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1.
Eur J Cancer ; 125: 12-21, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31830689

RESUMO

PURPOSE: DNA mismatch repair (MMR) genes play important roles in maintaining genome stability. Mutations in MMR genes disrupt their mismatch repair function, cause genome instability and lead to increased risk of cancer in the mutation carriers as represented by Lynch Syndrome. Studies have identified a large number of MMR variants, mostly in the Caucasian population, whereas data from non-Caucasian populations remain poorly illustrated. With the population size of 1.4 billion, knowledge of MMR variants in the Chinese population can be valuable in understanding the roles of ethnic MMR variation and cancer and to further guide clinical applications in MMR-related cancer prevention and treatment in the Chinese population. In this study, we systematically analysed the MMR variants from the Chinese population. EXPERIMENTAL DESIGN: We performed a comprehensive MMR data mining and collected all the MMR variation data reported from 33,998 Chinese individuals consisting of 23,938 cancer and 10,060 non-cancer cases between January 1997 to May 2019. For the collected data, we performed standardisation following Human Genome Variation Society nomenclature and reannotated the MMR variant data following American College of Medical Genetics and Genomics guidelines and comparing with non-Chinese MMR data on various aspects. RESULTS: We identified a total of 540 MMR variants in the Chinese population, including 194 in MLH1, 181 in MSH2, 59 in MSH6, 53 in PMS2 single-base/indel changes and 53 large deletions/duplications in MLH1, MSH2, MSH6 and PMS2, respectively. We determined that the pathogenic/likely pathogenic carrier rate in the Chinese population was 1.6%. Comparative analysis in variant spectrum, variant types, clinical classification and founder mutations showed substantial differences of MMR variation between Chinese and non-Chinese populations and the fact that over 90% of the variants were only present in the Chinese ethnicity reveals the highly ethnic-specific nature of the Chinese MMR variation . We also developed an open-access database, dbMMR-Chinese, to host all data (https://dbMMR-chinese.fhs.um.edu.mo). The rich MMR data from a large non-Caucasian population should be valuable to study MMR variation and its relationship with cancer and provide a valuable reference resource for MMR-related cancer prevention and treatment. CONCLUSION: Our study provides the largest MMR data set from a single non-Caucasian population and reveals that MMR variation in the humans can be highly ethnic-specific.

2.
Mol Genet Genomic Med ; 8(2): e1079, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31867841

RESUMO

BACKGROUND: One of the major challenges in managing invasive breast cancer (BC) is the lack of reliable biomarkers to track response. Circulating tumor DNA (ctDNA) from liquid biopsy, as a candidate biomarker, provides a valuable assessment of BC patients. In this retrospective study, we evaluated the utility of ctDNA to reflect the efficacy of treatment and to monitor resistance mechanisms. METHODS: Targeted next-generation sequencing (NGS) of 416 cancer-relevant genes was performed on 41 plasma biopsy samples of 19 HER2+ and 12 HER2- BC patients. Longitudinal ctDNA samples were analyzed in three BC patients over the treatment course for detecting acquired mutations. RESULTS: In HER2+ BC patients, ERBB2 somatic copy numbers in ctDNA samples were significantly higher in patients progressed on HER2-targeted therapy than those who were still responding to the treatment. Recurrent acquired mutations were detected in genes including ERBB2, TP53, EGFR, NF1, and SETD2, which may contribute to trastuzumab resistance. In longitudinal analyses, the observed mutation allele frequencies were tracked closely in concordance with treatment responses. A novel ERBB2 p.(Leu869Arg) mutation was acquired in one patient upon resistant to trastuzumab therapy, which was further validated as an oncogenic mutation in vitro and contributed to resistance. In HER2- BC patients with chemotherapy resistance, genetic alterations on TP53, PIK3CA, and DNA damage repair genes were frequently observed. CONCLUSIONS: In summary, ctDNA monitoring, particularly longitudinal analyses, provides valuable insights into the assessment of targeted therapy efficacy and gene alterations underlying trastuzumab resistance and chemotherapy resistance in HER2+ and HER2- BC patients, respectively.

3.
Med Sci Monit ; 25: 9786-9793, 2019 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-31860635

RESUMO

BACKGROUND The aim of this study was to assess a radiomic scheme that combines image features from digital mammography and dynamic contrast-enhanced MRI to improve classification accuracy of nonpalpable breast lesion (NBL) with Breast Imaging-Reporting and Data System (BI-RADS) 3-5 microcalcifications-only in mammography. MATERIAL AND METHODS This retrospective study was approved by the Internal Research Review and Ethical Committee of our hospital. We included 81 patients who underwent a three-dimensional digital breast X-ray wire positioning for local resection between October 2012 and November 2016. All patients underwent breast MRI and mammography before the treatment, and all obtained pathological confirmation. According to the pathological results, 41 patients with benign lesions were assigned to the benign group and 40 patients with malignant lesions were assigned to the malignant group. We used the random forest algorithm to select significant features and to test the single and multimodal classifiers using the Leave-One-Out-Cross-Validation method. An area under the receiver operating characteristic curve was also used to evaluate its discriminating performance. RESULTS The multimodal classifier achieved AUC of 0.903, with a sensitivity of 82.5% and a specificity of 80.48%, which was better than any single modality. CONCLUSIONS Multimodal radiomics classification shows promising power in discriminating malignant lesions from benign lesions in NBL patients with BI-RADS 3-5 microcalcifications-only in mammography.

4.
Cancer Med ; 8(12): 5544-5553, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31385461

RESUMO

BACKGROUND: Previous case reports have shown the promising antitumor activity of everolimus in solid tumors containing molecular aberrations in PI3K/ATK/mTOR pathway, however, whether it is effective in patients with breast cancer remains unknown. Therefore, we conducted this retrospective cohort study to compare the efficacy of molecularly matched targeted therapy with everolimus to conventional therapy in refractory breast cancer patients harboring PI3K/ATK/mTOR pathway activating mutations. METHODS: Refractory metastatic breast cancer patients who have received molecular screening using next-generation sequencing (NGS) between September 8, 2015 and October 30, 2017 in two sites were screened for this study. The primary outcome was progression-free survival (PFS). The secondary outcomes were overall response rate (ORR), disease control rate (DCR), and safety profile. RESULTS: A total of 78 patients were screened for analysis, amongst all, 52 (66.7%) had at least one gene mutation in PI3K/AKT/mTOR pathway. The most common mutation fell in PIK3CA (76.9%, 40/52) with a mutational prevalence of 51.3%. Of the 32 patients who were eligible for efficacy analysis, patients in the everolimus group (n = 19) exhibited shorter PFS than those in the conventional group (n = 13) (median, 1.9 vs 6.1 months; HR, 3.6; 95% CI, 1.48-8.81; P = .0005). ORR was 15.4% (2/13) in the everolimus group and 23.1% (3/13) in the conventional group (P = 1.000), and DCR was 30.8% (4/13) and 100% (13/13) for each group, respectively (P = .000). The incidence of grade 3-5 adverse events was relatively higher in the conventional group (38.5%, 5/13) than that in the everolimus group (26.3%, 5/19). CONCLUSIONS: Our findings suggested that everolimus might not be effective for cancer patients harboring mutations in PI3K/ATK/mTOR pathway and physicians should be cautious about its off-label use in clinical practice.

5.
Breast Cancer Res Treat ; 178(1): 63-73, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31364001

RESUMO

BACKGROUND: Chromosomal instabilities (CIN) of plasma cell-free DNA (cfDNA) are common in breast cancer. We aimed to investigate the value of cfDNA CIN in monitoring the breast cancer relapse and additionally to compare it with the traditional biomarkers (CA15-3 and CEA). METHODS: Overall 62 recurrent breast cancer patients and 20 healthy controls were recruited. Low-pass whole-genome sequencing (LPWGS) was performed to detect cfDNA CIN. A CIN score was calculated. The performance of CA15-3, CEA, and CIN score in monitoring the recurrence was investigated with receiver operating characteristic (ROC) curve and the area under curve (AUC). Multivariable Cox proportional hazard model was established to analyze the correlations between copy number gain/loss and disease-free survival (DFS). RESULTS: cfDNA CIN achieved the positive rate of 77.6% [(95% confidence interval (CI) 73.4-95.3%)] among recurrent breast cancer patients, with an AUC value of 0.933, superior to CA15-3 (positive rate: 38.7%; AUC: 0.864) and CEA (positive rate: 41.93%; AUC: 0.878) (P < 0.01). The combination of cfDNA CIN with two biomarkers further increased the positive rate to 88.7% (95% confidence interval 77.5-95.0%). cfDNA CIN achieved better performance in patients with shorter DFS (≤ 41 months), with an AUC value of 0.975. CONCLUSIONS: cfDNA CIN yields a higher accuracy in monitoring breast cancer recurrence compared to traditional biomarkers (CA15-3 and CEA), especially for biomarker-negative patients. The combination of cfDNA CIN to traditional biomarkers further improved the detection rate of recurrence, which may provide a new method for monitoring the early relapse of breast cancer, though further investigations are warranted.

6.
Artigo em Inglês | MEDLINE | ID: mdl-31265410

RESUMO

The class imbalance problem has become a leading challenge. Although conventional imbalance learning methods are proposed to tackle this problem, they have some limitations: 1) undersampling methods suffer from losing important information and 2) cost-sensitive methods are sensitive to outliers and noise. To address these issues, we propose a hybrid optimal ensemble classifier framework that combines density-based undersampling and cost-effective methods through exploring state-of-the-art solutions using multi-objective optimization algorithm. Specifically, we first develop a density-based undersampling method to select informative samples from the original training data with probability-based data transformation, which enables to obtain multiple subsets following a balanced distribution across classes. Second, we exploit the cost-sensitive classification method to address the incompleteness of information problem via modifying weights of misclassified minority samples rather than the majority ones. Finally, we introduce a multi-objective optimization procedure and utilize connections between samples to self-modify the classification result using an ensemble classifier framework. Extensive comparative experiments conducted on real-world data sets demonstrate that our method outperforms the majority of imbalance and ensemble classification approaches.

7.
BMC Cancer ; 19(1): 551, 2019 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-31174498

RESUMO

BACKGROUND: Mutated BRCA1/2 genes are associated with hereditary breast and ovarian cancer (HBOC). So far most of the identified BRCA1/2 pathogenic variants are single nucleotide variants (SNVs) or insertions/deletions (Indels). However, large genomic rearrangements (LGRs) such as copy number variants (CNVs) are also playing an important role in HBOC predisposition. Their frequency and spectrum have been well studied in western populations but remain largely unknown for Chinese population. METHODS: Peripheral blood samples were collected from 218 unrelated familial breast and/or ovarian cancer (FBOC) patients living in Eastern China. PCR-based Sanger sequencing and panel-based next-generation sequencing (NGS) were performed to detect pathogenic SNVs and Indels in BRCA1/2 genes. For the patients lacking small pathogenic variants, multiplex ligation dependent probe amplification (MLPA) assay was conducted to screen for LGRs. RESULTS: In total, we identified 44 samples (20.1%) carrying small pathogenic variants (26 in BRCA1 and 18 in BRCA2, respectively). Among the rest of 174 samples, five were found carrying novel deleterious LGRs in BRCA1 which are exon5-7dup (1 patient), exon13-14dup (2 patients), and exon1-22del (2 patients). No LGR was found in BRCA2. Overall, LGRs accounted for 16.1% (5/31) of BRCA1 pathogenic variants, and were detected in 2.3% (5/218) of all FBOC patients. , CONCLUSIONS: LGR variants in BRCA1 gene play a significant role in Chinese HBOC patients. MLPA or other similar LGR-detecting methods should be recommended along with nucleotide sequencing as the initial screening approach for Chinese HBOC women.


Assuntos
Rearranjo Gênico , Genes BRCA1 , Genes BRCA2 , Predisposição Genética para Doença , Genômica , Síndrome Hereditária de Câncer de Mama e Ovário/genética , Mutação , Alelos , Substituição de Aminoácidos , China , Feminino , Genômica/métodos , Genótipo , Humanos , Linhagem , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNA
8.
IEEE Trans Cybern ; 2019 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-31180903

RESUMO

Healthcare question answering (HQA) system plays a vital role in encouraging patients to inquire for professional consultation. However, there are some challenging factors in learning and representing the question corpus of HQA datasets, such as high dimensionality, sparseness, noise, nonprofessional expression, etc. To address these issues, we propose an inception convolutional autoencoder model for Chinese healthcare question clustering (ICAHC). First, we select a set of kernels with different sizes using convolutional autoencoder networks to explore both the diversity and quality in the clustering ensemble. Thus, these kernels encourage to capture diverse representations. Second, we design four ensemble operators to merge representations based on whether they are independent, and input them into the encoder using different skip connections. Third, it maps features from the encoder into a lower-dimensional space, followed by clustering. We conduct comparative experiments against other clustering algorithms on a Chinese healthcare dataset. Experimental results show the effectiveness of ICAHC in discovering better clustering solutions. The results can be used in the prediction of patients' conditions and the development of an automatic HQA system.

9.
Front Oncol ; 9: 169, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30967997

RESUMO

Introduction: FANCC is reported as a novel susceptibility gene for breast cancer, however, its mutation remains unclear in Chinese population. We aimed to identify the germline mutations of FANCC in high-risk breast cancer patients in China. Methods: 255 BRCA1/2-negative Chinese familial breast and/or ovarian cancer (FBOC) patients were recruited for FANCC germline mutations screen. For whom 90 patients were detected by PCR-sequencing assay, and another 165 patients were detected by a 98-gene panel sequencing assay. The 98-gene panel sequencing assay was also used to screen other possible gene mutations for the patients with FANCC mutations detected by PCR-sequencing assay. Two hundred and fifty sporadic breast cancer (SBC) patients and 248 female non-cancer controls (FNCCs) were recruited for the genotyping analysis. Immunohistochemistry (IHC) analysis was used to evaluate the FANCC expression in patients with FANCC mutation. Results: We found one rare FANCC deleterious mutation (c.339G>A, p.W113X, 0.4%) and two novel non-synonymous variants (c.51G>C, p.Q17H, 0.4% and c.758C>A, p.A253E, 0.4%) in FBOC patients, whereas none of above mutations was identified in SBC patients or FNCCs. We also found that one novel synonymous variant (c.903A>G, p.A301A) existed in one FBOC patient. Additionally, two non-synonymous SNPs rs201407189 (c.973G>A, p.A325T) and rs1800367 (c.1345G>A, p.V449M), and two synonymous SNPs rs55719336 (c.816C>T, p.I272I) and rs79722116 (c.1407G>A, p.T469T) were identified in FBOC patients. Conclusion: FANCC deleterious mutations exist in Chinese FBOC patients and investigations on the penetrance and spectrum of FANCC mutations need to be further conducted.

10.
Br J Cancer ; 120(7): 728-745, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30816325

RESUMO

BACKGROUND: SHON nuclear expression (SHON-Nuc+) was previously reported to predict clinical outcomes to tamoxifen therapy in ERα+ breast cancer (BC). Herein we determined if SHON expression detected by specific monoclonal antibodies could provide a more accurate prediction and serve as a biomarker for anthracycline-based combination chemotherapy (ACT). METHODS: SHON expression was determined by immunohistochemistry in the Nottingham early-stage-BC cohort (n = 1,650) who, if eligible, received adjuvant tamoxifen; the Nottingham ERα- early-stage-BC (n = 697) patients who received adjuvant ACT; and the Nottingham locally advanced-BC cohort who received pre-operative ACT with/without taxanes (Neo-ACT, n = 120) and if eligible, 5-year adjuvant tamoxifen treatment. Prognostic significance of SHON and its relationship with the clinical outcome of treatments were analysed. RESULTS: As previously reported, SHON-Nuc+ in high risk/ERα+ patients was significantly associated with a 48% death risk reduction after exclusive adjuvant tamoxifen treatment compared with SHON-Nuc- [HR (95% CI) = 0.52 (0.34-0.78), p = 0.002]. Meanwhile, in ERα- patients treated with adjuvant ACT, SHON cytoplasmic expression (SHON-Cyto+) was significantly associated with a 50% death risk reduction compared with SHON-Cyto- [HR (95% CI) = 0.50 (0.34-0.73), p = 0.0003]. Moreover, in patients received Neo-ACT, SHON-Nuc- or SHON-Cyto+ was associated with an increased pathological complete response (pCR) compared with SHON-Nuc+ [21 vs 4%; OR (95% CI) = 5.88 (1.28-27.03), p = 0.012], or SHON-Cyto- [20.5 vs. 4.5%; OR (95% CI) = 5.43 (1.18-25.03), p = 0.017], respectively. After receiving Neo-ACT, patients with SHON-Nuc+ had a significantly lower distant relapse risk compared to those with SHON-Nuc- [HR (95% CI) = 0.41 (0.19-0.87), p = 0.038], whereas SHON-Cyto+ patients had a significantly higher distant relapse risk compared to SHON-Cyto- patients [HR (95% CI) = 4.63 (1.05-20.39), p = 0.043]. Furthermore, multivariate Cox regression analyses revealed that SHON-Cyto+ was independently associated with a higher risk of distant relapse after Neo-ACT and 5-year tamoxifen treatment [HR (95% CI) = 5.08 (1.13-44.52), p = 0.037]. The interaction term between ERα status and SHON-Nuc+ (p = 0.005), and between SHON-Nuc+ and tamoxifen therapy (p = 0.007), were both statistically significant. CONCLUSION: SHON-Nuce+ in tumours predicts response to tamoxifen in ERα+ BC while SHON-Cyto+ predicts response to ACT.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/metabolismo , Carcinoma Ductal de Mama/metabolismo , Proteínas Oncogênicas/metabolismo , Tamoxifeno/uso terapêutico , Adolescente , Adulto , Idoso , Antraciclinas/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Carcinoma Ductal de Mama/tratamento farmacológico , Núcleo Celular/metabolismo , Quimioterapia Adjuvante , Intervalo Livre de Doença , Receptor alfa de Estrogênio/metabolismo , Feminino , Humanos , Pessoa de Meia-Idade , Terapia Neoadjuvante , Recidiva Local de Neoplasia/epidemiologia , Prognóstico , Adulto Jovem
11.
Clin Lab ; 65(1)2019 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-30775882

RESUMO

BACKGROUND: Recent studies have established non-coding RNAs, which include microRNAs and lncRNAs, are aberrantly expressed in breast cancer. In this study, we explore the expression profile of microRNAs and lncRNAs in ER positive (ER+) breast and paracancerous tissues and define their possible correlations. METHODS: We collected ER+ breast cancer patients' and paracancerous tissues from the specimen bank of Zhejiang Cancer Hospital to extract total RNA for obtaining the expression level of microRNAs and lncRNAs by qRT-PCR. RESULTS: The relative expression results indicated that microRNAs such as MIR-191, MIR-213, MIR-122A had significantly higher expression and MIR-125B-1, MIR-125B-2, MIR-145 had lower expression in ER positive breast cancer compared to normal breast. The interaction of microRNA and lncRNA results exhibited upregulated MIR382-5P and lncRNA 362 in ER+ breast cancer compared to non-cancerous breast. By contrast, MIR222 and NFIA-AS1 are down-regulated. Furthermore, MIR222 and NFIA-AS1 showed different expressions in different TNM stages. CONCLUSIONS: MicroRNAs and lncRNAs are aberrantly expressed in ER+ breast cancer. It is inferred that these microRNAs and lncRNAs may be promising biomarkers for ER positive breast cancer.


Assuntos
Neoplasias da Mama/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , RNA Longo não Codificante/genética , Receptores Estrogênicos/genética , Adulto , Idoso , Biomarcadores Tumorais/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Regulação para Baixo , Feminino , Humanos , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Estadiamento de Neoplasias , RNA Longo não Codificante/metabolismo , Receptores Estrogênicos/metabolismo , Regulação para Cima
12.
Inflammation ; 42(3): 811-817, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30465301

RESUMO

To identify differentially expressed genes in sepsis and potential key role of reactive oxygen species (ROS) genes associated with sepsis. Gene expression dataset was available from GSE46599. Firstly, we screened the differentially expressed genes between sepsis and healthy samples. Then, the Database for Annotation, Visualization and Integrated Discovery (DAVID) online tools were utilized to perform gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses at the functional level. Differentially expressed genes mediating ROS levels were validated in the next investigation and analysis. We identified 1094 genes expressed differentially between normal and sepsis samples, including 655 upregulated genes and 439 downregulated genes. At the functional level, GO and KEGG pathway enrichment analysis showed that those differentially expressed genes were majorly associated with the immune response and metabolic process in sepsis. Further analysis revealed that neutrophil cytosolic factor 1(NCF1), a critical gene in the ROS system, upregulated in THP-1 cell and monocytes under lipopolysaccharides stimulation. Moreover, we identified the upregulation of NCF1 in a sepsis model. We screened the differentially expressed genes from the global level and identified NCF1 might be a critical target gene in sepsis.


Assuntos
Perfilação da Expressão Gênica , NADPH Oxidases/genética , Sepse/etiologia , Estudos de Casos e Controles , Regulação da Expressão Gênica , Ontologia Genética , Redes Reguladoras de Genes , Humanos , NADPH Oxidases/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Sepse/genética
13.
Oncogene ; 38(11): 1905-1919, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30390073

RESUMO

Tumor cells with p53 inactivation frequently exhibit chemotherapy resistance, which poses a long-standing challenge to cancer treatment. Here we unveiled a previously unrecognized role of TET2 in mediating p53-loss induced chemotherapy resistance in colon cancer. Deletion of TET2 in p53-null colon cancer cells enhanced DNA damage and restored chemotherapy sensitivity. By taking a two-pronged approach that combined pharmacological inhibition with genetic depletion, we discovered that p53 destabilized TET2 at the protein level by promoting its autophagic degradation. At the molecular level, we further revealed a physical association between TET2 and p53 that facilitated the nucleoplasmic shuttling of TET2, as well as its recruitment to the autophagosome for degradation. Our study has unveiled a functional interplay between TET2 and p53 during anti-cancer therapy. Our findings establish the rationale for targeting TET2 to overcome chemotherapy resistance associated with mutant p53 tumors.


Assuntos
Autofagia , Proteínas de Ligação a DNA/metabolismo , Resistencia a Medicamentos Antineoplásicos , Neoplasias/tratamento farmacológico , Proteínas Proto-Oncogênicas/metabolismo , Proteína Supressora de Tumor p53/fisiologia , Animais , Autofagia/genética , Resistencia a Medicamentos Antineoplásicos/genética , Células HCT116 , Células HEK293 , Células HT29 , Humanos , Células MCF-7 , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Proteólise , Células Tumorais Cultivadas
14.
IEEE Trans Neural Netw Learn Syst ; 30(2): 355-368, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29994135

RESUMO

Multitask clustering methods are proposed to improve performances of related tasks concurrently, because they explore the relationship among tasks via exploiting the coefficient matrix or the shared feature matrix. However, divergent effects of features in learning this relationship are seldom considered. To further improve performances, we propose a new multitask clustering approach through exploring correlations among tasks, clusters, and features based on effects of features on clusters. First, a Feature-Cluster (FeaCluster) matrix is introduced to capture the similarity and the distinct task-feature information simultaneously for each task. With the FeaCluster matrix, two affinities are calculated to constitute the interdependencies among tasks: the former is the graphical affinity based on feature-task and task-cluster correlations, while the latter is the reconstructive affinity. Here, the feature-task correlation considers effects of features on tasks, and the task-cluster correlation considers the overall effects of features on clusters. The reconstructive affinity is obtained by minimizing the reconstruction error when representing the FeaCluster matrix for a given task with a linear combination of others. The interdependencies among tasks allow transferring asymmetric shared information, exploring significant features and preserving key information when mapping data into the subspace. The experimental results on multiple data sets reveal that the proposed approach outperforms the state-of-the-art clustering methods in terms of accuracy and normal mutual information.

15.
J Cancer Res Ther ; 14(7): 1515-1518, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30589032

RESUMO

Background: Metastases to the thyroid gland are uncommon and often occur in patients with advanced metastatic diseases. The management and prognosis of secondary thyroid malignancies (STMs) are not well established. This retrospective study reported the incidence, clinical characteristics, treatment, and prognosis of STM in patients with metastatic tumors. Subjects and Methods: A total of 21 cases (1.2% incidence) diagnosed by fine-needle aspiration between January 2006 to December 2014 in a single center were reviewed. Survival analysis was made by Kaplan-Meier method. Results: The primary malignancies included esophagus cancer (7/21, 33.33%), breast cancer (6/21, 28.57%), head and neck cancer (3/21, 14.29%), unknown primary cancer (3/21, 14.29%), and lung cancer (2/21, 9.52%). The mean overall survival (OS) from diagnosis of primary malignancies was 57.26 months (95% confidence interval [CI]: 31.19-83.34) and the 2-year OS rate was 61.9%, and the mean OS from diagnosis of thyroid metastases was 31.20 months (95% CI: 12.23-50.18) and the 2-year OS rate was 34.3%. Patients with the head and neck cancer and breast cancer had better survival than other patients (from diagnosis of primary malignancies, P < 0.001; from diagnosis of thyroid metastases, P = 0.03). Histological types were also related to OS (from diagnosis of primary malignancies, P = 0.039; from diagnosis of thyroid metastases, P = 0.130). In addition, thyroidectomy may improve OS for patients with isolated metastases. Conclusion: The prognosis of STMs basically depends on the anatomic sites and histological types of primary cancers, and thyroidectomy may be considered for patients with isolated metastases.


Assuntos
Neoplasias da Glândula Tireoide/diagnóstico , Neoplasias da Glândula Tireoide/secundário , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Masculino , Estudos Retrospectivos , Análise de Sobrevida , Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/mortalidade , Neoplasias da Glândula Tireoide/terapia
16.
Compr Physiol ; 8(3): 981-1002, 2018 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-29978901

RESUMO

The calcium release-activated calcium (CRAC) channel, composed of ORAI and stromal interaction molecules (STIM), represents a prototypical example of store-operated calcium entry in mammals. The ORAI-STIM signaling occurs at membrane contact sites formed by close appositions between the endoplasmic reticulum (ER) and the plasma membrane. ORAI1 is a four-pass transmembrane protein that forms a highly calcium-selective ion channel in the plasma membrane. STIM1 is an ER-resident, a single-pass transmembrane protein that serves as a calcium sensor within the ER lumen and a potent activator of ORAI1 calcium channels. The intricate interplay between ORAI and STIM controls calcium entry into cells to regulate a myriad of physiological processes. We highlight herein the current knowledge on the structure-function relationship of CRAC channel, with a focus on key structural elements that mediate STIM1 conformational switch and the dynamic coupling between STIM1 and ORAI1. Furthermore, we discuss the physiological roles of STIM-ORAI signaling in various tissues and organs, as well as major pathological conditions arising from loss- or gain-of-function mutations in human ORAI1 and STIM1. © 2017 American Physiological Society. Compr Physiol 8:981-1002, 2018.


Assuntos
Canais de Cálcio/fisiologia , Sinalização do Cálcio/fisiologia , Cálcio/metabolismo , Moléculas de Interação Estromal/fisiologia , Animais , Humanos
17.
Artigo em Inglês | MEDLINE | ID: mdl-29601258

RESUMO

Capsaicinoids are pungent components in hot peppers, which have been detected in waste cooking oil. However, trace analysis of capsaicinoids in edible and crude vegetable oils is a challenging task due to the complex matrix. In this study, a simple liquid-liquid extraction and solid phase extraction (SPE) coupled with RP-UPLC-ESI-MS/MS method was developed for the quantification of capsaicinoids in edible and crude vegetable oils to screen the adulteration with waste cooking oil. This method was used to simultaneously determine 3 capsaicinoids (capsaicin, dihydrocapsaicin, and nordihydrocapsaicin) with capsaicin-d3, and dihydrocapsaicin-d3 as internal standards. This method allows the complete analysis of a sample in only an hour, even including sample preparation and chromatographic separation. The linear range of 3 capsaicinoids ranged between 0.5 and 40 µg/kg. The limit of detection (LOD) and limit of quantification (LOQ) for capsaicinoids were calculated as 0.15 and 0.5 µg/kg, respectively. Quantitative recoveries ranging from 92.9% to 105% were obtained by the analysis of spiked oil. The relative standard deviations were less than 5% (n = 6). The established method can potentially overcome the interference of triacylglycerols and fatty acids in edible and crude vegetable oils, and have been successfully applied to analyse real oil samples. This method provided a rapid and reliable method for the detection of adulteration of vegetable oils with waste cooking oils.


Assuntos
Capsaicina/análogos & derivados , Capsaicina/análise , Contaminação de Alimentos/análise , Óleos Vegetais/química , Cromatografia Líquida de Alta Pressão , Extração Líquido-Líquido , Extração em Fase Sólida , Espectrometria de Massas em Tandem
18.
Nucleic Acids Res ; 46(6): 2883-2900, 2018 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-29394393

RESUMO

Dynamic changes in DNA methylation and demethylation reprogram transcriptional outputs to instruct lineage specification during development. Here, we applied an integrative epigenomic approach to unveil DNA (hydroxy)methylation dynamics representing major endodermal lineage intermediates during pancreatic differentiation of human embryonic stem cells (hESCs). We found that 5-hydroxymethylcytosine (5hmC) marks genomic regions to be demethylated in the descendent lineage, thus reshaping the DNA methylation landscapes during pancreatic lineage progression. DNA hydroxymethylation is positively correlated with enhancer activities and chromatin accessibility, as well as the selective binding of lineage-specific pioneer transcription factors, during pancreatic differentiation. We further discovered enrichment of hydroxymethylated regions (termed '5hmC-rim') at the boundaries of large hypomethylated functional genomic regions, including super-enhancer, DNA methylation canyon and broad-H3K4me3 peaks. We speculate that '5hmC-rim' might safeguard low levels of cytosine methylation at these regions. Our comprehensive analysis highlights the importance of dynamic changes of epigenetic landscapes in driving pancreatic differentiation of hESC.


Assuntos
Diferenciação Celular/genética , Metilação de DNA , Endoderma/citologia , Células-Tronco Embrionárias Humanas/citologia , Pâncreas/citologia , 5-Metilcitosina/análogos & derivados , 5-Metilcitosina/metabolismo , Linhagem Celular , Linhagem da Célula/genética , Endoderma/metabolismo , Epigênese Genética , Epigenômica , Regulação da Expressão Gênica no Desenvolvimento , Células-Tronco Embrionárias Humanas/metabolismo , Humanos
19.
Sci Rep ; 6: 38011, 2016 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-27991505

RESUMO

Neuroblastoma (NB) is the most common extracranial tumor in children. Unlike in most adult tumors, tumor suppressor protein 53 (p53) mutations occur with a relatively low frequency in NB and the downstream function of p53 is intact in NB cell lines. Wip1 is a negative regulator of p53 and hindrance of Wip1 activity by novel inhibitor GSK2830371 is a potential strategy to activate p53's tumor suppressing function in NB. Yet, the in vivo efficacy and the possible mechanisms of GSK2830371 in NB have not yet been elucidated. Here we report that novel Wip1 inhibitor GSK2830371 induced Chk2/p53-mediated apoptosis in NB cells in a p53-dependent manner. In addition, GSK2830371 suppressed the colony-formation potential of p53 wild-type NB cell lines. Furthermore, GSK2830371 enhanced doxorubicin- (Dox) and etoposide- (VP-16) induced cytotoxicity in a subset of NB cell lines, including the chemoresistant LA-N-6 cell line. More importantly, GSK2830371 significantly inhibited tumor growth in an orthotopic xenograft NB mouse model by inducing Chk2/p53-mediated apoptosis in vivo. Taken together, this study suggests that GSK2830371 induces Chk2/p53-mediated apoptosis both in vitro and in vivo in a p53 dependent manner.


Assuntos
Aminopiridinas/administração & dosagem , Quinase do Ponto de Checagem 2/metabolismo , Dipeptídeos/administração & dosagem , Doxorrubicina/administração & dosagem , Etoposídeo/administração & dosagem , Neuroblastoma/tratamento farmacológico , Proteína Supressora de Tumor p53/metabolismo , Aminopiridinas/farmacologia , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Dipeptídeos/farmacologia , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Sinergismo Farmacológico , Etoposídeo/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Neuroblastoma/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
20.
J Zhejiang Univ Sci B ; 17(11): 882-891, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27819135

RESUMO

Camellia seed oil (CSO) is rich in oleic acid and has a high number of active components, which give the oil high nutritional value and a variety of biological activity. The aim of the present study was to determine the changes in the content and distribution of total polar compounds (TPC) in CSO during heating. TPC were isolated by means of preparative flash chromatography and further analyzed by high-performance size-exclusion chromatography (HPSEC). The TPC content of CSO increased from 4.74% to 25.29%, showing a significantly lower formation rate as compared to that of extra virgin olive oil (EVOO) and soybean oil (SBO) during heating. Furthermore, heating also resulted in significant differences (P<0.05) in the distribution of TPC among these oils. Though the content of oxidized triacylglycerol dimers, oxidized triacylglycerol oligomers, and oxidized triacylglycerol monomers significantly increased in all these oils, their increased percentages were much less in CSO than those in EVOO, indicating that CSO has a greater ability to resist oxidation. This work may be useful for the food oil industry and consumers in helping to choose the correct oil and to decide on the useful lifetime of the oil.


Assuntos
Camellia/química , Cromatografia em Gel/métodos , Óleos Vegetais/análise , Ácidos Graxos/análise , Calefação , Sementes/química , Fatores de Tempo
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