Characterization of Wildland Firefighters' Exposure to Coarse, Fine, and Ultrafine Particles; Polycyclic Aromatic Hydrocarbons; and Metal(loid)s, and Estimation of Associated Health Risks.

Firefighters' occupational activity causes cancer, and the characterization of exposure during firefighting activities remains limited. This work characterizes, for the first time, firefighters' exposure to (coarse/fine/ultrafine) particulate matter (PM) bound polycyclic aromatic hydrocarbons (PAHs) and metal(loid)s during prescribed fires, Fire 1 and Fire 2 (210 min). An impactor collected 14 PM fractions, the PM levels were determined by gravimetry, and the PM-bound PAHs and metal(loid)s were determined by chromatographic and spectroscopic methodologies, respectively. Firefighters were exposed to a total PM level of 1408.3 and 342.5 µg/m3 in Fire 1 and Fire 2, respectively; fine/ultrafine PM represented more than 90% of total PM. Total PM-bound PAHs (3260.2 ng/m3 in Fire 1; 412.1 ng/m3 in Fire 2) and metal(loid)s (660.8 ng/m3 versus 262.2 ng/m3), distributed between fine/ultrafine PM, contained 4.57-24.5% and 11.7-12.6% of (possible/probable) carcinogenic PAHs and metal(loid)s, respectively. Firefighters' exposure to PM, PAHs, and metal(loid)s were below available occupational limits. The estimated carcinogenic risks associated with the inhalation of PM-bound PAHs (3.78 × 10-9 - 1.74 × 10-6) and metal(loid)s (1.50 × 10-2 - 2.37 × 10-2) were, respectively, below and 150-237 times higher than the acceptable risk level defined by the USEPA during 210 min of firefighting activity and assuming a 40-year career as a firefighter. Additional studies need to (1) explore exposure to (coarse/fine/ultrafine) PM, (2) assess health risks, (3) identify intervention needs, and (4) support regulatory agencies recommending mitigation procedures to reduce the impact of fire effluents on firefighters.

Prevention of drug diversion and substance use disorders among anesthesiologists: a narrative review

Abstract Diversion of substances from the care of the intended patient is a significant problem in healthcare. Patients are harmed by the undertreatment of pain and suffering, transmission of disease, as well as the risk associated with impaired vigilance. Healthcare providers may be harmed by the physical and mental impact of their addictions. Healthcare systems are placed in jeopardy by the legal impact associated with illegal routes of drug release including sanction and financial liability and loss of public trust. Healthcare institutions have implemented many measures to reduce diversion from the perioperative area. These efforts include education, medical record surveillance, automated medication dispensing systems, urine drug testing, substance waste management systems, and drug diversion prevention teams. This narrative review evaluates strengths, weaknesses, and effectiveness of these systems and provides recommendations for leaders and care providers.

A Novel MDM2-Binding Chalcone Induces Apoptosis of Oral Squamous Cell Carcinoma.

Oral squamous cell carcinoma (OSCC) represents ~90% of all oral cancers, being the eighth most common cancer in men. The overall 5-year survival rate is only 39% for metastatic cancers, and currently used chemotherapeutics can cause important side effects. Thus, there is an urgency in developing new and effective anti-cancer agents. As both chalcones and 1,2,3-triazoles are valuable pharmacophores/privileged structures in the search for anticancer compounds, in this work, new 1,2,3-triazole-chalcone hybrids were synthesized and evaluated against oral squamous cell carcinoma. By using different in silico, in vitro, and in vivo approaches, we demonstrated that compound 1f has great cytotoxicity and selectivity against OSCC (higher than carboplatin and doxorubicin) and other cancer cells in addition to showing minimal toxicity in mice. Furthermore, we demonstrate that induced cell death occurs by apoptosis and cell cycle arrest at the G2/M phase. Moreover, we found that 1f has a potential affinity for MDM2 protein, similar to the known ligand nutlin-3, and presents a better selectivity, pharmacological profile, and potential to be orally absorbed and is not a substrate of Pg-P when compared to nutlin-3. Therefore, we conclude that 1f is a good lead for a new chemotherapeutic drug against OSCC and possibly other types of cancers.

Exposure to PAHs during Firefighting Activities: A Review on Skin Levels, In Vitro/In Vivo Bioavailability, and Health Risks.

Occupational exposure as a firefighter is a complex activity that continuously exposes subjects to several health hazards including fire emissions during firefighting. Firefighters are exposed to polycyclic aromatic hydrocarbons (PAHs), known as toxic, mutagenic, and carcinogenic compounds, by inhalation, dermal contact, and ingestion. In this work, a literature overview of firefighters' dermal exposure to PAHs after firefighting and data retrieved from skin in vitro/in vivo studies related to their dermal absorption, bioavailability, and associated toxicological and carcinogenic effects are reviewed. The evidence demonstrates the contamination of firefighters' skin with PAHs, mainly on the neck (2.23-62.50 ng/cm2), wrists (0.37-8.30 ng/cm2), face (2.50-4.82 ng/cm2), and hands (1.59-4.69 ng/cm2). Concentrations of possible/probable carcinogens (0.82-33.69 ng/cm2), including benzopyrene isomers, were found on firefighters' skin. PAHs penetrate the skin tissues, even at low concentrations, by absorption and/or diffusion, and are locally metabolized and distributed by the blood route to other tissues/organs. Lighter PAHs presented increased dermal permeabilities and absorption rates than heavier compounds. Topical PAHs activate the aryl hydrocarbon receptor and promote the enzymatic generation of reactive intermediates that may cause protein and/or DNA adducts. Future research should include in vitro/in vivo assays to perform a more realistic health risk assessment and to explore the contribution of dermal exposure to PAHs total internal dose.

Atenção plena e equilíbrio emocional: experiência de uma disciplina durante a pandemia de Covid-19 / Mindfulness and emotional balance: experience of a course during the Covid-19 pandemic

Resumo: Introdução: Os estudantes de Medicina vivem experiências de adoecimento e dificuldades em saúde mental frequentes e, muitas vezes, graves. Essas experiências se acentuaram durante a pandemia de doença por coronavírus (Covid-19). Nesse contexto, o treinamento em atenção plena e regulação emocional pode ser uma ferramenta útil de promoção da saúde mental nessa população. Relato de Experiência: Com o objetivo de disponibilizar esse treinamento para os estudantes de Medicina de uma instituição de ensino de Minas Gerais, foi ofertada uma disciplina sobre atenção plena e equilíbrio emocional. Ofereceu-se essa disciplina entre setembro e dezembro de 2020, com 13 aulas síncronas remotas semanais, com duas horas de duração, para 16 estudantes. Após o transcurso da disciplina, aplicou-se um questionário on-line com perguntas abertas e fechadas com três seções: informações sociodemográficas, avaliação da disciplina baseada na Escala de Satisfação com a Experiência Acadêmica (ESEA) e avaliação de impactos no bem-estar subjetivo por meio do Questionário de Saúde Geral 12 (General Health Questionnaire 12 - GHQ-12). Treze estudantes responderam ao questionário da pesquisa. A disciplina foi considerada satisfatória pela maioria dos estudantes em todos os itens avaliados. Nos 12 aspectos de saúde mental pesquisados, a concordância com os impactos positivos da disciplina variou de oito a 12 respondentes. Discussão: Em consonância com as revisões sistemáticas sobre o tema, a disciplina "Atenção plena e equilíbrio emocional" parece ter impactado de forma positiva a saúde mental, a sociabilidade e a autoimagem dos estudantes. Todos os aspectos pedagógicos avaliados foram considerados satisfatórios por mais de 80% dos participantes, com exceção dos que avaliavam especificamente o formato remoto. O caráter optativo da oferta da disciplina pode ter contribuído de forma relevante para esse resultado. Conclusão: Considerando as particularidades do contexto pandêmico, foi possível disponibilizar uma proposta original de disciplina sobre atenção plena e equilíbrio emocional positivamente avaliada pelos estudantes. Novas pesquisas são necessárias para confirmar a associação entre a participação na disciplina e a promoção do bem-estar mental.

Abstract: Introduction: Medical students experience frequent and often severe mental illness and difficulties in mental health. These experiences were accentuated during the covid 19 pandemic. In this context, training in mindfulness and emotional balance can represent a useful tool for promoting mental health in this student group. Experience Report: In order to make this training available to medical students at a university in Minas Gerais, a course on Mindfulness and Emotional Balance was offered between September and December 2020 with 13 synchronous remote weekly classes, lasting two hours. After the course, the 16 participant students were invited to answer an online questionnaire with three sections: sociodemographic information, evaluation of the course based on the Satisfaction with Academic Experience Scale (ESEA); and assessment of impacts on subjective well-being based on the General Health Questionnaire 12 (General Health Questionnaire 12 - GHQ-12). Thirteen students answered the survey questionnaire. The discipline was considered satisfactory in all evaluated items. Within the 12 aspects of mental health surveyed, agreement with the impacts of the discipline ranged between 8 and 12 respondents. Discussion: In line with systematic reviews on the topic, the course of mindfulness and emotional balance seems to have positively impacted the students' mental health, sociability and self-image. All pedagogical aspects evaluated were considered satisfactory by more than 80% of the participants, with the exception of those who specifically evaluated the remote format. The optional nature of the course may have significantly contributed to this result. Conclusion: Considering the particular circumstances of the pandemic, it was possible to provide an original proposal for a discipline on mindfulness and emotional balance that was positively evaluated by students. Further research is needed to confirm the association between participation in the discipline and the promotion of mental well-being.

Association of aerobic fitness and body composition in people with down syndrome / Associação de aptidão aeróbia e composição corporal em pessoas com síndrome de down

ABSTRACT People with Down Syndrome (DS) present metabolic differences when compared to the general population, which ends up at a higher prevalence of overweight and lower rates of aerobic fitness. The aim of this study was analysing the association of aerobic fitness and body composition in individuals with DS. Thirty individuals with DS from the city of Londrina / Brazil with a mean age of 18.00±3.66 years were evaluated. The variables body mass index, body fat, and aerobic fitness (VO²peak) were investigated. Men were taller than women, presented a higher percentage of lean body mass and higher VO²peak, while women showed higher means for android, gynoid and total fat. Aerobic fitness was positively associated with bone mineral density and inversely associated with nutritional status, lean body mass and body fat.

RESUMO Pessoas com Síndrome de Down (SD) apresentam diferenças metabólicas quando comparadas à população em geral, o que resulta em maior prevalência de sobrepeso e menores índices de aptidão aeróbia. O objetivo deste estudo foi analisar a associação da aptidão aeróbia com a composição corporal em indivíduos com SD. Foram avaliados 30 indivíduos com SD da cidade de Londrina / Brasil com média de idade 18,00±3,66 anos. Foram investigadas as variáveis índice de massa corporal, gordura corporal, e aptidão aeróbia (VO²pico). Os homens foram mais altos que as mulheres, apresentaram maior percentual de massa magra e maior VO²pico, enquanto as mulheres apresentaram maiores médias para gordura andróide, ginóide e total. A aptidão aeróbia associou-se inversamente ao índice de massa corporal, massa magra e gordura corporal.

The potential use of Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA) in a Brazilian hospital. / O uso potencial do Balão de Oclusão Endovascular da Aorta para Ressuscitação em um hospital brasileiro.

AIM: To evaluate the potential use of REBOA in a Brazilian hospital. METHODS: We performed a retrospective analysis of all requests for emergency surgical evaluation for patients with suspected massive hemorrhage, hospitalized in a private Brazilian general hospital, from April 1, 2017 to March 31, 2018. Inclusion criteria for REBOA eligibility were: suspected abdominal and/or pelvic bleeding, hemorrhagic shock and older than 18 years of age. Exclusion criteria were: older than 70 years of age, and pre-existing terminal disease or significant comorbidities. RESULTS: 90 evaluations were requested during the study period. However, according to our inclusion/exclusion criteria, only on 14 occasions (15.6%) there was a recommendation for the use of REBOA. Gynecological/obstetric conditions were the indication in 11 cases (78.6%) and elective oncologic surgery in three cases (21.4%). CONCLUSIONS: The use of REBOA is not common in our country, but it can be an essential tool, and perhaps the last resource in extremely severe conditions until the definitive surgical, endovascular or endoscopic treatment is performed.

OBJETIVO: Este estudo objetivou analisar o uso potencial Balão de Oclusão Endovascular da Aorta para Ressuscitação (REBOA) em um hospital brasileiro. MÉTODOS: Foi realizada uma revisão da literatura e uma análise retrospectiva de todas as avaliações cirúrgicas de emergência para pacientes com suspeita de hemorragia maciça internados em um hospital brasileiro, de 1 de abril de 2017 a 31 de março de 2018. Os critérios de elegibilidade do REBOA foram: origem abdominal e/ou pélvica, choque hemorrágico e acima de 18 anos de idade. Os critérios de exclusão foram: acima de 70 anos e doença terminal pré-existente ou comorbidades significativas. RESULTADOS: No período, foram solicitadas 90 avaliações. Em 14 ocasiões (15,6%) havia indicação para o uso do REBOA. Os casos em que isso foi possível foram devidos a causas ginecológicas/obstétricas em 11 casos (78,6%) e cirurgia oncológica eletiva em três casos (21,4%). CONCLUSÕES: O REBOA é ainda pouco utilizado em nosso país, mas pode ser uma ferramenta de extrema importância, e talvez o último recurso em pacientes extremamente graves, até que o tratamento definitivo, cirúrgico, endovascular ou endoscópico seja efetuado.

O uso potencial do Balão de Oclusão Endovascular da Aorta para Ressuscitação em um hospital brasileiro / The potential use of Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA) in a Brazilian hospital

RESUMO Objetivo: Este estudo objetivou analisar o uso potencial Balão de Oclusão Endovascular da Aorta para Ressuscitação (REBOA) em um hospital brasileiro. Métodos: Foi realizada uma revisão da literatura e uma análise retrospectiva de todas as avaliações cirúrgicas de emergência para pacientes com suspeita de hemorragia maciça internados em um hospital brasileiro, de 1 de abril de 2017 a 31 de março de 2018. Os critérios de elegibilidade do REBOA foram: origem abdominal e/ou pélvica, choque hemorrágico e acima de 18 anos de idade. Os critérios de exclusão foram: acima de 70 anos e doença terminal pré-existente ou comorbidades significativas. Resultados: No período, foram solicitadas 90 avaliações. Em 14 ocasiões (15,6%) havia indicação para o uso do REBOA. Os casos em que isso foi possível foram devidos a causas ginecológicas/obstétricas em 11 casos (78,6%) e cirurgia oncológica eletiva em três casos (21,4%). Conclusões: O REBOA é ainda pouco utilizado em nosso país, mas pode ser uma ferramenta de extrema importância, e talvez o último recurso em pacientes extremamente graves, até que o tratamento definitivo, cirúrgico, endovascular ou endoscópico seja efetuado.

ABSTRACT Aim: To evaluate the potential use of REBOA in a Brazilian hospital. Methods: We performed a retrospective analysis of all requests for emergency surgical evaluation for patients with suspected massive hemorrhage, hospitalized in a private Brazilian general hospital, from April 1, 2017 to March 31, 2018. Inclusion criteria for REBOA eligibility were: suspected abdominal and/or pelvic bleeding, hemorrhagic shock and older than 18 years of age. Exclusion criteria were: older than 70 years of age, and pre-existing terminal disease or significant comorbidities. Results: 90 evaluations were requested during the study period. However, according to our inclusion/exclusion criteria, only on 14 occasions (15.6%) there was a recommendation for the use of REBOA. Gynecological/obstetric conditions were the indication in 11 cases (78.6%) and elective oncologic surgery in three cases (21.4%). Conclusions: The use of REBOA is not common in our country, but it can be an essential tool, and perhaps the last resource in extremely severe conditions until the definitive surgical, endovascular or endoscopic treatment is performed.

Do athletes with physical disabilities perceive their quality of life similarly when involved in different Paralympic Sports?

This study aimed to compare the quality of life perception among Boccia, Para-Athletics, and Wheelchair Tennis athletes. Methods: Eighty-six athletes with physical disabilities participated (Boccia = 41; Para Athletics = 14; Wheelchair Tennis = 31) in the study. The data were collected by applying the Brazilian Portuguese version of the WHOQOL-Bref questionnaire and a short survey for demographics. Descriptive and inferential statistics were used to analyze the relationship among the variables considering a confidence level of 95%. Results: Wheelchair Tennis athletes were older and Para-Athletics athletes were involved in this sport for a longer period. The majority of participants perceived positively their overall quality of life and health. Wheelchair Tennis athletes presented higher total quality of life perception scores in comparison to Boccia athletes. Regarding the specific domains of quality of life, Para-Athletics athletes presented higher scores in the psychological domain in comparison to Boccia and Wheelchair Tennis. Wheelchair Tennis presented higher social scores in comparison to Boccia and higher environment scores in comparison to Boccia and Para-Athletics. No differences were found in the physical domain in all groups. Conclusion: The evidence points to the influence of athletes' demographics, the specific nuances of their impairments, and the Paralympic Sports practiced in perceiving the quality of life. Suggestions are made to further explore the factors that may influence the quality of life perception among Paralympic Sports athletes.(AU)

Sedentary behavior based on screen time: prevalence and associated sociodemographic factors in adolescents / Comportamento sedentário baseado em tempo de tela: prevalência e fatores sociodemográficos associados em adolescentes

Abstract The aim of this study to estimate the prevalence of sedentary behavior based on screen time (≥ 2-hour day) and to identify the association with sociodemographic factors among adolescents in a city in southern Brazil. This is an epidemiological survey of school-based cross-sectional study with students aged 14-19 years in the city of São José/SC - Brazil. Self-administered questionnaire was used, containing information sociodemographic, level of physical activity and about screen time. Descriptive statistics were performed, and odds ratios were estimated using binary logistic regression and 95% confidence level. The prevalence of excess screen time was 86.37% followed by computer use (55.24%), TV use (51.56%) and Videogame use (15.35%). Boys had higher prevalence of excessive video game use. Those of skin color different from white and mothers who studied less than eight years were more likely to watch too much TV, and those of low economic level were more likely of having excessive screen time. Girls of skin color different from white were more likely to watch too much TV, and those aged 14-16 years were more likely to have videogame use time and total time screen above recommended.

Resumo O objetivo deste estudo foi estimar a prevalência de comportamentos sedentários baseado em tempo de tela (≥ 2 horas por dia) e identificar a associação com fatores sociodemográficos em adolescentes, de uma cidade do Sul do Brasil. Esta é uma pesquisa epidemiológica de base escolar com delineamento transversal, em estudantes de 14 a 19 anos na cidade de São José/SC, Brasil. Foi utilizado questionário autoaplicado, com informações sociodemográficas, atividade física e tempo de uso de tela. Foi realizada estatística descritiva, e as razões de chances estimadas por regressão logística binária. A prevalência de uso excessivo de tela foi de 86,37% seguido de uso de computador (PC) (55,24%), televisão (TV) (51,56%) e videogame (VG) (15,35%). Os meninos tiveram maior prevalência de uso excessivo de VG. Aqueles de cor de pele diferente de branca e que mães estudaram menos de oito anos tiveram mais chances de assistirem TV em excesso, e aqueles, de baixo nível econômico tiveram mais chances de terem tempo total de tela excessivo. Meninas de cor de pele diferente de branca tiveram mais de assistirem TV em excesso, e aquelas com 14 a 16 anos tiveram mais chances de estarem com tempo de uso de VG e tempo total de tela acima do recomendado.

Presença simultânea de excesso de peso e horas de sono insuficientes em adolescentes: prevalência e fatores correlatos / Simultaneous presence of excess weight and insufficient hours of sleep in adolescents: prevalence and related factors

INTRODUCTION: An increase in excess body fat and a decrease in the number of hours of sleep per day are health problems affecting the paediatric population. OBJECTIVE: To estimate the combined prevalence of overweight and insufficient sleep/day in adolescents, and the association with sociodemographic characteristics, physical activity and sedentary behaviour. METHODS: A cross-sectional school-based study was conducted with 1,132 participants from 14 to 19 years old in São José, Santa Catarina, Brazil. Body fat was assessed by body mass index (BMI) and classified by the Z-score, while adolescents reported the total hours of sleep/day. Sociodemographic data, physical activity and sedentary behaviour were collected by self-filled questionnaire. RESULTS: The simultaneous prevalence of overweight and insufficient sleep/day was 17.5%. The factors associated with this condition were to meet the recommendations of the practice of physical activity per week, participate in gym class twice/week and period greater/equal to four hours/day in front of the screen. CONCLUSION: Guidelines in the school environment in relation to health problems posed by weight excess and the amount of insufficient hours sleep can be present when recommendations on physical activity and sedentary behaviour are given to students.

INTRODUÇÃO: O aumento do excesso de gordura corporal e a diminuição do número de horas de sono/dia são agravos à saúde que atingem a população pediátrica. OBJETIVO: Estimar a prevalência combinada de excesso de peso e horas de sono/dia insuficientes em adolescentes, e verificar a associação com características sociodemográficas, de atividade física e comportamento sedentário. MÉTODO: Estudo transversal de base escolar, realizado com 1.132 participantes de 14 a 19 anos de idade, em São José, Brasil. A gordura corporal foi avaliada pelo Índice de Massa Corporal (IMC) e classificado por meio do escore-Z, enquanto o total de horas de sono/dia foi relatado pelos adolescentes. Os dados sociodemográficos, de atividade física e comportamento sedentário foram levantados por questionário autopreenchível. RESULTADOS: A prevalência simultânea de excesso de peso e horas de sono/dia insuficientes foi de 17,5%. Os fatores associados a esta condição foram atender as recomendações de prática de atividade física semanal, participar da aula de educação física duas vezes/semana e período maior/igual a quatro horas/dia em frente a tela. CONCLUSÃO: Orientações no ambiente escolar em relação aos problemas à saúde acarretados pelo excesso de peso e pela quantidade de horas de sono insuficientes podem se fazer presentes quando recomendações sobre atividade física e comportamento sedentário forem dadas aos estudantes.

Associação do estado nutricional com aptidão física relacionada à saúde em adultos com deficiência intelectual / Association between nutritional status and of health-related fitness in adults with intellectual disabilities

Resumo A obesidade é um problema da saúde pública que tem reflexo direto nos níveis de aptidão física relacionada à saúde, principalmente em pessoas com deficiência intelectual (DI) por uma série de limitações cognitivas e sociais devido à deficiência. O objetivo do estudo é identificar a associação do estado nutricional com os níveis de aptidão física relacionado à saúde em pessoas com DI. A pesquisa foi realizada em uma instituição com 31 homens adultos, tendo a avaliação do estado nutricional sido realizada por meio do IMC, e os testes de aptidão física relacionado à saúde com uso da Bateria de Brockport adaptada (avaliação da adiposidade, teste de flexibilidade, força/resistência muscular e capacidade aeróbia). Utilizou-se a análise de covariância para comparar os grupos eutróficos e o excesso de peso em relação aos componentes de aptidão física relacionados à saúde e o teste exato de Fisher para verificar associação entre as variáveis. A maioria dos adultos não atingiu os critérios mínimos para a saúde. Adultos com excesso de peso (IMC) apresentaram maiores valores de percentual de gordura corporal e menores níveis de força/resistência muscular do que os eutróficos. Os indícios da associação entre excesso de peso com altos níveis de percentual de gordura e baixos níveis de força/resistência muscular alerta para a necessidade de programas específicos para população com DI.

Abstract Obesity is a public health problem that has a direct impact on levels of physical fitness and health, especially in people with intellectual disabilities (ID) for a series of cognitive and social limitations due to disability. The objective of the study is to identify the association between nutritional status and levels of health-related fitness in people with ID. The research was conducted in an institution with 31 adult men that the assessment of nutritional status was performed using BMI, and physical fitness tests related to health with use of adapted Brockport battery (assessment of adiposity, flexibility test, muscular strength / endurance and aerobic capacity). If you used the covariance analysis to compare groups eutrophic and overweight in relation to the components of physical fitness and health and the Fisher exact test to verify the association between variables. Most adults did not meet the minimum criteria for health. Adults who are overweight (BMI) had higher percentage values of body fat and lower levels of muscular strength / endurance than eutrophic. The Association of evidence between overweight with high percentage of fat levels and low levels of muscular strength / endurance alert to the need for specific programs for people with ID.

Antiangiogenesis beyond VEGF inhibition: a journey from antiangiogenic single-target to broad-spectrum agents.

Although the inhibition of angiogenesis is an established modality of cancer treatment, concerns regarding toxicity and drug resistance still constitute barriers to be overcome. For almost a decade since the approval of bevacizumab in 2004, the efforts on antiangiogenic therapeutics have been mainly focused in inhibiting the VEGF pathway. The ongoing understanding of the complexity of the angiogenic process has broadened the spotlight to include concurrent and downstream players to the list of targeted inhibitors. In this review, we summarize the currently existing and the promising antiangiogenic treatments, envisioning an apparent evolutionary trend towards the development of angiogenesis inhibitors of three modalities: single-target, multi-target, and broad-spectrum agents. The clinical efficacy and some structural aspects of monoclonal antibodies, small molecules, endogenous and synthetic angiogenesis inhibitors and their molecular targets are discussed, and the targeting of endothelial cells with the use of cytotoxic drugs in a metronomic schedule is appraised. The reader is invited to revisit current expectations about antiangiogenic therapy in an attempt to set consistent clinical endpoints from which patients could gain real and lasting clinical benefits.

Simulation of the mutation F76del on the von Hippel-Lindau tumor suppressor protein: mechanism of the disease and implications for drug development.

The von Hippel-Lindau tumor suppressor protein (pVHL) plays a central role in the oxygen-sensing pathway by regulating the degradation of the hypoxia-inducible factor (HIF-1α). The capture of HIF-1α by pVHL is regulated by an oxygen-dependent hydroxylation of a specific conserved prolyl residue. The VHL gene is mutated in the von Hippel-Lindau cancer predisposition syndrome, which is characterized by the development of highly vascularized tumors and is associated with constitutively high levels of HIF-1α. The disturbance of the dynamic coupling between HIF-1α and pVHL bearing the commonly found mutation F76del was experimentally confirmed but the mechanism of such complex disruption is still not clear. Performing unbiased molecular dynamics simulations, we show that the F76del mutation may enlarge the HIF binding pocket in pVHL and induce the formation of an internal cavity in the hydrophobic core of the ß-domain, which can lead to a partial destabilization of the ß-sheets S1, S4, and S7 and a consequent loss of hydrogen bonds with a conserved recognition motif in HIF. The newly formed cavity has a significant druggability score and may be a suitable target for stabilizing ligands. Studies of this nature may help to fill the information gap between genotype-phenotype correlations with details obtained at atomic level and provide basis for future development of drug candidates, such as pharmacological chaperones, with the specific aim of reverting the dysfunction of such pathological protein complexes found in patients with VHL.

Serum levels of Th17 associated cytokines in chronic hepatitis C virus infection.

The Th17-mediated immune response was investigated in patients chronically infected with hepatitis C virus (HCV) by determining the serum levels of the cytokines involved in the induction of the Th17 response (TGF-ß and IL-6), the cytokines produced by Th17 cells (IL-17A, IL-17F and IL-22) and the cytokines whose production is stimulated by Th17 lymphocytes (IL-8 and GM-CSF). We investigated the relationships among the levels of these cytokines by assessing clinical findings, liver histology and viremia. Sixty untreated patients and 28 healthy individuals were included in the study. Cytokine levels were determined using ELISA. Differences between HCV and control groups were identified in the median levels of IL-17F (controls=172.4 pg/mL; HCV=96.8 pg/mL, p<0.001) and IL-8 (controls=30.1 pg/mL; HCV=18.1 pg/mL, p<0.05). IL-6 levels were higher in patients presenting moderate liver necroinflammation than in patients with mild or no liver necroinflammation (p<0.05). IL-17F levels were increased in patients that had increased ALT levels. Additionally, a strong positive correlation was observed between IL-17F and IL-22 levels in the two groups investigated, and the IL-17F/IL-22 ratio was lower in the patients infected with HCV (p<0.0001). Patients with low HCV viral loads had higher median levels of IL-8 (32.5 pg/mL) than did patients with high HCV loads (16.7 pg/mL, p<0.05). These results suggest that in chronic hepatitis C infection, IL-17F and IL-8 could be associated with the control of liver injury and infection, respectively.

Structural analysis of the N-terminal fragment of the antiangiogenic protein endostatin: a molecular dynamics study.

Endostatin is a potent antiangiogenic protein derived from the noncollagenous domain 1 (NC1) of collagen XVIII. The mechanism by which endostatin exerts its antiangiogenic effect is still incompletely understood. It has been shown that the 27 amino acid N-terminal fragment of murine endostatin has antitumor, antimigration, and antipermeability activities comparable to the full soluble protein. To understand how this peptide can exert such elaborate function, we performed structural analysis using molecular dynamics to evaluate the behavior of this fragment in aqueous environment. Here, we show that the N-terminal peptide of murine endostatin is able to assume a well-defined structure, folding into a zinc-dependent ß-hairpin conformation. Analyzing the folding mechanism, we were able to understand why the N-terminal peptide of human endostatin with the same length failed to acquire a stable conformation. Conversely, we were able to predict the successful folding of the R4Q mutant and of a shorter form of the human peptide with 25 residues. Finally, we show that the ß-hairpin conformation assumed by the zinc-bound peptide of murine endostatin has a high structural similarity with fragments of another family of angiogenesis inhibitors: the integrin-binding portion of the NC1 domain of collagen IV. Indeed, our docking simulations show that arresten, canstatin, and the endostatin peptide bind to the same spot of αVß3 integrin, suggesting similar interactions via a common binding site on this receptor.

Smooth muscle antibodies and cryoglobulinemia are associated with advanced liver fibrosis in Brazilian hepatitis C virus carriers.

Cryoglobulinemia and non-organ-specific-autoantibody are biomarkers of autoimmunity of the chronic infection caused by hepatitis C virus (HCV). In this work, we report the association between the presence of smooth muscle antibodies (SMA) and cryoglobulinemia and chronic liver disease in HCV carriers. Sixty-five untreated HCV patients, 38 women and 27 men were included in this study. Cryoglobulinemia was tested by cryoprecipitation, SMA by indirect fluorescent antibody test, and liver fibrosis and hepatocellular inflammation activity was investigated by histology of liver biopsy using the METAVIR score. The prevalence of SMA in the patients was 33.8% and cryoglobulinemia was demonstrated in 36.9% patients. Cryoglobulinemia and SMA seropositivity was associated with advanced fibrosis (p < 0.05). The presence of SMA and cryoglobulinemia was not associated with hepatocellular inflammation activity, age, carrier gender or HCV genotype. We concluded that liver biopsy should be recommended for HCV carriers that are seropositive for SMA or cryoglobulinemia.

Smooth muscle antibodies and cryoglobulinemia are associated with advanced liver fibrosis in Brazilian hepatitis C virus carriers

Cryoglobulinemia and non-organ-specific-autoantibody are biomarkers of autoimmunity of the chronic infection caused by hepatitis C virus (HCV). In this work, we report the association between the presence of smooth muscle antibodies (SMA) and cryoglobulinemia and chronic liver disease in HCV carriers. Sixty-five untreated HCV patients, 38 women and 27 men were included in this study. Cryoglobulinemia was tested by cryoprecipitation, SMA by indirect fluorescent antibody test, and liver fibrosis and hepatocellular inflammation activity was investigated by histology of liver biopsy using the METAVIR score. The prevalence of SMA in the patients was 33.8 percent and cryoglobulinemia was demonstrated in 36.9 percent patients. Cryoglobulinemia and SMA seropositivity was associated with advanced fibrosis (p < 0.05). The presence of SMA and cryoglobulinemia was not associated with hepatocellular inflammation activity, age, carrier gender or HCV genotype. We concluded that liver biopsy should be recommended for HCV carriers that are seropositive for SMA or cryoglobulinemia.

Serum cytokine profile in hepatitis C virus carriers presenting cryoglobulinaemia and non-organ-specific autoantibodies.

This work investigated the serum cytokine profile (IL-2, IL-4, IL-5, IL-10, IFN-gamma and BAFF) of hepatitis C virus (HCV) carriers with autoimmunity. Forty-seven HCV carriers and 28 healthy controls were evaluated. Cytokine levels were measured by ELISA. Patients and controls presented similar levels of IL-2, IL-4, IL-5, IL-10, IFN-gamma and BAFF (p>0.05). Cryoglobulinaemic HCV carriers had increased IL-2 (p=0.013), IL-5 (p=0.018) and BAFF (p=0.050). IFN-gamma level was decreased in HCV carriers with rheumatoid factor in comparison with those that were RF-seronegative (p=0.035). Patients with beta2GPI IgA antibodies when were compared with those without this autoantibody, had more serum IL-2 (p=0.009), IL-5 (p=0.018) and BAFF (p=0.039). Interleukin-2 was increased in HCV carriers with positive ANA when they were compared with ANA-seronegative carriers (p=0.044). Interleukins IL-4 and IL-10 were not associated with autoimmunity (P>0.05). In HCV carriers, IL-2 was correlated with IL-5 (p<0.0001) and IFN-gamma (p=0.015), and IL-5 with IFN-gamma (p=0.015). We concluded that the serum profile of cytokines in HCV carriers presenting autoimmune markers may be mainly represented by increased IL-2, IL-5 and BAFF.