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"Liu, Y. C."
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Genetic alterations and their clinical implications in older patients with acute myeloid leukemia
A number of patient-specific and leukemia-associated factors are related to the poor outcome in older patients with acute myeloid leukemia (AML). However, comprehensive studies regarding the impact of genetic alterations in this group of patients are limited. In this study, we compared relevant mutations in 21 genes between AML patients aged 60 years or older and those younger and exposed their prognostic implications. Compared with the younger patients, the elderly had significantly higher incidences of
PTPN11
,
NPM1
,
RUNX1
,
ASXL1
,
TET2
,
DNMT3A
and
TP53
mutations but a lower frequency of
WT1
mutations. The older patients more frequently harbored one or more adverse genetic alterations. Multivariate analysis showed that
DNMT3A
and
TP53
mutations were independent poor prognostic factors among the elderly, while
NPM1
mutation in the absence of
FLT3
/ITD was an independent favorable prognostic factor. Furthermore, the status of mutations could well stratify older patients with intermediate-risk cytogenetics into three risk groups. In conclusion, older AML patients showed distinct genetic alterations from the younger group. Integration of cytogenetics and molecular mutations can better risk-stratify older AML patients. Development of novel therapies is needed to improve the outcome of older patients with poor prognosis under current treatment modalities.
Journal Article
Increased TEAD4 expression and nuclear localization in colorectal cancer promote epithelial–mesenchymal transition and metastasis in a YAP-independent manner
Dysregulation of the Hippo pathway occurs in a variety of cancers and often correlates with a poor prognosis. To further explore the potential role of Hippo pathway dysregulation in tumor development and progression, we investigated its downstream transcription factor TEAD4 in colorectal cancer (CRC). Increased expression and nuclear localization of TEAD4 were found in a significant portion of CRC tissues, in association with metastasis and a poor prognosis. In CRC cells, TEAD4 knockdown induced the mesenchymal–epithelial transition and decreased cell mobility
in vitro
and metastasis
in vivo
. Microarray analysis revealed that TEAD4 promoted cell adhesion and upregulated the epithelial–mesenchymal transition-related transcriptome in CRC cells. Vimentin was identified as a new direct target gene mediating TEAD4 function in CRC cells, whereby forced vimentin expression markedly reversed TEAD4-knockdown-induced cell morphological changes and decreased mobility. Interestingly, rescued expression of both WT TEAD4 and a Y429H mutant can reverse the mesenchymal–epithelial transition and increase vimentin expression, cell mobility and metastatic potential in TEAD4-knockdown CRC cells. The discrepant expression of YAP and TEAD4 in CRC tissues, the rescue ability of TEAD4 mutant defect in YAP binding and no effect on vimentin expression by YAP knockdown in CRC cells, all implicated a YAP-independent manner of TEAD4 function in CRC. Furthermore, vimentin positively correlated and CDH1 reversely correlated with the level of TEAD4 in CRC tissues and xenograft tumors. Our results suggest that TEAD4 nuclear expression can serve as a biomarker for CRC progression and poor prognosis. The transcription factor TEAD4 regulates a pro-metastasis transcription program in a YAP-independent manner in CRC, thus providing a novel mechanism of TEAD4 transcriptional regulation and its oncogenic role in CRC, independently of the Hippo pathway.
Journal Article
Integration of cytogenetic and molecular alterations in risk stratification of 318 patients with de novo non-M3 acute myeloid leukemia
Conventionally, acute myeloid leukemia (AML) patients are categorized into good-, intermediate- and poor-risk groups according to cytogenetic changes. However, patients with intermediate-risk cytogenetics represent a largely heterogeneous population regarding treatment response and clinical outcome. In this study, we integrated cytogenetics and molecular mutations in the analysis of 318 patients with
de novo
non-M3 AML who received standard chemotherapy. According to the mutation status of eight genes, including
NPM1
,
CEBPA
,
IDH2
,
RUNX1
,
WT1
,
ASXL1
,
DNMT3A
and
FLT3
, that had prognostic significance, 229 patients with intermediate-risk cytogenetics could be refinedly stratified into three groups with distinct prognosis (
P
<0.001); patients with good-risk genotypes had a favorable outcome (overall survival, OS, not reached) similar to those with good-risk cytogenetics, whereas those with poor-risk genotypes had an unfavorable prognosis (OS, 10 months) similar to those with poor-risk cytogenetics (OS, 13.5 months), and the remaining patients with other genotypes had an intermediate outcome (OS, 25 months). Integration of cytogenetic and molecular profiling could thus reduce the number of intermediate-risk AML patients from around three-fourth to one-fourth. In conclusion, integration of cytogenetic and molecular changes improves the prognostic stratification of AML patients, especially those with intermediate-risk cytogenetics, and may lead to better decision on therapeutic strategy.
Journal Article
CIP2A mediates effects of bortezomib on phospho-Akt and apoptosis in hepatocellular carcinoma cells
Previously, we reported that Akt inactivation determines the sensitivity of hepatocellular carcinoma (HCC) cells to bortezomib. In this study, we report that cancerous inhibitor of protein phosphatase 2A (CIP2A), a cellular inhibitor of protein phosphatase 2A (PP2A), mediates the apoptotic effect of bortezomib in HCC. Silencing PP2A by small interference RNA (siRNA) abolishes bortezomib-induced down-regulation of phospho-Akt and apoptosis. Bortezomib increases PP2A activity in sensitive HCC cells, including Sk-Hep1, Hep3B and Huh-7, but not in resistant PLC5 cells. Bortezomib down-regulates CIP2A in a dose- and time-dependent manner in all sensitive HCC cells, whereas no alterations in CIP2A were found in resistant PLC5 cells. Knockdown of CIP2A by siRNA restored bortezomib’s effects on apoptosis and PP2A activity in PLC5 cells. Moreover, over-expression of CIP2A up-regulated phospho-Akt and protected Sk-Hep1 cells from bortezomib-induced apoptosis. It is significant that, ectopic expression of CIP2A decreased Akt-related PP2A activity, whereas silencing CIP2A increased this activity, indicating that CIP2A negatively regulates Akt-related PP2A activity in HCC cells, furthermore, our
in vivo
data showed that bortezomib down-regulates CIP2A and up-regulates PP2A activity in Huh-7 tumors, but not in PLC5 tumors. In conclusion, inhibition of CIP2A determines the effects of bortezomib on apoptosis and PP2A-dependent Akt inactivation in HCC.
Journal Article
A new role of NUAK1: directly phosphorylating p53 and regulating cell proliferation
It has been suggested that adenosine monophosphate-activated protein kinase (AMPK) and 12 AMPK-related kinases (ARK), including novel (nua) kinase family 1 (NUAK1), are activated by master kinase LKB1, a major tumor suppressor. Apart from evidence to suggest that NUAK1 participates in induction of tumor survival, invasion and p53-independent cellular senescence, its detailed biological functions remain unclear. Here we showed that in the presence of wild-type LKB1, NUAK1 directly interacts with and phosphorylates p53
in vitro
and
in vivo
. The phosphorylation of p53 induced by LKB1 required the kinase activity of NUAK1 and phosphorylation of NUAK1 at Thr211 by LKB1 was essential for its kinase activity, which leads to the conclusion that LKB1 activates NUAK1 and regulates phosphorylation of p53 through the NUAK1 kinase, at least partially. LKB1/NUAK1 activation leads to cell cycle arrest at the G
1
/S border by inducing expression of p21/WAF1. Under the regulation of LKB1, NUAK1 interacts with p53 in the nucleus and binds to the p53-responsive element of p21/WAF1 promoter. These findings have highlighted a novel role for NUAK1 in LKB1-related signaling pathways; NUAK1 can regulate cell proliferation and exert tumor suppression through direct interaction with p53.
Journal Article
The long noncoding RNA NRF regulates programmed necrosis and myocardial injury during ischemia and reperfusion by targeting miR-873
Emerging evidences suggest that necrosis is programmed and is one of the main forms of cell death in the pathological process in cardiac diseases. Long noncoding RNAs (lncRNAs) are emerging as new players in gene regulation. However, it is not yet clear whether lncRNAs can regulate necrosis in cardiomyocytes. Here, we report that a long noncoding RNA, named necrosis-related factor (NRF), regulates cardiomyocytes necrosis by targeting miR-873 and RIPK1 (receptor-interacting serine/threonine-protein kinase 1)/RIPK3 (receptor-interacting serine/threonine-protein kinase 3). Our results show that RIPK1 and RIPK3 participate in H
2
O
2
-induced cardiomyocytes necrosis. miR-873 suppresses the translation of RIPK1/RIPK3 and inhibits RIPK1/RIPK3-mediated necrotic cell death in cardiomyocytes. miR-873 reduces myocardial infarct size upon ischemia/reperfusion (I/R) injury in the animal model. In exploring the molecular mechanism by which miR-873 expression is regulated, we identify NRF as an endogenous sponge RNA and repress miR-873 expression. NRF directly binds to miR-873 and regulates RIPK1/RIPK3 expression and necrosis. Knockdown of NRF antagonizes necrosis in cardiomyocytes and reduces necrosis and myocardial infarction upon I/R injury. Further, we identify that p53 transcriptionally activates NRF expression. P53 regulates cardiomyocytes necrosis and myocardial I/R injury through NRF and miR-873.Our results identify a novel mechanism involving NRF and miR-873 in regulating programmed necrosis in the heart and suggest a potential therapeutic avenue for cardiovascular diseases.
Journal Article
Application of GA-BP Neural Network Optimized by Grey Verhulst Model around Settlement Prediction of Foundation Pit
Due to the limitation in the prediction of the foundation pit settlement, this paper proposed a new methodology which takes advantage of the grey Verhulst model and a genetic algorithm. In the previous study, excavation times are often the only factor to predict the settlement, which is mainly because the correspondence between real-time excavation depth and the excavation time is hard to determine. To solve this issue, the supporting times are precisely recorded and the excavation depth rate can be obtained through the excavation time length and excavation depth between two adjacent supports. After the correspondence between real-time excavation depth and the excavation time is obtained, the internal friction angle, cohesion, bulk density, Poisson’s ratio, void ratio, water level changes, permeability coefficient, number of supports, and excavation depth, which can influence the settlement, are taken to be considered in this study. For the application of the methodology, the settlement monitoring point of D4, which is near the bridge pier of the highway, is studied in this paper. The predicted values of the BP neural network, GA-BP neural network, BP neural network optimized by the grey Verhulst model, and GA-BP neural network optimized by the grey Verhulst model are detailed compared with the measured values. And the evaluation indexes of RMSE, MAE, MSE, MAPE, and R2 are calculated for these models. The results show that the grey Verhulst model can greatly improve the consistency between predicted values and measured values, while the accuracy and resolution is still low. The genetic algorithm (GA) can greatly improve the accuracy of the predicted values, while the GA-BP neural network shows low reflection to the fluctuation of measured values. The GA-BP neural network optimized by the grey Verhulst model, which has taken the advantages of GA and the grey Verhulst model, has extremely high accuracy and well consistency with the measured values.
Journal Article
Low prevalence of major depressive disorder in Taiwanese adults: possible explanations and implications
This study examined the prevalence of major depressive disorder (MDD), and the correlations and co-morbid conditions associated with MDD, in the adult Taiwanese population, which a previous estimate in the 1980s had found to be at the lower end of the spectrum worldwide. Possible explanations for the reported low prevalence of MDD were evaluated.
As part of a survey of common psychiatric disorders in a nationally representative sample of individuals aged ≥ 18 years who were non-institutionalized civilians in Taiwan, a face-to-face interview using the paper version of the World Mental Health Survey of the World Health Organization (WHO) Composite International Diagnostic Interview (WMH-CIDI) was conducted between 2003 and 2005. Functional impairment and help-seeking behaviors were compared between Taiwanese subjects with MDD and their counterparts in the USA.
Among the 10 135 respondents, the lifetime prevalence of MDD was 1.20% [standard error (S.E.)=0.2%]. Individuals who were divorced or widowed, aged ≤ 40 years, and female were at increased risk, whereas rural residents were at lower risk for MDD. The proportion of MDD cases co-morbid with other psychiatric disorders in this study was much lower than in the US study. Only one-third of Taiwanese individuals with MDD sought help despite having twice the number of lost workdays compared with the US sample.
Despite the low prevalence of MDD in Taiwanese adults, the pattern of low help-seeking behavior and profound functional impairment indicates much room for improvement in the early detection of and intervention in major depression in this population.
Journal Article