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Due to the high recurrence, the HCC prognosis remains poor. Yet, the biomarkers for predicting the recurrence of high-risk patients are currently lacking. We aimed to develop a signature to predict the recurrence of HCC based on NKG2D ligands.The multivariate Cox proportional hazards regression was used to select recurrence-related variables of NKG2D ligands in HCC patients from The Cancer Genome Atlas (TCGA). HCC patients from the OEP000321 dataset and Guilin cohort were used to validate the predictive signature. The mRNA expression of NKG2D ligands was measured by QRT-PCR. Immunohistochemistry analysis of HCC tissue microarray samples was used to identify the expression of NKG2D ligands.In this study, NKG2D ligands expression in the mRNA and protein level was both abnormally expressed in HCC and associated with recurrence-free survival (RFS). Then, the recurrence-related variables of NKG2D ligands in HCC were selected by the multivariate Cox proportional hazards regression. Among the eight NKG2D ligands, MICA (HR = 1.347; 95% CI = 1.012-1.793; p = 0.041), ULBP3 (HR = 0.453; 95% CI = 0.231-0.889; p = 0.021) and ULBP5 (HR = 3.617; 95% CI = 1.819-7.194; p 0.001) were significantly correlated with RFS in the TCGA-LIHC cohort. Then, the signature was constructed by the three NKG2D ligands. The predictive effectiveness of this signature was also validated in the OEP000321 dataset and Guilin cohort. Further, HCC patients were classified into low-risk and high-risk subgroups by the predictive score. Compared with the low-risk group, the high-risk group had poor RFS in both training and validation cohorts. Importantly, compared with the low-risk patients with the G1-G2 stage, the levels of infiltrated NK-activated cells and NKG2D expression were both lower in the high-risk patients.The signature based on MICA, ULBP3, and ULBP5 could predict HCC recurrence.

Tingfeng Xu,1,* Liying Ren,1,* Minjun Liao,1,2,* Bigeng Zhao,1 Rongyu Wei,1 Zhipeng Zhou,3 Yong He,4 Hao Zhang,3 Dongbo Chen,5 Hongsong Chen,5 Weijia Liao1 1Laboratory of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Guilin Medical University, Guilin, 541001, Guangxi, People’s Republic of China; 2Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, People’s Republic of China; 3Department of Radiology, Affiliated Hospital of Guilin Medical University, Guilin, 541001, Guangxi, People’s Republic of China; 4Department of Radiology, the Second Affiliated Hospital of Guilin Medical University, Guilin, 541001, Guangxi, People’s Republic of China; 5Peking University People’s Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Disease, Beijing, 100044, People’s Republic of China*These authors contributed equally to this workCorrespondence: Weijia Liao, Laboratory of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Guilin Medical University, Guilin, 541001, Guangxi, People’s Republic of China, Tel +86 773 2833021, Fax +86 773 2822703, Email liaoweijia288@163.com Hongsong Chen, Peking University People’s Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Disease, No. 11 Xizhimen South Street, Beijing, 100044, People’s Republic of China, Tel +86 10 88325724, Email chenhongsong2999@163.comPurpose: Microvascular invasion (MVI) impairs long-term prognosis of patients with hepatocellular carcinoma (HCC). We aimed to develop a novel nomogram to predict MVI and patients’ prognosis based on radiomic features of contrast-enhanced CT (CECT).Patients and Methods: HCC patients who underwent curative resection were enrolled. The radiomic features were extracted from the region of tumor, and the optimal MVI-related radiomic features were selected and applied to construct radiomic signature (Rad-score). The prediction models were created according to the logistic regression and evaluated. Biomarkers were analyzed via q-PCR from randomly selected HCC patients. Correlations between biomarkers and radiomic signature were analyzed.Results: A total of 421 HCC patients were enrolled. A total of 1962 radiomic features were extracted from the region of tumor, and the 11 optimal MVI-related radiomic features showed a favor predictive ability with area under the curves (AUCs) of 0.796 and 0.810 in training and validation cohorts, respectively. Aspartate aminotransferase (AST), tumor number, alpha-fetoprotein (AFP) level, and radiomics signature were independent risk factors of MVI. The four factors were integrated into the novel nomogram, named as CRM, with AUCs of 0.767 in training cohort and 0.793 in validation cohort for predicting MVI, best among radiomics signature alone and clinical model. The nomogram was well-calibrated with favorable clinical value demonstrated by decision curve analysis and can divide patients into high- or low-risk subgroups of recurrence and mortality. In addition, gene BCAT1, DTGCU2, DOCK3 were analyzed via q-PCR and serum AFP were identified as having significant association with radiomics signature.Conclusion: The novel nomogram demonstrated good performance in preoperatively predicting the probability of MVI, which might guide clinical decision.Keywords: hepatocellular carcinoma, microvascular invasion, preoperative noninvasive diagnosis, contrast-enhanced CT, biologic correlation

Background Although the phase II clinical study confirmed the effectiveness of camrelizumab combined with apatinib, the role of camrelizumab plus apatinib versus sorafenib for primary liver cancer (PLC) remains unverified. Methods The data of PLC patients who received camrelizumab plus apatinib or sorafenib as first-line treatment were collected retrospectively. Results The 12-month overall survival (OS) rate of camrelizumab plus apatinib was 70.4% and the OS rate of sorafenib was 48.6%. Compared with sorafenib, The median progression-free survival (PFS) time of the two groups was 6.0 months (95% CI 4.2–7.8) and 3 months (95% CI 2.3–3.7), respectively. The median OS was 19.0 months (95% CI 16.4–21.6) and 12.0 months (95% CI 8.9–15.1), respectively. Grade 3 or 4 adverse events occurred in 70.4% of 71 patients who received camrelizumab/apatinib at least once and in 26.4% of 72 patients who received sorafenib at least one cycle. In the camrelizumab plus apatinib group, the most common grade 3 to 4 adverse reactions were hypertension, aspartate aminotransferase increased and thrombocytopenia, no other high-level toxic effects were observed. Conclusion Clinically meaningful improvements in OS and PFS observed with camrelizumab/apatinib versus sorafenib suggest that camrelizumab/apatinib may become a practice-changing treatment for patients with PLC.

IntroductionAbscisic acid (ABA) is an important sesquiterpene compound that regulates the stress resistance of plants. Botrytis cinerea can synthesize ABA via the mevalonic acid pathway. To identify the functional genes that are involved in the biosynthesis of ABA, we performed insertion mutagenesis into B. cinerea TB-31.MethodsWe obtained the ABA-reduced mutant E154 by insertion mutagenesis, and we identified the insertion site was located upstream of the gene bcfrp1 by Thermal asymmetric interlaced PCR. We performed a detailed phenotypic characterization of the bcfrp1 knockout and complementation mutants in TB-31. Furthermore, transcriptome and proteome analyses were conducted to explore how bcfrp1 affects the level of the ABA biosynthesis.ResultsThe bcfrp1 gene encodes an F-box protein. The phenotypic results confirmed the positive contribution of bcfrp1 to the biosynthesis of ABA and growth. Between TB-31 and ΔBcfrp1, we obtained 4,128 and 1,073 differentially expressed genes and proteins, respectively. The impaired ABA biosynthesis in the ΔBcfrp1 mutants was primarily affected by the different levels of expression of the ABA biosynthetic gene cluster and the genes involved in the mevalonic acid pathway. In addition, we further characterized the differentially expressed genes and proteins that participated in the growth, secondary metabolism, and signal transduction in B. cinerea based on the transcriptome and proteome data.DiscussionThis research based on the transcriptome and proteome analyses to display the changes after the deletion of bcfrp1 in B. cinerea TB-31, will help us to explore the molecular mechanism of ABA biosynthesis in B. cinerea.

Background/aims : Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease. The imbalance of Th17/Treg cells has been reported in PBC patients. low-dose IL-2 can alleviate disease severity through modulating CD4 + T cell subsets in patients with autoimmune diseases. Hence, the present study aimed to examine the effects and mechanism of low-dose IL-2 in PBC mouse models. Methods PBC models were induced in female C57BL/6 mice by two immunizations with 2OA-BSA at two-week intervals, and poly I: C every three days. PBC mice were divided into the IL-2 treated and untreated groups and low-dose IL-2 was injected at three different time points. Th17 and Tregs were analyzed by flow cytometry, and the related cytokines were analyzed by ELISA. Liver histopathology was examined by H&E and immunohistochemical staining. Results Twelve weeks after modeling, the serum AMA was positive and the ALP was significantly increased in PBC mice (P༜0.05). The pathology showed lymphocyte infiltration in the portal area, damage, and reactive proliferation of the small bile duct (P༜0.05). The flow cytometric showed the imbalance of Th17/Treg cells in the liver of PBC mice, with decreased Treg cells, increased Th17 cells and Th17/Treg ratio (P

Artemisiapollen is the major cause of seasonal allergic respiratory diseases in the northern hemisphere. About 28.57% ofArtemisiaallergic patients’ IgE can recognize ArtCaM, a novel allergenic calmodulin fromArtemisiaidentified in this study. These patients exhibited stronger allergic reactions and a longer duration of allergic symptoms. However, the signaling mechanism that triggers these allergic reactions is not fully understood. In this study, we found that extracellular ArtCaM directly induces the maturation of human dendritic cells (DCs), which is attributed to a series of Ca2+relevant cascades, including Ca2+/NFAT/CaMKs. ArtCaM alone induces inflammatory response toward Th1, Th17, and Treg. Interestingly, a combination of ArtCaM and anti-ArtCaM IgE led to Th2 polarization. The putative mechanism is that anti-ArtCaM IgE partially blocks the ArtCaM-induced ERK signal, but does not affect Ca2+-dependent cascades. The crosstalk between ERK and Ca2+signal primes DCs maturation and Th2 polarization. In summary, ArtCaM related to clinical symptoms when combined with anti-ArtCaM IgE, could be a novel allergen to activate DCs and promote Th2 polarization. Such findings provide mechanistic insights into Th2 polarization in allergic sensitization and pave the way for novel preventive and therapeutic strategies for efficient management of such pollen allergic disease.

PD-(L)1 inhibitor could improve the survival of locally advanced esophageal cancer (ESCA) patients, but we cannot tailor the treatment to common biomarkers. WNT signaling activation was associated with primary resistance to immunotherapy. In this study, we used our two clinical cohorts (BJCH

There is no strong evidence regarding the optimal treatment and specific prognosis prediction model for upper esophageal squamous cell carcinoma (UESCC). This study aimed to investigate the real-world treatment patterns and develop models to predict overall survival (OS) and esophageal cancer-specific survival (ECSS) in patients with stage I-III UESCC.Patients with T1-4N0-3M0 UESCC in the Surveillance, Epidemiology, and End Results (SEER) database were identified from 2010 to 2017, and randomized to a training cohort and a validation cohort. The effect of treatment patterns on survival were comprehensively analyzed. Nomograms were developed by incorporating independent prognostic factors analyzed by Cox regression in the training cohort and evaluated by the concordance index (C-index), receiver operating characteristic (ROC) curves, calibration curves, and decision curve analyses (DCA) in two cohorts.A total of 677 patients were identified, including 452 in the training cohort and 225 in the validation cohort. Among all populations, 71.9% (487) received chemoradiotherapy without surgery, and chemoradiotherapy or/and surgery showed better survival than other treatments. However, surgery was rarely carried out for patients with stage II-III. T stage, N stage, surgery, chemotherapy, and radiotherapy were independent risks for both OS and ECSS, while age was also an independent risk for OS. The C-indexes for nomograms to predict OS (0.71 and 0.72) and ECSS (0.70 and 0.73) were greater than 7th AJCC staging system to predict OS (0.61 and 0.64) and ECSS (0.64 and 0.64) in both the training cohort and the validation cohort. Time-dependent ROC curves and DCA also suggested that nomograms performed consistently better than 7th AJCC staging system. The calibration curves demonstrated good consistency in predicting survival.Chemoradiotherapy was a major treatment with preferable survival for patients with stage I-III UESCC. We have firstly developed and validated prognostic nomograms in patients with stage I-III UESCC, which would play a supplementary role in the current staging system.

Accurate and rapid detection of small targets against complex background is a fundamental requirement of various computer vision systems. This article is the first attempt to apply the superpixel segmentation technology to the field of low resolution infrared small target detection in the extremely complex backgrounds. The main contributions are as follows. First of all, the simple linear iterative cluster (SLIC) algorithm is utilized to accurately classify the raw infrared image into three components: outlier superpixels, stable background superpixels, and target superpixels, which appropriately aggregate similar background components as the basic unit of subsequent processing. In SLIC, an optional range of superpixels numbers is specified to robustly implement superpixel segmentation strategy on low resolution infrared images. Second, an outlier superpixel masking model is proposed to perform accurate identification and masking of the outlier superpixels with highly heterogeneous backgrounds, thus minimizing false alarm rate. Specially, a three-dimensional Gaussian filter matching the target distribution is introduced to blur the remaining boundary and pixel-sized noises with high brightness (PNHB) while maximizing the signal-to-noise ratio. Finally, a singular value truncation strategy with entropy weighted sparse factor (SVT-EW) is proposed to implement the final target extraction, which assigns specific sparsity weights for small infrared targets. SVT-EW effectively resolves the background residuals in gray-based threshold segmentation, and therefore, generates precise target detection results. Extensive experimental results on 14 extremely complex infrared natural scenes validate the superiority of the proposed method over the state-of-the-arts with respect to robustness and real-time performance.

BackgroundPrevious studies confirmed that most neoantigens predicted by algorithms do not work in clinical practice, and experimental validations remain indispensable for confirming immunogenic neoantigens. In this study, we identified the potential neoantigens with tetramer staining, and established the Co-HA system, a single-plasmid system coexpressing patient human leukocyte antigen (HLA) and antigen, to detect the immunogenicity of neoantigens and verify new dominant hepatocellular carcinoma (HCC) neoantigens.MethodsFirst, we enrolled 14 patients with HCC for next-generation sequencing for variation calling and predicting potential neoantigens. Then, the Co-HA system was established. To test the feasibility of the system, we constructed target cells coexpressing HLA-A*11:01 and the reportedKRASG12D neoantigen as well as specific T-cell receptor (TCR)-T cells. The specific cytotoxicity generated by this neoantigen was shown using the Co-HA system. Moreover, potential HCC-dominant neoantigens were screened out by tetramer staining and validated by the Co-HA system using methods including flow cytometry, enzyme-linked immunospot assay and ELISA. Finally, antitumor test in mouse mode and TCR sequencing were performed to further evaluate the dominant neoantigen.ResultsFirst, 2875 somatic mutations in 14 patients with HCC were identified. The main base substitutions were C>T/G>A transitions, and the main mutational signatures were 4, 1 and 16. The high-frequency mutated genes includedHMCN1,TTNandTP53. Then, 541 potential neoantigens were predicted. Importantly, 19 of the 23 potential neoantigens in tumor tissues also existed in portal vein tumor thrombi. Moreover, 37 predicted neoantigens restricted by HLA-A*11:01, HLA-A*24:02 or HLA-A*02:01 were performed by tetramer staining to screen out potential HCC-dominant neoantigens. HLA-A*24:02-restricted epitope 5'-FYAFSCYYDL-3' and HLA-A*02:01-restricted epitope 5'-WVWCMSPTI-3' demonstrated strong immunogenicity in HCC, as verified by the Co-HA system. Finally, the antitumor efficacy of 5'-FYAFSCYYDL-3'-specific T cells was verified in the B-NDG-B2mtm1Fcrntm1(mB2m)mouse and their specific TCRs were successfully identified.ConclusionWe found the dominant neoantigens with high immunogenicity in HCC, which were verified with the Co-HA system.

Chemokines are a family of cytokines that orchestrate the migration and positioning of immune cells within tissues and are critical for the function of the immune system. CCR2 participates in liver pathology, including acute liver injury, chronic hepatitis, fibrosis/cirrhosis, and tumor progression, by mediating the recruitment of immune cells to inflammation and tumor sites. Although a variety of chemokines have been well studied in various diseases, there is no comprehensive review presenting the roles of all known chemokine ligands of CCR2 (CCL2, CCL7, CCL8, CCL12, CCL13, CCL16, and PSMP) in liver disease, and this review aims to fill this gap. The introduction of each chemokine includes its discovery, its corresponding chemotactic receptors, physiological functions and roles in inflammation and tumors, and its impact on different immune cell subgroups.

A finite-time control strategy is proposed to solve the problem of position tracking control for a permanent magnet synchronous motor servo system. It can guarantee that the motor’s desired position can be tracked in a finite time. Firstly, for the d-axis voltage, a first-order finite-time controller is designed based on the vector control principle. Then, for the q-axis voltage, based on a radial basis function (RBF) neural network, an integral high-order terminal sliding mode controller is designed. Theoretical analysis shows that under the proposed controller, the desired position can be tracked by the motor position in a finite time. Simulation results are given to show that the proposed control method has a strong anti-disturbance ability and a fast convergence performance.

PD-(L)1 inhibitor could improve the survival of locally advanced esophageal cancer (ESCA) patients, but we cannot tailor the treatment to common biomarkers. WNT signaling activation was associated with primary resistance to immunotherapy. In this study, we used our two clinical cohorts (BJCH n = 95, BJIM n = 21) and three public cohorts to evaluate and verify a new immunotherapeutic biomarker based on WNT signaling in ESCA patients. Our findings showed that WNT signaling-related genes stratified TCGA patients into Cluster 1, 2, and 3, among which, Cluster 3 had the worst prognosis. The most up- and down-regulated genes in Cluster 3 were IGFBP1 and WNT3A. Further analysis validated that IGFBP1hiWNT3Alo ESCA patients had significantly poor RFS and OS in the TCGA and BJCH cohorts. Interestingly, IGFBP1hiWNT3Alo patients had a good response and prognosis with immunotherapy in three independent cohorts, exhibiting better predictive value than PD-L1 expression (signature AUC = 0.750; PD-L1 AUC = 0.571). Moreover, IGFBP1hiWNT3Alo patients may benefit more from immunotherapy than standard treatment (p = 0.026). Immune cell infiltration analysis revealed a significant increase in DC infiltration in IGFBP1hiWNT3Alo patients post-immunotherapy (p = 0.022), which may enhance immune response. The IGFBP1hiWNT3Alo signature could predict patients who benefited from PD-(L)1 inhibitor treatment and may serve as a biomarker in ESCA.

At the end of 2019, an outbreak of pneumonia took place caused by a new coronavirus (SARS-CoV-2 virus), named coronavirus disease 2019 (COVID-19). A series of strict prevention and control measures were then implemented to reduce the spread of the epidemic. Influenza, another respiratory tract virus, may also respond to these measures. To assess the impact of these measures, we used the total number of passengers movement in mainland China from 2018 to 2020 and daily number of railway passenger flow during the 2020 Spring Festival travel rush to reflect the population movement and to analyze newly and cumulatively confirmed COVID-19 and influenza cases. We found that implementing the series of measures against COVID-19 mitigated both COVID-19 and influenza epidemics in China. Prevention and control measures for COVID-19 might be used to control respiratory tract infections to reduce the national health economic burden caused by these pathogens.

Background Since it’s a challenging task to precisely predict the prognosis of patients with hepatocellular carcinoma (HCC). We developed a nomogram based on a novel indicator GMWG [(Geometric Mean of gamma-glutamyltranspeptidase (GGT) and white blood cell (WBC)] and explored its potential in the prognosis for HCC patients. Methods The patients enrolled in this study were randomly assigned to training and validation cohorts. And we performed the Least Absolute Shrinkage and Selection Operator proportional hazards model (LASSO Cox) model with clinical characteristics, serum indexes, and novel GMWG. Multivariate analysis was performed to build a nomogram. The performance of the nomogram was evaluated by C-index, the area under the receiver operating characteristic curve (AUC), and the calibration curve. Kaplan-Meier curves showed discrimination of the nomogram. Clinical utility was assessed by decision curve analysis (DCA). The discrimination ability of the nomogram was determined by the net reclassification index (NRI). Results The geometric mean of GGT and white WBC count (GMWG), neutrophil to lymphocyte ratio (NLR), and tumor size were significantly associated with the overall survival (OS). The variables above were used to develop the nomogram. The indexes of nomogram were 0.70 and 071 in the training or validation cohort, respectively. AUC of 1-, 3- and 5-year OS showed satisfactory accuracy as well. The calibration curve showed agreement between the ideal and predicted values. Kaplan-Meier curves based on the overall survival (OS) and disease-free survival (DFS) showed significant differences between nomogram predictive low and high groups. DCA showed clinical utilities while NRI showed discrimination ability in both training or validation cohort. Conclusions GMWG might be a potential prognostic indicator for patients with HCC. The nomogram containing GMWG also showed satisfaction prediction capacity.

Background: Repeat hepatectomy is an important treatment for patients with repeat recurrent hepatocellular carcinoma (HCC).Methods: This study was a multicenter retrospective analysis of 1,135 patients who underwent primary curative liver resection for HCC. One hundred recurrent patients with second hepatectomy were included to develop a nomogram to predict the risk of post-recurrence survival (PRS). Thirty-eight patients in another institution were used to externally validate the nomogram. Univariate and multivariate Cox regression analyses were used to identify independent risk factors of PRS. Discrimination, calibration, and the Kaplan–Meier curves were used to evaluate the model performance.Results: The nomogram was based on variables associated with PRS after HCC recurrence, including the tumor, node, and metastasis (TNM) stage; albumin and aspartate aminotransferase levels at recurrence; tumor size, site, differentiation of recurrences; and time to recurrence (TTR). The discriminative ability of the nomogram, as indicated by the C statistics (0.758 and 0.811 for training cohort and external validation cohorts, respectively), was shown, which was better than that of the TNM staging system (0.609 and 0.609, respectively). The calibration curves showed ideal agreement between the prediction and the real observations. The area under the curves (AUCs) of the training cohort and external validation cohorts were 0.843 and 0.890, respectively. The Kaplan–Meier curve of the established nomogram also performed better than those of both the TNM and the BCLC staging systems.Conclusions: We constructed a nomogram to predict PRS in patients with repeat hepatectomy (RH) after repeat recurrence of HCC.

Tumor-specific neoantigens, which are expressed on tumor cells, can induce an effective antitumor cytotoxic T-cell response and mediate tumor regression. Among tumor immunotherapies, neoantigen vaccines are in early human clinical trials and have demonstrated substantial efficiency. Compared with more neoantigens in melanoma, the paucity and inefficient identification of effective neoantigens in hepatocellular carcinoma (HCC) remain enormous challenges in effectively treating this malignancy. In this review, we highlight the current development of HCC neoantigens in its generation, screening, and identification. We also discuss the possibility that there are more effective neoantigens in hepatitis B virus (HBV)-related HCC than in non-HBV-related HCC. In addition, since HCC is an immunosuppressive tumor, strategies that reverse immunosuppression and enhance the immune response should be considered for the practical exploitation of HCC neoantigens. In summary, this review offers some strategies to solve existing problems in HCC neoantigen research and provide further insights for immunotherapy.

Objective: This paper aimed to explore the effects of radiotherapy after thoracic and laparoscopic surgery (TLS) in patients with esophageal cancer and on their prognoses. Methods: Altogether 118 patients with esophageal cancer diagnosed in our hospital were recruited as the study cohort and randomly divided into a postoperative radiotherapy group (59 cases) and a postoperative chemotherapy group (59 cases). All the patients were treated with TLS. In addition to the TLS, the patients in the postoperative radiotherapy group underwent radiotherapy, and the patients in the postoperative chemotherapy group were administered cisplatin and 5-fluorouracil (PF) chemotherapy. Before the treatment and at 6 months after the treatment, the serum carbohydrate antigen 199 (CA199), carbohydrate antigen 153 (CA153), and carcinoembryonic antigen (CEA) levels were measured using immunity transmission turbidity (ITT). The expression levels of Bax and Bcl-2 in the peripheral blood mononuclear cells (PBMCs) were measured using Western blot (WB). The CD4(+), CD8(+) and CD3(+) levels in the peripheral venous blood were measured using a flow cytometer. The two groups were compared in terms of their effective treatment rates, their incidences of complications, and their postoperative survival rates. Results: After the treatment, the serum CEA, CA153, and CA199 levels in the postoperative radiotherapy group were significantly lower than they were in the postoperative chemotherapy group (P0.05). After the treatment, the overall response rate (ORR) and the total incidence of adverse reactions were significantly higher in the postoperative radiotherapy group (P

Regulatory factor X-5 (RFX5) represents a key transcription regulator of MHCII gene expression in the immune system. This study aims to explore the molecular mechanisms and biological significance of RFX5. Firstly, by analyzing ENCODE chromatin immunoprecipitation (ChIP)-seq in HepG2 and TCGA RNA-seq data, we discovered lysine-specific demethylase 4A (KDM4A), also named JMJD2A, to be a major downstream target gene of RFX5. Moreover, RFX5 was verified to bind directly to the KDM4A’s promoter region and sequentially promoted its transcription determined by the ChIP-PCR assay and luciferase assay. In addition, RFX5-dependent regulation of KDM4A was demonstrated in HCC. Compared with adjacent non-tumor tissues, the expression levels of KDM4A were significantly raised in HCC tumor tissues. Notably, elevated levels of KDM4A were strongly correlated with HCC patient prognosis. Functionally, KDM4A overexpression largely rescued the growth inhibitory effects of RFX5 deletion, highlighting KDM4A as a downstream effector of RFX5. Mechanistically, the RFX5-KDM4A pathway promoted the progression of the cell cycle from G0/G1 to S phase and was protective against cell apoptosis through regulation of p53 and its downstream genes in HCC. In conclusion, RFX5 could promote HCC progression via transcriptionally activating KDM4A expression.

The crosstalk between the estrogen receptor (ER) and NF-κB signalling pathways has merged in vertebrates and plays a key role in the control of genes involved in inflammation, cell proliferation and apoptosis. However, such crosstalk between the endocrine and immune systems needs to be explored in lower invertebrates. In this study, we identified a 2856-bp homologue of the estrogen receptor from Hong Kong oyster (ChER), containing a 5' untranslated region (UTR) of 234 bp, a 3' UTR of 387 bp, and an open reading frame (ORF) of 2235 bp. We observed that overexpression of ChER suppressed ChRel-dependent NF-kappaB (NF-κB) activation in the HEK293T (human embryonic kidney 293T) cell line, and depletion of ChER in vivo resulted in upregulation of two NF-κB-responsive marker genes, namely, TNF-α and IL-17, which confirmed its potential role in controlling NF-κB signalling. Furthermore, an EMSA (electrophoretic mobility shift assay) showed that ChER could negatively regulate the binding of ChRel to NF-κB probe-responsive elements. Serial domain requirement analysis showed that both region C (DNA-binding domain) and region E (ligand-binding domain) of ChER were essential for mediating the crosstalk underlying ChER-dependent NF-κB suppression. In conclusion, we demonstrate for the first time the negative regulatory role of the ER in NF-κB signalling in oysters, strongly indicating the presence of complex crosstalk between the endocrine and immune systems in lower marine molluscs.

NEMO (NF-κB essential modulator) is one of the important regulatory subunits of the IκB kinase (IκK) complex that controls the activation of the NF-κB signaling pathway. Here, we have identified the homolog of NEMO from the pacific oyster Crassostrea gigas. CgNEMO harbors the conserved the IκK binding region, NEMO ubiquitin binding domain and Zinc finger domain. In terms of tissue distribution, CgNEMO is expressed in various tissues with an observed highest expression in the hemocytes. Furthermore, infection by two related Vibrio strains significantly increased CgNEMO expression in the hemocytes. Cell culture based luciferase reporter assays showed that CgNEMO activates the NF-κB reporter in a dose-pendent manner. Moreover, CgNEMO was also found to counter the IkB-dependent inhibitory effect on NF-κB activation, providing a plausible mechanism of NF-κB activation by CgNEMO. Meanwhile, site-directed mutagenesis demonstrated that the putative ubiquitination site K535 is required for the activation of NF-κB, implying that ubiquitination of NEMO may be involved in regulating its activity. Finally, RNAi mediated knockdown of CgNEMO in vivo significantly compromised the bacterial induction of key cytokines TNF-α and IL-17, strongly suggesting a role for CgNEMO in acute immune defense in oyster. In conclusion, this study provides new insights into our understanding about the evolution of NEMO mediated NF-κB activation and the induction of cytokine. Our findings may provide valuable information about diseases control and management in oyster aquaculture.

Sulfur particles carried by high-speed flow impact pipelines, which may cause equipment malfunctions and even failure. This paper investigates the scouring effect of mist gas containing sulfur particles on elbows in highly sour gas fields. The multiphase-flow hydrodynamic model of the 90° elbow was established by using the computational fluid dynamics (CFD) method. The scouring effects of the gas-liquid mist fluid with the water-liquid fraction of 20% and particles with the diameter of 0.01–0.05 mm on elbows were explored within the flow velocity range of 0–20 m/s. In addition, the influences of secondary collision, mean curvature radius to diameter (R/D) ratio, inertial force, drag force, and Stokes number on trajectories of sulfur particles were studied. Moreover, the influences of hydrodynamic parameters of multiphase flow on corrosion inhibitor film were analyzed with the wall shear stress as the reference value. Serious erosion mainly occurred in the extrados of elbow as well as the junction between downstream pipeline and the intrados of elbow, the maximum erosion area occurs at 61.9°. When the incident position of the particle was far away from the top of the inlet plane, the probability of secondary collision became smaller. Furthermore, the erosion rate decreased with the rise in the R/D radio. The maximum erosion rate of elbow increased with the increase in the Stoke number. The maximum erosion rate reached 0.428 mm/a at 0.05 mm particle diameter and 20 m/s fluid velocity. The wall shear stress increased with the increase in fluid velocity and mass flow rate of particle, the fitting function of the wall shear stress curve was the Fourier type. The results indicated that high-velocity particles had a serious erosion effect on elbows and affected the stability of the corrosion inhibitor film. The erosion effect could be retarded by controlling the velocity and diameter of particles. The results provided technical supports for the safe production in highly sour gas fields. Keywords: Sour gas field, Elbow, Sulfur particle, Trajectory, Erosion, Numerical simulation

In bivalve mollusks, circulating hemocyte mediated phagocytosis is one of the primary ways to eliminate invading microbes. Here, we have identified one CgLRFN (leucine-rich repeat and fibronectin type-III domain-containing protein) in the Crassostrea gigas as a novel transmembrane LRR (Leucine-rich repeat) domain containing protein in C. gigas, homologous to the jawless fish VLR protein, that plays an important role in recognizing bacteria and promoting hemocytic phagocytosis. Tissue distribution analysis of CgLRFN in Pacific oyster showed that it is widely expressed in various tissues like the gills, adductor muscles, digestive glands, gonads, heart and in the hemocytes. Furthermore, infection of Pacific oysters with two marine Vibrio strains V. alginolyticus and V. parahaemolyticus was found to significantly increase CgLRFN expression in the hemocytes. Analysis of subcellular localization showed that CgLRFN is primarily localized in the cell membrane. Additionally, CgLRFN was found to be able to bind both the bacterial strains, indicating its possible role as a cell surface receptor. Flow cytometry analysis revealed that CgLRFN coated bacteria was phagocytosed by oyster hemocytes at a significantly higher rate compared to the uncoated bacteria. Finally, RNAi mediated knockdown of CgLRFN in vivo resulted in reduced clearance of both the bacterial strains from the oyster hemolymph. Overall, our study demonstrates that CgLRFN acts as a pattern recognition receptor for Vibrio spp. and promotes hemocytic phagocytosis in the Pacific oyster, which is critical for understanding the mechanism of bacterial infection in lower invertebrates, and also contributes to disease management of this economically and ecologically important marine mollusk.

It is increasingly appreciated that neuroendocrine-immune interactions hold the key to understand the complex immune system. In this study, we explored the role of a reproductive regulation-related hormone, GnRH, in the regulation of immunity in Hong Kong oysters. We found that vibrio bacterial strains injection increased the expression of ChGnRH. Moreover, ChGnRH neuropeptide promotes the phagocytic ability and bacterial clearance effect of hemocytes which regarded to be the central immune organ. The content of cAMP after incubation with ChGnRH peptide was increased, which could be blocked by adenylyl cyclase inhibitor SQ 22,536. Furthermore, the stimulated effect of ChGnRH peptide on the phagocytosis and bacterial clearance was also blocked by SQ 22,536, H89 and enzastaurin, strongly demonstrating that cAMP dependent PKA and PKC signaling pathway was involved in ChGnRH mediated immune regulation. In conclusion, this study confirms the presence of neuroendocrine-immune regulatory system in marine invertebrates, which contributes to understand the complexity of oyster immune defense system.

In vertebrates, embryonic hematopoietic stem and progenitor cells (HSPCs) are derived from a subset of endothelial cells, the hemogenic endothelium (HE), through the endothelial-to-hematopoietic transition (EHT). Notch signaling is essential for HSPC development during embryogenesis across vertebrates. However, whether and how it regulates EHT remains unclear. Here, we show that G protein-coupled receptor 183 (Gpr183) signaling serves as an indispensable switch for HSPC emergence by repressing Notch signaling before the onset of EHT. Inhibition of Gpr183 significantly upregulates Notch signaling and abolishes HSPC emergence. Upon activation by its ligand 7α-25-OHC, Gpr183 recruits β-arrestin1 and the E3 ligase Nedd4 to degrade Notch1 in specified HE cells and then facilitates the subsequent EHT. Importantly, 7α-25-OHC stimulation promotes HSPC emergence in vivo and in vitro, providing an attractive strategy for enhancing the in vitro generation of functional HSPCs.

Aiming at the speed regulation system of permanent magnet synchronous motor (PMSM), the research and analysis of PMSM speed regulating system are made. Based on the finite time control technique, a finite time controller is designed in this paper. This design utilizes the error between the output of the speed and the reference speed, to be controlled by a finite time controller to obtain the q-axis current reference iq∗. And, based on the second-order model of speed control system, the reference speed can be tracked by the output speed in finite time. At the same time, the feasibility and validity of the verification is simulated by Matlab. The simulation results show that the proposed method guarantee that the output speed track the reference speed in finite time.

A class of finite-time control strategy is proposed to solve the problem of position tracking of permanent magnet synchronous motor servo system. Which guarantees that the motor's desired position can be tracked in a finite time. Based on the vector control principle, a first-order finite-time controller is firstly designed for the d-axis voltage. And then for the q-axis voltage, an integral high-order terminal sliding mode controller is designed. Theoretical analysis shows that under the proposed controller, the desired position can be tracked by the motor position in a finite time. Simulation results are given to show that the proposed control method has a stronger anti-disturbance ability and a better convergence performance.

Lichens are structured associations of a fungus with a cyanobacteria and/or green algae in a symbiotic relationship, which provide specific habitats for diverse bacterial communities, including actinomycetes. However, few studies have been performed on the phylogenetic relationships and biosynthetic potential of actinomycetes across lichen species. In the present study, a total of 213 actinomycetes strains were isolated from 35 lichen samples (22 lichen genera) collected in Yunnan Province, China. 16S rRNA gene sequence analysis revealed an unexpected level of diversity among these isolates, which were distributed into 38 genera, 19 families, and 9 orders within the Actinobacteria phylum. The detailed taxa of isolates had no clear relationship to the taxonomic affiliations of the associated lichens. To the best of our knowledge, this is the first report to describe the isolation of Actinophytocola, Angustibacter, Herbiconiux, Kibdelosporangium, Kineosporia, Kitasatospora, Nakamurella, Nonomuraea, Labedella, Lechevalieria, Lentzea, Schumannella, and Umezawaea species from lichens. At least 40 isolates (18.78%) are likely to represent novel actinomycetes taxa within 15 genera. In addition, all 213 isolates were tested for antimicrobial activity and screened for genes associated with secondary metabolite production to evaluate their biosynthetic potential. These results demonstrate that the lichens of Yunnan Province represent an extremely rich reservoir for the isolation of a significant diversity of actinomycetes, including novel species, which are potential source for discovering biologically active compounds.

Irritable bowel syndrome (IBS) is one of the most common functional disorders of the gastrointestinal tract. It is characterized by abdominal pain and changes in bowel habits. Various studies have investigated the pathophysiologic processes underlying IBS, but the mechanism remains poorly understood. In the present study, we established an IBS model and identified differentially expressed proteins in colon tissue of IBS rats compared with healthy controls by 2-D gel electrophoresis, MALDI-TOF-MS, and Western blot analysis. Our results showed that 13 of the 1396 protein spots on 2-D gel were differently expressed between the IBS and control groups. Ontological analysis of these proteins revealed primary roles in catalytic activity (protein disulfide-isomerase A3, glyoxalase I, cathepsin S, alpha-enolase), structural support (cytokeratin 8), antioxidant activity (peroxiredoxin-6), protein binding (transgelin, serpin peptidase inhibitor B5), and signal transduction (40S ribosomal protein SA). Protein disulfide-isomerase A3 and cytokeratin 8 overexpression in IBS were confirmed by Western blot. The findings indicate that multiple proteins are involved in IBS processes that influence intestinal tract immunity, inflammation, and nerve regulation. Our study provides useful candidate genes and proteins for further investigation.

To evaluate the efficacy of percutaneous transhepatic gallbladder drainage (PTGD) for high-risk elderly patients with acute cholecystitis.Retrospective analysis of 159 acute cholecystitis patients who were admitted to General Surgery Division III of the First Affiliated Hospital of Dalian Medical University between January 2005 and November 2012. A total of 123 patients underwent laparoscopic cholecystectomy (LC), and 36 received only PTGD treatment. The LC patients were divided into 3 groups based on their preoperative treatment: group A, emergency patients (33 patients); group B (26 patients), patients who were treated with PTGD prior to LC; and group C (64 patients), patients who received nonsurgical treatment prior to LC. General conditions, LC surgery duration, intraoperative blood loss, rate of conversion to open surgery, incidence of postoperative complications, total fasting time, and total hospitalization time were analyzed and compared among the 3 groups.The remission rates of patients in the PTGD treatment groups (including group B and PTGD treatment only group) were significantly higher within 24 and 48 hours than those of patients who received nonsurgical treatment prior to LC (P < 0.05). Among the patients in the 3 surgery groups, the operation conversion rate (19.2%) of group B was significantly higher than that of group A (3.0%) and group C (1.6%) (P < 0.05). The total hospitalization time of the patients in group B (18.5 ± 4.5 days) was longer than that of the patients in group A (8.2 ± 3.9 days) and group C (10.5 ± 6.4 days). The total fasting time of the patients in group A (2.4 ± 1.2 days) was significantly shorter than that of those in group B (4.1 ± 1.7 days) and group C (3.4 ± 2.7 days) (P < 0.05).For high-risk elderly patients, if there is any emergency surgery contraindication, PTGD therapy may be safe and effective and can relieve the symptoms within a short time. For acute cholecystitis patients without surgery contraindications, emergency surgery should be performed as soon as possible after diagnosis.

Silver dendritic hierarchical structures have been prepared using a simple, surfactant-free method by carrying out the silver mirror reaction on the surface of a porous anodic aluminium oxide (AAO)...

Silver dendritic hierarchical structures have been synthesized simply by carrying out the silver mirror reaction on the surface of a porous anodic aluminium oxide (AAO) template in a surfactant-free system. The length of the stem is several tens of micrometres, and that of each leaf ranges from 0.5 to 4 µm with a width of 100–300 nm. Our studies indicate that the growth mechanism of silver dendritic hierarchical structures is a diffusion-limited preferential growth of oriented attachment of silver nanocrystals. Also, the surface of the AAO template has a guiding effect in the formation process of the silver dendritic hierarchical nanostructure. We have observed the transformation from sliver dendritic hierarchical structures to silver nanobelts under ultrasonic treatment. This transformation is due to the dissociation of silver dendritic hierarchical structures covering over the Ag nanobelts under ultrasonic treatment.