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Antioxidant-rich foods may favorably influence lung function. We examined possible associations between the total dietary antioxidant capacity (TAC) and pulmonary function in a healthy Italian population.Until May 2009, 22,300 persons were randomly recruited from the general population in the Moli-sani project. A sample only including healthy women (5824) and men (5848) was analyzed. TAC was measured in foods by three different assays and the ferric reducing-antioxidant power (FRAP) assay was selected as the better indicator of dietary TAC. The European Investigation into Cancer and Nutrition Food Frequency Questionnaire was used for dietary assessment. The association between quintiles of dietary FRAP and pulmonary indexes was assessed using analysis of variance separately for men and women.After adjustment for confounders, women in the highest quintile of FRAP intake had +39 ml forced expiratory volume in the first second (FEV(1)) and +54 ml forced vital capacity, compared with those in the lowest quintile (P for trend ≤0.006). Stratified analysis showed that this relationship only occurred in women who were premenopausal/never smokers. In this subgroup, the observed effect of higher FRAP intake on FEV(1) was equivalent to an improvement in pulmonary age of 3.3 years. In men, all significant associations between pulmonary function and TAC were lost after adjustment for confounding.Dietary TAC may have a favorable role in respiratory health, particularly in premenopausal/never smoker women.

The invention provides isolated stem cells of non-embryonic origin that can be maintained in culture in the undifferentiated state or differentiated to form cells of multiple tissue types. Also provided are methods of isolation and culture, as well as therapeutic uses for the isolated cells.

In spite of the remarkable progress in basic and preclinical studies of acute myeloid leukemia (AML), the five-year survival rate of AML patients remains poor, highlighting the urgent need for novel and synergistic therapies. Over the past decade, increased attention has been focused on identifying suitable immunotherapeutic strategies for AML, and in particular on targeting leukemic cells and their progenitors. However, recent studies have also underlined the important contribution of the leukemic microenvironment in facilitating tumor escape mechanisms leading to disease recurrence. Here, we describe the immunological features of the AML niche, with particular attention to the crosstalk between the AML blasts and the cellular components of the altered tumor microenvironment (TME) and the mechanisms of immune escape that hamper the therapeutic effects of the most advanced treatments. Considering the AML complexity, immunotherapy approaches may benefit from a rational combination of complementary strategies aimed at preventing escape mechanisms without increasing toxicity.

The next future strategies for improved occupational safety and health management could largely benefit from wearable and Internet of Things technologies, enabling the real-time monitoring of health-related and environmental information to the wearer, to emergency responders, and to inspectors. The aim of this study is the development of a wearable gas sensor for the detection of NH3 at room temperature based on the organic semiconductor poly(3,4-ethylenedioxythiophene) (PEDOT), electrochemically deposited iridium oxide particles, and a hydrogel film. The hydrogel composition was finely optimised to obtain self-healing properties, as well as the desired porosity, adhesion to the substrate, and stability in humidity variations. Its chemical structure and morphology were characterised by infrared spectroscopy and scanning electron microscopy, respectively, and were found to play a key role in the transduction process and in the achievement of a reversible and selective response. The sensing properties rely on a potentiometric-like mechanism that significantly differs from most of the state-of-the-art NH3 gas sensors and provides superior robustness to the final device. Thanks to the reliability of the analytical response, the simple two-terminal configuration and the low power consumption, the PEDOT:PSS/IrOx Ps/hydrogel sensor was realised on a flexible plastic foil and successfully tested in a wearable configuration with wireless connectivity to a smartphone. The wearable sensor showed stability to mechanical deformations and good analytical performances, with a sensitivity of 60 ± 8 μA decade−1 in a wide concentration range (17–7899 ppm), which includes the safety limits set by law for NH3 exposure.

Despite its uniqueness, the Bargellini multicomponent reaction remains barely known by the most part of chemists. This can be ascribed to the fact that this transformation has not been adequately reviewed in the classic books of named reactions in organic chemistry. Nevertheless, several works on this reaction have been carried out over the years, many of them were written in Italian in the period 1929–1966. In this review article we extensively cover, in a chronological order, the most important applications of the Bargellini reaction reported to date, with the hope that this knowledge-sharing will help chemists to properly use this multicomponent transformation and imagine novel reactivities based on it.

Purpose: Oxidative stress might play an important role in the development of osteoarthritis, but not much is known about the effect of antioxidants on osteoarthritis risk. We, therefore, aimed to investigate the effect of dietary vitamin C, E, beta-carotene, and non-enzymatic antioxidant capacity (NEAC), which measures overall antioxidant activity from the diet, on the risk of osteoarthritis. Methods: For this study 43,865 men and women from the Swedish National March Cohort (SNMC) were followed for up to 19years. We computed dietary intake of vitamin C, E and beta-carotene using information from a Food Frequency Questionnaire (FFQ). To estimate dietary NEAC we combined the information from the FFQ with food item-specific antioxidant capacity values from an antioxidant food database. Cases of osteoarthritis were identified through the Swedish National Patient Registers. We categorized all exposure variables into sex-specific quartiles and used multivariable-adjusted Cox proportional hazards regression models to estimate hazard ratios (HRs) with 95% confidence intervals (95% CIs). Results: In total, we observed 5976 cases of OA during 469,148 person-years of follow-up. After adjusting for potential confounders, we did not find any association between vitamin C, beta-carotene and NEAC (p-values for trend > 0.5), but a positive association was found with higher dietary vitamin E intake (HR Q4 vs Q1: 1.11; 95% CI 1.02–1.21; p for trend = 0.01) and the risk of OA. Conclusion: Our findings do not provide evidence for dietary antioxidants to protect from the development of OA, and a higher dietary vitamin E intake might even increase the risk.

ObjectiveTo determine whether high baseline dietary antioxidants and total nonenzymatic antioxidant capacity (NEAC) is associated with a lower risk of Parkinson disease (PD) in men and women, we prospectively studied 43,865 men and women from a large Swedish cohort.MethodsIn the Swedish National March Cohort, 43,865 men and women aged 18–94 years were followed through record linkages to National Health Registries from 1997 until 2016. Baseline dietary vitamin E, vitamin C, and beta-carotene intake, as well as NEAC, were assessed by a validated food frequency questionnaire collected at baseline. All exposure variables were adjusted for energy intake and categorized into tertiles. Multivariable Cox proportional hazard regression models were fitted to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) for PD.ResultsAfter a mean follow-up time of 17.6 years, we detected 465 incidence cases of PD. In the multivariable adjusted model, dietary vitamin E (HR 0.68, 95% CI 0.52–0.90; p for trend 0.005) and vitamin C (HR 0.68, 95% CI 0.52–0.89; p for trend 0.004) were inversely associated with the risk of PD when comparing participants in the highest vs the lowest tertiles of exposure. No association was found with estimated intake of dietary beta-carotene or NEAC.ConclusionOur findings suggest that dietary vitamin E and C intake might be inversely associated with the risk of PD. No association was found with dietary beta-carotene or NEAC.Classification of EvidenceThis study provides Class III evidence that dietary vitamin E and C intake are inversely associated with the risk of PD.

Epidemiological evidence has confirmed the potential causal relationship between specific dietary factors and non-communicable diseases. However, currently nutrition was shown to be insufficiently integrated into medical education, regardless of the country. Without an adequate nutrition education, it is reasonable to assume that future physicians, as well as other health care professionals, will be not able to provide the highest quality care to patients in preventing and treating non-communicable diseases. Furthermore, the insufficient availability of physicians with specializations in nutrition has posed the basis for the development of non-medical careers in the field of nutrition. The present document was drafting by the Italian College of Academic Nutritionists, MED-49 (ICAN-49), with the aim to provide an overview on the nutritional competency standards covered by several health care professionals (Physicians Clinical Nutrition Specialists, Clinical Dietitians, Professional Clinical Nutrition Specialists, etc) for the prevention of diseases and/or support of pharmacological therapies. The aim of the ICAN 49 is to suggest a major shift in practice opportunities and roles for many nutritionists, especially for the management of the metabolic diseases, and promote a paradigm change: a clinical and educational leadership role for Physician Clinical Nutrition Specialists in the hospital setting.

Despite extensive research and development of new treatments, acute myeloid leukemia (AML)-backbone therapy has remained essentially unchanged over the last decades and is frequently associated with poor outcomes. Eradicating the leukemic stem cells (LSCs) is the ultimate challenge in the treatment of AML. Emerging evidence suggests that AML remodels the bone marrow (BM) niche into a leukemia-permissive microenvironment while suppressing normal hematopoiesis. The mechanism of stromal-mediated protection of leukemic cells in the BM is complex and involves many adhesion molecules, chemokines, and cytokines. Targeting these factors may represent a valuable approach to complement existing therapies and overcome microenvironment-mediated drug resistance. Some strategies for dislodging LSCs and leukemic blasts from their protective niche have already been tested in patients and are in different phases of the process of clinical development. Other strategies, such as targeting the stromal cells remodeling processes, remain at pre-clinical stages. Development of humanized xenograft mouse models, which overcome the mismatch between human leukemia cells and the mouse BM niche, is required to generate physiologically relevant, patient-specific human niches in mice that can be used to unravel the role of human AML microenvironment and to carry out preclinical studies for the development of new targeted therapies.

The successful implementation of chimeric antigen receptor (CAR)-T cell therapy in the clinical context of B cell malignancies has paved the way for further development in the more critical setting of acute myeloid leukemia (AML). Among the potentially targetable AML antigens, CD33 is insofar one of the main validated molecules. Here, we describe the feasibility of engineering cytokine-induced killer (CIK) cells with a CD33.CAR by using the latest optimized version of the non-viral Sleeping Beauty (SB) transposon system "SB100X-pT4." This offers the advantage of improving CAR expression on CIK cells, while reducing the amount of DNA transposase as compared to the previously employed "SB11-pT" version. SB-modified CD33.CAR-CIK cells exhibited significant antileukemic activity invitro and invivo in patient-derived AML xenograft models, reducing AML development when administered as an "early treatment" and delaying AML progression in mice with established disease. Notably, by exploiting an already optimized xenograft chemotherapy model that mimics human induction therapy in mice, we demonstrated for the first time that CD33.CAR-CIK cells are also effective toward chemotherapy resistant/residual AML cells, further supporting its future clinical development and implementation within the current standard regimens.

Mesenchymal stromal cells (MSCs) represent an essential component of the bone marrow (BM) niche and display disease-specific alterations in several myeloid malignancies. The aim of this work was to study possible MSC abnormalities in Philadelphia-negative myeloproliferative neoplasms (MPNs) in relationship to the degree of BM fibrosis. MSCs were isolated from BM of 6 healthy donors (HD) and of 23 MPN patients, classified in 3 groups according to the diagnosis and the grade of BM fibrosis: polycythemia vera and essential thrombocythemia (PV/ET), low fibrosis myelofibrosis (LF-MF), and high fibrosis MF (HF-MF). MSC cultures were established from 21 of 23 MPN patients. MPN-derived MSCs did not exhibit any functional impairment in their adipogenic/osteogenic/chondrogenic differentiation potential and displayed a phenotype similar to HD-derived MSCs but with a decreased expression of CD146. All MPN-MSC lines were negative for the patient-specific hematopoietic clone mutations (JAK2, MPL, CALR). MSCs derived from HF-MF patients displayed a reduced clonogenic potential and a lower growth kinetic compared to MSCs from HD, LF-MF, and PV/ET patients. mRNA levels of hematopoiesis regulatory molecules were unaffected in MSCs from HF-MF compared to HD. Finally, in vitro ActivinA secretion by MSCs was increased in HF-MF compared to LF-MF patients, in association with a lower hemoglobin value. Increased ActivinA immunolabeling on stromal cells and erythroid precursors was also observed in HF-MF BM biopsies. In conclusion, higher grade of BM fibrosis is associated with functional impairment of MSCs and the increased secretion of ActivinA may represent a suitable target for anemia treatment in MF patients.

Mucopolysaccharidosis type I (MPS-I), a lysosomal storage disorder caused by a deficiency of alpha-L-iduronidase enzyme, results in the progressive accumulation of glycosaminoglycans and consequent multiorgan dysfunction. Despite the effectiveness of hematopoietic stem cell transplantation (HSCT) and enzyme replacement therapy (ERT) in correcting clinical manifestations related to visceral organs, complete improvement of musculoskeletal and neurocognitive defects remains an unmet challenge and provides an impact on patients' quality of life. We tested the therapeutic efficacy of combining HSCT and ERT in the neonatal period. Using a mouse model of MPS-I, we demonstrated that the combination therapy improved clinical manifestations in organs usually refractory to current treatment. Moreover, combination with HSCT prevented the production of anti-IDUA antibodies that negatively impact ERT efficacy. The added benefits of combining both treatments also resulted in a reduction of skeletal anomalies and a trend towards decreased neuroinflammation and metabolic abnormalities. As currently there are limited therapeutic options for MPS-I patients, our findings suggest that the combination of HSCT and ERT during the neonatal period may provide a further step forward in the treatment of this rare disease.

Eradicating the malignant stem cell is the ultimate challenge in the treatment of leukaemia. Leukaemic stem cells (LSC) hijack the normal haemopoietic niche, where they are mainly protected from cytotoxic drugs. The anti-leukaemic effect of L-asparaginase (ASNase) has been extensively investigated in acute lymphoblastic leukaemia, but only partially in acute myeloid leukaemia (AML). We explored the susceptibility of AML-LSC to ASNase as well as the role of the two major cell types that constitute the bone marrow (BM) microenvironment, i.e., mesenchymal stromal cells (MSC) and monocytes/macrophages. Whilst ASNase was effective on both CD34+ CD38+ and CD34+ CD38- LSC fractions, MSC and monocytes/macrophages partially counteracted the effect of the drug. Indeed, the production of cathepsin B, a lysosomal cysteine protease, by BM monocytic cells and by AML cells classified as French-American-British M5 is related to the inactivation of ASNase. Our work demonstrates that, while MSC and monocytes/macrophages may provide a protective niche for AML cells, ASNase has a cytotoxic effect on AML blasts and, importantly, LSC subpopulations. Thus, these features should be considered in the design of future clinical studies aimed at testing ASNase efficacy in AML patients.

Umbilical cord blood (UCB) is a promising source of stem cells to use in early haematopoietic stem cell transplantation (HSCT) approaches for several genetic diseases that can be diagnosed at birth. Mucopolysaccharidosis type I (MPS-I) is a progressive multi-system disorder caused by deficiency of lysosomal enzyme α-L-iduronidase, and patients treated with allogeneic HSCT at the onset have improved outcome, suggesting to administer such therapy as early as possible. Given that the best characterized MPS-I murine model is an immunocompetent mouse, we here developed a transplantation system based on murine UCB. With the final aim of testing the therapeutic efficacy of UCB in MPS-I mice transplanted at birth, we first defined the features of murine UCB cells and demonstrated that they are capable of multi-lineage haematopoietic repopulation of myeloablated adult mice similarly to bone marrow cells. We then assessed the effectiveness of murine UCB cells transplantation in busulfan-conditioned newborn MPS-I mice. Twenty weeks after treatment, iduronidase activity was increased in visceral organs of MPS-I animals, glycosaminoglycans storage was reduced, and skeletal phenotype was ameliorated. This study explores a potential therapy for MPS-I at a very early stage in life and represents a novel model to test UCB-based transplantation approaches for various diseases.

Objective Both observational studies and randomized trials have shown that a diet rich in antioxidants can reduce systemic inflammation and oxidative stress, two conditions that, together with obesity and smoking, are established risk factors for stroke. However, the association between antioxidant intake and risk for stroke is poorly understood, particularly when studying possible interaction with sex. We investigated the relationship of nonenzymatic antioxidant capacity (NEAC) on risk for stroke in a large Swedish prospective cohort. Methods The cohort study included 34 555 men and women from the Swedish National March Cohort. NEAC was assessed using a detailed food frequency questionnaire, collected at baseline. We achieved complete follow-up from enrollment in 1997 through 2010 by record linkage to nationwide registers. We identified 1186 incident cases of a first stroke, of which 860 were ischemic, 201 hemorrhagic, and 125 unspecified. We used multivariable Cox proportional hazards models to estimate adjusted hazard ratios (HR) with 95% confidence intervals (CIs). Results Compared with women in the lowest quartile of NEAC, women in the highest quartile had a 27% lower incidence of total stroke (HR, 0.73; 95% CI, 0.53–0.99; P trend = 0.03) and 35% lower incidence of ischemic stroke (HR, 0.65; 95% CI, 0.43–0.99; P trend = 0.01). Among men, the relationship between NEAC and risk for stroke was not statistically significant and all HRs were close to unity. Conclusion Findings from the present study suggest that dietary antioxidant capacity from different foods and beverages is inversely associated with risk for stroke, more specifically ischemic stroke, in women.

The meadow froghopper, Philaenus spumarius L., is endemic in Italy and was not considered a harmful species until 2014, when the olive quick decline syndrome (OQDS) showed up in Apulia (southern Italy). It was immediately suspected and then verified as the main vector of Xylella fastidiosa, the bacterium responsible for the disease. Currently, EU Directives consider the fight against P. spumarius compulsory in member states and recommend Integrated Pest Management (IPM), both in uncultivated and cultivated infested areas, to minimise the environmental impact of chemical pesticides. This should be based on an improved knowledge of the vector with its seasonal trends and feeding habits linked to specific herbaceous species. In this context, our field study was aimed to improve the understanding of the vector nutritional behaviour, especially at its critical nymph stage, by monitoring its presence on different herbaceous target species, using its typical feeding foams as key indicator. The study area was in Lazio region (central Italy), dedicated to olive growing and still unaffected by the X. fastidiosa plague. Over twoyears, during the nymph development period, field data have been acquired over the test area and then analysed by coupling statistical (ANOVA), geographical information system (GIS) and geo-referenced field sampling approaches. Results highlighted that P. spumarius exhibits significant preferences for specific herbaceous plants, especially at its early development stages, detectable by tenuous spittle. This indicates female oviposition activity, which seems also not influenced by olive tree proximity. Furthermore, the non-host plant species identified here could be suitable for creating green barriers for limiting the vector diffusion to contiguous areas where sensible plantations are growing. In the final section, applied implications arising from the present findings for P. spumarius population management are discussed.

Allogenic hematopoietic stem cell transplantation (HSCT) has proven to be a viable treatment option for a selected group of patients with mucopolysaccharidoses (MPS), including those with MPS types I, II, IVA, VI, and VII. Early diagnosis and timely referral to an expert in MPS are critical, followed by a complete examination and evaluation by a multidisciplinary team, including a transplantation physician. Treatment recommendations for MPS are based on multiple biological, sociological, and financial factors, including type of MPS, clinical severity, prognosis, present clinical signs and symptoms (disease stage), age at onset, rate of progression, family factors and expectations, financial burden, feasibility, availability, risks and benefits of available therapies such as HSCT, enzyme replacement therapy (ERT), surgical interventions, and other supportive care. International collaboration and data review are critical to evaluating the therapeutic efficacy and adverse effects of HSCT for MPS. Collaborative efforts to assess HSCT for MPS have been ongoing since the first attempt at HSCT in a patient with MPS reported in 1981. The accumulation of data since then has made it possible to identify early outcomes (ie, transplantation outcomes) and long-term disease-specific outcomes resulting from HSCT. The recent identification of predictive factors and the development of innovative regimens have significantly improved the outcomes of both engraftment failure and transplantation-related mortality. Assessment of long-term outcomes has considered a variety of factors, including type of MPS, type of graft, age at transplantation, and stage of disease progression, among others. Studies on long-term outcomes are considered a key factor in the use of HSCT in patients with MPS. These studies have shown the effects and limitations of HSCT on improving disease manifestations and quality of life. In this review, we summarize the efficacy, side effects, risks, and cost of HSCT for each type of MPS.

Background: Pancreatic cancer is one of the leading causes of cancer mortality. Diet may be associated with pancreatic cancer, but it is unknown whether specific dietary components contribute to its risk. The potential differential role of dietary antioxidants warrants further investigation. Methods: We analysed data from a case-control study of 326 pancreatic cancer cases and 652 controls conducted between 1991 and 2008 in Northern Italy. Subjects' usual diet was assessed through a validated and reproducible food frequency questionnaire. Using this information and an Italian food composition database, we calculated three indices of dietary total antioxidant capacity (TAC): Trolox equivalent antioxidant capacity (TEAC), total radical-trapping antioxidant parameter (TRAP) and ferric-reducing antioxidant power (FRAP). We estimated the odds ratios (ORs) and 95% confidence intervals (CIs) for pancreatic cancer using multiple logistic regression models conditioned on study centre, sex and age, and adjusted for major known pancreatic cancer risk factors. Results: Significant inverse associations were found for the highest tertile of TAC compared with the lowest tertile for both TEAC and FRAP. The ORs were 0.61 (95% CI 0.39-0.94, P-value for trend 0.03) and 0.63 (95% CI 0.41-0.99, P-value for trend 0.05), respectively. Total radical-trapping antioxidant parameter was inversely, but not significantly, associated with pancreatic cancer risk, with an OR of 0.78 (95% CI 0.49-1.24, P-value for trend 0.27). Conclusions: Diet high in TAC, as measured by TEAC and FRAP, is inversely associated with pancreatic cancer risk. © 2016 Cancer Research UK.

Aging is a risk factor for the development of multiple chronic diseases, including cardiovascular disease, cancer and dementia. Life expectancy has increased in certain countries but this phenomenon is associated with a reduction of years of healthy life. Aging is associated with a number of physical and functional changes, especially sarcopenia. Sarcopenia is a clinical condition associated with a decrease in skeletal muscle and muscle strength, however, sarcopenia is a reversible condition. On the basis of the current scientific literature, sarcopenia could more appropriately capture an individual’s vulnerability to negative health-related outcomes since it represents an early form of the chronic diseases. Recognition of this clinical condition can improve the management of older individuals in many different clinical settings. Despite the limitations of the indirect methods used to study body composition, the Italian College of the Academic Nutritionists ME/49 recommends that health authorities and health professionals around the world should make a greater effort to diagnose sarcopenia earlier and to manage it more effectively. In line with the development of cancer screening, the use of two diagnostic tools for sarcopenia (BIA and DXA) should be implemented.

Objective Consumption of antioxidant-rich foods has been associated with a reduced risk for stroke. However, antioxidant supplementation is not recommended owing to controversial findings reported in clinical trials. The aim of this study was to better understand the effect of dietary antioxidants by investigating the effect of dietary non-enzymatic antioxidant capacity (NEAC), reflecting the antioxidant potential of the whole diet, on the risk for stroke. Methods In the Women's Lifestyle and Health Cohort, 45 882 women 30 to 49 y of age and free from cardiovascular diseases were followed through record linkages from 1991 to 2012. Dietary NEAC was assessed by a validated food frequency questionnaire collected at baseline and categorized into quintiles. Multivariable Cox proportional hazard regression models were fitted to estimate hazard ratios with 95% confidence intervals for overall stroke and ischemic and hemorrhagic stroke separately. Results During a mean follow-up time of 20.2 y, we detected 871 incidence cases of stroke (516 ischemic, 296 hemorrhagic, and 59 unspecified strokes). After adjusting for potential confounders, we did not find any association between dietary NEAC and stroke, either overall, or ischemic or hemorrhagic stroke (Ptrend > 0.05). Conclusion Higher dietary NEAC was not associated with any type of stroke in young and middle-aged Swedish women.

Distant metastases (DM) in head and neck squamous cell carcinoma (HNSCC) remain a challenge as treatment options are limited. To identify biomarkers predictive of DM in primary tumors (PT), gene expression profiling was performed in PT from patients who did, or did not develop DM (T-with and T-without, n = 25 and 24, respectively), and in matched DM. A total of 185 and 42 differentially expressed genes were identified in the T-with vs. T-without and the T-with vs. DM comparisons, respectively. The intersection between these two comparisons identified COX7A1 and TBX5 as common genes. In three independent datasets, both genes were able to significantly distinguish patients according to their DM-free survival. By functional biological analyses, the T-without group showed enrichment in immune-response pathways, whereas the T-with group showed an enrichment in B-plasma cells and Tregs. Increased enrichment of proliferation-related pathways was observed in the T-with group compared with that in the DM group. Further comparisons with/without DM are needed to confirm these data in order to improve clinical management of HNSCC.

Background: Results from randomized trials of antioxidant supplementation have cast doubt on observational data linking diets high in antioxidants to a reduced risk of cardiovascular diseases. We hypothesized that supplementation of one or a few antioxidants might not simulate the complex actions of all antioxidants in the human diet. We therefore investigated the association between dietary Non Enzymatic Antioxidant Capacity (NEAC), reflecting the antioxidant potential of the whole diet, and the risk of myocardial infarction (MI). Methods: In the Swedish National March Cohort, 34 543 men and women free from cardiovascular diseases and cancer were followed through record linkages from 1997 until 2010. NEAC was assessed with a validated food-frequency questionnaire at baseline. The distribution of NEAC was categorized into sex-specific quartiles. We fitted multivariable Cox proportional hazards regression models to estimate hazard ratios (HRs) with 95% confidence intervals (CIs). Results: During a mean follow-up time of 12.7 years, we identified 1142 incident cases of MI. Successively higher quartiles (Qs) of dietary NEAC were accompanied by a monotonic trend of decreasing MI incidence, both for overall MI (HR Q4 vs Q1: 0.77; 95% CI: 0.61–0.96; p for trend ¼ 0.008) and non-fatal MI (HR Q4 vs Q1: 0.72; 95% CI: 0.56–0.92; p for trend ¼ 0.004). No such association was found for fatal MI. Conclusions: A diet rich in antioxidants might protect from MI.

There is still an unmet need for xenotransplantation models that efficiently recapitulate normal and malignant human hematopoiesis. Indeed, there are a number of strategies to generate humanized mice and specific protocols, including techniques to optimize the cytokine environment of recipient mice and drug alternatives or complementary to the standard conditioning regimens, that can be significantly modulated. Unfortunately, the high costs related to the use of sophisticated mouse models may limit the application of these models to studies that require an extensive experimental design. Here, using an affordable and convenient method, we demonstrate that the administration of fludarabine (FludaraTM) promotes the extensive and rapid engraftment of human normal hematopoiesis in immunodeficient mice. Quantification of human CD45+ cells in bone marrow revealed approximately a 102-fold increase in mice conditioned with irradiation plus fludarabine. Engrafted cells in the bone marrow included hematopoietic stem cells, as well as myeloid and lymphoid cells. Moreover, this model proved to be sufficient for robust reconstitution of malignant myeloid hematopoiesis, permitting primary acute myeloid leukemia cells to engraft as early as 8 weeks after the transplant. Overall, these results present a novel and affordable model for engraftment of human normal and malignant hematopoiesis in immunodeficient mice.

Foods rich in antioxidants have been associated with a reduced risk of myocardial infarction. However, findings from randomized clinical trials on the role of antioxidant supplementation remain controversial. It has been suggested that antioxidants interact with each other to promote cardiovascular health. We therefore investigated the association between dietary Non Enzymatic Antioxidant Capacity (NEAC), measuring the total antioxidant potential of the whole diet, and the risk of myocardial infarction. We followed 45,882 women aged 30–49 years and free from cardiovascular diseases through record linkages from 1991 until 2012. Dietary NEAC was assessed by a validated food frequency questionnaire collected at baseline. Total dietary NEAC was categorized into quintiles and multivariable Cox proportional hazard regression models were fitted to estimate hazard ratios (HR) with 95% confidence intervals (CI). During a mean follow-up time of 20.3 years we detected 657 incident cases of myocardial infarction. After adjusting for potential confounders, we found a significant 28% lower risk of myocardial infarction among women in the fourth (HR: 0.72; 95% CI 0.55–0.95) and a 40% lower risk among women in the fifth quintile (HR: 0.60, 95% CI 0.45–0.81) of dietary NEAC compared to women in the first quintile, with a significant trend (p-value

Mucopolysaccharidoses (MPSs) are a group of lysosomal storage disorders (LSDs). The increasing interest in newborn screening procedures for LSDs underlines the need for alternative cellular and gene therapy approaches to be developed during the perinatal period, supporting the treatment of MPS patients before the onset of clinical signs and symptoms. The rationale for considering these early therapies results from the clinical experience in the treatment of MPSs and other genetic disorders. The normal or gene-corrected hematopoiesis transplanted in patients can produce the missing protein at levels sufficient to improve and/or halt the disease-related abnormalities. However, these current therapies are only partially successful, probably due to the limited efficacy of the protein provided through the hematopoiesis. An alternative explanation is that the time at which the cellular or gene therapy procedures are performed could be too late to prevent pre-existing or progressive organ damage. Considering these aspects, in the last several years, novel cellular and gene therapy approaches have been tested in different animal models at birth, a highly early stage, showing that precocious treatment is critical to prevent long-term pathological consequences. This review provides insights into the state-of-art accomplishments made with neonatal cellular and gene-based therapies and the major barriers that need to be overcome before they can be implemented in the medical community.

Purpose: To investigate the role of the overall antioxidant activity of diet, we estimated the relation between three dietary indices of total antioxidant capacity (TAC) and endometrial cancer risk Methods: We analyzed data from an Italian case–control study including 454 women with incident, histologically confirmed endometrial cancer, and 908 frequency-matched controls admitted to the same hospitals as cases for acute non-neoplastic conditions. A reproducible and valid food frequency questionnaire was used to assess subjects’ habitual diet. TAC was measured using Italian food composition tables in terms of Ferric-reducing antioxidant power (FRAP), Trolox equivalent antioxidant capacity (TEAC), and total radical-trapping antioxidant parameter (TRAP). We computed odds ratios (OR) and corresponding 95 % confidence intervals (CIs) using conditional multiple logistic regression models, including terms for recognized endometrial cancer risk factors and total energy intake. Results: TAC was inversely related to endometrial cancer risk with ORs for the highest versus the lowest quartile of 0.69 (95 % CI 0.47–1.00) for FRAP, 0.68 (95 % CI 0.46–0.99) for TEAC, and 0.68 (95 % CI 0.47–0.98) for TRAP. The relations appeared consistent in strata of selected risk factors and decreased when considering TAC without the contribution of coffee. Conclusions: Our findings suggest a favorable role of a diet high in TAC on endometrial cancer risk, which can be partially driven by coffee consumption.

Background Dietary antioxidants may play an important role in the prevention of bone loss and associated fractures by reducing levels of oxidative stress. We prospectively investigated the association between dietary Non Enzymatic Antioxidant Capacity (NEAC) and the risk of hip fracture and whether this effect was modified by smoking. Method In the Swedish National March Cohort 13,409 men and women over the age of 55 who had not experienced cancer, cardiovascular disease or hip fracture, were followed through record-linkages from 1997 through 2010. NEAC was assessed by a validated food frequency questionnaire collected at baseline. We categorized the distribution of NEAC into sex-specific quartiles and used multivariable adjusted Cox proportional hazards regression models to estimate hazard ratios (HRs) with 95% confidence intervals (95% CI). Results During a mean follow-up time of 12.4 years, we identified 491 incident cases of first hip fracture. Subjects in the highest quartile of dietary NEAC had a 39% lower risk of incident hip fracture compared to those in the lowest quartile (HR: 0.61; 95% CI: 0.44–0.85). The association was non-linear (p for non-linearity: 0.004) with a potential threshold between the first and the second quartile and no further risk reduction at higher levels of dietary NEAC. Due to a low smoking prevalence in our study population, we had limited power to detect effect modification between dietary NEAC and smoking on a multiplicative or additive scale. Conclusion Higher dietary NEAC intake is associated with lower risk of hip fracture in the elderly.

Background Consumption of fruit and vegetables has been inversely related to gastric cancer. Two studies found that dietary antioxidant capacity has some role in explaining this association. We investigated the overall antioxidant effect from diet on gastric cancer using three measures of non-enzymatic antioxidant capacity (NEAC). Methods We used data from an Italian case-control study including 230 patients with incident, histologically confirmed gastric cancer, and 547 frequency matched controls admitted to the same hospitals for acute non-neoplastic diseases. A reproducible and valid food frequency questionnaire was used to assess subjects’ usual diet. NEAC was measured using Italian food composition tables in terms of Trolox equivalent antioxidant capacity (TEAC), Ferric reducing-antioxidant power (FRAP) and Total radical-trapping antioxidant parameter (TRAP). We estimated the odds ratios (OR) of gastric cancer and the corresponding 95% confidence intervals (CI) using conditional logistic regression models including terms for recognized gastric cancer risk factors and total energy intake. Results NEAC was inversely related with gastric cancer risk with ORs for the highest versus the lowest quintile of 0.54 (95%CI, 0.33–0.88) for TEAC, 0.67 (95%CI, 0.42–1.07) for FRAP and 0.57 (95%CI, 0.36–0.90) for TRAP. Conclusions A diet rich in antioxidant capacity reduced gastric cancer risk, suggesting a high consumption of fruit and vegetables and a moderate consumption of wine and whole cereals.

Neonatal bone marrow transplantation (nBMT) could offer a novel therapeutic opportunity for genetic disorders by providing sustainable levels of the missing protein at birth, thus preventing tissue damage. We tested this concept in Mucopolysaccharidosis type I (MPS IH, Hurler syndrome), a lysosomal storage disorder caused by deficiency of α-L-iduronidase (IDUA). MPS IH is characterized by a broad spectrum of clinical manifestations including severe progressive skeletal abnormalities. Although BMT increases the life span of MPS IH patients, musculoskeletal manifestations are only minimally responsive if the timing of BMT delays, suggesting already irreversible bone damage. In this study, we tested the hypothesis that transplanting normal bone marrow into newborn MPS I mice, soon after birth, can prevent skeletal dysplasia. 1- to 2-day-old mutant mice were conditioned using a single administration of 20 mg/kg busulfan and then injected via the superficial temporal vein with 2 x 106 bone marrow cells from wild type (WT) donors. Age-matched WT and untreated MPS I mice were used as controls. Transplantation of normal bone marrow cells into preconditioned MPS I and WT neonates led to a similar engraftment level at 37 weeks after nBMT (peripheral blood, median MPS I nBMT 81.30%, range from 0.80% to 95.80% vs. median WT nBMT 67.45%, range from 16.00% to 95.86%, p = 0.714). Spleen, PB and thymus cells of nBMT MPS I mice were repopulated with committed lymphoid and myeloid populations similar to the transplanted WT mice. The >50% replacement of the hematopoiesis resulted in a measurable increase in IDUA activity in visceral organs, especially in the spleen, showing a correlation between engraftment levels and enzyme activity with clearance of GAGs from blood and tissues. At the time of euthanasia (37-week-old), reconstitution of normal hematopoiesis in MPS I mice was associated with a consistent amelioration of bone pathology, as revealed by radiographic skeletal examination. Radiographic analysis has shown that the width of the humerus, radius/ulna, femur and tibia of untreated MPS I mice was significantly larger at comparison with WT littermates. For MPS I nBMT mice, long bone widths, including the humerus (p = 0.0014, vs. untreated MPS I mice), the radius/ulna (p = 0.0003, vs. untreated MPS I mice), the femur (p = 0.0003, vs. untreated MPS I mice), and the tibia (p = 0.0003, vs. untreated MPS I mice) significantly decreased, compared to untreated MPS I mice. Furthermore, several three-dimensional architectural parameters in femurs such as trabecular number and separation, cortical thickness and bone mineral volume were analyzed by micro-CT, resulting in a significant difference between untreated and nBMT MPS I mice. All examined nBMT MPS I mice displayed bone parameter values comparable to WT mice, confirming that nBMT mice had significant improvements in skeletal phenotype approaching complete normalization of each parameter tested. Histologically, in MPS I cortical bone, osteocytes were increased and contained vacuoles, likely reflecting GAGs storage. Histological amelioration of these features was consistently observed in femurs of all nBMT mice with a definite reduction in both hyperosteocytosis and lysosomal vacuolization, confirming that the perinatal treatment of the disease can positively impact the skeletal phenotype in MPS I. We also evaluated KS levels in the blood as a biomarker of MPS with skeletal dysplasia. Normalization of blood KS level strongly supports the notion that nBMT corrects the pathological and clinical bone lesions in nBMT MPS I mice. Our findings demonstrate that nBMT prevents some of the relevant abnormalities of the skeletal pathology in the MPS I mouse model. Moreover, improvements in bone parameters correlated with high levels of bone marrow-derived cell engraftment in multiple hematopoietic compartments, suggesting that the early and complete restoration of normal hematopoiesis can have significant impact on the bone development of newborn MPS I mice. Future clinical trials are needed to confirm our findings. Disclosures No relevant conflicts of interest to declare.

Background and aims Oxidative processes have been related to atherosclerosis, but there is scanty information on the role of dietary antioxidants in the prevention of acute myocardial infarction (AMI). Methods and results The relationship between non-enzymatic antioxidant capacity (NEAC) and the risk of nonfatal AMI was investigated in a case-control study conducted in Milan, Italy, between 1995 and 2003. Cases were 760 patients below 75 years with a first episode of AMI and controls were 682 patients admitted to hospitals for acute conditions, who completed an interviewer-administered food frequency questionnaire, tested for validity and reproducibility. NEAC (excluding coffee) was measured using Italian food composition tables in terms of ferric reducing-antioxidant power (FRAP), Trolox equivalent antioxidant capacity (TEAC) and total radical-trapping antioxidant parameter (TRAP). The odds ratios (OR) of AMI, and the corresponding 95% confidence intervals (CI), were obtained by multiple logistic regression models including terms for main risk factors of AMI and total energy intake. NEAC was inversely related with the risk of AMI. The ORs for the highest quintile compared with the lowest one were 0.41 (95% CI, 0.27–0.63) for FRAP, 0.42 (95% CI, 0.27–0.65) for TEAC and 0.41 (95% CI, 0.27–0.62) for TRAP, with significant trends in risk. The inverse relationship was apparently stronger in women and in subjects aged ≥60 years. Conclusions Our results support a favorable role of dietary NEAC in the prevention of AMI, and encourage a high consumption of fruit and vegetables and a moderate consumption of wine and whole cereals.

Shwachman-Diamond syndrome (SDS) is a rare inherited disorder characterized by bone marrow (BM) dysfunction and exocrine pancreatic insufficiency. SDS patients have an increased risk for myelodisplastic syndrome and acute myeloid leukemia. Mesenchymal stem cells (MSCs) are the key component of the hematopoietic microenvironment and are relevant in inducing genetic mutations leading to leukemia. However, their role in SDS is still unexplored. We demonstrated that morphology, growth kinetics and expression of surface markers of MSCs from SDS patients (SDS-MSCs) were similar to normal MSCs. Moreover, SDS-MSCs were able to differentiate into mesengenic lineages and to inhibit the proliferation of mitogen-activated lymphocytes. We demonstrated in an in vitro coculture system that SDS-MSCs, significantly inhibited neutrophil apoptosis probably through interleukin-6 production. In a long-term coculture with CD34+-sorted cells, SDS-MSCs were able to sustain CD34+ cells survival and to preserve their stemness. Finally, SDS-MSCs had normal karyotype and did not show any chromosomal abnormality observed in the hematological components of the BM of SDS patients. Despite their pivotal role in the hematopoietic stem cell niche, our data suggest that MSC themselves do not seem to be responsible for the hematological defects typical of SDS patients. © 2012 Macmillan Publishers Limited All rights reserved.

Background: To study the impact of the dietary antioxidant quercetin on risk of gastric adenocarcinoma. Patients and methods: Using data from a large Swedish population-based case-control study of gastric cancer (505 cases and 1116 controls), we studied the association between quercetin and risk of anatomic (cardia/noncardia) and histological (intestinal and diffuse) subtypes of gastric cancer. Results: We found strong inverse associations between quercetin and the risk of noncardia gastric adenocarcinoma, with an adjusted odds ratio (OR) of 0.57 (95% confidence interval 0.40-0.83) for the highest quintile (≥11.9 mg) of daily quercetin intake relative to the lowest quintile of intake (

Background & Aims: Dietary antioxidants, with additive and synergistic effects, can mediate the observed inverse association between plant food intake and risk of gastric cancer. We investigated whether the total dietary antioxidant potential of fruit and vegetables is an appropriate means of estimating the antioxidant impact on gastric cancer risk in a large population-based study. Methods: With a population-based case-control design, data were collected through face-to-face interviews with 505 newly diagnosed gastric adenocarcinoma patients and 1116 control subjects to assess dietary habits 20 years before interview. The total radical-trapping antioxidant potential (TRAP) of different plant foods was used to convert food frequency intake into antioxidant potential. Gastric cancer risk in groups exposed to higher levels of oxidative stress (smoking and Helicobacter pylori infection) was also examined. Results: Intake of antioxidant equivalents was inversely associated with the risk of both cardia and distal gastric cancer (odds ratio [OR], 0.65; 95% confidence interval [CI], 0.48–0.89 for the highest quartile of TRAP). Controlling for smoking, the inverse relationship between TRAP values displayed a clearer dose-response pattern. Never-smokers with the highest antioxidant intake had the lowest risk of cancer, 0.44 (95% CI, 0.27–0.71). Among H. pylori –infected subjects, the ORs varied between 0.66 and 0.41 for increasing levels of antioxidant potential. Conclusions: Our results suggest that dietary intake of antioxidants measured as total antioxidant potential is inversely associated with risk of both cardia and distal cancer. The innovative approach used in this study provides a new tool for investigating the relationship between dietary antioxidants and oxidative stress-related carcinogenesis. GASTROENTEROLOGY 2002;123:985-991