The HPV E6 oncoprotein targets histone methyltransferases for modulating specific gene transcription.

Expression of viral proteins causes important epigenetic changes leading to abnormal cell growth. Whether viral proteins directly target histone methyltransferases (HMTs), a key family enzyme for epigenetic regulation, and modulate their enzymatic activities remains elusive. Here we show that the E6 proteins of both low-risk and high-risk human papillomavirus (HPV) interact with three coactivator HMTs, CARM1, PRMT1 and SET7, and downregulate their enzymatic activities in vitro and in HPV-transformed HeLa cells. Furthermore, these three HMTs are required for E6 to attenuate p53 transactivation function. Mechanistically, E6 hampers CARM1- and PRMT1-catalyzed histone methylation at p53-responsive promoters, and suppresses the binding of p53 to chromatinized DNA independently of E6-mediated p53 degradation. p53 pre-methylated at lysine-372 (p53K372 mono-methylation) by SET7 protects p53 from E6-induced degradation. Consistently, E6 downregulates p53K372 mono-methylation and thus reduces p53 protein stability. As a result of the E6-mediated inhibition of HMT activity, expression of p53 downstream genes is suppressed. Together, our results not only reveal a clever approach for the virus to interfere with p53 function, but also demonstrate the modulation of HMT activity as a novel mechanism of epigenetic regulation by a viral oncoprotein.

A prospective cohort study among new Chinese coal miners: the early pattern of lung function change.

AIMS: To investigate the early pattern of longitudinal change in forced expiratory volume in 1 second (FEV1) among new Chinese coal miners, and the relation between coal mine dust exposure and the decline of lung function. METHODS: The early pattern of lung function changes in 317 newly hired Chinese underground coal miners was compared to 132 referents. This three year prospective cohort study involved a pre-employment and 15 follow up health surveys, including a questionnaire and spirometry tests. Twice a month, total and respirable dust area sampling was done. The authors used a two stage analysis and a linear mixed effects model approach to analyse the longitudinal spirometry data, and to investigate the changes in FEV1 over time, controlling for age, height, pack years of smoking, mean respirable dust concentration, the room temperature during testing, and the groupxtime interaction terms. RESULTS: FEV1 change over time in new miners is non-linear. New miners experience initial rapid FEV1 declines, primarily during the first year of mining, little change during the second year, and partial recovery during the third year. Both linear and quadratic time trends in FEV1 change are highly significant. Smoking miners lost more FEV1 than non-smokers. Referents, all age less than 20 years, showed continued lung growth, whereas the miners who were under age 20 exhibited a decline in FEV1. CONCLUSION: Dust and smoking affect lung function in young, newly hired Chinese coal miners. FEV1 change over the first three years of employment is non-linear. The findings have implications for both methods and interpretation of medical screening in coal mining and other dusty work: during the first several years of employment more frequent testing may be desirable, and caution is required in interpreting early FEV1 declines.

Historical total and respirable silica dust exposure levels in mines and pottery factories in China.

Historical exposure estimates of total dust and respirable silica were made in a recent nested case-referent study of lung cancer among mine and pottery workers in China. Exposure to total dust and respirable silica was assessed in 20 mines and 9 pottery factories. The average total dust concentration was 7.26 mg center dot m-3, with a range from 17.68 mg center dot m-3 in the 1950s to 3.85 mg center dot m-3 in the 1980s, while the average respirable silica dust was 1.22 mg center dot m-3, with a range from 3.89 mg center dot m-3 in the 1950s to 0.43 mg center dot m-3 in the 1980s. The highest respirable silica dust occurred in the underground mining operations (1.43 mg center dot m-3), particularly for manual drillers (9.03 mg center dot m-3). Among all facility types, tungsten mines had the highest respirable silica dust exposure (1.75 mg center dot m-3), while the lowest exposure occurred in copper-iron mines (0.32 mg center dot m-3).

Indirect validation of a retrospective method of exposure assessment used in a nested case-control study of lung cancer and silica exposure.

Validations of retrospective methods of assessment used in occupational epidemiological studies have rarely been published. This study is an indirect validation of a quantitative retrospective assessment of exposure to silica used in a nested case-control study of lung cancer among workers at 29 metal mines and pottery factories in China. Indices of cumulative total dust and cumulative respirable dust were calculated by merging work histories with the historical exposure profile for each subject. To validate indirectly the methods of exposure assessment used in the study of lung cancer, trends for exposure response relation between the two indices of exposure to silica and risk of silicosis were evaluated with 376 patients with silicosis from the study population as the cases, and 1262 controls without silicosis for comparison. Age adjusted odds ratios (ORs) as a measure of risk of silicosis showed striking trends with both indices of exposure to silica. For cumulative respirable dust, the OR (95% confidence interval) rose from 7.6 (5.1-11.4) for low exposure to 20.0 (13.2-30.6) for medium exposure, and to 51.7 (31.0-86.8) for high exposure. The strength of the association between exposure to silica and risk of silicosis suggests that the retrospective assessment of exposure used in the case-control study of lung cancer would accurately reflect an exposure response relation between silica and lung cancer, if it existed.

Estimating historical exposure to silica among mine and pottery workers in the People's Republic of China.

A quantitative retrospective exposure assessment method was developed for use in a nested case-control study of lung cancer among mine and pottery workers exposed to silica dust in the People's Republic of China. Exposure assessment was carried out in 20 mines (10 tungsten, 6 iron/copper, and 4 tin) and nine pottery factories. A job title dictionary was developed and used in both the collection of historical exposure information and work histories of 1,668 (316 cases and 1,352 controls) study subjects. Several data abstraction forms were developed to collect historical and current exposure information and employees' work histories, starting in 1950. A retrospective exposure matrix was developed on the basis of facility/job title/calendar year combinations using available historical exposure information and current exposure profiles. Information on the amount of respirable, thoracic, and free silica content in total dust was used in estimating exposure to silica. Starting in 1950, 6,805 historical estimates had been carried out for 14 calendar-year periods. We estimated the average total dust concentration to be 9 mg/M3, with a range from 28 mg/M3 in earlier years to 3 mg/M3 in recent years. Several exposure indices [such as cumulative dust, average dust, cumulative respirable (< 5 mu in particle size) and thoracic (< 10 mu in particle size) silica dust, average respirable and thoracic silica dust, exposure-weighted duration, and the highest/longest exposure] were calculated for individuals by merging work history and historical exposure matrix for each study subject. We developed these various measures of exposure to allow investigators to compare and contrast different indices of historical exposure to silica.

Suicide in Singapore, 1986.

Three hundred and forty-two cases of suicide in Singapore (1986) were studied. The rates were highest among Indians males. Jumping from a height was the method used by 60% of the subjects, and the predominant associated factor as ascertained by the coroner was illness (51%), both physical and mental. About 40% had seen a doctor in the year prior to their death, and 20% had a history of a previous suicide attempt. The majority of cases killed themselves during the daylight hours.

Suicide and parasuicide in Singapore (1986).

Suicide and parasuicide rates have increased in Singapore since 1980 and in 1986 were estimated to be 13.1 per 100,000 and 92 per 100,000 respectively. Those most prone to suicidal behaviour are the Indians and the aged above 70 years. Jumping from a height is still the commonest method of suicide and self-poisoning is the most popular method of parasuicide.

A Malay cultural explanation for epilepsy.

The causal explanation given by a 24-year-old Malay woman from a low socioeconomic class for her epilepsy is described. This case illustrates how cultural explanations can protect an individual from the stigma of illness. The Malay concept of the supernatural and the causation of illness is discussed.