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Abstract In addition to the ubiquitous loss of the VHL gene in clear cell renal cell carcinoma (ccRCC), co-deletions of chromatin-regulating genes are common drivers of tumorigenesis, suggesting potential vulnerability to epigenetic manipulation. A library of chemical probes targeting a spectrum of epigenetic regulators is screened using a panel of ccRCC models. MS023, a type I protein arginine methyltransferase (PRMT) inhibitor, is identified as an antitumorigenic agent. Individual knockdowns indicate PRMT1 as the specific critical dependency for cancer growth. Further analyses demonstrate impairments to cell cycle and DNA damage repair pathways upon MS023 treatment or PRMT1 knockdown. PRMT1-specific proteomics reveals an interactome rich in RNA binding proteins and further investigation indicates significant widespread disruptions in mRNA metabolism with both MS023 treatment and PRMT1 knockdown, resulting in R-loop accumulation and DNA damage over time. Our data supports PRMT1 as a target in ccRCC and informs a mechanism-based strategy for translational development.

The occupational risk of operators using display screen equipment (DSE) is usually evaluated according to the extent of time spent in active operator–DSE interactions. Risk assessment is based on activity data collected through questionnaires. We evaluated an original and innovative system that can objectively assess active operator–DSE interactions by collecting electrical impulses generated by the activation of mouse, keyboard and a camera that collects attentive eye-screen fixation. The main aim of this study was to evaluate the system’s performance on an employee sample involved in the task of active reading and copying at a DSE workstation connected to the system. In the context of mandatory health surveillance at work, we enrolled 38 DSE operators with normal neuropsychological and eye assessments who were required to complete two predefined reading and writing tasks. The obtained results show that the system is able to collect activity data derived from operator–DSE interactions through screen fixation, keyboard tapping and mouse handling. In the copying task, the session duration as recorded by the system was highly related to the screen fixation time. In the copying task, mouse and keyboard activities were more strongly related to session duration than screen fixation. For the copying task, it was also possible to obtain individual profiles of operator–DSE interactions while performing the same standardized tasks. Collected data can allow an objective evaluation of active time spent by DSE operators at their workstations, thus allowing a more accurate occupational health risk assessment and management. Prospective analysis of individual operator–DSE interaction profiles can favor the setup of targeted preventive and organizational interventions from an of even wider worker wellbeing perspective.

Abstract Healthcare workers (HCWs) are at increased risk of being infected with SARS-CoV-2, yet limited information is available on risk factors of infection. We pooled data on occupational surveillance of 10,654 HCW who were tested for SARS-CoV-2 infection in six Italian centers. Information was available on demographics, job title, department of employment, source of exposure, use of personal protective equipment (PPEs), and COVID-19-related symptoms. We fitted multivariable logistic regression models to calculate odds ratios and 95% confidence intervals of infection. The prevalence of infection ranged from 3.0 to 22.0%, and was correlated with that of the respective areas. Women were at lower risk of infection compared to men. Fever, cough, dyspnea and malaise were the symptoms most strongly associated with infection, together with anosmia and ageusia. No differences in the risk of infection were detected according to job title, or working in a COVID-19 designated department. Reported contact with a patient inside or outside the workplace was a risk factor. Use of a mask was strongly protective against risk of infection as was use of gloves. The use of a mask by the source of exposure (patient or colleague) had an independent effect in reducing infection risk.

Background: Several methods with which to assess the risk of biomechanical overload of the upper limb are described in the literature. Methods: We retrospectively analysed the results of the risk assessment of the biomechanical overload of the upper limb in multiple settings by comparing the application of the Washington State Standard, the threshold limit values (TLV) proposed by the American Conference of Governmental Industrial Hygienists (ACGIH), based on hand-activity levels (HAL) and normalised peak force (PF), the Occupational Repetitive Actions (OCRA) checklist, the Rapid Upper-Limb Assessment (RULA), and the Strain Index and Outil de Repérage et d’Evaluation des Gestes of INRS (Institut National de Recherche et de Sécurité). Results: Overall, 771 workstations were analysed for a total of 2509 risk assessments. The absence of risk demonstrated for the Washington CZCL, used as the screening method, was in good agreement with the other methods, with the sole exception of the OCRA CL, which showed at-risk conditions in a higher percentage of workstations. Differences in the assessment of the frequency of actions were observed among the methods, while their assessments of strength appeared to be more uniform. However, the greatest discrepancies were observed in the assessment of posture. Conclusions: The use of multiple assessment methods ensures a more adequate analysis of biomechanical risk, allowing researchers to investigate the factors and segments in which different methods show different specificities.

Abstract Background Formaldehyde, a widely used chemical, is considered a human carcinogen. We report the results of a meta-analyses of studies on the relationship between occupational exposure to formaldehyde and risk of non-Hodgkin lymphoma (NHL). Methods We performed a systematic review and meta-analysis according to international guidelines and we identified 12 reports of occupational populations exposed to formaldehyde. We evaluated inter-study heterogeneity and we applied a random effects model. We conducted a cumulative meta-analysis and a meta-analysis according to estimated average exposure of each study population. Results The meta-analysis resulted in a summary relative risk (RR) for NHL of 0.93 (95% confidence interval 0.83–1.04). The cumulative meta-analysis suggests that higher RRs were detected in studies published before 1986, while studies available after 1986 did not show an association. No differences were found between different levels of occupational exposure. Conclusions Notwithstanding some limitations, the results of this meta-analysis do not support the hypothesis of an association between occupational exposure to formaldehyde and risk of NHL.

Objective: This study aimed to analyse the role of several environmental and time variables, as well as individual and psychosocial factors, on the perception of exertion, expressed by using the Borg scale, on logistics workers performing heavy manual tasks.Materials and Methods: We enrolled 56 subjects working in logistics sector that were interviewed on the perceived exertion required to execute a task of manual lifting of heavy loads, by using the Borg scale. The interviews were carried out during different shifts, at different times during the shifts and during several different months of the year. We also assessed the workers' anthropometric characteristics, length of service, any musculoskeletal diseases, and physical activity outside work. Workers were also interviewed using the structured OREGE questionnaire, in order to evaluate the main symptoms of stress and work-related psychosocial risk factors.Results: Overall, the subjective perception of the strength exerted by the workers exposed to a high risk of manual handling of loads was moderate. The rating attributed using the Borg scale showed no correlation with any of the investigated variables. 100% of the workers denied to suffer from symptoms of stress, whereas in terms of psychosocial factors, the workload was globally perceived as positive.Conclusion: The study results support the hypothesis that optimal work conditions—from a psychosocial point of view—reduce the subjective perception of exertion by workers even if exposed to a high risk of biomechanical overload.

Abstract Aceruloplasminemia is a monogenic disease caused by mutations in the ceruloplasmin gene that result in loss of protein ferroxidase activity. Ceruloplasmin plays a role in iron homeostasis, and its activity impairment leads to iron accumulation in liver, pancreas, and brain. Iron deposition promotes diabetes, retinal degeneration, and progressive neurodegeneration. Current therapies mainly based on iron chelation, partially control systemic iron deposition but are ineffective on neurodegeneration. We investigated the potential of ceruloplasmin replacement therapy in reducing the neurological pathology in the ceruloplasmin‐knockout (CpKO) mouse model of aceruloplasminemia. CpKO mice were intraperitoneal administered for 2 months with human ceruloplasmin that was able to enter the brain inducing replacement of the protein levels and rescue of ferroxidase activity. Ceruloplasmin‐treated mice showed amelioration of motor incoordination that was associated with diminished loss of Purkinje neurons and reduced brain iron deposition, in particular in the choroid plexus. Computational analysis showed that ceruloplasmin‐treated CpKO mice share a similar pattern with wild‐type animals, highlighting the efficacy of the therapy. These data suggest that enzyme replacement therapy may be a promising strategy for the treatment of aceruloplasminemia.

We introduce and study a minimal 1D model for the simulation of dynamic friction and dissipation at the atomic scale. This model consists of a point mass (slider) that moves over and interacts weakly with a linear chain of particles interconnected by springs, representing a crystalline substrate. This interaction converts a part of the kinetic energy of the slider into phonon waves in the substrate. As a result, the slider experiences a friction force. As a function of the slider speed, we observe dissipation peaks at specific values of the slider speed, whose nature we understand by means of a Fourier analysis of the excited phonon modes. By relating the phonon phase velocities with the slider velocity, we obtain an equation whose solutions predict which phonons are being excited by the slider moving at a given speed.

PURPOSE: The aim of this study was to evaluate the comprehension and acceptance of HPV vaccination in parents of adolescent boys aged 11 to 15 years. METHODS: A cross-sectional survey was conducted by means of questionnaires sent directly to the homes of all families with young males aged between 11 and 15, residents of three municipalities of the Province of Brescia, Italy. The documentation also contained an informative leaflet summarizing the HPV-related disease characteristics, the burden of disease and the available strategies for prevention and treatment, illustrating the rationale of vaccination and describing the project and its phases. The questionnaire included questions on demographic data, acceptance and motivations for HPV vaccination. The collected data was analyzed using descriptive statistics. At the end of the study, parents who received the questionnaires were also offered the possibility of vaccinating their male sons for free. RESULTS: From a total of 1072 questionnaires sent, 161 where returned from the three selected municipalities (average response rate 15%); 97% of adolescent males involved in the study were Italian and 91% Catholic; 97% of parents declared themselves to be willing to vaccinate their sons: the principal motivation given (92%) was prevention of the disease, cancerous or not, related to viral infection. Among the respondents not willing to vaccinate their sons, the motivation was lack of information about the vaccine and the disease. At the end of the study, around 71 boys were vaccinated. DISCUSSION: To our knowledge, this is the first survey in Italy exclusively conducted on parents of adolescent males about the acceptability and feasibility of vaccination against HPV: a very high percentage of respondents was favorable to accept the vaccination for their sons, the main motivation being the fact that parents considered protecting their sons from HPV-related diseases highly important. Of the 161 boys targeted by the questionnaire, 71 decided to receive the 3 doses of HPV vaccination (44%). Data suggests that HPV vaccination is acceptable to families for their male sons and that information is important in the decision-making process.

Introduction. Chronic poisoning may result in home setting after mercury (Hg) vapours inhalation from damaged devices. We report a chronic, nonoccupational Hg poisoning due to 10-year indoor exposure to mercury spillage. Case Report. A 72-year-old man with polyneuropathy of suspected toxic origin. At hospitalization, toxicological clinical evaluations confirmed the altered neurological picture documented across the last decade. Periodic blood and urine Hg levels (BHg, UHg) monitoring were performed from admission (t0), until 1 year later (t2), paralleled by blood neurochemical markers assessment, that is, lymphocytes muscarinic receptors (l-MRs). At t0: BHg and UHg were 27 and 1.4 microg/L, respectively (normal values: BHg 1–4.5; UHg 0.1–4.5), associated with l-MRs increase, 185.82 femtomoL/million lymphocytes (normal range: 8.0–16.0). At t1 (two days after DMSA-mobilization test), BHg weak reduction, paralleled by UHg 3.7-fold increase, was measured together with further l-MRs enhancement (205.43 femtomoL/million lymphocytes). At t2 (eight months after two cycles of DMSA chelating therapy ending), gradual improving of clinical manifestations was accompanied by progressive decrease of BHg and UHg (4.0 and 2.8 microg/L, resp.) and peripheral l-MRs neurochemical marker (24.89 femtomoL/million lymphocytes). Conclusion. l-MRs modulatory effect supports their use as peripheral neurochemical marker in Hg poisoning diagnosis and chelation therapy monitoring.

Bmp6 is the main activator of hepcidin, the liver hormone that negatively regulates plasma iron influx by degrading the sole iron exporter ferroportin in enterocytes and macrophages. Bmp6 expression is modulated by iron but the molecular mechanisms are unknown. Although hepcidin is expressed almost exclusively by hepatocytes (HCs), Bmp6 is produced also by non-parenchymal cells (NPCs), mainly sinusoidal endothelial cells (LSECs). To investigate the regulation of Bmp6 in HCs and NPCs, liver cells were isolated from adult wild type mice whose diet was modified in iron content in acute or chronic manner and in disease models of iron deficiency (Tmprss6 KO mouse) and overload (Hjv KO mouse). With manipulation of dietary iron in wild-type mice, Bmp6 and Tfr1 expression in both HCs and NPCs was inversely related, as expected. When hepcidin expression is abnormal in murine models of iron overload (Hjv KO mice) and deficiency (Tmprss6 KO mice), Bmp6 expression in NPCs was not related to Tfr1. Despite the low Bmp6 in NPCs from Tmprss6 KO mice, Tfr1 mRNA was also low. Conversely, despite body iron overload and high expression of Bmp6 in NPCs from Hjv KO mice, Tfr1 mRNA and protein were increased. However, in the same cells ferritin L was only slightly increased, but the iron content was not, suggesting that Bmp6 in these cells reflects the high intracellular iron import and export. We propose that NPCs, sensing the iron flux, not only increase hepcidin through Bmp6 with a paracrine mechanism to control systemic iron homeostasis but, controlling hepcidin, they regulate their own ferroportin, inducing iron retention or release and further modulating Bmp6 production in an autocrine manner. This mechanism, that contributes to protect HC from iron loading or deficiency, is lost in disease models of hepcidin production.

This article focuses on sustainability understood as a source of political legitimation. I explore political imaginaries and the future as a cognitive resource among two small farming communities in Northern Italy, discussing what transformation towards sustainability means at a concrete level and how this definition may be used strategically in political negotiations to access resources. Ethnographically rooted, this study uses reflexivity and researcher's positioning as a tool to better understand the farmer's social and cultural frameworks, related conflicts, and strategies for surviving. Rhetoric and practices about sustainability establish a symbolic resource that allows gaining new agency spaces. Temporalities regimes are examined here, in order to grasp the identity-making and the selfdifferentiation processes among the farmers. [ABSTRACT FROM AUTHOR]

Neste trabalho, é apresentado um panorama das discussões teóricas sobre as potencialidades da utilização do monitoramento biológico (MB) na vigilância à saúde, nos casos de exposição a substâncias químicas, particularmente em ações de saúde ambiental e dos trabalhadores, considerando os seus diferentes conceitos; aplicação e limitações dos indicadores biológicos e sua disponibilidade para a quantificação das substâncias; valores de referência para interpretação dos resultados; os problemas éticos e sociais na prática do MB e sua inserção entre as diversas práticas preventivas e seu uso em saúde pública. Na prática, o MB constitui-se em um laudo de uma situação de exposição, tendo suas conclusões fundamentadas em valores científicos, de negociações internas, normas e legislações. Como um processo contínuo e relacionado a casos concretos de observação, tem sido uma prática promissora, para a melhoria constante dos ambientes de trabalho. Como uma etapa de um processo decisório nas análises de risco, o monitoramento biológico deve ser permeado pela avaliação crítica no que se refere aos aspectos éticos, a que se destinam os resultados, e aos próprios valores que referenciam a sua aplicação.This study provides an overview of the theoretical discussion on potential uses for biological monitoring of exposure to chemical substances as related to human health, considering different concepts: definitions, uses, and limitations of internal dose and biological effect indicators and their availability for the substances to be quantified; knowledge of reference values, action levels, and limits based on health and negotiated patterns in biological monitoring interpretation and perspectives; and ethical and social problems in practice and within different preventive practices and their use in public health. Biological monitoring is the result of an exposure situation with conclusions based on scientific and consensus values, rules, and legislation. Biological monitoring as a continuous process and related to actually observed cases has helped establish technological exposure reference values and consensus levels as indicators for improving the environment and the workplace. As a step in the decision-making process in risk analysis, biological monitoring needs to be critically assessed as to its ethical aspects in light of the end use of results and values, which are references for application of this methodology.

Neste trabalho, é apresentado um panorama das discussões teóricas sobre as potencialidades da utilização do monitoramento biológico (MB) na vigilância à saúde, nos casos de exposição a substâncias químicas, particularmente em ações de saúde ambiental e dos trabalhadores, considerando os seus diferentes conceitos; aplicação e limitações dos indicadores biológicos e sua disponibilidade para a quantificação das substâncias; valores de referência para interpretação dos resultados; os problemas éticos e sociais na prática do MB e sua inserção entre as diversas práticas preventivas e seu uso em saúde pública. Na prática, o MB constitui-se em um laudo de uma situação de exposição, tendo suas conclusões fundamentadas em valores científicos, de negociações internas, normas e legislações. Como um processo contínuo e relacionado a casos concretos de observação, tem sido uma prática promissora, para a melhoria constante dos ambientes de trabalho. Como uma etapa de um processo decisório nas análises de risco, o monitoramento biológico deve ser permeado pela avaliação crítica no que se refere aos aspectos éticos, a que se destinam os resultados, e aos próprios valores que referenciam a sua aplicação.

Background. Polychlorinated biphenyls (PCBs) have been found to be associated with diabetes in some, but not all, studies performed so far. The aim of this study was to assess the association between PCB serum levels and glycaemia and diabetes in people living in Brescia, a highly industrialised PCB-polluted town in Northern Italy. Design and Methods. 527 subjects were enrolled in a cross-sectional population-based study: they were interviewed face-to-face in 2003 and also provided a blood sample under fasting conditions. The concentration of 24 PCB congeners was determined using gas-chromatography (GC/MS). Subsequently, all subjects were included in a follow-up (cohort) study. According to the Local Health Authority health-care database, subjects were considered to be diabetic if they had diabetes at interview time (prevalent cases) or during a 7-year follow-up (incident cases). Results. A total of 53 subjects (10.0%) were diabetics: 28 had dia- betes at enrolment and other 25 developed the disease subsequently. Diabetes frequency increased according to the serum concentrations of total PCBs and single PCB congeners, but no association was found when estimates were adjusted for education, body mass index, age and gender by logistic regression analysis. Accordingly, glycaemia increased with PCB serum levels, but no association was observed when multiple regression analysis, including confounding factors, was performed. Conclusions. This study does not support the hypothesis that PCB environmental exposure is strictly associated with diabetes or glycaemia.

DNA methylation is an epigenetic mechanism that has been increasingly investigated in observational human studies, particularly on blood leukocyte DNA. Characterizing the degree and determinants of DNA methylation stability can provide critical information for the design and conduction of human epigenetic studies.We measured DNA methylation in 12 gene-promoter regions (APC, p16, p53, RASSF1A, CDH13, eNOS, ET-1, IFNγ, IL-6, TNFα, iNOS, and hTERT) and 2 of non-long terminal repeat elements, i.e., L1 and Alu in blood samples obtained from 63 healthy individuals at baseline (Day 1) and after three days (Day 4). DNA methylation was measured by bisulfite-PCR-Pyrosequencing. We calculated intraclass correlation coefficients (ICCs) to measure the within-individual stability of DNA methylation between Day 1 and 4, subtracted of pyrosequencing error and adjusted for multiple covariates.Methylation markers showed different temporal behaviors ranging from high (IL-6, ICC = 0.89) to low stability (APC, ICC = 0.08) between Day 1 and 4. Multiple sequence and marker characteristics were associated with the degree of variation. Density of CpG dinucleotides nearby the sequence analyzed (measured as CpG(o/e) or G+C content within ±200 bp) was positively associated with DNA methylation stability. The 3' proximity to repeat elements and range of DNA methylation on Day 1 were also positively associated with methylation stability. An inverted U-shaped correlation was observed between mean DNA methylation on Day 1 and stability.The degree of short-term DNA methylation stability is marker-dependent and associated with sequence characteristics and methylation levels.

ATP-dependent binding cassette (ABC) transporters are a family of transmembrane proteins that pump a variety of hydrophobic compounds across cellular and subcellular barriers and are implicated in human diseases such as cancer and atherosclerosis. Inhibition of ABC transporter activity showed promise in early preclinical studies; however, the outcomes in clinical trials with these agents have not been as encouraging. Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that regulate genes involved in fat and glucose metabolism, and inflammation. Activation of PPAR signaling is also reported to regulate ABC gene expression. This suggests the potential of PPAR medicines as a novel means of controlling ABC transporter activity at the transcriptional level. This paper summarizes the advances made in understanding how PPAR medicines affect ABC transporters, and the potential implications for impacting on human diseases, in particular with respect to cancer and atherosclerosis.

Background Macrophages play a key role in iron homeostasis. In peripheral tissues, they are known to polarize into classically activated (or M1) macrophages and alternatively activated (or M2) macrophages. Little is known on whether the polarization program influences the ability of macrophages to store or recycle iron and the molecular machinery involved in the processes.Design and Methods Inflammatory/M1 and alternatively activated/M2 macrophages were propagated in vitro from mouse bone-marrow precursors and polarized in the presence of recombinant interferon-γ or interleukin-4. We characterized and compared their ability to handle radioactive iron, the characteristics of the intracellular iron pools and the expression of molecules involved in internalization, storage and export of the metal. Moreover we verified the influence of iron on the relative ability of polarized macrophages to activate antigen-specific T cells.Results M1 macrophages have low iron regulatory protein 1 and 2 binding activity, express high levels of ferritin H, low levels of transferrin receptor 1 and internalize – albeit with low efficiency -iron only when its extracellular concentration is high. In contrast, M2 macrophages have high iron regulatory protein binding activity, express low levels of ferritin H and high levels of transferrin receptor 1. M2 macrophages have a larger intracellular labile iron pool, effectively take up and spontaneously release iron at low concentrations and have limited storage ability. Iron export correlates with the expression of ferroportin, which is higher in M2 macrophages. M1 and M2 cells activate antigen-specific, MHC class II-restricted T cells. In the absence of the metal, only M1 macrophages are effective.Conclusions Cytokines that drive macrophage polarization ultimately control iron handling, leading to the differentiation of macrophages into a subset which has a relatively sealed intracellular iron content (M1) or into a subset endowed with the ability to recycle the metal (M2).

This study was aimed at: (i) investigating the expression profiles of some antioxidant and epidermal growth factor receptor genes in cancerous and unaffected tissues of patients undergoing lung resection for non-small cell lung cancer (NSCLC) (cross-sectional phase), (ii) evaluating if gene expression levels at the time of surgery may be associated to patients' survival (prospective phase). Antioxidant genes included heme oxygenase 1 (HO-1), superoxide dismutase-1 (SOD-1), and -2 (SOD-2), whereas epidermal growth factor receptor genes consisted of epidermal growth factor receptor (EGFR) and v-erb-b2 erythroblastic leukaemia viral oncogene homolog 2 (HER-2). Twenty-eight couples of lung biopsies were obtained and gene transcripts were quantified by Real Time RT-PCR. The average follow-up of patients lasted about 60 months. In the cancerous tissues, antioxidant genes were significantly hypo-expressed than in unaffected tissues. The HER-2 transcript levels prevailed in adenocarcinomas, whereas EGFR in squamocellular carcinomas. Patients overexpressing HER-2 in the cancerous tissues showed significantly lower 5-year survival than the others.

The first human deaths due to air pollution were recorded in the mid-20th century. There were 6,000 cases of illness recorded in Donora, Pennsylvania, in 1948 and 20,000 in London in 1952; 15 and 4,000 cases of death, respectively, were allegedly ascribed to air pollution. Since then, many countries have adopted standards of air quality in order to protect environmental and human health, although the quality of the air in some industrialized countries remains worrying. Emerging countries in the Far East and South America are also cause for concern because of the growth in the population, industrialization and transport. The WHO World Health Report 2002 estimated that air pollutants, particularly PM10, are associated with a mortality rate of 5% for cancer of the respiratory system, 2% for cardiovascular diseases and about 1% for respiratory tract infections. These estimates consider the mortality but not the morbidity rate, which would increase proportionally the number of cases of these pathologies, despite the difficulty in evaluation.