An outbreak of coronavirus disease 2019 (COVID‐19) occurred in Wuhan and it has rapidly spread to almost all parts of the world. For coronaviruses, RNA‐dependent RNA polymerase (RdRp) is an important ...protease that catalyzes the replication of RNA from RNA template and is an attractive therapeutic target. In this study, we screened these chemical structures from traditional Chinese medicinal compounds proven to show antiviral activity in severe acute respiratory syndrome coronavirus (SARS‐CoV) and the similar chemical structures through a molecular docking study to target RdRp of SARS‐CoV‐2, SARS‐CoV, and Middle East respiratory syndrome coronavirus (MERS‐CoV). We found that theaflavin has a lower idock score in the catalytic pocket of RdRp in SARS‐CoV‐2 (−9.11 kcal/mol), SARS‐CoV (−8.03 kcal/mol), and MERS‐CoV (−8.26 kcal/mol) from idock. To confirm the result, we discovered that theaflavin has lower binding energy of −8.8 kcal/mol when it docks in the catalytic pocket of SARS‐CoV‐2 RdRp by using the Blind Docking server. Regarding contact modes, hydrophobic interactions contribute significantly in binding and additional hydrogen bonds were found between theaflavin and RdRp. Moreover, one π‐cation interaction was formed between theaflavin and Arg553 from the Blind Docking server. Our results suggest that theaflavin could be a potential SARS‐CoV‐2 RdRp inhibitor for further study.
Highlights
Theaflavin has a lower idock score in the catalytic pocket of RdRp in SARS‐CoV‐2, SARS‐CoV and MERS‐CoV from idock.
Theaflavin has a lowest binding energy when it docks in the catalytic pocket of SARS‐CoV‐2 RdRp.
Theaflavin could be potential SARS‐CoV‐2 RdRp inhibitor.
Sclerostin is an osteocyte-derived inhibitor of osteoblast activity. The monoclonal antibody romosozumab binds to sclerostin and increases bone formation.
In a phase 2, multicenter, international, ...randomized, placebo-controlled, parallel-group, eight-group study, we evaluated the efficacy and safety of romosozumab over a 12-month period in 419 postmenopausal women, 55 to 85 years of age, who had low bone mineral density (a T score of -2.0 or less at the lumbar spine, total hip, or femoral neck and -3.5 or more at each of the three sites). Participants were randomly assigned to receive subcutaneous romosozumab monthly (at a dose of 70 mg, 140 mg, or 210 mg) or every 3 months (140 mg or 210 mg), subcutaneous placebo, or an open-label active comparator--oral alendronate (70 mg weekly) or subcutaneous teriparatide (20 μg daily). The primary end point was the percentage change from baseline in bone mineral density at the lumbar spine at 12 months. Secondary end points included percentage changes in bone mineral density at other sites and in markers of bone turnover.
All dose levels of romosozumab were associated with significant increases in bone mineral density at the lumbar spine, including an increase of 11.3% with the 210-mg monthly dose, as compared with a decrease of 0.1% with placebo and increases of 4.1% with alendronate and 7.1% with teriparatide. Romosozumab was also associated with large increases in bone mineral density at the total hip and femoral neck, as well as transitory increases in bone-formation markers and sustained decreases in a bone-resorption marker. Except for mild, generally nonrecurring injection-site reactions with romosozumab, adverse events were similar among groups.
In postmenopausal women with low bone mass, romosozumab was associated with increased bone mineral density and bone formation and with decreased bone resorption. (Funded by Amgen and UCB Pharma; ClinicalTrials.gov number, NCT00896532.).
Background
Women and their health care providers need a reliable answer to this important question: If a woman chooses to participate in regular mammography screening, then how much will this choice ...improve her chances of avoiding a death from breast cancer compared with women who choose not to participate?
Methods
To answer this question, we used comprehensive registries for population, screening history, breast cancer incidence, and disease‐specific death data in a defined population in Dalarna County, Sweden. The annual incidence of breast cancer was calculated along with the annual incidence of breast cancers that were fatal within 10 and within 11 to 20 years of diagnosis among women aged 40 to 69 years who either did or did not participate in mammography screening during a 39‐year period (1977‐2015). For an additional comparison, corresponding data are presented from 19 years of the prescreening period (1958‐1976). All patients received stage‐specific therapy according to the latest national guidelines, irrespective of the mode of detection.
Results
The benefit for women who chose to participate in an organized breast cancer screening program was a 60% lower risk of dying from breast cancer within 10 years after diagnosis (relative risk, 0.40; 95% confidence interval, 0.34‐0.48) and a 47% lower risk of dying from breast cancer within 20 years after diagnosis (relative risk, 0.53; 95% confidence interval, 0.44‐0.63) compared with the corresponding risks for nonparticipants.
Conclusions
Although all patients with breast cancer stand to benefit from advances in breast cancer therapy, the current results demonstrate that women who have participated in mammography screening obtain a significantly greater benefit from the therapy available at the time of diagnosis than do those who have not participated.
After 20 years of follow‐up, women who participate in mammography screening have a 47% lower risk of dying from breast cancer. Although all patients with breast cancer potentially can benefit from advances in breast cancer therapy, women who participate in mammography screening obtain a significantly greater benefit from the therapy available at the time of diagnosis than those who do not participate.
Abstract
Background
The crude extract of the fruit bearing plant,
Physalis peruviana
(golden berry), demonstrated anti-hepatoma and anti-inflammatory activities. However, the cellular mechanism ...involved in this process is still unknown.
Methods
Herein, we isolated the main pure compound, 4β-Hydroxywithanolide (4βHWE) derived from golden berries, and investigated its antiproliferative effect on a human lung cancer cell line (H1299) using survival, cell cycle, and apoptosis analyses. An alkaline comet-nuclear extract (NE) assay was used to evaluate the DNA damage due to the drug.
Results
It was shown that DNA damage was significantly induced by 1, 5, and 10 μg/mL 4βHWE for 2 h in a dose-dependent manner (
p
< 0.005). A trypan blue exclusion assay showed that the proliferation of cells was inhibited by 4βHWE in both dose- and time-dependent manners (
p
< 0.05 and 0.001 for 24 and 48 h, respectively). The half maximal inhibitory concentrations (IC
50
) of 4βHWE in H1299 cells for 24 and 48 h were 0.6 and 0.71 μg/mL, respectively, suggesting it could be a potential therapeutic agent against lung cancer. In a flow cytometric analysis, 4βHWE produced cell cycle perturbation in the form of sub-G
1
accumulation and slight arrest at the G
2
/M phase with 1 μg/mL for 12 and 24 h, respectively. Using flow cytometric and annexin V/propidium iodide immunofluorescence double-staining techniques, these phenomena were proven to be apoptosis and complete G
2
/M arrest for H1299 cells treated with 5 μg/mL for 24 h.
Conclusions
In this study, we demonstrated that golden berry-derived 4βHWE is a potential DNA-damaging and chemotherapeutic agent against lung cancer.
Abstract
Dual supermassive black holes (SMBHs) at ∼kiloparsec scales are the progenitor population of SMBH mergers and play an important role in understanding the pairing and dynamical evolution of ...massive black holes in galaxy mergers. Because of the stringent resolution requirement and the apparent rareness of these small-separation pairs, there are scarce observational constraints on this population, with few confirmed dual SMBHs at <10 kpc separations at
z
> 1. Here we present results from a pilot search for kiloparsec-scale dual quasars selected with Gaia Data release 2 (DR2) astrometry and followed up with Hubble Space Telescope (HST) Wide Field Camera 3 dual-band (F475W and F814W) snapshot imaging. Our targets are quasars primarily selected with the varstrometry technique, i.e., light centroid jitter caused by asynchronous variability from both members in an unresolved quasar pair, supplemented by subarcsecond pairs already resolved by Gaia DR2. We find an overall high fraction of HST-resolved pairs among the varstrometry-selected quasars (unresolved in Gaia DR2), ∼30%–50%, increasing toward high redshift (∼60%–80% at
z
> 1.5). We discuss the nature of the 45 resolved subarcsecond pairs based on HST and supplementary data. A substantial fraction (∼40%) of these pairs are likely physical quasar pairs or gravitationally lensed quasars. We also discover a triple quasar candidate and a quadruply lensed quasar, which is among the smallest-separation quadruple lenses. These results provide important guidelines to improve varstrometry selection and follow-up confirmation of ~kiloparsec-scale dual SMBHs at high redshift.
Fouling of thin tubes is a major problem, leading to various infections and associated morbidities, while cleaning is difficult or even impossible. Here, a generic method is introduced to activate ...and coat the inside of meter‐long and at the same time thin (down to 1 mm) tubes with a super‐liquid‐repellent layer of nanofilaments, exhibiting even antibacterial properties. Activation is facilitated by pumping an oxidative Fenton solution through the tubes. Subsequent pumping of a silane solution renders the surface of the tubes super‐liquid‐repellent. The wide applicability of the method is demonstrated by coating stiff and flexible tubes made of polymers, inorganic/organic hybrids, metals, and ceramics. Coated medical catheters show excellent antibacterial properties. Notably, the nanofilaments retain their antibacterial properties even in the superhydrophilic state. These findings open new avenues toward the design of biocide‐free, antibacterial tubings and catheters.
An effective procedure to activate and coat the inside of thin and meter‐long tubes with a super‐liquid‐repellent layer consisting of nanofilaments is developed. Wide applicability to a broad range of materials is demonstrated. The biocide‐free coating shows excellent stability against high flow velocities and successfully restrains adhesion of bacteria, which is demonstrated by coated medical catheters.
Danshen (salvia miltiorrhiza Bunge) is widely used in traditional Chinese medicine. However, it is definite clinical effort and mechanism on breast cancer is unclear. In our study, we used the ...real-world database to investigate
in vivo
protective effort of danshen in the breast cancer patients through using population-based data from the Taiwan National Health Insurance Research Database (NHIRD).
In vitro
, human breast cancer cells (MCF-7 cells and MDA-MB-231 cells) were used to investigate the effect and the underlying mechanism through XTT assay, flow cytometry, glutathione peroxidase (GPX) activity assay, GSH (reduced glutathione)/GSSG (oxidized glutathione), malondialdehyde (MDA), and western blot analysis. The
in vivo
effect was investigated through a xenograft nude mouse model. We found that dihydroisotanshinone I (DT), a pure compound present in danshen, can inhibit the growth of breast carcinoma cells, including MCF-7 cells and MDA-MB-231 cells. Moreover, DT induced apoptosis and ferroptosis in these breast cancer cells. DT also repressed the protein expression of GPX4 (Glutathione peroxidase 4). For
in vivo
study, DT treatment also significantly inhibited the final tumor volume without adverse effects in a xenograft nude mouse model. In conclusion, danshen has protective efforts in breast cancer patients, which could be attributed to DT through inducing apoptosis and ferroptosis of breast cancer cells.
A disintegrin and metalloprotease with thrombospondin motifs (ADAMTS) family are widely implicated in tissue remodeling events manifested in cancer development. ADAMTS1, the most fully characterized ...ADAMTS, plays conflicting roles in different cancer types; however, the role of ADAMTS1 in renal cell carcinoma (RCC) remains unclear. Herein, we found that ADAMTS1 is highly expressed in RCC tissues compared to normal renal tissues, and its expression was correlated with an advanced stage and a poor prognosis of RCC patients. In vitro, we observed higher expression of ADAMTS1 in metastatic (m)RCC cells compared to primary cells, and manipulation of ADAMTS1 expression affected cell invasion and clonogenicity. Results from protease array showed that ADAMTS1 is modulated by melatonin through mechanisms independent of the MT1 receptor in mRCC cells, and overexpression of ADAMTS1 relieved the invasion/clonogenicity and growth/metastasis inhibition imposed by melatonin treatment in vitro and in an orthotopic xenograft model. The human microRNA (miR) OneArray showed that miR‐181d and miR‐let‐7f were induced by melatonin and, respectively, targeted the 3’‐UTR and non‐3'‐UTR of ADAMTS1 to suppress its expression and mRCC invasive ability. Clinically, RCC patients with high levels of miR‐181d or miR‐let‐7f and a low level of ADAMTS1 had the most favorable prognoses. In addition, ubiquitin/proteasome‐mediated degradation of ADAMTS1 can also be triggered by melatonin. Together, our study indicates that ADAMTS1 may be a useful biomarker for predicting RCC progression. The novel convergence between melatonin and ADAMTS1 post‐transcriptional and post‐translational regulation provides new insights into the role of melatonin‐induced molecular regulation in suppressing RCC progression.
Osteoporosis is a critical problem during aging. Ultrasound signals backscattered from bone contain information associated with microstructures. This study proposed using entropy imaging to collect ...the information in bone microstructures as a possible solution for ultrasound bone tissue characterization. Bone phantoms with different pounds per cubic foot (PCF) were used for ultrasound scanning by using single-element transducers of 1 (nonfocused) and 3.5 MHz (nonfocused and focused). Clinical measurements were also performed on lumbar vertebrae (L3 spinal segment) in participants with different ages (n = 34) and postmenopausal women with low or moderate-to-high risk of osteoporosis (n = 50; identified using the Osteoporosis Self-Assessment Tool for Taiwan). The signals backscattered from the bone phantoms and subjects were acquired for ultrasound entropy imaging by using sliding window processing. The independent t-test, one-way analysis of variance, Spearman correlation coefficient r
, and the receiver operating characteristic (ROC) curve were used for statistical analysis. The results indicated that ultrasound entropy imaging revealed changes in bone microstructures. Using the 3.5-MHz focused ultrasound, small-window entropy imaging (side length: one pulse length of the transducer) was found to have high performance and sensitivity in detecting variation among the PCFs (r
= - 0.83; p < 0.05). Small-window entropy imaging also performed well in discriminating young and old participants (p < 0.05) and postmenopausal women with low versus moderate-to-high osteoporosis risk (the area under the ROC curve = 0.80; cut-off value = 2.65; accuracy = 86.00%; sensitivity = 71.43%; specificity = 88.37%). Ultrasound small-window entropy imaging has great potential in bone tissue characterization and osteoporosis assessment.
The performance of hybrid perovskite‐based light‐emitting diodes (LEDs) is markedly enhanced by the application of a NiOx electrode interlayer and moderate methylamine treatment. A hybrid ...perovskite‐based LED exhibits a peak luminous efficiency of 15.9 cd A−1 biased at 8.5 V, 407.65 mA cm−2, and 65 300 cd m−2, showing a distinctive impact for future applications.
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