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.

To survive or to thrive? China's luxury hotel restaurants entering O2O food delivery platforms amid the COVID-19 crisis.

COVID-19 presents luxury hotels with an unenviable task of maneuvering to secure survival. One of the contingency measures of China's five-star hotels is to salvage revenues by entering online-to-offline (O2O) food delivery platforms. However, both opportunities and risks will ensue. Study 1 has content analyzed customer reviews on the largest O2O food delivery platform in China to probe the key factors of concern. The results show that taste, freshness, and brand credibility remain salient, as in dine-in experiences, while packaging and delivery quality emerge as a result of the integration of the O2O platform, and hygiene due to the COVID-19 pandemic. Interestingly, interaction quality between restaurant staff and customers still plays significant roles with the online channel. Study 2 has further deepened the understanding of luxury restaurants' O2O services through semi-structured interviews with F&B professionals. The results have paved the way for hotel operators to employ tactics on O2O platforms.

Spatial variations of particulate matter and air toxics in communities adjacent to the Port of Oakland.

The Bay Area Air Quality Management District (BAAQMD) sponsored the West Oakland Monitoring Study (WOMS) to provide supplemental air quality monitoring that will be used by the BAAQMD to evaluate local-scale dispersion modeling of diesel emissions and other toxic air contaminants for the area within and around the Port of Oakland. The WOMS was conducted during two seasonal periods of 4 weeks in summer 2009 and winter 2009/2010. Monitoring data showed spatial patterns of pollutant concentrations that were generally consistent with proximity to vehicle traffic. Concentrations of directly emitted pollutants were highest on heavily traveled roads with consistently lower concentrations away from the roadways. Pollutants that have higher emission rates from diesel trucks (nitric oxide, black carbon) tended to exhibit sharper gradients than pollutants that are largely associated with gasoline vehicles, such as carbon monoxide and volatile organic compounds, including benzene, toluene, ethylbenzene, and xylenes (BTEX). BTEX concentrations in West Oakland were similar to those measured at the three air toxics monitoring network sites in the Bay Area (San Francisco, Fremont, and San Jose). Aldehyde levels were higher in Fremont and San Jose than in West Oakland, reflecting greater contributions from photo-oxidation of hydrocarbons downwind of the Bay Area. A 2005 modeling-based health risk assessment of diesel particulate matter concentrations is consistent with aerosol carbon concentrations measured during the WOMS after adjusting for recent mitigation measures and improved estimates of heavy-duty truck traffic volumes.

Noninvasive prenatal diagnosis of fetal chromosomal aneuploidy by massively parallel genomic sequencing of DNA in maternal plasma.

Chromosomal aneuploidy is the major reason why couples opt for prenatal diagnosis. Current methods for definitive diagnosis rely on invasive procedures, such as chorionic villus sampling and amniocentesis, and are associated with a risk of fetal miscarriage. Fetal DNA has been found in maternal plasma but exists as a minor fraction among a high background of maternal DNA. Hence, quantitative perturbations caused by an aneuploid chromosome in the fetal genome to the overall representation of sequences from that chromosome in maternal plasma would be small. Even with highly precise single molecule counting methods such as digital PCR, a large number of DNA molecules and hence maternal plasma volume would need to be analyzed to achieve the necessary analytical precision. Here we reasoned that instead of using approaches that target specific gene loci, the use of a locus-independent method would greatly increase the number of target molecules from the aneuploid chromosome that could be analyzed within the same fixed volume of plasma. Hence, we used massively parallel genomic sequencing to quantify maternal plasma DNA sequences for the noninvasive prenatal detection of fetal trisomy 21. Twenty-eight first and second trimester maternal plasma samples were tested. All 14 trisomy 21 fetuses and 14 euploid fetuses were correctly identified. Massively parallel plasma DNA sequencing represents a new approach that is potentially applicable to all pregnancies for the noninvasive prenatal diagnosis of fetal chromosomal aneuploidies.