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1.
JNCI Cancer Spectr ; 4(5): pkaa042, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32923935

RESUMO

Background: Postmenopausal hormone therapy (HT) is associated with a decreased colorectal cancer (CRC) risk. As CRC is a heterogeneous disease, we evaluated whether the association of HT and CRC differs across etiologically relevant, molecularly defined tumor subtypes and tumor location. Methods: We pooled data on tumor subtypes (microsatellite instability status, CpG island methylator phenotype status, BRAF and KRAS mutations, pathway: adenoma-carcinoma, alternate, serrated), tumor location (proximal colon, distal colon, rectum), and HT use among 8220 postmenopausal women (3898 CRC cases and 4322 controls) from 8 observational studies. We used multinomial logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CIs) for the association of ever vs never HT use with each tumor subtype compared with controls. Models were adjusted for study, age, body mass index, smoking status, and CRC family history. All statistical tests were 2-sided. Results: Among postmenopausal women, ever HT use was associated with a 38% reduction in overall CRC risk (OR =0.62, 95% CI = 0.56 to 0.69). This association was similar according to microsatellite instability, CpG island methylator phenotype and BRAF or KRAS status. However, the association was attenuated for tumors arising through the serrated pathway (OR = 0.81, 95% CI = 0.66 to 1.01) compared with the adenoma-carcinoma pathway (OR = 0.63, 95% CI = 0.55 to 0.73; P het =.04) and alternate pathway (OR = 0.61, 95% CI = 0.51 to 0.72). Additionally, proximal colon tumors had a weaker association (OR = 0.71, 95% CI = 0.62 to 0.80) compared with rectal (OR = 0.54, 95% CI = 0.46 to 0.63) and distal colon (OR = 0.57, 95% CI = 0.49 to 0.66; P het =.01) tumors. Conclusions: We observed a strong inverse association between HT use and overall CRC risk, which may predominantly reflect a benefit of HT use for tumors arising through the adenoma-carcinoma and alternate pathways as well as distal colon and rectal tumors.

2.
Cancer Res ; 80(20): 4578-4590, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32816852

RESUMO

Protective associations of fruits, vegetables, and fiber intake with colorectal cancer risk have been shown in many, but not all epidemiologic studies. One possible reason for study heterogeneity is that dietary factors may have distinct effects by colorectal cancer molecular subtypes. Here, we investigate the association of fruit, vegetables, and fiber intake with four well-established colorectal cancer molecular subtypes separately and in combination. Nine observational studies including 9,592 cases with molecular subtypes for microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and somatic mutations in BRAF and KRAS genes, and 7,869 controls were analyzed. Both case-only logistic regression analyses and polytomous logistic regression analyses (with one control set and multiple case groups) were used. Higher fruit intake was associated with a trend toward decreased risk of BRAF-mutated tumors [OR 4th vs. 1st quartile = 0.82 (95% confidence interval, 0.65-1.04)] but not BRAF-wildtype tumors [1.09 (0.97-1.22); P difference as shown in case-only analysis = 0.02]. This difference was observed in case-control studies and not in cohort studies. Compared with controls, higher fiber intake showed negative association with colorectal cancer risk for cases with microsatellite stable/MSI-low, CIMP-negative, BRAF-wildtype, and KRAS-wildtype tumors (P trend range from 0.03 to 3.4e-03), which is consistent with the traditional adenoma-colorectal cancer pathway. These negative associations were stronger compared with MSI-high, CIMP-positive, BRAF-mutated, or KRAS-mutated tumors, but the differences were not statistically significant. These inverse associations for fruit and fiber intake may explain, in part, inconsistent findings between fruit or fiber intake and colorectal cancer risk that have previously been reported. SIGNIFICANCE: These analyses by colorectal cancer molecular subtypes potentially explain the inconsistent findings between dietary fruit or fiber intake and overall colorectal cancer risk that have previously been reported.

3.
Nat Commun ; 11(1): 3644, 2020 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-32686686

RESUMO

Colorectal cancer (CRC) is a biologically heterogeneous disease. To characterize its mutational profile, we conduct targeted sequencing of 205 genes for 2,105 CRC cases with survival data. Our data shows several findings in addition to enhancing the existing knowledge of CRC. We identify PRKCI, SPZ1, MUTYH, MAP2K4, FETUB, and TGFBR2 as additional genes significantly mutated in CRC. We find that among hypermutated tumors, an increased mutation burden is associated with improved CRC-specific survival (HR = 0.42, 95% CI: 0.21-0.82). Mutations in TP53 are associated with poorer CRC-specific survival, which is most pronounced in cases carrying TP53 mutations with predicted 0% transcriptional activity (HR = 1.53, 95% CI: 1.21-1.94). Furthermore, we observe differences in mutational frequency of several genes and pathways by tumor location, stage, and sex. Overall, this large study provides deep insights into somatic mutations in CRC, and their potential relationships with survival and tumor features.


Assuntos
Neoplasias Colorretais/genética , Proteínas de Neoplasias/genética , Neoplasias do Colo/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mutação INDEL , Mutação , Prognóstico , Proteína Supressora de Tumor p53/genética
4.
Cancer Genet ; 243: 1-6, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32179488

RESUMO

Inherited germline mutations in the VHL gene cause predisposition to Von Hippel-Lindau (VHL) disease. Patients exhibit benign and cancerous lesions in multiple tissues, including hemangioblastomas, clear cell renal cell carcinoma, cysts in kidneys and pancreas, and pheochromocytomas. Although pathogenic germline mutations in the VHL gene have been widely described in different populations, only a single mutation was previously reported in a family from mixed Arab-Persian ethnicity. Here, we present five Arab patients with two new and two recurrent germline mutations in the VHL gene. These mutations include three in-frame deletions and a missense mutation. Infrequent in-frame deletions in previously described patients from other populations, as well as the presence of new mutations, suggests a distinct spectrum of VHL gene mutations in Arab patients. While pulmonary manifestation has been described rarely in VHL disease, we have identified two patients with a recurrent p.Phe76del in-frame deletion exhibiting multiple nodules in lungs. We also describe a first-ever in-frame deletion in the VHL gene in a patient with VHL type 2C disease, exhibiting bilateral pheochromocytoma. Overall, the study provides an insight into the genotype-phenotype relationship of VHL disease in Arab patients and provides a comparison with previously described patients from other ethnicities.


Assuntos
Proteína Supressora de Tumor Von Hippel-Lindau/genética , Doença de von Hippel-Lindau/complicações , Doença de von Hippel-Lindau/genética , Neoplasias das Glândulas Suprarrenais/diagnóstico , Neoplasias das Glândulas Suprarrenais/genética , Glândulas Suprarrenais/diagnóstico por imagem , Adulto , Idoso , Árabes/genética , Carcinoma de Células Renais/diagnóstico , Carcinoma de Células Renais/genética , Neoplasias Cerebelares/diagnóstico , Neoplasias Cerebelares/genética , Cerebelo/diagnóstico por imagem , Pré-Escolar , Análise Mutacional de DNA , Feminino , Mutação em Linhagem Germinativa , Hemangioblastoma/diagnóstico , Hemangioblastoma/genética , Humanos , Rim/diagnóstico por imagem , Neoplasias Renais/diagnóstico , Neoplasias Renais/genética , Pulmão/diagnóstico por imagem , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Imagem por Ressonância Magnética , Masculino , Anamnese , Pessoa de Meia-Idade , Feocromocitoma/diagnóstico , Feocromocitoma/genética , Arábia Saudita , Tomografia Computadorizada por Raios X , Doença de von Hippel-Lindau/diagnóstico
5.
Gastroenterology ; 158(8): 2158-2168.e4, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32088204

RESUMO

BACKGROUND AND AIMS: The heterogeneity among colorectal tumors is probably due to differences in developmental pathways and might associate with patient survival times. We studied the relationship among markers of different subtypes of colorectal tumors and patient survival. METHODS: We pooled data from 7 observational studies, comprising 5010 patients with colorectal cancer. All the studies collected information on microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and mutations in KRAS and BRAF in tumors. Tumors with complete marker data were classified as type 1 (MSI-high, CIMP-positive, with pathogenic mutations in BRAF but not KRAS), type 2 (not MSI-high, CIMP-positive, with pathogenic mutations in BRAF but not KRAS), type 3 (not MSI-high or CIMP, with pathogenic mutations in KRAS but not BRAF), type 4 (not MSI-high or CIMP, no pathogenic mutations in BRAF or KRAS), or type 5 (MSI-high, no CIMP, no pathogenic mutations in BRAF or KRAS). We used Cox regression to estimate hazard ratios (HR) and 95% confidence intervals (CIs) for associations of these subtypes and tumor markers with disease-specific survival (DSS) and overall survival times, adjusting for age, sex, stage at diagnosis, and study population. RESULTS: Patients with type 2 colorectal tumors had significantly shorter time of DSS than patients with type 4 tumors (HRDSS 1.66; 95% CI 1.33-2.07), regardless of sex, age, or stage at diagnosis. Patients without MSI-high tumors had significantly shorter time of DSS compared with patients with MSI-high tumors (HRDSS 0.42; 95% CI 0.27-0.64), regardless of other tumor markers or stage, or patient sex or age. CONCLUSIONS: In a pooled analysis of data from 7 observational studies of patients with colorectal cancer, we found that tumor subtypes, defined by combinations of 4 common tumor markers, were associated with differences in survival time. Colorectal tumor subtypes might therefore be used in determining patients' prognoses.

6.
J Clin Med ; 7(10)2018 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-30308959

RESUMO

Estimates of muscle tissue composition may have greater prognostic value than lean body mass levels regarding health-related outcomes. Ultrasound provides a relatively low cost, safe, and accessible mode of imaging to assess muscle morphology. The purpose of this study was to determine the construct validity of muscle echogenicity as a surrogate measure of muscle quality in a sample of older, predominantly African American (AA) participants. We examined the association of rectus femoris echogenicity with mid-thigh computed tomography (CT) scan estimates of intra- and intermuscular adipose tissue (IMAT), basic metabolic parameters via blood sample analysis, muscle strength, and mobility status. This observational study was conducted at a federal medical center and included 30 community-dwelling men (age, 62.5 ± 9.2; AA, n = 24; Caucasian, n = 6). IMAT estimates were significantly associated with echogenicity (r = 0.73, p < 0.001). Echogenicity and IMAT exhibited similar associations with the two-hour postprandial glucose values and high-density lipoproteins values (p < 0.04), as well as grip and isokinetic (180°/s) knee extension strength adjusted for body size (p < 0.03). The significant relationship between ultrasound and CT muscle composition estimates, and their comparative association with key health-related outcomes, suggests that echogenicity should be further considered as a surrogate measure of muscle quality.

7.
J Pediatr Endocrinol Metab ; 31(8): 861-868, 2018 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-29949513

RESUMO

BACKGROUND: Vitamin D regulates the concentrations of calcium and phosphate in blood and promotes the growth and remodeling of bones. The circulating active form of vitamin D, 1,25-dihydroxyvitamin D, binds to the vitamin D receptor (VDR), which heterodimerizes with the retinoid X receptor to regulate the expression of target genes. Inactivating mutations in the VDR gene cause hereditary vitamin D-resistant rickets (HVDRR), a rare disorder characterized by an early onset of rickets, growth retardation, skeletal deformities, hypocalcemia, hypophosphatemia and secondary hyperparathyroidism, and in some cases alopecia. METHODS: We describe eight new HVDRR patients from four unrelated consanguineous families. The VDR gene was sequenced to identify mutations. The management of patients over a period of up to 11 years following the initial diagnosis is assessed. RESULTS: Although all patients exhibit main features of HVDRR and carry the same c.885C>A (p.Y295*) loss of function mutation in the VDR gene, there was heterogeneity of the manifestations of HVDRR-associated phenotypes and developmental milestones. These eight patients were successfully treated over a period of 11 years. All clinical symptoms were improved except alopecia. CONCLUSIONS: The study concludes that VDR sequencing and laboratory tests are essential to confirm HVDRR and to assess the effectiveness of the treatment.


Assuntos
Árabes/genética , Conservadores da Densidade Óssea/uso terapêutico , Calcitriol/uso terapêutico , Resistência a Medicamentos , Raquitismo Hipofosfatêmico Familiar/genética , Mutação , Receptores de Calcitriol/genética , Criança , Pré-Escolar , Gerenciamento Clínico , Raquitismo Hipofosfatêmico Familiar/tratamento farmacológico , Raquitismo Hipofosfatêmico Familiar/patologia , Feminino , Seguimentos , Humanos , Lactente , Masculino , Linhagem , Prognóstico
8.
Cancer Discov ; 8(6): 730-749, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29510987

RESUMO

To understand the genetic drivers of immune recognition and evasion in colorectal cancer, we analyzed 1,211 colorectal cancer primary tumor samples, including 179 classified as microsatellite instability-high (MSI-high). This set includes The Cancer Genome Atlas colorectal cancer cohort of 592 samples, completed and analyzed here. MSI-high, a hypermutated, immunogenic subtype of colorectal cancer, had a high rate of significantly mutated genes in important immune-modulating pathways and in the antigen presentation machinery, including biallelic losses of B2M and HLA genes due to copy-number alterations and copy-neutral loss of heterozygosity. WNT/ß-catenin signaling genes were significantly mutated in all colorectal cancer subtypes, and activated WNT/ß-catenin signaling was correlated with the absence of T-cell infiltration. This large-scale genomic analysis of colorectal cancer demonstrates that MSI-high cases frequently undergo an immunoediting process that provides them with genetic events allowing immune escape despite high mutational load and frequent lymphocytic infiltration and, furthermore, that colorectal cancer tumors have genetic and methylation events associated with activated WNT signaling and T-cell exclusion.Significance: This multi-omic analysis of 1,211 colorectal cancer primary tumors reveals that it should be possible to better monitor resistance in the 15% of cases that respond to immune blockade therapy and also to use WNT signaling inhibitors to reverse immune exclusion in the 85% of cases that currently do not. Cancer Discov; 8(6); 730-49. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 663.


Assuntos
Neoplasias Colorretais/genética , Neoplasias Colorretais/imunologia , Evasão Tumoral , Variações do Número de Cópias de DNA , Metilação de DNA , Mutação em Linhagem Germinativa , Antígenos HLA/genética , Humanos , Perda de Heterozigosidade , Instabilidade de Microssatélites , Via de Sinalização Wnt , Microglobulina beta-2/genética
9.
Genomics ; 106(6): 340-7, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26368860

RESUMO

Blood-based epigenome-wide association studies that aim at comparing CpG methylation between colorectal cancer (CRC) patients and controls can lead to the discovery of diagnostic or prognostic biomarkers. Numerous confounders can lead to spurious associations. We aimed to see if 5-fluorouracil (5-FU)/leucovorin chemotherapy administered to cases prior to the collection of their blood has an effect on methylation. 304 patients who received treatment and 273 who did not were profiled on the HumanMethylation450 array. Association tests were adjusted for confounders, including proxies for leukocyte cell counts. There were substantial methylation differences between these two groups that vanished once the leukocyte heterogeneity was accounted for. We observed a significant decrease of T cells in the treatment group (CD4+: p=10(-6); CD8+: p=0.036) and significant increase of NK cells (p=0.05) and monocytes (p=0.0006). 5-FU/leucovorin has no effect on global and local blood-based methylation profiles, other than through differences in the leukocyte compositions that the treatment induced.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Ilhas de CpG/genética , Metilação de DNA/efeitos dos fármacos , Adulto , Idoso , Neoplasias Colorretais/sangue , Epigênese Genética/efeitos dos fármacos , Epigenômica/métodos , Feminino , Fluoruracila/administração & dosagem , Humanos , Leucovorina/administração & dosagem , Contagem de Leucócitos , Leucócitos/efeitos dos fármacos , Leucócitos/metabolismo , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Fumar
10.
Hum Genet ; 134(11-12): 1249-1262, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26404086

RESUMO

Over 50 loci associated with colorectal cancer (CRC) have been uncovered by genome-wide association studies (GWAS). Identifying additional loci has the potential to help elucidate aspects of the underlying biological processes leading to better understanding of the pathogenesis of the disease. We re-evaluated a GWAS by excluding controls that have family history of CRC or personal history of colorectal polyps, as we hypothesized that their inclusion reduces power to detect associations. This is supported empirically and through simulations. Two-phase GWAS analysis was performed in a total of 16,517 cases and 14,487 controls. We identified rs17094983, a SNP associated with risk of CRC [p = 2.5 × 10(-10); odds ratio estimated by re-including all controls (OR) = 0.87, 95% confidence interval (CI) 0.83-0.91; minor allele frequency (MAF) = 13%]. Results were replicated in samples of African descent (1894 cases and 4703 controls; p = 0.01; OR = 0.86, 95% CI 0.77-0.97; MAF = 16 %). Gene expression data in 195 colon adenocarcinomas and 59 normal colon tissues from two different studies revealed that this locus has genotypes that are associated with RTN1 (Reticulon 1) expression (p = 0.001), a protein-coding gene involved in survival and proliferation of cancer cells which is highly expressed in normal colon tissues but has significantly reduced expression in tumor cells (p = 1.3 × 10(-8)).


Assuntos
Adenocarcinoma/genética , Cromossomos Humanos Par 14/genética , Neoplasias Colorretais/genética , Loci Gênicos , Predisposição Genética para Doença , Adenocarcinoma/epidemiologia , Idoso , Estudos de Casos e Controles , Neoplasias Colorretais/epidemiologia , Feminino , Frequência do Gene , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de Risco
11.
Nat Commun ; 6: 6326, 2015 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-25716334

RESUMO

The interplay between genetic and epigenetic variation is only partially understood. One form of epigenetic variation is methylation at CpG sites, which can be measured as methylation quantitative trait loci (meQTL). Here we report that in a panel of lymphocytes from 1,748 individuals, methylation levels at 1,919 CpG sites are correlated with at least one distal (trans) single-nucleotide polymorphism (SNP) (P<3.2 × 10(-13); FDR<5%). These trans-meQTLs include 1,657 SNP-CpG pairs from different chromosomes and 262 pairs from the same chromosome that are >1 Mb apart. Over 90% of these pairs are replicated (FDR<5%) in at least one of two independent data sets. Genomic loci harbouring trans-meQTLs are significantly enriched (P<0.001) for long non-coding transcripts (2.2-fold), known epigenetic regulators (2.3-fold), piwi-interacting RNA clusters (3.6-fold) and curated transcription factors (4.1-fold), including zinc-finger proteins (8.75-fold). Long-range epigenetic networks uncovered by this approach may be relevant to normal and disease states.


Assuntos
Neoplasias do Colo/genética , Ilhas de CpG , Metilação de DNA , Epigênese Genética , Locos de Características Quantitativas , Doenças Autoimunes/genética , Estudos de Casos e Controles , Genótipo , Humanos , Linfócitos , Polimorfismo de Nucleotídeo Único
12.
Ann Saudi Med ; 34(2): 107-14, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24894778

RESUMO

BACKGROUND AND OBJECTIVES: L-2-hydroxyglutaric aciduria is a neurometabolic disorder with autosomal recessive mode of inheritance in which patients exhibit elevated L-2-hydroxyglutaric acid in body fluids, central nervous system manifestations, and increased risk of brain tumor formation. Mutations in L2HGDH gene have been described in L-2-hydroxyglutaric aciduria patients of different ethnicities. The present study was conducted to perform a detailed clinical, imaging and genetic analysis. DESIGN AND SETTINGS: A cross-sectional clinical genetic study of 16 L-2-hydroxyglutaric aciduria patients from 4 Arab consanguineous families examined at the metabolic clinic of the hospital. PATIENTS AND METHODS: Genomic DNA was isolated from the blood of 12 patients and 10 unaffected family members, and the L2HGDH gene was sequenced. DNA sequences were compared to the L2HGDH reference sequence from GenBank. RESULTS: All patients exhibit characteristic clinical, biochemical, and imaging features of L-2-hydroxyglutaric aciduria, and 4 patients exhibited increased incidence of brain tumors. The sequencing of the L2HGDH gene revealed the c.1015delA, c.1319C > A, and c.169G > A mutations in these patients. These mutations encode for the p.Arg339AspfsX351, p.Ser440Tyr, and p.Gly57Arg changes in the L2HGDH protein, respectively. The c.169G > A mutation, which was shown to have a common origin in Italian and Portuguese patients, was also discovered in Arab patients. Finding of the homozygous c.159T SNP associated with the c.169G > A mutation in Arab patients points to an independent origin of this mutation in Arab population. CONCLUSION: The detailed description of clinical manifestations and L2HGDH mutation in this study is useful for diagnosis of L-2-hydroxyglutaric aciduria in Arab patients. While reoccurrence of an L2HGDH mutation in L-2-hydroxyglutaric aciduria patients of different ethnicity is extremely rare, the c.169G mutation has an independent origin in Arab patients. It is likely that this mutation may also be present in patients of other ethnicities.


Assuntos
Oxirredutases do Álcool/genética , Árabes/genética , Encefalopatias Metabólicas Congênitas/genética , Mutação da Fase de Leitura , Mutação de Sentido Incorreto , Adolescente , Adulto , Encefalopatias Metabólicas Congênitas/complicações , Encefalopatias Metabólicas Congênitas/etnologia , Neoplasias Encefálicas/etiologia , Criança , Consanguinidade , Estudos Transversais , Família , Feminino , Testes Genéticos , Humanos , Imagem por Ressonância Magnética/métodos , Masculino , Neuroimagem/métodos , Linhagem , Fenótipo , Adulto Jovem
13.
J Recept Signal Transduct Res ; 34(6): 476-83, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24846582

RESUMO

CONTEXT: Regulator of G-protein signaling-2 (RGS2) inhibits Gq-mediated regulation of Ca(2+) signalling in vascular smooth muscle cells (VSMC). OBJECTIVE: RGS2 knockout (RGS2KO) mice are hypertensive and show arteriolar remodeling. VSMC proliferation modulates intracellular Ca(2+) concentration [Ca(2+)]i. RGS2 involvement in VSMC proliferation had not been examined. METHODS: Thymidine incorporation and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) conversion assays measured cell proliferation. Fura-2 ratiometric imaging quantified [Ca(2+)]i before and after UTP and thapsigargin. [(3)H]-labeled inositol was used for phosphoinositide hydrolysis. Quantitative RT-PCR and confocal immunofluorescence of select Ca(2+) transporters was performed in primary aortic VSMC. RESULTS AND DISCUSSION: Platelet-derived growth factor (PDGF) increased S-phase entry and proliferation in VSMC from RGS2KO mice to a greater extent than in VSMC from wild-type (WT) controls. Consistent with differential PDGF-induced changes in Ca(2+) homeostasis, RGS2KO VSMC showed lower resting [Ca(2+)]i but higher thapsigargin-induced [Ca(2+)]i as compared with WT. RGS2KO VSMC expressed lower mRNA levels of plasma membrane Ca(2+) ATPase-4 (PMCA4) and Na(+) Ca(2+) Exchanger (NCX), but higher levels of sarco-endoplasmic reticulum Ca(2+) ATPase-2 (SERCA2). Western blot and immunofluorescence revealed similar differences in PMCA4 and SERCA2 protein, while levels of NCX protein were not reduced in RGS2KO VSMC. Consistent with decreased Ca(2+) efflux activity, (45)Ca-extrusion rates were lower in RGS2KO VSMC. These differences were reversed by the PMCA inhibitor La(3+), but not by replacing extracellular Na(+) with choline, implicating differences in the activity of PMCA and not NCX. CONCLUSION: RGS2-deficient VSMC exhibit higher rates of proliferation and coordinate plasticity of Ca(2+)-handling mechanisms in response to PDGF stimulation.


Assuntos
Sinalização do Cálcio/fisiologia , Cálcio/metabolismo , Músculo Liso Vascular/citologia , Músculo Liso Vascular/fisiologia , Miócitos de Músculo Liso/citologia , Miócitos de Músculo Liso/fisiologia , Proteínas RGS/metabolismo , Animais , Sinalização do Cálcio/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/fisiologia , Células Cultivadas , Camundongos , Camundongos Knockout , Músculo Liso Vascular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Fator de Crescimento Derivado de Plaquetas/farmacologia , Proteínas RGS/genética
14.
Int J Cancer ; 134(10): 2330-41, 2014 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-24154973

RESUMO

A locus on human chromosome 11q23 tagged by marker rs3802842 was associated with colorectal cancer (CRC) in a genome-wide association study; this finding has been replicated in case-control studies worldwide. In order to identify biologic factors at this locus that are related to the etiopathology of CRC, we used microarray-based target selection methods, coupled to next-generation sequencing, to study 103 kb at the 11q23 locus. We genotyped 369 putative variants from 1,030 patients with CRC (cases) and 1,061 individuals without CRC (controls) from the Ontario Familial Colorectal Cancer Registry. Two previously uncharacterized genes, COLCA1 and COLCA2, were found to be co-regulated genes that are transcribed from opposite strands. Expression levels of COLCA1 and COLCA2 transcripts correlate with rs3802842 genotypes. In colon tissues, COLCA1 co-localizes with crystalloid granules of eosinophils and granular organelles of mast cells, neutrophils, macrophages, dendritic cells and differentiated myeloid-derived cell lines. COLCA2 is present in the cytoplasm of normal epithelial, immune and other cell lineages, as well as tumor cells. Tissue microarray analysis demonstrates the association of rs3802842 with lymphocyte density in the lamina propria (p = 0.014) and levels of COLCA1 in the lamina propria (p = 0.00016) and COLCA2 (tumor cells, p = 0.0041 and lamina propria, p = 6 × 10(-5)). In conclusion, genetic, expression and immunohistochemical data implicate COLCA1 and COLCA2 in the pathogenesis of colon cancer. Histologic analyses indicate the involvement of immune pathways.


Assuntos
Colo/metabolismo , Neoplasias Colorretais/genética , Regulação Neoplásica da Expressão Gênica , Predisposição Genética para Doença/genética , Sistema Imunitário/metabolismo , Polimorfismo de Nucleotídeo Único , Sequência de Aminoácidos , Western Blotting , Células CACO-2 , Linhagem Celular Tumoral , Colo/patologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Predisposição Genética para Doença/classificação , Células HCT116 , Células HEK293 , Células HL-60 , Células HT29 , Células HeLa , Humanos , Sistema Imunitário/patologia , Imuno-Histoquímica , Células Jurkat , Células K562 , Células MCF-7 , Dados de Sequência Molecular , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Filogenia , RNA , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Homologia de Sequência de Aminoácidos , Células U937
15.
Eur J Pediatr ; 169(6): 661-6, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20182745

RESUMO

Autosomal recessive severe congenital neutropenia (SCN) results from a maturation arrest of granulopoiesis at the level of promyelocytes and apoptosis of myeloid cells. In SCN patients, mutations have been described in the HAX1 gene. Most of the SCN patients who carry nonsense mutations that are common to both transcript variants of the HAX1 gene also exhibit neurological deficits. This study describes an SCN patient with neurological manifestations including daily episodes of atonic seizures, learning disabilities, and developmental delay. Sequencing of the HAX1 gene of this SCN patient identified a novel nonsense c.463_464insC homozygous mutation in exon 3, which is common to both transcript variants of the gene. This mutation encodes for a p.Gln155ProfsX14 change and causes premature truncation of the HAX1 protein. Neutrophils isolated from the patient exhibited spontaneous apoptosis and loss of inner mitochondrial membrane potential, which were further enhanced upon treatment with hydrogen peroxide. This study adds to the spectrum of novel HAX1 gene mutations and disease manifestations in ethnically distinct SCN patients. Our report describes the only nonsense mutation in the HAX1 gene present in SCN patients of Arab origin.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Árabes/genética , Códon sem Sentido , Deficiências do Desenvolvimento/etiologia , Epilepsia Generalizada/etiologia , Neutropenia/congênito , Neutropenia/genética , Apoptose , Criança , Análise Mutacional de DNA , Deficiências do Desenvolvimento/etnologia , Epilepsia Generalizada/etnologia , Humanos , Masculino , Potencial da Membrana Mitocondrial , Neutropenia/complicações , Neutropenia/etnologia , Neutrófilos/metabolismo , Linhagem , Arábia Saudita
16.
J Am Coll Cardiol ; 55(2): 135-43, 2010 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-20117381

RESUMO

OBJECTIVES: The aim of this study was to examine the function of the bone morphogenic protein growth differentiation factor 5 (Gdf5) in a mouse model of myocardial infarction (MI). BACKGROUND: The Gdf5 has been implicated in skeletal development, but a potential role in the heart had not been studied. METHODS: The Gdf5-knockout (KO) and wild-type (WT) mice were subjected to permanent left anterior descending coronary artery (LAD) ligation. Cardiac pathology, function, gene expression levels, and signaling pathways downstream of Gdf5 were examined. Effects of recombinant Gdf5 (rGdf5) were tested in primary cardiac cell cultures. RESULTS: The WT mice showed increased cardiac Gdf5 levels after MI, with increased expression in peri-infarct cardiomyocytes and myofibroblasts. At 1 and 7 days after MI, no differences were observed in ischemic or infarct areas between WT and Gdf5-KO mice. However, by 28 days after MI, Gdf5-KO mice exhibited increased infarct scar expansion and thinning with decreased arteriolar density compared with WT. The Gdf5-KO hearts also displayed increased left ventricular dilation, with decreased contractility after MI. At 4 days after MI, Gdf5-KO mice exhibited increased cardiomyocyte apoptosis and decreased expression of anti-apoptotic genes Bcl2 and Bcl-xL compared with WT. Unexpectedly, Gdf5-KO hearts displayed increased Smad 1/5/8 phosphorylation but decreased p38-mitogen-activated protein kinase (MAPK) phosphorylation versus WT. The latter was associated with increased collagen gene (Col1a1, Col3a1) expression and fibrosis. In cultures, rGdf5 induced p38-MAPK phosphorylation in cardiac fibroblasts and Smad-dependent increases in Bcl2 and Bcl-xL in cardiomyocytes. CONCLUSIONS: Increased expression of Gdf5 after MI limits infarct scar expansion in vivo. These effects might be mediated by Gdf5-induced p38-MAPK signaling in fibroblasts and Gdf5-driven Smad-dependent pro-survival signaling in cardiomyocytes.


Assuntos
Fator 5 de Diferenciação de Crescimento/fisiologia , Infarto do Miocárdio/patologia , Animais , Apoptose , Técnicas de Cultura de Células , Modelos Animais de Doenças , Fibroblastos/efeitos dos fármacos , Fator 5 de Diferenciação de Crescimento/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Infarto do Miocárdio/etiologia , Infarto do Miocárdio/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Proteínas Recombinantes/farmacologia , Proteínas Smad Reguladas por Receptor/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
17.
Neuropsychopharmacology ; 35(6): 1315-24, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20107430

RESUMO

Antipsychotic-induced weight gain has emerged as a serious complication in the treatment of patients with atypical antipsychotic drugs. The cannabinoid receptor 1 (CNR1) is expressed centrally in the hypothalamic region and associated with appetite and satiety, as well as peripherally. An antagonist of CNR1 (rimonabant) has been effective in causing weight loss in obese patients indicating that CNR1 might be important in antipsychotic-induced weight gain. Twenty tag SNPs were analyzed in 183 patients who underwent treatment (with either clozapine, olanzapine, haloperidol, or risperidone) for chronic schizophrenia were evaluated for antipsychotic-induced weight gain for up to 14 weeks. The polymorphism rs806378 was nominally associated with weight gain in patients of European ancestry treated with clozapine or olanzapine. 'T' allele carriers (CT+TT) gained more weight (5.96%), than the CC carriers (2.76%, p=0.008, FDR q-value=0.12). This translated into approximately 2.2 kg more weight gain in patients carrying the T allele than the patients homozygous for the CC genotype (CC vs CT+TT, 2.21+/-4.51 vs 4.33+/-3.89 kg; p=0.022). This was reflected in the allelic analysis (C vs T allele, 3.84 vs 5.83%, p=0.035). We conducted electrophoretic mobility shift assays which showed that the presence of the T allele created a binding site for arylhydrocarbon receptor translocator (ARNT), a member of the basic helix-loop-helix/Per-Arnt-Sim protein family. In this study, we provide evidence that the CNR1 gene may be associated with antipsychotic-induced weight gain in chronic schizophrenia patients. However, these observations were made in a relatively small patient population; therefore these results need to be replicated in larger sample sets.


Assuntos
Antipsicóticos/efeitos adversos , Obesidade/induzido quimicamente , Obesidade/genética , Polimorfismo Genético/genética , Receptor CB1 de Canabinoide/genética , Ganho de Peso/efeitos dos fármacos , Adolescente , Adulto , Translocador Nuclear Receptor Aril Hidrocarboneto/metabolismo , Análise Mutacional de DNA , Grupo com Ancestrais do Continente Europeu , Feminino , Frequência do Gene/efeitos dos fármacos , Predisposição Genética para Doença/genética , Testes Genéticos , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/metabolismo , Ligação Proteica/genética , Ganho de Peso/genética , Adulto Jovem
18.
Int Arch Allergy Immunol ; 151(2): 149-54, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-19752569

RESUMO

BACKGROUND: Autosomal dominant hereditary angioedema (HAE) results in episodes of subcutaneous edema in any body part and/or submucosal edema of the upper respiratory or gastrointestinal tracts. This disorder is caused by mutations in the C1NH gene, many of which have been described primarily in European patients. However, the genetic cause of HAE in Middle Eastern Arab patients has not yet been determined. METHODS: Four unrelated Arab families, in which 15 patients were diagnosed with HAE, were studied. DNA from 13 patients was analyzed for mutations in the C1NH gene by DNA sequencing. RESULTS: Three novel and 2 recurrent mutations were identified in the C1NH gene of HAE patients. In family 1, the patient was heterozygous for a novel c.856C>T and a recurrent c.1361T>A missense mutation encoding for p.Arg264Cys and p.Val432Glu, respectively. In patients from family 2, a novel c.509C>T missense mutation encoding for a p.Ser148Phe was identified. In patients from family 3, a novel c.1142delC nonsense mutation encoding for a p.Ala359AlafsX15 was discovered. In family 4, a recurrent c.1397G>A missense mutation encoding for a p.Arg444His was present. CONCLUSION: This is the first ever report of C1NH gene mutations in Middle Eastern Arab patients. Our study suggests that, despite the numerous existing mutations in the C1NH gene, there are novel and recurrent mutations in HAE patients of non-European origin. We conclude that the spectrum of C1NH gene mutations in HAE patients is wider due to the likely presence of novel and recurrent mutations in patients of other ethnicities.


Assuntos
Árabes/genética , Proteínas Inativadoras do Complemento 1/genética , Angioedema Hereditário Tipos I e II/genética , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Códon sem Sentido/genética , Proteínas Inativadoras do Complemento 1/metabolismo , Proteína Inibidora do Complemento C1 , Complemento C3/metabolismo , Complemento C4/metabolismo , Danazol/uso terapêutico , Feminino , Angioedema Hereditário Tipos I e II/sangue , Angioedema Hereditário Tipos I e II/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Oriente Médio , Mutação de Sentido Incorreto/genética , Linhagem , Adulto Jovem
19.
Eur J Pediatr ; 168(12): 1467-71, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19259699

RESUMO

UNLABELLED: Deficiency of fructose-1,6-bisphosphatase (FBP) results in impaired gluconeogenesis, which is characterized by episodes of hyperventilation, apnea, hypoglycemia, and metabolic and lactic acidosis. This autosomal recessive disorder is caused by mutations in the FBP1 gene, which encodes for fructose-1,6-bisphosphatase 1 (FBP1). Although FBP1 gene mutations have been described in FBP-deficient individuals of various ethnicities, there has been limited investigation into the genetics of this disorder in Arab patients. This study employed five consanguineous Arab families, in which 17 patients were clinically diagnosed with FBP deficiency. Seven patients and six carrier parents were analyzed for mutations in the FBP1 gene. DNA sequencing of the FBP1 gene identified two novel mutations in these families. A novel six nucleotide repetitive insertion, c114_119dupCTGCAC, was identified in patients from three families. This mutation encodes for a duplication of two amino acids (p.Cys39_Thr40dup) in the N-terminal domain of FBP1. A novel nonsense c.841G>T mutation encoding for a p.Glu281X truncation in the active site of FBP1 was discovered in patients from two families. The newly identified mutations in the FBP1 gene are predicted to produce FBP1 deficiency. These mutations are the only known genetic causes of FBP deficiency in Arab patients. The p.Cys39_Thr40dup is the first reported amino acid duplication in FBP deficiency patients. CONCLUSION: This study provides a strong rationale for genetic testing of FBP deficient patients of Arab ethnicity for recurrent or novel mutations in the FBP1 gene.


Assuntos
Deficiência de Frutose-1,6-Difosfatase/etnologia , Deficiência de Frutose-1,6-Difosfatase/genética , Adulto , Consanguinidade , Análise Mutacional de DNA , Feminino , Humanos , Mutagênese Insercional , Mutação , Linhagem
20.
Cases J ; 2(1): 62, 2009 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-19149905

RESUMO

Hydatid disease is a considerable health problem worldwide. Two case reports of relatively uncommon presentations of the disease are presented.The first case is that of a 25 years old female from region of Afghanistan that borders Pakistan's Baluchistan province. She presented with cough, hemoptysis and left hypochondrium pain due to concurrent involvement of the right lung and the spleen due to hydatid disease, whilst sparing the liver.The second case is that of a 32 years male from the same region of Afghanistan as above. He presented with upper abdominal discomfort, postprandial vomiting and jaundice due to a hydatid cyst involving the head of the pancreas only.

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