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1.
Int J Gynecol Cancer ; 28(3): 428-436, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29465505

RESUMO

BACKGROUND: Mucinous epithelial ovarian cancers (mEOCs) respond poorly to conventional chemotherapy and have a poor prognosis in advanced stages. The genomic landscape for mEOC in the Asian settings is ill defined. We seek to identify various mutational aberrations present in mEOC and correlate them with clinical outcomes. METHODS: A total of 199 cases of mEOC were identified from a prospectively maintained gynecologic oncology tumor database. DNA was extracted and analyzed for KRAS mutations by using Sanger sequencing. Further MassArray sequencing was performed on 45 samples. Clinicopathologic correlation was performed with the results obtained. FINDINGS: KRAS mutation status was evaluable in 124 cases. Fifty-five percent (68/124) were KRAS negative, whereas 45% (56/124) harbored a KRAS mutation, lower than that in Western populations. Successful ascertainment of both KRAS and HER2 statuses by Sanger sequencing occurred for 105 cases. The proportion of the double-positive subtype (HER2+ and KRAS positive) was 8% (8/105); double-negative subtype (HER2- and KRAS negative), 34% (36/105); and cases with mutation in either KRAS or HER2, 58% (61/105). The KRAS mutation rate was 44%, 50%, and 29% among Chinese, Indians, and Malays, respectively. There was no significant difference in overall survival (P = 0.952) or progression-free survival (P = 0.635) between KRAS-positive and KRAS-negative patients. Similar results were observed for progression-free survival (P = 0.206) and overall survival (P = 0.440) when outcomes were examined between the 4 groups based on KRAS and HER2 mutation. Patients in the double-negative mutation subgroup had higher risk for death/progression compared with patients in the other 3 mutation subgroups. Further MassARRAY multiplexed profiling was performed in patients with sufficient DNA material (n = 45) and yielded KRAS mutations (n = 16), PDGFRA mutations (n = 3), PIK3CA (n = 1) and KIT (n = 1), and HRAS, FGFR, MET, and NRAS (n = 1 each). CONCLUSIONS: Our study provides further knowledge about the mutational aberrations in mEOC in Asian populations. Neither the presence of KRAS mutation nor their correlation with HER2 mutations influenced outcomes.


Assuntos
Adenocarcinoma Mucinoso/genética , Povo Asiático/genética , Mutação , Neoplasias Ovarianas/genética , Adenocarcinoma Mucinoso/patologia , Adulto , Análise Mutacional de DNA , DNA de Neoplasias/genética , DNA de Neoplasias/isolamento & purificação , Intervalo Livre de Doença , Feminino , Humanos , Imuno-Histoquímica , Hibridização In Situ , Pessoa de Meia-Idade , Neoplasias Ovarianas/patologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Receptor ErbB-2/genética
2.
Am J Hum Genet ; 92(5): 820-6, 2013 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-23643385

RESUMO

Myopia, or near-sightedness, is an ocular refractive error of unfocused image quality in front of the retinal plane. Individuals with high-grade myopia (dioptric power greater than -6.00) are predisposed to ocular morbidities such as glaucoma, retinal detachment, and myopic maculopathy. Nonsyndromic, high-grade myopia is highly heritable, and to date multiple gene loci have been reported. We performed exome sequencing in 4 individuals from an 11-member family of European descent from the United States. Affected individuals had a mean dioptric spherical equivalent of -22.00 sphere. A premature stop codon mutation c.157C>T (p.Gln53*) cosegregating with disease was discovered within SCO2 that maps to chromosome 22q13.33. Subsequent analyses identified three additional mutations in three highly myopic unrelated individuals (c.341G>A, c.418G>A, and c.776C>T). To determine differential gene expression in a developmental mouse model, we induced myopia by applying a -15.00D lens over one eye. Messenger RNA levels of SCO2 were significantly downregulated in myopic mouse retinae. Immunohistochemistry in mouse eyes confirmed SCO2 protein localization in retina, retinal pigment epithelium, and sclera. SCO2 encodes for a copper homeostasis protein influential in mitochondrial cytochrome c oxidase activity. Copper deficiencies have been linked with photoreceptor loss and myopia with increased scleral wall elasticity. Retinal thinning has been reported with an SC02 variant. Human mutation identification with support from an induced myopic animal provides biological insights of myopic development.


Assuntos
Proteínas de Transporte/genética , Cromossomos Humanos Par 22/genética , Regulação da Expressão Gênica/genética , Predisposição Genética para Doença/genética , Proteínas Mitocondriais/genética , Miopia/genética , Animais , Sequência de Bases , Códon sem Sentido/genética , Cobre/metabolismo , Exoma/genética , Genes Dominantes/genética , Humanos , Imuno-Histoquímica , Camundongos , Chaperonas Moleculares , Dados de Sequência Molecular , Miopia/patologia , Mutação Puntual/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Análise de Sequência de DNA , Estados Unidos , População Branca/genética
3.
Gut ; 64(5): 707-19, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25053715

RESUMO

OBJECTIVE: Gastric cancer (GC) is a deadly malignancy for which new therapeutic strategies are needed. Three transcription factors, KLF5, GATA4 and GATA6, have been previously reported to exhibit genomic amplification in GC. We sought to validate these findings, investigate how these factors function to promote GC, and identify potential treatment strategies for GCs harbouring these amplifications. DESIGN: KLF5, GATA4 and GATA6 copy number and gene expression was examined in multiple GC cohorts. Chromatin immunoprecipitation with DNA sequencing was used to identify KLF5/GATA4/GATA6 genomic binding sites in GC cell lines, and integrated with transcriptomics to highlight direct target genes. Phenotypical assays were conducted to assess the function of these factors in GC cell lines and xenografts in nude mice. RESULTS: KLF5, GATA4 and GATA6 amplifications were confirmed in independent GC cohorts. Although factor amplifications occurred in distinct sets of GCs, they exhibited significant mRNA coexpression in primary GCs, consistent with KLF5/GATA4/GATA6 cross-regulation. Chromatin immunoprecipitation with DNA sequencing revealed a large number of genomic sites co-occupied by KLF5 and GATA4/GATA6, primarily located at gene promoters and exhibiting higher binding strengths. KLF5 physically interacted with GATA factors, supporting KLF5/GATA4/GATA6 cooperative regulation on co-occupied genes. Depletion and overexpression of these factors, singly or in combination, reduced and promoted cancer proliferation, respectively, in vitro and in vivo. Among the KLF5/GATA4/GATA6 direct target genes relevant for cancer development, one target gene, HNF4α, was also required for GC proliferation and could be targeted by the antidiabetic drug metformin, revealing a therapeutic opportunity for KLF5/GATA4/GATA6 amplified GCs. CONCLUSIONS: KLF5/GATA4/GATA6 may promote GC development by engaging in mutual crosstalk, collaborating to maintain a pro-oncogenic transcriptional regulatory network in GC cells.


Assuntos
Fator de Transcrição GATA4/genética , Fator de Transcrição GATA6/genética , Regulação Neoplásica da Expressão Gênica/genética , Fatores de Transcrição Kruppel-Like/genética , Neoplasias Gástricas/genética , Animais , Proliferação de Células , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Fator de Transcrição GATA4/biossíntese , Fator de Transcrição GATA6/biossíntese , Perfilação da Expressão Gênica/métodos , Inativação Gênica , Predisposição Genética para Doença , Xenoenxertos , Humanos , Fatores de Transcrição Kruppel-Like/biossíntese , Camundongos Nus , Transplante de Neoplasias , Oncogenes/genética , Regiões Promotoras Genéticas , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Células Tumorais Cultivadas
4.
Carcinogenesis ; 36(4): 441-51, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25742747

RESUMO

Gastric cancer (GC) is the second leading cause of global cancer mortality worldwide. However, the molecular mechanism underlying its carcinogenesis and drug resistance is not well understood. To identify novel functionally important genes that were differentially expressed due to combinations of genetic and epigenetic changes, we analyzed datasets containing genome-wide mRNA expression, DNA copy number alterations and DNA methylation status from 154 primary GC samples and 47 matched non-neoplastic mucosa tissues from Asian patients. We used concepts of 'within' and 'between' statistical analysis to compare the difference between tumors and controls within each platform, and assessed the correlations between platforms. This 'multi-regulated gene (MRG)' analysis identified 126 differentially expressed genes that underwent a combination of copy number and DNA methylation changes. Most genes were located at genomic loci associated with GC. Statistical enrichment analysis showed that MRGs were enriched for cancer, GC and drug response. We analysed several MRGs that previously had not been associated with GC. Knockdown of DDX27, TH1L or IDH3G sensitized cells to epirubicin or cisplatin, and knockdown of RAI14 reduced cell proliferation. Further studies showed that overexpression of DDX27 reduced epirubicin-induced DNA damage and apoptosis. Levels of DDX27 mRNA and protein were increased in early-stage gastric tumors, and may be a potential diagnostic and prognostic marker for GC. In summary, we used an integrative bioinformatics strategy to identify novel genes that are altered in GC and regulate resistance of GC cells to drugs in vitro.


Assuntos
Antineoplásicos/farmacologia , RNA Helicases DEAD-box/genética , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética , Apoptose/efeitos dos fármacos , Apoptose/genética , Proteínas de Ligação ao Cálcio , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Cisplatino/farmacologia , Proteínas do Citoesqueleto/genética , RNA Helicases DEAD-box/biossíntese , Variações do Número de Cópias de DNA/genética , Dano ao DNA/efeitos dos fármacos , Dano ao DNA/genética , Metilação de DNA/genética , Bases de Dados de Ácidos Nucleicos , Epirubicina/farmacologia , Mucosa Gástrica/citologia , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Histonas/genética , Humanos , Proteínas do Tecido Nervoso/genética , Prognóstico , Interferência de RNA , RNA Interferente Pequeno , Estudos Retrospectivos , Fatores de Transcrição/genética
6.
PLoS Genet ; 8(6): e1002753, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22685421

RESUMO

As one of the leading causes of visual impairment and blindness, myopia poses a significant public health burden in Asia. The primary determinant of myopia is an elongated ocular axial length (AL). Here we report a meta-analysis of three genome-wide association studies on AL conducted in 1,860 Chinese adults, 929 Chinese children, and 2,155 Malay adults. We identified a genetic locus on chromosome 1q41 harboring the zinc-finger 11B pseudogene ZC3H11B showing genome-wide significant association with AL variation (rs4373767, ß = -0.16 mm per minor allele, P(meta) =2.69 × 10(-10)). The minor C allele of rs4373767 was also observed to significantly associate with decreased susceptibility to high myopia (per-allele odds ratio (OR) =0.75, 95% CI: 0.68-0.84, P(meta) =4.38 × 10(-7)) in 1,118 highly myopic cases and 5,433 controls. ZC3H11B and two neighboring genes SLC30A10 and LYPLAL1 were expressed in the human neural retina, retinal pigment epithelium, and sclera. In an experimental myopia mouse model, we observed significant alterations to gene and protein expression in the retina and sclera of the unilateral induced myopic eyes for the murine genes ZC3H11A, SLC30A10, and LYPLAL1. This supports the likely role of genetic variants at chromosome 1q41 in influencing AL variation and high myopia.


Assuntos
Proteínas de Transporte/genética , Cromossomos Humanos Par 1/genética , Estudo de Associação Genômica Ampla , Miopia/genética , Polimorfismo de Nucleotídeo Único/genética , Adulto , Animais , Proteínas de Transporte de Cátions/genética , Criança , China , Modelos Animais de Doenças , Feminino , Expressão Gênica , Predisposição Genética para Doença , Humanos , Lisofosfolipase/genética , Masculino , Camundongos , Pessoa de Meia-Idade , Proteínas Nucleares , Proteínas de Ligação a RNA , Retina/metabolismo , Retina/patologia , Epitélio Pigmentado da Retina/metabolismo , Esclera/metabolismo , Esclera/patologia , Transportador 8 de Zinco
7.
Gastroenterology ; 145(3): 554-65, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23684942

RESUMO

BACKGROUND & AIMS: Almost all gastric cancers are adenocarcinomas, which have considerable heterogeneity among patients. We sought to identify subtypes of gastric adenocarcinomas with particular biological properties and responses to chemotherapy and targeted agents. METHODS: We compared gene expression patterns among 248 gastric tumors; using a robust method of unsupervised clustering, consensus hierarchical clustering with iterative feature selection, we identified 3 major subtypes. We developed a classifier for these subtypes and validated it in 70 tumors from a different population. We identified distinct genomic and epigenomic properties of the subtypes. We determined drug sensitivities of the subtypes in primary tumors using clinical survival data, and in cell lines through high-throughput drug screening. RESULTS: We identified 3 subtypes of gastric adenocarcinoma: proliferative, metabolic, and mesenchymal. Tumors of the proliferative subtype had high levels of genomic instability, TP53 mutations, and DNA hypomethylation. Cancer cells of the metabolic subtype were more sensitive to 5-fluorouracil than the other subtypes. Furthermore, in 2 independent groups of patients, those with tumors of the metabolic subtype appeared to have greater benefits with 5-fluorouracil treatment. Tumors of the mesenchymal subtype contain cells with features of cancer stem cells, and cell lines of this subtype are particularly sensitive to phosphatidylinositol 3-kinase-AKT-mTOR inhibitors in vitro. CONCLUSIONS: Based on gene expression patterns, we classified gastric cancers into 3 subtypes, and validated these in an independent set of tumors. The subgroups have differences in molecular and genetic features and response to therapy; this information might be used to select specific treatment approaches for patients with gastric cancer.


Assuntos
Adenocarcinoma/classificação , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/genética , Fluoruracila/uso terapêutico , Regulação Neoplásica da Expressão Gênica , Inibidores de Fosfoinositídeo-3 Quinase , Neoplasias Gástricas/classificação , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Idoso , Teorema de Bayes , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Análise por Conglomerados , Estudos de Associação Genética , Humanos , Pessoa de Meia-Idade , Modelos Estatísticos , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Análise de Regressão , Estudos Retrospectivos , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Análise de Sobrevida , Serina-Treonina Quinases TOR/antagonistas & inibidores , Resultado do Tratamento
8.
PLoS Genet ; 7(12): e1002402, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22144915

RESUMO

Corneal astigmatism refers to refractive abnormalities and irregularities in the curvature of the cornea, and this interferes with light being accurately focused at a single point in the eye. This ametropic condition is highly prevalent, influences visual acuity, and is a highly heritable trait. There is currently a paucity of research in the genetic etiology of corneal astigmatism. Here we report the results from five genome-wide association studies of corneal astigmatism across three Asian populations, with an initial discovery set of 4,254 Chinese and Malay individuals consisting of 2,249 cases and 2,005 controls. Replication was obtained from three surveys comprising of 2,139 Indians, an additional 929 Chinese children, and an independent 397 Chinese family trios. Variants in PDGFRA on chromosome 4q12 (lead SNP: rs7677751, allelic odds ratio = 1.26 (95% CI: 1.16-1.36), P(meta) = 7.87×10(-9)) were identified to be significantly associated with corneal astigmatism, exhibiting consistent effect sizes across all five cohorts. This highlights the potential role of variants in PDGFRA in the genetic etiology of corneal astigmatism across diverse Asian populations.


Assuntos
Astigmatismo/genética , Doenças da Córnea/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Erros de Refração/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Ásia , Astigmatismo/patologia , Estudos de Casos e Controles , Criança , Pré-Escolar , Estudos de Coortes , Doenças da Córnea/patologia , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Erros de Refração/patologia
9.
Cureus ; 16(2): e53681, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38455780

RESUMO

The removal of an ectopic molar tooth at the pterygomaxillary junction may be challenging. This paper presents the use of three-dimensional (3D) printing of the paranasal sinus for careful planning in a way that reduces the risk and makes surgical procedures more effective. A 26-year-old gentleman presented to the ENT department with a left antrochoanal polyp and an incidental ectopic tooth at the pterygomaxillary junction. Pre-operative 3D reconstruction of the maxillary cavity and subsequent 3D printing were used to guide the surgery and counsel the patient on potential outcomes. Left anterior functional endoscopic sinus surgery was subsequently done, and the antrochoanal polyp was completely removed. The preoperative computed tomography scan allowed for the production of the printed model to the exact size and dimensions of the ectopic molar tooth to facilitate the planning of the surgery and to aid in consenting the patient for the treatment.

10.
Hum Mol Genet ; 20(4): 649-58, 2011 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-21098505

RESUMO

Central corneal thickness (CCT) is a risk factor of glaucoma, the most common cause of irreversible blindness worldwide. The identification of genetic determinants affecting CCT in the normal population will provide insights into the mechanisms underlying the association between CCT and glaucoma, as well as the pathogenesis of glaucoma itself. We conducted two genome-wide association studies for CCT in 5080 individuals drawn from two ethnic populations in Singapore (2538 Indian and 2542 Malays) and identified novel genetic loci significantly associated with CCT (COL8A2 rs96067, p(meta) = 5.40 × 10⁻¹³, interval of RXRA-COL5A1 rs1536478, p(meta) = 3.05 × 10⁻9). We confirmed the involvement of a previously reported gene for CCT and brittle cornea syndrome (ZNF469) [rs9938149 (p(meta) = 1.63 × 10⁻¹6) and rs12447690 (p(meta) = 1.92 × 10⁻¹4)]. Evidence of association exceeding the formal threshold for genome-wide significance was observed at rs7044529, an SNP located within COL5A1 when data from this study (n = 5080, P = 0.0012) were considered together with all published data (reflecting an additional 7349 individuals, p(Fisher) = 1.5 × 10⁻9). These findings implicate the involvement of collagen genes influencing CCT and thus, possibly the pathogenesis of glaucoma.


Assuntos
Povo Asiático/genética , Colágeno/genética , Córnea/patologia , Estudo de Associação Genômica Ampla , Glaucoma/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Colágeno Tipo VIII/genética , Feminino , Glaucoma/etnologia , Humanos , Malásia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Fatores de Risco , Singapura
11.
Hum Mol Genet ; 20(18): 3693-8, 2011 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-21665993

RESUMO

Corneal curvature (CC) is a key determinant of major eye diseases, such as keratoconus, myopia and corneal astigmatism. No prior studies have discovered the genes for CC. Here we report the findings from four genome-wide association studies of CC in 10 008 samples from three population groups in Singapore. Our discovery phase surveyed 2867 Chinese and 3072 Malays, allowing us to identify two loci that were associated with CC variation: FRAP1 on chromosome 1p36.2 and PDGFRA on chromosome 4q12. These findings were subsequently replicated in a validation study involving an additional 2953 Asian Indians and a further collection of 1116 Chinese children. The effect sizes of the identified variants were consistent across all four cohorts, with seven single nucleotide polymorphisms (SNPs) in FRAP1 (lead SNP: rs17036350, meta P-value = 4.06 × 10(-13)) and six SNPs in PDGFRA (lead SNP: rs2114039, meta P-value = 1.33 × 10(-9)) attaining genome-wide significance in the SNP-based meta-analysis of the four studies. This is the first genome-wide survey of CC variation and we have identified two implicated loci in three genetically diverse Asian populations, suggesting the presence of common genetic etiology across multiple populations.


Assuntos
Doenças da Córnea/genética , Variação Genética , Estudo de Associação Genômica Ampla , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Serina-Treonina Quinases TOR/genética , Adolescente , Adulto , Idoso , Povo Asiático/genética , Criança , Cromossomos Humanos Par 1/genética , Cromossomos Humanos Par 4/genética , Estudos de Coortes , Doenças da Córnea/etnologia , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Singapura/etnologia , Serina-Treonina Quinases TOR/metabolismo , Adulto Jovem
12.
Gut ; 61(5): 673-84, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22315472

RESUMO

OBJECTIVE: Gastric cancer is a major gastrointestinal malignancy for which targeted therapies are emerging as treatment options. This study sought to identify the most prevalent molecular targets in gastric cancer and to elucidate systematic patterns of exclusivity and co-occurrence among these targets, through comprehensive genomic analysis of a large panel of gastric cancers. DESIGN: Using high-resolution single nucleotide polymorphism arrays, copy number alterations were profiled in a panel of 233 gastric cancers (193 primary tumours, 40 cell lines) and 98 primary matched gastric non-malignant samples. For selected alterations, their impact on gene expression and clinical outcome were evaluated. RESULTS: 22 recurrent focal alterations (13 amplifications and nine deletions) were identified. These included both known targets (FGFR2, ERBB2) and also novel genes in gastric cancer (KLF5, GATA6). Receptor tyrosine kinase (RTK)/RAS alterations were found to be frequent in gastric cancer. This study also demonstrates, for the first time, that these alterations occur in a mutually exclusive fashion, with KRAS gene amplifications highlighting a clinically relevant but previously underappreciated gastric cancer subgroup. FGFR2-amplified gastric cancers were also shown to be sensitive to dovitinib, an orally bioavailable FGFR/VEGFR targeting agent, potentially representing a subtype-specific therapy for FGFR2-amplified gastric cancers. CONCLUSION: The study demonstrates the existence of five distinct gastric cancer patient subgroups, defined by the signature genomic alterations FGFR2 (9% of tumours), KRAS (9%), EGFR (8%), ERBB2 (7%) and MET (4%). Collectively, these subgroups suggest that at least 37% of gastric cancer patients may be potentially treatable by RTK/RAS directed therapies.


Assuntos
Amplificação de Genes , Deleção de Genes , Polimorfismo de Nucleotídeo Único , Neoplasias Gástricas/genética , Antineoplásicos/uso terapêutico , Receptores ErbB/genética , Marcadores Genéticos , Terapia de Alvo Molecular , Análise de Sequência com Séries de Oligonucleotídeos , Modelos de Riscos Proporcionais , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas c-met/genética , Proteínas Proto-Oncogênicas p21(ras) , Receptor ErbB-2/genética , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/mortalidade , Proteínas ras/genética
13.
Indian J Otolaryngol Head Neck Surg ; 75(2): 1259-1262, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-37275017

RESUMO

Background: Endoscopic nasal surgery is often a tedious process due to repeated removal of the Hopkins rod telescope from the nasal cavity for manual defogging of the tip due to the presence of blood, smoke, and secretions. Objective: To design and print a 3-dimensional (3D) low-cost telescopic sleeve to allow the defogging solution to clean the rigid telescope tip without removing it from the nasal cavity. In addition, the sleeve must also act as a conduit for suction and irrigation to provide a clear surgical field view intraoperatively. Results and conclusion: A 3D printed low-cost telescopic sleeve, when used in conjunction with other add-ons, can be a helpful and cost-effective adjunct during endoscopic nasal surgery. Supplementary Information: The online version contains supplementary material available at 10.1007/s12070-022-03281-0.

14.
Hum Genet ; 131(9): 1467-80, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22665138

RESUMO

Myopia is a complex genetic disorder and a common cause of visual impairment among working age adults. Genome-wide association studies have identified susceptibility loci on chromosomes 15q14 and 15q25 in Caucasian populations of European ancestry. Here, we present a confirmation and meta-analysis study in which we assessed whether these two loci are also associated with myopia in other populations. The study population comprised 31 cohorts from the Consortium of Refractive Error and Myopia (CREAM) representing 4 different continents with 55,177 individuals; 42,845 Caucasians and 12,332 Asians. We performed a meta-analysis of 14 single nucleotide polymorphisms (SNPs) on 15q14 and 5 SNPs on 15q25 using linear regression analysis with spherical equivalent as a quantitative outcome, adjusted for age and sex. We calculated the odds ratio (OR) of myopia versus hyperopia for carriers of the top-SNP alleles using a fixed effects meta-analysis. At locus 15q14, all SNPs were significantly replicated, with the lowest P value 3.87 × 10(-12) for SNP rs634990 in Caucasians, and 9.65 × 10(-4) for rs8032019 in Asians. The overall meta-analysis provided P value 9.20 × 10(-23) for the top SNP rs634990. The risk of myopia versus hyperopia was OR 1.88 (95 % CI 1.64, 2.16, P < 0.001) for homozygous carriers of the risk allele at the top SNP rs634990, and OR 1.33 (95 % CI 1.19, 1.49, P < 0.001) for heterozygous carriers. SNPs at locus 15q25 did not replicate significantly (P value 5.81 × 10(-2) for top SNP rs939661). We conclude that common variants at chromosome 15q14 influence susceptibility for myopia in Caucasian and Asian populations world-wide.


Assuntos
Cromossomos Humanos Par 15 , Miopia/genética , Alelos , Humanos , Fenótipo , Polimorfismo de Nucleotídeo Único
15.
Oncologist ; 17(10): 1286-93, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22829569

RESUMO

BACKGROUND: In 2008, the Federation of Gynecology and Obstetrics (FIGO) revised their 1988 staging system for uterine leiomyosarcomas. In this article, we compare performance of the 2008 and 1988 FIGO systems. METHODS: Individual case data were manually culled. Staging was retrospectively assessed according to revised and 1998 FIGO criteria. Overall survival distribution was assessed by the Kaplan-Meier method. Harrell's concordance index was used to assess the discriminative ability of a fitted Cox model to predict overall survival. RESULTS: A total of 110 cases of uterine leiomyosarcomas were reviewed and data from 88 patients were analyzed. In all, 71% of cases were classified as stage I, 7% as stage II, 3% as stage III, and 19% as stage IV under the revised FIGO staging system. Nine patients (10.2%) were downstaged and none were upstaged. The revised FIGO system did not show a significant improvement over the 1988 FIGO system in the ability to discriminate the risk of death of patients between stages, with concordance indexes of 0.70 and 0.71, respectively. Most patients were classified as stage I with age, tumor grade, tumor size, and lymphovascular invasion as prognostic factors. CONCLUSION: The 2008 revised FIGO staging system for uterine leiomyosarcomas does not perform better than the 1988 system for uterine endometrial carcinomas. A better staging system is needed for these cases.


Assuntos
Leiomiossarcoma/patologia , Neoplasias Uterinas/patologia , Adulto , Idoso , Povo Asiático , Feminino , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Análise de Sobrevida
16.
Mol Vis ; 18: 1436-48, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22736935

RESUMO

PURPOSE: The aim of this study was to identify the genes and pathways underlying the growth of the mouse sclera during postnatal development. METHODS: Total RNA was isolated from each of 30 single mouse sclera (n=30, 6 sclera each from 1-, 2-, 3-, 6-, and 8-week-old mice) and reverse-transcribed into cDNA using a T7-N(6) primer. The resulting cDNA was fragmented, labeled with biotin, and hybridized to a Mouse Gene 1.0 ST Array. ANOVA analysis was then performed using Partek Genomic Suite 6.5 beta and differentially expressed transcript clusters were filtered based on a selection criterion of ≥ 2 relative fold change at a false discovery rate of ≤ 5%. Genes identified as involved in the main biologic processes during postnatal scleral development were further confirmed using qPCR. A possible pathway that contributes to the postnatal development of the sclera was investigated using Ingenuity Pathway Analysis software. RESULTS: The hierarchical clustering of all time points showed that they did not cluster according to age. The highest number of differentially expressed transcript clusters was found when week 1 and week 2 old scleral tissues were compared. The peroxisome proliferator- activated receptor gamma coactivator 1-alpha (Ppargc1a) gene was found to be involved in the networks generated using Ingenuity Pathway Studio (IPA) from the differentially expressed transcript cluster lists of week 2 versus 1, week 3 versus 2, week 6 versus 3, and week 8 versus 6. The gene expression of Ppargc1a varied during scleral growth from week 1 to 2, week 2 to 3, week 3 to 6, and week 6 to 8 and was found to interact with a different set of genes at different scleral growth stages. Therefore, this indicated that Ppargc1a might play a role in scleral growth during postnatal weeks 1 to 8. CONCLUSIONS: Gene expression of eye diseases should be studied as early as postnatal weeks 1-2 to ensure that any changes in gene expression pattern during disease development are detected. In addition, we propose that Ppargc1a might play a role in regulating postnatal scleral development by interacting with a different set of genes at different scleral growth stages.


Assuntos
Proteínas do Olho/genética , Regulação da Expressão Gênica no Desenvolvimento , Redes Reguladoras de Genes , Genoma , Esclera/metabolismo , Transativadores/genética , Animais , Animais Recém-Nascidos , Proteínas do Olho/metabolismo , Perfilação da Expressão Gênica , Camundongos , Camundongos Endogâmicos BALB C , Família Multigênica , Análise de Sequência com Séries de Oligonucleotídeos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , RNA Mensageiro , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Esclera/crescimento & desenvolvimento , Software , Fatores de Tempo , Transativadores/metabolismo , Fatores de Transcrição
17.
Nucleic Acids Res ; 38(9): e105, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20142258

RESUMO

Determination of copy number variants (CNVs) inferred in genome wide single nucleotide polymorphism arrays has shown increasing utility in genetic variant disease associations. Several CNV detection methods are available, but differences in CNV call thresholds and characteristics exist. We evaluated the relative performance of seven methods: circular binary segmentation, CNVFinder, cnvPartition, gain and loss of DNA, Nexus algorithms, PennCNV and QuantiSNP. Tested data included real and simulated Illumina HumHap 550 data from the Singapore cohort study of the risk factors for Myopia (SCORM) and simulated data from Affymetrix 6.0 and platform-independent distributions. The normalized singleton ratio (NSR) is proposed as a metric for parameter optimization before enacting full analysis. We used 10 SCORM samples for optimizing parameter settings for each method and then evaluated method performance at optimal parameters using 100 SCORM samples. The statistical power, false positive rates, and receiver operating characteristic (ROC) curve residuals were evaluated by simulation studies. Optimal parameters, as determined by NSR and ROC curve residuals, were consistent across datasets. QuantiSNP outperformed other methods based on ROC curve residuals over most datasets. Nexus Rank and SNPRank have low specificity and high power. Nexus Rank calls oversized CNVs. PennCNV detects one of the fewest numbers of CNVs.


Assuntos
Algoritmos , Variações do Número de Cópias de DNA , Análise de Sequência com Séries de Oligonucleotídeos , Polimorfismo de Nucleotídeo Único , Simulação por Computador , Feminino , Humanos , Masculino , Miopia/genética
18.
Indian J Otolaryngol Head Neck Surg ; 74(Suppl 3): 5033-5036, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36742682

RESUMO

To describe the technique and outcome of a novel dual staged supraglottoplasty for the treatment of neurological induced adult onset laryngomalacia. A 55 year old male had a diagnosed neurodegenerative disorder with suspected Pompe's disease associated with Trap door epiglottis and proximal myopathy.This was complicated with emergency airway distress and subsequent tracheostomy.Trap-door epiglottis (also known as adult-onset laryngomalacia) associated with neurodegenerative disorders constitute a surgical challenge as it is often coupled with failure of tracheostomy decannulation when present. The patient underwent a novel dual staged endoscopic supraglottoplasty whereby an initial stage of epiglottopexy and submucosal diathermy was made at the vallecula.This was then followed by an interval of 6 weeks whereby a partial epiglottotectomy was made at the upper 3rd of the epiglottis and reduction of lingual tonsils was done using radiofrequency ablation.Trachesotomy was decannulated 1 month after the second stage procedure and his airway remains asymptomatic after 1 year of surgical treatment. This case report describes the success of tracheostomy decannulation after a novel dual staged supraglottoplasty for adult onset laryngomalcia (also known as trap-door epiglottis) .

19.
Indian J Otolaryngol Head Neck Surg ; 74(Suppl 3): 6032-6038, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36742789

RESUMO

Preoperative radiological assessment of parotid tumours represents a crucial step in the planning of a parotidectomy in order to avoid post-operative facial nerve paralysis. The purpose of this study is to determine the reliability of the novel 'M-line' in predicting the facial nerve position and compare it to various radiological methods in the same context. 66 patients whom had underwent parotidectomy for parotid tumours from January 2012 to February 2021 were analyzed. Parotid tumour location were identified using the retromandibular vein, facial nerve line, Conn's arc, Utrecht line and the 'M'-line were compared to the intraoperative location of parotid tumours.The 'M'-line is a novel hypothetical line (drawn between the lateral surface of the mandible to the lateral border of the mastoid process) used to identify the location of the facial nerve radiologically. The 'M-Line' and other methods of radiological assessments were associated with statistical significance in predicting if the parotid tumours were superficial or deep to the facial nerve (p-value < 0.05).The 'M-line' had demonstrated a sensitivity of 73.6% and 92.3% specificity.It had also yielded the highest accuracy (77.3%) in the prediction of the parotid tumour location in relation to the facial nerve. While the radiological lines represented by the Retromandibular vein,facial nerve line,Utrecht line and Conn's arc were statistically significant in predicting the location of the parotid tumour in relation to the facial nerve, the M-line was the most accurate and sensitive predictor in our study.The M-Line is a potentially useful tool to predict the location of the facial nerve in relation to a parotid tumour.

20.
Ophthalmology ; 118(2): 368-75, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21095009

RESUMO

OBJECTIVE: To determine susceptibility genes for high myopia in Singaporean Chinese. DESIGN: A meta-analysis of 2 genome-wide association (GWA) datasets in Chinese and a follow-up replication cohort in Japanese. PARTICIPANTS AND CONTROLS: Two independent datasets of Singaporean Chinese individuals aged 10 to 12 years (Singapore Cohort Study of the Risk factors for Myopia [SCORM]: cases = 65, controls = 238) and more than 21 years (Singapore Prospective Study Program [SP2]: cases = 222, controls = 435) for GWA studies, and a Japanese dataset aged more than 20 years (cases = 959, controls = 2128) for replication. METHODS: Genomic DNA samples from SCORM and SP2 were genotyped using various Illumina Beadarray platforms (>HumanHap 500). Single-locus association tests were conducted for each dataset with meta-analysis using pooled z-scores. The top-ranked genetic markers were examined for replication in the Japanese dataset. Fisher P was calculated for the combined analysis of all 3 cohorts. MAIN OUTCOME MEASURES: High myopia, defined by spherical equivalent (SE) ≤ -6.00 diopters (D); controls defined by SE between -0.50 and +1.00 D. RESULTS: Two SNPs (rs12716080 and rs6885224) in the gene CTNND2 on chromosome 5p15 ranked top in the meta-analysis of our Chinese datasets (meta P = 1.14 × 10(-5) and meta P = 1.51 × 10(-5), respectively) with strong supporting evidence in each individual dataset analysis (max P = 1.85 × 10(-4) in SCORM: max P = 8.8 × 10(-3) in SP2). Evidence of replication was observed in the Japanese dataset for rs6885224 (P = 0.035, meta P of 3 datasets: 7.84 × 10(-6)). CONCLUSIONS: This study identified a strong association of CTNND2 for high myopia in Asian datasets. The CTNND2 gene maps to a known high myopia linkage region on chromosome 5p15.


Assuntos
Povo Asiático/genética , Cateninas/genética , Miopia Degenerativa/genética , Polimorfismo de Nucleotídeo Único/genética , Criança , Mapeamento Cromossômico , Feminino , Seguimentos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Japão/epidemiologia , Masculino , Metanálise como Assunto , Pessoa de Meia-Idade , Fenótipo , Estudos Prospectivos , Fatores de Risco , Singapura/epidemiologia , delta Catenina
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