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1.
Bioengineered ; 12(2): 11578-11585, 2021 12.
Article in English | MEDLINE | ID: mdl-34874791

ABSTRACT

Adenomyoepithelioma (AME) of the breast is a rare tumor that is composed of proliferating epithelial and myoepithelial cells. The pathogenesis of AME remains unclear, and no breast cancer cells have been identified in such tumor tissues. In this study, we established patient-derived breast cancer organoids from the surgical tumor samples of an elderly Chinese woman with an AME of the breast. Our findings confirmed the successful establishment of organoids from an AME of the breast of this patient. A short tandem repeat analysis revealed that the DNA signature of the AME of the breast organoids matched the DNA signature of the original tumor specimen. Moreover, diameter assay confirmed that the organoids from the breast AME showed sensitivity to paclitaxel and doxorubicin treatments, which was similar to, but lesser than that of primary culture cells. In conclusion, we established an efficient 3-dimensional breast cancer organoid culture platform from an AME of the breast. This platform can be effectively used for exploring clinicopathological and genomic characteristics of AME of the breast to identify possible treatments and increase awareness about this disease entity.


Subject(s)
Adenomyoepithelioma/pathology , Breast Neoplasms/pathology , Organoids/pathology , Adenomyoepithelioma/diagnostic imaging , Adenomyoepithelioma/drug therapy , Adenomyoepithelioma/genetics , Aged , Breast Neoplasms/diagnostic imaging , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Female , Humans , Microsatellite Repeats/genetics , Tumor Cells, Cultured
2.
J Biochem ; 169(6): 693-700, 2021 Sep 07.
Article in English | MEDLINE | ID: mdl-33479730

ABSTRACT

We investigated the expression and functions of circular RNA (circRNA) circNINL and miR-921 in breast cancer (BC) in this study. We found that the expression of circNINL increased while the expression of miR-921 decreased in BC tissues and cell lines, and their anomalous expressions were associated with malignant features and poor prognostic of BC. Then, we demonstrated that circNINL could interact with miR-921 and facilitate BC cells malignant process including proliferation acceleration, migration enhancement and apoptosis evasion via sponging miR-921 in vitro. Further investigations revealed that circNINL/miR-921 axis could mediate the expression of ADAM9 which was a direct target of miR-921. In addition, we exhibited that ADAM9 may activate ß-catenin signaling by interacting with E-cadherin. We presented the vital roles of circNINL/miR-921/ADAM9/ß-catenin signaling in the progression of BC.


Subject(s)
ADAM Proteins/metabolism , Breast Neoplasms/pathology , Gene Expression Regulation, Neoplastic , Membrane Proteins/metabolism , MicroRNAs/genetics , Microtubule-Associated Proteins/genetics , Nuclear Proteins/genetics , RNA, Circular/genetics , beta Catenin/metabolism , ADAM Proteins/genetics , Apoptosis , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Cell Movement , Cell Proliferation , Female , Humans , Membrane Proteins/genetics , Middle Aged , Prognosis , Survival Rate , Tumor Cells, Cultured , beta Catenin/genetics
3.
J Med Genet ; 56(10): 647-653, 2019 10.
Article in English | MEDLINE | ID: mdl-30981987

ABSTRACT

BACKGROUND: Early detection of lung cancer to allow curative treatment remains challenging. Cell-free circulating tumour (ct) DNA (ctDNA) analysis may aid in malignancy assessment and early cancer diagnosis of lung nodules found in screening imagery. METHODS: The multicentre clinical study enrolled 192 patients with operable occupying lung diseases. Plasma ctDNA, white cell count genomic DNA (gDNA) and tumour tissue gDNA of each patient were analysed by ultra-deep sequencing to an average of 35 000× of the coding regions of 65 lung cancer-related genes. RESULTS: The cohort consists of a quarter of benign lung diseases and three quarters of cancer patients with all histopathology subtypes. 64% of the cancer patients are at stage I. Gene mutations detection in tissue gDNA and plasma ctDNA results in a sensitivity of 91% and specificity of 88%. When ctDNA assay was used as the test, the sensitivity was 69% and specificity 96%. As for the lung cancer patients, the assay detected 63%, 83%, 94% and 100%, for stages I, II, III and IV, respectively. In a linear discriminant analysis, combination of ctDNA, patient age and a panel of serum biomarkers boosted the overall sensitivity to 80% at a specificity of 99%. 29 out of the 65 genes harboured mutations in the patients with lung cancer with the largest number found in TP53 (30% plasma and 62% tumour tissue samples) and EGFR (20% and 40%, respectively). CONCLUSION: Plasma ctDNA was analysed in lung nodule assessment and early cancer detection, while an algorithm combining clinical information enhanced the test performance. TRIAL REGISTRATION NUMBER: NCT03081741.


Subject(s)
Circulating Tumor DNA/analysis , Lung Neoplasms/diagnosis , Lung Neoplasms/genetics , Adult , Aged , Cell-Free Nucleic Acids , Cohort Studies , Female , High-Throughput Nucleotide Sequencing , Humans , Lung Neoplasms/pathology , Male , Middle Aged , Mutation , Neoplasms/genetics , Prospective Studies , Sensitivity and Specificity , Sequence Analysis, DNA
4.
Mar Pollut Bull ; 125(1-2): 271-281, 2017 Dec 15.
Article in English | MEDLINE | ID: mdl-28844777

ABSTRACT

For tidal range power plants to be sustainable, the environmental impacts caused by the implement of various tidal barrage schemes must be assessed before construction. However, several problems exist in the current researches: firstly, evaluation criteria of the tidal barrage schemes environmental impact assessment (EIA) are not adequate; secondly, uncertainty of criteria information fails to be processed properly; thirdly, correlation among criteria is unreasonably measured. Hence the contributions of this paper are as follows: firstly, an evaluation criteria system is established from three dimensions of hydrodynamic, biological and morphological aspects. Secondly, cloud model is applied to describe the uncertainty of criteria information. Thirdly, Choquet integral with respect to λ-fuzzy measure is introduced to measure the correlation among criteria. On the above bases, a multi-criteria decision-making decision framework for tidal barrage scheme EIA is established to select the optimal scheme. Finally, a case study demonstrates the effectiveness of the proposed framework.


Subject(s)
Decision Making , Environment , Power Plants , Uncertainty
5.
Stroke ; 41(4): 757-64, 2010 Apr.
Article in English | MEDLINE | ID: mdl-20185789

ABSTRACT

BACKGROUND AND PURPOSE: Carotid ACCULINK/ACCUNET Post Approval Trial to Uncover Rare Events (CAPTURE 2) is an ongoing prospective, nonrandomized, multicenter clinical trial enrolling patients undergoing carotid artery stenting. The aim of this analysis is to identify risk predictors for periprocedural stroke in patients > or = 80 years old. METHODS: Symptomatic patients with > or = 50% stenosis and asymptomatic patients with > or = 80% stenosis were enrolled. Patients' neurological status was assessed by an independent neurologist before as well as 24 hours and 30 days postprocedure. All strokes and suspected strokes were adjudicated by an independent committee. Logistic regression analysis was conducted to identify baseline demographic, lesion, procedural, or comorbidity parameters associated with outcomes in patients > or = 80 years of age. RESULTS: As of January 10, 2009, 5297 patients underwent carotid artery stenting in 186 US CAPTURE 2 clinical centers and 1166 were > or = 80 years old. Octogenarians were similar to nonoctogenarians in terms of gender and symptomatic status but had fewer of certain risk factors (prior myocardial infarction or carotid endarterectomy, diabetes, smoking history) and more cardiac arrhythmia and renal insufficiency. For the overall cohort, death/stroke rate was 3.3%; stroke rate was 2.7% (0.8% major, 1.9% minor). Death/stroke rates were significantly higher for octogenarians than nonoctogenarians (4.5% versus 3.0%) as were stroke rates (3.8% versus 2.4%). Symptomatic status, embolic protection device dwell time, and lesion length were risk predictors for periprocedural stroke in octogenarians. CONCLUSIONS: Patients > or = 80 years old have higher periprocedural event rates than nonoctogenarians. Age, symptomatic status, and lesion length should be considered when identifying appropriate candidates for the procedure.


Subject(s)
Aged, 80 and over , Carotid Arteries/surgery , Carotid Stenosis , Stents/adverse effects , Stroke/etiology , Aged , Carotid Arteries/pathology , Carotid Stenosis/complications , Carotid Stenosis/surgery , Endarterectomy, Carotid/adverse effects , Female , Humans , Male , Prospective Studies , Regression Analysis , Risk Assessment , Risk Factors , Stroke/prevention & control , Treatment Outcome
6.
Heart Rhythm ; 1(5): 600-7, 2004 Nov.
Article in English | MEDLINE | ID: mdl-15851227

ABSTRACT

OBJECTIVES: The purpose of this study was to determine the prevalence and spectrum of nonsynonymous polymorphisms (amino acid variants) in the cardiac sodium channel among healthy subjects. BACKGROUND: Pathogenic mutations in the cardiac sodium channel gene, SCN5A, cause approximately 15 to 20% of Brugada syndrome (BrS1), 5 to 10% of long QT syndrome (LQT3), and 2 to 5% of sudden infant death syndrome. METHODS: Using single-stranded conformation polymorphism, denaturing high-performance liquid chromatography, and/or direct DNA sequencing, mutational analysis of the protein-encoding exons of SCN5A was performed on 829 unrelated, anonymous healthy subjects: 319 black, 295 white, 112 Asian, and 103 Hispanic. RESULTS: In addition to the four known common polymorphisms (R34C, H558R, S1103Y, and R1193Q), four relatively ethnic-specific polymorphisms were identified: R481W, S524Y, P1090L, and V1951L. Overall, 39 distinct missense variants (28 novel) were elucidated. Nineteen variants (49%) were found only in the black cohort. Only seven variants (18%) localized to transmembrane-spanning domains. Four variants (F1293S, R1512W, and V1951L cited previously as BrS1-causing mutations and S1787N previously published as a possible LQT3-causing mutation) were identified in this healthy cohort. CONCLUSIONS: This study provides the first comprehensive determination of the prevalence and spectrum of cardiac sodium channel variants in healthy subjects from four distinct ethnic groups. This compendium of SCN5A variants is critical for proper interpretation of SCN5A genetic testing and provides an essential hit list of targets for future functional studies to determine whether or not any of these variants mediate genetic susceptibility for arrhythmias in the setting of either drugs or disease.


Subject(s)
Gene Frequency , Polymorphism, Single-Stranded Conformational , Racial Groups/genetics , Sodium Channels/genetics , Bundle-Branch Block/genetics , Chromatography, High Pressure Liquid , DNA Mutational Analysis , Exons , Genetic Predisposition to Disease , Humans , Long QT Syndrome/genetics , Mutation, Missense , NAV1.5 Voltage-Gated Sodium Channel , Syndrome , Ventricular Fibrillation/genetics
7.
Pharmacogenomics ; 4(6): 779-89, 2003 Nov.
Article in English | MEDLINE | ID: mdl-14596641

ABSTRACT

The public SNP databases are an important resource for groups performing genetic association and linkage studies. Both academic and commercial groups are developing large numbers of genotyping assays for SNPs in candidate genes or spread across the genome. These databases now contain in excess of 6 million SNPs that have been generated using a large number of methods and cohorts. Today, however, only a small fraction of these SNPs are well characterized and validated. The latest release of dbSNP contains approximately 3.7 million non-redundant entries, only 0.5 million of which are validated, and 0.2 million of which have frequency information. Users of these databases have several common questions. How many of the SNPs are real? What is the frequency spectrum of the SNPs in these databases? What is the distribution picture of these SNPs across different ethnic and geographical populations? What fraction of the total number of SNPs is already captured by these databases? In order to address these questions, we compared the public SNPs against a well-characterized collection of gene-centric SNPs that we have developed. From this comparison, we find that > 50% of high frequency SNPs in the genome (> 20% minor allele frequency) have already been captured by these databases. The coverage drops dramatically below frequencies of 10%. At high frequencies, there is no sampling bias with respect to ethnicity or to regions of the genome. Finally, a relatively large fraction (> 40%) of SNPs in these databases were not seen in our study, which means that they are either of very low frequency, mismapped, or not polymorphic at all.


Subject(s)
Databases, Genetic/statistics & numerical data , Genome, Human , Polymorphism, Single Nucleotide/genetics , Databases, Genetic/trends , Humans
8.
Psychiatr Genet ; 12(2): 89-96, 2002 Jun.
Article in English | MEDLINE | ID: mdl-12131761

ABSTRACT

The treatment of seriously mentally ill patients is complicated by variability in individual response to psychotropic drugs. Some patients remain treatment refractory even after two to three therapeutic modalities. Other patients experience adverse events that range from mild discomfort, to poor compliance, to life threatening. Genaissance Pharmaceuticals is actively engaged in a candidate gene-based haplotype (HAP Marker) approach to the pharmacogenetics of drug response and adverse events. In the present article, we review reasons why HAP Markers are more useful than single nucleotide polymorphisms (SNPs) for discovering genetic correlations to clinical response. In addition, we review our approach to HAP Marker discovery, which involves discovering SNPs in the functional regions of genes by sequencing, organizing these SNPs into HAP Markers for an index population of ethnically diverse individuals and calculating population frequencies for these HAP Markers. For clinical correlations, HAP Markers are defined and correlated to clinical data using the in-house DecoGen Informatics System. This approach has clear implications for the discovery of psychiatric disease-associated genes as well as for the development of safer, more efficacious psychiatric drugs.


Subject(s)
Haplotypes , Pharmacogenetics/methods , Psychotropic Drugs/pharmacology , Drug Industry/trends , Genetic Markers , Humans , Mental Disorders/drug therapy , Mental Disorders/genetics
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