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Chinese Journal of Medical Genetics ; (6): 1128-1133, 2023.
Article in Chinese | WPRIM | ID: wpr-1009263


OBJECTIVE@#To explore the genetic basis for a Chinese pedigree affected with Branchio-Oto syndrome (BOS).@*METHODS@#A pedigree with BOS which had presented at the Genetics and Prenatal Diagnosis Center of the First Affiliated Hospital of Zhengzhou University in May 2021 was selected as the study subject. Clinical data of the pedigree was collected. Peripheral blood samples of the proband and her parents were collected. Whole exome sequencing (WES) was carried out for the proband. Multiplex ligation-dependent probe amplification (MLPA) was used to verify the result of WES, short tandem repeat (STR) analysis was used to verify the relationship between the proband and her parents, and the pathogenicity of the candidate variant was analyzed.@*RESULTS@#The proband, a 6-year-old girl, had manifested severe congenital deafness, along with inner ear malformation and bilateral branchial fistulae. WES revealed that she has harbored a heterozygous deletion of 2 466 kb at chromosome 8q13.3, which encompassed the EYA1 gene. MLPA confirmed that all of the 18 exons of the EYA1 gene were lost, and neither of her parents has carried the same deletion variant. STR analysis supported that both of her parents are biological parents. Based on the guidelines from the American College of Medical Genetics and Genomics, the deletion was classified as pathogenic (PVS1+PS2+PM2_Supporting+PP4).@*CONCLUSION@#The heterozygous deletion of EYA1 gene probably underlay the pathogenicity of BOS in the proband, which has provided a basis for the clinical diagnosis.

Humans , Female , Pregnancy , Child , Pedigree , Family , Parents , Chromosomes, Human, Pair 3 , Exons , Nuclear Proteins/genetics , Protein Tyrosine Phosphatases , Intracellular Signaling Peptides and Proteins/genetics
Chinese Journal of Lung Cancer ; (12): 78-85, 2022.
Article in English | WPRIM | ID: wpr-928783


BACKGROUND@#The occurrence and development of lung cancer are closely linked to epigenetic modification. Abnormal DNA methylation in the CpG island region of genes has been found in many cancers. Protein kinase C delta binding protein (PRKCDBP) is a potential tumor suppressor and its epigenetic changes are found in many human malignancies. This study investigated the possibility of PRKCDBP methylation as a potential biomarker for non-small cell lung cancer (NSCLC).@*METHODS@#We measured the methylation levels of PRKCDBP in the three groups of NSCLC tissues. Promoter activity was measured by the dual luciferase assay, with 5'-aza-deoxycytidine to examine the effect of demethylation on the expression level of PRKCDBP.@*RESULTS@#The methylation levels of PRKCDBP in tumor tissues and 3 cm para-tumor were higher than those of distant (>10 cm) non-tumor tissues. Receiver operating characteristic (ROC) curve analysis between tumor tissues and distant non-tumor tissues showed that the area under the line (AUC) was 0.717. Dual luciferase experiment confirmed that the promoter region was able to promote gene expression. Meanwhile, in vitro methylation of the fragment (PRKCDBP_Me) could significantly reduce the promoter activity of the fragment. Demethylation of 5'-aza-deoxycytidine in lung cancer cell lines A549 and H1299 showed a significant up-regulation of PRKCDBP mRNA levels.@*CONCLUSIONS@#PRKCDBP methylation is a potential and promising candidate biomarker for non-small cell lung cancer.

Humans , Biomarkers/metabolism , Carcinoma, Non-Small-Cell Lung/pathology , Cell Line, Tumor , DNA Methylation , Gene Expression Regulation, Neoplastic , Intracellular Signaling Peptides and Proteins/genetics , Lung Neoplasms/pathology , Promoter Regions, Genetic
Chinese Journal of Medical Genetics ; (6): 374-377, 2022.
Article in Chinese | WPRIM | ID: wpr-928422


OBJECTIVE@#To analyze the clinical phenotype and genetic basis for a Chinese pedigree suspected for branchiootic syndrome (BOS).@*METHODS@#The proband was subjected to target-capture high-throughput sequencing to detect potential variant of deafness-associated genes. Candidate variants were verified by Sanger sequencing of the family members.@*RESULTS@#The proband was found to harbor a c.1627C>T (p.Gln543Ter) nonsense variant of the EYA1 gene. Sanger sequencing confirmed that all of the 4 patients with the BOS phenotype from the pedigree have harbored the same heterozygous variant. Based on the guidelines of the American College of Medical Genetics and Genomics, the variant was predicted to be pathogenic (PVS1+PS+PP3+PP4).@*CONCLUSION@#The c.1627C>T (p.Gln543Ter) variant of the EYA1 gene probably underlay the BOS phenotype in this pedigree. Above finding has provided a basis for its clinical diagnosis.

Humans , Branchio-Oto-Renal Syndrome , China , Intracellular Signaling Peptides and Proteins/genetics , Mutation , Nuclear Proteins/genetics , Pedigree , Protein Tyrosine Phosphatases/genetics
Arch. endocrinol. metab. (Online) ; 65(3): 295-304, May-June 2021. tab, graf
Article in English | LILACS | ID: biblio-1285147


ABSTRACT Objective: To analyze the clinical, laboratory, and radiological findings and management of patients with clinical pituitary apoplexy and to screen for aryl hydrocarbon receptor-interacting protein (AIP) mutations. Subjects and methods: The clinical findings were collected from the medical records of consecutive sporadic pituitary adenoma patients with clinical apoplexy. Possible precipitating factors, laboratory data, magnetic resonance imaging (MRI) findings and treatment were also analyzed. Peripheral blood samples were obtained for DNA extraction from leukocytes, and the entire AIP coding region was sequenced. Results: Thirty-five patients with pituitary adenoma were included, and 23 (67%) had non-functioning pituitary adenomas. Headache was observed in 31 (89%) patients. No clear precipitating factor was identified. Hypopituitarism was observed in 14 (40%) patients. MRI from 20 patients was analyzed, and 10 (50%) maintained a hyperintense signal in MRI performed more than three weeks after pituitary apoplexy (PA). Surgery was performed in ten (28%) patients, and 25 (72%) were treated conservatively with good outcomes. No AIP mutation was found in this cohort. Conclusion: Patients with stable neuroophthalmological impairments can be treated conservatively if no significant visual loss is present. Our radiological findings suggest that hematoma absorption lasts more than that observed in other parts of the brain. Additionally, our study suggests no benefits of AIP mutation screening in sporadic patients with apoplexy.

Humans , Pituitary Neoplasms/genetics , Pituitary Neoplasms/diagnostic imaging , Pituitary Apoplexy/etiology , Pituitary Apoplexy/genetics , Adenoma/genetics , Adenoma/diagnostic imaging , Referral and Consultation , Genetic Testing , Intracellular Signaling Peptides and Proteins/genetics , Mutation
Chinese Journal of Otorhinolaryngology Head and Neck Surgery ; (12): 966-971, 2021.
Article in Chinese | WPRIM | ID: wpr-942557


Objective: To analyze the clinical manifestations of a patient with branchiootic syndrome(BOS) and her families and to carry out genetic testing in order to specify the biological pathogenesis. Methods: Clinical data of the patient and her families were collected. Genomic DNA in the peripheral blood of the proband and her family members was extracted. All exons of 406 deafness-related susceptible genes as well as their flanking regions were sequenced by high-throughput sequencing, and the mutation sites of the proband and her parents were validated by Sanger sequencing. Results: There were nine members in three generations, of whom four presented with hearing loss, preauricular fistula and branchial fistula which met the diagnostic criteria of BOS. Proband and her mother presented with auricle malformation and inner ear malformation. And no one had abnormalities in the kidneys of all the patients. Pedigree analysis revealed that the mode of inheritance in the family was consistent with the autosomal dominant pattern. Mutational analysis showed that all the affected patients detected a heterozygous frameshift variation c.1255delT in the EYA1 gene, which had not been reported. Genotype and phenotype were co-isolated in this family. Such a frameshift variation produced a premature termination codon, thereby causing premature termination of translation (p.C419VFS*12). ACMG identified that the mutation was pathogenic. This mutation was novel and not detected in controls. A heterozygous missense variation mutation c.403G>A(p.G135S) in EYA1 gene was also detected in three members of this family. ACMG identified that the mutation clinical significance was uncertain. However, two of whom were normal, which seemed the disease was not caused by this mutation in this family. Conclusions: A novel frameshift mutation in EYA1(c.1255delT) is the main molecular etiology of BOS in the Chinese family. This study expands the mutational spectrum of EYA1 gene. The clinical manifestations are heterogeneous among patients in this family. The diagnosis of BOS should combine gene tests with clinical phenotypes analysis.

Female , Humans , Branchio-Oto-Renal Syndrome/genetics , DNA Mutational Analysis , Genetic Testing , Intracellular Signaling Peptides and Proteins/genetics , Mutation , Nuclear Proteins , Pedigree , Protein Tyrosine Phosphatases/genetics
Arch. endocrinol. metab. (Online) ; 63(4): 385-393, July-Aug. 2019. tab, graf
Article in English | LILACS | ID: biblio-1019354


ABSTRACT Introduction Gigantism is a rare pediatric disease characterized by increased production of growth hormone (GH) before epiphyseal closure, that manifests clinically as tall stature, musculoskeletal abnormalities, and multiple comorbidities. Materials and methods Case series of 6 male patients with gigantism evaluated at the Endocrinology Service of Hospital de San José (Bogotá, Colombia) between 2010 and 2016. Results All patients had macroadenomas and their mean final height was 2.01 m. The mean age at diagnosis was 16 years, and the most common symptoms were headache (66%) and hyperhidrosis (66%). All patients had acral changes, and one had visual impairment secondary to compression of the optic chiasm. All patients underwent surgery, and 5 (83%) required additional therapy for biochemical control, including radiotherapy (n = 4, 66%), somatostatin analogues (n = 5, 83%), cabergoline (n = 3, 50%), and pegvisomant (n = 2, 33%). Three patients (50%) achieved complete biochemical control, while 2 patients showed IGF-1 normalization with pegvisomant. Two patients were genetically related and presented a mutation in the aryl hydrocarbon receptor-interacting protein (AIP) gene (pathogenic variant, c.504G>A in exon 4, p.Trp168*), fulfilling the diagnostic criteria of familial isolated pituitary adenoma. Conclusions This is the largest case series of patients with gigantism described to date in Colombia. Transsphenoidal surgery was the first-choice procedure, but additional pharmacological therapy was usually required. Mutations in the AIP gene should be considered in familial cases of GH-producing adenomas.

Humans , Male , Adolescent , Young Adult , Pituitary Neoplasms/therapy , Adenoma/therapy , Gigantism/therapy , Pedigree , Pituitary Neoplasms/diagnosis , Insulin-Like Growth Factor I/analysis , Growth Hormone/blood , Adenoma/diagnosis , Retrospective Studies , Follow-Up Studies , Treatment Outcome , Sex Distribution , Colombia , Intracellular Signaling Peptides and Proteins/genetics , Growth Hormone-Secreting Pituitary Adenoma/genetics , Gigantism/diagnosis , Mutation/genetics
São Paulo med. j ; 137(3): 255-261, May-June 2019. tab, graf
Article in English | LILACS | ID: biblio-1020958


ABSTRACT BACKGROUND: There is evidence that genetic predisposition and epigenetic alteration (e.g. DNA methylation) play major roles in lung cancer. In our genetic epidemiological studies, rs1970764 in oncogene PPP1R13L was most consistently associated with lung cancer risk. Here, we explored the role of PPP1R13L methylation in lung cancer development. DESIGN AND SETTING: Analytical cross-sectional study (45 lung cancer cases and 45 controls), conducted in China. METHODS: We investigated the DNA methylation status of 2,160 cytosine-phosphate-guanine (CpG) sites in the PPP1R13L promoter region using the EpiTYPER assay of the Sequenom MassARRAY platform. RESULTS: In the whole study group, the methylation levels of CpG-6, CpG-9, CpG-20 and CpG-21 were significantly lower and those of CpG-16 were significantly higher in cases than in controls. Among smokers, the methylation levels at five CpG sites (CpG-6, CpG-11, CpG-15, CpG-20 and CpG-21) were statistically significantly lower among cases. Among men, the methylation levels at four CpG sites (CpG-11, CpG-15, CpG-20 and CpG-21) were significantly lower among cases. Regarding smokers, the methylation levels at CpG-7.8 and CpG-21 among cases and at CpG-22 among controls were significantly lower, compared with nonsmokers. The frequency of positivity for methylation was not significantly different between lung cancer cases and controls (68.22% for cases and 71.87% for controls; P = 0.119). CONCLUSION: Our study on a Chinese population suggests that lung cancer patients have aberrant methylation status (hypomethylation tended to be more frequent) in peripheral blood leukocytes at several CpG sites in the PPP1R13L promoter region and that exposure to smoking may influence methylation status.

Humans , Male , Female , Middle Aged , Aged , Repressor Proteins/genetics , DNA Methylation/genetics , Genetic Predisposition to Disease/genetics , Intracellular Signaling Peptides and Proteins/genetics , Lung Neoplasms/genetics , Case-Control Studies , Cross-Sectional Studies , Promoter Regions, Genetic
Braz. j. med. biol. res ; 52(6): e8399, 2019. graf
Article in English | LILACS | ID: biblio-1011582


Imatinib is the first line of therapy for patients with metastatic or gastrointestinal stromal tumors (GIST). However, drug resistance limits the long-term effect of imatinib. Long non-coding RNAs (lncRNAs) are emerging as key players in regulating drug resistance in cancer. In this study, we investigated the association between lncRNA CCDC26 and IGF-1R in GIST and their involvement in drug resistance. Considering the key role of lncRNAs in drug resistance in cancer, we hypothesized that IGF-1R is regulated by lncRNAs. The expression of a series of reported drug resistance-related lncRNAs, including CCDC26, ARF, H19, NBR2, NEAT1, and HOTAIR, in GIST cells treated with imatinib H19 was examined at various time-points by qRT-PCR. Based on our results and published literature, CCDC26, a strongly down-regulated lncRNA following imatinib treatment, was chosen as our research target. GIST cells with high expression of CCDC26 were sensitive to imatinib treatment while knockdown of CCDC26 significantly increased the resistance to imatinib. Furthermore, we found that CCDC26 interacted with c-KIT by RNA pull down, and that CCDC26 knockdown up-regulated the expression of IGF-1R. Moreover, IGF-1R inhibition reversed CCDC26 knockdown-mediated imatinib resistance in GIST. These results indicated that treatments targeting CCDC26-IGF-1R axis would be useful in increasing sensitivity to imatinib in GIST.

Humans , Receptors, Somatomedin/genetics , Drug Resistance, Neoplasm , Intracellular Signaling Peptides and Proteins/genetics , RNA, Long Noncoding/genetics , Imatinib Mesylate/pharmacology , Antineoplastic Agents/pharmacology , Signal Transduction , Down-Regulation/genetics , Gene Expression Regulation, Neoplastic , Receptors, Somatomedin/metabolism , Receptor, IGF Type 1 , Apoptosis , Cell Line, Tumor , Intracellular Signaling Peptides and Proteins/metabolism , RNA, Long Noncoding/metabolism , Flow Cytometry
IBJ-Iranian Biomedical Journal. 2017; 21 (4): 261-269
in English | IMEMR | ID: emr-189235


Background: Obesity is a very common disorder resulting from an imbalance between food intake and energy expenditure, and it has a substantial impact on the development of chronic diseases. The aim of this study was to examine the association of INSIG2 [rs7566605] gene polymorphism with obesity and obesity associated phenotypes in North Indian subjects

Methods: The variants were investigated for association in 642 obese and non-obese individuals. The genotyping of INSIG2 [rs7566605] single nucleotide polymorphism was analyzed by the TaqMan allelic discrimination protocol

Results: A significant association was observed for INSIG2 [rs7566605] single nucleotide polymorphism with obesity and obesity-related phenotypes. Furthermore, a significant relationship was found between the rs7566605 and insulin, homeostasis model of assessment-insulin resistance, the percentage of body fat, fat mass, leptin, and adiponectin

Conclusion: The present study observed significant association between INSIG2 [rs7566605] single nucleotide polymorphism and obesity, as well as obesity associated phenotypes in North Indian population

Humans , Male , Female , Adult , Membrane Proteins/genetics , Intracellular Signaling Peptides and Proteins/genetics , Polymorphism, Genetic , Phenotype , Polymorphism, Single Nucleotide , Body Mass Index , Insulin , Insulin Resistance
Rev. chil. pediatr ; 87(4): 288-292, ago. 2016. ilus, graf
Article in Spanish | LILACS | ID: lil-796817


El síndrome de Sotos (SS) es una enfermedad genética con un patrón de herencia autosómico dominante, causado por haploinsuficiencia del gen NSD1 secundaria a mutaciones puntuales o microdeleciones del locus 5q35 en el que está ubicado el gen. Es un síndrome poco frecuente, presentándose en 7 de cada 100.000 nacimientos. El objetivo de este reporte es presentar el caso de una paciente de 4 años con retardo global del desarrollo, y hallazgos físicos especiales que sugerían un sindrome genético. Caso clínico: Paciente de 4 años, género femenino, cabello ralo, fascie triangular, fisura palpebral alargada, papadar ojival, mandíbula prominente, escápula alada y clinodactilia del quinto dedo de ambas manos. La prueba molecular de hibridación genómica comparativa por microarreglos, mostró microdeleción de la región 5q35.2 q35.3 de 2.082 MB, que incluye el gen NSD1. Conclusión: Proponemos realizar la prueba de hibridación genómica comparativa en pacientes con retraso global del desarrollo y hallazgos fenotípicos menores.

Sotos Syndrome (SS) is a genetic disease with an autosomal dominant pattern caused by haplo-insufficiency of NSD1 gene secondary to point mutations or microdeletion of the 5q35 locus where the gene is located. It is a rare syndrome, occurring in 7 out of every 100,000 births. The objective of this report is to present the case of a 4 year-old patient with a global developmental delay, as well as specific physical findings suggesting a syndrome of genetic origin. Clinical case: Female patient, 4 years of age, thinning hair, triangular facie, long palpebral fissure, arched palate, prominent jaw, winged scapula and clinodactilia of the fifth finger both hands. The molecular test comparative genomic hybridisation test by microarray was subsequently performed, with the result showing 5q35.2 q35.3 region microdeletion of 2,082 MB, including the NSD1 gene. Conclusion: Finally, this article also proposes the performing of comparative genomic hybridisation as the first diagnostic option in cases where clinical findings are suggestive of SS.

Humans , Female , Child, Preschool , Nuclear Proteins/genetics , Intracellular Signaling Peptides and Proteins/genetics , Comparative Genomic Hybridization/methods , Sotos Syndrome/diagnosis , Chromosome Deletion , Histone-Lysine N-Methyltransferase , Sotos Syndrome/physiopathology , Sotos Syndrome/genetics , Histone Methyltransferases
Rev. chil. pediatr ; 87(1): 31-36, feb. 2016. ilus, tab
Article in Spanish | LILACS | ID: lil-779471


Resumen: La podocina es una proteína localizada en el diafragma de filtración glomerular donde participa en la regulación de la filtración glomerular. Las mutaciones del gen NPHS2, que codifica a la podocina, son la principal causa de síndrome nefrótico corticorresistente (SNCR) autosómico recesivo en niños. Objetivos: Identificar mutaciones de NPHS2 en niños chilenos con SNCR, y establecer la prevalencia de las variantes más frecuentes en un grupo de adultos sanos. Pacientes y método: Análisis mutacional de NPHS2 en 34 niños chilenos con SNCR. Una vez identificadas las dos variantes de NPHS2 de mayor frecuencia, se realizó un screening de estas mutaciones en 223 adultos sanos. El análisis mutacional se realizó por secuenciación directa de los ocho exones codificantes amplificados por reacción de polimerasa en cadena. La secuenciación del DNA se realizó mediante método fluorométrico y las secuencias fueron evaluadas con el software SeqPilot. La asociación entre la presencia de variantes de NPHS2 y SNCR se calculó comparando las frecuencias alélicas entre los pacientes con SNCR y los voluntarios sanos utilizando prueba exacta de Fisher. Se consideró significativo p < 0,05. Resultados: Se detectaron mutaciones patogénicas de NPHS2 en siete de los 34 pacientes (21%) estudiados, de los cuales seis resultaron heterocigotos para p.R229Q y p.A284 V. En voluntarios sanos la prevalencia de p.R229Q fue de 2,46%. Conclusiones: Este estudio muestra que p.R229Q y p.A284 V son las variantes de NPHS2 más frecuentes en niños chilenos con SNCR. Por primera vez se describe esta asociación en niños chilenos, en base a la cual es posible proponer una estrategia de screening para estudio genético en pacientes con SNCR y sus familias. Se propone una estrategia de búsqueda de p.R229Q y p.A284 V en forma paralela o secuencial en estos pacientes.

Abstract: Podocin is a protein located in the glomerular slit diaphragm where it takes part in the regulation of glomerular filtration. Mutations of the NPHS2 gene that codes podocin are the main cause of autosomal recessive steroid resistant nephrotic syndrome (SRNS). Objectives: To identify the NPHS2 mutations in Chilean children with SRNS, and to determine the prevalence of the most common variants in a group of healthy adults. Patients and methods: Mutation analysis of NPHS2 in 34 Chilean children with SRNS. Once the two most common variants of NPHS2 were identified, screening for these mutations was performed on 233 healthy adults. The mutation analysis was performed by the direct sequencing of the eight coding exons by polymerase chain reaction amplification. The DNA sequencing was performed using a fluorometric method, and then evaluated with SeqPilot™ software. The relationship between the presence of NPHS2 variants and SRNS was calculated by comparing the allele frequency between patients with SRNS and those of the healthy volunteers using the exact Fisher test. A P < .05 was considered significant. Results: Pathogenic NPHS2 mutations were detected in 7 (21%) of the 34 patients studied, of which 6 were heterozygotes for p.R229Q and p.A284 V. The presence of p.R229Q was 2.46% in the healthy volunteers. Conclusions: This study shows that p.R229Q and p.A284 V are the most frequent variants in Chilean children with SRNS. It is the first time that this relationship has been reported in Chilean children. Based on this, a screening strategy is proposed for the genetic study in patients with SRNS and their families. A parallel or sequential search strategy for p.R229Q and p.A284 V in these patients is proposed.

Humans , Male , Female , Child , Adolescent , Adult , Middle Aged , Aged , Young Adult , Intracellular Signaling Peptides and Proteins/genetics , Membrane Proteins/genetics , Mutation , Nephrotic Syndrome/congenital , DNA Mutational Analysis , Chile , Polymerase Chain Reaction , Exons , Cross-Sectional Studies , Sequence Analysis, DNA , Fluorometry , Gene Frequency , Nephrotic Syndrome/genetics
Rev. bras. epidemiol ; 18(supl.2): 17-32, Out.-Dez. 2015. tab, graf
Article in English | LILACS | ID: lil-776702


Resumo: Objetivo: Descrever medidas do cuidado assistencial destinadas ao paciente com diabetes mellitus autorreferido no Brasil. Métodos: Foram utilizados dados da Pesquisa Nacional de Saúde(2013), estudo transversal de base populacional, referentes ao cuidado em saúde com o diabetes mellitus autorreferido, quanto ao uso de serviços de saúde e acesso a medicamentos. Resultados: A prevalência de diabetes mellitus autorreferido foi de 6,2%, e 11,5% da população nunca fez uma glicemia na vida. Dos adultos que referiram diabetes mellitus , 80,2% tomaram medicamentos nas duas semanas anteriores à entrevista, 57,4% usaram o Programa Farmácia Popular, 73,2% receberam assistência médica e 47,1% realizaram o atendimento nas Unidades Básicas de Saúde. Em 65,2%, o médico que atendeu na última consulta era o mesmo das consultas anteriores, 95,3% dos pacientes conseguiram realizar os exames complementares solicitados e 83,3% conseguiram fazer as consultas com o médico especialista. A avaliação de pés e olhos foi relatada por 35,6 e 29,1% dos portadores de diabetes mellitus , respectivamente. Relataram internação hospitalar por causa do diabetes ou de alguma complicação 13,4% dos adultos, e outros 7,0% relataram limitações nas atividades diárias. Em geral, mulheres, assim como a população mais idosa, de maior escolaridade, brancos e residentes nas regiões Sul e Sudeste, tiveram maior prevalência da doença e maior acesso aos serviços, medicamentos e consultas. Discussão: Os cuidados aos portadores de diabetes foram recebidos de forma adequada, na maioria dos casos, o que é essencial para manter a qualidade de vida dos pacientes e prevenir desfechos mais graves.

Abstract: Objective: To describe the care measurements provided to patients with self-reported diabetes mellitus in Brazil. Methods: Data from the Brazilian National Health Survey (2013) were used. This is a cross-sectional population-based study in which the subjects with self-reported diabetes mellitus answered questions concerning their use of health services and access to medicine. Results: The prevalence of self-reported diabetes mellitus was 6.2%, while 11.5% of the population had never undergone a glucose testing. From the adults with diabetes mellitus, 80.2% had taken medications two weeks before the interview, 57.4% used the Popular Pharmacy Program, 73.2% received medical care, and 47.1% were cared for in the Health Basic Units. In 65.2%, the physician who cared for them in the last appointment was the same from previous ones, 95.3% of the patients were able to perform the required complementary examinations, and 83.3% could go to the appointments with a specialist. About 35.6 and 29.1% of the subjects with diabetes mellitus reported feet and eyes examination, respectively. About 13.4% declared previous hospitalization owing to diabetes or any complications, and 7.0% mentioned limitations in their daily activities owing to the disease. In general, women and the elderly people, those with higher education levels, white, and those living in the south and southeastern regions showed a higher prevalence of the disease and greater access to services, medicine, and appointments. Discussion: The care reported by patients with diabetes, which is essential to maintain their quality of life and prevent serious outcomes, seemed, in most cases, to be adequate.

Adolescent , Adult , Aged , Female , Humans , Male , Middle Aged , Young Adult , DNA-Binding Proteins/genetics , Hepatitis B virus/physiology , Hepatitis B, Chronic/genetics , Intracellular Signaling Peptides and Proteins/genetics , Nuclear Proteins/genetics , Polymorphism, Single Nucleotide , Asian People/ethnology , Asian People/genetics , China/ethnology , Genetic Predisposition to Disease , Genotype , Hepatitis B, Chronic/ethnology , Hepatitis B, Chronic/virology
Rev. méd. Chile ; 143(1): 77-84, ene. 2015. ilus
Article in Spanish | LILACS | ID: lil-742554


A higher frequency of chronic renal disease is observed in obese patients, suggesting a pathogenic association between both conditions. Obesity unmasks clinical manifestations of chronic kidney disease such as high blood pressure, which may accelerate its progression. Obesity also promotes hyper filtration and the appearance of microalbuminuria, activates the renin-angiotensin-aldosterone system and is associated with high levels of pro-inflammatory cytokines. Therefore weight reduction may slow the progression of chronic renal disease and reduce its associated cardiovascular risk factors.

Female , Humans , Male , Adiposity/genetics , Genetic Variation/genetics , Insulin Receptor Substrate Proteins/genetics , Metabolome/genetics , Obesity/genetics , Polymorphism, Single Nucleotide/genetics , Adiponectin/blood , Alleles , Body Fat Distribution , Body Mass Index , Body Weight , Genome-Wide Association Study , Intracellular Signaling Peptides and Proteins/genetics , Membrane Proteins , Meta-Analysis as Topic , Subcutaneous Fat
Braz. j. med. biol. res ; 47(4): 273-278, 8/4/2014. graf
Article in English | LILACS | ID: lil-705769


Overexpression of cytokine-induced apoptosis inhibitor 1 (CIAPIN1) contributes to multidrug resistance (MDR) in breast cancer. This study aimed to evaluate the potential of CIAPIN1 gene silencing by RNA interference (RNAi) as a treatment for drug-resistant breast cancer and to investigate the effect of CIAPIN1 on the drug resistance of breast cancer in vivo. We used lentivirus-vector-based RNAi to knock down CIAPIN1 in nude mice bearing MDR breast cancer tumors and found that lentivirus-vector-mediated silencing of CIAPIN1 could efficiently and significantly inhibit tumor growth when combined with chemotherapy in vivo. Furthermore, Western blot analysis showed that both CIAPIN1 and P-glycoprotein expression were efficiently downregulated, and P53 was upregulated, after RNAi. Therefore, we concluded that lentivirus-vector-mediated RNAi targeting of CIAPIN1 is a potential approach to reverse MDR of breast cancer. In addition, CIAPIN1 may participate in MDR of breast cancer by regulating P-glycoprotein and P53 expression.

Animals , Female , Humans , Antibiotics, Antineoplastic/therapeutic use , Breast Neoplasms/drug therapy , Doxorubicin/therapeutic use , Drug Resistance, Neoplasm/genetics , Gene Silencing , Intracellular Signaling Peptides and Proteins/genetics , Blotting, Western , Breast Neoplasms/genetics , Carcinoma/drug therapy , Carcinoma/genetics , Disease Models, Animal , Genes, MDR , Genetic Vectors/genetics , Growth Inhibitors/genetics , Intracellular Signaling Peptides and Proteins/metabolism , Lentivirus/genetics , Mice, Inbred BALB C , Mice, Nude , ATP Binding Cassette Transporter, Subfamily B, Member 1/drug effects , RNA Interference , RNA, Small Interfering/genetics , /drug effects
Gut and Liver ; : 487-494, 2014.
Article in English | WPRIM | ID: wpr-108133


BACKGROUND/AIMS: To investigate the differential expression of RING finger (RNF) proteins in Barrett esophagus (BE) and esophageal adenocarcinoma (EAC). METHODS: The differential expression of RNFs in normal esophagus (NE), BE, and EAC was screened using microarray assay. Real-time quantitative polymerase chain reaction (PCR), tissue microarray assay, and Western blot analysis were independently performed to detect the mRNA and protein expression of screened RNFs. RESULTS: The expression of nine RNFs in the BE or EAC was 2-fold higher than those in NE. Among these proteins, the RNF32 and RNF121 expression in BE was 20.3-fold and 16.4-fold higher, respectively, than that in NE, and the expression of RNF24, RNF130, RNF141, RNF139, RNF11, RNF14, and RNF159 was upregulated more than 2-fold compared with NE. The expression of nine RNFs was not only upregulated in the EAC but was also positively related to the RNF expression in BE. The PCR results also indicated increased expression of these RNFs in BE and EAC compared to NE. Furthermore, the mRNA expression of all RNFs, except for RNF141 in EAC, was dramatically higher than those in the BE. Similar results were also obtained from the Western blot analysis. CONCLUSIONS: A total of nine RNFs play critical roles in the progression of BE to EAC.

Adult , Aged , Female , Humans , Male , Middle Aged , Adenocarcinoma/enzymology , Barrett Esophagus/enzymology , Carrier Proteins/genetics , Disease Progression , Esophageal Neoplasms/enzymology , Gene Expression Profiling , Intracellular Signaling Peptides and Proteins/genetics , Proteins/genetics , RING Finger Domains , Receptors, Cell Surface/genetics , Ubiquitin-Protein Ligases/genetics
Gut and Liver ; : 508-518, 2014.
Article in English | WPRIM | ID: wpr-108130


BACKGROUND/AIMS: Doublecortin and CaM kinase-like-1 (DCAMKL1) is a marker of stem cells expressed predominantly in the crypt base in the intestine. However, DCAMKL1-positive cells have been shown to be differentiated tuft cells rather than quiescent progenitors. Tuft cells are the only epithelial cells that express cyclooxygenase 2 (COX-2) in the normal intestinal epithelium. We previously generated Cdx2-transgenic mice as model mice for intestinal metaplasia and gastric carcinoma. In the current study, we investigated the association between COX-2 and DCAMKL1 in gastric carcinoma. METHODS: We examined the association between COX-2 and DCAMKL1 expression in gastric carcinomas in clinical samples (early gastric well-differentiated adenocarcinoma) and Cdx2-transgenic mice; and the DCAMKL1-transgenic mouse stomach using immunohistochemistry and quantitative real-time polymerase chain reaction. RESULTS: The COX-2-expressing cells were scattered, not diffusely expressed, in gastric carcinomas from humans and Cdx2-transgenic mice. DCAMKL1-positive cells were also scattered in the gastric carcinomas, indicating that tuft cells could still be present in gastric carcinoma. COX-2 was expressed in DCAMKL1-positive tuft cells in Cdx2- and DCAMKL1-transgenic mouse stomachs, whereas the Sox9 transcription factor was ubiquitously expressed in gastric carcinomas, including COX-2-positive cells. CONCLUSIONS: COX-2 is expressed in DCAMKL1-expressing quiescent tuft cells in gastric carcinoma.

Animals , Humans , Mice , Adenocarcinoma/metabolism , Cyclooxygenase 2/genetics , Epithelial Cells/metabolism , Gastric Mucosa/metabolism , Intestinal Mucosa/cytology , Intracellular Signaling Peptides and Proteins/genetics , Mice, Transgenic , Protein Serine-Threonine Kinases/genetics , SOX9 Transcription Factor/genetics , Stomach Neoplasms/enzymology
Experimental & Molecular Medicine ; : e125-2014.
Article in English | WPRIM | ID: wpr-113786


Lysophosphatidic acid (LPA) is a bioactive lysophospholipid involved in numerous physiological responses. However, the expression of LPA receptors and the role of the Hippo signaling pathway in epithelial cells have remained elusive. In this experiment, we studied the functional expression of LPA receptors and the associated signaling pathway using reverse transcriptase-PCR, microspectrofluorimetry, western blotting and immunocytochemistry in salivary gland epithelial cells. We found that LPA receptors are functionally expressed and involved in activating the Hippo pathway mediated by YAP/TAZ through Lats/Mob1 and RhoA/ROCK. Upregulation of YAP/TAZ-dependent target genes, including CTGF, ANKRD1 and CYR61, has also been observed in LPA-treated cells. In addition, based on data suggesting that tumor necrosis factor (TNF)-alpha induces cell apoptosis, LPA upregulates TNF-induced caspase-3 and cleaved Poly(ADP-ribose)polymerase (PARP). However, small interfering RNA treatment to Yes-associated protein (YAP) or transcriptional co-activator with a PDZ-binding motif (TAZ) significantly decreased TNF-alpha- and LPA-induced apoptosis, suggesting that YAP and TAZ modulate the apoptotic pathway in salivary epithelial cells.

Humans , Adaptor Proteins, Signal Transducing/genetics , Apoptosis , Cell Line , Epithelial Cells/cytology , Gene Expression Regulation , Intracellular Signaling Peptides and Proteins/genetics , Lysophospholipids/metabolism , Phosphoproteins/genetics , Protein Serine-Threonine Kinases/metabolism , RNA Interference , RNA, Small Interfering/genetics , Receptors, Lysophosphatidic Acid/genetics , Salivary Glands/cytology , Signal Transduction , Tumor Necrosis Factor-alpha/metabolism , rho-Associated Kinases/metabolism , rhoA GTP-Binding Protein/metabolism
Clinics ; 68(5): 628-631, maio 2013. tab, graf
Article in English | LILACS | ID: lil-675765


OBJECTIVES: Familial steroid-sensitive idiopathic nephrotic syndrome is rare, and only approximately 3% of patients have affected siblings. METHODS: Herein, we report seven cases of patients with steroid-sensitive idiopathic nephrotic syndrome from three Chinese families. Mutational screening of the Nphs2 gene was performed in all the patients. RESULTS: All seven of the familial steroid-sensitive idiopathic nephrotic syndrome cases in our sample exhibited minimal change disease, and one case also presented with mesangial proliferative glomerulonephritis, according to the renal pathology. No significant was associations were found between Nphs2 gene mutations and the onset of proteinuria and nephrotic syndrome in these familial cases. CONCLUSIONS: The presence of minimal change disease is important, but it is not an unusual finding in patients with familial steroid-sensitive idiopathic nephrotic syndrome, which appears to be clinically benign and genetically distinct from other types of nephrosis. .

Adolescent , Adult , Child , Child, Preschool , Female , Humans , Male , Intracellular Signaling Peptides and Proteins/genetics , Membrane Proteins/genetics , Mutation/genetics , Nephrotic Syndrome/genetics , Polymorphism, Genetic/genetics , Rare Diseases/genetics , China , Nephrotic Syndrome/pathology , Pedigree , Rare Diseases/pathology
Rio de Janeiro; s.n; 2013. 145 p. ilus, tab.
Thesis in Portuguese | LILACS | ID: lil-716900


A doença de Parkinson (DP) é uma das desordens neurodegenerativas mais comuns associada ao envelhecimento, alcançando 2% aos 70 anos. É uma doença caracterizada pela degeneração progressiva de neurônios dopaminérgicos nigrais nos gânglios basais e pela presença de inclusões protéicas citoplasmáticas denominadas corpúsculos e neuritos de Lewy nos neurônios sobreviventes. A etiologia da DP é pouco conhecida, sendo considerada, na maioria dos casos, idiopática. Conhecimentos alcançados nos últimos 15 anos sobre a base genética da DP demonstram, claramente, que os fatores genéticos desempenham um importante papel na etiologia desta desordem. Neste trabalho, rastreamos mutações nos genes que codificam proteínas participantes de vias metabólicas mitocondriais (Parkin, PINK1 e DJ-1) em 136 pacientes brasileiros com manifestação precoce da DP, através do sequenciamento automático e da técnica de MLPA. Avaliamos a presença de variantes de sequência por meio do sequenciamento dos exons 1 a 12 do gene Parkin e dos exons 1 a 8 do gene PINK1. Em Parkin foram identificadas três mutações patogênicas ou potencialmente patogênicas, ambas em heterozigose: p.T240M, p.437L e p.S145N. Em PINK1 não encontramos variantes de ponto patogênicas. Através da técnica de MLPA investigamos alterações de dosagem nos genes Parkin, PINK1 e DJ-1. Identificamos cinco alterações no gene Parkin em quatro pacientes: uma duplicação heterozigota do exon 4 no paciente PAR2256, uma deleção heterozigota do exon 4 no probando PAR2099, uma deleção homozigota do exon 4 na paciente PAR3380 e um probando heterozigoto composto (PAR2396) com duas alterações, uma duplicação do exon 3 e uma deleção dos exons 5 e 6. No gene PINK1 identificamos uma deleção heterozigota do exon 1, que nunca foi descrita na literatura, em um paciente (PAR2083). Não encontramos alteração quantitativa no gene DJ-1. Neste estudo obtivemos uma frequência total de mutações patogênicas (pontuais e de dosagem) nos genes estudados ...

Parkinson's disease (PD) is one of the most common neurodegenerative disorders associated with aging, reaching 2% at age 70. It is a disease characterized by progressive degeneration of nigra dopaminergic neurons in the basal ganglia and the presence of cytoplasmic protein inclusions known as Lewy bodies and neurites in surviving neurons. The etiology of PD is poorly understood, being considered, in most cases, idiopathic. Knowledge achieved in the last 15 years about the genetic basis of PD clearly shows that genetic factors play an important role in the etiology of this disorder. In this study, we screened mutations in genes that encode proteins participating in mitochondrial metabolic pathways (Parkin, PINK1 and DJ-1) in 136 Brazilian patients with early onset PD, through automatic sequencing and MLPA technique. We evaluated the presence of sequence variants by means of sequencing of exons 1 to 12 of Parkin gene and exons 1 to 8 of PINK1 gene. In Parkin gene were identified three pathogenic or potentially pathogenic mutations, both in heterozygous state: p.T240M, p.437L e p.S145N. In PINK1 gene we did not find pathogenic point mutations. Through the MLPA technique we investigated dosage changes in Parkin, PINK1 and DJ-1 genes. We identified five exon rearrangements in Parkin gene in four patients: a heterozygous duplication of exon 4 in patient PAR2256, a heterozygous deletion of exon 4 in proband PAR2099, a homozygous deletion of exon 4 in patient PAR3380 and a compound heterozygote (PAR2396) with two changes, a duplication of exon 3 and a deletion of exons 5 and 6. In PINK1 gene we identified a heterozygous deletion of exon 1, which has never been described in literature, in one patient (PAR2083). We found no quantitative change in DJ-1 gene. In this study, we obtained an overall frequency of pathogenic mutations (sequence and dosage) in the genes studied of 7.3%, being 6.6% in Parkin gene and 0.7% in PINK1 gene

Humans , Parkinson Disease/genetics , Mutation/genetics , DNA Mutational Analysis , Exons/genetics , Gene Duplication , Mitochondria/genetics , Point Mutation , Intracellular Signaling Peptides and Proteins/genetics , Oncogene Proteins/genetics , Protein Kinases/genetics , Nucleic Acid Amplification Techniques/methods , Ubiquitin-Protein Ligases/genetics
Experimental & Molecular Medicine ; : 45-51, 2012.
Article in English | WPRIM | ID: wpr-211719


Diabetic nephropathy (DN) is a progressive kidney disease that is caused by injury to kidney glomeruli. Podocytes are glomerular epithelial cells and play critical roles in the glomerular filtration barrier. Recent studies have shown the importance of regulating the podocyte actin cytoskeleton in early DN. The phosphoinositide 3-kinase (PI3K) inhibitor, wortmannin, simultaneously regulates Rac1 and Cdc42, which destabilize the podocyte actin cytoskeleton during early DN. In this study, in order to evaluate the reno-protective effects of wortmannin in early DN by regulating Rac1 and Cdc42, streptozotocin (STZ)-induced proteinuric renal disease (SPRD) rats were treated with wortmannin. The albuminuria value of the SPRD group was 3.55 +/- 0.56 mg/day, whereas wortmannin group was 1.77 +/- 0.48 mg/day. Also, the albumin to creatinine ratio (ACR) value of the SPRD group was 53.08 +/- 10.82 mg/g, whereas wortmannin group was 20.27 +/- 6.41 mg/g. Changes in the expression level of nephrin, podocin and Rac1/Cdc42, which is related to actin cytoskeleton in podocytes, by wortmannin administration were confirmed by Western blotting. The expression levels of nephrin (79.66 +/- 0.02), podocin (87.81 +/- 0.03) and Rac1/Cdc42 (86.12 +/- 0.02) in the wortmannin group were higher than the expression levels of nephrin (55.32 +/- 0.03), podocin (53.40 +/- 0.06) and Rac1/Cdc42 (54.05 +/- 0.04) in the SPRD group. In addition, expression and localization of nephrin, podocin and desmin were confirmed by immunofluorescence. In summary, we found for the first time that wortmannin has a reno-protective effect on SPRD rats during the early DN. The beneficial effects of wortmannin in SPRD rats indicate that this compound could be used to delay the progression of the disease during the early DN stage.

Animals , Humans , Rats , Albumins/metabolism , Androstadienes/administration & dosage , Creatinine/blood , Desmin/genetics , Diabetes Mellitus, Experimental/drug therapy , Diabetic Nephropathies/drug therapy , Disease Models, Animal , Intracellular Signaling Peptides and Proteins/genetics , Kidney/pathology , Membrane Proteins/genetics , Phosphatidylinositol 3-Kinases/antagonists & inhibitors , Podocytes/drug effects , Rats, Inbred Strains , cdc42 GTP-Binding Protein/genetics , rac1 GTP-Binding Protein/genetics