Antiapoptotic and Prometastatic Roles of Cytokine FAM3B in Triple-Negative Breast Cancer.

BACKGROUND: Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer. FAM3B, a secreted protein, has been extensively studied in various types of tumors. However, its function in breast cancer remains poorly understood. METHODS: We analyzed FAM3B expression data from breast cancer patients available at TCGA database and overall survival was analyzed by using the Kaplan-Meier plotter. MDA-MB-231 TNBC tumor cell line and hormone-responsive MCF-7 cell lines were transfected to overexpress FAM3B. We assessed cell death, tumorigenicity, and invasiveness in vitro through MTT analysis, flow cytometry assays, anchorage-independent tumor growth, and wound healing assays, respectively. We performed in vivo evaluation by tumor xenograft in nude mice. RESULTS: In silico analysis revealed that FAM3B expression was lower in all breast tumors. However, TNBC patients with high FAM3B expression had a poor prognosis. FAM3B overexpression protected MDA-MB-231 cells from cell death, with increased expression of Bcl-2 and Bcl-xL, and reduced caspase-3 activity. MDA-MB-231 cells overexpressing FAM3B also exhibited increased tumorigenicity and migration rates in vitro, displaying increased tumor growth and reduced survival rates in xenotransplanted nude mice. This phenotype is accompanied by the upregulation of EMT-related genes Slug, Snail, TGFBR2, vimentin, N-cadherin, MMP-2, MMP-9, and MMP-14. However, these effects were not observed in the MCF-7 cells overexpressing FAM3B. CONCLUSION: FAM3B overexpression contributes to tumor growth, promotion of metastasis, and, consequently, leads to a poor prognosis in the most aggressive forms of breast cancer. Future clinical research is necessary to validate FAM3B as both a diagnostic and a therapeutic strategy for TNBC.

Zoonotic Sporotrichosis outbreak: Emerging public health threat in the Amazon State, Brazil.

BACKGROUND: Sporotrichosis is the most common subcutaneous mycosis caused by Sporothrix spp. Traditionally, it is transmitted through injuries involving plant debris. However, over the past few decades, there has been an epidemic increase in human cases resulting from contact with infected animals, particularly cats, in various regions of Brazil. In this report, we report a notable increase in both human and animal cases within the Brazilian Amazon state. METHODOLOGY/PRINCIPAL FINDINGS: An ecological study was conducted by analyzing official records of human and animal sporotrichosis diagnosed in the state of Amazon from 2020 to 2023. Data including patient demographics, clinical manifestations, mycological examination results, and species identification through PCR confirmation were evaluated. During this period, a total of 950 human cases and 2,823 animal cases of sporotrichosis were reported at an exponential rate, since no human cases were registered in 2020. The spatial and temporal dispersion of human sporotrichosis followed that of animal cases, moving from downtown areas to the periphery. Contact with infected animals was reported in 77.7% of cases, with cats being the most commonly implicated (73.5%). Only 66.7% of individuals underwent mycological examination. Among the positive cultures for Sporothrix spp., 65.4% were identified as S. brasiliensis. All patients were treated with systemic antifungals. CONCLUSIONS/SIGNIFICANCE: This study highlights a rising incidence of sporotrichosis among animals and humans in the Brazilian Amazon region over the past four years, with S. brasiliensis being the predominant agent. Collaborative efforts involving healthcare professionals, veterinarians, and public health authorities are crucial to implement effective control measures, educate populations at risk, and promote responsible guidance for pet guardians. These measures are essential to mitigate the burden of epidemic sporotrichosis in Brazil.

Chronic supplementation of noni in diabetic type 1-STZ rats: effects on glycemic levels, kidney toxicity and exercise performance.

Noni is a fruit with potential medicinal use preventing elevated blood glucose levels in diabetes mellitus. Its effects have been attributed to an antioxidant property in several other diseases. However, the effects of noni-chronic supplementation on exercise performance in the presence of diabetes conditions are not known. Thirty-two male Wistar rats were used to verify the effects of chronic noni (Morinda citrifolia L) juice administration on glycemia, triglyceride levels, and its relation to physical performance. In addition, it was verified if chronic noni supplementation is safe for clinical use through kidney morphology analysis. In half of the rats, diabetes mellitus (DM) was induced with STZ. All rats were submitted to an incremental workload running test (IWT) until fatigued so that oxygen consumption and performance indexes (exercise time to fatigue and workload) could be analyzed before noni administration. Then, the control and DM groups received a placebo (saline solution) or noni juice (dilution 2:1) at a dose of 2 mL/kg once a day for 60 days. The result was four groups: control + placebo (CP), control + noni (CN), DM + placebo (DMP), and DM + noni (DMN). Our dose was based on in previous study by Nayak et al. (2011) that observed a significant reduction in glycemia with 2 ml/kg of the noni juice without any toxicity effect cited. Groups were then given a third IWT to verify the effect of the noni juice on exercise performance (exercise time to fatigue, workload, maximal oxygen consumption) and glycemia. Twenty-four hours after the third test, all animals were euthanized and blood and kidneys were removed for posterior analysis. The DM induction with STZ impaired the performance by 39%. Noni administration improved the time to fatigue and workload in DM rats beyond reducing hyperglycemia. These results could be associated with an improved energy efficiency promoted by noni ingestion, since the oxygen consumption was not different between the groups, although the exercise was longer in animals with noni ingestion. Our results provided evidence that chronic noni administration causes kidney damage since increased Bowman's space area in the control rats, suggesting glomerular hyperfiltration at the same magnitude as the non-treated DM group.In conclusion, chronic noni ingestion promoted glycemic control and improved the performance in DM rats but caused kidney toxicity.

Blocking the HGF-MET pathway induces resolution of neutrophilic inflammation by promoting neutrophil apoptosis and efferocytosis.

Inflammation resolution is an active process that involves cellular events such as apoptosis and efferocytosis, which are key steps in the restoration of tissue homeostasis. Hepatocyte growth factor (HGF) is a growth factor mostly produced by mesenchymal-origin cells and has been described to act via MET receptor tyrosine kinase. The HGF/MET axis is essential for determining the progression and severity of inflammatory and immune-mediated disorders. Here, we investigated the effect of blocking the HGF/MET signalling pathway by PF-04217903 on the resolution of established models of neutrophilic inflammation. In a self-resolving model of gout induced by MSU crystals, HGF expression on periarticular tissue peaked at 12 h, the same time point that neutrophils reach their maximal accumulation in the joints. The HGF/MET axis was activated in this model, as demonstrated by increased levels of MET phosphorylation in neutrophils (Ly6G+ cells). In addition, the number of neutrophils was reduced in the knee exudate after PF-04217903 treatment, an effect accompanied by increased neutrophil apoptosis and efferocytosis and enhanced expression of Annexin A1, a key molecule for inflammation resolution. Reduced MPO activity, IL-1ß and CXCL1 levels were also observed in periarticular tissue. Importantly, PF-04217903 reduced the histopathological score and hypernociceptive response. Similar findings were obtained in LPS-induced neutrophilic pleurisy. In human neutrophils, the combined use of LPS and HGF increased MET phosphorylation and provided a prosurvival signal, whereas blocking MET with PF-04217903 induced caspase-dependent neutrophil apoptosis. Taken together, these data demonstrate that blocking HGF/MET signalling may be a potential therapeutic strategy for inducing the resolution of neutrophilic inflammatory responses.

Aspectos relacionados ao estudante na construção da identidade médica: uma revisão integrativa / Student-related aspects in the construction of the Medical Identity: an integrative review

Resumo: Introdução: A construção da identidade médica (IM) é fenômeno dinâmico influenciado por fatores relacionados ao estudante, ao ambiente educacional e à sociedade. Objetivo: Este estudo teve como objetivo sintetizar o conhecimento produzido a respeito dos aspectos referentes ao estudante na construção da IM. Método: Trata-se de uma revisão integrativa de estudos empíricos publicados em periódicos indexados na MEDLINE e LILACS, utilizando a expressão medical identity e os descritores identity crisis, social identification, physician's role e professional role. Os critérios de inclusão foram: textos completos disponíveis em português, espanhol, francês ou inglês de estudos empíricos sobre fatores que influenciam na formação da IM com foco nos aspectos relacionados ao estudante e tendo médicos ou estudantes de graduação em Medicina como participantes. Resultado: Na primeira etapa, identificaram-se 1.365 artigos. Foram triados 194 artigos para leitura em profundidade. Destes, incluíram-se 18 para análise temática com classificação em categorias em diálogo com a literatura, tendo como base o conceito de IM saudável. A maioria dos artigos foi publicada na última década. Identificaram-se três categorias: expectativa versus realidade, referente ao que o estudante pensa sobre o que um médico é ou deveria ser; médico "super-herói", relativa à percepção caricaturada da medicina criada pelos próprios alunos e oferecida pela sociedade por meio de programas, séries e filmes televisivos; e modelagem de papéis, que diz respeito à importância da experiência prática do estudante supervisionada por um preceptor ou docente. A IM construída ao longo do curso médico influencia na forma como a medicina é exercida e, quando ela não é congruente com a realidade que o recém-formado encontra, provoca sofrimento no médico e interfere na atuação profissional dele. Conclusão: Instituições de ensino, professores e preceptores devem estar atentos às expectativas e às idealizações de seus alunos sobre o que é ser um médico e o papel desse profissional na sociedade, de maneira a promover intervenções que auxiliem em uma construção identitária mais saudável e mais resiliente às intempéries peculiares à profissão médica.

Abstract: Introduction: The Medical Identity (MI) construction is a dynamic phenomenon influenced by factors related to the student, the educational environment and society. Objective: To synthesize the produced knowledge about the student-related aspects regarding the construction of the MI. Method: This is an integrative review of empirical studies published in journals indexed in the MEDLINE and LILACS databases, using the term Medical Identity and the descriptors Identity Crisis, Social Identification, Physician's Role and Professional Role. The inclusion criteria were: full texts available in Portuguese, Spanish, French or English of empirical studies on factors that influence the development of MI focused on student-related aspects and having physicians or undergraduate medical students as participants. Results: In the first stage, 1,365 articles were identified. Subsequently, 194 articles were chosen for in-depth reading. Of these, 18 were included for thematic analysis with classification into categories in dialogue with the literature, based on the concept of healthy MI. Most articles were published in the last decade. Three categories were identified: expectation versus reality, related to what the student thinks about what a physician is or should be; the 'superhero' physician, related to the caricatured perception of Medicine created by the students themselves and offered by society through TV programs, series and films; and role modeling, which concerns the importance of the student's practical experience supervised by a preceptor or teacher. The MI built throughout the medical course influences the way medicine is practiced and when it is not consistent with the reality that the recently graduated student encounters, it causes suffering to the physician and interferes with their professional performance. Conclusion: Educational institutions, teachers and preceptors must be aware of the expectations and ideals of their students about what it means to be a physician and the role of this professional in society, aiming to promote interventions that help establishing a healthier and more resilient identity construction, particular to the medical profession.

Pandemic clone USA300 in a Brazilian hospital: detection of an emergent lineage among methicillin-resistant Staphylococcus aureus isolates from bloodstream infections.

BACKGROUND: Staphylococcus aureus is one of the leading causes of bloodstream infections (BSI) worldwide. In Brazil, the hospital-acquired methicillin-resistant S. aureus USA100/SCCmecII lineage replaced the previously well-established clones. However, the emergence of community-associated (CA) MRSA lineages among hospitalized patients is an increasing issue. METHODS: Consecutive S. aureus isolates recovered from BSI episodes of patients admitted between January 2016 and December 2018 in a Brazilian teaching hospital were tested for antimicrobial resistance, their genotypic features were characterized, and the clinical characteristics of the patients were evaluated. RESULTS: A total of 123 S. aureus isolates were recovered from 113 patients. All isolates were susceptible to linezolid, teicoplanin and vancomycin and 13.8% were not susceptible to daptomycin. Vancomycin MIC50 and MIC90 of 2 mg/L were found for both MRSA and MSSA isolates. The MRSA isolation rate was 30.1% (37/123), and 51.4% of them carried the SCCmec type II, followed by SCCmecIV (40.5%). Among the 37 MRSA isolates, the main lineages found were USA100/SCCmecII/ST5 and ST105 (53.7%) and USA800/ST5/SCCmecIV (18.9%). Surprisingly, six (16%) CA-MRSA isolates, belonging to USA300/ST8/SCCmecIVa that carried PVL genes and the ACME cassette type I, were detected. These six patients with USA300 BSI had severe comorbidities, including cancer, and most had a Charlson score ≥ 5; furthermore, they were in wards attended by the same health professionals. MRSA isolates were associated with hospital acquired infections (p = 0.02) in more elderly patients (p = 0.03) and those diagnosed with hematologic cancer (p = 0.04). Among patients diagnosed with MRSA BSI, 19 (54.3%) died. CONCLUSIONS: The pandemic MRSA USA300 was detected for the first time in the Brazilian teaching hospital under study, and its cross-transmission most probably occurred between patients with BSI. This lineage may already be circulating among other Brazilian hospitals, which highlights the importance of carrying out surveillance programs to fight multidrug resistant and hypervirulent isolates.

Effects of the breath stacking technique after upper abdominal surgery: a randomized clinical trial.

OBJECTIVE: To evaluate the effect of the association of the breath stacking (BS) technique associated with routine physiotherapy on pulmonary function, lung volumes, maximum respiratory pressures, vital signs, peripheral oxygenation, thoracoabdominal mobility, and pain in the surgical incision in patients submitted to upper abdominal surgery during the postoperative period, as well as to analyze BS safety. METHODS: This was a randomized clinical trial involving 34 patients divided into a control group (CG; n = 16), who underwent conventional physiotherapy only, and the BS group (BSG; n = 18), who underwent conventional physiotherapy and BS. Both groups performed two daily sessions from postoperative day 2 until hospital discharge. The primary outcomes were FVC and Vt. The safety of BS was assessed by the incidence of gastrointestinal, hemodynamic, and respiratory repercussions. RESULTS: Although FVC significantly increased at hospital discharge in both groups, the effect was greater on the BSG. Significant increases in FEV1, FEV1/FVC ratio, PEF, and FEF25-75% occurred only in the BSG. There were also significant increases in Ve and Vt in the BSG, but not when compared with the CG values at discharge. MIP and MEP significantly increased in both groups, with a greater effect on the BSG. There was a significant decrease in RR, as well as a significant increase in SpO2 only in the BSG. SpO2 acutely increased after BS; however, no changes were observed in the degree of dyspnea, vital signs, or signs of respiratory distress, and no gastrointestinal and hemodynamic repercussions were observed. CONCLUSIONS: BS has proven to be safe and effective for recovering pulmonary function; improving lung volumes, maximum respiratory pressures, and peripheral oxygenation; and reducing respiratory work during the postoperative period after upper abdominal surgery.

GLP-1: 10-year follow-up after Roux-en-Y gastric bypass.

PURPOSE: Glucagon-like peptide-1 (GLP-1) is a hormone widely studied in the short-term postoperative follow-up of Roux-en-Y gastric bypass due to its elevation and association with improvement of the glucose metabolism, but there are few studies in 10 years after RYGB follow-up with the same patient. METHODS: Twenty morbidity obesity patients were submitted to RYGB; these patients were divided into two groups: normal glucose-tolerant morbidly obese patients (NGT) 11 patients and abnormal glucose metabolism morbidly obese patients (AGM) 9 patients. Oral glucose tolerance test (OGTT) was done during four different periods: T1 (first evaluation), T2 (pre-surgery), T3 (9 months after surgery) and T4 (10 years after surgery). RESULTS: Groups were matched for age and gender, and as NGT and AGM had BMI of 46.31 ± 5.03 kg/m2 and 50.87 ± 10.31 kg/m2. After 10 years of RYGB, they were obesity grade I with BMI for NGT 32.45 ± 4.99 kg/m2 and AGM 34.85 ± 4.46 kg/m2. Plasma glucose levels decreased NGT group at T4 period had a significant reduction at 120 min after OGTT for NGT 55.49 ± 17.15 mg/dL (p˂0.001). Insulin levels changed from T1 to T4 for the NGT group. GLP-1 curves were statistically different between the NGT and AGM groups. The AGM group had a higher mean for GLP-1 secretion at T4 period and at 30 min of OGTT 63.85 ± 37.98 pmol/L when compared to NGT 50.73 ± 24.82 pmol/L with AGM > NGT with p˂0.001. CONCLUSION: Evaluation of the same patient during 4 different periods shows that, even with weight regain, after 10-years of RYGB high levels of GLP-1 remained which can be associated with metabolic improvement especially at the NGT group.

Phytochemical profile and antiproliferative activity of human lymphocytes of Gomphrena virgata Mart. (Amaranthaceae).

Gomphrena virgata Mart. popularly known as 'Cangussu-branco', is used in Brazilian folk medicine to treat inflammations and infections. This work aimed to carry out phytochemical analysis and evaluate the anti-inflammatory potential of Gomphrena virgata. In the phytochemical investigation, in addition to the presence of two ecdysteroids, 20 R-dihydroxyecdysone and 20-hydroxyecdysone, identified by HPLC-PDA-MS and NMR, 22 compounds were identified by GC-MS. In the cytotoxicity study, the aqueous extract of the roots of this species did not show in vitro toxicity of PBMCs in the concentrations of 250, 500 and 1000 µg/mL when analyzed by the trypan blue exclusion method. Also, it was effective in reducing lymphocyte proliferation, stimulated with the mitogen PHA, by 26.02%, 48.57% and 50.49% when compared to dexamethasone, respectively. In this work we present information about the phytochemicals of G. virgata, showing that the species is promising in obtaining compounds with medicinal potential mainly anti-inflammatory potential.

Effects of the breath stacking technique after upper abdominal surgery: a randomized clinical trial / Efeitos da técnica de breath stacking após cirurgia abdominal alta: ensaio clínico randomizado

ABSTRACT Objective: To evaluate the effect of the association of the breath stacking (BS) technique associated with routine physiotherapy on pulmonary function, lung volumes, maximum respiratory pressures, vital signs, peripheral oxygenation, thoracoabdominal mobility, and pain in the surgical incision in patients submitted to upper abdominal surgery during the postoperative period, as well as to analyze BS safety. Methods: This was a randomized clinical trial involving 34 patients divided into a control group (CG; n = 16), who underwent conventional physiotherapy only, and the BS group (BSG; n = 18), who underwent conventional physiotherapy and BS. Both groups performed two daily sessions from postoperative day 2 until hospital discharge. The primary outcomes were FVC and Vt. The safety of BS was assessed by the incidence of gastrointestinal, hemodynamic, and respiratory repercussions. Results: Although FVC significantly increased at hospital discharge in both groups, the effect was greater on the BSG. Significant increases in FEV1, FEV1/FVC ratio, PEF, and FEF25-75% occurred only in the BSG. There were also significant increases in Ve and Vt in the BSG, but not when compared with the CG values at discharge. MIP and MEP significantly increased in both groups, with a greater effect on the BSG. There was a significant decrease in RR, as well as a significant increase in SpO2 only in the BSG. SpO2 acutely increased after BS; however, no changes were observed in the degree of dyspnea, vital signs, or signs of respiratory distress, and no gastrointestinal and hemodynamic repercussions were observed. Conclusions: BS has proven to be safe and effective for recovering pulmonary function; improving lung volumes, maximum respiratory pressures, and peripheral oxygenation; and reducing respiratory work during the postoperative period after upper abdominal surgery.

RESUMO Objetivo: Avaliar o efeito da técnica de breath stacking (BS) associada à fisioterapia de rotina na função pulmonar, volumes pulmonares, pressões respiratórias máximas, sinais vitais, oxigenação periférica, mobilidade toracoabdominal e dor na incisão cirúrgica em pacientes no pós-operatório de cirurgia abdominal alta, bem como analisar a segurança do BS. Métodos: Trata-se de um ensaio clínico randomizado com 34 pacientes divididos em grupo controle (n = 16), que realizou apenas a fisioterapia convencional, e grupo BS (n = 18), que realizou a fisioterapia convencional e BS. Ambos os grupos realizaram duas sessões diárias desde o 2º dia do pós-operatório até a alta hospitalar. Os desfechos primários foram CVF e Vt. A segurança do BS foi avaliada pela incidência de repercussões gastrointestinais, hemodinâmicas e respiratórias. Resultados: Embora a CVF tenha aumentado significativamente no momento da alta hospitalar em ambos os grupos, o efeito foi maior no grupo BS. Aumentos significativos do VEF1, VEF1/CVF, PFE e FEF25-75% ocorreram apenas no grupo BS. Também houve aumentos significativos do Ve e do Vt no grupo BS, mas não em comparação com os valores do grupo controle no momento da alta. A PImáx e a PEmáx aumentaram significativamente em ambos os grupos, com efeito maior no grupo BS. Houve uma diminuição significativa da FR e um aumento significativo da SpO2 apenas no grupo BS. A SpO2 aumentou agudamente após o BS; entretanto, não foram observadas alterações no grau de dispneia, sinais vitais e sinais de desconforto respiratório, e não foram observadas repercussões gastrointestinais e hemodinâmicas. Conclusões: O BS mostrou-se seguro e eficaz na recuperação da função pulmonar; melhoria dos volumes pulmonares, pressões respiratórias máximas e oxigenação periférica; e redução do trabalho respiratório no pós-operatório de cirurgia abdominal alta.

A construção da Identidade Médica na concepção de médicos recém-graduados / The construction of Medical Identity in the conception of newly graduated physicians

A Identidade Médica (IM) é uma contrução social dinâmica e é influenciada por fatores relacionados ao estudante, ao docente/preceptor e à sociedade, além de moldar a forma como o futuro médico exercerá sua profissão. O objetivo desta tese é analisar a construção da IM e os fatores que a influenciam a partir das percepções de médicos recém-graduados, além de realizar uma revisão da literatura atual, pesquisar os fatores intrínsecos e extrínsecos formadores da IM, a influência dos primeiros anos do exercício profissional e das Diretrizes Curriculares Nacionais (DCN) no perfil e na consolidação da IM. Estudo observacional de corte transversal de caráter qualitativo realizado com médicos-residentes de um hospital universitário de um grande centro urbano brasileiro. Os dados foram coletados por meio de doze entrevistas virtuais no período de setembro a novembro de 2021 e três grupos focais presenciais, com seis participantes cada, em agosto de 2022. O material produzido foi submetido à análise de conteúdo, seguindo os seguintes passos: leitura e releitura flutuante, busca de semelhanças e divergências, classificação em categorias temáticas, contextualização espaço-social-temporal, discussão com a literatura científica e síntese interpretativa. Além disso, foram pesquisadas as bases de dados PubMed®/MEDLINE, SciELO, LILACS, Cochrane Library e BVS para realização da revisão da literatura. Para a revisão, estruturação da fundamentação teórica e discussão dos dados da pesquisa, foram estudados, na íntegra, os 154 artigos encontrados. Pouco mais da metade (51%) dos artigos trata-se de pesquisas empíricas que possuem como foco um dos três eixos formadores da IM (estudante / docente / sociedade), enquanto 40% são revisões da literatura e 9% são editoriais. A maioria das pesquisas (73%) foi desenvolvida no eixo América do Norte / Europa. Apesar disso, o Brasil configura-se como o 5º país em número de publicações. O material produzido no campo revelou que as expectativas dos estudantes com relação ao médico que imaginam se tornar, a influência de docentes e preceptores e o perfil de médico exigido pela sociedade moldam a IM dos participantes. Os primeiros anos da carreira profissional constituem um período de turbulência e de conflitos identitários que são suavizados durante a Residência Médica, quando esta se configura como um ambiente de prática e de ensino-aprendizagem salutar. Os médicos-residentes desconhecem as DCN e isso impacta negativamente na forma que vivenciam as expectativas da sociedade traduzidas pelas Diretrizes. Na percepção dos médicos recém-graduados, há uma incongruência entre o que é preconizado nas DCN, a formação que é efetivamente oferecida nos cursos de medicina e o mercado de trabalho que eles encontram após estarem habilitados a exercer a profissão. Essa incongruência gera uma IM pouco saudável que é prejudicial ao exercício qualificado da profissão e gera sofrimento e insatisfação nos novos médicos. Os resultados desse estudo podem contribuir com o trabalho daqueles envolvidos no processo de formação identitária dos médicos, auxiliando-os a empreender ações que favoreçam a formação de uma IM mais saudável em benefício dos atuais e futuros médicos e da população por eles assistida.(AU)

The Medical Identity (MI) is a dynamic social construction and is influenced by factors related to the student, the professor/preceptor and society, in addition to shaping the way the future physician will exercise his profession. The objective of this thesis is to analyze the construction of MI and the factors that influence it based on the perceptions of newly graduated physicians, in addition to carrying out a review of the current literature, researching the intrinsic and extrinsic factors that form MI, the influence of the first years of professional practice and the National Curriculum Guidelines (NCG) for Brazilian Medicine courses in the profile and consolidation of MI. A qualitative, cross-sectional observational study carried out with resident physicians at a university hospital in a large Brazilian urban center. Data were collected through twelve virtual interviews from September to November 2021 and three face-to-face focus groups, with six participants each, in August 2022. The material produced was subjected to content analysis, following the steps below: reading and fluctuating rereading, search for similarities and divergences, classification into thematic categories, spatio-social-temporal contextualization, discussion with the scientific literature and interpretative synthesis. In addition, the PubMed®/MEDLINE, SciELO, LILACS, Cochrane Library and BVS databases were searched to carry out the literature review. For the review, structuring of the theoretical foundation and discussion of the research data, the 154 articles found were studied in full. A little more than half (51%) of the articles are empirical research that focus on one of the three axes that form MI (student / teacher / society), while 40% are literature reviews and 9% are editorials. Most of the surveys (73%) were developed in the North America / Europe axis. Despite this, Brazil ranks 5th in number of publications. The material produced in the field revealed that the students' expectations regarding the doctor they imagine becoming, the influence of professors and preceptors and the profile of a doctor required by society shape the participants' MI. The first years of the professional career constitute a period of turbulence and identity conflicts that are softened during the Medical Residency Program, when it is configured as an environment of practice and healthy teaching-learning. Medical residents are unaware of the NCG and this negatively impacts the way they experience society's expectations translated by the Guidelines. In the perception of newly graduated physicians, there is an inconsistency between what is recommended in the NCG, the training that is effectively offered in medical courses and the job market that they find after being qualified to practice the profession. This incongruity generates an unhealthy MI that is harmful to the qualified exercise of the profession and generates suffering and dissatisfaction in new physicians. The results of this study can contribute to the work of those involved in the physicians' identity formation process, helping them to undertake actions that favor the formation of a healthier MI for the benefit of current and future physicians and the population they assist.(AU)

miR-138-5p induces aggressive traits by targeting Trp53 expression in murine melanoma cells, and correlates with poor prognosis of melanoma patients.

Deregulation of miRNAs contributes to the development of distinct cancer types, including melanoma, an aggressive form of skin cancer characterized by high metastatic potential and poor prognosis. The expression of a set of 580 miRNAs was investigated in a model of murine melanoma progression, comprising non-metastatic (4C11-) and metastatic melanoma (4C11+) cells. A significant increase in miR-138-5p expression was found in the metastatic 4C11+ melanoma cells compared to 4C11-, which prompted us to investigate its role in melanoma aggressiveness. Functional assays, including anoikis resistance, colony formation, collective migration, serum-deprived growth capacity, as well as in vivo tumor growth and experimental metastasis were performed in 4C11- cells stably overexpressing miR-138-5p. miR-138-5p induced an aggressive phenotype in mouse melanoma cell lines leading to increased proliferation, migration and cell viability under stress conditions. Moreover, by overexpressing miR-138-5p, low-growing and non-metastatic 4C11- cells became highly proliferative and metastatic in vivo, similar to the metastatic 4C11+ cells. Luciferase reporter analysis identified the tumor suppressor Trp53 as a direct target of miR-138-5p. Using data sets from independent melanoma cohorts, miR-138-5p and P53 expression were also found deregulated in human melanoma samples, with their levels negatively and positively correlated with prognosis, respectively. Our data shows that the overexpression of miR-138-5p contributes to melanoma metastasis through the direct suppression of Trp53.

Biochanin A Regulates Key Steps of Inflammation Resolution in a Model of Antigen-Induced Arthritis via GPR30/PKA-Dependent Mechanism.

Biochanin A (BCA) is a natural organic compound of the class of phytochemicals known as flavonoids and isoflavone subclass predominantly found in red clover (Trifolium pratense). It has anti-inflammatory activity and some pro-resolving actions, such as neutrophil apoptosis. However, the effect of BCA in the resolution of inflammation is still poorly understood. In this study, we investigated the effects of BCA on the neutrophilic inflammatory response and its resolution in a model of antigen-induced arthritis. Male wild-type BALB/c mice were treated with BCA at the peak of the inflammatory process (12 h). BCA decreased the accumulation of migrated neutrophils, and this effect was associated with reduction of myeloperoxidase activity, IL-1ß and CXCL1 levels, and the histological score in periarticular tissues. Joint dysfunction, as seen by mechanical hypernociception, was improved by treatment with BCA. The resolution interval (Ri) was also quantified, defining profiles of acute inflammatory parameters that include the amplitude and duration of the inflammatory response monitored by the neutrophil infiltration. BCA treatment shortened Ri from ∼23 h observed in vehicle-treated mice to ∼5.5 h, associated with an increase in apoptotic events and efferocytosis, both key steps for the resolution of inflammation. These effects of BCA were prevented by H89, an inhibitor of protein kinase A (PKA) and G15, a selective G protein-coupled receptor 30 (GPR30) antagonist. In line with the in vivo data, BCA also increased the efferocytic ability of murine bone marrow-derived macrophages. Collectively, these data indicate for the first time that BCA resolves neutrophilic inflammation acting in key steps of the resolution of inflammation, requiring activation of GPR30 and via stimulation of cAMP-dependent signaling.

Individual, household and environmental factors associated with arboviruses in rural human populations, Brazil.

Landscape change is one of the foremost drivers of the emergence of infectious diseases. Exploring demographic, household and environmental conditions under which infectious diseases occur may inform strategies to prevent disease emergence in human populations. We collected blood samples from 523 humans and explore factors for arbovirus emergence in Bahia, Brazil. The overall arbovirus seroprevalence was 65.2%, with the genus Flavivirus most prevalent (64.4%). Based on monotypic reactions, the population had contact with five arbovirus: Dengue 3, Ilheus, Oropouche, Caraparu and Eastern equine encephalitis virus. To our knowledge, this is the first study reporting exposure to Oropouche, Caraparu and Eastern equine encephalitis virus in human populations in Bahia, Northeast of Brazil. The best model fit demonstrated that household and environmental variables were more predictive of the risk of arbovirus exposure than demographic variables. The presence of forest and free-living monkeys in the areas close to the communities had a protective effect for the human population (i.e. lower seroprevalence). The dilution effect is considered as one explanation for this finding. These results highlight the important ecological role of wildlife-friendly agriculture.

Survivin modulation in the antimelanoma activity of prodiginines.

Melanoma is a type of skin cancer with an elevated incidence of metastasis and chemoresistance. Such features hamper treatment success of these neoplasms, demanding the search for new therapeutic options. Using a two-step resin-based approach, we recently demonstrated that cytotoxic prodiginines bind to the inhibitor of apoptosis protein, survivin. Herein, we explore the role of survivin in melanoma and whether its modulation is related to the antimelanoma properties of three cytotoxic prodiginines (prodigiosin, cyclononylprodigiosin, and nonylprodigiosin) isolated from marine bacteria. In melanoma patients and cell lines, survivin is overexpressed, and higher levels negatively impact survival. All three prodiginines caused a decrease in cell growth with reduced cytotoxicity after 24 h compared to 72 h treatment, suggesting that low concentrations promote cytostatic effects in SK-Mel-19 (BRAF mutant) and SK-Mel-28 (BRAF mutant), but not in SK-Mel-147 (NRAS mutant). An increase in G1 population was observed after 24 h treatment with prodigiosin and cyclononylprodigiosin in SK-Mel-19. Further studies indicate that prodigiosin induced apoptosis and DNA damage, as detected by increased caspase-3 cleavage and histone H2AX phosphorylation, further arguing for the downregulation of survivin. Computer simulations suggest that prodigiosin and cyclononylprodigiosin bind to the BIR domain of survivin. Moreover, knockdown of survivin increased long-term toxicity of prodigiosin, as observed by reduced clonogenic capacity, but did not alter short-term cytotoxicity. In summary, prodiginine treatment provoked cytostatic rather than cytotoxic effects, cell cycle arrest at G0/G1 phase, induction of apoptosis and DNA damage, downregulation of survivin, and decreased clonogenic capacity in survivin knockdown cells.

Case for diagnosis. Pruritic erythematosquamous lesion in the auricle

Abstract Chromoblastomycosis is a subcutaneous mycosis with chronic evolution that mainly affects the lower limbs and, less frequently, the auricles. Clinically, it presents with papillary verrucous, nodular, and/or tumoral lesions, whether isolated or infiltrated, forming plaques and, sometimes, atrophic in some areas. Histopathologically, it is characterized by a dermal granulomatous inflammatory infiltrate, and the diagnosis can be confirmed by the presence of fumagoid bodies in anatomopathological or direct mycological exams. The treatment to be indicated will depend on the extent and location of the lesions, using systemic antifungals, surgical removal, cryotherapy, thermotherapy, and immunoadjuvants. The present study reports an atypical presentation of chromoblastomycosis on the auricle.

Amerindian genetic ancestry as a risk factor for tuberculosis in an amazonian population.

In recent years, the incidence of tuberculosis (TB) has declined worldwide, although this disease still occurs at relatively high rates in Amerindian populations. This suggests that the genetic ancestry of Amerindians may be an important factor in the development of infections, and may account for at least some of the variation in infection rates in the different populations. The present study investigated the potential influence of Amerindian genetic ancestry on susceptibility to tuberculosis in an Amazon population. The study included 280 patients diagnosed with tuberculosis and 138 asymptomatic hospital employees with no history of TB, but who were in contact with bacterially active TB patients. Ancestry analysis was run on a set of 61 Ancestry-Informative Markers to estimate European, African, and Amerindian genetic ancestry using STRUCTURE v2.2. The TB group had significantly higher Amerindian ancestry in comparison with the control group, and significantly lower European ancestry. Amerindian ancestry in the 20-60% range was found to be the principal risk factor for increased susceptibility to TB. The results of the study indicate that Amerindian ancestry is an important risk factor for susceptibility to TB in the admixed population of the Brazilian Amazon region.

Case for diagnosis. Pruritic erythematosquamous lesion in the auricle.

Chromoblastomycosis is a subcutaneous mycosis with chronic evolution that mainly affects the lower limbs and, less frequently, the auricles. Clinically, it presents with papillary verrucous, nodular, and/or tumoral lesions, whether isolated or infiltrated, forming plaques and, sometimes, atrophic in some areas. Histopathologically, it is characterized by a dermal granulomatous inflammatory infiltrate, and the diagnosis can be confirmed by the presence of fumagoid bodies in anatomopathological or direct mycological exams. The treatment to be indicated will depend on the extent and location of the lesions, using systemic antifungals, surgical removal, cryotherapy, thermotherapy, and immunoadjuvants. The present study reports an atypical presentation of chromoblastomycosis on the auricle.

In vivo antitumoral effect of 4-nerolidylcatechol (4-NC) in NRAS-mutant human melanoma.

NRAS-mutations arise in 15-20% of all melanomas and are associated with aggressive disease and poor prognosis. Besides, the treatment for NRAS-mutant melanoma are not very efficient and is currently limited to immune checkpoints inhibitors or aggressive chemotherapy. 4-nerolidylcathecol (4-NC), a natural product extracted from Pothomorphe umbellata, induces apoptosis in melanoma cells by ROS production, DNA damage and increased p53 expression, in addition to inhibiting invasion in reconstructed skin. Moreover, 4-NC showed cytotoxicity in BRAF/MEKi-resistant and naive melanoma cells by Endoplasmic Reticulum (ER) stress induction in vitro. We evaluated the in vivo efficacy and the systemic toxicity of 4-NC in a NRAS-mutant melanoma model. 4-NC was able to significantly suppress tumor growth 4-fold compared to controls. Cleaved PARP and p53 expression were increased indicating cell death. As a proof of concept, MMP-2 and MMP-14 gene expression were decreased, demonstrating a possible role of 4-NC in melanoma invasion inhibition. Toxicological analysis indicated minor changes in the liver and bone marrow, but this toxicity was very mild when compared to other proteasome inhibitors and ER stress inductors already described. Our data indicate that 4-NC can counteract melanoma growth in vivo with minor adverse effects, suggesting further investigation as a potential NRAS-mutant melanoma treatment.

The Role of SIRT1 on DNA Damage Response and Epigenetic Alterations in Cancer.

Sirtuin-1 (SIRT1) is a class-III histone deacetylase (HDAC), an NAD+-dependent enzyme deeply involved in gene regulation, genome stability maintenance, apoptosis, autophagy, senescence, proliferation, aging, and tumorigenesis. It also has a key role in the epigenetic regulation of tissue homeostasis and many diseases by deacetylating both histone and non-histone targets. Different studies have shown ambiguous implications of SIRT1 as both a tumor suppressor and tumor promoter. However, this contradictory role seems to be determined by the cell type and SIRT1 localization. SIRT1 upregulation has already been demonstrated in some cancer cells, such as acute myeloid leukemia (AML) and primary colon, prostate, melanoma, and non-melanoma skin cancers, while SIRT1 downregulation was described in breast cancer and hepatic cell carcinomas. Even though new functions of SIRT1 have been characterized, the underlying mechanisms that define its precise role on DNA damage and repair and their contribution to cancer development remains underexplored. Here, we discuss the recent findings on the interplay among SIRT1, oxidative stress, and DNA repair machinery and its impact on normal and cancer cells.