Publications by authors named "Zhenxun Wang"

23 Publications

  • Page 1 of 1

Association of the CYP39A1 G204E genetic variant with increased risk of glaucoma and blindness in patients with exfoliation syndrome.

Ophthalmology 2021 Nov 8. Epub 2021 Nov 8.

Singapore Eye Research Institute and Singapore National Eye Center, Singapore; Duke-NUS Medical School, Singapore; Yong Loo Lin School of Medicine, National University of Singapore, Singapore. Electronic address:

Purpose: Carriers of functionally deficient mutations in the CYP39A1 gene have been recently reported to have a 2-fold increased risk of exfoliation syndrome (XFS). The aim of this study was to evaluate the risk of blindness and related clinical phenotypes of XFS patients carrying the loss-of-function CYP39A1 G204E mutation in comparison to XFS patients without any CYP39A1 mutation.

Design: Retrospective case study PARTICIPANTS: 35 patients diagnosed with XFS carrying the CYP39A1 G204E mutation and 150 XFS patients without any CYP39A1 mutation, who were randomly selected from the Japanese XFS cohort.

Methods: Two-sided Fisher's Exact Test with an α-level <0.05 was used to estimate the significance of the calculated Odds Ratio (OR) for all categorical measures. Comparisons between groups of subjects were performed using linear mixed effect models with group as random effect and taking possible dependence between eyes within a subject into account.

Main Outcome Measures: Primary analysis compared the incidence of blindness (defined as visual acuity [VA]<0.05 decimal), prevalence of exfoliation glaucoma (XFG), history of glaucoma surgery, and indices of glaucoma severity such as visual field mean deviation (MD), intraocular pressure (IOP) and vertical cup-disc ratio (CDR), between CYP39A1 G204E carriers and those without any CYP39A1 mutation.

Results: The overall risk for blindness was significantly higher in XFS patients carrying the CYP39A1 G204E variant (10/35 [28.6%]) compared to XFS patients without any CYP39A1 mutations (8/150 [5.3%]; OR7.1 [95%CI:2.7-20.2]; p<0.001). A higher proportion of XFS patients with the CYP39A1 G204E mutation (23/35 [65.7%]) had evidence of XFG in at least one eye compared to the comparison group (41/150 [27.3%]; OR5.1 [95%CI:2.4-11.4]; p<0.0001). Significantly higher peak IOP, larger vertical CDR and worse visual field MD were also found in CYP39A1 G204E variant carriers (p<0.001). Additionally, patients with the CYP39A1 G204E mutation (18/35 [51.4%]) required more laser or glaucoma surgical interventions compared to those without any CYP39A1 mutation (32/150 [21.3%], p<0.001).

Conclusions: Patients with XFS carrying the CYP39A1 G204E mutation had significantly increased risk of blindness, higher occurrence of XFG and more severe glaucoma compared to patients with XFS without any CYP39A1 mutation.
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http://dx.doi.org/10.1016/j.ophtha.2021.11.001DOI Listing
November 2021

Romosozumab Followed by Antiresorptive Treatment Increases the Probability of Achieving Bone Mineral Density Treatment Goals.

JBMR Plus 2021 Nov 6;5(11):e10546. Epub 2021 Oct 6.

University of California San Francisco San Francisco Coordinating Center San Francisco CA USA.

Increases in bone mineral density (BMD) with osteoporosis treatment are associated with reduced fracture risk. Increasing BMD is therefore a goal of osteoporosis therapy. Here, we compare the probability of achieving a -score of > -2.5 over 3 years at the total hip (TH) or lumbar spine (LS) in women with osteoporosis, ≥55 years of age, after the following treatment sequences: 1 year romosozumab followed by 2 years denosumab (FRAME and FRAME extension trials), 1 year romosozumab followed by 2 years alendronate, or alendronate-only for 3 years (ARCH trial). Probabilities of attaining the BMD target within 1 year of treatment were also determined. At both skeletal sites, in women with a baseline score ≥ -2.7, there was >50% probability of achieving the BMD target with any 3-year regimen. The probability of achieving the target BMD in those with a baseline TH score equal to -3.0 was 61% with romosozumab/denosumab, 38% with romosozumab/alendronate, and 9% with alendronate. In those with a baseline LS score equal to -3.0, the probability of achieving a -score > -2.5 was 93% with romosozumab/denosumab, 81% with romosozumab/alendronate, and 55% with alendronate. With 1 year of treatment, in patients with a baseline TH -score equal to -2.7, the probability of reaching the target score with romosozumab was 71% to 78% and 38% with alendronate. For patients with an initial LS -score equal to -3.0, the probability of achieving the target -score over 1 year was 85% to 86% with romosozumab and 25% for alendronate. Our findings suggest baseline BMD and the probability of achieving BMD -score goals are factors to consider when selecting initial treatment for patients with osteoporosis. As baseline -score falls below -2.7 (TH) and -3.0 (LS), alendronate has <50% likelihood of achieving a BMD goal above osteoporosis range, whereas these probabilities remain relatively high for regimens beginning with romosozumab. © 2021 The Authors. published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbm4.10546DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8567484PMC
November 2021

Romosozumab reduces incidence of new vertebral fractures across severity grades among postmenopausal women with osteoporosis.

Bone 2021 Sep 20;154:116209. Epub 2021 Sep 20.

UCB Pharma, Brussels, Belgium.

Vertebral fractures (VFs) are the most common type of osteoporotic fracture, and their prevalence and severity are key risk factors for future fragility fractures. Here, we assess the treatment effect of romosozumab on the incidence of new on-study VFs according to Genant severity grades (mild, moderate, and severe). Data are reported from two phase 3 clinical studies for patients who received romosozumab versus placebo through 12 months, followed by denosumab through 24 months (FRAME: NCT01575834), and for patients who received romosozumab through 12 months, followed by alendronate through 24 months, versus alendronate only through 24 months (ARCH: NCT01631214). The treatment effect of romosozumab is reported for all included patients, and for patients with prevalent and severe baseline VFs. The incidence of new moderate-or-severe VFs was reduced through 12 months for patients treated with romosozumab versus placebo (FRAME; 0.25% versus 1.42%, respectively; p < 0.001) or alendronate (ARCH; 2.78% versus 4.00%, respectively; p = 0.042). Furthermore, the treatment effect of romosozumab on the incidence of new VFs across moderate and severe severity grades was independent of baseline VF prevalence or severity; through 12 months, consistent reductions in new moderate-or-severe VFs were observed regardless of prevalent (FRAME; p = 0.18) or severe (ARCH; p = 0.52) VFs at baseline. Reductions in the incidence of new moderate and severe VFs were sustained through 24 months, after transition from romosozumab to denosumab or alendronate, independent of baseline VF prevalence or severity; no significant interactions were observed between the incidence of new moderate-or-severe VFs and the presence of prevalent (FRAME; p = 0.81) or severe (ARCH; p = 0.99) VFs at baseline. With increasing recommendations for initial treatment with bone-forming agents for postmenopausal women with osteoporosis, these analyses will help to inform treatment decisions for patients at very high risk of VF.
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http://dx.doi.org/10.1016/j.bone.2021.116209DOI Listing
September 2021

Romosozumab improves lumbar spine bone mass and bone strength parameters relative to alendronate in postmenopausal women: results from the Active-Controlled Fracture Study in Postmenopausal Women With Osteoporosis at High Risk (ARCH) trial.

J Bone Miner Res 2021 Nov 10;36(11):2139-2152. Epub 2021 Aug 10.

UCB Pharma, Brussels, Belgium.

The Active-Controlled Fracture Study in Postmenopausal Women With Osteoporosis at High Risk (ARCH) trial (NCT01631214; https://clinicaltrials.gov/ct2/show/NCT01631214) showed that romosozumab for 1 year followed by alendronate led to larger areal bone mineral density (aBMD) gains and superior fracture risk reduction versus alendronate alone. aBMD correlates with bone strength but does not capture all determinants of bone strength that might be differentially affected by various osteoporosis therapeutic agents. We therefore used quantitative computed tomography (QCT) and finite element analysis (FEA) to assess changes in lumbar spine volumetric bone mineral density (vBMD), bone volume, bone mineral content (BMC), and bone strength with romosozumab versus alendronate in a subset of ARCH patients. In ARCH, 4093 postmenopausal women with severe osteoporosis received monthly romosozumab 210 mg sc or weekly oral alendronate 70 mg for 12 months, followed by open-label weekly oral alendronate 70 mg for ≥12 months. Of these, 90 (49 romosozumab, 41 alendronate) enrolled in the QCT/FEA imaging substudy. QCT scans at baseline and at months 6, 12, and 24 were assessed to determine changes in integral (total), cortical, and trabecular lumbar spine vBMD and corresponding bone strength by FEA. Additional outcomes assessed include changes in aBMD, bone volume, and BMC. Romosozumab caused greater gains in lumbar spine integral, cortical, and trabecular vBMD and BMC than alendronate at months 6 and 12, with the greater gains maintained upon transition to alendronate through month 24. These improvements were accompanied by significantly greater increases in FEA bone strength (p < 0.001 at all time points). Most newly formed bone was accrued in the cortical compartment, with romosozumab showing larger absolute BMC gains than alendronate (p < 0.001 at all time points). In conclusion, romosozumab significantly improved bone mass and bone strength parameters at the lumbar spine compared with alendronate. These results are consistent with greater vertebral fracture risk reduction observed with romosozumab versus alendronate in ARCH and provide insights into structural determinants of this differential treatment effect. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
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http://dx.doi.org/10.1002/jbmr.4409DOI Listing
November 2021

Association of Rare CYP39A1 Variants With Exfoliation Syndrome Involving the Anterior Chamber of the Eye.

JAMA 2021 02;325(8):753-764

Department of Ophthalmology, Asahikawa Medical University, Asahikawa, Japan.

Importance: Exfoliation syndrome is a systemic disorder characterized by progressive accumulation of abnormal fibrillar protein aggregates manifesting clinically in the anterior chamber of the eye. This disorder is the most commonly known cause of glaucoma and a major cause of irreversible blindness.

Objective: To determine if exfoliation syndrome is associated with rare, protein-changing variants predicted to impair protein function.

Design, Setting, And Participants: A 2-stage, case-control, whole-exome sequencing association study with a discovery cohort and 2 independently ascertained validation cohorts. Study participants from 14 countries were enrolled between February 1999 and December 2019. The date of last clinical follow-up was December 2019. Affected individuals had exfoliation material on anterior segment structures of at least 1 eye as visualized by slit lamp examination. Unaffected individuals had no signs of exfoliation syndrome.

Exposures: Rare, coding-sequence genetic variants predicted to be damaging by bioinformatic algorithms trained to recognize alterations that impair protein function.

Main Outcomes And Measures: The primary outcome was the presence of exfoliation syndrome. Exome-wide significance for detected variants was defined as P < 2.5 × 10-6. The secondary outcomes included biochemical enzymatic assays and gene expression analyses.

Results: The discovery cohort included 4028 participants with exfoliation syndrome (median age, 78 years [interquartile range, 73-83 years]; 2377 [59.0%] women) and 5638 participants without exfoliation syndrome (median age, 72 years [interquartile range, 65-78 years]; 3159 [56.0%] women). In the discovery cohort, persons with exfoliation syndrome, compared with those without exfoliation syndrome, were significantly more likely to carry damaging CYP39A1 variants (1.3% vs 0.30%, respectively; odds ratio, 3.55 [95% CI, 2.07-6.10]; P = 6.1 × 10-7). This outcome was validated in 2 independent cohorts. The first validation cohort included 2337 individuals with exfoliation syndrome (median age, 74 years; 1132 women; n = 1934 with demographic data) and 2813 individuals without exfoliation syndrome (median age, 72 years; 1287 women; n = 2421 with demographic data). The second validation cohort included 1663 individuals with exfoliation syndrome (median age, 75 years; 587 women; n = 1064 with demographic data) and 3962 individuals without exfoliation syndrome (median age, 74 years; 951 women; n = 1555 with demographic data). Of the individuals from both validation cohorts, 5.2% with exfoliation syndrome carried CYP39A1 damaging alleles vs 3.1% without exfoliation syndrome (odds ratio, 1.82 [95% CI, 1.47-2.26]; P < .001). Biochemical assays classified 34 of 42 damaging CYP39A1 alleles as functionally deficient (median reduction in enzymatic activity compared with wild-type CYP39A1, 94.4% [interquartile range, 78.7%-98.2%] for the 34 deficient variants). CYP39A1 transcript expression was 47% lower (95% CI, 30%-64% lower; P < .001) in ciliary body tissues from individuals with exfoliation syndrome compared with individuals without exfoliation syndrome.

Conclusions And Relevance: In this whole-exome sequencing case-control study, presence of exfoliation syndrome was significantly associated with carriage of functionally deficient CYP39A1 sequence variants. Further research is needed to understand the clinical implications of these findings.
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http://dx.doi.org/10.1001/jama.2021.0507DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903258PMC
February 2021

UniPath: a uniform approach for pathway and gene-set based analysis of heterogeneity in single-cell epigenome and transcriptome profiles.

Nucleic Acids Res 2021 02;49(3):e13

Department for Computational Biology, Indraprastha Institute of Information Technology, Delhi 110020, India.

Recent advances in single-cell open-chromatin and transcriptome profiling have created a challenge of exploring novel applications with a meaningful transformation of read-counts, which often have high variability in noise and drop-out among cells. Here, we introduce UniPath, for representing single-cells using pathway and gene-set enrichment scores by a transformation of their open-chromatin or gene-expression profiles. The robust statistical approach of UniPath provides high accuracy, consistency and scalability in estimating gene-set enrichment scores for every cell. Its framework provides an easy solution for handling variability in drop-out rate, which can sometimes create artefact due to systematic patterns. UniPath provides an alternative approach of dimension reduction of single-cell open-chromatin profiles. UniPath's approach of predicting temporal-order of single-cells using their pathway enrichment scores enables suppression of covariates to achieve correct order of cells. Analysis of mouse cell atlas using our approach yielded surprising, albeit biologically-meaningful co-clustering of cell-types from distant organs. By enabling an unconventional method of exploiting pathway co-occurrence to compare two groups of cells, our approach also proves to be useful in inferring context-specific regulations in cancer cells. Available at https://reggenlab.github.io/UniPathWeb/.
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http://dx.doi.org/10.1093/nar/gkaa1138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7897496PMC
February 2021

A variance shrinkage method improves arm-based Bayesian network meta-analysis.

Stat Methods Med Res 2021 01 5;30(1):151-165. Epub 2020 Aug 5.

Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN, USA.

Network meta-analysis is a commonly used tool to combine direct and indirect evidence in systematic reviews of multiple treatments to improve estimation compared to traditional pairwise meta-analysis. Unlike the contrast-based network meta-analysis approach, which focuses on estimating relative effects such as odds ratios, the arm-based network meta-analysis approach can estimate absolute risks and other effects, which are arguably more informative in medicine and public health. However, the number of clinical studies involving each treatment is often small in a network meta-analysis, leading to unstable treatment-specific variance estimates in the arm-based network meta-analysis approach when using non- or weakly informative priors under an unequal variance assumption. Additional assumptions, such as equal (i.e. homogeneous) variances for all treatments, may be used to remedy this problem, but such assumptions may be inappropriately strong. This article introduces a variance shrinkage method for an arm-based network meta-analysis. Specifically, we assume different treatment variances share a common prior with unknown hyperparameters. This assumption is weaker than the homogeneous variance assumption and improves estimation by shrinking the variances in a data-dependent way. We illustrate the advantages of the variance shrinkage method by reanalyzing a network meta-analysis of organized inpatient care interventions for stroke. Finally, comprehensive simulations investigate the impact of different variance assumptions on statistical inference, and simulation results show that the variance shrinkage method provides better estimation for log odds ratios and absolute risks.
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http://dx.doi.org/10.1177/0962280220945731DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862427PMC
January 2021

School Toileting Environment, Bullying, and Lower Urinary Tract Symptoms in a Population of Adolescent and Young Adult Girls: Preventing Lower Urinary Tract Symptoms Consortium Analysis of Avon Longitudinal Study of Parents and Children.

Urology 2021 May 15;151:86-93. Epub 2020 Jul 15.

Division of Urology, Children's Hospital of Philadelphia, Philadelphia, PA; Prevention of Lower Urinary Tract Symptoms (PLUS) Research Consortium, University of Minnesota, Minneapolis, MN.

Objectives: To examine whether the school toilet environment at age 13, including bullying at toilets, is associated with female lower urinary tract symptoms (LUTS) at ages 13 and 19, as little is known about the association among school toilet environment, voiding behaviors, and LUTS in adolescent girls.

Methods: The sample comprised 3962 female participants from the Avon Longitudinal Study of Parents and Children. At age 13, participants reported on 7 school toilet environment characteristics and a range of LUTS items. At age 19, participants completed the Bristol Female Lower Urinary Tract Symptoms questionnaire.

Results: All toilet environmental factors were associated with at least 1 LUTS outcome at age 13. Holding behavior was associated with all school toilet environmental factors, with odds ratios ranging from 1.36 (95% confidence interval [CI]: 1.05, 1.76) for dirty toilets to 2.38 (95% CI: 1.60, 3.52) for feeling bullied at toilets. Bullying was associated with all daytime LUTS symptoms and nocturia; odds ratios ranged from 1.60 (95% CI: 1.04, 2.07) for nocturia to 2.90 (95% CI: 1.77, 4.75) for urgency. Associations between age 13 school toilets and age 19 LUTS were in the same direction as age 13 LUTS.

Conclusion: This is the first examination of associations between school toilets and LUTS. Toileting environments were cross-sectionally associated with LUTS in adolescent girls. While further work is needed to determine whether these associations are causal, school toilet environments are modifiable and thus a promising target for LUTS prevention.
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http://dx.doi.org/10.1016/j.urology.2020.06.060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8074340PMC
May 2021

The impact of covariance priors on arm-based Bayesian network meta-analyses with binary outcomes.

Stat Med 2020 09 3;39(22):2883-2900. Epub 2020 Jun 3.

Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, Minnesota, USA.

Bayesian analyses with the arm-based (AB) network meta-analysis (NMA) model require researchers to specify a prior distribution for the covariance matrix of the treatment-specific event rates in a transformed scale, for example, the treatment-specific log-odds when a logit transformation is used. The commonly used conjugate prior for the covariance matrix, the inverse-Wishart (IW) distribution, has several limitations. For example, although the IW distribution is often described as noninformative or weakly informative, it may in fact provide strong information when some variance components are small (eg, when the standard deviation of study-specific log-odds of a treatment is smaller than 1/2), as is common in NMAs with binary outcomes. In addition, the IW prior generally leads to underestimation of correlations between treatment-specific log-odds, which are critical for borrowing strength across treatment arms to estimate treatment effects efficiently and to reduce potential bias. Alternatively, several separation strategies (ie, separate priors on variances and correlations) can be considered. To study the IW prior's impact on NMA results and compare it with separation strategies, we did simulation studies under different missing-treatment mechanisms. A separation strategy with appropriate priors for the correlation matrix and variances performs better than the IW prior, and should be recommended as the default vague prior in the AB NMA approach. Finally, we reanalyzed three case studies and illustrated the importance, when performing AB-NMA, of sensitivity analyses with different prior specifications on variances.
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http://dx.doi.org/10.1002/sim.8580DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7486995PMC
September 2020

A Near-Infrared Probe Tracks and Treats Lung Tumor Initiating Cells by Targeting HMOX2.

J Am Chem Soc 2019 09 4;141(37):14673-14686. Epub 2019 Sep 4.

Laboratory of Bioimaging Probe Development, Singapore Bioimaging Consortium, Agency for Science , Technology and Research (A*STAR) , Singapore 138667 , Singapore.

Tumor initiating cells (TIC) are resistant to conventional anticancer therapy and associated with metastasis and relapse in cancer. Although various TIC markers and their antibodies have been proposed, it is limited to the use of antibodies for in vivo imaging or treatment of TIC. In this study, we discovered heme oxygenase 2 (HMOX2) as a novel biomarker for TIC and developed a selective small molecule probe TiNIR (tumor initiating cell probe with near infrared). TiNIR detects and enriches the functionally active TIC in human lung tumors, and through the photoacoustic property, TiNIR also visualizes lung TIC in the patient-derived xenograft (PDX) model. Furthermore, we demonstrate that TiNIR inhibits tumor growth by blocking the function of HMOX2, resulting in significantly increased survival rates of the cancer model mice. The novel therapeutic target HMOX2 and its fluorescent ligand TiNIR will open a new path for the molecular level of lung TIC diagnosis and treatment.
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http://dx.doi.org/10.1021/jacs.9b06068DOI Listing
September 2019

Publisher Correction: Methionine is a metabolic dependency of tumor-initiating cells.

Nat Med 2019 Jun;25(6):1022

Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.

In the version of this article originally published, there is an error in Fig. 5a. Originally, 'MAT2A' appeared between 'Methionine' and 'Homocysteine'. 'MAT2A' should have been 'MTR'. The error has been corrected in the PDF and HTML versions of this article.
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http://dx.doi.org/10.1038/s41591-019-0486-3DOI Listing
June 2019

Methionine is a metabolic dependency of tumor-initiating cells.

Nat Med 2019 05 6;25(5):825-837. Epub 2019 May 6.

Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.

Understanding cellular metabolism holds immense potential for developing new classes of therapeutics that target metabolic pathways in cancer. Metabolic pathways are altered in bulk neoplastic cells in comparison to normal tissues. However, carcinoma cells within tumors are heterogeneous, and tumor-initiating cells (TICs) are important therapeutic targets that have remained metabolically uncharacterized. To understand their metabolic alterations, we performed metabolomics and metabolite tracing analyses, which revealed that TICs have highly elevated methionine cycle activity and transmethylation rates that are driven by MAT2A. High methionine cycle activity causes methionine consumption to far outstrip its regeneration, leading to addiction to exogenous methionine. Pharmacological inhibition of the methionine cycle, even transiently, is sufficient to cripple the tumor-initiating capability of these cells. Methionine cycle flux specifically influences the epigenetic state of cancer cells and drives tumor initiation. Methionine cycle enzymes are also enriched in other tumor types, and MAT2A expression impinges upon the sensitivity of certain cancer cells to therapeutic inhibition.
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http://dx.doi.org/10.1038/s41591-019-0423-5DOI Listing
May 2019

Contribution of epicardial and abdominopelvic visceral adipose tissues in Chinese adults with impaired glucose regulation and diabetes.

Acta Diabetol 2019 Sep 26;56(9):1061-1071. Epub 2019 Apr 26.

Department of Radiology, Ruijin Hospital Affiliated with Shanghai Jiaotong University School of Medicine, No. 197 Ruijin 2nd Rd, Shanghai, 200025, People's Republic of China.

Aims: To quantify epicardial adipose tissue (EAT) and visceral adipose tissue (VAT) in Chinese adults with impaired glucose regulation (IGR) or diabetes and compare the contributions of EAT and VAT to the occurrence of IGR and diabetes with those of traditional obesity indices.

Methods: Cardiac and abdominopelvic noncontrast computed tomographic images of 668 individuals were used to measure EAT and VAT volume. Multivariable logistic regression and area under the receiver operating characteristic (ROC) curve were used to illustrate the contributions of these tissues.

Results: Patients with IGR or diabetes had larger EAT and VAT volumes than did the controls, and the VAT volume was significantly different between the IGR and diabetic groups. In multivariable models, higher EAT or VAT volume was positively associated with the presence of IGR and diabetes. After adjusting further for body mass index (BMI) and waist-to-hip ratio (WHR), a higher EAT volume was still positively associated with IGR (odds ratio (OR) = 1.46; 95% confidence interval (CI), 1.04-2.03), and a higher VAT volume was positively associated with IGR (OR = 1.86; 95% CI, 1.15-3.02) and diabetes (OR = 1.86; 95% CI, 1.16-2.99). The areas under the curve (AUCs) of the association of EAT (AUC = 0.751; 95% CI, 0.712-0.789) and VAT (AUC = 0.752; 95% CI, 0.713-0.792) with dysglycemia (IGR + diabetes) were significantly larger than those of the traditional obesity indices (all P < 0.05).

Conclusions: High EAT or VAT volume is positively associated with IGR and diabetes in Chinese adults. With a given WHR and BMI, such an association still exists to some extent. The correlation may be stronger than those of the traditional obesity indices.
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http://dx.doi.org/10.1007/s00592-019-01348-zDOI Listing
September 2019

Identification of Tumor Initiating Cells with a Small-Molecule Fluorescent Probe by Using Vimentin as a Biomarker.

Angew Chem Int Ed Engl 2018 03 14;57(11):2851-2854. Epub 2018 Feb 14.

Singapore Bioimaging Consortium, Agency for Science Technology and Research (A*STAR), Singapore, 138667, Singapore.

Tumor initiating cells (TICs) have been implicated in clinical relapse and metastasis of a variety of epithelial cancers, including lung cancer. While efforts toward the development of specific probes for TIC detection and targeting are ongoing, a universal TIC probe has yet to be developed. We report the first TIC-specific fluorescent chemical probe, TiY, with identification of the molecular target as vimentin, a marker for epithelial-to-mesenchymal transition (EMT). TiY selectively stains TICs over differentiated tumor cells or normal cells, and facilitates the visualization and enrichment of functionally active TICs from patient tumors. At high concentration, TiY also shows anti-TIC activity with low toxicity to non-TICs. With the unexplored target vimentin, TiY shows potential as a first universal probe for TIC detection in different cancers.
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http://dx.doi.org/10.1002/anie.201712920DOI Listing
March 2018

Induced-Decay of Glycine Decarboxylase Transcripts as an Anticancer Therapeutic Strategy for Non-Small-Cell Lung Carcinoma.

Mol Ther Nucleic Acids 2017 Dec 7;9:263-273. Epub 2017 Oct 7.

Department of Pharmacology, National University of Singapore, 16 Medical Drive, Singapore 117660, Singapore; Bioprocessing Technology Institute, A*STAR, 20 Biopolis Way, Singapore 138668, Singapore; Institute of Molecular and Cellular Biology, A*STAR, 61 Biopolis Drive, Singapore 138673, Singapore. Electronic address:

Self-renewing tumor-initiating cells (TICs) are thought to be responsible for tumor recurrence and chemo-resistance. Glycine decarboxylase, encoded by the GLDC gene, is reported to be overexpressed in TIC-enriched primary non-small-cell lung carcinoma (NSCLC). GLDC is a component of the mitochondrial glycine cleavage system, and its high expression is required for growth and tumorigenic capacity. Currently, there are no therapeutic agents against GLDC. As a therapeutic strategy, we have designed and tested splicing-modulating steric hindrance antisense oligonucleotides (shAONs) that efficiently induce exon skipping (half maximal inhibitory concentration [IC] at 3.5-7 nM), disrupt the open reading frame (ORF) of GLDC transcript (predisposing it for nonsense-mediated decay), halt cell proliferation, and prevent colony formation in both A549 cells and TIC-enriched NSCLC tumor sphere cells (TS32). One candidate shAON causes 60% inhibition of tumor growth in mice transplanted with TS32. Thus, our shAONs candidates can effectively inhibit the expression of NSCLC-associated metabolic enzyme GLDC and may have promising therapeutic implications.
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http://dx.doi.org/10.1016/j.omtn.2017.10.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5675722PMC
December 2017

Scn2b Deletion in Mice Results in Ventricular and Atrial Arrhythmias.

Circ Arrhythm Electrophysiol 2016 12;9(12)

From the Department of Pharmacology, University of Michigan Medical School, Ann Arbor (Y.B., C.R.F., L.F.L.-S., C.C., L.L.I.); Center for Arrhythmia Research and Department of Medicine/Cardiovascular Medicine, University of Michigan, Ann Arbor (B.C.W., R.R.-M., J.A., H.H.V., J.J.); Leon H. Charney Division of Cardiology, New York University School of Medicine, NY (X.L., M.D.); Department of Pharmacology and Physiology, University of Rochester Medical Center, NY (D.S.A.); and Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis (Z.W.).

Background: Mutations in SCN2B, encoding voltage-gated sodium channel β2-subunits, are associated with human cardiac arrhythmias, including atrial fibrillation and Brugada syndrome. Because of this, we propose that β2-subunits play critical roles in the establishment or maintenance of normal cardiac electric activity in vivo.

Methods And Results: To understand the pathophysiological roles of β2 in the heart, we investigated the cardiac phenotype of Scn2b null mice. We observed reduced sodium and potassium current densities in ventricular myocytes, as well as conduction slowing in the right ventricular outflow tract region. Functional reentry, resulting from the interplay between slowed conduction, prolonged repolarization, and increased incidence of premature ventricular complexes, was found to underlie the mechanism of spontaneous polymorphic ventricular tachycardia. Scn5a transcript levels were similar in Scn2b null and wild-type ventricles, as were levels of Na1.5 protein, suggesting that similar to the previous work in neurons, the major function of β2-subunits in the ventricle is to chaperone voltage-gated sodium channel α-subunits to the plasma membrane. Interestingly, Scn2b deletion resulted in region-specific effects in the heart. Scn2b null atria had normal levels of sodium current density compared with wild type. Scn2b null hearts were more susceptible to atrial fibrillation, had increased levels of fibrosis, and higher repolarization dispersion than wild-type littermates.

Conclusions: Genetic deletion of Scn2b in mice results in ventricular and atrial arrhythmias, consistent with reported SCN2B mutations in human patients.
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http://dx.doi.org/10.1161/CIRCEP.116.003923DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5161227PMC
December 2016

Manipulation of PK-M mutually exclusive alternative splicing by antisense oligonucleotides.

Open Biol 2012 Oct;2(10):120133

Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724 , USA; Watson School of Biological Sciences, Cold Spring Harbor, NY 11724, USA.

Alternative splicing of the pyruvate kinase M gene involves a choice between mutually exclusive exons 9 and 10. Use of exon 10 to generate the M2 isoform is crucial for aerobic glycolysis (the Warburg effect) and tumour growth. We previously demonstrated that splicing enhancer elements that activate exon 10 are mainly found in exon 10 itself, and deleting or mutating these elements increases the inclusion of exon 9 in cancer cells. To systematically search for new enhancer elements in exon 10 and develop an effective pharmacological method to force a switch from PK-M2 to PK-M1, we carried out an antisense oligonucleotide (ASO) screen. We found potent ASOs that target a novel enhancer in exon 10 and strongly switch the splicing of endogenous PK-M transcripts to include exon 9. We further show that the ASO-mediated switch in alternative splicing leads to apoptosis in glioblastoma cell lines, and this is caused by the downregulation of PK-M2, and not by the upregulation of PK-M1. These data highlight the potential of ASO-mediated inhibition of PK-M2 splicing as therapy for cancer.
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http://dx.doi.org/10.1098/rsob.120133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3498831PMC
October 2012

Shutoff of BZLF1 gene expression is necessary for immortalization of primary B cells by Epstein-Barr virus.

J Virol 2012 Aug 23;86(15):8086-96. Epub 2012 May 23.

McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.

The BZLF1 gene controls the switch between latent and lytic infection by Epstein-Barr virus (EBV). We previously reported that both the ZV and ZIIR elements within the BZLF1 promoter, Zp, are potent transcription silencers within the context of an intact EBV genome. We report here identification of another sequence element, ZV', which synergized with ZV in repressing Zp via binding ZEB1 or ZEB2. We then determined the phenotype of a variant of EBV strain B95.8 in which the ZV, ZV', and ZIIR elements were concurrently mutated. HEK293 cell lines infected with this triple mutant (tmt) virus spontaneously synthesized 6- to 10-fold more viral BZLF1, BRLF1, BMRF1, and BLLF1 RNAs, 3- to 6-fold more viral Zta, Rta, and EAD proteins, 3- to 5-fold more viral DNA, and 7- to 9-fold more infectious virus than did 293 cell lines latently infected with either the ZV ZV' double mutant (dmt) or ZIIR mutant (mt) virus. While ZV ZV' ZIIR tmt EBV efficiently infected human primary blood B cells in vitro, it was highly defective in immortalizing them. Instead of the nearly complete silencing of BZLF1 gene expression that occurs within 4 days after primary infection with wild-type EBV, the ZV ZV' ZIIR tmt-infected cells continued to synthesize BZLF1 RNA, with 90% of them dying within 9 days postinfection. BL41 cells infected with this "superlytic" virus also exhibited increased synthesis of BZLF1 and BMRF1 RNAs. Thus, we conclude that the ZV, ZV', and ZIIR silencing elements act synergistically to repress transcription from Zp, thereby tightly controlling BZLF1 gene expression, which is crucial for establishing and maintaining EBV latency.
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http://dx.doi.org/10.1128/JVI.00234-12DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3421699PMC
August 2012

Exon-centric regulation of pyruvate kinase M alternative splicing via mutually exclusive exons.

J Mol Cell Biol 2012 Apr 1;4(2):79-87. Epub 2011 Nov 1.

Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.

Alternative splicing of the pyruvate kinase M gene (PK-M) can generate the M2 isoform and promote aerobic glycolysis and tumor growth. However, the cancer-specific alternative splicing regulation of PK-M is not completely understood. Here, we demonstrate that PK-M is regulated by reciprocal effects on the mutually exclusive exons 9 and 10, such that exon 9 is repressed and exon 10 is activated in cancer cells. Strikingly, exonic, rather than intronic, cis-elements are key determinants of PK-M splicing isoform ratios. Using a systematic sub-exonic duplication approach, we identify a potent exonic splicing enhancer in exon 10, which differs from its homologous counterpart in exon 9 by only two nucleotides. We identify SRSF3 as one of the cognate factors, and show that this serine/arginine-rich protein activates exon 10 and mediates changes in glucose metabolism. These findings provide mechanistic insights into the complex regulation of alternative splicing of a key regulator of the Warburg effect, and also have implications for other genes with a similar pattern of alternative splicing.
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http://dx.doi.org/10.1093/jmcb/mjr030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3493165PMC
April 2012

Either ZEB1 or ZEB2/SIP1 can play a central role in regulating the Epstein-Barr virus latent-lytic switch in a cell-type-specific manner.

J Virol 2010 Jun 7;84(12):6139-52. Epub 2010 Apr 7.

McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706-1599, USA.

We previously reported that the cellular protein ZEB1 can repress expression of the Epstein-Barr virus (EBV) BZLF1 gene in transient transfection assays by directly binding its promoter, Zp. We also reported that EBV containing a 2-bp substitution mutation in the ZEB-binding ZV element of Zp spontaneously reactivated out of latency into lytic replication at a higher frequency than did wild-type EBV. Here, using small interfering RNA (siRNA) and short hairpin RNA (shRNA) technologies, we definitively show that ZEB1 is, indeed, a key player in maintaining EBV latency in some epithelial and B-lymphocytic cell lines. However, in other EBV-positive epithelial and B-cell lines, another zinc finger E-box-binding protein, ZEB2/SIP1, is the key player. Both ZEB1 and ZEB2 can bind Zp via the ZV element. In EBV-positive cells containing only ZEB1, knockdown of ZEB1 led to viral reactivation out of latency, with synthesis of EBV immediate-early and early lytic gene products. However, in EBV-positive cells containing both ZEBs, ZEB2, not ZEB1, was the primary ZEB family member bound to Zp. Knockdown of ZEB2, but not ZEB1, led to EBV lytic reactivation. Thus, we conclude that either ZEB1 or ZEB2 can play a central role in the maintenance of EBV latency, doing so in a cell-type-dependent manner.
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http://dx.doi.org/10.1128/JVI.02706-09DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2876653PMC
June 2010

The alternative splicing repressors hnRNP A1/A2 and PTB influence pyruvate kinase isoform expression and cell metabolism.

Proc Natl Acad Sci U S A 2010 Feb 19;107(5):1894-9. Epub 2010 Jan 19.

Division of Signal Transduction, Department of Systems Biology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.

Cancer cells preferentially metabolize glucose by aerobic glycolysis, characterized by increased lactate production. This distinctive metabolism involves expression of the embryonic M2 isozyme of pyruvate kinase, in contrast to the M1 isozyme normally expressed in differentiated cells, and it confers a proliferative advantage to tumor cells. The M1 and M2 pyruvate-kinase isozymes are expressed from a single gene through alternative splicing of a pair of mutually exclusive exons. We measured the expression of M1 and M2 mRNA and protein isoforms in mouse tissues, tumor cell lines, and during terminal differentiation of muscle cells, and show that alternative splicing regulation is sufficient to account for the levels of expressed protein isoforms. We further show that the M1-specific exon is actively repressed in cancer-cell lines--although some M1 mRNA is expressed in cell lines derived from brain tumors--and demonstrate that the related splicing repressors hnRNP A1 and A2, as well as the polypyrimidine-tract-binding protein PTB, contribute to this control. Downregulation of these splicing repressors in cancer-cell lines using shRNAs rescues M1 isoform expression and decreases the extent of lactate production. These findings extend the links between alternative splicing and cancer, and begin to define some of the factors responsible for the switch to aerobic glycolysis.
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http://dx.doi.org/10.1073/pnas.0914845107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2838216PMC
February 2010

ZEB1 regulates the latent-lytic switch in infection by Epstein-Barr virus.

PLoS Pathog 2007 Dec;3(12):e194

McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, United States of America.

The immediate-early (IE) BZLF1 gene of Epstein-Barr virus (EBV) regulates the switch between latent and lytic infection by EBV. We previously showed that the cellular transcription factor ZEB1 binds to a sequence element, ZV, located at nt -17 to -12 relative to the transcription initiation site of the BZLF1 promoter, Zp, repressing transcription from Zp in a transient transfection assay. Here, we report the phenotype in the context of a whole EBV genome of a variant of EBV strain B95.8 containing a 2-bp substitution mutation in the ZV element of Zp that reduced, but did not eliminate, ZEB1 binding to Zp. Strikingly, epithelial 293 cells latently infected with the EBV ZV mutant spontaneously produced IE-, early-, and late-gene products and infectious virus, while wild-type (WT)-infected 293 cells did not and have never been reported to do so. Furthermore, treatment with the chemical inducers sodium butyrate and 12-O-tetradecanoyl-phorbol-13-acetate (TPA) led to an additional order-of-magnitude production of infectious virus in the ZV mutant-infected 293 cells, but still no virus in the WT-infected 293 cells. Similarly, ZV mutant-infected Burkitt's lymphoma BJAB cells accumulated at least 10-fold more EBV IE mRNAs than did WT-infected BJAB cells, with TPA or sodium butyrate treatment leading to an additional 5- to 10-fold accumulation of EBV IE mRNAs in the ZV mutant-infected cells. Thus, we conclude that ZEB1 binding to Zp plays a central role in regulating the latent-lytic switch in EBV-infected epithelial and B cells, suggesting ZEB1 as a target for lytic-induction therapies in EBV-associated malignancies.
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http://dx.doi.org/10.1371/journal.ppat.0030194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2134958PMC
December 2007
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