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Background: Tricuspid valve repair during mitral valve replacement surgery remains a controversial topic. The risk-benefit ratio in some populations remains uncertain, especially in rheumatic heart disease patients. Therefore, we aimed to evaluate the impact of concomitant tricuspid repair on surgical mortality in patients undergoing cardiac surgery due to rheumatic mitral valve disease who have moderate to severe functional tricuspid regurgitation. Methods: This is a prospective cohort study from January 1, 2017, to December 30, 2022. All patients over 18 years of age who underwent cardiac surgery to correct rheumatic mitral valve disease with concomitant moderate to severe tricuspid regurgitation were included. The primary outcome was a surgical death. In an exploratory analysis, clinical and echocardiographic data were obtained 2 years after the procedure. Results: Of the 144 patients included, 83 (57.6%) underwent tricuspid valve repair. The mean age was 46.2 (±12.3) years with 107 (74.3%) female individuals, the median left ventricular ejection fraction was 61.0% (55-67), and systolic pulmonary artery pressure (sPAP) was 55.0 mmHg (46-74), with 45 (31.3%) individuals with right ventricular dysfunction. The total in-hospital mortality was 15 (10.4%) individuals, and there was no difference between the groups submitted or not to tricuspid repair: 10 (12.0%) vs. 5 (7.5%); p = 0.46, respectively. There was an association with one variable independently: the sPAP value, relative risk 1.04 (1.01-1.07), p = 0.01. The estimated cut-off value of sPAP that indicates higher early mortality through the receiver operating characteristic curve (area 0.70, p = 0.012) was 73.5 mmHg. Conclusions: Performing tricuspid repair in individuals who were undergoing cardiac surgery to correct rheumatic mitral valve disease was not associated with increased surgical mortality. Our results suggest the safety of tricuspid repair even in this high-risk population, reinforcing the recommendations in current guidelines.
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Hypertrophic cardiomyopathy (HCM) is a heart condition characterized by cellular and metabolic dysfunction, with mitochondrial dysfunction playing a crucial role. Although the direct relationship between genetic mutations and mitochondrial dysfunction remains unclear, targeting mitochondrial dysfunction presents promising opportunities for treatment, as there are currently no effective treatments available for HCM. This review adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Extension for Scoping Reviews guidelines. Searches were conducted in databases such as PubMed, Embase, and Scopus up to September 2023 using "MESH terms". Bibliographic references from pertinent articles were also included. Hypertrophic cardiomyopathy (HCM) is influenced by ionic homeostasis, cardiac tissue remodeling, metabolic balance, genetic mutations, reactive oxygen species regulation, and mitochondrial dysfunction. The latter is a common factor regardless of the cause and is linked to intracellular calcium handling, energetic and oxidative stress, and HCM-induced hypertrophy. Hypertrophic cardiomyopathy treatments focus on symptom management and complication prevention. Targeted therapeutic approaches, such as improving mitochondrial bioenergetics, are being explored. This includes coenzyme Q and elamipretide therapies and metabolic strategies like therapeutic ketosis. Understanding the biomolecular, genetic, and mitochondrial mechanisms underlying HCM is crucial for developing new therapeutic modalities.
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Cardiomiopatia Hipertrófica , Mutação , Oxirredução , Transdução de Sinais , Humanos , Cardiomiopatia Hipertrófica/genética , Cardiomiopatia Hipertrófica/metabolismo , Animais , Mitocôndrias/metabolismo , Mitocôndrias/genética , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismoRESUMO
BACKGROUND: Programmed cell death-1 (PD-1) and PD ligand-1 (PD-L1) expression predict the biological behaviour, aggressiveness, and response to immune checkpoint inhibitors in different cancers. We reviewed the published data on PD-L1 expression in pituitary tumours from the perspective of its biological role and prognostic usefulness. SUMMARY: A literature review focused on PD-L1 expression in pituitary tumours was performed. Six immunohistochemistry-based studies which assessed PD-L1 positivity in pituitary tumours were included, encompassing 704 patients. The cohort consisted of 384 (54.5%) nonfunctioning tumours and 320 (43.5%) functioning pituitary tumours. PD-L1 expression was positive in 248 cases (35.2%). PD-L1 positivity rate was higher in functioning than in nonfunctioning tumours (46.3% vs. 26.0%; p < 0.001) but also higher in growth hormone-secreting tumours (56.7%) and prolactinomas (53.6%) than in thyrotroph (33.3%) or corticotroph tumours (20.6%). While proliferative pituitary tumours showed higher rate of PD-L1 positivity than non-proliferative tumours (p < 0.001), no association with invasion or recurrence was found. KEY MESSAGES: PD-L1 is expressed in a substantial number of pituitary tumours, predominantly in the functioning ones. PD-L1 positivity rates were significantly higher in proliferative pituitary tumours in comparison to non-proliferative tumours, but no differences were found concerning invasive or recurrent pituitary tumours. More studies following homogeneous and standardised methodologies are needed to fully elucidate the role and usefulness of PD-L1 expression in pituitary tumours.
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Antígeno B7-H1 , Neoplasias Hipofisárias , Neoplasias Hipofisárias/metabolismo , Humanos , Antígeno B7-H1/metabolismoRESUMO
Introduction: Management of pediatric cancer patients involves invasive procedures such as punctures, injections, catheter placements, and chemotherapy which can generate fatigue, nausea, vomiting, anxiety, and pain. Virtual Reality (VR) is a nonpharmacological intervention classified as a cognitive-behavioral method to relieve symptoms. Methods: We designed a crossover protocol and included 20 patients between 9 and 12 years old; ten were male. All patients had acute lymphoblastic leukemia diagnosis and were treatedwith St. Jude's XV protocol in the maintenance phase. Pain and anxiety were measured with validated scales in the pediatric population. Results: Although we used a small group of patients, we found statistical difference in the reduction of anxiety and perception of time. Discussion: These results open a window to non-pharmacological treatments and show a strategy to improve quality of life in children inside the hospital.
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BACKGROUND: Although motorcycle helmets can save lives in case of a crash, no helmet use data are available for many countries. When data is available, it is often only analysed as a global average, preventing targeted road safety education and legislative action. In this study, we conducted a detailed analysis of motorcycle helmet use in the capital of Madagascar. METHODS: Using a cross-sectional observational field survey framework, we observed 17 230 individual motorcycles. We systematically recorded motorcycle riders' helmet use, position on the motorcycle, rider numbers and gender. RESULTS: We found a general helmet use of 76.1%. Observed drivers had a significantly higher helmet use (84.6%) than passengers (47.7%), and subsequently helmet use per motorcycle decreased significantly when the number of riders per motorcycle increased. Female drivers had significantly higher helmet use than male drivers, and female passengers had significantly higher helmet use than male passengers. That is, on the same position of the motorcycle, female riders behaved safer than male riders. However, since female riders were more often passengers than drivers, their average helmet use was lower than that of male riders overall. Contrary to findings from other countries, motorcycle helmet use did not differ significantly throughout the day but was relatively constant. CONCLUSION: Our results show the potential for injury and fatality prevention in Madagascar through increased passenger helmet use. This increase would also proportionally benefit female riders more than male riders. Findings regarding road safety legislation's applied impact, education, enforcement and future research needs are discussed.
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BACKGROUND AND PURPOSE: Undiagnosed atrial fibrillation (AF) is a major risk factor for stroke that can go unnoticed in individuals with embolic stroke of undetermined source (ESUS) or cryptogenic stroke (CS). Early detection is critical for stroke prognosis and secondary prevention. This study aimed to determine if blood biomarkers of myocardial stress can accurately predict AF in patients with ESUS/CS, which would allow the identification of those who would benefit from closer monitoring. METHODS: In February 2023 we performed a systematic date-unrestricted search of three databases for studies on patients with ESUS/CS who were subsequently diagnosed with AF. We examined the relationships between AF and serum myocardial stress markers such as brain natriuretic peptide (BNP), N-terminal-pro-BNP (NT-proBNP), midregional proatrial natriuretic peptide, and troponin. RESULTS: Among the 1,527 studies reviewed, 23 eligible studies involving 6,212 participants, including 864 with AF, were analyzed. A meta-analysis of 9 studies indicated that they demonstrated a clear association between higher NT-proBNP levels and an increased risk of AF, with adjusted and raw data indicating 3.06- and 9.03-fold higher AF risks, respectively. Lower NT-proBNP levels had a pooled negative predictive value of 91.7%, indicating the potential to rule out AF with an 8% false-negative rate. CONCLUSIONS: Further research is required to fully determine the potential of biomarkers for AF detection after stroke, as results from previous studies lack homogeneity. However, lower NT-proBNP levels have potential in ruling out AF in patients with ESUS/CS. Combining them with other relevant biomarkers may enhance the precision of identifying patients who will not benefit from extended monitoring, which would optimize resource allocation and patient care.
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Objetivo Los Servicios de Salud en Chile tienen una demanda insatisfecha en ortodoncia y muchas de las interconsultas no son pertinentes. Buscando una solución, el Servicio de Salud Metropolitano Norte (SSMN) implementó la "Guía de Referencia Clínica Ortodoncia (GRCO) para Servicios Públicos de Salud". El objetivo de este estudio fue evaluar si existe asociación entre utilizar GRCO y pertinencia en derivaciones a Ortodoncia realizadas por odontólogos de Atención Primaria. Materiales y Métodos Se realizó un estudio observacional analítico en 167 pacientes derivados por odontólogos que utilizaron la GRCO y 167 pacientes derivados por odontólogos que no la utilizaron. Una especialista en ortodoncia evaluó pertinencia en la derivación. Los datos se analizaron mediante la prueba de chi-cuadrado, y la prueba t-test. Resultados De los odontólogos que usaron la guía solo un 3% de sus derivaciones fueron no pertinentes, mientras que aquellos que no la usaron, tuvieron un 54% de derivaciones no pertinentes (p <0,001). Odontólogos que no usan la GRCO presentan 38 veces más probabilidad de realizar una derivación no pertinente. (OR 38,8; IC 14,9 - 125,9). Conclusión El uso de Guía de Referencia Clínica a Ortodoncia se asocia fuertemente con la pertinencia en la derivación de pacientes a la especialidad ortodoncia.
Objective. Health Services in Chile have an unsatisfied demand in orthodontics and the largest waiting list for dental specialties, with many of the referrals being irrelevant. Seeking a solution, the North Metropolitan Health Service (SSMN) implemented the "Orthodontic Clinical Referral Guideline (GRCO) for Public Health Services", to define the appropriateness of referrals. The objective of this study was to assess whether there is an association between the GRCO and the appropriateness of orthodontic referrals made by Primary Health Care dentists of the SSMN. Materials and methods. An analytical observational study was carried out in 167 patients referred by dentists who used the GRCO and 167 patients referred by dentists who did not use it. A calibrated orthodontic specialist assessed the relevance of the referral. The data was analyzed using the chi-square test, and the t-test. Results. Only 3% of the referrals made by dentists who used the GRCO were inappropriate, compared to 54% of those who did not use it. Dentists who do not use the GRCO are 38 times more likely to make an inappropriate referral than those who adhere to the GRCO (OR 38.8; CI 14.9 - 125.9) Conclusion. The use of the Orthodontic Clinical Referral Guideline is strongly associated with appropriateness in referring patients to the orthodontic specialty.
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Humanos , Masculino , Feminino , Ortodontia , Pacientes , Guia de Prática Clínica , Serviços de Saúde BucalRESUMO
When an initial marketing authorization of a pharmaceutical product is granted, a substantial number of chemistry, manufacturing and control (CMC) post approval changes (PACs) have to be managed by the manufacturers. Despite efforts undertaken over the years by multiple regulatory jurisdictions, there is still heterogeneity in terms of regulatory requirements and timelines across national regulatory authorities (NRAs). This creates complexity in managing global CMC PACs, putting the supply of medical products at risk. Regulators have developed regulatory mechanisms which aim at accelerating the reviews and approvals of PACs by NRAs. The World Health Organization (WHO) is supporting the concept of 'reliance' amongst NRAs which are encouraged to rely on the assessment completed by a â³high-performing authorityâ³. The objective is to accelerate the overall process for PACs, ultimately fostering more equitable and timely access of medical products to populations who need them. With the support of Health Canada, WHO, Pan American Health Organization, and the Paul-Ehrlich-Institut, Sanofi has launched a pilot using the principles of reliance for a CMC PAC for a vaccine, with 21 NRAs who accepted to participate in the pilot. The objective of this pilot was to apply these principles to reduce the approval timeline to a maximum of 6 months, in all countries after an initial approval is granted by a reference authority. We discussed the opportunities and challenges of implementing reliance principles for CMC PACs. We also described the pilot experience, by sharing initial lessons learned from the Step 1 of this pilot, which consist of engaging the reference authority and the NRAs.
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CONTEXT: Studies that analyze the temporal trend and spatial clustering of medical education indicators are scarce, especially in developing countries such as Brazil. This analysis is essential to subsidize more equitable policies for the medical workforce in the states and regions of Brazil. Thus, this study aimed to analyze the temporal trend and identify spatial clusters of medical education indicators in Brazil disaggregated by public and private education, states, and regions. METHODS: A time-series ecological study was conducted using data from the Higher Education Census of the Ministry of Education from 2010 to 2021. The study analyzed vacancy density indicators of active and former students/100,000 population, disaggregated by public and private education, 27 states, and 5 regions in Brazil. Prais-Winsten regression was used for trend analyses of indicators. Hot Spot Analysis (Getis-Ord Gi*) was used to identify spatial clusters of indicators. RESULTS: The number of medical schools increased by 102.2% between 2010 and 2021. A total of 366 medical schools offered 54,870 vacancies at the end of 2021. Vacancy density and active and former students increased significantly in the period, but this increase was greater in private institutions. Most states and regions showed an increasing trend in the indicators, with higher increase percentages in private than in public schools. Hot spot spaces changed over time, concentrated in the southeast, center-west, and north at the end of 2021. Medical education remains uneven in Brazil, with a low provision in regions with low socioeconomic development, academic structure, and health services, represented by regions in the north and northeast. CONCLUSIONS: There is a growing trend in medical education indicators in Brazil, especially in the private sector. Spatial clusters were found predominantly in the southeast, center-west, and north. These results indicate the need for more equitable medical education planning between the regions.
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Educação Médica , Humanos , Fatores de Tempo , Brasil/epidemiologia , Faculdades de Medicina , Análise por ConglomeradosRESUMO
Objetivo: Ponderar, através de um relato de caso, os benefícios da escolha por um tratamento conservador em casos de ameloblastoma unicístico. Relato de caso: O presente trabalho relata um ameloblastoma unicístico em uma paciente do sexo feminino com 20 anos que procurou atendimento 2 anos após notar a presença da lesão. Foi realizado um protocolo de tratamento conservador, e após 1 anos e 6 meses de proservação constatou-se uma recidiva, que foi removida por enucleação e curetagem. Conclusão: O ameloblastoma não é um tumor maligno com capacidade de metástase e não deve ser tratado como tal. O tratamento radical dessa patologia cria sequelas que tornam a reabilitação difícil. Em contrapartida, o tratamento conservador pode ser realizado em ambiente ambulatorial, trazendo baixos impactos funcionais, estéticos e psicológicos ao paciente... (AU)
Objective: To consider, through a case report, the benefits of choosing a conservative treatment in cases of unicystic ameloblastoma. Case report: This paper reports a unicystic ameloblastoma in a 20-year-old female patient who sought care 2 years after noticing the presence of the lesion. A conservative treatment protocol was performed, and after 1 year and 6 months of follow-up, a recurrence was found, which was removed by enucleation and curettage. Conclusion: Ameloblastoma is not a malignant tumor capable of metastasizing and should not be treated as such. The radical treatment of this pathology creates sequelae that make rehabilitation difficult. On the other hand, conservative treatment can be performed in an outpatient setting, bringing low functional, aesthetic and psychological impacts to the patient... (AU)
Objetivo: Considerar, a través de un reporte de caso, los beneficios de elegir un tratamiento conservador en casos de ameloblastoma uniquístico. Reporte de caso: Este trabajo reporta un ameloblastoma uniquístico en una paciente de 20 años de edad que acude a consulta 2 años después de notar la presencia de la lesión. Se realizó un protocolo de tratamiento conservador y luego de 1 año y 6 meses de seguimiento se encontró una recidiva, la cual fue extirpada mediante enucleación y curetaje. Conclusión: El ameloblastoma no es un tumor maligno capaz de metastatizar y no debe ser tratado como tal. El tratamiento radical de esta patología deja secuelas que dificultan la rehabilitación. Por otro lado, el tratamiento conservador puede realizarse en forma ambulatoria, trayendo bajo impacto funcional, estético y psicológico al paciente... (AU)
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Humanos , Feminino , Adulto , Tumores Odontogênicos , Tratamento ConservadorRESUMO
As the World slowly emerged from the then-ongoing pandemic, War broke out in Europe with the invasion of Ukraine by Russia. The enduring military conflict in Ukraine has had sweeping consequences at the human, social, economic, and environmental levels, not only for the nations involved but across Europe and globally. Damaged infrastructures, severe disruption of economic activity, and forced migration have led to negative impacts on sustainability. The COVID-19 pandemic has added another layer of complexity to this already challenging situation, as the virus has further disrupted economic activity and strained healthcare systems. Herein, we examine how the intersection of war and COVID-19 affect the United Nations' 2030 Agenda for Sustainable Development. How these intersecting challenges have impacted efforts to build a more sustainable future, and how these impacts have a global reach are also assessed. The broader implications of this case for understanding the linkages between conflict, pandemics, and sustainability more generally are also considered, relating these with the United Nations' Sustainable Development Goals (SDG) Agenda for 2030.
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COVID-19 , Militares , Humanos , Ucrânia/epidemiologia , Pandemias , COVID-19/epidemiologia , Europa (Continente)RESUMO
The aim of this study was to analyze the scenario of medical residency programs (MRPs) in the north region of Brazil as well as the contextual determinants (socioeconomic, structural, and epidemiological) influencing the number of MRPs in this region. An ecological study was conducted using MRPs data from 2022. This study used multiple data sources. MRP indicators were described based on the Brazilian state and specialty. The dependent variable was the number of MRPs. The independent variables included sociodemographic, structural, and epidemiological factors. Poisson regression was performed to analyze the association between contextual variables and the number of MRPs. The results showed that only 3.6% of the municipalities had authorized MRPs. The idleness rate in the region was 46.0%, with family and community medicine as the specialties with the greatest idleness. The total density of authorized vacancies in the MRPs was 14.0 vacancies per 100,000 inhabitants. The models showed that with each increase of one unit of the vulnerability index (Socioeconomic Index in the Geographic Context for Health Studies-GeoSES), the number of MRPs increased, ranging from 8122 (p value < 0.001) to 11,138 (p value < 0.001). With each increase in undergraduate degrees in medicine, the number of MRPs increased by 0.945 (p value < 0.001). With each increase of 1 physician per 1000 population, the number of MRPs increased from 0.537 (p value < 0.001) to 0.845 (p value < 0.001). With each increase of one unit in general hospitals, specialized hospitals, teaching hospitals, and primary healthcare units, the number of MRPs increased by 0.176 (p value < 0.001), 0.168 (p value < 0.001), 0.022 (p value < 0.001) and 0.032 (p value < 0.001), respectively. Finally, with each increase of one death per 100,000 inhabitants, the overall mortality rate increased, ranging from 0.006 (p value < 0.001) to 0.022 (p value < 0.001). The study showed a low supply of MRPs in the northern region, a high rate of idleness, and important socioeconomic, structural, and epidemiological determinants of the number of MRPs.
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PURPOSE: A clinicopathological classification has been designed to predict recurrence/progression in patients with pituitary adenomas (PAs). We aimed to study its usefulness in predicting PAs that will have a challenging disease course and may require more often complex multimodal and multiple therapeutic approaches. METHODS: Retrospective analysis of 129 patients with PAs operated in our institution between 2001 and 2020 (84 non-clinically functioning PAs, 32 acromegaly, 9 Cushing's disease, 2 prolactinomas and 2 thyrotropinomas). Grading was based on invasion and proliferation: 1a (non-invasive, non-proliferative; n = 59), 1b (non-invasive, proliferative; n = 17), 2a (invasive, non-proliferative; n = 38), and 2b (invasive, proliferative; n = 15). RESULTS: Of the 129 patients, 68 (52.7%) were females, and the mean age at diagnosis was 53.7 ± 15.4 years. The mean follow-up duration was 93.1 ± 61.8 months. Grade 2b PAs when compared to other grades (2b-2a-1b-1a) had significantly higher rates of persistent tumor remnant within 1-year after operation (93-78-18-30%; p < 0.001), active disease at last follow-up (40-27-12-10%; p = 0.004), re-operation (27-16-0-5%; p = 0.023), irradiation (53-38-12-7%; p < 0.001), multimodal treatment (67-49-18-25%; p = 0.003), multiple treatment (33-27-6-9%; p = 0.017). Patients with grade 2b PAs also required a higher mean number of treatments (2.6-2.1-1.2-1.4; p < 0.001). CONCLUSIONS: This clinicopathological classification appears to be a useful grading system to identify PAs that may be more refractory and more often require complex multimodal and multiple therapeutic approaches. Invasive PAs, especially grade 2b tumors, may be more likely to need complex treatment approach, including radiotherapy, and may display higher rates of active disease at last follow-up, despite receiving higher number of treatments.
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Adenoma , Neoplasias Hipofisárias , Feminino , Humanos , Adulto , Pessoa de Meia-Idade , Idoso , Masculino , Neoplasias Hipofisárias/patologia , Estudos Retrospectivos , Portugal , Hipófise/patologia , Adenoma/patologiaRESUMO
In recent years, lycopene has been highlighted due to its antioxidant and anti-inflammatory properties, associated with a beneficial effect on human health. The aim of this study was to advance the studies of antioxidant and anti-inflammatory mechanisms on human keratinocytes cells (HaCaT) of a self-emulsifying drug delivery system (SEDDS) loaded with lycopene purified from red guava (nanoLPG). The characteristics of nanoLPG were a hydrodynamic diameter of 205 nm, a polydispersity index of 0.21 and a zeta potential of -20.57, providing physical stability for the nanosystem. NanoLPG demonstrated antioxidant capacity, as shown using the ORAC methodology, and prevented DNA degradation (DNA agarose). Proinflammatory activity was evaluated by quantifying the cytokines TNF-α, IL-6 and IL-8, with only IL-8 showing a significant increase (p < 0.0001). NanoLPG showed greater inhibition of the tyrosinase and elastase enzymes, involved in the skin aging process, compared to purified lycopene (LPG). In vitro treatment for 24 h with 5.0 µg/mL of nanoLPG did not affect the viability of HaCaT cells. The ultrastructure of HaCaT cells demonstrated the maintenance of morphology. This contrasts with endoplasmic reticulum stresses and autophagic vacuoles when treated with LPG after stimulation or not with LPS. Therefore, the use of lycopene in a nanoemulsion may be beneficial in strategies and products associated with skin health.
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Antioxidantes , Interleucina-8 , Humanos , Licopeno , Antioxidantes/farmacologia , Sistemas de Liberação de Medicamentos/métodos , Anti-Inflamatórios/farmacologia , DNARESUMO
Atrial fibrillation (AF) is a cardiac arrhythmia caused by electrophysiological anomalies in the atrial tissue, tissue degradation, structural abnormalities, and comorbidities. A direct relationship exists between AF and altered mitochondrial activity resulting from membrane potential loss, contractile dysfunction, or decreased ATP levels. This review aimed to elucidate the role of mitochondrial oxidative mechanisms in AF pathophysiology, the impact of mitochondrial oxidative stress on AF initiation and perpetuation, and current therapies. This review followed the Preferred Reporting Items for Systematic Reviews and the Meta-Analysis Extension for Scoping Reviews. PubMed, Excerpta Medica Database, and Scopus were explored until June 2023 using "MESH terms". Bibliographic references to relevant papers were also included. Oxidative stress is an imbalance that causes cellular damage from excessive oxidation, resulting in conditions such as AF. An imbalance in reactive oxygen species production and elimination can cause mitochondrial damage, cellular apoptosis, and cardiovascular diseases. Oxidative stress and inflammation are intrinsically linked, and inflammatory pathways are highly correlated with the occurrence of AF. AF is an intricate cardiac condition that requires innovative therapeutic approaches. The involvement of mitochondrial oxidative stress in the pathophysiology of AF introduces novel strategies for clinical treatment.
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Fibrilação Atrial , Cardiopatias , Doenças Mitocondriais , Humanos , Fibrilação Atrial/tratamento farmacológico , Doença do Sistema de Condução Cardíaco , Estresse OxidativoRESUMO
While most cases of differentiated thyroid carcinoma (DTC) are associated with a good prognosis, a significant number progress to advanced disease exhibiting aggressive clinical characteristics and often becoming refractory to radioactive iodine (RAI) treatment, the current gold-standard therapeutic option for metastatic disease. RAI-refractoriness is caused by defective functional expression of the sodium-iodide symporter (NIS), which is responsible for the active transport of iodide across the plasma membrane (PM) into thyroid follicles. NIS deficiency in these tumors often reflects a transcriptional impairment, but also its defective targeting and retention at the cells' PM. Using proteomics, we previously characterized an intracellular signaling pathway derived from SRC kinase that acts through the small GTPase RAC1 to recruit and bind the actin-anchoring adaptor EZRIN to NIS, regulating its retention at the PM of both non-transformed and cancer thyroid cells. Here, we describe how by reanalyzing the proteomics data, we identified cell-cell adhesion as the molecular event upstream the pathway involved in the anchoring and retention at the PM. We show that by interacting with NIS at the PM, adherens junction (AJ)-associated P120-catenin recruits and is phosphorylated by SRC, allowing it to recruit RAC1 to the complex. This enables SRC-phosphorylated VAV2 exchange factor to activate RAC1 GTPase, inducing NIS retention at the PM, thus increasing its abundance and function at the surface of thyroid cells. Our findings indicate that the loss of epithelial cell-cell adhesion may contribute to RAI refractoriness, indicating that in addition to stimulating NIS expression, successful resensitization therapies might require the employment of agents that improve cell-cell adhesion and NIS PM retention in refractory TC cells.
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Metal pollution in aquatic ecosystems translates into increased concentrations of sediment-bound metals, representing a risk for benthic species. This risk might be enhanced in soft and moderately hard waters, world widely distributed, due to the protective role of hardness against metal toxicity. As lead (Pb) and nickel (Ni) are amongst the more abundant metals in aquatic systems, and since their combined effects to benthic species have been overlooked, in this study we aimed to investigate the life-cycle toxicity of Pb and Ni (using spiked sediment) to the benthic species Chironomus riparius, considering both single and mixture exposures, in moderately hard water. Environmentally relevant concentrations of each metal were used (25 and 75 mg kg-1, based on a scenario of pollution by runoff waters from burnt forests), following a full factorial design. Effects of the mixture with the highest metal concentrations (Pb 75 mg kg-1 dw + Ni 75 mg kg-1 dw) were also assessed in the second generation. In the first generation, exposure to Pb increased emergence and the weight of males, and decreased time to emergence of both males and females. Conversely, exposure to Ni delayed female emergence and decreased the weight of imagoes. Summarizing, Pb affected more endpoints but showed an apparent positive effect, whereas Ni affected less endpoints but exhibited adverse effects. Reproduction was not affected by these metals. In the second generation, the mixture Pb 75 mg kg-1 + Ni 75 mg kg-1 dw delayed emergence and reduced the emerged female fraction and their weight. These results highlight that Pb and Ni can alter the structure of C. riparius populations at environmentally relevant concentrations, which signals potential repercussions in the dynamics and functioning of freshwater ecosystems under these contamination scenarios. The findings of the present study are relevant not only for metal-polluted environments, in general, but also for fire-affected ecosystems.
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Chironomidae , Poluentes Químicos da Água , Animais , Feminino , Níquel/toxicidade , Sedimentos Geológicos/química , Chumbo/toxicidade , Poluentes Químicos da Água/toxicidade , EcossistemaRESUMO
This work reports the application of Mn-doped Co3O4 oxides in the electrocatalytic oxygen evolution reaction (OER). The materials were characterized by structural, morphological, and electrochemical techniques. The oxides with higher Co : Mn molar ratio presented a lower electron transfer resistance, and consequently the most promising OER activities. Pure Co3O4 shows an overpotential at j = 10 mA cm-2 of 761, 490, and 240 mV, at pH 1, 7, and 14, respectively, and a high TOF of 1.01 × 10-1 s-1 at pH 14. Tafel slopes around 120 mV dec-1 at acidic pH and around 60 mV dec-1 at alkaline pH indicate different OER mechanisms. High stability for Co3O4 was achieved for up to 15 h in all pHs, and no change in the structure and morphology after the electrocatalysis was observed. The reported excellent OER activity of the Mn-Co oxides in a wide pH range is important to broaden the practical applicability in different electrolyte solutions.
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BACKGROUND: RNA is a critical analyte for unambiguous detection of actionable mutations used to guide treatment decisions in oncology. Currently available methods for gene fusion detection include molecular or antibody-based assays, which suffer from either being limited to single-gene targeting, lack of sensitivity, or long turnaround time. The sensitivity and predictive value of next generation sequencing DNA-based assays to detect fusions by sequencing intronic regions is variable, due to the extensive size of introns. The required depth of sequencing and input nucleic acid required can be prohibitive; in addition it is not certain that predicted gene fusions are actually expressed. RESULTS: Herein we describe a method based on pyrophosphorolysis to include detection of gene fusions from RNA, with identical assay steps and conditions to detect somatic mutations in DNA [1], permitting concurrent assessment of DNA and RNA in a single instrument run. CONCLUSION: The limit of detection was under 6 molecules/ 6 µL target volume. The workflow and instrumentation required are akin to PCR assays, and the entire assay from extracted nucleic acid to sample analysis can be completed within a single day.
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Fusão Gênica , RNA , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Mutação , RNA/genética , Análise de Sequência de RNARESUMO
The microenvironment of pituitary adenomas (PAs) includes a range of non-tumoral cells, such as immune and stromal cells, as well as cell signaling molecules such as cytokines, chemokines and growth factors, which surround pituitary tumor cells and may modulate tumor initiation, progression, invasion, angiogenesis and other tumorigenic processes. The microenvironment of PAs has been actively investigated over the last years, with several immune and stromal cell populations, as well as different cytokines, chemokines and growth factors being recently characterized in PAs. Moreover, key microenvironment-related genes as well as immune-related molecules and pathways have been investigated, with immune check point regulators emerging as promising targets for immunotherapy. Understanding the microenvironment of PAs will contribute to a deeper knowledge of the complex biology of PAs, as well as will provide developments in terms of diagnosis, clinical management and ultimately treatment of patients with aggressive and/or refractory PAs.