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1.
Gut ; 68(5): 854-865, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30661054

RESUMO

OBJECTIVE: Diverticular disease is a common complex disorder characterised by mucosal outpouchings of the colonic wall that manifests through complications such as diverticulitis, perforation and bleeding. We report the to date largest genome-wide association study (GWAS) to identify genetic risk factors for diverticular disease. DESIGN: Discovery GWAS analysis was performed on UK Biobank imputed genotypes using 31 964 cases and 419 135 controls of European descent. Associations were replicated in a European sample of 3893 cases and 2829 diverticula-free controls and evaluated for risk contribution to diverticulitis and uncomplicated diverticulosis. Transcripts at top 20 replicating loci were analysed by real-time quatitative PCR in preparations of the mucosal, submucosal and muscular layer of colon. The localisation of expressed protein at selected loci was investigated by immunohistochemistry. RESULTS: We discovered 48 risk loci, of which 12 are novel, with genome-wide significance and consistent OR in the replication sample. Nominal replication (p<0.05) was observed for 27 loci, and additional 8 in meta-analysis with a population-based cohort. The most significant novel risk variant rs9960286 is located near CTAGE1 with a p value of 2.3×10-10 and 0.002 (ORallelic=1.14 (95% CI 1.05 to 1.24)) in the replication analysis. Four loci showed stronger effects for diverticulitis, PHGR1 (OR 1.32, 95% CI 1.12 to 1.56), FAM155A-2 (OR 1.21, 95% CI 1.04 to 1.42), CALCB (OR 1.17, 95% CI 1.03 to 1.33) and S100A10 (OR 1.17, 95% CI 1.03 to 1.33). CONCLUSION: In silico analyses point to diverticulosis primarily as a disorder of intestinal neuromuscular function and of impaired connective fibre support, while an additional diverticulitis risk might be conferred by epithelial dysfunction.


Assuntos
Doenças do Colo/genética , Tecido Conjuntivo/fisiologia , Doenças Diverticulares/genética , Epitélio/fisiologia , Estudo de Associação Genômica Ampla , Junção Neuromuscular/fisiologia , Adulto , Idoso , Estudos de Casos e Controles , Doenças do Colo/patologia , Bases de Dados Genéticas , Doenças Diverticulares/patologia , Feminino , Predisposição Genética para Doença/genética , Humanos , Masculino , Pessoa de Meia-Idade , Reino Unido
2.
Biosci Rep ; 39(1)2019 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-30559147

RESUMO

Purpose: Melanosis coli (MC) is a disorder of pigmentation of the wall of the colon, often identified at the time of colonoscopy. The aim of the present study is to identify candidate biomarkers for MC. Methods: The transcriptome data for MC (GSE78933) with five MC tissues and five corresponding normal tissues is obtained from the NCBI Gene Expression Omnibus (GEO) database. R/Bioconductor package limma was used to screen differently expressed genes (DEGs). ClueGO of cytoscape was applied for Gene Ontology (GO) functional and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment. Based on STRING V10 database, protein-protein interaction (PPI) network was constructed. The pathological tissue and normal tissue from 23 MC patients and 23 controls were collected, respectively. The relative expression of hub nodes was detected by qRT-PCR and Western blot. For regulating the expression of these genes, overexpression vector was constructed or siRNA transfection was used. Finally, apoptosis was detected by flow cytometry. Results: Total 1342 DEGs were screened, including 786 up-regulated and 556 down-regulated genes. These genes were mainly enriched in stimulatory C-type lectin receptor signaling pathway, polysaccharide biosynthetic process, intracellular, and oxidative phosphorylation. PPI network was then constructed with 426 DEGs and 895 interactions. Thereinto, G-protein subunit γ 5 (GNG5), lysophosphatidic acid receptor 3 (LPAR3), mitogen-activated protein kinase 8 (MAPK8), NHP2L1, proteasome 26S subunit, ATPase 6 (PSMC6), and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit ß (PIK3CB) were hub nodes with higher degree. RT-PCR and Western blot results showed that GNG5, LPAR3, MAPK8, and PSMC6 were differently expressed with significance. The expression of these screened genes is also related with cell apoptosis. Conclusion: GNG5, LPAR3, MAPK8, and PSMC6 might be candidate biomarkers associated with apoptosis in MC.


Assuntos
ATPases Associadas a Diversas Atividades Celulares/genética , Doenças do Colo/genética , Subunidades gama da Proteína de Ligação ao GTP/genética , Melanose/genética , Proteína Quinase 8 Ativada por Mitógeno/genética , Complexo de Endopeptidases do Proteassoma/genética , Receptores de Ácidos Lisofosfatídicos/genética , ATPases Associadas a Diversas Atividades Celulares/metabolismo , Apoptose/fisiologia , Biomarcadores , Estudos de Casos e Controles , Subunidades gama da Proteína de Ligação ao GTP/metabolismo , Humanos , Proteína Quinase 8 Ativada por Mitógeno/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Mapas de Interação de Proteínas , Receptores de Ácidos Lisofosfatídicos/metabolismo , Transcriptoma
3.
Sci Rep ; 8(1): 6646, 2018 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-29703930

RESUMO

We demonstrate the application of whole exome sequencing to discover the rare variants for congenital pouch colon, acronymed CPC. For 18 affected individuals in a total of 64 samples, we sequenced coding regions to a mean coverage of 100×. A sufficient depth of ca. 94% of targeted exomes was achieved. Filtering against the public SNP/variant repositories, we identified a host of candidate genes, EPB41L4A and CTC1 associated with colon, neural/brain muscles and Dyskeratosis Congenita maladies. Furthermore, the stop gain mutations in the form of JAG1,OR5AR1,SLC22A24,PEX16,TSPAN32,TAF1B,MAP2K3 and SLC25A19 appears to be localized to Chromosomes 2, 11, 17 and 20 in addition to the three stop lost mutants across three genes, viz. OAS2, GBA3 and PKD1L2 affecting the colon tissue. While our results have paved way for transcendence of monogenic traits in identifying the genes underlying rare genetic disorders, it will provide helpful clues for further investigating genetic factors associated with anorectal anomalies, particularly CPC.


Assuntos
Colo/anormalidades , Doenças do Colo/congênito , Doenças do Colo/genética , Predisposição Genética para Doença , Exoma , Feminino , Humanos , Recém-Nascido , Masculino , Sequenciamento Completo do Exoma
4.
J Clin Invest ; 128(5): 1919-1936, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29629900

RESUMO

Mucosal-associated invariant T (MAIT) cells are a unique innate-like T cell subset that responds to a wide array of bacteria and yeast through recognition of riboflavin metabolites presented by the MHC class I-like molecule MR1. Here, we demonstrate using MR1 tetramers that recipient MAIT cells are present in small but definable numbers in graft-versus-host disease (GVHD) target organs and protect from acute GVHD in the colon following bone marrow transplantation (BMT). Consistent with their preferential juxtaposition to microbial signals in the colon, recipient MAIT cells generate large amounts of IL-17A, promote gastrointestinal tract integrity, and limit the donor alloantigen presentation that in turn drives donor Th1 and Th17 expansion specifically in the colon after BMT. Allogeneic BMT recipients deficient in IL-17A also develop accelerated GVHD, suggesting MAIT cells likely regulate GVHD, at least in part, by the generation of this cytokine. Indeed, analysis of stool microbiota and colon tissue from IL-17A-/- and MR1-/- mice identified analogous shifts in microbiome operational taxonomic units (OTU) and mediators of barrier integrity that appear to represent pathways controlled by similar, IL-17A-dependent mechanisms. Thus, MAIT cells act to control barrier function to attenuate pathogenic T cell responses in the colon and, given their very high frequency in humans, likely represent an important population in clinical BMT.


Assuntos
Transplante de Medula Óssea , Colo/imunologia , Doenças do Colo/imunologia , Doença Enxerto-Hospedeiro/imunologia , Células T Invariáveis Associadas à Mucosa/imunologia , Células Th17/imunologia , Aloenxertos , Animais , Colo/patologia , Doenças do Colo/genética , Doenças do Colo/patologia , Feminino , Doença Enxerto-Hospedeiro/genética , Doença Enxerto-Hospedeiro/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Células T Invariáveis Associadas à Mucosa/patologia , Células Th17/patologia
5.
World J Gastroenterol ; 23(16): 2819-2825, 2017 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-28522900

RESUMO

RNA sequencing is the use of high throughput next generation sequencing technology to survey, characterize, and quantify the transcriptome of a genome. RNA sequencing has been used to analyze the pathogenesis of several malignancies such melanoma, lung cancer, and colorectal cancer. RNA sequencing can identify differential expression of genes (DEG's), mutated genes, fusion genes, and gene isoforms in disease states. RNA sequencing has been used in the investigation of several colorectal diseases such as colorectal cancer, inflammatory bowel disease (ulcerative colitis and Crohn's disease), and irritable bowel syndrome.


Assuntos
Doenças do Colo/diagnóstico , Doenças do Colo/genética , Sequenciamento de Nucleotídeos em Larga Escala , RNA/genética , Análise de Sequência de RNA/métodos , Biomarcadores Tumorais/genética , Colite Ulcerativa/diagnóstico , Colite Ulcerativa/genética , Doenças do Colo/terapia , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/genética , Doença de Crohn/diagnóstico , Doença de Crohn/genética , Marcadores Genéticos , Predisposição Genética para Doença , Humanos , Síndrome do Intestino Irritável/diagnóstico , Síndrome do Intestino Irritável/genética , Fenótipo , Valor Preditivo dos Testes , Prognóstico , RNA Neoplásico/genética , Fatores de Risco
7.
Rinsho Ketsueki ; 58(1): 20-25, 2017.
Artigo em Japonês | MEDLINE | ID: mdl-28190860

RESUMO

A 13-year-old boy was admitted to our hospital because of persistent diarrhea, abdominal pain, and bloody stools. The patient had experienced repeated hospitalizations for the treatment of respiratory infections since early childhood. Colonoscopic and pathological studies led to a diagnosis of gut-associated T-cell lymphoproliferative disease (T-cell LPD). Laboratory data showed T-lymphocytopenia (492/µl), increased serum IgG levels (1,984 mg/dl), and low serum antibody titers for specific pathogens. Combined immunodeficiency accompanied by T-LPD suggested the diagnosis of activated PI3Kδ syndrome (APDS). Genetic analyses identified a heterozygous mutation of the PIK3CD gene (c.1573 G to A p.Glu525Lys). Although prednisolone and cyclosporine therapy has controlled the T-cell LPD, this patient awaits allogeneic hematopoietic cell transplantation to achieve a complete cure of his APDS.


Assuntos
Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Doenças do Colo/diagnóstico por imagem , Transtornos Linfoproliferativos/diagnóstico por imagem , Linfócitos T , Adolescente , Classe I de Fosfatidilinositol 3-Quinases/genética , Doenças do Colo/genética , Ativação Enzimática , Humanos , Transtornos Linfoproliferativos/genética , Masculino , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons
8.
Clin J Gastroenterol ; 9(5): 298-301, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27412026

RESUMO

We report a 54-year-old female patient with myelodysplastic syndrome (MDS) associated with trisomy 8, who had multiple colonic ulcers. The patient had been diagnosed as having MDS of refractory cytopenia with trisomy 8 10 years previously. She underwent colonoscopy for abdominal pain, which revealed severe circumferential stenosis with multiple ulcers in the ileocecal region and a discrete excavating ulcer in the transverse colon. The patient had been free from any dermatological, oral, genital or ocular symptoms suggestive of Behçet's disease (BD). A diagnosis of multiple colonic ulcers associated with MDS with trisomy 8 was thus suggested. Follow-up colonoscopies 5 and 6 years later revealed progression of the ileocecal stenosis to a circumferential ulcer, while the ulcer in the transverse colon had not changed. Because our patient lacked extraintestinal symptoms of BD, trisomy 8 was presumed to be responsible for her colonic ulcers.


Assuntos
Doenças do Colo/genética , Síndromes Mielodisplásicas/genética , Trissomia , Úlcera/genética , Doenças do Ceco/genética , Cromossomos Humanos Par 8 , Doenças do Colo/diagnóstico , Colonoscopia , Progressão da Doença , Feminino , Seguimentos , Humanos , Doenças do Íleo/genética , Obstrução Intestinal/genética , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/diagnóstico , Úlcera/diagnóstico
9.
Neurochem Res ; 40(6): 1274-82, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25968478

RESUMO

This project was focused on the study of the effect of the different acupoints on visceral hypersensitivity and the correlation with the brain-gut axis. By using a mouse model of zymosan-induced colorectal hypersensitivity, and observing the response of hypersensitivity model to colorectal distension stimulation in acupuncture at different acupoints, we selected the specific acupoints. With immunohistochemical staining method, we observed c-fos expression, distribution and changes after acupuncture on sensory pathway, including colorectum, spinal dorsal horn and different regions of brain center in the model with colorectal distension stimulation, and evaluated the acupuncture effect on brain-gut axis. The results revealed that the effectiveness of acupuncture for alleviating visceral hypersensitivity was different at individual acupoint, meaning Tianshu (ST25), Zusanli (ST36) and Shangjuxu (ST37) > Quchi (LI11) and Dachangshu (BL25) > Ciliao (BL32). C-fos expression was concentrated in anterior cingulate cortex, hypothalamus, spinal dorsal horn and colorectum in model of zymosan-induced colorectal hypersensitivity and it was down-regulated after acupuncture. The results demonstrates that the acupoint specificity presents in acupuncture for relieving visceral hypersensitivity and the effects are more predominated at the acupoints on stomach meridian innervated by the same or adjacent spinal ganglion segments. The model of zymosan-induced colorectal hypersensitivity can be the animal model simulating brain-gut interaction.


Assuntos
Pontos de Acupuntura , Terapia por Acupuntura/métodos , Encéfalo/fisiopatologia , Doenças do Colo/terapia , Gastroenteropatias/fisiopatologia , Hiperalgesia/terapia , Doenças Retais/terapia , Animais , Doenças do Colo/induzido quimicamente , Doenças do Colo/genética , Eletromiografia , Expressão Gênica , Genes fos , Hiperalgesia/induzido quimicamente , Hiperalgesia/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estimulação Física , Doenças Retais/induzido quimicamente , Doenças Retais/genética , Zimosan
10.
Ann Surg ; 259(6): 1132-7, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24814505

RESUMO

OBJECTIVE: To determine if single nuclear polymorphisms (SNPs) in the TFNSF15 gene play a role in patients requiring surgery for diverticulitis. BACKGROUND: A role for a genetic predisposition in diverticulitis is suggested by its association with hereditary connective tissue disorders, youthful onset in some patients, and the observation of families with multiple affected individuals. The TNFSF15 gene has been associated with other inflammatory diseases affecting the colon such as medically refractory ulcerative colitis (UC), aggressive Crohn's disease (CD), and pouchitis after restorative proctocolectomy. METHODS: In the discovery phase of this study, 21 sporadic surgical diverticulitis (SD) patients (9 female, mean age = 52 ± 5) and 5 individuals from a single family with surgically managed diverticulitis [familial diverticulitis (FD), 4 female, mean age = 51.1 ± 7] were studied. SD patients were age and sex matched with 3 separate groups of healthy, CD and UC control patients. All patients were genotyped for 5 known TNFSF15-associated SNPs. The SNP discovered to be associated with diverticulitis (rs7848647) was then confirmed in a separate test group composed of 34 additional patients (20 female, mean age 57.7 ± 2) who also underwent surgical treatment for diverticulitis. These patients were age matched to a new control cohort of patients having no history of diverticulitis (26 female). Patients were genotyped using a TaqMan assay. In the discovery phase, logistical regression on matched subjects was performed to determine an association of TNFSF SNP with diverticulitis versus the control groups. In the test phase, significance for the rs7848647 SNP was assessed by the Fischer's exact test. RESULTS: In the discovery phase, the TNFSF15 SNP rs7848647 was significantly associated with SD (p = 0.0003) versus all control groups studied. The risk allele for this SNP (G substituted for A) was found in all SD patients. The homozygous GG allele was found in 62% (13/21) of SD patients versus only 5% (1/21) of healthy controls (p = 0.001) and 24% (10/42) of all UC + CD controls (p = 0.002). All 5 members of the FD cohort were homozygous for the at-risk "G" allele. In the test group, the homozygous GG genotype was found in 56% of SD patients compared with 17% of healthy controls (p = 0.006). Risk of SD seemed to increase with number of the G alleles with 8% of SD patients having AA homozygosity, 35% of SD patients having AG heterozygosity, and 56% of SD patients having GG homozygosity. CONCLUSIONS: The SNP rs7848647 associated with the TNFSF15 gene is associated with surgical diverticulitis. This finding suggests a fundamental role for TNFSF15, a T-cell receptor gene involved in T-cell maturation, in the pathophysiology of diverticulitis requiring surgery. This SNP may be a marker of diverticular disease severity that might assist in surgical decision making.


Assuntos
Colectomia/métodos , Doenças do Colo/genética , DNA/genética , Diverticulite/genética , Polimorfismo de Nucleotídeo Único , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/genética , Adulto , Idoso , Alelos , Doenças do Colo/cirurgia , Diverticulite/cirurgia , Feminino , Seguimentos , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Estudos Retrospectivos
11.
Int J Tuberc Lung Dis ; 17(5): 662-8, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23575333

RESUMO

BACKGROUND: Intestinal tuberculosis (TB) and Crohn's disease closely resemble each other clinically and morphologically. Little is known of cytokine regulation in intestinal TB. OBJECTIVE: To compare cytokine gene expression in colonic mucosa and peripheral blood mononuclear cells (PBMC) in TB with that in Crohn's disease. METHODS: Biopsies were obtained from normal and ulcerated colonic mucosa of 12 intestinal TB and 11 Crohn's disease patients, and PBMC from 15 intestinal TB and 12 Crohn's disease patients and 11 healthy volunteers. RNA was extracted, and the expression of selected cytokines, chemokines and pattern recognition receptors quantified by reverse transcriptase real-time polymerase chain reaction using SYBR green. RESULTS: The mRNA expression of interleukin-8 (IL-8), induced protein-10, tumour necrosis factor-alpha, IL-23 p19 and IL-12 p40, and Toll-like receptors (TLR) 1 and 2 in the ulcerated mucosa was increased in both intestinal TB and Crohn's disease. Expression of growth-related oncogene-alpha was increased in intestinal TB, while expression of interferon-gamma (IFN-) and TLR 4, 5 and 9 was increased in Crohn's disease. Expression of RANTES (regulated upon activation, normal T-cell expressed and secreted) was decreased in Crohn's disease. Secretion of IFN- or IL-10 from PBMC was not significantly altered in either disease. PBMC mRNA expression of IL-1, IL-6 and IL-8 mRNA was upregulated in Crohn's disease, while that of IL-17 was upregulated in intestinal TB. CONCLUSIONS: Cytokine gene expression patterns in intestinal mucosa and PBMC of intestinal TB were remarkably similar to Crohn's disease, and demonstrated innate immune activation and T-helper 1 polarisation.


Assuntos
Colo/imunologia , Doenças do Colo/imunologia , Doença de Crohn/imunologia , Citocinas/genética , Mucosa Intestinal/imunologia , Leucócitos Mononucleares/imunologia , Tuberculose Gastrointestinal/imunologia , Adulto , Idoso , Biópsia , Estudos de Casos e Controles , Colo/microbiologia , Doenças do Colo/genética , Doenças do Colo/microbiologia , Colonoscopia , Doença de Crohn/genética , Citocinas/sangue , Feminino , Regulação da Expressão Gênica , Humanos , Imunidade Inata/genética , Mucosa Intestinal/microbiologia , Masculino , Pessoa de Meia-Idade , Mycobacterium tuberculosis/isolamento & purificação , RNA Mensageiro/análise , RNA Mensageiro/sangue , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Th1/imunologia , Tuberculose Gastrointestinal/genética , Tuberculose Gastrointestinal/microbiologia , Adulto Jovem
12.
J Dig Dis ; 14(8): 417-24, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23551431

RESUMO

OBJECTIVE: To determine the hedgehog (Hh) signaling pathway correlated with the development of colon cancer and melanosis coli. METHODS: Protein and mRNA levels of Hh signaling pathway components (sonic hedgehog [Shh], protein patched homolog 1 [Ptch 1], GLI family zinc finger 1 [Gli 1] and suppressor of fused homolog [Drosophila] [Sufu]) in 127 patients with colon cancer, 36 with melanosis coli and 20 adjacent normal mucosal tissues taken from surgical specimens were evaluated using antibody staining and quantitative real-time polymerase chain reaction. RESULTS: In adjacent normal tissue Shh and Ptch1, but not Gli1 or Sufu, were weakly expressed and mainly in the lining epithelium of the colonic mucosa. In cancerous tissues Shh and Gli1 were uniformly strong while Ptch1 was patchy and weak, and Sufu uniformly weak, which paralleled their levels of corresponding mRNA. Elevated protein levels of Shh and Ptch were significantly associated with mucinous colonic tissues. Elevated Sufu protein levels were positively correlated with the diameter and invasion of the tumor. In patients with melanosis coli, mRNA levels of Shh, Ptch1, Gli1 and Sufu were very low, which was similar to those of adjacent normal tissues; but protein levels of Shh, Ptch1 and Gli1, but not Sufu, were high, which was similar to those of cancerous tissues. CONCLUSIONS: The mRNA and protein levels of Hh pathway components are aberrantly elevated in colon cancer, which may be the potential molecular classification markers. Further studies are required to determine the role of melanosis coli in the colon tumorigenesis.


Assuntos
Neoplasias do Colo/metabolismo , Proteínas Hedgehog/biossíntese , Melanose/metabolismo , Proteínas de Neoplasias/biossíntese , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/biossíntese , Biomarcadores Tumorais/genética , Doenças do Colo/genética , Doenças do Colo/metabolismo , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Feminino , Proteínas Hedgehog/genética , Humanos , Técnicas Imunoenzimáticas , Mucosa Intestinal/metabolismo , Masculino , Melanose/genética , Pessoa de Meia-Idade , Invasividade Neoplásica , Proteínas de Neoplasias/genética , RNA Mensageiro/genética , Transdução de Sinais/fisiologia
13.
Cancer Res ; 73(9): 2863-72, 2013 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-23539450

RESUMO

A subset of aggressive colorectal cancers exhibit BRAF mutation, MLH1 methylation, and a CpG island methylator phenotype (CIMP), but precursors are poorly established. In this study, we determined the status of these markers in colorectal polyps and evaluated associated risk factors. The study included 771 polyp cases and 1,027 controls who were ages 24 to 80 years, part of a group health program, received a colonoscopy from 1998 to 2007, and completed a structured questionnaire assessing risk factors. Following standard pathology review, polyps were assayed for BRAF mutation (V600E) and tested for MLH1 and CIMP methylation, the latter including the genes, CACNA1G, IGF2, NEUROG1, RUNX3, and SOCS1. Polytomous logistic regression was used to estimate ORs and 95% confidence intervals for the association between molecularly defined subsets of polyps and potential risk factors. There were 580 conventional adenomas and 419 serrated lesions successfully assayed. For adenomas, the prevalence of each marker was ≤1%. In contrast, 55% of serrated lesions harbored mutant BRAF, 26% were CIMP-high, and 5% had methylated MLH1. In these lesions, the highest prevalence of markers was in sessile-serrated polyps (SSP) of ≥10 mm that were in the right-side/cecal regions of the colon. Risk factors for CIMP-high-serrated lesions included Caucasian race, current smoking status, and a history of polyps, whereas for serrated lesions with mutant BRAF, the significant risk factors were male sex, current smoking status, obesity, and a history of polyps. Our results suggest that SSPs and other large, right-sided serrated lesions have a unique molecular profile that is similar to CIMP-high, BRAF-mutated colorectal cancers.


Assuntos
Adenoma/genética , Aberrações Cromossômicas , Doenças do Colo/genética , Neoplasias Colorretais/genética , Regulação Neoplásica da Expressão Gênica , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Ilhas de CpG , Metilação de DNA , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Genéticos , Mutação , Pólipos , Proteínas Proto-Oncogênicas B-raf/genética , Análise de Regressão , Fatores de Risco , Inquéritos e Questionários
14.
J Gastrointestin Liver Dis ; 21(2): 153-6, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22720303

RESUMO

BACKGROUND: The diagnosis of irritable bowel syndrome (IBS) is based on clinical criteria. Further diagnostic testing is advised for certain "red flag" alarm or warning signs. AIM: This investigation was designed to examine the yield of testing for "red flags". METHODS: Consecutive patients who were prospectively evaluated and met the ROME III criteria for IBS were reviewed for "red flags" which included: 1) rectal bleeding, 2) iron-deficiency anemia (IDA), 3) weight loss, 4) family history of colon cancer, 5) fever, and 6) age of onset after age 50. The evaluations were reviewed for type of testing and findings. Subjects with nocturnal symptoms and fecal soiling, although not traditional warning signs, were also reviewed. RESULTS: There were 200 patients who met the IBS criteria; 139 (70%) had a "red flag" alarm symptom or sign. Diarrhea predominant-IBS (D-IBS) was seen in 105, constipation predominant-IBS (C-IBS) in 57, alternating, mixed, or pain predominant-IBS in 38. There were 30 men and 170 women. Testing was not often performed in this setting and, when done, the yield was low with few clinically significant diagnostic findings. CONCLUSION: There was a high prevalence of "red flag" symptoms or signs in the prospectively evaluated IBS cohort, but a low frequency of diagnostic testing directed at the investigation of these symptoms or signs. Further systematic study may show that the yield for testing in IBS is low even when "red flags" prompt diagnostic testing.


Assuntos
Síndrome do Intestino Irritável/diagnóstico , Idade de Início , Anemia Ferropriva/etiologia , Doenças do Colo/genética , Constipação Intestinal/etiologia , Diarreia/etiologia , Feminino , Febre/etiologia , Hemorragia Gastrointestinal/etiologia , Humanos , Síndrome do Intestino Irritável/complicações , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Perda de Peso
15.
Dis Colon Rectum ; 54(8): 1020-5, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21730793

RESUMO

OBJECTIVE: : Our objective is to assess the effect of genetic and environmental factors on Crohn's disease location. DESIGN: : We identified 628 patients with Crohn's disease within the Washington University database (April 2005 through February 2010) that had complete information on 31 Crohn's disease-associated genotypes and clinical information on disease location (L1 to L4), smoking, sex, race, and age at diagnosis. For statistical reasons, the 3 major NOD2 alleles (rs2066844, rs2066845, and rs2066847) were grouped together. Logistic regression incorporating all of the genotypes and clinical covariates, including smoking, was performed with stepwise variable selection and by best subset selection. RESULTS: : Stepwise variable selection selected 3 major covariates, composite NOD2 genotype, smoking, and TNFSF15 genotype, which are also the 3 covariates selected by the best subset method. Whereas the NOD2 genotype and smoking are positively associated with ileal (L1 + L3) disease, the TNFSF15 genotype is positively associated with isolated colonic (L2) disease. LIMITATIONS: : The ability to detect disease site associations in this single-center study may be limited by the population size, low allelic frequency, and/or low odds ratio of certain Crohn's disease risk alleles. CONCLUSION: : These results indicate that NOD2 genotype, smoking status, and TNFSF15 genotype should be included as covariates in assessing the effect of genetic and environmental factors on Crohn's disease site location.


Assuntos
Doenças do Colo/genética , Doença de Crohn/genética , Doenças do Íleo/genética , Proteína Adaptadora de Sinalização NOD2/genética , Fumar , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/genética , Adolescente , Adulto , Alelos , Doença de Crohn/patologia , Feminino , Genótipo , Humanos , Modelos Logísticos , Masculino , Adulto Jovem
16.
J Biol Chem ; 285(43): 33485-98, 2010 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-20710027

RESUMO

Utilizing the Citrobacter rodentium-induced transmissible murine colonic hyperplasia (TMCH) model, we measured hyperplasia and NF-κB activation during progression (days 6 and 12 post-infection) and regression (days 20-34 post-infection) phases of TMCH. NF-κB activity increased at progression in conjunction with bacterial attachment and translocation to the colonic crypts and decreased 40% by day 20. NF-κB activity at days 27 and 34, however, remained 2-3-fold higher than uninfected control. Expression of the downstream target gene CXCL-1/KC in the crypts correlated with NF-κB activation kinetics. Phosphorylation of cellular IκBα kinase (IKK)α/ß (Ser(176/180)) was elevated during progression and regression of TMCH. Phosphorylation (Ser(32/36)) and degradation of IκBα, however, contributed to NF-κB activation only from days 6 to 20 but not at later time points. Phosphorylation of MEK1/2 (Ser(217/221)), ERK1/2 (Thr(202)/Tyr(204)), and p38 (Thr(180)/Tyr(182)) paralleled IKKα/ß kinetics at days 6 and 12 without declining with regressing hyperplasia. siRNAs to MEK, ERK, and p38 significantly blocked NF-κB activity in vitro, whereas MEK1/2-inhibitor (PD98059) also blocked increases in MEK1/2, ERK1/2, and IKKα/ß thereby inhibiting NF-κB activity in vivo. Cellular and nuclear levels of Ser(536)-phosphorylated (p65(536)) and Lys(310)-acetylated p65 subunit accompanied functional NF-κB activation during TMCH. RSK-1 phosphorylation at Thr(359)/Ser(363) in cellular/nuclear extracts and co-immunoprecipitation with cellular p65-NF-κB overlapped with p65(536) kinetics. Dietary pectin (6%) blocked NF-κB activity by blocking increases in p65 abundance and nuclear translocation thereby down-regulating CXCL-1/KC expression in the crypts. Thus, NF-κB activation persisted despite the lack of bacterial attachment to colonic mucosa beyond peak hyperplasia. The MEK/ERK/p38 pathway therefore seems to modulate sustained activation of NF-κB in colonic crypts in response to C. rodentium infection.


Assuntos
Citrobacter rodentium , Colo/metabolismo , Doenças do Colo/metabolismo , Infecções por Enterobacteriaceae/metabolismo , MAP Quinase Quinase 1/metabolismo , MAP Quinase Quinase 2/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Fator de Transcrição RelA/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Quimiocina CXCL1/biossíntese , Quimiocina CXCL1/genética , Colo/microbiologia , Colo/patologia , Doenças do Colo/genética , Doenças do Colo/microbiologia , Doenças do Colo/patologia , Infecções por Enterobacteriaceae/genética , Flavonoides/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Hiperplasia/genética , Hiperplasia/metabolismo , Hiperplasia/microbiologia , Quinase I-kappa B/genética , Quinase I-kappa B/metabolismo , Proteínas I-kappa B/genética , Proteínas I-kappa B/metabolismo , MAP Quinase Quinase 1/antagonistas & inibidores , MAP Quinase Quinase 1/genética , MAP Quinase Quinase 2/antagonistas & inibidores , MAP Quinase Quinase 2/genética , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/genética , Camundongos , Proteína Quinase 3 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 3 Ativada por Mitógeno/genética , Inibidor de NF-kappaB alfa , Fosforilação/efeitos dos fármacos , Fosforilação/genética , Proteínas Quinases S6 Ribossômicas 90-kDa/genética , Proteínas Quinases S6 Ribossômicas 90-kDa/metabolismo , Fatores de Tempo , Fator de Transcrição RelA/genética , Proteínas Quinases p38 Ativadas por Mitógeno/genética
17.
Indian J Med Res ; 131: 702-10, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20516544

RESUMO

BACKGROUND: Gangrene of stomach or intestines owing to non-occlusive bowel infarction (NOBI) is a rare event with unknown etiology. Since B19 may cause vasculitis, arteritis, angiopathy and more importantly, localized microvascular thrombi formation hence patients with bowel gangrene were investigated for B19 infection. METHODS: Twelve patients (8 male and 4 females; median age 40 yr) of ischemic unexplained gangrene of bowel underwent emergency laparotomy. Eight cases had NOBI while four had occlusive bowel infarction (OBI). Anti-B19 antibodies in sera by ELISA and Western-blot and B19 DNA by PCR in sera and resected tissues were analysed. RESULTS: All patients underwent resection of gangrenous bowel; with exteriorization followed by restoration wherever appropriate. Histopathology showed loss of bowel mucosa and crypts with inflammatory cell infiltration besides fibrin thrombus in gastric vessels. Sera of all 8 patents of NOBI had B19 genome by nested-PCR (VP1 unique) and in 6 by PCR (VP1-VP2). In three patients resected bowel tissues also had B19 DNA besides anti-B19 IgM and IgG antibodies. NOBI patients were reticulocytopenic and anaemic while one had necrotizing vasculitis of skin a year ago. No IgM antibodies to agents causing vasculitis (HTLV-I, HIV-1+2, CMV, HSV1+2, mumps virus and Mycobacterium tuberculosis) nor any abnormality in coagulation profiles were detected. In four OBI cases's sera and resected bowel tissues and in control bowel tissues (n=36) no anti-B19 IgM antibodies or B19 DNA were detected. CONCLUSIONS: Novel finding of active B19 infection in non-occlusive gangrene of the bowel may be causal rather than casual.


Assuntos
Doenças do Colo/imunologia , Gangrena/imunologia , Imunoglobulina M/imunologia , Parvovirus B19 Humano/imunologia , Gastropatias/imunologia , Adolescente , Adulto , Idoso , Western Blotting , Doenças do Colo/genética , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Parvovirus B19 Humano/genética , Gastropatias/genética , Adulto Jovem
18.
Blood ; 115(25): 5249-58, 2010 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-20382845

RESUMO

Allogeneic stem cell transplantation is the most potent form of effective adoptive immunotherapy. The graft-versus-leukemia (GVL) effect mediated by the allogeneic graft, however, is typically coexpressed with graft-versus-host disease (GVHD), which is the major complication of allogeneic stem cell transplantation. In this study, we used genetic and antibody-based strategies to examine the effect that blockade of interleukin 23 (IL-23) signaling had on GVH and GVL reactivity in murine transplantation recipients. These studies demonstrate that the selective protection of the colon that occurs as a consequence of inhibition of IL-23 signaling reduces GVHD without loss of the GVL effect. The separation of GVH and GVL reactivity was noted in both acute and chronic hematologic malignancy models, indicating that this approach was not restricted by the kinetic profile of the underlying leukemia. Furthermore, a potent GVL response could be mounted in the colon under conditions where tumor cells migrated to this site, indicating that this organ did not serve as a sanctuary site for subsequent systemic relapse in GVHD-protected animals. These studies demonstrate that blockade of IL-23 signaling is an effective strategy for separating GVH and GVL responses and identify IL-23 as a therapeutic target for the regulation of alloresponses in humans.


Assuntos
Doenças do Colo/prevenção & controle , Doença Enxerto-Hospedeiro/prevenção & controle , Efeito Enxerto vs Leucemia/imunologia , Subunidade p19 da Interleucina-23 , Leucemia/terapia , Transplante de Células-Tronco , Doença Aguda , Animais , Doença Crônica , Colo/imunologia , Colo/patologia , Doenças do Colo/genética , Doenças do Colo/imunologia , Doenças do Colo/patologia , Modelos Animais de Doenças , Doença Enxerto-Hospedeiro/genética , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/patologia , Efeito Enxerto vs Leucemia/genética , Humanos , Leucemia/genética , Leucemia/imunologia , Leucemia/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Transplante Homólogo
19.
BMC Genomics ; 11: 5, 2010 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-20047688

RESUMO

BACKGROUND: Studies using microarray analysis of colorectal cancer have been generally beleaguered by the lack of a normal cell population of the same lineage as the tumor cell. One of the main objectives of this study was to generate a reference gene expression data set for normal colonic epithelium which can be used in comparisons with diseased tissues, as well as to provide a dataset that could be used as a baseline for studies in alternative splicing. RESULTS: We present a dependable expression reference data set for non-neoplastic colonic epithelial cells. An enriched population of fresh colon epithelial cells were obtained from non-neoplastic, colectomy specimens and analyzed using Affymetrix GeneChip EXON 1.0 ST arrays. For demonstration purposes, we have compared the data derived from these cells to a publically available set of tumor and matched normal colon data. This analysis allowed an assessment of global gene expression alterations and demonstrated that adjacent normal tissues, with a high degree of cellular heterogeneity, are not always representative of normal cells for comparison to tumors which arise from the colon epithelium. We also examined alternative splicing events in tumors compared to normal colon epithelial cells. CONCLUSIONS: The findings from this study represent the first comprehensive expression profile for non-neoplastic colonic epithelial cells reported. Our analysis of splice variants illustrate that this is a very labor intensive procedure, requiring vigilant examination of the data. It is projected that the contribution of this set of data derived from pure colonic epithelial cells will enhance studies in colon-related disease and offer a vital baseline for studies aimed at elucidating the mechanisms of alternative splicing.


Assuntos
Processamento Alternativo , Colo/metabolismo , Epitélio/metabolismo , Perfilação da Expressão Gênica , Idoso , Idoso de 80 Anos ou mais , Colo/patologia , Doenças do Colo/genética , Neoplasias Colorretais/genética , Epitélio/patologia , Éxons , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Análise de Componente Principal , Padrões de Referência
20.
J Clin Endocrinol Metab ; 94(12): 4671-8, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19864451

RESUMO

OBJECTIVE: The aim of the study was to evaluate the impact of the genomic deletion of exon 3 of the GH receptor (d3GHR) on long-term clinical outcome of acromegaly in a well-characterized cohort of patients with long-term remission of acromegaly. DESIGN: We conducted a cross-sectional study. METHODS: The presence of the d3GHR polymorphism was assessed in 86 acromegalic patients with long-term disease control and related to anthropometric parameters, cardiovascular risk factors, osteoarthritis, bone mineral density, colonic polyps and diverticulae, and dolichocolon. RESULTS: Fifty-one patients had two wild-type alleles (59%), whereas 29 patients (34%) had one allele and six patients (7%) had two alleles encoding for the d3GHR isoform. Carriers of the d3GHR isoform showed increased prevalence of osteoarthritis, especially of the hip [adjusted odds ratio (OR), 5.2; 95% confidence interval (CI), 3.2-7.1], of adenomatous polyps (adjusted OR, 4.1; 95% CI, 2.4-5.6), and dolichocolon (adjusted OR, 3.2; 95% CI, 1.8-4.6). Anthropometric parameters, cardiovascular risk factors, bone mineral density, and (non)vertebral fractures were not significantly different between patients with and without the d3GHR allele. CONCLUSION: In patients with long-term cured acromegaly, the d3GHR polymorphism is associated with an increased prevalence of irreversible comorbidities such as osteoarthritis, dolichocolon, and adenomatous colonic polyps, but not with other comorbidities such as cardiovascular risk factors.


Assuntos
Acromegalia/complicações , Acromegalia/genética , Éxons/genética , Polimorfismo Genético/genética , Polimorfismo Genético/fisiologia , Receptores da Somatotropina/genética , Receptores da Somatotropina/fisiologia , Acromegalia/diagnóstico por imagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Antropometria , Densidade Óssea/genética , Densidade Óssea/fisiologia , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/genética , Estudos de Coortes , Doenças do Colo/epidemiologia , Doenças do Colo/genética , DNA/genética , DNA/isolamento & purificação , Feminino , Deleção de Genes , Predisposição Genética para Doença , Hormônio do Crescimento Humano/metabolismo , Hormônio do Crescimento Humano/fisiologia , Humanos , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Pessoa de Meia-Idade , Osteoartrite/diagnóstico por imagem , Osteoartrite/epidemiologia , Osteoartrite/genética , Osteoporose/epidemiologia , Osteoporose/genética , Radiografia , Fatores de Risco , Fraturas da Coluna Vertebral/epidemiologia , Fraturas da Coluna Vertebral/genética , Resultado do Tratamento
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