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1.  Molecular Findings Among Patients Referred for Clinical Whole-Exome Sequencing 
JAMA  2014;312(18):1870-1879.
Clinical whole-exome sequencing is increasingly used for diagnostic evaluation of patients with suspected genetic disorders.
To perform clinical whole-exome sequencing and report (1) the rate of molecular diagnosis among phenotypic groups, (2) the spectrum of genetic alterations contributing to disease, and (3) the prevalence of medically actionable incidental findings such as FBN1 mutations causing Marfan syndrome.
Observational study of 2000 consecutive patients with clinical whole-exome sequencing analyzed between June 2012 and August 2014. Whole-exome sequencing tests were performed at a clinical genetics laboratory in the United States. Results were reported by clinical molecular geneticists certified by the American Board of Medical Genetics and Genomics. Tests were ordered by the patient’s physician. The patients were primarily pediatric (1756 [88%]; mean age, 6 years; 888 females [44%], 1101 males [55%], and 11 fetuses [1% gender unknown]), demonstrating diverse clinical manifestations most often including nervous system dysfunction such as developmental delay.
Whole-exome sequencing diagnosis rate overall and by phenotypic category, mode of inheritance, spectrum of genetic events, and reporting of incidental findings.
A molecular diagnosis was reported for 504 patients (25.2%) with 58% of the diagnostic mutations not previously reported. Molecular diagnosis rates for each phenotypic category were 143/526 (27.2%; 95% CI, 23.5%–31.2%) for the neurological group, 282/1147 (24.6%; 95% CI, 22.1%–27.2%) for the neurological plus other organ systems group, 30/83 (36.1%; 95% CI, 26.1%–47.5%) for the specific neurological group, and 49/244 (20.1%; 95% CI, 15.6%–25.8%) for the nonneurological group. The Mendelian disease patterns of the 527 molecular diagnoses included 280 (53.1%) autosomal dominant, 181 (34.3%) autosomal recessive (including 5 with uniparental disomy), 65 (12.3%) X-linked, and 1 (0.2%) mitochondrial. Of 504 patients with a molecular diagnosis, 23 (4.6%) had blended phenotypes resulting from 2 single gene defects. About 30% of the positive cases harbored mutations in disease genes reported since 2011. There were 95 medically actionable incidental findings in genes unrelated to the phenotype but with immediate implications for management in 92 patients (4.6%), including 59 patients (3%) with mutations in genes recommended for reporting by the American College of Medical Genetics and Genomics.
Whole-exome sequencing provided a potential molecular diagnosis for 25% of a large cohort of patients referred for evaluation of suspected genetic conditions, including detection of rare genetic events and new mutations contributing to disease. The yield of whole-exome sequencing may offer advantages over traditional molecular diagnostic approaches in certain patients.
PMCID: PMC4326249  PMID: 25326635
2.  Autophagy in Diabetic Nephropathy 
The Journal of endocrinology  2014;224(1):R15-R30.
Diabetic nephropathy (DN) is the most common cause of end-stage kidney disease worldwide, and is associated with increased morbidity and mortality in patients with both type 1 and type 2 diabetes. Increasing prevalence of diabetes has made the need for effective treatment of DN critical, and identifying new therapeutic targets to improve clinical management. Autophagy is a highly conserved “self-eating” pathway by which cells degrade and recycle macromolecules and organelles. Autophagy serves as an essential mechanism to maintain homeostasis of glomeruli and tubules, and plays important roles in human health and diseases. Impairment of autophagy is implicated in the pathogenesis of DN. Emerging body of evidence suggests that targeting the autophagic pathway to activate and restore autophagy activity may be renoprotective. Here we review current advances in our understanding of the roles of autophagy in diabetic kidney injury, focusing on studies in renal cells in culture, human kidney tissues, and experimental animal models of diabetes. We discuss the major nutrient-sensing signal pathways, and diabetes-induced altered intracellular metabolism and cellular events, including accumulation of advanced glycation end-products, increased oxidative stress, endoplasmic reticulum stress, hypoxia, and activation of the renin angiotensin system, which modulate autophagic activity and contribute to the development of DN. We also highlight recent studies of autophagy and transforming growth factor-β in renal fibrosis, the final common response to injury that ultimately leads to end-stage kidney failure in both type 1 and type 2 diabetes. These findings suggest the possibility that autophagy can be a therapeutic target against DN.
PMCID: PMC4238413  PMID: 25349246
diabetes mellitus; macroautophagy; autophagy; kidney; nephropathy
3.  Expired nitric oxide and airway reactivity in infants at risk for asthma 
Family histories of atopy, as well as histories of atopic dermatitis and food allergy, are important risk factors for an infant to have asthma. Although atopic sensitization appears to contribute to the development of asthma, it is unclear when the airways become involved with the atopic process and whether airway function relates to the atopic characteristics of the infant.
We sought to evaluate whether atopic infants without prior episodes of wheezing have increased expired nitric oxide (eNO) levels and heightened airway reactivity.
Infants with eczema were recruited, and atopic status was defined by specific IgE levels to foods or aeroallergens and total IgE levels. eNO, forced expiratory flow at 75% exhaled volume (FEF75), and airway reactivity to inhaled methacholine were measured in sedated infants. Airway reactivity was quantified by using the provocative concentration to decrease FEF75 by 30%.
Median age for the 114 infants evaluated was 10.7 months (range, 2.6–19.1 months). Infants sensitized to egg or milk compared with infants sensitized to neither egg nor milk had lower flows (FEF75: 336 vs 285 mL/s, P < .003) and lower lnPC30 (mg/mL) provocative concentrations to decrease FEF75 by 30% (−0.6 vs −1.2, P < .02) but no difference in eNO levels. Infants with total serum IgE levels of greater than 20 IU/mL had higher eNO levels compared with infants with IgE levels of 20 IU/mL or less (14.6 vs 11.2 ppb, P < .023) but no difference in forced flows or airway reactivity.
Our findings suggest that atopic characteristics of the infant might be important determinants of the airway physiology of forced expiratory flows, airway reactivity, and eNO.
PMCID: PMC4308034  PMID: 18760452
Atopy; eczema; airway reactivity
4.  Regulation of Autophagy by TGF-β: Emerging Role in Kidney Fibrosis 
Seminars in nephrology  2013;34(1):62-71.
Autophagy is a highly conserved homoeostatic mechanism for cell survival under conditions of stress, and is widely implicated as an important pathway in many biological processes and diseases. In progressive kidney diseases, fibrosis represents the common pathway to end-stage kidney failure. Transforming growth factor-β1 (TGF-β1) is a pleiotropic cytokine that has been established as a central mediator of kidney fibrosis. Recently emerging body of evidence from studies in renal cells in culture and experimental animal models suggests that TGF-β1 regulates autophagy and that autophagy regulates many critical aspects of normal and disease conditions associated with kidney fibrosis, such as tubulointerstitial fibrosis, glomerulosclerosis, and diabetic nephropathy. Here, we review the recent advances exploring the process of autophagy, its regulation by TGF-β1, and implication in the pathogenesis of progressive kidney fibrosis and injury responses. Understanding the cellular and molecular bases of this process is crucial for identifying potential new diagnostic and therapeutic targets of kidney fibrosis.
PMCID: PMC3912517  PMID: 24485031
Autophagy; transforming growth factor-β1; fibrosis; chronic kidney disease
5.  Mouth-Level Intake of Benzo[a]pyrene from Reduced Nicotine Cigarettes 
Cigarette smoke is a known source of exposure to carcinogenic polycyclic aromatic hydrocarbons (PAHs), especially benzo[a]pyrene (BaP). Exposure to BaP in cigarette smoke is influenced by how a person smokes and factors, such as tobacco blend. To determine whether sustained use of reduced-nicotine cigarettes is associated with changes in exposure to nicotine and BaP, levels of BaP in spent cigarette filter butts were correlated with levels of BaP in cigarette smoke to estimate mouth-level intake (MLI) of BaP for 72 daily smokers given three progressively reduced nicotine content cigarettes. Urinary cotinine, a marker of nicotine exposure, and urinary 1-hydroxypyrene (1-HOP), a marker of PAH exposure, were measured throughout the study. Median daily BaP MLI and urine cotinine decreased in a similar manner as smokers switched to progressively lower nicotine cigarettes, despite relatively constant daily cigarette consumption. 1-HOP levels were less responsive to the use of reduced nicotine content cigarettes. We demonstrate that spent cigarette filter butt analysis is a promising tool to estimate MLI of harmful chemicals on a per cigarette or per-day basis, which partially addresses the concerns of the temporal influence of smoking behavior or differences in cigarette design on exposure.
PMCID: PMC4245650  PMID: 25411724
cigarette smoke; benzo[a]pyrene; mouth-level intake; cigarette filter; filter analysis; reduced nicotine cigarette; cotinine; smoking topography
6.  Clinical Whole-Exome Sequencing for the Diagnosis of Mendelian Disorders 
The New England journal of medicine  2013;369(16):1502-1511.
Whole-exome sequencing is a diagnostic approach for the identification of molecular defects in patients with suspected genetic disorders.
We developed technical, bioinformatic, interpretive, and validation pipelines for whole-exome sequencing in a certified clinical laboratory to identify sequence variants underlying disease phenotypes in patients.
We present data on the first 250 probands for whom referring physicians ordered whole-exome sequencing. Patients presented with a range of phenotypes suggesting potential genetic causes. Approximately 80% were children with neurologic pheno-types. Insurance coverage was similar to that for established genetic tests. We identified 86 mutated alleles that were highly likely to be causative in 62 of the 250 patients, achieving a 25% molecular diagnostic rate (95% confidence interval, 20 to 31). Among the 62 patients, 33 had autosomal dominant disease, 16 had auto-somal recessive disease, and 9 had X-linked disease. A total of 4 probands received two nonoverlapping molecular diagnoses, which potentially challenged the clinical diagnosis that had been made on the basis of history and physical examination. A total of 83% of the autosomal dominant mutant alleles and 40% of the X-linked mutant alleles occurred de novo. Recurrent clinical phenotypes occurred in patients with mutations that were highly likely to be causative in the same genes and in different genes responsible for genetically heterogeneous disorders.
Whole-exome sequencing identified the underlying genetic defect in 25% of consecutive patients referred for evaluation of a possible genetic condition. (Funded by the National Human Genome Research Institute.)
PMCID: PMC4211433  PMID: 24088041
7.  Mammalian Y chromosomes retain widely expressed dosage-sensitive regulators 
Nature  2014;508(7497):494-499.
The human X and Y chromosomes evolved from an ordinary pair of autosomes, but millions of years ago genetic decay ravaged the Y chromosome, and only three percent of its ancestral genes survived. We reconstructed the evolution of the Y chromosome across eight mammals to identify biases in gene content and the selective pressures that preserved the surviving ancestral genes. Our findings indicate that survival was non-random, and in two cases, convergent across placental and marsupial mammals. We conclude that the Y chromosome's gene content became specialized through selection to maintain the ancestral dosage of homologous X-Y gene pairs that function as broadly expressed regulators of transcription, translation and protein stability. We propose that beyond its roles in testis determination and spermatogenesis, the Y chromosome is essential for male viability, and plays unappreciated roles in Turner syndrome and in phenotypic differences between the sexes in health and disease.
PMCID: PMC4139287  PMID: 24759411
8.  Genetic Susceptibility to Anthracycline-Related Congestive Heart Failure in Survivors of Haematopoietic Cell Transplantation 
British journal of haematology  2013;163(2):205-213.
Haematopoietic cell transplantation (HCT) survivors are at increased risk for developing congestive heart failure (CHF), primarily due to pre-HCT exposure to anthracyclines. We examined the association between the development of CHF after HCT and polymorphisms in 16 candidate genes involved in anthracycline metabolism, iron homeostasis, anti-oxidant defence, and myocardial remodelling. A nested case-control study design was used. Cases (post-HCT CHF) were identified from 2,950 patients who underwent HCT between 1988 and 2007 at City of Hope and had survived ≥1 year. This cohort formed the sampling frame for selecting controls (without CHF) matched on: age, race/ethnicity, cumulative anthracycline exposure, stem cell source (allogeneic, autologous), and length of follow-up. Seventy-seven cases with pre-HCT germline DNA and 178 controls were genotyped. Multivariate analysis revealed that the odds of CHF was higher in females (Odds Ratio [OR]=2.9, p<0.01), individuals with pre-HCT chest radiation (OR=4.7, p=0.05), hypertension (OR=2.9, p=0.01), and with variants of genes coding for the NAD(P)H-oxidase subunit RAC2 (rs13058338, 7508T→A; OR=2.8, p<0.01), HFE (rs1799945, 63C→G; OR=2.5, p=0.05) or the doxorubicin efflux transporter ABCC2 (rs8187710, 1515G→A; OR=4.3, p<0.01). A combined (clinical and genetic) CHF predictive model performed better (area under the curve [AUC], 0.79) than the genetic (AUC=0.67) or the clinical (AUC=0.69) models alone.
PMCID: PMC3795883  PMID: 23927520
Anthracyclines; congestive heart failure; genetic susceptibility; haematopoietic cell transplantation; late effects
9.  A Heuristic Placement Selection of Live Virtual Machine Migration for Energy-Saving in Cloud Computing Environment 
PLoS ONE  2014;9(9):e108275.
The field of live VM (virtual machine) migration has been a hotspot problem in green cloud computing. Live VM migration problem is divided into two research aspects: live VM migration mechanism and live VM migration policy. In the meanwhile, with the development of energy-aware computing, we have focused on the VM placement selection of live migration, namely live VM migration policy for energy saving. In this paper, a novel heuristic approach PS-ES is presented. Its main idea includes two parts. One is that it combines the PSO (particle swarm optimization) idea with the SA (simulated annealing) idea to achieve an improved PSO-based approach with the better global search's ability. The other one is that it uses the Probability Theory and Mathematical Statistics and once again utilizes the SA idea to deal with the data obtained from the improved PSO-based process to get the final solution. And thus the whole approach achieves a long-term optimization for energy saving as it has considered not only the optimization of the current problem scenario but also that of the future problem. The experimental results demonstrate that PS-ES evidently reduces the total incremental energy consumption and better protects the performance of VM running and migrating compared with randomly migrating and optimally migrating. As a result, the proposed PS-ES approach has capabilities to make the result of live VM migration events more high-effective and valuable.
PMCID: PMC4177121  PMID: 25251339
10.  Metastatic cancer stem cells: from the concept to therapeutics 
Metastatic cancer stem cells (MCSCs) refer to a subpopulation of cancer cells with both stem cell properties and invasion capabilities that contribute to cancer metastasis. MCSCs have capability of self-renewal, potentials of multiple differentiation and development and/or reconstruction of cancer tissues. As compared with stationary cancer stem cells, MCSCs are capable of invasion to normal tissues such as vasculatures, resistance to chemo- and/or radio-therapies, escape from immune surveillance, survival in circulation and formation of metastasis. MCSCs are derived from invasive cancer stem cells (iCSCs) due to the plasticity of cancer stem cells, which is one of the characteristics of cancer cell heterogeneity. Both stages of iCSCs and MSCSs are the potential therapeutic targets for cancer metastasis in the future strategies of personalized cancer therapy.
PMCID: PMC4163604  PMID: 25232505
Cancer stem cells; invasion and metastasis; therapeutics
11.  Pathological changes in the maxillary sinus mucosae of patients with recurrent odontogenic maxillary sinusitis 
Objective: To study the structural and functional changes of maxillary sinus mucosae of patients with odontogenic maxillary sinusitis, and to improve the therapeutic effects.
Methods: Ten mucosal biopsy samples collected during the surgeries of patients with recurrent odontogenic maxillary sinusitis were selected as Group A. Another ten mucosal biopsy sample were collected during retention cyst-removing surgeries and referred to as Group B. The mucosae were put in 10% neutral formalin solution for 1 day and prepared into 5-7 µm thick paraffin sections which were subjected to hematoxylin-eosin staining. The reactions included: (1) Reaction with T-lymphocyte (CD-3); (2) reaction with T-helper cell (CD-4); (3) reaction with T-suppressing cell (CD-8); (4) reaction with B-lymphocyte (CD-20). Polymeric horseradish peroxidase visualized detection system was used. The contents of CD3, CD4, CD8 and CD20 in the stained cells of the maxillary sinus mucosal layer were calculated. The responses of receptors to muramidase were classified as mild, moderate and strong. All data were analyzed by Statistica 6.0 package for Windows based on Mann-Whitney non-parametric standards.
Results: The epithelial tissues in the maxillary sinus mucosa of Group B were covered with multiple rows of cilia. The epithelial cells of Group A suffered from degeneration, shrinkage and desquamation. Different cells were distributed in the autologous mucosal layer, of which macrophages, fibroblasts, lymphocytes and neutrophils were dominant. The average contents of macrophages and lymphocytes accounted for 42.8%. Lymphocyte subset analysis showed that the number of CD3 cells exceeded that of CD20 ones and there were more CD4+ cells than CD8+ ones. T-helper and T-suppressing cells were distributed remarkably differently. CD8+ cells were mainly located inside and under the epithelium, while CD4+ cells were scattered in the autologous matrix.
Conclusion: For patients with recurrent odontogenic maxillary sinusitis, the maxillary sinus mucosa mainly suffered from regeneration of epithelial tissues and inhibition of cell proliferation, which were accompanied by damages to the protective and shielding effects of the mucociliary transport system. Macrophages and lymphocytes dominated in the infiltration of autologous mucosal layer, and the coexisting copious fibroblasts indicated the onset of inflammation.
PMCID: PMC4163215  PMID: 25225509
Maxillary sinusitis; Mucosa; Odontogenic
12.  TALEN-mediated Nanog disruption results in less invasiveness, more chemosensitivity and reversal of EMT in Hela cells 
Oncotarget  2014;5(18):8393-8401.
Emerging evidence suggests that Nanog is involved in cervical tumorigenesis. However, the regulating role of Nanog in tumorigenesis and chemosensitivity are still poorly understood. In this study, Nanog was disrupted by transcription activatorlike effector nucleases (TALEN) in Hela cells and its expression was significantly decreased in a single-cell derived sub-clone with biallelic mutations. The disruption of Nanog not only induced down regulation of some other core transcription factor genes for cell self-renewal, such as Oct4, Sox2 and FoxD3, but also led to the down regulation of some mesenchymal representative genes, vimentin and N-adherin, and up regulation of the epithelial gene, E-cadherin. In addition, the invasiveness and clonogenicity of the Hela cells were obviously affected, and surprisingly their sensitivities to anti-cancer drugs were also significantly increased in vitro. After Xenograft into nude mice, the growth volumes of the neoplasms from the Nanog disrupted Hela cells were significantly smaller compared with those from wild type ones. In conclusion, these results suggest that disruption of Nanog may reverse the status of epithelial-mesenchymal transition, which is critical in tumorigenesis, and alleviate chemoresistance, as well as their invasiveness, in cervical cancer cells.
PMCID: PMC4226691  PMID: 25245189
Nanog; Hela cell; cervical cancer cell; TALEN; epithelial-mesenchymal transition
13.  Comparison study of tooth enamel ESR spectra of cows, goats and humans 
Journal of Radiation Research  2014;55(6):1101-1106.
The ESR radiation dosimetric properties of tooth enamel samples from cows and goats were investigated and compared with those of human samples. Samples were prepared first mechanically, and then chemically. The study results showed that the native signals from cow and goat samples were weaker than those from human samples; the radiation sensitivities for cow and goat samples were very close to those of human tooth enamel samples. These results indicated that cow and goat teeth could be alternative materials for radiation dose estimation.
PMCID: PMC4229931  PMID: 25037102
animal tooth enamel; ESR; EPR; dosimetry
14.  Analysis of the Dielectric Constant of Saline-Alkali Soils and the Effect on Radar Backscattering Coefficient: A Case Study of Soda Alkaline Saline Soils in Western Jilin Province Using RADARSAT-2 Data 
The Scientific World Journal  2014;2014:563015.
Soil salinity is a global problem, especially in developing countries, which affects the environment and productivity of agriculture areas. Salt has a significant effect on the complex dielectric constant of wet soil. However, there is no suitable model to describe the variation in the backscattering coefficient due to changes in soil salinity content. The purpose of this paper is to use backscattering models to understand behaviors of the backscattering coefficient in saline soils based on the analysis of its dielectric constant. The effects of moisture and salinity on the dielectric constant by combined Dobson mixing model and seawater dielectric constant model are analyzed, and the backscattering coefficient is then simulated using the AIEM. Simultaneously, laboratory measurements were performed on ground samples. The frequency effect of the laboratory results was not the same as the simulated results. The frequency dependence of the ionic conductivity of an electrolyte solution is influenced by the ion's components. Finally, the simulated backscattering coefficients measured from the dielectric constant with the AIEM were analyzed using the extracted backscattering coefficient from the RADARSAT-2 image. The results show that RADARSAT-2 is potentially able to measure soil salinity; however, the mixed pixel problem needs to be more thoroughly considered.
PMCID: PMC4102067  PMID: 25101317
15.  Antitumor effects of dammarane-type saponins from steamed Notoginseng 
Pharmacognosy Magazine  2014;10(39):314-317.
Six dammarane-type saponins were extracted from steamed Panax notoginseng. Their chemical structures were identified spectroscopically as ginsenosides Rh1 (1), Rg1 (2), 20 (S)-Rg3 (3), 20 (R)-Rg3 (4), Rb3 (5), and Rb1 (6). Compounds (0.1-10 μM) were tested for inhibition of tumor necrosis factor-α (TNF)-induced nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) luciferase reporter activity using a human kidney 293T cell-based assay. Ginsenoside Rb3 (5) showed the most significant activity with an IC50 of 8.2 μM. This compound also inhibited the induction of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) messenger Ribonucleic acid (mRNA) in a dose-dependent manner after HepG2 cells had been treated with TNF-α (10 ng/mL).
PMCID: PMC4159925  PMID: 25210319
Antitumor; dammarane-type ginsenoside; inhibitory activity; Panax notoginseng
16.  Tumor suppressor XAF1 induces apoptosis, inhibits angiogenesis and inhibits tumor growth in hepatocellular carcinoma 
Oncotarget  2014;5(14):5403-5415.
X-linked inhibitor of apoptosis (XIAP)-associated factor 1 (XAF1), a XIAP-binding protein, is a tumor suppressor gene. XAF1 was silent or expressed lowly in most human malignant tumors. However, the role of XAF1 in hepatocellular carcinoma (HCC) remains unknown. In this study, we investigated the effect of XAF1 on tumor growth and angiogenesis in hepatocellular cancer cells. Our results showed that XAF1 expression was lower in HCC cell lines SMMC-7721, Hep G2 and BEL-7404 and liver cancer tissues than that in paired non-cancer liver tissues. Adenovirus-mediated XAF1 expression (Ad5/F35-XAF1) significantly inhibited cell proliferation and induced apoptosis in HCC cells in dose- and time- dependent manners. Infection of Ad5/F35-XAF1 induced cleavage of caspase -3, -8, -9 and PARP in HCC cells. Furthermore, Ad5/F35-XAF1 treatment significantly suppressed tumor growth in a xenograft model of liver cancer cells. Western Blot and immunohistochemistry staining showed that Ad5/F35-XAF1 treatment suppressed expression of vascular endothelial growth factor (VEGF), which is associated with tumor angiogenesis, in cancer cells and xenograft tumor tissues. Moreover, Ad5/F35-XAF1 treatment prolonged the survival of tumor-bearing mice. Our results demonstrate that XAF1 inhibits tumor growth by inducing apoptosis and inhibiting tumor angiogenesis. XAF1 may be a promising target for liver cancer treatment.
PMCID: PMC4170645  PMID: 24980821
XAF1; Hepatocellular cancer; Apoptosis; Angiogenesis; VEGF
17.  Behavioral deficits, abnormal corticosterone, and reduced prefrontal metabolites of adolescent rats subject to early life stress 
Neuroscience letters  2013;545:132-137.
The present study investigated the effect of early life stress in adolescent rats on brain metabolites, serum corticosterone, and depressive-like behavior. A group of rats were subject to early life stress from postnatal day (PND) 1 to 14. A matched control group was studied. Behavioral tests, serum corticosterone and high-resolution proton magnetic resonance spectroscopy were conducted between PND 30 and 40. In this study, adolescent rats exposed to early life stress demonstrated depressive-like behavior and increased serum corticosterone during adolescence. They also showed reduced glutamate, glutamine, and N-acetyl aspartate (NAA) levels in the prefrontal cortex. A reduced myo-inositol level, consistent with astroglial deficits, was observed but was not statistically significant. Together, these findings characterize the effect of early life stress on adolescent animals and underscore the long-lasting and detrimental effects of childhood adversities.
PMCID: PMC3699722  PMID: 23643993
18.  Two-year prospective case-controlled study of a case management program for community-dwelling individuals with schizophrenia 
Shanghai Archives of Psychiatry  2014;26(3):119-128.
A community-based rehabilitation program is an essential element of the comprehensive treatment of individuals with schizophrenia.
Assess the long-term effects of a community-based case management program for providing rehabilitations services to individuals with schizophrenia.
A total of 730 community-residing participants who met ICD-10 diagnostic criteriafor schizophrenia were enrolled, 380 in the case management group and 350 in the control group from two districts in Shanghai. Case management involved monthly training visits with patients and their co-resident family members that focused on encouraging medication adherence. Participants were assessed every three months for 24 months with the Camberwell Assessment of Need (CAN), Positive and Negative Syndrome Scale (PANSS), WHO-Disability Assessment Scale (WHO-DAS), and the Quality of Life Scale (QOLS). Level of discomfort due to side-effects was also assessed every three months. Individuals who discontinued their antipsychotic medication without physician approval for one month or longer at any time during follow-up were classified as ‘self-determined medication discontinuation’.
Compared to the treatment as usual group (i.e., follow-up management every 3 months), by the end of the two-year follow-up those who participated in the case management program had significantly lower rates of medication discontinuation, significantly less severe negative symptoms, lower relapse rates and lower rehospitalization rates. Other factors that had an independent effect on discontinuation of medication included educational level (those with more education had higher discontinuation rates), lack of family supervision of medication, higher dosages of medication, and greater medication-related discomfort.
Case management is a feasible and effective long-term method for improving the rehabilitation outcomes of community residents with schizophrenia. Our results highlight the need to involve family members in the management of patients’ medication, to use the minimum effective dosage of medication, and to aggressively manage all side-effects.
PMCID: PMC4118008  PMID: 25114486
schizophrenia; community-based rehabilitation; case management; discontinuation rate; social function
19.  Increased expression of miRNA-182 in colorectal carcinoma: an independent and tissue-specific prognostic factor 
Increasing evidence has revealed that miRNAs play a pivotal role in multiple processes of carcinogenesis, and are being explored as diagnostic, prognostic and predictive biomarker. In this study, we investigated the status of miR-182 expression in colorectal carcinoma (CRC) by in situ hybridization and its underlying clinicopathologic significance for patients with CRC. We found that 79/138 (57.25%) CRCs had high-level expression of miR-182, while 17/67 (25.37%) normal mucosa tissues had high-level expression of miR-182. The expression level of miR-182 was remarkably up-regulated in CRC tissues compared with non-neoplastic normal tissues (P < 0.001). The over-expression of miR-182 in cancer parenchyma cells in CRC were strongly correlated with T-stage (P = 0.020), lymph node metastasis (P = 0.003), distant metastasis (P = 0.002), and Dukes’ stage (P = 0.005) in patients with CRC. Patients with high-level expression of miR-182 had short overall survival time than those with low-level expression of miR-182 (P < 0.001). Univariate and multivariate survival analyses further showed that miR-182 expression was a potential unfavorable prognostic factor for CRC, suggesting a potential application of miR-182 in prognosis prediction and therapeutic application in CRC.
PMCID: PMC4097234  PMID: 25031782
miR-182; in situ hybridization; prognosis; colorectal carcinoma
20.  Distinct patterns of ALDH1A1 expression predict metastasis and poor outcome of colorectal carcinoma 
Purpose: Aldehyde dehydrogenase 1A1 (ALDH1A1) has been proposed as a candidate biomarker for colorectal carcinoma (CRC). However, the heterogeneity of its expression makes it difficult to predict the outcome of CRC. The aim of this study was to evaluate the diagnostic and prognostic value of this molecule in CRC. Methods and Results: In this study, we examined ALDH1A1 expression by immunohistochemistry including 406 cases of primary CRC with corresponding adjacent mucosa, with confirmation of real-time PCR and Western blotting. We found that the expression patterns of ALDH1A1 were heterogeneous in the CRC and corresponding adjacent tissues. We defined the ratio of ALDH1A1 level in adjacent mucosa to that in tumor tissues as RA/C and found that the capabilities of tumor invasion and metastasis in the tumors with RA/C < 1 were significantly higher than those with RA/C ≥ 1. Follow-up data showed the worse prognoses in the CRC patients with RA/C < 1. For understanding the underlying mechanism, the localization of β-catenin was detected in the CRC tissues with different patterns of ALDH1A1 expression from 221 patients and β-catenin was found preferentially expressed in cell nuclei of the tumors with RA/C < 1 and ALDH1A1high expression of HT29 cell line, indicating that nuclear translocation of β-catenin might contribute to the increased potentials of invasion and metastasis. Conclusion: Our results indicate that RA/C is a novel biomarker to reflect the distinct expression patterns of ALDH1A1 for predicting metastasis and prognosis of CRC.
PMCID: PMC4097282  PMID: 25031716
Colorectal carcinoma; metastasis; prognosis; aldehyde dehydrogenase 1A1; β-catenin
21.  microRNA-182 targets special AT-rich sequence-binding protein 2 to promote colorectal cancer proliferation and metastasis 
Increasing evidence has revealed that microRNAs (miRNA) played a pivotal role in regulating cancer cell proliferation and metastasis. The deregulation of miR-182 has been identified in colorectal cancer (CRC). However, the role and mechanism of miR-182 in CRC have not been completely understood yet.
The expression levels of miR-182 in CRC tissues and CRC cell lines were examined by performing stem-loop quantitative RT-PCR. The stable over-expression miR-182 cell lines and control cell lines were constructed by lentivirus infection. Subsequently, CCK-8 assay, plate colony formation assay, cell migration, invasion assay and experimental animal models were performed to detect the biological functions of miR-182 in vitro and in vivo. A luciferase reporter assay was conducted to confirm target associations. Western blot and immunohistochemical analysis were performed to examine the expression changes of molecular markers that are regulated by miR-182.
We found that miR-182 expression is increased in CRC cells that originated from metastatic foci and human primary CRC tissues with lymph node metastases. The ectopic expression of miR-182 enhanced cell proliferation, invasion, and migration in vitro. Stable overexpression of miR-182 also facilitated tumor growth and metastasis in vivo too. Further research showed that miR-182 could directly target the 3’untranslated region (3’UTR) of SATB2 mRNA and subsequently repress both the mRNA and protein expressions of SATB2, which we identified in previous studies as a CRC metastasis-associated protein. Restoring SATB2 expression could reverse the effects of miR-182 on CRC cell proliferation and migration. Investigations of possible mechanisms underlying these behaviors induced by miR-182 revealed that miR-182 induced epithelial-mesenchymal transition (EMT) by modulating the expression of key cellular molecules in EMT.
Our results illustrated that the up-regulation of miR-182 played a pivotal role in CRC tumorigenesis and metastasis, which suggesting a potential implication of miR-182 in the molecular therapy for CRC.
PMCID: PMC4020308  PMID: 24884732
miR-182; Colorectal cancer; SATB2; Metastasis; EMT
22.  Combination of a Fast Cleanup Procedure and a DR-CALUX® Bioassay for Dioxin Surveillance in Taiwanese Soils 
Our goal was to determine dioxin levels in 800 soil samples collected from Taiwan. An in vitro DR-CALUX® assay was carried out with the help of an automated Soxhlet system and fast cleanup column. The mean dioxin level of 800 soil samples was 36.0 pg-bioanalytical equivalents (BEQs)/g dry weight (d.w.). Soil dioxin-BEQs were higher in northern Taiwan (61.8 pg-BEQ/g d.w.) than in central, southern, and eastern Taiwan (22.2, 24.9, and 7.80 pg-BEQ/g d.w., respectively). Analysis of multiple linear regression models identified four major predictors of dioxin-BEQs including soil sampling location (β = 0.097, p < 0.001), land use (β = 0.065, p < 0.001), soil brightness (β = 0.170, p < 0.001), and soil moisture (β = 0.051, p = 0.020), with adjusted R2 = 0.947 (p < 0.001) (n = 662). An univariate logistic regression analysis with the cut-off point of 33.4 pg-BEQ/g d.w. showed significant odds ratios (ORs) for soil sampling location (OR = 2.43, p < 0.001), land use (OR = 1.47, p < 0.001), and soil brightness (OR = 2.83, p = 0.009). In conclusion, four variables, including soil sampling location, land use, soil brightness, and soil moisture, may be related to soil-dioxin contamination. Soil samples collected in northern Taiwan, and especially in Bade City, soils near industrial areas, and soils with darker color may contain higher dioxin-BEQ levels.
PMCID: PMC4053921  PMID: 24806195
polychlorinated dibenzo-p-dioxins/furans; soil; aryl hydrocarbon receptor (AhR); bioassay; DR-CALUX®; dioxin survey
23.  Village Doctors’ Acceptability to a Syndromic Surveillance System in Rural China 
PMCID: PMC4050779
Syndromic surveillance; Acceptability; Village doctors; Rural China
24.  Acute Ethanol-Induced Changes in Edema and Metabolite Concentrations in Rat Brain 
BioMed Research International  2014;2014:351903.
The aim of this study is to describe the acute effects of EtOH on brain edema and cerebral metabolites, using diffusion weight imaging (DWI) and proton magnetic resonance spectroscopy (1H-MRS) at a 7.0T MR and to define changes in apparent diffusion coefficient (ADC) values and the concentration of metabolites in the rat brain after acute EtOH intoxication. ADC values in each ROI decreased significantly at 1 h and 3 h after ethanol administration. ADC values in frontal lobe were decreased significantly compared with other regions at 3 h. For EtOH/Cr+PCr and cerebral metabolites (Cho, Tau, and Glu) differing over time, no significant differences for Ins, NAA, and Cr were observed in frontal lobes. Regression analysis revealed a significant association between TSEtOH/Cr+PCr and TSCho, TSTau, TSGlu, and TSADC. The changes of ADC values in different brain regions reflect the process of the cytotoxic edema in vivo. The characterization of frontal lobes metabolites changes and the correlations between TSEtOH/Cr+PCr and TSCho, TSTau, and TSGlu provide a better understanding for the biological mechanisms in neurotoxic effects of EtOH on the brain. In addition, the correlations between TSEtOH/Cr+PCr and TSADC will help us to understand development of the ethanol-induced brain cytotoxic edema.
PMCID: PMC3982422  PMID: 24783201
25.  RNA Sequencing Reveals Upregulation of RUNX1-RUNX1T1 Gene Signatures in Clear Cell Renal Cell Carcinoma 
BioMed Research International  2014;2014:450621.
In the past few years, therapies targeted at the von Hippel-Lindau (VHL) and hypoxia-inducible factor (HIF) pathways, such as sunitinib and sorafenib, have been developed to treat clear cell renal cell carcinoma (ccRCC). However, the majority of patients will eventually show resistance to antiangiogenesis therapies. The purpose of our study was to identify novel pathways that could be potentially used as targets for new therapies. Whole transcriptome sequencing (RNA-Seq) was conducted on eight matched tumor and adjacent normal tissue samples. A novel RUNX1-RUNX1T1 pathway was identified which was upregulated in ccRCC through gene set enrichment analysis (GSEA). We also confirmed the findings based on previously published gene expression microarray data. Our data shows that upregulated of the RUNX1-RUNX1T1 gene set maybe an important factor contributing to the etiology of ccRCC.
PMCID: PMC3982423  PMID: 24783204

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