Primary cell cultures for the personalized therapy in aggressive thyroid cancer of follicular origin.

Thyroid cancer (TC) is the most prevalent endocrine malignancy. More than 90 % of TC is represented by differentiated TC (DTC) arising from the follicular thyroid cells. DTC includes papillary TC (PTC), follicular TC (FTC), and Hürthle cell TC. Anaplastic TC (ATC) accounts for 1% of TC, and it represents 15-40 % of TC death. Current treatment strategies are not completely effective against aggressive DTC or ATC, and mortality is one of the most important challenges. Recently, progresses have been obtained in the understanding of the molecular/genetic basis of TC progression, and new drugs have been introduced [i.e. tyrosine kinase inhibitors (TKIs)], able to block the oncogenic or signaling kinases, associated with cellular growth. Thyroid cell lines, obtained from tumoral cells and chosen for high proliferation in vitro, have been used as preclinical models. Actually, these cells lose the characteristic features of the primary tumor, because they adapt to in vitro growth conditions. For these reasons, the use of these cell lines has important limitations, and more recently human primary cell cultures have been established as monolayer cultures, and investigated for their biological behavior. Moreover, in the past, primary TC cells could be collected only through surgical biopsies, while recently human primary cell cultures can be established also from samples of fine-needle aspiration citology from aggressive dedifferentiated DTC or ATC. Testing in vitro different TKIs in each patient can help to develop new personalized treatments, without using ineffective drugs. In conclusion, personalized medicine and precise oncology, which consider both patients and their disease features, represent the future of the treatment approach, and further progress is needed in this direction.

Heart rate variability, serum cortisol levels and temperament in a sample of workers exposed to occupational stress: a preliminary report.

Work-related stress is an emerging risk for psychiatric occupational disorders including Adjustment Disorders (AD). The aim of this study was to investigate in workers exposed to occupational stress suffering from AD about putative indices of stress and mental health resilience such as serum cortisol (seC) levels, Heart Rate Variability (HRV) and affective temperaments. We consecutively recruited 15 male and 15 female AD patients between workers evaluated for occupational stress at an Italian Occupational Medicine Unit. SeC levels were measured by specific immunoassay. HRV indices were recorded using Task Force® Monitor system (CNSystems, Graz, Austria). Specific questionnaires were used to measure perceived and occupational stress, psychopathological symptoms and temperament. Women presented higher levels of occupational stress, higher High-Frequency HRV (HF-HRV) and lower Low-Frequency HRV (LF-HRV) than men. SeC levels were positively correlated with LF-HRV values and negatively with HF-HRV values. The LF/HF ratio resulted to be inversely correlated with the score of Harm Avoidance temperament dimension and directly with the score of Reward Dependence temperament dimension. In conclusion, in AD patients exposed to occupational stress high seC levels and reward dependence appear to be associated with a pattern of HRV reflecting less mental health resilience.

Diversity & Inclusion: Fitness for Work Through a Personalized Work Plan For Workers With Disabilities and Chronic Diseases According to the Iso 30415/2021.

The recent standard ISO 30415-2021 - Human resources management - Diversity and inclusion -  was developed internationally within the technical committee ISO/TC 260 "Human resources management" (Working group WG 8 "Diversity and inclusion") and underlines the need for actions to create a work environment that is inclusive of diversity (e.g. in terms of health, gender, age, ethnicity, culture). Developing an inclusive work environment requires ongoing commitment and input from the entire organization regarding policies, processes, organizational practices, and individual behavior. As far as the role of occupational medicine is concerned, this direction can be supported by the correct management of disabled workers and workers with chronic pathologies that affect their fitness for duty. The "reasonable accommodation" is the way by which the European Union first, and the United Nations then intended to support the inclusion of disabled people in the world of work. The Personalized Work Plan includes different approaches (organizational, technical, procedural) meant for modifying the work activity envisaged for the disabled worker or for any worker suffering from chronic diseases or dysfunctions. The adoption of the Personalized Work Plan implies the effort of redesigning the workstation, the work procedures, or even the planning of different micro and macro tasks etc., in order to prioritize the adaptation of the working environment to the worker, safeguarding the value of the worker's productivity according to the principle of reasonable accommodation.

Combination Strategies Involving Immune Checkpoint Inhibitors and Tyrosine Kinase or BRAF Inhibitors in Aggressive Thyroid Cancer.

Thyroid cancer is the most common (~90%) type of endocrine-system tumor, accounting for 70% of the deaths from endocrine cancers. In the last years, the high-throughput genomics has been able to identify pathways/molecular targets involved in survival and tumor progression. Targeted therapy and immunotherapy individually have many limitations. Regarding the first one, although it greatly reduces the size of the cancer, clinical responses are generally transient and often lead to cancer relapse after initial treatment. For the second one, although it induces longer-lasting responses in cancer patients than targeted therapy, its response rate is lower. The individual limitations of these two different types of therapies can be overcome by combining them. Here, we discuss MAPK pathway inhibitors, i.e., BRAF and MEK inhibitors, combined with checkpoint inhibitors targeting PD-1, PD-L1, and CTLA-4. Several mutations make tumors resistant to treatments. Therefore, more studies are needed to investigate the patient's individual tumor mutation burden in order to overcome the problem of resistance to therapy and to develop new combination therapies.

Analysis of survival at cardiac arrest in events occurred in work environments in the territory served by an operations center of the 118 of Tuscany.

BACKGROUND: Every year in Italy and all around the world, cardiac arrest hits almost 1 person every 1000 people; a great deal of these events is likely to strike people outside their private houses. OBJECTIVES: Analyzing a cohort of cardiac arrest events occurred in various public- and work-places across a territorial area concerning an Emergency Unit related to the national emergency number (118) and assessing the efficacy of a first-aid intervention and the usage of a defibrillator while handling an acute cardiac event. METHODS: We analyzed data of 32 sanitary interventions on cardiac arrest events occurred from January 2015 to June 2018 across USL Toscana Centro - Pistoia and Empoli's territory. RESULTS: The acute cardiac event occurred in a "strictly speaking workplace" in 28.2% of cases, and in 18.7% during work activity. An AED was present for immediate cardiac arrest treatment in 15.6% of cases with a survival rate of 100% (n=5/5) (p=0.04); in 84.4% of cases the AED was available only after the arrival of national emergency rescuers and the relative survival rate was 40.74% (n=11/27). Regarding cardiopulmonary resuscitation, the survival rate appears to be higher (55.5% Vs 42.8%) when it was started by witnesses. CONCLUSIONS: The results of this study suggest that early defibrillation provided by work-related First Aid Emergency Procedure, may be a primary aid and a desirable standard to improve both workers' and private citizens' survival rate after cardiac arrest.

The polymorphism rs2480258 within CYP2E1 is associated with different rates of acrylamide metabolism in vivo in humans.

In a recent study, we demonstrated that the variant allele of rs2480258 within intron VIII of CYP2E1 is associated with reduced levels of mRNA, protein, and enzyme activity. CYP2E1 is the most important enzyme in the metabolism of acrylamide (AA) by operating its oxidation into glycidamide (GA). AA occurs in food, is neurotoxic and classified as a probable human carcinogen. The goal of the present study was to further assess the role of rs2480258 by measuring the rate of AA > GA biotransformation in vivo. In blood samples from a cohort of 120 volunteers, the internal doses of AA and GA were assessed by AA and GA adducts to hemoglobin (Hb) measured by mass spectrometry. The rate of biotransformation was assessed by calculating the GA-Hb/AA-Hb ratio. To maximize the statistical power, 60 TT was compared to 60 CC-homozygotes and the results showed that TT homozygotes had a statistically significant reduced rate of biotransformation. Present results reinforced the notion that T-allele of rs2480258 is a marker of low functional activity of CYP2E1. Moreover, we studied the role of polymorphisms (SNPs) within glutathione-S-transferases (GSTs) enzymes and epoxide hydrolase (EPHX), verifying previous findings that SNPs within GSTs and EPHX influence the metabolism rate.

Mesothelin promoter variants are associated with increased soluble mesothelin-related peptide levels in asbestos-exposed individuals.

BACKGROUND: Soluble mesothelin-related peptide (SMRP) is a promising diagnostic biomarker for malignant pleural mesothelioma (MPM), but various confounders hinder its usefulness in surveillance programmes. We previously showed that a single nucleotide polymorphism (SNP) within the 3'untranslated region (3'UTR) of the mesothelin (MSLN) gene could affect the levels of SMRP. OBJECTIVES: To focus on SNPs located within MSLN promoter as possible critical genetic variables in determining SMRP levels. METHODS: The association between SMRP and SNPs was tested in 689 non-MPM subjects and 70 patients with MPM. Reporter plasmids carrying the four most common haplotypes were compared in a dual luciferase assay, and in silico analyses were performed to investigate the putative biological role of the SNPs. RESULTS: We found a strong association between serum SMRP and variant alleles of rs3764247, rs3764246 (in strong linkage disequilibrium with rs2235504) and rs2235503 in non-MPM subjects. Inclusion of the genotype information led to an increase in SMRP specificity from 79.9% to 85.5%. Although not statistically significant, the group with MPM showed the same trend of association. According to the in vitro luciferase study, rs3764247 itself had a functional role. In silico approaches showed that the binding sites for transcription factors such as Staf and ZNF143 could be affected by this SNP. The other SNPs were shown to interact with each other in a more complex way. CONCLUSIONS: These data support the suggestion that SMRP performance is affected by individual (ie, genetic) variables and that MSLN expression is influenced by SNPs located within the promoter regulatory region.

[Health and work in a gender perspective.] / Salute e lavoro in un'ottica di genere.

OBJECTIVES: A literature review was performed to highlight which work-related diseases express sex/gender differences in health outcomes and focus the main limits of studies in this field. METHODS: The research, carried out on PubMed by specific search string, identified 4828 articles (1997-2017 period) of which 381 are eligible for review (4-22%, depending on the disease). RESULTS: Among them, 68% reported sex/gender differences in health outcomes, which in most cases appear to be due to different exposure and/or work segregation rather than to biological differences. However, few studies place this assessment among the research goals and results are almost never discussed and hypothesis are seldom formulated about any observed differences. CONCLUSIONS: It seems necessary to use research methodologies and study design that can detect and explain the described complexity and useful in defining appropriate preventive strategies.

[Gender-sensitive risk assessment and health medical surveillance: some operative tools.] / Valutazione dei rischi e sorveglianza sanitaria in ottica di genere: proposta di strumenti operativi.

OBJECTIVES: A thorough and fully application of the principles of gender mainstreaming, in accordance with the European Community guidelines, to the health and safety at work, implies the systematic review of the whole prevention from the gendered point of view. This means that both biology- and gender-based differences between male and female workers should be conceived not only as determinants of health but also as factors affecting either positively or negatively the health and safety risk prevention. In this evolutionary cultural step the role of the occupational physician is particularly important. METHODS: In this paper we propose some operative tools that can concretely implement gender perspective in all the various areas of prevention, where the occupational physician has a leading, if not even exclusive, role such as risk assessment, training and health medical surveillance.

ChatGPT in Occupational Medicine: A Comparative Study with Human Experts.

The objective of this study is to evaluate ChatGPT's accuracy and reliability in answering complex medical questions related to occupational health and explore the implications and limitations of AI in occupational health medicine. The study also provides recommendations for future research in this area and informs decision-makers about AI's impact on healthcare. A group of physicians was enlisted to create a dataset of questions and answers on Italian occupational medicine legislation. The physicians were divided into two teams, and each team member was assigned a different subject area. ChatGPT was used to generate answers for each question, with/without legislative context. The two teams then evaluated human and AI-generated answers blind, with each group reviewing the other group's work. Occupational physicians outperformed ChatGPT in generating accurate questions on a 5-point Likert score, while the answers provided by ChatGPT with access to legislative texts were comparable to those of professional doctors. Still, we found that users tend to prefer answers generated by humans, indicating that while ChatGPT is useful, users still value the opinions of occupational medicine professionals.

Evaluation of Smallpox Vaccination Coverage and Attitude towards Monkeypox Vaccination among Healthcare Workers in an Italian University Hospital.

(1) Background: In 2022, monkeypox (Mpox) was declared a public health emergency. The European Medicines Agency has authorized the use of Imvanex/Jynneos, a smallpox vaccine, for coverage against pox. Healthcare workers (HCWs) are all considered by the European Centre for Disease Prevention and Control to be at risk, but in Italy, vaccination was offered only to laboratory personnel. The present study aims to investigate smallpox vaccination coverage (VC) that provides protection against Mpox among HCWs in an Italian university hospital and to assess HCWs' attitudes towards the possibility of getting vaccinated against Mpox. (2) Methods: We conducted a cross-sectional survey. 336 HCWs from selected wards were asked to fill out a self-declaration to collect their sex, profession, ward, vaccination status, and attitude toward Mpox vaccination. (3) Results: 60.71% of HCWs involved provided the requested data; 38.7% of them were previously vaccinated against smallpox, which corresponds to 23.5% of the total HCWs in the wards considered. Considering those born before 1979 as vaccinated, VC increases from 23.5% to 41.7%; the percentage of HCWs who adhered to vaccination is 23%; laboratory technicians showed a lower willingness to be vaccinated. The ward with the highest willingness to vaccinate is proctological surgery. (4) Conclusions: Based on our experience, a variability in smallpox VC and in willingness to vaccination has emerged both among different job titles and age categories and across the wards analyzed. Additionally, our survey reveals that vaccination attitudes are higher among HCWs from wards that currently do not have free access to such vaccinations.

Comparison between Standard Expository Cognitive Behavioral Therapy (CBT-E) and Immersive Virtual Reality CBT (CBT-VR) for Rehabilitation of Patients Affected by Occupational Stress Disorders: Study Protocol.

Work-related stress presents a significant impact on work performance and physical health. It has been associated with the onset of a multitude of symptoms that can lead to occupational stress diseases, namely Adjustment Disorder and Post-Traumatic Stress Disorder. The literature has evidenced that "exposure therapy" of cognitive-behavioral training (CBT-E) seems to be the most effective technique to manage stress symptoms, including work stress diseases, and several studies have considered Virtual Reality (VR) as an adjuvant tool to exposure-based psychotherapy (CBT-VR) for the treatment of multiple psychiatric disorders. The aim of this study is to evaluate the effectiveness of CBT with exposure to stressful work scenarios in imaginative (CBT-E) and in immersive virtual reality (CBT-VR) scenarios in a group of workers affected by work-related stress disorders and compare the clinical and physiological outcomes between the two exposure techniques. A long-term goal would be to develop an evidence-based rehabilitation program as a treatment for the reintegration into work of patients affected by these psychiatric disorders.

A review of transcriptome studies combined with data mining reveals novel potential markers of malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM), a cancer of the serosal pleural cavities, is one of the most aggressive human tumors. In order to identify genes crucial for the onset and progression of MPM, we performed an extensive literature review focused on transcriptome studies (RTS). In this kind of studies a great number of transcripts are analyzed without formulating any a priori hypothesis, thus preventing any bias coming from previously established knowledge that could lead to an over-representation of specific genes. Each study was thoroughly analyzed paying particular attention to: (i) the employed microarray platform, (ii) the number and type of samples, (iii) the fold-change, and (iv) the statistical significance of deregulated genes. We also performed data mining (DM) on MPM using three different tools (Coremine, SNPs3D, and GeneProspector). Results from RTS and DM were compared in order to restrict the number of genes potentially deregulated in MPM. Our main requirement for a gene to be a "mesothelioma gene" (MG) is to be reproducibly deregulated among independent studies and confirmed by DM. A list of MGs was thus produced, including PTGS2, BIRC5, ASS1, JUNB, MCM2, AURKA, FGF2, MKI67, CAV1, SFRP1, CCNB1, CDK4, and MSLN that might represent potential novel biomarkers or therapeutic targets for MPM. Moreover, it was found a sub-group of MGs including ASS1, JUNB, PTGS2, EEF2, SULF1, TOP2A, AURKA, BIRC5, CAV1, IFITM1, PCNA, and PKM2 that could explain, at least in part, the mechanisms of resistance to cisplatin, one first-line chemotherapeutic drug used for the disease. Finally, the pathway analysis showed that co-regulation networks related to the cross-talk between MPM and its micro-environment, in particular involving the adhesion molecules, integrins, and cytokines, might have an important role in MPM. Future studies are warranted to better characterize the role played by these genes in MPM.

Big and Free Fractions of Gamma-Glutamyltransferase: New Diagnostic Biomarkers for Malignant Mesothelioma?

Malignant pleural mesothelioma (MPM) is a cancer mainly caused by asbestos fiber inhalation, characterized by an extremely long latency and poor prognosis. Recently, researchers have focused on testing the diagnostic ability of several biomarkers. Gamma-Glutamyltransferase (GGT) has been demonstrated to be the sum of several GGT sub-fractions activity, classified based on their molecular weight in big-GGT, medium-GGT, small-GGT, and free-GGT. This work aims to evaluate whether specific GGT fractional enzymatic activity patterns could be helpful in MPM diagnosis. We analyzed blood samples from 175 workers previously exposed to asbestos, 157 non-exposed healthy subjects, and 37 MPM patients through a molecular exclusion chromatographic method. We found a specific profile of GGT fractions activity, significantly associated with MPM, resulting in an increase in b-, m- activity, along with an evident, yet not significant, decrease in f-activity. Receiver-operating characteristic (ROC) analysis showed that the best Area Under Curve (AUC) value resulted from the combined index b/f (0.679, 95% CI: 0.582-0.777). Combining the b-/f-GGT activity with the levels of serum mesothelin-related protein (SMRP; another promising MPM biomarker) improved the diagnostic accuracy, increasing the AUC value to 0.875 (95% CI: 0.807-0.943, p = <0.0001). Since MPM has a specific pattern of GGT enzymatic activity, we could hypothesize that GGT fractions play different specific biochemical roles. The improvement in the diagnostic power given by the combination of these two biomarkers confirms that the strategy of biomarkers combination might be a better approach for MPM diagnosis.

Role of Prosaposin and Extracellular Sulfatase Sulf-1 Detection in Pleural Effusions as Diagnostic Biomarkers of Malignant Mesothelioma.

Malignant pleural mesothelioma is an aggressive malignancy with poor prognosis. Unilateral pleural effusion is frequently the initial clinical sign requiring therapeutic thoracentesis, which also offers a diagnostic opportunity. Detection of soluble biomarkers can support diagnosis, but few show good diagnostic accuracy. Here, we studied the expression levels and discriminative power of two putative biomarkers, prosaposin and extracellular sulfatase SULF-1, identified by proteomic and transcriptomic analysis, respectively. Pleural effusions from a total of 44 patients (23 with mesothelioma, 8 with lung cancer, and 13 with non-malignant disease) were analyzed for prosaposin and SULF-1 by enzyme-linked immunosorbent assay. Pleural effusions from mesothelioma patients had significantly higher levels of prosaposin and SULF-1 than those from non-malignant disease patients. Receiver-operating characteristic (ROC) analysis showed that both biomarkers have good discriminating power as pointed out by an AUC value of 0.853 (p = 0.0005) and 0.898 (p < 0.0001) for prosaposin and SULF-1, respectively. Combining data ensued a model predicting improvement of the diagnostic performance (AUC = 0.916, p < 0.0001). In contrast, prosaposin couldn't discriminate mesothelioma patients from lung cancer patients while ROC analysis of SULF-1 data produced an AUC value of 0.821 (p = 0.0077) but with low sensitivity. In conclusion, prosaposin and SULF-1 levels determined in pleural effusion may be promising biomarkers for differential diagnosis between mesothelioma and non-malignant pleural disease. Instead, more patients need to be enrolled before granting the possible usefulness of these soluble proteins in differentiating mesothelioma pleural effusions from those linked to lung cancer.

A Medical Resident with a History of Alcohol Abuse and Suicidal Ideation: A Challenge for Both Psychiatry and Occupational Medicine in the Context of the First Wave of the COVID-19 Pandemic.

This case study draws attention to the hazards of physicians with a history of alcohol addiction and a particular psychopathology framework in the context of occupational health surveillance, particularly during the challenging working conditions brought about by the COVID-19 pandemic. The case involves a hospital resident in her thirties, with a previous history of addiction and attempts at suicide, who was assigned to a COVID-19 unit of an Italian hospital. In this case study, we discuss the preventive intervention put in place in order to protect physicians' health and work. What emerges is the key role that rapid substantive communications between specialists play in formulating an effective strategy for dealing with these conditions. We believe this case is noteworthy for the lessons that can be learned for tailoring prevention and treatment pathways for health care workers with addiction.

Do Autistic Traits Correlate with Post-Traumatic Stress and Mood Spectrum Symptoms among Workers Complaining of Occupational Stress?

The adult autism subthreshold spectrum model appears to be a useful tool for detecting possible vulnerability factors in order to develop mental disorders in the contest of work-related stress. The aim of the present study is to analyze the relationship between autism, mood, and post-traumatic spectrum in a cohort of subjects complaining of work-related stress before the COVID-19 pandemic. The authors carried out a retrospective investigation of both medical records and self-assessment tools of a sample of subjects evaluated at the Occupational Health Department of a University hospital in central Italy. Data showed significant correlations between the AdAS spectrum, TALS-SR, and MOODS total and domain scores. A multiple linear regression evidenced that both the AdAS spectrum and TAL-SR significantly predict the MOODS scores. In particular, mediation analysis showed both a direct and indirect, mediated by TALS-SR, effect of the AdAS Spectrum on the MOODS-SR. These results corroborate the role of autistic traits in influencing the traumatic impact of work-related stress and the development of mood spectrum symptoms.

Affective temperament and mood spectrum symptoms in workers suffering from work-related stress disorders.

INTRODUCTION: Adjustment Disorders (AD) which develop in response to work-related stressors represent a model of psychiatric occupational disease. Major Depressive Episodes (MDE) although often associated to work-related stressors are unlikely recognized by insurance institutes as occupational diseases. Affective temperament and mood spectrum symptoms are possible factors of vulnerability to stress. The aim of this study was to investigate if temperaments and mood spectrum symptoms had a different distribution among workers exposed to occupational stress and suffering from different psychiatric disorders (AD, MDE). METHODS: 156 AD and 97 MDE patients were recruited and evaluated with scales for perceived stress (PSM) and work-related stress (JCQ), for psychopathological symptoms (BDI-II, SAS), for affective temperament (TEMPS-A[P]) and for lifetime mood spectrum symptoms (MOODS-SR). Group comparisons and correlation analyses between variables were performed by parametric or non-parametric statistical tests according to variables distribution. RESULTS: The diagnostic groups did not differ for perceived and occupational stress levels. MDE patients reported significantly higher BDI-II score and MOODS-SR scores than AD ones. The hyperthymic temperament was significantly more frequent in AD than in MDE group. The hyperthymic score, differently from other dimensions of temperament and from mood spectrum components, negatively correlated or did not correlate with psychopathological symptoms severity and perceived stress levels. LIMITATIONS: Predictive limitation because of cross-sectional design. CONCLUSIONS: The hyperthymic temperament as opposed to lifetime subtreshold mood symptoms appears to be more represented in patients suffering from occupational AD than in MDE ones. Acknowledging vulnerability factors to job stress could support clinicians in occupational diseases prevention and management.

Evaluation of the Anti-Spike (RDB) IgG Titer among Workers Employed at the University of Pisa Vaccinated with Different Types of SARS-CoV-2 Vaccines.

With the development of SARS-CoV-2 vaccines, many authors started evaluating the immunization efficacy of the available vaccines mainly through sero-positivity tests or by a quantitative assessment of the IgG against the spike protein of SARS-CoV-2 virus in vaccinated subjects. In this work, we compared the titers resulting from vaccination and tried to understand the potential factors affecting the immune response to the available SARS-CoV-2 vaccines. This study was conducted on 670 volunteers employed at the University of Pisa and undergoing a health surveillance program at the University Hospital of Pisa. For each participant, 10 mL of blood, information about contacts with confirmed cases of COVID-19, age, sex, SARS-CoV-2 vaccination status, previous SARS-CoV-2 infection and symptoms, type of vaccine and the date of administration were collected. In the multivariate analysis, the type of vaccine, the presence of symptoms in SARS-CoV-2 positive individuals, and the distance from the second dose significantly affected the antibody titer; the combined vaccination resulted in a faster decay over time compared with the other types of vaccination. No significant differences were observed between Spikevax and Comirnaty (p > 0.05), while the antibody levels remain more stable in subjects undergoing Vaxzevria vaccination (p < 0.01) compared with mRNA-based ones.