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Treatment efficacy of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) is diverse even in non-small cell lung cancer (NSCLC) patients with EGFR activating mutations. Extraordinary long-term responses sustained over 3 years among NSCLC patients treated with afatinib, an EGFR-TKI, have been reported, but how to predict such long-survivors has not been clarified. A multi-institutional prospective observational study, based on comprehensive genomic examination performed with next generation sequencing (NGS) of circulating tumor DNA (ctDNA), was conducted to identify potential predictive markers of long-term response to afatinib. Twenty-nine patients with advanced stage NSCLC and EGFR driver mutations detected by standard techniques were enrolled. ctDNA from plasma collected before afatinib treatment was analyzed by Guardant360®. ctDNA was detected in 25 of the 29 samples. Median progression-free survival was shorter in patients whose tumors having EGFR copy number gain (7.0 vs 23.0 months, p = 0.022). The impact of EGFR copy number on cell proliferation and the antitumor effect of afatinib were evaluated using genome-editing lung cancer cell lines. HCC827 with EGFR amplification were relatively resistant to afatinib at concentrations below 0.5 nM, but genome-edited derivatives of HCC827 with decreased EGFR copy number demonstrated growth inhibition with 0.1 nM afatinib. The absence of EGFR copy number gain detected in ctDNA may be predictive markers of long-term response to afatinib. Comprehensive genomic analysis could lead to more accurate prediction of EGFR-TKI efficacy.

O artigo tem como objetivo apresentar as principais discussões internacionais sobre formação docente, bem como resgatar as ideias do grande educador brasileiro Anísio Teixeira, que foi um visionário para sua época abordando temas importantes sobre educação e formação docente. As ideias inovadoras de Anísio Teixeira, nem sempre colocadas em prática, continuam atuais e vão ao encontro das iniciativas internacionais que obtiveram êxito no âmbito educacional, focando principalmente na formação docente.

Background: Cancer genome profiling using next-generation sequencing (NGS) has become widespread. Multiple genetic abnormalities including variant of unknown significance (VUS) have been detected in various cancer types. However, there is a lack of an integrated analysis system capable of identifying relationships among multiple genetic abnormalities and weighting them appropriately. Here, we report heat map analysis, a new integrated pathway scoring system for cancer genome profiling. Methods: In heat map analysis, approximately 180 cancer-related genes among 324 genes evaluated by FoundationOne CDxTM are scored based on gene annotation and variant allele fraction (VAF), and classified into 16 pathways. This system provides an overall picture of genetic abnormalities and easy recognition of abnormal pathways. To examine the usefulness of the heat map analysis, a retrospective observational study was conducted on 50 patients with solid tumors who underwent cancer genome profiling test at Saga University Hospital from June 2019 to February 2022. The primary end point was the presentation rate of pathways with significantly increased scores. Results: A total of 749 genetic abnormalities including VUS were detected in 50 patients with 15 cancer types: 571 single nucleotide variants (SNVs), 156 copy number variants (CNVs), and 22 fusions. The median number of abnormalities detected was 11 (2-20) SNVs, 2 (0-23) CNVs, and 0 (0-4) fusions, respectively. Heat map analysis presented active pathways with significant score elevation in 42 cases (84%). The TP53 pathway was the most common, followed by the Receptor Tyrosine Kinase pathway, PIK3-AKT, RAS, and DNA repair-related pathways. Conclusion: Heat map analysis could be a promising new method for integrated analysis using cancer genome profiling tests. Citation Format: Chiho Nakashima, Yukimasa Shiotsu, Yohei Harada, Hiroo Katsuya, Emi Ookuma, Masanori Nishi, Akemi Sato, Hideaki Nakamura, Naoko Sueoka-Aragane. Heat Map Analysis, a new integrated pathway scoring system for cancer genome profiling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 262.

Das circunstâncias históricas que resultaram na aprovação da Lei nº 13.415/2017, o artigo propõe, analisar como os grupos econômicos privados, Banco Mundial e Governo Federal atuam para expandir os negócios na educação básica pública no país. Parte da legislação, referências e do documento Uma ponte para o futuro (2015) para evidenciar como a contrarreforma do Ensino Médio atende aos interesses do setor produtivo lucrativo, empresas e corporações. Apurou-se que sob o manto da ordem e progresso, governos, corporações e empresários modificam a legislação constitucional, trabalhista e educacional a fim de manter segurança nos contratos, favorecer o setor privado e instituir que as escolas de ensino médio se assemelhem às empresas em suas finalidades. Afirma ainda, que apesar das resistências, as forças econômicas em consonância com proposições do Banco Mundial e Governo Federal agem na regulação da educação básica pública no currículo, no financiamento e nas finalidades das escolas do país.

Adult T-cell leukemia-lymphoma (ATL) is an aggressive hematological malignancy of CD4+ T cells transformed by human T-cell lymphotropic virus-1 (HTLV-1). Most HTLV-1–infected individuals are asymptomatic, and only 3% to 5% of carriers develop ATL. Here, we describe the contribution of aberrant DNA methylation to ATL leukemogenesis. HTLV-1–infected T-cells and their uninfected counterparts were separately isolated based on CADM1 and CD7 expression status, and differentially methylated positions (DMPs) specific to HTLV–infected T cells were identified through genome-wide DNA methylation profiling. Accumulation of DNA methylation at hypermethylated DMPs correlated strongly with ATL development and progression. In addition, we identified 22 genes downregulated because of promoter hypermethylation in HTLV-1–infected T cells, including THEMIS, LAIR1, and RNF130, which negatively regulate T-cell receptor (TCR) signaling. Phosphorylation of ZAP-70, a transducer of TCR signaling, was dysregulated in HTLV-1–infected cell lines but was normalized by reexpression of THEMIS. Therefore, we hypothesized that DNA hypermethylation contributes to growth advantages in HTLV-1–infected cells during ATL leukemogenesis. To test this idea, we investigated the anti-ATL activities of OR-1200 and OR-2100 (OR21), novel decitabine (DAC) prodrugs with enhanced oral bioavailability. Both DAC and OR21 inhibited cell growth, accompanied by global DNA hypomethylation, in xenograft tumors established by implantation of HTLV-1–infected cells. OR21 was less hematotoxic than DAC, whereas tumor growth inhibition was almost identical between the 2 compounds, making it suitable for long-term treatment of ATL patient-derived xenograft mice. Our results demonstrate that regional DNA hypermethylation is functionally important for ATL leukemogenesis and an effective therapeutic target.

Purpose Dealing with variants of unknown significance (VUS) is an important issue in the clinical application of NGS-based cancer gene panel tests. We detected a novel ERBB2 extracellular domain VUS, c.1157A > G p.(E401G), in a cancer gene panel test. Since the mechanisms of activation by ERBB2 extracellular domain (ECD) variants are not fully understood, we aimed to clarify those mechanisms and the biological functions of ERBB2 E401G. Methods ERBB2 E401G was selected as VUS for analysis because multiple software tools predicted its pathogenicity. We prepared ERBB2 expression vectors with the E401G variant as well as vectors with S310F and E321G, which are known to be activating mutations. On the basis of wild-type ERBB2 or mutant ERBB2 expression in cell lines without ERBB2 amplification or variants, we evaluated the phosphorylation of human epidermal growth factor receptor 2 and related proteins, and investigated with molecular dynamics (MD) simulation the mechanisms conferred by the variants. The biological effects of ERBB2 E401G were also investigated, both in vitro and in vivo. Results We found that ERBB2 E401G enhances C-terminal phosphorylation in a way similar to S310F. MD simulation analysis revealed that these variants maintain the stability of the EGFR-HER2 heterodimer in a ligand-independent manner. Moreover, ERBB2 E401G-transduced cells showed an increased invasive capacity in vitro and an increased tumor growth capacity in vivo. Conclusion Our results provide important information on the activating mechanisms of ERBB2 extracellular domain (ECD) variants and illustrate a model workflow integrating wet and dry bench processes for the analysis of VUS detected with cancer gene panel tests.

Introduction Clinical sequencing has provided molecular and therapeutic insights into the field of clinical oncology. However, despite its significance, its clinical utility in Japanese patients remains unknown. Here, we examined the clinical utility of tissue-based clinical sequencing with FoundationOne® CDx and FoundationOne® Heme. Between August 2018 and August 2019, 130 Japanese pretreated patients with advanced solid tumors were tested with FoundationOne® CDx or FoundationOne® Heme. Results The median age of 130 patients was 60.5 years (range: 3 to 84 years), and among them, 64 were males and 66 were females. Major cancer types were gastrointestinal cancer (23 cases) and hepatic, biliary, and pancreatic cancer (21 cases). A molecular tumor board had been completed on all 130 cases by October 31, 2019. The median number of gene alterations detected by Foundation testing, excluding variants of unknown significance (VUS) was 4 (ranged 0 to 21) per case. Of the 130 cases, one or more alterations were found in 123 cases (94.6%), and in 114 cases (87.7%), actionable alterations with candidates for therapeutic agents were found. In 29 (22.3%) of them, treatment corresponding to the gene alteration was performed. Regarding secondary findings, 13 cases (10%) had an alteration suspected of a hereditary tumor. Of the 13 cases, only one case received a definite diagnosis of hereditary tumor. Conclusions Our study showed that clinical sequencing might be useful for detecting gene alterations in various cancer types and exploring treatment options. However, many issues still need to be improved.

We describe the clinical course of two patients who developed tracheal compression and deviation by multinodular goiter (MNG). Case 1: A 66-year-old woman presented with thyroid swelling. Five years after the initial admission, she was diagnosed with hyperthyroidism by Graves' disease and increased bilateral thyroid lobes compressing the trachea. Thyroglobulin was elevated from 210 to 472 ng/mL. Case 2: A 52-year-old woman presented with thyroid swelling. Five years after the initial admission, the increased right lobe deviated the trachea and compressed the right recurrent laryngeal nerve. Thyroglobulin was elevated from 122 to 392 ng/mL. Two cases and literature review indicated that MNG with >50 mm, solid components, and extension to the mediastinum or paralarynx were risk factors of tracheal compression and deviation. Monitoring thyroglobulin elevation can help predict the clinical course.

ObjectiveTuberous sclerosis complex (TSC) is a genetic disease that arises from TSC1 or TSC2 abnormalities and induces the overactivation of the mammalian/mechanistic target of rapamycin pathways. The neurological symptoms of TSC include epilepsy and tuberous sclerosis complex-associated neuropsychiatric disorders (TAND). Although TAND affects TSC patients' quality of life, the specific region in the brain associated with TAND remains unknown. We examined the association between white matter microstructural abnormalities and TAND, using diffusion tensor imaging (DTI).MethodsA total of 19 subjects with TSC and 24 age-matched control subjects were enrolled. Tract-based spatial statistics (TBSS) were performed to assess group differences in fractional anisotropy (FA) between the TSC and control groups. Atlas-based association analysis was performed to reveal TAND-related white matter in subjects with TSC. Multiple linear regression was performed to evaluate the association between TAND and the DTI parameters; FA and mean diffusivity in seven target regions and projection fibers.ResultsThe TBSS showed significantly reduced FA in the right hemisphere and particularly in the inferior frontal occipital fasciculus (IFOF), inferior longitudinal fasciculus (ILF), superior longitudinal fasciculus (SLF), uncinate fasciculus (UF), and genu of corpus callosum (CC) in the TSC group relative to the control group. In the association analysis, intellectual disability was widely associated with all target regions. In contrast, behavioral problems and autistic features were associated with the limbic system white matter and anterior limb of the internal capsule (ALIC) and CC.ConclusionThe disruption of white matter integrity may induce underconnectivity between cortical and subcortical regions. These findings suggest that TANDs are not the result of an abnormality in a specific brain region, but rather caused by connectivity dysfunction as a network disorder. This study indicates that abnormal white matter connectivity including the limbic system is relevant to TAND. The analysis of brain and behavior relationship is a feasible approach to reveal TAND related white matter and neural networks. TAND should be carefully assessed and treated at an early stage.

Blindness affect the daily life activities and the causes and prevalence are different worldwide. This study aimed to investigate the pattern of the autonomic nervous system modulation on the heart in blind and normal vision subjects submitted acutely to low vision. Normal vision (NV) subjects (N = 32) and blind patients (N = 24) were submitted to HRV analysis during resting, intervention and recovery periods. Intervention consisted of handling objects, short walking, and cognitive activities performed with pedagogic games while using sleeping masks. No difference was observed in indexes in the time and frequency domain, and in the geometric indexes comparing blind and NV subjected to acute low vision during resting and recovery. Nevertheless, during intervention, RMSSD, pNN50, and SD1were found lower in blind than in NV subjects. Therefore, blind patients showed similar HRV at resting or upon possible stressful challenges compared to NV subjects acutely subjected to low vision, indicating absence of differences in the cardiovascular risk between groups. In addition, blind patients show a smaller reduction in parasympathetic modulation on the heart during possible stressful challenges than NV individuals submitted to low vision, which is likely an important physiological adaptation for an adequate function of the cardiovascular system in blindness.

The development of Angiotensin II (Ang II)-induced hypertension is associated with mitochondrial dysfunction and kidney injury. Sirtuin 3 (SIRT3), a key mitochondrial protein, plays an important role in maintaining mitochondrial homeostasis. However, it remains unknown whether deletion of SIRT3 in the proximal tubules will alter the pressor and renal responses to Ang II in sex-different manners. In the present study, adult male, and female wild-type (WT) and mutant mice with proximal tubule-specific knockout of SIRT3, PT- Sirt3 -/- , were infused with or without a slow pressor dose of Ang II via an osmotic minipump (0.5 mg/kg/day, i.p.), supplemented with a 2% NaCI diet or losartan, 20 mg/kg/day, for 2 weeks. Systolic (SBP), diastolic (DBP), and mean arterial blood (MAP) pressure were determined using the tail-cuff method, whereas 24 hr. urinary sodium and potassium excretion were determined using a metabolic cage. Serum and urine creatinine were measured using colorimetric assays, whereas glomerular and tubulointerstitial injury was evaluated by Masson’s Trichrome staining. Basal SBP levels were lower in PT- Sirt3 -/- than in WT mice (SBP-WT: 112 ± 2 vs. SBP-PT- Sirt3 -/- : 93 ± 2 mmHg, P Sirt3 -/- mice with or without losartan treatment. Serum creatinine levels and urinary creatinine excretion were higher in PT- Sirt3 -/- mice than in WT mice ( P Sirt3 -/- mice with lower 24 hr. urine and urinary creatinine excretion in response to Ang II infusion or losartan. Losartan significantly increased 24 hr. urinary potassium and chloride excretion in Ang II-infused male and female PT- Sirt3 -/- mice ( P Sirt3 -/- mice showed significant renal cortical tubulointerstitial fibrotic responses ( P Sirt3 -/- mice and that Ang II induces similar hypertensive and renal fibrotic responses in male and female PT- Sirt3 -/- mice without significant sex differences.

The activation of the renin-angiotensin system (RAS) in the clipped kidney plays a critical role in the development of two-kidney, one-clip Goldblatt hypertension (2K1C), but the roles of angiotensin II (Ang II) and AT 1a receptors in the proximal tubules has not been determined previously. The present study tested the hypothesis that genetic deletion of AT 1a receptors selectively in the proximal tubules attenuates the development of 2K1C Goldblatt hypertension via AT 1a receptor-mediated, Na + /H + exchanger 3 (NHE3)-dependent mechanisms. To test the hypothesis, 2K1C Goldblatt hypertension was induced by placing a silver clip, 0.2 mm internal diameter, on the left renal artery for 4 weeks in adult male wild-type (WT), global AT 1a receptor knockout ( Agtr1a -/- ), proximal tubule (PT)-specific Agtr1a -/- (PT- Agtr1a -/- ), or PT- Nhe3 -/- mice, respectively. In WT mice, systolic blood pressure increased in a time-dependent manner reaching a maximal response by Week 3 (Basal: 112 ± 2 vs. 2K1C: 149 ± 4 mmHg, n=12, P P P P P Agtr1a -/- (Basal: 88 ± 4 vs. 2K1C: 92 ± 2 mmHg, n=9, n.s .), PT- Agtr1a -/- mice (Basal: 101 ± 2 vs. 2K1C: 104 ± 3 mmHg, n=12, n.s .) and PT- Nhe3 -/- mice (Basal: 103 ± 3 vs. 109 ± 5 mmHg, n=12, n.s .). Renin mRNA expression was not different in clipped and nonclipped kidney of Agtr1a -/- mice, but it was decreased in the nonclipped kidney of PT- Agtr1a -/- mice ( P 1a receptors selectively in the proximal tubules attenuates the development of 2K1C Goldblatt hypertension via AT 1a receptor-mediated, Na + /H + exchanger 3 (NHE3)-dependent mechanisms.

Inflammation has been associated with cardiovascular diseases and the key point is the generation of reactive oxygen species (ROS). Exercise modulates medullary neurons involved in cardiovascular control. We investigated the effect of chronic exercise training (Tr) in treadmill running on gene expression (GE) of ROS and inflammation in commNTS and RVLM neurons. Male Wistar rats (N = 7/group) were submitted to training in a treadmill running (1 h/day, 5 days/wk/10 wks) or maintained sedentary (Sed). Superoxide dismutase (SOD), catalase (CAT), neuroglobin (Ngb), Cytoglobin (Ctb), NADPH oxidase (Nox), cicloxigenase-2 (Cox-2), and neuronal nitric oxide synthase (NOS1) gene expression were evaluated in commNTS and RVLM neurons by qPCR. In RVLM, Tr rats increased Ngb (1.285 ± 0.03 vs. 0.995 ± 0.06), Cygb (1.18 ± 0.02 vs.0.99 ± 0.06), SOD (1.426 ± 0.108 vs. 1.00 ± 0.08), CAT (1.34 ± 0.09 vs. 1.00 ± 0.08); and decreased Nox (0.55 ± 0.146 vs. 1.001 ± 0.08), Cox-2 (0.335 ± 0.05 vs. 1.245 ± 0.02), NOS1 (0.51 ± 0.08 vs. 1.08 ± 0.209) GE compared to Sed. In commNTS, Tr rats increased SOD (1.384 ± 0.13 vs. 0.897 ± 0.101), CAT GE (1.312 ± 0.126 vs. 0.891 ± 0.106) and decreased Cox-2 (0.052 ± 0.011 vs. 1.06 ± 0.207) and NOS1 (0.1550 ± 0.03559 vs. 1.122 ± 0.26) GE compared to Sed. Therefore, GE of proteins of the inflammatory process reduced while GE of antioxidant proteins increased in the commNTS and RVLM after training, suggesting a decrease in oxidative stress of downstream pathways mediated by nitric oxide.

Made available in DSpace on 2021-06-26T06:17:40Z (GMT). No. of bitstreams: 0 Previous issue date: 2021-05-01 BACKGROUND: In mechanically ventilated subjects, intra-tracheal secretions can be aspirated with either open suction systems (OSS) or closed suction systems (CSS). In contrast to CSS, conventional OSS require temporarily disconnecting the patient from the ventilator, which briefly diminishes PEEP and oxygen supply. On the other hand, CSS are more expensive and less effective at aspirating secretions. Thus, it was hypothesized that the 2 procedures differentially affect pulmonary and cardiovascular parameters after suction. METHODS: Subjects in the ICU (N = 66) were quasi-randomized for initial treatment with OSS or CSS in a crossover design. To compare the potential for these suction systems to compromise cardiorespiratory stability, changes in cardiopulmonary physiology were assessed from before to just after use of each suction system (three 10-s aspirations). RESULTS: For most pulmonary and cardiovascular parameters (ie, peak inspiratory pressure, airway resistance, pressure plateau, heart rate, and arterial pressures), the effects of aspiration inversely correlated with baseline values for that parameter, with a similar regression slope between suction systems. However, when controlling for baseline values, OSS caused significantly greater increases in airway resistance and peak inspiratory pressure (P < .001 and < .01 vs CSS, respectively). CONCLUSIONS: Elevated airway resistance prior to endotracheal suction may justify use of a CSS and contraindicate a conventional OSS in mechanically ventilated subjects. Adoption of this approach into clinical guidelines may prevent suction-induced pulmonary injury in subjects, especially for those with underlying diseases involving increased airway resistance or increased alveolar pressure. Fac Med ABC, Lab Delineamento Estudos & Escrita Cient, Santo Andre, SP, Brazil Univ Fed Espirito Santo UFES, Dept Educ Integrada Saude, Vitoria, ES, Brazil Harvard Sch Publ Hlth, Dept Environm Hlth, 677 Huntington Ave, Boston, MA 02115 USA Univ Fed Sao Paulo, Dept Cardiol, Sao Paulo, SP, Brazil Univ Cidade Sao Paulo, Fac Med, Sao Paulo, Brazil Univ Estadual Paulista, Dept Escudos Sistema Nervoso Auton, Fac Ciencias & Tecnol, Presidente Prudente, SP, Brazil Univ Louisville, Diabet & Obes Ctr, Christina Lee Brown Envirome Inst, Sch Med, Louisville, KY USA Univ Louisville, Dept Physiol, Sch Med, Louisville, KY USA Univ Estadual Paulista, Dept Escudos Sistema Nervoso Auton, Fac Ciencias & Tecnol, Presidente Prudente, SP, Brazil

The article presents a comparative analysis between the financing of works in public schools, through the Plan of Articulated Actions (PAR), between 2011 and 2015, the complementary transfers from the Federal Government within the scope of the Fund for Maintenance and Development of Basic Education and Valorization of Education Professionals (Fundeb), and the evolution of the Basic Education Development Index (Ideb). It is a descriptive and exploratory research, through a bibliographical and documentary review. The approach is quantitative, using data from the Ministry of Education (MEC), the National Education Development Fund (FNDE) and the National Institute of Educational Studies and Research Anisio Teixeira (Inep). It is concluded that the voluntary transfers of the FNDE through the PAR, to carry out the works, are not necessarily carried out to the states with greater financial difficulties and educational deficiencies, impairing the achievement of goal 7 of the PNE.

The article presents a comparative analysis between the financing of works in public schools, through the Plan of Articulated Actions (PAR), between 2011 and 2015, the complementary transfers from the Federal Government within the scope of the Fund for Maintenance and Development of Basic Education and Valorization of Education Professionals (Fundeb), and the evolution of the Basic Education Development Index (Ideb). It is a descriptive and exploratory research, through a bibliographical and documentary review. The approach is quantitative, using data from the Ministry of Education (MEC), the National Education Development Fund (FNDE) and the National Institute of Educational Studies and Research Anísio Teixeira (Inep). It is concluded that the voluntary transfers of the FNDE through the PAR, to carry out the works, are not necessarily carried out to the states with greater financial difficulties and educational deficiencies, impairing the achievement of goal 7 of the PNE., O artigo apresenta uma análise comparativa entre o financiamento de obras em escolas públicas, por meio do Plano de Ações Articuladas (PAR), entre 2011 e 2015, as transferências complementares da União, no âmbito do Fundo de Manutenção e Desenvolvimento da Educação Básica e de Valorização dos Profissionais da Educação (Fundeb), e a evolução do Índice de Desenvolvimento da Educação Básica (Ideb). Trata-se de pesquisa descritiva e exploratória, por intermédio de revisão bibliográfica e documental. A abordagem é quantitativa, utilizando os dados do Ministério da Educação (MEC), do Fundo Nacional de Desenvolvimento da Educação (FNDE) e do Instituto Nacional de Estudos e Pesquisas Educacionais Anísio Teixeira (Inep). Conclui-se que as transferências voluntárias do FNDE por meio do PAR, para realização de obras, não são realizadas, necessariamente, aos estados com maiores dificuldades financeiras e deficiências educacionais, prejudicando o alcance da meta 7 do PNE.

O livro didático de língua portuguesa é um símbolo do cotidiano escolar de várias gerações, influenciado por renovações no discurso acadêmico e adaptado a diferentes programas oficiais e tecnologias. É, desse modo, uma importante fonte de recuperação da memória cultural e, enquanto vetor da língua, da cultura e dos valores das classes dirigentes, um importante instrumento político. O objetivo deste trabalho é analisar as formas de apresentação da dissertação, gênero escolar, em duas coleções didáticas de língua portuguesa de 2° grau do início da redemocratização brasileira: Fundamentos de Língua e Literatura (MARTOS; MESQUITA, 1987) e Português: Linguagens (CEREJA; MAGALHÃES, 1990). No período entre o final da ditadura militar e o início da redemocratização, a aula de língua portuguesa era tida por alguns linguistas aplicados como um espaço de promoção da transformação social, e a produção de texto, um elemento didático em prol da cidadania. Com base nas redações dos vestibulandos, foram desenvolvidas diversas teorias que convocavam o aluno a tomar um posicionamento diante de questões sociais em sua escrita, em uma tentativa de se vencer as práticas e as concepções autoritárias. À luz dos conceitos de enunciado concreto (BAKHTIN, 2016; VOLÓCHINOV, 2017) e de discurso alheio (BAKHTIN, 2015; VOLÓCHINOV, 2017) e do modelo ideológico de letramento (STREET, 2014), busca-se uma análise que explicite as consequências da relação entre o trabalho enunciativo e o trabalho interacional na materialidade linguística dessas coleções. Para tanto, os objetivos específicos são: (i) descrever e analisar as formas composicionais, os estilos e os temas das seções dedicadas à dissertação, enunciados concretos; (ii) reconhecer como o discurso alheio é apresentado nessas seções; (iii) interpretar, à luz do modelo ideológico de letramento, com quais efeitos de sentido para o aluno esses discursos alheios são reconstruídos e ressignificados no ensino da dissertação. Em Fundamentos de Língua e Literatura (MARTOS; MESQUITA, 1987), parte-se da literatura e, na gramática e na redação, tem-se categorizações que visam articular pensamento, língua e mundo em uma única relação termo a termo, cujo domínio é sinônimo de escrever bem e pensar bem. O intuito da dissertação é estritamente disciplinar. Já em Português: Linguagens (CEREJA; MAGALHÃES, 1990), a (re)apresentação dos conceitos de argumentação e de parágrafo como objetos de ensino e as propostas de pesquisa e debate revelam a preocupação em se fazer com que o aluno assuma posicionamentos nas produções de texto dissertativo. A inferência de transparência e objetividade nas seções de redação de ambas as coleções indicam, no entanto, que, apesar de tematicamente, haver significativas mudanças, a concepção de língua(gem) que subjaz à escolha e à organização dos objetos de ensino da dissertação privilegia uma atitude grafocêntrica que hierarquiza os estudantes. A dissertação, desse modo, é (re)apresentada como um objeto de distinção (BOURDIEU, 1979), como em décadas anteriores. Portuguese school textbooks are not only a daily school life symbol for multiple generations, influenced by renewals in academic discourse and constantly subject to adaptations brought by ever-changing government programmes and technologies, but are also a crucial source in maintaining and recovering a cultural memory, given that they function as a vector to language, culture and the dominating classes\' moral values. Thusly, school textbooks are an important political instrument. This essay\'s objective is to analyse the representation of the dissertative genre in two highschool Portuguese textbook collections from the early years of democracy\'s resurgence, subsequent to military rule: Fundamentos de Língua e Literatura (MARTOS; MESQUITA, 1987) and Português: Linguagens (CEREJA; MAGALHÃES, 1990). In the period between the military dictatorship\'s ending and the beginning of the so-called redemocratization process, the teaching of the Portuguese language was seen by some applied linguists as a means to promote social change, and text production, understood as a didactic element favourable to enabling citizenship. In that sense, numerous theories have been developed on top of texts written in the aforementioned university admission exams, urging students to take a stand in regards to social issues, through their dissertations, in an attempt to battle and conquer the ideological struggle against authoritarianism and its practices. In light of concepts such as concrete statements (BAKHTIN, 2016; VOLÓCHINOV, 2017), alien speech (VOLÓCHINOV, 2017) and ideological model of literacy (STREET, 2014), this essay aims to provide an analysis portraying the consequences produced by the relationship between enunciative and interactive work throughout the linguistic materiality in these textbook collections. Hence, the key objectives are: to (i) describe and analyse text composition, styles and themes within dissertation sections, as concrete statements; to (ii) understand how alien speech is represented in these sections; and to (iv) interpret, per ideological model of literacy, how these alien speeches are reconstructed and resignified to the student, and with which meanings, via text composition teaching. Firstly, Fundamentos de Língua e Literatura (MARTOS; MESQUITA, 1987) approaches literature, and further in its grammar and writing sections, the textbook offers categorisations directed at structuring thought, language and world in a single relation, one by one, in a domain closely related to the ideas of writing and thinking well. Hence, the dissertation\'s core is strictly disciplinary. Diversely, in Português: Linguagens (CEREJA; MAGALHÃES, 1990), the (re)presentation of the notions of argumentation and paragraph as teaching objects, as well as the proposed research and debate activities, indicate the authors\' intentions in eliciting positions from the students alongside dissertative text production. The inference of transparency and objectivity, and the mostly inductive conduction observed in the writing sections of both collections illustrates, however thematically, that there are significant alterations, the concept of language pertaining to the choice and organization of the teaching objects of dissertation favours a graphocentric attitude that submits the students to hierarchy. Dissertation is, therefore, represented as an object of distinction (BOURDIEU, 1979), as in previous decades.

The potential benefits of treating subclinical hypothyroidism (SCH) are unclear and still controversial. Thus, we surgically induced SCH in rats and evaluated the effects of thyroxine (T4) replacement on the gene expression levels of deiodinases and thyroid hormone (TH) transporters in different tissues. SCH was induced by hemithyroid electrocauterization. The control animals underwent the same surgical procedure but were not subjected to electrocauterization (sham). After 14 days, half of the SCH animals were treated with T4 (SCH + T4). At the end of the experimental protocol, all of the rats were euthanized, serum hormone concentrations were measured, and RNA analyses were performed on different tissues and organs. Consistent with previous studies, we observed increased TSH levels, normal TH levels, and reduced hypothalamic TRH expression in the SCH group. Additionally, Dio2 mRNA expression was downregulated in the hippocampus and pituitary, and Dio1 was upregulated in the kidney and pituitary of the SCH animals. The changes in Dio3 expression were tissue-specific. Concerning TH transporters, Mct10 expression was upregulated in the pituitary, kidney, hypothalamus, and hippocampus, and Mct8 expression was downregulated in the kidney of the SCH group. Crym expression was upregulated in the kidney and pituitary. Notably, T4 replacement significantly attenuated serum TSH levels and reverted Dio1, Dio2, Mct10, and Crym expression in the pituitary, hippocampus, and kidney to levels that were similar to the sham group. Tissue-specific responses were also observed in the liver and hypothalamus. Our results indicate that treatment of SCH should be considered before the appearance of clinical symptoms of hypothyroidism.

Introduction: Joint cartilage injury can occur due to joint diseases, especially osteoarthritis, genetic or metabolic conditions, or as a result of trauma. The articular cartilage is a specialized tissue, formed by hyaline matrix and does not present vascularization, innervation or lymphatic network,[for full text, please go to the a.m. URL], 14th Triennial Congress of the International Federation of Societies for Surgery of the Hand (IFSSH), 11th Triennial Congress of the International Federation of Societies for Hand Therapy (IFSHT), 11th Triennial Congress of the International Federation of Societies for Hand Therapy (IFSHT)

Introduction: Polytrauma patients usually have severe wounds, which require prolonged and costly treatment. Deep skin lesions are characterized by destruction of epithelial tissue and exposure of structures such as fascia, muscles, tendons, and nerves. The healing process occurs through contraction [for full text, please go to the a.m. URL], 14th Triennial Congress of the International Federation of Societies for Surgery of the Hand (IFSSH), 11th Triennial Congress of the International Federation of Societies for Hand Therapy (IFSHT), 11th Triennial Congress of the International Federation of Societies for Hand Therapy (IFSHT)

Objectives/Interrogation: Polytrauma patients usually have severe wounds, which require prolonged and costly treatment. Deep skin lesions are characterized by destruction of epithelial tissue and exposure of structures such as fascia, muscles, tendons, and nerves. The healing process occurs through[for full text, please go to the a.m. URL], 14th Triennial Congress of the International Federation of Societies for Surgery of the Hand (IFSSH), 11th Triennial Congress of the International Federation of Societies for Hand Therapy (IFSHT), 11th Triennial Congress of the International Federation of Societies for Hand Therapy (IFSHT)

Serum levels of estrogen decrease at climacterium and directly interfere with the urogenital tract. Urinary bladder (UB) is responsive to hormonal changes, especially estrogen. Resistance exercise elicits benefits on severe chronic diseases. Nevertheless, it is still unclear whether the resistance exercise directly affects the UB in ovariectomized (OVx) rats. This study focused on investigating the effects of resistance exercise on UB function and morphology in OVx and control rats. Adult female Wistar rats (∼250–300 g, 14–16 weeks old) [control (n = 20) and OVx (n = 20)] were divided in the following groups: sedentary (SED), and trained over 1 week (acute), 3 weeks (intermediate), and 10 weeks (chronic). Training was carried out in a ladder, with six bouts in alternate days with 75% of body weight load attached to the tail of the animal. Afterward, the animals were isoflurane anesthetized for evaluation of intravesical pressure (IP) changes upon topical administration of acetylcholine (Ach) and noradrenaline (NE) on the UB. At the end of the experiment, the UB was harvested for histological analysis and stained with hematoxylin–eosin and picrosirius red. Ach increased the IP in both OVx and control rats, whereas NE decreased the IP. However, the acute and intermediate groups showed attenuated responses to Ach and NE, while the chronic groups recovered the responses to Ach and NE close to those observed in SED groups. Acute and intermediate groups also showed decreased thickness of the muscular layer, with a reversal of the process with chronic training. In the OVx groups, the acute training reduced the thickness of the smooth muscle and mucosal layers, whereas chronic training increased it. Urothelium thickness decreased in the OVx SED and acute groups. Collagen type I fibers (CI-F) reduced in OVx SED acute and intermediate groups, while collagen type III fibers (CIII-F) increased in the OVx acute group. In the mucosal layer, the volume density of CFs reduced in OVx rats compared to control groups and chronic training resulted in their recovery. Our data suggest that chronic resistance exercise for 10 weeks reversed the functional and morphological changes caused by hypoestrogenism.

Moderate exercise reduces arterial pressure (AP) and heart rate (HR) in spontaneously hypertensive rats (SHR) and changes neurotransmission in medullary areas involved in cardiovascular regulation. We investigated if regularly swimming exercise (SW) affects the cardiovascular adjustments mediated by opioidergic neuromodulation in the RVLM in SHR and Wistar-Kyoto (WKY) rats. Rats were submitted to 6 wks of SW. The day after the last exercise bout, α-chloralose-anesthetized rats underwent a cannulation of the femoral artery for AP and HR recordings, and Doppler flow probes were placed around the lower abdominal aorta and superior mesenteric artery. Bilateral injection of endomorphin-2 (EM-2, 0.4 mmol/L, 60 nL) into the RVLM increased MAP in SW-SHR (20 ± 4 mmHg, N = 6), which was lower than in sedentary (SED)-SHR (35 ± 4 mmHg, N = 6). The increase in MAP in SW-SHR induced by EM-2 into the RVLM was similar in SED- and SW-WKY. Naloxone (0.5 mmol/L, 60 nL) injected into the RVLM evoked an enhanced hypotension in SW-SHR (-66 ± 8 mmHg, N = 6) compared to SED-SHR (-25 ± 3 mmHg, N = 6), which was similar in SED- and SW-WKY. No significant changes were observed in HR after EM-2 or naloxone injections into the RVLM. Changes in hindquarter and mesenteric conductances evoked by EM-2 or naloxone injections into the RVLM in SW- or SED-SHR were not different. Mu Opioid Receptor expression by Western blotting was reduced in SW-SHR than in SED-SHR and SW-WKY. Therefore, regularly SW alters the opioidergic neuromodulation in the RVLM in SHR and modifies the mu opioid receptor expression in this medullary area.

Objectives Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (i.e., EGFR-TKIs) improve the survival of lung cancer patients harboring EGFR mutations. Despite the initial efficacy of EGFR-TKIs, the disease progression caused by acquired resistance to these inhibitors is inevitable. T790M mutations represent a major resistance mechanism to EGFR-TKIs but can be overcome using osimertinib. The IMPRESS trial revealed that the continuation of EGFR-TKI beyond progressive disease (PD) concurrent with platinum-doublet chemotherapy was not beneficial. However, various clinical trials have suggested that EGFR-TKI beyond PD plus single-agent chemotherapy may be a possible treatment strategy. Materials and Methods This study was a single-arm phase II trial. Patients with EGFR-activating mutations (del19 and L858R) that progressed using first-line gefitinib treatment were enrolled and treated with gefitinib beyond PD plus pemetrexed 500 mg/m2 q3w. The primary endpoint was progression-free survival (PFS). Mutation-biased polymerase chain reaction quenching probe, which is the original method for detecting T790M mutations in cell-free plasma DNA, was used prior to treatment. Results Thirty-six patients were enrolled between May 1, 2013, and March 31, 2016. One patient was excluded before starting the treatment. Among the 35 patients, 15 patients had del19 mutations, and 20 patients had L858R mutations; 33 patients were evaluable for response by using radiographic findings. The median PFS was 6.7 months (95% confidence interval: 4.4–7.7 months). Nineteen patients were T790M positive. No significant difference in PFS was found in a subgroup analysis of EGFR mutation status and T790M positivity. All toxicities were tolerable. Conclusion Gefitinib plus pemetrexed treatment following relapse using gefitinib in patients with Non-small cell lung cancer harboring EGFR mutations demonstrated preferable PFS with mild toxicity. This combination therapy may be considered for platinum-unfit patients without T790M with disease progression using first-line gefitinib. (This clinical trial was registered in UMIN-CTGR as UMIN000010709).

Urinary bladder dysfunctions show high prevalence in women. We focused to investigate the intravenous and in situ (topic) vasopressin effects on the bladder and also to characterize the vasopressin receptor subtypes in the bladder. Adult female Wistar rats anesthetized with isoflurane underwent to the cannulation of the femoral artery and vein, and also urinary bladder for mean arterial pressure, heart rate and intravesical pressure (IP) recordings, respectively. Doppler flow probe was placed around the renal artery for blood flow measurement. After baseline recordings, intravenous injection of saline or vasopressin at different doses (0.25, 0.5, 1.0 ng/ml/kg of b.w.); or 0.1 ml of saline or 0.1 ml of vasopressin at different doses (0.25, 0.5, 1.0 ng/ml) was randomly dropped on the bladder. In another group of rats, the UB was harvest for gene expression by qPCR and also for protein expression by Western blotting of the vasopressin receptor subtypes. We observed that either intravenous or in situ vasopressin evoked a huge increase in the IP in a dose-dependent manner compared to saline, whilst no differences were observed in the cardiovascular parameters. The genes and the protein expression of V1a, V1b and V2 vasopressin receptors subtypes were found in the bladder. Intravenous injection of V1a or V2 receptor antagonist evoked a huge fall in IP and 30 min later, i.v or in situ vasopressin evoked responses on IP were significantly attenuated. Therefore, intravenous or in situ vasopressin increases the IP due to binding in V1a or V2 receptors localized in the bladder.

Liquid biopsy with circulating free DNA (cfDNA) is a recommended alternative method of re-biopsy. Quality control with cfDNA is indispensable for precise examinations, and it is desirable to achieve high-quality cfDNA separation. We investigated two issues: the influence of pre-analytical procedures on cfDNA analysis performed as a routine procedure in a standard clinical laboratory, and the extent of deterioration of cfDNA quality due to long-term storage. Comparisons among blood collection tube types, storage temperatures, and periods of blood separation were performed in terms of cfDNA quantification, cfDNA size distribution, and detection of EGFR mutations. Quality of cfDNA was better with collection tubes containing 3.2% sodium citrate than with those containing EDTA 2K, and was maintained with storage at 4° C for up to 72 h after blood collection, equivalent to results with cell-stabilizing blood collection tubes. Analysis of cfDNA stored for 7 years showed that samples with low allele frequency (AF) deteriorated more readily than samples with high AF. Despite the same storage period and extraction method, AF of plasma stored for 7 years was remarkably lower than that of cfDNA. However, deterioration due to long-term plasma storage was overcome by changing the DNA extraction method from a silica membrane spin column to a cellulose magnetic beads system. These results can guide the establishment of standardized pre-analytical procedures for liquid biopsy with cfDNA.

Hairy cell leukemia (HCL) is a rare B-cell lymphoid malignancy that is difficult to distinguish from other morphological variants. The frequency of HCL has not been determined accurately in Japan. Recent studies revealed that the BRAF V600E mutation is the causal genetic event in HCL. We assessed the BRAF mutation in Japanese patients with HCL and related diseases using the quenching probe (QP) method, a single-nucleotide polymorphism detection system, and evaluated the incidence rate of HCL among Japanese patients with chronic lymphocytic leukemia, and related diseases. We identified 18 cases (33.3%) harboring the BRAF mutation among 54 patients diagnosed with, or suspected of having HCL. Of BRAF V600E-positive patients, 7 were only detected using the QP method, not by direct sequencing, whereas 11 were positive using both tests. In a larger cohort of Japanese patients diagnosed with chronic lymphoid leukemia or related diseases, the frequency of HCL was 4%. Patients with the BRAF V600E mutation had a significantly higher frequency of neutropenia, thrombocytopenia, and elevated soluble interleukin-2 receptor and common B-cell surface markers than patients without the mutation. Our results confirm that BRAF V600E-positive HCL is a relatively rare disorder in the Japanese leukemia patient population.

The clinical utility of plasma DNA for detecting cancer-specific mutations has rapidly achieved recognition, but reliability has not been established because of relatively low mutation-detection rates compared with those from tissue re-biopsy. To address this shortcoming we examined efficiency, in terms of mutation detection, of an automated DNA extraction system that uses cellulose magnetic beads. A fully automated, highly sensitive point-mutation-detection method, mutation-biased PCR and quenching probe (MBP-QP) system, was used for this study. Plasma DNA was extracted from 61 plasma samples collected from patients with advanced non-small cell lung cancer. Extraction was performed manually with 200 μl plasma (200-M) by using a silica membrane spin column system or an automated system using 200 μl (200-A) or 1000 μl (1000-A) plasma. Median DNA yield quantified by real-time PCR was 4.4, 4.5, and 17.3 ng with the three methods, respectively. Sensitivity for detecting epidermal growth factor receptor (EGFR) L858R point mutation was 36.6%, 58.5%, and 77.5%, and specificity was 93.3%, 100%, and 96.7%, respectively. Concordance rates were 60.6%, 76.1%, and 85.7%. The size distribution of plasma DNA with automated extraction was bimodal with modes at about 170 bp and 5 Kb, and plasma DNA of both sizes included tumor-derived DNA. In this report, we demonstrate that automated DNA extraction using cellulose magnetic beads can improve mutation-detection rates with plasma DNA in association with two overall sizes of DNA fragments recovered by this DNA isolation system. Examining the biological characteristics of these fragments will be the subject of further investigation.