Acil-hidrazino-peptômeros : síntese via reações de Ugi e Ugi-hidrazino consecutivas, caracterização estrutural e toxicidade contra células normais e de câncer de mama in vitro

Trabalho de Conclusão de Curso (graduação)—Universidade de Brasília, Faculdade de Ceilândia, 2017.Os peptídeos são biomoléculas compostas por resíduos de aminoácidos ligados por meio de ligações peptídicas e sua diversidade estrutural faz com que esses compostos sejam versáteis e se destaquem como macromoléculas promissoras na busca de novos fármacos. Peptídeos bioativos possuem ampla aplicabilidade, podendo atuar como antifúngicos, antibacterianos, anti-inflamatórios, além de desempenharem funções hormonais e sinalizadores neurais. Alguns estudos apontam ainda seu potencial na atuação da terapia do câncer. Embora esses compostos exibam grandes vantagens como agentes terapêuticos, algumas limitações ainda restringem seu uso clínico. Por essa razão, nos últimos anos vem crescendo o interesse na síntese de miméticos, a fim de minimizar essas limitações por meio de modificações estruturais e viabilizar esses peptidomiméticos como potenciais candidatos a fármacos. O presente trabalho tem como objetivo realizar a síntese de acil-hidrazino-peptômeros, uma nova classe de peptidomiméticos, por meio de reações multicomponentes consecutivas. A ideia geral se baseia na obtenção dos compostos via reação de Ugi-hidrazino seguida por reação de hidrazinólise ou hidrólise e subsequente reação de Ugi-hidrazino ou reação clássica de Ugi. Essa metodologia permitiu a obtenção de peptidomiméticos com moderados a bons rendimentos (47-90%). Após realizada a síntese, os compostos foram submetidos a ensaios biológicos in vitro pelo método de MTT visando avaliar a citotoxicidade dos peptidomiméticos em células normais da linhagem NIH-3T3 (fibroblastos) e câncer de mama (4T1). Observou-se que a maioria dos compostos não são citotóxicos para células normais e não foram capazes de promover redução significativa da viabilidade das células cancerígenas.Peptides are biomolecules composed of amino acid residues linked by peptide bonds and their structural diversity makes these compounds more versatile and stand out as promising macromolecules in the search for new drugs. Bioactive peptides have broad applicability, act as antifungal, antibacterial, anti-inflammatory, in addition to performing hormonal functions and neural flags. A few studies also point out its potential in the performance of cancer therapy. Although these compounds exhibit great advantages as therapeutic agents, some limitations still restrict their clinical use. For this reason, in recent years the interest in mimetic synthesis has increased, in order to minimize these limitations by means of structural modifications and to make these peptidomimetics feasible as potential drug candidates. The present work aims at the synthesis of acyl- hydrazino-peptomers, a new class of peptidomimetics, by means of consecutive multicomponent reactions. The general idea is based on obtaining the compounds by Ugi-hydrazino reaction followed by hydrazinolysis or hydrolysis reaction and subsequent reaction of Ugi-hydrazino or classical Ugi reaction. After synthesis, the compounds were submitted to in vitro biological assays by the MTT method to evaluate the cytotoxicity of the peptidomimetics in normal cells NIH-3T3 (fibroblasts) and verify their biological behavior in breast cancer cells (4T1). It was noted that the most of the compounds are not toxic to normal cells and haven’t been able to promote significant reduction of the viability of cancer cells

ESTUDO E DIAGNÓSTICO DO GERENCIAMENTO DO LODO, GERADO EM UMA ESTAÇÃO DE TRATAMENTO DE EFLUENTES, EM UMA INDÚSTRIA DE RAÇÕES E PROTEÍNAS DE SOJA

O presente projeto discorre sobre o gerenciamento de lodo industrial, este também denominado de biossólido, é o principal subproduto residual do tratamento das águas residuárias industriais, necessita de um gerenciamento adequado a fim de evitar impactos ambientais. Este projeto teve por objetivo diagnosticar o gerenciamento de lodo e propor alternativa para destinação do mesmo que seja ambientalmente segura e sustentável em uma indústria de rações e proteínas de soja. A metodologia empregada quantificou e caracterizou o lodo através de análises físico-químicas. Os resultados obtidos evidenciaram que são geradas 13,56 ton/dia de lodo centrifugado com PCI de 3.932,00 kcal/kg. De acordo com as condições encontradas in loco na planta industrial e, com os resultados obtidos, concluíu-se ser uma ótima alternativa com viabilidade técnica a co-combustão do lodo com cavaco de lenha na caldeira de geração de vapor. Porém, estudos posteriores devem ser realizados para analizar os constituintes químicos do lodo e os possíveis residuais atmosféricos que serão formados se a queima for efetua. Se o sistema de incineração de biossólido proposto for instalado na indústria, o gerenciamento do lodo será otimizado, promovendo o aproveitamento do seu potencial energético de forma alternativa e sustentável promovendo a valoração deste resíduo

Clinical, Pathological and Immunohistochemical Evaluation of a Primary Hemangiosarcoma in a Pinscher Dog

Background: Hemangiosarcoma (HSA) is a malignant tumor that arises from the vascular endothelium affecting more often dogs than other species as cats, cows and horses. It comprises approximately 2% of all tumors in dogs. The most common primary site for the HSA in dogs is the spleen, and other locations include the right atrium, pericardium, liver andprostate. Other authors have reported this tumor in lungs, kidney, oral cavity, muscle, bone, urinary bladder, left ventricle, tongue and retroperitoneum. Due to the importance of the HSA in canine species, the aim of this study was to describe the clinical and pathological fndings, besides therapeutic protocol in an unusual case of HSA.Case:A six-year-old male pinscher was referred to the veterinary hospital with a history of cyanosis and choking. The animal was submitted to radiographic examination in lateral cervical view, which identifed the presence of a mass of 1.2 cm in diameter near the pharynx. In order to evaluate the oral cavity, general anesthesia was performed, and it was possible to see a soft, rosy, circumscribed and vascularized lump in pharyngeal region. Due to suspicion of neoplasm, excisional biopsywithout surgical margin was performed. The histopathological exam diagnosed hemangiosarcoma. Immunohistochemistry against vimentin, factor VIII, VEGF and Ki67 was performed and confrmed diagnosis of low grade hemangiosarcoma. Antineoplastic chemotherapy protocol was initiated with doxorubicin and cyclophosphamide every 21 days totaling sixsessions. However, the animal died after the cyclophosphamide intoxication with a three-fold recommended dose (660 mg/m² total in the last session), showing a median survival rate of 220 days.Discussion: The most common primary site for HSA in dogs is the spleen. The pharyngeal location is rare, with only a few reports in literature. In the present case, solitary tumor was observed in pharynx with no involvement of other organs, evidenced by radiographic examination, abdominal ultrasound and echocardiogram, suggesting that pharynx was theprimary location of the tumor. Main features of HSA comprise a solitary nodule or multifocal lesions within the organ or widely disseminated. Histologically, they consist of pleomorphic immature endothelial cells with formation of vascular spaces with variable amount of blood and/or thrombi. In some cases, HSA shows a polymorphic subtype and immunohistochemistry is necessary to provide a defnitive diagnosis. The sample was submitted to histopathological examination which revealed proliferation of endothelial cells with pronounced pleomorphism ranging from polygonals to ovoid, sparse cytoplasm, round to oval nucleus with visible nucleolus, few mitotic fgures, some of them, aberrant, which confrmed diagnosis of HAS. Due to the unusual location, we performed immunohistochemical staining for vimentin, factor VIII,VEGF and Ki67 antibodies to confrm mesenchymal origin of the tumor. In IHC, it was possible to identify positive reac tion for vimentin protein, factor VIII, VEGF and few Ki67 positive cells, confrming histopathological diagnosis. Despite literature describes an aggressive biological behavior of canine HSA, with common occurrence of metastasis, recurrencewas not observed at the site of the removal of the tumor. In histopathological evaluation, it was observed low number ofmitoses, besides the low Ki67 expression on IHC, featuring a low grade tumor with minor ability to metastasize. To the author’s knowledge, this case describes an unusual presentation of HSA, with low metastatic potential, in which chemo therapy protocol achieved survival time of 220 days.Keywords: angiosarcoma, dogs, immunohistochemistry, pharynx

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

ESTUDOS SOBRE HABILIDADES SOCIAIS EM CRIANÇAS COM IDADE ESCOLAR

Este artigo tem como principal objetivo discutir e avaliar a importância das habilidades sociais em crianças com idade escolar. O termo habilidades sociais refere-se à existência de diferentes classes de comportamentos sociais no repertório do indivíduo para lidar de maneira assertiva com as demandas das situações interpessoais. Foi realizada uma revisão bibliográfica em seis estudos publicados por pesquisadores da área, entre os anos de 2002 a 2016. Os resultados evidenciaram que habilidades sociais são reconhecidas como fator de proteção no curso do desenvolvimento humano. Tais habilidades são atenuadas em contexto escolar pois dizem respeito a comportamentos necessários a uma relação interpessoal bem-sucedida, conforme parâmetros típicos de cada contexto e cultura, podendo incluir os comportamentos de iniciar, manter e finalizar conversas; pedir ajuda; fazer e responder a perguntas; fazer e recusar pedidos; defender-se; expressar sentimentos, agrado e desagrado; pedir mudança no comportamento do outro; lidar com críticas e elogios; admitir erro e pedir desculpas e escutar empaticamente, dentre outros. Para isso foi realizado um levantamento nas seguintes bases de dados: BVS PSI, Pepsic, Google Acadêmico e Scielo, Portal de periódicos CAPES/MEC considerando o que tem sido produzido a respeito deste tema nos últimos anos no Brasil. STUDIES ON SOCIAL SKILLS IN SCHOOL-AGED CHILDREN ABSTRACT This article aims to discuss and evaluate the importance of social skills in school-aged children. The term social skills refers to the existence of different classes of social behaviors in the repertoire of the individual to deal assertively with the demands of interpersonal situations. A bibliographic review was carried out in six studies published by researchers from the area between 2002 and 2016. The results showed that social skills are recognized as a protection factor in the course of human development. Such skills are attenuated in the school context because they relate to the behaviors necessary for a successful interpersonal relationship, according to typical parameters of each context and culture, which may include the behaviors of starting, maintaining and ending conversations ask for help; ask and answer questions; make and refuse orders; defend yourself; expressing feelings, liking and displeasure; ask for change in the behavior of the other; dealing with criticism and praise; admit mistakes and apologize and listen empathically, among others. For that, a survey was carried out in the following databases: BVS PSI, Pepsic, Google Scholar and Scielo, periodicals portal of CAPES/MEC journals, considering what has been produced about this topic in recent years in Brazil

Synthesis of acylhydrazino-peptomers, a new class of peptidomimetics, by consecutive Ugi and hydrazino-Ugi reactions

Herein we describe a versatile approach for the synthesis of acylhydrazino-peptomers, a new class of peptidomimetics. The key idea in this approach is based on a simple route using a one-pot hydrazino-Ugi four-component reaction followed by a hydrazinolysis or hydrolysis reaction and subsequent hydrazino-Ugi reaction or classical Ugi reaction for the construction of acyclic acylhydrazino-peptomers. The consecutive multicomponent reactions produced a variety of acylhydrazino-peptomers in moderate to excellent yields (47–90%). These compounds are multifunctional intermediates that can be further functionalized to obtain new peptidomimetics with potential biological activity

Consecutive hydrazino-Ugi-azide reactions: synthesis of acylhydrazines bearing 1,5-disubstituted tetrazoles

Isocyanide-based multicomponent reactions (IMCRs) allow the construction of relatively complex molecules through a one-pot synthesis. The combination of IMCRs in a consecutive or sequential fashion further extends the complexity of the molecules obtained. Herein, we report the efficient application of this approach to the synthesis of acylhydrazines bearing 1,5-disubstituted tetrazoles. Our strategy was accomplished in only three steps: first, a one-pot hydrazino-Ugi-azide four-component reaction; second a hydrazinolysis and finally an additional hydrazino-Ugi-azide reaction. This sequence provides the title compounds in moderate to excellent yields. The products synthesized herein contain functional groups within their structures that can be easily modified to obtain new acylhydrazino 1,5-disubstituted tetrazoles