To have an overview of the role of BRCA1 and BRCA2 genes among Chinese high-risk breast cancer patients, we analyzed 489 such high-risk breast cancer patients from four breast disease clinical centers in China, by using PCR-DHPLC or SSCP-DNA sequencing analysis. Allelotype analysis was done at five short tandem repeat (STR) markers in or adjacent to BRCA1 on the recurrent mutation carriers. For those analyzed both genes, 8.7% of early-onset breast cancer cases and 12.9% of familial breast cancer cases had a BRCA1 or BRCA2 mutation, as compared with the 26.1% of cases with both early-onset breast cancer and affected relatives. For those reporting malignancy family history other than breast/ovarian cancer, the prevalence of BRCA1/2 mutation is about 20.5%, and it was significantly higher than the patients only with family history of breast/ovarian cancer (P = 0.02). The family history of ovarian cancer (26.7% vs. 11.9%) and stomach cancer (23.8% vs. 11.8%) doubled the incidence of BRCA1/2, but the difference did not reach the statistical significance. Two recurrent mutations in BRCA1, 1100delAT and 5589del8, were identified. The recurrent mutations account for 34.8% BRCA1 mutations in our series. Similar allelotypes were detected in most STR status for those harboring the same mutations. The BRCA1 associated tumors were more likely to exhibit a high tumor grade, negative C-erbB-2/neu status and triple negative (ER, PgR and C-erbB-2/neu negative) status (P < 0.05). We recommended the BRCA1 and BRCA2 genetic analysis could be done for high-risk breast cancer patient in Chinese population, especially for those with both early-onset breast cancer and affected relatives. There may be some degree of shared ancestry for the two recurrent BRCA1 mutations in Chinese.
Origin of the continental-scale Tan-Lu fault zone (TLFZ), East China, remains controversial. About 550 km sinistral offset of the Dabie orogenic belt (DOB) and Sulu orogenic belt (SOB) is shown along the NE-NNEstriking TLFZ. Syn-collisional, sinistral ductile shear belts in the TLFZ have been identified. Thirteen phengite bulk separates from the mylonites were dated by the 40 Ar/ 39 Ar method. They gave cooling ages of the 198-181 Ma for the shear belts along the eastern margin of the DOB and 221-210 Ma from the western margin of the SOB. Distribution of the foreland basin deposits suggests that sinistral offset of the DOB and SOB by the TLFZ took place prior to deposition of the Upper Triassic strata. The marginal structures around the DOB and SOB support syn-collisional faulting, and indicate anticlockwise rotation of the DOB during the displacement. The folding and thrust faulting related to crustal subduction, coeval with the TanLu faulting, is older than the foreland basin deposition related to the orogenic exhumation. Several lines of evidence demonstrate that the TLFZ was developed as a syncollisional transform fault during latest Middle to earliest Late Triassic time when the DOB and SOB experienced crustal subduction of the South China Block (SCB). Eastward increase of the crustal subduction rates is believed to be responsible for the sinistral transform faulting.
Nucleocapsid protein (NP), an essential RNA-binding viral protein in human coronavirus (CoV)-infected cells, is required for the replication and transcription of viral RNA. Recent studies suggested that human CoV NP is a valid target for antiviral drug development. Based on this aspect, structure-based virtual screening targeting nucleocapsid protein (NP) was performed to identify good chemical starting points for medicinal chemistry. The present study utilized structure-based virtual screening against human CoV-OC43 using the Zinc database, which is performed through docking with varying precisions and computational intensities to identify eight potential compounds. The chosen potential leads were further validated experimentally using biophysical means. Surface plasmon resonance (SPR) analysis indicated that one among the potential leads, 6-chloro-7-(2-morpholin-4-yl-ethylamino) quinoxaline-5,8-dione (small-compound H3), exhibited a significant decrease of RNA-binding capacity of NP by more than 20%. The loss of binding activity was manifested as a 20% decrease in the minimum on-rate accompanied with a 70% increase in the maximum off-rate. Fluorescence titration and X-ray crystallography studies indicated that H3 antagonizes the binding between HCoV-OC43 NP and RNA by interacting with the N-terminal domain of the NP. Our findings provide insight into the development of new therapeutics that disrupt the interaction between RNA and viral NP in the HCoV. The discovery of the new compound would be an impetus to design novel NP inhibitors against human CoV.
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