Prenatal programming during pregnancy sets physiological outcomes in the offspring by integrating external or internal stimuli.Accordingly,pregnancy is an important stage of physiological adaptations to the environmen...Prenatal programming during pregnancy sets physiological outcomes in the offspring by integrating external or internal stimuli.Accordingly,pregnancy is an important stage of physiological adaptations to the environment where the fetus becomes exposed and adapted to the maternal milieu.Maternal exposure to high-energy dense diets can affect motivated behavior in the offs p ring leading to addiction and impaired sociability.A high-energy dense exposure also increases the pro-inflammatory cytokines profile in plasma and brain and favors microglia activation in the offspring.While still under investigation,prenatal exposure to high-energy dense diets promotes structural abnormalities in selective brain regions regulating motivation and social behavior in the offspring.The current review addresses the role of energy-dense foods programming central and peripheral inflammatory profiles during embryonic development and its effect on motivated behavior in the offspring.We provide preclinical and clinical evidence that supports the contribution of prenatal programming in shaping immune profiles that favor structural and brain circuit disruption leading to aberrant motivated behaviors after birth.We hope this minireview encourages future research on novel insights into the mechanisms underlying maternal programming of motivated behavior by central immune networks.展开更多
This paper presents a new method .linear programming method. to calculate the proportion of the cement raw material. Its advanlages are as following : good practicability, convenience for analysis, and being easy for ...This paper presents a new method .linear programming method. to calculate the proportion of the cement raw material. Its advanlages are as following : good practicability, convenience for analysis, and being easy for controlling. The mathematical model given in the paper is apt to be realized on computer.展开更多
UML Class diagram generation from textual requirements is an important task in object-oriented design and programing course.This study proposes a method for automatically generating class diagrams from Chinese textual...UML Class diagram generation from textual requirements is an important task in object-oriented design and programing course.This study proposes a method for automatically generating class diagrams from Chinese textual requirements on the basis of Natural Language Processing(NLP)and mapping rules for sentence pattern matching.First,classes are identified through entity recognition rules and candidate class pruning rules using NLP from requirements.Second,class attributes and relationships between classes are extracted using mapping rules for sentence pattern matching on the basis of NLP.Third,we developed an assistant tool integrated into a precision micro classroom system for automatic generation of class diagram,to effectively assist the teaching of object-oriented design and programing course.Results are evaluated with precision,accuracy and recall from eight requirements of object-oriented design and programing course using truth values created by teachers.Our research should benefit beginners of object-oriented design and programing course,who may be students or software developers.It helps them to create correct domain models represented in the UML class diagram.展开更多
The concept of the spacecraft Reachable Domain(RD)has garnered significant scholarly attention due to its crucial role in space situational awareness and on-orbit service applications.While the existing research has l...The concept of the spacecraft Reachable Domain(RD)has garnered significant scholarly attention due to its crucial role in space situational awareness and on-orbit service applications.While the existing research has largely focused on single-impulse RD analysis,the challenge of Multi-Impulse RD(MIRD)remains a key area of interest.This study introduces a methodology for the precise calculation of spacecraft MIRD.The reachability constraints specific to MIRD are first formulated through coordinate transformations.Two restricted maneuvering strategies are examined.The derivation of two extremum conditions allows for determining the accessible orientation range and the nodes encompassing the MIRD.Subsequently,four nonlinear programming models are developed to address two types of MIRD by skillfully relaxing constraints using scale factors.Numerical results validate the robustness and effectiveness of the proposed approach,showing substantial agreement with Monte Carlo simulations and confirming its applicability to spacecraft on various elliptical orbits.展开更多
BACKGROUND Hepatocellular carcinoma(HCC)is an inflammation-associated tumor with a dismal prognosis.Immunotherapy has become an important treatment strategy for HCC,as immunity is closely related to inflammation in th...BACKGROUND Hepatocellular carcinoma(HCC)is an inflammation-associated tumor with a dismal prognosis.Immunotherapy has become an important treatment strategy for HCC,as immunity is closely related to inflammation in the tumor microenvir-onment.Inflammation regulates the expression of programmed death ligand-1(PD-L1)in the immunosuppressive tumor microenvironment and affects im-munotherapy efficacy.Interleukin-17A(IL-17A)is involved in the remodeling of the tumor microenvironment and plays a protumor or antitumor role in different tumors.We hypothesized that IL-17A participates in tumor progression by affe-cting the level of immune checkpoint molecules in HCC.The upregulation of PD-L1 expression in HCC cells by IL-17A was assessed by reverse transcription PCR,western blotting,and flow cytometry.Mechanistic studies were conducted with gene knockout models and pathway inhibitors.The function of IL-17A in immune evasion was explored through coculture of T cells and HCC cells.The effects of IL-17A on the malignant biological behaviors of HCC cells were evaluated in vitro,and the antitumor effects of an IL-17A inhibitor and its synergistic effects with a PD-L1 inhibitor were studied in vivo.RESULTS IL-17A upregulated PD-L1 expression in HCC cells in a dose-dependent manner,whereas IL-17A receptor knockout or treatment with a small mothers against decapentaplegic 2 inhibitor diminished the PD-L1 expression induced by IL-17A.IL-17A enhanced the survival of HCC cells in the coculture system.IL-17A increased the viability,G2/M ratio,and migration of HCC cells and decreased the apoptotic index.Cyclin D1,VEGF,MMP9,and Bcl-1 expression increased after IL-17A treatment,whereas BAX expression decreased.The combination of IL-17A and PD-L1 inhibitors showed synergistic antitumor efficacy and increased cluster of differentiation 8+T lymphocyte infiltration in an HCC mouse model.CONCLUSION IL-17A upregulates PD-L1 expression via the IL-17A receptor/phosphorylation-small mothers against decapenta-plegic 2 signaling pathway in HCC cells.Blocking IL-17A enhances the therapeutic efficacy of PD-L1 antibodies in HCC in vivo.展开更多
In many research disciplines, hypothesis tests are applied to evaluate whether findings are statistically significant or could be explained by chance. The Wilcoxon-Mann-Whitney （WMW） test is among the most popular h...In many research disciplines, hypothesis tests are applied to evaluate whether findings are statistically significant or could be explained by chance. The Wilcoxon-Mann-Whitney （WMW） test is among the most popular hypothesis tests in medicine and life science to analyze if two groups of samples are equally distributed. This nonparametric statistical homogeneity test is commonly applied in molecular diagnosis. Generally, the solution of the WMW test takes a high combinatorial effort for large sample cohorts containing a significant number of ties. Hence, P value is frequently approximated by a normal distribution. We developed EDISON-WMW, a new approach to calcu- late the exact permutation of the two-tailed unpaired WMW test without any corrections required and allowing for ties. The method relies on dynamic programing to solve the combinatorial problem of the WMW test efficiently. Beyond a straightforward implementation of the algorithm, we pre- sented different optimization strategies and developed a parallel solution. Using our program, the exact P value for large cohorts containing more than 1000 samples with ties can be calculated within minutes. We demonstrate the performance of this novel approach on randomly-generated data, benchmark it against 13 other commonly-applied approaches and moreover evaluate molec- ular biomarkers for lung carcinoma and chronic obstructive pulmonary disease （COPD）. We foundthat approximated P values were generally higher than the exact solution provided by EDISON- WMW. Importantly, the algorithm can also be applied to high-throughput omics datasets, where hundreds or thousands of features are included. To provide easy access to the multi-threaded version of EDISON-WMW, a web-based solution of our algorithm is freely available at http：// www.ccb.uni-saarland.de/software/wtest/.展开更多
Generating dynamically feasible trajectory for fixed-wing Unmanned Aerial Vehicles(UAVs)in dense obstacle environments remains computationally intractable.This paper proposes a Safe Flight Corridor constrained Sequent...Generating dynamically feasible trajectory for fixed-wing Unmanned Aerial Vehicles(UAVs)in dense obstacle environments remains computationally intractable.This paper proposes a Safe Flight Corridor constrained Sequential Convex Programming(SFC-SCP)to improve the computation efficiency and reliability of trajectory generation.SFC-SCP combines the front-end convex polyhedron SFC construction and back-end SCP-based trajectory optimization.A Sparse A^(*)Search(SAS)driven SFC construction method is designed to efficiently generate polyhedron SFC according to the geometric relation among obstacles and collision-free waypoints.Via transforming the nonconvex obstacle-avoidance constraints to linear inequality constraints,SFC can mitigate infeasibility of trajectory planning and reduce computation complexity.Then,SCP casts the nonlinear trajectory optimization subject to SFC into convex programming subproblems to decrease the problem complexity.In addition,a convex optimizer based on interior point method is customized,where the search direction is calculated via successive elimination to further improve efficiency.Simulation experiments on dense obstacle scenarios show that SFC-SCP can generate dynamically feasible safe trajectory rapidly.Comparative studies with state-of-the-art SCP-based methods demonstrate the efficiency and reliability merits of SFC-SCP.Besides,the customized convex optimizer outperforms off-the-shelf optimizers in terms of computation time.展开更多
BACKGROUND Gastric cancer(GC)is one of the most common malignancies worldwide,and Helicobacter pylori(HP)infection is a well-established risk factor for its development.Programmed death-ligand 1(PD-L1)expression is a ...BACKGROUND Gastric cancer(GC)is one of the most common malignancies worldwide,and Helicobacter pylori(HP)infection is a well-established risk factor for its development.Programmed death-ligand 1(PD-L1)expression is a crucial biomarker for predicting the efficacy of immune checkpoint inhibitors in cancer treatment.While HP infection and PD-L1 expression in GC may be linked,the relationship between them remains unclear,in part because there have been conflicting results reported from various studies.AIM To perform a meta-analysis to assess the relationship between HP and PD-L1 expression in patients with GC.METHODS A systematic literature review was conducted using PubMed,Embase,Cochrane Library,and Web of Science databases.Observational studies that examined the association between HP infection and PD-L1 expression in patients with GC were included.Odds ratios and 95%confidence intervals were calculated to estimate the association.Heterogeneity was assessed using Cochrane’s Q test and I²statistic.A random-effects model was used due to significant heterogeneity across studies.RESULTS Fourteen studies involving a total of 3069 patients with GC were included.The pooled analysis showed a significant association between HP infection and increased PD-L1 expression in GC tissues(odd ratio=1.69,95%confidence interval:1.24-2.29,P<0.001,I^(2)=59%).Sensitivity analyses confirmed the robustness of these findings.Subgroup analyses did not show significant variation based on geographic region,sample size,or method of PD-L1 assessment.Publication bias was minimal,as shown by funnel plots and Egger’s regression test.CONCLUSION HP infection is associated with increased PD-L1 expression in GC,suggesting that HP status may influence the response to programmed cell death protein 1/PD-L1 blockade therapy.展开更多
BACKGROUND Breast cancer(BC)continues to occupy a leading position in terms of morbidity and mortality from malignant neoplasms among the female population.One of the promising markers associated with BC progression i...BACKGROUND Breast cancer(BC)continues to occupy a leading position in terms of morbidity and mortality from malignant neoplasms among the female population.One of the promising markers associated with BC progression is programmed death ligand 1(PD-L1).Previously,we investigated PD-L1 expression in BC via a new antibody against programmed cell death protein 1 ligand 1(PDCD1 LG1)and reported that high PDCD1 LG1 expression in tumor cells is an independent factor for a high risk of regional metastasis in patients with BC.However,the prognostic significance of PDCD1 LG1 expression in BC stromal cells has not been adequately studied.AIM To study the features of PDCD1 LG1 expression in BC stromal cells and its relationship with BC clinicopathological characteristics.METHODS In a prospective single-center observational study,tumor samples from 148 patients with newly diagnosed BC were examined.The tumor sections were immunohistochemically stained with antibodies against PDCD1 LG1.In the tumor samples,the PDCD1 LG1-positive lymphocyte(PDCD1 LG1+LF)score,presence of nuclear PDCD1 LG1 expression in the LFs,PDCD1 LG1 expression in polymorphic cell infiltrates(PDCD1 LG1+polymorphic cell infiltrates[PCIs]),and cells of the fibroblastic stroma and endothelial cells of the tumor microvessels were assessed.Statistical analyses were performed using Statistica 10.0 software.RESULTS A PDCD1 LG1+LF score≥3 was detected more often at stages N0 and N3 than at N1 and N2(P=0.03).Moderate and pronounced PDCD1 LG1+PCIs and the presence of PDCD1 LG1+fibroblastic stroma were associated with negative estrogen receptor status(P=0.0008 and P=0.03,respectively),human epidermal growth factor receptor 2-positive(HER2+)BC(P<0.00001 and P=0.0005),and luminal B HER2+,non-luminal HER2+and triple-negative BC(P<0.00001 and P=0.004).The risk of metastasis to regional lymph nodes(RLNs)depend on lymphovascular invasion(LVI)and the PDCD1 LG1+LF score.In the absence of LVI and a PDCD1 LG1+LF score<3 or≥3,metastases in RLNs were absent in 66.6%and 93.9%of patients with BC,respectively.In the presence of LVI and a PDCD1 LG1+LF score<3 or≥3,metastases in RLNs were detected in 82.6%and 92.7%of patients with BC,respectively.CONCLUSION The results indicated that the combined assessment of the PDCD1 LG1+LF score and LVI can improve the accuracy of predicting the risk of metastasis to RLNs in patients with BC.展开更多
Ship outfitting is a key process in shipbuilding.Efficient and high-quality ship outfitting is a top priority for modern shipyards.These activities are conducted at different stations of shipyards.The outfitting plan ...Ship outfitting is a key process in shipbuilding.Efficient and high-quality ship outfitting is a top priority for modern shipyards.These activities are conducted at different stations of shipyards.The outfitting plan is one of the crucial issues in shipbuilding.In this paper,production scheduling and material ordering with endogenous uncertainty of the outfitting process are investigated.The uncertain factors in outfitting equipment production are usually decision-related,which leads to difficulties in addressing uncertainties in the outfitting production workshops before production is conducted according to plan.This uncertainty is regarded as endogenous uncertainty and can be treated as non-anticipativity constraints in the model.To address this problem,a stochastic two-stage programming model with endogenous uncertainty is established to optimize the outfitting job scheduling and raw material ordering process.A practical case of the shipyard of China Merchants Heavy Industry Co.,Ltd.is used to evaluate the performance of the proposed method.Satisfactory results are achieved at the lowest expected total cost as the complete kit rate of outfitting equipment is improved and emergency replenishment is reduced.展开更多
Lung cancer-derived exosomes are a kind of valuable and clinically-predictable biomarkers for lung cancer, but they have the limitations in individual differences when being applied in liquid biopsy. To improve their ...Lung cancer-derived exosomes are a kind of valuable and clinically-predictable biomarkers for lung cancer, but they have the limitations in individual differences when being applied in liquid biopsy. To improve their application value and accuracy in clinical diagnosis, a dual-labelled electrochemical method is herein reported for precise assessment of lung cancer-derived exosomes. To do so, two probes are prepared for the dual labeling of exosome membrane to run DNA assembly reactions: One is modified with cholesterol and can insert into exosome membrane through hydrophobic interaction;another one is linked with programmed death ligand-1(PD-L1) antibody and can bind to exosome surface-expressing PD-L1 via specific immunoreaction. Quantum dots-tagged signal strands are used to collect respective DNA products, and produce stripping signals corresponding to the amounts of total exosome and surfaceexpressing PD-L1, respectively. A wide linear relationship is established for the quantitative determination of lung cancer-derived exosomes in the range from 103to 1010particles/m L, whereas the ratiometric value of the two stripping signals is proven to have a better diagnostic use in screening and staging of lung cancer when being applied to clinical samples. Therefore, our method might provide a new insight into precise diagnosis of lung cancer, and offer sufficient information to refiect the biomarker level and guide the personalized treatment level even at an early stage in clinic.展开更多
Over the last two decades,the dogma that cell fate is immutable has been increasingly challenged,with important implications for regenerative medicine.The brea kth rough discovery that induced pluripotent stem cells c...Over the last two decades,the dogma that cell fate is immutable has been increasingly challenged,with important implications for regenerative medicine.The brea kth rough discovery that induced pluripotent stem cells could be generated from adult mouse fibroblasts is powerful proof that cell fate can be changed.An exciting extension of the discovery of cell fate impermanence is the direct cellular reprogram ming hypothesis-that terminally differentiated cells can be reprogrammed into other adult cell fates without first passing through a stem cell state.展开更多
Objective:To investigate the anti-tumor effects of an E1B55KD-deleted oncolytic adenovirus,H101,in combination with a humanized anti-PD-1(Programmed cell death protein 1)monoclonal antibody,Camrelizumab.Methods:Anti-t...Objective:To investigate the anti-tumor effects of an E1B55KD-deleted oncolytic adenovirus,H101,in combination with a humanized anti-PD-1(Programmed cell death protein 1)monoclonal antibody,Camrelizumab.Methods:Anti-tumor efficacy of intratumoral injection of H101 or/and intraperitoneal injection of Camrelizumab were evaluated in an immune system humanized NOD Prkdc^(scid) Il2rg^(-/-)mice subcutaneous(S.C.)tumor model,established with human glioblastoma of unknown origin cell line U87-MG,and human bladder cancer cell line T24 and YTS-1.The mechanism by which H101 induced anti-tumor immunity were also investigated.Results:Combining H101 with Camrelizumab demonstrated more potent anti-tumor effects than monotherapy in mouse S.C.tumor model.Increased tumor-infiltrating T cells were observed in the combined treatment group.H101 infection decreased the expression of CD47 in cancer cells,thereby promoting macrophages to phagocytose cancer cells.Following the H101-mediated activation of macrophages,increased levels of cytokines,including TNF,IL-12 and IFN-γwere observed.Moreover,when induced THP-1 cells were co-cultured with H101-treated cancer cells,expression of IFN-γwas increased in T cells.Elimination of IL-12 using an anti-IL-12 antibody abolished IFN-γproduction from T cells.In addition,infection with H101 increased PD-L1 expression in YTS-1 cells.These results suggested that H101 may act synergistically to enhance the therapeutic efficacy of PD-1 blockade in cancer via suppressing CD47 signaling,which may promote macrophages to phagocytose tumor cells and activate CD8^(+)T cells.Conclusion:The combination of H101 with PD-1 blockade exhibits potential as a novel strategy for the treatment of cancer.展开更多
Interference significantly impacts the performance of the Global Navigation Satellite Systems(GNSS),highlighting the need for advanced interference localization technology to bolster anti-interference and defense capa...Interference significantly impacts the performance of the Global Navigation Satellite Systems(GNSS),highlighting the need for advanced interference localization technology to bolster anti-interference and defense capabilities.The Uniform Circular Array(UCA)enables concurrent estimation of the Direction of Arrival(DOA)in both azimuth and elevation.Given the paramount importance of stability and real-time performance in interference localization,this work proposes an innovative approach to reduce the complexity and increase the robustness of the DOA estimation.The proposed method reduces computational complexity by selecting a reduced number of array elements to reconstruct a non-uniform sparse array from a UCA.To ensure DOA estimation accuracy,minimizing the Cramér-Rao Bound(CRB)is the objective,and the Spatial Correlation Coefficient(SCC)is incorporated as a constraint to mitigate side-lobe.The optimization model is a quadratic fractional model,which is solved by Semi-Definite Relaxation(SDR).When the array has perturbations,the mathematical expressions for CRB and SCC are re-derived to enhance the robustness of the reconstructed array.Simulation and hardware experiments validate the effectiveness of the proposed method in estimating interference DOA,showing high robustness and reductions in hardware and computational costs associated with DOA estimation.展开更多
BACKGROUND Irreversible electroporation(IRE)is a novel local tumor ablation approach with the potential to activate the host’s immune system.However,this approach is insufficient to prevent cancer progression,and com...BACKGROUND Irreversible electroporation(IRE)is a novel local tumor ablation approach with the potential to activate the host’s immune system.However,this approach is insufficient to prevent cancer progression,and complementary approaches are required for effective immunotherapy.AIM To assess the immunomodulatory effects and mechanism of IRE combined antiprogrammed cell death protein 1(PD-1)treatment in subcutaneous pancreatic cancer models.METHODS C57BL-6 tumor-bearing mice were randomly divided into four groups:Control group;IRE group;anti-PD-1 group;and IRE+anti-PD-1 group.Tumor-infiltrating T,B,and natural killer cell levels and plasma concentrations of T helper type 1 cytokines(interleukin-2,interferon-γ,and tumor necrosis factor-α)were evaluated.Real-time PCR was used to determine the expression of CD8(marker of CD8+T cells)in tumor tissues of the mice of all groups at different points of time.The growth curves of tumors were drawn.RESULTS The results demonstrated that the IRE+anti-PD-1 group exhibited significantly higher percentages of T lymphocyte infiltration,including CD4+and CD8+T cells compared with the control group.Additionally,the IRE+anti-PD-1 group showed increased infiltration of natural killer and B cells,elevated cytokine levels,and higher CD8 mRNA expression.Tumor volume was significantly reduced in the IRE+anti-PD-1 group,indicating a more pronounced therapeutic effect.CONCLUSION The combination of IRE and anti-PD-1 therapy promotes CD8+T cell immunity responses,leading to a more effective reduction in tumor volume and improved therapeutic outcomes,which provides a new direction for ablation and immunotherapy of pancreatic cancer.展开更多
Deep-time Earth research plays a pivotal role in deciphering the rates,patterns,and mechanisms of Earth's evolutionary processes throughout geological history,providing essential scientific foundations for climate...Deep-time Earth research plays a pivotal role in deciphering the rates,patterns,and mechanisms of Earth's evolutionary processes throughout geological history,providing essential scientific foundations for climate prediction,natural resource exploration,and sustainable planetary stewardship.To advance Deep-time Earth research in the era of big data and artificial intelligence,the International Union of Geological Sciences initiated the“Deeptime Digital Earth International Big Science Program”(DDE)in 2019.At the core of this ambitious program lies the development of geoscience knowledge graphs,serving as a transformative knowledge infrastructure that enables the integration,sharing,mining,and analysis of heterogeneous geoscience big data.The DDE knowledge graph initiative has made significant strides in three critical dimensions:(1)establishing a unified knowledge structure across geoscience disciplines that ensures consistent representation of geological entities and their interrelationships through standardized ontologies and semantic frameworks;(2)developing a robust and scalable software infrastructure capable of supporting both expert-driven and machine-assisted knowledge engineering for large-scale graph construction and management;(3)implementing a comprehensive three-tiered architecture encompassing basic,discipline-specific,and application-oriented knowledge graphs,spanning approximately 20 geoscience disciplines.Through its open knowledge framework and international collaborative network,this initiative has fostered multinational research collaborations,establishing a robust foundation for next-generation geoscience research while propelling the discipline toward FAIR(Findable,Accessible,Interoperable,Reusable)data practices in deep-time Earth systems research.展开更多
The brain's extracellular matrix(ECM),which is comprised of protein and glycosaminoglycan(GAG)scaffolds,constitutes 20%-40% of the human brain and is considered one of the largest influencers on brain cell functio...The brain's extracellular matrix(ECM),which is comprised of protein and glycosaminoglycan(GAG)scaffolds,constitutes 20%-40% of the human brain and is considered one of the largest influencers on brain cell functioning(Soles et al.,2023).Synthesized by neural and glial cells,the brain's ECM regulates a myriad of homeostatic cellular processes,including neuronal plasticity and firing(Miyata et al.,2012),cation buffering(Moraws ki et al.,2015),and glia-neuron interactions(Anderson et al.,2016).Considering the diversity of functions,dynamic remodeling of the brain's ECM indicates that this understudied medium is an active participant in both normal physiology and neurological diseases.展开更多
BACKGROUND Hepatocellular carcinoma(HCC)is the most common form of liver cancer that has limited treatment options and a poor prognosis.Transarterial chemoembolization(TACE)is the first-line treatment for intermediate...BACKGROUND Hepatocellular carcinoma(HCC)is the most common form of liver cancer that has limited treatment options and a poor prognosis.Transarterial chemoembolization(TACE)is the first-line treatment for intermediate-stage HCC but can induce tumour hypoxia,thereby promoting angiogenesis.Recent studies suggested that combining TACE with anti-angiogenic therapies and immunotherapy might im-prove efficacy.Lenvatinib,a tyrosine kinase inhibitor,has demonstrated superior outcomes compared to sorafenib,while immune checkpoint inhibitors such as sintilimab show potential when combined with TACE.However,the efficacy and safety of TACE combined with lenvatinib and sintilimab(TACE+SL)compared to TACE with lenvatinib alone(TACE+L)in patients with intermediate-ad-vanced HCC has not yet been investigated.AIM To evaluate the efficacy and safety of TACE+SL therapy in comparison to TACE+L therapy in patients with intermediate-advanced HCC.METHODS A retrospective analysis was performed on patients with intermediate-advanced HCC who received TACE plus lenvatinib with or without sintilimab between September 2019 and September 2022.Baseline characteristics were compared,and propensity score matching was applied.Overall survival(OS),progression-free survival(PFS),and objective response rate(ORR)were evaluated between the two groups,and adverse events were analyzed.RESULTS The study included 57 patients,with 30 in the TACE+SL group and 27 in the TACE+L group.The TACE+SL group demonstrated significantly improved median PFS and OS compared to the TACE+L group(PFS:14.1 months vs 9.6 months,P=0.016;OS:22.4 months vs 14.1 months,P=0.039),along with a higher ORR(70.0%vs 55.6%).After propensity score matching,30 patients were included,with the TACE+SL group again showing longer median PFS and a trend toward improved OS(PFS:14.6 months vs 9.2 months,P=0.012;OS:23.9 months vs 16.3 months,P=0.063),and a higher ORR(73.3%vs 53.3%).No severe adverse events were reported.CONCLUSION TACE+SL demonstrated superior outcomes in terms of OS and PFS,compared to TACE+L.These findings suggest that the addition of sintilimab might enhance the therapeutic response in patients with intermediate-advanced HCC.展开更多
BACKGROUND C-X-C chemokine receptor type 5(CXCR5)^(+)CD8^(+)T cells represent a unique immune subset with dual roles,functioning as cytotoxic cells in persistent viral infections while promoting B cell responses.Despi...BACKGROUND C-X-C chemokine receptor type 5(CXCR5)^(+)CD8^(+)T cells represent a unique immune subset with dual roles,functioning as cytotoxic cells in persistent viral infections while promoting B cell responses.Despite their importance,the specific role of CXCR5^(+)CD8^(+)T cells in chronic hepatitis B(CHB),particularly during interferon-alpha(IFN-α)treatment,is not fully understood.This study aims to elucidate the relationship between CXCR5^(+)CD8^(+)T cells and sustained serologic response(SR)in patients undergoing 48 weeks of pegylated IFN-α(peg-IFN-α)treatment for CHB.AIM To elucidate the relationship between CXCR5^(+)CD8^(+)T cells and sustained SR in patients undergoing 48 weeks of peg-IFN-αtreatment for CHB.METHODS This study enrolled 60 patients with hepatitis Be antigen(HBeAg)-positive CHB undergoing 48 weeks of peg-IFN-αtreatment.Participants were assessed for eligibility based on criteria such as persistent HBsAg-positive status for at least six months,HBeAb-negative,hepatitis B virus DNA levels exceeding 2×10^(4) copies/mL,and alanine aminotransferase(ALT)levels between 2 and 10 times the upper limit of normal.Blood samples were collected at baseline and at weeks 12,24,48,and a 24-week treatment-free follow-up(week 72)to measure serum interleukin(IL)-21 concentration via ELISA and to analyze CXCR5 and programmed death-ligand 1(PD-L1)expression on CD8^(+)T cells by flow cytometry,CXCR5 is a chemokine receptor that directs immune cells to specific tissues,while PD-L1 is a protein that regulates immune responses by inhibiting T cell activity.RESULTS Patients with CHB exhibited significantly lower levels of circulating CXCR5^(+)CD8^(+)T cells compared to healthy controls(P<0.01).Notably,CXCR5^(+)CD8^(+)T cells were prominently expressed in patients who achieved sustained SR compared to non-SR(NSR).A significant correlation was observed between CXCR5 and PD-L1 expression(r=-0.189,P=0.002).However,there was no significant correlation between serum IL-21 levels and CXCR5+CD8+lymphocytes(r=-0.03,P=0.625)or serum ALT levels(r=0.026,P=0.678).CONCLUSION The enhanced expression of CXCR5^(+)CD8^(+)T cells in patients achieving HBeAg seroconversion during IFN-αtreatment suggests that these cells play a crucial role in antiviral immune responses against hepatitis B.This study highlights the potential of CXCR5^(+)CD8^(+)T cells as immune regulators in CHB,which may inform future therapeutic strategies to optimize antiviral treatments.展开更多
In the context of the“dual carbon”goals,to address issues such as high energy consumption,high costs,and low power quality in the rapid development of electrified railways,this study focused on the China Railways Hi...In the context of the“dual carbon”goals,to address issues such as high energy consumption,high costs,and low power quality in the rapid development of electrified railways,this study focused on the China Railways High-Speed 5 Electric Multiple Unit and proposed a mathematical model and capacity optimization method for an onboard energy storage system using lithium batteries and supercapacitors as storage media.Firstly,considering the electrical characteristics,weight,and volume of the storage media,a mathematical model of the energy storage system was established.Secondly,to tackle problems related to energy consumption and power quality,an energy management strategy was proposed that comprehensively considers peak shaving and valley filling and power quality by controlling the charge/discharge thresholds of the storage system.Thecapacity optimization adopted a bilevel programming model,with the series/parallel number of storage modules as variables,considering constraints imposed by the Direct Current to Direct Current converter,train load,and space.An improved Particle Swarm Optimization algorithm and linear programming solver were used to solve specific cases.The results show that the proposed onboard energy storage system can effectively achieve energy savings,reduce consumption,and improve power qualitywhile meeting the load and space limitations of the train.展开更多
基金supported by the National Council of Science and Technology in Mexico(CONACYT)708452 CONACYT to LMM855559 CONACYT to GCC+1 种基金573686 CONACYT to RMRPAICYT 2021 to ACM。
文摘Prenatal programming during pregnancy sets physiological outcomes in the offspring by integrating external or internal stimuli.Accordingly,pregnancy is an important stage of physiological adaptations to the environment where the fetus becomes exposed and adapted to the maternal milieu.Maternal exposure to high-energy dense diets can affect motivated behavior in the offs p ring leading to addiction and impaired sociability.A high-energy dense exposure also increases the pro-inflammatory cytokines profile in plasma and brain and favors microglia activation in the offspring.While still under investigation,prenatal exposure to high-energy dense diets promotes structural abnormalities in selective brain regions regulating motivation and social behavior in the offspring.The current review addresses the role of energy-dense foods programming central and peripheral inflammatory profiles during embryonic development and its effect on motivated behavior in the offspring.We provide preclinical and clinical evidence that supports the contribution of prenatal programming in shaping immune profiles that favor structural and brain circuit disruption leading to aberrant motivated behaviors after birth.We hope this minireview encourages future research on novel insights into the mechanisms underlying maternal programming of motivated behavior by central immune networks.
文摘This paper presents a new method .linear programming method. to calculate the proportion of the cement raw material. Its advanlages are as following : good practicability, convenience for analysis, and being easy for controlling. The mathematical model given in the paper is apt to be realized on computer.
基金This work is supported by the Collaborative education project of QST Innovation Technology Group Co.,Ltd and the Ministry of Education of PRC(NO.201801243022).
文摘UML Class diagram generation from textual requirements is an important task in object-oriented design and programing course.This study proposes a method for automatically generating class diagrams from Chinese textual requirements on the basis of Natural Language Processing(NLP)and mapping rules for sentence pattern matching.First,classes are identified through entity recognition rules and candidate class pruning rules using NLP from requirements.Second,class attributes and relationships between classes are extracted using mapping rules for sentence pattern matching on the basis of NLP.Third,we developed an assistant tool integrated into a precision micro classroom system for automatic generation of class diagram,to effectively assist the teaching of object-oriented design and programing course.Results are evaluated with precision,accuracy and recall from eight requirements of object-oriented design and programing course using truth values created by teachers.Our research should benefit beginners of object-oriented design and programing course,who may be students or software developers.It helps them to create correct domain models represented in the UML class diagram.
基金supported by the National Natural Science Foundation of China(Nos.12372052,12125207)the Young Elite Scientists Sponsorship Program,China(No.2021JCJQ-QT-047)+1 种基金the Natural Science Foundation of Hunan Province,China(No.2023JJ20047)the Technology Innovation Team of Manned Space Engineering,China。
文摘The concept of the spacecraft Reachable Domain(RD)has garnered significant scholarly attention due to its crucial role in space situational awareness and on-orbit service applications.While the existing research has largely focused on single-impulse RD analysis,the challenge of Multi-Impulse RD(MIRD)remains a key area of interest.This study introduces a methodology for the precise calculation of spacecraft MIRD.The reachability constraints specific to MIRD are first formulated through coordinate transformations.Two restricted maneuvering strategies are examined.The derivation of two extremum conditions allows for determining the accessible orientation range and the nodes encompassing the MIRD.Subsequently,four nonlinear programming models are developed to address two types of MIRD by skillfully relaxing constraints using scale factors.Numerical results validate the robustness and effectiveness of the proposed approach,showing substantial agreement with Monte Carlo simulations and confirming its applicability to spacecraft on various elliptical orbits.
基金Supported by the Natural Science Foundation of Gansu Province,No.21JR7RA373 and No.24JRRA295.
文摘BACKGROUND Hepatocellular carcinoma(HCC)is an inflammation-associated tumor with a dismal prognosis.Immunotherapy has become an important treatment strategy for HCC,as immunity is closely related to inflammation in the tumor microenvir-onment.Inflammation regulates the expression of programmed death ligand-1(PD-L1)in the immunosuppressive tumor microenvironment and affects im-munotherapy efficacy.Interleukin-17A(IL-17A)is involved in the remodeling of the tumor microenvironment and plays a protumor or antitumor role in different tumors.We hypothesized that IL-17A participates in tumor progression by affe-cting the level of immune checkpoint molecules in HCC.The upregulation of PD-L1 expression in HCC cells by IL-17A was assessed by reverse transcription PCR,western blotting,and flow cytometry.Mechanistic studies were conducted with gene knockout models and pathway inhibitors.The function of IL-17A in immune evasion was explored through coculture of T cells and HCC cells.The effects of IL-17A on the malignant biological behaviors of HCC cells were evaluated in vitro,and the antitumor effects of an IL-17A inhibitor and its synergistic effects with a PD-L1 inhibitor were studied in vivo.RESULTS IL-17A upregulated PD-L1 expression in HCC cells in a dose-dependent manner,whereas IL-17A receptor knockout or treatment with a small mothers against decapentaplegic 2 inhibitor diminished the PD-L1 expression induced by IL-17A.IL-17A enhanced the survival of HCC cells in the coculture system.IL-17A increased the viability,G2/M ratio,and migration of HCC cells and decreased the apoptotic index.Cyclin D1,VEGF,MMP9,and Bcl-1 expression increased after IL-17A treatment,whereas BAX expression decreased.The combination of IL-17A and PD-L1 inhibitors showed synergistic antitumor efficacy and increased cluster of differentiation 8+T lymphocyte infiltration in an HCC mouse model.CONCLUSION IL-17A upregulates PD-L1 expression via the IL-17A receptor/phosphorylation-small mothers against decapenta-plegic 2 signaling pathway in HCC cells.Blocking IL-17A enhances the therapeutic efficacy of PD-L1 antibodies in HCC in vivo.
文摘In many research disciplines, hypothesis tests are applied to evaluate whether findings are statistically significant or could be explained by chance. The Wilcoxon-Mann-Whitney （WMW） test is among the most popular hypothesis tests in medicine and life science to analyze if two groups of samples are equally distributed. This nonparametric statistical homogeneity test is commonly applied in molecular diagnosis. Generally, the solution of the WMW test takes a high combinatorial effort for large sample cohorts containing a significant number of ties. Hence, P value is frequently approximated by a normal distribution. We developed EDISON-WMW, a new approach to calcu- late the exact permutation of the two-tailed unpaired WMW test without any corrections required and allowing for ties. The method relies on dynamic programing to solve the combinatorial problem of the WMW test efficiently. Beyond a straightforward implementation of the algorithm, we pre- sented different optimization strategies and developed a parallel solution. Using our program, the exact P value for large cohorts containing more than 1000 samples with ties can be calculated within minutes. We demonstrate the performance of this novel approach on randomly-generated data, benchmark it against 13 other commonly-applied approaches and moreover evaluate molec- ular biomarkers for lung carcinoma and chronic obstructive pulmonary disease （COPD）. We foundthat approximated P values were generally higher than the exact solution provided by EDISON- WMW. Importantly, the algorithm can also be applied to high-throughput omics datasets, where hundreds or thousands of features are included. To provide easy access to the multi-threaded version of EDISON-WMW, a web-based solution of our algorithm is freely available at http：// www.ccb.uni-saarland.de/software/wtest/.
基金supported by the National Natural Science Foundation of China(No.62203256)。
文摘Generating dynamically feasible trajectory for fixed-wing Unmanned Aerial Vehicles(UAVs)in dense obstacle environments remains computationally intractable.This paper proposes a Safe Flight Corridor constrained Sequential Convex Programming(SFC-SCP)to improve the computation efficiency and reliability of trajectory generation.SFC-SCP combines the front-end convex polyhedron SFC construction and back-end SCP-based trajectory optimization.A Sparse A^(*)Search(SAS)driven SFC construction method is designed to efficiently generate polyhedron SFC according to the geometric relation among obstacles and collision-free waypoints.Via transforming the nonconvex obstacle-avoidance constraints to linear inequality constraints,SFC can mitigate infeasibility of trajectory planning and reduce computation complexity.Then,SCP casts the nonlinear trajectory optimization subject to SFC into convex programming subproblems to decrease the problem complexity.In addition,a convex optimizer based on interior point method is customized,where the search direction is calculated via successive elimination to further improve efficiency.Simulation experiments on dense obstacle scenarios show that SFC-SCP can generate dynamically feasible safe trajectory rapidly.Comparative studies with state-of-the-art SCP-based methods demonstrate the efficiency and reliability merits of SFC-SCP.Besides,the customized convex optimizer outperforms off-the-shelf optimizers in terms of computation time.
文摘BACKGROUND Gastric cancer(GC)is one of the most common malignancies worldwide,and Helicobacter pylori(HP)infection is a well-established risk factor for its development.Programmed death-ligand 1(PD-L1)expression is a crucial biomarker for predicting the efficacy of immune checkpoint inhibitors in cancer treatment.While HP infection and PD-L1 expression in GC may be linked,the relationship between them remains unclear,in part because there have been conflicting results reported from various studies.AIM To perform a meta-analysis to assess the relationship between HP and PD-L1 expression in patients with GC.METHODS A systematic literature review was conducted using PubMed,Embase,Cochrane Library,and Web of Science databases.Observational studies that examined the association between HP infection and PD-L1 expression in patients with GC were included.Odds ratios and 95%confidence intervals were calculated to estimate the association.Heterogeneity was assessed using Cochrane’s Q test and I²statistic.A random-effects model was used due to significant heterogeneity across studies.RESULTS Fourteen studies involving a total of 3069 patients with GC were included.The pooled analysis showed a significant association between HP infection and increased PD-L1 expression in GC tissues(odd ratio=1.69,95%confidence interval:1.24-2.29,P<0.001,I^(2)=59%).Sensitivity analyses confirmed the robustness of these findings.Subgroup analyses did not show significant variation based on geographic region,sample size,or method of PD-L1 assessment.Publication bias was minimal,as shown by funnel plots and Egger’s regression test.CONCLUSION HP infection is associated with increased PD-L1 expression in GC,suggesting that HP status may influence the response to programmed cell death protein 1/PD-L1 blockade therapy.
基金Supported by Russian Science Foundation,No.23-25-00183.
文摘BACKGROUND Breast cancer(BC)continues to occupy a leading position in terms of morbidity and mortality from malignant neoplasms among the female population.One of the promising markers associated with BC progression is programmed death ligand 1(PD-L1).Previously,we investigated PD-L1 expression in BC via a new antibody against programmed cell death protein 1 ligand 1(PDCD1 LG1)and reported that high PDCD1 LG1 expression in tumor cells is an independent factor for a high risk of regional metastasis in patients with BC.However,the prognostic significance of PDCD1 LG1 expression in BC stromal cells has not been adequately studied.AIM To study the features of PDCD1 LG1 expression in BC stromal cells and its relationship with BC clinicopathological characteristics.METHODS In a prospective single-center observational study,tumor samples from 148 patients with newly diagnosed BC were examined.The tumor sections were immunohistochemically stained with antibodies against PDCD1 LG1.In the tumor samples,the PDCD1 LG1-positive lymphocyte(PDCD1 LG1+LF)score,presence of nuclear PDCD1 LG1 expression in the LFs,PDCD1 LG1 expression in polymorphic cell infiltrates(PDCD1 LG1+polymorphic cell infiltrates[PCIs]),and cells of the fibroblastic stroma and endothelial cells of the tumor microvessels were assessed.Statistical analyses were performed using Statistica 10.0 software.RESULTS A PDCD1 LG1+LF score≥3 was detected more often at stages N0 and N3 than at N1 and N2(P=0.03).Moderate and pronounced PDCD1 LG1+PCIs and the presence of PDCD1 LG1+fibroblastic stroma were associated with negative estrogen receptor status(P=0.0008 and P=0.03,respectively),human epidermal growth factor receptor 2-positive(HER2+)BC(P<0.00001 and P=0.0005),and luminal B HER2+,non-luminal HER2+and triple-negative BC(P<0.00001 and P=0.004).The risk of metastasis to regional lymph nodes(RLNs)depend on lymphovascular invasion(LVI)and the PDCD1 LG1+LF score.In the absence of LVI and a PDCD1 LG1+LF score<3 or≥3,metastases in RLNs were absent in 66.6%and 93.9%of patients with BC,respectively.In the presence of LVI and a PDCD1 LG1+LF score<3 or≥3,metastases in RLNs were detected in 82.6%and 92.7%of patients with BC,respectively.CONCLUSION The results indicated that the combined assessment of the PDCD1 LG1+LF score and LVI can improve the accuracy of predicting the risk of metastasis to RLNs in patients with BC.
基金supported in part by the High-tech ship scientific research project of the Ministry of Industry and Information Technology of the People’s Republic of China,and the National Nature Science Foundation of China(Grant No.71671113)the Science and Technology Department of Shaanxi Province(No.2020GY-219)the Ministry of Education Collaborative Project of Production,Learning and Research(No.201901024016).
文摘Ship outfitting is a key process in shipbuilding.Efficient and high-quality ship outfitting is a top priority for modern shipyards.These activities are conducted at different stations of shipyards.The outfitting plan is one of the crucial issues in shipbuilding.In this paper,production scheduling and material ordering with endogenous uncertainty of the outfitting process are investigated.The uncertain factors in outfitting equipment production are usually decision-related,which leads to difficulties in addressing uncertainties in the outfitting production workshops before production is conducted according to plan.This uncertainty is regarded as endogenous uncertainty and can be treated as non-anticipativity constraints in the model.To address this problem,a stochastic two-stage programming model with endogenous uncertainty is established to optimize the outfitting job scheduling and raw material ordering process.A practical case of the shipyard of China Merchants Heavy Industry Co.,Ltd.is used to evaluate the performance of the proposed method.Satisfactory results are achieved at the lowest expected total cost as the complete kit rate of outfitting equipment is improved and emergency replenishment is reduced.
基金supported by the National Natural Science Foundation of China (Nos. 81972799, 82202834, and 81871449)。
文摘Lung cancer-derived exosomes are a kind of valuable and clinically-predictable biomarkers for lung cancer, but they have the limitations in individual differences when being applied in liquid biopsy. To improve their application value and accuracy in clinical diagnosis, a dual-labelled electrochemical method is herein reported for precise assessment of lung cancer-derived exosomes. To do so, two probes are prepared for the dual labeling of exosome membrane to run DNA assembly reactions: One is modified with cholesterol and can insert into exosome membrane through hydrophobic interaction;another one is linked with programmed death ligand-1(PD-L1) antibody and can bind to exosome surface-expressing PD-L1 via specific immunoreaction. Quantum dots-tagged signal strands are used to collect respective DNA products, and produce stripping signals corresponding to the amounts of total exosome and surfaceexpressing PD-L1, respectively. A wide linear relationship is established for the quantitative determination of lung cancer-derived exosomes in the range from 103to 1010particles/m L, whereas the ratiometric value of the two stripping signals is proven to have a better diagnostic use in screening and staging of lung cancer when being applied to clinical samples. Therefore, our method might provide a new insight into precise diagnosis of lung cancer, and offer sufficient information to refiect the biomarker level and guide the personalized treatment level even at an early stage in clinic.
基金supported by Canada First Research Excellence Fund,Medicine by Design(to CMM)。
文摘Over the last two decades,the dogma that cell fate is immutable has been increasingly challenged,with important implications for regenerative medicine.The brea kth rough discovery that induced pluripotent stem cells could be generated from adult mouse fibroblasts is powerful proof that cell fate can be changed.An exciting extension of the discovery of cell fate impermanence is the direct cellular reprogram ming hypothesis-that terminally differentiated cells can be reprogrammed into other adult cell fates without first passing through a stem cell state.
基金supported by Techpool Bio-Pharma Co.,Ltd.(grant no.AKR-S005).
文摘Objective:To investigate the anti-tumor effects of an E1B55KD-deleted oncolytic adenovirus,H101,in combination with a humanized anti-PD-1(Programmed cell death protein 1)monoclonal antibody,Camrelizumab.Methods:Anti-tumor efficacy of intratumoral injection of H101 or/and intraperitoneal injection of Camrelizumab were evaluated in an immune system humanized NOD Prkdc^(scid) Il2rg^(-/-)mice subcutaneous(S.C.)tumor model,established with human glioblastoma of unknown origin cell line U87-MG,and human bladder cancer cell line T24 and YTS-1.The mechanism by which H101 induced anti-tumor immunity were also investigated.Results:Combining H101 with Camrelizumab demonstrated more potent anti-tumor effects than monotherapy in mouse S.C.tumor model.Increased tumor-infiltrating T cells were observed in the combined treatment group.H101 infection decreased the expression of CD47 in cancer cells,thereby promoting macrophages to phagocytose cancer cells.Following the H101-mediated activation of macrophages,increased levels of cytokines,including TNF,IL-12 and IFN-γwere observed.Moreover,when induced THP-1 cells were co-cultured with H101-treated cancer cells,expression of IFN-γwas increased in T cells.Elimination of IL-12 using an anti-IL-12 antibody abolished IFN-γproduction from T cells.In addition,infection with H101 increased PD-L1 expression in YTS-1 cells.These results suggested that H101 may act synergistically to enhance the therapeutic efficacy of PD-1 blockade in cancer via suppressing CD47 signaling,which may promote macrophages to phagocytose tumor cells and activate CD8^(+)T cells.Conclusion:The combination of H101 with PD-1 blockade exhibits potential as a novel strategy for the treatment of cancer.
基金the financial support from the National Key Research and Development Program of China(No.2023YFB3907001)the National Natural Science Foundation of China(Nos.U2233217,62371029)the UK Engineering and Physical Sciences Research Council(EPSRC),China(Nos.EP/M026981/1,EP/T021063/1 and EP/T024917/)。
文摘Interference significantly impacts the performance of the Global Navigation Satellite Systems(GNSS),highlighting the need for advanced interference localization technology to bolster anti-interference and defense capabilities.The Uniform Circular Array(UCA)enables concurrent estimation of the Direction of Arrival(DOA)in both azimuth and elevation.Given the paramount importance of stability and real-time performance in interference localization,this work proposes an innovative approach to reduce the complexity and increase the robustness of the DOA estimation.The proposed method reduces computational complexity by selecting a reduced number of array elements to reconstruct a non-uniform sparse array from a UCA.To ensure DOA estimation accuracy,minimizing the Cramér-Rao Bound(CRB)is the objective,and the Spatial Correlation Coefficient(SCC)is incorporated as a constraint to mitigate side-lobe.The optimization model is a quadratic fractional model,which is solved by Semi-Definite Relaxation(SDR).When the array has perturbations,the mathematical expressions for CRB and SCC are re-derived to enhance the robustness of the reconstructed array.Simulation and hardware experiments validate the effectiveness of the proposed method in estimating interference DOA,showing high robustness and reductions in hardware and computational costs associated with DOA estimation.
基金Science and Technology Program of Guangzhou,No.202102010077International Science Foundation of Guangzhou Fuda Cancer Hospital,No.Y2020-ZD-03.
文摘BACKGROUND Irreversible electroporation(IRE)is a novel local tumor ablation approach with the potential to activate the host’s immune system.However,this approach is insufficient to prevent cancer progression,and complementary approaches are required for effective immunotherapy.AIM To assess the immunomodulatory effects and mechanism of IRE combined antiprogrammed cell death protein 1(PD-1)treatment in subcutaneous pancreatic cancer models.METHODS C57BL-6 tumor-bearing mice were randomly divided into four groups:Control group;IRE group;anti-PD-1 group;and IRE+anti-PD-1 group.Tumor-infiltrating T,B,and natural killer cell levels and plasma concentrations of T helper type 1 cytokines(interleukin-2,interferon-γ,and tumor necrosis factor-α)were evaluated.Real-time PCR was used to determine the expression of CD8(marker of CD8+T cells)in tumor tissues of the mice of all groups at different points of time.The growth curves of tumors were drawn.RESULTS The results demonstrated that the IRE+anti-PD-1 group exhibited significantly higher percentages of T lymphocyte infiltration,including CD4+and CD8+T cells compared with the control group.Additionally,the IRE+anti-PD-1 group showed increased infiltration of natural killer and B cells,elevated cytokine levels,and higher CD8 mRNA expression.Tumor volume was significantly reduced in the IRE+anti-PD-1 group,indicating a more pronounced therapeutic effect.CONCLUSION The combination of IRE and anti-PD-1 therapy promotes CD8+T cell immunity responses,leading to a more effective reduction in tumor volume and improved therapeutic outcomes,which provides a new direction for ablation and immunotherapy of pancreatic cancer.
基金Strategic Priority Research Program of the Chinese Academy of Sciences,No.XDB0740000National Key Research and Development Program of China,No.2022YFB3904200,No.2022YFF0711601+1 种基金Key Project of Innovation LREIS,No.PI009National Natural Science Foundation of China,No.42471503。
文摘Deep-time Earth research plays a pivotal role in deciphering the rates,patterns,and mechanisms of Earth's evolutionary processes throughout geological history,providing essential scientific foundations for climate prediction,natural resource exploration,and sustainable planetary stewardship.To advance Deep-time Earth research in the era of big data and artificial intelligence,the International Union of Geological Sciences initiated the“Deeptime Digital Earth International Big Science Program”(DDE)in 2019.At the core of this ambitious program lies the development of geoscience knowledge graphs,serving as a transformative knowledge infrastructure that enables the integration,sharing,mining,and analysis of heterogeneous geoscience big data.The DDE knowledge graph initiative has made significant strides in three critical dimensions:(1)establishing a unified knowledge structure across geoscience disciplines that ensures consistent representation of geological entities and their interrelationships through standardized ontologies and semantic frameworks;(2)developing a robust and scalable software infrastructure capable of supporting both expert-driven and machine-assisted knowledge engineering for large-scale graph construction and management;(3)implementing a comprehensive three-tiered architecture encompassing basic,discipline-specific,and application-oriented knowledge graphs,spanning approximately 20 geoscience disciplines.Through its open knowledge framework and international collaborative network,this initiative has fostered multinational research collaborations,establishing a robust foundation for next-generation geoscience research while propelling the discipline toward FAIR(Findable,Accessible,Interoperable,Reusable)data practices in deep-time Earth systems research.
基金supported by National Institute on Aging(NIH-NIA)R21 AG074152(to KMA)National Institute of Allergy and Infectious Diseases(NIAID)grant DP2 AI171150(to KMA)Department of Defense(DoD)grant AZ210089(to KMA)。
文摘The brain's extracellular matrix(ECM),which is comprised of protein and glycosaminoglycan(GAG)scaffolds,constitutes 20%-40% of the human brain and is considered one of the largest influencers on brain cell functioning(Soles et al.,2023).Synthesized by neural and glial cells,the brain's ECM regulates a myriad of homeostatic cellular processes,including neuronal plasticity and firing(Miyata et al.,2012),cation buffering(Moraws ki et al.,2015),and glia-neuron interactions(Anderson et al.,2016).Considering the diversity of functions,dynamic remodeling of the brain's ECM indicates that this understudied medium is an active participant in both normal physiology and neurological diseases.
文摘BACKGROUND Hepatocellular carcinoma(HCC)is the most common form of liver cancer that has limited treatment options and a poor prognosis.Transarterial chemoembolization(TACE)is the first-line treatment for intermediate-stage HCC but can induce tumour hypoxia,thereby promoting angiogenesis.Recent studies suggested that combining TACE with anti-angiogenic therapies and immunotherapy might im-prove efficacy.Lenvatinib,a tyrosine kinase inhibitor,has demonstrated superior outcomes compared to sorafenib,while immune checkpoint inhibitors such as sintilimab show potential when combined with TACE.However,the efficacy and safety of TACE combined with lenvatinib and sintilimab(TACE+SL)compared to TACE with lenvatinib alone(TACE+L)in patients with intermediate-ad-vanced HCC has not yet been investigated.AIM To evaluate the efficacy and safety of TACE+SL therapy in comparison to TACE+L therapy in patients with intermediate-advanced HCC.METHODS A retrospective analysis was performed on patients with intermediate-advanced HCC who received TACE plus lenvatinib with or without sintilimab between September 2019 and September 2022.Baseline characteristics were compared,and propensity score matching was applied.Overall survival(OS),progression-free survival(PFS),and objective response rate(ORR)were evaluated between the two groups,and adverse events were analyzed.RESULTS The study included 57 patients,with 30 in the TACE+SL group and 27 in the TACE+L group.The TACE+SL group demonstrated significantly improved median PFS and OS compared to the TACE+L group(PFS:14.1 months vs 9.6 months,P=0.016;OS:22.4 months vs 14.1 months,P=0.039),along with a higher ORR(70.0%vs 55.6%).After propensity score matching,30 patients were included,with the TACE+SL group again showing longer median PFS and a trend toward improved OS(PFS:14.6 months vs 9.2 months,P=0.012;OS:23.9 months vs 16.3 months,P=0.063),and a higher ORR(73.3%vs 53.3%).No severe adverse events were reported.CONCLUSION TACE+SL demonstrated superior outcomes in terms of OS and PFS,compared to TACE+L.These findings suggest that the addition of sintilimab might enhance the therapeutic response in patients with intermediate-advanced HCC.
基金Supported by Changsha Science and Technology Program,No.kq2022397Natural Science Foundation of Hunan Province(Departmental Joint Fund),No.2023JJ60440+2 种基金Research Program of Health Commission of Hunan Province,No.202303088786Clinical Medical Research Center for Viral Hepatitis of Hunan Province,No.2023SK4009the Scientific Research Program of FuRong Laboratory,No.2023SK2108.
文摘BACKGROUND C-X-C chemokine receptor type 5(CXCR5)^(+)CD8^(+)T cells represent a unique immune subset with dual roles,functioning as cytotoxic cells in persistent viral infections while promoting B cell responses.Despite their importance,the specific role of CXCR5^(+)CD8^(+)T cells in chronic hepatitis B(CHB),particularly during interferon-alpha(IFN-α)treatment,is not fully understood.This study aims to elucidate the relationship between CXCR5^(+)CD8^(+)T cells and sustained serologic response(SR)in patients undergoing 48 weeks of pegylated IFN-α(peg-IFN-α)treatment for CHB.AIM To elucidate the relationship between CXCR5^(+)CD8^(+)T cells and sustained SR in patients undergoing 48 weeks of peg-IFN-αtreatment for CHB.METHODS This study enrolled 60 patients with hepatitis Be antigen(HBeAg)-positive CHB undergoing 48 weeks of peg-IFN-αtreatment.Participants were assessed for eligibility based on criteria such as persistent HBsAg-positive status for at least six months,HBeAb-negative,hepatitis B virus DNA levels exceeding 2×10^(4) copies/mL,and alanine aminotransferase(ALT)levels between 2 and 10 times the upper limit of normal.Blood samples were collected at baseline and at weeks 12,24,48,and a 24-week treatment-free follow-up(week 72)to measure serum interleukin(IL)-21 concentration via ELISA and to analyze CXCR5 and programmed death-ligand 1(PD-L1)expression on CD8^(+)T cells by flow cytometry,CXCR5 is a chemokine receptor that directs immune cells to specific tissues,while PD-L1 is a protein that regulates immune responses by inhibiting T cell activity.RESULTS Patients with CHB exhibited significantly lower levels of circulating CXCR5^(+)CD8^(+)T cells compared to healthy controls(P<0.01).Notably,CXCR5^(+)CD8^(+)T cells were prominently expressed in patients who achieved sustained SR compared to non-SR(NSR).A significant correlation was observed between CXCR5 and PD-L1 expression(r=-0.189,P=0.002).However,there was no significant correlation between serum IL-21 levels and CXCR5+CD8+lymphocytes(r=-0.03,P=0.625)or serum ALT levels(r=0.026,P=0.678).CONCLUSION The enhanced expression of CXCR5^(+)CD8^(+)T cells in patients achieving HBeAg seroconversion during IFN-αtreatment suggests that these cells play a crucial role in antiviral immune responses against hepatitis B.This study highlights the potential of CXCR5^(+)CD8^(+)T cells as immune regulators in CHB,which may inform future therapeutic strategies to optimize antiviral treatments.
基金funded by the National Natural Science Foundation of China(52167013)the Key Program of Natural Science Foundation of Gansu Province(24JRRA225)Natural Science Foundation of Gansu Province(23JRRA891).
文摘In the context of the“dual carbon”goals,to address issues such as high energy consumption,high costs,and low power quality in the rapid development of electrified railways,this study focused on the China Railways High-Speed 5 Electric Multiple Unit and proposed a mathematical model and capacity optimization method for an onboard energy storage system using lithium batteries and supercapacitors as storage media.Firstly,considering the electrical characteristics,weight,and volume of the storage media,a mathematical model of the energy storage system was established.Secondly,to tackle problems related to energy consumption and power quality,an energy management strategy was proposed that comprehensively considers peak shaving and valley filling and power quality by controlling the charge/discharge thresholds of the storage system.Thecapacity optimization adopted a bilevel programming model,with the series/parallel number of storage modules as variables,considering constraints imposed by the Direct Current to Direct Current converter,train load,and space.An improved Particle Swarm Optimization algorithm and linear programming solver were used to solve specific cases.The results show that the proposed onboard energy storage system can effectively achieve energy savings,reduce consumption,and improve power qualitywhile meeting the load and space limitations of the train.
