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Articles by J Qian
Total Records ( 12 ) for J Qian
  Z Zhu , Y Yan , Q Wang , J Qian and J. Ge

The serum proteins creatine kinase isoenzyme MB (CK-MB) and cardiac troponin T are classic biomarkers of cardiac ischemic damage in clinical practice, which can sensitively detect myocardial necrosis, while other two serum proteins, ischemia-modified albumin and N-terminal pro-B-type natriuretic peptide (NT-proBNP), have been recently identified as novel biomarkers of myocardial ischemia. In this study, the four biomarkers were detected in sera from 44 eligible patients with suspected coronary heart disease (CHD) before and after treadmill exercise test (TET), electrocardiogram (ECG) was measured during TET (TET-ECG) and invasive examination of coronary angiography (CAG), which is the ‘gold standard’ of CHD diagnosis, was also performed. For CAG, 25 patients were positive and 19 were negative, whereas for TET-ECG the numbers were 19 and 25, respectively. Among these four biomarkers, the NT-proBNP level in CAG positive group was much higher than those in CAG negative group both before and after TET, with statistical significance before TET (P = 0.008). Furthermore, according to receiver operating characteristic (ROC) curve, the serum biomarker NT-proBNP showed diagnostic effect of CHD and its cutoff value was 67 pg/ml, thus 30 of the patients in this study were NT-proBNP positive and 14 were negative. And it was found that NT-proBNP obviously enhanced the sensitivity of examinations whether analyzed alone or in combination with TET-ECG. More importantly, all the patients who were negative in both NT-proBNP and TET-ECG tests turned out to be CAG negative, which means that the combination of these two non-invasive examinations might take the place of invasive examination of CAG for CHD diagnosis. Further studies with more patients are warranted to validate the findings in this paper.

  J Qian and L. Peng

Quantile regression offers a flexible approach to analyzing survival data, allowing each covariate effect to vary with quantiles. In practice, constancy is often found to be adequate for some covariates. In this paper, we study censored quantile regression tailored to the partially functional effect setting with a mixture of varying and constant effects. Such a model can offer a simpler view regarding covariate-survival association and, moreover, can enable improvement in estimation efficiency. We propose profile estimating equations and present an iterative algorithm that can be readily and stably implemented. Asymptotic properties of the resultant estimators are established. A simple resampling-based inference procedure is developed and justified. Extensive simulation studies demonstrate efficiency gains of the proposed method over a naive two-stage procedure. The proposed method is illustrated via an application to a recent renal dialysis study.

  C Wu , Z Hu , D Yu , L Huang , G Jin , J Liang , H Guo , W Tan , M Zhang , J Qian , D Lu , T Wu , D Lin and H. Shen

Recent three genome-wide association studies have mapped a lung cancer susceptibility locus to chromosome 15q25 in Caucasians. However, the reported risk single nucleotide polymorphisms (SNPs) are extremely rare in Asians, arguing against any of these being causative variants. This study sought to identify other variants on 15q25 associated with lung cancer susceptibility in Chinese. Two-stage case-control studies were conducted in subjects derived from both Northern and Southern China. The first-stage, consisting of 576 cases and 576 controls, was to discover novel risk variants using a haplotype-tagging SNP approach, and these variants were then replicated in the second-stage, consisting of 2,989 cases and 2,880 controls. Associations were estimated by logistic regression models, and function of the variants was examined by biochemical assays. We found that the three risk SNPs reported in Caucasians were not associated with lung cancer risk in Chinese. However, we identified four novel SNPs (rs2036534C>T, rs667282C>T, rs12910984G>A, and rs6495309T>C) that were associated with significantly increased lung cancer risk and smoking behavior, which were all confirmed in the replication analyses [odds ratios (95% confidence intervals) in the dominant model: 1.39 (1.23–1.57; P = 2.3 x 10–7), 1.52 (1.35–1.71; P = 2.0 x 10–12), 1.44 (1.28–1.63; P = 2.7 x 10–9), and 1.43 (1.27–1.61; P = 2.6 x 10–9), respectively]. We characterized the rs6495309T>C change in the CHRNA3 promoter as a functional variant because it affected the Oct-1 binding ability, resulting in increased CHRNA3 expression. These results support 15q25 as a susceptibility region for lung cancer in Chinese but underscore the difference in genetic markers among different ethnic populations. [Cancer Res 2009;69(12):5065–72]

  F Ji , W Wang , Z. L Xia , Y. J Zheng , Y. L Qiu , F Wu , W. B Miao , R. F Jin , J Qian , L Jin , Y. L Zhu and D. C. Christiani

Vinyl chloride (VC) was classified as a group 1 carcinogen by IARC in 1987. Although the relationship between VC exposure and liver cancer has been established, the mechanism of VC-related carcinogenesis remains largely unknown. Previous epidemiological studies have shown that VC exposure is associated with increased genotoxicity in humans. To explore chromosomal damage and its progression, and their association to genetic susceptibility, we investigated 402 workers exposed to VC, a 77 VC-exposed cohort and 141 unexposed subjects. We measured the frequencies of cytokinesis-block micronucleus (CBMN) to reflect chromosomal damage and conducted genotyping for six xenobiotic metabolisms and five DNA repair genes' polymorphism. Data indicate that 95% of the control workers had CBMN frequencies ≤3, whereas VC-exposed workers had the 3.73-fold increase compared with the controls. Among the cohort workers who were followed from 2004 to 2007, the mean CBMN frequency was higher in 2007 than in 2004 with ratio of 2.08. Multiple Poisson regression analysis showed that mean CBMN frequencies were significantly elevated for the intermediate and high exposure groups than the low. Exposed workers with CYP2E1 or XRCC1 variance showed a higher CBMN frequency than their wild-type homozygous counterparts, so did workers with GSTP1 or ALDH2 genotype. This study provides evidence that cumulative exposure dose of VC and common genetic variants in genes relevant to detoxification of carcinogens are the major factors that modulate CBMN induction in VC-exposed workers.

  J Qian , X Ren , X Wang , P Zhang , W. K Jones , J. D Molkentin , G. C Fan and E. G. Kranias

Rationale: The levels of a small heat shock protein (Hsp)20 and its phosphorylation are increased on ischemic insults, and overexpression of Hsp20 protects the heart against ischemia/reperfusion injury. However, the mechanism underlying cardioprotection of Hsp20 and especially the role of its phosphorylation in regulating ischemia/reperfusion–induced autophagy, apoptosis, and necrosis remain to be clarified.

Objective: Herein, we generated a cardiac-specific overexpression model, carrying nonphosphorylatable Hsp20, where serine 16 was substituted with alanine (Hsp20S16A). By subjecting this model to ischemia/reperfusion, we addressed whether: (1) the cardioprotective effects of Hsp20 are associated with serine 16 phosphorylation; (2) blockade of Hsp20 phosphorylation influences the balance between autophagy and cell death; and (3) the aggregation pattern of Hsp20 is altered by its phosphorylation.

Methods and Results: Our results demonstrated that Hsp20S16A hearts were more sensitive to ischemia/reperfusion injury, evidenced by lower recovery of contractile function and increased necrosis and apoptosis, compared with non-TG hearts. Interestingly, autophagy was activated in non-TG hearts but significantly inhibited in Hsp20S16A hearts following ischemia/reperfusion. Accordingly, pretreatment of Hsp20S16A hearts with rapamycin, an activator of autophagy, resulted in improvement of functional recovery, compared with saline-treated Hsp20S16A hearts. Furthermore, on ischemia/reperfusion, the oligomerization pattern of Hsp20 appeared to shift to higher aggregates in Hsp20S16A hearts.

Conclusions: Collectively, these data indicate that blockade of Ser16-Hsp20 phosphorylation attenuates the cardioprotective effects of Hsp20 against ischemia/reperfusion injury, which may be attributable to suppressed autophagy and increased cell death. Therefore, phosphorylation of Hsp20 at serine 16 may represent a potential therapeutic target in ischemic heart disease.

  W Wu , W Zhang , R Qiao , D Chen , H Wang , Y Wang , S Zhang , G Gao , A Gu , J Shen , J Qian , W Fan , L Jin , B Han and D. Lu

Purpose: Platinum agents cause DNA cross-linking and adducts. Xeroderma pigmentosum group D (XPD) plays a key role in the nucleotide excision repair pathway of DNA repair. Genetic polymorphisms of XPD may affect the capacity to remove the deleterious DNA lesions in normal tissues and lead to greater treatment-related toxicity. This study aimed to investigate the association of three polymorphisms of XPD at codons 156, 312, and 711, with the occurrence of grade 3 or 4 toxicity in advanced non–small cell lung cancer patients.

Experimental Design: We used matrix-assisted laser desorption/ionization time-of-flight mass spectrometry to genotype the three polymorphisms in 209 stage III and IV non–small cell lung cancer patients treated with platinum-based chemotherapy.

Results: The variant homozygotes of XPD p.Arg156Arg (rs238406) polymorphism were associated with a significantly increased risk of grade 3 or 4 hematologic toxicity (adjusted odds ratios, 3.24; 95% confidence interval, 1.35-7.78; P for trend = 0.009), and, more specifically, severe leukopenia toxicity (P for trend = 0.005). No statistically significant association was found for the three polymorphisms and grade 3 or 4 gastrointestinal toxicity. Consistent with these results of single-locus analysis, both the haplotype and the diplotype analyses revealed a protective effect of the haplotype "CG" (in the order of p.Arg156Arg-p.Asp312Asn) on the risk of grade 3 or 4 hematologic toxicity.

Conclusions: This investigation, for the first time, provides suggestive evidence of an effect of XPD p.Arg156Arg polymorphism on severe toxicity variability among platinum-treated non–small cell lung cancer patients.

  A Lin , J Qian , X Li , X Yu , W Liu , Y Sun , N Chen , C Mei and for the Icodextrin National Multi center Cooperation Group

Background and objectives: While peritoneal dialysis with icodextrin is commonly used in patients with poor peritoneal membrane characteristics, the data on the usefulness of this solution in patients with lower transport characteristics are limited. The study was designed to compare icodextrin to glucose in Chinese prevalent peritoneal dialysis patients of different peritoneal transport characteristics (PET) categories.

Design, setting, participants, & measurements: This was a randomized, double-blind, perspective control study. Stable prevalent continuous ambulatory peritoneal dialysis (CAPD) patients were randomized to either 7.5% icodextrin (ICO) or 2.5% glucose (GLU) solution for 4 wk. Peritoneal membrane function was measured to define PET category in baseline. Creatinine clearance (Ccr), urea nitrogen clearance (CBUN), ultrafiltration (UF) during the long night dwell, dialysate, and metabolic biomarkers were measured at baseline, 2, and 4 wk. UF, Ccr, and CBUN were compared among different PET categories.

Results: A total of 201 CAPD patients were enrolled in the study. There were no baseline differences between the groups. Following 2 and 4 wk of therapy, Ccr, CBUN, and UF were all significantly higher in the ICO versus the GLU group. Additionally, switching to ICO resulted in a significant increase in UF in high, high-average, and low-average transporters as compared with baseline. The extent of increased UF was more obvious in higher transporters. Blood cholesterol level in the ICO group decreased significantly than that in the GLU group.

Conclusion: Compared with glucose-based solution, 7.5% icodextrin significantly improved UF and small solute clearance, even in patients with low-average peritoneal transport.

  P. N Tsao , M Vasconcelos , K. I Izvolsky , J Qian , J Lu and W. V. Cardoso
  Po-Nien Tsao, Michelle Vasconcelos, Konstantin I. Izvolsky, Jun Qian, Jining Lu, and Wellington V. Cardoso

Although there is accumulated evidence of a role for Notch in the developing lung, it is still unclear how disruption of Notch signaling affects lung progenitor cell fate and differentiation events in the airway epithelium. To address this issue, we inactivated Notch signaling conditionally in the endoderm using a Shh-Cre deleter mouse line and mice carrying floxed alleles of the Pofut1 gene, which encodes an O-fucosyltransferase essential for Notch-ligand binding. We also took the same conditional approach to inactivate expression of Rbpjk, which encodes the transcriptional effector of canonical Notch signaling. Strikingly, these mutants showed an almost identical lung phenotype characterized by an absence of secretory Clara cells without evidence of cell death, and showed airways populated essentially by ciliated cells, with an increase in neuroendocrine cells. This phenotype could be further replicated in cultured wild-type lungs by disrupting Notch signaling with a gamma-secretase inhibitor. Our data suggest that Notch acts when commitment to a ciliated or non-ciliated cell fate occurs in proximal progenitors, silencing...

  D. R Brims , J Qian , I Jarchum , L Mikesh , E Palmieri , U. A Ramagopal , V. N Malashkevich , R. J Chaparro , T Lund , M Hattori , J Shabanowitz , D. F Hunt , S. G Nathenson , S. C Almo and T. P. DiLorenzo

Type 1 diabetes (T1D) is an autoimmune disease characterized by T cell-mediated destruction of insulin-producing pancreatic β cells. In both humans and the non-obese diabetic (NOD) mouse model of T1D, class II MHC alleles are the primary determinant of disease susceptibility. However, class I MHC genes also influence risk. These findings are consistent with the requirement for both CD4+ and CD8+ T cells in the pathogenesis of T1D. Although a large body of work has permitted the identification of multiple mechanisms to explain the diabetes-protective effect of particular class II MHC alleles, studies examining the protective influence of class I alleles are lacking. Here, we explored this question by performing biochemical and structural analyses of the murine class I MHC molecule H-2Kwm7, which exerts a diabetes-protective effect in NOD mice. We have found that H-2Kwm7 molecules are predominantly occupied by the single self-peptide VNDIFERI, derived from the ubiquitous protein histone H2B. This unexpected finding suggests that the inability of H-2Kwm7 to support T1D development could be due, at least in part, to the failure of peptides from critical β-cell antigens to adequately compete for binding and be presented to T cells. Predominant presentation of a single peptide would also be expected to influence T-cell selection, potentially leading to a reduced ability to select a diabetogenic CD8+ T-cell repertoire. The report that one of the predominant peptides bound by T1D-protective HLA-A*31 is histone derived suggests the potential translation of our findings to human diabetes-protective class I MHC molecules.

  Y Zhong , Y Huang , T Zhang , C Ma , S Zhang , W Fan , H Chen , J Qian and D. Lu

O6-methylguanine-DNA methyltransferase is one of the rare proteins to directly remove alkylating agents in the human DNA direct reversal repair pathway. Its two common single-nucleotide polymorphisms, Leu84Phe and Ile143Val, had previously been identified to contribute to susceptibility of cancer. However, there are conflicting results in studies on the association of the two polymorphisms with cancer. Therefore, we conducted a meta-analysis to clarify the paradox with a large collected sample (13 069 cancer patients and 20 290 controls). We found significant association between the T allele (84Phe) and cancer risk, under the recessive genetic model [P = 0.023, odds ratio (OR) = 1.251, 95% confidence interval (CI) 1.031–1.517, Pheterogeneity = 0.270], TT versus CC comparison (P = 0.035, OR = 1.239, 95% CI 1.015–1.511, Pheterogeneity = 0.225) and TT versus CT comparison (P = 0.007, OR = 1.292, 95% CI 1.071–1.559, Pheterogeneity = 0.374), using the random-effect model. In the ethnicity subgroup analysis, a significant association with cancer among Caucasians was found under the recessive genetic model, homozygote comparison and TT versus TC comparison. In the tumour sites subgroup analysis, only the protective effects of Leu84Phe polymorphism were found in colorectal cancer, under CT versus CC comparison. No significant association between the G allele of Ile143Val and cancer risk was found. The G allele showed an increased lung cancer risk under the dominant genetic model and AG versus AA comparison in all Hardy–Weinberg equilibrium subjects, only when the fixed-effect model was used. However, it was insignificant in the random-effect model.

  A. I Chernyavsky , J Arredondo , V Galitovskiy , J Qian and S. A. Grando

SLURP-1 (secreted mammalian Ly-6/urokinase plasminogen activator receptor-related protein-1) is a novel auto/paracrine cholinergic peptide that can bind to 7-nicotinic acetylcholine receptor (nAChR), a high Ca2+-permeable ion channel coupled to regulation of nuclear factor-B (NF-B) expression. Elucidation of intracellular signaling events elicited by SLURP-1 is crucial for understanding the molecular mechanism of functioning of this novel hormone-like peptide that alters vital cell functions and can protect from tumorigenic transformation. In this study, we sought to dissect out the role of 7-nAChR in mediating the biologic effects of recombinant SLURP-1 on the immortalized line of human oral keratinocytes Het-1A. A multifold upregulation of the NF-B expression at the mRNA and protein levels by SLURP-1 was only slightly diminished due to elimination of Na+, whereas in Ca2+-free medium the effect of SLURP-1 was inhibited by >50%. Both in the absence of extracellular Ca2+ and in the presence of Cd2+ or Zn2+, the SLURP-1-dependent elevation of NF-B was almost completely blocked by inhibiting MEK1 activity. Downstream of 7-nAChR, the SLURP-1 signaling coupled to upregulation of NF-B also involved Jak2 as well as Ca2+/calmodulin-dependent kinase II (CaMKII) and protein kinase C (PKC), whose inhibition significantly (P < 0.05) reduced the SLURP-1-induced upregulation of NF-B. The obtained results indicated that activation of 7-nAChR by SLURP-1 leads to upregulation of the NF-B gene expression due to activation of the Raf-1/MEK1/ERK1/2 cascade that proceeds via two complementary signaling pathways. One is mediated by the Ca2+-entry dependent CaMKII/PKC activation and another one by Ca2+-independent involvement of Jak2. Thus, there exists a previously not appreciated network of noncanonical auto/paracrine ligands of nAChR of the Ly-6 protein family, which merits further investigations.

  J Liu , Y Song , B Tian , J Qian , Y Dong , B Liu and Z. Sun

It is well established that promyelocytic leukaemia nuclear bodies (PML NBs) play important roles in DNA damage responses (DDR). After irradiation, PML NBs dynamically recruit or release important proteins involved in cell-cycle regulation, DNA repair and apoptosis. As PML protein is the key molecule of PML NBs’ dynamic assembling, we aimed to characterize the PML-interacting proteins in 60Co-irradiated MCF-7 cells. A proteomic approach using CoIP, mono-dimensional electrophoresis and tandem mass spectrometry, allowed us to identify a total of 124 proteins that may associate with PML after irradiation. Bioinformatic analysis of the identified proteins showed that most of them were related to characterized PML functions, such as transcriptional regulation, cell-cycle regulation, cell-death regulation and response to stress. Four proteins, B23, MVP, G3BP1 and DHX9, were verified to co-localize with PML differentially before and after ionizing radiation (IR) treatment. The proteins identified in this study will significantly improve our understanding of the dynamic organization and multiple functions of PML NBs in DDR.

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