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1.  Hypercholesterolemia and Risk of Incident Psoriasis and Psoriatic Arthritis in US Women 
Psoriasis is a systemic inflammatory disorder associated with an increased risk of cardiovascular disease. Hypercholesterolemia is a major risk factor for cardiovascular disease, and patients with psoriasis or psoriatic arthritis (PsA) have been shown to have elevated cholesterol levels. However, whether hypercholesterolemia is associated with an increased risk of psoriasis or PsA is unknown. We aim to evaluate whether a history of hypercholesterolemia is associated with the risk of developing psoriasis and PsA in a cohort of US women.
A total of 95,540 participants were included from the Nurses' Health Study II (1991–2005). Information on personal history of physician-diagnosed hypercholesterolemia and related medication use was collected during the follow-up. Clinician-diagnosed psoriasis and PsA was ascertained and confirmed by supplementary questionnaires.
During 1,320,765 person-years of follow-up, we documented 646 incident psoriasis and 165 concomitant PsA cases. Hypercholesterolemia was associated with an elevated risk of incident psoriasis [Hazard ratio (HR)=1.25, 95% confidence interval (CI): 1.04, 1.50] and PsA (HR=1.58, 95% CI: 1.13, 2.23) in multivariate adjusted models. Participants with hypercholesterolemia duration time ≥ 7 years were at a higher risk of developing psoriasis (HR=1.29, 95% CI: 1.03, 1.61) (Ptrend=0.0002) and PsA (HR=1.68, 95% CI: 1.12, 2.52) (Ptrend=0.002). These associations persisted among participants who never took cholesterol-lowering medications. There was no association between cholesterol-lowering drugs and risk of psoriasis or PsA.
Our study provides evidence that hypercholesterolemia, a well-known cardiovascular risk factor, is also associated with an elevated risk of psoriasis and PsA.
PMCID: PMC4082661  PMID: 24504802
hypercholesterolemia; inflammation; psoriasis; psoriatic arthritis
2.  Genetic variants in DNA repair pathway genes and risk of esophageal squamous cell carcinoma and gastric adenocarcinoma in a Chinese population 
Carcinogenesis  2013;34(7):1536-1542.
The DNA repair pathways help to maintain genomic integrity and therefore genetic variation in the pathways could affect the propensity to develop cancer. Selected germline single nucleotide polymorphisms (SNPs) in the pathways have been associated with esophageal cancer and gastric cancer (GC) but few studies have comprehensively examined the pathway genes. We aimed to investigate associations between DNA repair pathway genes and risk of esophageal squamous cell carcinoma (ESCC) and GC, using data from a genome-wide association study in a Han Chinese population where ESCC and GC are the predominant cancers. In sum, 1942 ESCC cases, 1758 GC cases and 2111 controls from the Shanxi Upper Gastrointestinal Cancer Genetics Project (discovery set) and the Linxian Nutrition Intervention Trials (replication set) were genotyped for 1675 SNPs in 170 DNA repair-related genes. Logistic regression models were applied to evaluate SNP-level associations. Gene- and pathway-level associations were determined using the resampling-based adaptive rank-truncated product approach. The DNA repair pathways overall were significantly associated with risk of ESCC (P = 6.37 × 10− 4), but not with GC (P = 0.20). The most significant gene in ESCC was CHEK2 (P = 2.00 × 10− 6) and in GC was CLK2 (P = 3.02 × 10− 4). We observed several other genes significantly associated with either ESCC (SMUG1, TDG, TP53, GTF2H3, FEN1, POLQ, HEL308, RAD54B, MPG, FANCE and BRCA1) or GC risk (MRE11A, RAD54L and POLE) (P < 0.05). We provide evidence for an association between specific genes in the DNA repair pathways and the risk of ESCC and GC. Further studies are warranted to validate these associations and to investigate underlying mechanisms.
PMCID: PMC3697889  PMID: 23504502
3.  Genetic Variants in Epidermal Growth Factor Receptor Pathway Genes and Risk of Esophageal Squamous Cell Carcinoma and Gastric Cancer in a Chinese Population 
PLoS ONE  2013;8(7):e68999.
The epidermal growth factor receptor (EGFR) signaling pathway regulates cell proliferation, differentiation, and survival, and is frequently dysregulated in esophageal and gastric cancers. Few studies have comprehensively examined the association between germline genetic variants in the EGFR pathway and risk of esophageal and gastric cancers. Based on a genome-wide association study in a Han Chinese population, we examined 3443 SNPs in 127 genes in the EGFR pathway for 1942 esophageal squamous cell carcinomas (ESCCs), 1758 gastric cancers (GCs), and 2111 controls. SNP-level analyses were conducted using logistic regression models. We applied the resampling-based adaptive rank truncated product approach to determine the gene- and pathway-level associations. The EGFR pathway was significantly associated with GC risk (P = 2.16×10−3). Gene-level analyses found 10 genes to be associated with GC, including FYN, MAPK8, MAP2K4, GNAI3, MAP2K1, TLN1, PRLR, PLCG2, RPS6KB2, and PIK3R3 (P<0.05). For ESCC, we did not observe a significant pathway-level association (P = 0.72), but gene-level analyses suggested associations between GNAI3, CHRNE, PAK4, WASL, and ITCH, and ESCC (P<0.05). Our data suggest an association between specific genes in the EGFR signaling pathway and risk of GC and ESCC. Further studies are warranted to validate these associations and to investigate underlying mechanisms.
PMCID: PMC3715462  PMID: 23874846
4.  Psoriasis, psoriatic arthritis and increased risk of incident Crohn’s disease in US women 
Annals of the rheumatic diseases  2012;72(7):1200-1205.
Inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), shares clinical and immunological features with psoriasis. Genome-wide association studies have found common susceptibility genes. However, epidemiologic data evaluating the association between psoriasis, psoriatic arthritis and risk of IBD are sparse. We aimed to evaluate the association between psoriasis, psoriatic arthritis and incident CD and UC among women in the USA.
174 476 women were enrolled in the Nurses’ Health Study (NHS) (1996–2008) and NHS II (1991–2007). Lifetime history of physician-diagnosed psoriasis and psoriatic arthritis was confirmed by supplementary questionnaires. Information on CD and UC was obtained by self-reported questionnaires and confirmed by medical record review.
We documented 188 incident cases of CD and 240 incident cases of UC during follow-up. Psoriasis was associated with a significantly increased risk of subsequent CD with a multivariate-adjusted relative risk (RR) of 4.00 (95% CI 1.72 to 9.27) for NHS and 3.76 (1.82 to 7.74) for NHS II. By contrast, we did not observe a significant increase in risk of UC associated with psoriasis. In a pooled analysis of both cohorts, women with psoriasis experienced a significantly increased risk of CD (RR, 3.86, 95% CI 2.23 to 6.67), but not UC (RR, 1.17, 95% CI 0.41 to 3.36). The risk of CD was especially pronounced among psoriatics with concomitant psoriatic arthritis (RR, 6.43, 95% CI 2.04 to 20.32).
Psoriasis with concomitant psoriatic arthritis is associated with an increased risk of incident CD.
PMCID: PMC3547138  PMID: 22941766
5.  Risk factors associated with severe manifestations of 2009 pandemic influenza A (H1N1) infection in China: a case–control study 
Virology Journal  2013;10:149.
No studies on the risk factors of 2009 pandemic influenza A (H1N1) in China have been reported. We aimed to investigate the risk factors for severe manifestations of 2009 pandemic H1N1 influenza in China
A case–control study with 343 severe hospitalized patients and 343 randomly selected mild controls was conducted. The diagnosis was established by assessment of clinical symptoms and confirmed by the real-time reverse-transcriptase-polymerase chain reaction assay. Severe or mild patients were classified by uniform criteria issued by the Ministry of Health in China.
The multivariable logistic regression analysis showed that the overweight or obese subjects admitted to hospital with H1N1 influenza were more likely to experience severe manifestations. The ORs were 3.70 (95% CI: 2.04-6.72) and 35.61 (95% CI: 7.96-159.21) respectively. Subjects at age less than 5 years or older than 60 years had an increased risk of severe manifestations (OR = 21.14, 95% CI: 7.79-57.33). We also observed increased risk among subjects with longer time interval from symptom onset to hospital admission (OR = 3.26, 95% CI: 2.08-5.11) or peasants (OR = 9.79, 95% CI: 5.11-18.78). Those with chronic disorders had increased risk of severe manifestations of H1N1 influenza.
We provide evidence on the risk factors associated with severe manifestations of 2009 pandemic H1N1 influenza in a study of hospitalized subjects in China.
PMCID: PMC3656780  PMID: 23672278
Severe manifestation; Novel influenza A; Risk factor
6.  The ion implantation-induced properties of one-dimensional nanomaterials 
Nanoscale Research Letters  2013;8(1):175.
Nowadays, ion implantation is an extensively used technique for material modification. Using this method, we can tailor the properties of target materials, including morphological, mechanical, electronic, and optical properties. All of these modifications impel nanomaterials to be a more useful application to fabricate more high-performance nanomaterial-based devices. Ion implantation is an accurate and controlled doping method for one-dimensional nanomaterials. In this article, we review recent research on ion implantation-induced effects in one-dimensional nanostructure, such as nanowires, nanotubes, and nanobelts. In addition, the optical property of single cadmium sulfide nanobelt implanted by N+ ions has been researched.
PMCID: PMC3668221  PMID: 23594476
Nanomaterials; Ion implantation; Doping
7.  AU-Rich-Element-Dependent Translation Repression Requires the Cooperation of Tristetraprolin and RCK/P54 
Molecular and Cellular Biology  2012;32(5):913-928.
AU-rich elements (AREs), residing in the 3′ untranslated region (UTR) of many labile mRNAs, are important cis-acting elements that modulate the stability of these mRNAs by collaborating with trans-acting factors such as tristetraprolin (TTP). AREs also regulate translation, but the underlying mechanism is not fully understood. Here we examined the function and mechanism of TTP in ARE-mRNA translation. Through a luciferase-based reporter system, we used knockdown, overexpression, and tethering assays in 293T cells to demonstrate that TTP represses ARE reporter mRNA translation. Polyribosome fractionation experiments showed that TTP shifts target mRNAs to lighter fractions. In murine RAW264.7 macrophages, knocking down TTP produces significantly more tumor necrosis factor alpha (TNF-α) than the control, while the corresponding mRNA level has a marginal change. Furthermore, knockdown of TTP increases the rate of biosynthesis of TNF-α, suggesting that TTP can exert effects at translational levels. Finally, we demonstrate that the general translational repressor RCK may cooperate with TTP to regulate ARE-mRNA translation. Collectively, our studies reveal a novel function of TTP in repressing ARE-mRNA translation and that RCK is a functional partner of TTP in promoting TTP-mediated translational repression.
PMCID: PMC3295194  PMID: 22203041
8.  Interleukin-7 Regulates Bim Proapoptotic Activity in Peripheral T-Cell Survival▿  
Molecular and Cellular Biology  2009;30(3):590-600.
Interleukin-7 (IL-7) is critical for T-cell development and peripheral T-cell homeostasis. The survival of pro-T cells and mature T cells requires IL-7. The survival function of IL-7 is accomplished partly through induction of the antiapoptotic protein Bcl-2 and inhibition of proapoptotic proteins Bax and Bad. We show here that the proapoptotic protein Bim, a BH3-only protein belonging to the Bcl-2 family, also plays a role in peripheral T-cell survival. Deletion of Bim partially protected an IL-7-dependent T-cell line and peripheral T cells, especially cells with an effector memory phenotype, from IL-7 deprivation. However, T-cell development in the thymus was not restored in IL-7−/− Rag2−/− mice reconstituted with Bim−/− bone marrow. IL-7 withdrawal altered neither the intracellular location of Bim, which was constitutively mitochondrial, nor its association with Bcl-2; however, a reduction in its association with the prosurvival protein Mcl-1 was observed. IL-7 withdrawal did not increase Bim mRNA or protein expression but did induce changes in the isoelectric point of BimEL and its reactivity with an antiphosphoserine antibody. Our findings suggest that the maintenance of peripheral T cells by IL-7 occurs partly through inhibition of Bim activity at the posttranslational level.
PMCID: PMC2812241  PMID: 19933849
9.  Visualization and Identification of IL-7 Producing Cells in Reporter Mice 
PLoS ONE  2009;4(11):e7637.
Interleukin-7 (IL-7) is required for lymphocyte development and homeostasis although the actual sites of IL-7 production have never been clearly identified. We produced a bacterial artificial chromosome (BAC) transgenic mouse expressing ECFP in the Il7 locus. The construct lacked a signal peptide and ECFP (enhanced cyan fluorescent protein ) accumulated inside IL-7-producing stromal cells in thoracic thymus, cervical thymus and bone marrow. In thymus, an extensive reticular network of IL-7-containing processes extended from cortical and medullary epithelial cells, closely contacting thymocytes. Central memory CD8 T cells, which require IL-7 and home to bone marrow, physically associated with IL-7-producing cells as we demonstrate by intravital imaging.
PMCID: PMC2770321  PMID: 19907640
10.  IL-7 promotes T cell proliferation through destabilization of p27Kip1 
Interleukin (IL)-7 is required for survival and homeostatic proliferation of T lymphocytes. The survival effect of IL-7 is primarily through regulation of Bcl-2 family members; however, the proliferative mechanism is unclear. It has not been determined whether the IL-7 receptor actually delivers a proliferative signal or whether, by promoting survival, proliferation results from signals other than the IL-7 receptor. We show that in an IL-7–dependent T cell line, cells protected from apoptosis nevertheless underwent cell cycle arrest after IL-7 withdrawal. This arrest was accompanied by up-regulation of the cyclin-dependent kinase inhibitor p27Kip1 through a posttranslational mechanism. Overexpression of p27Kip1 induced G1 arrest in the presence of IL-7, whereas knockdown of p27Kip1 by small interfering RNA promoted S phase entry after IL-7 withdrawal. CD4 or CD8 T cells transferred into IL-7–deficient hosts underwent G1 arrest, whereas 27Kip1-deficient T cells underwent proliferation. We observed that IL-7 withdrawal activated protein kinase C (PKC)θ and that inhibition of PKCθ with a pharmacological inhibitor completely blocked the rise of p27Kip1 and rescued cells from G1 arrest. The conventional pathway to breakdown of p27Kip1 is mediated by S phase kinase-associated protein 2; however, our evidence suggests that PKCθ acts via a distinct, unknown pathway inducing G1 arrest after IL-7 withdrawal from T cells. Hence, IL-7 maintains T cell proliferation through a novel pathway of p27Kip1 regulation.
PMCID: PMC2118250  PMID: 16492801
11.  Cytokine-driven cell cycling is mediated through Cdc25A 
The Journal of Cell Biology  2005;169(5):755-763.
Lymphocytes are the central mediators of the immune response, requiring cytokines for survival and proliferation. Survival signaling targets the Bcl-2 family of apoptotic mediators, however, the pathway for the cytokine-driven proliferation of lymphocytes is poorly understood. Here we show that cytokine-induced cell cycle progression is not solely dependent on the synthesis of cyclin-dependent kinases (Cdks) or cyclins. Rather, we observe that in lymphocyte cell lines dependent on interleukin-3 or interleukin-7, or primary lymphocytes dependent on interleukin 7, the phosphatase Cdc25A is the critical mediator of proliferation. Withdrawal of IL-7 or IL-3 from dependent lymphocytes activates the stress kinase, p38 MAPK, which phosphorylates Cdc25A, inducing its degradation. As a result, Cdk/cyclin complexes remain phosphorylated and inactive and cells arrest before the induction of apoptosis. Inhibiting p38 MAPK or expressing a mutant Cdc25A, in which the two p38 MAPK target sites, S75 and S123, are altered, renders cells resistant to cytokine withdrawal, restoring the activity of Cdk/cyclin complexes and driving the cell cycle independent of a growth stimulus.
PMCID: PMC2171622  PMID: 15928203
12.  Mithramycin downregulates proinflammatory cytokine-induced matrix metalloproteinase gene expression in articular chondrocytes 
Arthritis Research & Therapy  2005;7(4):R777-R783.
Interleukin-1 (IL-1), IL-17 and tumor necrosis factor alpha (TNF-α) are the main proinflammatory cytokines implicated in cartilage breakdown by matrix metalloproteinase (MMPs) in arthritic joints. We studied the impact of an anti-neoplastic antibiotic, mithramycin, on the induction of MMPs in chondrocytes. MMP-3 and MMP-13 gene expression induced by IL-1β, TNF-α and IL-17 was downregulated by mithramycin in human chondrosarcoma SW1353 cells and in primary human and bovine femoral head chondrocytes. Constitutive and IL-1-stimulated MMP-13 levels in bovine and human cartilage explants were also suppressed. Mithramycin did not significantly affect the phosphorylation of the mitogen-activated protein kinases, extracellular signal-regulated kinase, p38 and c-Jun N-terminal kinase. Despite effective inhibition of MMP expression by mithramycin and its potential to reduce cartilage degeneration, the agent might work through multiple unidentified mechanisms.
PMCID: PMC1175029  PMID: 15987479
13.  Distinct Regions of the Interleukin-7 Receptor Regulate Different Bcl2 Family Members 
Molecular and Cellular Biology  2004;24(14):6501-6513.
The antiapoptotic function of the interleukin-7 (IL-7) receptor is related to regulation of three members of the Bcl2 family: synthesis of Bcl2, phosphorylation of Bad, and cytosolic retention of Bax. Here we show that, in an IL-7-dependent murine T-cell line, different regions of the IL-7 receptor initiate the signal transduction pathways that regulate these proteins. Both Box1 and Y449 are required to signal Bcl2 synthesis and Bax cytosolic retention. This suggests a sequential model in which Jak1, which binds to Box1, is first activated and then phosphorylates Y449, leading to Bcl2 and Bax regulation, accounting for approximately 90% of the survival function. Phosphorylation of Bad required Box1 but not Y449, suggesting that Jak1 also initiates an additional signaling cascade that accounts for approximately 10% of the survival function. Stat5 was activated from the Y449 site but only partially accounted for the survival signal. Proliferation required both Y449 and Box1. Thymocyte development in vivo showed that deletion of Y449 eliminated 90% of αβ T-cell development and completely eliminated γδ T-cell development, whereas deleting Box 1 completely eliminated both αβ and γδ T-cell development. Thus the IL-7 receptor controls at least two distinct pathways, in addition to Stat5, that are required for cell survival.
PMCID: PMC434255  PMID: 15226449

Results 1-13 (13)