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1.
Mov Disord ; 2020 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-32392383

RESUMO

BACKGROUND: Paroxysmal kinesigenic dyskinesia is a spectrum of involuntary dyskinetic disorders with high clinical and genetic heterogeneity. Mutations in proline-rich transmembrane protein 2 have been identified as the major pathogenic factor. OBJECTIVES: We analyzed 600 paroxysmal kinesigenic dyskinesia patients nationwide who were identified by the China Paroxysmal Dyskinesia Collaborative Group to summarize the clinical phenotypes and genetic features of paroxysmal kinesigenic dyskinesia in China and to provide new thoughts on diagnosis and therapy. METHODS: The China Paroxysmal Dyskinesia Collaborative Group was composed of departments of neurology from 22 hospitals. Clinical manifestations and proline-rich transmembrane protein 2 screening results were recorded using unified paroxysmal kinesigenic dyskinesia registration forms. Genotype-phenotype correlation analyses were conducted in patients with and without proline-rich transmembrane protein 2 mutations. High-knee exercises were applied in partial patients as a new diagnostic test to induce attacks. RESULTS: Kinesigenic triggers, male predilection, dystonic attacks, aura, complicated forms of paroxysmal kinesigenic dyskinesia, clustering in patients with family history, and dramatic responses to antiepileptic treatment were the prominent features in this multicenter study. Clinical analysis showed that proline-rich transmembrane protein 2 mutation carriers were prone to present at a younger age and have longer attack duration, bilateral limb involvement, choreic attacks, a complicated form of paroxysmal kinesigenic dyskinesia, family history, and more forms of dyskinesia. The new high-knee-exercise test efficiently induced attacks and could assist in diagnosis. CONCLUSIONS: We propose recommendations regarding diagnostic criteria for paroxysmal kinesigenic dyskinesia based on this large clinical study of paroxysmal kinesigenic dyskinesia. The findings offered some new insights into the diagnosis and treatment of paroxysmal kinesigenic dyskinesia and might help in building standardized paroxysmal kinesigenic dyskinesia clinical evaluations and therapies. © 2020 International Parkinson and Movement Disorder Society.

2.
Biomed Res Int ; 2020: 6784138, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32280695

RESUMO

Liver cancer is a lethal disease that is associated with poor prognosis. In order to identify the functionally important genes associated with liver cancer that may reveal novel therapeutic avenues, we performed integrated analysis to profile miRNA and mRNA expression levels for liver tumors compared to normal samples in The Cancer Genome Atlas (TCGA) database. We identified 405 differentially expressed genes and 233 differentially expressed miRNAs in tumor samples compared with controls. In addition, we also performed the pathway analysis and found that mitogen-activated protein kinases (MAPKs) and G-protein coupled receptor (GPCR) pathway were two of the top significant pathway nodes dysregulated in liver cancer. Furthermore, by examining these signaling networks, we discovered that FOS (Fos proto-oncogene, AP-1 transcription factor subunit), LAMC2 (laminin subunit gamma 2), and CALML3 (calmodulin like 3) were the most significant gene nodes with high degrees involved in liver cancer. The expression and disease prediction accuracy of FOS, LAMC2, CALML3, and their interacting miRNAs were further performed using a HCC cohort. Finally, we investigated the prognostic significance of FOS in another HCC cohort. Patients with higher FOS expression displayed significantly shorter time to recurrence (TTR) and overall survival (OS) compared with patients with lower expression. Collectively, our study demonstrates that FOS is a potential prognostic marker for liver cancer that may reveal a novel therapeutic avenue in this lethal disease.

3.
Liver Int ; 40(5): 1211-1223, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32077551

RESUMO

BACKGROUND AND AIMS: Heat shock factor (HSF4) plays a vital role in carcinogenesis and tumour progression. However, its clinical significance implications in hepatocellular carcinoma (HCC) remained elusive. METHODS: RT-PCR and western blot were used to detect the HSF4 expression levels in HCC cells and tissues. Immunohistochemistry staining was performed on a tissue microarray containing 104 HCC patients received radical resection. In vitro effects of HSF4 on proliferation, migration and invasion were determined by colony formation and transwell assays in HCCLM3, Huh7, MHCC97L and SMMC7721 cells. Epithelial-mesenchymal transition (EMT) was identified by RT-PCR, WB and immunofluorescence in HCCLM3 and MHCC97L cells. AKT pathway activation was detected by WB and dual luciferase report system in HCCLM3 and MHCC97L cells. RESULTS: HSF4 expression was higher in primary HCC tissues derived from recurrent patients, and positively correlated with invasiveness potentials of cell lines. Clinically, patients with high HSF4 expression had significant poorer prognosis. In vitro experiments showed HSF4 silencing inhibited HCC cell proliferation, migration and invasion, whereas HSF4 overexpression had inverse effects. Moreover, silence of HSF4 induced an epithelial-like phenotype, whereas the overexpression of HSF4 resulted in a mesenchymal-like phenotype in HCC by activating AKT pathway. Further experiments showed that HSF4 could activate AKT pathway in a hypoxia-inducible factor-1α (HIF-1α) dependent, but transforming growth factor-ß (TGF-ß) independent manner. CONCLUSIONS: HSF4 is upregulated in HCC, resulting in greater proliferation, migration and invasion capacities. Moreover, high HSF4 expression is a promising predictive indicator of poor outcome after radical resection. HSF4 may promote aggressive tumour behaviour by enhancing EMT through activating AKT pathway in a HIF1α-dependent manner.

4.
J Hematol Oncol ; 13(1): 11, 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-32024555

RESUMO

BACKGROUND: Aberrant AKT activation contributes to cancer stem cell (CSC) traits in hepatocellular carcinoma (HCC). We previously reported that CD73 activated AKT signaling via the Rap1/P110ß cascade. Here, we further explored the roles of CD73 in regulating CSC characteristics of HCC. METHODS: CD73 expression modulations were conducted by lentiviral transfections. CD73+ fractions were purified by magnetic-based sorting, and fluorescent-activated cell sorting was used to assess differentiation potentials. A sphere-forming assay was performed to evaluate CSC traits in vitro, subcutaneous NOD/SCID mice models were generated to assess in vivo CSC features, and colony formation assays assessed drug resistance capacities. Stemness-associated gene expression was also determined, and underlying mechanisms were investigated by evaluating immunoprecipitation and ubiquitylation. RESULTS: We found CD73 expression was positively associated with sphere-forming capacity and elevated in HCC spheroids. CD73 knockdown hindered sphere formation, Lenvatinib resistance, and stemness-associated gene expression, while CD73 overexpression achieved the opposite effects. Moreover, CD73 knockdown significantly inhibited the in vivo tumor propagation capacity. Notably, we found that CD73+ cells exhibited substantially stronger CSC traits than their CD73- counterparts. Mechanistically, CD73 exerted its pro-stemness activity through dual AKT-dependent mechanisms: activating SOX9 transcription via c-Myc, and preventing SOX9 degradation by inhibiting glycogen synthase kinase 3ß. Clinically, the combined analysis of CD73 and SOX9 achieved a more accurate prediction of prognosis. CONCLUSIONS: Collectively, CD73 plays a critical role in sustaining CSCs traits by upregulating SOX9 expression and enhancing its protein stability. Targeting CD73 might be a promising strategy to eradicate CSCs and reverse Lenvatinib resistance in HCC.

5.
Int J Cancer ; 146(6): 1606-1617, 2020 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-31310010

RESUMO

Using a method optimized in hepatocellular carcinoma (HCC), we established patient-derived xenograft (PDX) models with an increased take rate (42.2%) and demonstrated that FBS +10% dimethyl sulfoxide exhibited the highest tumor take rate efficacy. Among 254 HCC patients, 103 stably transplantable xenograft lines that could be serially passaged, cryopreserved and revived were established. These lines maintained the diversity of HCC and the essential features of the original specimens at the histological, transcriptome, proteomic and genomic levels. Tumor engraftment was associated with lack of encapsulation, poor tumor differentiation, large size and overexpression of cancer stem cell biomarkers, and was an independent predictor for overall survival and tumor recurrence after resection. To confirm the preclinical value of the PDX model in HCC treatment, several antitumor agents were tested in 16 selected PDX models. The results revealed a high degree of pharmacologic heterogeneity in the cohort, as well as heterogeneity to different agents in the same individual. The sorafenib responses observed between HCC patients and the corresponding PDXs were also consistent. After molecular characterization of the PDX models, we explored the predictive markers for sorafenib response and found that mitogen-activated protein kinase kinase kinase 1 (MAP3K1) might play an important role in sorafenib resistance and sorafenib response is impaired in patients with MAP3K1 downexpression. Our results indicated that PDX models could accurately reproduce patient tumors biology and could aid in the discovery of new treatments to advance in precision medicine.


Assuntos
Biomarcadores Tumorais/análise , Carcinoma Hepatocelular/terapia , Neoplasias Hepáticas/terapia , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Quimiorradioterapia Adjuvante/métodos , Regulação para Baixo , Resistencia a Medicamentos Antineoplásicos , Feminino , Seguimentos , Perfilação da Expressão Gênica , Genômica , Hepatectomia , Humanos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/patologia , MAP Quinase Quinase Quinase 1/metabolismo , Masculino , Pessoa de Meia-Idade , Estudo de Prova de Conceito , Estudos Prospectivos , Inibidores de Proteínas Quinases/administração & dosagem , Sorafenibe/administração & dosagem , Resultado do Tratamento
6.
Future Oncol ; 15(34): 3917-3934, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31729887

RESUMO

Aim: To elucidate the integrative combinational gene regulatory network landscape of hepatocellular carcinoma (HCC) molecular carcinogenesis from diverse background. Materials & methods: Modified gene regulatory network analysis was used to prioritize differentially regulated genes and links. Integrative comparisons using bioinformatics methods were applied to identify potential critical molecules and pathways in HCC with different backgrounds. Results: E2F1 with its surrounding regulatory links were identified to play different key roles in the HCC risk factor dysregulation mechanisms. Hsa-mir-19a was identified as showed different effects in the three HCC differential regulation networks, and showed vital regulatory role in HBV-related HCC. Conclusion: We describe in detail the regulatory networks involved in HCC with different backgrounds. E2F1 may serve as a universal target for HCC treatment.


Assuntos
Carcinoma Hepatocelular/genética , Fator de Transcrição E2F1/metabolismo , Redes Reguladoras de Genes , Neoplasias Hepáticas/genética , MicroRNAs/genética , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/virologia , Biologia Computacional , Conjuntos de Dados como Assunto , Intervalo Livre de Doença , Fator de Transcrição E2F1/antagonistas & inibidores , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Hepacivirus/isolamento & purificação , Hepacivirus/patogenicidade , Vírus da Hepatite B/isolamento & purificação , Vírus da Hepatite B/patogenicidade , Humanos , Estimativa de Kaplan-Meier , Fígado/patologia , Fígado/virologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/virologia , MicroRNAs/metabolismo , Prognóstico
7.
Carcinogenesis ; 2019 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-31587040

RESUMO

Previous research suggests that Far Upstream-element Binding Protein 1 (FUBP1)plays an important role in various tumors including Hepatocellular carcinoma (HCC). However, the role of FUBP1 in liver cancer remains controversial, and the regulatory pathway by FUBP1 awaits to be determined. This study aims to identify the role of FUBP1 in hepatocellular carcinoma progression. Our result shows that high level of FUBP1 expression in HCC predicts poor prognosis after surgery. Overexpression of FUBP1 promotes HCC proliferation, invasion and metastasis by activating Transforming Growth Gactor-ß(TGF-ß)/Smad pathway and enhancing Epithelial-Mesenchymal Transition (EMT) in vitro and in vivo. Inhibitor of Thrombospondin-1 (LSKL)could inhibit HCC proliferation and invasion in vitro and in vivo by blocking the activation of TGF-ß/Smad pathway mediated by Thrombospondin-1 (THBS1). Our study identified the critical role of FUBP1-THBS1-TGF-ß signaling axis in HCC and provides potentially new therapeutic modalities in HCC.

8.
J Cancer ; 10(17): 3914-3925, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31417635

RESUMO

Sorafenib, a multikinase inhibitor, is a new standard treatment for patients with advanced hepatocellular carcinoma (HCC). However, resistance to this regimen is frequently observed in clinical practice, and the molecular basis of this resistance remains largely unknown. Herein, the antitumor activity of sorafenib was assessed in 16 patient-derived xenograft (PDX) models of HCC. Gene expression analysis was conducted to identify factors that promote sorafenib resistance. Quantitative RT-PCR and immunoblotting were used to determine gene expression and activation of signaling pathways. Cell proliferation, clone formation, and transwell assays were conducted to evaluate drug-sensitivity, proliferation, and invasiveness, respectively. Kaplan-Meier analysis was used to evaluate the predictive power of biomarkers for sorafenib response. Differential gene expression analysis suggested that sorafenib resistance correlated with high karyopherin subunit alpha 3 (KPNA3) expression. Overexpression of KPNA3 in HCC cells enhanced tumor cell growth and invasiveness. Interestingly, KPNA3 was found to trigger epithelial-mesenchymal transition (EMT), a key process mediating drug resistance. On a mechanistic level, KPNA3 increased phosphorylation of AKT, which then phosphorylated ERK, and ultimately promoted TWIST expression to induce EMT and sorafenib resistance. Moreover, retrospective analysis revealed that HCC patients with low KPNA3 expression had remarkably longer survival after sorafenib treatment. Finally, we have identified a novel KPNA3-AKT-ERK-TWIST signaling cascade that promotes EMT and mediates sorafenib resistance in HCC. These findings suggest that KPNA3 is a promising biomarker for predicting patient responsiveness to sorafenib. Targeting KPNA3 may also contribute to resolving sorafenib resistance in HCC.

9.
J Cell Biochem ; 120(4): 6035-6045, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30368883

RESUMO

BACKGROUND: Prognosis of hepatocellular carcinoma (HCC) remains poor due to high recurrence rate and ineffective treatment options, highlighting the need to better understand the mechanism of recurrence and metastasis in HCC. METHODS: We first collected messenger RNA (mRNA) expression data from 442 cases of HCC patients from The Cancer Genome Atlas (TCGA) database as well as 251 HCC patients from Zhongshan Hospital during 2009 and 2010 to analyze the expression pattern from tissue microarray (TMA) of baculoviral IAP repeat containing 3 (BIRC3). Then, we used BIRC3 gain-of-function (overexpression) and loss-of-function (knockdown) studies to examine the effect of BIRC3 on HCC cell proliferation and invasion. In addition, we also investigated the undying mechanism by which BIRC3 contributes to HCC tumor progression. Functionally, we also used a BIRC3-specific inhibitor AT-406 in HCC xenograft model to explore the potential therapeutic benefit of targeting BIRC3 in liver cancer. RESULTS: BIRC3 serves as a novel prognostic indicator for HCC patients undergoing curative resection. BIRC3 promotes HCC epithelial-mesenchymal transition (EMT), cell migration, and metastasis via upregulating MAP3K7, therefore, inducing ERK1/2 phosphorylation. The specific BIRC3 inhibitor AT-406 can inhibit HCC cell proliferation and reduce pulmonary metastases. CONCLUSION: BIRC3 induces tumor proliferation and metastasis in vitro and in vivo. BIRC3 may serve as a novel therapeutic target for liver cancer.

10.
Carcinogenesis ; 39(12): 1438-1446, 2018 12 31.
Artigo em Inglês | MEDLINE | ID: mdl-30169594

RESUMO

Accumulating evidence suggests that long non-coding RNA (lncRNA) plays important roles in some malignant tumors. However, the mechanism underlying how lncRNA regulates hepatocellular carcinoma (HCC) process remains largely unknown. In this study, we explored the potential role of lncRNA 00607 as a novel tumor suppressor in HCC. In this study, we examined the regulation of lncRNA 00607 by the important inflammatory cytokine tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). We also determined the expression of LINC000607 in 159 HCC tumors and paired adjacent tissues. Effects of LINC000607 in HCC proliferation and apoptosis were examined in vitro in HCC cell lines and in vivo tumor xenografts. Furthermore, we also examine underlying mechanism by which lncRNA 00607 regulates NF-κB p65 and how LIN00607 exerts its tumor suppressor role in HCC. We found that lncRNA 00607 expression level is lower in HCC tumors compared with matched normal liver tissue, and its low expression predicts worse prognosis in HCC. Functionally, lncRNA 00607 overexpression leads to decreased HCC cell proliferation in vitro and in vivo, enhanced apoptosis and chemotherapeutic drug sensitivity. Mechanistically, lncRNA 00607 inhibits the p65 transcription by binding to the p65 promoter region, therefore contributing to increased p53 levels in HCC. Taken together, the findings of this study show that the TNF-α/IL-6-lncRNA 00607-NF-κB p65/p53 signaling axis represents a novel therapeutic avenue in cancer chemotherapy.


Assuntos
Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , RNA Longo não Codificante/genética , Transdução de Sinais/genética , Fator de Transcrição RelA/genética , Proteína Supressora de Tumor p53/genética , Animais , Apoptose/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Células Hep G2 , Humanos , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Regiões Promotoras Genéticas/genética , Transcrição Genética/genética
11.
Parkinsons Dis ; 2018: 3201308, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30123489

RESUMO

Background: Previous studies suggested that visual evoked potential (VEP) was impaired in patients with Parkinson's disease (PD), but the results were inconsistent. Methods: We conducted a systematic review and meta-analysis to explore whether the VEP was significantly different between PD patients and healthy controls. Case-control studies of PD were selected through an electronic search of the databases PubMed, Embase, and the Cochrane Central Register of Controlled Trials. We calculated the pooled weighted mean differences (WMDs) and 95% confidence intervals (CIs) between individuals with PD and controls using the random-effects model. Results: Twenty case-control studies which met our inclusion criteria were included in the final meta-analysis. We found that the P100 latency in PD was significantly higher compared with healthy controls (pooled WMD = 6.04, 95% CI: 2.73 to 9.35, P=0.0003, n=20). However, the difference in the mean amplitude of P100 was not significant between the two groups (pooled WMD = 0.64, 95% CI: -0.06 to 1.33, P=0.07) based on 10 studies with the P100 amplitude values available. Conclusions: The higher P100 latency of VEP was observed in PD patients, relative to healthy controls. Our findings suggest that electrophysiological changes and functional defect in the visual pathway of PD patients are important to our understanding of the pathophysiology of visual involvement in PD.

12.
BMC Cancer ; 18(1): 550, 2018 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-29743053

RESUMO

BACKGROUND: Liver cancer is the second leading cause of cancer-related deaths and characterized by heterogeneity and drug resistance. Patient-derived xenograft (PDX) models have been widely used in cancer research because they reproduce the characteristics of original tumors. However, the current studies of liver cancer PDX mice are scattered and the number of available PDX models are too small to represent the heterogeneity of liver cancer patients. To improve this situation and to complement available PDX models related resources, here we constructed a comprehensive database, PDXliver, to integrate and analyze liver cancer PDX models. DESCRIPTION: Currently, PDXliver contains 116 PDX models from Chinese liver cancer patients, 51 of them were established by the in-house PDX platform and others were curated from the public literatures. These models are annotated with complete information, including clinical characteristics of patients, genome-wide expression profiles, germline variations, somatic mutations and copy number alterations. Analysis of expression subtypes and mutated genes show that PDXliver represents the diversity of human patients. Another feature of PDXliver is storing drug response data of PDX mice, which makes it possible to explore the association between molecular profiles and drug sensitivity. All data can be accessed via the Browse and Search pages. Additionally, two tools are provided to interactively visualize the omics data of selected PDXs or to compare two groups of PDXs. CONCLUSION: As far as we known, PDXliver is the first public database of liver cancer PDX models. We hope that this comprehensive resource will accelerate the utility of PDX models and facilitate liver cancer research. The PDXliver database is freely available online at: http://www.picb.ac.cn/PDXliver/.


Assuntos
Bases de Dados como Assunto , Modelos Animais de Doenças , Neoplasias Hepáticas/genética , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Feminino , Humanos , Fígado/patologia , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Pessoa de Meia-Idade , Mutação
13.
Oncol Lett ; 15(1): 467-474, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29387230

RESUMO

Hypoxia is a critical aspect of tumor biology and has been associated with poor prognosis and resistance to traditional therapy. In the present study, differentially expressed genes and microRNAs (miRNAs/miRs) were screened for in the hepatocellular carcinoma (HCC) cell line Huh7 under hypoxic conditions. On the basis of microarray data, 11,508 mRNAs and 58 miRNAs exhibiting ≥1.5-fold change in expression under hypoxic conditions were identified. Gene Ontology (GO) and Kyoto Encyclopedia or Genes and Genomes pathway analysis revealed that the differentially expressed genes were primarily involved in cell cycle regulation, cell division, transcription and G-protein-coupled receptor signaling pathways. Using the TargetScan and miRanda software packages with the miRNA-mRNA negative expression network, differentially expressed miRNA targets were predicted. GO analysis revealed that the primary function of these miRNAs was to regulate transcription and phosphorylation. The miRNA-mRNA networks for transcription and phosphorylation were analyzed. Network analysis revealed that the key miRNAs in these networks were miR-19a, miR-34a, miR-29a, mir-196a, miR-25 and miR-1207, whose potential gene targets include DNA-binding proteins, zinc-finger proteins and transcription factors. Certain protein kinases, includingmitogen-activated protein kinase (MAPK) 1, MAPK kinase kinase4 and cyclin-dependent kinase 18, were also revealed to be present in the network. In hypoxic HCC tissue, levels of several key miRNAs implicated in the network analyses (miR-19a, miR-34a, miR-25 and miR-1207) were revealed to exhibit increased expression levels compared with the surrounding tissue. The results of the present study provide evidence that miRNAs serve an important function in transcription and phosphorylation in the hypoxic response of HCC cells.

14.
Mov Disord ; 33(3): 459-467, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29356177

RESUMO

BACKGROUND: Paroxysmal kinesigenic dyskinesia is the most common type of paroxysmal dyskinesia. Approximately half of the cases of paroxysmal kinesigenic dyskinesia worldwide are attributable to proline-rich transmembrane protein 2 mutations. OBJECTIVE: The objective of this study was to investigate potential causative genes and clinical characteristics in proline-rich transmembrane protein 2-negative patients with paroxysmal kinesigenic dyskinesia. METHODS: We analyzed clinical manifestations and performed exome sequencing in a cohort of 163 proline-rich transmembrane protein 2-negative probands, followed by filtering data with a paroxysmal movement disorders gene panel. Sanger sequencing, segregation analysis, and phenotypic reevaluation were used to substantiate the findings. RESULTS: The clinical characteristics of the enrolled 163 probands were summarized. A total of 39 heterozygous variants were identified, of which 33 were classified as benign, likely benign, and uncertain significance. The remaining 6 variants (3 novel, 3 documented) were pathogenic and likely pathogenic. Of these, 3 were de novo (potassium calcium-activated channel subfamily M alpha 1, c.1534A>G; solute carrier family 2 member 1, c.418G>A; sodium voltage-gated channel alpha subunit 8, c.3640G>A) in 3 sporadic individuals, respectively. The other 3 (paroxysmal nonkinesiogenic dyskinesia protein, c.956dupA; potassium voltage-gated channel subfamily A member 1, c.765C>A; Dishevelled, Egl-10, and Pleckstrin domain containing 5, c.3311C>T) cosegregated in 3 families. All 6 cases presented with typical paroxysmal kinesigenic dyskinesia characteristics, except for the Dishevelled, Egl-10, and Pleckstrin domain containing 5 family, where the proband's mother had abnormal discharges in her temporal lobes in addition to paroxysmal kinesigenic dyskinesia episodes. CONCLUSIONS: Our findings extend the genotypic spectrum of paroxysmal kinesigenic dyskinesia and establish the associations between paroxysmal kinesigenic dyskinesia and genes classically related to other paroxysmal movement disorders. De novo variants might be a cause of sporadic paroxysmal kinesigenic dyskinesia. © 2018 International Parkinson and Movement Disorder Society.


Assuntos
Distonia/genética , Predisposição Genética para Doença/genética , Mutação/genética , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Distonia/diagnóstico , Saúde da Família , Feminino , Testes Genéticos , Transportador de Glucose Tipo 1/genética , Humanos , Subunidades alfa do Canal de Potássio Ativado por Cálcio de Condutância Alta/genética , Masculino , Proteínas Musculares/genética , Proteínas Repressoras/genética , Adulto Jovem
15.
Oncotarget ; 8(60): 102006-102019, 2017 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-29254221

RESUMO

The effects of long non-coding RNAs (lncRNAs) on hepatocellular carcinoma (HCC) remain largely unclear. In this study, we identified an interferon (IFN)-γ-induced LncRNA, LncRNA00364, in HCC by microarray. LncRNA00364 displays lower expression in HCC tumor samples compared to paired normal controls. Overexpression of LncRNA00364 inhibits cell proliferation, G1/S cell cycle progression and promotes apoptosis in HCC cell lines. Consistently, LncRNA00364 overexpression leads to decreased HCC tumor formation in vivo. Mechanistically, LncRNA00364 specifically binds with STAT3, resulting in inhibition of STAT3 phosphorylation and therefore leads to upregulation of IFIT2. In a clinical setting, LncRNA00364 shows an independent prognostic indicator for overall survival and cumulative recurrence in HCC patients, and correlates with IFIT2. Therefore, our study provides new insights into a novel therapeutic avenue targeting the LncRNA00364 signaling axis in HCC.

16.
Chin Med J (Engl) ; 130(17): 2088-2094, 2017 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-28836553

RESUMO

BACKGROUND: Paroxysmal kinesigenic dyskinesia (PKD) is a rare movement disorder characterized by recurrent dystonic or choreoathetoid attacks triggered by sudden voluntary movements. Under the condition of psychological burden, some patients' attacks may get worsened with longer duration and higher frequency. This study aimed to assess nonmotor symptoms and quality of life of patients with PKD in a large population. METHODS: We performed a cross-sectional survey in 165 primary PKD patients from August 2008 to October 2016 in Rui Jin Hospital, using Symptom Check List-90-Revised (SCL-90-R), World Health Organization Quality of Life-100 (WHOQoL-100), Self-Rating Depression Scale, and Self-Rating Anxiety Scale. We evaluated the differences of SCL-90-R and WHOQOL-100 scores in patients and Chinese normative data (taken from literature) by using the unpaired Student's t-test. We applied multivariate linear regression to analyze the relationships between motor manifestations, mental health, and quality of life among PKD patients. RESULTS: Compared with Chinese normative data taken from literature, patients with PKD exhibited significantly higher (worse) scores across all SCL-90-R subscales (somatization, obsessive-compulsive, interpersonal sensitivity, depression, anxiety, hostility, phobic anxiety, paranoid ideation, and psychoticism; P= 0.000 for all) and significantly lower (worse) scores of five domains in WHOQoL-100 (physical domain, psychological domain, independence domain, social relationship domain, and general quality of life; P= 0.000 for all). Nonremission of dyskinesia episodes (P = 0.011) and higher depression score (P = 0.000) were significantly associated with lower levels of quality of life. The rates of depression and anxiety in patients with PKD were 41.2% (68/165) and 26.7% (44/165), respectively. CONCLUSIONS: Depression, anxiety, and low levels of quality of life were prevalent in patients with PKD. Co-occurrence of depression and anxiety was common among these patients. Regular mental health interventions could set depression and anxiety as intervention targets. Considering that the motor episodes could be elicited by voluntary movements and sometimes also by emotional stress, and that symptoms may get worsened with longer duration and higher frequency when patients are stressed out, intervention or treatment of depression and anxiety might improve the motor symptoms and overall quality of life in PKD patients.


Assuntos
Ansiedade/epidemiologia , Depressão/epidemiologia , Distonia/epidemiologia , Adolescente , Adulto , Criança , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Qualidade de Vida , Adulto Jovem
17.
Oncotarget ; 7(38): 61996-62005, 2016 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-27566558

RESUMO

Some observational studies have examined the association between dietary whole grain intake and all-cause mortality, but the results were inconclusive. We therefore conducted a meta-analysis to summarize the evidence from cohort studies regarding the association between whole grain intake and all-cause mortality. Pertinent studies were identified by searching PubMed, Embase and Web of Knowledge, up to February 28, 2016. Study-specific estimates were combined using random-effects models. Eleven prospective cohort studies involving 101,282 deaths and 843,749 participants were included in this meta-analysis. The pooled relative risk of all-cause mortality for the highest category of whole grain intake versus lowest category was 0.82 (95% confidence interval: 0.78, 0.87). There was a 7% reduction in risk associated with each 1 serving/day increase in whole grain intake (relative risk = 0.93; 95% confidence interval: 0.89, 0.97). No publication bias was found. This analysis indicates that higher intake of whole grain is associated with a reduced risk of all-cause mortality. The findings support current recommendations for increasing whole grain consumption to promote health and overall longevity.


Assuntos
Dieta , Mortalidade , Grãos Integrais , Adulto , Idoso , Idoso de 80 Anos ou mais , Consumo de Bebidas Alcoólicas , Índice de Massa Corporal , Exercício Físico , Comportamento Alimentar , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Análise de Regressão , Fatores de Risco
18.
Sci Rep ; 6: 26983, 2016 05 31.
Artigo em Inglês | MEDLINE | ID: mdl-27243945

RESUMO

Observational studies evaluating the relation between dietary or circulating level of beta-carotene and risk of total mortality yielded inconsistent results. We conducted a comprehensive search on publications of PubMed and EMBASE up to 31 March 2016. Random effect models were used to combine the results. Potential publication bias was assessed using Egger's and Begg's test. Seven studies that evaluated dietary beta-carotene intake in relation to overall mortality, indicated that a higher intake of beta-carotene was related to a significant lower risk of all-cause mortality (RR for highest vs. lowest group = 0.83, 95%CI: 0.78-0.88) with no evidence of heterogeneity between studies (I(2) = 1.0%, P = 0.416). A random-effect analysis comprising seven studies showed high beta-carotene level in serum or plasma was associated with a significant lower risk of all-cause mortality (RR for highest vs. lowest group = 0.69, 95%CI: 0.59-0.80) with low heterogeneity (I(2) = 37.1%, P = 0.145). No evidence of publication bias was detected by Begg's and Egger's regression tests. In conclusion, dietary or circulating beta-carotene was inversely associated with risk of all-cause mortality. More studies should be conducted to clarify the dose-response relationship between beta-carotene and all-cause mortality.


Assuntos
Doenças Cardiovasculares/mortalidade , Doenças Metabólicas/mortalidade , Neoplasias/mortalidade , Compostos Fitoquímicos/administração & dosagem , beta Caroteno/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Doenças Cardiovasculares/metabolismo , Dieta/classificação , Feminino , Humanos , Masculino , Doenças Metabólicas/metabolismo , Pessoa de Meia-Idade , Neoplasias/metabolismo , Estudos Prospectivos , Análise de Sobrevida
19.
Biochem Biophys Res Commun ; 468(4): 525-32, 2015 Dec 25.
Artigo em Inglês | MEDLINE | ID: mdl-26482853

RESUMO

Curcumin, a yellow polyphenol extracted from the rhizome of turmeric root (Curcuma longa) has potent anti-cancer properties in many types of tumors with ability to reverse multidrug resistance of cancer cells. However, widespread clinical application of this agent in cancer and other diseases has been limited due to its poor aqueous solubility. The recent findings of polymeric nanoparticle formulation of curcumin (NFC) have shown the potential for circumventing the problem of poor solubility, however evidences for NFC's anti-cancer and reverse multidrug resistance properties are lacking. Here we provide models of human hepatocellular carcinoma (HCC), the most common form of primary liver cancer, in vitro and in vivo to evaluate the efficacy of NFC alone and in combination with sorafenib, a kinase inhibitor approved for treatment of HCC. Results showed that NFC not only inhibited the proliferation and invasion of HCC cell lines in vitro, but also drastically suppressed primary tumor growth and lung metastases in vivo. Moreover, in combination with sorafenib, NFC induced HCC cell apoptosis and cell cycle arrest. Mechanistically, NFC and sorafenib synergistically down-regulated the expression of MMP9 via NF-κB/p65 signaling pathway. Furthermore, the combination therapy significantly decreased the population of CD133-positive HCC cells, which have been reported as cancer initiating cells in HCC. Taken together, NanoCurcumin provides an opportunity to expand the clinical repertoire of this agent. Additional studies utilizing a combination of NanoCurcumin and sorafenib in HCC are needed for further clinical development.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/secundário , Neoplasias Hepáticas/tratamento farmacológico , Nanocápsulas/química , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Protocolos de Quimioterapia Combinada Antineoplásica/química , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Curcumina/administração & dosagem , Curcumina/química , Difusão , Sinergismo Farmacológico , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanocápsulas/ultraestrutura , Niacinamida/administração & dosagem , Niacinamida/análogos & derivados , Niacinamida/química , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/química , Polímeros/química , Sorafenibe , Resultado do Tratamento
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