Mechanisms of Oncogene Activation

The main modifications that characterize cancer are represented by alterations in oncogenes, tumor-suppressor genes, and non-coding RNA genes. Most of these alterations are somatic and the process is a multistep one. Tumors often arise from an initial transformed cell, and after subsequent genetic alterations different cytogenetically clones lead to tumor heterogeneity

Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019

Background: In an era of shifting global agendas and expanded emphasis on non-communicable diseases and injuries along with communicable diseases, sound evidence on trends by cause at the national level is essential. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) provides a systematic scientific assessment of published, publicly available, and contributed data on incidence, prevalence, and mortality for a mutually exclusive and collectively exhaustive list of diseases and injuries. Methods: GBD estimates incidence, prevalence, mortality, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life-years (DALYs) due to 369 diseases and injuries, for two sexes, and for 204 countries and territories. Input data were extracted from censuses, household surveys, civil registration and vital statistics, disease registries, health service use, air pollution monitors, satellite imaging, disease notifications, and other sources. Cause-specific death rates and cause fractions were calculated using the Cause of Death Ensemble model and spatiotemporal Gaussian process regression. Cause-specific deaths were adjusted to match the total all-cause deaths calculated as part of the GBD population, fertility, and mortality estimates. Deaths were multiplied by standard life expectancy at each age to calculate YLLs. A Bayesian meta-regression modelling tool, DisMod-MR 2.1, was used to ensure consistency between incidence, prevalence, remission, excess mortality, and cause-specific mortality for most causes. Prevalence estimates were multiplied by disability weights for mutually exclusive sequelae of diseases and injuries to calculate YLDs. We considered results in the context of the Socio-demographic Index (SDI), a composite indicator of income per capita, years of schooling, and fertility rate in females younger than 25 years. Uncertainty intervals (UIs) were generated for every metric using the 25th and 975th ordered 1000 draw values of the posterior distribution. Findings: Global health has steadily improved over the past 30 years as measured by age-standardised DALY rates. After taking into account population growth and ageing, the absolute number of DALYs has remained stable. Since 2010, the pace of decline in global age-standardised DALY rates has accelerated in age groups younger than 50 years compared with the 1990–2010 time period, with the greatest annualised rate of decline occurring in the 0–9-year age group. Six infectious diseases were among the top ten causes of DALYs in children younger than 10 years in 2019: lower respiratory infections (ranked second), diarrhoeal diseases (third), malaria (fifth), meningitis (sixth), whooping cough (ninth), and sexually transmitted infections (which, in this age group, is fully accounted for by congenital syphilis; ranked tenth). In adolescents aged 10–24 years, three injury causes were among the top causes of DALYs: road injuries (ranked first), self-harm (third), and interpersonal violence (fifth). Five of the causes that were in the top ten for ages 10–24 years were also in the top ten in the 25–49-year age group: road injuries (ranked first), HIV/AIDS (second), low back pain (fourth), headache disorders (fifth), and depressive disorders (sixth). In 2019, ischaemic heart disease and stroke were the top-ranked causes of DALYs in both the 50–74-year and 75-years-and-older age groups. Since 1990, there has been a marked shift towards a greater proportion of burden due to YLDs from non-communicable diseases and injuries. In 2019, there were 11 countries where non-communicable disease and injury YLDs constituted more than half of all disease burden. Decreases in age-standardised DALY rates have accelerated over the past decade in countries at the lower end of the SDI range, while improvements have started to stagnate or even reverse in countries with higher SDI. Interpretation: As disability becomes an increasingly large component of disease burden and a larger component of health expenditure, greater research and developm nt investment is needed to identify new, more effective intervention strategies. With a rapidly ageing global population, the demands on health services to deal with disabling outcomes, which increase with age, will require policy makers to anticipate these changes. The mix of universal and more geographically specific influences on health reinforces the need for regular reporting on population health in detail and by underlying cause to help decision makers to identify success stories of disease control to emulate, as well as opportunities to improve. Funding: Bill & Melinda Gates Foundation. © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licens

Global age-sex-specific fertility, mortality, healthy life expectancy (HALE), and population estimates in 204 countries and territories, 1950-2019 : a comprehensive demographic analysis for the Global Burden of Disease Study 2019

Background: Accurate and up-to-date assessment of demographic metrics is crucial for understanding a wide range of social, economic, and public health issues that affect populations worldwide. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 produced updated and comprehensive demographic assessments of the key indicators of fertility, mortality, migration, and population for 204 countries and territories and selected subnational locations from 1950 to 2019. Methods: 8078 country-years of vital registration and sample registration data, 938 surveys, 349 censuses, and 238 other sources were identified and used to estimate age-specific fertility. Spatiotemporal Gaussian process regression (ST-GPR) was used to generate age-specific fertility rates for 5-year age groups between ages 15 and 49 years. With extensions to age groups 10–14 and 50–54 years, the total fertility rate (TFR) was then aggregated using the estimated age-specific fertility between ages 10 and 54 years. 7417 sources were used for under-5 mortality estimation and 7355 for adult mortality. ST-GPR was used to synthesise data sources after correction for known biases. Adult mortality was measured as the probability of death between ages 15 and 60 years based on vital registration, sample registration, and sibling histories, and was also estimated using ST-GPR. HIV-free life tables were then estimated using estimates of under-5 and adult mortality rates using a relational model life table system created for GBD, which closely tracks observed age-specific mortality rates from complete vital registration when available. Independent estimates of HIV-specific mortality generated by an epidemiological analysis of HIV prevalence surveys and antenatal clinic serosurveillance and other sources were incorporated into the estimates in countries with large epidemics. Annual and single-year age estimates of net migration and population for each country and territory were generated using a Bayesian hierarchical cohort component model that analysed estimated age-specific fertility and mortality rates along with 1250 censuses and 747 population registry years. We classified location-years into seven categories on the basis of the natural rate of increase in population (calculated by subtracting the crude death rate from the crude birth rate) and the net migration rate. We computed healthy life expectancy (HALE) using years lived with disability (YLDs) per capita, life tables, and standard demographic methods. Uncertainty was propagated throughout the demographic estimation process, including fertility, mortality, and population, with 1000 draw-level estimates produced for each metric. Findings: The global TFR decreased from 2·72 (95% uncertainty interval [UI] 2·66–2·79) in 2000 to 2·31 (2·17–2·46) in 2019. Global annual livebirths increased from 134·5 million (131·5–137·8) in 2000 to a peak of 139·6 million (133·0–146·9) in 2016. Global livebirths then declined to 135·3 million (127·2–144·1) in 2019. Of the 204 countries and territories included in this study, in 2019, 102 had a TFR lower than 2·1, which is considered a good approximation of replacement-level fertility. All countries in sub-Saharan Africa had TFRs above replacement level in 2019 and accounted for 27·1% (95% UI 26·4–27·8) of global livebirths. Global life expectancy at birth increased from 67·2 years (95% UI 66·8–67·6) in 2000 to 73·5 years (72·8–74·3) in 2019. The total number of deaths increased from 50·7 million (49·5–51·9) in 2000 to 56·5 million (53·7–59·2) in 2019. Under-5 deaths declined from 9·6 million (9·1–10·3) in 2000 to 5·0 million (4·3–6·0) in 2019. Global population increased by 25·7%, from 6·2 billion (6·0–6·3) in 2000 to 7·7 billion (7·5–8·0) in 2019. In 2019, 34 countries had negative natural rates of increase; in 17 of these, the population declined because immigration was not sufficient to counteract the negative rate of decline. Globally, HALE increased from 58·6 years (56·1–60·8) in 2000 to 63·5 years (60·8–66·1) in 2019. HALE increased in 202 of 204 countries and territories between 2000 and 2019

COST Action CA19114, Network for Optimized Astatine labelled Radiopharmaceuticals

Cancer is a major health concerns for European citizens. Thus, the main research aim of this Network for Optimized Astatine labeled Radiopharmaceuticals (NOAR) COST Action is to successfully demonstrate that one of the most promising radionuclides for Targeted Alpha Therapy (TAT), namely astatine-211, can become the European standard for treatment of certain cancerous pathologies. To this end, an efficient networking is essential among all European stakeholders interested in promoting astatine-211 for medical applications. NOAR COST Action brings together European and international excellence labs, astatine-211 production centers, hospitals, industry and patient associations from more than 20 countries, thus covering the whole value chain of innovation: production, chemistry, radiochemistry, biology, preclinical and clinical research and delivery of radiopharmaceuticals to patients. A European web portal will be created containing information for patients, practitioners, researchers, Industry and as a contact point for National and European patient associations. The idea is to gather forces at the European level in order to implement actions to leverage hurdles to the development of this powerful radionuclide and to identify pathologies in which it will be particularly relevant. A special emphasis will be given to train a new generation of young researchers and PhD students, promoting interdisciplinary competencies through international and inter-sectoral mobility. The long-term goal of this project is to make Astatine-211 technology available to all European citizen

THE CYTOTOXIC POTENTIAL EFFECT OF SOME FLAVORING AGENTS ON A MOUSE FIBROBLAST CELL CULTURE

Abstract The study aimed to evaluate the proliferative action and cellular morphology induced by the following food flavoring agents: (±) -limonene p-methyl-1,8-diene (orange flavoring substance) and (±) -3,7-dimethyl-6-octenal (lemon flavoring substance) in cell cultures.The tests were performed on normal proliferating adherent cells from the 3T3 cell line (mouse fibroblast) grown in DMEM culture medium (Dulbecco's Modified Eagles Medium) supplemented with 10% fetal bovine serum (SFB), glutamine and antibioticantimycotic (complete culture medium). Tests for lactate dehydrogenase (LDH) release and 3-(4,5-dimethylthiazol-2-yl) -5-(3-carboxymethoxy phenyl) -2-(4-sulfophenyl) -2 Htetrazolium (MTS) reduction were achieved after 18 hours and 24 hours of cells incubation in the presence of the testing substances. For testing, we considered a wide range of dilutions (1:2560000-1:2000) for lemon and orange flavoring substances, compared with the corresponding dilutions of ethanol (used as reference solvent). Orange flavoring substance reduced the number of metabolically active cells in culture at dilution 1/2000 compared to the decreased effect exerted by the scent of lemon. Lemon flavoring substance had a moderate cytostatic effect, but the orange one was strongly cytotoxic at the dilution o

FINANCING CULTURE INSTITUTIONS IN EUROPEAN CONTEXT

The paper, on the coordinates of the analysis of the problematic of financing culture institutions within the European Union member states, performs a comparative analysis focused on the financing mechanism available to the cultural sector, created both at the level of the public, and of the private sector. For the comparative analysis, the paper selected several EU member states, grouped on four geographical areas (North, South, East and Center). The analysis performed in the paper emphasized that most EU member states make significant efforts to finance the cultural sector, but the effects of the economic crisis have had a negative impact on this financing, causing, from this perspective, a gap between the states in the north and center of the EU, on the one hand, and the states in the south and east of the EU, on the other hand and outlining a cultural Europe with two peripheries

Lipid profile after alpha-linolenic acid (ALA) enriched eggs diet: a study on healthy volunteers

ABSTRACT The correction of a subtle nutritional deficiency that may reduce the risk of a future chronic disease is indeed a challenge. One of the most intriguing current and future impacts on public health may come from a greater intake of omega-3 fatty acids such as alpha-linolenic acid (ALA). We investigated the effect of an increased amount of dietary a-linolenic acid (ALA) from enriched eggs on the lipid profile and inflammatory markers in healthy volunteers. 62 subjects were voluntary enrolled after they gave their informed consent. They were randomly assigned in either control or omega group. Control group consumed normal eggs while omega group consumed eggs enriched in omega 3 fatty acids. The content of ALA in omega 3 eggs was 5 times greater than that of control eggs. During the study, all subjects maintained their habitual diets except that egg consumption. Each subject had to consume 6 eggs a week during a 6-week period. Blood samples were collected at day 0 (baseline) and at the end of the study. Triglycerides, cholesterol, HDL, LDL cholesterol, ApoA, ApoB, CRP and fibrinogen were measured in serum samples. We compared the measured values of the biochemical parameters at baseline and after egg consumption both in control and omega group. Triglycerides were significantly reduced in omega group (p=0.002) after ALA enriched eggs consumption but not in control group. Fibrinogen level was significantly decreased (p<0.001) by ALA enriched eggs consumption whereas in control group there were no significant changes. No significant changes were found in the other parameters of the lipid profile or CRP. In conclusion, the alpha-linolenic acid dietary supplementation decreases tryglicerides and fibrinogen level. Alpha-linolenic acid enriched eggs can be considered as functional food with beneficial effects on human health

The Relationship between Advanced Oxidation Protein Products, Vascular Calcifications and Arterial Stiffness in Predialysis Chronic Kidney Disease Patients

Background and Objectives: Cardiovascular morbidity and mortality are increased in patients with chronic kidney disease (CKD). It is likely that the accumulation of uremic toxins resulting in increased oxidative stress (OS) is a major contributing factor, but no clear link has been identified. The purpose of this research is to establish if advanced oxidation protein product (AOPP) levels in the serum of predialysis patients are a contributing factor to vascular calcification and increased arterial stiffness. Materials and Methods: After obtaining the informed consent, 46 predialysis patients (CKD stages G3–G5) were included in the study. In order to identify vascular calcifications, hand and pelvic radiographs were performed. Valvular calcifications were identified using cardiac ultrasound. AOPP were measured using a commercially available ELISA kit. The relationships between serum AOPP values and biochemical parameters relevant in the evaluation of CKD patients were analyzed. In addition to identifying the differences in AOPP levels between patients with/without vascular or valvular calcifications, the research focused on describing the relationship between OS and arterial stiffness assessed by oscillometric pulse-wave velocity (PWV) measurement. Results: No significant relationship between serum AOPP and vascular or valvular calcifications was highlighted, but significant correlations of AOPP with C-reactive protein (p = 0.025), HDL-cholesterol levels (p = 0.04), HbA1c (p = 0.05) and PWV values (p = 0.02) were identified. Conclusions: The usefulness of (OS) measurement in clinical practice remains debatable; however, the relationship between AOPP and arterial stiffness could be valuable in improving cardiovascular risk assessment of patients with CKD

Preclinical Evaluation of NHS-Activated Gold Nanoparticles Functionalized with Bombesin or Neurotensin-Like Peptides for Targeting Colon and Prostate Tumours

Recent advances and large-scale use of hybrid imaging modalities like PET-CT have led to the necessity of improving nano-drug carriers that can facilitate both functional and metabolic screening in nuclear medicine applications. In this study, we focused on the evaluation of four potential imaging nanoparticle structures labelled with the 68Ga positron emitter. For this purpose, we functionalized NHS-activated PEG-gold nanoparticles with 68Ga-DOTA-Neuromedin B, 68Ga-DOTA-PEG(4)-BBN(7-14), 68Ga-DOTA-NT and 68Ga-DOTA-Neuromedin N. In vitro binding kinetics and specific binding to human HT-29 colon carcinoma cells and DU-145 prostate carcinoma cells respectively were assessed, over 75% retention being obtained in the case of 68Ga-DOTA-PEG(4)-BBN(7-14)-AuNP in prostate tumour cells and over 50% in colon carcinoma cells. Biodistribution in NU/J mice highlighted a three-fold uptake increase in tumours at 30 min post-injection of 68Ga-DOTA-NT-AuNP and 68Ga-DOTA-PEG(4)-BBN(7-14)-AuNP compared to 68Ga-DOTA-NT and 68Ga-DOTA-PEG(4)-BBN(7-14) respectively, therewith fast distribution in prostate and colon tumours and minimum accumulation in non-targeted tissues

Endoplasmic Reticulum Chaperones Are Potential Active Factors in Thyroid Tumorigenesis

The study aimed to evaluate the proteomic changes in benign follicular adenoma versus malignant follicular variant of papillary thyroid carcinoma. Tumor and nontumor adjacent samples were analyzed by liquid nanochromatography mass spectrometry, and protein abundance was evaluated by label-free quantification. Western blotting and quantitative real-time polymerase chain reaction were used to validate and complement the mass spectrometry data. The results demonstrated deregulated expression of four endoplasmic reticulum chaperones (78 kDa glucose-regulated protein, endoplasmin, calnexin, protein disulfide-isomerase A4), glutathione peroxidase 3 and thyroglobulin, all of them involved in thyroid hormone synthesis pathway. The altered tissue abundance of endoplasmic reticulum chaperones in thyroid cancer was correlated with serum expression levels. The identified proteins significantly discriminate between adenoma and carcinoma in both thyroid tissue and corresponding sera. Data are available via ProteomeXchange with identifier PXD004322