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1.
Nat Commun ; 10(1): 2115, 2019 05 09.
Artigo em Inglês | MEDLINE | ID: mdl-31073170

RESUMO

Approximately 30% of ERα breast cancer patients relapse with metastatic disease following adjuvant endocrine therapies. The connection between acquisition of drug resistance and invasive potential is poorly understood. In this study, we demonstrate that the type II keratin topological associating domain undergoes epigenetic reprogramming in aromatase inhibitors (AI)-resistant cells, leading to Keratin-80 (KRT80) upregulation. KRT80 expression is driven by de novo enhancer activation by sterol regulatory element-binding protein 1 (SREBP1). KRT80 upregulation directly promotes cytoskeletal rearrangements at the leading edge, increased focal adhesion and cellular stiffening, collectively promoting cancer cell invasion. Shearwave elasticity imaging performed on prospectively recruited patients confirms KRT80 levels correlate with stiffer tumors. Immunohistochemistry showed increased KRT80-positive cells at relapse and, using several clinical endpoints, KRT80 expression associates with poor survival. Collectively, our data uncover an unpredicted and potentially targetable direct link between epigenetic and cytoskeletal reprogramming promoting cell invasion in response to chronic AI treatment.


Assuntos
Antineoplásicos Hormonais/farmacologia , Neoplasias da Mama/patologia , Citoesqueleto/patologia , Queratinas Tipo II/genética , Recidiva Local de Neoplasia/patologia , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Antineoplásicos Hormonais/uso terapêutico , Inibidores da Aromatase/farmacologia , Inibidores da Aromatase/uso terapêutico , Mama/patologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Citoesqueleto/genética , Resistencia a Medicamentos Antineoplásicos/genética , Elementos Facilitadores Genéticos/genética , Epigênese Genética , Receptor alfa de Estrogênio/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Queratinas Tipo II/metabolismo , Células MCF-7 , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/mortalidade , Prognóstico , Domínios Proteicos/genética , Regulação para Cima
2.
J Drugs Dermatol ; 18(3): 246-250, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30909328

RESUMO

The purpose of this review is to discuss the disease process and wide variety of treatment options for psuedofolliculitis barbae (PFB), or razor bumps. PFB is caused by hair follicles penetrating the skin and causing an inflammatory response. PFB can occur to anyone who shaves, and is more likely in those with curly hair. PFB can cause significant hyperpigmentation and scarring, more noticeable in darker skin types. PFB can be treated with a variety of topical, systemic, or light/laser therapies. Minimal progress has been made in treating PFB in recent years, partially due to the success of well-established current treatments discussed in this review. The most effective treatments involve a multifaceted approach including behavioral changes in shaving habits as well as the use of topical therapies. J Drugs Dermatol. 2019;18(3):246-250.


Assuntos
Fármacos Dermatológicos/uso terapêutico , Doenças do Cabelo/terapia , Remoção de Cabelo/efeitos adversos , Terapia com Luz de Baixa Intensidade/métodos , Fotoquimioterapia/métodos , Administração Cutânea , Administração Oral , Antibacterianos/uso terapêutico , Face , Hábitos , Doenças do Cabelo/epidemiologia , Doenças do Cabelo/etiologia , Folículo Piloso/patologia , Folículo Piloso/efeitos da radiação , Humanos , Queratinas Específicas do Cabelo/genética , Queratinas Tipo II/genética , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
3.
Cell Death Dis ; 9(10): 1009, 2018 09 27.
Artigo em Inglês | MEDLINE | ID: mdl-30262880

RESUMO

Little is known about the function of Keratin 80 (KRT80), an epithelial keratin, in cancer. This study investigated the role of KRT80 in the prognosis of colorectal carcinoma (CRC) and the underlying mechanisms involved in CRC migration and invasion. We analyzed the expression of KRT80 using The Cancer Genome Atlas and Oncomine databases. Higher expression of KRT80 was found to be significantly associated with multiple pathological parameters, lower disease-free survival, and overall survival in CRC patients. Also, KRT80 was an independent prognostic indicator for CRC. Furthermore, altered KRT80 expression impacted migration and invasion of CRC cells, as well as the expression of epithelial-mesenchymal transition (EMT)-related markers and cell morphology via the AKT pathway. Inhibiting the expression of AKT could reverse these phenomena. Liquid Chromatograph Mass Spectrometer/Mass Spectromete, Co-immunoprecipitation, and laser scanning confocal microscopy techniques showed that KRT80 could interact with protein kinase, DNA-activated, catalytic polypeptide (PRKDC). Suppressing PRKDC could inhibit the expression of AKT and EMT, as well as the migration and invasion of CRC cells. Taken together, these results demonstrated that KRT80 was an independent prognostic biomarker for CRC and promoted CRC migration and invasion by interacting with PRKDC via activation of the AKT pathway.


Assuntos
Movimento Celular/genética , Neoplasias Colorretais/genética , Proteína Quinase Ativada por DNA/genética , Queratinas Tipo II/genética , Invasividade Neoplásica/genética , Proteínas Nucleares/genética , Proteínas Proto-Oncogênicas c-akt/genética , Transdução de Sinais/genética , Idoso , Linhagem Celular Tumoral , Neoplasias Colorretais/patologia , Intervalo Livre de Doença , Transição Epitelial-Mesenquimal/genética , Feminino , Humanos , Masculino , Invasividade Neoplásica/patologia , Prognóstico , Proteínas Quinases/genética
5.
Artigo em Inglês | MEDLINE | ID: mdl-29610398

RESUMO

Keratins-types I and II-are the intermediate-filament-forming proteins expressed in epithelial cells. They are encoded by 54 evolutionarily conserved genes (28 type I, 26 type II) and regulated in a pairwise and tissue type-, differentiation-, and context-dependent manner. Here, we review how keratins serve multiple homeostatic and stress-triggered mechanical and nonmechanical functions, including maintenance of cellular integrity, regulation of cell growth and migration, and protection from apoptosis. These functions are tightly regulated by posttranslational modifications and keratin-associated proteins. Genetically determined alterations in keratin-coding sequences underlie highly penetrant and rare disorders whose pathophysiology reflects cell fragility or altered tissue homeostasis. Furthermore, keratin mutation or misregulation represents risk factors or genetic modifiers for several additional acute and chronic diseases.


Assuntos
Queratinas Tipo II/fisiologia , Queratinas Tipo I/fisiologia , Apoptose , Movimento Celular , Proliferação de Células , Homeostase , Queratinas Tipo I/genética , Queratinas Tipo II/genética , Processamento de Proteína Pós-Traducional , Estresse Fisiológico
6.
Oncol Rep ; 37(5): 2964-2970, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28405679

RESUMO

Keratins are fibrous proteins. Hair keratins constitute hard structures such as the hair and nails, and cytokeratins have been used as markers of breast carcinoma. However, the expression and function of full-size hair keratin genes have not been previously demonstrated in breast cancer. We investigated the expression of the hair keratin, KRT81, and its function in human breast cancer and normal mammary epithelial cells. Western blotting showed full size 55-kDa KRT81 expression in the human breast cancer cell lines, MCF7, SKBR3 and MDA-MB-231, normal human mammary epithelial cells (HMEC), and non-neoplastic cells (MCF10A). Reverse transcription-polymerase chain reaction revealed that the full size KRT81, including its 5' region is expressed in breast cells. Immunohistochemical and immunofluorescence analyses showed that KRT81 was located in the cytoplasm. To investigate the function of KRT81, we knocked down KRT81 by siRNA in MCF10A cells. Microarray analysis revealed that the expression of genes related to invasion such as matrix metallopeptidase (MMP)9 was decreased. In KRT81-knockdown MDA-MB231 cells, zymography revealed a decrease in MMP9 activity, while scratch and invasion assays revealed that KRT81-knockdown decreased cell migration and invasion abilities. This is the first study showing that full size KRT81 is expressed in normal breast epithelial cells and breast cancer cells. Moreover, our results indicate that KRT81 contributes to the migration and invasion of breast cancer cells.


Assuntos
Neoplasias da Mama/metabolismo , Queratinas Específicas do Cabelo/genética , Queratinas Específicas do Cabelo/metabolismo , Queratinas Tipo II/genética , Queratinas Tipo II/metabolismo , Glândulas Mamárias Humanas/metabolismo , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Movimento Celular , Citoplasma/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Células MCF-7 , Invasividade Neoplásica , Análise de Sequência com Séries de Oligonucleotídeos/métodos
8.
J Med Genet ; 54(3): 186-189, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27965375

RESUMO

BACKGROUND: Progressive symmetric erythrokeratoderma (PSEK) is a rare skin disorder characterised by symmetrically distributed demarcated hyperkeratotic plaques, often with associated palmoplantar hyperkeratosis, with new plaques appearing over time. Most cases are inherited in an autosomal dominant manner, although a few cases exhibit apparent autosomal recessive inheritance. OBJECTIVE: To identify the gene underlying autosomal recessive PSEK in a large Pakistani kindred. METHODS: We first carried out autozygosity mapping using microsatellite markers in candidate regions of the genome. We then carried out exome sequencing of five family members, autozygosity mapping and mutation analysis using the exome data and verification by Sanger sequencing. RESULTS: Autozygosity mapping and exome sequencing identified a homozygous frameshift deletion (c.811delA; p.Ser271fs) in KRT83, which co-segregated with the PSEK phenotype in the family and which is expected to abolish keratin 83, a type II keratin of hair and skin. CONCLUSIONS: At least some cases of PSEK result from loss-of-function mutations in KRT83. Heterozygous missense substitutions in KRT83 have been implicated in autosomal dominant monilethrix, a rare hair disorder. Our findings indicate that at least some cases of autosomal recessive PSEK and autosomal dominant monilethrix are allelic, respectively resulting from loss-of-function and missense mutations in the KRT83 gene. Together, these findings indicate that different types of mutations in KRT83 can result in quite different skin and hair phenotypes.


Assuntos
Eritroceratodermia Variável/genética , Queratinas Específicas do Cabelo/genética , Queratinas Tipo II/genética , Monilétrix/genética , Alelos , Eritroceratodermia Variável/patologia , Exoma/genética , Feminino , Cabelo/metabolismo , Cabelo/patologia , Heterozigoto , Homozigoto , Humanos , Masculino , Monilétrix/patologia , Mutação de Sentido Incorreto , Paquistão , Linhagem , Fenótipo , Deleção de Sequência , Pele/metabolismo , Pele/patologia
9.
Cell Tissue Res ; 363(3): 735-50, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26340985

RESUMO

Among the 26 human type II keratins, K78 is the only one that has not yet been explored with regard to its expression characteristics. Here, we show that, at both the transcriptional and translational levels, K78 is strongly expressed in the basal and parabasal cell layers with decreasing intensity in the lower suprabasal cells of keratinising and non-keratinising squamous epithelia and keratinocyte cultures. The same pattern has been detected at the transcriptional level in the corresponding mouse epithelia. Murine K78 protein, which contains an extraordinary large extension of its tail domain, which is unique among all known keratins, is not detectable by the antibody used. Concomitant studies in human epithelia have confirmed K78 co-expression with the classical basal keratins K5 and K14. Similarly, K78 co-expression with the differentiation-related type I keratins K10 (epidermis) and K13 (non-keratinising epithelia) occurs in the parabasal cell layer, whereas that of the corresponding type II keratins K1 (epidermis) and K4 (non-keratinising epithelia) unequivocally starts subsequent to the respective type I keratins. Our data concerning K78 expression modify the classical concept of keratin pair K5/K14 representing the basal compartment and keratin pairs K1/K10 or K4/K13 defining the differentiating compartment of stratified epithelia. Moreover, the K78 expression pattern and the decoupled K1/K10 and K4/K13 expression define the existence of a hitherto unperceived early differentiation stage in the parabasal layer characterized by K78/K10 or K78/K13 expression.


Assuntos
Epitélio/metabolismo , Regulação da Expressão Gênica , Queratinas Tipo II/genética , Queratinas Tipo II/metabolismo , Adulto , Sequência de Aminoácidos , Animais , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Desenvolvimento Embrionário , Epiderme/metabolismo , Evolução Molecular , Imunofluorescência , Loci Gênicos , Humanos , Hibridização In Situ , Queratinócitos/metabolismo , Queratinas Tipo II/química , Camundongos Endogâmicos C57BL , Dados de Sequência Molecular , Transporte Proteico , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Análise de Sequência de Proteína
10.
Matrix Biol ; 52-54: 260-265, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26709044

RESUMO

Dental enamel is the hardest tissue in the human body, and although it starts as a tissue rich in proteins, by the time of eruption of the tooth in the oral cavity only a small fraction of the protein remains. While this organic matrix of enamel represents less than 1% by weight it plays essential roles in improving both toughness and resilience to chemical attacks. Despite the fact that the first studies of the enamel matrix began in the 19th century, its exact composition and mechanisms of its function remain poorly understood. It was proposed that keratin or a keratin-like primitive epithelial component exists in mature enamel, however due to the extreme insolubility of its organic matrix the presence of keratins there was never clearly established. We have recently identified expression of a number of hair keratins in ameloblasts, the enamel secreting cells, and demonstrated their incorporation into mature enamel. Mutation in epithelial hair keratin KRT75 leads to a skin condition called pseudofollicularis barbae. Carriers of this mutation have an altered enamel structure and mechanical properties. Importantly, these individuals have a much higher prevalence of caries. To the best of our knowledge, this is the first study showing a direct link between a mutation in a protein-coding region of a gene and increased caries rates. In this paper we present an overview of the evidence of keratin-like material in enamel that has accumulated over the last 150years. Furthermore, we propose potential mechanisms of action of KTR75 in enamel and highlight the clinical implications of the link between mutations in KRT75 and caries. Finally, we discuss the potential use of keratins for enamel repair.


Assuntos
Cárie Dentária/epidemiologia , Esmalte Dentário/química , Queratinas Específicas do Cabelo/genética , Queratinas Específicas do Cabelo/metabolismo , Queratinas Tipo II/genética , Queratinas Tipo II/metabolismo , Animais , Cárie Dentária/genética , Cárie Dentária/metabolismo , Esmalte Dentário/metabolismo , Esmalte Dentário/patologia , Doenças do Cabelo/complicações , Doenças do Cabelo/genética , Humanos , Mutação
13.
Clin Exp Dermatol ; 40(7): 781-5, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25809918

RESUMO

BACKGROUND: Monilethrix is a rare monogenic dystrophic hair loss disorder with high levels of intrafamilial and interfamilial variability. It is characterized by diffuse occipital or temporal alopecia, hair fragility and follicular hyperkeratosis of the occipital region. Mutations in the keratin genes KRT81, KRT83 and KRT86 lead to autosomal dominant monilethrix, whereas mutations in the desmoglein 4 gene (DSG4) cause an autosomal recessive form. AIM: To identify the mutation in a consanguineous Turkish family with three affected children and apparently unaffected parents. METHODS: Sequencing analysis of the genes DSG4 and KRT86 was performed. SNaPshot analysis was conducted to quantify the proportion of cells carrying the KRT86 mutation and to confirm maternal mosaicism of KRT86. RESULTS: No pathogenic mutation was found by sequencing analysis of DSG4; however, analysis of KRT86 revealed a novel mutation, c.1231G>T;p.Glu411*, in exon 7 in the three affected children and their mother. The mutation signal was weaker in the mother than in the three siblings, and SNaPshot analysis revealed substantial mutation-level variation between the children and their mother. CONCLUSIONS: Our results extend the spectrum of KRT86 mutations and indicate KRT86 mosaicism in the family examined. This study is the first, to our knowledge, to describe mosaicism for a monogenic hair loss disorder, and suggests that mosaicism leads to a mild manifestation of monilethrix.


Assuntos
Predisposição Genética para Doença/genética , Queratinas Específicas do Cabelo/genética , Queratinas Tipo II/genética , Monilétrix/genética , Mosaicismo , Mutação , Adolescente , Grupo com Ancestrais do Continente Asiático , Criança , Desmogleínas/genética , Feminino , Humanos , Masculino , Linhagem , Turquia
14.
Ann Oncol ; 26(6): 1142-8, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25716425

RESUMO

BACKGROUND: MicroRNAs (miRNAs) have a key role in carcinogenesis through negative regulation of their target genes. Therefore, genetic variations in miRNAs or their target sites may affect miRNA-mRNA interactions, thereby result in altered expression of target genes. This study was conducted to investigate the associations between single-nucleotide polymorphisms (SNP) located in the miRNA target sites (poly-miRTSs) and survival of patients with early-stage non-small-cell lung cancer (NSCLC). METHODS: Using public SNP database and miRNA target sites prediction program, 354 poly-miRTSs were selected for genotyping. Among these, 154 SNPs applicable to Sequenom's MassARRAY platform were investigated in 357 patients. A replication study was carried out on an independent patient population (n = 479). Renilla luciferase assay and reverse transcription-polymerase chain reaction were conducted to examine functional relevance of potentially functional poly-miRTSs. RESULTS: Of the 154 SNPs analyzed in a discovery set, 14 SNPs were significantly associated with survival outcomes. Among these, KRT81 rs3660G>C was found to be associated with survival outcomes in the validation cohort. In the combined analysis, patients with the rs3660 GC + CC genotype had a significantly better overall survival compared with those with GG genotype [adjusted hazard ratio (aHR) for OS, 0.65; 95% confidence interval (CI) 0.50-0.85; P = 0.001]. An increased expression of the reporter gene for the C allele of rs3660 compared with the G allele was observed by luciferase assay. Consistently, the C allele was associated with higher relative expression level of KRT81 in tumor tissues. CONCLUSION: The rs3660G>C affects KRT81 expression and thus influences survival in early-stage NSCLC. The analysis of the rs3660G>C polymorphism may be useful to identify patients at high risk of a poor disease outcome.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Queratinas Específicas do Cabelo/genética , Queratinas Tipo II/genética , Neoplasias Pulmonares/genética , MicroRNAs/genética , Polimorfismo de Nucleotídeo Único , Regiões 3' não Traduzidas , Idoso , Sítios de Ligação , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/terapia , Biologia Computacional , Bases de Dados Genéticas , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Frequência do Gene , Predisposição Genética para Doença , Células HEK293 , Humanos , Estimativa de Kaplan-Meier , Queratinas Específicas do Cabelo/metabolismo , Queratinas Tipo II/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Masculino , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Fenótipo , Modelos de Riscos Proporcionais , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fatores de Risco , Fatores de Tempo , Transfecção
16.
Exp Dermatol ; 24(3): 222-4, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25557232

RESUMO

Monilethrix is an autosomal dominant hair disorder caused by mutations in the hard keratins KRT81, KRT83 and KRT86. The affected hairs are fragile and break easily, leading to scarring alopecia. Follicular hyperkeratosis in the neck and on extensor sides of extremities is a frequently associated finding. The disorder is rare, but probably underreported because its manifestations may be mild. Mutations in KRT81 and KRT86 are the most common. Here, we report new cases from Venezuela, the Netherlands, Belgium and France. The Venezuelan kindred is special for having patients with digenic novel nucleotide changes, a KRT86 mutation associated with monilethrix and a KRT81 variant of unknown clinical significance. In the French and Dutch patients, we found novel KRT86 and KRT83 mutations. Our findings expand the mutational spectrum associated with monilethrix.


Assuntos
Queratinas Específicas do Cabelo/genética , Queratinas Tipo II/genética , Monilétrix/genética , Fenótipo , Feminino , Humanos , Masculino , Mutação
17.
Br J Dermatol ; 172(4): 878-84, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25255890

RESUMO

Pseudofolliculitis cutis (PFC) is a troublesome and potentially disfiguring cutaneous disorder characterized by a chronic inflammatory response to ingrown hair. Despite a simple precipitating stimulus, ingrown hair, PFC has a relatively complex aetiology that can involve grooming practices, hair type, genetic predisposition and medication history. Curly hair and a single-nucleotide substitution in the gene encoding keratin 75 may act synergistically to increase the risk for developing this condition. PFC is most common in men of sub-Saharan African lineage, but can occur in men and women of many different ethnicities, particularly in body areas where hair is coarse, abundant and subject to traumatic removal. Treatment options for PFC can be divided into three main categories: modifying hair removal practices, managing symptoms with medication, and long-term hair removal with laser therapy. Laser hair removal is safe and effective in most skin types and has become increasingly popular among dermatologists in the treatment of PFC. However, it is imperative that the laser system and parameters are specifically matched to the patient's skin type.


Assuntos
Foliculite/etiologia , Diagnóstico Diferencial , Feminino , Foliculite/diagnóstico , Foliculite/terapia , Remoção de Cabelo/efeitos adversos , Humanos , Queratinas Específicas do Cabelo/genética , Queratinas Tipo II/genética , Masculino , Polimorfismo de Nucleotídeo Único/genética , Prognóstico
18.
PLoS One ; 9(4): e93607, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24714551

RESUMO

Pure hair and nail ectodermal dysplasia (PHNED) comprises a heterogeneous group of rare heritable disorders characterized by brittle hair, hypotrichosis, onychodystrophy and micronychia. Autosomal recessive (AR) PHNED has previously been associated with mutations in either KRT85 or HOXC13 on chromosome 12p11.1-q14.3. We investigated a consanguineous Pakistani family with AR PHNED linked to the keratin gene cluster on 12p11.1 but without detectable mutations in KRT85 and HOXC13. Whole exome sequencing of affected individuals revealed homozygosity for a rare c.821T>C variant (p.Phe274Ser) in the KRT74 gene that segregates AR PHNED in the family. The transition alters the highly conserved Phe274 residue in the coil 1B domain required for long-range dimerization of keratins, suggesting that the mutation compromises the stability of intermediate filaments. Immunohistochemical (IHC) analyses confirmed a strong keratin-74 expression in the nail matrix, the nail bed and the hyponychium of mouse distal digits, as well as in normal human hair follicles. Furthermore, hair follicles and epidermis of an affected family member stained negative for Keratin-74 suggesting a loss of function mechanism mediated by the Phe274Ser substitution. Our observations show for the first time that homozygosity for a KRT74 missense variant may be associated with AR PHNED. Heterozygous KRT74 mutations have previously been associated with autosomal dominant woolly hair/hypotrichosis simplex (ADWH). Thus, our findings expand the phenotypic spectrum associated with KRT74 mutations and imply that a subtype of AR PHNED is allelic with ADWH.


Assuntos
Fissura Palatina/genética , Displasia Ectodérmica/genética , Cabelo/patologia , Hipotricose/genética , Deficiência Intelectual/genética , Queratinas Específicas do Cabelo/genética , Queratinas Tipo II/genética , Mutação de Sentido Incorreto , Unhas/patologia , Sindactilia/genética , Alelos , Sequência de Aminoácidos , Animais , Fissura Palatina/patologia , Consanguinidade , Displasia Ectodérmica/patologia , Cabelo/metabolismo , Homozigoto , Humanos , Hipotricose/patologia , Deficiência Intelectual/patologia , Queratinas Específicas do Cabelo/análise , Queratinas Tipo II/análise , Camundongos , Dados de Sequência Molecular , Unhas/metabolismo , Linhagem , Sindactilia/patologia
19.
Gene ; 539(2): 198-202, 2014 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-24530479

RESUMO

MicroRNA (miRNA), which plays an important role in tumorigenesis, can regulate post-transcriptional gene expression by binding to the 3' untranslated regions (3'-UTRs) of messenger RNAs and repressing its translation. Several single nucleotide polymorphisms (SNPs) are considered to have significant impacts on susceptibility of the role these genetic polymorphisms in development of carcinogenesis through that mechanism. But few of them focus their impact on non-Hodgkin's lymphoma (NHL). Therefore, we conducted this study to investigate the associations between the genetic variants and cancer risk or cancer outcome. MiRNA-related single nucleotide polymorphism (miR-SNP) sites rs3660 of KRT81, rs1044129 of RYR3, rs4901706 of f101, and rs1053667 of KIAA0423 were selected and analyzed in 210 patients in NHL to evaluate their association with cancer risk and prognosis. The results indicated that none of them is associated with the cancer risk in NHL. Otherwise KRT81 rs3660 GG type is associated with a shorter survival time (p=0.012), after being assessed by multivariate Cox analyses, its effect on prognosis was verified (p=0.003). It suggests that KRT81 rs3660 GG type is an independent prognostic marker in NHL.


Assuntos
Regiões 3' não Traduzidas/genética , Biomarcadores Tumorais/genética , Queratinas Específicas do Cabelo/genética , Queratinas Tipo II/genética , Linfoma não Hodgkin/diagnóstico , Linfoma não Hodgkin/genética , MicroRNAs/genética , Polimorfismo de Nucleotídeo Único/genética , Biomarcadores Tumorais/sangue , Estudos de Casos e Controles , DNA de Neoplasias/sangue , DNA de Neoplasias/genética , Feminino , Seguimentos , Genótipo , Humanos , Queratinas Específicas do Cabelo/sangue , Queratinas Tipo II/sangue , Linfoma não Hodgkin/sangue , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Reação em Cadeia da Polimerase , Prognóstico , Taxa de Sobrevida
20.
Int Forum Allergy Rhinol ; 4(3): 207-15, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24431132

RESUMO

BACKGROUND: Staphylococcus aureus (S. aureus) has been implicated in the pathogenesis of chronic rhinosinusitis (CRS). However, host factors contributing to susceptibility to S. aureus colonization in CRS remain unknown. We wish to investigate, using a pooled genomewide association study (pGWAS), single-nucleotide polymorphisms (SNPs) associated with S. aureus carriage in CRS patients. METHODS: An existing population of 408 CRS patients and 190 controls was prospectively recruited for genetic association studies. All CRS patients had an endoscopic swab culture as part of phenotyping. A pGWAS compared DNA pools from patients with and without S. aureus colonization using the Illumina HumanHap 1M BeadChip, which interrogates 1 million SNPs. Top-ranked SNPs associated with S. aureus colonization were selected according to biallelic differences and silhouette rank, and confirmed by individual genotyping using the Sequenom platform. PLINK software was used for genetic association tests. Ingenuity pathway analysis was used to identify canonical and signaling pathways enriched for genes neighboring associated SNPs, as well as identification of the underlying biological mechanisms. RESULTS: Thirty-nine top priority SNPs were selected for individual genotyping. Out of 39 SNPs, 23 were associated (p < 0.05) with S. aureus colonization in CRS patients. These SNPs are located within or near 21 genes reported to be implicated in several diseases, endocytic internalization, and bacterial recognition. CONCLUSION: These results suggest novel host genetic factors influencing susceptibility to S. aureus colonization in CRS. Identifying implicated mechanisms may offer new insights into pathogenesis of CRS.


Assuntos
Rinite/genética , Sinusite/genética , Infecções Estafilocócicas/genética , Staphylococcus aureus/imunologia , Adulto , Canadá , Adesão Celular/genética , Movimento Celular/genética , Doença Crônica , Análise Mutacional de DNA , Feminino , Interação Gene-Ambiente , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Receptores de Fator Neurotrófico Derivado de Linhagem de Célula Glial/genética , Humanos , Queratinas Específicas do Cabelo/genética , Queratinas Tipo II/genética , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Rinite/complicações , Transdução de Sinais/genética , Sinusite/complicações , Infecções Estafilocócicas/complicações , Proteínas rac1 de Ligação ao GTP/genética
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