To date, it remains poorly understood whether astrocytes can be easily reprogrammed into neurons. Mashl and Brn2 have been previously shown to cooperate to reprogram fibroblasts into neurons. In this study, we examine...To date, it remains poorly understood whether astrocytes can be easily reprogrammed into neurons. Mashl and Brn2 have been previously shown to cooperate to reprogram fibroblasts into neurons. In this study, we examined astrocytes from 2-month-old Sprague-Dawley rats, and found that Brn2 was expressed, but Mashl was not detectable. Thus, we hypothesized that Mashl alone could be used to reprogram astrocytes into neurons. We transfected a recombinant MSCV-MASH1 plasmid into astrocytes for 72 hours, and saw that all cells expressed Mashl. One week later, we observed the changes in morphology of astrocytes, which showed typical neuro- nal characteristics. Moreover, β-tubulin expression levels were significantly higher in astrocytes expressing Mashl than in control cells. These results indicate that Mashl alone can reprogram astrocytes into neurons.展开更多
At the first sight it seems that advanced operation research is not used enough in continuous production systems as comparison with mass production, batch production and job shop systems, but really in a comprehensive...At the first sight it seems that advanced operation research is not used enough in continuous production systems as comparison with mass production, batch production and job shop systems, but really in a comprehensive evaluation the advanced operation research techniques can be used in continuous production systems in developing countries very widely, because of initial inadequate plant layout, stage by stage development of production lines, the purchase of second hand machineries from various countries, plurality of customers. A case of production system planning is proposed for a chemical company in which the above mentioned conditions are almost presented. The goals and constraints in this issue are as follows： （1） Minimizing deviation of customer＇s requirements. （2） Maximizing the profit. （3） Minimizing the frequencies of changes in formula production. （4） Minimizing the inventory of final products. （5） Balancing the production sections with regard to rate in production. （6） Limitation in inventory of raw material. The present situation is in such a way that various techniques such as goal programming, linear programming and dynamic programming can be used. But dynamic production programming issues are divided into two categories, at first one with limitation in production capacity and another with unlimited production capacity. For the first category, a systematic and acceptable solution has not been presented yet. Therefore an innovative method is used to convert the dynamic situation to a zero- one model. At last this issue is changed to a goal programming model with non-linear limitations with the use of GRG algorithm and that＇s how it is solved.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 Chemotherapy,targeted therapy,and immunotherapy have all been shown to achieve some efficacy in treating intrahepatic cholangiocarcinoma(ICC).How-ever,these systemic treatments have not provided optimal res...BACKGROUND Chemotherapy,targeted therapy,and immunotherapy have all been shown to achieve some efficacy in treating intrahepatic cholangiocarcinoma(ICC).How-ever,these systemic treatments have not provided optimal results for some patients.Therefore,the combination of transarterial chemoembolization(TACE)and hepatic artery infusion chemotherapy or other local interventional therapy methods is being considered for the treatment of liver tumors.AIM To evaluate the efficacy and safety of combining chemotherapy,targeted therapy,and immunotherapy,with or without TACE,in patients with ICC.METHODS We recruited 83 patients with unresectable ICC from July 2021 to December 2023 at the Affiliated Hospital of Xuzhou Medical University.Forty-one patients received TACE combined with chemotherapy,tyrosine kinase inhibitors,and pro-grammed death 1(PD-1)/programmed cell death ligand 1(PD-L1)inhibitors(ex-perimental group),whereas 42 patients were treated with chemotherapy,tyrosine kinase inhibitors,and PD-1/PD-L1 inhibitors(control group).Short-term efficacy was assessed using the modified response evaluation criterion,and the objective response rate,disease control rate,progression-free survival,and incidence of adverse events were compared between groups.RESULTS The objective response rate in the experimental group was greater than that in the control group(39.0%vs 19.0%,P<0.05).The disease control rate in the experimental group was significantly greater than that in the control group(75.6%vs 52.4%,P<0.05).The median progression-free survival times were 14.3 months in the experimental group and 12.7 months in the control group(P<0.05).All 41 patients in the experimental group developed postembol-ization syndrome.Among the symptoms,fever and pain were significantly more common in the experimental group than in the control group(85.4%vs 11.9%,P<0.001 and 58.5%vs 9.5%,P<0.001).No grade 4 or 5 treatment-related adverse events were observed in either group.CONCLUSION In patients with unresectable ICC,TACE combined with chemotherapy,tyrosine kinase inhibitors,and PD-1/PD-L1 inhibitors has good efficacy and high safety,indicating potential benefits for these patients.展开更多
Cancer is a global health problem and one of the leading causes of mortality.Immune checkpoint inhibitors have revolutionized the field of oncology,emerging as a powerful treatment strategy.A key pathway that has garn...Cancer is a global health problem and one of the leading causes of mortality.Immune checkpoint inhibitors have revolutionized the field of oncology,emerging as a powerful treatment strategy.A key pathway that has garnered considerable attention is programmed cell death-1(PD-1)/programmed cell death-ligand 1(PD-L1).The interaction between PD-L1 expressed on tumor cells and PD-1 reduces the innate immune response and thus compromises the capability of the body’s immune system.Furthermore,it controls the phenotype and functionality of innate and adaptive immune components.A range of monoclonal antibodies,including avelumab,atezolizumab,camrelizumab,dostarlimab,durvalumab,sinitilimab,toripalimab,and zimberelimab,have been developed for targeting the interaction between PD-1 and PD-L1.These agents can induce a broad spectrum of autoimmune-like complications that may affect any organ system.Recent studies have focused on the effect of various natural compounds that inhibit immune checkpoints.This could contribute to the existing arsenal of anticancer drugs.Several bioactive natural agents have been shown to affect the PD-1/PD-L1 signaling axis,promoting tumor cell apoptosis,influencing cell proliferation,and eventually leading to tumor cell death and inhibiting cancer progression.However,there is a substantial knowledge gap regarding the role of different natural compounds targeting PD-1 in the context of cancer.Hence,this review aims to provide a common connection between PD-1/PD-L1 blockade and the anticancer effects of distinct natural molecules.Moreover,the primary focus will be on the underlying mechanism of action as well as the clinical efficacy of bioactive molecules.Current challenges along with the scope of future research directions targeting PD-1/PD-L1 interactions through natural substances are also discussed.展开更多
BACKGROUND Anti-programmed death therapy has thrust immunotherapy into the spotlight.However,such therapy has a modest response in hepatocellular carcinoma(HCC).Epigenetic immunomodulation is a suggestive combinatoria...BACKGROUND Anti-programmed death therapy has thrust immunotherapy into the spotlight.However,such therapy has a modest response in hepatocellular carcinoma(HCC).Epigenetic immunomodulation is a suggestive combinatorial therapy with immune checkpoint blockade.Non-coding ribonucleic acid(ncRNA)driven regulation is a major mechanism of epigenetic modulation.Given the wide range of ncRNAs that co-opt in programmed cell-death protein 1(PD-1)/programmed death ligand 1(PD-L1)regulation,and based on the literature,we hypothesized that miR-155-5p,miR-194-5p and long non-coding RNAs(lncRNAs)X-inactive specific transcript(XIST)and MALAT-1 are involved in a regulatory upstream pathway for PD-1/PD-L1.Recently,nutraceutical therapeutics in cancers have received increasing attention.Thus,it is interesting to study the impact of oleuropein on the respective study key players.AIM To explore potential upstream regulatory ncRNAs for the immune checkpoint PD-1/PD-L1.METHODS Bioinformatics tools including microrna.org and lnCeDB software were adopted to detect targeting of miR-155-5p,miR-194-5p and lncRNAs XIST and MALAT-1 to PD-L1 mRNA,respectively.In addition,Diana tool was used to predict targeting of both aforementioned miRNAs to lncRNAs XIST and MALAT-1.HCC and normal tissue samples were collected for scanning of PD-L1,XIST and MALAT-1 expression.To study the interaction among miR-155-5p,miR-194-5p,lncRNAs XIST and MALAT-1,as well as PD-L1 mRNA,a series of transfections of the Huh-7 cell line was carried out.RESULTS Bioinformatics software predicted that miR-155-5p and miR-194-5p can target PDL1,MALAT-1 and XIST.MALAT-1 and XIST were predicted to target PD-L1 mRNA.PD-L1 and XIST were significantly upregulated in 23 HCC biopsies compared to healthy controls;however,MALAT-1 was barely detected.MiR-194 induced expression elevated the expression of PD-L1,XIST and MALAT-1.However,overexpression of miR-155-5p induced the upregulation of PD-L1 and XIST,while it had a negative impact on MALAT-1 expression.Knockdown of XIST did have an impact on PD-L1 expression;however,following knockdown of the negative regulator of X-inactive specific transcript(TSIX),PD-L1 expression was elevated,and abolished MALAT-1 activity.Upon co-transfection of miR-194-5p with siMALAT-1,PD-L1 expression was elevated.Co-transfection of miR-194-5p with siXIST did not have an impact on PD-L1 expression.Upon co-transfection of miR-194 with siTSIX,PD-L1 expression was upregulated.Interestingly,the same PD-L1 expression pattern was observed following miR-155-5p cotransfections.Oleuropein treatment of Huh-7 cells reduced the expression profile of PD-L1,XIST,and miR-155-5p,upregulated the expression of miR-194-5p and had no significant impact on the MALAT-1 expression profile.CONCLUSION This study reported a novel finding revealing that opposing acting miRNAs in HCC,have the same impact on PD-1/PD-L1 immune checkpoint by sharing a common signaling pathway.展开更多
Even though immune checkpoint inhibitors(ICIs)are effective on multiple cancer types,there are still many non-responding patients.A possible factor put forward that may influence the efficacy of ICIs is the gut microb...Even though immune checkpoint inhibitors(ICIs)are effective on multiple cancer types,there are still many non-responding patients.A possible factor put forward that may influence the efficacy of ICIs is the gut microbiota.Additionally,faecal microbiota transplantation may enhance efficacy of ICIs.Nevertheless,the data available in this field are insufficient,and relevant scientific work has just commenced.As a result,the current work reviewed the latest research on the association of gut microbiota with ICI treatments based on anti-programmed cell death protein 1 antibody and anti-cytotoxic T-lymphocyte-associated protein 4 antibody and explored the therapeutic potential of faecal microbiota transplantation in combination with ICI therapy in the future.展开更多
BACKGROUND Nucleus accumbens-1(NAC-1)is highly expressed in a variety of tumors,including colon cancer,and is closely associated with tumor recurrence,metastasis,and invasion.AIM To determine whether and how NAC-1 aff...BACKGROUND Nucleus accumbens-1(NAC-1)is highly expressed in a variety of tumors,including colon cancer,and is closely associated with tumor recurrence,metastasis,and invasion.AIM To determine whether and how NAC-1 affects antitumor immunity in colon cancer.METHODS NAC-1-siRNA was transfected into RKO colon cancer cells to knock down NAC expression;tumor cells with or without knockdown of NAC-1 were treated with CD8+T cells to test their cytocidal effect.The level of the immune checkpoint programmed death receptor-1 ligand(PD-L1)in colon cancer cells with or without knockdown of NAC-1 was analyzed using Quantitative real-time polymerase chain reaction and Western blotting.A double luciferase reporter assay was used to examine the effects of NAC-1 on the transcription of PD-L1.Mice bearing MC-38-OVA colon cancer cells expressing NAC-shRNA or controlshRNA were treated with OT-I mouse CD8+T cells to determine the tumor response to immunotherapy.Immune cells in the tumor tissues were analyzed using flow cytometry.NAC-1,PD-L1 and CD8+T cells in colon cancer specimens from patients were examined using immunohistochemistry staining.RESULTS Knockdown of NAC-1 expression in colon cancer cells significantly enhanced the cytocidal effect of CD8+T cells in cell culture experiments.The sensitizing effect of NAC-1 knockdown on the antitumor action of cytotoxic CD8+T cells was recapitulated in a colon cancer xenograft animal model.Furthermore,knockdown of NAC-1 in colon cancer cells decreased the expression of PD-L1 at both the mRNA and protein levels,and this effect could be rescued by transfection of an RNAi-resistant NAC-1 expression plasmid.In a reporter gene assay,transient expression of NAC-1 in colon cancer cells increased the promoter activity of PD-L1,indicating that NAC-1 regulates PD-L1 expression at the transcriptional level.In addition,depletion of tumoral NAC-1 increased the number of CD8+T cells but decreased the number of suppressive myeloid-derived suppressor cells and regulatory T cells.CONCLUSION Tumor expression of NAC-1 is a negative determinant of immunotherapy.展开更多
In recent years,a number of targeted therapeutic agents have achieved success in phase III trials in patients with advanced hepatocellular carcinoma(HCC),including sorafenib,lenvatinib,and regorafenib.Immunotherapy is...In recent years,a number of targeted therapeutic agents have achieved success in phase III trials in patients with advanced hepatocellular carcinoma(HCC),including sorafenib,lenvatinib,and regorafenib.Immunotherapy is considered to be an effective treatment for advanced HCC.Immune checkpoint inhibitors targeting programmed cell death 1(PD-1)/programmed cell death ligand 1(PDL1)are important antitumor immunotherapy agents that represent breakthroughs in the treatment of advanced HCC.However,treating advanced HCC is still a great challenge,and the need for new treatments remains urgent.This review briefly summarizes the research progress in the use of PD-1/PD-L1 inhibitors combined with targeted therapy for treating HCC.展开更多
Lung cancer is the leading cause of cancer-related mortality worldwide. Despite great progress in the development of target agents, most people who do not harbor a mutation do not benefit from these agents. Immunother...Lung cancer is the leading cause of cancer-related mortality worldwide. Despite great progress in the development of target agents, most people who do not harbor a mutation do not benefit from these agents. Immunotherapy, which stimulates the body's immune system to improve the anti-tumor immunity effect, is a new therapeutic method for non-small cell lung cancer(NSCLC). Programmed cell death 1(PD-1) and its ligand(PD-L1) belong to the CD28/B7 immunoglobulin super-family and are co-stimulatory molecules that show negative regulation effects. Combined with its ligand, PD-1 can modulate the tumor microenvironment, enabling tumor cells to escape host immune surveillance and elimination and play a key role in the clinical significance of NSCLC. An increasing number of clinical trials have suggested that immune checkpoint inhibitors, including anti-PD-1 and anti-PD-L1 monoclonal antibodies, are beneficial and safe for NSCLC. Here, we review the brief history of PD-L1 as a biomarker, mechanism of action, and critical role of PD-1/PD-L1 in the treatment of NSCLC as well as the current research status and future directions.展开更多
This paper introduces some new generalizations of the concept of （~, p）-invexity for non- differentiable locally Lipschitz functions using the tools of Clarke subdifferential. These functions are used to derive the ...This paper introduces some new generalizations of the concept of （~, p）-invexity for non- differentiable locally Lipschitz functions using the tools of Clarke subdifferential. These functions are used to derive the necessary and sufficient optimality conditions for a class of nonsmooth semi-infinite minmax programming problems, where set of restrictions are indexed in a compact set. Utilizing the sufficient optimality conditions, the authors formulate three types of dual models and establish weak and strong duality results. The results of the paper extend and unify naturally some earlier results from the literature.展开更多
This is a brief report on our recent work in network piecewise linear programming (NPLP),and it consists of two parts. In the first park, we describe a generator for NPLP problems which is derived from the classical n...This is a brief report on our recent work in network piecewise linear programming (NPLP),and it consists of two parts. In the first park, we describe a generator for NPLP problems which is derived from the classical network linear program generator NETGEN. The generator creates networks of the same topological structures as NETGEN, but each arc is associated with a convex piecewise linear cost. The purpose of this program is to provide a set of standard test problems which can be used to compare the performance of various algorithms for NPLP. In the second part,we introduce a network simplex method that directly solves a network piecewise linear program without reformulating it as a network linear program of higher dimension. Forty benchmark NPLP problems are solved by this method and a reformulation method. The computational results are in favor of the direct method and show that solving an NPLP problem is not much harder than solving a network linear program of the same dimension.展开更多
Glioblastoma(GBM),the most aggressive and lethal primary brain tumor in adults,continues to resist conventional therapeutic approaches,withmedian survival remaining dismally low.Immune checkpoint inhibitors(ICIs),whic...Glioblastoma(GBM),the most aggressive and lethal primary brain tumor in adults,continues to resist conventional therapeutic approaches,withmedian survival remaining dismally low.Immune checkpoint inhibitors(ICIs),which have revolutionized the treatment of several solid tumors,have shown limited efficacy inGBMowing to the highly immunosuppressive and heterogeneousmicroenvironment of the tumor.The unique immune landscape of the central nervous system(CNS),characterized by low immunogenicity,restricted T-cell infiltration,and an abundance of regulatory and myeloid-derived suppressor cells,poses considerable barriers to effective immune reactivation.This review provides a comprehensive synthesis of the mechanistic barriers undermining ICI efficacy in GBM,including the blood-brain barrier,low tumor mutational burden,adaptive immune resistance,and iatrogenic immunosuppression.It also explores emerging predictive and prognostic biomarkers,such as programmed death-ligand 1(PD-L1)expression,immune gene signatures,tumor-infiltrating lymphocyte profiles,and circulating markers in cerebrospinal fluid and plasma,which hold promise for guiding patient selection and therapeutic monitoring.Importantly,recent breakthroughs in combinatorial immunotherapy strategies are highlighted,including the integration of ICIs with radiotherapy,anti-angiogenic agents,oncolytic viruses,personalized neoantigen vaccines,and tumor microenvironment reprogramming approaches.Innovative delivery platforms,such as nanoparticles,focused ultrasound,and convection-enhanced delivery,are also discussed for their potential to improve drug bioavailability and local immune activation in the CNS.This review hypothesizes that the therapeutic efficacy of ICIs in GBM can be considerably enhanced by disrupting immune exclusion and reversing immunosuppression through integrated,multimodal strategies guided by dynamic biomarker profiling and spatially resolved immunemapping.This hypothesisdriven approach aims to bridge translational gaps and inform next-generation clinical trial designs that may unlock the potential of immunotherapy for GBM.展开更多
Immunotherapy has been widely used in cancer treatment in recent years and functions by stimulating the immune system to kill tumor cells.Radiation therapy(RT)uses radiation to induce DNA damage and kill tumor cells.H...Immunotherapy has been widely used in cancer treatment in recent years and functions by stimulating the immune system to kill tumor cells.Radiation therapy(RT)uses radiation to induce DNA damage and kill tumor cells.However,this activates the body’s immune system,promoting the release of tumor-related antigens from inactive dendritic cells,which stimulates the recurrence and metastasis of tumors in immune system tissues.The combination of RT and immunotherapy has been increasingly evaluated in recent years,with studies confirming the synergistic effect of the two antitumor therapies.Particularly,the combination of RT by dose adjustment with different immunotherapies has positive implications on antitumor immunity as well as disease prognosis compared with respective monotherapies.This review summarizes the current research status,progress,and prospects of RT combined with immunotherapy in cancer treatment.It additionally discusses the prevalent concerns regarding the dose,time window,and toxicity of this combination therapy.展开更多
Background:This study aimed to investigate programmed death-ligand 1 tumor proportion score in predicting the safety and efficacy of PD-1/PD-L1 antibody-based therapy in treating patients with advanced non-small cell ...Background:This study aimed to investigate programmed death-ligand 1 tumor proportion score in predicting the safety and efficacy of PD-1/PD-L1 antibody-based therapy in treating patients with advanced non-small cell lung cancer(NSCLC)in a real-world setting.Methods:This retrospective,multicenter,observational study enrolled adult patients who received PD-1/PD-L1 antibody-based therapy in China and met the following criteria:(1)had pathologically confirmed,unresectable stage III–IV NSCLC;(2)had a baseline PD-L1 tumor proportion score(TPS);and(3)had confirmed efficacy evaluation results after PD-1/PD-L1 treatment.Logistic regression,Kaplan–Meier analysis,and Cox regression were used to assess the progression-free survival(PFS),overall survival(OS),and immune-related adverse events(irAEs)as appropriate.Results:A total of 409 patients,65.0%(n=266)with a positive PD-L1 TPS(≥1%)and 32.8%(n=134)with PD-L1 TPS≥50%,were included in this study.Cox regression confirmed that patients with a PD-L1 TPS≥1%had significantly improved PFS(hazard ratio[HR]0.747,95%confidence interval[CI]0.573–0.975,P=0.032).A total of 160(39.1%)patients experienced 206 irAEs,and 27(6.6%)patients experienced 31 grade 3–5 irAEs.The organs most frequently associated with irAEs were the skin(52/409,12.7%),thyroid(40/409,9.8%),and lung(34/409,8.3%).Multivariate logistic regression revealed that a PD-L1 TPS≥1%(odds ratio[OR]1.713,95%CI 1.054–2.784,P=0.030)was an independent risk factor for irAEs.Other risk factors for irAEs included pretreatment absolute lymphocyte count>2.5×10^(9)/L(OR 3.772,95%CI 1.377–10.329,P=0.010)and pretreatment absolute eosinophil count>0.2×109/L(OR 2.006,95%CI 1.219–3.302,P=0.006).Moreover,patients who developed irAEs demonstrated improved PFS(13.7 months vs.8.4 months,P<0.001)and OS(28.0 months vs.18.0 months,P=0.007)compared with patients without irAEs.Conclusions:A positive PD-L1 TPS(≥1%)was associated with improved PFS and an increased risk of irAEs in a real-world setting.The onset of irAEs was associated with improved PFS and OS in patients with advanced NSCLC receiving PD-1/PD-L1-based therapy.展开更多
Cholangiocarcinoma(CCA)is a fatal malignancy with steadily increasing incidence and poor prognosis.Since most CCA cases are diagnosed at an advanced stage,systemic therapies,including chemotherapy,radiotherapy,targete...Cholangiocarcinoma(CCA)is a fatal malignancy with steadily increasing incidence and poor prognosis.Since most CCA cases are diagnosed at an advanced stage,systemic therapies,including chemotherapy,radiotherapy,targeted therapy,and immunotherapy,play a crucial role in the management of unresectable CCA.The recent advances in targeted therapies and immunotherapies brought more options in the clinical management of unresectable CCA.This review depicts the advances of targeted therapies and immunotherapies for unresectable CCA,summarizes crucial clinical trials,and describes the efficacy and safety of different drugs,which may help further develop precision and individualization in the clinical treatment of unresectable CCA.展开更多
Rational design of nanomedicine can efficiently improve the therapeutic activity of anticancer drugs;however,the current design strategies are to increase the concentration of drugs within targeted cells,which is not ...Rational design of nanomedicine can efficiently improve the therapeutic activity of anticancer drugs;however,the current design strategies are to increase the concentration of drugs within targeted cells,which is not applicable to extracellular-targeted drugs.Herein,we report a nanoparticular aggregation strategy via magnetic actuation and host-vip interaction for extracellular drug delivery.Theβ-cyclodextrin(βCD)-decorated magnetic nanoparticles(βCDMNPs)were first administrated and infiltrated into tumor tissue under the magnetic actuation,and then generated mild hyperthermia under alternating magnetic field(AMF)to improve the infiltration of another adamantane(Ad)-decorated NPs(Ad-NPs)into the tumor tissue.Subsequently,theβCD-MNP and Ad-NP would form micro-sized aggregation via the host-vip interaction,which could significantly enhance the enrichment and retention of extracellular-targeted drugs and also minimize their cellular uptake.This nanoparticular aggregation strategy remarkably improved the therapeutic activity of batimastat and PD-1/PD-L1 inhibitor 1(BMS-1),both of which were extracellular-targeted drug.Such nanoparticular aggregation strategy represents a rational avenue for extracellular drug delivery.展开更多
In recent years,immune checkpoint inhibitors(ICIs)have made breakthroughs in the field of lung cancer and have become a focal point for research.Programmed death-1(PD-1)or programmed death-ligand 1(PD-L1)inhibitor mon...In recent years,immune checkpoint inhibitors(ICIs)have made breakthroughs in the field of lung cancer and have become a focal point for research.Programmed death-1(PD-1)or programmed death-ligand 1(PD-L1)inhibitor monotherapy was the first to break the treatment pattern for non-small cell lung cancer(NSCLC).However,owing to the limited benefit of ICI monotherapy at the population level and its hyper-progressive phenomenon,it may not meet clinical needs.To expand the beneficial range of immunotherapy and improve its efficacy,several research strategies have adopted the use of combination immunotherapy.At present,multiple strategies,such as PD-1/PD-L1 inhibitors combined with chemotherapy,anti-angiogenic therapy,cytotoxic T-lymphocyte-associated protein 4 inhibitors,and radiotherapy,as well as combined treatment with new target drugs,have been evaluated for clinical practice.To further understand the current status and future development direction of immunotherapy,herein,we review the recent progress of ICI combination therapies for NSCLC.展开更多
Bemisia tabaci(Gennadius) biotype B,called a "superbug",is one of the most harmful biotypes of this species complex worldwide.In this report,the invasive mechanism and management of B.tabaci biotype B,based ...Bemisia tabaci(Gennadius) biotype B,called a "superbug",is one of the most harmful biotypes of this species complex worldwide.In this report,the invasive mechanism and management of B.tabaci biotype B,based on our 5-year studies,are presented.Six B.tabaci biotypes,B,Q,ZHJ1,ZHJ2,ZHJ3 and FJ1,have been identified in China.Biotype B dominates the other biotypes in many regions of the country.Genetic diversity in biotype B might be induced by host plant,geographical conditions,and/or insecticidal application.The activities of CarE(carboxylesterase) and GSTs(glutathione-S-transferase) in biotype B reared on cucumber and squash were greater than on other host plants,which might have increased its resistance to insecticides.The higher activities of detoxification enzymes in biotype B might be induced by the secondary metabolites in host plants.Higher adaptive ability of biotype B adults to adverse conditions might be linked to the expression of heat shock protein genes.The indigenous B.tabaci biotypes were displaced by the biotype B within 225 d.The asymmetric mating interactions and mutualism between biotype B and begomoviruses via its host plants speed up widespread invasion and displacement of other biotypes.B.tabaci biotype B displaced Trialeurodes vaporariorum(Westwood) after 4-7 generations under glasshouse conditions.Greater adaptive ability of the biotype B to adverse conditions and its rapid population increase might be the reasons of its successful displacement of T.vaporariorum.Greater ability of the biotype B to switch to different host plants may enrich its host plants,which might enable it to better compete with T.vaporariorum.Native predatory natural enemies possess greater ability to suppress B.tabaci under field conditions.The kairomones in the 3rd and 4th instars of biotype B may provide an important stimulus in host searching and location by its parasitoids.The present results provide useful information in explaining the mechanisms of genetic diversity,evolution and molecular eco-adaptation of biotype B.Furthermore,it provides a base for sustainable management of B.tabaci using biological and ecological measures.展开更多
Immunotherapy has dramatically altered the treatment of non-small cell lung cancer.Currently,the emergence of combination strategies in immunotherapy has brightened the prospects of improved clinical outcomes and mana...Immunotherapy has dramatically altered the treatment of non-small cell lung cancer.Currently,the emergence of combination strategies in immunotherapy has brightened the prospects of improved clinical outcomes and manageable safety profiles in the first/second-line settings.However,sub-optimal response rates are still observed in several clinical trials.Hence,alternative combination models and candidate selection strategies need to be explored.Herein,we have critically reviewed and commented on the published data from several clinical trials,including combined immunotherapy and chemotherapy,anti-angiogenic agents,epidermal growth factor receptor/anaplastic lymphoma kinase tyrosine kinase inhibitors,radiotherapy,and other immune checkpoint inhibitors.展开更多
基金supported by the National Basic Research Program of China(973 Program),No.2010CB530400the Key Project of National Natural Science Foundation of China,No.30930111
文摘To date, it remains poorly understood whether astrocytes can be easily reprogrammed into neurons. Mashl and Brn2 have been previously shown to cooperate to reprogram fibroblasts into neurons. In this study, we examined astrocytes from 2-month-old Sprague-Dawley rats, and found that Brn2 was expressed, but Mashl was not detectable. Thus, we hypothesized that Mashl alone could be used to reprogram astrocytes into neurons. We transfected a recombinant MSCV-MASH1 plasmid into astrocytes for 72 hours, and saw that all cells expressed Mashl. One week later, we observed the changes in morphology of astrocytes, which showed typical neuro- nal characteristics. Moreover, β-tubulin expression levels were significantly higher in astrocytes expressing Mashl than in control cells. These results indicate that Mashl alone can reprogram astrocytes into neurons.
文摘At the first sight it seems that advanced operation research is not used enough in continuous production systems as comparison with mass production, batch production and job shop systems, but really in a comprehensive evaluation the advanced operation research techniques can be used in continuous production systems in developing countries very widely, because of initial inadequate plant layout, stage by stage development of production lines, the purchase of second hand machineries from various countries, plurality of customers. A case of production system planning is proposed for a chemical company in which the above mentioned conditions are almost presented. The goals and constraints in this issue are as follows： （1） Minimizing deviation of customer＇s requirements. （2） Maximizing the profit. （3） Minimizing the frequencies of changes in formula production. （4） Minimizing the inventory of final products. （5） Balancing the production sections with regard to rate in production. （6） Limitation in inventory of raw material. The present situation is in such a way that various techniques such as goal programming, linear programming and dynamic programming can be used. But dynamic production programming issues are divided into two categories, at first one with limitation in production capacity and another with unlimited production capacity. For the first category, a systematic and acceptable solution has not been presented yet. Therefore an innovative method is used to convert the dynamic situation to a zero- one model. At last this issue is changed to a goal programming model with non-linear limitations with the use of GRG algorithm and that＇s how it is solved.
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.
文摘BACKGROUND Chemotherapy,targeted therapy,and immunotherapy have all been shown to achieve some efficacy in treating intrahepatic cholangiocarcinoma(ICC).How-ever,these systemic treatments have not provided optimal results for some patients.Therefore,the combination of transarterial chemoembolization(TACE)and hepatic artery infusion chemotherapy or other local interventional therapy methods is being considered for the treatment of liver tumors.AIM To evaluate the efficacy and safety of combining chemotherapy,targeted therapy,and immunotherapy,with or without TACE,in patients with ICC.METHODS We recruited 83 patients with unresectable ICC from July 2021 to December 2023 at the Affiliated Hospital of Xuzhou Medical University.Forty-one patients received TACE combined with chemotherapy,tyrosine kinase inhibitors,and pro-grammed death 1(PD-1)/programmed cell death ligand 1(PD-L1)inhibitors(ex-perimental group),whereas 42 patients were treated with chemotherapy,tyrosine kinase inhibitors,and PD-1/PD-L1 inhibitors(control group).Short-term efficacy was assessed using the modified response evaluation criterion,and the objective response rate,disease control rate,progression-free survival,and incidence of adverse events were compared between groups.RESULTS The objective response rate in the experimental group was greater than that in the control group(39.0%vs 19.0%,P<0.05).The disease control rate in the experimental group was significantly greater than that in the control group(75.6%vs 52.4%,P<0.05).The median progression-free survival times were 14.3 months in the experimental group and 12.7 months in the control group(P<0.05).All 41 patients in the experimental group developed postembol-ization syndrome.Among the symptoms,fever and pain were significantly more common in the experimental group than in the control group(85.4%vs 11.9%,P<0.001 and 58.5%vs 9.5%,P<0.001).No grade 4 or 5 treatment-related adverse events were observed in either group.CONCLUSION In patients with unresectable ICC,TACE combined with chemotherapy,tyrosine kinase inhibitors,and PD-1/PD-L1 inhibitors has good efficacy and high safety,indicating potential benefits for these patients.
基金support provided by the Department of Science and Technology,Science and Engineering Research Board(DST-SERB),the Anusandhan National Research Foundation(ANRF),State University Research Excellence(SERB-SURE),Ministry of Science and Technology,Govt.of India(SUR/2022/001353).
文摘Cancer is a global health problem and one of the leading causes of mortality.Immune checkpoint inhibitors have revolutionized the field of oncology,emerging as a powerful treatment strategy.A key pathway that has garnered considerable attention is programmed cell death-1(PD-1)/programmed cell death-ligand 1(PD-L1).The interaction between PD-L1 expressed on tumor cells and PD-1 reduces the innate immune response and thus compromises the capability of the body’s immune system.Furthermore,it controls the phenotype and functionality of innate and adaptive immune components.A range of monoclonal antibodies,including avelumab,atezolizumab,camrelizumab,dostarlimab,durvalumab,sinitilimab,toripalimab,and zimberelimab,have been developed for targeting the interaction between PD-1 and PD-L1.These agents can induce a broad spectrum of autoimmune-like complications that may affect any organ system.Recent studies have focused on the effect of various natural compounds that inhibit immune checkpoints.This could contribute to the existing arsenal of anticancer drugs.Several bioactive natural agents have been shown to affect the PD-1/PD-L1 signaling axis,promoting tumor cell apoptosis,influencing cell proliferation,and eventually leading to tumor cell death and inhibiting cancer progression.However,there is a substantial knowledge gap regarding the role of different natural compounds targeting PD-1 in the context of cancer.Hence,this review aims to provide a common connection between PD-1/PD-L1 blockade and the anticancer effects of distinct natural molecules.Moreover,the primary focus will be on the underlying mechanism of action as well as the clinical efficacy of bioactive molecules.Current challenges along with the scope of future research directions targeting PD-1/PD-L1 interactions through natural substances are also discussed.
文摘BACKGROUND Anti-programmed death therapy has thrust immunotherapy into the spotlight.However,such therapy has a modest response in hepatocellular carcinoma(HCC).Epigenetic immunomodulation is a suggestive combinatorial therapy with immune checkpoint blockade.Non-coding ribonucleic acid(ncRNA)driven regulation is a major mechanism of epigenetic modulation.Given the wide range of ncRNAs that co-opt in programmed cell-death protein 1(PD-1)/programmed death ligand 1(PD-L1)regulation,and based on the literature,we hypothesized that miR-155-5p,miR-194-5p and long non-coding RNAs(lncRNAs)X-inactive specific transcript(XIST)and MALAT-1 are involved in a regulatory upstream pathway for PD-1/PD-L1.Recently,nutraceutical therapeutics in cancers have received increasing attention.Thus,it is interesting to study the impact of oleuropein on the respective study key players.AIM To explore potential upstream regulatory ncRNAs for the immune checkpoint PD-1/PD-L1.METHODS Bioinformatics tools including microrna.org and lnCeDB software were adopted to detect targeting of miR-155-5p,miR-194-5p and lncRNAs XIST and MALAT-1 to PD-L1 mRNA,respectively.In addition,Diana tool was used to predict targeting of both aforementioned miRNAs to lncRNAs XIST and MALAT-1.HCC and normal tissue samples were collected for scanning of PD-L1,XIST and MALAT-1 expression.To study the interaction among miR-155-5p,miR-194-5p,lncRNAs XIST and MALAT-1,as well as PD-L1 mRNA,a series of transfections of the Huh-7 cell line was carried out.RESULTS Bioinformatics software predicted that miR-155-5p and miR-194-5p can target PDL1,MALAT-1 and XIST.MALAT-1 and XIST were predicted to target PD-L1 mRNA.PD-L1 and XIST were significantly upregulated in 23 HCC biopsies compared to healthy controls;however,MALAT-1 was barely detected.MiR-194 induced expression elevated the expression of PD-L1,XIST and MALAT-1.However,overexpression of miR-155-5p induced the upregulation of PD-L1 and XIST,while it had a negative impact on MALAT-1 expression.Knockdown of XIST did have an impact on PD-L1 expression;however,following knockdown of the negative regulator of X-inactive specific transcript(TSIX),PD-L1 expression was elevated,and abolished MALAT-1 activity.Upon co-transfection of miR-194-5p with siMALAT-1,PD-L1 expression was elevated.Co-transfection of miR-194-5p with siXIST did not have an impact on PD-L1 expression.Upon co-transfection of miR-194 with siTSIX,PD-L1 expression was upregulated.Interestingly,the same PD-L1 expression pattern was observed following miR-155-5p cotransfections.Oleuropein treatment of Huh-7 cells reduced the expression profile of PD-L1,XIST,and miR-155-5p,upregulated the expression of miR-194-5p and had no significant impact on the MALAT-1 expression profile.CONCLUSION This study reported a novel finding revealing that opposing acting miRNAs in HCC,have the same impact on PD-1/PD-L1 immune checkpoint by sharing a common signaling pathway.
基金Science Research Start-up Fund for Doctor of Shanxi Medical University,No.XD1807Science Research Start-up Fund for Doctor of Shanxi Province,No.SD1807+1 种基金Scientific and Technological Innovation Programs of Higher Education Institutions in Shanxi,No.2019L0425Shanxi Province Science Foundation for Youths,No.201901D211314.
文摘Even though immune checkpoint inhibitors(ICIs)are effective on multiple cancer types,there are still many non-responding patients.A possible factor put forward that may influence the efficacy of ICIs is the gut microbiota.Additionally,faecal microbiota transplantation may enhance efficacy of ICIs.Nevertheless,the data available in this field are insufficient,and relevant scientific work has just commenced.As a result,the current work reviewed the latest research on the association of gut microbiota with ICI treatments based on anti-programmed cell death protein 1 antibody and anti-cytotoxic T-lymphocyte-associated protein 4 antibody and explored the therapeutic potential of faecal microbiota transplantation in combination with ICI therapy in the future.
基金the Changsha Municipal Natural Science Foundation,No.kq2014258.
文摘BACKGROUND Nucleus accumbens-1(NAC-1)is highly expressed in a variety of tumors,including colon cancer,and is closely associated with tumor recurrence,metastasis,and invasion.AIM To determine whether and how NAC-1 affects antitumor immunity in colon cancer.METHODS NAC-1-siRNA was transfected into RKO colon cancer cells to knock down NAC expression;tumor cells with or without knockdown of NAC-1 were treated with CD8+T cells to test their cytocidal effect.The level of the immune checkpoint programmed death receptor-1 ligand(PD-L1)in colon cancer cells with or without knockdown of NAC-1 was analyzed using Quantitative real-time polymerase chain reaction and Western blotting.A double luciferase reporter assay was used to examine the effects of NAC-1 on the transcription of PD-L1.Mice bearing MC-38-OVA colon cancer cells expressing NAC-shRNA or controlshRNA were treated with OT-I mouse CD8+T cells to determine the tumor response to immunotherapy.Immune cells in the tumor tissues were analyzed using flow cytometry.NAC-1,PD-L1 and CD8+T cells in colon cancer specimens from patients were examined using immunohistochemistry staining.RESULTS Knockdown of NAC-1 expression in colon cancer cells significantly enhanced the cytocidal effect of CD8+T cells in cell culture experiments.The sensitizing effect of NAC-1 knockdown on the antitumor action of cytotoxic CD8+T cells was recapitulated in a colon cancer xenograft animal model.Furthermore,knockdown of NAC-1 in colon cancer cells decreased the expression of PD-L1 at both the mRNA and protein levels,and this effect could be rescued by transfection of an RNAi-resistant NAC-1 expression plasmid.In a reporter gene assay,transient expression of NAC-1 in colon cancer cells increased the promoter activity of PD-L1,indicating that NAC-1 regulates PD-L1 expression at the transcriptional level.In addition,depletion of tumoral NAC-1 increased the number of CD8+T cells but decreased the number of suppressive myeloid-derived suppressor cells and regulatory T cells.CONCLUSION Tumor expression of NAC-1 is a negative determinant of immunotherapy.
基金Supported by CAMS Innovation Fund for Medical Science(CIFMS),No.CAMS-2016-I2M-3-025Beijing Hope Run Special Fund of Cancer Foundation of China,No.LC2020L05.
文摘In recent years,a number of targeted therapeutic agents have achieved success in phase III trials in patients with advanced hepatocellular carcinoma(HCC),including sorafenib,lenvatinib,and regorafenib.Immunotherapy is considered to be an effective treatment for advanced HCC.Immune checkpoint inhibitors targeting programmed cell death 1(PD-1)/programmed cell death ligand 1(PDL1)are important antitumor immunotherapy agents that represent breakthroughs in the treatment of advanced HCC.However,treating advanced HCC is still a great challenge,and the need for new treatments remains urgent.This review briefly summarizes the research progress in the use of PD-1/PD-L1 inhibitors combined with targeted therapy for treating HCC.
文摘Lung cancer is the leading cause of cancer-related mortality worldwide. Despite great progress in the development of target agents, most people who do not harbor a mutation do not benefit from these agents. Immunotherapy, which stimulates the body's immune system to improve the anti-tumor immunity effect, is a new therapeutic method for non-small cell lung cancer(NSCLC). Programmed cell death 1(PD-1) and its ligand(PD-L1) belong to the CD28/B7 immunoglobulin super-family and are co-stimulatory molecules that show negative regulation effects. Combined with its ligand, PD-1 can modulate the tumor microenvironment, enabling tumor cells to escape host immune surveillance and elimination and play a key role in the clinical significance of NSCLC. An increasing number of clinical trials have suggested that immune checkpoint inhibitors, including anti-PD-1 and anti-PD-L1 monoclonal antibodies, are beneficial and safe for NSCLC. Here, we review the brief history of PD-L1 as a biomarker, mechanism of action, and critical role of PD-1/PD-L1 in the treatment of NSCLC as well as the current research status and future directions.
基金supported by the National Board of Higher Mathematics(NBHM)Department of Atomic Energy,India,under Grant No.2/40(12)/2014/R&D-II/10054
文摘This paper introduces some new generalizations of the concept of （~, p）-invexity for non- differentiable locally Lipschitz functions using the tools of Clarke subdifferential. These functions are used to derive the necessary and sufficient optimality conditions for a class of nonsmooth semi-infinite minmax programming problems, where set of restrictions are indexed in a compact set. Utilizing the sufficient optimality conditions, the authors formulate three types of dual models and establish weak and strong duality results. The results of the paper extend and unify naturally some earlier results from the literature.
文摘This is a brief report on our recent work in network piecewise linear programming (NPLP),and it consists of two parts. In the first park, we describe a generator for NPLP problems which is derived from the classical network linear program generator NETGEN. The generator creates networks of the same topological structures as NETGEN, but each arc is associated with a convex piecewise linear cost. The purpose of this program is to provide a set of standard test problems which can be used to compare the performance of various algorithms for NPLP. In the second part,we introduce a network simplex method that directly solves a network piecewise linear program without reformulating it as a network linear program of higher dimension. Forty benchmark NPLP problems are solved by this method and a reformulation method. The computational results are in favor of the direct method and show that solving an NPLP problem is not much harder than solving a network linear program of the same dimension.
文摘Glioblastoma(GBM),the most aggressive and lethal primary brain tumor in adults,continues to resist conventional therapeutic approaches,withmedian survival remaining dismally low.Immune checkpoint inhibitors(ICIs),which have revolutionized the treatment of several solid tumors,have shown limited efficacy inGBMowing to the highly immunosuppressive and heterogeneousmicroenvironment of the tumor.The unique immune landscape of the central nervous system(CNS),characterized by low immunogenicity,restricted T-cell infiltration,and an abundance of regulatory and myeloid-derived suppressor cells,poses considerable barriers to effective immune reactivation.This review provides a comprehensive synthesis of the mechanistic barriers undermining ICI efficacy in GBM,including the blood-brain barrier,low tumor mutational burden,adaptive immune resistance,and iatrogenic immunosuppression.It also explores emerging predictive and prognostic biomarkers,such as programmed death-ligand 1(PD-L1)expression,immune gene signatures,tumor-infiltrating lymphocyte profiles,and circulating markers in cerebrospinal fluid and plasma,which hold promise for guiding patient selection and therapeutic monitoring.Importantly,recent breakthroughs in combinatorial immunotherapy strategies are highlighted,including the integration of ICIs with radiotherapy,anti-angiogenic agents,oncolytic viruses,personalized neoantigen vaccines,and tumor microenvironment reprogramming approaches.Innovative delivery platforms,such as nanoparticles,focused ultrasound,and convection-enhanced delivery,are also discussed for their potential to improve drug bioavailability and local immune activation in the CNS.This review hypothesizes that the therapeutic efficacy of ICIs in GBM can be considerably enhanced by disrupting immune exclusion and reversing immunosuppression through integrated,multimodal strategies guided by dynamic biomarker profiling and spatially resolved immunemapping.This hypothesisdriven approach aims to bridge translational gaps and inform next-generation clinical trial designs that may unlock the potential of immunotherapy for GBM.
基金supported by grants from the Science and Technology Cooperation and Exchange Program of Shanxi Provincial Science and Technology Department(No.202204041101042)the Innovation Talent Team of Shanxi Province(No.202204051001031)the Free Exploration Basic Research of Shanxi Provincial Science and Technology Department(No.YDZJSX20231A067).
文摘Immunotherapy has been widely used in cancer treatment in recent years and functions by stimulating the immune system to kill tumor cells.Radiation therapy(RT)uses radiation to induce DNA damage and kill tumor cells.However,this activates the body’s immune system,promoting the release of tumor-related antigens from inactive dendritic cells,which stimulates the recurrence and metastasis of tumors in immune system tissues.The combination of RT and immunotherapy has been increasingly evaluated in recent years,with studies confirming the synergistic effect of the two antitumor therapies.Particularly,the combination of RT by dose adjustment with different immunotherapies has positive implications on antitumor immunity as well as disease prognosis compared with respective monotherapies.This review summarizes the current research status,progress,and prospects of RT combined with immunotherapy in cancer treatment.It additionally discusses the prevalent concerns regarding the dose,time window,and toxicity of this combination therapy.
基金This study is funded by a grant from the National High Level Hospital Clinical Research Funding to Wei Zhong,grant number 2022-PUMCH-C-054.
文摘Background:This study aimed to investigate programmed death-ligand 1 tumor proportion score in predicting the safety and efficacy of PD-1/PD-L1 antibody-based therapy in treating patients with advanced non-small cell lung cancer(NSCLC)in a real-world setting.Methods:This retrospective,multicenter,observational study enrolled adult patients who received PD-1/PD-L1 antibody-based therapy in China and met the following criteria:(1)had pathologically confirmed,unresectable stage III–IV NSCLC;(2)had a baseline PD-L1 tumor proportion score(TPS);and(3)had confirmed efficacy evaluation results after PD-1/PD-L1 treatment.Logistic regression,Kaplan–Meier analysis,and Cox regression were used to assess the progression-free survival(PFS),overall survival(OS),and immune-related adverse events(irAEs)as appropriate.Results:A total of 409 patients,65.0%(n=266)with a positive PD-L1 TPS(≥1%)and 32.8%(n=134)with PD-L1 TPS≥50%,were included in this study.Cox regression confirmed that patients with a PD-L1 TPS≥1%had significantly improved PFS(hazard ratio[HR]0.747,95%confidence interval[CI]0.573–0.975,P=0.032).A total of 160(39.1%)patients experienced 206 irAEs,and 27(6.6%)patients experienced 31 grade 3–5 irAEs.The organs most frequently associated with irAEs were the skin(52/409,12.7%),thyroid(40/409,9.8%),and lung(34/409,8.3%).Multivariate logistic regression revealed that a PD-L1 TPS≥1%(odds ratio[OR]1.713,95%CI 1.054–2.784,P=0.030)was an independent risk factor for irAEs.Other risk factors for irAEs included pretreatment absolute lymphocyte count>2.5×10^(9)/L(OR 3.772,95%CI 1.377–10.329,P=0.010)and pretreatment absolute eosinophil count>0.2×109/L(OR 2.006,95%CI 1.219–3.302,P=0.006).Moreover,patients who developed irAEs demonstrated improved PFS(13.7 months vs.8.4 months,P<0.001)and OS(28.0 months vs.18.0 months,P=0.007)compared with patients without irAEs.Conclusions:A positive PD-L1 TPS(≥1%)was associated with improved PFS and an increased risk of irAEs in a real-world setting.The onset of irAEs was associated with improved PFS and OS in patients with advanced NSCLC receiving PD-1/PD-L1-based therapy.
基金funded by grants from the National Natural Science Foundation of China(Nos.82171824,82272906,82103087,82002625,and 82373133)the Scientific and Technological Innovation Project of Science and Technology Commission of Shanghai Municipality(No.21JC1404300)+7 种基金the Innovation Group Project of Shanghai Municipal Health Commission(No.2019CXJQ03)the Shanghai Municipal Commission of Health and Family Planning(No.2018ZHYL0223)Shanghai Municipal Education Commission-Gao Feng Clinical Medicine Grant Support(No.20161312)Shanghai Key Clinical Specialty(Oncology),Shanghai Leading Talents Project,Clinical Research Plan of SHDC(No.SHDC2020CR1035B)Shanghai Sailing Program(No.20YF1446400)the National Key R&D Program of China(No.2019YFC1315900)Project from CSCO Clinical Oncology Research Foundation(No.Y-2019AZZD-0513)the Innovative Research Team of High-Level Local Universities in Shanghai(No.SHSMU-ZDCX20210802).
文摘Cholangiocarcinoma(CCA)is a fatal malignancy with steadily increasing incidence and poor prognosis.Since most CCA cases are diagnosed at an advanced stage,systemic therapies,including chemotherapy,radiotherapy,targeted therapy,and immunotherapy,play a crucial role in the management of unresectable CCA.The recent advances in targeted therapies and immunotherapies brought more options in the clinical management of unresectable CCA.This review depicts the advances of targeted therapies and immunotherapies for unresectable CCA,summarizes crucial clinical trials,and describes the efficacy and safety of different drugs,which may help further develop precision and individualization in the clinical treatment of unresectable CCA.
基金supported by the National Natural Science Foundation of China(Nos.52425304,U22A20156,and 52173121)the Guangzhou Science and Technology Planning Project(No.2024A03J1181)the GuangDong Basic and Applied Basic Research Foundation(Nos.2024A1515011130 and 2024B1515020106).
文摘Rational design of nanomedicine can efficiently improve the therapeutic activity of anticancer drugs;however,the current design strategies are to increase the concentration of drugs within targeted cells,which is not applicable to extracellular-targeted drugs.Herein,we report a nanoparticular aggregation strategy via magnetic actuation and host-vip interaction for extracellular drug delivery.Theβ-cyclodextrin(βCD)-decorated magnetic nanoparticles(βCDMNPs)were first administrated and infiltrated into tumor tissue under the magnetic actuation,and then generated mild hyperthermia under alternating magnetic field(AMF)to improve the infiltration of another adamantane(Ad)-decorated NPs(Ad-NPs)into the tumor tissue.Subsequently,theβCD-MNP and Ad-NP would form micro-sized aggregation via the host-vip interaction,which could significantly enhance the enrichment and retention of extracellular-targeted drugs and also minimize their cellular uptake.This nanoparticular aggregation strategy remarkably improved the therapeutic activity of batimastat and PD-1/PD-L1 inhibitor 1(BMS-1),both of which were extracellular-targeted drug.Such nanoparticular aggregation strategy represents a rational avenue for extracellular drug delivery.
基金the Special Project for Significant New Drug Research and Development in the Major National Science and Technology Projects of China(No.2020ZX09201-024).
文摘In recent years,immune checkpoint inhibitors(ICIs)have made breakthroughs in the field of lung cancer and have become a focal point for research.Programmed death-1(PD-1)or programmed death-ligand 1(PD-L1)inhibitor monotherapy was the first to break the treatment pattern for non-small cell lung cancer(NSCLC).However,owing to the limited benefit of ICI monotherapy at the population level and its hyper-progressive phenomenon,it may not meet clinical needs.To expand the beneficial range of immunotherapy and improve its efficacy,several research strategies have adopted the use of combination immunotherapy.At present,multiple strategies,such as PD-1/PD-L1 inhibitors combined with chemotherapy,anti-angiogenic therapy,cytotoxic T-lymphocyte-associated protein 4 inhibitors,and radiotherapy,as well as combined treatment with new target drugs,have been evaluated for clinical practice.To further understand the current status and future development direction of immunotherapy,herein,we review the recent progress of ICI combination therapies for NSCLC.
基金Supported by the National Basic Research and Development Program of China(973 Program)of China(Grant No.2009CB119200)
文摘Bemisia tabaci(Gennadius) biotype B,called a "superbug",is one of the most harmful biotypes of this species complex worldwide.In this report,the invasive mechanism and management of B.tabaci biotype B,based on our 5-year studies,are presented.Six B.tabaci biotypes,B,Q,ZHJ1,ZHJ2,ZHJ3 and FJ1,have been identified in China.Biotype B dominates the other biotypes in many regions of the country.Genetic diversity in biotype B might be induced by host plant,geographical conditions,and/or insecticidal application.The activities of CarE(carboxylesterase) and GSTs(glutathione-S-transferase) in biotype B reared on cucumber and squash were greater than on other host plants,which might have increased its resistance to insecticides.The higher activities of detoxification enzymes in biotype B might be induced by the secondary metabolites in host plants.Higher adaptive ability of biotype B adults to adverse conditions might be linked to the expression of heat shock protein genes.The indigenous B.tabaci biotypes were displaced by the biotype B within 225 d.The asymmetric mating interactions and mutualism between biotype B and begomoviruses via its host plants speed up widespread invasion and displacement of other biotypes.B.tabaci biotype B displaced Trialeurodes vaporariorum(Westwood) after 4-7 generations under glasshouse conditions.Greater adaptive ability of the biotype B to adverse conditions and its rapid population increase might be the reasons of its successful displacement of T.vaporariorum.Greater ability of the biotype B to switch to different host plants may enrich its host plants,which might enable it to better compete with T.vaporariorum.Native predatory natural enemies possess greater ability to suppress B.tabaci under field conditions.The kairomones in the 3rd and 4th instars of biotype B may provide an important stimulus in host searching and location by its parasitoids.The present results provide useful information in explaining the mechanisms of genetic diversity,evolution and molecular eco-adaptation of biotype B.Furthermore,it provides a base for sustainable management of B.tabaci using biological and ecological measures.
基金the National Natural Science Foundation of China(No.81802301 and 81772500)the Social Development Foundation of China(No.BE2019719).
文摘Immunotherapy has dramatically altered the treatment of non-small cell lung cancer.Currently,the emergence of combination strategies in immunotherapy has brightened the prospects of improved clinical outcomes and manageable safety profiles in the first/second-line settings.However,sub-optimal response rates are still observed in several clinical trials.Hence,alternative combination models and candidate selection strategies need to be explored.Herein,we have critically reviewed and commented on the published data from several clinical trials,including combined immunotherapy and chemotherapy,anti-angiogenic agents,epidermal growth factor receptor/anaplastic lymphoma kinase tyrosine kinase inhibitors,radiotherapy,and other immune checkpoint inhibitors.
