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1.
Medicina (Kaunas) ; 58(10)2022 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-36295651

RESUMO

Background and Objectives: Catalase and glutathione peroxidase (GPx) are important antioxidant enzymes that break down hydrogen peroxide (H2O2) in order to control its intracellular concentration, thus enabling its physiological role and preventing toxic effects. A lack or disruption of their function leads to the accumulation of hydrogen peroxide and the occurrence of oxidative stress. Accumulating studies have shown that the activities of key antioxidant enzymes are impaired in patients with schizophrenia. Since the published results are contradictory, and our previous studies found significantly higher erythrocyte superoxide dismutase (SOD) activity in patients with schizophrenia, the aim of this study was to determine the activity of enzymes that degrade hydrogen peroxide in the same group of patients, as well as to examine their dependence on clinical symptoms, therapy, and parameters associated with this disease. Materials and Methods: Catalase and GPx activities were determined in the erythrocytes of 68 inpatients with schizophrenia and 59 age- and gender-matched healthy controls. The clinical assessment of patients was performed by using the Positive and Negative Syndrome Scale (PANSS). The catalase activity was measured by the kinetic spectrophotometric method, while the GPx activity was determined by the commercially available Ransel test. Results: Erythrocyte catalase and GPx activities were significantly lower (p < 0.001 and p < 0.01, respectively) in subjects with schizophrenia than they were in healthy individuals. Lower catalase activity does not depend on heredity, disease onset, the number of episodes, or disease duration, while GPx activity showed significant changes in patients who had more than one episode and in those who had been suffering from the disease for over a year. Significantly lower catalase activity was noted in the PANSS(+/−) group in comparison with the PANSS(+) and PANSS(−) groups. The lowest catalase activity was found in subjects who were simultaneously treated with first- and second-generation antipsychotics; this was significantly lower than it was in those who received only one class of antipsychotics. Conclusion: These results indicate the presence of oxidative stress in the first years of clinically manifested schizophrenia and its dependence on the number of psychotic episodes, illness duration, predominant symptomatology, and antipsychotic medication.


Assuntos
Antipsicóticos , Esquizofrenia , Humanos , Glutationa Peroxidase , Catalase , Esquizofrenia/tratamento farmacológico , Peróxido de Hidrogênio/metabolismo , Peróxido de Hidrogênio/uso terapêutico , Antioxidantes/uso terapêutico , Antipsicóticos/uso terapêutico , Superóxido Dismutase , Eritrócitos , Estresse Oxidativo/fisiologia , Glutationa
2.
Medicina (Kaunas) ; 58(4)2022 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-35454346

RESUMO

Background and Objectives: Women with cervical cancer may experience depression or anxiety, influencing their quality of life and even their adherence to cancer treatments. This study aimed to explore and measure the levels of anxiety and depression in patients suffering from cervical cancer and to identify the possible predictors among known risk factors such as age, cancer stage, smoking status, number of partners, use of contraceptives, and annual gynecological visits. Materials and Methods: In total, 59 patients with cervical cancer were included. A consecutive sampling method was used to select participants in this research. Depression and anxiety were assessed using the Zung Anxiety Scale (SAS) and Zung Depression Scale (SDS). The subjects were divided into three groups, according to the stage of cancer. Results: Scores of depression and anxiety were increased in all recruited cervical cancer patients. A significant correlation was found between disease stage and the scores of depression (p = 0.002) and anxiety (p = 0.016). More severe depressive symptoms correlated to a more advanced stage of the disease. A multiple linear regression showed that disease stage and annual visits to the gynecologist are the risk factors associated with higher depression scores. Conclusions: Patients diagnosed with cervical cancer are a vulnerable group for the development of the psychiatric disorders and they require screening programs, which could potentially detect candidates for co-psychiatric and/or psychotherapeutic treatment. They demand particular attention because anxiety and depression are associated with the significant burden of the underlying disease and unfavorable survival rates.


Assuntos
Depressão , Neoplasias do Colo do Útero , Ansiedade/diagnóstico , Ansiedade/epidemiologia , Ansiedade/etiologia , Depressão/diagnóstico , Depressão/epidemiologia , Depressão/etiologia , Feminino , Humanos , Qualidade de Vida , Fatores de Risco , Neoplasias do Colo do Útero/complicações , Neoplasias do Colo do Útero/epidemiologia
3.
Clin Case Rep ; 9(7): e04530, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34306702

RESUMO

The Pilomyxoid is rare tumor in elderly population, in addition to the occurrence of an isolated lesion in spinal cord is extremely rare in non-pediatric population. Taking biopsy and subtotal resection is the starting point in essential approach for the treatment. After defining the histopathological nature of the tumor and specified that is Pilomyxoid, the next step is the combination of reoperation and adjuvant therapy.

4.
Tumour Biol ; 37(10): 13391-13401, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27460089

RESUMO

The age-specific differences in the genetic mechanisms of myeloid leukemogenesis have been observed and studied previously. However, NGS technology has provided a possibility to obtain a large amount of mutation data. We analyzed DNA samples from 20 childhood (cAML) and 20 adult AML (aAML) patients, using NGS targeted sequencing. The average coverage of high-quality sequences was 2981 × per amplicon. A total of 412 (207 cAML, 205 aAML) variants in the coding regions were detected; out of which, only 122 (62 cAML and 60 aAML) were potentially protein-changing. Our results confirmed that AML contains small number of genetic alterations (median 3 mutations/patient in both groups). The prevalence of the most frequent single gene AML associated mutations differed in cAML and aAML patient cohorts: IDH1 (0 % cAML, 5 % aAML), IDH2 (0 % cAML, 10 % aAML), NPM1 (10 % cAML, 35 % aAML). Additionally, potentially protein-changing variants were found in tyrosine kinase genes or genes encoding tyrosine kinase associated proteins (JAK3, ABL1, GNAQ, and EGFR) in cAML, while among aAML, the prevalence is directed towards variants in the methylation and histone modifying genes (IDH1, IDH2, and SMARCB1). Besides uniform genomic profile of AML, specific genetic characteristic was exclusively detected in cAML and aAML.


Assuntos
Biomarcadores Tumorais/genética , Genômica/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Leucemia Mieloide Aguda/genética , Mutação/genética , Transcriptoma , Adulto , Criança , Biologia Computacional , Feminino , Humanos , Leucemia Mieloide Aguda/classificação , Masculino , Nucleofosmina , Reação em Cadeia da Polimerase , Prognóstico
5.
Int J Mol Sci ; 17(5)2016 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-27164089

RESUMO

The existence of a potential primary central nervous system lymphoma-specific genomic signature that differs from the systemic form of diffuse large B cell lymphoma (DLBCL) has been suggested, but is still controversial. We investigated 19 patients with primary DLBCL of central nervous system (DLBCL CNS) using the TruSeq Amplicon Cancer Panel (TSACP) for 48 cancer-related genes. Next generation sequencing (NGS) analyses have revealed that over 80% of potentially protein-changing mutations were located in eight genes (CTNNB1, PIK3CA, PTEN, ATM, KRAS, PTPN11, TP53 and JAK3), pointing to the potential role of these genes in lymphomagenesis. TP53 was the only gene harboring mutations in all 19 patients. In addition, the presence of mutated TP53 and ATM genes correlated with a higher total number of mutations in other analyzed genes. Furthermore, the presence of mutated ATM correlated with poorer event-free survival (EFS) (p = 0.036). The presence of the mutated SMO gene correlated with earlier disease relapse (p = 0.023), inferior event-free survival (p = 0.011) and overall survival (OS) (p = 0.017), while mutations in the PTEN gene were associated with inferior OS (p = 0.048). Our findings suggest that the TP53 and ATM genes could be involved in the molecular pathophysiology of primary DLBCL CNS, whereas mutations in the PTEN and SMO genes could affect survival regardless of the initial treatment approach.


Assuntos
Neoplasias do Sistema Nervoso Central/genética , Linfoma Difuso de Grandes Células B/genética , Mutação , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Oncogênicas/genética
6.
Vojnosanit Pregl ; 72(3): 225-32, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25958473

RESUMO

BACKGROUND/AIM: Intramyocardial bone marrow mononuclear cells (BMMNC) implantation concomitant to coronary artery bypass grafting (CABG) surgery as an option for regenerative therapy in chronic ischemic heart failure was tested in a very few number of studies, with not consistent conclusions regarding improvement in left ventricular function, and with a follow-up period between 6 months and 1 year. This study was focused on testing of the hypothesis that intramyocardial BMMNC implantation, concomitant to CABG surgery in ischemic cardiomyopathy patients, leads to better postoperative long-term results regarding the primary end-point of conditional status-functional capacity and the secondary endpoint of mortality than CABG surgery alone in a median follow-up period of 5 years. METHODS: A total of 30 patients with ischemic cardiomyopathy and the median left venticular ejection fraction (LVEF) of 35.9 ± 4.7% were prospectively and randomly enrolled in a single center interventional, open labeled clinical trial as two groups: group I of 15 patients designated as the study group to receive CABG surgery and intramyocardial implantation of BMMNC and group II of 15 patients as the control group to receive only the CABG procedure. All the patients in both groups received the average of 3.4 ± 0.7 implanted coronary grafts, and all of them received the left internal mammary artery (LIMA) to the left anterior descending (LAD) and autovenous to other coronaries. RESULTS: The group with BMMNC and CABG had the average of 17.5 ± 3.8 injections of BMMNC suspension with the average number of injected bone marrow mononuclear cells of 70.7 ± 32.4 x 10(6) in the total average volume of 5.7 ± 1.5 mL. In this volume the average count of CD34+ and CD133+ cells was 3.96 ± 2.77 x 10(6) and 2.65 ± 1.71 x 10(6), respectively. All the patients were followed up in 2.5 to 7.5 years (median, 5 years). At the end of the follow-up period, siginificantly more patients from the group that received BMMNC were in the functional class I compared to the CABG only group (14/15 vs 5/15; p = 0.002). After 6 months the results on 6-minute walk test (6-MWT) were significantly different between the groups (435 m in the BMMNC and CABG group and 315 m in the CABG only group; p = 0.001), and continued to be preserved and improved on the final follow-up (520 m in the BMMNC and CABG group vs 343 m in the CABG only group; p < 0.001). Cardiovascular mortality was also significantly reduced in the BMMNC and CABG group (p = 0.049). CONCLUSION: Implanatation of BMMNC concomitant to CABG is a safe and feasible procedure that demonstates not only the improved functional capacity but also a reduced cardiac mortality in a 5-year follow-up in patients with ischemic cardiomyopathy scheduled for CABG surgery.


Assuntos
Transplante de Medula Óssea , Cardiomiopatias/cirurgia , Ponte de Artéria Coronária , Isquemia Miocárdica/cirurgia , Cardiomiopatias/complicações , Cardiomiopatias/mortalidade , Teste de Esforço , Feminino , Seguimentos , Insuficiência Cardíaca/classificação , Insuficiência Cardíaca/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Isquemia Miocárdica/etiologia , Isquemia Miocárdica/mortalidade , Estudos Prospectivos
7.
World J Surg Oncol ; 13: 153, 2015 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-25896818

RESUMO

BACKGROUND: We present a surgical technique and the preliminary results of breast cancer excision after insertion of a specially constructed marking needle into the tumor, controlled by intraoperative ultrasound. Resection margins were projected in six directions by ultrasound measurements, determined in relation to the needle, and resection was done in accordance with those measurements. The main objective was to obtain resection margins similar (equal) to those projected by intraoperative ultrasound (10 mm). METHODS: Detailed description of the technique is given. Thirty-two female patients undergoing breast-conserving surgery, up to 30 mm in diameter, for palpable and non-palpable invasive breast cancer, were operated on using this technique. Its feasibility was tested by analyzing the success (rate) of needle placement in the tumor, the measurements executed, and the performance of the excision. RESULTS: All stages of the technique were successfully performed to completion on all 32 patients. The procedure of needle placement and ultrasound measurement of distances took 11 min on average (between 6 and 20 min). The average distance of the tumor margin from the resection margin was 12.9 mm (2 to 30 mm, 95% confidence interval [11.9, 14.06]). There was one patient with a positive resection margin (3%). CONCLUSIONS: The technique of excising palpable and non-palpable breast cancer by intraoperative ultrasound and an especially constructed marking needle is feasible and comfortable to perform. Preliminary results imply that resection volume can be rationalized, with the same or better oncological safety.


Assuntos
Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/cirurgia , Mastectomia Segmentar/métodos , Mastectomia Segmentar/normas , Ultrassonografia Mamária/métodos , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/diagnóstico por imagem , Carcinoma Ductal de Mama/patologia , Carcinoma Ductal de Mama/cirurgia , Carcinoma Lobular/diagnóstico por imagem , Carcinoma Lobular/patologia , Carcinoma Lobular/cirurgia , Estudos de Viabilidade , Feminino , Seguimentos , Humanos , Período Intraoperatório , Invasividade Neoplásica , Estadiamento de Neoplasias , Prognóstico
9.
Thromb Res ; 134(5): 1038-45, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25262107

RESUMO

INTRODUCTION: Coronary artery thrombosis in ST-elevation myocardial infarction (STEMI) is a dynamic process often preceded by episodes of silent plaque rupture and subocclusive thrombosis. Thrombus organization is achieved by ingrowth of endothelial and smooth muscle cells. Clinical significance and impact of thrombus neovascularization on primary percutaneous coronary intervention (pPCI) outcome remain unclear. Therefore we investigated composition and neovascularization of thrombi aspirated during pPCI and their association with clinical and angiographic parameters of STEMI patients. METHODS: Aspirated thrombi retrieved from 84 STEMI patients were classified as fresh (<1 day), lytic (1-5 days) or organized (>5 days). Thrombus neovascularization was evaluated immunohistochemically using CD34, CD31 and VEGF antibodies. CD34 and CD31 immunopositive (CD34/CD31+) cells were organized as single, clusters and microvessels. VEGF positivity was graded as low or high, based on thrombus surface immunopositive area. RESULTS: CD34/CD31+ cells were present in 67% of all aspirated thrombi. Thrombus CD34/CD31 positivity was associated with previous history of angina pectoris (χ(2)=6.142, p=0.013) and lower myocardial blush grade (MBG<3, χ(2)=12.602, p<0.001). Organization of CD34/CD31+ cells showed inverse association with the extent of VEGF positivity (χ(2)=10.607, p=0.005). Fresh thrombi were associated with shorter ischemic time (U=237.5, p=0.002) and MBG 3 (χ(2)=6.379, p=0.012). CONCLUSIONS: Older thrombus age and neovascularization are associated with suboptimal myocardial perfusion in STEMI patients. Thrombus VEGF expression is inversely associated with degree of CD34+ cell organization. Therefore, neovascularization of aspirated thrombi may indicate the duration of thrombosis, coronary microcirculation status and outcome in STEMI patients.


Assuntos
Trombose Coronária/complicações , Trombose Coronária/patologia , Células Endoteliais/patologia , Infarto do Miocárdio/complicações , Neovascularização Patológica/complicações , Idoso , Antígenos CD34/análise , Circulação Coronária , Trombose Coronária/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Neovascularização Patológica/patologia , Molécula-1 de Adesão Celular Endotelial a Plaquetas/análise , Trombectomia , Fator A de Crescimento do Endotélio Vascular/análise
10.
Srp Arh Celok Lek ; 141(3-4): 223-7, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23745348

RESUMO

INTRODUCTION: Congenital aomalies of the aortic arch, although numerous and heterogeneous, occur in less than 1% of individuals at autopsies. Left aortic arch with an aberrant right subclavian artery, also called arteria lusoria dextra, is the most common anomaly of the aortic arch, occurring in 0.5-2.5% of individuals. CASE OUTLINE: We report the case of a 48-year-old man suffering from acute inferoposterior-wall ST elevation myocardial infarction successfully treated by primary percutaneous coronary intervention.Ten years ago, the patient had undergone coronary artery bypass graft surgery with the implantation of two arterial grafts- left and right internal mammary arteries on both left anterior descending and right coronary artery. After several attempts to canulate truncus brachiocephalicus, angiogram revealed the left aortic arch with the aberrant right subclavian artery. To our knowledge, this is the first described case of primary percutaneous coronary intervention via the aberrant right subclavian artery and right internal mammary artery graft with stent implantation in the infarct related lesion of the distal segment of right coronary artery. Subsequent 64-multidetector computed tomography confirmed the angiographic findings. CONCLUSION: Early recognition of congenital anomalies of the aortic arch and its great vessels, even before coronary artery bypass graft surgery, could be crucial for the urgent and successful treatment of patients with life-threatening conditions, such as ST segment elevation myocardial infarction.


Assuntos
Angioplastia Coronária com Balão , Ponte de Artéria Coronária , Artéria Torácica Interna/transplante , Artéria Subclávia/anormalidades , Aneurisma , Aorta Torácica/anormalidades , Anormalidades Cardiovasculares , Transtornos de Deglutição , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/cirurgia , Recidiva , Artéria Subclávia/transplante
11.
Cancer Res ; 71(4): 1356-61, 2011 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-21303977

RESUMO

Genome-wide association studies (GWAS) have identified 3 genomic regions, at 15q24-25.1, 5p15.33, and 6p21.33, which associate with the risk of lung cancer. Large meta-analyses of GWA data have failed to find additional associations of genome-wide significance. In this study, we sought to confirm 7 variants with suggestive association to lung cancer (P < 10(-5)) in a recently published meta-analysis. In a GWA dataset of 1,447 lung cancer cases and 36,256 controls in Iceland, 3 correlated variants on 15q15.2 (rs504417, rs11853991, and rs748404) showed a significant association with lung cancer, whereas rs4254535 on 2p14, rs1530057 on 3p24.1, rs6438347 on 3q13.31, and rs1926203 on 10q23.31 did not. The most significant variant, rs748404, was genotyped in an additional 1,299 lung cancer cases and 4,102 controls from the Netherlands, Spain, and the United States and the results combined with published GWAS data. In this analysis, the T allele of rs748404 reached genome-wide significance (OR = 1.15, P = 1.1 × 10(-9)). Another variant at the same locus, rs12050604, showed association with lung cancer (OR = 1.09, 3.6 × 10(-6)) and remained significant after adjustment for rs748404 and vice versa. rs748404 is located 140 kb centromeric of the TP53BP1 gene that has been implicated in lung cancer risk. Two fully correlated, nonsynonymous coding variants in TP53BP1, rs2602141 (Q1136K) and rs560191 (E353D) showed association with lung cancer in our sample set; however, this association did not remain significant after adjustment for rs748404. Our data show that 1 or more lung cancer risk variants of genome-wide significance and distinct from the coding variants in TP53BP1 are located at 15q15.2.


Assuntos
Cromossomos Humanos Par 15 , Neoplasias Pulmonares/genética , Polimorfismo Genético , Adenocarcinoma/epidemiologia , Adenocarcinoma/genética , Adenocarcinoma de Pulmão , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Cromossomos Humanos Par 15/genética , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Islândia/epidemiologia , Peptídeos e Proteínas de Sinalização Intracelular/genética , Neoplasias Pulmonares/epidemiologia , Masculino , Metanálise como Assunto , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Polimorfismo Genético/fisiologia , Fatores de Risco , Espanha/epidemiologia , Proteína 1 de Ligação à Proteína Supressora de Tumor p53 , Estados Unidos/epidemiologia , Adulto Jovem
12.
Sci Transl Med ; 2(62): 62ra92, 2010 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-21160077

RESUMO

Measuring serum levels of the prostate-specific antigen (PSA) is the most common screening method for prostate cancer. However, PSA levels are affected by a number of factors apart from neoplasia. Notably, around 40% of the variability of PSA levels in the general population is accounted for by inherited factors, suggesting that it may be possible to improve both sensitivity and specificity by adjusting test results for genetic effects. To search for sequence variants that associate with PSA levels, we performed a genome-wide association study and follow-up analysis using PSA information from 15,757 Icelandic and 454 British men not diagnosed with prostate cancer. Overall, we detected a genome-wide significant association between PSA levels and single-nucleotide polymorphisms (SNPs) at six loci: 5p15.33 (rs2736098), 10q11 (rs10993994), 10q26 (rs10788160), 12q24 (rs11067228), 17q12 (rs4430796), and 19q13.33 [rs17632542 (KLK3: I179T)], each with P(combined) <3 × 10(-10). Among 3834 men who underwent a biopsy of the prostate, the 10q26, 12q24, and 19q13.33 alleles that associate with high PSA levels are associated with higher probability of a negative biopsy (odds ratio between 1.15 and 1.27). Assessment of association between the six loci and prostate cancer risk in 5325 cases and 41,417 controls from Iceland, the Netherlands, Spain, Romania, and the United States showed that the SNPs at 10q26 and 12q24 were exclusively associated with PSA levels, whereas the other four loci also were associated with prostate cancer risk. We propose that a personalized PSA cutoff value, based on genotype, should be used when deciding to perform a prostate biopsy.


Assuntos
Biomarcadores Tumorais/genética , Detecção Precoce de Câncer/métodos , Marcadores Genéticos/genética , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/diagnóstico , Biomarcadores Tumorais/sangue , Humanos , Calicreínas/genética , Masculino , Polimorfismo de Nucleotídeo Único/genética , Neoplasias da Próstata/sangue , Neoplasias da Próstata/genética , Proteínas Secretadas pela Próstata/genética , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Proteínas com Domínio T/genética , Telomerase/genética
13.
PLoS Genet ; 6(7): e1001029, 2010 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-20661439

RESUMO

We used an approach that we term ancestry-shift refinement mapping to investigate an association, originally discovered in a GWAS of a Chinese population, between rs2046210[T] and breast cancer susceptibility. The locus is on 6q25.1 in proximity to the C6orf97 and estrogen receptor alpha (ESR1) genes. We identified a panel of SNPs that are correlated with rs2046210 in Chinese, but not necessarily so in other ancestral populations, and genotyped them in breast cancer case:control samples of Asian, European, and African origin, a total of 10,176 cases and 13,286 controls. We found that rs2046210[T] does not confer substantial risk of breast cancer in Europeans and Africans (OR = 1.04, P = 0.099, and OR = 0.98, P = 0.77, respectively). Rather, in those ancestries, an association signal arises from a group of less common SNPs typified by rs9397435. The rs9397435[G] allele was found to confer risk of breast cancer in European (OR = 1.15, P = 1.2 x 10(-3)), African (OR = 1.35, P = 0.014), and Asian (OR = 1.23, P = 2.9 x 10(-4)) population samples. Combined over all ancestries, the OR was 1.19 (P = 3.9 x 10(-7)), was without significant heterogeneity between ancestries (P(het) = 0.36) and the SNP fully accounted for the association signal in each ancestry. Haplotypes bearing rs9397435[G] are well tagged by rs2046210[T] only in Asians. The rs9397435[G] allele showed associations with both estrogen receptor positive and estrogen receptor negative breast cancer. Using early-draft data from the 1,000 Genomes project, we found that the risk allele of a novel SNP (rs77275268), which is closely correlated with rs9397435, disrupts a partially methylated CpG sequence within a known CTCF binding site. These studies demonstrate that shifting the analysis among ancestral populations can provide valuable resolution in association mapping.


Assuntos
Neoplasias da Mama/genética , Receptor alfa de Estrogênio/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Grupos Raciais/genética , Neoplasias da Mama/epidemiologia , Cromossomos Humanos Par 6 , Feminino , Loci Gênicos , Predisposição Genética para Doença/epidemiologia , Humanos , Polimorfismo de Nucleotídeo Único
14.
Nat Genet ; 42(8): 692-7, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20622881

RESUMO

We performed a genome-wide association study on 1,292 individuals with abdominal aortic aneurysms (AAAs) and 30,503 controls from Iceland and The Netherlands, with a follow-up of top markers in up to 3,267 individuals with AAAs and 7,451 controls. The A allele of rs7025486 on 9q33 was found to associate with AAA, with an odds ratio (OR) of 1.21 and P = 4.6 x 10(-10). In tests for association with other vascular diseases, we found that rs7025486[A] is associated with early onset myocardial infarction (OR = 1.18, P = 3.1 x 10(-5)), peripheral arterial disease (OR = 1.14, P = 3.9 x 10(-5)) and pulmonary embolism (OR = 1.20, P = 0.00030), but not with intracranial aneurysm or ischemic stroke. No association was observed between rs7025486[A] and common risk factors for arterial and venous diseases-that is, smoking, lipid levels, obesity, type 2 diabetes and hypertension. Rs7025486 is located within DAB2IP, which encodes an inhibitor of cell growth and survival.


Assuntos
Aneurisma da Aorta Abdominal/genética , Alelos , Aneurisma da Aorta Abdominal/complicações , Aneurisma da Aorta Abdominal/mortalidade , Sequência de Bases , Suscetibilidade a Doenças/complicações , Estudo de Associação Genômica Ampla , Humanos , Hipertensão/complicações , Hipertensão/genética , Islândia , Infarto do Miocárdio/complicações , Infarto do Miocárdio/genética , Países Baixos , Razão de Chances , Fatores de Risco , Proteínas Ativadoras de ras GTPase
15.
Nat Genet ; 42(5): 415-9, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20348956

RESUMO

Previously, we reported germline DNA variants associated with risk of urinary bladder cancer (UBC) in Dutch and Icelandic subjects. Here we expanded the Icelandic sample set and tested the top 20 markers from the combined analysis in several European case-control sample sets, with a total of 4,739 cases and 45,549 controls. The T allele of rs798766 on 4p16.3 was found to associate with UBC (odds ratio = 1.24, P = 9.9 x 10(-12)). rs798766 is located in an intron of TACC3, 70 kb from FGFR3, which often harbors activating somatic mutations in low-grade, noninvasive UBC. Notably, rs798766[T] shows stronger association with low-grade and low-stage UBC than with more aggressive forms of the disease and is associated with higher risk of recurrence in low-grade stage Ta tumors. The frequency of rs798766[T] is higher in Ta tumors that carry an activating mutation in FGFR3 than in Ta tumors with wild-type FGFR3. Our results show a link between germline variants, somatic mutations of FGFR3 and risk of UBC.


Assuntos
Cromossomos Humanos Par 4 , Predisposição Genética para Doença , Variação Genética , Neoplasias da Bexiga Urinária/genética , Alelos , Intervalo Livre de Doença , Europa (Continente) , Feminino , Genótipo , Humanos , Masculino , Modelos Genéticos , Mutação , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Recidiva , Risco , Fumar
16.
Nat Genet ; 40(6): 703-6, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18438407

RESUMO

We carried out a genome-wide association study of breast cancer predisposition with replication and refinement studies involving 6,145 cases and 33,016 controls and identified two SNPs (rs4415084 and rs10941679) on 5p12 that confer risk, preferentially for estrogen receptor (ER)-positive tumors (OR = 1.27, P = 2.5 x 10(-12) for rs10941679). The nearest gene, MRPS30, was previously implicated in apoptosis, ER-positive tumors and favorable prognosis. A recently reported signal in FGFR2 was also found to associate specifically with ER-positive breast cancer.


Assuntos
Neoplasias da Mama/genética , Cromossomos Humanos Par 5/genética , Predisposição Genética para Doença , Variação Genética , Receptores de Estrogênio/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Apoptose , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/patologia , Carcinoma Intraductal não Infiltrante/genética , Carcinoma Intraductal não Infiltrante/metabolismo , Carcinoma Intraductal não Infiltrante/patologia , Carcinoma Lobular/genética , Carcinoma Lobular/metabolismo , Carcinoma Lobular/patologia , Carcinoma Medular/genética , Carcinoma Medular/metabolismo , Carcinoma Medular/patologia , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Humanos , Agências Internacionais , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Prognóstico , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/metabolismo , Proteínas Ribossômicas/genética , Proteínas Ribossômicas/metabolismo
17.
Nat Genet ; 40(3): 281-3, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18264098

RESUMO

We conducted a genome-wide SNP association study on prostate cancer on over 23,000 Icelanders, followed by a replication study including over 15,500 individuals from Europe and the United States. Two newly identified variants were shown to be associated with prostate cancer: rs5945572 on Xp11.22 and rs721048 on 2p15 (odds ratios (OR) = 1.23 and 1.15; P = 3.9 x 10(-13) and 7.7 x 10(-9), respectively). The 2p15 variant shows a significantly stronger association with more aggressive, rather than less aggressive, forms of the disease.


Assuntos
Cromossomos Humanos Par 2 , Cromossomos Humanos X , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/genética , Estudos de Casos e Controles , Frequência do Gene , Testes Genéticos , Humanos , Islândia , Desequilíbrio de Ligação , Masculino , Países Baixos , Espanha , Suécia , Estados Unidos
18.
Nat Genet ; 39(7): 865-9, 2007 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-17529974

RESUMO

Familial clustering studies indicate that breast cancer risk has a substantial genetic component. To identify new breast cancer risk variants, we genotyped approximately 300,000 SNPs in 1,600 Icelandic individuals with breast cancer and 11,563 controls using the Illumina Hap300 platform. We then tested selected SNPs in five replication sample sets. Overall, we studied 4,554 affected individuals and 17,577 controls. Two SNPs consistently associated with breast cancer: approximately 25% of individuals of European descent are homozygous for allele A of rs13387042 on chromosome 2q35 and have an estimated 1.44-fold greater risk than noncarriers, and for allele T of rs3803662 on 16q12, about 7% are homozygous and have a 1.64-fold greater risk. Risk from both alleles was confined to estrogen receptor-positive tumors. At present, no genes have been identified in the linkage disequilibrium block containing rs13387042. rs3803662 is near the 5' end of TNRC9 , a high mobility group chromatin-associated protein whose expression is implicated in breast cancer metastasis to bone.


Assuntos
Neoplasias da Mama/genética , Cromossomos Humanos Par 16/genética , Cromossomos Humanos Par 2/genética , Predisposição Genética para Doença , Variação Genética , Receptores de Estrogênio/biossíntese , Neoplasias da Mama/metabolismo , Estudos de Casos e Controles , Feminino , Humanos
19.
Nat Genet ; 39(5): 631-7, 2007 May.
Artigo em Inglês | MEDLINE | ID: mdl-17401366

RESUMO

Prostate cancer is the most prevalent noncutaneous cancer in males in developed regions, with African American men having among the highest worldwide incidence and mortality rates. Here we report a second genetic variant in the 8q24 region that, in conjunction with another variant we recently discovered, accounts for about 11%-13% of prostate cancer cases in individuals of European descent and 31% of cases in African Americans. We made the current discovery through a genome-wide association scan of 1,453 affected Icelandic individuals and 3,064 controls using the Illumina HumanHap300 BeadChip followed by four replication studies. A key step in the discovery was the construction of a 14-SNP haplotype that efficiently tags a relatively uncommon (2%-4%) susceptibility variant in individuals of European descent that happens to be very common (approximately 42%) in African Americans. The newly identified variant shows a stronger association with affected individuals who have an earlier age at diagnosis.


Assuntos
Cromossomos Humanos Par 8/genética , Ligação Genética , Predisposição Genética para Doença/genética , Variação Genética , Neoplasias da Próstata/genética , Negro ou Afro-Americano , Europa (Continente) , Genômica/métodos , Haplótipos/genética , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Estados Unidos , População Branca
20.
Neuroepidemiology ; 27(4): 212-6, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-17095875

RESUMO

The aim of this case-control study was to assess the risk of developing multiple sclerosis (MS) associated with certain lifestyle factors (cigarette smoking and coffee and alcohol consumption). The study groups consisted of 210 cases with clinically proven and/or laboratory-confirmed MS (Poser's criteria) and an identical number of sex- and age-matched hospital controls. In the MS patients, cigarette smoking was significantly more frequent than in the controls (OR = 1.6, p = 0.021). A dose-response relationship between the risk of MS and both duration (years) of smoking (p = 0.027) and number of cigarettes smoked daily (p = 0.021) was observed. Coffee consumption was significantly more frequent in the MS group (OR = 1.7, p = 0.047), with dose-response relationships. The analysis of alcohol drinking showed a significant association between consumption of hard liquor per day and risk of MS (OR = 6.7, p = 0.026). In multivariate logistic regression analysis, smoking was detected to be a significant independent risk factor for MS (OR = 2.4, p = 0.004).


Assuntos
Estilo de Vida , Esclerose Múltipla/epidemiologia , Adulto , Consumo de Bebidas Alcoólicas/epidemiologia , Estudos de Casos e Controles , Café , Coleta de Dados , Interpretação Estatística de Dados , Meio Ambiente , Feminino , Humanos , Modelos Logísticos , Masculino , Fatores de Risco , Fumar/epidemiologia , Iugoslávia/epidemiologia
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