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Frontotemporal dementia (FTD) includes a number of neurodegenerative diseases, often with early onset (before 65 years old), characterized by progressive, irreversible deficits in behavioral, linguistic, and executive functions, which are often difficult to diagnose due to their similar phenotypic characteristics to other dementias and psychiatric disorders. The genetic contribution is of utmost importance, although environmental risk factors also play a role in its pathophysiology. In fact, some metals are known to produce free radicals, which, accumulating in the brain over time, can induce oxidative stress, inflammation, and protein misfolding, all of these being key features of FTD and similar conditions. Therefore, the present review aims to summarize the current evidence about the environmental contribution to FTD―mainly dealing with toxic metal exposure―since the identification of such potential environmental risk factors can lead to its early diagnosis and the promotion of policies and interventions. This would allow us, by reducing exposure to these pollutants, to potentially affect society at large in a positive manner, decreasing the burden of FTD and similar conditions on affected individuals and society overall. Future perspectives, including the application of Artificial Intelligence principles to the field, with related evidence found so far, are also introduced.

Autoimmune thyroid diseases (AITD) are among the most frequent autoimmune disorders, with a multifactorial etiology in which both genetic and environmental determinants are probably involved. Celiac disease (CeD) also represents a public concern, given its increasing prevalence due to the recent improvement of screening programs, leading to the detection of silent subtypes. The two conditions may be closely associated due to common risk factors, including genetic setting, changes in the composition and diversity of the gut microbiota, and deficiency of nutrients like vitamin D. This comprehensive review discussed the current evidence on the pivotal role of vitamin D in modulating both gut microbiota dysbiosis and immune system dysfunction, shedding light on the possible relevance of an adequate intake of this nutrient in the primary prevention of AITD and CeD. While future technology-based strategies for proper vitamin D supplementation could be attractive in the context of personalized medicine, several issues remain to be defined, including standardized assays for vitamin D determination, timely recommendations on vitamin D intake for immune system functioning, and longitudinal studies and randomized controlled trials to definitely establish a causal relationship between serum vitamin D levels and the onset of AITD and CeD.

This population-based study aimed to assess the prevalence of congenital hypothyroidism (CH) and overt hypothyroidism (OH) and their association with congenital heart defects (CHDs) in patients with Down syndrome (DS). The population included all live births residing in Tuscany (Italy) diagnosed with DS recorded in the Registry of Congenital Defects and in the Registry of Rare Diseases of Tuscany in the years 2003–2017. The prevalence of CH and OH in DS patients was calculated by sex and by period. The association of CH and OH with CHDs in DS patients was assessed using multivariate logistic regression. The cohort included 228 subjects. The prevalence of CH and OH was 11.4% (95%CI: 7.4–16.7%) and 12.7% (95%CI: 8.5–12.3%), respectively, with no significant difference by sex. A significant increase in the prevalence of CH (p < 0.0001) was found in the years 2010–2017 compared to the previous period, and among preterm infants (p = 0.009). The presence of CH was associated with a higher prevalence of CHDs (adjusted OR = 2.24, p = 0.082). A significant association between ventricular septal defects (VSDs) and the occurrence of OH (adjusted OR = 3.07, p = 0.025) was also observed. This study confirmed the higher prevalence of both CH and OH in DS compared to the general population. Furthermore, the risk of association between DS and CHDs was higher in the presence of CH, while VSDs are associated with OH, providing relevant insights into the epidemiology of hypothyroidism in DS and associated anomalies.

Novel treatments in gastrointestinal stromal tumors (GISTs) are essential due to imatinib resistance and the modest results obtained with multi-target tyrosine kinase inhibitors. We investigated the possibility that the hydroalcoholic extract from the leaves of Arbutus unedo L. (AUN) could harbor novel chemotherapeutics. The bio-guided fractionation of AUN led to a subfraction, FR2-A, that affected the viability of both imatinib-sensitive and -resistant GIST cells. Cells treated with FR2-A were positive for Annexin V staining, a marker of apoptosis. A rapid PARP-1 downregulation was observed, although without the traditional caspase-dependent cleavage. The fractionation of FR2-A produced nine further active subfractions (FRs), indicating that different molecules contributed to the effect promoted by FR2-A. NMR analysis revealed that pyrogallol-bearing compounds, such as gallic acid, gallic acid hexoside, gallocatechin, myricetin hexoside, and trigalloyl-glucose, are the main components of active FRs. Notably, FRs similarly impaired the viability of GIST cells and peripheral blood mononuclear cells (PBMCs), suggesting a non-specific mechanism of action. Nevertheless, despite the lack of specificity, the established FRs showed promising chemotherapeutic properties to broadly affect the viability of GIST cells, including those that are imatinib-resistant, encouraging further studies to investigate whether pyrogallol-bearing compounds could represent an alternative avenue in GISTs.

Introduction Prevention of cardiovascular disease (CVD) is of key importance in reducing morbidity, disability and mortality worldwide. Observational studies suggest that digital health interventions can be an effective strategy to reduce cardiovascular (CV) risk. However, evidence from large randomised clinical trials is lacking.Methods and analysis The CV-PREVITAL study is a multicentre, prospective, randomised, controlled, open-label interventional trial designed to compare the effectiveness of an educational and motivational mobile health (mHealth) intervention versus usual care in reducing CV risk. The intervention aims at improving diet, physical activity, sleep quality, psycho-behavioural aspects, as well as promoting smoking cessation and adherence to pharmacological treatment for CV risk factors. The trial aims to enrol approximately 80 000 subjects without overt CVDs referring to general practitioners’ offices, community pharmacies or clinics of Scientific Institute for Research, Hospitalization and Health Care (Italian acronym IRCCS) affiliated with the Italian Cardiology Network. All participants are evaluated at baseline and after 12 months to assess the effectiveness of the intervention on short-term endpoints, namely improvement in CV risk score and reduction of major CV risk factors. Beyond the funded life of the study, a long-term (7 years) follow-up is also planned to assess the effectiveness of the intervention on the incidence of major adverse CV events. A series of ancillary studies designed to evaluate the effect of the mHealth intervention on additional risk biomarkers are also performed.Ethics and dissemination This study received ethics approval from the ethics committee of the coordinating centre (Monzino Cardiology Center; R1256/20-CCM 1319) and from all other relevant IRBs and ethics committees. Findings are disseminated through scientific meetings and peer-reviewed journals and via social media. Partners are informed about the study’s course and findings through regular meetings.Trial registration number NCT05339841.

Medulloblastoma (MB) is a highly malignant childhood tumor of the cerebellum. Transcriptional and epigenetic signatures have classified MB into four molecular subgroups, further stratified into biologically different subtypes with distinct somatic copy-number aberrations, driver genes, epigenetic alterations, activated pathways, and clinical outcomes. The brain tumor microenvironment (BTME) is of importance to regulate a complex network of cells, including immune cells, involved in cancer progression in brain malignancies. MB was considered with a “cold” immunophenotype due to the low influx of immune cells across the blood brain barrier (BBB). Recently, this assumption has been reconsidered because of the identification of infiltrating immune cells showing immunosuppressive phenotypes in the BTME of MB tumors. Here, we are providing a comprehensive overview of the current status of epigenetics alterations occurring during cancer progression with a description of the genomic landscape of MB by focusing on immune cells within the BTME. We further describe how new immunotherapeutic approaches could influence concurring epigenetic mechanisms of the immunosuppressive cells in BTME. In conclusion, the modulation of these molecular genetic complexes in BTME during cancer progression might enhance the therapeutic benefit, thus firing new weapons to fight MB.

Thyroid cancer (TC), the most frequent malignancy of the endocrine system, has recorded an increasing incidence in the last decades. The etiology of TC remains at least partly unknown and, among modifiable risk factors, the gut microbiota and dietary nutrients (vitamins, essential microelements, polyphenols, probiotics) have been recognized to not only influence thyroid function, but exert critical effects on TC development and progression. Recent discoveries on the existence of tumor microbiota also in the TC microenvironment provide further evidence for the essential role of tumor microorganisms in TC etiology and severity, as well as acting as prognostic markers and as a potential target of adjuvant care in the treatment of TC patients. Therefore, in this review, we summarize current knowledge on the relationship of the tumor microbiome with the clinical tumor characteristics and TC progression, also illustrating the molecular mechanisms underlying this association, and how antioxidant nutrients may be used as a novel strategy to both control gut health and reduce the risk for TC. Furthermore, we discuss how new technologies might be exploited for the development of new foods with high nutritional values, antioxidant capability, and even attractiveness to the individual in terms of sensory and emotional features.

8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG) is considered to be a premutagenic DNA lesion generated by 2'-deoxyguanosine (dG) oxidation due to reactive oxygen species (ROS). In recent years, the 8-oxodG distribution in human, mouse, and yeast genomes has been underlined using various next-generation sequencing (NGS)–based strategies. The present study reports the OxiDIP-Seq protocol, which combines specific 8-oxodG immuno-precipitation of single-stranded DNA with NGS, and the pipeline analysis that allows the genome-wide 8-oxodG distribution in mammalian cells. The development of this OxiDIP-Seq method increases knowledge on the oxidative DNA damage/repair field, providing a high-resolution map of 8-oxodG in human cells.

Abstract Background Rare diseases (RDs) encompass a heterogeneous group of life-threatening or chronically debilitating conditions that individually affect a small number of subjects but overall represent a major public health issue globally. There are still limited data on RD burden due to the paucity of large population-based epidemiological studies. The aim of this research was to provide survival estimates of patients with a RD residing in Tuscany, Italy. Methods Cases collected in the Rare Diseases Registry of Tuscany with diagnosis between 1st January 2000 and 31th December 2018 were linked to the regional health databases in order to retrieve information on mortality of all subjects. Survival at 1, 5 and 10 years from diagnosis with 95% confidence intervals (CI) was estimated by sex, age class, nosological group and subgroup using the Kaplan–Meier method. The effect of sex, age and period of diagnosis (years 2000–2009 or 2010–2018) on survival was estimated using Cox proportional hazards regression. Results Survival at 1, 5 and 10 years from diagnosis was 97.3%, 88.8% and 80.8%, respectively. Respiratory diseases and peripheral and central nervous system disorders were characterized by the lowest survival at 5 and 10 years. Despite a modest higher prevalence of RDs among females (54.0% of the total), male cases had a significant increased risk of death (hazard ratio, HR 1.48, 95% CI 1.38–1.58). Cases diagnosed during 2010–2018 period had a risk of death significantly lower than those diagnosed during 2000–2009 (HR 0.81, 95% CI 0.82–0.96), especially for immune system disorders (HR 0.48, 95% CI 0.26–0.87), circulatory system diseases (HR 0.61, 95% CI 0.45–0.84) and diseases of the musculoskeletal system and connective tissue (HR 0.64, 95% CI 0.49–0.84). Conclusions An earlier diagnosis as well as the improvement in the efficacy of treatment resulted in a decreased risk of death over the years for specific RDs. The linkage between a population-based registry and other regional databases exploited in this study provides a large and accurate mass of data capable of estimating patients’ life-expectancy and increasing knowledge on the collective burden of RDs.

Cervical cancer is a common female cancer, with nearly 600,000 cases and more than 300,000 deaths worldwide every year. From a clinical point of view, surgery plays a key role in early cancer management, whereas advanced stages are treated with chemotherapy and/or radiation as adjuvant therapies. Nevertheless, predicting the degree of cancer response to chemotherapy or radiation therapy at diagnosis in order to personalize the clinical approach represents the biggest challenge in locally advanced cancers. The feasibility of such predictive models has been repeatedly assessed using histopathological factors, imaging and nuclear methods, tissue and fluid scans, however with poor results. In this context, the identification of novel potential biomarkers remains an unmet clinical need, and microRNAs (miRNAs) represent an interesting opportunity. With this in mind, the aim of this systematic review was to map the current literature on tumor and circulating miRNAs identified as significantly associated with the therapeutic response in cervical cancer; finally, a perspective point of view sheds light on the challenges ahead in this tumor.Systematic Review RegistrationPROSPERO (CRD42021277980).

Background: Orphan drugs are used for the diagnosis, prevention and treatment of rare diseases that, in the European Union, are defined as disorders affecting no more than 5 persons in 10,000. So far, a total of around 800 orphan medicinal products have been approved by the European Medicines Agency, however the utilization profile of orphan drugs has yet to be explored. This study aimed at assessing the utilization profile of orphan drugs authorized for marketing by the Italian Medicines Agency using population-based data.Methods: A total of 21 orphan drugs used in outpatient settings, approved in the European Union before or during the 2008–2018 period and involving 15 rare diseases, were included in the study. The monitored population included patients with one of the conditions surveilled by the population-based Tuscany Registry of Rare Diseases and diagnosed between 2000–2018. A multi-database approach was applied, by linking data from the registry with information collected in drug prescriptions databases. The prevalence and intensity of use were estimated for the selected orphan drugs and other non-orphan medications, used to treat the same rare disease and for which a change in the prevalence of use was hypothesized after authorization of the orphan drug.Results: For some diseases (acquired aplastic anemia, tuberous sclerosis complex, most metabolic diseases) a low prevalence of orphan drugs use was observed (range between 1.1–12.5%). Conversely, orphan drugs were frequently used in hemophilia B, Wilson disease and idiopathic pulmonary fibrosis (maximum of 78.3, 47.6 and 41.8%, respectively). For hemophilia B and Leber’s hereditary optic neuropathy, there are currently no other medications used in clinical practice in addition to orphan drugs. Six orphan drugs were used for the treatment of pulmonary arterial hypertension, appearing the elective therapy for this disease, albeit with different utilization profiles (range of prevalence 1.7–55.6%).Conclusion: To the best of our knowledge, this is the first study investigating the utilization profile of orphan drugs prescribed in a defined geographical area, and providing relevant information to monitor over time potential changes in the prevalence of these medications as well as in the health care decision making.

Beyond its key role in calcium homeostasis, vitamin D has been found to significantly affect the cardiovascular (CV) system. In fact, low vitamin D levels have been associated with increased CV risk, as well as increased CV morbidity and mortality. The majority of effects of this molecule are related directly or indirectly to its antioxidative and anti-inflammatory properties. Generally, vitamin D insufficiency is considered for 25-hydroxyvitamin D (25(OH)D) levels between 21–29 ng/mL (corresponding to 52.5–72.5 nmol/L), deficiency as 25(OH)D levels less than 20 ng/mL (

The guanine base in nucleic acids is, among the other bases, the most susceptible to being converted into 8-Oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG) when exposed to reactive oxygen species. In double-helix DNA, 8-oxodG can pair with adenine; hence, it may cause a G > T (C > A) mutation; it is frequently referred to as a form of DNA damage and promptly corrected by DNA repair mechanisms. Moreover, 8-oxodG has recently been redefined as an epigenetic factor that impacts transcriptional regulatory elements and other epigenetic modifications. It has been proposed that 8-oxodG exerts epigenetic control through interplay with the G-quadruplex (G4), a non-canonical DNA structure, in transcription regulatory regions. In this review, we focused on the epigenetic roles of 8-oxodG and the G4 and explored their interplay at the genomic level.

Lipoprotein(a)-Lp(a), which retains proatherogenic and prothrombotic properties, may be modified by hormonal and metabolic factors. However, few studies have focused on differences related to sex and cardiometabolic risk factors in the relationship between Lp(a) and cardiovascular disease, especially in terms of prognosis. This study aimed at evaluating the predictive value of Lp(a) (cut-off 30 mg/dL) for hard events (HEs: mortality and non-fatal myocardial infarction) according to sex and cardiometabolic risk factors in 2110 patients (1501 males, mean age: 68 ± 9 years) undergoing coronary angiography for known or suspected coronary artery disease. There were 211 events over a median follow-up period of 33 months. Lp(a) > 30 mg/dL did not confer a worse prognosis on the overall population. However, Kaplan–Meier subgroup analysis evidenced a worse prognosis in type 2 diabetes (T2D) females with elevated Lp(a) (log-rank test: p = 0.03) vs. T2D males and no-T2D patients, but not in other high-risk cardiovascular states (e.g., smoking, hypertension, reduced left ventricular ejection fraction or obesity). After Cox multivariate adjustment, Lp(a) remained an independent determinant for HEs in the T2D female subgroup, conferring an HR of 2.9 (95% CI 1.1–7.7, p < 0.05). Lp(a) is therefore a strong independent predictor of HR in T2D women, but not in T2D men, or in noT2D patients.

Nonalcoholic fatty liver disease (NAFLD)-associated liver fibrosis is likely related to coronary artery disease (CAD) by the mediation of systemic inflammation. This study aimed at evaluating the predictive value of neutrophil-to-lymphocyte-ratio (NLR) and fibrosis-4 index (FIB-4), indices of inflammation and fibrosis, respectively, on CAD mortality. Data from 1460 CAD patients (1151 males, age: 68 ± 10 years, mean ± SD) were retrospectively analyzed. Over a median follow-up of 26 months (interquartile range (IQR) 12–45), 94 deaths were recorded. Kaplan–Meier survival analysis revealed worse outcomes in patients with elevation of one or both biomarkers (FIB-4 > 3.25 or/and NLR > 2.04, log-rank p-value < 0.001). In multivariate Cox regression analysis, the elevation of one biomarker (NLR or FIB-4) still confers a significant independent risk for mortality (hazard ratio (HR) = 1.7, 95% confidence interval (95% CI): 1.1–2.7, p = 0.023), whereas an increase in both biomarkers confers a risk corresponding to HR = 3.5 (95% CI: 1.6–7.8, p = 0.002). Categorization of patients with elevated FIB-4/NLR could provide valuable information for risk stratification and reduction of residual risk in CAD patients.

The role of lipids is essential in any phase of the atherosclerotic process, which is considered a chronic lipid-related and inflammatory condition. The traditional lipid profile (including the evaluation of total cholesterol, triglycerides, high-density lipoprotein, and low-density lipoprotein) is a well-established tool to assess the risk of atherosclerosis and as such has been widely used as a pillar of cardiovascular disease prevention and as a target of pharmacological treatments in clinical practice over the last decades. However, other non-traditional lipids have emerged as possible alternative predictors of cardiometabolic risk in addition to traditional single or panel lipids, as they better reflect the overall interaction between lipid/lipoprotein fractions. Therefore, this review deals with the lipid involvement characterizing the pathophysiology of atherosclerosis, discussing some recently proposed non-traditional lipid indices and, in the light of available knowledge, their actual potential as new additive tools to better stratify cardiovascular risk in patients with hyperlipidemia as well as possible therapeutic targets in the clinical practice.

IntroductionThe Cancer Genome Atlas (TCGA) project identified four distinct prognostic groups in endometrial cancer (EC), among which two are correlated with an intermediate prognosis: the MisMatch Repair-deficient (MMRd) and the No Specific Molecular Profile (NSMP) groups. The two groups represent a heterogeneous subset of patients frequently harboring CTNNB1 alterations with distinctive clinicopathologic features. The study aimed to evaluate the miRNA expression in ECs to identify potential biomarkers of prognosis.MethodsWe analyzed miRNA expression in 72 ECs classified as MMRd or NSMP including 15 ECs with CTNNB1 mutations. In the discovery step, miRNA expression was evaluated in 30 cases through TaqMan miRNA arrays. Subsequently, four miRNAs were validated in the total cohort of ECs. The data were further tested in the TCGA cohort, and correlations with overall survival (OS) and progression-free interval (PFI) were evaluated.ResultsmiR-499a-3p and miR-499a-5p resulted to be overexpressed in CTNNB1 mutant EC patients at intermediate risk. Similarly, in the TCGA cohort, miR-499a-3p and miR-499a-5p were differentially expressed between CTNNB1 mutant and wild-type patients (p < 0.0001). NSMP patients with low miR-499a-5p expression showed longer OS (p = 0.03, log-rank test). By combining miR-499a-3p or -5p expression levels with the CTNNB1 status, ECs with CTNNB1 mutation and lower miR-499a-5p expression showed better OS compared with the other subgroups (p = 0.03, log-rank test), among the NSMP patients. Moreover, in a multivariate analysis, combination of wild type CTNNB1 status and high miR-499a-5p expression was indipendently associated with high risk of death [HR (95%CI): 3.53 (1.1-10.5), p = 0.02].ConclusionOur results suggest that the combination of CTNNB1 status and miR-499a-5p allows a better stratification of NSMP patients and could promote a personalization of the treatment in intermediate-risk patients.

Gastrointestinal stromal tumors (GISTs) harboring mutations in the PDGFRA gene occur in only about 5–7% of patients. The most common PDGFRA mutation is exon 18 D842V, which is correlated with specific clinico-pathological features compared to the other PDGFRA mutated GISTs. Herein, we present a miRNA expression profile comparison of PDGFRA D842V mutant GISTs and PDGFRA with mutations other than D842V (non-D842V). miRNA expression profiling was carried out on 10 patients using a TLDA miRNA array. Then, miRNA expression was followed by bioinformatic analysis aimed at evaluating differential expression, pathway enrichment, and miRNA-mRNA networks. We highlighted 24 differentially expressed miRNAs between D842V and non-D842V GIST patients. Pathway enrichment analysis showed that deregulated miRNAs targeted genes that are mainly involved in the immune response pathways. The miRNA-mRNA networks highlighted a signature of miRNAs/mRNA that could explain the indolent behavior of the D842V mutated GIST. The results highlighted a different miRNA fingerprint in PDGFRA D842V GISTs compared to non-D842Vmutated patients, which could explain the different biological behavior of this GIST subset.

Type 2 diabetes (T2D) is considered one of the largest global public-health concerns, affecting approximately more than 400 million individuals worldwide. The pathogenesis of T2D is very complex and, among the modifiable risk factors, selenium (Se) has recently emerged as a determinant of T2D pathogenesis and progression. Selenium is considered an essential element with antioxidant properties, and is incorporated into the selenoproteins involved in the antioxidant response. Furthermore, deiodinases, the enzymes responsible for homeostasis and for controlling the activity of thyroid hormones (THs), contain Se. Given the crucial action of oxidative stress in the onset of insulin resistance (IR) and T2D, and the close connection between THs and glucose metabolism, Se may be involved in these fundamental relationships; it may cover a dual role, both as a protective factor and as a risk factor of T2D, depending on its basal plasma concentration and the individual’s diet intake. In this review we discuss the current evidence (from experimental, observational and randomized clinical studies) on how Se is associated with the occurrence of T2D and its influence on the relationship between thyroid pathophysiology, IR and T2D.

COVID-19 has overwhelmed healthcare systems and increased workload and distress in healthcare professionals (HCPs). The objective of this study was to evaluate baseline distress before and after the pandemic, and the effect of Mindfulness-Based Stress Reduction (MBSR) training on well-being (PGWBI), stress (PSS) and burnout (MBI) in Italian HCPs. Moreover, the “fear of COVID-19” (FCV-19S) questionnaire was administered to HCPs participating in the post-emergency MBSR program. Baseline distress results were moderate in all groups. No differences between baseline distress were observed between the groups of HCPs beginning the MBSR courses in the pre or post pandemic period. Total PGWBI lowered with aging. Additionally, FCV-19S positively correlated with age. MBSR was able to lower distress levels, except for depersonalization, which increased, while emotional exhaustion decreased in the group enrolled in the last post-pandemic MBSR course. Levels of fear of COVID-19 in HCPs significantly decreased after MBSR training. The lack of change in baseline distress over time indicates that it is more influenced by work-related distress than by the pandemic in our HCPs. In view of its beneficial effects on psycho-emotional status, MBSR training may represent an effective strategy to reduce distress in emergency periods as well as an essential part of HCPs’ general training.

Introduction Environmental pollution has been progressively becoming one of the main risk factors to human diseases. In particular, populations living in high-contaminated sites are particularly exposed to environmental toxicants, with consequent increased risks to human health. In Italy, there are currently ongoing three epidemiological etiological studies aimed at evaluating the association between exposure to inorganic and organic chemicals and presence of biological markers of early effects in population living in three National Priority Contaminated Sites (NPCSs). Specifically, the correlations concern preclinical indicators of liver disease in Priolo NPCS, thyroid diseases in Milazzo-Valle del Mela NPCS and cardiovascular risk and kidney damage in Crotone NPCS.Methods and analysis Overall, approximately 1300 subjects of both sexes will be enrolled in the three NPCSs according to specific inclusion criteria. For each subject, serum and urine specimens are collected, on which the determination of biological markers of exposure and early effects for the selected outcomes are performed. Individual information on environmental and occupational exposure, medical history, diet and life habits is obtained through questionnaires provided by web platform. In Milazzo-Valle del Mela and Crotone NPCSs, not invasive instrumental and imaging examinations are performed in order to evaluate further risk factors of thyroid carcinoma and cardiovascular disease, respectively.Ethics and dissemination The protocol studies have been approved by the Ethics Committees responsible for the three involved NPCSs: the Ethics Committee ‘Catania 2’ for the NPCS of Priolo (21 July 2017, n. 500/2017/CECT2), the Ethics Committee of the University Hospitals of Messina for the NPCS of Milazzo-Valle del Mela (19 February 2018, n.2/2018); the Ethics Committee of the Region of Calabria for the NPCS of Crotone (20 July 2017, n. 174). Results will be disseminated among policy-makers, citizens, stakeholders and scientific community through the organisation of conferences and events, and the publication on international peer/reviewed journals.

Summary: Heterotypic cellular and molecular interactions in the tumor microenvironment (TME) control cancer progression. Here, we show that CD1d-restricted invariant natural killer (iNKT) cells control prostate cancer (PCa) progression by sculpting the TME. In a mouse PCa model, iNKT cells restrained the pro-angiogenic and immunosuppressive capabilities of tumor-infiltrating immune cells by reducing pro-angiogenic TIE2+, M2-like macrophages (TEMs), and sustaining pro-inflammatory M1-like macrophages. iNKT cells directly contacted macrophages in the PCa stroma, and iNKT cell transfer into tumor-bearing mice abated TEMs, delaying tumor progression. iNKT cells modulated macrophages through the cooperative engagement of CD1d, Fas, and CD40, which promoted selective killing of M2-like and survival of M1-like macrophages. Human PCa aggressiveness associate with reduced intra-tumoral iNKT cells, increased TEMs, and expression of pro-angiogenic genes, underscoring the clinical significance of this crosstalk. Therefore, iNKT cells may control PCa through mechanisms involving differential macrophage modulation, which may be harnessed for therapeutically reprogramming the TME. : Cortesi et al. provide evidence that iNKT cells contribute to cancer immune surveillance. Due to differential tuning of tumor-associated macrophage populations, iNKT cells remodel the microenvironment of prostate cancer, enforcing a tumor-opposing state that controls tumor progression. Keywords: iNKT cells, CD1d, macrophage, tumor microenvironment, prostate cancer, immunotherapy, CD40, Fas, angiogenesis

Selenium (Se), a microelement essential for life, is critical for homeostasis of several critical functions, such as those related to immune–endocrine function and signaling transduction pathways. In particular, Se is critical for the function of the thyroid, and it is particularly abundant in this gland. Unfortunately, Se deficiency is a very common condition worldwide. Supplementation is possible, but as Se has a narrow safety level, toxic levels are close to those normally required for a correct need. Thus, whether the obtaining of optimal selenium concentration is desirable, the risk of dangerous concentrations must be equally excluded. This review addressed the contribution by environment and food intake on Se circulating levels (e.g., geographical factors, such as soil concentration and climate, and different quantities in food, such as nuts, cereals, eggs, meat and fish) and effects related to its deficiency or excess, together with the role of selenium and selenoproteins in the thyroid pathophysiology (e.g., Hashimoto’s thyroiditis and Graves’ disease).

Epithelial ovarian cancer (EOC) is one of the most lethal cancers worldwide, mostly due to nonspecific symptoms and a lack of screening tests, which, taken together, contribute to delayed diagnosis and treatment. The current clinical biomarker is serum CA-125, which allows the identification of most advanced primary and relapsed disease and correlates with disease burden; however, as well highlighted in the literature, CA-125 often lacks sensitivity and specificity, and is not helpful in monitoring chemotherapeutic response or in predicting the risk of relapse. Given that, the identification of novel biomarkers able to foster more precise medical approaches and the personalization of patient management represents an unmet clinical requirement. In this context, circulating miRNAs may represent an interesting opportunity as they can be easily detected in all biological fluids. This is particularly relevant when looking for non-invasive approaches that can be repeated over time, with no pain and stress for the oncological patient. Given that, the present review aims to describe the circulating miRNAs currently identified as associated with therapeutic treatments in OC and presents a complete overview of the available evidence.

The endothelium controls vascular homeostasis through a delicate balance between secretion of vasodilators and vasoconstrictors. The loss of physiological homeostasis leads to endothelial dysfunction, for which inflammatory events represent critical determinants. In this context, therapeutic approaches targeting inflammation-related vascular injury may help for the treatment of cardiovascular disease and a multitude of other conditions related to endothelium dysfunction, including COVID-19. In recent years, within the complexity of the inflammatory scenario related to loss of vessel integrity, hydrogen sulfide (H2S) has aroused great interest due to its importance in different signaling pathways at the endothelial level. In this review, we discuss the effects of H2S, a molecule which has been reported to demonstrate anti-inflammatory activity, in addition to many other biological functions related to endothelium and sulfur-drugs as new possible therapeutic options in diseases involving vascular pathobiology, such as in SARS-CoV-2 infection.

The incidence and prevalence of type 2 diabetes have increased in the last decades and are expected to further grow in the coming years. Chronic hyperglycemia triggers free radical generation and causes increased oxidative stress, affecting a number of molecular mechanisms and cellular pathways, including the generation of advanced glycation end products, proinflammatory and procoagulant effects, induction of apoptosis, vascular smooth-muscle cell proliferation, endothelial and mitochondrial dysfunction, reduction of nitric oxide release, and activation of protein kinase C. Among type 2 diabetes determinants, many data have documented the adverse effects of environmental factors (e.g., air pollutants) through multiple exposure-induced mechanisms (e.g., systemic inflammation and oxidative stress, hypercoagulability, and endothelial and immune responses). Therefore, here we discuss the role of air pollution in oxidative stress-related damage to glycemic metabolism homeostasis, with a particular focus on its impact on health. In this context, the improvement of new advanced tools (e.g., omic techniques and the study of epigenetic changes) may provide a substantial contribution, helping in the evaluation of the individual in his biological totality, and offer a comprehensive assessment of the molecular, clinical, environmental, and epidemiological aspects.

Studies of alterations in histone methylation in cancer have led to the identification of histone methyltransferases and demethylases as novel targets for therapy. Lysine-specific demethylase 1 (LSD1, also known as KDM1A), demethylates H3K4me1/2, or H3K9me1/2 in a context-dependent manner. In addition to the well-studied role of LSD1 in the epigenetic regulation of histone methylation changes, LSD1 regulates the methylation dynamic of several non-histone proteins and participates in the assembly of different long noncoding RNA (lncRNA_ complexes. LSD1 is highly expressed in various cancers, playing a pivotal role in different cancer-related processes. Here, we summarized recent findings on the role of LSD1 in the regulation of different biological processes in cancer cells through dynamic methylation of non-histone proteins and physical association with dedicated lncRNA.

La comunità scientifica del CNR ha partecipato all’edizione del Festival dedicata alla “bellezza” con mostre, laboratori, conferenze ed eventi speciali.

Tokyo, San Francisco, Los Angeles, Budapest. E ancora, Sofia, Algeri, Tripoli, Toronto, Vancouver e Baghdad. Sono le tappe della mostra realizzata dal CNR in collaborazione con altre istituzioni di ricerca nazionali, che per tutto il 2013 ha esposto in diversi Istituti Italiani di Cultura il meglio della ricerca italiana.

L’edizione 2012 della manifestazione genovese dedicata alla scienza e alla sua divulgazione ha registrato 226.000 visite in undici giorni. Un successo che prelude all’edizione del decennale, in programma dal 23 ottobre al 3 novembre 2013, dedicata al tema della bellezza.

“MateFitness - la palestra della matematica” del CNR, è stato l’unico progetto italiano selezionato nell’ambito delle azioni a sostegno dell’educazione promosse dal gruppo californiano. Il contributo, assegnato a fine 2011, ha permesso di potenziare e diffondere alcune delle sue attività a livello nazionale, a partire da un tour nelle scuole di cinque regioni italiane, che ha coinvolto oltre 4000 studenti.

Questo articolo esce in concomitanza con l’edizione 2011 del Festival della Scienza, manifestazione di cui il CNR è partner e socio fondatore, giunta alla sua nona edizione. Un’edizione difficile, come ha dichiarato alla stampa la sua presidente Manuela Arata, segnata da una importante riduzione di budget. Ma che, nonostante questo, è capace di far diventare ancora una volta Genova capitale mondiale della divulgazione scientifica, con ospiti da tutto il mondo e un programma di assoluto rilievo scientifico, a partire dai nomi di prestigio mondiale provenienti dal Paese ospite per l’edizione in corso: gli Stati Uniti d’America.

Uno sguardo all’edizione 2011 del Festival della Scienza attraverso il grande progetto itinerante promosso congiuntamente dal Cnr e dall’Associazione Festival della Scienza con l’obiettivo di scoprire le eccellenze scientifiche che la ricerca italiana ha prodotto negli ultimi 150 anni: dalle neuroscienze alle frontiere della rete, dalla genetica alla chimica all’agroalimentare…

La ricorrenza dell’anniversario e le celebrazioni dell’Unità d’Italia offrono lo spunto per riflettere e festeggiare anche i 150 anni della ricerca scientifica italiana e i suoi traguardi.

An increasing evidence supports the role of industrial chemicals as contributors to the development of neurobehavioral disorders, including autism spectrum disorders, whose prevalence has progressively increased in recent years. Heavy metals, in particular, are recognized as neurodevelopmental toxins since they can be responsible of fetal damages which lead to neurological defects, developmental delays, learning disabilities and behavioral abnormalities. Most of the reviewed studies reported a relationship between exposure to metals during perinatal and early childhood periods and increased risk for autism. Moreover, the effects resulting from co-exposure to multiple metals should not be underestimated, especially in the assessment of children who live in developing countries or near heavily contaminated sites.