Nowadays, the simultaneous inhibition of two or more pathways plays an increasingly important role in cancer treatment due to the complex and diverse pathogenesis of cancer, and the combination of ...the cyclin-dependent kinase 6 (CDK6) inhibitor and PIM1 inhibitor was found to generate synergistic effects in acute myeloid leukemia (AML) treatment. Therefore, we discovered a novel lead 1 targeting CDK6/PIM1 via pharmacophore-based and structure-based virtual screening, synthesized five different series of new derivates, and obtained a potent and balanced dual CDK6/PIM1 inhibitor 51, which showed high kinase selectivity. Meanwhile, 51 displayed an excellent safety profile and great pharmacokinetic properties. Furthermore, 51 displayed stronger potency in reducing the burden of AML than palbociclib and SMI-4a in vivo. In summary, we offered a new direction for AML treatment and provided a great lead compound for AML preclinical studies.
Seven isoflavones were isolated from sprouted chickpea seeds by chromatography on silica gel column, polyamide column, sephadex LH-20 column and preparing thin-layer chromatography (TLC), ...respectively. The structures were characterised with one- and two-dimensional NMR in combination with mass and IR spectrometry. The obtained isoflavones were biochanin A (5,7-dihydroxyflavone-4′-methoxyflavone, (
1); calycosin (7,3′-dihydroxy-4′-methoxyisoflavone, (
2); formononetin (7-hydroxy-4′-methoxyisoflavone, (
3); genistein (5,7,4′-trihydroxyisoflavone, (
4); trifolirhizin (maackiain-3-O-β-
d-glucopyranoside, (
5); ononin (7-O-β-
d-glucosyl-7-hydroxy-4′-methoxyisoflavone, (
6); sissotrin (7-O-β-
d-glucosyl-5,7-dihydroxy-4′-methoxyisoflavone, (
7).
Aldo-keto reductase 1C3 (AKR1C3) is correlated with tumor development and chemotherapy resistance. The catalytic activity of the enzyme has been recognized as one of the important factors in inducing ...anthracycline (ANT) resistance in cancer cells. Inhibition of AKR1C3 activity may provide a promising approach to restore the chemosensitivity of ANT-resistant cancers. Herein, a series of biaryl-containing AKR1C3 inhibitors has been developed. The best analogue S07-1066 selectively blocked AKR1C3-mediated reduction of doxorubicin (DOX) in MCF-7 transfected cell models. Furthermore, co-treatment of S07-1066 significantly synergized DOX cytotoxicity and reversed the DOX resistance in MCF-7 cells overexpressing AKR1C3. The potential synergism of S07-1066 over DOX cytotoxicity was demonstrated in vitro and in vivo. Our findings indicate that inhibition of AKR1C3 potentially enhances the therapeutic efficacy of ANTs and even suggests that AKR1C3 inhibitors may serve as effective adjuvants to overcome AKR1C3-mediated chemotherapy resistance in cancer treatment.
The DArk Matter Particle Explorer (DAMPE) is a general purpose satellite-borne high energy γ−ray and cosmic ray detector. Among the scientific objectives of DAMPE are the search for the origin of ...cosmic rays and an understanding of the Dark Matter particles. As one of the four detectors in DAMPE, the Plastic Scintillator Detector (PSD) plays an important role in the particle charge measurement and the photons/electrons discrimination. It can identify the atomic number Z/charge states of relativistic ions from H to Fe and the detection efficiency for Z = 1 particles can reach 0.9999. The PSD has been working reliably since the successfully launching of DAMPE on December 17, 2015. In this paper, the design, assembly, qualification tests of the PSD and some of the performance measured on the ground are presented in detail.
The single-cell platform provided revolutionary way to study cellular biology. Technologically, a sophistic protocol of isolating qualified single cells would be key to deliver to single-cell ...platform, which requires high cell viability, high cell yield and low content of cell aggregates or doublets. For musculoskeletal tissues, like bone, cartilage, nucleus pulposus and tendons, as well as their pathological state, which are tense and dense, it's full of challenge to efficiently and rapidly prepare qualified single-cell suspension. Conventionally, enzymatic dissociation methods were wildly used but lack of quality control. In the present study, we designed the rapid cycling enzymatic processing method using tissue-specific enzyme cocktail to treat different human pathological musculoskeletal tissues, including degenerated nucleus pulposus (NP), ossifying posterior longitudinal ligament (OPLL) and knee articular cartilage (AC) with osteoarthritis aiming to rapidly and efficiently harvest qualified single-cell suspensions for single-cell RNA-sequencing (scRNA-seq). We harvested highly qualified single-cell suspensions from NP and OPLL with sufficient cell numbers and high cell viability using the rapid cycling enzymatic processing method, which significantly increased the cell viability compared with the conventional long-time continuous digestion group (P < 0.05). Bioanalyzer trace showed expected cDNA size distribution of the scRNA-seq library and a clear separation of cellular barcodes from background partitions were verified by the barcode-rank plot after sequencing. T-SNE visualization revealed highly heterogeneous cell subsets in NP and OPLL. Unfortunately, we failed to obtain eligible samples from articular cartilage due to low cell viability and excessive cell aggregates and doublets. In conclusion, using the rapid cycling enzymatic processing method, we provided thorough protocols for preparing single-cell suspensions from human musculoskeletal tissues, which was timesaving, efficient and protective to cell viability. The strategy would greatly guarantee the cell heterogeneity, which is critical for scRNA-seq data analysis. The protocol to treat human OA articular cartilage should be further improved.
The Dayingezhuang deposit is a representative large gold deposit within the Zhao-Ping fault zone in Jiaodong Peninsula, eastern China, and contains gold reserves of 170 t with an average grade of ...3.10 g/t. The orebodies are hosted in the Late Jurassic Linglong granite intrusion and are Jiaojia-type (disseminated- or stockwork-style) ores. Mineralization and alteration are structurally controlled by the NE- to NNE-striking Linglong detachment fault located near the central section of the regional Zhao-Ping fault zone. Mineralization can be divided into primary and supergene periods. The primary period can be further divided into four hydrothermal stages: I) pyrite–(K-feldspar)–sericite–quartz; II) auriferous quartz–pyrite; III) quartz–gold–polymetallic sulfides; and IV) quartz–carbonate. Gold was mainly deposited in the second and third stages. Three types of fluid inclusion were observed (in decreasing order of abundance): AC-type (aqueous–carbonic), A-type (aqueous), and PC-type (pure carbonic). Based on petrographic, microthermometric, and laser Raman spectroscopic analyses of these fluid inclusions, three types of fluid inclusion assemblage (FIA) were identified in the quartz grains: FIA1 (AC- and PC-type), FIA2 (AC-, PC- and A-type), and FIA3 (A-type). First stage quartz grains contain mainly FIA1-type inclusions, with trapping temperatures of 305–388 °C and salinities of 4.28–8.51 wt% NaCl equivalent. Quartz grains that formed in the second and third mineralization stages contain all three types of FIA. Second stage inclusions homogenize completely at temperatures of 219–317 °C and have salinities of 1.56–11.12 wt% NaCl equivalent, while third stage inclusions homogenize completely at temperatures of 195–319 °C and have salinities of 2.73–13.33 wt% NaCl equivalent. In contrast, quartz grains that formed during the last mineralization stage contain mainly FIA3-type inclusions that yield homogenization temperatures of 126–233 °C and salinities of 0.48–6.72 wt% NaCl equivalent. The microthermometric data indicate that the ore-forming system evolved from a CO2-rich mesothermal fluid into a CO2-poor fluid. The existence and microthermometric characteristics of AC-, PC-, and A-type inclusion assemblages (FIA2) within a single thin section of grains that formed during the second and third stages show that ore fluids underwent unmixing during the syn-ore mineralization stages, due to pressure and temperature fluctuations. The microstructural deformation of auriferous samples indicates that both ductile and brittle deformation occurred during the syn-ore mineralization. Based on the inference that fluids were immiscible in FIA2, trapping pressures during ore formation are estimated at 127–276 MPa. Assuming a fluid pressure regime controlled by fault-valve activity, these pressures are equivalent to a mineralization depth of 9.2–14.0 km. The depth to which erosion occurred in the study area has been calculated as ~10.3 km since the formation of the deposit at 130 Ma, which suggests good prospecting potential for gold at depth in Dayingezhuang.
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•Three types of FIA were identified in the Dayingezhuang deposit.•Large scale fluid immiscibility did take place in syn-ore stages.•Metallogenic depth vs. erosion depth can be used for prospecting potential.•The space with deep gold exploration is expectable at Dayingezhuang gold.
BACKGROUND Esophageal cancer is a malignant tumor with a complex pathogenesis and a poor 5-year survival rate, which encourages researchers to explore its molecular mechanisms deeper to improve the ...prognosis. MATERIAL AND METHODS DEGs were from 4 Gene Expression Omnibus (GEO) databases (GSE92396, GSE20347, GSE23400, and GSE45168) including 87 esophageal tumor samples and 84 normal samples. We performed Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, Protein-Protein interaction (PPI) analysis, and GeneMANIA to identify the DEGs. Gene set enrichment analysis (GSEA) and Kaplan-Meier survival analyses were performed. RESULTS There was an overlapping subset consisting of 120 DEGs that was present in all esophageal tumor samples. The DEGs were enriched in extracellular matrix (ECM)-receptor interaction, as well as focal adhesion and transcriptional mis-regulation in cancer. The 2 most crucial regulatory pathways in esophageal cancer were the amebiasis pathway and the PI3K-Akt signaling pathway. Secreted phosphoprotein 1 (SPP1) and fibronectin 1 (FN1) were selected and verified in an independent cohort and samples using the TCGA and GTEx projects. Gene set enrichment analysis (GSEA) showed that proteasome and nucleotide excision repair were 2 most differentially enriched pathways in the SPP1 high-expression phenotype, and ECM-receptor interaction and focal adhesion in FN1 high-expression phenotype. Kaplan-Meier survival analysis showed that SPP1 and FN1 were significantly positively related to overall survival and had the potential to predict patient relapse. CONCLUSIONS Our analysis is the first to show that SPP1 and FN1 might work as biological markers of progression and prognosis in esophageal carcinoma (ESCA).
This paper presents a design for timing mismatch calibration in a TIADC (Time-Interleaved Analog-to-Digital Converter) with wideband inputs. By exploiting the approximately linear relationship ...between the autocorrelation properties of sub-ADCs and timing mismatch, we achieve rapid convergence of error estimation. A low-cost detection method is proposed based on the convergent monotonicity of the Least Mean Square (LMS) algorithm, which can automatically correct the calibration direction when the input signal goes beyond the Nyquist zone. Physical test results indicate that the spurs caused by timing mismatch can be suppressed by 26–30 dB using the proposed method.
Fundus fluorescein angiography (FFA) imaging is a standard diagnostic tool for many retinal diseases such as age-related macular degeneration and diabetic retinopathy. High-resolution FFA images ...facilitate the detection of small lesions such as microaneurysms, and other landmark changes, in the early stages; this can help an ophthalmologist improve a patient's cure rate. However, only low-resolution images are available in most clinical cases. Super-resolution (SR), which is a method to improve the resolution of an image, has been successfully employed for natural and remote sensing images. To the best of our knowledge, no one has applied SR techniques to FFA imaging so far.
In this work, we propose a SR method-based pipeline for FFA imaging. The aim of this pipeline is to enhance the image quality of FFA by using SR techniques. Several SR frameworks including neighborhood embedding, sparsity-based, locally-linear regression and deep learning-based approaches are investigated. Based on a clinical FFA dataset collected from Second Affiliated Hospital to Xuzhou Medical University, each SR method is implemented and evaluated for the pipeline to improve the resolution of FFA images.
As shown in our results, most SR algorithms have a positive impact on the enhancement of FFA images. Super-resolution forests (SRF), a random forest-based SR method has displayed remarkable high effectiveness and outperformed other methods. Hence, SRF should be one potential way to benefit ophthalmologists by obtaining high-resolution FFA images in a clinical setting.
Since the outbreak of COVID-19 in China at the end of 2019, the world has experienced a large-scale epidemic caused by the SARS-CoV-2. The epidemiological and clinical course of COVID-19 patients has ...been reported, but there have been few analyses about the characteristics, predictive risk factors, and outcomes of critical patients. In this single-center retrospective case-control study, 90 adult inpatients hospitalized at Tongji Hospital (Wuhan, China) were included. Demographic, clinical, laboratory tests, and treatment data were obtained and compared between critical and non-critical patients. We found that compared with non-critical patients, the critical patients had higher SOFA score and qSOFA scores. Critical patients had lower lymphocyte and platelet count, elevated D-dimer, decreased fibrinogen, and elevated high-sensitivity C-reactive protein (hsCRP), and interleukin-6(IL-6). More critical patients received treatment including antibiotics, anticoagulation, corticosteroid, and oxygen therapy than non-critical ones. Multivariable regression showed higher qSOFA score and elevation of IL-6 were related to critical patients. Antibiotic usage and anticoagulation were associated with decreased in-hospital mortality. And critical grouping contributed greatly to in-hospital death. Critical COVID-19 patients have a more severe clinical course. qSOFA score and elevation of IL-6 are risk factors for critical condition. Non-critical grouping, positive antibiotic application, and anticoagulation may be beneficial for patient survival.
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