•The COVID-19 emerged in Wuhan City and rapidly spread throughout China.•NLR exhibited the largest area under the curve, with the highest specificity and sensitivity.•Elevated NLR can be considered ...independent biomarkers for indicating poor clinical outcomes.
To accumulate evidence that indicated the key role played by virus-triggered inflammation in the 2019-novel coronavirus disease (COVID-19) which emerged in Wuhan City and rapidly spread throughout China.
Age, neutrophil(NEU)-to-lymphocyte (LYM) ratio (NLR), lymphocyte-to-monocyte (MON) ratio, platelet-to-lymphocyte ratio (PLR), and C-reactive protein (CRP) of 93 patients with laboratory confirmed COVID-19 were investigated and compared. The receiver operating characteristic curve was applied to determine the thresholds for five bio-markers, and their prognostic values were assessed via the Kaplan–Meier curve and multivariate COX regression models.
The median age was 46.4 years old, and 37cases were females. A total of 27.8% of patients had been to Wuhan, and 73.1% had contacted with people from Wuhan. Fever (83.8%) and cough (70.9%) were the two most common symptoms. Elevated NLR and age were significantly associated with illness severity. The binary logistic analysis identified elevated NLR (hazard risk HR 2.46, 95% confidence interval CI 1.98–4.57) and age (HR 2.52, 95% CI 1.65–4.83) as independent factors for poor clinical outcome of COVID-19. NLR exhibited the largest area under the curve at 0.841, with the highest specificity (63.6%) and sensitivity (88%).
Elevated age and NLR can be considered independent biomarkers for indicating poor clinical outcomes.
Sodium-ion batteries (SIBs) have demonstrated greater potential for application in large-scale energy storage devices than lithium-ion batteries (LIBs) owing to the natural abundance, low cost and ...environmental benignity of sodium resources. However, the low energy density and poor cycling life limit their commercial applications. The development of high-performance anode materials is one of the key issues for SIBs. Compared with carbonaceous materials, metallic Sn-, Sb- and SnSb alloy-based anodes have developed rapidly due to their high theoretical capacity, high electrical conductivity and safe reaction potential. The major challenge for them is the large volume change during the sodiation/desodiation process, resulting in rapid capacity decay. Numerous efforts have been devoted to solving this problem. This review summarizes recent progress on this cutting-edge topic. A range of Sn-, Sb- and SnSb-based anode materials have been introduced with respect to size control and nanostructure design. It is found that the use of ultra-small nanoparticles, elaborate interface design, heterogeneous element (N, S
etc.
) doping, multi-dimensional integration
etc.
are efficient strategies to enhance the electrochemical performance of these anode materials. The ingenious nanostructures and their synthesis methods reported in this review may provide new insights to the rational design of novel anode materials for practical application in advanced energy storage devices in the near future.
Sodium-ion batteries with metallic Sn- and Sb-based anodes have great potential for application in large-scale green energy storage devices.
Background
Molecular subtyping of triple‐negative breast cancers (TNBCs) via gene expression profiling is essential for understanding the molecular essence of this heterogeneous disease and for ...guiding individualized treatment. We aim to devise a clinically practical method based on immunohistochemistry (IHC) for the molecular subtyping of TNBCs.
Materials and Methods
By analyzing the RNA sequencing data on TNBCs from Fudan University Shanghai Cancer Center (FUSCC) (n = 360) and The Cancer Genome Atlas data set (n = 158), we determined markers that can identify specific molecular subtypes. We performed immunohistochemical staining on tumor sections of 210 TNBCs from FUSCC, established an IHC‐based classifier, and applied it to another two cohorts (n = 183 and 214).
Results
We selected androgen receptor (AR), CD8, FOXC1, and DCLK1 as immunohistochemical markers and classified TNBCs into five subtypes based on the staining results: (a) IHC‐based luminal androgen receptor (IHC‐LAR; AR‐positive +), (b) IHC‐based immunomodulatory (IHC‐IM; AR‐negative −, CD8+), (c) IHC‐based basal‐like immune‐suppressed (IHC‐BLIS; AR−, CD8−, FOXC1+), (d) IHC‐based mesenchymal (IHC‐MES; AR−, CD8−, FOXC1−, DCLK1+), and (e) IHC‐based unclassifiable (AR−, CD8−, FOXC1−, DCLK1−). The κ statistic indicated substantial agreement between the IHC‐based classification and mRNA‐based classification. Multivariate survival analysis suggested that our IHC‐based classification was an independent prognostic factor for relapse‐free survival. Transcriptomic data and pathological observations implied potential treatment strategies for different subtypes. The IHC‐LAR subtype showed relative activation of HER2 pathway. The IHC‐IM subtype tended to exhibit an immune‐inflamed phenotype characterized by the infiltration of CD8+ T cells into tumor parenchyma. The IHC‐BLIS subtype showed high expression of a VEGF signature. The IHC‐MES subtype displayed activation of JAK/STAT3 signaling pathway.
Conclusion
We developed an IHC‐based approach to classify TNBCs into molecular subtypes. This IHC‐based classification can provide additional information for prognostic evaluation. It allows for subgrouping of TNBC patients in clinical trials and evaluating the efficacy of targeted therapies within certain subtypes.
Implications for Practice
An immunohistochemistry (IHC)‐based classification approach was developed for triple‐negative breast cancer (TNBC), which exhibited substantial agreement with the mRNA expression‐based classification. This IHC‐based classification (a) allows for subgrouping of TNBC patients in large clinical trials and evaluating the efficacy of targeted therapies within certain subtypes, (b) will contribute to the practical application of subtype‐specific treatment for patients with TNBC, and (c) can provide additional information beyond traditional prognostic factors in relapse prediction.
This article describes an immunohistochemistry‐based approach to classification of triple‐negative breast cancers into molecular subtypes for purposes of the translation of TNBC molecular classification into clinical practice.
As the number of elucidated protein structures is rapidly increasing, the growing data call for methods to efficiently exploit the structural information for biological and pharmaceutical purposes. ...Given the three-dimensional (3D) structure of a protein and a ligand, predicting their binding sites and affinity are a key task for computer-aided drug discovery. To address this task, a variety of docking tools have been developed. Most of them focus on docking in the preset binding sites given by users. To automatically predict binding modes without information about binding sites, we developed a user-friendly blind docking web server, named CB-Dock, which predicts binding sites of a given protein and calculates the centers and sizes with a novel curvature-based cavity detection approach, and performs docking with a popular docking program, Autodock Vina. This method was carefully optimized and achieved ~70% success rate for the top-ranking poses whose root mean square deviation (RMSD) were within 2 Å from the X-ray pose, which outperformed the state-of-the-art blind docking tools in our benchmark tests. CB-Dock offers an interactive 3D visualization of results, and is freely available at http://cao.labshare.cn/cb-dock/.
Deregulation of the phosphoinositide 3-kinase (PI3K) pathway contributes to the development and progression of tumors. Here, we determine that somatic mutations in PIK3CA (44%), PIK3R1 (17%), AKT3 ...(15%), and PTEN (12%) are prevalent and diverse in Chinese breast cancer patients, with 60 novel mutations identified. A high proportion of tumors harbors multiple mutations, especially PIK3CA plus PIK3R1 mutations (9.0%). Next, we develop a recombination-based mutation barcoding (ReMB) library for impactful mutations conferring clonal advantage in proliferation and drug responses. The highest-ranking PIK3CA and PIK3R1 mutations include previously reported deleterious mutations, as well as mutations with unknown significance. These PIK3CA and PIK3R1 impactful mutations exhibit a mutually exclusive pattern, leading to oncogenesis and hyperactivity of PI3K pathway. The PIK3CA impactful mutations are tightly associated with hormone receptor positivity. Collectively, these findings advance our understanding of PI3K impactful mutations in breast cancer and have important implications for PI3K-targeted therapy in precision oncology.
Based on research into the applications of artificial intelligence （AI） technology in the manufacturing industry in recent years, we analyze the rapid development of core technologies in the new era ...of＇Internet plus AI＇, which is triggering a great change in the models, means, and ecosystems of the manufacturing industry, as well as in the development of AI. We then propose new models, means, and forms of intelligent manufacturing, intelligent manufacturing system architecture, and intelligent man- ufactudng technology system, based on the integration of AI technology with information communications, manufacturing, and related product technology. Moreover, from the perspectives of intelligent manufacturing application technology, industry, and application demonstration, the current development in intelligent manufacturing is discussed. Finally, suggestions for the application of AI in intelligent manufacturing in China are presented.
The objectives of the present study were to investigate heavy metal accumulation in 22 vegetable species and to assess the human health risks of vegetable consumption. Six vegetable types were ...cultivated on farmland contaminated with heavy metals (Pb, Cd, Cu, Zn, and As). The target hazard quotient (THQ) method was used to assess the human health risks posed by heavy metals through vegetable consumption. Clear differences were found in the concentrations of heavy metals in edible parts of the different vegetables. The concentrations of heavy metals decreased in the sequence as leafy vegetables > stalk vegetables/root vegetables/solanaceous vegetables > legume vegetables/melon vegetables. The ability of leafy vegetables to uptake and accumulate heavy metals was the highest, and that of melon vegetables was the lowest. This indicated that the low accumulators (melon vegetables) were suitable for being planted on contaminated soil, while the high accumulators (leafy vegetables) were unsuitable. In Shizhuyuan area, China, the total THQ values of adults and children through consumption of vegetables were 4.12 and 5.41, respectively, suggesting that the residents may be facing health risks due to vegetable consumption, and that children were vulnerable to the adverse effects of heavy metal ingestion.
Adhesion G-protein-coupled receptors (GPCRs) are a major family of GPCRs, but limited knowledge of their ligand regulation or structure is available1-3. Here we report that glucocorticoid stress ...hormones activate adhesion G-protein-coupled receptor G3 (ADGRG3; also known as GPR97)4-6, a prototypical adhesion GPCR. The cryo-electron microscopy structures of GPR97-Go complexes bound to the anti-inflammatory drug beclomethasone or the steroid hormone cortisol revealed that glucocorticoids bind to a pocket within the transmembrane domain. The steroidal core of glucocorticoids is packed against the 'toggle switch' residue W6-53, which senses the binding of a ligand and induces activation of the receptor. Active GPR97 uses a quaternary core and HLY motif to fasten the seven-transmembrane bundle and to mediate G protein coupling. The cytoplasmic side of GPR97 has an open cavity, where all three intracellular loops interact with the Go protein, contributing to the high basal activity of GRP97. Palmitoylation at the cytosolic tail of the Go protein was found to be essential for efficient engagement with GPR97 but is not observed in other solved GPCR complex structures. Our work provides a structural basis for ligand binding to the seven-transmembrane domain of an adhesion GPCR and subsequent G protein coupling.
Immune checkpoint inhibitors had a great effect in triple-negative breast cancer (TNBC); however, they benefited only a subset of patients, underscoring the need to co-target alternative pathways and ...select optimal patients. Herein, we investigated patient subpopulations more likely to benefit from immunotherapy and inform more effective combination regimens for TNBC patients.
We conducted exploratory analyses in the FUSCC cohort to characterize a novel patient selection method and actionable targets for TNBC immunotherapy. We investigated this in vivo and launched a phase 2 trial to assess the clinical value of such criteria and combination regimen. Furthermore, we collected clinicopathological and next-generation sequencing data to illustrate biomarkers for patient outcomes.
CD8-positivity could identify an immunomodulatory subpopulation of TNBCs with higher possibilities to benefit from immunotherapy, and angiogenesis was an actionable target to facilitate checkpoint blockade. We conducted the phase II FUTURE-C-Plus trial to assess the feasibility of combining famitinib (an angiogenesis inhibitor), camrelizumab (a PD-1 monoclonal antibody) and chemotherapy in advanced immunomodulatory TNBC patients. Within 48 enrolled patients, the objective response rate was 81.3% (95% CI, 70.2-92.3), and the median progression-free survival was 13.6 months (95% CI, 8.4-18.8). No treatment-related deaths were reported. Patients with CD8- and/or PD-L1- positive tumors benefit more from this regimen. PKD1 somatic mutation indicates worse progression-free and overall survival.
This study confirms the efficacy and safety of the triplet regimen in immunomodulatory TNBC and reveals the potential of combining CD8, PD-L1 and somatic mutations to guide clinical decision-making and treatments.
ClinicalTrials.gov: NCT04129996 . Registered 11 October 2019.
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