Integrating Citizen Scientist Data into the Surveillance System for Avian Influenza Virus, Taiwan.

The continuing circulation and reassortment with low-pathogenicity avian influenza Gs/Gd (goose/Guangdong/1996)-like avian influenza viruses (AIVs) has caused huge economic losses and raised public health concerns over the zoonotic potential. Virologic surveillance of wild birds has been suggested as part of a global AIV surveillance system. However, underreporting and biased selection of sampling sites has rendered gaining information about the transmission and evolution of highly pathogenic AIV problematic. We explored the use of the Citizen Scientist eBird database to elucidate the dynamic distribution of wild birds in Taiwan and their potential for AIV exchange with domestic poultry. Through the 2-stage analytical framework, we associated nonignorable risk with 10 species of wild birds with >100 significant positive results. We generated a risk map, which served as the guide for highly pathogenic AIV surveillance. Our methodologic blueprint has the potential to be incorporated into the global AIV surveillance system of wild birds.

Carboxypeptidase E is a prediction marker for tumor recurrence in early-stage hepatocellular carcinoma.

Tumor recurrence and metastasis are the major causes of death for hepatocellular carcinoma (HCC) patients who are able to receive curative resection. Identifying the predicting biomarkers for tumor recurrence would improve their survival. RNA extracted from fresh frozen tumors and adjacent non-tumor liver tissues of 120 HCC patients were obtained from Taiwan Liver Cancer Network (TLCN) in year 2010 for determination of the carboxypeptidase E (CPE) expression level (including its splicing mutant CPE-ΔN) in the tumor tissue (T) and paired non-tumor liver tissue (N) by real-time quantitative polymerase chain reaction. All patients were male, had chronic hepatitis B virus infection, were in the early pathology stage, and received curative resection. The T/N ratio of the CPE expression level was correlated with the updated survival data from TLCN in 2015. The CPE expression level in the 120 HCC patients was divided into three groups according to the T/N ratio: <1, ≥1 and ≤2, and >2, respectively. By multivariate analyses, the recurrence-free survival (RFS) was only significantly associated with the pathology stage and the CPE expression level. For overall survival (OS), only the CPE expression level was the significant prognostic factor. The CPE expression level was also significantly correlated with the tumor recurrence for both stage I (p = 0.0106) and stage II patients (p = 0.0006). The CPE mRNA expression level in HCC can be a useful biomarker for predicting tumor recurrence in HCC patients who are in the early pathology stage and able to receive curative resection.

Two-stage algorithms for visually exploring spatio-temporal clustering of avian influenza virus outbreaks in poultry farms.

The development of visual tools for the timely identification of spatio-temporal clusters will assist in implementing control measures to prevent further damage. From January 2015 to June 2020, a total number of 1463 avian influenza outbreak farms were detected in Taiwan and further confirmed to be affected by highly pathogenic avian influenza subtype H5Nx. In this study, we adopted two common concepts of spatio-temporal clustering methods, the Knox test and scan statistics, with visual tools to explore the dynamic changes of clustering patterns. Since most (68.6%) of the outbreak farms were detected in 2015, only the data from 2015 was used in this study. The first two-stage algorithm performs the Knox test, which established a threshold of 7 days and identified 11 major clusters in the six counties of southwestern Taiwan, followed by the standard deviational ellipse (SDE) method implemented on each cluster to reveal the transmission direction. The second algorithm applies scan likelihood ratio statistics followed by AGC index to visualize the dynamic changes of the local aggregation pattern of disease clusters at the regional level. Compared to the one-stage aggregation approach, Knox-based and AGC mapping were more sensitive in small-scale spatio-temporal clustering.

Pulmonary vein volume and myocardial sleeve extension estimated by 3D computed tomography and voltage mapping predict arrhythmogenic triggers of paroxysmal atrial fibrillation.

PURPOSE: Relationship between pulmonary vein (PV) anatomy and the pathophysiology of paroxysmal atrial fibrillation (PAF) remains incompletely studied. The aim of this study was to determine whether PV anatomy predicts arrhythmogenic PVs. METHODS: Twenty-six consecutive PAF patients with spontaneous PAF or consistently frequent ectopic beats during electrophysiological study were enrolled. Computed tomography (CT) images for PVs were reconstructed into 3D images. The PV diameter and volume were measured based on the 3D images. The PV myocardial sleeve area was measured based on the 3D voltage mapping results. The PV myocardial sleeve area index was calculated by dividing the sleeve area of each PV by the average sleeve area of all PVs in each patient. RESULTS: The diameter and volume of the arrhythmogenic PVs were larger than those of the non-arrhythmogenic PVs (21.08 ± 4.57 mm vs. 16.47 ± 3.31 mm, P < 0.001 and 7.70 ± 3.28 cm3 vs. 4.09 ± 1.99 cm3, P < 0.001, respectively). The myocardial sleeve area and sleeve area index of the arrhythmogenic PVs were also larger than those of the non-arrhythmogenic PVs (8.62 ± 5.33 cm2 vs. 4.77 ± 3.84 cm2, P < 0.001 and 1.59 ± 0.35 vs. 0.81 ± 0.38, P < 0.001, respectively). Multivariate analysis showed the PV myocardial sleeve area index was the independent predictor for arrhythmogenic PVs (P < 0.001). CONCLUSIONS: PV size plays an important role in triggering PAF. A large myocardial sleeve extension is a powerful and independent predictor for arrhythmogenic PV, which may be useful anatomical markers to facilitate PAF ablation.

Model-based prediction of length of stay for rehabilitating stroke patients.

BACKGROUND/PURPOSE: Accurate length-of-stay (LOS) estimates have an impact on medical costs for stroke patients. Most studies have reported only descriptive sample means or have provided linear-model-based estimates for LOS. This study calculated point and interval estimates by treating hospital discharge as an event, and utilizing the proportional hazards (PH) model to provide the estimation of hospital stay for first-ever stroke patients in a rehabilitation department of a clinical center. METHODS: Pairwise analysis for correlations between age, sex, comorbidity status, modified Barthel index (MBI) and functional independence measure (FIM) was performed. These explanatory variables are used in the K-sample comparisons, the Chi-squared test for association, the PH regression analysis, and log-transformed linear (LTL) regression. RESULTS: The PH model gave a prediction on estimated mean LOS, with an absolute bias of 0.85 days, by combining MBI and FIM into a single variable, or a bias of 1.15 days and 1.16 days with MBI and FIM variables, respectively. The LTL-based estimation generated a bias of 5.91 days. The PH model has relatively shorter confidence intervals than those obtained by sample-mean and LTL methods. CONCLUSION: We recommend using the PH model for predicting mean LOS when the PH assumption for patients with different clinical characteristics is satisfied. However, the proposed method only applies to rehabilitating stroke patients.

Survival analysis: comparing peritoneal dialysis and hemodialysis in Taiwan.

OBJECTIVES: Comparisons of survival in patients on peritoneal dialysis (PD) and on hemodialysis (HD) have been conducted in many Western countries, but publications on this subject in Asian populations are scarce. The present study estimated the survival and the relative mortality hazard for HD and PD patients in Taiwan. METHODS: Incident end-stage renal disease patients reported to the Taiwan Renal Registry during 1995 - 2002 were included in the study. Patients had to be 20 years of age or older and had to have survived for the first 90 days on dialysis. A total of 45,820 incident HD and 2,809 incident PD patients formed the study population. Patients on PD were treated mainly with traditional glucose-based solutions. Using an intent-to-treat analysis, the Cox proportional hazards (CPH) model was applied to identify the factors that predict survival by treatment modality. Subgroup analyses were conducted by stratifying patients according to sex, comorbidity, age, and diabetes status. Kaplan-Meier estimates were used to explore the survival of HD and PD patients. Adjustments were implemented using the CPH model. RESULTS: The overall 1-year, 2-year, 3-year, 5-year and 10-year survival rates for PD patients were 89.8%, 77.6%, 67.6%, 55.5%, and 35% respectively. The equivalent survival rates for HD patients were 87.5%, 76.6%, 68.1%, 54.3%, and 33.8%. The differences were not statistically significant (p = 0.125). The CPH analysis stratified by diabetes status and age revealed that PD patients 55 years of age or younger and nondiabetic had a lower mortality ratio (MR) of 0.94. But the MR increased to 1.31 for nondiabetic patients older than 55. The MR for PD versus HD further increased to 1.72 for diabetic patients 55 years of age or younger, and to 1.99 for diabetic patients older than 55. CONCLUSIONS: After adjusting for both demographic and clinical case-mix differences, PD and HD patients were observed to have similar long-term survival. Subgroup analyses revealed that, among diabetic patients and patients older than 55, those on HD experienced better survival than did those on PD.

Schedule effect and laparoscopic-assisted vaginal hysterectomy.

BACKGROUND: Prolonged surgical workload and different starting times of laparoscopic-assisted vaginal hysterectomy (LAVH) might be factors influencing surgical and patient's outcomes. AIMS: The aim of this study is to elucidate possible detrimental results of the schedule effect on LAVH. METHODS: Retrospective cohort study based on patient charts and hospital's electronic database in a tertiary teaching hospital. A total of 217 consecutive women who underwent LAVH for gynecological diseases were enrolled. Among them, 159 LAVHs performed by four surgeons were divided into three groups according to three different starting times of the operation. Among 159 LAVHs, 110 performed by the same surgeon were divided into three groups in the same way. Variables related to operative and medical outcomes were compared and analysed by one-way anova and chi-squared test. RESULTS: Data on both all women (159 cases) and subgroup women (110 cases) revealed that no statistical significant differences among the three groups including length of hospital stay, shift of serum haemoglobin, shift of serum haematocrit, flatulence-relief time, surgical blood loss, blood transfusion rate, rate of postoperative fluid injection over two days after surgery or complication rate. Interestingly, the first LAVH scheduled within the 08.30 to 10.29 hours time slot had the longest mean operation time. LAVHs starting within the 15.30 to 17.29 hours time slot had the shortest mean operation time. CONCLUSION: The time of day in which LAVH is performed does not have a detrimental effect on outcome. Successful LAVH is dependent on multidisciplinary team work to achieve good surgical and patient outcomes.

Associations among genetic susceptibility, DNA damage, and pregnancy outcomes of expectant mothers exposed to environmental tobacco smoke.

This study determined the effects of environmental tobacco smoke (ETS) on fetal growth by measuring neonatal birth outcomes and the extent of maternal DNA damage, and investigating the relationships among gene polymorphisms, genotoxicity, and pregnancy outcomes of expectant mothers who had exposed to tobacco smoke. This prospective study enrolled 685 pregnant women who completed an initial questionnaire at three central Taiwan hospitals between 2003 and 2004. Genotype analyses of CYP1A1, GSTT1, GSTM1, and NAT2 were performed from 421 women. A total of 398 women completed the follow-up analysis and successfully delivered a live single baby (n=384). Comet assay was performed for 18 smokers, 143 ETS-exposed subjects and 130 non-smokers to measure DNA damage. Analytical findings indicated that the levels of DNA damage among smokers and ETS-exposed subjects were significantly higher than that of non-smokers. DNA damage score in the ETS-exposed group was 84.3+/-44.3 and 63.5+/35.0 [corrected] for the nonsmoking group (p<0.001). Risk of DNA damage (DNA strand breakage, sister chromatid exchange, cell transformation and escalation of cytotoxicity) for subjects exposed to ETS was 7.49 times (adjusted odds ratio; 95% CI, 1.27-44.20) [corrected] greater than that of non-exposed to tobacco smoke at home. Average birth weight of neonates born to subjects with extremely serious DNA damage (within the 90th percentile, DNA damage score >or =129.5) was 141 g lighter than that of those with DNA damage score <129.5 (p=0.068) [corrected] The degree of DNA lesion was not related to metabolic polymorphic genes. The results of this study suggest that comet assay are reliable biomarkers for monitoring pregnant women exposed to tobacco smoke and indicate fetal growth effects from environmental exposure to tobacco smoke.

Overexpression of MutL homolog 1 and MutS homolog 2 proteins have reversed prognostic implications for stage I-II colon cancer patients.

BACKGROUND: The outcome of colon cancer patients without lymph node metastasis is heterogeneous. Searching for new prognostic markers is warranted. METHODS: One hundred twenty stage I-II colon cancer patients who received complete surgical excision during 1995-2004 were selected for this biomarker study. Immunohistochemical method was used to assess p53, epidermal growth factor receptor, MLH1, and MSH2 status. KRAS mutation was examined by direct sequencing. RESULTS: Thirty three patients (27.5%) developed metachronous metastasis during follow up. By multivariate analysis, only female gender (p = 0.03), high serum carcinoembryonic antigen (CEA) level (≧5 ng/ml) (p = 0.04), and MLH1 overexpression (p = 0.003) were associated with the metastasis group. The 5-year-survival rate were also significantly lower for female gender (71.7% versus 88.9%, p = 0.025), high CEA level (64.9% versus 92.4%, p < 0.001), and MLH1 overexpression (77.5% versus 94.4%, p = 0.039). In contrast, MSH2 overexpression was associated with better survival, 95.1% versus 75.5% (p = 0.024). CONCLUSIONS: The reversed prognostic implications in the overexpression of MLH1 and MSH2 for stage I-II colon cancer patients is a novel finding and worthy of further confirmation.

Differentiation of serum levels of trace elements in normal and malignant breast patients.

The objective of this study was to determine which elements in serum best differentiated breast cancer in a case-control study. Concentrations of 13 elements in serum of 68 breast tumor patients (25 malignant and 43 benign) and 26 healthy controls were measured. Logistic regression with different variable-selection procedures was used to determine a possible configuration of elements. Sensitivity and specificity of the model were calculated to obtain the optimal cutoff point for discriminating malignant breast cancers vs other individuals (including benign breast disease and normal ones). Acombination of Cd, Mn, and Fe was found to have a specificity and sensitivity of 100% using forward-type logistic regression, when the cutoff value of the combination score was 52.71. Using stepwise-type logistic regression, a combination of Cr and Mn had a sensitivity of 100% and a specificity of 97.1% when the combination score of 17.4 was chosen as the cutoff. Similar analysis could be implemented to compare the malignant and control groups. Specificity and sensitivity were 100% for Mn (forward and stepwise type) with a cutoff point of 6.40. For the backward regression, specificity was 84.6% and sensitivity was 100% for Zn, with a cutoff point of 869.1. In conclusion, there was a significant difference in concentrations of all 13 elements in serum between breast cancer patients and controls. A combination among Cd, Mn, Fe, Cr, and Zn might be important to determine a differentiating reference for breast cancers if a long-term followed-up study is to be conducted.

Transforming Growth Factor-ß1 T869C Gene Polymorphism Is Associated with Acquired Sick Sinus Syndrome via Linking a Higher Serum Protein Level.

BACKGROUND: Familial sick sinus syndrome is associated with gene mutations and dysfunction of ion channels. In contrast, degenerative fibrosis of the sinus node tissue plays an important role in the pathogenesis of acquired sick sinus syndrome. There is a close relationship between transforming growth factor-ß1 mediated cardiac fibrosis and acquired arrhythmia. It is of interest to examine whether transforming growth factor-ß1 is involved in the pathogenesis of acquired sick sinus syndrome. METHODS: Overall, 110 patients with acquired SSS and 137 age/gender-matched controls were screened for transforming growth factor-ß1 and cardiac sodium channel gene polymorphisms using gene sequencing or restriction fragment length polymorphism methods. An enzyme-linked immunosorbent assay was used to determine the serum level of transforming growth factor-ß1. RESULTS: Two transforming growth factor-ß1 gene polymorphisms (C-509T and T+869C) and one cardiac sodium channel gene polymorphism (H588R) have been identified. The C-dominant CC/CT genotype frequency of T869C was significantly higher in acquired sick sinus syndrome patients than in controls (OR 2.09, 95% CI 1.16-3.75, P = 0.01). Consistently, the level of serum transforming growth factor-ß1 was also significantly greater in acquired sick sinus syndrome group than in controls (5.3±3.4 ng/ml vs. 3.7±2.4 ng/ml, P = 0.01). In addition, the CC/CT genotypes showed a higher transforming growth factor-ß1 serum level than the TT genotype (4.25 ± 2.50 ng/ml vs. 2.71± 1.76 ng/ml, P = 0.028) in controls. CONCLUSION: Transforming growth factor-ß1 T869C polymorphism, correlated with high serum transforming growth factor-ß1 levels, is associated with susceptibility to acquired sick sinus syndrome.

The Hepatitis Viral Status in Patients With Hepatocellular Carcinoma: a Study of 3843 Patients From Taiwan Liver Cancer Network.

Hepatocellular carcinoma (HCC) is the leading cancer death in Taiwan. Chronic viral hepatitis infections have long been considered as the most important risk factors for HCC in Taiwan. The previously published reports were either carried out by individual investigators with small patient numbers or by large endemic studies with limited viral marker data. Through collaboration with 5 medical centers across Taiwan, Taiwan liver cancer network (TLCN) was established in 2005. All participating centers followed a standard protocol to recruit liver cancer patients along with their biosamples and clinical data. In addition, detailed viral marker analysis for hepatitis B virus (HBV) and hepatitis C virus (HCV) were also performed. This study included 3843 HCC patients with available blood samples in TLCN (recruited from November 2005 to April 2011). There were 2153 (56.02%) patients associated with HBV (HBV group); 969 (25.21%) with HCV (HCV group); 310 (8.07%) with both HBV and HCV (HBV+HCV group); and 411 (10.69%) were negative for both HBV and HCV (non-B non-C group). Two hundred two of the 2463 HBV patients (8.20%) were HBsAg(-), but HBV DNA (+). The age, gender, cirrhosis, viral titers, and viral genotypes were all significantly different between the above 4 groups of patients. The median age of the HBV group was the youngest, and the cirrhotic rate was lowest in the non-B non-C group (only 25%). This is the largest detailed viral hepatitis marker study for HCC patients in the English literatures. Our study provided novel data on the interaction of HBV and HCV in the HCC patients and also confirmed that the HCC database of TLCN is highly representative for Taiwan and an important resource for HCC research.

Early radiographic response to epidermal growth factor receptor-tyrosine kinase inhibitor in non-small cell lung cancer patients with epidermal growth factor receptor mutations: A prospective study.

BACKGROUND: The time schedules for response evaluation of epidermal growth factor receptor-tyrosine kinase Inhibitor (EGFR-TKI) in non-small cell lung cancer (NSCLC) patients are still ill-defined. METHODS: Stage IIIB/IV patients with histologically proven NSCLC were enrolled in this study if the tumor cells bore EGFR mutations other than T790M. Eligible patients were treated with either 250 mg of gefitinib or 150 mg of erlotinib once daily. The early response rate [computed tomography (CT) scan on Day 14], definitive response rate determined on Day 56, progression-free survival (PFS), overall survival (OS), and toxicity profile were assessed prospectively. RESULTS: Thirty-nine patients were enrolled in this study. A total of 29 patients (29/39, 74.4%) achieved partial response (PR). Twenty-one patients (21/39, 53.8%) had early radiological response on Day 14. The early radiological response rate in patients with PR was 72.4% (21/29). Only eight patients without a PR on early CT still ended with PR. Among the 29 patients with PR, the PFS (8.1 months) and OS (18.3 months) of the 21 patients with early CT response were shorter than those of the 8 patients without early CT response (11.9 and 24.0 months for PFS and OS, respectively). But the survival differences were statistically non-significant. CONCLUSIONS: A very high percentage (72.4%, 21/29) of NSCLC patients with EGFR mutations with PR demonstrates early radiological response to EGFR-TKIs, which would advocate early radiological examination for EGFR-TKI therapy in NSCLC patients.

Psychometric comparisons of the timed up and go, one-leg stand, functional reach, and Tinetti balance measures in community-dwelling older people.

OBJECTIVES: To compare the practicality, reliability, validity, and responsiveness of the timed up and go (TUG), one-leg stand (OLS), functional reach (FR), and Tinetti balance (TB) performance measures in people aged 65 and older. DESIGN: A prospective study. SETTING: Shin-Sher Township of Taichung County, west-central Taiwan. PARTICIPANTS: Twelve hundred community-dwelling older people. MEASUREMENTS: During an initial assessment at their residences, participants were interviewed for demographics, cognition, fall history, use of a walking aid, and activities of daily living (ADLs), in addition to completing the four balance tests. Falls were ascertained by telephone every 3 months for a 1-year follow-up; the four balance measures and ADLs were also reassessed at the end of the follow-up year. RESULTS: Of the four balance measures, the OLS had the lowest participation rate, and participation of people who were cognitively impaired had fallen in the previous year, used a walking aid, or suffered from an ADL disability was lower than for their counterparts. The time to complete the tests ranged from 58 seconds for OLS, to 160 seconds for the TB. All four balance measures exhibited excellent test-retest reliability and discriminant validity but poor responsiveness to fall status. The TB showed better discriminant, convergent, and predictive validities and responsiveness to ADL changes than the other three tests. CONCLUSION: According to psychometric properties, the most suitable performance measure for evaluating balance in community-dwelling older people was the TB, followed by the TUG.

The effect of crash experience on changes in risk taking among urban and rural young people.

A 20-month prospective study was conducted to investigate the effect of motorcycle crash experience on changes in risk taking among 2514 urban and 2304 rural students in Taiwan. Risk taking was assessed using a 14-item self-administered questionnaire at the beginning and end of the study. A risk-taking score for each student at the initial and the last follow-up assessments was generated from adding up points across all 14 items. For exposure variables, the study documented past motorcycle crash history at the initial assessment and collected detailed information about any motorcycle crash involvement that occurred during the study period. A general linear mixed model was applied to assess the effects of prior and recent crash involvements on the path of risk-taking behavior. The results show that at the initial assessment, students with crash experience had higher risk-taking levels than those without crash experience. However, crash experience, irregardless of whether it was measured in terms of crash history prior to the study, crash frequency, time elapsed since the last crash, or crash severity, did not significantly change the risk-taking path among students, even though its effect differed between urban and rural areas.

The temporal trend of influenza-associated morbidity and the impact of early appearance of antigenic drifted strains in a Southeast Asian country.

Globally, influenza infection is a major cause of morbidity and mortality in the elderly, who are suggested to be the major target group for trivalent influenza vaccine (TIV) vaccination by World Health Organization. In spite of an increasing trend in vaccine coverage rates in many countries, the effect of vaccination among the elderly in reducing hospitalization and mortality remains controversial. In this study, we conducted a historical cohort study to evaluate the temporal pattern of influenza-associated morbidity among persons older than 64 years over a decade. The temporal patterns of influenza-associated morbidity rates among the elderly older than 64 years indicated that Taiwan's elderly P&I outpatient visits have been decreasing since the beginning of the 1999-2000 influenza season; however, hospitalization has been increasing despite significant increases in vaccine coverage. The propensity score logistic regression model was implemented to evaluate the source of bias and it was found that the TIV-receiving group had a higher propensity score than the non-receiving group (P<0.0001). In order to investigate the major factors affecting the temporal pattern of influenza-associated morbidity, we then used the propensity score as a summary confounder in a multivariate Poisson regression model based on the trimmed data. Our final models suggested that the factors affected the temporal pattern of morbidity differently. The variables including co-morbidity, vaccination rate, influenza virus type A and B isolation rate were associated with increased outpatient visits and hospitalization (p<0.05). In contrast, variables including high propensity score, increased 1°C in temperature, matching vaccine strains of type A/H1N1 and type B were associated with decreased outpatient visits and hospitalization (p<0.05). Finally, we assessed the impact of early appearance of antigenic-drifted strains and concluded that an excess influenza-associated morbidity substantial trends toward higher P&I hospitalization, but not outpatient visits, during the influenza season with early appearance of antigenic-drifted strains.

Identification of transforming hepatitis B virus S gene nonsense mutations derived from freely replicative viruses in hepatocellular carcinoma.

BACKGROUND & AIMS: The correlation between chronic hepatitis B virus (HBV) infection and hepatocellular carcinoma (HCC) has been well-established. But the roles of viral factor remain uncertain. Only HBV X gene and nonsense mutations of S gene (C-terminal truncation of HBV surface protein) have been demonstrated to have transforming activity. Whether they play a significant role in hepatocarcinogenesis is still uncertain. METHODS: Twenty-five HBV-related HCC patients were positive for hepatitis B core antigen (HBcAg) in the cancerous parts of their HCC liver tissues by immunohistochemistry studies, and had available tissue for whole HBV genome sequence analysis. The results were compared with 25 gender and age-matched HBcAg negative HCCs. Plasmids encoding HBV S gene nonsense mutations identified from HBcAg (+) HCC tissue were constructed to investigate their cell proliferation, transformation activity and the oncogenic potentials by xenograft study and in vivo migration assay. RESULTS: HBcAg (+) HCC patients were significantly associated with cirrhosis and small tumor size (≦2 cm) when compared with HBcAg (-) HCC patients. Southern blot analyses revealed freely replicative forms of HBV in the cancerous parts of HBcAg(+) HCC. Three nonsense mutations of S gene (sL95*, sW182*, and sL216*) were identified in the HBcAg(+) HCC tumor tissues. sW182* and sL216* were recurrently found in the 25 HBcAg (-) HCC tumor tissue, too. Functional studies of the above 3 non-sense mutations all demonstrated higher cell proliferation activities and transformation abilities than wild type S, especially sW182*. Tumorigenicity analysis by xenograft experiments and in vitro migration assay showed potent oncogenic activity of sW182* mutant. CONCLUSIONS: This study has demonstrated potent oncogenic activity of nonsense mutations of HBV S gene, suggesting they may play an important role in hepatocarcinogenesis.

Varicella vaccination alters the chronological trends of herpes zoster and varicella.

BACKGROUND: Population studies on trends of varicella and herpes zoster (HZ) associated with varicella zoster vaccination and climate is limited. METHODS: This study used insurance claims data to investigate the chronological changes in incident varicella and HZ associated with varicella zoster vaccination. Poisson regression was used to estimate the occurrence of varicella associated with the occurrence of HZ and vice versa by year, season, sex, temperature, and sunny hours. RESULTS: The varicella incidence declined from 7.14 to 0.76 per 1,000 person-years in 2000-2009, whereas the HZ incidence increased from 4.04 to 6.24 per 1,000 person-years. Females tended to have a higher risk than men for HZ (p<0.0001) but not varicella. The monthly mean varicella incidence was the lowest in September (160 cases) and the highest in January (425 cases), while the mean HZ incidence was lower in February (370 cases) and higher in August (470 cases). HZ was negatively associated with the incidence of varicella before and after the varicella zoster vaccination (p<0.001), increased 1.6% within one week post-vaccination. The effect of temperature on HZ was attenuated by 18.5% (p<0.0001) in association with vaccination. The varicella risk was positively associated with sun exposure hours, but negatively associated with temperature only before vaccination. CONCLUSIONS: The varicella vaccination is effective in varicella prevention, but the incidence of HZ increases after vaccination. HZ has a stronger association with temperature and UV than with seasonality while varicella risk associated with temperature and UV is diminished.

Promoter polymorphism G-6A, which modulates angiotensinogen gene expression, is associated with non-familial sick sinus syndrome.

BACKGROUND: It is well known that familial sick sinus syndrome (SSS) is caused by functional alterations of ion channels and gap junction. Limited information is available on the mechanism of age-related non-familial SSS. Although evidence shows a close link between arrhythmia and the renin-angiotensin system (RAS), it remains to be determined whether the RAS is involved in the pathogenesis of non-familial SSS. METHODS: In this study, 113 patients with documented non-familial SSS and 125 controls were screened for angiotensinogen (AGT) and gap junction protein-connexin 40 (Cx40) promoter polymorphisms by gene sequencing, followed by an association study. A luciferase assay was used to determine the transcriptional activity of the promoter polymorphism. The interaction between nuclear factors and the promoter polymorphism was characterized by an electrophoretic mobility shift assay (EMSA). RESULTS: Association study showed the Cx40 -44/+71 polymorphisms are not associated with non-familial SSS; however, it indicated that four polymorphic sites at positions -6, -20, -152, and -217 in the AGT promoter are linked to non-familial SSS. Compared to controls, SSS patients had a lower frequency of the G-6A AA genotype (OR 2.88, 95% CI 1.58-5.22, P = 0.001) and a higher frequency of the G allele at -6 position (OR 2.65, 95% CI 1.54-4.57, P = 0.0003). EMSA and luciferase assays confirmed that nucleotide G at position -6 modulates the binding affinity with nuclear factors and yields a lower transcriptional activity than nucleotide A (P<0.01). CONCLUSION: G-6A polymorphism, which modulates the transcriptional activity of the AGT promoter, may contribute to non-familial SSS susceptibility.

Clinical implications of high MET gene dosage in non-small cell lung cancer patients without previous tyrosine kinase inhibitor treatment.

INTRODUCTION: Recently, two studies revealed that MET amplification was associated with secondary epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) resistance in non-small cell lung cancer (NSCLC) patients. But it remains uncertain whether MET amplification could be related to primary TKI resistance in NSCLC because of limited data. MATERIALS AND METHODS: MET gene dosage of the tumor tissues from 208 NSCLC patients was investigated by real time quantitative polymerase chain reaction and compared with molecular and clinical features, including EGFR mutations, KRAS mutations, EGFR gene copy numbers, and patient survivals. Three copies were used as the cutoff. Among them, 25 patients were also evaluable for EGFR TKI responsiveness. RESULTS: The proportion of high MET gene dosage was 10.58% (22/208) with higher incidence in squamous cell carcinoma (11.86%) and smokers (16.18%), although the differences with adenocarcinoma and nonsmokers were nonsignificant. Coexisting EGFR mutations were identified, and the incidence (8.54%) was similar to wild type (12.0%). High MET gene dosage was significantly associated with higher tumor stage (stage I + II versus stage III + IV; p = 0.0254) and prior chemotherapy for stage III + IV adenocarcinoma patients (35.71% versus 7.41%; p = 0.0145) but not correlated with primary TKI resistance. Among the 155 surgically resectable patients (stage I to IIIA), high MET gene dosage was significantly associated with shorter median survival (21.0 months versus 47.1 months; p = 0.042) by univariate analysis. CONCLUSIONS: High MET gene dosage was not related to primary TKI resistance and the incidence was increased after chemotherapy, suggesting high MET gene dosage may also be related to chemotherapy resistance.