Selective, broad-spectrum antiviral photodynamic disinfection with dicationic imidazolyl chlorin photosensitizers.

The COVID-19 pandemic exposes our vulnerability to viruses that acquire the ability to infect our cells. Classical disinfection methods are limited by toxicity. Existing medicines performed poorly against SARS-CoV-2 because of their specificity to targets in different organisms. We address the challenge of mitigating known and prospective viral infections with a new photosensitizer for antimicrobial photodynamic therapy (aPDT). Photodynamic inactivation is based on local oxidative stress, which is particularly damaging to enveloped viruses. We synthesized a cationic imidazolyl chlorin that reduced by > 99.999% of the percentage inhibition of amplification of SARS-CoV-2 collected from patients at 0.2 µM concentration and 4 J cm-2. Similar results were obtained in the prevention of infection of human ACE2-expressing HEK293T cells by a pseudotyped lentiviral vector exhibiting the S protein of SARS-CoV-2 at its surface. No toxicity to human epidermal keratinocytes (HaCaT) cells was found under similar conditions. aPDT with this chlorin offers fast and safe broad-spectrum photodisinfection and can be repeated with low risk of resistance.

Proposing a holistic research framework for university strategic alliances in sustainable entrepreneurship.

This study presents a systematic literature review aimed at mapping the main areas of study on the relationship between higher education institutions' strategic alliances and sustainable entrepreneurship. To that end, it carried out three complementary analyses: topic mapping, co-citation, and overlay visualization, in order to provide a comprehensive picture of that relationship from 1994 to 2022. The empirical approach is based on a total sample of 207 articles published in the Web of Science database, which was screened in terms of title, abstract and keywords, and subject to a search protocol involving inclusion and exclusion criteria. Using VOSviewer software, a three-pronged approach is used to identify five topic clusters: (1) The impact of entrepreneurship on community sustainability and social innovation; (2) Strategic alliances for sustainable development, innovation, and performance; (3) Value creation through social entrepreneurship partnerships; (4) Challenges for knowledge-based sustainable cities; and (5) Collaboration between businesses and social enterprises; revealing the role of knowledge, co-creation, sustainable entrepreneurship, and social innovation as levers of sustainable development. As a result of this systematic literature review, a holistic research framework is proposed, positioning sustainable entrepreneurship as a priority target for strategic alliances in higher education institutions, with reference to the experience of implementing the European University concept. This framework helps to position joint cooperation and strategic alliances among the major stakeholders in knowledge-based economies, which frequently leads to knowledge-based development based on sustainable entrepreneurship.

Extracellular vesicle-based delivery of silencing sequences for the treatment of Machado-Joseph disease/spinocerebellar ataxia type 3.

Machado-Joseph disease (MJD)/spinocerebellar ataxia type 3 (SCA3) is the most common autosomal dominantly inherited ataxia worldwide. It is caused by an over-repetition of the trinucleotide CAG within the ATXN3 gene, which confers toxic properties to ataxin-3 (ATXN3) species. RNA interference technology has shown promising therapeutic outcomes but still lacks a non-invasive delivery method to the brain. Extracellular vesicles (EVs) emerged as promising delivery vehicles due to their capacity to deliver small nucleic acids, such as microRNAs (miRNAs). miRNAs were found to be enriched into EVs due to specific signal motifs designated as ExoMotifs. In this study, we aimed at investigating whether ExoMotifs would promote the packaging of artificial miRNAs into EVs to be used as non-invasive therapeutic delivery vehicles to treat MJD/SCA3. We found that miRNA-based silencing sequences, associated with ExoMotif GGAG and ribonucleoprotein A2B1 (hnRNPA2B1), retained the capacity to silence mutant ATXN3 (mutATXN3) and were 3-fold enriched into EVs. Bioengineered EVs containing the neuronal targeting peptide RVG on the surface significantly decreased mutATXN3 mRNA in primary cerebellar neurons from MJD YAC 84.2 and in a novel dual-luciferase MJD mouse model upon daily intranasal administration. Altogether, these findings indicate that bioengineered EVs carrying miRNA-based silencing sequences are a promising delivery vehicle for brain therapy.

A standardised protocol for blood and cerebrospinal fluid collection and processing for biomarker research in ataxia.

The European Spinocerebellar Ataxia Type 3/Machado-Joseph Disease Initiative (ESMI) is a consortium established with the ambition to set up the largest European longitudinal trial-ready cohort of Spinocerebellar Ataxia Type 3/Machado-Joseph Disease (SCA3/MJD), the most common autosomal dominantly inherited ataxia worldwide. A major focus of ESMI has been the identification of SCA3/MJD biomarkers to enable future interventional studies. As biosample collection and processing variables significantly impact the outcomes of biomarkers studies, biosampling procedures standardisation was done previously to study visit initiation. Here, we describe the ESMI consensus biosampling protocol, developed within the scope of ESMI, that ultimately might be translated to other neurodegenerative disorders, particularly ataxias, being the first step to protocol harmonisation in the field.

SIRT1 activation and its circadian clock control: a promising approach against (frailty in) neurodegenerative disorders.

With the increase in life expectancy, the incidence of neurodegenerative disorders and their impact worldwide has been increasing in recent years. Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and Huntington's disease, have complex and varied mechanisms of pathogenesis. Importantly, they share the common feature of disrupted circadian rhythms. This hallmark is believed to underlie the symptoms of such diseases and even potentially contribute to their onset. In addition, the association of physical frailty with dementia and neurodegenerative disorders has been demonstrated. In fact, frail persons are 8 times more likely to have some form of dementia and population studies report a significant prevalence for frailty in older patients with AD and PD. SIRT1 regulates the acetylation status of clock components and controls circadian amplitude of clock genes. However, the mechanisms responsible for this circadian clock control have been the subject of contradictory findings. Importantly, the activation of SIRT1 has been shown to have very relevant therapeutic potential against neurodegeneration. Nevertheless, few studies have attempted to connect the therapeutic reestablishing of SIRT1 as an approach against circadian disruption in neurodegenerative diseases. In this review, we address: circadian rhythms as an important early biomarker of neurodegenerative disorders; mechanisms for SIRT1 activation and the novel sirtuin-activating compounds (STACs); SIRT1 circadian paradox and subsequent studies in an unprecedented way in the literature; the beneficial role of SIRT1 activation in neurodegeneration; innovative proposals of how circadian-based interventions (e.g., SIRT1 activators) may become an important therapeutic approach against neurodegenerative disorders and how non-pharmacologic interventions (e.g., Mediterranean-style diet) might help in the prevention and/or treatment of these high-burden disorders, while tackling frailty and enhancing robustness.

Burnout and Quality of Work Life among Municipal Workers: Do Motivating and Economic Factors Play a Mediating Role?

This study analyzes the relationship between burnout and quality of work life among municipal workers subjected to higher levels of stress and emotional exhaustion, impacting their occupational health in the context of the COVID-19 pandemic. With a sample of 459 municipal workers, the relationship between burnout and quality of work life is tested by considering the isolated mediating effect of the feeling of contributing to productivity and the combined effects of two mediators representing the feeling of contributing to productivity and receiving an appropriate salary. The main findings include a negative association between the three dimensions of burnout: emotional exhaustion, feelings of cynicism, and a sense of being less effective, and the mediators: contribution to productivity and appropriate salary. Also detected was an important mediating role associated with the effects of not feeling contributive at work, as well as not being well paid, on the relation between the burnout syndrome dimension of low effectiveness and quality of work life. For future action by public authorities and public managers, the need is highlighted to create innovative human resource management frameworks and flexible work organization, with remuneration plans based on productivity goals and aimed at an improved balance between personal life and work.

Photodynamic disinfection of SARS-CoV-2 clinical samples using a methylene blue formulation.

The amplitude of the coronavirus disease 2019 (COVID-19) pandemic motivated global efforts to find therapeutics that avert severe forms of this illness. The urgency of the medical needs privileged repositioning of approved medicines. Methylene blue (MB) has been in clinical use for a century and proved especially useful as a photosensitizer for photodynamic disinfection (PDI). We describe the use of MB to photo-inactivate SARS-CoV-2 in samples collected from COVID-19 patients. One minute of treatment can reduce the percentage inhibition of amplification by 99.99% under conditions of low cytotoxicity. We employed a pseudotyped lentiviral vector (LVs) encoding the luciferase reporter gene and exhibiting the S protein of SARS-CoV-2 at its surface, to infect human ACE2-expressing HEK293T cells. Pre-treatment of LVs with MB-PDI prevented infection at low micromolar MB concentrations and 1 min of illumination. These results reveal the potential of MB-PDI to reduce viral loads in the nasal cavity and oropharynx in the early stages of COVID-19, which may be employed to curb the transmission and severity of the disease.

ULK overexpression mitigates motor deficits and neuropathology in mouse models of Machado-Joseph disease.

Machado-Joseph disease (MJD) is a fatal neurodegenerative disorder clinically characterized by prominent ataxia. It is caused by an expansion of a CAG trinucleotide in ATXN3, translating into an expanded polyglutamine (polyQ) tract in the ATXN3 protein, that becomes prone to misfolding and aggregation. The pathogenesis of the disease has been associated with the dysfunction of several cellular mechanisms, including autophagy and transcription regulation. In this study, we investigated the transcriptional modifications of the autophagy pathway in models of MJD and assessed whether modulating the levels of the affected autophagy-associated transcripts (AATs) would alleviate MJD-associated pathology. Our results show that autophagy is impaired at the transcriptional level in MJD, affecting multiple AATs, including Unc-51 like autophagy activating kinase 1 and 2 (ULK1 and ULK2), two homologs involved in autophagy induction. Reinstating ULK1/2 levels by adeno-associated virus (AAV)-mediated gene transfer significantly improved motor performance while preventing neuropathology in two in vivo models of MJD. Moreover, in vitro studies showed that the observed positive effects may be mainly attributed to ULK1 activity. This study provides strong evidence of the beneficial effect of overexpression of ULK homologs, suggesting these as promising instruments for the treatment of MJD and other neurodegenerative disorders.

Quality of Work Life and Contribution to Productivity: Assessing the Moderator Effects of Burnout Syndrome.

This study is focused on assessing the effects of burnout as a moderator of the relationship between employees' quality of work life (QWL) and their perceptions of their contribution to the organization's productivity by integrating the QWL factors into the trichotomy of (de)motivators of productivity in the workplace. The empirical findings resulting from an OLS multiple regression, with interaction terms, applied to a survey administered at 514 employees in 6 European countries, point out two important insights: (i) QWL hygiene factors (e.g., safe work environment and occupational healthcare) positively and significantly influence the contribution to productivity; and (ii) burnout de-motivator factors (that is, low effectiveness, cynicism, and emotional exhaustion) significantly moderate the relationship between QWL and the contribution to productivity. Combining burnout with other QWL components, such as occupational health, safe work, and appropriate salary, new insights are provided concerning the restricting (i.e., low effectiveness and cynicism) and catalyzing (emotional exhaustion) burnout components of contribution to productivity. These findings are particularly relevant given the increased weight of burnout, mental disorders and absenteeism in the labor market, affecting individuals' quality of life and organizations' performance and costs.

As lesões músculo-esqueléticas relacionadas com o trabalho nos enfermeiros, em cuidados de saúde diferenciados / Work-related musculoskeletal injuries in nurses in differentiated health care

Enquadramento: As Lesões Músculo-Esqueléticas Relacionadas com o Trabalho (LMERT) continuam a ser um problema de saúde comum, e originam uma sobrecarga de custos para os indivíduos, empresas e sociedade em geral. Este fenómeno não é só um desafio de saúde ocupacional, mas também um desafio de saúde pública e social, para o qual os Enfermeiros Especialistas em Enfermagem de Reabilitação (EEER) devem contribuir na implementação de medidas para a sua diminuição. Objetivo: Avaliar a prevalência das LMERT nos enfermeiros e a sua relação com as condições laborais e a condição de saúde dos trabalhadores. Metodologia: O estudo é quantitativo, observacional e transversal. A amostra é de conveniência, não probabilística, composta por 104 enfermeiros de sete serviços de um Hospital Distrital, da região centro. A colheita de dados foi feita em dois momentos, inicialmente através da aplicação de um questionário autopreenchido, que incluía o Questionário Nórdico de Lesões Músculo-Esqueléticas (QNM) e, posteriormente, foi aplicado o Índice Movement and Assitance of Hospital Patients (MAPO) para avaliação dos locais de trabalho, sendo salvaguardados os procedimentos ético-deontológicos. Resultados: As taxas de prevalência de sintomatologia autorreferida mais exuberantes, nos últimos 12 meses, são a região lombar (66,3%), a região dorsal (59,6%) e a região cervical (55,8%); nos últimos 7 dias, a região lombar destaca-se com taxas de incidência de 40,4%. No último ano, a região lombar, punhos/mãos e tornozelos/pés impediram de trabalhar 3,8% dos inquiridos. Os níveis de exposição dos enfermeiros a fatores de risco, obtido pelo Índice MAPO, foram elevados nos serviços de Medicina III A (7,91) e Especialidades Cirúrgicas (7,19) e moderado nos restantes serviços. Observaram-se algumas relações significativas entre a prevalência de LMERT em diferentes segmentos corporais e alguns fatores de risco, nomeadamente fumar, idade, Índice de Massa Corporal (IMC), peso, tempo de serviço, horas/semana, rácios e segundo emprego. Conclusão: O EEER, inserido numa equipa multidisciplinar, deve promover a alteração de estilos de vida, através de sessões de educação para a saúde, alteração de hábitos de vida, bem como sessões de ginástica laboral, já praticadas internacionalmente, com resultados muito positivos. Sugerem-se planos de intervenção a curto e médio prazo para diminuir os níveis de exposição dos enfermeiros a fatores de risco de LMERT dos diferentes serviços, cujo impacto deverá ser avaliado oportunamente.

The blood-brain barrier is disrupted in Machado-Joseph disease/spinocerebellar ataxia type 3: evidence from transgenic mice and human post-mortem samples.

Blood-brain barrier (BBB) disruption is a common feature in neurodegenerative diseases. However, BBB integrity has not been assessed in spinocerebellar ataxias (SCAs) such as Machado-Joseph disease/SCA type 3 (MJD/SCA3), a genetic disorder, triggered by polyglutamine-expanded ataxin-3. To investigate that, BBB integrity was evaluated in a transgenic mouse model of MJD and in human post-mortem brain tissues.Firstly, we investigated the BBB permeability in MJD mice by: i) assessing the extravasation of the Evans blue (EB) dye and blood-borne proteins (e.g fibrinogen) in the cerebellum by immunofluorescence, and ii) in vivo Dynamic Contrast Enhanced-Magnetic Resonance Imaging (DCE-MRI). The presence of ataxin-3 aggregates in brain blood vessels and the levels of tight junction (TJ)-associated proteins were also explored by immunofluorescence and western blotting. Human brain samples were used to confirm BBB permeability by evaluating fibrinogen extravasation, co-localization of ataxin-3 aggregates with brain blood vessels and neuroinflammation.In the cerebellum of the mouse model of MJD, there was a 5-fold increase in EB accumulation when compared to age-matched controls. Moreover, vascular permeability displayed a 13-fold increase demonstrated by DCE-MRI. These results were validated by the 2-fold increase in fibrinogen extravasation in transgenic animals comparing to controls. Interestingly, mutant ataxin-3 aggregates were detected in cerebellar blood vessels of transgenic mice, accompanied by alterations of TJ-associated proteins in cerebellar endothelial cells, namely a 29% decrease in claudin-5 oligomers and a 10-fold increase in an occludin cleavage fragment. These results were validated in post-mortem brain samples from MJD patients as we detected fibrinogen extravasation across BBB, the presence of ataxin-3 aggregates in blood vessels and associated microgliosis.Altogether, our results prove BBB impairment in MJD/SCA3. These findings contribute for a better understanding of the disease mechanisms and opens the opportunity to treat MJD with medicinal products that in normal conditions would not cross the BBB.

Neuropeptide Y Enhances Progerin Clearance and Ameliorates the Senescent Phenotype of Human Hutchinson-Gilford Progeria Syndrome Cells.

Hutchinson-Gilford progeria syndrome (HGPS, or classical progeria) is a rare genetic disorder, characterized by premature aging, and caused by a de novo point mutation (C608G) within the lamin A/C gene (LMNA), producing an abnormal lamin A protein, termed progerin. Accumulation of progerin causes nuclear abnormalities and cell cycle arrest ultimately leading to cellular senescence. Autophagy impairment is a hallmark of cellular aging, and the rescue of this proteostasis mechanism delays aging progression in HGPS cells. We have previously shown that the endogenous Neuropeptide Y (NPY) increases autophagy in hypothalamus, a brain area already identified as a central regulator of whole-body aging. We also showed that NPY mediates caloric restriction-induced autophagy. These results are in accordance with other studies suggesting that NPY may act as a caloric restriction mimetic and plays a role as a lifespan and aging regulator. The aim of the present study was, therefore, to investigate if NPY could delay HGPS premature aging phenotype. Herein, we report that NPY increases autophagic flux and progerin clearance in primary cultures of human dermal fibroblasts from HGPS patients. NPY also rescues nuclear morphology and decreases the number of dysmorphic nuclei, a hallmark of HGPS cells. In addition, NPY decreases other hallmarks of aging as DNA damage and cellular senescence. Altogether, these results show that NPY rescues several hallmarks of cellular aging in HGPS cells, suggesting that NPY can be considered a promising strategy to delay or block the premature aging of HGPS.

Quality of Work Life and Organizational Performance: Workers' Feelings of Contributing, or Not, to the Organization's Productivity.

This is a pioneering study on the relationship between quality of work life and the employee's perception of their contribution to organizational performance. It unveils the importance of subjective and behavioral components of quality of work life and their influence on the formation of the collaborator's individual desire to contribute to strengthening the organization's productivity. The results obtained indicate that for workers: feeling their supervisors' support through listening to their concerns and by sensing they take them on board; being integrated in a good work environment; and feeling respected both as professionals and as people; positively influence their feeling of contributing to organizational performance. The results are particularly relevant given the increased weight of services in the labor market, together with intensified automation and digitalization of collaborators' functions. The findings also contribute to the ongoing debate about the need for more work on the subjective and behavioral components of so-called smart and learning organizations, rather than focusing exclusively on remuneration as the factor stimulating organizational productivity based on the collaborator's contribution.

Repeated Mesenchymal Stromal Cell Treatment Sustainably Alleviates Machado-Joseph Disease.

Machado-Joseph disease (MJD) or spinocerebellar ataxia type 3, the most common dominant spinocerebellar ataxia (SCA) worldwide, is caused by over-repetition of a CAG repeat in the ATXN3/MJD1 gene, which translates into a polyglutamine tract within the ataxin-3 protein. There is no treatment for this fatal disorder. Despite evidence of the safety and efficacy of mesenchymal stromal cells (MSCs) in delaying SCA disease progression in exploratory clinical trials, unanticipated regression of patients to the status prior to treatment makes the investigation of causes and solutions urgent and imperative. In the present study, we compared the efficacy of a single intracranial injection with repeated systemic MSC administration in alleviating the MJD phenotype of two strongly severe genetic rodent models. We found that a single MSC transplantation only produces transient effects, whereas periodic administration promotes sustained motor behavior and neuropathology alleviation, suggesting that MSC therapies should be re-designed to get sustained beneficial results in clinical practice. Furthermore, MSC promoted neuroprotection, increased the levels of GABA and glutamate, and decreased the levels of Myo-inositol, which correlated with motor improvements, indicating that these metabolites may serve as valid neurospectroscopic biomarkers of disease and treatment. This study makes important contributions to the design of new clinical approaches for MJD and other SCAs/polyglutamine disorders.

Molecular Mechanisms and Cellular Pathways Implicated in Machado-Joseph Disease Pathogenesis.

Machado-Joseph disease (MJD) is a dominantly inherited disorder originally described in people of Portuguese descent, and associated with the expansion of a CAG tract in the coding region of the causative gene MJD1/ATX3. The CAG repeats range from 10 to 51 in the normal population and from 55 to 87 in SCA3/MJD patients. MJD1 encodes ataxin-3, a protein whose physiological function has been linked to ubiquitin-mediated proteolysis. Despite the identification of the causative mutation, the pathogenic process leading to the neurodegeneration observed in the disease is not yet completely understood. In the past years, several studies identified different molecular mechanisms and cellular pathways as being impaired or deregulated in MJD. Autophagy, proteolysis or post-translational modifications, among other processes, were implicated in MJD pathogenesis. From these studies it was possible to identify new targets for therapeutic intervention, which in some cases proved successful in models of disease.

Thyroid and parathyroid tumours in patients submitted to X-ray scalp epilation during the tinea capitis eradication campaign in the North of Portugal (1950-1963).

Tinea capitis attained epidemical proportions in the fifth and sixth decades in Portugal, as in other countries. Before starting the utilization of griseofulvin in 1959, the best approach to treat tinea capitis infection was X-ray scalp epilation combined with topical antimycotic ointments. A long-term side effect of this therapy is thyroid disease, namely thyroid cancer; data on parathyroid lesions (hyperplasia, adenoma and carcinoma) are scarce. We observed clinically 1,375 individuals irradiated in childhood for tinea capitis treatment in the North of Portugal with the main purpose of evaluating thyroid and parathyroid tumours as possible sequelae of the irradiation treatment. For each individual, a cervical ultrasound and a serum calcium measurement were proposed. Fine needle aspiration cytology was suggested whenever ultrasound thyroid nodules presented suspicious features. We observed a 54 % frequency of thyroid nodules and a 2.8 % frequency of thyroid carcinoma (38/1,375). Nineteen of the 38 (50 %) carcinomas were diagnosed by us, whereas the remaining 19 carcinomas had been diagnosed and treated prior to our observation. The carcinomas were significantly more frequent in women than in men. Benign excised lesions were also significantly more frequent in women and in patients irradiated at younger ages. Seven women, considered asymptomatic until our clinical observation, had laboratory signs of hyperparathyroidism. The data we have obtained, namely high thyroid cancer frequency, corroborate previous data from childhood irradiated cohorts and highlight the need for the close follow-up of these populations in order to identify and treat early undiagnosed head and neck lesions. No evidence of increased parathyroid disease was found in this cohort of head and neck X-irradiated patients.

Crosstalk between inflammation, iron metabolism and endothelial function in Behçet's disease.

Behçet's disease (BD) is a rare chronic vasculitis of unclear etiology. It has been suggested that inflammatory response has an important role in BD pathophysiology. Herein, we aimed to study the interplay between inflammation, iron metabolism and endothelial function in BD and search for its putative association with disease activity. Twenty five patients clinically diagnosed with BD were selected and twenty four healthy age-sex matched individuals participated as controls. Results showed an increase of total number of circulating white blood cells and neutrophils, serum transferrin, total iron binding capacity, mieloperoxidase (MPO), ceruloplasmin (Cp), C reactive protein, ß2 microglobulin and Cp surface expression in peripheral blood monocytes in BD patients comparatively to healthy individuals (p < 0,05). Of notice, the alterations observed were associated to disease activity status. No significant differences between the two groups were found in serum nitric oxide concentration. The results obtained suggest an important contribution from innate immunity in the pathogenesis of this disease. In particular, surface expression of leukocyte-derived Cp may constitute a new and relevant biomarker to understand BD etiology.

Mitochondrial D310 D-Loop instability and histological subtypes in radiation-induced cutaneous basal cell carcinomas.

BACKGROUND: Basal cell carcinoma (BCC) is the most frequent skin cancer. An elevated prevalence of BCC has been associated with radiation, namely after the Tinea capitis epilation treatment, being these tumors described as more aggressive. Mitochondrial DNA (mtDNA) mutations have been reported in many human tumors, but their occurrence in BCC is poorly documented. OBJECTIVE: The purpose of this work was to evaluate BCC histological subtypes in individuals subjected to X-ray epilation for Tinea capitis treatment when compared to non-irradiated patients. Moreover we also wanted to evaluate mitochondrial D-Loop instability in both groups of BCCs in order to compare the frequency of D-Loop mutations in post-irradiation BCC versus sporadic BCC. METHODS: 228 histological specimens corresponding to BCCs from 75 irradiated patients and 60 non-irradiated patients were re-evaluated for histological subtype. Subsequently, we sequenced the D-Loop 310 repeat in blood, oral mucosa, tumor lesions and, whenever available, non-tumoral adjacent tissue from these patients. RESULTS: The infiltrative subtype of BCC, considered to be more aggressive, was significantly more frequent in irradiated patients. BCC D-Loop D310 mutation rate was significantly higher in irradiated BCCs than in the non-irradiated ones. Moreover, it was associated with a higher irradiation dose. The presence of mtDNA heteroplasmy in patients' blood was associated with a higher mutation rate in the BCCs suggesting that a more unstable genotype could predispose to mtDNA somatic mutation. CONCLUSIONS: Our results suggest that radiation-induced BCCs may be considered to be more aggressive tumors. Further studies are needed to clarify the role of mtDNA D-Loop mutations in tumors from irradiated patients.

Genetic alterations in thyroid tumors from patients irradiated in childhood for tinea capitis treatment.

OBJECTIVE: Exposure to ionizing radiation at young age is the strongest risk factor for the occurrence of papillary thyroid carcinoma (PTC). RET/PTC rearrangements are the most frequent genetic alterations associated with radiation-induced PTC, whereas BRAF and RAS mutations and PAX8-PPARG rearrangement have been associated with sporadic PTC. We decided to search for such genetic alterations in PTCs of patients subjected in childhood to scalp irradiation. DESIGN: We studied 67 thyroid tumors from 49 individuals irradiated in childhood for tinea capitis scalp epilation: 36 malignant (12 cases of conventional PTC (cPTC), two cPTC metastases, 20 cases of follicular variant PTC (FVPTC), one oncocytic variant of PTC and one follicular carcinoma) and 31 follicular thyroid adenomas. METHODS: The lesions were screened for the BRAF(V600E) and NRAS mutations and for RET/PTC and PAX8-PPARG rearrangements. RESULTS: BRAF(V600E) mutation was detected in seven of 14 (50%) cPTC and two of 20 FVPTC (10%) (P=0.019). NRAS mutation was present in one case of FVPTC (5%). RET/PTC1 rearrangement was found, by RT-PCR, in one of 17 cases (5.9%) and by fluorescence in situ hybridization in two of six cases (33%). PAX8-PPARG rearrangement was not detected in any carcinoma. None of the follicular adenomas presented any of the aforementioned genetic alterations. CONCLUSIONS: The prevalence of BRAF(V600E) mutation in our series is the highest reported in series of PTCs arising in radiation-exposed individuals. The prevalence of RET/PTC1 rearrangement fits with the values recently described in a similar setting.

Head and neck basal cell carcinoma prevalence in individuals submitted to childhood X-ray epilation for tinea capitis treatment.

BACKGROUND: A higher prevalence for basal cell carcinoma (BCC) has been associated with radiation, namely with tinea capitis epilation treatment. OBJECTIVE: To evaluate the prevalence of head and neck basal cell carcinoma (BCC) and to identify the major risk factors for BCC in individuals irradiated in childhood for tinea capitis treatment. METHODS: We clinically observed 1,308 individuals from an original cohort of 5,356 irradiated between 1950 and 1963, registering previous skin lesions excisions and proposing for surgery all the suspicious lesions detected. In 585 participants, 47 with BCC, the skin pigmentation was measured. RESULTS: The overall prevalence of BCC was 8.0% and of multiple BCC was 2.4%. Both total (14.7%) and multiple BCC (6.6%) were significantly more common in the individuals who had received a higher radiation dose. Multiple BCC was more prevalent (3.7%) in younger irradiated individuals and total BCC (9.4%) in women. Participants with BCC and without BCC presented similar skin pigmentation. CONCLUSION: Younger age at irradiation, higher dose and female gender increased the risk of developing BCC in these irradiated individuals.