Replication and Functional Genomic Analyses of the Breast Cancer Susceptibility Locus at 6q25.1 Generalize Its Importance in Women of Chinese, Japanese, and European Ancestry

We evaluated the generalizability of a single nucleotide polymorphism (SNP), rs2046210 (A/G allele), associated with breast cancer risk that was initially identified at 6q25.1 in a genome-wide association study conducted among Chinese women. In a pooled analysis of over 31,000 women of East-Asian, European, and African ancestry, we found a positive association for rs2046210 and breast cancer risk in Chinese women [ORs (95%CI)=1.30(1.22–1.38) and 1.64(1.50–1.80) for the AG and AA genotypes, respectively, P for trend = 1.54 × 10−30], Japanese women [ORs (95%CI)=1.31(1.13–1.52) and 1.37(1.06–1.76), P for trend = 2.51 × 10−4], and European-ancestry American women [ORs (95%CI)=1.07(0.99–1.16) and 1.18(1.04–1.34), P for trend = 0.0069]. No association with this SNP, however, was observed in African American women [ORs (95%CI)=0.81(0.63–1.06) and 0.85(0.65–1.11) for the AG and AA genotypes, respectively, P for trend = 0.4027). In vitro functional genomic studies identified a putative functional variant, rs6913578. This SNP is 1,440 bp downstream of rs2046210 and is in high LD with rs2046210 in Chinese (r2=0.91) and European-ancestry (r2=0.83) populations, but not in Africans (r2=0.57). SNP rs6913578 was found to be associated with breast cancer risk in Chinese and European-ancestry American women. After adjusting for rs2046210, the association of rs6913578 with breast cancer risk in African Americans approached borderline significance. Results from this large consortium study confirmed the association of rs2046210 with breast cancer risk among women of Chinese, Japanese, and European ancestry. This association may be explained in part by a putatively functional variant (rs6913578) identified in the region

Promoter Hypermethylation of Multiple Genes in Hydatidiform Mole and Choriocarcinoma

The methylation status of genes in hydatidiform mole and choriocarcinoma and its significance is relatively unexplored. We investigated the methylation status of the promoter regions of six genes, p16, HIC-1, TIMP3, GSTP1, death-associated protein kinase (DAPK), and E-cadherin in 54 hydatidiform moles, five choriocarcinomas, and 10 first trimester placenta by methylation-specific polymerase chain reaction (PCR). Immunohistochemical expression of p16, TIMP3, and E-cadherin, and quantitative real-time RT-PCR of p16 was also performed. Among the six genes examined, the promoter region of four genes (E-cadherin, HIC-1, p16, TIMP3) in choriocarcinoma and three genes (E-cadherin, HIC-1, p16) in hydatidiform mole exhibited aberrant methylation whereas none was hypermethylated in normal placenta. There was a significant correlation between methylation and reduced expression of p16, E-cadherin, and TIMP3 (P < 0.001). Fifteen of the 54 patients with hydatidiform mole developed gestational trophoblastic neoplasia requiring chemotherapy. Promoter hypermethylation of p16 alone, or combined with E-cadherin, was significantly correlated to such development (P = 0.001, 0.0005, respectively). Hypermethylation of multiple genes, especially p16, might be related to the subsequent development of gestational trophoblastic neoplasia

Overexpression of NANOG in Gestational Trophoblastic Diseases : Effect on Apoptosis, Cell Invasion, and Clinical Outcome

Gestational trophoblastic disease includes choriocarcinoma, a frankly malignant tumor, and hydatidiform mole (HM), which often leads to the development of persistent gestational trophoblastic neoplasia and requires chemotherapy. NANOG is an important transcription factor that is crucial for maintaining embryonic stem cell self-renewal and pluripotency. We postulated that NANOG is involved in the pathogenesis of gestational trophoblastic disease. In this study, significantly higher NANOG mRNA and protein expression levels, by quantitative PCR and immunoblotting, respectively, were demonstrated in HMs, particularly those that developed persistent disease, when compared with normal placentas. In addition, significantly increased nuclear NANOG immunoreactivity was found by immunohistochemistry in HMs (P < 0.001) and choriocarcinoma (P = 0.002). Higher NANOG expression levels were demonstrated in HMs that developed persistent disease, as compared with those that regressed (P = 0.025). Nuclear localization of NANOG was confirmed by confocal microscopy and immunoblotting in choriocarcinoma cell lines. There was a significant inverse correlation between NANOG immunoreactivity and apoptotic index assessed by M30 CytoDeath antibody (P = 0.012). After stable knockdown of NANOG in the choriocarcinoma cell line JEG-3 by an shRNA approach, increased apoptosis was observed in relation to with enhanced caspases and poly(ADP-ribose) polymerase activities. NANOG knockdown was also associated with decreased mobility and invasion of JEG-3 and down-regulation of matrix metalloproteases 2 and 9. These findings suggest that NANOG is involved in the pathogenesis and clinical progress of gestational trophoblastic disease, likely through its effect on apoptosis, cell migration, and invasion

Replication and Functional Genomic Analyses of the Breast Cancer Susceptibility Locus at 6q25.1 Generalize Its Importance in Women of Chinese, Japanese, and European Ancestry

We evaluated the generalizability of a single nucleotide polymorphism (SNP), rs2046210 (A/G allele), associated with breast cancer risk that was initially identified at 6q25.1 in a genome-wide association study conducted among Chinese women. In a pooled analysis of over 31,000 women of East-Asian, European, and African ancestry, we found a positive association for rs2046210 and breast cancer risk in Chinese women [ORs (95%CI)=1.30(1.22–1.38) and 1.64(1.50–1.80) for the AG and AA genotypes, respectively, P for trend = 1.54 × 10(−30)], Japanese women [ORs (95%CI)=1.31(1.13–1.52) and 1.37(1.06–1.76), P for trend = 2.51 × 10(−4)], and European-ancestry American women [ORs (95%CI)=1.07(0.99–1.16) and 1.18(1.04–1.34), P for trend = 0.0069]. No association with this SNP, however, was observed in African American women [ORs (95%CI)=0.81(0.63–1.06) and 0.85(0.65–1.11) for the AG and AA genotypes, respectively, P for trend = 0.4027). In vitro functional genomic studies identified a putative functional variant, rs6913578. This SNP is 1,440 bp downstream of rs2046210 and is in high LD with rs2046210 in Chinese (r(2)=0.91) and European-ancestry (r(2)=0.83) populations, but not in Africans (r(2)=0.57). SNP rs6913578 was found to be associated with breast cancer risk in Chinese and European-ancestry American women. After adjusting for rs2046210, the association of rs6913578 with breast cancer risk in African Americans approached borderline significance. Results from this large consortium study confirmed the association of rs2046210 with breast cancer risk among women of Chinese, Japanese, and European ancestry. This association may be explained in part by a putatively functional variant (rs6913578) identified in the region

Elucidation of the mechanisms underlying the angiogenic effects of ginsenoside Rg(1) in vivo and in vitro.

Metadata onlyThe major active constituents of ginseng are ginsenosides, and Rg(1) is a predominant compound of the total extract. Recent studies have demonstrated that Rg(1) can promote angiogenesis in vivo and in vitro. In this study, we used a DNA microarray technology to elucidate the mechanisms of action of Rg(1). We report that Rg(1) induces the proliferation of HUVECs, monitored using [(3)H]-thymidine incorporation and Trypan blue exclusion assays. Furthermore, Rg(1) (150-600 nM) also showed an enhanced tube forming inducing effect on the HUVEC. Rg(1) was also demonstrated to promote angiogenesis in an in vivo Matrigel plug assay, and increase endothelial sprouting in the ex vivo rat aorta ring assay. Differential gene expression profile of HUVEC following treatment with Rg(1) revealed the expression of genes related to cell adhesion, migration and cytoskeleton, including RhoA, RhoB, IQGAP1, CALM2, Vav2 and LAMA4. Our results suggest that Rg(1) can promote angiogenesis in multiple models, and this effect is partly due to the modulation of genes that are involved in the cytoskeletal dynamics, cell-cell adhesion and migration

Proceedings of The HKIE Geotechnical Division 43rd Annual Seminar: Towards a Smart-Green-Resilient Geo-Future for World-class City

This seminar proceedings contain articles on the various research ideas of the academic community and practitioners presented at The HKIE Geotechnical Division 43rd Annual Seminar (GDAS2023). This seminarprovides a platform for policymakers, practitioners, and academia to share their insights and brainstorm ideas with a view to seizing future opportunities and shaping the new future of Hong Kong. GDAS2023 was organized by the Geotechnical Division, The Hong Kong Institution of Engineers on 19th May 2023. Seminar Title: The HKIE Geotechnical Division 43rd Annual SeminarSeminar Acronym: GDAS2023Seminar Date: 19 May 2023Seminar Location:  Hong KongSeminar Organizers: Geotechnical Division, The Hong Kong Institution of Engineers Link to the GDAS2021 Proceedings: Proceedings of The HKIE Geotechnical Division 41st Annual Seminar Link to the GDAS2022 Proceedings: Proceedings of The HKIE Geotechnical Division 42nd Annual Semina