Impacto da análise do proto-oncogene RET na conduta clínica da neoplasia endócrina múltipla tipo 2

Multiple endocrine neoplasia type 2 (MEN2) is an autosomal dominant disease characterized by the presence of medullary thyroid carcinoma, primary hyperparathyroidism, and pheochromocytoma. Multiple endocrine neoplasia type 2 is still an underdiagnosed, or late-diagnosed condition in many areas of the world. Since 1993, when the first missense RET proto-oncogene (RET) mutations were reported in MEN2, up to 46 different RET-causing disease mutations have been described. Since a strong genotype-phenotype correlation exists for MEN2, the detection of RET mutations has produced a major impact in early recognition and treatment of MTC and MEN2. Presently, RET mutation analysis should be performed for all MEN2 cases and their at-risk familial relatives. Further, prophylactic total thyroidectomy is indicated in all cases harboring activating gametic RET mutations. In most RET mutation carriers, prophylactic total thyroidectomy is indicated at ages as early as a few months to 4 years of age, promoting longer survival and improvement of quality of life or even definitive cure. We discuss the large impact of RET proto-oncogene analysis on the clinical management of MEN2 and the role of early RET molecular DNA diagnosis in providing clinicians and surgeons with valuable information that enables them to indicate early total thyroidectomy.A neoplasia endócrina múltipla tipo 2 (NEM2) é caracterizada pela ocorrência do carcinoma medular de tireóide (CMT), hiperparatiroidismo primário (HPT) e feocromocitoma (FEO).1-12 Desde 1993, quando as primeiras mutações do tipo missense no proto-oncogene RET (RET), associadas a NEM2 foram identificadas, 46 diferentes mutações causadoras de doenças foram descritas.13-17 Como há uma forte correlação genótipo-fenótipo na NEM2, a detecção de mutações no RET adquiriu grande impacto no tratamento precoce do CMT e NEM2. A NEM2 persiste como uma doença subdiagnosticada e/ou tardiamente diagnosticada em várias áreas geográficas do globo. A análise de mutações do RET deve ser realizada em todas os casos de NEM2 e atualmente, a tireoidectomia total profilática é indicada para todos os indivíduos portadores de mutações no RET.¹ Para a grande maioria dos portadores de mutações gaméticas ativadoras no RET este procedimento cirúrgico é indicado nos primeiros anos de vida, promovendo melhora na qualidade de vida, aumento da sobrevida ou mesmo levando à cura definitiva.¹ Discutimos nesta revisão, o impacto da análise do proto-oncogene RET na conduta clínica da neoplasia endócrina múltipla tipo 2. Além disso, o diagnóstico molecular do RET fornece à clínicos e cirurgiões a mais valiosa das informações, permitindo indicação de tireoidectomia total profilática

The uncertain consequences of transferring bacterial strains between laboratories - rpoS instability as an example

Abstract\ud \ud \ud \ud Background\ud \ud Microbiological studies frequently involve exchanges of strains between laboratories and/or stock centers. The integrity of exchanged strains is vital for archival reasons and to ensure reproducible experimental results. For at least 50 years, one of the most common means of shipping bacteria was by inoculating bacterial samples in agar stabs. Long-term cultures in stabs exhibit genetic instabilities and one common instability is in rpoS. The sigma factor RpoS accumulates in response to several stresses and in the stationary phase. One consequence of RpoS accumulation is the competition with the vegetative sigma factor σ70. Under nutrient limiting conditions mutations in rpoS or in genes that regulate its expression tend to accumulate. Here, we investigate whether short-term storage and mailing of cultures in stabs results in genetic heterogeneity.\ud \ud \ud \ud Results\ud \ud We found that samples of the E. coli K-12 strain MC4100TF exchanged on three separate occasions by mail between our laboratories became heterogeneous. Reconstruction studies indicated that LB-stabs exhibited mutations previously found in GASP studies in stationary phase LB broth. At least 40% of reconstructed stocks and an equivalent proportion of actually mailed stock contained these mutations. Mutants with low RpoS levels emerged within 7 days of incubation in the stabs. Sequence analysis of ten of these segregants revealed that they harboured each of three different rpoS mutations. These mutants displayed the classical phenotypes of bacteria lacking rpoS. The genetic stability of MC4100TF was also tested in filter disks embedded in glycerol. Under these conditions, GASP mutants emerge only after a 3-week period. We also confirm that the intrinsic high RpoS level in MC4100TF is mainly due to the presence of an IS1 insertion in rssB.\ud \ud \ud \ud Conclusions\ud \ud Given that many E. coli strains contain high RpoS levels similar to MC4100TF, the integrity of such strains during transfers and storage is questionable. Variations in important collections may be due to storage-transfer related issues. These results raise important questions on the integrity of bacterial archives and transferred strains, explain variation like in the ECOR collection between laboratories and indicate a need for the development of better methods of strain transfer.We are grateful to Fundação de Amparo á Pesquisa do Estado de São Paulo (FAPESP-Brazil), who supported this study and provided a travel allowance for TF. TF was also supported by the the Australian Research Council and the US Army Research Office. We also thank K. C. Murphy and S. Kushner for respectively providing strain KM32 and plasmid pWKS130

A INTERSECCIONALIDADE NA EDUCAÇÃO ESCOLAR INDÍGENA E O PROJETO POLÍTICO PEDAGÓGICO DA ESCOLA ESTADUAL INDÍGENA ARANDU RENDA DE ITAIPULÂNDIA-PR

O presente artigo visa expor os condicionantes que auxiliam ou inibem a categoria interseccional estar presente no contexto educacional indígena. Para isso, a metodologia está pautada em uma pesquisa bibliográfica e documental, em que foram utilizados autores que tratam sobre a temática indígena e sobre o conceito de interseccionalidade e, também, se faz uma análise do Projeto Político Pedagógico da Escola Estadual Indígena Arandu Renda, localizada no município de Itaipulândia, no estado do Paraná. A hipótese é de que alguns condicionantes dificultam e, ao mesmo tempo, facilitam que a escola indígena seja diferenciada, específica, intercultural, bilíngue/multilíngue

Endocrine and Neuroendocrine Tumors Special Issue—Checkpoint Inhibitors for Adrenocortical Carcinoma and Metastatic Pheochromocytoma and Paraganglioma: Do They Work?

Adrenocortical cancer; Checkpoint inhibitors; Metastatic paragangliomaCáncer adrenocortical; Inhibidores de puntos de control; Paraganglioma metastásicoCàncer adrenocortical; Inhibidors de punts de control; Paraganglioma metastàticAdrenocortical cancers and metastatic pheochromocytomas are the most common malignancies originating in the adrenal glands. Metastatic paragangliomas are extra-adrenal tumors that share similar genetic and molecular profiles with metastatic pheochromocytomas and, subsequently, these tumors are studied together. Adrenocortical cancers and metastatic pheochromocytomas and paragangliomas are orphan diseases with limited therapeutic options worldwide. As in any other cancers, adrenocortical cancers and metastatic pheochromocytomas and paragangliomas avoid the immune system. Hypoxia-pseudohypoxia, activation of the PD-1/PD-L1 pathway, and/or microsatellite instability suggest that immunotherapy with checkpoint inhibitors could be a therapeutic option for patients with these tumors. The results of clinical trials with checkpoint inhibitors for adrenocortical carcinoma or metastatic pheochromocytoma or paraganglioma demonstrate limited benefits; nevertheless, these results also suggest interesting mechanisms that might enhance clinical responses to checkpoint inhibitors. These mechanisms include the normalization of tumor vasculature, modification of the hormonal environment, and vaccination with specific tumor antigens. Combinations of checkpoint inhibitors with classical therapies, such as chemotherapy, tyrosine kinase inhibitors, radiopharmaceuticals, and/or novel therapies, such as vaccines, should be evaluated in clinical trials

Impacto do rastreamento clínico e genético para neoplasia endócrina múltipla tipo 1

PURPOSE: To perform clinical and genetic screening for multiple endocrine neoplasia type 1 (MEN1) in patients at the Academic Hospital of the University of São Paulo School of Medicine, and to analyze its impact on clinical management of patients with MEN1. METHODS: The clinical diagnosis of MEN1 was made in accordance with the Consensus on multiple endocrine neoplasias. Mutation analysis of the entire MEN1 tumor suppressor gene and genetic screening of at-risk family members were performed by direct sequencing. To analyze the implementation of genetic diagnosis, the studied patients were separated into 3 groups: MEN1 index cases (group I), clinically diagnosed MEN1 cases (group II), and genetically diagnosed MEN1 cases (group III). RESULTS: In total, 154 individuals were clinically and genetically studied. We identified 12 different MEN1 mutations. Fifty-two MEN1 cases were identified: 13 in group I, 28 in group II, and 11 in group III. The mean age in group III (27.0 years) was significantly lower than in groups I (39.5 years) and II (42.4 years; P = 0.03 and P = 0.01, respectively). Patients in groups I and II mostly presented 2 or 3 MEN1-related tumors, while 81.8% of those in group III presented 1 or no MEN1-related tumor. Additionally, in group III, 45.4% of cases were asymptomatic, and no metastasis or death was verified. Surveillance for MEN1 mutations allowed the exclusion of 102 noncarriers, including a case of MEN1 phenocopy. CONCLUSION: Our data supports the benefits of clinical and genetic screening for multiple endocrine neoplasia type 1 in the management of this syndrome.OBJETIVOS: Realizar rastreamentos clínico e gênico para Neoplasia Endócrina Múltipla tipo 1 (NEM1) e analisar seu impacto no seguimento clínico desses pacientes no Hospital das Clínicas, SP. MÉTODOS: O diagnóstico clínico de NEM1 foi realizado de acordo com o Consenso sobre neoplasias endócrinas múltiplas. A análise genética para identificação de mutações foi realizada por sequenciamento automático de todas as regiões codificadoras e fronteiras exon/intron do gene MEN1. Os casos afetados foram sub-divididos em 3 grupos e analisados separadamente: casos-índices (grupo I), familiares diagnosticados clinicamente (grupo II) e genicamente (grupo III). RESULTADOS: Um total de 154 casos participou desse estudo, sendo 52 diagnosticados com NEM1: 13 do grupo I, 28 do grupo II e 11 do grupo III. A idade média ao diagnóstico no grupo III (27 anos) foi significativamente menor que a dos grupos I (39,5 anos; p = 0,03) e II (42,4 anos; p = 0,01). A maioria dos pacientes dos grupos I e II apresentou 2 ou 3 tumores, enquanto que 81,8% dos casos do grupo III apresentavam 1 ou nenhum tumor relacionado à NEM1. Além disto, 45,4% dos casos do grupo III eram assintomáticos, não sendo observados nenhuma metástase ou óbito. Os demais 102 familiares sob-risco estudados não herdaram mutação MEN1 e foram excluídos do rastreamento clínico. Um caso de fenocópia NEM1 foi também localizado. DISCUSSÃO: Nossos dados demonstraram importantes benefícios no seguimento dos pacientes NEM1, obtidos pela implementação dos rastreamentos clínico e gênico para essa doença

Genomic and immune landscape Of metastatic pheochromocytoma and paraganglioma

Adrenal gland diseases; Cancer genomics; Prognostic markersMalalties de les glàndules suprarenals; Genòmica del càncer; Marcadors pronòsticsEnfermedades de las glándulas suprarrenales; Genómica del cáncer; Marcadores pronósticosThe mechanisms triggering metastasis in pheochromocytoma/paraganglioma are unknown, hindering therapeutic options for patients with metastatic tumors (mPPGL). Herein we show by genomic profiling of a large cohort of mPPGLs that high mutational load, microsatellite instability and somatic copy-number alteration burden are associated with ATRX/TERT alterations and are suitable prognostic markers. Transcriptomic analysis defines the signaling networks involved in the acquisition of metastatic competence and establishes a gene signature related to mPPGLs, highlighting CDK1 as an additional mPPGL marker. Immunogenomics accompanied by immunohistochemistry identifies a heterogeneous ecosystem at the tumor microenvironment level, linked to the genomic subtype and tumor behavior. Specifically, we define a general immunosuppressive microenvironment in mPPGLs, the exception being PD-L1 expressing MAML3-related tumors. Our study reveals canonical markers for risk of metastasis, and suggests the usefulness of including immune parameters in clinical management for PPGL prognostication and identification of patients who might benefit from immunotherapy.This work was supported by Project PI17/01796 and PI20/01169 to M.R. [Instituto de Salud Carlos III (ISCIII), Acción Estratégica en Salud, cofinanciado a través del Fondo Europeo de Desarrollo Regional (FEDER)], Paradifference Foundation [no grant number applicable to M.R.], Pheipas Association [no grant number applicable to M.R.], the Clinical Research Priority Program of the University of Zurich for the CRPP HYRENE to F.B., the Deutsche Forschungsgemeinschaft (DFG) within the CRC/Transregio 205/1 (Project No. 314061271-TRR205 to to F.B., M.F., N.B., and G.E.) and the Instituto de Salud Carlos III (ISCIII), Spanish Ministry of Science and Innovation (Project No. PID2019-111356RA-I00 to G.M.). B.C. was supported by the Rafael del Pino Foundation (Becas de Excelencia Rafael del Pino 2017). A.M.M.-M. was supported by CAM (S2017/BMD-3724; TIRONET2-CM). A.F.-S. and J.L. received the support of a fellowship from La Caixa Foundation (ID 100010434; LCF/BQ/DR21/11880009 and LCF/BQ/DR19/11740015, respectively). M.M., S.M., and M.S. were supported by the Spanish Ministry of Science, Innovation and Universities “Formación del Profesorado Universitario— FPU” fellowship with ID number FPU18/00064, FPU19/04940 and FPU16/05527. A.D.-T. is supported by the Centro de Investigacion Biomédica en Red de Enfermedades Raras (CIBERER). L.J.L.-G. was supported both by the Banco Santander Foundation and La Caixa Postdoctoral Junior Leader Fellowship (LCF/BQ/PI20/11760011). C.M.-C. was supported by a grant from the AECC Foundation (AIO15152858 MONT). We thank the Spanish National Tumor Bank Network (RD09/0076/00047) for the support in obtaining tumorsamples and all patients, physicians and tumor biobanks involved in the study

Total parathyroidectomy in a large cohort of cases with hyperparathyroidism associated with multiple endocrine neoplasia type 1: experience from a single academic center

Most cases of sporadic primary hyperparathyroidism present disturbances in a single parathyroid gland and the surgery of choice is adenomectomy. Conversely, hyperparathyroidism associated with multiple endocrine neoplasia type 1 (hyperparathyroidism/multiple endocrine neoplasia type 1) is an asynchronic, asymmetrical multiglandular disease and it is surgically approached by either subtotal parathyroidectomy or total parathyroidectomy followed by parathyroid auto-implant to the forearm. In skilful hands, the efficacy of both approaches is similar and both should be complemented by prophylactic thymectomy

The impact of clinical and genetic screenings on the management of the multiple endocrine neoplasia type 1

PURPOSE: To perform clinical and genetic screening for multiple endocrine neoplasia type 1 (MEN1) in patients at the Academic Hospital of the University of São Paulo School of Medicine, and to analyze its impact on clinical management of patients with MEN1. METHODS: The clinical diagnosis of MEN1 was made in accordance with the Consensus on multiple endocrine neoplasias. Mutation analysis of the entire MEN1 tumor suppressor gene and genetic screening of at-risk family members were performed by direct sequencing. To analyze the implementation of genetic diagnosis, the studied patients were separated into 3 groups: MEN1 index cases (group I), clinically diagnosed MEN1 cases (group II), and genetically diagnosed MEN1 cases (group III). RESULTS: In total, 154 individuals were clinically and genetically studied. We identified 12 different MEN1 mutations. Fifty-two MEN1 cases were identified: 13 in group I, 28 in group II, and 11 in group III. The mean age in group III (27.0 years) was significantly lower than in groups I (39.5 years) and II (42.4 years; P = 0.03 and P = 0.01, respectively). Patients in groups I and II mostly presented 2 or 3 MEN1-related tumors, while 81.8% of those in group III presented 1 or no MEN1-related tumor. Additionally, in group III, 45.4% of cases were asymptomatic, and no metastasis or death was verified. Surveillance for MEN1 mutations allowed the exclusion of 102 noncarriers, including a case of MEN1 phenocopy. CONCLUSION: Our data supports the benefits of clinical and genetic screening for multiple endocrine neoplasia type 1 in the management of this syndrome.OBJETIVOS: Realizar rastreamentos clínico e gênico para Neoplasia Endócrina Múltipla tipo 1 (NEM1) e analisar seu impacto no seguimento clínico desses pacientes no Hospital das Clínicas, SP. MÉTODOS: O diagnóstico clínico de NEM1 foi realizado de acordo com o Consenso sobre neoplasias endócrinas múltiplas. A análise genética para identificação de mutações foi realizada por sequenciamento automático de todas as regiões codificadoras e fronteiras exon/intron do gene MEN1. Os casos afetados foram sub-divididos em 3 grupos e analisados separadamente: casos-índices (grupo I), familiares diagnosticados clinicamente (grupo II) e genicamente (grupo III). RESULTADOS: Um total de 154 casos participou desse estudo, sendo 52 diagnosticados com NEM1: 13 do grupo I, 28 do grupo II e 11 do grupo III. A idade média ao diagnóstico no grupo III (27 anos) foi significativamente menor que a dos grupos I (39,5 anos; p = 0,03) e II (42,4 anos; p = 0,01). A maioria dos pacientes dos grupos I e II apresentou 2 ou 3 tumores, enquanto que 81,8% dos casos do grupo III apresentavam 1 ou nenhum tumor relacionado à NEM1. Além disto, 45,4% dos casos do grupo III eram assintomáticos, não sendo observados nenhuma metástase ou óbito. Os demais 102 familiares sob-risco estudados não herdaram mutação MEN1 e foram excluídos do rastreamento clínico. Um caso de fenocópia NEM1 foi também localizado. DISCUSSÃO: Nossos dados demonstraram importantes benefícios no seguimento dos pacientes NEM1, obtidos pela implementação dos rastreamentos clínico e gênico para essa doença

Nutritional situation of children under five years old in Brazil’s northeastern cities

ResumoOBJETIVOS: Descrever a situação nutricional de crianças menores de cinco anos residentes em três municípios do Nordeste brasileiro. MÉTODO: Realizou-se um estudo epidemiológico transversal, com a participação de 1.378 crianças. Foram calculados os índices antropométricos altura/idade, peso/idade e peso/altura, segundo os valores em escore Z. As Curvas de Crescimento Infantil da Organização Mundial de Saúde foram utilizadas como referência. RESULTADOS: Identificaram-se maiores proporções de excesso de peso/altura (8,3% em Barra de São Miguel, 10,3% em Cabedelo e 5,9% em Tibau do Sul), quando comparadas às proporções de déficit de peso/altura (1,5% em Barra de São Miguel, 1,9% em Cabedelo e 0,9% em Tibau do Sul). Observaram-se, ainda, prevalênciasmais elevadas de déficit de altura/idade (5,9% em Barra de São Miguel, 5,5% em Cabedelo e 4,6% em Tibau do Sul), quando comparadas às prevalências de déficit de peso/idade (3,6% em Barra de São Miguel, 2,5% em Cabedelo e 1,5% em Tibau do Sul). CONCLUSÕES: Observou-se uma situaçãonutricional desfavorável no grupo estudado. Assim, ações voltadas para a promoção de uma alimentação adequada devem ser priorizadas no âmbito dos programas e políticas de alimentação e nutrição. As prevalências elevadas de déficit estatural e de excesso de peso reafirmam a vulnerabilidade deste grupo e a soma destas ações deve impactar na reversão deste perfil nutricional. OBJECTIVE: To describe the nutritional situation of children under five years old resident in three cities of Brazil’s northeastern region. METHODS: A transversal epidemiological study was undertaken with the participation of 1,378 children. The anthropometric measurements height/age, weight/age and weight/height were calculated in terms of the Z score. Children’s growth curves of the World Health Organization were used as reference. RESULTS: Higher proportions were found of overweight/ height (8.3% in Barra de São Miguel, 10.3% in Cabedelo and 5.9% in Tibau do Sul) than of deficit (1.5% in Barra de São Miguel, 1.9% in Cabedelo and 0.9% in Tibau do Sul). A higher prevalence of the height deficit was observed (5.9% in Barra de São Miguel, 5.5% in Cabedelo and 4.6% in Tibau do Sul) than of the weight deficit (3.6% in Barra de São Miguel, 2.5 % in Cabedelo and 1.5% in Tibau do Sul). CONCLUSION: The nutritional status of the group studied was unfavorable. Actions to promote adequate eating habits within the context of food and nutrition programs and policies should, therefore, be prioritized. The high prevalence of height deficit and overweight highlights the vulnerability of this group and the sum of the necessary actions should produce an impact by reversing this nutritional profile

O INSIGHT NO TRANSTORNO BIPOLAR

The research addressed the topic of insight in bipolar disorder through an exploratory literature review. The objective was to analyze the concept of insight and its relationship with bipolar disorder, as well as to identify factors that influence its development and possible therapeutic approaches. The problem explored was the difficulty in acquiring and maintaining insight into this disorder, a factor that can impact the treatment and prognosis of patients. The results pointed to the importance of the role of the family and the medical team in the development of insight, as well as the use of specific therapeutic interventions, such as Cognitive-Behavioral Therapy, to assist in the construction and maintenance of this process. The methodology used was the analysis of scientific articles and specialized books, allowing a broad understanding of the subject. The contribution of the work to the academic area was to provide theoretical and practical subsidies for professionals who work with patients with bipolar disorder, in addition to stimulating discussions about the importance of insight in this context. It is concluded that insight is a crucial element in the management of bipolar disorder and should be addressed comprehensively in the treatment of these patients.A pesquisa abordou o tema do insight no transtorno bipolar por meio de uma revisão bibliográfica exploratória. O objetivo foi analisar o conceito de insight e sua relação com o transtorno bipolar, além de identificar fatores que influenciam seu desenvolvimento e possíveis abordagens terapêuticas. A problemática explorada foi a dificuldade em adquirir e manter o insight nesse transtorno, fator que pode impactar no tratamento e prognóstico dos pacientes. Os resultados apontaram para a importância do papel da família e da equipe médica no desenvolvimento do insight, assim como a utilização de intervenções terapêuticas específicas, como a Terapia Cognitivo-Comportamental, para auxiliar na construção e manutenção desse processo. A metodologia utilizada foi a análise de artigos científicos e livros especializados, permitindo uma ampla compreensão do tema. A contribuição do trabalho para a área acadêmica foi fornecer subsídios teóricos e práticos para profissionais que atuam com pacientes com transtorno bipolar, além de estimular discussões sobre a importância do insight nesse contexto. Conclui-se que o insight é um elemento crucial no manejo do transtorno bipolar e deve ser abordado de forma integral no tratamento desses pacientes