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Articles by Q Liu
Total Records ( 17 ) for Q Liu
  H Li , Q Liu , X Hu , D Feng , S Xiang , Z He , J Zhou , X Ding , C Zhou and J. Zhang

Mouse zinc finger CCHC domain containing 12 gene (ZCCHC12) has been identified as a transcriptional co-activator of bone morphogenetic protein (BMP) signaling, and human ZCCHC12 was reported to be related to non-syndromic X-linked mental retardation (NS-XLMR). However, the details of how human ZCCHC12 involve in the NS-XLMR still remain unclear. In this study, we identified a novel nuclear localization signal (NLS) in the middle of human ZCCHC12 protein which is responsible for the nuclear localization. Multiple-tissue northern blot analysis indicated that ZCCHC12 is highly expressed in human brain. Furthermore, in situ hybridization showed that ZCCHC12 is specifically expressed in neuroepithelium of forebrain, midbrain, and diencephalon regions of mouse E10.5 embryos. Luciferase reporter assays demonstrated that ZCCHC12 enhanced the transcriptional activities of activator protein 1 (AP-1) and cAMP response element binding protein (CREB) as a co-activator. In conclusion, we identified a new NLS in ZCCHC12 and figured out that ZCCHC12 functions as a transcriptional co-activator of AP-1 and CREB.

  L Zhang , Q Liu , Y Zhou and Y. Zhang

The male reproductive tracts in different species are characterized by similar patterns of male-dependent overexpression of carboxylesterases. This phenomenon indicates male sex-associated functions of these enzymes for spermatogenesis, sperm maturation, and sperm use. Recently, a novel epididymis-specific gene named Ces7 was cloned and characterized, which belongs to the carboxylesterase family. To study the functions of CES7 in sperm maturation and storage, CES7 recombinant protein was expressed in baculovirus system. The recombinant protein had carboxylesterase activity hydrolyzing cholesterol ester and choline ester. CES7 as carboxylesterase might be involved in ester hydrolysis, sperm maturation, and storage in male reproductive tract.

  L Zhang , Z Hu , C Zhu , Q Liu , Y Zhou and Y. Zhang

Carboxylesterases (CEs) represent a multigene family of serine-dependent enzymes. Male-dependent CEs are over-expressed in the male reproductive tract of different animal species (bivalve mollusks, fruit-flies, and mammals). Here, a novel rat epididymis-specific gene named Ces7 was cloned and characterized. It was a novel member of CE family, which was mainly expressed and secreted to the lumens of the corpus and cauda epididymis. CES7 protein was highly glycosylated as other mammalian CEs. Furthermore, Ces7 increased with age growth until sex maturation and then maintained at high level. CES7 might be one of the major CEs in male reproductive tract and contribute to the sperm fertilization.

  Q Liu , Z Dai , Z Liu , X Liu , C Tang , Z Wang , G Yi , L Liu , Z Jiang , Y Yang and Z. Yuan

It has been reported that oxidized low-density lipoprotein (Ox-LDL) can increase the expression of adipophilin. However, the detailed mechanisms are not fully understood. The aim of this study was to investigate the mechanism of Ox-LDL on adipophilin expression and the intracellular lipid droplet accumulation. A mouse macrophage-like cell line, RAW264.7, was used throughout, and it was found that Ox-LDL induced adipophilin expression in a dose-dependent manner. Moreover, Ox-LDL induced peroxisome proliferator-activated receptor- (PPAR) expression and PPAR-specific inhibitor T0070907 abrogated Ox-LDL-induced adipophilin expression, but specific agonist GW1929 not. Furthermore, Ox-LDL induced phosphorylation of ERK1/2, and ERK1/2-specific inhibition by PD98059 suppressed the Ox-LDL-induced PPAR and adipophilin expression. The results showed that ERK1/2 or PPAR-specific inhibition decreased the amounts of intracellular lipid droplets. Meanwhile, the PPAR-specific agonist increased intracellular lipid droplets. These results suggested that Ox-LDL-induced increase in adipophilin level via ERK1/2 activation is one of the mechanisms of inducing greater amounts of intracellular lipid droplets in RAW264.7 cells, which indicated that adipophilin is involved in atherosclerotic progression.

  W Gu , K. A Winters , A. S Motani , R Komorowski , Y Zhang , Q Liu , X Wu , I. C Rulifson , G Sivits , M Graham , H Yan , P Wang , S Moore , T Meng , R. A Lindberg and M. M. Veniant

Antagonism of the glucagon receptor (GCGR) is associated with increased circulating levels of glucagon-like peptide-1 (GLP-1). To investigate the contribution of GLP-1 to the antidiabetic actions of GCGR antagonism, we administered an anti-GCGR monoclonal antibody (mAb B) to wild-type mice and GLP-1 receptor knockout (GLP-1R KO) mice. Treatment of wild-type mice with mAb B lowered fasting blood glucose, improved glucose tolerance, and enhanced glucose-stimulated insulin secretion during an intraperitoneal glucose tolerance test (ipGTT). In contrast, treatment of GLP-1R KO mice with mAb B had little efficacy during an ipGTT. Furthermore, pretreatment with the GLP-1R antagonist exendin-(9–39) diminished the antihyperglycemic effects of mAb B in wild-type mice. To determine the mechanism whereby mAb B improves glucose tolerance, we generated a monoclonal antibody that specifically antagonizes the human GLP-1R. Using a human islet transplanted mouse model, we demonstrated that pancreatic islet GLP-1R signaling is required for the full efficacy of the GCGR antagonist. To identify the source of the elevated GLP-1 observed in GCGR mAb-treated mice, we measured active GLP-1 content in pancreas and intestine from db/db mice treated with anti-GCGR mAb for 8 wk. Elevated GLP-1 in GCGR mAb-treated mice was predominantly derived from increased pancreatic GLP-1 synthesis and processing. All together, these data show that pancreatic GLP-1 is a significant contributor to the glucose-lowering effects observed in response to GCGR antagonist treatment.

  L. R Meacham , C. A Sklar , S Li , Q Liu , N Gimpel , Y Yasui , J. A Whitton , M Stovall , L. L Robison and K. C. Oeffinger

Background  Childhood cancer survivors are at increased risk of morbidity and mortality. To further characterize this risk, this study aimed to compare the prevalence of diabetes mellitus (DM) in childhood cancer survivors and their siblings.

Methods  Participants included 8599 survivors in the Childhood Cancer Survivor Study (CCSS), a retrospectively ascertained North American cohort of long-term survivors who were diagnosed between 1970 and 1986 as well as 2936 randomly selected siblings of the survivors. The main outcome was self-reported DM.

Results  The mean ages of the survivors and the siblings were 31.5 years (age range, 17.0-54.1 years) and 33.4 years (age range, 9.6-58.4 years), respectively. Diabetes mellitus was reported in 2.5% of the survivors and 1.7% of the siblings. After adjustment for body mass index, age, sex, race/ethnicity, household income, and insurance, the survivors were 1.8 times more likely than the siblings to report DM (95% confidence interval [CI], 1.3-2.5; P < .001), with survivors who received total body irradiation (odds ratio [OR], 12.6; 95% CI, 6.2-25.3; P < .001), abdominal irradiation (OR, 3.4; 95% CI, 2.3-5.0; P < .001), and cranial irradiation (OR, 1.6; 95% CI 1.0-2.3; P = .03) at increased risk. In adjusted models, an increased risk of DM was associated with total body irradiation (OR, 7.2; 95% CI, 3.4-15.0; P < .001), abdominal irradiation (OR, 2.7; 95% CI, 1.9-3.8; P < .001), use of alkylating agents (OR, 1.7; 95% CI, 1.2-2.3; P < .01), and younger age at diagnosis (0-4 years; OR, 2.4; 95% CI, 1.3-4.6; P < .01).

Conclusion  Childhood cancer survivors treated with total body or abdominal irradiation have an increased risk of diabetes that appears unrelated to body mass index or physical inactivity.

  Z. x Duan , W Gu , L. y Zhang , D. y Du , P Hu , J Huang , Q Liu , Z. g Wang , J Hao and J. x. Jiang

Objective  To investigate the clinical relevance of the TLR4 11367 polymorphism in patients with major trauma.

Design  Genetic functional and association study.

Setting  Daping Hospital and Chongqing Emergency Medical Center, Chongqing, China.

Patients  A total of 132 patients with major trauma were prospectively recruited.

Main Outcome Measures  The TLR4 11367 polymorphism was genotyped using single-tube, bidirectional, allele-specific amplification method. Whole peripheral blood samples obtained within 24 hours after admission were stimulated with lipopolysaccharide and then tested for production of tumor necrosis factor and interleukin 6. Sepsis morbidity rate and multiple organ dysfunction scores were assessed.

Results  The 11367 polymorphism was shown to be strongly associated with less capacity of peripheral leukocytes to produce tumor necrosis factor and interleukin 6 in response to ex vivo lipopolysaccharide stimulation in patients with trauma at admission. Results from association study indicated that patients with trauma who carry the 11367C allele were less likely to have sepsis and multiple organ dysfunction.

Conclusions  Combined with our previous in vitro functional study, the results suggest that the TLR4 11367 polymorphism might be a good predictor of who is more likely to develop complications such as sepsis or multiple organ dysfunction syndrome, depending on genotype.

  M Zhang , L Zhang , J Zou , C Yao , H Xiao , Q Liu , J Wang , D Wang , C Wang and Z. Guo

Motivation: According to current consistency metrics such as percentage of overlapping genes (POG), lists of differentially expressed genes (DEGs) detected from different microarray studies for a complex disease are often highly inconsistent. This irreproducibility problem also exists in other high-throughput post-genomic areas such as proteomics and metabolism. A complex disease is often characterized with many coordinated molecular changes, which should be considered when evaluating the reproducibility of discovery lists from different studies.

Results: We proposed metrics percentage of overlapping genes-related (POGR) and normalized POGR (nPOGR) to evaluate the consistency between two DEG lists for a complex disease, considering correlated molecular changes rather than only counting gene overlaps between the lists. Based on microarray datasets of three diseases, we showed that though the POG scores for DEG lists from different studies for each disease are extremely low, the POGR and nPOGR scores can be rather high, suggesting that the apparently inconsistent DEG lists may be highly reproducible in the sense that they are actually significantly correlated. Observing different discovery results for a disease by the POGR and nPOGR scores will obviously reduce the uncertainty of the microarray studies. The proposed metrics could also be applicable in many other high-throughput post-genomic areas.

  L Peng , Y. L Ran , H Hu , L Yu , Q Liu , Z Zhou , Y. M Sun , L. C Sun , J Pan , L. X Sun , P Zhao and Z. H. Yang

The purpose of this study was to investigate invasion- and metastasis-related genes in gastric cancer. To this end, we used the transwell system to select a highly invasive subcell line from minimally invasive parent cells and compared gene expression in paired cell lines with high- and low-invasive potentials. Lysyl oxidase-like 2 (LOXL2) was overexpressed in the highly invasive subcell line. Immunohistochemical analysis revealed that LOXL2 expression was markedly increased in carcinoma relative to normal epithelia, and this overexpression in primary tumor was significantly associated with depth of tumor invasion, lymph node metastasis and poorer overall survival. Moreover, LOXL2 expression was further increased in lymph node metastases compared with primary cancer tissues. RNA interference-mediated knockdown and ectopic expression of LOXL2 showed that LOXL2 promoted tumor cell invasion in vitro and increased gastric carcinoma metastasis in vivo. Subsequent mechanistic studies showed that LOXL2 could activate both the Snail/E-cadherin and Src kinase/Focal adhesion kinase (Src/FAK) pathways. However, secreted LOXL2 induced gastric tumor cell invasion and metastasis exclusively via the Src/FAK pathway. Expression correlation analysis in gastric carcinoma tissues also revealed that LOXL2 promoted invasion via the Src/FAK pathway but not the Snail/E-cadherin pathway. We then evaluated secreted LOXL2 as a target for gastric carcinoma treatment and found that an antibody against LOXL2 significantly inhibited tumor growth and metastasis. Overall, our data revealed that LOXL2 overexpression, a frequent event in gastric carcinoma progression, contributes to tumor cell invasion and metastasis, and LOXL2 may be a therapeutic target for preventing and treating metastases.

  Q Liu , X Chen , S. M MacDonnell , E. G Kranias , J. N Lorenz , M Leitges , S. R Houser and J. D. Molkentin

Protein kinase (PK)C, PKCβ, and PKC comprise the conventional PKC isoform subfamily, which is thought to regulate cardiac disease responsiveness. Indeed, mice lacking the gene for PKC show enhanced cardiac contractility and reduced susceptibility to heart failure. Recent data also suggest that inhibition of conventional PKC isoforms with Ro-32-0432 or Ro-31-8220 enhances heart function and antagonizes failure, although the isoform responsible for these effects is unknown. Here, we investigated mice lacking PKC, PKCβ, and PKC for effects on cardiac contractility and heart failure susceptibility. PKC–/– mice, but not PKCβ–/– mice, showed increased cardiac contractility, myocyte cellular contractility, Ca2+ transients, and sarcoplasmic reticulum Ca2+ load. PKC–/– mice were less susceptible to heart failure following long-term pressure-overload stimulation or 4 weeks after myocardial infarction injury, whereas PKCβ–/– mice showed more severe failure. Infusion of ruboxistaurin (LY333531), an orally available PKC/β/ inhibitor, increased cardiac contractility in wild-type and PKCβ–/– mice, but not in PKC–/– mice. More importantly, ruboxistaurin prevented death in wild-type mice throughout 10 weeks of pressure-overload stimulation, reduced ventricular dilation, enhanced ventricular performance, reduced fibrosis, and reduced pulmonary edema comparable to or better than metoprolol treatment. Ruboxistaurin was also administered to PKCβ–/– mice subjected to pressure overload, resulting in less death and heart failure, implicating PKC as the primary target of this drug in mitigating heart disease. As an aside, PKCβ triple-null mice showed no defect in cardiac hypertrophy following pressure-overload stimulation. In conclusion, PKC functions distinctly from PKCβ and PKC in regulating cardiac contractility and heart failure, and broad-acting PKC inhibitors such as ruboxistaurin could represent a novel therapeutic approach in treating human heart failure.

  Q Liu , M. A Sargent , A. J York and J. D. Molkentin

Rationale: Apoptosis signal-regulating kinase (ASK)1 is a central upstream kinase in the greater mitogen-activated protein kinase cascade that mediates growth and death decisions in cardiac myocytes in response to diverse pathological stimuli.

Objective: However, the role that ASK1 plays in regulating the cardiac hypertrophic response in vivo remains controversial.

Methods and Results: Here, we generated mice with cardiac-specific and inducible overexpression of ASK1 in the heart to assess its gain-of-function effect. ASK1 transgenic mice exhibited no induction of cardiac hypertrophy or pathology at 3 and 12 months of age, and these mice showed an identical hypertrophic response to controls following 2 weeks of pressure-overload stimulation or isoproterenol infusion. Although ASK1 overexpression did not alter the cardiac hypertrophic response, it promoted cardiomyopathy and greater TUNEL following pressure-overload stimulation and myocardial infarction. Indeed, ASK1 transgenic mice showed a greater than 2-fold increase in ischemia reperfusion-induced injury to the heart compared with controls. Examination of downstream signaling showed a prominent activation of mitogen-activated protein kinase kinase 4/6 and c-Jun NH2-terminal kinase (JNK)1/2 (but not p38 or extracellular signal-regulated kinases [ERKs]), inhibition of calcineurin-NFAT (nuclear factor of activated T cells), and induction of Bax in the hearts of ASK1 transgenic mice following 1 and 8 weeks of pressure-overload stimulation. Mechanistically, cardiomyopathy associated with ASK1 overexpression after 8 weeks of pressure overload was significantly reduced in the calcineurin Aβ–null (CnAβ–/–) background.

Conclusions: These results indicate that ASK1 does not directly regulate the cardiac hypertrophic response in vivo, but it does alter cell death and propensity to cardiomyopathy, in part, through a calcineurin-dependent mechanism.

  C Laverdiere , Q Liu , Y Yasui , P. C Nathan , J. G Gurney , M Stovall , L. R Diller , N. K Cheung , S Wolden , L. L Robison and C. A. Sklar

The 5-year survival rate for individuals with neuroblastoma is approaching 70%. Few data exist, however, on the long-term outcomes of these patients, who are often treated at a very young age.


Outcome data were obtained for 954 5-year neuroblastoma survivors who were diagnosed in 1970–1986 and enrolled in the Childhood Cancer Survivor Study (CCSS). Late mortality, second malignant neoplasms, and chronic health conditions were analyzed in relation to treatment factors using Poisson regression models and their modification with generalized estimating equations. Neuroblastoma survivors were compared with a cohort of 3899 siblings of CCSS participants for risk of chronic health conditions and selected sociodemographic outcomes. All statistical tests were two-sided.


Six percent of patients died more than 5 years after their diagnosis (standardized mortality ratio = 5.6; 95% confidence interval [CI] = 4.4 to 6.9). The most common causes of death were disease recurrence (n = 43) and second malignant neoplasms (n = 13). The cumulative incidence of second malignant neoplasms was 3.5% at 25 years and 7.0% at 30 years after diagnosis. Compared with the sibling cohort, survivors had an increased risk of selected chronic health conditions (risk ratio [RR] = 8.3; 95% CI = 7.1 to 9.7) with a 20-year cumulative incidence of 41.1%. The most prevalent outcomes involved the neurological, sensory, endocrine, and musculoskeletal systems, with 20-year cumulative incidences of 29.8%, 8.6%, 8.3%, and 7.8%, respectively. Neuroblastoma survivors who were treated with multimodality therapy were more likely to develop a chronic health condition than survivors treated with surgery alone (RR = 2.2; 95% CI = 1.6 to 3.0). Neuroblastoma survivors were less likely than siblings to have ever been employed (P = .04) or to be married (P < .001) and had a lower personal income (P = .009).


Neuroblastoma survivors have an increased rate of mortality and second malignant neoplasms, relative to the age- and sex-comparable US population, and of chronic health conditions, relative to their siblings, which underscores the need for long-term medical surveillance.

  K Wasilewski Masker , Q Liu , Y Yasui , W Leisenring , L. R Meacham , S Hammond , A. T Meadows , L. L Robison and A. C. Mertens

An increasing percentage of childhood cancer patients are surviving their disease, but there is limited research on late recurrence. We sought to estimate late recurrence rates for the most common pediatric cancers and to determine risk factors for late recurrence.


The incidence of late recurrences, or first recurrences that occurred more than 5 years after diagnosis, was analyzed for the most common pediatric cancers using data from the Childhood Cancer Survivor Study, a retrospective cohort of 5-year survivors of childhood and adolescent cancers who were diagnosed between 1970 and 1986. A total of 12 795 survivors with no history of recurrence within 5 years after their original cancer diagnosis were included in the analysis, with a total of 217 127 person-years of follow-up. Cumulative incidence of late recurrence at 5, 10, 15, and 20 years after diagnosis was calculated using death as a competing risk. Adjusted relative rates of late recurrence were obtained using multivariable Poisson regression. All statistical tests were two-sided.


Overall, 5-year survivors of pediatric cancers experienced a cumulative incidence of recurrent disease of 4.4%, 5.6%, and 6.2% at 10, 15, and 20 years, respectively. Cumulative incidence varied by diagnosis: Survivors of Ewing sarcoma and astrocytoma had the highest 20-year cumulative incidences at 13.0% (95% confidence interval [CI] = 9.4 to 16.5) and 14.4% (95% CI = 12.3 to 16.6), respectively. In multivariable analysis, the greatest risk factors for late recurrence included diagnosis, combination treatment with chemotherapy and radiation, earlier treatment era, and fewer years since diagnosis (P < .001 for all).


Late recurrence is a risk for some pediatric cancers. By understanding diagnosis-specific risks, patients, families, and their medical providers can be better informed of the probability of cure.

  S Hu , G Yao , X Guan , Z Ni , W Ma , E. M Wilson , F. S French , Q Liu and Y. Zhang

Epididymal function depends on androgen signaling through the androgen receptor (AR), although most of the direct AR target genes in epididymis remain unknown. Here we globally mapped the AR binding regions in mouse caput epididymis in which AR is highly expressed. Chromatin immunoprecipitation sequencing indicated that AR bound selectively to 19,377 DNA regions, the majority of which were intergenic and intronic. Motif analysis showed that 94% of the AR binding regions harbored consensus androgen response elements enriched with multiple binding motifs that included nuclear factor 1 and activator protein 2 sites consistent with combinatorial regulation. Unexpectedly, AR binding regions showed limited conservation across species, regardless of whether the metric for conservation was based on local sequence similarity or the presence of consensus androgen response elements. Further analysis suggested the AR target genes are involved in diverse biological themes that include lipid metabolism and sperm maturation. Potential novel mechanisms of AR regulation were revealed at individual genes such as cysteine-rich secretory protein 1. The composite studies provide new insights into AR regulation under physiological conditions and a global resource of AR binding sites in a normal androgen-responsive tissue.

  W Huang , Q Liu , S. G Rhee and L. Zhang

The empirical evidence on the cross-sectional relation between idiosyncratic risk and expected stock returns is mixed. We demonstrate that the omission of the previous month's stock returns can lead to a negatively biased estimate of the relation. The magnitude of the omitted variable bias depends on the approach to estimating the conditional idiosyncratic volatility. Although a negative relation exists when the estimate is based on daily returns, it disappears after return reversals are controlled for. Return reversals can explain both the negative relation between value-weighted portfolio returns and idiosyncratic volatility and the insignificant relation between equal-weighted portfolio returns and idiosyncratic volatility. In contrast, there is a significantly positive relation between the conditional idiosyncratic volatility estimated from monthly data and expected returns. This relation remains robust after controlling for return reversals.

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