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1.
Pharmacogenomics J ; 20(1): 136-158, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31616044

RESUMO

Colorectal cancer is one of the leading causes of cancer death worldwide. Over the last decades, several studies have shown that tumor-related genomic alterations predict tumor prognosis, drug response, and toxicity. These observations have led to the development of several therapies based on individual genomic profiles. As part of these approaches, pharmacogenomics analyses genomic alterations which may predict an efficient therapeutic response. Studying these mutations as biomarkers for predicting drug response is of a great interest to improve precision medicine. We conduct a comprehensive review of the main pharmacogenomics biomarkers and genomic alterations affecting enzyme activity, transporter capacity, channels, and receptors; and therefore the new advances in CRC precision medicine to select the best therapeutic strategy in populations worldwide, with a focus on Latin America.

2.
Mol Genet Genomic Med ; 8(2): e1087, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31830383

RESUMO

BACKGROUND: Detection of chromosomal abnormalities is crucial in various medical areas; to diagnose birth defects, genetic disorders, and infertility, among other complex phenotypes, in individuals across a wide range of ages. Hence, the present study wants to contribute to the knowledge of type and frequency of chromosomal alterations and polymorphisms in Ecuador. METHODS: Cytogenetic registers from different Ecuadorian provinces have been merged and analyzed to construct an open-access national registry of chromosome alterations and polymorphisms. RESULTS: Of 28,806 karyotypes analyzed, 6,008 (20.9%) exhibited alterations. Down syndrome was the most frequent autosome alteration (88.28%), followed by Turner syndrome (60.50%), a gonosome aneuploidy. A recurrent high percentage of Down syndrome mosaicism (7.45%) reported here, as well as by previous Ecuadorian preliminary registries, could be associated with geographic location and admixed ancestral composition. Translocations (2.46%) and polymorphisms (7.84%) were not as numerous as autosomopathies (64.33%) and gonosomopathies (25.37%). Complementary to conventional cytogenetics tests, molecular tools have allowed identification of submicroscopic alterations regions or candidate genes which can be possibly implicated in patients' symptoms and phenotypes. CONCLUSION: The Ecuadorian National Registry of Chromosome Alterations and Polymorphisms provides a baseline to better understand chromosomal abnormalities in Ecuador and therefore their clinical management and awareness. This data will guide public policy makers to promote and financially support cytogenetic and genetic testing.

3.
Front Mol Biosci ; 6: 65, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31440515

RESUMO

Colorectal cancer (CRC) is a major health problem with an estimated 1. 8 million new cases worldwide. To date, most CRC studies have focused on DNA-related aberrations, leaving post-transcriptional processes under-studied. However, post-transcriptional alterations have been shown to play a significant part in the maintenance of cancer features. RNA binding proteins (RBPs) are uprising as critical regulators of every cancer hallmark, yet little is known regarding the underlying mechanisms and key downstream oncogenic targets. Currently, more than a thousand RBPs have been discovered in humans and only a few have been implicated in the carcinogenic process and even much less in CRC. Identification of cancer-related RBPs is of great interest to better understand CRC biology and potentially unveil new targets for cancer therapy and prognostic biomarkers. In this work, we reviewed all RBPs which have a role in CRC, including their control by microRNAs, xenograft studies and their clinical implications.

4.
Sci Rep ; 9(1): 9247, 2019 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-31239502

RESUMO

The history of Ecuador was marked by the arrival of Europeans with Africans, resulting in the mixture of Native Americans with Africans and Europeans. The present study contributes to the knowledge of the Ecuadorian mestizo population by offering information about ancestry and ethnic heterogeneity. Forty-six AIM-InDels (Ancestry Informative Insertion/Deletion Markers) were used to obtain information on 240 Ecuadorian individuals from three regions (Amazonia, the Highlands, and the Coast). As a result, the population involved a significant contribution from Native Americans (values up to 51%), followed by Europeans (values up to 33%) and Africans (values up to 13%). Furthermore, we compared the data obtained with nine previously reported scientific articles on autosomal, mitochondrial DNA and Y chromosomes. The admixture results correspond to Ecuador's historical background and vary slightly between regions.

5.
PLoS Comput Biol ; 15(5): e1006918, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31071077

RESUMO

Scientific data recording and reporting systems are of a great interest for endorsing reproducibility and transparency practices among the scientific community. Current research generates large datasets that can no longer be documented using paper lab notebooks (PLNs). In this regard, electronic laboratory notebooks (ELNs) could be a promising solution to replace PLNs and promote scientific reproducibility and transparency. We previously analyzed five ELNs and performed two survey-based studies to implement an ELN in a biomedical research institute. Among the ELNs tested, we found that Microsoft OneNote presents numerous features related to ELN best functionalities. In addition, both surveyed groups preferred OneNote over a scientifically designed ELN (PerkinElmer Elements). However, OneNote remains a general note-taking application and has not been designed for scientific purposes. We therefore provide a quick guide to adapt OneNote to an ELN workflow that can also be adjusted to other nonscientific ELNs.


Assuntos
Armazenamento e Recuperação da Informação/métodos , Projetos de Pesquisa/tendências , Pesquisa Biomédica , Laboratórios , Reprodutibilidade dos Testes , Software , Fluxo de Trabalho
6.
Biomed Res Int ; 2019: 1386710, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31950030

RESUMO

Background: Many studies, comparing the health associated risks of electronic cigarettes with conventional cigarettes focus mainly on the common chemical compounds found between them. Aim: Review chemical compounds found exclusively in electronic cigarettes and describe their toxic effects, focusing on electronic-cigarette-only and dual electronic-cigarette and conventional cigarette users. Data Sources: Literature search was carried out using PubMed. Study Eligibility Criteria: Articles related exclusively to conventional and electronic cigarettes' chemical composition. Articles which reported to be financed from tobacco or electronic cigarettes industries, not reporting source of funding, not related to the chemical composition of electronic and conventional cigarettes and not relevant to tobacco research were excluded. Methods and Results: Chemical compounds reported in the selected studies were tabulated using the Chemical Abstracts Service registry number for chemical substances information. A total of 50 chemical compounds were exclusively reported to be present in electronic cigarettes. Crucial health risks identified were: eye, skin, and respiratory tract irritation, with almost 50% of incidence, an increment of 10% in cytotoxic effects, when compared to compounds in common with conventional cigarettes and around 11% of compounds with unknown effects to human health. Limitations: Articles reporting conflicts of interest. Conclusions and Implications of Key Findings: Despite being considered as less harmful for human health, compounds found in electronic cigarettes are still a matter of research and their effects on health are yet unknown. The use of these devices is not recommended for first time users and it is considered hazardous for dual users.

7.
Univ. med ; 60(2): 1-10, 2019. ilus, tab
Artigo em Espanhol | LILACS, COLNAL | ID: biblio-994595

RESUMO

Introducción: La enfermedad de Caffey también se ha denominado hiperostosis cortical infantil, caracterizada por la presencia de un episodio en la infancia con neoformación subperióstica en las diáfisis de huesos largos, el maxilar inferior y las clavículas. Casos clínicos: Se evaluó a un recién nacido con hallazgos clínico-radiológicos que comprendieron deformidad angular anterior del antebrazo izquierdo y miembros inferiores. La radiografía simple del nacimiento certificó la hiperostosis cortical con curvatura anterior del radio izquierdo, asociado con importante engrosamiento cortical en la diáfisis de tibias. La radiografía de control a los tres y ocho meses de edad mostró disminución de la hiperostosis cortical. El segundo caso es el de una niña de siete años que ha presentado dos exacerbaciones de hiperostosis cortical. En el examen físico presentó hiperextensibilidad de pabellones auriculares, hipermovilidad de articulaciones pequeñas y manchas de hemosiderina múltiples difusas localizadas en las piernas. El tercer caso correspondió a un lactante menor de un mes y tres días de vida, con radiografía que evidenció la hiperostosis cortical de tibias. Conclusión: La familia con neoformación diafisiaria constituye casos de interés por tratarse de un diagnóstico infrecuente en la edad pediátrica y cuya sospecha clínica puede generarse a partir de un buen examen clínico y estudio del caso índice, complementado con la interpretación de la genealogía asociado con el estudio molecular que lo corrobora.


Introduction: Also called infantile cortical hyperostosis, characterized by the presence of an episode in childhood with subperiosteal neoformation in the diaphysis of long bones, jaw and clavicles. Case description: a newborn was evaluated with clinical-radiological findings that included anterior angular deformity of the left forearm and lower limbs. The simple bone scan birth certified cortical hyperostosis with anterior curvature of the left radius, associated with important cortical thickening in the diaphysis of tibias. The control radiograph at three months of age showed a decrease in cortical hyperostosis. The second case is a seven-year-old patient who has presented two exacerbations of cortical hyperostosis. Upon physical examination, he presented hyperextensibility of auricular pavilions, hypermobility of small joints and diffuse multiple hemosiderin spots located on the legs. The third case corresponded to an infant younger than one month three days of life, with radiography that showed the cortical hyperostosis of tibias. Conclusion: We conclude that the family with diaphyseal neoformation constitute cases of interest because it is an infrequent diagnosis in the pediatric age and whose clinical suspicion can be generated from a good clinical examination and study of the index case, supplemented with the interpretation of the genealogy associated with the molecular study that corroborates it.


Assuntos
Humanos , Hiperostose Cortical Congênita , Colágeno Tipo I , Osso Cortical , Mutação
8.
BMC Med Genomics ; 12(1): 167, 2019 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-32293439

RESUMO

BACKGROUND: Since 1969, 49 cases have been presented on ring chromosome 4. All of these cases have been characterized for the loss of genetic material. The genes located in these chromosomal regions are related to the phenotype. CASE PRESENTATION: A 10-year-old Ecuadorian Mestizo girl with ring chromosome 4 was clinically, cytogenetically and molecularly analysed. Clinical examination revealed congenital anomalies, including microcephaly, prominent nose, micrognathia, low set ears, bilateral clinodactyly of the fifth finger, small sacrococcygeal dimple, short stature and mental retardation. Cytogenetic studies showed a mosaic karyotype, mos 46,XX,r(4)(p16.3q35.2)/46,XX, with a ring chromosome 4 from 75 to 79% in three studies conducted over ten years. These results were confirmed by fluorescence in situ hybridization (FISH). Loss of 1.7 Mb and gain of 342 kb in 4p16.3 and loss of 3 Mb in 4q35.2 were identified by high-resolution mapping array. CONCLUSION: Most cases with ring chromosome 4 have deletion of genetic material in terminal regions; however, our case has inv dup del rearrangement in the ring chromosome formation. Heterogeneous clinical features in all cases reviewed are related to the amount of genetic material lost or gained. The application of several techniques can increase our knowledge of ring chromosome 4 and its deviations from typical "ring syndrome."

9.
Biomed Res Int ; 2018: 9792730, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30584540

RESUMO

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer with the highest incidence worldwide. HNSCC is often diagnosed at advanced stages, incurring significant high mortality and morbidity. The use of saliva, as a noninvasive tool for the diagnosis of cancer, has recently increased. Salivary microRNAs (miRNAs) have emerged as a promising molecular tool for early diagnosis of HNSCC. The aim was to identify the differential expression of salivary miRNAs associated with HNSCC in the high altitude mestizo Ecuadorian population. Using PCR Arrays, miR-122-5p, miR-92a-3p, miR-124-3p, miR-205-5p, and miR-146a-5p were found as the most representative ones. Subsequently, miRNAs expression was confirmed in saliva samples from 108 cases and 108 controls. miR-122-5p, miR-92a-3p, miR-124-3p, and miR-146a-5p showed significant statistical difference between cases and controls with areas under the curve (AUC) of 0.73 (p < 0.001), 0.70 (p < 0.001), 0.71 (p = 0.002), and 0.66 (p = 0.008), respectively. miRNAs were also deregulated in between HNSCC localizations. A differentiated expression of miR-122-5p between oral cancer and oropharynx cancer (AUC of 0.96 p = 0.01) was found: miR-124-3p between larynx and pharynx (AUC = 0.97, p < 0.01) and miR-146a-5p between larynx, oropharynx, and oral cavity (AUC = 0.96, p = 0.01). Moreover, miR-122-5p, miR-124-3p, miR-205-5p, and miR-146a-5p could differentiate between HPV+ and HPV- (p=0.004). Finally, the expression profiles of the five miRNAs were evaluated to discriminate HNSCC patient's tumor stages (TNM 2-4). miR-122-5p differentiates TNM 2 and 3 (p = 0.002, AUC = 0.92), miR-124-3p TNM 2, 3, and 4 (p < 0.001, AUC = 98), miR-146a-5p TNM 2 and 3 (p < 0.001, AUC = 0.97), and miR-92a-3p TNM 3 (p < 0.001, AUC = 0.99). Taken together, these findings show that altered expression of miRNAs could be used as biomarkers for HNSCC diagnosis in the high altitude mestizo Ecuadorian population.


Assuntos
Neoplasias de Cabeça e Pescoço/diagnóstico , Neoplasias de Cabeça e Pescoço/metabolismo , MicroRNAs/metabolismo , Saliva/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/diagnóstico , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Altitude , Biomarcadores Tumorais/metabolismo , Estudos de Casos e Controles , Detecção Precoce de Câncer/métodos , Equador , Feminino , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica/fisiologia , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia
10.
J Med Case Rep ; 12(1): 340, 2018 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-30442194

RESUMO

BACKGROUND: Ring chromosome 15 has been associated in previous studies with different clinical characteristic such as cardiac problems, digit and musculoskeletal abnormalities, and mental and motor problems among others. Only 97 clinical cases of ring chromosome 15 syndrome have been reported since 1966 and a common phenotype for these patients has not been established. CASE PRESENTATION: The present case report describes a 15-month-old girl from the Amazon region of Ecuador, of Mestizo ancestry, who after cytogenetic tests showed a 46,XX,r(15) karyotype in more than 70% of metaphases observed. Her parents were healthy and non-related. The pregnancy was complicated and was positive for intrauterine growth retardation. Her birth weight was 1950 g, her length was 43.5 cm, and she had a head circumference of 29.3. In addition to postnatal growth delay, she had scant frontal hair, small eyes, hypertelorism, low-set of ears, flattened nasal bridge, anteverted nostrils, down-turned mouth, three café au lait spots, and delayed dentition. CONCLUSIONS: Despite the frequency of some phenotypes expressed in the different clinical cases reviewed and the present case, a common phenotype for patients with ring 15 could not be determined and it is restricted to the region of the chromosome lost during the ring formation.


Assuntos
Anormalidades Múltiplas/genética , Mapeamento Cromossômico , Cromossomos Humanos Par 15/genética , Citogenética , Transtornos do Crescimento/genética , Anormalidades Múltiplas/diagnóstico , Aberrações Cromossômicas , Feminino , Humanos , Lactente , Cariotipagem , Fenótipo , Cromossomos em Anel , Síndrome
11.
Sci Rep ; 8(1): 13978, 2018 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-30228363

RESUMO

Over the past decades, consistent studies have shown that race/ethnicity have a great impact on cancer incidence, survival, drug response, molecular pathways and epigenetics. Despite the influence of race/ethnicity in cancer outcomes and its impact in health care quality, a comprehensive understanding of racial/ethnic inclusion in oncological research has never been addressed. We therefore explored the racial/ethnic composition of samples/individuals included in fundamental (patient-derived oncological models, biobanks and genomics) and applied cancer research studies (clinical trials). Regarding patient-derived oncological models (n = 794), 48.3% have no records on their donor's race/ethnicity, the rest were isolated from White (37.5%), Asian (10%), African American (3.8%) and Hispanic (0.4%) donors. Biobanks (n = 8,293) hold specimens from unknown (24.56%), White (59.03%), African American (11.05%), Asian (4.12%) and other individuals (1.24%). Genomic projects (n = 6,765,447) include samples from unknown (0.6%), White (91.1%), Asian (5.6%), African American (1.7%), Hispanic (0.5%) and other populations (0.5%). Concerning clinical trials (n = 89,212), no racial/ethnic registries were found in 66.95% of participants, and records were mainly obtained from Whites (25.94%), Asians (4.97%), African Americans (1.08%), Hispanics (0.16%) and other minorities (0.9%). Thus, two tendencies were observed across oncological studies: lack of racial/ethnic information and overrepresentation of Caucasian/White samples/individuals. These results clearly indicate a need to diversify oncological studies to other populations along with novel strategies to enhanced race/ethnicity data recording and reporting.


Assuntos
Bancos de Espécimes Biológicos/estatística & dados numéricos , Pesquisa Biomédica , Ensaios Clínicos como Assunto/estatística & dados numéricos , Grupos de Populações Continentais/estatística & dados numéricos , Grupos Étnicos/estatística & dados numéricos , Genômica/métodos , Neoplasias/epidemiologia , Sistema de Registros/estatística & dados numéricos , Feminino , Humanos , Masculino , Neoplasias/diagnóstico , Neoplasias/terapia , Participação do Paciente , Estados Unidos/epidemiologia
12.
Biomed Res Int ; 2018: 7463832, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30065942

RESUMO

Breast cancer is the leading cause of cancer-related death among women worldwide. AKT1 encodes the kinase B alpha protein. The rs121434592, rs12881616, rs11555432, rs11555431, rs2494732, and rs3803304 single nucleotide polymorphisms have been identified in the AKT1 kinase gene. Activated AKT1 phosphorylates downstream substrates regulating cell growth, metabolism, apoptosis, angiogenesis, and drug responses. It is essential to know how breast cancer risk is associated with histopathological and immunohistochemical characteristics and genotype polymorphisms in a high altitude Ecuadorian mestizo population. This is a retrospective case-control study. DNA was extracted from 185 healthy and 91 affected women who live 2,800 meters above sea level. Genotypes were determined by genomic sequencing. We found a possible association between the noncoding intronic variant rs3803304 and breast cancer risk development: GG (odds ratio [OR] = 5.2; 95% confidence interval [CI] = 1.3-20.9; P ≤ 0.05; Q > 0.05). Regarding pathologic characteristics, we found significant risk between estrogen receptor, progesterone receptor, and HER2 status and molecular subtypes (P ≤ 0.001; Q ≤ 0.05). On the other hand, we did not find risk between variants and histopathological characteristics. Despite the small sample size, we found that the intronic variant, AKT1 rs3803304, may act as a predictive biomarker in the risk of developing breast cancer in the high altitude Ecuadorian mestizo population.


Assuntos
Altitude , Neoplasias da Mama/genética , Predisposição Genética para Doença , Proteínas Proto-Oncogênicas c-akt/genética , Biomarcadores Tumorais , Estudos de Casos e Controles , Equador , Feminino , Genótipo , Humanos , Pessoa de Meia-Idade , Oncogenes , Polimorfismo de Nucleotídeo Único , Estudos Retrospectivos , Risco
13.
Biomed Res Int ; 2017: 3507671, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28685147

RESUMO

Prostate cancer (PC) is the second most commonly diagnosed type of cancer in males with 1,114,072 new cases in 2015. The MTHFR enzyme acts in the folate metabolism, which is essential in methylation and synthesis of nucleic acids. MTHFR C677T alters homocysteine levels and folate assimilation associated with DNA damage. Androgens play essential roles in prostate growth. The SRD5A2 enzyme metabolizes testosterone and the V89L polymorphism reduces in vivo SRD5A2 activity. The androgen receptor gene codes for a three-domain protein that contains two polymorphic trinucleotide repeats (CAG, GGC). Therefore, it is essential to know how PC risk is associated with clinical features and polymorphisms in high altitude Ecuadorian mestizo populations. We analyzed 480 healthy and 326 affected men from our three retrospective case-control studies. We found significant association between MTHFR C/T (odds ratio [OR] = 2.2; P = 0.009), MTHFR C/T+T/T (OR = 2.22; P = 0.009), and PC. The SRD5A2 A49T substitution was associated with higher pTNM stage (OR = 2.88; P = 0.039) and elevated Gleason grade (OR = 3.15; P = 0.004). Additionally, patients with ≤21 CAG repeats have an increased risk of developing PC (OR = 2.99; P < 0.001). In conclusion, genotype polymorphism studies are important to characterize genetic variations in high altitude mestizo populations.


Assuntos
3-Oxo-5-alfa-Esteroide 4-Desidrogenase/genética , Proteínas de Membrana/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Mutação , Proteínas de Neoplasias/genética , Polimorfismo Genético , Neoplasias da Próstata/genética , Alelos , Equador/epidemiologia , Equador/etnologia , Humanos , Índios Sul-Americanos/etnologia , Índios Sul-Americanos/genética , Masculino , Neoplasias da Próstata/epidemiologia , Neoplasias da Próstata/etnologia
14.
Mol Med Rep ; 14(2): 1791-8, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27357524

RESUMO

Prostate cancer (PC) is the most frequently diagnosed cancer in Ecuador (15.6%). The androgen receptor gene codes for a protein that has an androgen­binding domain, DNA­binding domain and N­terminal domain, which contains two polymorphic trinucleotide repeats (CAG and GGC). The aim of the present study was to determine whether variations in the number of repetitions of CAG and GGC are associated with the pathological features and the risk of developing PC. The polymorphic CAG and GGC repeat lengths in 108 mestizo patients with PC, 148 healthy mestizo individuals, and 78 healthy indigenous individuals were examined via a retrospective case­control study. Genotypes were determined by genomic sequencing. The results demonstrated that patients with ≤21 CAG repeats have an increased risk of developing PC [odds ratio (OR)=2.99, 95% confidence interval (CI) =1.79­5.01; P<0.001]. The presence of ≤21 CAG repeats was also associated with a tumor stage ≥T2c (OR=4.75; 95% CI=1.77­12.72; P<0.005) and a Gleason score ≥7 (OR=2.9; 95% CI=1.1­7.66; P=0.03). In addition, the combination of ≤21 CAG and ≥17 GGC repeats was associated with the risk of developing PC (OR=2.42; 95% CI=1.38­4.25; P=0.002) and with tumor stage ≥T2c (OR=2.77; 95% CI=1.13­6.79; P=0.02). In conclusion, the histopathological characteristics and PC risk in Ecuadorian indigenous and mestizo populations differs in association with the CAG repeats, and the combination of CAG and GGC repeats.


Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença , Polimorfismo Genético , Neoplasias da Próstata/genética , Receptores Androgênicos/genética , Repetições de Trinucleotídeos , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais , Estudos de Casos e Controles , Ordem dos Genes , Loci Gênicos , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Razão de Chances , Neoplasias da Próstata/patologia
16.
Am J Med Sci ; 350(4): 296-301, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26351775

RESUMO

BACKGROUND: Alzheimer's disease (AD) is the most common cause of senile dementia. In Ecuador, the number of deaths caused by AD increases each year. Epidemiologically, the Ecuadorian population is composed of a mixture of several genetic backgrounds along with environmental factors, that make it unique and ideal for population studies. The main objective of this study was to determine the prevalence of Cystatin C (CST3), Cathepsin D (CTSD) and Manganese superoxide dismutase (MnSOD) amino acid-altering polymorphisms and their influence on the development of AD in the Ecuadorian population. METHODS: This is a case-control study consisting of 56 patients with AD, from the Department of Neurology at Carlos Andrade Marín Hospital. The control group (n = 55) comprised healthy elderly adults. The inclusion period was from January to August of 2012. Peripheral blood was collected from both groups for DNA extraction, polymerase chain reaction and capillary sequencing. RESULTS: There was a positive association between a CTSD polymorphism (Ala224Val) and the development of AD (odds ratio = 8.1, 95% confidence interval: 0.9-85.7; P < 0.025). However, the 3 other polymorphisms investigated did not show significant associations with AD. CONCLUSIONS: Variations in CTSD and MnSOD showed no association with the development of AD, whereas the presence of the Ala224Val polymorphism in CTSD had a positive association with the development of AD.


Assuntos
Alanina/genética , Doença de Alzheimer/genética , Catepsina D/genética , Polimorfismo de Nucleotídeo Único , Valina/genética , Idoso , Alelos , Estudos de Casos e Controles , Cistatina C/genética , Equador , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Variação Genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Prevalência , Fatores de Risco
17.
J Cell Mol Med ; 16(12): 3009-21, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22947336

RESUMO

To further contribute to the understanding of multiple myeloma, we have focused our research interests on the mechanisms by which tumour plasma cells have a higher survival rate than normal plasma cells. In this article, we study the expression profile of genes involved in the regulation and protection of telomere length, telomerase activity and apoptosis in samples from patients with monoclonal gammopathy of undetermined significance, smouldering multiple myeloma, multiple myeloma (MM) and plasma cell leukaemia (PCL), as well as several human myeloma cell lines (HMCLs). Using conventional cytogenetic and fluorescence in situ hybridization studies, we identified a high number of telomeric associations (TAs). Moreover, telomere length measurements by terminal restriction fragment (TRF) assay showed a shorter mean TRF peak value, with a consistent correlation with the number of TAs. Using gene expression arrays and quantitative PCR we identified the hTERT gene together with 16 other genes directly involved in telomere length maintenance: HSPA9, KRAS, RB1, members of the Small nucleolar ribonucleoproteins family, A/B subfamily of ubiquitously expressed heterogeneous nuclear ribonucleoproteins, and 14-3-3 family. The expression levels of these genes were even higher than those in human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs), which have unlimited proliferation capacity. In conclusion, the gene signature suggests that MM tumour cells are able to maintain stable short telomere lengths without exceeding the short critical length, allowing cell divisions to continue. We propose that this could be a mechanism contributing to MM tumour cells expansion in the bone marrow (BM).


Assuntos
Mieloma Múltiplo/genética , Mieloma Múltiplo/metabolismo , Homeostase do Telômero/genética , Telômero/genética , Proteínas 14-3-3/genética , Proteínas 14-3-3/metabolismo , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular , Instabilidade Cromossômica , Células-Tronco Embrionárias/metabolismo , Feminino , Perfilação da Expressão Gênica , Proteínas de Choque Térmico HSP70/genética , Proteínas de Choque Térmico HSP70/metabolismo , Ribonucleoproteínas Nucleares Heterogêneas/genética , Ribonucleoproteínas Nucleares Heterogêneas/metabolismo , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Leucemia Plasmocitária/genética , Leucemia Plasmocitária/metabolismo , Masculino , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Gamopatia Monoclonal de Significância Indeterminada/genética , Gamopatia Monoclonal de Significância Indeterminada/metabolismo , Plasmócitos/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas p21(ras) , Proteína do Retinoblastoma/genética , Proteína do Retinoblastoma/metabolismo , Ribonucleoproteínas Nucleolares Pequenas/genética , Ribonucleoproteínas Nucleolares Pequenas/metabolismo , Telomerase/genética , Telomerase/metabolismo , Telômero/metabolismo , Transcriptoma , Proteínas ras/genética , Proteínas ras/metabolismo
18.
Ann Surg Oncol ; 19(7): 2367-79, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22395973

RESUMO

BACKGROUND: Glioblastoma multiforme (GBM) is the most common primary tumor of the central nervous system in adults. Patients with GBM have few treatment options, and their disease is invariably fatal. Molecularly targeted agents offer the potential to improve patient treatment; however, the use of these will require a fuller understanding of the genetic changes in this complex tumor. METHODS: We analyzed a series of 32 patients with GBM with array comparative genomic hybridization in combination with gene expression analysis. We focused on the recurrent breakpoints found by spectral karyotyping (SKY). RESULTS: By SKY we identified 23 recurrent breakpoints of the 202 translocations found in GBM cases. Gains and losses were identified in chromosomal regions close to the breakpoints by array comparative genomic hybridization. We evaluated the genes located in the regions involved in the breakpoints in depth. A list of 406 genes that showed a level of expression significantly different between patients and control subjects was selected to determine their effect on survival. Genes CACNA2D3, PPP2R2B, SIK, MAST3, PROM1, and PPP6C were significantly associated with shorter survival (median 200 days vs. 450 days, P≤0.03). CONCLUSIONS: We present a list of genes located in regions of breakpoints that could be grounds for future studies to determine whether they are crucial in the pathogenesis of this type of tumor, and we provide a list of six genes associated with the clinical outcome of patients with GBM.


Assuntos
Biomarcadores Tumorais/genética , Aberrações Cromossômicas , Hibridização Genômica Comparativa , Perfilação da Expressão Gênica , Glioblastoma/genética , Glioblastoma/patologia , Cariotipagem Espectral , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Glioblastoma/mortalidade , Humanos , Cariotipagem , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Análise de Sequência com Séries de Oligonucleotídeos , Prognóstico , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Risco , Taxa de Sobrevida
19.
Blood ; 116(15): e56-65, 2010 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-20616218

RESUMO

To obtain a comprehensive genomic profile of presenting multiple myeloma cases we performed high-resolution single nucleotide polymorphism mapping array analysis in 114 samples alongside 258 samples analyzed by U133 Plus 2.0 expression array (Affymetrix). We examined DNA copy number alterations and loss of heterozygosity (LOH) to define the spectrum of minimally deleted regions in which relevant genes of interest can be found. The most frequent deletions are located at 1p (30%), 6q (33%), 8p (25%), 12p (15%), 13q (59%), 14q (39%), 16q (35%), 17p (7%), 20 (12%), and 22 (18%). In addition, copy number-neutral LOH, or uniparental disomy, was also prevalent on 1q (8%), 16q (9%), and X (20%), and was associated with regions of gain and loss. Based on fluorescence in situ hybridization and expression quartile analysis, genes of prognostic importance were found to be located at 1p (FAF1, CDKN2C), 1q (ANP32E), and 17p (TP53). In addition, we identified common homozygously deleted genes that have functions relevant to myeloma biology. Taken together, these analyses indicate that the crucial pathways in myeloma pathogenesis include the nuclear factor-κB pathway, apoptosis, cell-cycle regulation, Wnt signaling, and histone modifications. This study was registered at http://isrctn.org as ISRCTN68454111.


Assuntos
Aberrações Cromossômicas , Cromossomos Humanos/genética , Variações do Número de Cópias de DNA/genética , Mieloma Múltiplo/genética , Idoso , Deleção Cromossômica , Feminino , Rearranjo Gênico de Cadeia Pesada de Linfócito B , Humanos , Hibridização in Situ Fluorescente , Estimativa de Kaplan-Meier , Perda de Heterozigosidade , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/imunologia , Análise de Sequência com Séries de Oligonucleotídeos , Polimorfismo de Nucleotídeo Único , Prognóstico , Translocação Genética , Dissomia Uniparental
20.
Cancer Res ; 70(10): 4185-94, 2010 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-20442289

RESUMO

Sarcomas have been modeled in mice by the expression of specific fusion genes in mesenchymal stem cells (MSC), supporting the concept that MSCs might be the target initiating cell in sarcoma. In this study, we evaluated the potential oncogenic effects of p53 and/or retinoblastoma (Rb) deficiency in MSC transformation and sarcomagenesis. We derived wild-type, p53(-/-), Rb(-/-), and p53(-/-)Rb(-/-) MSC cultures and fully characterized their in vitro growth properties and in vivo tumorigenesis capabilities. In contrast with wild-type MSCs, Rb(-/-), p53(-/-), and p53(-/-)Rb(-/-) MSCs underwent in vitro transformation and showed severe alterations in culture homeostasis. More importantly, p53(-/-) and p53(-/-)Rb(-/-) MSCs, but not Rb(-/-) MSCs, were capable of tumor development in vivo after injection into immunodeficient mice. p53(-/-) or p53(-/-)Rb(-/-) MSCs originated leiomyosarcoma-like tumors, linking this type of smooth muscle sarcoma to p53 deficiency in fat tissue-derived MSCs. Sca1+ and Sca1 low/- cell populations isolated from ex vivo-established, transformed MSC lines from p53(-/-)Rb(-/-) tumors showed identical sarcomagenesis potential, with 100% tumor penetrance and identical latency, tumor weight, and histologic profile. Our findings define the differential roles of p53 and Rb in MSC transformation and offer proof-of-principle that MSCs could provide useful tools to dissect the sarcoma pathogenesis.


Assuntos
Transformação Celular Neoplásica , Leiomiossarcoma/patologia , Células-Tronco Mesenquimais/patologia , Proteína do Retinoblastoma/fisiologia , Sarcoma Experimental/patologia , Proteína Supressora de Tumor p53/fisiologia , Animais , Western Blotting , Adesão Celular , Diferenciação Celular , Movimento Celular , Proliferação de Células , Imunofluorescência , Técnicas In Vitro , Integrases/metabolismo , Leiomiossarcoma/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sarcoma Experimental/metabolismo
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