The ubiquitin system plays an important role in endoplasmic reticulum (ER)-associated degradation of proteins that are misfolded, that fail to associate with their oligomerization partners, or whose levels are metabolically regulated. E3 ubiquitin ligases are key enzymes in the ubiquitination process as they recognize the substrate and facilitate coupling of multiple ubiquitin units to the protein that is to be degraded. The Saccharomyces cerevisiae ER-resident E3 ligase Hrd1p/Der3p functions in the metabolically regulated degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase and additionally facilitates the degradation of a number of misfolded proteins from the ER. In this study we characterized the structure and function of the putative human orthologue of yeast Hrd1p/Der3p, designated human HRD1. We show that human HRD1 is a nonglycosylated, stable ER protein with a cytosolic RING-H2 finger domain. In the presence of the ubiquitin-conjugating enzyme UBC7, the RING-H2 finger has in vitro ubiquitination activity for Lys 48 -specific polyubiquitin linkage, suggesting that human HRD1 is an E3 ubiquitin ligase involved in protein degradation. Human HRD1 appears to be involved in the basal degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase but not in the degradation that is regulated by sterols. Additionally we show that human HRD1 is involved in the elimination of two model ER-associated degradation substrates, TCR-␣ and CD3-␦.When a newly synthesized protein molecule is translocated into the ER, 1 there is a fair chance that it may never reach its final destination as a functional molecule, since a significant proportion of newly synthesized proteins is degraded via the endoplasmic reticulum-associated degradation (ERAD) pathway (1). In particular, proteins that misfold along the folding pathway or cannot be appropriately folded as a result of mutations are degraded via this route. The cystic fibrosis transmembrane conductance regulator (CFTR) and its common mutation ⌬F508 in cystic fibrosis serve as an example in this context (2). In addition, proteins that lack their oligomerization partner(s) are prone to degradation, e.g. individual subunits of the T-cell receptor like TCR-␣ and CD3-␦ (3). Finally, ERAD also functions in the homeostatic regulation of metabolic pathways to degrade proteins whose activity needs to be attenuated at a certain metabolic state. Examples include 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGR) (4), which is further described below, and apolipoprotein B (5).Degradation of proteins from the ER requires dislocation of the substrate from the ER to the cytosol followed by proteolysis via the ubiquitin-proteasome pathway. The dislocation process is thought to require components of the translocon channel, including Sec61␣ (6 -8), as well as a complex of proteins designated CDC48/p97-Ufd1-Npl4 (9 -11). Ubiquitination also plays an essential role in dislocation as illustrated by the inhibition of protein dislocation when the ubiquitination machinery is disrupted (9...

ObjectiveColorectal cancer (CRC) screening has been widely implemented in many countries. However, evidence on participation and diagnostic yield of population-based CRC screening in China is sparse.DesignThe analyses were conducted in the context of the Cancer Screening Program in Urban China, which recruited 1 381 561 eligible participants aged 40–69 years from 16 provinces in China from 2012 to 2015. 182 927 participants were evaluated to be high risk for CRC by an established risk score system and were subsequently recommended for colonoscopy. Participation rates and detection of colorectal neoplasms in this programme were reported and their associated factors were explored.Results25 593 participants undertook colonoscopy as recommended, with participation rate of 14.0%. High level of education, history of faecal occult blood test, family history of CRC and history of colonic polyp were found to be associated with the participation in colonoscopy screening. Overall, 65 CRC (0.25%), 785 advanced adenomas (3.07%), 2091 non-advanced adenomas (8.17%) and 1107 hyperplastic polyps (4.33%) were detected. Detection rates of colorectal neoplasms increased with age and were higher for men. More advanced neoplasms were diagnosed in the distal colon/rectum (65.2%). Several factors including age, sex, family history of CRC, dietary intake of processed meat and smoking were identified to be associated with the presence of colorectal neoplasms.ConclusionThe diagnostic yield was not optimal using colonoscopy screening in high-risk populations given the relatively low participation rate. Our findings will provide important references for designing effective population-based CRC screening strategies in the future.

To investigate the prevalence of, and risk factors for, cervical infection with human papillomavirus (HPV) in the rural province of Shanxi, People's Republic of China, which has relatively high cervical cancer mortality rates, we interviewed and obtained cervical cell samples from 662 women aged 15 -59 years. A total of 24 different HPV types were identified using a GP5 þ /6 þ -based PCR assay able to detect 44 different HPV types. Human papillomavirus prevalence was 14.8% overall and 9.6% among women without cervical abnormalities (14.2 and 8.9%, respectively, age standardised to the world standard population). Multiple-type infections accounted for 30.6% of all infections. By far the most commonly found type was HPV16 (5.7% of all women and 38.8% of HPV-positive women), followed by HPV 58, 52, 33 and 18. Unlike most previous studies published, HPV prevalence was lower among women younger than 35 years (8.7%) than those older than 35 years (17.8%). High-risk HPV types predominated in all age groups. Although low-risk HPV types were rare in young women, they became more common with increasing age. 92.3% of women with cervical intraepithelial neoplasia grade 3 were infected with high-risk HPV types, but none with low-risk types only. No significant difference in HPV positivity was observed by educational level, sexual habits, reproductive history or use of contraceptive methods in this rural lowincome Chinese population.

Cancer is the leading death cause in urban China and the second one in rural China. Lung cancer is the most common cancer, followed by stomach cancer, liver cancer, esophageal cancer and colorectal cancer. Cancer Control Programs in China focus on prevention, early diagnosis and treatment. The prevention program includes an anti-smoking campaign and immunization against hepatitis B for infants and children under the age of 15. Screening for breast and cervix cancers is among efforts for the early detection and treatment. Public education and the promotion of healthy lifestyles have been actively carried out.