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1.
Mol Cancer ; 20(1): 36, 2021 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-33608029

RESUMO

Early detection is crucial to improve breast cancer (BC) patients' outcomes and survival. Mammogram and ultrasound adopting the Breast Imaging Reporting and Data System (BI-RADS) categorization are widely used for BC early detection, while suffering high false-positive rate leading to unnecessary biopsy, especially in BI-RADS category-4 patients. Plasma cell-free DNA (cfDNA) carrying on DNA methylation information has emerged as a non-invasive approach for cancer detection. Here we present a prospective multi-center study with whole-genome bisulfite sequencing data to address the clinical utility of cfDNA methylation markers from 203 female patients with breast lesions suspected for malignancy. The cfDNA is enriched with hypo-methylated genomic regions. A practical computational framework was devised to excavate optimal cfDNA-rich DNA methylation markers, which significantly improved the early diagnosis of BI-RADS category-4 patients (AUC from 0.78-0.79 to 0.93-0.94). As a proof-of-concept study, we performed the first blood-based whole-genome DNA methylation study for detecting early-stage breast cancer from benign tumors at single-base resolution, which suggests that combining the liquid biopsy with the traditional diagnostic imaging can improve the current clinical practice, by reducing the false-positive rate and avoiding unnecessary harms.

2.
Future Oncol ; 16(32): 2611-2617, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32820651

RESUMO

Background: Lymph node metastasis (LNM) is an independent risk factor for prognosis in patients with early breast cancer (EBC). Here we explored whether peripheral lymphocyte subtypes could be used as surrogate markers for LNM in patients with EBC. Materials & methods: The lymphocyte subpopulations in peripheral blood were measured in 152 EBC patients and 43 patients with benign breast tumors. Results: The cytotoxic T cell count was significantly lower in patients with EBC than in patients with benign tumors (244.17 ± 105.83 vs 289.97 ± 121.72; p = 0.02), especially in patients with LNM (218.36 ± 86.21; p = 0.04). Conclusion: A decreased level of peripheral CD8+CD28+ T lymphocytes is associated with LNM in patients with EBC and could be used as a potential therapeutic target for breast cancer.

3.
Breast Cancer ; 2020 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-32812198

RESUMO

BACKGROUND: To investigate the prognosis of females with invasive ductal carcinoma (IDC), invasive lobular carcinoma (ILC), and mixed invasive ductal and lobular carcinoma (IDLC) according to hormone receptor (HR) and HER2 status. METHODS: Data of 171,881 patients from the SEER database were analyzed. Propensity score matching was used to balance the covariates. Breast cancer-specific survival (BCSS) and overall survival (OS) of IDC, ILC, and IDLC were investigated. RESULTS: Patients with ILC were older, had lower tumor grade, higher tumor stage, larger tumor size, more nodal metastasis, higher estrogen receptor(+), lower HER2(-), and less likely to receive partial mastectomy and chemotherapy compared with IDC and IDLC. ILC and IDLC showed better prognosis than IDC after matching by Kaplan-Meier curves. Multivariate Cox regression showed better OS of ILC and IDLC compared with IDC with hazard ratio and a 95% confidence interval of 0.84 (0.77-0.90) and 0.91 (0.83-1.00), respectively. For HR(+)HER2(-) subgroup, ILC showed better OS than IDC; IDC showed worse BCSS and OS than IDLC. For HR(+)HER2(+); ILC showed better OS compared with IDLC; there were no survival differences of IDC, ILC, and IDLC for HER2(+). For HR(-)HER2(-), ILC and IDC showed better BCSS and OS compared with IDLC by multivariate analysis. CONCLUSIONS: The prognoses of female patients with IDC, ILC or IDLC were associated with the molecular subtypes of breast carcinoma. Management decisions should be based on pathological types and molecular subtypes.

4.
Int J Biol Macromol ; 163: 476-484, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32593759

RESUMO

In this preliminary study, the acidic hydrolysate fingerprints of polysaccharides based on hydrophilic-interaction chromatography-evaporative light scattering detection-electrospray time-of-flight mass spectrometry (HILIC-ELSD/ESI-TOF/MS) combined with multivariate statistical analysis was developed and applied to investigate the quality of Ganoderma lucidum from different regions. Projection-to-latent-structure discrimination analysis (PLS-DA) could distinguish samples of Zhejiang regions from those of other regions. Orthogonal-projection-to-latent-structure discrimination analysis (OPLS-DA) provided clear discrimination between G. lucidum samples cultivated in Zhejiang and that from other regions, in which Polysaccharides and D-galactose could be considered as candidate biomarkers. In addition, the intraspecific differentiation of G. lucidum was preliminarily investigated with samples from Shaanxi region. They were classified into four groups by PCA and PLS-DA, in which L-rhamnose, D-xylose, L-arabinose, and mannose were considered as potential chemical markers. These preliminary results contributed to our understanding of the variance of polysaccharides in Ganoderma spp. from different geographic origins and the intraspecific differentiation from the same region, which suggest great potential in the quality control of Ganoderma spp.

5.
J Med Genet ; 2020 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-32381727

RESUMO

BACKGROUND: Early-onset scoliosis (EOS), defined by an onset age of scoliosis less than 10 years, conveys significant health risk to affected children. Identification of the molecular aetiology underlying patients with EOS could provide valuable information for both clinical management and prenatal screening. METHODS: In this study, we consecutively recruited a cohort of 447 Chinese patients with operative EOS. We performed exome sequencing (ES) screening on these individuals and their available family members (totaling 670 subjects). Another cohort of 13 patients with idiopathic early-onset scoliosis (IEOS) from the USA who underwent ES was also recruited. RESULTS: After ES data processing and variant interpretation, we detected molecular diagnostic variants in 92 out of 447 (20.6%) Chinese patients with EOS, including 8 patients with molecular confirmation of their clinical diagnosis and 84 patients with molecular diagnoses of previously unrecognised diseases underlying scoliosis. One out of 13 patients with IEOS from the US cohort was molecularly diagnosed. The age at presentation, the number of organ systems involved and the Cobb angle were the three top features predictive of a molecular diagnosis. CONCLUSION: ES enabled the molecular diagnosis/classification of patients with EOS. Specific clinical features/feature pairs are able to indicate the likelihood of gaining a molecular diagnosis through ES.

6.
Brief Bioinform ; 2020 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-32436954

RESUMO

An accurate prognosis assessment for cancer patients could aid in guiding clinical decision-making. Reliance on traditional clinical features alone in a complex clinical environment is challenging and unsatisfactory in the era of precision medicine; thus, reliable prognostic biomarkers are urgently required to improve a patient staging system. In this study, we proposed a patient-level computational framework from mechanistic and translational perspectives to establish a personalized prognostic signature (named PLPPS) in high-grade serous ovarian carcinoma (HGSOC). The PLPPS composed of 68 immune genes achieved accurate prognostic risk stratification for 1190 patients in the meta-training cohort and was rigorously validated in multiple cross-platform independent cohorts comprising 792 HGSOC patients. Furthermore, the PLPPS was shown to be the better prognostic factor compared with clinical parameters in the univariate analysis and retained a significant independent association with prognosis after adjusting for clinical parameters in the multivariate analysis. In benchmark comparisons, the performance of PLPPS (hazard ratio (HR), 1.371; concordance index (C-index), 0.604 and area under the curve (AUC), 0.637) is comparable to or better than other published gene signatures (HR, 0.972 to 1.340; C-index, 0.495 to 0.592 and AUC, 0.48-0.624). With further validation in prospective clinical trials, we hope that the PLPPS might become a promising genomic tool to guide personalized management and decision-making of HGSOC in clinical practice.

7.
J Cell Mol Med ; 24(9): 4931-4943, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32277576

RESUMO

Tumour-induced osteomalacia (TIO) is a very rare paraneoplastic syndrome with bone pain, fractures and muscle weakness, which is mostly caused by phosphaturic mesenchymal tumours (PMTs). Cell-free DNA (cfDNA) has been regarded as a non-invasive liquid biopsy for many malignant tumours. However, it has not been studied in benign tumours, which prompted us to adopt the targeted next-generation sequencing approach to compare cfDNAs of 4 TIO patients, four patients with bone metastasis (BM) and 10 healthy controls. The mutational landscapes of cfDNA in TIO and BM groups were similar in the spectrum of allele frequencies and mutation types. Markedly, deleterious missense mutations in FGFR1 and loss-of-function mutations in MED12 were found in 3/4 TIO patients but none of BM patients. The gene ontology analysis strongly supported that these mutated genes found in TIOs would play a potential role in PMTs' process. The genetic signatures and corresponding change in expression of FGFR1 and FGF23 were further validated in PMT tissues from a test cohort of another three TIO patients. In summary, we reported the first study of the mutational landscape and genetic signatures of cfDNA in TIO/PMTs.

8.
Mol Ther Nucleic Acids ; 19: 339-349, 2020 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-31877410

RESUMO

Circular RNAs (circRNAs) represent a class of noncoding RNAs with a wide expression pattern, and they constitute an important layer of the genome regulatory network. To date, the expression pattern and regulatory potency of circRNAs in the retina, a key part of the central nervous system, are not yet well understood. In this study, RNAs from five stages (E18.5, P1, P7, P14, and P30) of mouse retinal development were sequenced. A total of 9,029 circRNAs were identified. Most circRNAs were expressed in different stages with a specific signature, and their expression patterns were different from those of their host linear transcripts. Some circRNAs could act as sponges for several retinal microRNAs (miRNAs). Furthermore, circTulp4 could function as a competitive endogenous RNA (ceRNA) to regulate target genes. Remarkably, silencing circTulp4 in vivo led to mice having a thin outer nuclear layer (ONL) and defective retinal function. In addition, we found that circRNAs were dysregulated at a much earlier time point than that of disease onset in a retinal degeneration model (rd8 mice). In summary, we provide the first circRNA expression atlas during retinal development and highlight a key biological role for circRNAs in retinal development and degeneration.

9.
Nucleic Acids Res ; 48(D1): D40-D44, 2020 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-31428785

RESUMO

Epigenetic alterations, including 5-methylcytosine (5mC), 5-hydroxymethylcytosine (5hmC) and nucleosome positioning (NP), in cell-free DNA (cfDNA) have been widely observed in human diseases, and many available cfDNA-based epigenome-wide profiles exhibit high sensitivity and specificity in disease detection and classification. However, due to the lack of efficient collection, standardized quality control, and analysis procedures, efficiently integrating and reusing these data remain considerable challenges. Here, we introduce CFEA (http://www.bio-data.cn/CFEA), a cell-free epigenome database dedicated to three types of widely adopted epigenetic modifications (5mC, 5hmC and NP) involved in 27 human diseases. We developed bioinformatic pipelines for quality control and standard data processing and an easy-to-use web interface to facilitate the query, visualization and download of these cell-free epigenome data. We also manually curated related biological and clinical information for each profile, allowing users to better browse and compare cfDNA epigenomes at a specific stage (such as early- or metastasis-stage) of cancer development. CFEA provides a comprehensive and timely resource to the scientific community and supports the development of liquid biopsy-based biomarkers for various human diseases.


Assuntos
Ácidos Nucleicos Livres , Bases de Dados Genéticas , Epigênese Genética , Epigenoma , Epigenômica/métodos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla/métodos , Biomarcadores , Biologia Computacional/métodos , Epigenômica/normas , Humanos , Software , Navegador
10.
J Hum Genet ; 65(3): 221-230, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31827250

RESUMO

Congenital scoliosis (CS) is a form of scoliosis caused by congenital vertebral malformations. Genetic predisposition has been demonstrated in CS. We previously reported that TBX6 loss-of-function causes CS in a compound heterozygous model; however, this model can explain only 10% of CS. Many monogenic and polygenic CS genes remain to be elucidated. In this study, we analyzed exome sequencing (ES) data of 615 Chinese CS from the Deciphering Disorders Involving Scoliosis and COmorbidities (DISCO) project. Cosegregation studies for 103 familial CS identified a novel heterozygous nonsense variant, c.2649G>A (p.Trp883Ter) in FBN1. The association between FBN1 and CS was then analyzed by extracting FBN1 variants from ES data of 574 sporadic CS and 828 controls; 30 novel variants were identified and prioritized for further analyses. A mutational burden test showed that the deleterious FBN1 variants were significantly enriched in CS subjects (OR = 3.9, P = 0.03 by Fisher's exact test). One missense variant, c.2613A>C (p.Leu871Phe) was recurrent in two unrelated CS subjects, and in vitro functional experiments for the variant suggest that FBN1 may contribute to CS by upregulating the transforming growth factor beta (TGF-ß) signaling. Our study expanded the phenotypic spectrum of FBN1, and provided nove insights into the genetic etiology of CS.


Assuntos
Anormalidades Congênitas/genética , Fibrilina-1/genética , Predisposição Genética para Doença , Escoliose/genética , Criança , Pré-Escolar , Códon sem Sentido/genética , Anormalidades Congênitas/diagnóstico por imagem , Anormalidades Congênitas/fisiopatologia , Exoma/genética , Feminino , Estudos de Associação Genética , Humanos , Lactente , Masculino , Mutação , Mutação de Sentido Incorreto/genética , Linhagem , Escoliose/diagnóstico por imagem , Escoliose/fisiopatologia , Coluna Vertebral/diagnóstico por imagem , Coluna Vertebral/fisiopatologia , Fator de Crescimento Transformador beta/genética
11.
Brief Bioinform ; 21(5): 1742-1755, 2020 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-31665214

RESUMO

Emerging evidence revealed the critical roles of long non-coding RNAs (lncRNAs) in maintaining genomic instability. However, identification of genome instability-associated lncRNAs and their clinical significance in cancers remain largely unexplored. Here, we developed a mutator hypothesis-derived computational frame combining lncRNA expression profiles and somatic mutation profiles in a tumor genome and identified 128 novel genomic instability-associated lncRNAs in breast cancer as a case study. We then identified a genome instability-derived two lncRNA-based gene signature (GILncSig) that stratified patients into high- and low-risk groups with significantly different outcome and was further validated in multiple independent patient cohorts. Furthermore, the GILncSig correlated with genomic mutation rate in both ovarian cancer and breast cancer, indicating its potential as a measurement of the degree of genome instability. The GILncSig was able to divide TP53 wide-type patients into two risk groups, with the low-risk group showing significantly improved outcome and the high-risk group showing no significant difference compared with those with TP53 mutation. In summary, this study provided a critical approach and resource for further studies examining the role of lncRNAs in genome instability and introduced a potential new avenue for identifying genomic instability-associated cancer biomarkers.

12.
Mol Ther Nucleic Acids ; 18: 590-604, 2019 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-31678735

RESUMO

Although our knowledge of human diseases has increased dramatically, the molecular basis, phenotypic traits, and therapeutic targets of most diseases still remain unclear. An increasing number of studies have observed that similar diseases often are caused by similar molecules, can be diagnosed by similar markers or phenotypes, or can be cured by similar drugs. Thus, the identification of diseases similar to known ones has attracted considerable attention worldwide. To this end, the associations between diseases at the molecular, phenotypic, and taxonomic levels were used to measure the pairwise similarity in diseases. The corresponding performance assessment strategies for these methods involving the terms "category-based," "simulated-patient-based," and "benchmark-data-based" were thus further emphasized. Then, frequently used methods were evaluated using a benchmark-data-based strategy. To facilitate the assessment of disease similarity scores, researchers have designed dozens of tools that implement these methods for calculating disease similarity. Currently, disease similarity has been advantageous in predicting noncoding RNA (ncRNA) function and therapeutic drugs for diseases. In this article, we review disease similarity methods, evaluation strategies, tools, and their applications in the biomedical community. We further evaluate the performance of these methods and discuss the current limitations and future trends for calculating disease similarity.

13.
Mol Ther Oncolytics ; 14: 299-312, 2019 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-31508487

RESUMO

Poor prognosis in pancreatic cancer (PanCa) is partially due to chemoresistance to gemcitabine (GEM). Glucose metabolism has been revealed to contribute to the therapeutic resistance and pluripotent state of PanCa cells. However, few studies have focused on the effects of GEM on cancer cell metabolism, stemness of tumor cells, and molecular mechanisms that critically influence PanCa treatment. We demonstrate that GEM treatment induces metabolic reprogramming, reducing mitochondrial oxidation and upregulating aerobic glycolysis, and promotes stem-like behaviors in cancer cells. Inhibiting aerobic glycolysis suppresses cancer cell stemness and strengthens GEM's cytotoxicity. GEM-induced metabolic reprogramming is KRAS dependent, as knockdown of KRAS reverses the metabolic shift. GEM-induced metabolic reprogramming also activates AMP-activated protein kinase (AMPK), which promotes glycolytic flux and cancer stemness. In addition, GEM-induced reactive oxygen species (ROS) activate the KRAS/AMPK pathway. This effect was validated by introducing exogenous hydrogen peroxide (H2O2). Taken together, these findings reveal a counterproductive GEM effect during PanCa treatment. Regulating cellular redox, targeting KRAS/AMPK signaling, or reversing metabolic reprogramming might be effective approaches to eliminate cancer stem cells (CSCs) and enhance chemosensitivity to GEM to improve the prognosis of PanCa patients.

14.
J Pharm Biomed Anal ; 176: 112797, 2019 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-31404800

RESUMO

Profiling the endogenous tissue metabolites with spatial features is significant for our understanding of molecular histology, and provides an insightful way to uncover the complex associations between tissue metabolic response and external stimuli. Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) is an effective molecular imaging technology to illustrate the spatial locations of molecules in tissue. However, due to the limited sensitivity and the presence of multiple matrix-related ions, it is still challenging to globally image the small molecule metabolites (SMMs) using MALDI, especially for those low-content functional ones. Here, a simple acetone washing method was developed to improve the sensitivity of MALDI-MS for imaging SMMs. After immersing in acetone and shaken for 15 min, key functional SMMs were well-visualized with significantly enhanced ion intensities. In addition to lipids, more than 160 SMM ions, including polyamines, cholines, carnitines, amino acids, nitrogenous bases, nucleosides, carbohydrates, organic acids, vitamins were imaged. The acetone washes-based MALDI-MSI was then applied to profile the metabolic alternations that occurred in osteosarcoma, and the abnormally altered SMMs and lipids were clearly visualized. Moreover, with the protection of acetone against tissue antigenicity, we successfully characterized the expression of three metabolites-related enzymes, fatty acid synthase (FASN), glutaminase (GLS), and cytosolic phospholipase A2 (cPLA2) in osteosarcoma. The spatially-resolved metabolite and corresponding enzyme information reveals what occured in osteosarcoma at the molecular level, providing new insights into the understanding of tumour metabolic reprogramming.


Assuntos
Acetona/química , Técnicas de Preparação Histocitológica/métodos , Imagem Molecular/métodos , Osteossarcoma/diagnóstico por imagem , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Animais , Modelos Animais de Doenças , Ácido Graxo Sintase Tipo I/análise , Ácido Graxo Sintase Tipo I/metabolismo , Glutaminase/análise , Glutaminase/metabolismo , Humanos , Imersão , Camundongos , Osteossarcoma/metabolismo , Osteossarcoma/patologia , Fosfolipases A2 Citosólicas/análise , Fosfolipases A2 Citosólicas/metabolismo , Ratos
15.
J Pharm Biomed Anal ; 175: 112758, 2019 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-31330279

RESUMO

Flos Lonicerae Japonicae(Jinyinhua) possesses clearing heat and detoxification activity, and has been used as a traditional Chinese medicine to treat influenza for many years. Due to the complex chemical composition and diverse content of Jinyinhua, especially the many trace ingredients, the effective components are unknown. In this study, an improved two-dimensional high performance liquid chromatography-ultrafiltration combined with electrospray ionization-time-of-flight/mass spectroscopy (ESI-TOF/MS) approach was designed and used for the enrichment, screening and characterization of minor neuraminidase inhibitors in Jinyinhua. In the first dimension, semi-prep-HPLC was employed for the preliminary separation of different polarity components and enrichment of low content components from Jinyinhua extract. In the second dimension, hydrophilic interaction liquid chromatography and reverse phase-HPLC were used to separate the different polar fractions, respectively. The fractions then underwent ultrafiltration and ESI-TOF/MS for the comprehensive screening and characterization of potential neuraminidase inhibitors. As a result, a total of 44 compounds were found to have neuraminidase inhibitory activity, and 22 of these compounds were preliminarily identified by accurate molecular weight and UV absorption data compared with standards and references. The activity of 16 of these compounds was verified by the neuraminidase inhibition assay. This study provides support for the rapid screening of minor neuraminidase inhibitors from complex natural medicines.


Assuntos
Inibidores Enzimáticos/química , Neuraminidase/antagonistas & inibidores , Extratos Vegetais/química , Cromatografia Líquida de Alta Pressão/métodos , Medicamentos de Ervas Chinesas/química , Lonicera/química , Espectrometria de Massas por Ionização por Electrospray/métodos , Ultrafiltração/métodos
16.
J Cell Mol Med ; 23(8): 5270-5281, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31140730

RESUMO

Colorectal cancer (CRC) is highly heterogeneous leading to variable prognosis and treatment responses. Therefore, it is necessary to explore novel personalized and reproducible prognostic signatures to aid clinical decision-making. The present study combined large-scale gene expression profiles and clinical data of 1828 patients with CRC from multi-centre studies and identified a personalized gene prognostic signature consisting of 46 unique genes (called function-derived personalized gene signature [FunPGS]) from an integrated statistics and function-derived perspective. In the meta-training and multiple independent validation cohorts, the FunPGS effectively discriminated patients with CRC with significantly different prognosis at the individual level and remained as an independent factor upon adjusting for clinical covariates in multivariate analysis. Furthermore, the FunPGS demonstrated superior performance for risk stratification with respect to other recently reported signatures and clinical factors. The complementary value of the molecular signature and clinical factors was further explored, and it was observed that the composite signature called IMCPS greatly improved the predictive performance of survival estimation relative to molecular signatures or clinical factors alone. With further prospective validation in clinical trials, the FunPGS may become a promising and powerful personalized prognostic tool for stratifying patients with CRC in order to achieve an optimal systemic therapy.


Assuntos
Neoplasias Colorretais/genética , Proteínas de Neoplasias/genética , Medicina de Precisão , Transcriptoma/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Neoplasias Colorretais/patologia , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Fatores de Risco
17.
J Exp Clin Cancer Res ; 38(1): 192, 2019 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-31088566

RESUMO

BACKGROUND: Modulation of cell surface expression of MHC class I chain-related protein A/B (MICA/B) has been proven to be one of the mechanisms by which tumor cells escape from NK cell-mediated killing. Abnormal metabolic condition, such as high glucose, may create a cellular stress milieu to induce immune dysfunction. Hyperglycemia is frequently presented in the majority of pancreatic cancer patients and is associated with poor prognosis. In this study, we aimed to detect the effects of high glucose on NK cell-mediated killing on pancreatic cancer cells through reduction of MICA/B expression. METHODS: The lysis of NK cells on pancreatic cancer cells were compared at different glucose concentrations through lactate dehydrogenase release assay. Then, qPCR, Western Blot, Flow cytometry and Immunofluorescence were used to identify the effect of high glucose on expression of MICA/B, Bmi1, GATA2, phosphorylated AMPK to explore the underlying mechanisms in the process. Moreover, an animal model with diabetes mellitus was established to explore the role of high glucose on NK cell-mediated cytotoxicity on pancreatic cancer in vivo. RESULTS: In our study, high glucose protects pancreatic cancer from NK cell-mediated killing through suppressing MICA/B expression. Bmi1, a polycomb group (PcG) protein, was found to be up-regulated by high glucose, and mediated the inhibition of MICA/B expression through promoting GATA2 in pancreatic cancer. Moreover, high glucose inhibited AMP-activated protein kinase signaling, leading to high expression of Bmi1. CONCLUSION: Our findings identify that high glucose may promote the immune escape of pancreatic cancer cells under hyperglycemic tumor microenvironment. In this process, constitutive activation of AMPK-Bmi1-GATA2 axis could mediate MICA/B inhibition, which may serve as a therapeutic target for further intervention of pancreatic cancer immune evasion.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Fator de Transcrição GATA2/metabolismo , Glucose/metabolismo , Antígenos de Histocompatibilidade Classe I/imunologia , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/metabolismo , Complexo Repressor Polycomb 1/metabolismo , Evasão Tumoral/imunologia , Animais , Glicemia , Linhagem Celular Tumoral , Membrana Celular/metabolismo , Citotoxicidade Imunológica , Expressão Gênica , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Masculino , Camundongos , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/genética , Transdução de Sinais , Microambiente Tumoral
18.
J Trace Elem Med Biol ; 53: 16-21, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30910201

RESUMO

The relationship between iodine intake and clinicopathologic characteristics of papillary thyroid cancer (PTC) is unclear. We aim to investigate the relationship between iodine intake and central lymph node metastasis (CLNM) of PTC. A total of 4040 consecutive patients with PTC receiving thyroidectomy and central lymph node dissection were enrolled from 2013 to 2018. Pathological features of tumors and urinary iodine concentration (UIC) were recorded. Multivariate analysis was performed to investigate the association between iodine intake and CLNM of PTC. More than adequate (UIC: 200.0-299.9 µg/L) and excessive iodine intake (UIC ≥ 300.0 µg/L) were present in 1741 cases (43.09%). Iodine deficiency (UIC ≤ 99.9 µg/L) was inversely associated with female PTC risk only with OR (95% CI): 0.48 (0.29-0.80) relative to adequate iodine intake (UIC: 100.0-199.9 µg/L). However, more than adequate and excessive iodine intake was not associated with PTC risk among the general population and patients with thyroid nodules. In addition, high iodine intake was not associated CLNM risk of PTC. After defining CLNM as metastatic lymph nodes ≥ 2, excessive iodine intake was marginally associated with CLNM among female PTC patients with OR (95% CI): 1.25 (0.99-1.57) by multivariate analysis. Additionally, excessive iodine intake was marginally associated with larger tumor size and capsular invasion. Furthermore, we found that female PTC patients were more closely linked with iodine intake than male ones. In conclusion, high iodine intake appears not to be an initiator, but may be a weak promoter for female PTC progression, which needs further validation.


Assuntos
Iodo/administração & dosagem , Iodo/efeitos adversos , Metástase Linfática , Câncer Papilífero da Tireoide/patologia , Neoplasias da Glândula Tireoide/patologia , Progressão da Doença , Feminino , Humanos , Iodo/deficiência , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estado Nutricional , Fatores de Risco , Caracteres Sexuais
19.
Surgery ; 166(1): 55-60, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30876667

RESUMO

BACKGROUND: Lymph node metastases from papillary thyroid cancer is believed to disseminate sequentially, first to the central neck and later to the lateral neck. Skip metastases of papillary thyroid cancer, however, are defined as lateral lymph node metastasis without central lymph node metastasis. The aim of this study was to investigate the risk factors for skip metastases and lateral lymph node metastasis of papillary thyroid cancer. METHODS: We reviewed 721 papillary thyroid cancer patients undergoing total thyroidectomy with central lymph node dissection and lateral lymph node dissection during 2013 to 2018. Multivariate logistic regression analysis was performed to identify clinicopathologic risk factors for skip metastasis and lateral lymph node metastasis of papillary thyroid cancer. RESULTS: The rate of skip metastases was 7.4% (42 of 567 patients). Multivariate analysis showed that female sex and papillary thyroid microcarcinoma (≤ 1 cm) were independent risk factors for skip metastases, with odds ratios ([OR], 95% confidence interval [CI]) of 2.29 (1.02-5.16) and 2.84 (1.46-5.16), respectively. Intrathyroidal spread of papillary thyroid cancer and an increased number of central lymph nodes dissected were inversely associated with skip metastases with ORs (95% CI) of 0.13 (0.02-0.99) and 0.88 (0.83-0.94), respectively. In contrast, a greater tumor size, central lymph node metastasis, an increased number of central lymph nodes dissected, and an increased number of lateral lymph nodes dissected were associated with a lateral lymph node metastasis risk of papillary thyroid cancer, with ORs (95% CI) as follow: 1.67 (1.08-2.59), 3.07 (1.71-5.52), 1.25 (1.14-1.37), and 1.07 (1.04-1.10), respectively, by multivariate analysis. CONCLUSION: Greater tumor size, central lymph node metastasis, and an increased number of both central lymph nodes and lateral lymph nodes dissected were predictors for lateral lymph node metastasis of papillary thyroid cancer. In addition, papillary thyroid microcarcinoma was an independent risk factor for skip metastases. A complete and comprehensive central compartment dissection may decrease the false-positive detection of skip metastases of papillary thyroid cancer.


Assuntos
Excisão de Linfonodo/métodos , Esvaziamento Cervical/métodos , Câncer Papilífero da Tireoide/patologia , Câncer Papilífero da Tireoide/cirurgia , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/cirurgia , Adulto , Idoso , Estudos de Coortes , Bases de Dados Factuais , Intervalo Livre de Doença , Feminino , Humanos , Modelos Logísticos , Linfonodos/patologia , Linfonodos/cirurgia , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Invasividade Neoplásica/patologia , Recidiva Local de Neoplasia/epidemiologia , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Estudos Retrospectivos , Medição de Risco , Análise de Sobrevida , Câncer Papilífero da Tireoide/mortalidade , Neoplasias da Glândula Tireoide/mortalidade , Tireoidectomia/métodos
20.
Eur J Radiol ; 112: 14-21, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30777203

RESUMO

PURPOSE: To evaluate the performance of preoperative ultrasound in the diagnosis of cervical lymph nodes metastases (CLNM) of papillary thyroid cancer (PTC) and its value in assisting cervical lymph node dissection (CLND). METHODS: PubMed, EMBASE and Cochrane Library databases were searched to identify relevant studies up to Sep. 2017. Overall sensitivity, specificity, and diagnostic odds ratio (DOR) were used to assess the diagnostic efficacy of ultrasound in detecting central and lateral CLNM of PTC. RESULTS: Nineteen studies comprising 4014 patients were included in the meta-analysis. The pooled sensitivity, specificity, DOR and area under curve (AUC) of ultrasound in detecting central CLNM were 0.33 (95% confidence interval (95% CI): 0.31-0.35), 0.93 (95% CI: 0.92-0.94), 5.63 (95% CI: 3.50-9.04), and 0.69, respectively; and lateral CLNM were 0.70 (95% CI: 0.68-0.72), 0.84 (95% CI: 0.82-0.85), 18.7 (95% CI: 10.3-33.9) and 0.88, respectively. We found that the rate of central CLNM of PTC was 48.0%, and 36.2% of the dissected lymph nodes were metastatic, meanwhile, the rate of lateral CLNM of PTC was 59.2%, and 46.6% of the dissected lymph nodes were metastatic in the meta-analysis. CONCLUSIONS: Preoperative ultrasound demonstrates poor sensitivity in the diagnosis of central CLNM, and good diagnostic efficacy for lateral CLNM of PTC. Prophylactic central CLND is recommended to PTC patients due to the high incidence of central CLNM and low diagnostic efficacy of ultrasound.


Assuntos
Câncer Papilífero da Tireoide/diagnóstico por imagem , Neoplasias da Glândula Tireoide/diagnóstico por imagem , Adulto , Idoso , Feminino , Humanos , Linfonodos/diagnóstico por imagem , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Pescoço/diagnóstico por imagem , Esvaziamento Cervical/métodos , Fatores de Risco , Sensibilidade e Especificidade , Câncer Papilífero da Tireoide/cirurgia , Neoplasias da Glândula Tireoide/cirurgia , Ultrassonografia , Adulto Jovem
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