Considerações sobre a farmacogenética da diabetes mellitus tipo 2 como subsídio para a P&D de medicamentos

Farmacogenética estuda a influência das variantes genéticas nas respostas terapêuticas individuais. Embora essa ciência esteja sendo amplamente utilizada para as mais variadas doenças, ainda permanece relativamente sub-explorada na área de diabetes mellitus (DM). Para a maioria dos pacientes com DM tipo 2, os hipoglicemiantes orais são a primeira linha de tratamento medicamentoso após falha nas medidas de mudança no estilo de vida. Os secretagogos de insulina são os principais grupos de fármacos antidiabéticos utilizados na prática clínica, no entanto possuem a desvantagem da imprevisibilidade de eficácia. Esta revisão explora as implicações clínicas da complexa interação entre doenças multigênicas e o tratamento farmacológico, utilizando como modelo o DM tipo 2. As terapias atuais são um resultado direto da compreensão das bases epidemiológicas, moleculares, e genéticas do diabetes, aliadas às aplicações na prática clínica e na pesquisa e desenvolvimento de novos medicamentos. A complexidade das doenças multigenéticas assim como a potencial aplicação clínica da farmacogenética exigirá, em um futuro próximo, a melhoria dos métodos de avaliação de medicamentos, incluindo a necessidade de novos métodos estatísticos, bioinformática e novos modelos de triagem clínica, com capacidade de detectar diferenças nas terapias. Deve haver um esforço continuo para aplicar o conhecimento adquirido com estudos farmacogenéticos no entendimento da doença e da farmacologia, a fim de desenvolver novas idéias e conceitos que melhorem o tratamento e a qualidade de vida do paciente

A Case of Severe Carotid Stenosis in a Patient with Familial Hypercholesterolemia without Significant Coronary Artery Disease

Familial hypercholesterolemia (FH) is an inherited metabolic disorder characterized by elevated low-density lipoprotein cholesterol levels in the blood. In its heterozygous form, it occurs in 1 in 500 individuals in the general population. It is an important contributor to the early onset of coronary artery disease (CAD), accounting for 5–10% of cases of cardiovascular events in people younger than 50 years. Atherogenesis triggered by hypercholesterolemia generally progresses faster in the coronary arteries, followed by the subsequent involvement of other arteries such as the carotids. Thus, symptoms of CAD commonly appear before the onset of significant carotid stenosis. Herein, we report the case of a patient with untreated FH who had severe carotid atherosclerosis at the age of 46 years but had no evidence of significant CAD

<i>Lhia</i>: A Smart Chatbot for Breastfeeding Education and Recruitment of Human Milk Donors

Human milk is the most important way to feed and protect newborns as it has the components to ensure human health. Human Milk Banks (HMBs) form a network that offers essential services to ensure that newborns and mothers can take advantage of the benefits of human milk. Despite this, there is low adherence to exclusive breastfeeding in Brazil, and human milk stocks available in HMBs are usually below demand. This study aimed to co-develop a smart conversational agent (Lhia chatbot) for breastfeeding education and human milk donor recruitment for HMBs. The co-design methodology was carried out with health professionals from the HMB of the University Hospital of the Federal University of Maranhão (HMB-UHFUMA). Five natural language processing pipelines based on deep learning were trained to classify different user intents. During the rounds in the co-design procedure, improvements were made in the content and structure of the conversational flow, and the data produced were used in subsequent training sessions of pipelines. The best-performing pipeline achieved an accuracy of 93%, with a fallback index of 15% for 1851 interactions. In addition, the conversational flow improved, reaching 2904 responses given by the chatbot during the last co-design round. The pipeline with the best performance and the most improved conversational flow were deployed in the Lhia chatbot to be put into production

Menadione reduces <i>CDC25B</i> expression and promotes tumor shrinkage in gastric cancer

Background: Gastric cancer is one of the most incident types of cancer worldwide and presents high mortality rates and poor prognosis. MYC oncogene overexpression is a key event in gastric carcinogenesis and it is known that its protein positively regulates CDC25B expression which, in turn, plays an essential role in the cell division cycle progression. Menadione is a synthetic form of vitamin K that acts as a specific inhibitor of the CDC25 family of phosphatases. Methods: To better understand the menadione mechanism of action in gastric cancer, we evaluated its molecular and cellular effects in cell lines and in Sapajus apella, nonhuman primates from the new world which had gastric carcinogenesis induced by N-Methyl-N-nitrosourea. We tested CDC25B expression by western blot and RT-qPCR. In-vitro assays include proliferation, migration, invasion and flow cytometry to analyze cell cycle arrest. In in-vivo experiments, in addition to the expression analyses, we followed the preneoplastic lesions and the tumor progression by ultrasonography, endoscopy, biopsies, histopathology and immunohistochemistry. Results: Our tests demonstrated menadione reducing CDC25B expression in vivo and in vitro. It was able to reduce migration, invasion and proliferation rates, and induce cell cycle arrest in gastric cancer cell lines. Moreover, our in-vivo experiments demonstrated menadione inhibiting tumor development and progression. Conclusions: We suggest this compound may be an important ally of chemotherapeutics in the treatment of gastric cancer. In addition, CDC25B has proven to be an effective target for investigation and development of new therapeutic strategies for this malignancy. </jats:sec

Genetic screening analysis of patients with hereditary diffuse gastric cancer from northern and northeastern Brazil

BACKGROUND: Hereditary diffuse gastric cancer (HDGC) is a hereditary autosomal inherited syndrome associated with CDH1 germline mutations. In Brazil, gastrointestinal tumors are among the most prevalent tumor types and constitute a serious public health problem, especially in the northern and northeastern regions. This study aimed to investigate germline mutations, methylation pattern and genomic rearrangements in the CDH1 gene and quantitative changes in the DNA of HDGC patients in northern and northeastern Brazil. METHODS: Twenty-seven DNA samples from the members of four families affected by HDGC were analyzed using array comparative genomic hybridization (aCGH), DNA sequencing and methylation pattern. RESULTS: No evidence of gain and loss events or any rearrangements were found in any of the samples tested using aCGH. No promoter region hypermethylation was observed either. Two of the four families presented different types of germline mutations. The 185G > T and 1018A > G germline mutations detected in this study have been described in Asian and European families, respectively. The ancestors of the two families carrying these mutations had originated from those continents. CONCLUSION: This is the first study to evaluate CDH1 gene germline mutations in Brazilian families with HDGC. In our study, 50% of the families showed no CDH1 gene alterations, and it is possible that in regions with a high incidence of gastric cancer, such as northern and northeastern Brazil, environmental factors might have induced the different genetic alterations analyzed in this study

Menadione reduces CDC25B expression and promotes tumor shrinkage in gastric cancer.

Gastric cancer is one of the most incident types of cancer worldwide and presents high mortality rates and poor prognosis. MYC oncogene overexpression is a key event in gastric carcinogenesis and it is known that its protein positively regulates CDC25B expression which, in turn, plays an essential role in the cell division cycle progression. Menadione is a synthetic form of vitamin K that acts as a specific inhibitor of the CDC25 family of phosphatases. To better understand the menadione mechanism of action in gastric cancer, we evaluated its molecular and cellular effects in cell lines and in Sapajus apella, nonhuman primates from the new world which had gastric carcinogenesis induced by N-Methyl-N-nitrosourea. We tested CDC25B expression by western blot and RT-qPCR. In-vitro assays include proliferation, migration, invasion and flow cytometry to analyze cell cycle arrest. In in-vivo experiments, in addition to the expression analyses, we followed the preneoplastic lesions and the tumor progression by ultrasonography, endoscopy, biopsies, histopathology and immunohistochemistry. Our tests demonstrated menadione reducing CDC25B expression in vivo and in vitro. It was able to reduce migration, invasion and proliferation rates, and induce cell cycle arrest in gastric cancer cell lines. Moreover, our in-vivo experiments demonstrated menadione inhibiting tumor development and progression. We suggest this compound may be an important ally of chemotherapeutics in the treatment of gastric cancer. In addition, CDC25B has proven to be an effective target for investigation and development of new therapeutic strategies for this malignancy