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Objective: To analyze the mechanism of action and compatibility of the active compounds of the traditional herb pair Bupleuri Radix (Chai Hu, CH, 柴胡) - Paeoniae Radix Alba (Bai Shao, BS, 白芍). Methods: All chemical compounds related to CH and BS were retrieved from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP), Traditional Chinese Medicine Integrated Database (TCMID), Bioinformatics Analysis Tool for Molecular mechANism of Traditional Chinese Medicine (Batman-TCM), Traditional Chinese Medicine Database@Taiwan (TCM Database@Taiwan), and the literature. Relevant compounds were screened for oral bioavailability (OB), drug-likeness (DL), and the Caco-2 cell model. The Uniprot, Genecard, and CTD databases were used to obtain information on potential targets and diseases of associated compounds. Based on this, Cytoscape 3.2.1 software, GO enrichment analysis, and KEGG pathway enrichment were used to analyze the potential mechanism of action and pathways of the CH - BS drug combination. Results: A total of 23 active compounds of CH and BS were indentified after meeting specific criteria by network pharmacology, showing 79 predicted targets of active compounds. Among them, all targets were associated with 344 diseases, and the compounds in CH and BS were connected to 94 pathways and biological, such as calcium signaling pathway, neuroactive ligand-receptor interaction and TNF signaling pathway. Conclusions: Our results preliminarily validated the main compounds in CH - BS herb pair interacted with multiple targets in different diseases, and the molecular mechanism of these compounds involves multiple pathways, thereby establishing a good foundation for further studies. Keywords: Bupleuri Radix (Chai Hu, 柴 胡), Paeoniae Radix Alba (Bai Shao, 白芍), Herb pair, Network pharmacology, Mechanism of action

A compact frequency-selective surface (FSS) having a quasi-elliptic bandpass response is presented in this paper. This was realized by vertically cascading substrate integrated waveguide (SIW) cavities. A single SIW cavity FSS has been fully studied and approximate analytical formulas are introduced to calculate its resonant frequencies. Two different resonances can be excited by a plane wave in the single SIW cavity FSS. According to theories of the cascading cavity filter and dual-mode filter, cross coupling can be realized in cascading SIW cavity FSSs, thus a compact FSS with a quasi-elliptic bandpass response is implemented. A K a-band sample was fabricated by a printed circuit board (PCB) process. Experiments were carried out to validate this design method. Measured results are in agreement with predicted ones. The proposed quasi-elliptic FSS presents a number of advantages, namely, high selectivity, stable performance, and much reduced volume. Index Terms--Cascading cavities, dual-mode filter, frequency-selective surface (FSS), substrate integrated waveguide (SIW), quasi-elliptic.

Cisplatin (DDP) is one of the first-line chemotherapeutic agents for non-small cell lung cancer (NSCLC). However, repeated use of cisplatin in clinical practice often induces chemoresistance. The aims of this study were to investigate whether rosmarinic acid (RA) could reverse multidrug resistance (MDR) in NSCLC and to explore the underlying mechanisms. Our data demonstrated that RA significantly inhibited NSCLC cell proliferation and cell colony formation in a dose-dependent manner, induced G1 phase cell cycle arrest and apoptosis, and increased the sensitivity of cell lines resistant to DDP. Mechanistically, RA inhibited NSCLC cell growth, arrested cell cycle, and induced apoptosis by activating MAPK and inhibiting the expression of P-gp and MDR1, which correspondingly enhanced p21 and p53 expression. We observed that the growth of xenograft tumors derived from NSCLC cell lines in nude mice was significantly inhibited by combination therapy. We demonstrate that RA is a potentially effective MDR reversal agent for NSCLC, based on downregulation of MDR1 mRNA expression and P-gp. Together, these results emphasize the putative role of RA as a resistance reversal agent in NSCLC. [ABSTRACT FROM AUTHOR]

Globally, non-small cell lung cancer (NSCLC) is the most common malignancy and its prognosis remains poor because of the lack of reliable early diagnostic biomarkers. The competitive endogenous RNA (ceRNA) network plays an important role in the tumorigenesis and prognosis of NSCLC. Tumor immune microenvironment (TIME) is valuable for predicting the response to immunotherapy and determining the prognosis of NSCLC patients. To understand the TIME-related ceRNA network, the RNA profiling datasets from the Genotype-Tissue Expression and The Cancer Genome Atlas databases were analyzed to identify the mRNAs, microRNAs, and lncRNAs associated with the differentially expressed genes. Weighted gene co-expression network analysis revealed that the brown module of mRNAs and the turquoise module of lncRNAs were the most important. Interactions among microRNAs, lncRNAs, and mRNAs were prognosticated using miRcode, miRDB, TargetScan, miRTarBase, and starBase databases. A prognostic model consisting of 13 mRNAs was established using univariate and multivariate Cox regression analyses and validated by the receiver operating characteristic (ROC) curve. The 22 immune infiltrating cell types were analyzed using the CIBERSORT algorithm, and results showed that the high-risk score of this model was related to poor prognosis and an immunosuppressive TIME. A lncRNA–miRNA–mRNA ceRNA network that included 69 differentially expressed lncRNAs (DElncRNAs) was constructed based on the five mRNAs obtained from the prognostic model. ROC survival analysis further showed that the seven DElncRNAs had a substantial prognostic value for the overall survival (OS) in NSCLC patients; the area under the curve was 0.65. In addition, the high-risk group showed drug resistance to several chemotherapeutic and targeted drugs including cisplatin, paclitaxel, docetaxel, gemcitabine, and gefitinib. The differential expression of five mRNAs and seven lncRNAs in the ceRNA network was supported by the results of the HPA database and RT-qPCR analyses. This comprehensive analysis of a ceRNA network identified a set of biomarkers for prognosis and TIME prediction in NSCLC. [ABSTRACT FROM AUTHOR]

Background: Cisplatin-based chemotherapy was previously considered as the standard adjuvant therapy for improved overall survival (OS) in patients with non-small cell lung cancer (NSCLC) after surgery. However, the benefit was limited due to high risks of recurrence and adverse events. In the present study, the efficacy of adjuvant epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) for EGFR-mutant patients after surgery was investigated using the latest updated data. Methods: This meta-analysis included a comprehensive range of relevant studies identified from database searches. Disease-free survival (DFS) and OS with hazard ratios (HRs) were calculated using random-effect or fixed-effect models. Subgroup analysis was also performed. Results: A total of seven randomized clinical trials were included in the meta-analysis and involved 1,283 NSCLC patients harboring EGFR mutations. In resected EGFR-mutant NSCLC patients, adjuvant EGFR-TKIs were significantly better than chemotherapy in terms of DFS (HR: 0.41; 95%CI: 0.24–0.70, P = 0.001), without showing any benefit in OS (HR: 0.72; 95%CI: 0.37–1.41, P = 0.336). No significant difference in DFS was observed between patients with EGFR exon 19 deletion and those with L858R mutation. Resected EGFR-mutant NSCLC patients treated with osimertinib experienced improved DFS and a lower risk of brain recurrence than those treated with gefitinib or erlotinib. Adjuvant EGFR-TKIs reduced the risk of bone and lung relapse, without decreasing the risk of local recurrence and liver relapse. Conclusion: This meta-analysis shows that adjuvant EGFR-TKI therapy could significantly prolong DFS in patients with resected EGFR-mutant NSCLC. Treatment with osimertinib showed improved DFS with a lower risk of brain recurrence than treatment with gefitinib or erlotinib for resected disease. [ABSTRACT FROM AUTHOR]

Cisplatin represents one of the first-line drugs used for non-small-cell lung cancer treatment. However, considerable side effects and the emergence of drug resistance are becoming critical limitations to its application. Combinatorial strategies may be able to extend the use of cisplatin. Both Tanshinone IIA and cisplatin inhibit non-small-cell lung cancer cell growth in a time- and dose-dependent manner. When Tanshinone IIA was combined with cisplatin at a ratio of 20:1, they were observed to exert a synergistic inhibitory effect on non-small-cell lung cancer cells. The combination treatment was shown to impair cell migration and invasion, arrest the cell cycle in the S phases, and induce apoptosis in A549 and PC9 cells in a synergistic manner. KEGG pathway analysis and molecular docking indicated that Tanshinone IIA might mainly influence the phosphatidylinositol 3-kinase-Akt signalling pathway. In all treated groups, the expression levels of Bax and cleaved Caspase-3 were up-regulated, whereas the expression levels of Bcl-2, Caspase-3, p-Akt, and p-PI3K proteins were down-regulated. Among these, the combination of Tan IIA and cisplatin exhibited the most significant difference. Tanshinone IIA may function as a novel option for combination therapy for non-small-cell lung cancer treatment. [ABSTRACT FROM AUTHOR]

Background: Limited treatment strategies are available for squamous-cell lung cancer (SQLC) patients. Few studies have addressed whether immune-related genes (IRGs) or the tumor immune microenvironment can predict the prognosis for SQLC patients. Our study aimed to construct a signature predict prognosis for SQLC patients based on IRGs. Methods: We constructed and validated a signature from SQLC patients in The Cancer Genome Atlas (TCGA) using bioinformatics analysis. The underlying mechanisms of the signature were also explored with immune cells and mutation profiles. Results: A total of 464 eligible SQLC patients from TCGA dataset were enrolled and were randomly divided into the training cohort (n = 232) and the testing cohort (n = 232). Eight differentially expressed IRGs were identified and applied to construct the immune signature in the training cohort. The signature showed a significant difference in overall survival (OS) between low-risk and high-risk cohorts (P < 0.001), with an area under the curve of 0.76. The predictive capability was verified with the testing and total cohorts. Multivariate analysis revealed that the 8-IRG signature served as an independent prognostic factor for OS in SQLC patients. Naive B cells, resting memory CD4 T cells, follicular helper T cells, and M2 macrophages were found to significantly associate with OS. There was no statistical difference in terms of tumor mutational burden between the high-risk and low-risk cohorts. Conclusion: Our study constructed and validated an 8-IRG signature prognostic model that predicts clinical outcomes for SQLC patients. However, this signature model needs further validation with a larger number of patients. [ABSTRACT FROM AUTHOR]

Objective: Metastasis and therapeutic resistance are the major determinants of lung cancer progression and high mortality. Epithelial–mesenchymal transition (EMT) plays a key role in the metastasis and therapeutic resistance. Highly expressed glucose-regulated protein 78 (GRP78) is a poor prognostic factor in lung cancer and possibly correlated with EMT. This study aims to examine whether the up-regulation of GRP78 is involved in EMT in lung adenocarcinoma and explore the underlying downstream molecular pathways. Study Design: EMT was assessed by analysis of cell morphology and expression of EMT protein markers in A549 cells under normoxia, hypoxia and silencing GRP78 conditions. The expression levels of Smad2/3, Src, and MAPK (p38, ERK, and JNK) proteins were examined by Western blot analysis under hypoxia and treatments with phosphorylation inhibitors. Results: Under hypoxic conditions, the EMT morphology significantly changed and the GRP78 expression was significantly up-regulated in A549 cells compared with those in normoxia control. The expression and phosphorylation levels of smad2/3, Src, p38, ERK, and JNK were also upregulated. When GRP78 was silenced, EMT was inhibited, and the levels of phospho-smad2/3, phospho-Src, phospho-p38, phospho-ERK, and phospho-JNK were suppressed. When the activation of Smad2/3, Src, p38, ERK, and JNK was inhibited, EMT was also inhibited. The inhibition effect on EMT by these phosphorylation inhibitors was found to be weaker than that of GRP78 knockdown. Conclusions: Hypoxia-induced EMT in A549 cells is regulated by GRP78 signaling pathways. GRP78 promotes EMT by activating Smad2/3 and Src/MAPK pathways. Hence, GRP78 might be a potential target for treatment of lung adenocarcinoma. [ABSTRACT FROM AUTHOR]

A novel fast adaptive-gain complementary filter algorithm is developed for Unmanned Aerial Vehicle (UAV) attitude estimation. This approach provides an accurate, robust and simple method for attitude estimation with minimised attitude errors and reduced computation. UAV attitude data retrieved from accelerometer data is transformed to the solution of a linearly discrete dynamic system. A novel complementary filter is designed to fuse accelerometer and gyroscope data, with a self-adjusted gain to achieve a good performance in accuracy. The performance of the proposed algorithm is compared with an Adaptive-gain Complementary Filter (ACF) and Extended Kalman Filtering (EKF). Simulation and experimental results show that the accuracy of the proposed filter has the same performance as an EKF in high dynamic operating conditions. Therefore, the proposed algorithm can balance accuracy and time consumption, and it has a better price/performance ratio in engineering applications. [ABSTRACT FROM AUTHOR]

Keywords: lung cancer; lung adenocarcinoma; epithelial mesenchymal transition; hypoxia; glucose-regulated protein 78; GRP78 EN lung cancer lung adenocarcinoma epithelial mesenchymal transition hypoxia glucose-regulated protein 78 GRP78 N.PAG N.PAG 3 12/18/20 20201215 NES 201215 In the original article, there was a mistake in Figure 1 and 2 as published. * P < 0.05, compared with A549 cells in the normal oxygen environments, the Smad2/3, Src, and MAPK proteins of A549 cells are highly regulated and activated in hypoxia environments. * P < 0.05, compared with A549 cells in the normal oxygen environments, the EMT process of A549 cells under hypoxia is activated; # P < 0.05, compared with A549 cells in the hypoxia environments, the EMT process of A549 cells under hypoxia is inhibited separately by Smad2/3, Src, p38, ERK, and JNK inhibitors. [Extracted from the article]

Objective: To review the clinical details and further treatments for recurrent spinal giant cell tumors (SGCT), and to analyze the risk factors of recurrence and shed new light on the treatment options and prognosis of recurrent SGCT. Methods: A retrospective analysis of recurrent SGCT between April 2003 and January 2014 was performed. A total of 10 patients comprising 3 men and 7 women with a mean age of 28.9 years (range, 21–40 years) were included in the study. All complete clinical data, radiographs, CT, MRI, scans and pathological data were reviewed. The tumor locations and the regions involved were evaluated by CT and MRI. The blood supply of the tumors was evaluated by enhanced CT and MRI. The mean follow‐up was 81.3 months (range, 35.7–172.1 months). Results: All patients had Enneking stage 3 tumors; 9 (90%) of them had different extents of spinal canal involvement in the primary time period. All patients underwent intralesional resection during their first surgery. Only 1 patient received local adjuvant treatments; no patient underwent selective arterial embolization or used denosumab at that time. Only 1 patient underwent adjuvant radiotherapy postoperatively, and another patient used bisphosphonates. After recurrence, 1 patient was cured using denosumab, and 2 patients' disease was controlled through use of other medical treatments or adjuvant treatments. There were 3 repeated recurrences and 7 repeated surgical procedures were performed in 5 patients. There were 6 intralesional excisions and 1 decompression surgery. The mean relapse‐free time after the first surgery was 32.3 months (range, 10.5–62.6 months). The overall mean relapse‐free time was 40.2 months (range, 10.5–157 months). No distant metastasis was found in our series. At the final follow‐up, 4 patients were disease free, 3 patients' disease was under control, 2 has progressive disease aggravation, while 1 patient died as a result of progression of disease 133.9 months after first surgery. Conclusion: Intralesional excision for recurrent spinal giant cell tumors is an effective option that may have satisfactory prognosis. However, the excision and the inactivation of the lesion should be carried out carefully and thoroughly without missing any corners. Early diagnosis of recurrence may be associated with better prognosis. Adjuvant treatments perioperatively and systemic medical treatments can decrease recurrence rates and can have therapeutic effects in the recurrent SGCT. [ABSTRACT FROM AUTHOR]

The design of high-performance radio frequency power amplifiers requires accurate and simple characterization of power transistors. Behavioral modeling technique provides an efficient and convenient way to tackle this issue. This study presents a novel behavioral model, which is based on quadratic polynomial expansion of nonlinear scattering function with high-order components included. This method was implemented in Computer Aided Design (CAD) program with the help of the frequency-domain defined device component. The comparisons of the output voltage are presented and discussed under different load impedance and input power on a practical circuit operating at 20 GHz, and the results show that the model is capable of accurately characterizing the strong nonlinear behavior the device expressed while the fundamental and harmonic frequency load impedance located anywhere inside the Smith Chart. [ABSTRACT FROM AUTHOR]

In this letter, a high-power microwave (HPM) hardened structure for a split-gate enhanced power U-shaped trench-gate metal–oxide–semiconductor (SGE-UMOS) field-effect transistor is proposed. Also, a mathematical model of HPM induced voltage is established. Compared with the standard SGE-UMOS structure, the radiation immunity of the proposed structure has been improved by a value exceeding 200, with burnout time improving from 120 ns to 27.76~\mu \texts . Additionally, a detailed investigation is carried out by a 2-D numerical mixed mode simulation via ATLAS to optimize the HPM hardened SGE-UMOS structure. The simulation results demonstrate that a 106% improvement in the figure of merit (including the breakdown voltage and ON-resistance) is achieved in the optimized structure. [ABSTRACT FROM AUTHOR]

This paper presents the 2-D numerical simulation results of the single-event burnout (SEB) in the floating field ring (FFR) termination of a power MOSFET for the first time. We investigate the SEB triggering mechanism and SEB performance based on a 140-V typical FFR termination, and find that the structure is sensitive to SEB because of a sharp temperature rise appearing at the p+ base/n-drift junction. A 140-V hardened FFR termination (an n-type buffer layer is added between the epitaxial layer and substrate layer) is also studied in this paper that can demonstrate much better SEB performance without sacrificing the basic characteristics compared to the standard one. In addition, the hardening mechanism is explained, and the performances of the hardened structures with different buffer layer thickness are discussed. As a result, the safe operating area can reach the value of the breakdown voltage when the thickness achieves or exceeds 3~\mu \textm . [ABSTRACT FROM AUTHOR]

A 60-GHz 4-bit vector-summing phase shifter has been implemented in a 90-nm CMOS process. Based on a tunable current-splitting technique with $\pi $ -type low-pass filter (LPF) and T-type high-pass filter (HPF), a quadrature adjustable amplitude generator is developed to improve the insertion loss and adjust quadrature signals’ amplitudes. Variable gain amplifiers (VGAs) that are widely used in traditional phase shifters are replaced by the generator to reduce power consumption. In addition, a balun-based current-reuse technique is applied to further save dc power. The overall consumed direct current is 11 mA under 1.8-V voltage supply. The measured results show that the phase shifter with an output balun (with loss of 1.6 dB) achieves gain of $-{{0.4}}{\sim }{{2.5}}~{\text {dB}}$ at 60 GHz and root mean square (rms) gain error is ${{0.75}}{\sim }{{1.6}}~{\text {dB}}$ in the frequency regime from 57 to 64 GHz. The peak average gain is 1.1 dB at 59.7 GHz. By employing a calibration method, the measured rms phase error ranges from 2.3° to 7.6° from 57 to 64 GHz. The tested 60-GHz input 1-dB compression point (P_{1\mathrm {dB}}) and noise figure (NF) for 16 phase states are −9.8 ± 0.8 dBm and 11 ± 1.3 dB, respectively. [ABSTRACT FROM PUBLISHER]

Summary Autophagy transports cytosolic materials into lysosomes/vacuoles either in bulk or selectively. Selective autophagy requires cargo receptor proteins, which usually link cargos to the macroautophagy machinery composed of core autophagy-related (Atg) proteins. Here, we show that fission yeast Nbr1, a homolog of mammalian autophagy receptor NBR1, interacts with and facilitates the transport of two cytosolic hydrolases into vacuoles, in a way reminiscent of the budding yeast cytoplasm-to-vacuole targeting (Cvt) pathway, a prototype of selective autophagy. We term this pathway Nbr1-mediated vacuolar targeting (NVT). Surprisingly, unlike the Cvt pathway, the NVT pathway does not require core Atg proteins. Instead, it depends on the endosomal sorting complexes required for transport (ESCRTs). NVT components colocalize with ESCRTs at multivesicular bodies (MVBs) and rely on ubiquitination for their transport. Our findings demonstrate the ability of ESCRTs to mediate highly selective autophagy of soluble cargos, and suggest an unexpected mechanistic versatility of autophagy receptors. [ABSTRACT FROM AUTHOR]

Preliminary studies of Vγ9Vδ2 T cells and zoledronate (ZOL) present promising reasons to exploit their immunotherapeutic potential for osteosarcoma treatment (OS). ZOL is a third-generation aminobisphosphonate (ABP) and is well established in the management of cancer-induced bone disease. However, ZOL is characterized by high tropism for bone matrix, and the efficacy of ZOL for sensitizing tumors remains to be optimized. Vγ9Vδ2 T cells are important effectors of antibody-dependent cell-mediated cytotoxicity (ADCC). In this study, we investigated whether Vγ9Vδ2 T cell-mediated killing of ZOL-pretreated OS cells could be increased by the anti-HER-2 monoclonal antibody trastuzumab (TTZ). The cytotoxic activity of Vγ9Vδ2 T cells against osteosarcoma was assessed by an MTS assay in the presence or absence of TTZ. A CD107a assay was used to measure degranulation in cytotoxic Vγ9Vδ2 T cells. Blocking studies were used to determine the effect of relative ligands on Vγ9Vδ2 T cell recognition. TTZ induced an ADCC response in the OS cell line, U2OS; however, it had no effect on another OS cell line HOS with low levels of surface HER2 expression. Although the OS cells pretreated with ZOL for clinically relevant time periods (2 hours) stimulated a suboptimal immune response of Vγ9Vδ2 T cells, TTZ could further enhance the cytotoxicity of Vγ9Vδ2 T cells. These results demonstrate that combining TTZ and ZOL significantly increases the cytotoxic potential of Vγ9Vδ2 T cells. This study raises the possibility of utilizing ZOL and TTZ in Vγ9Vδ2 T cell-based immunotherapy for OS. [ABSTRACT FROM AUTHOR]