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ObjectiveTo investigate the mechanism and clinical significance of miR-18a-5p and retinoid acid receptor-related orphan receptor-α (RORA) in the proliferation and progression of colorectal cancer (CRC) cells. MethodsThe expressions of miR-18a-5p and RORA in CRC cells and tissues were detected via qRT-PCR, FISH, and IHC. Cell proliferation capability was detected through EdU and CFSE assay, cell apoptosis by flow cytometry assay, and cell migration and invasion abilities by cell scratch and Transwell invasion assays, respectively. The targeted regulation of miR-18a-5p on RORA was further verified via dual-luciferase reporter assay, cell function rescue test, RT-PCR, and Western blot assay. Finally, bioinformatics was used to explore the molecular mechanism of miR-18a-5p promoting malignant proliferation, invasion, and progression of CRC via regulating RORA. ResultsmiR-18a-5p exhibited a high expression in CRC tissues and cells (P

Abstract We evaluate the value of oral contrast-enhanced gastric ultrasonography (OCUS) by comparing it with conventional gastroscopy in diagnosing and staging benign peptic ulcer. From July 2018 to December 2020, 44 patients with gastroscopy-confirmed benign peptic ulcers (a total of 45 ulcers were detected), who also received OCUS, were retrospectively reviewed. Each patient’s ultrasound images were compared with gastroscopy and pathology findings. The characteristics of ultrasonic images of different stages of ulcer were analysed. A total of 43 ulcers were detected by OCUS in 44 patients with benign peptic ulcers. There were no false positive results among the OCUS exams, but two ulcers were misdiagnosed. OCUS for benign peptic ulcer staging also shows acceptable clinical practice results. OCUS is useful for detecting and staging benign peptic ulcer, and may be considered an alternative method for conventional gastroscopy. OCUS is especially useful in the follow-up of BPU treatment, but futher study is needed to improve the diagnostic accuracy of benign and malignant ulcers.

Highlights A comprehensive introduction into organic cathode materials for aqueous zinc-ion batteries with specific focus on their structural–property relationship based on the variations in composition, geometry, and molecular size. For each representative organic cathode, the unique electrochemistry has been discussed to provide insight into the underlying working mechanism. Summarized pros and cons of different organic cathodes and outlined challenges plus future research directions.

Abstract Rationally designed organic redox‐active materials have attracted numerous interests due to their excellent electrochemical performance and reasonable sustainability. However, they often suffer from poor cycling stability, intrinsic low operating potential, and poor rate performance. Herein, a novel Donor–Acceptor (D–A) bipolar polymer with n‐type pyrene‐4,5,9,10‐tetraone unit storing Li cations and p‐type carbazole unit which attracts anions and provides polymerization sites is employed as a cathode for lithium‐ion batteries through in situ electropolymerization. The multiple redox reactions and boosted kinetics by the D–A structure lead to excellent electrochemical performance of a high discharge capacity of 202 mA h g−1 at 200 mA g−1, impressive working potential (2.87 and 4.15 V), an outstanding rate capability of 119 mA h g−1 at 10 A g−1 and a noteworthy energy density up to 554 Wh kg−1. This strategy has significant implications for the molecule design of bipolar organic cathode for high cycling stability and high energy density.

This study explores storm floods in the Yangtze Estuary to investigate how extreme sea levels and storm surges change in the context of global warming. Previous studies focused on the long-term variations in amplitude or frequency of storm surges, with limited research conducted on the timing of extreme storm surge events. Based on the methods of non-stationary extreme value theory, we explored the last 33-year tidal levels at Xuliujing Station and found that the annual extreme water level has exhibited a slight downward trend, which is directly attributed to the decrease in mean sea level resulting from reduced upstream river flow. The storm surge season of the Yangtze Estuary experienced a significant lag in the period 2005–2018, which is not restricted to the Yangtze Estuary but is rather a large-scale climate characteristic of a broad oceanic region. The reason for this shift is the sustained increase in the intensity of the western Pacific subtropical high in the last 15 years, leading to the appearance of low-pressure channels in the East China Sea in September and October and thus causing more typhoons to enter the East China Sea during the later period of the storm surge season.

IntroductionOil palm is the world's highest yielding oil crop and its palm oil has high nutritional value, making it an oilseed plant with important economic value and application prospects. After picking, oil palm fruits exposed to air will gradually become soft and accelerate the process of fatty acid rancidity, which will not only affect their flavor and nutritional value, but also produce substances harmful to the human body. As a result, studying the dynamic change pattern of free fatty acids and important fatty acid metabolism-related regulatory genes during oil palm fatty acid rancidity can provide a theoretical basis for improving palm oil quality and extending its shelf life.MethodsThe fruit of two shell types of oil palm, Pisifera (MP) and Tenera (MT), were used to study the changes of fruit souring at different times points of postharvesting, combined with LC-MS/MS metabolomics and RNA-seq transcriptomics techniques to analyze the dynamic changes of free fatty acids during fruit rancidity, and to find out the key enzyme genes and proteins in the process of free fatty acid synthesis and degradation according to metabolic pathways.Results and discussionMetabolomic study revealed that there were 9 different types of free fatty acids at 0 hours of postharvest, 12 different types of free fatty acids at 24 hours of postharvest, and 8 different types of free fatty acids at 36 hours of postharvest. Transcriptomic research revealed substantial changes in gene expression between the three harvest phases of MT and MP. Combined metabolomics and transcriptomics analysis results show that the expression of SDR, FATA, FATB and MFP four key enzyme genes and enzyme proteins in the rancidity of free fatty acids are significantly correlated with Palmitic acid, Stearic acid, Myristic acid and Palmitoleic acid in oil palm fruit. In terms of binding gene expression, the expression of FATA gene and MFP protein in MT and MP was consistent, and both were expressed higher in MP. FATB fluctuates unevenly in MT and MP, with the level of expression growing steadily in MT and decreasing in MP before increasing. The amount of SDR gene expression varies in opposite directions in both shell types. The above findings suggest that these four enzyme genes and enzyme proteins may play an important role in regulating fatty acid rancidity and are the key enzyme genes and enzyme proteins that cause differences in fatty acid rancidity between MT and MP and other fruit shell types. Additionally, differential metabolite and differentially expressed genes were present in the three postharvest times of MT and MP fruits, with the difference occurring 24 hours postharvest being the most notable. As a result, 24 hours postharvest revealed the most obvious difference in fatty acid tranquility between MT and MP shell types of oil palm. The results from this study offer a theoretical underpinning for the gene mining of fatty acid rancidity of various oil palm fruit shell types and the enhancement of oilseed palm acid-resistant germplasm cultivation using molecular biology methods.

Background: Chemotherapy combined with antivascular endothelial growth factor (VEGF) or anti-epidermal growth factor receptor monoclonal antibodies is the most promising approach to prolong survival and improve the quality of life of patients with unresectable metastatic colorectal cancer (mCRC). Anlotinib is an oral antiangiogenic tyrosine kinase inhibitor that targets VEGF receptors 1/2/3, fibroblast growth factor receptors 1-4, and platelet-derived growth factor receptors a/β. Since anlotinib combined with oxaliplatin and capecitabine (CAPEOX) as a first-line treatment was previously shown to be effective and safe for patients with RAS/BRAF wild-type (WT) mCRC, we designed this randomized, open-label, parallel-group, non-inferiority, phase III study to evaluate the efficacy and safety of anlotinib plus CAPEOX versus bevacizumab plus CAPEOX in patients with RAS/BRAF WT mCRC. Methods/design: The primary inclusion criteria are Eastern Cooperative Oncology Group performance status 0/1, confirmed RAS/BRAF WT colorectal adenocarcinoma, and unresectable metastases assessed by a multidisciplinary team. The main exclusion criteria are as follows: high microsatellite instability or deficient mismatch repair status, resectable or potentially resectable metastases, and previous systemic therapy for mCRC. A total of 698 patients will be randomized into the anlotinib and bevacizumab groups in a 1:1 ratio. Patients will receive 4 to 8 cycles of induction therapy (CAPEOX plus anlotinib or bevacizumab), followed by maintenance treatment (capecitabine plus anlotinib or bevacizumab) until disease progression or unacceptable toxicity. Progression-free survival (PFS) assessed by an independent review committee is the primary endpoint, whereas investigator-assessed PFS, overall survival, objective response rate, disease control rate, duration of response, resection rate of liver metastases, quality of life, and safety are the secondary endpoints. Enrollment commenced in May 2021. Discussion: A prospective, randomized, phase III trial will provide a meaningful comparison of the efficacy and safety of anlotinib plus CAPEOX with standard treatment for patients with unresectable RAS/BRAF WT mCRC.

Topological insulators supply robust edge states and can be used to compose novel waveguides to protect energy propagation against various defects. For practical applications, topological waveguides with a large working bandwidth and highly localized interface mode are desired. In the present work, mechanical valley Hall insulators are described by explicit geometry parameters using the moving morphable component method first. From the geometry parameters, artificial neural networks (ANN) are then well-trained to predict the topological property and the bounds of nontrivial bandgaps. Incorporating those ANN models, mathematical formulation for designing optimal mechanical topological waveguides can be solved efficiently, with an acceleration of more than 10,000 times than the traditional topology optimization approach.

Cytotoxic CD8+ T cells are the primary effector cells mediating anti-tumor responses. In vivo monitoring of CD8+ T cells has broad implications for the development of novel cancer therapies. Here we describe the development of a genetically engineered mouse model (GEMM) in which CD8+ T cells are labeled with an optical reporter, enabling in vivo, longitudinal monitoring using bioluminescence imaging (BLI). Firefly luciferase (Luc2), human diphtheria toxin receptor (DTR), and enhanced green fluorescence protein (eGFP) cDNAs are engineered under the CD8α promoter to generate a transgenic mouse line. Luciferase mRNA and CD8α mRNA were generally correlated in various tissues from these mice. Sorted splenic CD8+ T cells, CD4+ T cells and CD3- non-T cells verified that the luciferase signal is specific to CD8+ T cells. In vivo imaging showed that luciferase signal was detected in various immune organs, such as lymph nodes, thymus, and spleen, and the detection was confirmed by ex vivo examination. Administration of diphtheria toxin markedly reduced luciferase signal systemically, confirming the function of the DTR. In the MC38 mouse syngeneic model, we observed significant increases in CD8+ T cells with mDX400 treatment, an anti PD-1 mouse monoclonal antibody that correlated with tumor growth inhibition. This novel reporter GEMM is a valuable drug discovery tool for profiling compounds and understanding mechanisms of action in immunotherapy of cancer.

Roof-breaking characteristics and ground pressure behavior of the coalface are instrumental in guiding deep Jurassic coal seam mining, in particular in the Shaanxi and Inner Mongolia regions of China. A thick-plate mechanical model (TPMM) of the main roof was developed and applied to the case study of 21102 first-mined coalface (FMC) of the Hulusu Coal Mine (HCM) in the Hujirt Mining Area (HMA), China. A theoretical analysis performed via the developed model revealed that the first and periodic breaking intervals of the main roof were 40.6 and 25.0 m, respectively. The roof failure occurred in the tensile mode, was controlled by the internal stress σx in the rock strata, and started from the center of the long side with the fixed support in the goaf. The field measurement of roof weighting was also performed for the coalface advance from zero to 400 m. The measurement results showed that the first weighting average interval was 41.4 m, and the average interval of periodic weighting was 22.0 m, which agreed with the theoretical calculation and proved the proposed model’s feasibility. Finally, the frequency distribution features of the hydraulic support working resistance in the FMC were analyzed statistically. The results showed that the ZY10000-16/32D supports could adapt to the mining geological conditions of the FMC. However, the margin of the rated working resistance of supports was still small. Thus, roof management enhancement during the mining process was strongly recommended. These research findings could offer theoretical guidance for safe and high-efficiency production in the coal mines under similar geological conditions.

Abstract Organic electrode materials have become a hot research field in lithium‐ion batteries. However, the dissolution issue of organic materials (especially small molecules) in traditional electrolytes has become one of the important reasons to limit their application. The usage of highly concentrated electrolyte (HCE, >3 M) has been demonstrated to solve this problem, where the electrochemical performance of Pillar[5]quinone (P5Q) in 4.2 M LiTFSA/AN electrolyte was investigated. The HCE can avoid the reaction between acetonitrile molecules and lithium metal anode, reduce the dissolution of organic materials, and display excellent battery performance. At a current density of 0.2 C, a high specific capacity of 310 mAh g−1 (Ctheo = 446 mAh g−1) was maintained after 900 cycles, and the reversible capacity is higher than 113 mAh g−1 even at 10 C, indicating a good rate capability. This research would expand the new application of acetonitrile‐based electrolyte in organic secondary battery.

Abstract Background Solid papillary carcinoma (SPC) is a rare variant of breast papillary carcinoma with unique pathological morphology and biological behavior. There is only one case report on T1-MRI of SPC. In this study, we report our findings on this new category of papillary carcinoma to fill the gap in MRI characterization of SPC. Methods This retrospective study included four pathology-confirmed in situ SPC patients. Conventional MRI, diffusion weighted imaging (DWI), and magnetic resonance spectroscopy (MRS) were performed with a 1.5 T whole-body MR scanner before surgical operation. The following characteristics of each lesion were recorded: signal intensity on T2WI/STIR and T1FSPGR, morphology, maximum lesion size, and time intensity curve (TIC) on dynamic contrast enhancement MRI (DCE-MRI), apparent diffusion coefficient (ADC) value from DWI, and Cho peak from MRS. Results Signal intensities of all lesions were heterogenous on T2WI/STIR and T1FSPGR. Mass enhancements were observed for all lesions with either oval or irregular shapes on DCE-MRI. The maximum lesion size ranged from 0.8 cm to 3.2 cm. All lesion margins were circumscribed, and internal enhancements were homogeneous or heterogeneous from DCE-MRI. TIC appeared with a rapid increase in initial contrast phases of all lesions. All lesions on DWI (b = 1000s/mm2) were slightly hyperintense with an ADC value range of 1.3 × 10−3 mm2/s to 1.9 × 10−3 mm2/s. Cho peak was absent at 3.2 ppm for all lesions. Conclusions MRI characteristics of SPC include heterogeneous signal intensity within the lesion on T2WI/STIR and T1FSPGR, mass enhancement with circumscribed margins, either oval or irregular shapes, and a rapid initial enhancement of TIC on DCE-MRI. ADC values and the absence of Cho peak may provide valuable information to distinguish SPC from other invasive breast carcinomas.

The primary problem needed to be solved in mining close coal seams is to understand quantitatively the floor failure depth of the upper coal seam. In this study, according to the mining and geological conditions of close coal seams (#10 and #11 coal seams) in the Second Mining Zone of Caocun Coal Mine, the mechanical model of floor failure of the upper coal seam was built. Calculation results show that the advanced abutment pressure caused by the mining of the upper coal seam, resulted in the floor failure depth with a maximum of 26.1 m, which is 2.8 times of the distance between two coal seams. On this basis, the mechanical model of the remaining protective coal pillar was established and the stress distribution status under the remaining protective coal pillar in the 10# coal seam was then theoretically analysed. Analysis results show that stress distribution under the remaining protective coal pillar was significantly heterogeneous. It was also determined that the interior staggering distance should be at least 4.6 m to arrange the gateways of the #209 island coalface in the lower coal seam. Taken into account a certain safety coefficient (1.6–1.7), as well as reducing the loss of coal resources, the reasonable interior staggering distance was finally determined as 7.5 m. Finally, a novel method using radon was initially proposed to detect the floor failure depth of the upper coal seam in mining close coal seams, which could overcome deficiencies of current research methods.

The purpose of our study was to assess the differentially diagnostic value of radiographic characteristics of pure ground glass nodules (GGNs) between minimally invasive adenocarcinoma and non-invasive neoplasm.Sixty-seven pure GGNs (28 minimally invasive adenocarcinomas (MIA) and 39 pre-invasive lesions) were analyzed from June 2012 to June 2015. Pre-invasive lesions consisted of 15 atypical adenomatous hyperplasia (AAH) and 24 adenocarcinomas in situ (AIS). High-resolution computed tomography (HRCT) features and volume of MIA and pre-invasive lesions were assessed. Fisher exact test, independent sample t test, Mann-Whitney U test and receiver operating characteristic (ROC) curve analysis were performed.Inter-observer agreement indexes for the diameter, mean HRCT attenuations and volume of pure GGNs were all high (ICC>0.75). Univariate analyses showed that lesion diameter, mean HRCT attenuation, and volume value differed significantly between two groups. Among HRCT findings, GGN shape as round or oval (F = 13.456, P = 0.002) and lesion borders as smooth or notched (F = 15.742, P = 0.001) frequently appeared in pre-invasive lesions in comparison with MIA. Type II and type III of the relationship between blood vessels and pure GGNs suggested higher possibility of malignancy than type I.HRCT features of pure GGNs can help to differentiate MIA from non-invasive neoplasms.

OBJECTIVE To investigate the detection of sentinel lymph node (SLN) micrometastasis (MM) and the clinical significance in patients with Dukes-B colorectal carcinoma (CRC) using H&E stained slides. METHODS In a prospective study of 64 patients with DukesB CRC undergoing radical surgery, routine H&E staining combined with the immunohistochemical SP method was used to detect the expression of the cytokeratin 20 (CK20) and telomerase (TLMA) in 122 SLNs from 61 of the 64 cases. During a 3-year follow up, the patients’ clinicopathologic parameters data, survival and their relationship were collected and analyzed. RESULTS i) In 6 out of the 61 cases with successful mapping, 9 SLNs were positive after routine detection using H&E staining. ii ) In the other 55 with negative results from H&E staining, the positive rate of CK20 expression was 27.3% (15/55), and the positive rate of TLMA 21.8% (12/55), at er immunohistochemical examination (IHC) on the SLN. iii ) Detection by combining the 2 methods showed that the micrometastasis rate was 38.2% (21/55). iv ) The recurrence or metastasis rate of CRC was significantly higher in the Dukes-B patients with sentinel lymph node micrometastasis (SLNMM) (+) than in those with SLNMM (-) ( P < 0.05), and simultaneously, the survival rate decreased by a large margin in the patients with SLNMM (+), compared to those with SLNMM (-) (P < 0.05). There were significant differences in the recurrence or metastasis rate of cancer and the survival rate between the Dukes-B patients with SLNMM (-) and the Dukes-C patients (P < 0.05). CONCLUSION Examination of anti-CK20 and anti-TLMA using immunohistochemical staining can be used to detect SLNMM, and the combined examination of the 2 can increase the detection rate. The detection of SLNMM can precisely determine the Dukes stage of colorectal carcinoma, which is of help in directing postoperative adjunctive therapy and in assessing prognosis.

Two genetically engineered, conditional mouse models of lung tumor formation, K-rasLSL-G12D and K-rasLSL-G12D/p53LSL-R270H, are commonly used to model human lung cancer. Developed by Tyler Jacks and colleagues, these models have been invaluable to study in vivo lung cancer initiation and progression in a genetically and physiologically relevant context. However, heterogeneity, multiplicity and complexity of tumor formation in these models make it challenging to monitor tumor growth in vivo and have limited the application of these models in oncology drug discovery. Here, we describe a novel analytical method to quantitatively measure total lung tumor burden in live animals using micro-computed tomography imaging. Applying this methodology, we studied the kinetics of tumor development and response to targeted therapy in vivo in K-ras and K-ras/p53 mice. Consistent with previous reports, lung tumors in both models developed in a time- and dose (Cre recombinase)-dependent manner. Furthermore, the compound K-rasLSL-G12D/p53LSL-R270H mice developed tumors faster and more robustly than mice harboring a single K-rasLSL-G12D oncogene, as expected. Erlotinib, a small molecule inhibitor of the epidermal growth factor receptor, significantly inhibited tumor growth in K-rasLSL-G12D/p53LSL-R270H mice. These results demonstrate that this novel imaging technique can be used to monitor both tumor progression and response to treatment and therefore supports a broader application of these genetically engineered mouse models in oncology drug discovery and development.

A high percentage of patients with the myeloproliferative disorder polycythemia vera (PV) harbor a Val617→Phe activating mutation in the Janus kinase 2 (JAK2) gene, and both cell culture and mouse models have established a functional role for this mutation in the development of this disease. We describe the properties of MRLB-11055, a highly potent inhibitor of both the WT and V617F forms of JAK2, that has therapeutic efficacy in erythropoietin (EPO)-driven and JAK2V617F-driven mouse models of PV. In cultured cells, MRLB-11055 blocked proliferation and induced apoptosis in a manner consistent with JAK2 pathway inhibition. MRLB-11055 effectively prevented EPO-induced STAT5 activation in the peripheral blood of acutely dosed mice, and could prevent EPO-induced splenomegaly and erythrocytosis in chronically dosed mice. In a bone marrow reconstituted JAK2V617F-luciferase murine PV model, MRLB-11055 rapidly reduced the burden of JAK2V617F-expressing cells from both the spleen and the bone marrow. Using real-time in vivo imaging, we examined the kinetics of disease regression and resurgence, enabling the development of an intermittent dosing schedule that achieved significant reductions in both erythroid and myeloid populations with minimal impact on lymphoid cells. Our studies provide a rationale for the use of non-continuous treatment to provide optimal therapy for PV patients.

Many enzymes are therapeutic targets for drug discovery, whereas other enzymes are important for understanding drug metabolism and pharmacokinetics during compound testing in animals. Testing of drug efficacy and metabolism in an animal model requires the measurement of disease endpoints as well as assays of enzyme activity in specific tissues at selected time points during treatment. This requires the removal of tissue and biochemical assays. Techniques to noninvasively assess drug effects on enzyme activity using imaging technology would facilitate understanding of drug efficacy, pharmacokinetics, and drug metabolism. Using a commercially available cytochrome P −450 3A substrate whose oxidized product is a luciferase substrate, we show for the first time that cytochrome P −450 enzyme activity can be measured in vivo in real time by bioluminescent imaging. This imaging approach could be applicable to study drug effects on therapeutic target enzymes, as well as drug metabolism enzymes.

Heme oxygenase (HO) is the rate-limiting step in the heme degradation pathway and is a potential target for the control, or prevention, of pathologic jaundice in neonates. Metalloporphyrins (Mps), a diverse set of synthetic derivatives of heme, can competitively inhibit the HO enzymes. However, certain Mps are phototoxic and some increase transcription of HO-1, the inducible HO isozyme. Therefore, effective development of this class of compounds as therapeutics for treating pathologic jaundice will require rapid and integrated biological screens to identify the most efficacious and safe Mps. To study the safety of these compounds, we assessed their cytotoxic effects and measured luciferase activity by bioluminescent imaging (BLI) as an index of HO-1 transcription, first in live cell cultures and then in living transgenic reporter mice. A total of 12 Mps were first evaluated in the correlative cell culture assay. Based on results from this study, 2 Mps, zinc protoporphyrin (ZnPP) and zinc bis glycol porphyrin (ZnBG), were selected for further studies in the live animal model. In vitro BLI showed ZnPP to be a strong inducer of HO-1 transcription in comparison to ZnBG, which showed minimal induction. Cytotoxicity studies revealed that ZnPP was phototoxic, whereas ZnBG had no effect on cell viability. In vivo BLI showed that both ZnPP and ZnBG had minimal effects on the levels of HO-1 transcription in the animals. Furthermore, serum enzyme assays indicated that neither caused detectable liver toxicity. These findings, and especially those with ZnBG, support the use of selected Mps as therapies for pathologic jaundice. Coupling the high throughput advantage of cell culture with the capability of imaging for whole-body temporal analyses could accelerate and refine the preclinical phases of drug development. Thus, this study serves as a model for understanding the effects of specific compounds in relation to defined targets using an integrated approach.