Monopolar spindle 1 contributes to tamoxifen resistance in breast cancer through phosphorylation of estrogen receptor α.

PURPOSE: The overexpression of mitotic kinase monopolar spindle 1 (Mps1) has been identified in many tumor types, and targeting Mps1 for tumor therapy has shown great promise in multiple preclinical cancer models. However, the role played by Mps1 in tamoxifen (TAM) resistance in breast cancer has never been reported. METHODS: The sensitivity of breast cancer cells to tamoxifen was analysed in colony formation assays and wound healing assays. Enhanced transactivational activity of estrogen receptor α (ERα) led by Mps1 overexpression was determined by luciferase assays. The interaction between Mps1 and ERα was verified by co-immunoprecipitation and proximity ligation assay. Phosphorylation of ERα by Mps1 was detected by in vitro kinase assay and such phosphorylation process in vivo was proven by co-immunoprecipitation. The potential phosphorylation site(s) of ERα were analyzed by mass spectrometry. RESULTS: Mps1 determines the sensitivity of breast cancer cells to tamoxifen treatment. Mps1 overexpression rendered breast cancer cells more resistant to tamoxifen, while an Mps1 inhibitor or siMps1 oligos enabled cancer cells to overcome tamoxifen resistance. Mechanistically, Mps1 interacted with estrogen receptor α and stimulated its transactivational activity in a kinase activity-dependent manner. Mps1 was critical for ERα phosphorylation at Thr224 amino acid site. Importantly, Mps1 failed to enhance the transactivational activity of the ERα-T224A mutant. CONCLUSION: Mps1 contributes to tamoxifen resistance in breast cancer and is a potential therapeutic that can overcome tamoxifen resistance in breast cancer.

(-)-Epigallocatechin-3-gallate (EGCG) prevents aminoglycosides-induced ototoxicity via anti-oxidative and anti-apoptotic pathways.

OBJECTIVES: Aminoglycoside-induced cochlear ototoxicity causes inner ear hair cells (HCs) loss and leads to hearing impairment in patients, but no treatment completely eliminates the ototoxic effect. This study aims to determine the effectiveness of (-)-Epigallocatechin-3-gallate (EGCG) as a protective agent against aminoglycoside-induced ototoxicity. METHODS: Zebrafish were exposed to EGCG for 24 h and then co-treated with EGCG and ototoxic agent (amikacin and gentamicin) for 5 h to explore the protective effect of EGCG on zebrafish HCs. Network pharmacology analysis and molecular docking simulation were conducted to explore its potential mechanism, and in vitro cell experiments were used to validate the outcome of the result. RESULT: EGCG against ototoxicity of aminoglycosides in zebrafish HCs. Network pharmacology analysis and molecular docking showing that molecules related to cellular response regulation to oxidative stress, including AKT1, DHFR, and MET, may be the target proteins of EGCG, which were verified in vitro experiments. Further experiments demonstrated thatEGCG can antagonize the death of HCs caused by amikacin and gentamicin by reducing intracellular reactive oxygen species (ROS) accumulation and anti-apoptosis. CONCLUSION: EGCG can be an otoprotective drug against aminoglycosides-induced ototoxicity, prevent cellular apoptosis and significantly reduce oxidative stress.

Effects of nicorandil on systemic inflammation and oxidative stress induced by percutaneous coronary intervention in patients with coronary heart disease.

OBJECTIVE: The present study investigated the effects of a bolus intracoronary injection of nicorandil on systemic inflammation and oxidative stress induced by percutaneous coronary intervention (PCI) in patients with coronary heart disease (CHD). METHODS: Patients undergoing coronary angiography (CAG) were enrolled into the CAG group (n = 30). Patients undergoing PCI were randomly divided into the PCI (n = 30) and PCI + nicorandil groups (n = 30). RESULTS: Blood taken from patients in the placebo group 24 hours after PCI exhibited significant increases in the expression of inflammatory indicators and mild increases in the expression of anti-inflammatory indicators. The intracoronary injection of nicorandil reversed the elevation of inflammatory indicators and significantly increased the levels of anti-inflammatory indicators in the blood of patients with PCI. Blood taken from patients in the placebo group 24 hours after PCI also displayed significant decreased superoxide dismutase levels and increased malondialdehyde levels. Nicorandil treatment reversed these changes of oxidative stress marker levels. CONCLUSIONS: These results indicated the possible medical application of intracoronary injections of nicorandil for reducing systemic inflammation and oxidative stress in the peripheral blood of patients undergoing PCI.

A stereo photogrammetry system for model position and attitude measurement in hypersonic wind tunnel testing.

In this paper, a measurement system based on stereo photogrammetry is proposed for position and attitude measurements of test models in hypersonic wind tunnel testing. Several adaptations were made to an existing stereo photogrammetry system to promote its routine use as a primary wind tunnel measurement system. First, cameras were installed in the wind tunnel test section to decrease the measurement distance and increase the base length, which helped improve the measurement accuracy. To deal with camera vibration caused by the freestream, a camera orientation method is proposed to estimate the exterior parameters of each frame relative to the tunnel coordinate system. Second, a scheme to determine the model coordinate system is proposed, which does not require placement of the targets at known locations of the model. Third, to solve the recognition problem of motion-blurred target images, a network was adopted for stereo deblurring and a stereo blur dataset simulating the wind tunnel test environment was generated for network training. To develop the novel stereo photogrammetry system, experiments were conducted in both the laboratory and a hypersonic wind tunnel at the China Aerodynamics Research and Development Center. The experimental results suggest that the proposed measurement system is practicable for position and attitude measurements of test models in hypersonic wind tunnel testing.

HDL-scavenger receptor B type 1 facilitates SARS-CoV-2 entry.

Responsible for the ongoing coronavirus disease 19 (COVID-19) pandemic, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects host cells through binding of the viral spike protein (SARS-2-S) to the cell-surface receptor angiotensin-converting enzyme 2 (ACE2). Here we show that the high-density lipoprotein (HDL) scavenger receptor B type 1 (SR-B1) facilitates ACE2-dependent entry of SARS-CoV-2. We find that the S1 subunit of SARS-2-S binds to cholesterol and possibly to HDL components to enhance viral uptake in vitro. SR-B1 expression facilitates SARS-CoV-2 entry into ACE2-expressing cells by augmenting virus attachment. Blockade of the cholesterol-binding site on SARS-2-S1 with a monoclonal antibody, or treatment of cultured cells with pharmacological SR-B1 antagonists, inhibits HDL-enhanced SARS-CoV-2 infection. We further show that SR-B1 is coexpressed with ACE2 in human pulmonary tissue and in several extrapulmonary tissues. Our findings reveal that SR-B1 acts as a host factor that promotes SARS-CoV-2 entry and may help explain viral tropism, identify a possible molecular connection between COVID-19 and lipoprotein metabolism, and highlight SR-B1 as a potential therapeutic target to interfere with SARS-CoV-2 infection.

Prediction of outcome in breast cancer patients using test parameters from complete blood count.

The aim of this study was to evaluate the prognostic effect of test parameters from pretreatment complete blood count (CBC) for predicting outcome in breast cancer patients. A total of 162 patients with breast cancer and a long follow-up were enrolled in this study. Red cell indices (RCIs) and neutrophil-lymphocyte ratio (NLR) from CBC prior to treatment, as well as related clinical data, were retrospectively collected. We evaluated the association of RCI and NLR with tumor size, clinical stage, histological grade, estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 status. We further performed survival analysis and Cox multivariate analysis, stratified by RCI and NLR median values, to evaluate their prognostic effects. In the disease-free survival (DFS) analysis, patients in the higher mean corpuscular hemoglobin (MCH) and NLR groups exhibited shorter DFS times compared with those in the lower MCH and NLR groups (P=0.017 for MCH and P=0.039 for NLR). The univariate analysis revealed that both MCH and NLR were significantly associated with DFS. The Cox multivariate analysis demonstrated that only MCH was an independent predictor associated with disease relapse (hazard ratio = 1.975, 95% confidence interval: 1.118-3.487, P=0.019), whereas no index was associated with overall survival. Our results suggest that MCH prior to treatment may be a predictive marker associated with DFS in breast cancer.