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1.  Risk factors and natural history of breast cancer in younger Chinese women 
World Journal of Clinical Oncology  2014;5(5):1097-1106.
AIM: To investigate the age differences in the risk factors, clinicopathological characteristics and patterns of treatment of female breast cancer patients.
METHODS: Seven thousand one hundred and fifty-two women with primary breast cancer from the Hong Kong Breast Cancer Registry were recruited after receiving patients’ consent, they were asked to complete standardized questionnaires which captured their sociodemographic characteristics and risk factors associated with breast cancer development. Among them, clinicopathological data and patterns of treatment were further collected from medical records of 5523 patients with invasive breast cancers. Patients were divided into two groups according to the age at diagnosis: younger (< 40 years old) vs older patients (≥ 40 years old) for subsequent analyses.
RESULTS: Analysis on the sociodemographic characteristics and exposure to risk factors were performed on 7152 women with primary breast cancer and the results revealed that younger patients were more likely to have unhealthy lifestyles; these include a lack of exercise (85.4% vs 73.2%, P < 0.001), having high stress in life (46.1% vs 35.5%, P < 0.001), having dairy/meat-rich diets (20.2% vs 12.9%, P < 0.001), having alcohol drinking habit (7.7% vs 5.2%, P = 0.002). Younger patients were also more likely to have hormone-related risk factors including nulliparity (43.3% vs 17.8%, P < 0.001) and an early age at menarche (20.7% vs 13.2%, P < 0.001). Analyses on clinicopathological characteristics and patterns of treatment were performed on 5523 women diagnosed with invasive breast cancer. The invasive tumours in younger patients showed more aggressive pathological features such as having a higher percentage of grade 3 histology (45.7% vs 36.5%, P < 0.001), having a higher proportion of tumours with lymphovascular invasion (39.6% vs 33.2%, P = 0.003), and having multifocal disease (15.7% vs 10.3%, P < 0.001); they received different patterns of treatment than their older counterparts.
CONCLUSION: Younger patients in Hong Kong are more likely to encounter risk factors associated with breast cancer development and have more aggressive tumours than their older counterparts.
doi:10.5306/wjco.v5.i5.1097
PMCID: PMC4259937  PMID: 25493246
Hong Kong Breast Cancer Registry; Breast cancer; Younger Chinese women; Sociodemographic characteristics; Risk factors; Clinicopathological characteristics; Breast cancer treatment
2.  A Novel Psittacine Adenovirus Identified During an Outbreak of Avian Chlamydiosis and Human Psittacosis: Zoonosis Associated with Virus-Bacterium Coinfection in Birds 
Chlamydophila psittaci is found worldwide, but is particularly common among psittacine birds in tropical and subtropical regions. While investigating a human psittacosis outbreak that was associated with avian chlamydiosis in Hong Kong, we identified a novel adenovirus in epidemiologically linked Mealy Parrots, which was not present in healthy birds unrelated to the outbreak or in other animals. The novel adenovirus (tentatively named Psittacine adenovirus HKU1) was most closely related to Duck adenovirus A in the Atadenovirus genus. Sequencing showed that the Psittacine adenovirus HKU1 genome consists of 31,735 nucleotides. Comparative genome analysis showed that the Psittacine adenovirus HKU1 genome contains 23 open reading frames (ORFs) with sequence similarity to known adenoviral genes, and six additional ORFs at the 3′ end of the genome. Similar to Duck adenovirus A, the novel adenovirus lacks LH1, LH2 and LH3, which distinguishes it from other viruses in the Atadenovirus genus. Notably, fiber-2 protein, which is present in Aviadenovirus but not Atadenovirus, is also present in Psittacine adenovirus HKU1. Psittacine adenovirus HKU1 had pairwise amino acid sequence identities of 50.3–54.0% for the DNA polymerase, 64.6–70.7% for the penton protein, and 66.1–74.0% for the hexon protein with other Atadenovirus. The C. psittaci bacterial load was positively correlated with adenovirus viral load in the lung. Immunostaining for fiber protein expression was positive in lung and liver tissue cells of affected parrots, confirming active viral replication. No other viruses were found. This is the first documentation of an adenovirus-C. psittaci co-infection in an avian species that was associated with a human outbreak of psittacosis. Viral-bacterial co-infection often increases disease severity in both humans and animals. The role of viral-bacterial co-infection in animal-to-human transmission of infectious agents has not received sufficient attention and should be emphasized in the investigation of disease outbreaks in human and animals.
Author Summary
Chlamydophila psittaci is a bacterial pathogen which can cause avian chlamydiosis and human psittacosis. Although C. psittaci is frequently detected in birds from the tropical and subtropical regions, large outbreaks of human infections rarely occur. During the investigation of a human psittacosis outbreak that was associated with avian chlamydiosis in Hong Kong, we identified a novel adenovirus in epidemiologically linked Mealy Parrots, which was not present in healthy birds unrelated to the outbreak or in other animals. Since there was a positive correlation between the adenovirus viral load and C. psittaci bacterial load in the lungs of the infected Mealy parrots and because adenoviruses are known to cause immunosuppression in birds, we speculate that our novel Psittacine adenovirus may have caused immunosuppression among infected parrots resulting in a larger number of Mealy Parrots being infected by C. psittaci with a higher bacterial load, leading to a greater chance of zoonotic transmission to humans.
doi:10.1371/journal.pntd.0003318
PMCID: PMC4256287  PMID: 25474263
3.  Prevalence and Psychosocial Correlates of Depressive Symptoms in Urban Chinese Women during Midlife 
PLoS ONE  2014;9(11):e110877.
Objective
Depression is common in women with much research focusing on hormonal changes and menopausal symptoms but with little exploration of psychosocial problems in midlife. This study investigates the prevalence of clinically relevant depressive symptoms in midlife Chinese women and its association with psychosocial factors.
Methods
A cross-sectional, community-based household survey of women aged 45 to 64 years of age was conducted in Hong Kong from September 2010 to March 2011. The structured questionnaire included demographic data, educational status, marital status and household income, as well as perceived current stressful events and significant life events in the past 12 months. Information on clinically relevant depressive symptoms was measured by the validated chinese Patient Health Questionnaire (PHQ-9).
Results
A total of 402 participants were recruited in the study period. Of the 393 women who completed the questionnaire, the prevalence of clinically relevant depressive symptoms (PHQ-9 score≧10) was 11.0%. In multiple regression analysis, being single/divorced/separated/widowed, having an educational level of primary school level or below, having multiple chronic diseases, loss of hobby or loss of close social support in the past 12 months in midlife were associated with clinically relevant depressive symptoms.
Conclusions
Correlates of clinically relevant depressive symptoms in midlife Chinese women can be used to identify those at increased risk and potentiate further studies to explore early psychosocial and community interventions.
doi:10.1371/journal.pone.0110877
PMCID: PMC4232349  PMID: 25398009
4.  Synthesis of 8-Hydroxyquinoline Derivatives as Novel Antitumor Agents 
ACS Medicinal Chemistry Letters  2012;4(2):170-174.
This letter describes the preparation of quinoline derivatives and their cytotoxic potentials toward human carcinoma cell lines. Among the selected compounds, 8-hydroxy-2-quinolinecarbaldehyde (3) showed the best in vitro cytotoxicity against the human cancer cell lines, including MDA231, T-47D, Hs578t, SaoS2, K562, SKHep1 (with a MTS50 range of 12.5–25 μg/mL) and Hep3B (with a MTS50 range of 6.25±0.034 μg/mL). The in vivo antitumor activity of compound 3 on subcutenaous Hep3B hepatocellular carcinoma xenograft in athymic nude mice was then studied. The results showed that the dose of 10 mg/kg/day of compound 3 with intraperitoneal injection for 9 days totally abolished the growth of the xenograft tumor of Hep3B with no histological damage on vital organs as compared with the control. The experimental results suggested that compound 3 has a good potential as an antitumor agent.
doi:10.1021/ml300238z
PMCID: PMC4027363  PMID: 24900641
quinoline derivatives; 8-hydroxy-2-quinolinecarbaldehyde; antitumor; hepatocellular carcinoma
5.  Oncogene GAEC1 regulates CAPN10 expression which predicts survival in esophageal squamous cell carcinoma 
AIM: To identify the downstream regulated genes of GAEC1 oncogene in esophageal squamous cell carcinoma and their clinicopathological significance.
METHODS: The anti-proliferative effect of knocking down the expression of GAEC1 oncogene was studied by using the RNA interference (RNAi) approach through transfecting the GAEC1-overexpressed esophageal carcinoma cell line KYSE150 with the pSilencer vector cloned with a GAEC1-targeted sequence, followed by MTS cell proliferation assay and cell cycle analysis using flow cytometry. RNA was then extracted from the parental, pSilencer-GAEC1-targeted sequence transfected and pSilencer negative control vector transfected KYSE150 cells for further analysis of different patterns in gene expression. Genes differentially expressed with suppressed GAEC1 expression were then determined using Human Genome U133 Plus 2.0 cDNA microarray analysis by comparing with the parental cells and normalized with the pSilencer negative control vector transfected cells. The most prominently regulated genes were then studied by immunohistochemical staining using tissue microarrays to determine their clinicopathological correlations in esophageal squamous cell carcinoma by statistical analyses.
RESULTS: The RNAi approach of knocking down gene expression showed the effective suppression of GAEC1 expression in esophageal squamous cell carcinoma cell line KYSE150 that resulted in the inhibition of cell proliferation and increase of apoptotic population. cDNA microarray analysis for identifying differentially expressed genes detected the greatest levels of downregulation of calpain 10 (CAPN10) and upregulation of trinucleotide repeat containing 6C (TNRC6C) transcripts when GAEC1 expression was suppressed. At the tissue level, the high level expression of calpain 10 protein was significantly associated with longer patient survival (month) of esophageal squamous cell carcinoma compared to the patients with low level of calpain 10 expression (37.73 ± 16.33 vs 12.62 ± 12.44, P = 0.032). No significant correction was observed among the TNRC6C protein expression level and the clinocopathologcial features of esophageal squamous cell carcinoma.
CONCLUSION: GAEC1 regulates the expression of CAPN10 and TNRC6C downstream. Calpain 10 expression is a potential prognostic marker in patients with esophageal squamous cell carcinoma.
doi:10.3748/wjg.v19.i18.2772
PMCID: PMC3653151  PMID: 23687414
Esophageal squamous cell carcinoma; Oncogene; RNA interference; Calpain 10; Tissue microarray
6.  Clinical and pathological characteristics of Chinese patients with BRCA related breast cancer 
The HUGO Journal  2010;3(1-4):63-76.
Breast cancers related to BRCA mutations are associated with particular biological features. Here we report the clinical and pathological characteristics of breast cancer in Chinese women with and without BRCA mutations and of carriers of BRCA1 mutations compared to BRCA2 mutations. Two hundred and 26 high-risk Hong Kong Chinese women were tested for BRCA mutations, medical information was obtained from medical records, and risk and demographic information was obtained from personal interviews. In this cohort, 28 (12.4%) women were BRCA mutation carriers and among these carriers, 39.3% were BRCA1 and 60.7% were BRCA2 mutations. Mutation carriers were more likely to have a familial history of breast and ovarian cancer, high-grade cancers, and triple negative (TN) cancers. Prevalence of TN was 48.3% in BRCA carriers and 25.6% in non-carriers and was 67.7% in BRCA1 and 35.3% in BRCA2 carriers. Estrogen receptor (ER) negative cancer was significantly associated with BRCA1 mutations, especially in those under 40 years of age. BRCA-related breast cancer in this Chinese population is associated with family history and adverse pathological/prognostic features, with BRCA2 mutations being more prevalent but BRCA1 carriers having more aggressive and TN cancers. Compared to Caucasian populations, prevalence of BRCA2 mutations and TN cancer in BRCA2 mutation carriers in Chinese population are elevated.
doi:10.1007/s11568-010-9136-z
PMCID: PMC2881322  PMID: 20535403
Breast cancer; BRCA mutation; Pathology; Clinical features; Chinese
7.  Clinical and pathological characteristics of Chinese patients with BRCA related breast cancer 
The Hugo Journal  2010;3(1-4):63-76.
Breast cancers related to BRCA mutations are associated with particular biological features. Here we report the clinical and pathological characteristics of breast cancer in Chinese women with and without BRCA mutations and of carriers of BRCA1 mutations compared to BRCA2 mutations. Two hundred and 26 high-risk Hong Kong Chinese women were tested for BRCA mutations, medical information was obtained from medical records, and risk and demographic information was obtained from personal interviews. In this cohort, 28 (12.4%) women were BRCA mutation carriers and among these carriers, 39.3% were BRCA1 and 60.7% were BRCA2 mutations. Mutation carriers were more likely to have a familial history of breast and ovarian cancer, high-grade cancers, and triple negative (TN) cancers. Prevalence of TN was 48.3% in BRCA carriers and 25.6% in non-carriers and was 67.7% in BRCA1 and 35.3% in BRCA2 carriers. Estrogen receptor (ER) negative cancer was significantly associated with BRCA1 mutations, especially in those under 40 years of age. BRCA-related breast cancer in this Chinese population is associated with family history and adverse pathological/prognostic features, with BRCA2 mutations being more prevalent but BRCA1 carriers having more aggressive and TN cancers. Compared to Caucasian populations, prevalence of BRCA2 mutations and TN cancer in BRCA2 mutation carriers in Chinese population are elevated.
doi:10.1007/s11568-010-9136-z
PMCID: PMC2881322  PMID: 20535403
Breast cancer; BRCA mutation; Pathology; Clinical features; Chinese
8.  Effect of peroxisome proliferator activated receptor γ ligands on growth and gene expression profiles of gastric cancer cells 
Gut  2004;53(3):331-338.
Background and aims: Although peroxisome proliferator activated receptor γ (PPARγ) agonists have been implicated in differentiation and growth inhibition of cancer cells, the potential therapeutic and chemopreventive effects on gastric cancer are poorly defined. We examined the in vitro and in vivo effects of PPARγ ligands on growth of gastric cancer, and the effect of PPARγ activation on expression of cyclooxygenase 2 (COX-2) and cancer related genes.
Methods: Gastric cell lines (MKN28 and MKN45) were treated with two specific PPARγ ligands: ciglitazone and 15-deoxy-Δ12,14-prostaglandin J2. Cell growth was determined by bromodeoxyuridine incorporation assay and apoptosis was measured by DNA fragmentation. Expression of COX-2 was determined by western blot and real time quantitative polymerase chain reaction (PCR). Expression profiles of cancer related genes were screened with cDNA array. In vivo growth of implanted MKN45 cells in nude mice was monitored after oral treatment with rosiglitazone.
Results: PPARγ ligands suppressed the in vitro growth of MKN45 cells in a dose dependent manner whereas prostacyclin, a PPARδ agonist, had no growth inhibitory effect. Growth inhibition was more pronounced in MKN45 cells, which was accompanied by DNA fragmentation and downregulation of COX-2. Screening by cDNA microarray showed that PPARγ ligand treatment was associated with upregulation of bad and p53, and downregulation of bcl-2, bcl-xl, and cyclin E1 in MKN45 cells, which was confirmed by quantitative real time PCR. In contrast, MKN28 cells with lower PPARγ and COX-2 expression levels had lower growth inhibitory responses to PPARγ ligands. Microarray experiments only showed induction of the bad gene in MKN28 cells. In vivo growth of MKN45 cells in nude mice was retarded by rosiglitazone. Mean tumour volume in rosiglitazone treated mice was significantly lower than controls at six weeks (p = 0.019) and seven weeks (p = 0.001) after treatment.
Conclusions: PPARγ ligands suppress both in vitro and in vivo growth of gastric cancer and may play a major role in cancer therapy and prevention.
doi:10.1136/gut.2003.021105
PMCID: PMC1773979  PMID: 14960510
peroxisome proliferator activated receptor; apoptosis; cyclooxygenase; gene expression; gastric cancer
9.  DNA analysis of Huntington's disease in southern Chinese. 
Journal of Medical Genetics  1995;32(2):120-124.
Allelic frequencies of RFLPs at loci closely linked to the HD gene, D4S95, D4S91, D4S141, and D4S90, were determined in 13 Huntington's disease (HD) patients from nine Chinese families and 129 normal subjects. These were similar for non-HD and HD chromosomes and the HD gene in Chinese is associated with multiple haplotypes. Hence the HD gene probably arose independently in the background haplotypes of the Chinese population. The heterozygosity rates for the two most useful RFLP sites are 0.659 for D4S95-AccI VNTR and 0.494 for D4S141-HindIII. (CAG)n repeat numbers ranged from 12 to 27 in 174 normal chromosomes. In 52 meiotic recombinations, the (CAG)n repeats were stably inherited in normal families. In HD families, 12 of 13 HD patients had expanded (CAG)n repeats of 40 to 58. Additionally, 10 asymptomatic family members had expanded (CAG)n repeats and the inheritance of the expanded repeat was unstable in these families.
Images
PMCID: PMC1050233  PMID: 7760321
10.  TP53-induced glycolysis and apoptosis regulator promotes proliferation and invasiveness of nasopharyngeal carcinoma cells 
Oncology Letters  2014;9(2):569-574.
The TP53-induced glycolysis and apoptosis regulator (TIGAR) is the protein product of the p53 target gene, C12orf5. TIGAR blocks glycolysis and promotes cellular metabolism via the pentose phosphate pathway; it promotes the production of cellular nicotinamide adenine dinucleotide phosphate (NADPH), which leads to enhanced scavenging of intracellular reactive oxygen species, and inhibition of oxidative stress-induced apoptosis in normal cells. Our previous study identified a novel nucleoside analog that inhibited cellular growth and induced apoptosis in nasopharyngeal carcinoma (NPC) cell lines via downregulation of TIGAR expression. Furthermore, the growth inhibitory effects of c-Met tyrosine kinase inhibitors were ameliorated by the overexpression of TIGAR in the NPC cell lines. These results indicate a significant role for TIGAR expression in the survival of NPCs. The present study aimed to further define the function of TIGAR expression in NPC cells. In total, 36 formalin-fixed, paraffin-embedded NPC tissue samples were obtained for the immunohistochemical determination of TIGAR expression. The effects of TIGAR expression on cell proliferation, NADPH production and cellular invasiveness were also assessed in NPC cell lines. Overall, TIGAR was overexpressed in 27/36 (75%) of the NPC tissues compared with the adjacent non-cancer epithelial cells. Similarly, TIGAR overexpression was also observed in a panel of six NPC cell lines compared with normal NP460 hTert and Het1A cell lines. TIGAR overexpression led to increased cellular growth, NADPH production and invasiveness of the NPC cell lines, whereas a knockdown of TIGAR expression resulted in significant inhibition of cellular growth and invasiveness. The expression of the two mesenchymal markers, fibronectin and vimentin, was increased by TIGAR overexpression, but reduced following TIGAR-knockdown. The present study revealed that TIGAR overexpression led to increased cellular growth, NADPH production and invasiveness, and the maintenance of a mesenchymal phenotype, in NPC tissues.
doi:10.3892/ol.2014.2797
PMCID: PMC4301475  PMID: 25621025
nasopharyngeal carcinoma; TP53-induced glycolysis and apoptosis regulator; cell growth; invasiveness; mesenchymal
12.  International validation of the Chinese University Prognostic Index for staging of hepatocellular carcinoma: a joint United Kingdom and Hong Kong study 
Chinese Journal of Cancer  2014;33(10):481-491.
The outcome of hepatocellular carcinoma (HCC) patients significantly differs between western and eastern population centers. Our group previously developed and validated the Chinese University Prognostic Index (CUPI) for the prognostication of HCC among the Asian HCC patient population. In the current study, we aimed to validate the CUPI using an international cohort of patients with HCC and to compare the CUPI to two widely used staging systems, the Barcelona Clinic Liver Cancer (BCLC) classification and the Cancer of the Liver Italian Program (CLIP). To accomplish this goal, two cohorts of patients were enrolled in the United Kingdom (UK; n = 567; 2006-2011) and Hong Kong (HK; n = 517; 2007-2012). The baseline clinical data were recorded. The performances of the CUPI, BCLC, and CLIP were compared in terms of a concordance index (C-index) and were evaluated in subgroups of patients according to treatment intent. The results revealed that the median follow-up durations of the UK and HK cohorts were 27.9 and 29.8 months, respectively. The median overall survival of the UK and HK cohorts were 22.9 and 8.6 months, respectively. The CUPI stratified the patients in both cohorts into three risk subgroups corresponding to distinct outcomes. The median overall survival of the CUPI low-, intermediate-, and high-risk subgroups were 3.15, 1.24, and 0.29 years, respectively, in the UK cohort and were 2.07, 0.32, and 0.10 years, respectively, in the HK cohort. For the patients who underwent curative treatment, the prognostic performance did not differ between the three staging systems, and all were suboptimal. For those who underwent palliative treatment, the CUPI displayed the highest C-index, indicating that this staging system was the most informative for both cohorts. In conclusion, the CUPI is applicable to both western and eastern HCC patient populations. The performances of the three staging systems differed according to treatment intent, and the CUPI was demonstrated to be optimal for those undergoing palliative treatment. A more precise staging system for early-stage disease patients is required.
doi:10.5732/cjc.014.10133
PMCID: PMC4198751  PMID: 25223914
Liver neoplasms; staging; international cooperation; therapeutics
13.  A novel missense mutation in CCDC88C activates the JNK pathway and causes a dominant form of spinocerebellar ataxia 
Journal of Medical Genetics  2014;51(9):590-595.
Background
Spinocerebellar ataxias (SCAs) are a group of clinically and genetically diverse and autosomal-dominant disorders characterised by neurological deficits in the cerebellum. At present, there is no cure for SCAs. Of the different distinct subtypes of autosomal-dominant SCAs identified to date, causative genes for only a fraction of them are currently known. In this study, we investigated the cause of an autosomal-dominant SCA phenotype in a family that exhibits cerebellar ataxia and pontocerebellar atrophy along with a global reduction in brain volume.
Methods and results
Whole-exome analysis revealed a missense mutation c.G1391A (p.R464H) in the coding region of the coiled-coil domain containing 88C (CCDC88C) gene in all affected individuals. Functional studies showed that the mutant form of CCDC88C activates the c-Jun N-terminal kinase (JNK) pathway, induces caspase 3 cleavage and triggers apoptosis.
Conclusions
This study expands our understanding of the cause of autosomal-dominant SCAs, a group of heterogeneous congenital neurological conditions in humans, and unveils a link between the JNK stress pathway and cerebellar atrophy.
doi:10.1136/jmedgenet-2014-102333
PMCID: PMC4145425  PMID: 25062847
Neurology; Clinical Genetics
14.  Continuation of Dabigatran Therapy in “Real-World” Practice in Hong Kong 
PLoS ONE  2014;9(8):e101245.
Background
Dabigatran, an oral direct thrombin inhibitor, possesses several advantages over warfarin that can in principle simplify the management of stroke prevention in atrial fibrillation (AF). Nonetheless it remains unclear whether these advantages can translate to clinical practice and encourage long-term therapy. The objective was to describe long-term dabigatran therapy for stroke prevention in AF and to identify risk factors for discontinuation of therapy.
Methods and Results
We studied 467 consecutive Chinese patients (72±11 years, male: 53.8%) with a mean CHA2DS2-VASc score of 3.6 prescribed dabigatran for stroke prevention in AF from March 2010 to September 2013. Over a mean follow-up of 16 months, 101 patients (21.6%) permanently discontinued dabigatran. The mean time-to-discontinuation was 8 months. The most common reason for discontinuation was dyspepsia (30.7%), followed by other adverse events (17.8%) such as minor bleeding (8.9%), major gastrointestinal bleeding (7.9%), and intracranial hemorrhage (1%). Other reasons included dosing frequency (5.9%), fear of side effects (4.0%), lack of laboratory monitoring (1.0%), and cost (1.0%). Multivariable analysis revealed that low baseline estimated glomerular filtration rate (p = 0.02), absence of hypertension (p = 0.01), and prior use of a proton-pump inhibitor (p = 0.02) and H2-receptor blocker (p = 0.01) were independent predictors of drug discontinuation. In addition, there were altogether 9 ischemic strokes (1.5%/years), 3 intracranial hemorrhages (0.5%/year), and 24 major gastrointestinal bleedings (4.1%/year).
Conclusion
Dabigatran discontinuation is very common amongst Chinese AF patients. This reveals a management gap in the prevention of stroke in AF.
doi:10.1371/journal.pone.0101245
PMCID: PMC4118845  PMID: 25084117
15.  Whole-genome bisulfite sequencing of multiple individuals reveals complementary roles of promoter and gene body methylation in transcriptional regulation 
Genome Biology  2014;15(7):408.
Background
DNA methylation is an important type of epigenetic modification involved in gene regulation. Although strong DNA methylation at promoters is widely recognized to be associated with transcriptional repression, many aspects of DNA methylation remain not fully understood, including the quantitative relationships between DNA methylation and expression levels, and the individual roles of promoter and gene body methylation.
Results
Here we present an integrated analysis of whole-genome bisulfite sequencing and RNA sequencing data from human samples and cell lines. We find that while promoter methylation inversely correlates with gene expression as generally observed, the repressive effect is clear only on genes with a very high DNA methylation level. By means of statistical modeling, we find that DNA methylation is indicative of the expression class of a gene in general, but gene body methylation is a better indicator than promoter methylation. These findings are general in that a model constructed from a sample or cell line could accurately fit the unseen data from another. We further find that promoter and gene body methylation have minimal redundancy, and either one is sufficient to signify low expression. Finally, we obtain increased modeling power by integrating histone modification data with the DNA methylation data, showing that neither type of information fully subsumes the other.
Conclusion
Our results suggest that DNA methylation outside promoters also plays critical roles in gene regulation. Future studies on gene regulatory mechanisms and disease-associated differential methylation should pay more attention to DNA methylation at gene bodies and other non-promoter regions.
Electronic supplementary material
The online version of this article (doi:10.1186/s13059-014-0408-0) contains supplementary material, which is available to authorized users.
doi:10.1186/s13059-014-0408-0
PMCID: PMC4189148  PMID: 25074712
16.  Infection of swine ex vivo tissues with avian viruses including H7N9 and correlation with glycomic analysis 
Objectives
Swine have been regarded as intermediate hosts in the spread of influenza from birds to humans but studies of the sialylated glycans that comprise their respiratory tract have not been extensively studied in the past. This study analyzed the sialylated N‐glycan and O‐glycan profile of swine trachea and lung and correlated this with ex‐vivo infection of swine explants with avian influenza viruses.
Sample
Lungs and tracheal samples were obtained from normal farm and laboratory raised swine and used for ex vivo infection as well as mass spectrometric analysis. Infection of the ex vivo tissues used high pathogenic and low pathogenic avian viruses including the novel H7N9 virus that emerged in China in early 2013.
Main outcome measures
Assessment of successful replication was determined by TCID50 as well as virus immunohistochemistry. The N‐glycan and O‐glycan profiles were measured by MALDI‐TOF and sialylated linkages were determined by sialidase treatment. Lectin binding histochemistry was also performed on formalin fixed tissue samples with positive binding detected by chromogen staining.
Results
The swine respiratory tract glycans differed from the human respiratory tact glycans in two main areas. There was a greater abundance of Gal‐α‐Gal linkages resulting in a relative decrease in sialylated glycans. The swine respiratory tract also had a greater proportion of glycans containing Neu5Gc and Siaα2‐6 glycans than the human respiratory tract. Infection with avian viruses was confined primarily to lung bronchioles rather than trachea and parenchyma.
Conclusions
In contrast to previous studies we found that there was not as much expression of Siaα2‐3 glycans on the surface of the trachea. Infection of Siaα2‐3 binding avian viruses was restricted to the lower respiratory tract bronchioles. This finding may diminish the ability of the swine to act as an intermediary in the transmission of avian viruses to humans.
doi:10.1111/irv.12144
PMCID: PMC4114536  PMID: 24001121
Glycomics; influenza A virus; swine
17.  Systemic treatment for inoperable pancreatic adenocarcinoma: review and update 
Chinese Journal of Cancer  2014;33(6):267-276.
There have been many clinical trials conducted to evaluate novel systemic regimens for unresectable pancreatic cancer. However, most of the trial results were negative, and gemcitabine monotherapy has remained the standard systemic treatment for years. A number of molecular targeted agents, including those against epidermal growth factor receptor and vascular endothelial growth factor receptors, have also been tested. In recent years, there have been some breakthroughs in the deadlock: three regimens, namely gemcitabine-erlotinib, FOLFIRINOX, and gemcitabine-nab-paclitaxel, have been shown to prolong the overall survival of patients when compared with gemcitabine monotherapy. In addition, emerging data suggested that the membrane protein human equilibrative nucleotide transporter 1 is a potential biomarker with which to predict the efficacy of gemcitabine. Here we review the literature on the development of systemic agents for pancreatic cancer, discuss the current choices of treatment, and provide future directions on the development of novel agents.
doi:10.5732/cjc.013.10134
PMCID: PMC4059864  PMID: 24472302
Pancreatic cancer; chemotherapy; biologics; review; literature
18.  Rational Design of Berberine-Based FtsZ Inhibitors with Broad-Spectrum Antibacterial Activity 
PLoS ONE  2014;9(5):e97514.
Inhibition of the functional activity of Filamenting temperature-sensitive mutant Z (FtsZ) protein, an essential and highly conserved bacterial cytokinesis protein, is a promising approach for the development of a new class of antibacterial agents. Berberine, a benzylisoquinoline alkaloid widely used in traditional Chinese and native American medicines for its antimicrobial properties, has been recently reported to inhibit FtsZ. Using a combination of in silico structure-based design and in vitro biological assays, 9-phenoxyalkyl berberine derivatives were identified as potent FtsZ inhibitors. Compared to the parent compound berberine, the derivatives showed a significant enhancement of antibacterial activity against clinically relevant bacteria, and an improved potency against the GTPase activity and polymerization of FtsZ. The most potent compound 2 strongly inhibited the proliferation of Gram-positive bacteria, including methicillin-resistant S. aureus and vancomycin-resistant E. faecium, with MIC values between 2 and 4 µg/mL, and was active against the Gram-negative E. coli and K. pneumoniae, with MIC values of 32 and 64 µg/mL respectively. The compound perturbed the formation of cytokinetic Z-ring in E. coli. Also, the compound interfered with in vitro polymerization of S. aureus FtsZ. Taken together, the chemical modification of berberine with 9-phenoxyalkyl substituent groups greatly improved the antibacterial activity via targeting FtsZ.
doi:10.1371/journal.pone.0097514
PMCID: PMC4019636  PMID: 24824618
19.  A Robust Parameter Estimation Method for Estimating Disease Burden of Respiratory Viruses 
PLoS ONE  2014;9(3):e90126.
Background
Poisson model has been widely applied to estimate the disease burden of influenza, but there has been little success in providing reliable estimates for other respiratory viruses.
Methods
We compared the estimates of excess hospitalization rates derived from the Poisson models with different combinations of inference methods and virus proxies respectively, with the aim to determine the optimal modeling approach. These models were validated by comparing the estimates of excess hospitalization attributable to respiratory viruses with the observed rates of laboratory confirmed paediatric hospitalization for acute respiratory infections obtained from a population based study.
Results
The Bayesian inference method generally outperformed the classical likelihood estimation, particularly for RSV and parainfluenza, in terms of providing estimates closer to the observed hospitalization rates. Compared to the other proxy variables, age-specific positive counts provided better estimates for influenza, RSV and parainfluenza, regardless of inference methods. The Bayesian inference combined with age-specific positive counts also provided valid and reliable estimates for excess hospitalization associated with multiple respiratory viruses in both the 2009 H1N1 pandemic and interpandemic period.
Conclusions
Poisson models using the Bayesian inference method and virus proxies of age-specific positive counts should be considered in disease burden studies on multiple respiratory viruses.
doi:10.1371/journal.pone.0090126
PMCID: PMC3961249  PMID: 24651832
20.  A randomized controlled trial to investigate the impact of a low glycemic index (GI) diet on body mass index in obese adolescents 
BMC Public Health  2014;14:180.
Background
The role of a low glycemic index (GI) diet in the management of adolescent obesity remains controversial. In this study, we aim to evaluate the impact of low GI diet versus a conventional Chinese diet on the body mass index (BMI) and other obesity indices of obese adolescents.
Methods
Obese adolescents aged 15–18 years were identified from population-recruited, territory-wide surveys. Obesity was defined as BMI ≥95th percentile of Hong Kong local age- and sex-specific references. Eligible subjects were randomized to either an intervention with low GI diet (consisting of 45-50% carbohydrate, 30-35% fat and 15-20% protein) or conventional Chinese diet as control (consisting of 55-60% carbohydrate, 25-30% fat and 10-15% protein). We used random intercept mixed effects model to compare the differential changes across the time points from baseline to month 6 between the 2 groups.
Results
104 obese adolescents were recruited (52 in low GI group and 52 in control group; 43.3% boys). Mean age was 16.7 ± 1.0 years and 16.8 ±1.0 years in low GI and control group respectively. 58.7% subjects completed the study at 6 months (65.4% in low GI group and 51.9% in control group). After adjustment for age and sex, subjects in the low GI group had a significantly greater reduction in obesity indices including BMI, body weight and waist circumference (WC) compared to subjects in the control group (all p <0.05). After further adjustment for physical activity levels, WC was found to be significantly lower in the low GI group compared to the conventional group (p = 0.018).
Conclusion
Low GI diet in the context of a comprehensive lifestyle modification program may be an alternative to conventional diet in the management of obese adolescents.
Trial registration number
ClinicalTrials.gov Ref. No: NCT01278563
doi:10.1186/1471-2458-14-180
PMCID: PMC3937245  PMID: 24552366
Glycemic index; Obesity; Adolescents; Chinese
21.  Identification of Specific Cell-Surface Markers of Adipose-Derived Stem Cells from Subcutaneous and Visceral Fat Depots 
Stem Cell Reports  2014;2(2):171-179.
Summary
Adipose-derived stem/stromal cells (ASCs) from the anatomically distinct subcutaneous and visceral depots of white adipose tissue (WAT) differ in their inherent properties. However, little is known about the molecular identity and definitive markers of ASCs from these depots. In this study, ASCs from subcutaneous fat (SC-ASCs) and visceral fat (VS-ASCs) of omental region were isolated and studied. High-content image screening of over 240 cell-surface markers identified several potential depot-specific markers of ASCs. Subsequent studies revealed consistent predominant expression of CD10 in SC-ASCs and CD200 in VS-ASCs across 12 human subjects and in mice. CD10-high-expressing cells sorted from SC-ASCs differentiated better than their CD10-low-expressing counterparts, whereas CD200-low VS-ASCs differentiated better than CD200-high VS-ASCs. The expression of CD10 and CD200 is thus depot-dependent and associates with adipogenic capacities. These markers will offer a valuable tool for tracking and screening of depot-specific stem cell populations.
Graphical Abstract
Highlights
•Cell-surface markers were comprehensively screened for subcutaneous and visceral ASCs•CD10 is specifically expressed in subcutaneous fat-depot-derived ASCs•CD200 is predominantly expressed in visceral fat-depot-derived ASCs•CD10 shows positive whereas CD200 negative correlation with adipogenic capacity
Little is known about the molecular identity and definitive markers of adipose-derived stem cells (ASCs) from pathophysiologically distinct subcutaneous and visceral fat depots. Through high-content image screening, Sugii and colleagues identified CD10 as subcutaneous-specific and CD200 as visceral-selective ASC markers. Their expression levels are correlated with ASC’s adipogenic capacities, implicating their potential use for tracking and screening of depot-specific cells.
doi:10.1016/j.stemcr.2014.01.002
PMCID: PMC3923222  PMID: 24527391
22.  Managing stress and anxiety through qigong exercise in healthy adults: a systematic review and meta-analysis of randomized controlled trials 
Background
An increasing number of studies have documented the effectiveness of qigong exercise in helping people reduce psychological stress and anxiety, but there is a scarcity of systematic reviews evaluating evidence from randomized controlled trials (RCTs) conducted among healthy subjects.
Methods
Thirteen databases were searched for RCTs from their inception through June 2013. Effects of qigong exercise were pooled across trials. Standardized mean differences (SMDs) were calculated for the pooled effects. Heterogeneity was assessed using the I 2 test. The risk of bias was assessed using the Cochrane criteria.
Results
Seven RCTs met the inclusion criteria. Two RCTs suggested that qigong exercise immediately relieved anxiety among healthy adults, compared to lecture attendance and structured movements only. Four RCTs suggested qigong exercise relieved anxiety (pooled SMD = -0.75; 95% CI, -1.11 to -0.40), and three RCTs suggested that qigong exercise reduced stress (pooled SMD = -0.88; 95% CI, -1.22 to -0.55) among healthy subjects following one to three months of qigong practice, compared to wait-list controls.
Conclusions
The available evidence suggests that qigong exercise reduces stress and anxiety in healthy adults. However, given the limited number of RCTs and their methodological flaws, further rigorously designed RCTs are needed.
doi:10.1186/1472-6882-14-8
PMCID: PMC3893407  PMID: 24400778
stress; anxiety; qigong; systematic review; meta-analysis
23.  Tropism of and Innate Immune Responses to the Novel Human Betacoronavirus Lineage C Virus in Human Ex Vivo Respiratory Organ Cultures 
Journal of Virology  2013;87(12):6604-6614.
Since April 2012, there have been 17 laboratory-confirmed human cases of respiratory disease associated with newly recognized human betacoronavirus lineage C virus EMC (HCoV-EMC), and 7 of them were fatal. The transmissibility and pathogenesis of HCoV-EMC remain poorly understood, and elucidating its cellular tropism in human respiratory tissues will provide mechanistic insights into the key cellular targets for virus propagation and spread. We utilized ex vivo cultures of human bronchial and lung tissue specimens to investigate the tissue tropism and virus replication kinetics following experimental infection with HCoV-EMC compared with those following infection with human coronavirus 229E (HCoV-229E) and severe acute respiratory syndrome coronavirus (SARS-CoV). The innate immune responses elicited by HCoV-EMC were also investigated. HCoV-EMC productively replicated in human bronchial and lung ex vivo organ cultures. While SARS-CoV productively replicated in lung tissue, replication in human bronchial tissue was limited. Immunohistochemistry revealed that HCoV-EMC infected nonciliated bronchial epithelium, bronchiolar epithelial cells, alveolar epithelial cells, and endothelial cells. Transmission electron microscopy showed virions within the cytoplasm of bronchial epithelial cells and budding virions from alveolar epithelial cells (type II). In contrast, there was minimal HCoV-229E infection in these tissues. HCoV-EMC failed to elicit strong type I or III interferon (IFN) or proinflammatory innate immune responses in ex vivo respiratory tissue cultures. Treatment of human lung tissue ex vivo organ cultures with type I IFNs (alpha and beta IFNs) at 1 h postinfection reduced the replication of HCoV-EMC, suggesting a potential therapeutic use of IFNs for treatment of human infection.
doi:10.1128/JVI.00009-13
PMCID: PMC3676115  PMID: 23552422
24.  Clinical Significance of Frizzled Homolog 3 Protein in Colorectal Cancer Patients 
PLoS ONE  2013;8(11):e79481.
Frizzled homolog 3 receptor was up-regulated in several gastrointestinal cancers such as esophageal and gastric cancers. Moreover, frizzled homolog 3 has recently reported to be expressed in colorectal adenoma specimens. In the present study, we investigated the clinical significance of frizzled homolog 3 protein in colorectal cancer patients. Using immunocytochemical staining, frizzled homolog 3 expression was examined in 186 colorectal cancer specimens, 79 colorectal adenoma specimens, 133 colorectal polyp specimens, 127 colorectal cancer specimens with lymph node and/or distant metastasis, 310 specimens of various non-colorectal cancer metastatic carcinomas and 40 specimens with simultaneous occurrence of colorectal cancer, colorectal adenoma and colorectal polyp. Statistical analysis was used to correlate frizzled homolog 3 protein expression to the clinicohistopathological factors, recurrence/metastasis and survival after follow-up for 42 months in colorectal cancer patients. Frizzled homolog 3 protein was expressed in 100% colorectal cancer specimens, 89% colorectal adenoma specimens, 75% colorectal polyp specimens and 69% normal colorectal epithelial tissues. Moreover, frizzled homolog 3 immunocytochemical scores were highly correlated with colorectal cancer progression. Furthermore, frizzled homolog 3 was expressed in a comparatively lower percentage of metastatic hepatocellular carcinoma and metastatic renal clear cell carcinoma with focal and very weak staining than other metastatic tumor types. On the other hand, the frizzled homolog 3 immunocytochemical scores of colorectal adenomas with synchronous colorectal carcinomas were significantly higher than those of pure colorectal adenomas. Statistical analysis showed that frizzled homolog 3 immunocytochemical scores were associated with Dukes stage and lymph node status. Finally, stratified groups of colorectal cancer patients had significant differences in their recurrence/metastasis and survival. In conclusion, the present large-scale study has clearly showed that frizzled homolog 3 protein can generate clinically important information for colorectal cancer patients.
doi:10.1371/journal.pone.0079481
PMCID: PMC3821856  PMID: 24255701
25.  The impact on patient health and service outcomes of introducing nurse consultants: a historically matched controlled study 
Background
The position of nurse consultant (NC) was introduced in Hong Kong by the Hospital Authority in January 2009. Seven NCs were appointed in five clinical specialties: diabetes, renal, wound and stoma care, psychiatrics, and continence. This was a pilot to explore the impact of the introduction of NCs on patient health and service outcomes.
Methods
The present paper describes a historically matched controlled study. A total of 280 patients, 140 in each cohort under NC or non-NC care, participated in the study. The patient health and service outcomes of both cohorts were evaluated and compared: accident and emergency visits, hospital admissions, length of hospital stays, number of acute complications, number of times of treatment or regimen altered by nurses according to patient’s condition, glycated haemoglobin A1c (HbA1c) levels, urea and urea-to-creatinine ratios, and number of wound dressings for patients in corresponding specialty units. A patient satisfaction instrument was also used to assess the NC cohort.
Results
The study showed that patients under NC care had favourable patient health and service outcomes compared with those under non-NC care. The NC cohort also reported a high level of patient satisfaction.
Conclusions
The study demonstrates that the introduction of NCs in specialty units may have a positive impact on patients’ health and service outcomes. The high level of patient satisfaction scores indicates that patients appreciate the care they are receiving with the introduction of NCs.
doi:10.1186/1472-6963-13-431
PMCID: PMC4016548  PMID: 24152979
Nurse consultant; Patient outcomes; Patient satisfaction; Hong Kong

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