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Articles by J Lin
Total Records ( 15 ) for J Lin
  J Wan , J Lin , D. J Zack and J. Qian

Motivation: The relationship between nucleosome positioning and gene regulation is fundamental yet complex. Previous studies on genomic nucleosome positions have revealed a correlation between nucleosome occupancy on promoters and gene expression levels. Many of these studies focused on individual nucleosomes, especially those proximal to transcription start sites. To study the collective effect of multiple nucleosomes on the gene expression, we developed a mathematical approach based on autocorrelation to relate genomic nucleosome organization to gene regulation.

Results: We found that nucleosome organization in gene promoters can be well described by autocorrelation transformation. Some promoters show obvious periods in their nucleosome organization, while others have no clear periodicity. The genes with periodic nucleosome organization in promoters tend to be lower expressed than the genes without periodic nucleosome organization. These suggest that regular organization of nucleosomes plays a critical role in gene regulation. To quantitatively associate nucleosome organization and gene expression, we predicted gene expression solely based on nucleosome status and found that nucleosome status accounts for ~25% of the observed gene expression variability. Furthermore, we explored the underlying forces that maintain the periodicity in nucleosome organization, namely intrinsic (i.e. DNA sequence) and extrinsic forces (i.e. chromatin remodeling factors). We found that the extrinsic factors play a critical role in maintaining the periodic nucleosome organization.

  J Lin , J Wang , A. J Greisinger , H. B Grossman , M. R Forman , C. P Dinney , E. T Hawk and X. Wu

We evaluated the association between energy balance and risk of bladder cancer and assessed the joint effects of genetic variants in the mammalian target of rapamycin (mTOR) pathway genes with energy balance. The study included 803 Caucasian bladder cancer patients and 803 healthy Caucasian controls matched to cases by age (±5 years) and gender. High energy intake [odds ratio, 1.60; 95% confidence interval (95% CI), 1.23-2.09] and low physical activity (odds ratio, 2.82; 95% CI, 2.10-3.79) were each associated with significantly increased risk of bladder cancer with dose-response pattern (Ptrend < 0.001). However, obesity (body mass index, ≥30) was not associated with the risk. Among 222 single nucleotide polymorphisms, 28 single nucleotide polymorphisms located in six genes of mTOR pathway were significantly associated with the risk. Further, the risk associated with high energy intake and low physical activity was only observed among subjects carrying a high number of unfavorable genotypes in the pathway. Moreover, when physical activity, energy intake, and genetic variants were analyzed jointly, the study population was clearly stratified into a range of low- to high-risk subgroups as defined energy balance status. Compared with subjects within the most favorable energy balance category (low energy intake, intensive physical activity, low number of unfavorable genotypes), subjects in the worst energy balance category (high energy intake, low physical activity, and carrying ≥7 unfavorable genotypes) had 21.93-fold increased risk (95% CI, 6.7-71.77). Our results provide the first strong evidence that physical activity, energy intake, and genetic variants in the mTOR pathway jointly influence bladder cancer susceptibility and that these results have implications for bladder cancer prevention. Cancer Prev Res; 3(4); 505–17. ©2010 AACR.

  M Chen , M. A. T Hildebrandt , J Clague , A. M Kamat , A Picornell , J Chang , X Zhang , J Izzo , H Yang , J Lin , J Gu , S Chanock , M Kogevinas , N Rothman , D. T Silverman , M Garcia Closas , H. B Grossman , C. P Dinney , N Malats and X. Wu

Sonic hedgehog (Shh) pathway genetic variations may affect bladder cancer risk and clinical outcomes. Therefore, we genotyped 177 single-nucleotide polymorphisms (SNP) in 11 Shh pathway genes in a study including 803 bladder cancer cases and 803 controls. We assessed SNP associations with cancer risk and clinical outcomes in 419 cases of non–muscle-invasive bladder cancer (NMIBC) and 318 cases of muscle-invasive and metastatic bladder cancer (MiMBC). Only three SNPs (GLI3 rs3823720, rs3735361, and rs10951671) reached nominal significance in association with risk (P ≤ 0.05), which became nonsignificant after adjusting for multiple comparisons. Nine SNPs reached a nominally significant individual association with recurrence of NMIBC in patients who received transurethral resection (TUR) only (P ≤ 0.05), of which two (SHH rs1233560 and GLI2 rs11685068) were replicated independently in 356 TUR-only NMIBC patients, with P values of 1.0 x 10–3 (SHH rs1233560) and 1.3 x 10–3 (GLI2 rs11685068). Nine SNPs also reached a nominally significant individual association with clinical outcome of NMIBC patients who received Bacillus Calmette-Guérin (BCG; P ≤ 0.05), of which two, the independent GLI3 variants rs6463089 and rs3801192, remained significant after adjusting for multiple comparisons (P = 2 x 10–4 and 9 x 10–4, respectively). The wild-type genotype of either of these SNPs was associated with a lower recurrence rate and longer recurrence-free survival (versus the variants). Although three SNPs (GLI2 rs735557, GLI2 rs4848632, and SHH rs208684) showed nominal significance in association with overall survival in MiMBC patients (P ≤ 0.05), none remained significant after multiple-comparison adjustments. Germ-line genetic variations in the Shh pathway predicted clinical outcomes of TUR and BCG for NMIBC patients. Cancer Prev Res; 3(10); 1235–45. ©2010 AACR.

  M Chen , A Cassidy , J Gu , G. L Delclos , F Zhen , H Yang , M. A.T Hildebrandt , J Lin , Y Ye , R. M Chamberlain , C. P Dinney and X. Wu

Genetic variations in phosphoinositide-3 kinase (PI3K)-AKT-mammalian target of rapamycin (mTOR) pathway may affect critical cellular functions and increase an individual's cancer risk. We systematically evaluate 231 single-nucleotide polymorphisms (SNPs) in 19 genes in the PI3K-AKT-mTOR signaling pathway as predictors of bladder cancer risk. In individual SNP analysis, four SNPs in regulatory associated protein of mTOR (RAPTOR) remained significant after correcting for multiple testing: rs11653499 [odds ratio (OR): 1.79, 95% confidence interval (CI): 1.24–2.60, P = 0.002], rs7211818 (OR: 2.13, 95% CI: 1.35–3.36, P = 0.001), rs7212142 (OR: 1.57, 95% CI: 1.19–2.07, P = 0.002) and rs9674559 (OR: 2.05, 95% CI: 1.31–3.21, P = 0.002), among which rs7211818 and rs9674559 are within the same haplotype block. In haplotype analysis, compared with the most common haplotypes, haplotype containing the rs7212142 wild-type allele showed a protective effect of bladder cancer (OR: 0.83, 95% CI: 0.70–0.97). In contrast, the haplotype containing the rs7211818 variant allele showed a 1.32-fold elevated bladder cancer risk (95% CI: 1.09–1.60). In combined analysis of three independent significant RAPTOR SNPs (rs11653499, rs7211818 and rs7212142), a significant trend was observed for increased risk with an increase in the number of unfavorable genotypes (P for trend <0.001). Compared with the subjects without any of the unfavorable genotypes, those carrying all three unfavorable genotypes showed a 2.22-fold (95% CI: 1.33–3.71) increased bladder cancer risk. This is the first study to evaluate the role of germ line genetic variations in PI3K-AKT-mTOR pathway as cancer susceptibility factors that will help us identify high-risk individuals for bladder cancer.

  J Wang , S. M Lippman , J. J Lee , H Yang , F. R Khuri , E Kim , J Lin , D. W Chang , R Lotan , W. K Hong and X. Wu

Curatively treated patients with early-stage head and neck squamous cell carcinoma (HNSCC) are at high risks for second primary tumor (SPT) and recurrence. The regulator of G-protein signaling (RGS) is important in essential signaling transduction and cellular activities. We hypothesize that genetic variations of RGS may modulate the risk of SPT/recurrence in patients with early-stage HNSCC. In a nested case–control study, we evaluated 98 single-nucleotide polymorphisms (SNPs) in 17 RGS genes for the risk of SPT/recurrence among 450 HNSCC patients. Eight SNPs showed significant associations with the risk of SPT/recurrence, with the most significant one of rs2179653, which is located in the 5'-flanking region of RGS2 gene. Under a recessive genetic model, the homozygous variant genotype of this SNP was associated with 2.95-fold [95% confidence interval (CI): 1.52–5.74] increased risk of SPT/recurrence. This association remained significant after the adjustment for multiple comparisons. Cumulative effects analysis revealed that the risk increased significantly with the increasing numbers of unfavorable genotypes. Compared with subjects carrying 0–2 unfavorable genotypes, the hazard ratios (95% CIs) for those carrying 3 or 4+ were 1.73 (1.10–2.70) and 3.05 (1.92–4.83), respectively. Furthermore, survival tree analysis revealed potential higher order gene–gene interactions and indicated different outcomes based on distinct genotype profiles. Genetic variations of RGS genes may modulate the susceptibility to SPT/recurrence in early-stage HNSCC patients individually and cumulatively. Our results stressed the importance of taking a polygenic approach to evaluate the cumulative and interaction effects of genetic variations in the prediction of cancer risk and prognosis.

  J Lin , Y Horikawa , P Tamboli , J Clague , C. G Wood and X. Wu

We took a polygenic approach to evaluate the effects of 41 potentially functional single-nucleotide polymorphisms (SNPs) in microRNAs (miRNAs)-related genes on survival and recurrence among renal cell carcinoma (RCC) patients. During a median follow-up of 21.8 months, among 316 RCC patients, 64 died and 56 developed recurrence. In single-SNP analysis, we identified seven SNPs significantly associated with RCC survival and five SNPs with recurrence. The most significant associations were SNPs in GEMIN4 with the variant alleles of both rs7813 and rs910925 associated with 1.74-fold [95% confidence interval (CI) = 1.15–2.62] increased risk of death, whereas the variant allele of rs3744741 conferred a decreased risk of death [hazard ratio (HR) = 0.39; 95% CI = 0.19–0.77]. Several SNPs belonging to the pre-miRNA and were identified to be significantly associated with RCC recurrence. Haplotypes of DICER and DROSHA were also associated with altered patient survival and recurrence. More importantly, we observed cumulative effects of multiple SNPs on RCC survival. Compared with subjects carrying zero to two unfavorable genotypes, those carrying three to five and six and more unfavorable genotypes had an increased risk of death with a HR of 2.49 (95% CI = 1.24–5.00) and 6.66 (95% CI = 2.49–17.86), respectively, with significant dose–response trend (P for trend<0.001). As the first study of miRNA-related genetic polymorphisms on RCC clinical outcome, our results strongly suggested that miRNA-related SNPs may impact the recurrence and survival in RCC patients. Future investigation in larger populations and functional characterizations are necessary to validate these results.

  J Lin , C Steenbergen , E Murphy and J. Sun

Background— It has been shown that the activation of estrogen receptor-β (ER-β) plays an important cardioprotective role against ischemia/reperfusion injury. However, the mechanism for this protection is not clear. We hypothesize that estrogen protects by ER-β activation, which leads to S-nitrosylation (SNO) of key cardioprotective proteins.

Methods and Results— We treated ovariectomized C57BL/6J mice with the ER-β selective agonist 2,2-bis(4-hydroxyphenyl)-proprionitrile (DPN), 17β-estradiol (E2), or vehicle using Alzet minipumps for 2 weeks. Isolated hearts were Langendorff perfused and subjected to ischemia and reperfusion. Compared with vehicle-treated hearts, DPN- and E2-treated hearts had significantly better postischemic functional recovery and decreased infarct size. To test the specificity of DPN, we treated ER-β–knockout mice with DPN. However, no cardioprotective effect of DPN was found in ER-β–knockout mice, indicating that the DPN-induced cardioprotection occurs through the activation of ER-β. Using DyLight-maleimide fluors and a modified biotin switch method, we used a 2-dimensional DyLight fluorescence difference gel electrophoresis proteomic method to quantify differences in SNO of proteins. DPN- and E2-treated hearts showed an increase in SNO of a number of proteins. Interestingly, many of these proteins also had been shown to have increased SNO in preconditioned hearts. In addition, the DPN-induced cardioprotection and increased SNO were abolished by treatment with a nitric oxide synthase inhibitor.

Conclusion— The activation of ER-β by DPN treatment leads to increased protein SNO and cardioprotection against ischemia/reperfusion injury, suggesting that long-term estrogen exposure protects hearts largely via activation of ER-β and nitric oxide/SNO signaling.

  J Lin , F. B Hu and G. C. Curhan

Background and objectives: Sparse longitudinal data exist on how diet influences microalbuminuria and estimated GFR (eGFR) decline in people with well-preserved kidney function.

Design, settings, participants, & measurements: Of the 3348 women participating in the Nurses' Health Study who had data on urinary albumin to creatinine ratio in 2000, 3296 also had data on eGFR change between 1989 and 2000. Cumulative average intake of nutrients over 14 years was derived from semiquantitative food frequency questionnaires answered in 1984, 1986, 1990, 1994, and 1998. Microalbuminuria presence and eGFR decline ≥30% were the outcomes of interest.

Results: Compared with the lowest quartile, the highest quartile of animal fat (odds ratio (OR): 1.72; 95% confidence interval (CI): 1.12 to 2.64) and two or more servings of red meat per week (OR: 1.51; 95% CI: 1.01 to 2.26) were directly associated with microalbuminuria. After adjustment for other nutrients individually associated with eGFR decline ≥30%, only the highest quartile of sodium intake remained directly associated (OR: 1.52; 95% CI: 1.10 to 2.09), whereas β-carotene appeared protective (OR: 0.62, 95% CI: 0.43 to 0.89). Results did not vary by diabetes status for microalbuminuria and eGFR outcomes or in those without hypertension at baseline for eGFR decline. No significant associations were seen for other types of protein, fat, vitamins, folate, fructose, or potassium.

Conclusions: Higher dietary intake of animal fat and two or more servings per week of red meat may increase risk for microalbuminuria. Lower sodium and higher β-carotene intake may reduce risk for eGFR decline.

  J Lin , M Takata , H Murata , Y Goto , K Kido , S Ferrone and T. Saida

Melanocytic nevi are thought to be senescent clones of melanocytes that have acquired an oncogenic BRAF mutation. BRAF mutation is considered to be a crucial step in the initiation of melanocyte transformation. However, using immunomagnetic separation or laser-capture microdissection, we examined BRAF mutations in sets of approximately 50 single cells isolated from acquired melanocytic nevi from 13 patients and found a substantial number of nevus cells that contained wild-type BRAF mixed with nevus cells that contained BRAFV600E. Furthermore, we simultaneously amplified BRAF exon 15 and a neighboring single nucleotide polymorphism (SNP), rs7801086, from nevus cell samples obtained from four patients who were heterozygous for this SNP. Subcloning and sequencing of the polymerase chain reaction products showed that both SNP alleles harbored the BRAFV600E mutation, indicating that the same BRAFV600E mutation originated from different cells. The polyclonality of BRAF mutations in acquired melanocytic nevi suggests that mutation of BRAF may not be an initial event in melanocyte transformation.

  Y Yu , Y Li , L Li , J Lin , C Zheng and L. Zhang

Tubulin genes are intimately associated with cell division and cell elongation, which are central to plant secondary cell wall development. However, their roles in pollen tube polar growth remain elusive. Here, a TUA1 gene from Picea wilsonii, which is specifically expressed in pollen, was isolated. Semi-quantitative RT-PCR analysis showed that the amount of PwTUA1 transcript varied at each stage of growth of the pollen tube and was induced by calcium ions and boron. Transient expression analysis in P. wilsonii pollen indicated that PwTUA1 improved pollen germination and pollen tube growth. The pollen of transgenic Arabidopsis overexpressing PwTUA1 also showed a higher percentage of germination and faster growth than wild-type plants not only in optimal germination medium, but also in medium supplemented with elevated levels of exogenous calcium ions or boron. Immunofluorescence and electron microscopy showed -tubulin to be enriched and more vesicles accumulated in the apex region in germinating transgenic Arabidopsis pollen compared with wild-type plants. These results demonstrate that PwTUA1 up-regulated by calcium ions and boron contributes to pollen tube elongation by altering the distribution of -tubulin and regulating the deposition of pollen cell wall components during the process of tube growth. The possible role of PwTUA1 in microtubule dynamics and organization was discussed.

  L Xue , F Zhang , X Chen , J Lin and J. Shi

The insertion of amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors into the plasma membrane and removal via internalization are essential for regulating synaptic strength, which underlies the basic mechanism of learning and memory. The retinocollicular pathway undergoes synaptic refinement during development and shows a wide variety of long-term synaptic changes; however, still little is known about its underlying molecular regulation. Here we report a rapid developmental long-term potentiation (LTP)/long-term depression (LTD) switch and its intracellular mechanism at the rat retinocollicular pathway from postnatal day 5 (P5) to P14. Before P9, neurons always exhibited LTP, whereas LTD was observed only after P10. Blockade of GluR2/3-glutamate receptor-interacting protein (GRIP)/AMPA-receptor-binding protein (ABP)/protein interacting with C kinase 1 (PICK1) interactions with pep2-SVKI could sustain the LTP after P10. This suggests that the LTP/LTD switch relied on PDZ protein activities. Selective interruption of GluR2/3-PICK1 binding by pep2-EVKI blocked the long-lasting effects of both LTP and LTD, suggesting a role for PICK1 in the maintenance of long-term synaptic plasticity. Interestingly, synaptic expression of GRIP increased more than twofold from P7 to P11, whereas ABP and PICK1 expression levels remained stable. Blockade of spontaneous retinal input suppressed this increase and abolished the LTP/LTD switch. These results suggest that the increased GRIP synaptic expression may be a key regulatory factor in mediating the activity-dependent developmental LTP/LTD switch, whereas PICK1 may be required for both LTP and LTD to maintain their long-term effects.

  Y Hu , B Tian , G Xu , L Yin , X Hua , J Lin and Y. Hua

The bacterium Deinococcus radiodurans is extremely resistant to the intense ionizing irradiation which causes extensive DNA double-strand breaks (DSBs). The deinococcal SbcCD complex (drSbcCD) is required for DSB repair. The drSbcC and drSbcD genes were cloned and overexpressed in Escherichia coli cells, respectively. The nearly homogeneous drSbcC and drSbcD proteins were purified and reconstituted to form a stable complex in vitro. The drSbcCD complex has an ATP-independent 3'->5' exonuclease activity to cleave both dsDNA and ssDNA substrates in the presence of either Mn2+ or Mg2+ ion. The drSbcCD complex also has an ATP-independent endonuclease activity. It can cleave the circular ssDNA, nick the supercoiled circular dsDNA, cleave the 3' flap DNA substrate at the site of the single-strand branch adjacent to duplex DNA, and cleave the hairpin DNA taking no account of the DNA end free or not. It is a kind of secondary structure-specific endonuclease. The drSbcCD complex still has a 3'->5' exonuclease activity when the DNA termini are blocked by the proteins. These results suggest that the drSbcCD complex takes part in the metabolism of DNA, and its nuclease activities may play important roles in DNA repair process.

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