Repurposing hyperpolarization-activated cyclic nucleotide-gated channels as a novel therapy for breast cancer.

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are members of the voltage-gated cation channel family known to be expressed in the heart and central nervous system. Ivabradine, a small molecule HCN channel-blocker, is FDA-approved for clinical use as a heart rate-reducing agent. We found that HCN2 and HCN3 are overexpressed in breast cancer cells compared with normal breast epithelia, and the high expression of HCN2 and HCN3 is associated with poorer survival in breast cancer patients. Inhibition of HCN by Ivabradine or by RNAi, aborted breast cancer cell proliferation in vitro and suppressed tumour growth in patient-derived tumour xenograft models established from triple-negative breast cancer (TNBC) tissues, with no evident side-effects on the mice. Transcriptome-wide analysis showed enrichment for cholesterol metabolism and biosynthesis as well as lipid metabolism pathways associated with ER-stress following Ivabradine treatment. Mechanistic studies confirmed that HCN inhibition leads to ER-stress, in part due to disturbed Ca2+ homeostasis, which subsequently triggered the apoptosis cascade. More importantly, we investigated the synergistic effect of Ivabradine and paclitaxel on TNBC and confirmed that both drugs acted synergistically in vitro through ER-stress to amplify signals for caspase activation. Combination therapy could suppress tumour growth of xenografts at much lower doses for both drugs. In summary, our study identified a new molecular target with potential for being developed into targeted therapy, providing scientific grounds for initiating clinical trials for a new treatment regimen of combining HCN inhibition with chemotherapy

Towards a global partnership model in interprofessional education for cross-sector problem-solving

Objectives A partnership model in interprofessional education (IPE) is important in promoting a sense of global citizenship while preparing students for cross-sector problem-solving. However, the literature remains scant in providing useful guidance for the development of an IPE programme co-implemented by external partners. In this pioneering study, we describe the processes of forging global partnerships in co-implementing IPE and evaluate the programme in light of the preliminary data available. Methods This study is generally quantitative. We collected data from a total of 747 health and social care students from four higher education institutions. We utilized a descriptive narrative format and a quantitative design to present our experiences of running IPE with external partners and performed independent t-tests and analysis of variance to examine pretest and posttest mean differences in students’ data. Results We identified factors in establishing a cross-institutional IPE programme. These factors include complementarity of expertise, mutual benefits, internet connectivity, interactivity of design, and time difference. We found significant pretest–posttest differences in students’ readiness for interprofessional learning (teamwork and collaboration, positive professional identity, roles, and responsibilities). We also found a significant decrease in students’ social interaction anxiety after the IPE simulation. Conclusions The narrative of our experiences described in this manuscript could be considered by higher education institutions seeking to forge meaningful external partnerships in their effort to establish interprofessional global health education

Genome-Wide Association Study in East Asians Identifies Novel Susceptibility Loci for Breast Cancer

Genetic factors play an important role in the etiology of both sporadic and familial breast cancer. We aimed to discover novel genetic susceptibility loci for breast cancer. We conducted a four-stage genome-wide association study (GWAS) in 19,091 cases and 20,606 controls of East-Asian descent including Chinese, Korean, and Japanese women. After analyzing 690,947 SNPs in 2,918 cases and 2,324 controls, we evaluated 5,365 SNPs for replication in 3,972 cases and 3,852 controls. Ninety-four SNPs were further evaluated in 5,203 cases and 5,138 controls, and finally the top 22 SNPs were investigated in up to 17,423 additional subjects (7,489 cases and 9,934 controls). SNP rs9485372, near the TGF-β activated kinase (TAB2) gene in chromosome 6q25.1, showed a consistent association with breast cancer risk across all four stages, with a P-value of 3.8×10−12 in the combined analysis of all samples. Adjusted odds ratios (95% confidence intervals) were 0.89 (0.85–0.94) and 0.80 (0.75–0.86) for the A/G and A/A genotypes, respectively, compared with the genotype G/G. SNP rs9383951 (P = 1.9×10−6 from the combined analysis of all samples), located in intron 5 of the ESR1 gene, and SNP rs7107217 (P = 4.6×10−7), located at 11q24.3, also showed a consistent association in each of the four stages. This study provides strong evidence for a novel breast cancer susceptibility locus represented by rs9485372, near the TAB2 gene (6q25.1), and identifies two possible susceptibility loci located in the ESR1 gene and 11q24.3, respectively

Identification of novel breast cancer susceptibility loci in meta-analyses conducted among Asian and European descendants

Abstract: Known risk variants explain only a small proportion of breast cancer heritability, particularly in Asian women. To search for additional genetic susceptibility loci for breast cancer, here we perform a meta-analysis of data from genome-wide association studies (GWAS) conducted in Asians (24,206 cases and 24,775 controls) and European descendants (122,977 cases and 105,974 controls). We identified 31 potential novel loci with the lead variant showing an association with breast cancer risk at P < 5 × 10−8. The associations for 10 of these loci were replicated in an independent sample of 16,787 cases and 16,680 controls of Asian women (P < 0.05). In addition, we replicated the associations for 78 of the 166 known risk variants at P < 0.05 in Asians. These findings improve our understanding of breast cancer genetics and etiology and extend previous findings from studies of European descendants to Asian women

Identification of novel breast cancer susceptibility loci in meta-analyses conducted among Asian and European descendants

Abstract: Known risk variants explain only a small proportion of breast cancer heritability, particularly in Asian women. To search for additional genetic susceptibility loci for breast cancer, here we perform a meta-analysis of data from genome-wide association studies (GWAS) conducted in Asians (24,206 cases and 24,775 controls) and European descendants (122,977 cases and 105,974 controls). We identified 31 potential novel loci with the lead variant showing an association with breast cancer risk at P < 5 × 10−8. The associations for 10 of these loci were replicated in an independent sample of 16,787 cases and 16,680 controls of Asian women (P < 0.05). In addition, we replicated the associations for 78 of the 166 known risk variants at P < 0.05 in Asians. These findings improve our understanding of breast cancer genetics and etiology and extend previous findings from studies of European descendants to Asian women

The Impact on Infectivity and Neutralization Efficiency of SARS-CoV-2 Lineage B.1.351 Pseudovirus

A new variant of SARS-CoV-2 B.1.351 lineage (first found in South Africa) has been raising global concern due to its harboring of multiple mutations in the spike that potentially increase transmissibility and yield resistance to neutralizing antibodies. We here tested infectivity and neutralization efficiency of SARS-CoV-2 spike pseudoviruses bearing particular mutations of the receptor-binding domain (RBD) derived either from the Wuhan strains (referred to as D614G or with other sites) or the B.1.351 lineage (referred to as N501Y, K417N, and E484K). The three different pseudoviruses B.1.351 lineage related significantly increased infectivity compared with other mutants that indicated Wuhan strains. Interestingly, K417N and E484K mutations dramatically enhanced cell–cell fusion than N501Y even though their infectivity were similar, suggesting that K417N and E484K mutations harboring SARS-CoV-2 variant might be more transmissible than N501Y mutation containing SARS-CoV-2 variant. We also investigated the efficacy of two different monoclonal antibodies, Casirivimab and Imdevimab that neutralized SARS-CoV-2, against several kinds of pseudoviruses which indicated Wuhan or B.1.351 lineage. Remarkably, Imdevimab effectively neutralized B.1.351 lineage pseudoviruses containing N501Y, K417N, and E484K mutations, while Casirivimab partially affected them. Overall, our results underscore the importance of B.1.351 lineage SARS-CoV-2 in the viral spread and its implication for antibody efficacy

Disease Occurrence in Transgenic Rice Plant Transformed with Silbene Synthase Gene and Evaluation of Possible Horizontal Gene Transfer to Plant Pathogens

Genetic engineering is being used to enhance disease resistance and nutritional value of crops including rice plant. Considering the fast-growing agricultural biotechnology and rapidly increasing global area of transgenic crops, the risk evaluation on environment is necessary. In this study, we surveyed the difference of disease occurrence between transgenic rice variety, Iksan526 transformed with peanut stilbene synthase gene and non-transgenic rice varieties, Dongjin and Nampyeong in the field. Moreover, the possibility of gene transfer from transgenic rice to bacterial and fungal pathogens was investigated. The results of this study indicated that there was no significant difference in the occurrence and severity of the diseases between Iksan526 and Dongjin or Nampyeong. In addition, the results suggested that rice pathogen, such as Xanthomonas oryzae pv. oryzae, Rhizoctonia solani and Magnaporthe grisea did not take up stilbene synthase and bar genes under natural conditions. Moreover the transformed DNA was not transferred to the pathogens even in repetitive contacts

Inhibitory Effects of Resveratrol and Piceid against Pathogens of Rice Plant, and Disease Resistance Assay of Transgenic Rice Plant Transformed with Stilbene Synthase Gene

Resvestrol has been known to inhibit bacterial and fungal growth in vitro, and can be accumulated in plant to concentrations necessary to inhibit microbial pathogens. Hence, stilbene synthase gene has been used to transform to synthesize resveratrol in heterologous plant species to enhance resistance against pathogens. In the present study, we investigated the antimicrobial activities of resveratrol and piceid to bacterial and fungal pathogens, which causing severe damages to rice plants. In addition, disease resistance was compared between transgenic rice varieties, Iksan 515 and Iksan 526 transformed with stlibene synthase gene and nontransgenic rice varieties, Dongjin and Nampyeong. Minimum inhibitory concentration of resveratrol for Burkolderia glumae was 437.5 μM, and the mycelial growth of Biplaris oryzae was slightly inhibited at concentration of 10 μM. However, other bacterial and fungal pathogens are not inhibited by resveratrol and piceid. The expression of the stilbene synthase gene in Iksan 515 and Iksan 526 did not significantly enhanced resistance against bacterial grain rot, bacterial leaf blight, sheath blight, and leaf blight. This study is the first report on the effect of resveratrol and piceid against pathogens of rice plant, and changes of disease resistance of transgenic rice plants transformed with stilbene synthase gene

The association between urinary cotinine level and metabolic syndrome profiles among adolescents: findings from the Ewha Birth and growth study

Abstract Background: Secondhand smoke (SHS) exposure among adolescents who are still developing can negatively affect their physical and psychological health, including metabolic syndrome (MetS), which is a risk factor for cardiovascular disease. However, the relationship between exposure to SHS and MetS in adolescence has not been evaluated. Methods: A total of 240 subjects aged 13–15 years who were followed up in the Ewha Birth and Growth Study were included in this study. Using the urinary cotinine level, the participants’ exposure to SHS was divided into tertiles, and the continuous MetS score (cMetS) and its components were compared among the three groups using a generalized linear model and trend analysis. Univariate and multivariate linear regression analyses were performed. We adjusted for several confounding variables including sex, father’s education level, father’s current alcohol consumption status, moderate physical activity, and overweight status. Results: The association between cMetS and the urinary cotinine level was not significant. However, the higher the urinary cotinine level, the lower the high-density lipoprotein cholesterol (HDL-C) level. In particular, the significance of the HDL-C level was maintained after adjusting for covariates. Conclusions: This study supports an association between SHS exposure and the components of MetS in adolescents aged 13–15 years, and it suggests the need to address SHS exposure in adolescents to reduce the cardiovascular risk in later life