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1.  Predictive value of vascular endothelial growth factor polymorphisms on the clinical outcome of renal cell carcinoma patients 
Oncology Letters  2014;9(2):651-656.
A cohort study was conducted to investigate the association between vascular endothelial growth factor (VEGF) polymorphisms −2578C/A, −1154G/A and −634C/G and the clinical outcome of renal cell carcinoma (RCC), as well as the interaction of VEGF polymorphisms with tumor stage, metastasis and size. A total of 310 RCC patients were recruited from the First Affiliated Hospital of Zhengzhou University (Zhengzhou, China) between January 2006 and December 2007, and were followed up until December 2012. The association between the three single nucleotide polymorphisms and the overall survival of RCC patients was estimated using Cox’s proportional hazard regression model. The median follow-up duration was 34.7 months and 74 of the RCC patients succumbed due to cancer during the follow-up period. The frequency of the VEGF −2578 AA genotype was significantly higher in patients classed as tumor stages III–IV (odds ratio [OR], 0.47; 95% confidence interval [CI], 0.24–0.95) and larger tumors (longest diameter, >4 cm; OR, 0.44; 95% CI, 0.22–0.89). Furthermore, the frequency of VEGF −634 GG was significantly higher in patients with larger tumors (longest diameter, >4 cm; OR, 0.68; 95% CI, 0.48–0.97). The VEGF −2578 AA genotype was correlated with a 2.96-fold increase in the risk of RCC-associated mortality and was associated with a five-year survival rate of ~25%. Therefore, the present study identified that the VEGF −2578C/A polymorphism may be associated with the prognosis of RCC patients, and may interact with the tumor stage and size.
doi:10.3892/ol.2014.2798
PMCID: PMC4301497  PMID: 25621033
renal cell carcinomas; vascular endothelial growth factor; clinical outcome; polymorphism
2.  Oral Health Education for Pediatric Nurse Practitioner Students 
Journal of dental education  2013;77(5):581-590.
The aim of this study was to evaluate whether an interdisciplinary, multifaceted oral health education program delivered to pediatric nurse practitioner students at the University of California, San Francisco, would improve their knowledge, confidence, attitudes, and behaviors regarding the provision of oral health assessments, consultations, referrals, and services to young children during well-child visits. Thirty pediatric nurse practitioner students were included in the study. Participants completed a written survey before and after receiving an interdisciplinary educational intervention that included didactic education, simulation exercises, and clinical observation by a pediatric dental resident. Between pre-intervention and post-intervention, a significant improvement was seen in the pediatric nurse practitioners’ knowledge of oral health topics (p<0.001), confidence when providing oral health counseling (p<0.001), and attitudes about including oral health counseling in their examinations (p=0.006). In the post-intervention survey, 83 percent of the subjects reported having incorporated oral examinations into their well-child visits. Our study suggests that providing an interdisciplinary oral health educational program for pediatric nurse practitioner students can improve their knowledge, confidence, attitudes, and behaviors regarding the incorporation of oral health care services during routine well-child visits.
PMCID: PMC4259151  PMID: 23658403
oral health education; pediatric nurse practitioner students; interdisciplinary education; interprofessional education; well-child visits
3.  KCNJ10 May Not Be a Contributor to Nonsyndromic Enlargement of Vestibular Aqueduct (NSEVA) in Chinese Subjects 
PLoS ONE  2014;9(11):e108134.
Background
Nonsyndromic enlargement of vestibular aqueduct (NSEVA) is an autosomal recessive hearing loss disorder that is associated with mutations in SLC26A4. However, not all patients with NSEVA carry biallelic mutations in SLC26A4. A recent study proposed that single mutations in both SLC26A4 and KCNJ10 lead to digenic NSEVA. We examined whether KCNJ10 excert a role in the pathogenesis of NSEVA in Chinese patients.
Methods
SLC26A4 was sequenced in 1056 Chinese patients with NSEVA. KCNJ10 was screened in 131 patients who lacked mutations in either one or both alleles of SLC26A4. Additionally, KCNJ10 was screened in 840 controls, including 563 patients diagnosed with NSEVA who carried biallelic SLC26A4 mutations, 48 patients with nonsyndromic hearing loss due to inner ear malformations that did not involve enlargement of the vestibular aqueduct (EVA), 96 patients with conductive hearing loss due to various causes, and 133 normal-hearing individuals with no family history of hereditary hearing loss.
Results
925 NSEVA patients were found carrying two-allele pathogenic SLC26A4 mutations. The most frequently detected KCNJ10 mutation was c.812G>A (p.R271H). Compared with the normal-hearing control subjects, the occurrence rate of c.812G>A in NSEVA patients with lacking mutations in one or both alleles of SLC26A4 had no significant difference(1.53% vs. 5.30%, χ2 = 2.798, p = 0.172), which suggested that it is probably a nonpathogenic benign variant. KCNJ10 c.1042C>T (p.R348C), the reported EVA-related mutation, was not found in patients with NSEVA who lacked mutations in either one or both alleles of SLC26A4. Furthermore, the normal-hearing parents of patients with NSEVA having two SLC26A4 mutations carried the KCNJ10 c.1042C>T or c.812G>A mutation and a SLC26A4 pathogenic mutation.
Conclusion
SLC26A4 is the major genetic cause in Chinese NSEVA patients, accounting for 87.59%. KCNJ10 may not be a contributor to NSEVA in Chinese population. Other genetic or environmental factors are possibly play a role in the etiology of Chinese EVA patients with zero or monoallelic SLC26A4 mutation.
doi:10.1371/journal.pone.0108134
PMCID: PMC4220913  PMID: 25372295
4.  Systematic profiling of mRNA and miRNA expression in the pancreatic islets of spontaneously diabetic Goto-Kakizaki rats 
Molecular Medicine Reports  2014;11(1):67-74.
Type 2 diabetes (T2DM) is a complex multifactorial metabolic disorder that affects >100 million individuals worldwide, yet the mechanisms involved in the development and progression of the disease have not yet been fully elucidated. The present study examined the mRNA and micro (mi)RNA expression profiles by microarray analysis in the pancreas islets of spontaneously diabetic Goto-Kakizaki rats with the aim to identify regulatory mechanisms underlying the pathogenesis of T2DM. A total of 9 upregulated and 10 downregulated miRNAs were identified, including miR-150, miR-497, miR-344-3p and let-7f, which were independently validated by quantitative polymerase chain reaction assays. In addition, differential expression of 670 genes was detected by mRNA microarray analysis, including 370 upregulated and 247 downregulated genes. The differentially expressed genes were statistically associated with major cellular pathways, including the immune response pathway and the extracellular matrix (ECM)-receptor interaction pathway. Finally, a reverse regulatory association of differentially expressed miRNAs and their predicted target genes was constructed, supported by analysis of their mRNA and miRNA expression profiles. A number of key pairs of miRNA-mRNA was proposed to have significant roles in the pathogenesis of T2DM rats based on bioinformatics analysis, one example being the let-7f/collagen, type II, alpha 1 pair that may regulate ECM-receptor interactions.
doi:10.3892/mmr.2014.2723
PMCID: PMC4237099  PMID: 25333294
type 2 diabetes; gene expression array; microRNA microarray; microRNA-mRNA regulatory correlation
5.  Effects of zedoary turmeric oil on P450 activities in rats with liver cirrhosis induced by thioacetamide 
The aim of this study was to elucidate the effects of zedoary turmeric oil (ZTO) on P450 activities (CYP1A2, CYP2C9, CYP2C19, CYP2B6, CYP2D6 and CYP3A4) in rats with liver cirrhosis induced by thioacetamide (TAA). For the induction of liver cirrhosis, rats were given TAA in their drinking water at a concentration of 0.03% for consecutive 5 weeks and then 0.04% for the next consecutive 5 weeks throughout the establishment of cirrhosis. Then the cirrhotic rats were ip given saline, ZTO 100, 200 and 400 mg/kg, respectively, once daily for 2 weeks. When cirrhosis model was established at week 10, all rats of five groups were administered intragastrically with 15 mg/kg phenacetin, 0.6 mg/kg tolbutamide, 15 mg/kg omeprazole, 15 mg/kg bupropion, 15 mg/kg metoprolol, and 10 mg/kg midazolam. Blood samples were collected at a series of time-points and the concentrations of probe drugs in plasma were determined by HPLC-MS/MS. The degree of liver cirrhosis was assessed by HE staining. The serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) from the model group increased by approximately 4-fold, and a decreased level of albumin (Alb) was also observed, as compared to the control group (P < 0.05). However, ZTO was found to reverse those changes of serum levels observed in the model group, and the 200 mg/kg ZTO treatment group showed the most obvious reverse tendency with significantly decreased ALT, AST and increased Alb levels (P < 0.05). The results indicated that ZTO with the dose of 100 mg/kg could inhibit the activities of CYP450 isoforms CYP2C9 and CYP2D6 in vivo in cirrhotic rats induced by TAA, while ZTO with the dose of 400 mg/kg could induce the activity of CYP2C19 in vivo in cirrhotic rats induced by TAA. However, ZTO showed no influence on cirrhotic rat hepatic CYP1A2, CYP2B6 and CYP3A4 activity in vivo. This has certain guiding significance to clinical treatment.
PMCID: PMC4270516  PMID: 25550825
Zedoary turmeric oil; CYP450; liver cirrhosis; rat; thioacetamide
6.  Diet Type and Changes in Food Cravings following Weight Loss: Findings from the POUNDS LOST Trial 
Eating and weight disorders : EWD  2012;17(2):e101-e108.
Few well-controlled trials have evaluated the effects that macronutrient composition has on changes in food cravings during weight loss treatment. The present study, which was part of the POUNDS LOST trial, investigated whether the fat and protein content of four different diets affected changes in specific food cravings in overweight and obese adults. A sample of 811 adults were recruited across two clinical sites, and each participant was randomly assigned to one of four macronutrient prescriptions: (1) Low fat (20% of energy), average protein (15% of energy); (2) Moderate fat (40%), average protein (15%); (3) Low fat (20%), high protein (25%); (4) Moderate fat (40%), high protein (25%). With few exceptions, the type of diet that participants were assigned did not differentially affect changes in specific food cravings. Participants assigned to the high fat diets, however, had reduced cravings for carbohydrates at Month12 (p< .05) and fruits and vegetables at Month 24. Also, participants assigned to high protein diets had increased cravings for sweets at Month 6 (p< .05). Participants in all four dietary conditions reported significant reductions in food cravings for specific types of foods (i.e., high fat foods, fast food fats, sweets, and carbohydrates/starches; all ps< .05). Cravings for fruits and vegetables, however, were increased at Month 24 (p< .05). Calorically restricted diets (regardless of their macronutrient composition) yielded significant reductions in cravings for fats, sweets, and starches whereas cravings for fruits and vegetables were increased.
PMCID: PMC4189179  PMID: 23010779
Macronutrient composition; Caloric restriction; Food type; Fat; Carbohydrate; Protein
7.  An Efficient Genotyping Method for Genome-modified Animals and Human Cells Generated with CRISPR/Cas9 System 
Scientific Reports  2014;4:6420.
The rapid generation of various species and strains of laboratory animals using CRISPR/Cas9 technology has dramatically accelerated the interrogation of gene function in vivo. So far, the dominant approach for genotyping of genome-modified animals has been the T7E1 endonuclease cleavage assay. Here, we present a polyacrylamide gel electrophoresis-based (PAGE) method to genotype mice harboring different types of indel mutations. We developed 6 strains of genome-modified mice using CRISPR/Cas9 system, and utilized this approach to genotype mice from F0 to F2 generation, which included single and multiplexed genome-modified mice. We also determined the maximal detection sensitivity for detecting mosaic DNA using PAGE-based assay as 0.5%. We further applied PAGE-based genotyping approach to detect CRISPR/Cas9-mediated on- and off-target effect in human 293T and induced pluripotent stem cells (iPSCs). Thus, PAGE-based genotyping approach meets the rapidly increasing demand for genotyping of the fast-growing number of genome-modified animals and human cell lines created using CRISPR/Cas9 system or other nuclease systems such as TALEN or ZFN.
doi:10.1038/srep06420
PMCID: PMC4168274  PMID: 25236476
8.  Urinary interleukin-18 as an early indicator to predict contrast-induced nephropathy in patients undergoing percutaneous coronary intervention 
Contrast-induced nephropathy (CIN) is at present the third leading cause of hospital-acquired acute kidney injury (AKI). Traditionally, it is diagnosed by measuring an increase of the serum creatinine (SCr) concentration. However, SCr is an insensitive marker for detecting CIN. This study was designed to investigate whether human urinary interleukin-18 (IL-18) is early predictive marker for CIN following coronary interventional procedures. The general clinical data of 180 patients who underwent coronary interventional procedures at the Department of Cardiology, Affiliated Hospital of Xuzhou Medical College from March 1, 2012 to September 31, 2012 were collected. A nonionic, low osmolality contrast agent was used in the laboratory at this time. SCr values and estimated glomerular filtration rate (eGFR) were measured prior to and within 24 and 48 h after the administration of contrast agents. Urine samples were collected prior to and 2, 6, 12, 24 and 48 h after the coronary interventional procedure, and urinary IL-18 levels were measured using an ELISA kit. CIN was defined as an increase of ≥0.5 mg/dl or ≥25% in SCr concentration over baseline 24–48 h after the procedure. CIN occurred in 16 of 180 (8.9%) patients. The levels of urinary IL-18 measured 2 h after the procedure were increased in the CIN group, but the increase was not significant (P>0.05). There were significant differences (P<0.05) between the urinary IL-18 levels 6, 12, 24 and 48 h after the procedure and those before the procedure. No significant difference was identified between the SCr levels measured prior to and 24 h after the procedure. The area under the receiver operating characteristic (ROC) curve of urinary IL-18 12 h after the procedure was 0.811 and the 95% confidence interval of the area under the curve was 0.735–0.888. If the critical point of the diagnosis of CIN was 815.61 pg/ml, the sensitivity was 87.5% and the specificity was 62.2%. Univariate analysis indicated that the urinary IL-18 level was positively correlated with the SCr concentration pre- and postprocedure. In conclusion, urinary IL-18 may be a promising indicator for the early prediction of CIN.
doi:10.3892/etm.2014.1898
PMCID: PMC4151647  PMID: 25187836
interleukin-18; coronary artery angiography; contrast-induced nephropathy
9.  Regulation of NF-κB induction by TCR/CD28 
Immunologic research  2011;50(0):113-117.
NF-κB family transcription factors are a common downstream target for inducible transcription mediated by many different cell-surface receptors, especially those receptors involved in inflammation and adaptive immunity. It is now clear that different classes of receptors employ different proximal signaling strategies to activate the common NF-jB signaling components, such as the IKK complex. For antigen receptors expressed by T and B cells, this pathway requires a complex of proteins including the proteins Carma1, Bcl10, and Malt1. Here, we discuss some of what is known about regulation of these proteins downstream of TCR/CD3 and co-stimulatory CD28 signaling. We also discuss another unique aspect of TCR-mediated NF-κB activation, i.e., the spatial restriction imposed on signaling events by the formation of the immunological synapse between a T cell and antigen-presenting cell presenting specific peptide/MHC.
doi:10.1007/s12026-011-8216-z
PMCID: PMC4066383  PMID: 21717079
T cells; NF-κB; Signal transduction
10.  Decreased LINE-1 methylation levels in aldosterone-producing adenoma 
Purpose: Abnormal global DNA methylation levels are associated with many diseases. In this study, we examined long interspersed nuclear elements-1 (LINE-1) methylation as a biomarker for abnormal global DNA methylation and aldosterone-producing adenoma (APA). Methods: Tissues from 25 APA and 6 normal adrenal glands (NAs) were analyzed for LINE-1 methylation by real-time methylation-specific polymerase chain reaction. The estimated LINE-1 methylation level was then tested for correlation with the clinicopathologic parameters of APA patients. Results: The methylation index (MI) level for LINE-1 was 0.91 in NA samples and 0.77 in APA samples (P < 0.001). For the APA samples, there were no statistical correlations between the MI level and various clinicopathologic parameters such as gender (P = 0.07). Conclusion : LINE-1 methylation is significantly lower in APA samples than in NA samples. LINE-1 methylation is not correlated with the clinical characteristics of APA.
PMCID: PMC4129024  PMID: 25120789
Long interspersed nuclear elements-1; global DNA methylation; aldosterone-producing adenoma
11.  The ARL2 GTPase Is Required for Mitochondrial Morphology, Motility, and Maintenance of ATP Levels 
PLoS ONE  2014;9(6):e99270.
ARF-like 2 (ARL2) is a member of the ARF family and RAS superfamily of regulatory GTPases, predicted to be present in the last eukaryotic common ancestor, and essential in a number of model genetic systems. Though best studied as a regulator of tubulin folding, we previously demonstrated that ARL2 partially localizes to mitochondria. Here, we show that ARL2 is essential to a number of mitochondrial functions, including mitochondrial morphology, motility, and maintenance of ATP levels. We compare phenotypes resulting from ARL2 depletion and expression of dominant negative mutants and use these to demonstrate that the mitochondrial roles of ARL2 are distinct from its roles in tubulin folding. Testing of current models for ARL2 actions at mitochondria failed to support them. Rather, we found that knockdown of the ARL2 GTPase activating protein (GAP) ELMOD2 phenocopies two of three phenotypes of ARL2 siRNA, making it a likely effector for these actions. These results add new layers of complexity to ARL2 signaling, highlighting the need to deconvolve these different cell functions. We hypothesize that ARL2 plays essential roles inside mitochondria along with other cellular functions, at least in part to provide coupling of regulation between these essential cell processes.
doi:10.1371/journal.pone.0099270
PMCID: PMC4050054  PMID: 24911211
12.  A Smart Web Aid for Preventing Diabetes in Rural China: Preliminary Findings and Lessons 
Background
Increasing cases of diabetes, a general lack of routinely operational prevention, and a long history of separating disease prevention and treatment call for immediate engagement of frontier clinicians. This applies especially to village doctors who work in rural China where the majority of the nation’s vast population lives.
Objective
This study aims to develop and test an online Smart Web Aid for Preventing Type 2 Diabetes (SWAP-DM2) capable of addressing major barriers to applying proven interventions and integrating diabetes prevention into routine medical care.
Methods
Development of SWAP-DM2 used evolutionary prototyping. The design of the initial system was followed by refinement cycles featuring dynamic interaction between development of practical and effective standardized operation procedures (SOPs) for diabetes prevention and Web-based assistance for implementing the SOPs. The resulting SOPs incorporated proven diabetes prevention practices in a synergetic way. SWAP-DM2 provided support to village doctors ranging from simple educational webpages and record maintenance to relatively sophisticated risk scoring and personalized counseling. Evaluation of SWAP-DM2 used data collected at baseline and 6-month follow-up assessment: (1) audio recordings of service encounters; (2) structured exit surveys of patients’ knowledge, self-efficacy, and satisfaction; (3) measurement of fasting glucose, body mass index, and blood pressure; and (4) qualitative interviews with doctors and patients. Data analysis included (1) descriptive statistics of patients who received SWAP-DM2–assisted prevention and those newly diagnosed with prediabetes and diabetes; (2) comparison of the variables assessed between baseline and follow-up assessment; and (3) narratives of qualitative data.
Results
The 17 participating village doctors identified 2219 patients with elevated diabetes risk. Of these, 84.85% (1885/2219) consented to a fasting glucose test with 1022 new prediabetes and 113 new diabetes diagnoses made within 6 months. The prediabetic patients showed substantial improvement from baseline to 6-month follow-up in vegetable intake (17.0%, 43/253 vs 88.7%, 205/231), calorie intake (1.6%, 4/253 vs 71.4%, 165/231), leisure-time exercises (6.3%, 16/253 vs 21.2%, 49/231), body weight (mean 62.12 kg, SD 9.85 vs mean 58.33 kg, SD 9.18), and body mass index (mean 24.80 kg/m2, SD 3.21 vs mean 23.36 kg/m2, SD 2.95). The prediabetic patients showed improvement in self-efficacy for modifying diet (mean 5.31, SD 2.81 vs mean 8.53, SD 2.25), increasing physical activities (mean 4.52, SD 3.35 vs mean 8.06, SD 2.38), engaging relatives (mean 3.93, SD 3.54 vs mean 6.93, SD 2.67), and knowledge about diabetes and risks of an imbalanced diet and inadequate physical activity. Most participating doctors and patients viewed SWAP-DM2 as useful and effective.
Conclusions
SWAP-DM2 is helpful to village doctors, acceptable to patients, and effective in modifying immediate determinants of diabetes at least in the short term, and may provide a useful solution to the general lack of participation in diabetes prevention by frontier clinicians in rural China.
Trial Registration
International Standard Randomized Controlled Trial Number (ISRCTN): 66772711; http://www.controlled-trials.com/ISRCTN66772711 (Archived by WebCite at http://www.webcitation.org/6OMkAqyEy).
doi:10.2196/jmir.3228
PMCID: PMC4004141  PMID: 24691410
diabetes mellitus; prediabetic state; Internet; prevention; evaluation; eHealth
13.  Selective Inhibition of PI3K/Akt/mTOR Signaling Pathway Regulates Autophagy of Macrophage and Vulnerability of Atherosclerotic Plaque 
PLoS ONE  2014;9(3):e90563.
Macrophage infiltration contributes to the instability of atherosclerotic plaques. In the present study, we investigated whether selective inhibition of PI3K/Akt/mTOR signaling pathway can enhance the stability of atherosclerotic plaques by activation of macrophage autophagy. In vitro study, selective inhibitors or siRNA of PI3K/Akt/mTOR pathways were used to treat the rabbit's peritoneal primary macrophage cells. Inflammation related cytokines secreted by macrophages were measured. Ultrastructure changes of macrophages were examined by transmission electron microscope. mRNA or protein expression levels of autophagy related gene Beclin 1, protein 1 light chain 3 II dots (LC3-II) or Atg5-Atg12 conjugation were assayed by quantitative RT-PCR or Western blot. In vivo study, vulnerable plaque models were established in 40 New Zealand White rabbits and then drugs or siRNA were given for 8 weeks to inhibit the PI3K/Akt/mTOR signaling pathway. Intravascular ultrasound (IVUS) was performed to observe the plaque imaging. The ultrastructure of the abdominal aortic atherosclerosis lesions were analyzed with histopathology. RT-PCR or Western blot methods were used to measure the expression levels of corresponding autophagy related molecules. We found that macrophage autophagy was induced in the presence of Akt inhibitor, mTOR inhibitor and mTOR-siRNA in vitro study, while PI3K inhibitor had the opposite role. In vivo study, we found that macrophage autophagy increased significantly and the rabbits had lower plaque rupture incidence, lower plaque burden and decreased vulnerability index in the inhibitors or siRNA treated groups. We made a conclusion that selective inhibition of the Akt/mTOR signal pathway can reduce macrophages and stabilize the vulnerable atherosclerotic plaques by promoting macrophage autophagy.
doi:10.1371/journal.pone.0090563
PMCID: PMC3944201  PMID: 24599185
14.  Genome-wide association study in Han Chinese identifies four new susceptibility loci for coronary artery disease 
Nature genetics  2012;44(8):890-894.
We performed a meta-analysis of 2 genome-wide association studies of coronary artery disease comprising 1,515 cases with coronary artery disease and 5,019 controls, followed by de novo replication studies in 15,460 cases and 11,472 controls, all of Chinese Han descent. We successfully identified four new loci for coronary artery disease reaching genome-wide significance (P < 5 × 10−8), which mapped in or near TTC32-WDR35, GUCY1A3, C6orf10-BTNL2 and ATP2B1. We also replicated four loci previously identified in European populations (PHACTR1, TCF21, CDKN2A/B and C12orf51). These findings provide new insights into biological pathways for the susceptibility of coronary artery disease in Chinese Han population.
doi:10.1038/ng.2337
PMCID: PMC3927410  PMID: 22751097
15.  A new mutation in the CSB gene in a Chinese patient with mild Cockayne syndrome 
Clinical Case Reports  2014;2(2):33-36.
Key Clinical Message
Cockayne syndrome (CS) is a rare autosomal recessive genetic disease characterized by growth failure and progressive neurological degeneration. Here we report a mild form of CS patient who was homozygous for the C526T transition resulting in a new nonsense mutation, which converts Arg176 to a stop codon.
doi:10.1002/ccr3.47
PMCID: PMC4184625  PMID: 25356239
Cockayne syndrome; CSB gene; mutation
16.  Case Definition and Design Sensitivity 
In a case-referent study, cases of disease are compared to non-cases with respect to their antecedent exposure to a treatment in an effort to determine whether exposure causes some cases of the disease. Because exposure is not randomly assigned in the population, as it would be if the population were a vast randomized trial, exposed and unexposed subjects may differ prior to exposure with respect to covariates that may or may not have been measured. After controlling for measured pre-exposure differences, for instance by matching, a sensitivity analysis asks about the magnitude of bias from unmeasured covariates that would need to be present to alter the conclusions of a study that presumed matching for observed covariates removes all bias. The definition of a case of disease affects sensitivity to unmeasured bias. We explore this issue using: (i) an asymptotic tool, the design sensitivity, (ii) a simulation for finite samples, and (iii) an example. Under favorable circumstances, a narrower case definition can yield an increase in the design sensitivity, and hence an increase in the power of a sensitivity analysis. Also, we discuss an adaptive method that seeks to discover the best case definition from the data at hand while controlling for multiple testing. An implementation in R is available as SensitivityCaseControl.
doi:10.1080/01621459.2013.820660
PMCID: PMC3904399  PMID: 24482549
Case-control study; matching; observational study; sensitivity analysis
17.  Design and Statistical Analyses of Oral Medicine Studies:Common Pitfalls 
Oral diseases  2009;16(3):10.1111/j.1601-0825.2009.01634.x.
A growing number of articles are emerging in the medical and statistics literature that describe epidemiological and statistical flaws of research studies. Many examples of these deficiencies are encountered in the oral, craniofacial and dental literature. However, only a handful of methodological articles have been published in the oral literature warning investigators of potential errors that may arise early in the study and that can irreparably bias the final results.
In this paper we briefly review some of the most common pitfalls that our team of epidemiologists and statisticians has identified during the review of submitted or published manuscripts and research grant applications. We use practical examples from the oral medicine and dental literature to illustrate potential shortcomings in the design and analyses of research studies, and how these deficiencies may affect the results and their interpretation.
A good study design is essential, because errors in the analyses can be corrected if the design was sound, but flaws in study design can lead to data that are not salvageable. We recommend consultation with an epidemiologist or a statistician during the planning phase of a research study to optimize study efficiency, minimize potential sources of bias, and document the analytic plan.
doi:10.1111/j.1601-0825.2009.01634.x
PMCID: PMC2879019  PMID: 19874532
Public health; bias; epidemiology; guideline; methods; statistics
18.  A Novel PRPF31 Mutation in a Large Chinese Family with Autosomal Dominant Retinitis Pigmentosa and Macular Degeneration 
PLoS ONE  2013;8(11):e78274.
Purpose
This study was intended to identify the disease causing genes in a large Chinese family with autosomal dominant retinitis pigmentosa and macular degeneration.
Methods
A genome scan analysis was conducted in this family for disease gene preliminary mapping. Snapshot analysis of selected SNPs for two-point LOD score analysis for candidate gene filter. Candidate gene PRPF31 whole exons' sequencing was executed to identify mutations.
Results
A novel nonsense mutation caused by an insertion was found in PRPF31 gene. All the 19 RP patients in 1085 family are carrying this heterozygous nonsense mutation. The nonsense mutation is in PRPF31 gene exon9 at chr19:54629961-54629961, inserting nucleotide “A” that generates the coding protein frame shift from p.307 and early termination at p.322 in the snoRNA binding domain (NOP domain).
Conclusion
This report is the first to associate PRPF31 gene's nonsense mutation and adRP and JMD. Our findings revealed that PRPF31 can lead to different clinical phenotypes in the same family, resulting either in adRP or syndrome of adRP and JMD. We believe our identification of the novel “A” insertion mutation in exon9 at chr19:54629961-54629961 in PRPF31 can provide further genetic evidence for clinical test for adRP and JMD.
doi:10.1371/journal.pone.0078274
PMCID: PMC3823919  PMID: 24244300
20.  Inhibition of T-Cell Activation by PIK3IP1 
European journal of immunology  2012;42(10):2754-2759.
The PI-3 kinase (PI3K) pathway is critical for T-cell development and activation. Several negative regulators of this pathway have already been described and characterized: the lipid phosphatases SHIP, PHLPP and PTEN, the latter of which are tumor suppressors. PIK3IP1 is a recently described transmembrane protein that has the ability to bind the catalytic protein p110 and prevent its activation by the p85 family adaptor proteins. Thus far, nothing is known about the possible role of PIK3IP1 in the regulation of lymphocyte development or activation. Here, we show for the first time that PIK3IP1 is expressed in T cells. Ectopic expression of PIK3IP1 in Jurkat or D10 T cell lines inhibited activation of an NFAT/AP-1 transcriptional reporter. Conversely, siRNA-mediated silencing of PIK3IP1 in the same cell lines modestly augmented Akt phosphorylation, T-cell activation and production of IL-2. These results suggest that the novel PI3K regulator PIK3IP1 plays an inhibitory role in T-cell activation.
doi:10.1002/eji.201141653
PMCID: PMC3654810  PMID: 22706993
T cells; activation; signal transduction
21.  Quantitative analysis of tumor shrinkage due to chemotherapy and its implication for radiation treatment planning in limited-stage small-cell lung cancer 
Background
The optimal timing of chemoradiotherapy in limited-stage small-cell lung cancer (LS-SCLC) hasn’t been established, although evidence from studies supported that patients can benefit from early radiation therapy. The purpose of this study was to quantify tumor shrinkage in response to induction chemotherapy (IC), evaluate the impact of tumor shrinkage on radiation dosimetric parameters and determine its implication for the timing of radiation therapy for patients with LS-SCLC.
Methods
Twenty patients with LS-SCLC who were treated with IC followed by concomitant radiation therapy were investigated retrospectively. Ten patients received 1 cycle of IC, and 10 patients received 2 cycles of IC. Pre-IC CT imaging was coregistered with a simulation CT, and virtual radiation plans were created for pre- and post-IC thoracic disease in each case. The changes in the gross target volume (GTV), planning target volume (PTV) and dosimetric factors associated with the lungs, esophagus and heart were analyzed.
Results
The mean GTV and PTV for all of the patients decreased by 60.9% and 40.2%, respectively, which resulted in a significant reduction in the radiation exposure to the lungs, esophagus and heart. Changes in the PTV and radiation exposure of normal tissue were not significantly affected by the number of chemotherapy cycles delivered, although patients who received 2 cycles of IC had a greater decrease in GTV than those who received only 1 cycle of IC (69.6% vs. 52.1%, p = 0.273).
Conclusions
Our data showed that targeting the tumor post-IC may reduce the radiation dose to normal tissue in patients with LS-SCLC. However, the benefit to the normal tissue was not increased by an additional cycle of IC. These findings suggest that the first cycle of chemotherapy is very important for tumor shrinkage and that initiating thoracic radiation therapy at the second cycle of chemotherapy may be a reasonable strategy for timing of radiation therapy in LS-SCLC treatment.
doi:10.1186/1748-717X-8-216
PMCID: PMC3851276  PMID: 24040865
Small-cell lung cancer; Chemotherapy; Radiation therapy; Treatment planning
22.  Preimplantation Genetic Diagnosis for a Chinese Family with Autosomal Recessive Meckel-Gruber Syndrome Type 3 (MKS3) 
PLoS ONE  2013;8(9):e73245.
Meckel-Gruber syndrome type 3 is an autosomal recessive genetic defect caused by mutations in TMEM67 gene. In our previous study, we have identified a homozygous TMEM67 mutation in a Chinese family exhibiting clinical characteristics of MKS3, which provided a ground for further PGD procedure. Here we report the development and the first clinical application of the PGD for this MKS3 family. Molecular analysis protocol for clinical PGD procedure was established using 50 single cells in pre-clinical set-up. After whole genomic amplification by multiple displacement amplification with the DNA from single cells, three techniques were applied simultaneously to increase the accuracy and reliability of genetic diagnosis in single blastomere, including real-time PCR with Taq Man-MGB probe, haplotype analysis with polymorphic STR markers and Sanger sequencing. In the clinical PGD cycle, nine embryos at cleavage-stage were biopsied and subjected to genetic diagnosis. Two embryos diagnosed as free of TMEM67 mutation were transferred and one achieving normal pregnancy. Non-invasive prenatal assessment of trisomy 13, 18 and 21 by multiplex DNA sequencing at 18 weeks’ gestation excluded the aneuploidy of the analyzed chromosomes. A healthy boy was delivered by cesarean section at 39 weeks’ gestation. DNA sequencing from his cord blood confirmed the result of genetic analysis in the PGD cycle. The protocol developed in this study was proved to be rapid and safe for the detection of monogenic mutations in clinical PGD cycle.
doi:10.1371/journal.pone.0073245
PMCID: PMC3764130  PMID: 24039893
23.  Association Study of Polymorphisms in Selenoprotein Genes and Kashin–Beck Disease and Serum Selenium/Iodine Concentration in a Tibetan Population 
PLoS ONE  2013;8(8):e71411.
Background
Kashin-Beck disease is a kind of degenerative osteoarthropathy. Genetic factors may play an important role in the pathogenesis of KBD.
Objective
To investigate the association of the selenoprotein genes GPX1 (rs1050450, rs1800668, and rs3811699), TrxR2 (rs5748469), and DIO2 (rs225014) with Kashin-Beck disease (KBD) in a Tibetan population and to investigate the association of these SNPs with the serum iodine/selenium concentration in the Tibetan population.
Design
Five SNPs including rs1050450, rs1800668, and rs3811699 in the GPX1 gene, rs5748469 in the TrxR2 gene, and rs225014 in the DIO2 gene were analyzed in Tibetan KBD patients and controls using the SNaPshot method. P trend values of the SNPs were calculated using an additive model.
Results
None of the five SNPs in the three genes showed a significant association with KBD. Haplotypes TCC, TTC and TTT of rs1050450, rs1800668 and rs3811699 in GPX1 showed a significant association with KBD and controls with P value of 0.0421, 5.0E-4 and 0.0066, respectively. The GPX1 gene (rs1050450) showed a potential significant association with the iodine concentration in the Tibetan study population (P = 0.02726). However, no such association was detected with the selenium concentration (P = 0.2849).
Conclusion(s)
In this study, we showed that single SNPs in the genes GPX1 (rs1050450, rs1800668 and rs3811699), TrxR2 (rs5748469), and DIO2 (rs225014) may not be significantly associated with KBD in a Tibetan population. However, haplotype analysis of SNPs rs1050450, rs1800668 and rs3811699 in GPX1 gene showed a significant association with KBD. The results suggested that GPX1 gene play a protective role in the susceptivity of KBD in Tibetans. Furthermore, the GPX1 gene (rs1050450) may be significantly associated with the serum iodine concentration in Tibetans.
doi:10.1371/journal.pone.0071411
PMCID: PMC3751926  PMID: 24058403
24.  Toward integrated and sustainable prevention against diabetes in rural China: study rationale and protocol of eCROPS 
Background
Being an intermediate stage in the development of diabetes, pre-diabetics were estimated as high as 14% to 63% in China and one to three quarters of them will develop into diabetes within 10 years. It is well established that the risk of diabetes progression can be modified substantially and a whole range of proven guidelines, protocols and methodologies are available. Unfortunately, most proven interventions are seldom used in daily practice and this is especially true in resource poor rural China. This project aims at demonstrating that an evolutionary intervention package featuring low cost, integration with routine services, cultural sensitization and self-optimization, is effective and sustainable in preventing diabetes.
Methods/design
This project utilizes a quasi cluster randomized controlled trial and a batched implementation strategy in which villages are recruited in 7 blocks within 7 consecutive years respectively. Block 0 involves 3 villages and provides an opportunity for piloting and refining primitive intervention methodologies and protocols. The following 6 blocks consist of 14 villages each and serve as intervention arm; while all the villages not yet started intervention form the control arm. For each block, measurement happens at baseline and every 12 months (for plasma glucose) or monthly (for body weight and blood pressure) after baseline. These arrangements enable documentation of up to 6 years of consecutive measures and detection of lower incidence of progression into diabetes, improved body max index and blood pressure, and increased service use and involvement in healthy dietary and physical activities among pre-diabetics receiving the experimental intervention compared to themselves at baseline or those in the delayed-intervention control condition.
Discussion
China has a long history of separating disease prevention and treatment systems and there is a clear need to leverages key success factors in a synergetic way toward integrated and sustainable diabetes prevention. This project is owned and managed by local health authorities and utilizes available resources. It introduces a package of long-term incentives, establishes ongoing mechanisms for continuous capacity building and quality improvement, and builds up an operational cycle for catalyzing similar efforts in the local prefecture even throughout rural China.
Trial registration
Current Controlled Trials: ISRCTN66772711.
doi:10.1186/1472-6823-13-28
PMCID: PMC3750596  PMID: 23919331
25.  Identification of a Novel TECTA Mutation in a Chinese DFNA8/12 Family with Prelingual Progressive Sensorineural Hearing Impairment 
PLoS ONE  2013;8(7):e70134.
Tectorial membrane, an extracellular matrix of the cochlea, plays a crucial role in the transmission of sound to the sensory hair cells. Alpha-tectorin is the most important noncollagenous component of the tectorial membrane and the otolith membrane in the maculae of the vestibular system. Defects in TECTA, the gene encodes alpha-tectorin, are cause of both dominant (DFNA8/12) and recessive (DFNB21) forms of deafness. Here, we report a three-generation Chinese family characterized by prelingual progressive sensorineural hearing impairment. We mapped the disease locus to chromosome 11q23-24 region, overlapping with the DFNA8/12 locus. Sequencing of candidate gene TECTA revealed a heterozygous c.5945C>A substitution in exon 19, causing amino acid substitution of Ala to Asp at a conservative position 1982. The A1982D substitution is consistent with hearing loss in this Chinese family and has not been found in 200 random control chromosomes. To our knowledge, this is the first TECTA mutation identified in Chinese population. Our data provides additional molecular and clinical information for establishing a better genotype–phenotype understanding of DFNA8/12.
doi:10.1371/journal.pone.0070134
PMCID: PMC3729559  PMID: 23936151

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