Publications by authors named "Hsin-Wen Chang"

35 Publications

Associations among phthalate exposure, DNA methylation of TSLP, and childhood allergy.

Clin Epigenetics 2021 Apr 9;13(1):76. Epub 2021 Apr 9.

Department of Environmental and Occupational Health, College of Medicine, National Cheng Kung University, Cheng-Hsing Campus, No. 1, University Road, Tainan City, Taiwan.

Background: Dysregulation of thymic stromal lymphopoietin (TSLP) expressions is linked to asthma and allergic disease. Exposure to phthalate esters, a widely used plasticizer, is associated with respiratory and allergic morbidity. Dibutyl phthalate (DBP) causes TSLP upregulation in the skin. In addition, phthalate exposure is associated with changes in environmentally induced DNA methylation, which might cause phenotypic heterogeneity. This study examined the DNA methylation of the TSLP gene to determine the potential mechanism between phthalate exposure and allergic diseases.

Results: Among all evaluated, only benzyl butyl phthalate (BBzP) in the settled dusts were negatively correlated with the methylation levels of TSLP and positively associated with children's respiratory symptoms. The results revealed that every unit increase in BBzP concentration in the settled dust was associated with a 1.75% decrease in the methylation level on upstream 775 bp from the transcription start site (TSS) of TSLP (β =  - 1.75, p = 0.015) after adjustment for child's sex, age, BMI, parents' smoking status, allergic history, and education levels, PM, formaldehyde, temperature; and relative humidity. Moreover, every percentage increase in the methylation level was associated with a 20% decrease in the risk of morning respiratory symptoms in the children (OR 0.80, 95% CI 0.65-0.99).

Conclusions: Exposure to BBzP in settled dust might increase children's respiratory symptoms in the morning through decreasing TSLP methylation. Therefore, the exposure to BBzP should be reduced especially for the children already having allergic diseases.
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http://dx.doi.org/10.1186/s13148-021-01061-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8035749PMC
April 2021

Single-cell RNA sequencing of psoriatic skin identifies pathogenic Tc17 cell subsets and reveals distinctions between CD8 T cells in autoimmunity and cancer.

J Allergy Clin Immunol 2020 Dec 9. Epub 2020 Dec 9.

Department of Dermatology, University of California San Francisco, San Francisco, Calif. Electronic address:

Background: Psoriasis is an inflammatory, IL-17-driven skin disease in which autoantigen-induced CD8 T cells have been identified as pathogenic drivers.

Objective: Our study focused on comprehensively characterizing the phenotypic variation of CD8 T cells in psoriatic lesions.

Methods: We used single-cell RNA sequencing to compare CD8 T-cell transcriptomic heterogeneity between psoriatic and healthy skin.

Results: We identified 11 transcriptionally diverse CD8 T-cell subsets in psoriatic and healthy skin. Among several inflammatory subsets enriched in psoriatic skin, we observed 2 Tc17 cell subsets that were metabolically divergent, were developmentally related, and expressed CXCL13, which we found to be a biomarker of psoriasis severity and which achieved comparable or greater accuracy than IL17A in a support vector machine classifier of psoriasis and healthy transcriptomes. Despite high coinhibitory receptor expression in the Tc17 cell clusters, a comparison of these cells with melanoma-infiltrating CD8 T cells revealed upregulated cytokine, cytolytic, and metabolic transcriptional activity in the psoriatic cells that differed from an exhaustion program.

Conclusion: Using high-resolution single-cell profiling in tissue, we have uncovered the diverse landscape of CD8 T cells in psoriatic and healthy skin, including 2 nonexhausted Tc17 cell subsets associated with disease severity.
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http://dx.doi.org/10.1016/j.jaci.2020.11.028DOI Listing
December 2020

Precision therapeutic opioid dosing implications from genetic biomarkers and craving score.

Medicine (Baltimore) 2020 May;99(22):e20429

Department of Public Health, China Medical University, Taichung.

Determining the clinically optimal dose in methadone maintenance therapy (MMT) is a time-consuming procedure, which considers clinical signs and symptoms.To perform a quantitative trait locus association for identifying genetic variants for MMT dosage that underlie heroin addiction and methadone metabolism and then integrate several genotypic and phenotypic factors are potential predictors for clinically optimal MMT dose for personalized prescription.In total, 316 heroin-dependent patients undergoing MMT were recruited at the Addiction Center of the China Medical University Hospital. A multinomial logistic regression model was used to assess associations between genetic polymorphisms and MMT dosing. The data were randomly separated into training and testing sets. In order to enhance the prediction accuracy and the reliability of the prediction model, we used areas under the receiver operating characteristic curves to evaluate optimal MMT dose in both training and testing sets.Four single nucleotide polymorphisms, namely rs806368 in CNR1, s1386493 in TPH2, s16974799 in CYP2B6, and rs2229205 in OPRL1, were significantly associated with the maximum MMT dose (P < .05). The genetic risk score (GRS) was associated with maximum MMT dose, and after adjustments for age, sex, and body mass index, the GRS remained independently associated with the maximum MMT dose. The area under the receiver operating characteristic curve of the combined GRS and craving score was 0.77 for maximum MMT dose, with 75% sensitivity and 60% specificity.Integrating the GRS and craving scores may be useful in the evaluation of individual MMT dose requirements at treatment initiation. Optimal dose prediction allows clinicians to tailor MMT to each patient's needs.
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http://dx.doi.org/10.1097/MD.0000000000020429DOI Listing
May 2020

The gut microbiome in psoriasis and psoriatic arthritis.

Best Pract Res Clin Rheumatol 2019 12 29;33(6):101494. Epub 2020 Apr 29.

University of California San Francisco Department of Dermatology, San Francisco, CA, USA. Electronic address:

This review summarizes existing research on the gut microbiome composition and function in psoriasis and psoriatic arthritis, exploring potential roles in disease pathogenesis, progression, and management. A strong relationship between skin, joint, and gastrointestinal inflammation exists, as demonstrated by an increased prevalence of psoriasis, psoriatic arthritis, and inflammatory bowel disease co-occurring together; however, the link between them has not been fully elucidated. Studies analyzing the gut microbiome in psoriasis and psoriatic arthritis reveal a unique pattern of dysbiosis. With regard to the gut microbiome's role in psoriasis and psoriatic arthritis pathogenesis, we discuss several theories including intestinal permeability, altered immune homeostasis, and imbalance of short- and medium-chain fatty acid-producing bacteria. We also discuss how the gut microbiome affects patient risk of psoriatic arthritis and other serious comorbidities, and how fecal microbes could be used clinically as therapeutic targets or markers of disease.
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http://dx.doi.org/10.1016/j.berh.2020.101494DOI Listing
December 2019

Molecular Modeling of ALK L1198F and/or G1202R Mutations to Determine Differential Crizotinib Sensitivity.

Sci Rep 2019 08 6;9(1):11390. Epub 2019 Aug 6.

Department of Life Sciences, National University of Kaohsiung, Kaohsiung, Taiwan.

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase that has been recognized as a therapeutic target for EML4-ALK fusion-positive nonsmall cell lung cancer (NSCLC) treatment using type I kinase inhibitors such as crizotinib to take over the ATP binding site. According to Shaw's measurements, ALK carrying G1202R mutation shows reduced response to crizotinib (IC = 382 nM vs. IC = 20 nM for wild-type), whereas L1198F mutant is more responsive (IC = 0.4 nM). Interestingly, the double mutant L1198F/G1202R maintains a similar response (IC = 31 nM) to the wild-type. Herein we conducted molecular modeling simulations to elucidate the varied crizotinib sensitivities in three mutants carrying L1198F and/or G1202R. Both L1198 and G1202 are near the ATP pocket. Mutation G1202R causes steric hindrance that blocks crizotinib accessibility, which greatly reduces efficacy, whereas mutation L1198F enlarges the binding pocket entrance and hydrophobically interacts with crizotinib to enhance sensitivity. With respect to the double mutant L1198F/G1202R, F1198 indirectly pulls R1202 away from the binding entrance and consequently alleviates the steric obstacle introduced by R1202. These results demonstrated how the mutated residues tune the crizotinib response and may assist kinase inhibitor development especially for ALK G1202R, analogous to the ROS1 G2302R and MET G1163R mutations that are also resistant to crizotinib treatment in NSCLC.
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http://dx.doi.org/10.1038/s41598-019-46825-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6684801PMC
August 2019

NONPARAMETRIC TESTING FOR MULTIPLE SURVIVAL FUNCTIONS WITH NON-INFERIORITY MARGINS.

Ann Stat 2019 Feb 30;47(1):205-232. Epub 2018 Nov 30.

Department of Biostatistics, Columbia University, 722 West 168th Street, New York, NY 10032, U.S.A.

New nonparametric tests for the ordering of multiple survival functions are developed with the possibility of right censorship taken into account. The motivation comes from non-inferiority trials with multiple treatments. The proposed tests are based on nonparametric likelihood ratio statistics, which are known to provide more powerful tests than Wald-type procedures, but in this setting have only been studied for pairs of survival functions or in the absence of censoring. We introduce a novel type of pool adjacent violator algorithm that leads to a complete solution of the problem. The limit distributions can be expressed as weighted sums of squares involving projections of certain Gaussian processes onto the given ordered alternative. A simulation study shows that the new procedures have superior power to a competing combined-pairwise Cox model approach. We illustrate the proposed methods using data from a three-arm non-inferiority trial.
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http://dx.doi.org/10.1214/18-AOS1686DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6580843PMC
February 2019

Associations between urate-lowering therapy and the risk of type 2 diabetes mellitus.

PLoS One 2019 7;14(1):e0210085. Epub 2019 Jan 7.

Department of Public Health, China Medical University, Taichung, Taiwan.

Background: Gout is independently associated with increased risk of type 2 diabetes mellitus (T2DM). Urate-lowering therapy (ULT) might be beneficial in lowering the risks of T2DM. Therefore, we conducted a nested case-control study to evaluate the associations between ULT and T2DM.

Methods: This study retrieved the data of 29,765 gout patients from the period of 1998-2010 by using data from Taiwan's National Health Insurance Research Database. Controls (n = 59,530) were matched at a 1:2 ratio by age, sex, and region. Multivariate Cox proportional hazards regression were performed to examine the dose-dependent relationship between ULT and T2DM.

Results: The adjusted Hazard ratio (HR) for the association of T2DM with allopurinol or benzbromarone exposure was 1.17 (95% confidence interval (CI) 1.07-1.28) and1.09 (95% CI 1.03-1.15), respectively. The HR for the cumulative allopurinol dose was 0.87 (95% CI 0.71-1.07) for patients with dose ≤1.3 mg/day and was 1.31 (95% CI 1.13-1.52) for those with a dose >15.2 mg/day. Similarly, the HR for the cumulative benzbromarone dose was 0.85(95% CI 0.75-0.96) for patients with a dose ≤1.3 mg/day and 1.42 (95% CI 1.30-1.55) for patients with a dose>9.4 mg/day, respectively. Moreover, the average exposure dose of >100 mg/day for allopurinol and >100 mg/day for benzbromarone was associated with a 1.28-fold (95% CI 1.11-1.48) and 1.47-fold (95% CI 1.23-1.76) T2DM risk respectively. The HR for patients in aged >50 years group with cumulative dose ≤1.3 mg/day of allopurinol or benzbromarone had lower risk of T2DM (HR = 0.74, 95% CI 0.58-0.94 for allopurinol; HR = 0.79, 95% CI 0.69-0.90 for benzbromarone).

Conclusion: Gout patients with prolonged ULT and a high dose of ULT were associated with a significant increase in T2DM risk. Although gout patients with age greater than 50 years and a lower dose of ULT may be beneficial in lowering T2DM risk, further clinical studies need to be confirmed these associations.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0210085PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6322774PMC
September 2019

Alteration of the cutaneous microbiome in psoriasis and potential role in Th17 polarization.

Microbiome 2018 09 5;6(1):154. Epub 2018 Sep 5.

Department of Dermatology, University of California, San Francisco, CA, 94115, USA.

Background: Psoriasis impacts 1-3% of the world's population and is characterized by hyper-proliferation of keratinocytes and increased inflammation. At the molecular level, psoriasis is commonly driven by a Th17 response, which serves as a major therapeutic target. Microbiome perturbations have been associated with several immune-mediated diseases such as atopic dermatitis, asthma, and multiple sclerosis. Although a few studies have investigated the association between the skin microbiome and psoriasis, conflicting results have been reported plausibly due to the lack of standardized sampling and profiling protocols, or to inherent microbial variability across human subjects and underpowered studies. To better understand the link between the cutaneous microbiota and psoriasis, we conducted an analysis of skin bacterial communities of 28 psoriasis patients and 26 healthy subjects, sampled at six body sites using a standardized protocol and higher sequencing depth compared to previous studies. Mouse studies were employed to examine dermal microbial-immune interactions of bacterial species identified from our study.

Results: Skin microbiome profiling based on sequencing the 16S rRNA V1-V3 variable region revealed significant differences between the psoriasis-associated and healthy skin microbiota. Comparing the overall community structures, psoriasis-associated microbiota displayed higher diversity and more heterogeneity compared to healthy skin bacterial communities. Specific microbial signatures were associated with psoriatic lesional, psoriatic non-lesional, and healthy skin. Specifically, relative enrichment of Staphylococcus aureus was strongly associated with both lesional and non-lesional psoriatic skin. In contrast, Staphylococcus epidermidis and Propionibacterium acnes were underrepresented in psoriatic lesions compared to healthy skin, especially on the arm, gluteal fold, and trunk. Employing a mouse model to further study the impact of cutaneous Staphylcoccus species on the skin T cell differentiation, we found that newborn mice colonized with Staphylococcus aureus demonstrated strong Th17 polarization, whereas mice colonized with Staphylococcus epidermidis or un-colonized controls showed no such response.

Conclusion: Our results suggest that microbial communities on psoriatic skin is substantially different from those on healthy skin. The psoriatic skin microbiome has increased diversity and reduced stability compared to the healthy skin microbiome. The loss of community stability and decrease in immunoregulatory bacteria such as Staphylococcus epidermidis and Propionibacterium acnes may lead to higher colonization with pathogens such as Staphylococcus aureus, which could exacerbate cutaneous inflammation along the Th17 axis.
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http://dx.doi.org/10.1186/s40168-018-0533-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6125946PMC
September 2018

RNA-seq and flow-cytometry of conventional, scalp, and palmoplantar psoriasis reveal shared and distinct molecular pathways.

Sci Rep 2018 07 27;8(1):11368. Epub 2018 Jul 27.

Department of Dermatology, University of California, San Francisco, San Francisco, CA, United States.

It has long been recognized that anatomic location is an important feature for defining distinct subtypes of plaque psoriasis. However, little is known about the molecular differences between scalp, palmoplantar, and conventional plaque psoriasis. To investigate the molecular heterogeneity of these psoriasis subtypes, we performed RNA-seq and flow cytometry on skin samples from individuals with scalp, palmoplantar, and conventional plaque psoriasis, along with samples from healthy control patients. We performed differential expression analysis and network analysis using weighted gene coexpression network analysis (WGCNA). Our analysis revealed a core set of 763 differentially expressed genes common to all sub-types of psoriasis. In contrast, we identified 605, 632, and 262 genes uniquely differentially expressed in conventional, scalp, and palmoplantar psoriasis, respectively. WGCNA and pathway analysis revealed biological processes for the core genes as well as subtype-specific genes. Flow cytometry analysis revealed a shared increase in the percentage of CD4+ T regulatory cells in all psoriasis subtypes relative to controls, whereas distinct psoriasis subtypes displayed differences in IL-17A, IFN-gamma, and IL-22 production. This work reveals the molecular heterogeneity of plaque psoriasis and identifies subtype-specific signaling pathways that will aid in the development of therapy that is appropriate for each subtype of plaque psoriasis.
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http://dx.doi.org/10.1038/s41598-018-29472-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6063960PMC
July 2018

The metabolomics of psoriatic disease.

Psoriasis (Auckl) 2017;7:1-15. Epub 2017 Jan 31.

Department of Dermatology, University of California-San Francisco, San Francisco, CA, USA.

Metabolomics is an emerging new "omics" field involving the systematic analysis of the metabolites in a biologic system. These metabolites provide a molecular snapshot of cellular activity and are thus important for understanding the functional changes in metabolic pathways that drive disease. Recently, metabolomics has been used to study the local and systemic metabolic changes in psoriasis and its cardiometabolic comorbidities. Such studies have revealed novel insights into disease pathogenesis and suggest new biochemical signatures that may be used as a marker of psoriatic disease. This review will discuss common strategies in metabolomics analysis, current findings in the metabolomics of psoriasis, and emerging trends in psoriatic metabolomics.
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http://dx.doi.org/10.2147/PTT.S118348DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5562362PMC
January 2017

The Role of the Skin and Gut Microbiome in Psoriatic Disease.

Curr Dermatol Rep 2017 Jun 22;6(2):94-103. Epub 2017 Apr 22.

Department of Dermatology, University of California-San Francisco, San Francisco, CA, USA.

Purpose: To understand the changes in the microbiome in psoriatic disease, we conducted a systematic review of studies comparing the skin and gut microbiota in psoriatic individuals and healthy controls.

Findings: Our review of studies pertaining to the cutaneous microbiome showed a trend towards an increased relative abundance of and a decreased level of in psoriasis patients compared to controls. In the gut microbiome, the ratio of and was perturbed in psoriatic individuals compared to healthy controls. was also relatively underrepresented in psoriasis patients relative to healthy individuals.

Summary: Although the field of the psoriatic microbiome is relatively new, these first studies reveal interesting differences in microbiome composition that may be associated with the development of psoriatic comorbidities and serve as novel therapeutic targets.
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http://dx.doi.org/10.1007/s13671-017-0178-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5552074PMC
June 2017

Transcription factors CEP-1/p53 and CEH-23 collaborate with AAK-2/AMPK to modulate longevity in Caenorhabditis elegans.

Aging Cell 2017 08 30;16(4):814-824. Epub 2017 May 30.

Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY, 14853, USA.

A decline in mitochondrial electron transport chain (ETC) function has long been implicated in aging and various diseases. Recently, moderate mitochondrial ETC dysfunction has been found to prolong lifespan in diverse organisms, suggesting a conserved and complex role of mitochondria in longevity determination. Several nuclear transcription factors have been demonstrated to mediate the lifespan extension effect associated with partial impairment of the ETC, suggesting that compensatory transcriptional response to be crucial. In this study, we showed that the transcription factors CEP-1/p53 and CEH-23 act through a similar mechanism to modulate longevity in response to defective ETC in Caenorhabditis elegans. Genomewide gene expression profiling comparison revealed a new link between these two transcription factors and AAK-2/AMP kinase (AMPK) signaling. Further functional analyses suggested that CEP-1/p53 and CEH-23 act downstream of AAK-2/AMPK signaling and CRTC-1 transcriptional coactivator to promote stress resistance and lifespan. As AAK-2, CEP-1, and CEH-23 are all highly conserved, our findings likely provide important insights for understanding the organismal adaptive response to mitochondrial dysfunction in diverse organisms and will be relevant to aging and pathologies with a mitochondrial etiology in human.
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http://dx.doi.org/10.1111/acel.12619DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5506430PMC
August 2017

Influence of diet on the gut microbiome and implications for human health.

J Transl Med 2017 04 8;15(1):73. Epub 2017 Apr 8.

Department of Dermatology, University of California, San Francisco, 2340 Sutter St. Room N431, Box 0808, San Francisco, CA, 94115, USA.

Recent studies have suggested that the intestinal microbiome plays an important role in modulating risk of several chronic diseases, including inflammatory bowel disease, obesity, type 2 diabetes, cardiovascular disease, and cancer. At the same time, it is now understood that diet plays a significant role in shaping the microbiome, with experiments showing that dietary alterations can induce large, temporary microbial shifts within 24 h. Given this association, there may be significant therapeutic utility in altering microbial composition through diet. This review systematically evaluates current data regarding the effects of several common dietary components on intestinal microbiota. We show that consumption of particular types of food produces predictable shifts in existing host bacterial genera. Furthermore, the identity of these bacteria affects host immune and metabolic parameters, with broad implications for human health. Familiarity with these associations will be of tremendous use to the practitioner as well as the patient.
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http://dx.doi.org/10.1186/s12967-017-1175-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5385025PMC
April 2017

Association Between Gout and Incident Type 2 Diabetes Mellitus: A Retrospective Cohort Study.

Am J Med 2016 Nov 21;129(11):1219.e17-1219.e25. Epub 2016 Jul 21.

Department of Public Health and Environmental Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Taiwan; PhD Program in Environmental and Occupational Medicine, College of Medicine, Kaohsiung Medical University, Taiwan. Electronic address:

Objective: We investigated the association between gout and the risk of type 2 diabetes mellitus.

Methods: Population-based representative insurance (outpatient and inpatient) claims data of 29,765 patients with gout and 59,530 controls without gout (1:2 case:control ratio) between 1998 and 2010 in Taiwan were identified. The association between gout and type 2 diabetes was evaluated using the Cox proportional hazards model. Moreover, the combined effects of sex and incident gout on the risk of type 2 diabetes were estimated.

Results: In total, 3940 patients (13.24%) with gout and 6334 controls (10.64%) developed type 2 diabetes in the follow-up period. Multivariate analyses revealed a significant association between gout and type 2 diabetes. Compared with the control group, the adjusted hazard ratios (95% confidence intervals) for type 2 diabetes were 1.62 (1.54-1.70) in men, 1.97 (1.81-2.14) in women, and 1.70 (1.62-1.77) overall. The multiplicative interaction was β = 0.18 and P = .0001, suggesting a positive interaction between sex and incident gout. Moreover, compared with men without gout, a significantly higher risk of type 2 diabetes was noted in women without gout (adjusted relative risk [95% confidence interval], 1.17 [1.10-1.24]), men with gout (1.11 [1.06-1.16]), and women with gout (1.47 [1.37-1.57]) (P for interaction = .0058).

Conclusions: Gout is a strong and independent risk factor for type 2 diabetes, and female patients with gout are at a higher risk of type 2 diabetes than are male patients with gout.
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http://dx.doi.org/10.1016/j.amjmed.2016.06.041DOI Listing
November 2016

Empirical likelihood based tests for stochastic ordering under right censorship.

Electron J Stat 2016 8;10(2):2511-2536. Epub 2016 Sep 8.

Department of Biostatistics, Mailman School of Public Health, Columbia University.

This paper develops an empirical likelihood approach to testing for stochastic ordering between two univariate distributions under right censorship. The proposed test is based on a maximally selected local empirical likelihood statistic. The asymptotic null distribution is expressed in terms of a Brownian bridge. The new procedure is shown via a simulation study to have superior power to the log-rank and weighted Kaplan-Meier tests under crossing hazard alternatives. The approach is illustrated using data from a randomized clinical trial involving the treatment of severe alcoholic hepatitis.
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http://dx.doi.org/10.1214/16-EJS1180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6550486PMC
September 2016

Tests for stochastic ordering under biased sampling.

J Nonparametr Stat 2016 5;28(4):659-682. Epub 2016 Oct 5.

Department of Biostatistics, Columbia University, New York, NY 10032, U.S.A.

In two-sample comparison problems it is often of interest to examine whether one distribution function majorizes the other, i.e., for the presence of stochastic ordering. This paper develops a nonparametric test for stochastic ordering from size-biased data, allowing the pattern of the size bias to differ between the two samples. The test is formulated in terms of a maximally-selected local empirical likelihood statistic. A Gaussian multiplier bootstrap is devised to calibrate the test. Simulation results show that the proposed test outperforms an analogous Wald-type test, and that it provides substantially greater power over ignoring the size bias. The approach is illustrated using data on blood alcohol concentration of drivers involved in car accidents, where the size bias is due to drunker drivers being more likely to be involved in accidents. Further, younger drivers tend to be more affected by alcohol, so in making comparisons with older drivers the analysis is adjusted for differences in the patterns of size bias.
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http://dx.doi.org/10.1080/10485252.2016.1225048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5473665PMC
October 2016

Intraoperative navigation for single-splint two-jaw orthognathic surgery: From model to actual surgery.

J Craniomaxillofac Surg 2015 Sep 18;43(7):1119-26. Epub 2015 Jun 18.

Plastic & Reconstructive Surgery, and Craniofacial Research Center, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan. Electronic address:

Objective: This study reported an intraoperative navigation system for single-splint two-jaw orthognathic surgery, and assessed the accuracy of transferring the computer assisted surgical simulation.

Methods: A skull model was used for validation, and twenty patients receiving such procedure were enrolled. The procedure contained five phases, including virtual surgery on three-dimensional images, fabrication of surgical positioning guides, preparation of registration and validation landmarks, confirmation of bony position during surgery, and postoperative assessment. Target registration error (TRE) and differences between simulation (T0) and postoperative images (T1) were measured from landmarks to Frankfort horizontal plane (FHP), mid-sagittal plane (MSP), and coronal plane (COP).

Results: For the model experiment, mean TRE was lowest using the hard tissue landmarks (0.60 ± 0.27 mm), and the mean difference (T1-T0) was less than 1 mm to all three planes. For the patients, mean TRE was 1.07 ± 0.18 mm from the hard tissue landmarks. The mean difference was 0.96. ± 0.60 mm from MSP, 1.39 ± 1.11 mm from FHP, and 2.12 ± 1.82 mm from COP. The differences were not significant. Both surgeons and patients were satisfied with the surgical outcome.

Conclusion: This study showed that the navigation system had acceptable accuracy and was useful for the two-jaw orthognathic surgery using single-splint method.
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http://dx.doi.org/10.1016/j.jcms.2015.06.009DOI Listing
September 2015

Development of customized positioning guides using computer-aided design and manufacturing technology for orthognathic surgery.

Int J Comput Assist Radiol Surg 2015 Dec 16;10(12):2021-33. Epub 2015 May 16.

Department of Plastic and Reconstructive Surgery, Chang Gung Memorial Hospital, Chang Gung University, 5, Fu-Shin Street, Kwei Shan, Taoyuan, 333, Taiwan.

Purpose: The purpose of this study was to devise a method for producing customized positioning guides for translating virtual plans to actual orthognathic surgery, and evaluation of the feasibility and validity of the devised method.

Methods: Patients requiring two-jaw orthognathic surgery were enrolled and consented before operation. Two types of positioning guides were designed and fabricated using computer-aided design and manufacturing technology: One of the guides was used for the LeFort I osteotomy, and the other guide was used for positioning the maxillomandibular complex. The guides were fixed to the medial side of maxilla. For validation, the simulation images and postoperative cone beam computed tomography images were superimposed using surface registration to quantify the difference between the images. The data were presented in root-mean-square difference (RMSD) values.

Results: Both sets of guides were experienced to provide ideal fit and maximal contact to the maxillary surface to facilitate their accurate management in clinical applications. The validation results indicated that RMSD values between the images ranged from 0.18 to 0.33 mm in the maxilla and from 0.99 to 1.56 mm in the mandible. The patients were followed up for 6 months or more, and all of them were satisfied with the results.

Conclusion: The proposed customized positioning guides are practical and reliable for translation of virtual plans to actual surgery. Furthermore, these guides improved the efficiency and outcome of surgery. This approach is uncomplicated in design, cost-effective in fabrication, and particularly convenient to use.
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http://dx.doi.org/10.1007/s11548-015-1223-0DOI Listing
December 2015

Combined effects of prenatal polycyclic aromatic hydrocarbons and material hardship on child IQ.

Neurotoxicol Teratol 2015 May-Jun;49:74-80. Epub 2015 Apr 23.

Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, 722 W. 168th Street, New York, NY 10032, USA; Columbia Center for Children's Environmental Health, Mailman School of Public Health, Columbia University, 722 W. 168th Street, New York, NY 10032, USA. Electronic address:

Importance: Polycyclic aromatic hydrocarbons are common carcinogenic and neurotoxic urban air pollutants. Toxic exposures, including air pollution, are disproportionately high in communities of color and frequently co-occur with chronic economic deprivation.

Objectives: We examined whether the association between child IQ and prenatal exposure to polycyclic aromatic hydrocarbons differed between groups of children whose mothers reported high vs. low material hardship during their pregnancy and through child age 5. We tested statistical interactions between hardships and polycyclic aromatic hydrocarbons, as measured by DNA adducts in cord blood, to determine whether material hardship exacerbated the association between adducts and IQ scores.

Design: Prospective cohort. Participants were recruited from 1998 to 2006 and followed from gestation through age 7 years.

Setting: Urban community (New York City)

Participants: A community-based sample of 276 minority urban youth EXPOSURE MEASURE: Polycyclic aromatic hydrocarbon-DNA adducts in cord blood as an individual biomarker of prenatal polycyclic aromatic hydrocarbon exposure. Maternal material hardship self-reported prenatally and at multiple timepoints through early childhood.

Main Outcome Measure: Child IQ at 7 years assessed using the Wechsler Intelligence Scale for Children.

Results: Significant inverse effects of high cord PAH-DNA adducts on full scale IQ, perceptual reasoning and working memory scores were observed in the groups whose mothers reported a high level of material hardship during pregnancy or recurring high hardship into the child's early years, and not in those without reported high hardship. Significant interactions were observed between high cord adducts and prenatal hardship on working memory scores (β = -8.07, 95% CI (-14.48, -1.66)) and between high cord adducts and recurrent material hardship (β = -9.82, 95% CI (-16.22, -3.42)).

Conclusion: The findings add to other evidence that socioeconomic disadvantage can increase the adverse effects of toxic physical "stressors" like air pollutants. Observed associations between high cord adducts and reduced IQ were significant only among the group of children whose mothers reported high material hardship. These results indicate the need for a multifaceted approach to prevention.
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http://dx.doi.org/10.1016/j.ntt.2015.04.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4458400PMC
March 2016

Three-dimensional computer-assisted orthognathic surgery: experience of 37 patients.

Ann Plast Surg 2015 May;74 Suppl 2:S118-26

From the *Craniofacial Research Center, and †Plastic and Reconstructive Surgery, Chang Gung Memorial Hospital, Taoyuan, Taiwan.

Purpose: Three-dimensional computer-assisted orthognathic surgery has been applied to improve planning and outcome. This study presents our experience with this promising modality for simulation of surgery, prefabrication of positioning guides, and navigation of the surgery.

Methods: Thirty-seven patients who received surgical simulation and intraoperative navigation for 2-jaw orthognathic surgery were recruited. Preoperative 3-dimensional cone-beam computed tomographic images were used for surgical simulation and design of intraoperative guidance. An initial surgical plan was developed and transferred for 3-dimensional virtual surgery. Modification of the surgical plan was made if facial symmetry and skeletal harmony or collision of ramus segments were concerned. The result of virtual surgery was used to design and manufacture positioning guides and perform preoperative navigation planning. During the operation, the positioning guides were used to transfer the virtual planning to actual surgery, and a real-time navigation system was used to confirm the predetermined position of the maxillomandibular complex. For assessment of the computer-assisted surgical system, the simulation image was superimposed to the postoperative image for comparison.

Results: The computer-assisted orthognathic surgery was successfully carried out in all patients. The initial surgical plan was modified in 17 patients in whom the position of maxillomandibular complex was changed. The positioning guides were helpful in controlling the spatial position of the maxillomandibular complex. The BrainLabTR navigation system was useful to further confirm the position of the facial bone. Superimposition of the simulation and postoperative images revealed satisfactory result with acceptable errors. The difference ranged from 0.05 to 1.46 mm, with a mean value of 0.66 mm, for patients using the positioning guides; and the difference ranged from 0.07 to 2.30 mm, with a mean value of 1.20 mm, for patients using the navigation system. Overall, patient and doctor satisfaction was high.

Conclusion: This computer-assisted orthognathic surgery system helps to improve surgical planning, reduce surgical difficulty, facilitate positioning and fixation of the maxillomandibular complex, and improve outcome.
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http://dx.doi.org/10.1097/SAP.0000000000000455DOI Listing
May 2015

Exploitation of the ability of γ-tocopherol to facilitate membrane co-localization of Akt and PHLPP1 to develop PHLPP1-targeted Akt inhibitors.

J Med Chem 2015 Mar 27;58(5):2290-8. Epub 2015 Feb 27.

Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University , Columbus, Ohio 43210, United States.

Previously, we reported that Akt inactivation by γ-tocopherol (2) in PTEN-negative prostate cancer cells resulted from its unique ability to facilitate membrane co-localization of Akt and PHLPP1 (PH domain leucine-rich repeat protein phosphatase isoform 1), a Ser473-specific Akt phosphatase, through pleckstrin homology (PH) domain binding. This finding provided a basis for exploiting 2 to develop a novel class of PHLPP1-targeted Akt inhibitors. Here, we used 3 (γ-VE5), a side chain-truncated 2 derivative, as a scaffold for lead optimization. The proof-of-concept of this structural optimization was obtained by 20, which exhibited higher antitumor efficacy than 3 in PTEN-negative cancer cells through PHLPP1-facilitated Akt inactivation. Like 3, 20 preferentially recognized the PH domains of Akt and PHLPP1, as its binding affinities for other PH domains, including those of ILK and PDK1, were an order-of-magnitude lower. Moreover, 20 was orally active in suppressing xenograft tumor growth in nude mice, which underlines the translational potential of this new class of Akt inhibitor in PTEN-deficient cancers.
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http://dx.doi.org/10.1021/jm501751bDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4720140PMC
March 2015

Nasal changes after orthognathic surgery for patients with prognathism and Class III malocclusion: analysis using three-dimensional photogrammetry.

J Formos Med Assoc 2015 Feb 20;114(2):112-23. Epub 2014 Dec 20.

Craniofacial Research Center, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan; Department of Plastic and Reconstructive Surgery, Craniofacial Center, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan. Electronic address:

Background/purpose: Orthognathic surgery alters the position of maxilla and mandible, and consequently changes the nasal shape. The nasal change remains a concern to Asian patients. The aim of this study was to measure the nasal changes using a novel three-dimensional photographic imaging method.

Methods: A total of 38 patients with Class III malocclusion and prognathism were enrolled. All patients underwent two-jaw surgery with the standard technique. A nasal alar cinching suture was included at the end of procedure. Facial landmarks and nasal morphology were defined and measured from pre- and postoperative three-dimensional photographic images. Intra-rater errors on landmark identification were controlled. Patient's reports of perceptual nasal changes were recorded.

Results: The average width of the alar base and subalare remained similar after surgery. Alar width was increased by 0.74 mm. Nasal height and length remained the same. Nasolabial angle increased significantly. The area of nostril show revealed a significant increase and was correlated with a decrease of columella inclination. Nasal tip projection decreased significantly, by 1.99 mm. Preoperative nasal morphology was different between patients with and without cleft lip/palate, but most nasal changes were concordant. In the self-perception, 37% of patients reported improved nasal appearance, 58% reported no change, and 5% were not satisfied with the nasal changes.

Conclusion: After the surgery, characteristic nasal changes occurred with an increase of nasolabial angle and nostril show, but a preserved nasal width. The majority of patients did not perceive adverse nasal changes.
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http://dx.doi.org/10.1016/j.jfma.2014.10.003DOI Listing
February 2015

CFS-1686 causes cell cycle arrest at intra-S phase by interference of interaction of topoisomerase 1 with DNA.

PLoS One 2014 2;9(12):e113832. Epub 2014 Dec 2.

Department of Biotechnology, Kaohsiung Medical University, Kaohsiung, Taiwan.

CFS-1686 (chemical name (E)-N-(2-(diethylamino)ethyl)-4-(2-(2-(5-nitrofuran-2-yl)vinyl)quinolin-4-ylamino)benzamide) inhibits cell proliferation and triggers late apoptosis in prostate cancer cell lines. Comparing the effect of CFS-1686 on cell cycle progression with the topoisomerase 1 inhibitor camptothecin revealed that CFS-1686 and camptothecin reduced DNA synthesis in S-phase, resulting in cell cycle arrest at the intra-S phase and G1-S boundary, respectively. The DNA damage in CFS-1686 and camptothecin treated cells was evaluated by the level of ATM phosphorylation, γH2AX, and γH2AX foci, showing that camptothecin was more effective than CFS-1686. However, despite its lower DNA damage capacity, CFS-1686 demonstrated 4-fold higher inhibition of topoisomerase 1 than camptothecin in a DNA relaxation assay. Unlike camptothecin, CFS-1686 demonstrated no activity on topoisomerase 1 in a DNA cleavage assay, but nevertheless it reduced the camptothecin-induced DNA cleavage of topoisomerase 1 in a dose-dependent manner. Our results indicate that CFS-1686 might bind to topoisomerase 1 to inhibit this enzyme from interacting with DNA relaxation activity, unlike campothecin's induction of a topoisomerase 1-DNA cleavage complex. Finally, we used a computer docking strategy to localize the potential binding site of CFS-1686 to topoisomerase 1, further indicating that CFS-1686 might inhibit the binding of Top1 to DNA.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0113832PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4252032PMC
July 2015

Collaboration between mitochondria and the nucleus is key to long life in Caenorhabditis elegans.

Free Radic Biol Med 2015 Jan 4;78:168-78. Epub 2014 Nov 4.

Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14850, USA. Electronic address:

Recent findings in diverse organisms strongly support a conserved role for mitochondrial electron transport chain dysfunction in longevity modulation, but the underlying mechanisms are not well understood. One way cells cope with mitochondrial dysfunction is through a retrograde transcriptional reprogramming response. In this review, we primarily focus on the work that has been performed in Caenorhabditis elegans to elucidate these mechanisms. We describe several transcription factors that participate in mitochondria-to-nucleus signaling and discuss how they mediate the relationship between mitochondrial dysfunction and life span.
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http://dx.doi.org/10.1016/j.freeradbiomed.2014.10.576DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4280335PMC
January 2015

Early-life exposure to polycyclic aromatic hydrocarbons and ADHD behavior problems.

PLoS One 2014 5;9(11):e111670. Epub 2014 Nov 5.

Columbia Center for Children's Environmental Health, Columbia University, New York, New York, United States of America; The Heilbrunn Department of Population and Family Health, Columbia University, New York, New York, United States of America.

Importance: Polycyclic aromatic hydrocarbons are widespread urban air pollutants from combustion of fossil fuel and other organic material shown previously to be neurotoxic.

Objective: In a prospective cohort study, we evaluated the relationship between Attention Deficit Hyperactivity Disorder behavior problems and prenatal polycyclic aromatic hydrocarbon exposure, adjusting for postnatal exposure.

Materials And Methods: Children of nonsmoking African-American and Dominican women in New York City were followed from in utero to 9 years. Prenatal polycyclic aromatic hydrocarbon exposure was estimated by levels of polycyclic aromatic hydrocarbon- DNA adducts in maternal and cord blood collected at delivery. Postnatal exposure was estimated by the concentration of urinary polycyclic aromatic hydrocarbon metabolites at ages 3 or 5. Attention Deficit Hyperactivity Disorder behavior problems were assessed using the Child Behavior Checklist and the Conners Parent Rating Scale- Revised.

Results: High prenatal adduct exposure, measured by elevated maternal adducts was significantly associated with all Conners Parent Rating Scale-Revised subscales when the raw scores were analyzed continuously (N = 233). After dichotomizing at the threshold for moderately to markedly atypical symptoms, high maternal adducts were significantly associated with the Conners Parent Rating Scale-Revised DSM-IV Inattentive (OR = 5.06, 95% CI [1.43, 17.93]) and DSM-IV Total (OR = 3.37, 95% CI [1.10, 10.34]) subscales. High maternal adducts were positivity associated with the DSM-oriented Attention Deficit/Hyperactivity Problems scale on the Child Behavior Checklist, albeit not significant. In the smaller sample with cord adducts, the associations between outcomes and high cord adduct exposure were not statistically significant (N = 162).

Conclusion: The results suggest that exposure to polycyclic aromatic hydrocarbons encountered in New York City air may play a role in childhood Attention Deficit Hyperactivity Disorder behavior problems.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0111670PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4221082PMC
June 2015

Feedback regulation via AMPK and HIF-1 mediates ROS-dependent longevity in Caenorhabditis elegans.

Proc Natl Acad Sci U S A 2014 Oct 6;111(42):E4458-67. Epub 2014 Oct 6.

Department of Life Sciences, Division of Information Technology Convergence Engineering, School of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology, Pohang 790-784, South Korea;

Mild inhibition of mitochondrial respiration extends the lifespan of many species. In Caenorhabditis elegans, reactive oxygen species (ROS) promote longevity by activating hypoxia-inducible factor 1 (HIF-1) in response to reduced mitochondrial respiration. However, the physiological role and mechanism of ROS-induced longevity are poorly understood. Here, we show that a modest increase in ROS increases the immunity and lifespan of C. elegans through feedback regulation by HIF-1 and AMP-activated protein kinase (AMPK). We found that activation of AMPK as well as HIF-1 mediates the longevity response to ROS. We further showed that AMPK reduces internal levels of ROS, whereas HIF-1 amplifies the levels of internal ROS under conditions that increase ROS. Moreover, mitochondrial ROS increase resistance to various pathogenic bacteria, suggesting a possible association between immunity and long lifespan. Thus, AMPK and HIF-1 may control immunity and longevity tightly by acting as feedback regulators of ROS.
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http://dx.doi.org/10.1073/pnas.1411199111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4210294PMC
October 2014

Neighborhood Social Context and Individual Polycyclic Aromatic Hydrocarbon Exposures Associated with Child Cognitive Test Scores.

J Child Fam Stud 2014 Jul;23(5):785-799

Department of Environmental Health Sciences, Columbia University Mailman School of Public Health, New York, NY, USA.

Childhood cognitive and test-taking abilities have long-term implications for educational achievement and health, and may be influenced by household environmental exposures and neighborhood contexts. This study evaluates whether age 5 scores on the Wechsler Preschool and Primary Scale of Intelligence-Revised (WPPSI-R, administered in English) are associated with polycyclic aromatic hydrocarbon (PAH) exposure and neighborhood context variables including poverty, low educational attainment, low English language proficiency, and inadequate plumbing. The Columbia Center for Children's Environmental Health enrolled African-American and Dominican-American New York City women during pregnancy, and conducted follow-up for subsequent childhood health outcomes including cognitive test scores. Individual outcomes were linked to data characterizing 1-km network buffers around prenatal addresses, home observations, interviews, and prenatal PAH exposure data from personal air monitors. Prenatal PAH exposure above the median predicted 3.5 point lower total WPPSI-R scores and 3.9 point lower verbal scores; the association was similar in magnitude across models with adjustments for neighborhood characteristics. Neighborhood-level low English proficiency was independently associated with 2.3 point lower mean total WPPSI-R score, 1.2 point lower verbal score, and 2.7 point lower performance score per standard deviation. Low neighborhood-level educational attainment was also associated with 2.0 point lower performance scores. In models examining effect modification, neighborhood associations were similar or diminished among the high PAH exposure group, as compared with the low PAH exposure group. Early life exposure to personal PAH exposure or selected neighborhood-level social contexts may predict lower cognitive test scores. However, these results may reflect limited geographic exposure variation and limited generalizability.
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http://dx.doi.org/10.1007/s10826-013-9731-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4075963PMC
July 2014

Motor impairments screened by the movement assessment battery for children-2 are related to the visual-perceptual deficits in children with developmental coordination disorder.

Res Dev Disabil 2014 Sep 7;35(9):2172-9. Epub 2014 Jun 7.

Graduate Institute of Early Intervention, College of Medicine, Chang Gung University, 259 Wen-Hua 1st Road, Kwei-Shan, Tao-Yuan 333, Taiwan. Electronic address:

This study was to examine to what extent the motor deficits of children with Developmental Coordination Disorder (DCD) verified by the Movement Assessment Battery for Children-2 (MABC-2) are linked to their visual-perceptual abilities. Seventeen children with DCD and seventeen typically developing children (TD) aged 5-10 years screened from a total of 250 children were recruited. The assessments included MABC-2, traditional test of visual perceptual skills (TVPS-R), and computerized test for sequential coupling of eye and hand as well as motion coherence. The results indicated that children with DCD scored lower than TD in MABC-2, and their total scores were highly correlated with manual dexterity component scores. DCD group also showed poor visual-perceptual abilities in various aspects. The visual discrimination and visual sequential memory from the TVPS-R, the sequential coupling of eye and hand, and the motion coherence demonstrated a moderate or strong correlation with the MABC-2 in the DCD rather than the TD group. It was concluded that the motor problems screened by MABC-2 were significantly related to the visual-perceptual deficits of children with DCD. MABC-2 is suggested to be a prescreening tool to identify the visual-perceptual related motor deficits.
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http://dx.doi.org/10.1016/j.ridd.2014.05.009DOI Listing
September 2014

Molecular modeling of p38α mitogen-activated protein kinase inhibitors through 3D-QSAR and molecular dynamics simulations.

J Chem Inf Model 2013 Jul 10;53(7):1775-86. Epub 2013 Jul 10.

Institute of Biotechnology, National University of Kaohsiung, Taiwan.

The p38 mitogen-activated protein kinase (MAPK) signaling pathway plays an essential role in inflammation and other physiological processes. Because specific inhibitors of p38α and p38β MAPK block the production of the major inflammatory cytokines and other proteins, p38α and p38β MAPK represent promising targets for the treatment of inflammation. In this work, a series of p38α inhibitors based on the structural scaffold of 4-benzoyl-5-aminopyrazole were analyzed using a combination of molecular modeling techniques. We generated three-dimensional quantitative structure-activity relationship (3D-QSAR) models for both comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) to highlight the structural requirements for p38 MAPK inhibition. Furthermore, we employed molecular dynamics (MD) simulations and the MM/GBSA method to compare the binding modes and binding free energies of a potent and selective compound interacting with p38α, p38β, p38γ, and p38δ MAPK in detail. Contour maps generated via 3D-QSAR analysis identified several key interactions that were also indicated through MD simulations. The binding free energies calculated via the MM/GBSA method were strongly correlated with experimentally observed biological activities and explained the selective inhibition of p38α and p38β, but not p38γ and p38δ detected here. On the basis of the obtained results, we provide insights regarding the development of novel potent p38α MAPK inhibitors.
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http://dx.doi.org/10.1021/ci4000085DOI Listing
July 2013

The homeobox protein CEH-23 mediates prolonged longevity in response to impaired mitochondrial electron transport chain in C. elegans.

PLoS Biol 2011 Jun 21;9(6):e1001084. Epub 2011 Jun 21.

Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York, United States of America.

Recent findings indicate that perturbations of the mitochondrial electron transport chain (METC) can cause extended longevity in evolutionarily diverse organisms. To uncover the molecular basis of how altered METC increases lifespan in C. elegans, we performed an RNAi screen and revealed that three predicted transcription factors are specifically required for the extended longevity of mitochondrial mutants. In particular, we demonstrated that the nuclear homeobox protein CEH-23 uniquely mediates the longevity but not the slow development, reduced brood size, or resistance to oxidative stress associated with mitochondrial mutations. Furthermore, we showed that ceh-23 expression levels are responsive to altered METC, and enforced overexpression of ceh-23 is sufficient to extend lifespan in wild-type background. Our data point to mitochondria-to-nucleus communications to be key for longevity determination and highlight CEH-23 as a novel longevity factor capable of responding to mitochondrial perturbations. These findings provide a new paradigm for how mitochondria impact aging and age-dependent diseases.
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http://dx.doi.org/10.1371/journal.pbio.1001084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3119657PMC
June 2011