Publications by authors named "Wilson Leung"

38 Publications

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MicroPubl Biol 2021 Feb 16;2021. Epub 2021 Feb 16.

Washington University in St. Louis, St. Louis, MO 63130.

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http://dx.doi.org/10.17912/micropub.biology.000371DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890423PMC
February 2021

G-OnRamp: Generating genome browsers to facilitate undergraduate-driven collaborative genome annotation.

PLoS Comput Biol 2020 06 4;16(6):e1007863. Epub 2020 Jun 4.

Department of Biology, Washington University in St. Louis, St. Louis, Missouri, United States of America.

Scientists are sequencing new genomes at an increasing rate with the goal of associating genome contents with phenotypic traits. After a new genome is sequenced and assembled, structural gene annotation is often the first step in analysis. Despite advances in computational gene prediction algorithms, most eukaryotic genomes still benefit from manual gene annotation. This requires access to good genome browsers to enable annotators to visualize and evaluate multiple lines of evidence (e.g., sequence similarity, RNA sequencing [RNA-Seq] results, gene predictions, repeats) and necessitates many volunteers to participate in the work. To address the technical barriers to creating genome browsers, the Genomics Education Partnership (GEP; https://gep.wustl.edu/) has partnered with the Galaxy Project (https://galaxyproject.org) to develop G-OnRamp (http://g-onramp.org), a web-based platform for creating UCSC Genome Browser Assembly Hubs and JBrowse genome browsers. G-OnRamp also converts a JBrowse instance into an Apollo instance for collaborative genome annotations in research and educational settings. The genome browsers produced can be transferred to the CyVerse Data Store for long-term access. G-OnRamp enables researchers to easily visualize their experimental results, educators to create Course-based Undergraduate Research Experiences (CUREs) centered on genome annotation, and students to participate in genomics research. In the process, students learn about genes/genomes and about how to utilize large datasets. Development of G-OnRamp was guided by extensive user feedback. Sixty-five researchers/educators from >40 institutions participated through in-person workshops, which produced >20 genome browsers now available for research and education. Genome browsers generated for four parasitoid wasp species have been used in a CURE engaging students at 15 colleges and universities. Our assessment results in the classroom demonstrate that the genome browsers produced by G-OnRamp are effective tools for engaging undergraduates in research and in enabling their contributions to the scientific literature in genomics. Expansion of such genomics research/education partnerships will be beneficial to researchers, faculty, and students alike.
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http://dx.doi.org/10.1371/journal.pcbi.1007863DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7272004PMC
June 2020

Facilitating Growth through Frustration: Using Genomics Research in a Course-Based Undergraduate Research Experience.

J Microbiol Biol Educ 2020 28;21(1). Epub 2020 Feb 28.

Biology, University of San Diego, San Diego, CA 92110, USA.

A hallmark of the research experience is encountering difficulty and working through those challenges to achieve success. This ability is essential to being a successful scientist, but replicating such challenges in a teaching setting can be difficult. The Genomics Education Partnership (GEP) is a consortium of faculty who engage their students in a genomics Course-Based Undergraduate Research Experience (CURE). Students participate in genome annotation, generating gene models using multiple lines of experimental evidence. Our observations suggested that the students' learning experience is continuous and recursive, frequently beginning with frustration but eventually leading to success as they come up with defendable gene models. In order to explore our "formative frustration" hypothesis, we gathered data from faculty via a survey, and from students via both a general survey and a set of student focus groups. Upon analyzing these data, we found that all three datasets mentioned frustration and struggle, as well as learning and better understanding of the scientific process. Bioinformatics projects are particularly well suited to the process of iteration and refinement because iterations can be performed quickly and are inexpensive in both time and money. Based on these findings, we suggest that a dynamic of "formative frustration" is an important aspect for a successful CURE.
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http://dx.doi.org/10.1128/jmbe.v21i1.2005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7048401PMC
February 2020

G-OnRamp: a Galaxy-based platform for collaborative annotation of eukaryotic genomes.

Bioinformatics 2019 11;35(21):4422-4423

Computational Biology Program, Oregon Health and Science University, Portland, OR, USA.

Summary: G-OnRamp provides a user-friendly, web-based platform for collaborative, end-to-end annotation of eukaryotic genomes using UCSC Assembly Hubs and JBrowse/Apollo genome browsers with evidence tracks derived from sequence alignments, ab initio gene predictors, RNA-Seq data and repeat finders. G-OnRamp can be used to visualize large genomics datasets and to perform collaborative genome annotation projects in both research and educational settings.

Availability And Implementation: The virtual machine images and tutorials are available on the G-OnRamp web site (http://g-onramp.org/deployments). The source code is available under an Academic Free License version 3.0 through the goeckslab GitHub repository (https://github.com/goeckslab).

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/btz309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6821377PMC
November 2019

Association of Markers of Proinflammatory Phenotype and Beige Adipogenesis with Metabolic Syndrome in Chinese Centrally Obese Adults.

J Diabetes Res 2018 18;2018:8956509. Epub 2018 Feb 18.

School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong.

Background: Visceral adiposity is associated with higher productions of C-reactive protein (CRP) and interleukin-6 (IL-6). Inflammation of obese adipose tissues could contribute to systemic metabolic dysregulation, especially thermogenic activity of white adipose tissues, namely, beige adipogenesis, characterized by altered irisin expression. Thus, we investigated the roles of inflammation and adipocyte beiging in Chinese centrally obese (CO) adults with metabolic syndrome (MetS).

Methods: This cross-sectional study was conducted on 54 CO and 58 non-CO subjects drawn from 1492 Chinese people with age and sex matched during November 2010 and August 2013. Twenty (37.0%) of the CO subjects fulfilled the IDF worldwide definition of MetS. Serum CRP, IL-6, and irisin levels were examined.

Results: Higher CRP and IL-6, but lower irisin, levels were manifested in MetS versus non-MetS subjects with or without CO. Multiple linear regression identified high-density lipoprotein cholesterol level as the only independent risk factor for irisin level. Categorized by median of CRP and IL-6 levels, a lower irisin level was only observed in high CRP group.

Conclusion: Under the condition of central obesity, chronic inflammation and impaired beige adipogenesis are associated with MetS in Chinese adults.
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http://dx.doi.org/10.1155/2018/8956509DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5835251PMC
October 2018

Response to the Letter to the Editor by Dunning Hotopp and Klasson.

G3 (Bethesda) 2018 01 4;8(1):375. Epub 2018 Jan 4.

Department of Biology, Washington University in St. Louis, Missouri 63130

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http://dx.doi.org/10.1534/g3.117.300379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5764750PMC
January 2018

Association between sonographically measured mesenteric fat thickness and brachial artery flow-mediated dilation in Chinese young male adults.

J Int Med Res 2017 Dec 16;45(6):1930-1938. Epub 2017 Mar 16.

1 Department of Health Technology and Informatics, the Hong Kong Polytechnic University, Hung Hom, Hong Kong.

Objective To investigate the potential correlation between sonographically measured mesenteric fat thickness (MFT) and brachial artery flow-mediated dilation (FMD) in a sample of healthy Chinese male young adults. Methods Healthy male participants were recruited from Hong Kong Polytechnic University for this prospective observational study. The physical activity readiness questionnaire and ultrasound measurements of carotid intima media thickness were used to screen for clinically healthy subjects. MFT and brachial artery FMD were measured by ultrasound, and body mass index (BMI) was recorded. Results A total of 34 healthy male subjects, aged 19-26 years (mean ± SD BMI, 21.7 ± 3.2 kg/m) were included. Pearson's correlation coefficient test showed that brachial artery FMD had a statistically significant inverse relationship with BMI and with Log (MFT). Further stepwise multiple linear regression analysis showed that Log (MFT), and not BMI, was an independent predictor of impaired brachial artery FMD. Conclusions Sonographic measurements of MFT were an independent predictor of brachial artery FMD in Chinese male young adults.
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http://dx.doi.org/10.1177/0300060516688407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5805196PMC
December 2017

Sonographic evaluation of the immediate effects of eccentric heel drop exercise on Achilles tendon and gastrocnemius muscle stiffness using shear wave elastography.

PeerJ 2017 19;5:e3592. Epub 2017 Jul 19.

Department of Health Technology and Informatics, Hong Kong Polytechnic University, Hung Hom, Hong Kong.

Background: Mechanical loading is crucial for muscle and tendon tissue remodeling. Eccentric heel drop exercise has been proven to be effective in the management of Achilles tendinopathy, yet its induced change in the mechanical property (i.e., stiffness) of the Achilles tendon (AT), medial and lateral gastrocnemius muscles (MG and LG) was unknown. Given that shear wave elastography has emerged as a powerful tool in assessing soft tissue stiffness with promising intra- and inter-operator reliability, the objective of this study was hence to characterize the stiffness of the AT, MG and LG in response to an acute bout of eccentric heel drop exercise.

Methods: Forty-five healthy young adults (36 males and nine females) performed 10 sets of 15-repetition heel drop exercise on their dominant leg with fully-extended knee, during which the AT and gastrocnemius muscles, but not soleus, were highly stretched. Before and immediately after the heel drop exercise, elastic moduli of the AT, MG and LG were measured by shear wave elastography.

Results: After the heel drop exercise, the stiffness of AT increased significantly by 41.8 + 33.5% ( < 0.001), whereas the increases in the MG and LG stiffness were found to be more drastic by 75 + 47.7% ( < 0.001) and 71.7 + 51.8% ( < 0.001), respectively. Regarding the AT, MG and LG stiffness measurements, the inter-operator reliability was 0.940, 0.987 and 0.986, and the intra-operator reliability was 0.916 to 0.978, 0.801 to 0.961 and 0.889 to 0.985, respectively.

Discussion: The gastrocnemius muscles were shown to bear larger mechanical loads than the AT during an acute bout of eccentric heel drop exercise. The findings from this pilot study shed some light on how and to what extent the AT and gastrocnemius muscles mechanically responds to an isolated set of heel drop exercise. Taken together, appropriate eccentric load might potentially benefit mechanical adaptations of the AT and gastrocnemius muscles in the rehabilitation of patients with Achilles tendinopathy.
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http://dx.doi.org/10.7717/peerj.3592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5520961PMC
July 2017

Retrotransposons Are the Major Contributors to the Expansion of the Muller F Element.

G3 (Bethesda) 2017 08 7;7(8):2439-2460. Epub 2017 Aug 7.

Department of Biological Sciences, California Polytechnic State University, San Luis Obispo, CA 93405.

The discordance between genome size and the complexity of eukaryotes can partly be attributed to differences in repeat density. The Muller F element (∼5.2 Mb) is the smallest chromosome in , but it is substantially larger (>18.7 Mb) in To identify the major contributors to the expansion of the F element and to assess their impact, we improved the genome sequence and annotated the genes in a 1.4-Mb region of the F element, and a 1.7-Mb region from the D element for comparison. We find that transposons (particularly LTR and LINE retrotransposons) are major contributors to this expansion (78.6%), while sequences integrated into the genome are minor contributors (0.02%). Both and F-element genes exhibit distinct characteristics compared to D-element genes (, larger coding spans, larger introns, more coding exons, and lower codon bias), but these differences are exaggerated in Compared to , the codon bias observed in F-element genes can primarily be attributed to mutational biases instead of selection. The 5' ends of F-element genes in both species are enriched in dimethylation of lysine 4 on histone 3 (H3K4me2), while the coding spans are enriched in H3K9me2. Despite differences in repeat density and gene characteristics, F-element genes show a similar range of expression levels compared to genes in euchromatic domains. This study improves our understanding of how transposons can affect genome size and how genes can function within highly repetitive domains.
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http://dx.doi.org/10.1534/g3.117.040907DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5555453PMC
August 2017

Diabetic nephropathy and endothelial dysfunction: Current and future therapies, and emerging of vascular imaging for preclinical renal-kinetic study.

Life Sci 2016 Dec 17;166:121-130. Epub 2016 Oct 17.

Department of Health Technology and Informatics, Hong Kong Polytechnic University, Hung Hom, HKSAR, China. Electronic address:

An explosion in global epidemic of type 2 diabetes mellitus poses major rise in cases with vascular endothelial dysfunction ranging from micro- (retinopathy, nephropathy and neuropathy) to macro-vascular (atherosclerosis and cardiomyopathy) conditions. Functional destruction of endothelium is regarded as an early event that lays the groundwork for the development of renal microangiopathy and subsequent clinical manifestation of nephropathic symptoms. Recent research has shed some light on the molecular mechanisms of type 2 diabetes-associated comorbidity of endothelial dysfunction and nephropathy. Stemming from currently proposed endothelium-centered therapeutic strategies for diabetic nephropathy, this review highlighted some most exploited pathways that involve the intricate coordination of vasodilators, vasoconstrictors and vaso-modulatory molecules in the pathogenesis of diabetic nephropathy. We also emphasized the emerging roles of oxidative and epigenetic modifications of microvasculature as our prospective therapeutics for diabetic renal diseases. Finally, this review in particular addressed the potential use of multispectral optoacoustic tomography in real-time, minimally-invasive vascular imaging of small experimental animals for preclinical renal-kinetic drug trials.
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http://dx.doi.org/10.1016/j.lfs.2016.10.015DOI Listing
December 2016

Differential secretion pathways of proteins fused to the Escherichia coli maltose binding protein (MBP) in Pichia pastoris.

Protein Expr Purif 2016 08 11;124:1-9. Epub 2016 Apr 11.

Department of Biological Sciences, University of the Pacific, Stockton, CA 95211, United States. Electronic address:

The Escherichia coli maltose binding protein (MBP) is an N-terminal fusion partner that was shown to enhance the secretion of some heterologous proteins from the yeast Pichia pastoris, a popular host for recombinant protein expression. The amount of increase in secretion was dependent on the identity of the cargo protein, and the fusions were proteolyzed prior to secretion, limiting its use as a purification tag. In order to overcome these obstacles, we used the MBP as C-terminal partner for several cargo peptides. While the Cargo-MBP proteins were no longer proteolyzed in between these two moieties when the MBP was in this relative position, the secretion efficiency of several fusions was lower than when MBP was located at the opposite end of the cargo protein (MBP-Cargo). Furthermore, fluorescence analysis suggested that the MBP-EGFP and EGFP-MBP proteins followed different routes within the cell. The effect of several Pichia pastoris beta-galactosidase supersecretion (bgs) strains, mutants showing enhanced secretion of select reporters, was also investigated on both MBP-EGFP and EGFP-MBP. While the secretion efficiency, proteolysis and localization of the MBP-EGFP was influenced by the modified function of Bgs13, EGFP-MBP behavior was not affected in the bgs strain. Taken together, these results indicate that the location of the MBP in a fusion affects the pathway and trans-acting factors regulating secretion in P. pastoris.
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http://dx.doi.org/10.1016/j.pep.2016.04.005DOI Listing
August 2016

Targeting of P-Element Reporters to Heterochromatic Domains by Transposable Element 1360 in Drosophila melanogaster.

Genetics 2016 Feb 17;202(2):565-82. Epub 2015 Dec 17.

Biology Department, Washington University, St. Louis, Missouri 63130

Heterochromatin is a common DNA packaging form employed by eukaryotes to constitutively silence transposable elements. Determining which sequences to package as heterochromatin is vital for an organism. Here, we use Drosophila melanogaster to study heterochromatin formation, exploiting position-effect variegation, a process whereby a transgene is silenced stochastically if inserted in proximity to heterochromatin, leading to a variegating phenotype. Previous studies identified the transposable element 1360 as a target for heterochromatin formation. We use transgene reporters with either one or four copies of 1360 to determine if increasing local repeat density can alter the fraction of the genome supporting heterochromatin formation. We find that including 1360 in the reporter increases the frequency with which variegating phenotypes are observed. This increase is due to a greater recovery of insertions at the telomere-associated sequences (∼50% of variegating inserts). In contrast to variegating insertions elsewhere, the phenotype of telomere-associated sequence insertions is largely independent of the presence of 1360 in the reporter. We find that variegating and fully expressed transgenes are located in different types of chromatin and that variegating reporters in the telomere-associated sequences differ from those in pericentric heterochromatin. Indeed, chromatin marks at the transgene insertion site can be used to predict the eye phenotype. Our analysis reveals that increasing the local repeat density (via the transgene reporter) does not enlarge the fraction of the genome supporting heterochromatin formation. Rather, additional copies of 1360 appear to target the reporter to the telomere-associated sequences with greater efficiency, thus leading to an increased recovery of variegating insertions.
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http://dx.doi.org/10.1534/genetics.115.183228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4788236PMC
February 2016

Wnt/β-Catenin activates MiR-183/96/182 expression in hepatocellular carcinoma that promotes cell invasion.

Cancer Lett 2015 Jun 23;362(1):97-105. Epub 2015 Mar 23.

Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Shatin, Hong Kong, China; State Key Laboratory in Oncology in South China, The Chinese University of Hong Kong, Shatin, Hong Kong, China. Electronic address:

Nearly 50% of known miRNAs are found in clusters and transcribed as polycistronic transcripts. In this study, we showed that over-expression of miR-183/96/182 cluster is frequent in hepatocellular carcinoma (HCC), a highly aggressive malignancy that is commonly fatal. In a cohort of HCC patients (n = 81), miR-183/96/182 up-regulation correlated with metastatic features including presence of microvascular invasion, advanced tumor differentiation, and shorter recurrence-free survival. Univariate and multivariate analyses further showed miR-183/96/182 over-expression represented an independent prognostic factor (Relative Risk: 2.0471; P = 0.0289). Functional investigation using siRNA against miR-183/96/182 in two invasive HCC cells indicated significant inhibition on cell migration and invasion without affecting cell viability. Forkhead boxO1 (FOXO1) was further validated as a downstream target of these three miRNAs. In investigating the regulatory mechanism underlining miR-183/96/182 over-expression, a direct interaction of CTNNB1 on the promoter region was confirmed by ChIP-PCR and luciferase reporter validations. Knockdown of CTNNB1 also showed concordant down-regulations of miR-183, -96 and -182, and the re-expression of FOXO1. Our findings demonstrated that over-expression of miR-183/96/182 confers an oncogenic function in HCC cell dissemination, and could serve as an independent prognostic predictor for HCC patients.
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http://dx.doi.org/10.1016/j.canlet.2015.03.023DOI Listing
June 2015

Drosophila muller f elements maintain a distinct set of genomic properties over 40 million years of evolution.

G3 (Bethesda) 2015 Mar 4;5(5):719-40. Epub 2015 Mar 4.

Department of Biology, Albion College, Albion, MI 49224.

The Muller F element (4.2 Mb, ~80 protein-coding genes) is an unusual autosome of Drosophila melanogaster; it is mostly heterochromatic with a low recombination rate. To investigate how these properties impact the evolution of repeats and genes, we manually improved the sequence and annotated the genes on the D. erecta, D. mojavensis, and D. grimshawi F elements and euchromatic domains from the Muller D element. We find that F elements have greater transposon density (25-50%) than euchromatic reference regions (3-11%). Among the F elements, D. grimshawi has the lowest transposon density (particularly DINE-1: 2% vs. 11-27%). F element genes have larger coding spans, more coding exons, larger introns, and lower codon bias. Comparison of the Effective Number of Codons with the Codon Adaptation Index shows that, in contrast to the other species, codon bias in D. grimshawi F element genes can be attributed primarily to selection instead of mutational biases, suggesting that density and types of transposons affect the degree of local heterochromatin formation. F element genes have lower estimated DNA melting temperatures than D element genes, potentially facilitating transcription through heterochromatin. Most F element genes (~90%) have remained on that element, but the F element has smaller syntenic blocks than genome averages (3.4-3.6 vs. 8.4-8.8 genes per block), indicating greater rates of inversion despite lower rates of recombination. Overall, the F element has maintained characteristics that are distinct from other autosomes in the Drosophila lineage, illuminating the constraints imposed by a heterochromatic milieu.
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http://dx.doi.org/10.1534/g3.114.015966DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4426361PMC
March 2015

A central support system can facilitate implementation and sustainability of a Classroom-based Undergraduate Research Experience (CURE) in Genomics.

CBE Life Sci Educ 2014 ;13(4):711-23

Department of Biological Sciences, George Washington University, Washington, DC 20052.

In their 2012 report, the President's Council of Advisors on Science and Technology advocated "replacing standard science laboratory courses with discovery-based research courses"-a challenging proposition that presents practical and pedagogical difficulties. In this paper, we describe our collective experiences working with the Genomics Education Partnership, a nationwide faculty consortium that aims to provide undergraduates with a research experience in genomics through a scheduled course (a classroom-based undergraduate research experience, or CURE). We examine the common barriers encountered in implementing a CURE, program elements of most value to faculty, ways in which a shared core support system can help, and the incentives for and rewards of establishing a CURE on our diverse campuses. While some of the barriers and rewards are specific to a research project utilizing a genomics approach, other lessons learned should be broadly applicable. We find that a central system that supports a shared investigation can mitigate some shortfalls in campus infrastructure (such as time for new curriculum development, availability of IT services) and provides collegial support for change. Our findings should be useful for designing similar supportive programs to facilitate change in the way we teach science for undergraduates.
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http://dx.doi.org/10.1187/cbe.13-10-0200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4255357PMC
August 2015

A course-based research experience: how benefits change with increased investment in instructional time.

CBE Life Sci Educ 2014 ;13(1):111-30

Department of Biology, Washington University in St. Louis, St. Louis, MO 63130 Department of Computer Science and Engineering, Washington University in St. Louis, St. Louis, MO 63130 Department of Biological and Environmental Sciences, Longwood University, Farmville, VA 23909 Chemistry Department, Lindenwood University, St. Charles, MO 63301 Science Department, Cabrini College, Radnor, PA 19087 Department of Chemistry and Biochemistry, California Polytechnic State University, San Luis Obispo, CA 93405 Department of Biology, Linfield College, McMinnville, OR 97128 Department of Biology, Georgetown University, Washington, DC 20057 Biology Department, Hampden-Sydney College, Hampden-Sydney, VA 23943 Department of Biochemistry, University of Nebraska-Lincoln, Lincoln, NE 68588 Biology Department, Worcester State University, Worcester, MA 01602 Department of Biological Sciences, St. John's University, Queens, NY 11439 Department of Biology, Adams State University, Alamosa, CO 81101 Department of Computer Science & Engineering, Johnson C. Smith University, Charlotte, NC 28216 Department of Biology, Saint Joseph's University, Philadelphia, PA 19131 Departments of Biomedical Sciences & Cell and Molecular Biology, Grand Valley State, Allendale, MI 49401 Department of Biology, Saint Mary's College of California, Moraga, CA 94556 Department of Biology, University of West Florida, Pensacola, FL 32514 Technology Leadership & Innovation Department, Purdue University, West Lafayette, IN 47907 Department of Biology, Calvin College, Grand Rapids, MI 49546 Department of Biology, Hofstra University, Hempstead, NY 11549 Department of Biology & Molecular Biology, Montclair State University, Montclair, NJ 07043 Department of Biology, Missouri Western State University, St. Joseph, MO 64507 Department of Biology, University of the Cumberlands, Williamsburg, KY 40769 Department of Biology, Amherst College, Amherst, MA 01002 Department of Biological Sciences, Mount Holyoke, South Hadley, MA

There is widespread agreement that science, technology, engineering, and mathematics programs should provide undergraduates with research experience. Practical issues and limited resources, however, make this a challenge. We have developed a bioinformatics project that provides a course-based research experience for students at a diverse group of schools and offers the opportunity to tailor this experience to local curriculum and institution-specific student needs. We assessed both attitude and knowledge gains, looking for insights into how students respond given this wide range of curricular and institutional variables. While different approaches all appear to result in learning gains, we find that a significant investment of course time is required to enable students to show gains commensurate to a summer research experience. An alumni survey revealed that time spent on a research project is also a significant factor in the value former students assign to the experience one or more years later. We conclude: 1) implementation of a bioinformatics project within the biology curriculum provides a mechanism for successfully engaging large numbers of students in undergraduate research; 2) benefits to students are achievable at a wide variety of academic institutions; and 3) successful implementation of course-based research experiences requires significant investment of instructional time for students to gain full benefit.
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http://dx.doi.org/10.1187/cbe-13-08-0152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3940452PMC
October 2014

Novel therapeutic potential in targeting microtubules by nanoparticle albumin-bound paclitaxel in hepatocellular carcinoma.

Int J Oncol 2011 Mar 14;38(3):721-31. Epub 2011 Jan 14.

Department of Clinical Oncology, Chinese University of Hong Kong, Shatin, Hong Kong, People's Republic of China.

Hepatocellular carcinoma (HCC) shows low response to most conventional chemotherapies. To facilitate target identification for novel therapeutic development, we deployed gene expression profiling on 43 paired HCC tumors and adjacent non-tumoral liver, which is also considered as the pre-malignant liver lesion. In conjunction with ontology analysis, a major functional process found to play a role in the malignant transformation of HCC was microtubule-related cellular assembly. We further examined the potential use of microtubule targeting taxane drugs, including paclitaxel and docetaxel, and compared with findings to results from doxorubicin, a common chemotherapeutic agent used in HCC. Recent studies showed that drug delivery by nanoparticles have enhanced efficacy with reduced side effects. In this regard, the nanoparticle albumin-bound (nab)-paclitaxel was also examined. In a panel of HCC cell lines studied, a high sensitivity towards taxane drugs was generally found, although the effect from nab-paclitaxel was most profound. The nab-paclitaxel showed an effective IC50 dose at 15-fold lower than paclitaxel alone or the derivative analogue docetaxel, and ~450-fold less compared to doxorubicin. Flow cytometric analysis confirmed a cell cycle blockade at the G2/M phase and increased apoptosis following nab-paclitaxel treatment. In vivo animal studies also showed that nab-paclitaxel readily inhibited xenograft growth with less toxicity to host cells compared to other anti-microtubule drugs and doxorubicin. Gene silencing of the microtubule regulatory gene STMN1 by RNAi suggested a distinct synergistic effect in the combined treatment with nab-paclitaxel. Our findings in this study highly suggest that the microtubule assembly represents a promising therapeutic target development in HCC.
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http://dx.doi.org/10.3892/ijo.2011.902DOI Listing
March 2011

Phosphorylation of Caldesmon by PFTAIRE1 kinase promotes actin binding and formation of stress fibers.

Mol Cell Biochem 2011 Apr 24;350(1-2):201-6. Epub 2010 Dec 24.

Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, Chinese University of Hong Kong, Shatin, N. T, Hong Kong, China.

Caldesmon (CaD) is an actin-binding protein that is capable of stabilizing actin filaments. Phosphorylation of CaD is widely accepted in the actin cytoskeletal modeling and promotion of cell migration. In this study, we show that CaD is a downstream phosphorylation substrate of PFTK1, a novel Cdc-2-related ser/thr protein kinase. Our study stemmed from an earlier investigation where we demonstrated that PFTK1 kinase conferred cell migratory advantages in human hepatocellular carcinoma (HCC) cells. Here, we showed that PFTK1-knockdown cells exhibited much reduced CaD phosphorylation and consequently caused dissociation of CaD from the F-actin fibers. The cellular localization of CaD was also altered in the absence of PFTK1. Immunofluorescence analysis revealed that PFTK1-abrogated cells exhibited a diffused and blurred appearance of CaD localization, whereas intact co-localization with F-actins was apparent in PFTK1-expressing cells. Without the binding of CaD to actin, disappearance of actin stress fibers was also evident in PFTK1-abrogated cells. In addition, we found that CaD is also commonly up-regulated in HCC tumors when compared to adjacent non-malignant liver (P = 0.022). Taken together, our results highlight a novel biological cascade that involved the phosphorylation activation of CaD by PFTK1 kinase in promoting formation of actin stress fibers.
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http://dx.doi.org/10.1007/s11010-010-0699-8DOI Listing
April 2011

Discoloration of nail beds and skin from minocycline.

CMAJ 2011 Feb 22;183(2):224. Epub 2010 Nov 22.

Faculty of Medicine, University of Ottawa, Ottawa, Ont., Canada.

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http://dx.doi.org/10.1503/cmaj.091498DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3033929PMC
February 2011

Evolution of a distinct genomic domain in Drosophila: comparative analysis of the dot chromosome in Drosophila melanogaster and Drosophila virilis.

Genetics 2010 Aug 17;185(4):1519-34. Epub 2010 May 17.

Department of Biology, Washington University, St. Louis, Missouri 63130, USA.

The distal arm of the fourth ("dot") chromosome of Drosophila melanogaster is unusual in that it exhibits an amalgamation of heterochromatic properties (e.g., dense packaging, late replication) and euchromatic properties (e.g., gene density similar to euchromatic domains, replication during polytenization). To examine the evolution of this unusual domain, we undertook a comparative study by generating high-quality sequence data and manually curating gene models for the dot chromosome of D. virilis (Tucson strain 15010-1051.88). Our analysis shows that the dot chromosomes of D. melanogaster and D. virilis have higher repeat density, larger gene size, lower codon bias, and a higher rate of gene rearrangement compared to a reference euchromatic domain. Analysis of eight "wanderer" genes (present in a euchromatic chromosome arm in one species and on the dot chromosome in the other) shows that their characteristics are similar to other genes in the same domain, which suggests that these characteristics are features of the domain and are not required for these genes to function. Comparison of this strain of D. virilis with the strain sequenced by the Drosophila 12 Genomes Consortium (Tucson strain 15010-1051.87) indicates that most genes on the dot are under weak purifying selection. Collectively, despite the heterochromatin-like properties of this domain, genes on the dot evolve to maintain function while being responsive to changes in their local environment.
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http://dx.doi.org/10.1534/genetics.110.116129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2927774PMC
August 2010

Secretion and proteolysis of heterologous proteins fused to the Escherichia coli maltose binding protein in Pichia pastoris.

Protein Expr Purif 2010 Jul 15;72(1):113-24. Epub 2010 Mar 15.

Department of Chemistry, University of the Pacific, Stockton, CA 95211, USA.

The Escherichia coli maltose binding protein (MBP) has been utilized as a translational fusion partner to improve the expression of foreign proteins made in E. coli. When located N-terminal to its cargo protein, MBP increases the solubility of intracellular proteins and improves the export of secreted proteins in bacterial systems. We initially explored whether MBP would have the same effect in the methylotrophic yeast Pichia pastoris, a popular eukaryotic host for heterologous protein expression. When MBP was fused as an N-terminal partner to several C-terminal cargo proteins expressed in this yeast, proteolysis occurred between the two peptides, and MBP reached the extracellular region unattached to its cargo. However, in two of three instances, the cargo protein reached the extracellular region as well, and its initial attachment to MBP enhanced its secretion from the cell. Extensive mutagenesis of the spacer region between MBP and its C-terminal cargo protein could not inhibit the cleavage although it did cause changes in the protease target sites in the fusion proteins, as determined by mass spectrometry. Taken together, these results suggested that an uncharacterized P. pastoris protease attacked at different locations in the region C-terminal of the MBP domain, including the spacer and cargo regions, but the MBP domain could still act to enhance the secretion of certain cargo proteins.
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http://dx.doi.org/10.1016/j.pep.2010.03.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2860017PMC
July 2010

The genomics education partnership: successful integration of research into laboratory classes at a diverse group of undergraduate institutions.

CBE Life Sci Educ 2010 ;9(1):55-69

Department of Biology, Washington University in St. Louis, MO 63130, USA.

Genomics is not only essential for students to understand biology but also provides unprecedented opportunities for undergraduate research. The goal of the Genomics Education Partnership (GEP), a collaboration between a growing number of colleges and universities around the country and the Department of Biology and Genome Center of Washington University in St. Louis, is to provide such research opportunities. Using a versatile curriculum that has been adapted to many different class settings, GEP undergraduates undertake projects to bring draft-quality genomic sequence up to high quality and/or participate in the annotation of these sequences. GEP undergraduates have improved more than 2 million bases of draft genomic sequence from several species of Drosophila and have produced hundreds of gene models using evidence-based manual annotation. Students appreciate their ability to make a contribution to ongoing research, and report increased independence and a more active learning approach after participation in GEP projects. They show knowledge gains on pre- and postcourse quizzes about genes and genomes and in bioinformatic analysis. Participating faculty also report professional gains, increased access to genomics-related technology, and an overall positive experience. We have found that using a genomics research project as the core of a laboratory course is rewarding for both faculty and students.
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http://dx.doi.org/10.1187/09-11-0087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2830162PMC
May 2010

Lack of benefits for prevention of cardiovascular disease with aspirin therapy in type 2 diabetic patients--a longitudinal observational study.

Cardiovasc Diabetol 2009 Oct 30;8:57. Epub 2009 Oct 30.

Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, PR China.

Background: The risk-benefit ratio of aspirin therapy in prevention of cardiovascular disease (CVD) remains contentious, especially in type 2 diabetes. This study examined the benefit and harm of low-dose aspirin (daily dose < 300 mg) in patients with type 2 diabetes.

Methods: This is a longitudinal observational study with primary and secondary prevention cohorts based on history of CVD at enrollment. We compared the occurrence of primary composite (non-fatal myocardial infarction or stroke and vascular death) and secondary endpoints (upper GI bleeding and haemorrhagic stroke) between aspirin users and non-users between January 1995 and July 2005.

Results: Of the 6,454 patients (mean follow-up: median [IQR]: 4.7 [4.4] years), usage of aspirin was 18% (n = 1,034) in the primary prevention cohort (n = 5731) and 81% (n = 585) in the secondary prevention cohort (n = 723). After adjustment for covariates, in the primary prevention cohort, aspirin use was associated with a hazard-ratio of 2.07 (95% CI: 1.66, 2.59, p < 0.001) for primary endpoint. There was no difference in CVD event rate in the secondary prevention cohort. Overall, aspirin use was associated with a hazard-ratio of 2.2 (1.53, 3.15, p < 0.001) of GI bleeding and 1.71 (1.00, 2.95, p = 0.051) of haemorrhagic stroke. The absolute risk of aspirin-related GI bleeding was 10.7 events per 1,000 person-years of treatment.

Conclusion: In Chinese type 2 diabetic patients, low dose aspirin was associated with a paradoxical increase in CVD risk in primary prevention and did not confer benefits in secondary prevention. In addition, the risk of GI bleeding in aspirin users was rather high.
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http://dx.doi.org/10.1186/1475-2840-8-57DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2777137PMC
October 2009

Effects of structured versus usual care on renal endpoint in type 2 diabetes: the SURE study: a randomized multicenter translational study.

Diabetes Care 2009 Jun;32(6):977-82

Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China.

Objective: Multifaceted care has been shown to reduce mortality and complications in type 2 diabetes. We hypothesized that structured care would reduce renal complications in type 2 diabetes.

Research Design And Methods: A total of 205 Chinese type 2 diabetic patients from nine public hospitals who had plasma creatinine levels of 150-350 micromol/l were randomly assigned to receive structured care (n = 104) or usual care (n = 101) for 2 years. The structured care group was managed according to a prespecified protocol with the following treatment goals: blood pressure <130/80 mmHg, A1C <7%, LDL cholesterol <2.6 mmol/l, triglyceride <2 mmol/l, and persistent treatment with renin-angiotensin blockers. The primary end point was death and/or renal end point (creatinine >500 micromol/l or dialysis).

Results: Of these 205 patients (mean +/- SD age 65 +/- 7.2 years; disease duration 14 +/- 7.9 years), the structured care group achieved better control than the usual care group (diastolic blood pressure 68 +/- 12 vs. 71 +/- 12 mmHg, respectively, P = 0.02; A1C 7.3 +/- 1.3 vs. 8.0 +/- 1.6%, P < 0.01). After adjustment for age, sex, and study sites, the structured care (23.1%, n = 24) and usual care (23.8%, n = 24; NS) groups had similar end points, but more patients in the structured care group attained >or=3 treatment goals (61%, n = 63, vs. 28%, n = 28; P < 0.001). Patients who attained >or=3 treatment targets (n = 91) had reduced risk of the primary end point (14 vs. 34; relative risk 0.43 [95% CI 0.21-0.86] compared with that of those who attained
Conclusions: Attainment of multiple treatment targets reduced the renal end point and death in type 2 diabetes. In addition to protocol, audits and feedback are needed to improve outcomes.
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http://dx.doi.org/10.2337/dc08-1908DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2681013PMC
June 2009

An investigation of heterochromatin domains on the fourth chromosome of Drosophila melanogaster.

Genetics 2008 Mar 1;178(3):1177-91. Epub 2008 Feb 1.

Department of Biology, Washington University, St. Louis, Missouri 63130, USA.

The banded portion of Drosophila melanogaster chromosome 4 exhibits euchromatic and heterochromatic characteristics. Reminiscent of heterochromatin, it contains a high percentage of repetitive elements, does not undergo recombination, and exhibits high levels of HP1 and histone-3 lysine-9 dimethylation. However, in the distal 1.2 Mb, the gene density is typical of euchromatin, and this region is polytene in salivary gland nuclei. Using P-element reporters carrying a copy of hsp70-white, alternative chromatin packaging domains can be distinguished by the eye color phenotype. Mapping studies identified the repetitive element 1360 as a candidate for heterochromatin targeting in the fourth chromosome Hcf region. We report here two new screens using this reporter to look for additional heterochromatin target sites. We confirm that reporter elements within 10 kb of 1360 are usually packaged as heterochromatin; however, heterochromatin packaging occurs in the sv region in the absence of 1360. Analyses of the sequences adjacent to P-element reporters show no simple association between specific repeated elements and transgene expression phenotype on a whole chromosome level. The data require that heterochromatin formation as a whole depends on a more complex pattern of sequence organization rather than the presence of a single sequence element.
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http://dx.doi.org/10.1534/genetics.107.081828DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2278077PMC
March 2008

Effectiveness of telephone counselling by a pharmacist in reducing mortality in patients receiving polypharmacy: randomised controlled trial.

BMJ 2006 Sep 17;333(7567):522. Epub 2006 Aug 17.

Department of Medicine and Therapeutics, Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR.

Objective: To investigate the effects of compliance and periodic telephone counselling by a pharmacist on mortality in patients receiving polypharmacy.

Design: Two year randomised controlled trial.

Setting: Hospital medical clinic.

Participants: 502 of 1011 patients receiving five or more drugs for chronic disease found to be non-compliant at the screening visit were invited for randomisation to either the telephone counselling group (n = 219) or control group (n = 223) at enrollment 12-16 weeks later.

Main Outcome Measures: Primary outcome was all cause mortality in randomised patients. Associations between compliance and mortality in the entire cohort of 1011 patients were also examined. Patients were defined as compliant with a drug if they took 80-120% of the prescribed daily dose. To calculate a compliance score for the whole treatment regimen, the number of drugs that the patient was fully compliant with was divided by the total number of prescribed drugs and expressed as a percentage. Only patients who complied with all recommended drugs were considered compliant (100% score).

Results: 60 of the 502 eligible patients defaulted and only 442 patients were randomised. After two years, 31 (52%) of the defaulters had died, 38 (17%) of the control group had died, and 25 (11%) of the intervention group had died. After adjustment for confounders, telephone counselling was associated with a 41% reduction in the risk of death (relative risk 0.59, 95% confidence interval 0.35 to 0.97; P = 0.039). The number needed to treat to prevent one death at two years was 16. Other predictors included old age, living alone, rate of admission to hospital, compliance score, number of drugs for chronic disease, and non-treatment with lipid lowering drugs at screening visit. In the cohort of 1011 patients, the adjusted relative risk for death was 1.61 (1.05 to 2.48; P = 0.029) and 2.87 (1.80 to 2.57; P < 0.001) in patients with compliance scores of 34-66% and 0-33%, respectively, compared with those who had a compliance score of 67% or more.

Conclusion: In patients receiving polypharmacy, poor compliance was associated with increased mortality. Periodic telephone counselling by a pharmacist improved compliance and reduced mortality.

Trial Registration: International Standard Randomised Controlled Trial Number Register: SRCTN48076318.
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http://dx.doi.org/10.1136/bmj.38905.447118.2FDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1562472PMC
September 2006

Extrinsic context affects perceptual normalization of lexical tone.

J Acoust Soc Am 2006 Mar;119(3):1712-26

Department of Speech, Language and Hearing Sciences, Purdue University, Heavilon Hall, 500 Oval Drive, West Lafayette, Indiana 47907, USA.

The present study explores the use of extrinsic context in perceptual normalization for the purpose of identifying lexical tones in Cantonese. In each of four experiments, listeners were presented with a target word embedded in a semantically neutral sentential context. The target word was produced with a mid level tone and it was never modified throughout the study, but on any given trial the fundamental frequency of part or all of the context sentence was raised or lowered to varying degrees. The effect of perceptual normalization of tone was quantified as the proportion of non-mid level responses given in F0-shifted contexts. Results showed that listeners' tonal judgments (i) were proportional to the degree of frequency shift, (ii) were not affected by non-pitch-related differences in talker, (iii) and were affected by the frequency of both the preceding and following context, although (iv) following context affected tonal decisions more strongly than did preceding context. These findings suggest that perceptual normalization of lexical tone may involve a "moving window" or "running average" type of mechanism, that selectively weights more recent pitch information over older information, but does not depend on the perception of a single voice.
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http://dx.doi.org/10.1121/1.2149768DOI Listing
March 2006

Comparison of dot chromosome sequences from D. melanogaster and D. virilis reveals an enrichment of DNA transposon sequences in heterochromatic domains.

Genome Biol 2006 20;7(2):R15. Epub 2006 Feb 20.

Biology Department, Washington University, St Louis, MO 63130, USA.

Background: Chromosome four of Drosophila melanogaster, known as the dot chromosome, is largely heterochromatic, as shown by immunofluorescent staining with antibodies to heterochromatin protein 1 (HP1) and histone H3K9me. In contrast, the absence of HP1 and H3K9me from the dot chromosome in D. virilis suggests that this region is euchromatic. D. virilis diverged from D. melanogaster 40 to 60 million years ago.

Results: Here we describe finished sequencing and analysis of 11 fosmids hybridizing to the dot chromosome of D. virilis (372,650 base-pairs) and seven fosmids from major euchromatic chromosome arms (273,110 base-pairs). Most genes from the dot chromosome of D. melanogaster remain on the dot chromosome in D. virilis, but many inversions have occurred. The dot chromosomes of both species are similar to the major chromosome arms in gene density and coding density, but the dot chromosome genes of both species have larger introns. The D. virilis dot chromosome fosmids have a high repeat density (22.8%), similar to homologous regions of D. melanogaster (26.5%). There are, however, major differences in the representation of repetitive elements. Remnants of DNA transposons make up only 6.3% of the D. virilis dot chromosome fosmids, but 18.4% of the homologous regions from D. melanogaster; DINE-1 and 1360 elements are particularly enriched in D. melanogaster. Euchromatic domains on the major chromosomes in both species have very few DNA transposons (less than 0.4 %).

Conclusion: Combining these results with recent findings about RNAi, we suggest that specific repetitive elements, as well as density, play a role in determining higher-order chromatin packaging.
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http://dx.doi.org/10.1186/gb-2006-7-2-r15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1431729PMC
July 2006

Effects of structured care by a pharmacist-diabetes specialist team in patients with type 2 diabetic nephropathy.

Am J Med 2005 Dec;118(12):1414

Department of Medicine and Therapeutics, The Chinese University of Hong Kong, The Prince of Wales Hospital, Shatin, Hong Kong.

Purpose: We developed a disease management program for patients with Type 2 diabetic nephropathy and evaluated its effects on the time to onset of end-stage renal disease or all-cause death compared with usual care.

Methods: In a 2-year, prospective cohort study, we compared the clinical outcomes of patients managed by a structured care protocol (n = 80) to a group receiving usual care (n=80) in the same hospital. Patients aged < or =80 years with type 2 diabetes, serum creatinine 150-400 micromol/L, and micro- or macroalbuminuria were recruited. The structured care protocol was implemented by a pharmacist-diabetes specialist team with particular emphasis on periodic laboratory assessments, patient adherence, risk factors control, and use of renin-angiotensin system inhibitor. The primary endpoint was the composite of end-stage renal disease or all-cause death. Other endpoints were the rate of renal decline, processes-of-care measures, and control of risk factors.

Results: During 22.8+/-7.9 months of follow-up, the primary endpoint developed in 24 and 40 patients in the structured care and usual care groups, respectively (adjusted risk reduction, 60%, P< .001). Structured care (hazard ratio [95% confidence interval (CI)], 0.40 [0.23-0.68]), age (0.95 [0.93-0.98]), baseline systolic blood pressure (BP) (1.014 [1.003-1.026]), logarithm (base 10) of baseline serum creatinine (34 441 [2290-517915]), and macroalbuminuria (8.95 [1.22-65.38]) were independent predictors for the primary endpoint. Structured care slowed the rate of renal decline (P=.032). More intensive laboratory measurements, increased use of renin-angiotensin system inhibitor, and greater reductions in BP and low-density lipoprotein (LDL) cholesterol were reported by patients receiving structured care.

Conclusions: Structured care delivered by a pharmacist-diabetes specialist team reduced the incidence of end-stage renal disease or death compared with usual care in patients with type 2 diabetic nephropathy.
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http://dx.doi.org/10.1016/j.amjmed.2005.07.050DOI Listing
December 2005

The renoprotective effects of structured care in a clinical trial setting in type 2 diabetic patients with nephropathy.

Nephrol Dial Transplant 2004 Oct 27;19(10):2519-25. Epub 2004 Jul 27.

Department of Medicine and Therapeutics, The Chinese University of Hong Kong, The Prince of Wales Hospital, Shatin, N.T., Hong Kong, SAR.

Background: The RENAAL Study has confirmed the renoprotective effects of Losartan in type 2 diabetes. In this subgroup analysis from the RENAAL Study, we hypothesized that the intensive care received by patients in a clinical trial setting also reduced the rate of decline in renal function through optimization of all risk factors.

Methods: We compared the rate of deterioration in renal function, expressed as the regression coefficient of the monthly serum creatinine (SeCr) reciprocal (beta-1/Cr) in 55 Chinese type 2 diabetic patients before and after entry into the RENAAL Study.

Results: Of the 55 patients, 44 had at least three out-patient SeCr measurements both before (2.9+/-2.4 years) and after (3.3+/-0.8 years) entry into the study for evaluation. In the Losartan group (n = 24), the median beta-1/Cr fell from -11.4 x 10(-5) l micro mol(-1) month(-1) before entry into the trial to -4.7 x 10(-5) l micro mol(-1) month(-1) following entry (P = 0.001). The respective figures were -9.1 x 10(-5) and -5.0 x 10(-5) l micro mol(-1) month(-1) (P = 0.01) in the placebo group (n = 20). A decrease in beta-1/Cr was observed in 21 (87.5%) and 14 (70.0%) patients in the Losartan and placebo groups, respectively. Spot urinary albumin-to-creatinine ratio was reduced by 56% (P = 0.001) in the Losartan group but the change was not significant in the placebo group. At the end of the study, patients in both groups had lower blood pressure and better lipid control. The frequency of patient visits to doctors and nurses were doubled.

Conclusions: The rate of renal function decline was significantly reduced in the majority of patients allocated to either Losartan or placebo following entry into the RENAAL study. These results suggest that in patients with diabetic nephropathy, implementation of a structured care protocol in a clinical trial setting facilities intensive treatment of risk factors confering renoprotective effects in addition to those resulting from Losartan treatment.
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http://dx.doi.org/10.1093/ndt/gfh408DOI Listing
October 2004
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