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Gallbladder cancer (GBC) is an aggressive cancer with poor prognosis. PARP inhibitors (PARPi) target PARP enzymes and have shown efficacy in patients with breast cancer gene (BRCA) mutations. Immunotherapy, especially immune checkpoint inhibitors (ICIs), has transformed cancer treatment. However, the combined impact of PARPi and ICIs in GBC remains unclear. We present a groundbreaking case of a GBC patient with BRCA2 mutations who received combination therapy with PARPi and ICIs after failing multiple lines of treatment. Next-generation sequencing (NGS-Seq) identified BRCA gene mutations. To further investigate potential mechanisms, we developed a PARP1-BRCA1-BRCA2 pathway-related risk score (PBscore) system to evaluate the impact of PARPi on the tumor immune microenvironment via RNA-Seq data. Gene expression and functional analysis identified potential mechanisms associated with the PBscore. Experimental validation assessed the impact of the combination therapy on the tumor microenvironment using multiplexed immunofluorescence imaging and immunohistochemistry in patients with BRCA gene wild type or mutations. RNA-Seq analysis revealed correlations between PBscore, immune checkpoint levels, tumor-infiltrating immune cells (TIICs), and the cancer-immunity cycle. Multiplexed immunofluorescence imaging validated that low PBscore patients might have an active tumor microenvironment. Furthermore, upon drug resistance, we observed an upregulation of negative immune checkpoints such as CEACAM1, indicating that the tumor immune microenvironment becomes suppressed after resistance. Our study revealed that PBscore could serve as a biomarker to predict immunotherapy efficacy, offering a promising alternative for BRCA2-mutated GBC patients.

This article proposes a novel soft multiprototype clustering algorithm (SMP) for high-dimensional data clustering with noisy and complex structural patterns. SMP integrates dimensionality reduction, multiprototype clustering, and multiprototype merge clustering under a two-layer seminonnegative matrix factorization (semi-NMF) architecture. Specifically, the first semi-NMF layer performs multiprototype clustering, which solves the problem that a single prototype cannot represent complex data structures. Meanwhile, the multiprototype fuzzy clustering constraints ensure that the multiprototypes better characterize the original data structure. The second semi-NMF layer performs multiprototype merge clustering to mitigate the issues of heavy computation burden and poor antinoise performance of the spectral clustering algorithm. The introduction of the Laplace graph matrix regularization constraint in this layer assists SMP in completing the merging of multiprototypes with complex data structures. Comprehensive experiments demonstrate that the proposed method outperforms the state-of-the-art algorithms.

The impulse features are typical characteristics in vibration signals when rotating equipment failures occur, such as faults of bearings and gears. Accurate capture of impulse features can help better monitor the operating status of equipment. As an energy-concentrated time–frequency analysis (TFA) tool, time-reassigned synchrosqueezing transform (TSST) is an effective means to characterize impulse features in vibration signals. However, the existence of some obvious defects limits its application. For example, strong frequency-varying signals cannot be effectively processed, and in a noisy environment, transient impact characteristics cannot be accurately captured. To improve the performance of TSST, we use the properties of the window function to search for the local optimum of the short-time Fourier transform (STFT) result to obtain a new time rearrangement operator termed as local optimum time rearrangement operator. Compared with the original rearrangement operator, this operator can more accurately capture the instant when the transient impact occurs when addressing strong frequency-varying signals. With the assistance of this operator, an effective TFA technique termed local optimum TSST (LOTSST) can be constructed. Compared with TSST, LOTSST can generate time–frequency representation (TFR) with more concentrated energy and has better noise robustness. In addition, LOTSST allows the transient characteristics to be completely reconstructed, from which we can more intuitively observe the instant when the impact occurs. Finally, this article employs the proposed method for bearing fault diagnosis, considering both constant speed and variable speed conditions. The simulation and experimental results show that the proposed method is promising and competitive with other TFA technologies.

Human leukocyte antigen antibodies are important immunologic mediators of renal allograft loss and are difficult to control. The inability to permanently eliminate donor-specific antibodies (DSA) is partly due to an incomplete understanding of the cellular mechanisms driving alloantibody formation, recurrence, and maintenance. Memory T follicular helper (mTfh) cells rapidly interact with memory B cells upon antigen re-exposure for anamnestic humoral responses, but little is known about Tfh memory in transplantation. We hypothesized that alloreactive mTfh cells form after transplantation and play a critical role in DSA formation following alloantigen re-encounter. To test this hypothesis, we utilized murine skin allograft models to identify and characterize Tfh memory and interrogate its ability to mediate alloantibody responses. We identified alloreactive Tfh memory as a mediator of accelerated humoral alloresponses independent of memory B cells and primary germinal center, or DSA, formation. Furthermore, we demonstrate that mTfh-driven alloantibody formation is susceptible to CD28 costimulation blockade. These findings provide novel insight into a pathologic role for memory Tfh in alloantibody responses and strongly support shifting therapeutic focus from the singular targeting of B cell lineage cells and alloantibodies themselves to multimodal strategies that include inhibition of mTfh cells to treat DSA.

AbstractBackgroundAxillary venipuncture for pacemaker lead implantation has been demonstrated to be an effective method without fatal complications encountered with standard subclavian access approach, but the relatively high complexity limits its clinical practicability.ObjectiveWe are proposing a simple technique for axillary venipuncture using single point on clavicle as anatomical landmark with the possibility of alternative fluoroscopic assisted puncture as a backup.MethodsConnecting point of medial to middle third of clavicle is located as the landmark. Deflected lateral 45°from sagittal line, an 18-guage needle tip is laid on the point and tangential to upper border of clavicle. Penetrated from the hub site, the needle is directed to the landmark at approximately 30–45° relative to body surface for venipuncture. If blind puncture failed, an alternative fluoroscopic method is performed. Upon successful venipuncture, a guide wire is positioned in inferior vena cava and a skin incision and subcutaneous pocket is made at the puncture site.ResultsAxillary vein puncture was successful for 106 of 113 patients (93.8%) in the study with mean access time of 3.6 ± 1.4 min. In 84 patients (74.3%), the vein was cannulated by blind puncture, and fluoroscopy guided method was required in other 22 patients (19.5%). The puncture of axillary artery occurred in one patient (0.09%) and no haemorrhage was observed after local pressure. No pneumothorax, hemothorax, or brachial plexus injury was found.ConclusionsThe approach of axillary vein puncture using single landmark on the clavicle is simple, effective and safe for pacemaker lead implantation.

Gastrointestinal stromal tumor (GIST) is the most common human sarcoma and is typically driven by a single mutation in the Kitor PDGFRAreceptor. While highly effective, tyrosine kinase inhibitors (TKIs) are not curative. The natural ligand for the Kit receptor is Kit ligand (KitL), which exists in both soluble and membrane-bound forms. While KitL is known to stimulate human GIST cell lines in vitro, we used a genetically engineered mouse model of GIST containing a common human KIT mutation to investigate the intratumoral sources of KitL, importance of KitL during GIST oncogenesis, and contribution of soluble KitL to tumor growth in vivo. We discovered that in addition to tumor cells, endothelia and smooth muscle cells produced KitL in KitV558Δ/+tumors, even after imatinib therapy. Genetic reduction of total KitL in tumor cells of KitV558Δ/+mice impaired tumor growth in vivo. Similarly, genetic reduction of tumor cell soluble KitL in KitV558Δ/+mice decreased tumor size. By RNA sequencing, quantitative PCR, and immunohistochemistry, KitL expression was heterogeneous in human GIST specimens. In particular, PDGFRA-mutant tumors had much higher KitL expression than Kit-mutant tumors, suggesting the benefit of Kit activation in the absence of mutant KIT. Serum KitL was higher in GIST patients with tumors resistant to imatinib and in those with tumors expressing more KitL RNA. Overall, KitL supports the growth of GIST at baseline and after imatinib therapy and remains a potential biomarker and therapeutic target.

Glioma is a primary brain tumor with limited treatment approaches and glioblastoma stem cells (GSCs) are manifested with the self-renewal capability and high tumorigenic capacity. This study was performed to investigate the regulatory effect of the SUMO-specific protease 1 (SENP1)/methyltransferase-like 3 (METTL3)/MYC axis on the self-renewal of GSCs mediated by transcription factor Yin Yang 1 (YY1). Following bioinformatics analysis and clinical and cellular experiments, we found that YY1 was highly expressed in GBM tissues and cells, while silencing its expression reduced the self-renewal ability of GSCs. Functionally, YY1 promoted the transcriptional expression of SENP1 by binding to the promoter region of SENP1, while the deSUMOase SENP1 facilitated the methylase activity of m6A through deSUMOylation of the methylase METTL3, thereby promoting the m6A modification of MYC mRNA via METL3 and promoting the expression of MYC. A nude mouse xenograft model of GBM was also constructed to examine the tumorigenicity of GSCs. The obtained findings demonstrated that YY1 promoted tumorigenicity of GSCs by promoting the expression of MYC in vivo. Conclusively, YY1 can transcriptionally upregulate the SUMOylase SENP1 and enhance the methylase activity of METTL3, resulting in the increased m6A modification level of MYC mRNA, thereby promoting the self-renewal of GSCs.

Clustering noisy, high-dimensional, and structurally complex data have always been a challenging task. As most existing clustering methods are not able to deal with both the adverse impact of noisy samples and the complex structures of data, in this article, we propose a novel robust and sparse possibilistic K-subspace (RSPKS) clustering algorithm to integrate subspace recovery and possibilistic clustering algorithms under a unified sparse framework. First, the proposed method sparsifies the membership matrix and the subspace projection vector under a dual-sparse framework to handle high-dimensional noisy data. This unifies dimensionality reduction and clustering using one objective function for which the optimization can be realized through synchronous iteration. Second, the reconstruction error of each sample in the local subspace is used as the distance metric for classification. That is, each sample itself is treated as a clustering prototype so as not to be affected by the structure of the overall data distribution. Therefore, the clustering prototype construction problem of the data with complex structures can be better addressed. Finally, to deal with nonlinear regions, our RSPKS method is further extended into a kernelized version, namely the kernelized RSPKS clustering algorithm. The experimental results on both synthetic and real-world datasets demonstrate that our proposed method outperforms state-of-the-art algorithms in terms of clustering accuracy.

K Nearest Neighbor (kNN) has gained popularity in machine learning due to its simplicity and good performance. However, kNN faces two problems with classification tasks. The first is that an appropriate distance measurement is required to compute distances between test sample and training samples. The other is the highly computational complexity due to the requirement of searching the nearest neighbors in the whole training data. In order to mitigate these two problems, we propose a novel method named KCNN to enhance the performance of kNN. KCNN uses convolutional neural networks (CNN) to learn a suitable distance metric as well as prototype reduction to learn a reduced set of prototypes which can represent the original set. It has several superiorities compared with related methods. The combination of CNN and kNN empowers it to extract discriminative hierarchical features with which kNN can easily classify. KCNN learns spatial information on an image instead of considering it as a vector to learn distance metric. Moreover, KCNN simultaneously learns a reduced set of prototypes, which help improve classification efficiency and avoid noisy samples of the massive training set. The proposed method has a better robustness and convergence than CNN, especially when projecting input data into a rather low-dimension space.

As the research on deep learning methods gradually progresses, more and more classification models are applied in the classification of hyperspectral image (HSI). High-dimensional and low-resolution characteristics of HSI, however, make it difficult for conventional models to process its data effectively. In this article, a novel HSI classification model, namely, spatial–spectral pyramid network (SSPN), is designed by combining a 3-D convolutional neural network (3D CNN) with feature pyramid structure. SSPN taking advantage of 3-D convolution coupled with multiscale convolutional extraction is used to obtain a large set of diverse spatial–spectral features. Multiscale interfusion is also applied in SSPN to enrich the features contained in a single feature map and to improve the sensitivity on HSI spatial–spectral information, allowing it to better learn spatial–spectral features. Moreover, the losses of each combination based on multiscale interfusion are calculated via weighted average, which enables SSPN to avoid the excessive influence of single combination in the updating of model parameters. Four HSI public datasets and several comparison models are employed to validate the classification effect of SSPN. Experimental results show that SSPN achieves the highest overall accuracy (OA) in all datasets compared with other classification models, with 100%, 98.8%, 99.8%, and 98.7% on the datasets of Chikusei, Pavia University, Botswana, and Houston 2013, respectively. SSPN is demonstrated to possess higher classification accuracy and better generalization performance on HSI.

PurposeTo investigate the efficacy and safety of programmed cell death 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) plus cytotoxic T lymphocyte antigen-4 (CTLA-4) antibodies ± other therapies in patients with advanced lung cancer.MethodsIn accordance with the retrieval strategy, we searched electronic databases for randomised controlled trials testing PD-1/PD-L1 plus CTLA-4 antibodies in patients with lung cancer; RR (for objective response rate (ORR), overall survival (OS), progression-free survival (PFS), and immune-related adverse events (irAEs)) from individual studies were calculated and pooled by using random-effects models or fixed-effects models; heterogeneity and publication bias analyses were also performed, using Review Manager 5.3 and Stata 15.1 for statistical analysis.ResultsWe included six studies. Four different immune checkpoint inhibitors (nivolumab, pembrolizumab, durvalumab, tremelimumab) were used. Dual checkpoint inhibitors ± other therapies for advanced lung cancer showed significant improvements in ORR (RR 1.49, 95% CI 1.11 to 1.98; p=0.007), OS (HR 0.72, 95% CI 0.63 to 0.83; p<0.00001), and PFS (HR 0.72, 95% CI 0.63 to 0.82; p<0.00001). The subgroup analyses were consistent with the pooled results. The PD-L1 ≥1% (HR 0.67, 95% CI 0.54 to 0.82; p<0.0001) subgroup differences indicated a statistically significant subgroup effect, but the PD-L1 <1% subgroup (HR 0.88, 95% CI 0.75 to 1.05; p=0.15) was not statistically significant. The incidence of adverse events (grade ≥3) was lower than that of the control group (RR 0.90, 95% CI 0.80 to 1.02; p=0.09), but was not significant.ConclusionsPD-1/PD-L1 inhibitors combined with CTLA-4 inhibitors ± other therapies can improve the ORR, OS and PFS of patients with advanced or metastatic lung cancer, but the incidence of adverse reactions is high although generally tolerable.PROSPERO registrationCRD42020149216.

Purpose: The LHAASO project collects trillions of cosmic ray events every year, generating about 10 PB of raw data annually, which brings big challenges for data processing platform. Method: The LHAASO data processing platform is built to handle such a large amount of data, which is composed of some subsystems such as data transfer, data storage, high throughput computing and metadata management. Results and conclusions: The platform was under construction since 2018 and has been working well since 2021. In this paper, the details of the design, implementation and performance of the data processing platform are presented.

Purpose: Goal for the present research is investigating the effect of scale effect on free vibration of piezoelectric sandwich nanobeams on Winkler foundation. For this purpose, the effects of nonlocal parameters and strain gradient parameters on the free vibration of the model are studied. Methods: Based on the nonlocal strain gradient theory and Timoshenko beam theory, the nonlinear vibration of piezoelectric sandwich nanobeams on Winkler foundation is investigated. The nonlinear governing equations and boundary conditions are derived using the Hamilton's principle. The partial differential equation is transformed into ordinary differential equation by Galerkin's method, and then the nonlinear vibration of piezoelectric nanobeam is numerically analyzed using the Runge-Kutta method. Results and Conclusions: The results show that the nonlinear frequency ratio decreases with the increase of length-to-thickness ratio. When the nonlocal parameter is not less than the strain gradient length scale parameter, the piezoelectric nanobeam exhibits stiffness softening effect. When the nonlocal parameter is not greater than the strain gradient length scale parameter, the piezoelectric nanobeam exhibits stiffness hardening effect. It is also observed that both large length-to-thickness ratios and shear deformation can attenuate the nonlocal strain gradient effect. In addition, changes in the external applied voltage have a significant effect on the natural frequency of the piezoelectric nanobeams and increasing the thickness of the piezoelectric layer can enhance the structural stiffness.

Oyster hydrolysates exhibit promising potential as a zinc supplement for its significant amounts of zinc, however, the zinc chemical speciation which determines zinc nutrition in oyster hydrolysates has not been investigated. This study optimized the oyster hydrolysis conditions using the Response surface methodology (RSM) method, and the zinc chemical speciation, the sequence of zinc-containing peptides, and the binding sites of zinc and peptides were further investigated. Results showed that inorganic and organic zinc in oysters were 60.15% and 36.53% of total zinc respectively, while organic zinc in oysters aqueous extract was 4.54% of which 3.56% was present in the polysaccharide fraction. The zinc yield was 84.20% of total zinc under optimal hydrolysis conditions, while the organic zinc increased to 52.93% of which 38.14% existed in the protein/peptides fraction. Zinc in protein/peptide fraction primarily was bound to low-molecular-weight peptides (Mw < 1000 Da). Further, 42 shared zinc-containing peptides (mainly 3–4 peptides) were identified. Molecular docking indicated that Glu, Leu, and Tyr might be the binding sites for zinc and peptides. These findings provided a theoretical basis for the development of novel and safe zinc dietary supplements.

Gastrointestinal stromal tumor (GIST) is the most common human sarcoma and arises in the gastrointestinal tract. Most GISTs are caused by activating mutations in the KIT receptor tyrosine kinase, such as the exon 11 KITV559? mutation. The small molecule imatinib inhibits KIT and has been a mainstay of therapy in GIST. Unfortunately, imatinib-treated patients typically relapse, most often due to clonal emergence of the resistance-associated KITV654A mutation. To determine the biologic impact of this second-site mutation in vivo, we created a mouse model with the corresponding V558?;V653A Kitdouble mutation restricted (a) spatially to ETV1+cells, which include the interstitial cells of Cajal (ICCs) from which GISTs presumably originate, and (b) temporally through tamoxifen treatment after birth. This resulted in the first in vivo model of the most common second-site mutation associated with imatinib resistance in GIST and the first in vivo demonstration that cell-autonomous expression of mutant KIT in the ICC lineage leads to GIST. GISTs driven by the V558?;V653A Kitdouble mutation were resistant to imatinib, while cabozantinib was more effective in overcoming resistance than sunitinib. Compared to control mice with a single V558? Kitmutation, mice with a double V558?; V653A Kitmutation had increased tumor oncogenesis and associated KIT-dependent STAT activation. Our findings demonstrate that the biologic consequences of a second-site mutation in an oncogenic driver may include not only a mechanism for drug resistance, but changes in tumor oncogenic potential and differential activation of signaling pathways.

Supplemental digital content is available in the text.INTRODUCTION:Epilepsy is a common chronic disease with transient brain dysfunction and critically influences the quality of patients' family life. The aim of this study was to analyze the effectiveness of family management style on family quality of life in children. METHODS:We randomized 130 children to either the intervention group (n = 65) or the control group (n = 65). Family management style combined with routine care was applied in the intervention group within the first 24 hours after admission, whereas only routine care was applied in the control group. Family management style contains 3 steps: involve families into the intervention group and determine treatment plan, educate parents on how to manage their family, and monitor quality of home management. Scores on the Beach Center Family Quality of Life Scale (FQOL) of 2 groups were collected at 3 time points: within the first 24 hours after admission (T1), 6 months after discharge (T2), and 12 months after discharge (T3). Repeated-measures analysis of variance of FQOL scores was used to evaluate difference. RESULTS:Full scores and each subscale's scores on FQOL in the control group and the intervention group at T1 had no statistical significance (P> .05). Scores on FQOL at T2 and T3 increased in the intervention group, but there was almost no change in the control group, with statistical significance between the intervention group and the control group (P< .05). Scores on FQOL at T1, T2, and T3 showed that score of subscale except parenting FQOL improved in the intervention group (P< .05), but no difference was shown in the control group (P> .05). There was no difference shown among the control group and the intervention group that interacted with time (P> .05). CONCLUSION:The family management style can effectively improve the family quality of life in children with epilepsy, especially at the satisfaction level of family emotional well-being and disability-related support.

BACKGROUND:Seventy percent of intrahepatic cholangiocarcinoma (ICC) patients are inoperable. Treatment for unresectable patients is essential to improve poor survival. AIMS:We aimed to evaluate the prognostic factors for ICC patients, and investigate the potential treatment strategies for unresectable patients. METHODS:ICC patients were identified in SEER registry in 2004–2013. Univariate and multivariate Cox proportional hazard regression analysis were performed to evaluate the effect of treatment strategies. RESULTS:Of 2248 cases diagnosed in 2010–2013 and staged according to the American Joint Committee on Cancer (AJCC) 7th edition, 1706 (76.13%) did not receive cancer-directed surgery. This portion increased compared to those diagnosed between 2004 and 2009 and staged according to the AJCC 6th edition (72.87%). In addition, the percentage of stage 4 cases increased, while stage 3 cases decreased, because AJCC 7th staging system categorized both T4 and N1 patients into stage IV, which were previously categorized into stage III by AJCC 6th staging system. Patients with radiofrequency ablation (RFA) showed a poorer survival in 2004–2009 (P = .0213), but an almost the same survival as patients with tumor resection in 2010–2013 (P = .51), suggesting that RFA performed better in recent years. Lymphadenectomy showed protective effect for unresectable patients. Radiotherapy improved cancer-specific survival in non-surgery patients (P < .0001).The proportion of stage IV patients increased tremendously from 37.4% in 2004–2009 to 58.7% in 2010–2013. Among 1319 stage IV patients (2010–2013), surgery at distant metastatic sites improved cancer-specific survival. CONCLUSIONS:For unresectable tumors, RFA, radiotherapy, lymphadenectomy, and surgery of distant metastases showed significant benefits to improve cancer-specific survival.

We report a multicenter, phase 2 study evaluating the efficacy of pucotenlimab, an anti-PD-1 antibody, in patients with mismatch repair-deficient (dMMR) or microsatellite instability-high (MSI-H) tumors, and potential biomarkers for response. Overall, 100 patients with previously treated, advanced solid tumors centrally confirmed as dMMR or MSI-H received pucotenlimab at 200 mg every 3 weeks. The most common cancer type is colorectal cancer (n = 71). With a median follow-up of 22.5 months, the objective response rate is 49.0% (95% confidence interval 38.86%–59.20%) as assessed by the independent review committee, while the median progression-free survival and overall survival have not been reached. Grade ≥3 treatment-related adverse events were observed in 18 patients. For the biomarker analysis, responders are enriched in patients with mutations in the KMT2Dgene. Pucotenlimab is an effective treatment option for previously treated advanced dMMR/MSI-H solid tumors, and the predictive value of KMT2Dmutation warrants further research. This study is registered with ClinicalTrials.gov: NCT03704246.

Introduction

Gastrointestinal stromal tumor (GIST) is driven by an activating mutation in the KIT proto-oncogene. Using a mouse model of GIST and human specimens, we show that intratumoral murine CD103+CD11b− dendritic cells (DCs) and human CD141+ DCs are associated with CD8+ T cell infiltration and differentiation. In mice, the antitumor effect of the Kit inhibitor imatinib is partially mediated by CD103+CD11b− DCs, and effector CD8+ T cells initially proliferate. However, in both mice and humans, chronic imatinib therapy decreases intratumoral DCs and effector CD8+ T cells. The mechanism in our mouse model depends on Kit inhibition, which reduces intratumoral GM-CSF, leading to the accumulation of Batf3-lineage DC progenitors. GM-CSF is produced by γδ T cells via macrophage IL-1β. Stimulants that expand and mature DCs during imatinib treatment improve antitumor immunity. Our findings identify the importance of tumor cell oncogene activity in modulating the Batf3-dependent DC lineage and reveal therapeutic limitations for combined checkpoint blockade and tyrosine kinase inhibition.

Measuring human monocyte subsets (CD14++CD16−, CD14++CD16+, and CD14 + CD16++) and subset‐specific monocyte‐platelet aggregates (MPA) is vulnerable to analytical bias due to unavailability of a standardized methodology. We aimed to address this issue by focusing on the impacts of time‐delayed sample processing and measurement between two commonly used anticoagulants. Ethylenediaminetetraacetic acid (EDTA)‐ and sodium citrate (SC)‐anticoagulated blood samples from 12 healthy donors were subject to either delayed (2‐h delay, kept at 4°C) or immediate processing (without fixation) before four‐color flow cytometry (FCM) analysis. In SC‐anticoagulated samples, a 2‐h delay in sample processing contributed to a significant decrease in CD14++CD16− monocyte percent and a reciprocal increase in CD14++CD16+ monocytes, as well as increases in all three subset‐specific MPA. Similar slight, but non‐significant changes were observed in EDTA‐treated samples. In samples processed immediately and stored at 4°C, delayed measurement at 0, 1, 3, and 5 h after processing led to a time‐dependent decrease in CD14++CD16− monocyte percent and a reciprocal increase in CD14++CD16+ subset in SC‐treated, but not in EDTA‐treated, samples. Moreover, a time‐dependent increase in all three subset‐specific MPA was observed in SC‐treated samples, which, to a lesser extent, was only observed in CD14++CD16+ MPA in EDTA‐treated samples after storage at 4°C for 3–5 h after processing. We recommend EDTA for anticoagulation. Additionally, sample should be stored at 4°C and processing and measuring should be performed within 2 h after harvest and 3 h after processing, respectively. © 2016 International Clinical Cytometry Society

Treatment options for treatment-naive patients with advanced NSCLC harboring EGFRexon 20 insertion (ex20ins) mutations are limited. This study evaluated the safety, tolerability, and pharmacokinetics of YK-029A, a third-generation EGFRtyrosine kinase inhibitor, and the preliminary efficacy of YK-029A in treatment-naive patients with EGFRex20ins mutation.

This paper presents the experiment results conducted on three kinds of composite stiffened panels under compressive static load. The panels with scarfed holes and scarfed bonded repairs are analyzed with the virgin panels. The analysis shows that the scarfed bonded repair method has recovered the failure load and the stiffness above those of the virgin panel while the panel with a scarfed hole has remained 70% strength of the virgin panel. The scarfed hole has an effect on the buckling load as well as the stiffness and the failure load.

Gastric cancer is a major cause of mortality and morbidity around world. However the effectiveness of the current approaches to the diagnosis and treatment of gastric cancer is limited. Recombinant targeted toxins may represent a novel direction of cancer therapy. In this study, we aimed to explore whether recombinant toxins fused with the truncated forms of G17 could target to kill cancer cells by recognizing CCK2R. Four recombinant Pseudomonas toxins PE38 fused with the forward or reverse truncated forms of G17 (G14 and G13) were successfully constructed, expressed, and purified. Their characteristics were further analyzed by SDS-PAGE, western blot and indirect immunofluorescence assay. The cytotoxicity assay demonstrated that only reversely fused recombinant toxins rG14PE38 and rG13PE38 exhibited certain toxicity on several cancer cell lines, and a competition assay indicated that the binding of the reverse gastrin-endotoxin to CCK2R (+) cells may be mediated by interaction between gastrin/gastrin-like and CCK2R.

Esculetin (6,7-dihydroxycoumarin, ET) and 4-methylesculetin (6,7-dihydroxy-4-methylcoumarin, 4-ME) are typical coumarin derivatives that are attracting considerable attention because of their wide spectrum of biologic activities, but their metabolism remains unknown. This study aimed to elucidate the in vitro UDP-glucuronosyltransferase (UGT) metabolism characteristics of ET and 4-ME. 7-O-monoglucuronide esculetin (ET-G) and 7-O-monoglucuronide 4-methylesculetin (4-ME-G) were identified by liquid chromatography-mass spectrometry (LC-MS) and 1H-nuclear magnetic resonance (1HNMR) when ET or 4-ME was incubated with human liver (HLM) in the presence of UDP-glucuronic acid. Screening assays with 12 human expressed UGTs demonstrated that the formations of ET-G and 4-ME-G were almost exclusively catalyzed by UGT1A6 and UGT1A9. Phenylbutazone and carvacrol (UGT1A6 and UGT1A9 chemical inhibitors, respectively) at different concentrations (50, 100, and 200 μM) significantly inhibited the formation of glucuronidates of ET and 4-ME in HLM, UGT1A6, and UGT1A9 when the concentrations of ET and 4-ME ranged from 10 to 300 μM (P< 0.05). Clearance rates of ET in HLM, HIM, UGT1A6, and UGT1A9 were 0.54, 0.16, 0.69, and 0.14 ml/min/mg, respectively. Corresponding clearance rates values of 4-ME were 0.59, 0.03, 0.14, and 0.04 ml/min/mg, respectively. In conclusion, 7-O-monoglucuronidation by UGT1A6 and UGT1A9 was the predominant UGT metabolic pathway for both ET and 4-ME in vitro. The liver is probably the major contributor to the glucuronidation metabolism of ET and 4-ME. ET showed more rapid metabolism than 4-ME in glucuronidation.

A three dimensional analysis model is developed on the fatigue life prediction of composite laminates based on a progressive damage analysis. This model consists of stress analysis, fatigue failure analysis and material property degradation. Teserpe’s failure criteria is used to fatigue damage analysis. Fiber tensile/compressive breakage, matrix tensile/compressive cracking, matrix/fiber shear failure and tension/compression delamination are considered in fatigue damage analysis. The methodologies of sudden degradation and gradual degradation are both applied in the material property degradation. The stiffness and strength gradual degradation is based on the Shokrieh fatigue model, which is based on fatigue test for unidirectional laminates. In order to consider the scatter of the material in the practical structures, the stiffness and strength of the material are randomly distributed using normal distribution in the numerical model. The progressive fatigue damage model is developed in finite element code ABAQUS through user subroutine UMAT, which can simulate the fatigue damage process. Fatigue life of different ply stacking sequences and geometries composite laminates under different cycle loading are predicted. The predicted fatigue life is in good agreement with the experimental results.

This paper aims at evaluating the damage resistance of thin core sandwich structures, composed of aramid paper honeycomb core and carbon/ epoxy laminates face-sheets subjected to low velocity impact. The impact tests are performed using the instrumented impact-testing machine and resulting impact damages are inspected by Ultrasonic C-scan. In order to study the failure process of the core, which is important in the damage of the structures, flatwise compression test was carried out. Four parameters have been analyzed as follows: maximum load, total energy absorbed during impact, impact dent depth, and impact damage area. Nearly all impact force histories of panels have “twin peaks”, but the second peak of the 3mm-core structure is much larger than the first, which is quite different from others, when impact energy reached 5J, which were caused by the thickness of the core. Impact damages of thin-core sandwich structures are mainly delamination in the face-sheet and core crushing at low energy, and fiber breakage at relatively high energy. The damage processes of different groups of structures are essentially different and the impact resistance of the sandwich structure is greatly influenced by the face-sheet and core thickness.

The pre-processing method of blind source separation based on multifactor analysis is proposed to solve the blind source with noise. Firstly, the shortcomings of existing methods of blind source separation are point out after analyzing their principles. The multifactor analysis is introduced in blind source separation and the maximum likelihood estimate based on expectation maximum is used to estimate the common factor and random error. Finally the FastICA algorithm is used to separate BSS result. The validity and the advantage of this method are illustrated by an example.

The adhesive structural mechanical performance is influenced by debond flaw. This paper presents a research on the effect of flaws on the mechanical performance of composite scarf joints. The experimental results show that the load-carrying capacity of composite scarf joints changed along with the location of the debond flaw. The location of the flaw in the bondline influences the failure mode. Additionally, the finite element method was employed to obtain the failure mode of the composite scarf joint. The adhesively bonded joints were modeled using ABAQUS software. The computational results show that flaws located at the edge of the bond region result in more pronounced load reduction than which located at the middle of bond region.

We propose and develop a passive alignment technique of 4 output waveguides of PLC-based 90° OH and a 1×4 PD array. This alignment technique only uses an infrared CCD camera and an infrared light.

In this study, a highly sensitive and reliable analytical micro-plate chemiluminescence enzyme immunoassay (CLEIA) based on a monoclonal antibody (McAb) against okadaic acid (OA) was developed and validated for the detection of okadaic acid from a shellfish matrix. A competitive immunocomplex was formed through the binding of an immobilised antigen, OA, in analyzed samples and the McAb against OA. The conjugate OA–BSA was immobilised physically on a polystyrene micro-plate well as a solid phase antigen. Subsequently, free toxins in the analyzed samples competed with the solid phase antigen to bind the McAb against OA. The assay conditions, including the composition and pH of the coating solution, the dilution ratios and amounts of the McAb and the HRP-labelled goat anti-mouse IgG antibody, the time of the antibody-coating, incubation and chemiluminescence reactions and other relevant variables were studied and optimised. The optimised system allowed OA determination in a linear working range from 0.0098–10 μg kg−1(R= 0.99), and the calibration curve obtained for OA revealed a detection limit of 0.0098 μg kg−1. Importantly, the CLEIA was approximately 10 times more sensitive than an ELISA using the same antibody. In addition, the intra- and inter-assay RSDs were both less than 10.0%. Moreover, this method was successfully applied to the evaluation of OA in seashells, with recoveries of 97.2%, 111.2% and 104.7%, respectively, for low-, medium- and high-concentration samples. Good recoveries were obtained from spiked food samples, and the results correlated well with those obtained using conventional indirect competition ELISA, indicating the potential utilisation of the CLEIA as a preliminary screening tool for analyzing OA contamination in shellfish.

Tumor-associated macrophages (TAMs) are a major component of the cancer microenvironment. Modulation of TAMs is under intense investigation because they are thought to be nearly always of the M2 subtype, which supports tumor growth. Gastrointestinal stromal tumor (GIST) is the most common human sarcoma and typically results from an activating mutation in the KIT oncogene. Using a spontaneous mouse model of GIST and 57 freshly procured human GISTs, we discovered that TAMs displayed an M1-like phenotype and function at baseline. In both mice and humans, the KIT oncoprotein inhibitor imatinib polarized TAMs to become M2-like, a process which involved TAM interaction with apoptotic tumor cells leading to the induction of CCAAT/enhancer binding protein (C/EBP) transcription factors. In human GISTs that eventually developed resistance to imatinib, TAMs reverted to an M1-like phenotype and had a similar gene expression profile as TAMs from untreated human GISTs. Therefore, TAM polarization depends on tumor cell oncogene activity and has important implications for immunotherapeutic strategies in human cancers.

In order to realize the real-time environmental monitoring for shipboard TT&C antenna-centrosome, this paper designs a monitoring system based on Modbus by analyzing current conditions, which contains sensor data acquisition terminal and video switcher. The designed system has many advantages, such as less project-related work, higher cost performance, convenient installation, easy debugging and etc. Actual application shows that temperature & humidity data and video information gathered meet the requirement need completely. Techniques in this paper can be referenced in other related fields.

The weighted Semi-supervised FCM Algorithm which is based on HPR multiplier (SSFCM-HPR) [1] is used for neuron classification in this paper. 231 groups of neuron data from NeuronMorpho.Org [2] are used in experiments as training samples and testing samples. The classification accuracy of testing samples can reach 93.90% in the experiment. The classification accuracies of testing samples are above 90% if the percentage of training samples is higher than 20%.

Recent studies have shown that anisomycin significantly inhibits mammalian cell proliferation, but its mechanism remains unclear. In this study, Jurkat T cells were used to first explore a relationship between effect of anisomycin on them and alteration of cell cycle-regulating proteins.

Forecasting the distortion of civil engineer projects need the support of mathematical statistical theories. The mathematical statistical theories have many different types, such as auto-regression and subsection-regression. The author supervises the tunnel settlement by those two theories, the result shows that: the auto-regression theory is suitable for the project safety & quality forecasting; if the project has regularity changing during distortion process, the subsection-regression theory is a very good tool when the supervision situation needs different mathematical models to describing.

This paper uses the steel and rubber redesigned the packer rubber. The new rubber make the packer have a big expansion, the large expansion packer can solve the problem of seal the deformation pipe. According to finite element analysis, calculation and modification, the result show that our new packer can completely seal the sleeve deformation, meet the deformation sleeve sealing requirements.

Nonmetallic material by stress which less the yield stresses long time, it would force creep. Nonmetallic materials’ operating life depended on the creep degree. The paper set up creep model using ANSYS, create the nonmetallic material creep strain-time curve, got the creep properties of nonmetallic material. To provide effective basis of calculate the nonmetal materials’ operating life.

In this paper, we First makes selection of the Zernike moment features of handwritten numerals based on the principles that the distinction degree of inside-class features is small and the dividing of the features between classes is huge; Then construct the similar matrix between handwritten numerals by the similarity measure based on Grey relational analysis and make transitivity transformation to similar matrix for better block symmetry after reformation; Finally make spectrum decomposition to the Laplacian matrix which from the reformation similar matrices, and recognize the handwritten numerals with the eigenvectors corresponding to the second minimal eigenvalues in Laplacian matrix as the spectral features. The experimental result indicates that the robustness of the algorithm proposed in this paper is great and the result is fine.

Corrugated fiberboard is considered as the world’s environmentally acceptable packaging that has a wide range of applications in packaging field. Through studying the characteristics of elastic wave propagation in the Corrugated fiberboard, this paper inferences variations of displacement and stress with time, when the corrugated fiberboard suffering the uniform load. It provides theoretical and mathematical basis for the design of cushioning package.

Through studying carton stiffness, the hopper design of packaging machine is improved. By using the elastic-plastic theory and finite element stress analysis method, the hopper baffle design of automatic tea packaging machine is optimized in order to reduce the requirements of equipment for paper, solve the problem that automatic packaging machine stop work. At the same time, the stress analysis of carton is taken through the ANSYS to derive that the suction of sucker satisfy the requirements of carton stiffness or not, the carton appear plastic deformation in the force process or not.

Aiming at the unreasonable phenomenon of the plywood box′ design in the current market, the mechanics research for the structure design of the plywood box was taken. In this paper, a damping spring-mass system for the plywood box is established by using the finite element analysis software ANSYS. In the case of simulated external pressure, analyzed the transient dynamic response, the relation between displacement and time, stress and time were gained in order to verify the structural reliability of the damped free vibration of plywood box during the carriage. Finally, the reliable basis for the design of plywood box was provided, the certain reference value of the standardized and the serialized production for plywood box was provided, as well as the basis of some analysis for the design of cushioning.

Formula for glass fiber/microcellular unsaturated polyester composites (GF/MCUP) using supersaturated gas technology was studied by the way of orthogonal experiment. The results showed that these factors affecting average cell size from strongly to weakly were styrene content, accelerant content, glass fiber length, curing agent and glass fiber content, respectively. The factors affecting average cell density from strongly to weakly were accelerant content, styrene content, glass fiber content, curing agent content and glass fiber length, respectively. Curing agent content was the major factor affecting impact strength of GF/MCUP. The factors revealed no obvious difference in affecting tensile strength. Under the optimizing processing condition, the average cell size of GF/MCUP was about 8 μm and the cell density was 1.19×109 cells/cm3. The 153.70 and 255.84 % increase in impact strength were gained over that of GF/UP and UP, respectively. The corresponding 20.24 and 82.51% increase in tensile strength-to-weight ratio were gained over that of GF/UP and UP, respectively.

Glass fiber/microcellular unsaturated polyester composites (GF/MCUP) were prepared using the supersaturated gas technology. Technological process included three stages. The effect of processing parameters on average cell size, cell density, impact strength and tensile strength was investigaed by orthogonal experiment. The results indicated that the major factor affecting them was the temperature in stageⅡ(T2). Under the optimizing processing condition, the average cell size of GF/MCUP was about 8 μm and the cell density was 1.57×109 cells/cm3. It was found that impact strength of GF/MCUP increased 88.81 and 188.12 % than that of glass fiber/unsaturated polyester composites (GF/UP) and unsaturated polyester plastics (UP), respectively. The corresponding 16.56 and 69.25 % increase in tensile strength-to-weight ratio were gained over that of GF/UP and UP, respectively.

Abstract: Objective: To investigate the recurrent patterns and factors involved in node-negative advanced gastric cancer after curative resection.Patients and Methods: Clinicopathological characteristics and prognostic outcomes of 310 patients who had lymph node-negative advanced gastric adenocarcinoma and received curative resection between 2002 and 2006 were retrospectively evaluated. Results: Among the 300 patients, 15 (5.0%) had locoregional recurrence, 5 (1.7%) had lymph node recurrence, 27 (9.0%) had peritoneal seeding recurrence, and 21 (7.0%) had hematogenous metastasis. Using multivariate analysis, we found that the maximum tumor diameter (P=0.014), histological type (P=0.001) and Borrmann type (P=0.033) were independent factors predicting the locoregional recurrence. Lymph node recurrence was significantly affected by lymph node dissection (P=0.029) and lymphovascular invasion (P=0.004). Clinicopathological factors predicting the peritoneal seeding recurrence were the depth of invasion (P=0.001) and Borrmann type (P=0.002). In addition, lymphovascular invasion (P=0.013) and histological type (P=0.001) were significantly associated with hematogenous metastasis. Conclusion: Node-negative advanced gastric cancer has a high amount of peritoneal seeding and hematogenous metastasis.