Partial thyroxine-binding globulin deficiency in a family with coding region mutations in the TBG gene.

PURPOSE: T4-binding globulin (TBG) is the main thyroid hormone (TH) transporter present in human serum. Inherited thyroxine-binding globulin (TBG) deficiency is caused by mutations in the TBG (SERPINA7) gene, which is located on the X chromosome. This study was performed to report and evaluate coding region mutations in TBG gene for partial thyroxine-binding globulin deficiency. METHODS: A pedigree spanning four generations is described in this study. The proband is a female with partial TBG deficiency. All members of this pedigree underwent thyroid function tests, while Sanger sequencing was used to identify the TBG gene mutations. Bioinformatics databases were used to evaluate the deleterious effects of the mutation(s). Two hundred and seven unrelated individuals were used to evaluate the thyroid function of individuals with different TBG mutations. A one-way ANOVA was used to analyze the impact of the TBG mutations on thyroid function. RESULTS: TBG gene sequencing results revealed that the proband had a novel mutation in codon 27 leading to alanine to valine substitution (p.A27V). This mutation was associated with lower serum T4 levels (p < 0.0001) when compared to the groups that did not carry the mutation. The previously reported p.L283F mutation was also found in the proband. The hemizygous p.L283F individuals presenting with lower T4 serum and TBG levels (p < 0.001) when compared to wildtype males and females. Both mutations were deleterious upon SIFT and PolyPhen-2 evaluation. CONCLUSION: Associated with partial thyroxine-binding globulin deficiency, this study reports a novel p.A27V mutation in the TBG gene.

The changing landscape of phase II/III metastatic sarcoma clinical trials-analysis of ClinicalTrials.gov.

BACKGROUND: Well-designed clinical trials are of great importance in validating novel treatments and ensuring an evidence-based approach for sarcoma. This study aimed to provide a comprehensive landscape of the characteristics of metastatic or advanced sarcoma clinical trials using the substantial resource of the ClincialTrials.gov database. METHODS: We identified 260,755 trials registered with ClinicalTrials.gov in the last 20 years, and 277 of them were eligible for inclusion. The baseline characteristics were ascertained for each trial. The trials were systematically reviewed to validate their classification into 96 trials registered before 2008 and 181 trials registered between 2008 and 2017. RESULTS: We found that in the last decade, metastatic and advanced sarcoma trials were predominantly phase II-III studies (p = 0.048), were more likely to be ≥2 arms (17.7% vs 35.3%, respectively; p = 0.007), and were more likely to use randomized (13.5% vs 30.4%; p = 0.002) and double-blinded (2.1% vs 9.4%; p = 0.024) assignment than trials registered before 2008. Furthermore, in the last 10-year period, metastatic sarcoma trials were more likely to be conducted in Asia. Treatment involving target therapy and immunotherapy were more common (71.8% vs 37.5%; p < 0.001) than in previous years. CONCLUSIONS: Our data showed provocative changes in the sarcoma landscape and demonstrated that the incidence of clinical trials with target therapy and immunotherapy is increasing. These findings emphasize the desperate need for novel strategies, including target therapy and immunotherapy, to improve the outcomes for patients with advanced sarcoma.

[The spatial distribution and epidemic trend of silicosis in Guangdong province].

Objective: To investigate the characteristics, temporal trend of silicosis, and provide basis for risk assessment and precise prevention and control of occupational diseases. Methods: Using descriptive statistics to analyze the reported cases of silicosis by SPSS 20.0 software. Reported silicosis cases, the constituent ratio, the incidence age and the working age at onset were analyzed by a linear trend test. Analyzing the variation trends of regional, industry, economic type and enterprise scale distributions by the chi-square trend test. Moreover, using Moran's I method for spatial autocorrelation analysis and trend-surface analysis. Results: (1) During 2006 to 2015, Guangdong province had reported 1, 428 cases of silicosis, mainly gathered in Foshan, Zhongshan, Guangzhou, Shenzhen, which included 1391 male cases accounting for 97.41%. And the average incidence age was 45 (39, 51) . The average working age of onset was 9 (5.5, 15) . In economic type distribution, the private economy took the main part, accounting for 59.1%. In enterprise scale distribution, it was dominated by small and medium enterprises (SMEs) , accounting for 32.4% and 37.3% respectively. In industry distribution, most cases were gathered in materials and mining industry, accounting for 32.1% and 22.9% respectively. (2) The number of silicosis cases, the incidence age and the working age of onset showed a rising trend (P<0.01) . Meanwhile, the constituent ratios of medium-sized enterprises and building materials industry were increasing (P<0.05) . The annual variation trends of regional, economic type and age distributions were not statistically significant (P> 0.05) . (3) The spatial distribution trend showed an inverted U type, which was firstly raised and then declined from south to north and from east to west. The distribution characteristic demonstrated some high-high cluster areas, including Chancheng, Nanhai, Shunde, Panyu, Dongguan, Pengjiang, and Zhongshan. While Wuhua showed a high-low outlier form (P<0.01) . Conclusion: Silicosis cases, age and working age of onset were on the rise, as well as the industry and enterprise scale distributions of occupational diseases presented a certain trend in Guangdong province from 2006 to 2015. There were high-high cluster and high-low outlier phenomena in spatial distribution with spatial correlation. Therefore, our work of silicosis epidemic trend and distribution may provide some bases for the occupational disease risk assessment and control.

[The analyze the epidemic trend and predict the incidence trend of occupational diseases in Guangdong province].

Objective: This study was aimed to analyze the epidemic trend and predict the incidence trend of occupational diseases during 2006-2015 in Guangdong province, which may provide the theoretical foundation for occupational disease risk assessment and precise control and prevention. Methods: We analyzed the number of reported occupational disease cases, the constituent ratio, the average age and working-age of patients. We also performed the linear-by-linear association test of new incidence, median age and median working-age by curve-fitting method, of which the diagnostic year was set as the independent variable. Meanwhile, we designed an ARIMA model to predict the variation tendency of occupational diseases in 2017-2020. Results: (1) During 2006-2015, the total reported cases of occupational disease is 5289, including 2101 cases of occupational pneumoconiosis (39.7%) , 1363 cases of occupational poisoning (25.8%) , and 864 cases of occupational otolaryngological and stomatological disease (16.3%) . (2) The number of occupational diseases and pneumoconiosis have a straight upward trend (R(2)=0.851, R(2)=0.856) , while the number of occupational otolaryngological and stomatological disease and occupational tumor have a exponential trend (R(2)=0.914, R(2)=0.696) . The constituent ratio of occupational poisoning is decreasing, and the constituent ratio of occupational otolaryngological and stomatological disease is increasing. (3) The average onset age is 40 (33, 46) years old, and the average onset working-age is 6 (3, 11) years. Both of them have a straight upward trend (R(2)=0.954、R(2)=0.792) . The onset age of pneumoconiosis, occupational poisoning and occupational otolaryngological and stomatological disease have a upward trend. In addition, the onset working-age of occupational poisoning and pneumoconiosis have a upward trend. (4) The number of occupational diseases in 2017-2020 is predicted to be between 902-1231. Conclusion: Occupational diseases in Guangdong province showed a trend of high incidence. The age and working-age of occupational diseases showed an extended trend. Therefore, our work of occupational epidemic trend may provide some bases for the occupational disease risk assessment and precise control and prevention.

Impact of the free-vaccine policy on timely initiation and completion of hepatitis B vaccination in Fujian, China.

The extent to which the free-vaccine policy impacts the initiation and completion of a hepatitis B vaccine series is poorly understood. The aim of this study was to evaluate the impact of the free-vaccine policy on hepatitis B vaccination. A provincial survey was conducted in 2006 in Fujian Province, south-east of China, where the free-vaccine policy for hepatitis B was announced in 2002 and implemented in 2003. A total of 1628 children were investigated, and 1443 (88.6%) were included in this analysis. Among the children studied, 55.2% were vaccinated within 24 h of birth, and 76.1% completed the hepatitis B vaccine series on time. The rate of hepatitis B surface antibody positivity increased from 29.9% among children born in 1992 to 90.5% among children born in 2005, while the corresponding HBV infection rate decreased from 30.4% to 1.72%. Logistic regression indicated that, compared to children born between 1996 and 2001, the odds ratios (ORs) for timely initiation were 2.57 (95% confidence interval [CI], 1.71-3.84), 5.24 (95% CI, 3.26-8.43) and 9.06 (95% CI, 4.48-18.34) among children born in 2003, 2004 and 2005, respectively; the corresponding ORs for completing the vaccine series were 4.23 (95% CI, 1.97-9.10), 3.76 (95% CI, 1.81-7.82) and 4.94 (95% CI, 1.74-14.00) among children born in 2003, 2004 and 2005, respectively. Children with delayed vaccine initiation (>24 h after birth) were less likely to complete the vaccine series than those who received a timely first dose (OR = 0.02, 95% CI, 0.005-0.09). The impact of the free-vaccine policy on vaccine initiation and vaccine series completion did not differ by children's residence area (rural vs urban). As hypothesized, the odds of completing the vaccine series increased after the free-vaccine policy was announced in 2002 among children with delayed initiation (>24 h after birth) but not among those with timely initiation (≤ 24 h after birth). In conclusion, the free-vaccine policy significantly improved the timely initiation and completion of the vaccine series. The impact of this policy on completion of the vaccine series was larger among children with delayed vaccine initiation.

Association between daily cigarette consumption and hypertension moderated by CYP2A6 genotypes in Chinese male current smokers.

The purpose of this study was to assess whether cytochrome P450 enzyme 2A6 (CYP2A6) genotypes moderate the association between smoking and hypertension. In this study, 954 Chinese male current smokers from a community-based chronic disease screening project in Guangzhou were interviewed with a structured questionnaire about socio-demographic status, smoking and other health-related behaviors. Blood was collected for DNA extraction and CYP2A6 genotyping. Hypertension was defined according to 2007 ESH-ESC Practice Guidelines. A multivariate logistic regression was performed to examine the interaction between smoking quantity and CYP2A6 genotypes on hypertension after adjusting for age, education level and other potential confounders. Multivariate analyses indicated that smoking more than 15 cigarettes per day significantly increased the risk of hypertension (odds ratio (OR)=1.59, 95% confidence interval (CI)=1.21-2.10) compared with smoking 1-15 cigarettes per day, and further suggested that smoking interacted with normal CYP2A6 metabolizer genotype to increase the risk of hypertension. Smokers consuming more than 15 cigarettes per day with normal CYP2A6 metabolizer genotypes had the highest risk of hypertension (OR=2.04, 95% CI=1.11-3.75) compared with those consuming 1-15 cigarettes per day with slower CYP2A6 metabolizer genotypes. These findings demonstrated that smoking quantity was positively associated with hypertension and that CYP2A6 genotypes may moderate this relationship.

Frequent epigenetic silencing of the bone morphogenetic protein 2 gene through methylation in gastric carcinomas.

Recently, it was reported that exogenous bone morphogenetic protein (BMP)-2 acted as an antiproliferative agent in a variety of cell lines, including normal and cancerous gastric cell lines, indicating that BMP-2 plays an important role during cell growth. However, despite the loss of BMP-2 expression in several cancers, the underlying mechanism remains unknown. Epigenetic silencing through DNA methylation is one of the key steps during carcinogenesis. In this study, we found, through analysis by the methylation-specific polymerase chain reaction technique, CpG island methylation of the BMP-2 promoter region in gastric and colon cancer cell lines. BMP-2 mRNA was found to be activated after 5-aza-2'-deoxycytidine treatment of the methylation-positive cells. Moreover, 24 of the 56 (42.9%) gastric cancer tissues exhibited promoter methylation. Immunohistochemical staining revealed that 18 of the 24 (75%) gastric cancer tissues without methylation signals exhibited BMP-2 expression, whereas among 20 cancer tissues with strong methylation signals only four (20%) expressed BMP-2 (P = 0.0003). These findings indicate that BMP-2 methylation is strongly associated with the loss of BMP-2 protein expression in the primary gastric carcinomas. BMP-2 methylation was more often observed in diffuse type (60.7%) than in intestinal type (25%) gastric carcinomas (P = 0.007). Thus, aberrant BMP-2 methylation and the resultant loss of BMP-2 expression may be related to gastric carcinogenesis, particularly in the diffuse type.