaker, orange and ripe fruits compared to the normal tomato counterparts during ripening, to unravel the effect of regulatory and structural transgenes on metabolic fluxes of primary and secondary metabolisms. Our results showed that the shikimate synthase (SK) gene was up-regulated in the Bronze fruit, and the transcriptional activation is consistent with the metabolic changes observed throughout fruit ripening. These results paralleled with a reduced level of simple sugars and malate, highlighting the consumption of primary metabolites to favor secondary metabolites production and accumulation. Finally, carotenoids quantification revealed a change in the lycopene/β-carotene ratio in the Bronze fruit as a consequence of significant lower level of the first and higher levels of the latter. The high polyphenols and β-carotene content displayed by the Bronze fruit at the later stages of fruit ripening renders this line an interesting model to study the additive or synergic effects of these phyto-chemicals in the prevention of human pathologies.
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Late Cardiological Sequelae and Long-Term Monitoring in Classical Hodgkin Lymphoma and Diffuse Large B-Cell Lymphoma Survivors: A Systematic Review by the Fondazione Italiana Linfomi.
Oliva, S, Puzzovivo, A, Gerardi, C, Allocati, E, De Sanctis, V, Minoia, C, Skrypets, T, Guarini, A, Gini, G
Cancers. 2021;(1)
Abstract
Cardiotoxicity represents the most frequent cause with higher morbidity and mortality among long-term sequelae affecting classical Hodgkin lymphoma (cHL) and diffuse large B-cell lymphoma (DLBCL) patients. The multidisciplinary team of Fondazione Italiana Linfomi (FIL) researchers, with the methodological guide of Istituto di Ricerche Farmacologiche "Mario Negri", conducted a systematic review of the literature (PubMed, EMBASE, Cochrane database) according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, in order to analyze the following aspects of cHL and DLBCL survivorship: (i) incidence of cardiovascular disease (CVD); (ii) risk of long-term CVD with the use of less cardiotoxic therapies (reduced-field radiotherapy and liposomal doxorubicin); and (iii) preferable cardiovascular monitoring for left ventricular (LV) dysfunction, coronary heart disease (CHD) and valvular disease (VHD). After the screening of 659 abstracts and related 113 full-text papers, 23 publications were eligible for data extraction and included in the final sample. There was an increased risk for CVD in cHL survivors of 3.6 for myocardial infarction and 4.9 for congestive heart failure (CHF) in comparison to the general population; the risk increased over the years of follow-up. In addition, DLBCL patients presented a 29% increased risk for CHF. New radiotherapy techniques suggested reduced risk of late CVD, but only dosimetric studies were available. The optimal monitoring of LV function by 2D-STE echocardiography should be structured according to individual CV risk, mainly considering as risk factors a cumulative doxorubicine dose >250 mg per square meter (m2) and mediastinal radiotherapy >30 Gy, age at treatment <25 years and age at evaluation >60 years, evaluating LV ejection fraction, global longitudinal strain, and global circumferential strain. The evaluation for asymptomatic CHD should be offered starting from the 10th year after mediastinal RT, considering ECG, stress echo, or coronary artery calcium (CAC) score. Given the suggested increased risks of cardiovascular outcomes in lymphoma survivors compared to the general population, tailored screening and prevention programs may be warranted to offset the future burden of disease.
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The Impact of Healthy Lifestyles on Late Sequelae in Classical Hodgkin Lymphoma and Diffuse Large B-Cell Lymphoma Survivors. A Systematic Review by the Fondazione Italiana Linfomi.
Minoia, C, Gerardi, C, Allocati, E, Daniele, A, De Sanctis, V, Bari, A, Guarini, A
Cancers. 2021;(13)
Abstract
BACKGROUND In recent years, the scientific community has been paying ever more attention to the promotion of lifestyles aimed at the prevention of late toxicities related to anti-cancer treatments. METHODS Fondazione Italiana Linfomi (FIL) researchers conducted a systematic review in order to evaluate the evidence in favor of the promotion of lifestyles aimed at the prevention of the main sequelae of long-term classical Hodgkin lymphoma (cHL) and diffuse large B-cell lymphoma (DLBCL) in survivors treated at adulthood with first-line or second-line therapy, including autologous stem cell transplants (ASCTs). Pubmed, Embase and Cochrane Library were searched up to December 2020. RESULTS Seven studies were ultimately included in this systematic review; some of them were eligible for multiple PICOS. The majority of the studies emerged from data extraction regarding cHL; less evidence resulted for DLBCL survivors. Five studies in favor of physical activity provided consistent data for a reduction of the cardiovascular risk in cHL and also in survivors who underwent ASCT. A beneficial effect of physical activity in reducing chronic fatigue was found. Being overweight was associated with a higher risk of coronary heart disease in cHL survivors in one of the two eligible studies. Studies aiming to evaluate the impact of the Mediterranean diet on late toxicities and secondary cancers were lacking. Tailored survivorship care plans (SCP) seemed to represent an optimal tool to guide the follow-up and promote healthier lifestyles in the one eligible study. Thus, promotion of healthy lifestyles and empowering of lymphoma survivors should be implemented through structured models. The study also brought to light numerous areas of future clinical research.
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Can Natural Polyphenols Help in Reducing Cytokine Storm in COVID-19 Patients?
Giovinazzo, G, Gerardi, C, Uberti-Foppa, C, Lopalco, L
Molecules (Basel, Switzerland). 2020;25(24)
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Plain language summary
During covid-19 infection the body experiences a hyper-immune reaction resulting in an extreme inflammatory response known as cytokine release syndrome (CRS), which correlates with poor prognosis and severe illness. There are no effective treatments for CRS, although there are ongoing trials. The use of natural plant chemicals known as polyphenols have been shown in previous trials to improve inflammation This review of over 90 studies aimed to summarise the use of polyphenols to fight severe covid-19 infection. The paper began by reviewing current drug therapies, which have been shown in studies to be of benefit to inflammation, with tocilizumab being heavily reviewed. The authors then reviewed several plant polyphenols and reviewed how they can modulate inflammation through inhibiting inflammatory molecules and viral activity. It was concluded that human studies are lacking data and so phytochemicals may be promising for the treatment of covid-19. This study could be used by health care professionals to understand the importance of recommending a whole food, plant rich diet with many different coloured foods for individuals who are suffering from covid-19.
Abstract
SARS-CoV-2 first emerged in China during late 2019 and rapidly spread all over the world. Alterations in the inflammatory cytokines pathway represent a strong signature during SARS-COV-2 infection and correlate with poor prognosis and severity of the illness. The hyper-activation of the immune system results in an acute severe systemic inflammatory response named cytokine release syndrome (CRS). No effective prophylactic or post-exposure treatments are available, although some anti-inflammatory compounds are currently in clinical trials. Studies of plant extracts and natural compounds show that polyphenols can play a beneficial role in the prevention and the progress of chronic diseases related to inflammation. The aim of this manuscript is to review the published background on the possible effectiveness of polyphenols to fight SARS-COV-2 infection, contributing to the reduction of inflammation. Here, some of the anti-inflammatory therapies are discussed and although great progress has been made though this year, there is no proven cytokine blocking agents for COVID currently used in clinical practice. In this regard, bioactive phytochemicals such as polyphenols may become promising tools to be used as adjuvants in the treatment of SARS-CoV-2 infection. Such nutrients, with anti-inflammatory and antioxidant properties, associated to classical anti-inflammatory drugs, could help in reducing the inflammation in patients with COVID-19.
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Letting post-marketing bridge the evidence gap: the case of orphan drugs.
Joppi, R, Gerardi, C, Bertele', V, Garattini, S
BMJ (Clinical research ed.). 2016;:i2978
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Deferiprone versus deferoxamine in thalassemia intermedia: Results from a 5-year long-term Italian multicenter randomized clinical trial.
Calvaruso, G, Vitrano, A, Di Maggio, R, Lai, E, Colletta, G, Quota, A, Gerardi, C, Rigoli, LC, Sacco, M, Pitrolo, L, et al
American journal of hematology. 2015;(7):634-8
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Abstract
In patients with thalassemia intermedia (TI), such as beta-TI, alpha-thalassemia (mainly HbH disease and mild/moderate forms of HbE/beta-thalassemia), iron overload is an important challenge in terms of diagnosis, monitoring, and treatment. Moreover, to date, the only possible chelators available are deferoxamine, deferasirox, and deferiprone. Here, we report the first 5-year long-term randomized clinical trial comparing the effectiveness of deferiprone versus deferoxamine in patients with TI. Body iron burden, which was determined by measuring serum ferritin levels in the same patient over 5 years and analyzed according to the generalized linear mixed model (GLMM), showed a linear decrease over time in the mean serum ferritin levels in both treatment groups (P-value = 0.035). The overall period of observation was 235.2 person-years for the deferiprone patients compared with 214.3 person-years for the deferoxamine patients. The results of the log-rank test suggested that the deferiprone treatment did not affect survival compared with the deferoxamine treatment (P-value = 0.360). The major adverse events observed included gastrointestinal symptoms and joint pain or arthralgia. Neutropenia and agranulocytosis were also detected, suggesting needing of strict hematological control. In conclusion, long-term iron chelation therapy with deferiprone is associated with an efficacy and safety similar to that of deferoxamine, suggesting that this drug is an alternative option in cases in which deferoxamine and deferasirox are contraindicated.
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Fast generation of T2* maps in the entire range of clinical interest: application to thalassemia major patients.
Positano, V, Meloni, A, Santarelli, MF, Gerardi, C, Bitti, PP, Cirotto, C, De Marchi, D, Salvatori, C, Landini, L, Pepe, A
Computers in biology and medicine. 2015;:200-10
Abstract
T2* maps obtained by the processing of multiecho MR sequences can be useful in several clinical applications. T2* map generation procedures should join a processing time compatible with on-line image analysis with a good precision in the entire T2* range of clinical interest. Fast generation of T2* maps can be achieved by the estimation of the T2* values by the weighted linear fitting of the logarithm of the signal (WLSL) method. This approach fails if the signal decay diverges from a pure exponential decay, as happens at low T2* values where the rapid decay in the signal intensity leads to a plateau in the later echo times (TE). The proposed method implements the automatic truncation of the signal decay curves to be fitted in order to compensate for the signal collapse at low T2* values, allowing the extension of the WLSL method through the entire clinical range of T2* values. Validation was performed on synthetic images and on 60 thalassemia major patients with different levels of myocardial iron overload. Phantom experiments showed that a 5% fitting error threshold represented the best compromise between T2* value measurement precision and processing time. A good agreement was found between T2* map pixel-wise measurements and ROI-based measurements performed by expert readers (CoV=1.84% in global heart T2*, CoV=5.8% in segmental analysis). In conclusion, the developed procedure was effective in generating correct T2* maps for the entire T2* clinical range.
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FOLFIRI and Cetuximab Every Second Week for First-Line Treatment of KRAS Wild-Type Metastatic Colorectal Cancer According to Phosphatase and Tensin Homolog Expression: A Phase II Study.
Personeni, N, Rimassa, L, Verusio, C, Barni, S, Rubino, L, Bozzarelli, S, Villa, E, Carnaghi, C, Tronconi, MC, Gerardi, C, et al
Clinical colorectal cancer. 2015;(3):162-9
Abstract
BACKGROUND Retrospective studies have suggested that phosphatase and tensin homolog (PTEN) expression might predict the efficacy of cetuximab in patients with KRAS wild-type metastatic colorectal cancer (mCRC). The present study was designed to prospectively evaluate the efficacy of first-line irinotecan, fluorouracil, and folinate (FOLFIRI) plus cetuximab every second week according to PTEN expression. PATIENTS AND METHODS Originally, patients with KRAS wild-type mCRC were randomly assigned to receive either FOLFIRI or cetuximab plus FOLFIRI (FOLFIRI-C). After a protocol amendment, the FOLFIRI arm was discontinued, and additional patients received FOLFIRI-C. Cox proportional hazard models were used to investigate the effect of PTEN and MET expression and BRAF and phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit α mutations on progression-free survival (PFS) and overall survival (OS). RESULTS A total of 35 and 54 patients received FOLFIRI and FOLFIRI-C, respectively. For the patients assigned to FOLFIRI and FOLFIRI-C, the median OS was 17.7 and 23.3 months and the median PFS was 8.2 and 6.6 months, respectively. For patients receiving FOLFIRI-C, the loss of PTEN expression did not affect PFS or OS. Significant interactions for PFS were detected between the MET expression levels (P = .047) and BRAF mutation (P = .018) and treatment. On univariate analysis, BRAF mutation was significantly associated with shorter OS for patients receiving either FOLFIRI-C (P = .016) or FOLFIRI (P = .035). Multivariate analysis confirmed the independent prognostic value of BRAF mutation on OS and that of MET expression levels on PFS (P = .025) and OS (P = .028) but only in the patients receiving FOLFIRI alone. Adverse events with FOLFIRI-C were consistent with those expected from FOLFIRI plus weekly cetuximab. CONCLUSION Although prospective analysis of PTEN did not allow a validation of the prognostic value of this biomarker, an every second week cetuximab schedule, in addition to first-line FOLFIRI, was effective and well tolerated. The possible predictive value of MET expression levels warrants additional investigation.
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Improving survival with deferiprone treatment in patients with thalassemia major: a prospective multicenter randomised clinical trial under the auspices of the Italian Society for Thalassemia and Hemoglobinopathies.
Maggio, A, Vitrano, A, Capra, M, Cuccia, L, Gagliardotto, F, Filosa, A, Magnano, C, Rizzo, M, Caruso, V, Gerardi, C, et al
Blood cells, molecules & diseases. 2009;(3):247-51
Abstract
The prognosis for thalassemia major has dramatically improved in the last two decades. However, many transfusion-dependent patients continue to develop progressive accumulation of iron. This can lead to tissue damage and eventually death, particularly from cardiac disease. Previous studies that investigated iron chelation treatments, including retrospective and prospective non-randomised clinical trials, suggested that mortality, due mainly to cardiac damage, was reduced or completely absent in patients treated with deferiprone (DFP) alone or a combined deferiprone-deferoxamine (DFP-DFO) chelation treatment. However, no survival analysis has been reported for a long-term randomised control trial. Here, we performed a multicenter, long-term, randomised control trial that compared deferoxamine (DFO) versus DFP alone, sequential DFP-DFO, or combined DFP-DFO iron chelation treatments. The trial included 265 patients with thalassemia major, with 128 (48.3%) females and 137 (51.7%) males. No deaths occurred with the DFP-alone or the combined DFP-DFO treatments. One death occurred due to graft versus host disease (GVHD) in a patient that had undergone bone marrow transplantation; this patient was censored at the time of transplant. Only one death occurred with the DFP-DFO sequential treatment in a patient that had experienced an episode of heart failure one year earlier. Ten deaths occurred with the deferoxamine treatment. The main factors that correlated with an increase in the hazard ratio for death were: cirrhosis, arrhythmia, previous episode of heart failure, diabetes, hypogonadism, and hypothyroidism. In a Cox regression model, the interaction effect of sex and age was statistically significant (p-value<0.013). For each increasing year of age, the hazard ratio for males was 1.03 higher than that for females (p-value<0.013). In conclusion, the results of this study show that the risk factors for predicting mortality in patients with thalassemia major are deferoxamine-treatment, complications, and the interaction effect of sex and age.
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Potential myocardial iron content evaluation by magnetic resonance imaging in thalassemia major patients treated with Deferoxamine or Deferiprone during a randomized multicenter prospective clinical study.
Galia, M, Midiri, M, Bartolotta, V, Morabito, A, Rizzo, M, Mangiagli, A, Malizia, R, Borsellino, Z, Capra, M, D'Ascola, DG, et al
Hemoglobin. 2003;(2):63-76
Abstract
The purpose of this study was to evaluate if the variations of heart magnetic resonance imaging in beta-thalassemia major patients treated with Deferoxamine B mesylate (DF) or Deferiprone (L1) chelation therapy is a useful tool of the indirect myocardial iron content determination. For this reason, a prospective study was carried out. Seventy-two consecutive patients with beta-thalassemia major (35 treated with DF and 37 with L1) were studied. The main outcome results were laboratory parameters including determination of the liver iron concentration (LIC) and magnetic resonance imaging (MRI) of the heart and liver. The heart to muscle signal intensity ratios (HSIRs) were significantly increased in both the DF (t = -2.8; p < 0.01) and L1 (t = -3.1; p < 0.01) groups after one year of treatment No statistically significant difference in the values of HSIRs was present between the two groups at the beginning of treatment (p = 0.25; t = 1.13), and after one year of treatment (p = 0.20; t = 1.28). The HSIR were inversely correlated to the LIC (r = -0.52; p < 0.001) but not with ferritin levels (r = 0.10; p = 0.18). A positive correlation was found between the variation of HSIRs and that of the liver signal intensity ratios (r=0.52; p < 0.001), and a mild correlation (r = 0.40; p < 0.001) was found between the gamma glutamyltransferase (gammaGt) levels and the HSIRs values. Our data confirm that heart MRI is sensitive enough to detect significant variations of the mean HSIR during iron chelation with DF or L1.