Cancer has nowadays become one of the leading causes of death worldwide.Conventional anticancer approaches are associated with different limitations.Therefore,innovative methodologies are being investigated,and severa...Cancer has nowadays become one of the leading causes of death worldwide.Conventional anticancer approaches are associated with different limitations.Therefore,innovative methodologies are being investigated,and several researchers propose the use of remotely activated nanoparticles to trigger cancer cell death.The idea is to conjugate two different components,i.e.,an external physical input and nanoparticles.Both are given in a harmless dose that once combined together act synergistically to therapeutically treat the cell or tissue of interest,thus also limiting the negative outcomes for the surrounding tissues.Tuning both the properties of the nanomaterial and the involved triggering stimulus,it is possible furthermore to achieve not only a therapeutic effect,but also a powerful platform for imaging at the same time,obtaining a nano-theranostic application.In the present review,we highlight the role of nanoparticles as therapeutic or theranostic tools,thus excluding the cases where a molecular drug is activated.We thus present many examples where the highly cytotoxic power only derives from the active interaction between different physical inputs and nanoparticles.We perform a special focus on mechanical waves responding nanoparticles,in which remotely activated nanoparticles directly become therapeutic agents without the need of the administration of chemotherapeutics or sonosensitizing drugs.展开更多
DNAzyme-based gene therapy faces some challenges including cell penetration,activity limitation,and co-delivery functions.Self-assembled DNA nanomedicine has attracted widespread attention due to its many advantages.I...DNAzyme-based gene therapy faces some challenges including cell penetration,activity limitation,and co-delivery functions.Self-assembled DNA nanomedicine has attracted widespread attention due to its many advantages.It is urgent to develop a universal DNA degradation strategy for precise programmable drug release.Herein,we reported a self-catabolic DNAzyme nanospheres(SCNS),which could simultaneously achieve cell penetration,activity enhancement,and co-delivery functions.The SCNS were assembled through Y-DNA stepwise hybridization with each other,which were then loaded with aptamer(Apt),doxorubicin(Dox),and zinc oxide nanoparticles(ZnO NPs).The acid-triggered dissociation of ZnO NPs leads to the generation of Zn^(2+)ions cofactors for immediately self-catabolic DNAzyme nanospheres.After the disassembly of the SCNS,three types of anticancer treatments would be activated,which include Zn^(2+)involved reactive oxygen species(ROS),Dox-induced chemotherapy,and DNAzyme-based gene therapy.The experimental results show that the nanoplatform(Apt-SCNS-Dox-ZnO)has a good tumor-killing effect and minimal side effects.As a smart self-driven drug delivery nanoplatform,it is anticipated to displace extraordinary potential in biomedicine and bioengineering.展开更多
The discovery of novel antitumor agents derived from natural plants is a principal objective of anticancer drug research.Frankincense,a widely recognized natural antitumor medicine,has undergone a systematic review en...The discovery of novel antitumor agents derived from natural plants is a principal objective of anticancer drug research.Frankincense,a widely recognized natural antitumor medicine,has undergone a systematic review encompassing its species,chemical constituents,and diverse pharmacological activities and mechanisms.The different species of frankincense include Boswellia serrata,Somali frankincense,Boswellia frereana,and Boswellia arabica.Various frankincense extracts and compounds exhibit antitumor,anti-inflammatory,and hepatoprotective properties and antioxidation,memory enhancement,and immunological regulation capabilities.They also have comprehensive effects on regulating flora.Frankincense and its principal chemical constituents have demonstrated promising chemoprophylactic and therapeutic abilities against tumors.This review provides a systematic summary of the mechanism of action underlying the antitumor effects of frankincense and its major constituents,thus laying the foundations for developing effective tumor-combating targets.展开更多
Current antitumor monotherapy has many limitations,highlighting the need for novel synergistic anticancer strategies.Ferroptosis is an iron-dependent form of nonapoptotic cell death that plays a pivotal regulatory rol...Current antitumor monotherapy has many limitations,highlighting the need for novel synergistic anticancer strategies.Ferroptosis is an iron-dependent form of nonapoptotic cell death that plays a pivotal regulatory role in tumorigenesis and treatment.Photodynamic therapy(PDT)causes irreversible chemical damage to target lesions and is widely used in antitumor therapy.However,PDT’s effectiveness is usually hindered by several obstacles,such as hypoxia,excess glutathione(GSH),and tumor resistance.Ferroptosis improves the anticancer efficacy of PDT by increasing oxygen and reactive oxygen species(ROS)or reducing GSH levels,and PDT also enhances ferroptosis induction due to the ROS effect in the tumor microenvironment(TME).Strategies based on nanoparticles(NPs)can subtly exploit the potential synergy of ferroptosis and PDT.This review explores recent advances and current challenges in the landscape of the underlyingmechanisms regulating ferroptosis and PDT,as well as nano delivery system-mediated synergistic anticancer activity.These include polymers,biomimetic materials,metal organic frameworks(MOFs),inorganics,and carrier-free NPs.Finally,we highlight future perspectives of this novel emerging paradigm in targeted cancer therapies.展开更多
There are several limitations to the application of nanoparticles in the treatment of cancer,including their low drug loading,poor colloidal stability,insufficient tumor penetration,and uncontrolled release of the dru...There are several limitations to the application of nanoparticles in the treatment of cancer,including their low drug loading,poor colloidal stability,insufficient tumor penetration,and uncontrolled release of the drug.Herein,gelatin/laponite(LP)/doxorubicin(GLD)nanoparticles are developed by crosslinking LP with gelatin for doxorubicin delivery.GLD shows high doxorubicin encapsulation efficacy(99%)and strong colloidal stability,as seen from the unchanged size over the past 21 days and reduced protein absorption by 48-fold compared with unmodified laponite/doxorubicin nanoparticles.When gelatin from 115 nm GLD reaches the tumor site,matrix metallopeptidase-2(MMP-2)from the tumor environment breaks it down to release smaller 40 nm LP nanoparticles for effective tumor cell endocytosis.As demonstrated by superior penetration in both in vitro three-dimensional(3D)tumor spheroids(138-fold increase compared to the free drug)and in vivo tumor models.The intracellular low pH and MMP-2 further cause doxorubicin release after endocytosis by tumor cells,leading to a higher inhibitory potential against cancer cells.The improved anticancer effectiveness and strong in vivo biocompatibility of GLD have been confirmed using a mouse tumor-bearing model.MMP-2/pH sequentially triggered anticancer drug delivery is made possible by the logical design of tumor-penetrating GLD,offering a useful method for anticancer therapy.展开更多
Necroptosis,a genetically programmed form of necrotic cell death,serves as an important pathway in human diseases.As a critical cell-killing mechanism,necroptosis is associated with cancer progression,metastasis,and i...Necroptosis,a genetically programmed form of necrotic cell death,serves as an important pathway in human diseases.As a critical cell-killing mechanism,necroptosis is associated with cancer progression,metastasis,and immunosurveillance.Targeting necroptosis pathway by small molecule modulators is emerging as an effective approach in cancer therapy,which has the advantage to bypass the apoptosis-resistance and maintain antitumor immunity.Therefore,a better understanding of the mechanism of necroptosis and necroptosis modulators is necessary to develop novel strategies for cancer therapy.This review will summarize recent progress of the mechanisms and detecting methods of necroptosis.In particular,the relationship between necroptosis and cancer therapy and medicinal chemistry of necroptosis modulators will be focused on.展开更多
Objective： To gain insight into the mechanism by which sex-determining region of Y chromosome （SRY）-related high-mobility-group box 2 （SOX2） involved in carcinogenesis and cancer stem cells （CSCs）. Data Sources...Objective： To gain insight into the mechanism by which sex-determining region of Y chromosome （SRY）-related high-mobility-group box 2 （SOX2） involved in carcinogenesis and cancer stem cells （CSCs）. Data Sources： The data used in this review were mainly published in English from 2000 to present obtained from PubMed. The search terms were ＂SOX2,＂ ＂cancer,＂ ＂tumor＂ or ＂CSCs.＂ Study Selection： Articles studying the mitochondria-related pathologic mechanism and treatment of glaucoma were selected and reviewed. Results： SOX2, a transcription factor that is the key in maintaining pluripotent properties of stem cells, is a member of SRV-related high-mobility group domain proteins. SOX2 participates in many biological processes, such as modulation of cell proliferation, regulation of cell death signaling, cell apoptosis, and most importantly, tumor formation and development. Although SOX2 has been implicated in the biology of various tumors and CSCs, the findings are highly controversial, and information regarding the underlying mechanism remains limited. Moreover, the mechanism by which SOX2 involved in carcinogenesis and tumor progression is rather unclear yet. Conclusions： Here, we review the important biological functions of SOX2 in different tumors and CSCs, and the function of SOX2 signaling in the pathobiology ofneoplasia, such as Wnt/β-catenin signaling pathway, Hippo signaling pathway, Survivin signaling pathway, P13K/Akt signaling pathway, and so on. Targeting towards SOX2 may be an effective therapeutic strategy for cancer therapy.展开更多
Hepatocellular carcinoma(HCC)is the third leading cause of cancer death globally,with 15%of cases arising on a background of non-alcoholic fatty liver disease(NAFLD).NAFLD is a heterogenous condition ranging from fatt...Hepatocellular carcinoma(HCC)is the third leading cause of cancer death globally,with 15%of cases arising on a background of non-alcoholic fatty liver disease(NAFLD).NAFLD is a heterogenous condition ranging from fatty liver to cirrhosis and is itself a growing global problem,with estimated worldwide prevalence of 50%in 2040.Pathophysiology of NAFLD-HCC is not well understood,there are no dedicated screening programs,and there have been no clinical studies of anticancer treatments in this population specifically.However,the NAFLD-HCC population appears different than other aetiologies-patients tend to be older,diagnosed at more advanced stages,have more comorbidities,and overall worse prognosis.Understanding of best treatment options for this group of patients is an urgent unmet clinical need.This narrative review discusses NAFLD-HCC pathophysiology and systemic treatment,and offers suggestions for future directions in this therapy area.展开更多
Epithelial-mesenchymal transition(EMT) has been linked with aggressive tumor biology and therapy resistance. It plays central role not only in the generation of cancer stem cells(CSCs) but also direct them across the ...Epithelial-mesenchymal transition(EMT) has been linked with aggressive tumor biology and therapy resistance. It plays central role not only in the generation of cancer stem cells(CSCs) but also direct them across the multiple organ systems to promote tumor recurrence and metastasis. CSCs are reported to express stem cell genes as well as specific cell surfacemarkers and allow aberrant differentiation of progenies.It facilitates cancer cells to leave primary tumor, acquire migratory characteristics, grow into new environment and develop radio-chemo-resistance. Based on the current information, present review discusses and summarizes the recent advancements on the molecular mechanisms that derive epithelial plasticity and its major role in generating a subset of tumor cells with stemness properties and pathophysiological spread of tumor. This paper further highlights the critical need to examine the regulation of EMT and CSC pathways in identifying the novel probable therapeutic targets.These improved therapeutic strategies based on the co-administration of inhibitors of EMT, CSCs as well as differentiated tumor cells may provide improved antineoplastic response with no tumor relapse.展开更多
Pre-mRNA splicing is an essential step in the process of gene expression in eukaryotes and consists of the removal ofintrons and the linking of exons to generate mature mRNAs. This is a highly regulated mechanism that...Pre-mRNA splicing is an essential step in the process of gene expression in eukaryotes and consists of the removal ofintrons and the linking of exons to generate mature mRNAs. This is a highly regulated mechanism that allows the alternative usage of exons, the retention ofintronic sequences and the generation of exonic sequences of variable length. Most human genes undergo splicing events, and disruptions of this process have been associated with a variety of diseases, including cancer. Hepatocellular carcinoma (HCC) is a molecularly heterogeneous type of tumor that usually develops in a cirrhotic liver. Alterations in pre-mRNA splicing of some genes have been observed in liver cancer, and although still scarce, the available data suggest that splicing defects may have a role in hepatocarcinogenesis. Here we briefly review the general mechanisms that regulatepre-mRNA splicing, and discuss some examples that illustrate how this process is impaired in liver tumorigenesis, and may contribute to HCC development. We believe that a more thorough examination of pre-mRNA splicing is still needed to accurately draw the molecular portrait of liver cancer. This will surely contribute to a better understanding of the disease and to the development of new effective therapies.展开更多
G protein coupled receptors(GPCRs)have emerged as the most potential target for a number of drug discovery programs ranging from control of blood pressure,diabetes,cure for genetic diseases to treatment of cancer.A pa...G protein coupled receptors(GPCRs)have emerged as the most potential target for a number of drug discovery programs ranging from control of blood pressure,diabetes,cure for genetic diseases to treatment of cancer.A panel of different ligands including hormones,peptides,ions and small molecules is responsible for activation of these receptors.Molecular genetics has identified key GPCRs,whose mutations or altered expressions are linked with tumorgenicity.In this review,we discussed recent advances regarding the involvement of GPCRs in the development of cancers and approaches to manipulating the mechanism behind GPCRs involved tumor growth and metastasis to treat different types of human cancer.This review provides an insight into the current scenario of GPCR-targeted therapy,progress to date and the challenges in the development of anticancer drugs.展开更多
Applying the fluorescent carbon dots as smart materials in anticancer therapy is of great interest.However,carbon dots for multimodal synergistic anticancer therapy,especially for the triple modality,is rarely reporte...Applying the fluorescent carbon dots as smart materials in anticancer therapy is of great interest.However,carbon dots for multimodal synergistic anticancer therapy,especially for the triple modality,is rarely reported.Herein,we successfully synthesized OCDs by citric acid and(1R,2S)-2-amino-1,2-diphenylethan-1-ol,which show aggregation-induced emission property and two-photon fluorescence imaging.Meanwhile,OCDs are ideal photosensitizers for photothermal therapy under 808 nm and TypeⅠphotodynamic therapy with white light.Hydroxyl radicals,generated by TypeⅠphotodynamic therapy based on OCDs can transform protumoral M2 macrophages into antitumoral M1 macrophages,which exhibited immunotherapy ability.The synergism trimodal of OCDs results in potent anticancer efficacy,showing great potential in cancer therapy.展开更多
In 2003, a 61-year old highly respected director of the Surgery Department of Dongfang Hospital Affiliated to Beijing University of Chinese Medicine was diagnosed as advanced lung cancer, moderately differentiated ade...In 2003, a 61-year old highly respected director of the Surgery Department of Dongfang Hospital Affiliated to Beijing University of Chinese Medicine was diagnosed as advanced lung cancer, moderately differentiated adenocarcinoma, coverinqmore than two thirds of the thoracic aorta, multiple mediastinal nodal metastases, pleural effusion ＂Only 3 months could be expected＂, a cruel fact came out after deliberation of many seasoned medical specialists. In the whole career of this surgery professor, he used the lancet as his weapon to save lives. But this time after weighing the pros and cons again and again, he required a ＂tender＂ plan with no lancet.展开更多
Cancer remains a major cause of mortality worldwide,and urological cancers are the most common cancers among men.Several therapeutic agents have been used to treat urological cancer,leading to improved survival for pa...Cancer remains a major cause of mortality worldwide,and urological cancers are the most common cancers among men.Several therapeutic agents have been used to treat urological cancer,leading to improved survival for patients.However,this has been accompanied by an increase in the frequency of survivors with cardiovascular complications caused by anticancer medications.Here,we propose the novel discipline of uro-cardio-oncology,an evolving subspecialty focused on the complex interactions between cardiovascular disease and urological cancer.In this comprehensive review,we discuss the various cardiovascular toxicities induced by different classes of antineoplastic agents used to treat urological cancers,including androgen deprivation therapy,vascular endothelial growth factor receptor tyrosine kinase inhibitors,immune checkpoint inhibitors,and chemotherapeutics.In addition,we discuss possible mechanisms underlying the cardiovascular toxicity associated with anticancer therapy and outline strategies for the surveillance,diagnosis,and effective management of cardiovascular complications.Finally,we provide an analysis of future perspectives in this emerging specialty,identifying areas in need of further research.展开更多
Combination therapy involves the simultaneous administration of compounds with varying mechanisms of action that can improve the efficacy of antitumor therapy and reduce toxicity.The most widely used combination regim...Combination therapy involves the simultaneous administration of compounds with varying mechanisms of action that can improve the efficacy of antitumor therapy and reduce toxicity.The most widely used combination regimen is chemotherapy combined with focused immunotherapy.This is implemented to induce the apoptosis of tumor cells and can activate immune responses,improving the clearance rate of primary lesions and maintaining the resistance to postoperative tumor recurrence and metastasis.Advances in micro/nanotechnology,nanomedicine and biomaterials have contributed to the development of enhanced local drug co-delivery systems for cancer treatment,improving tumor targeting and ameliorating severe systemic complications.Carrier materials can achieve the local long-term controllable release of multiple drugs,which not only avoids rapid drug diffusion from the pathological site,but can achieve synergistic effects at lower drug concentrations.Polymeric carriers display excellent biocompatibility and biodegradability;especially,some of them also have anti-tumor effects.The aim of this article was to review recent progress in the use of organic and polymeric materials for local tumor chemo-immunotherapy,which can be used as carriers for chemotherapeutic drugs,immune adjuvants and genes,including amphiphilic nanoparticles,nanocapsules,nano-disks,nano-polyplex particles,hydrogels and implantable materials.展开更多
Great efforts have been made in investigating the neurotoxicity of dopamine(DA)in the presence of manganous ions.In contrast,here,we probe the possibility of DA-based cancer chemotherapy by leveraging intratumoral red...Great efforts have been made in investigating the neurotoxicity of dopamine(DA)in the presence of manganous ions.In contrast,here,we probe the possibility of DA-based cancer chemotherapy by leveraging intratumoral redox reactions of DA for producing cytotoxic species in situ.For this purpose,we have constructed a Mn-engineered,DA-loaded nanomedicine.Based on the unique size effect of the nanocarrier,this nanomedicine will not enter the central nervous system but can effectively accumulate in the tumor region,after which the nanocarrier can degrade to release Mn^(2+)and DA in response to the mild acidic intracelluar microenvironment of cancer cells.DA can chelate Mn^(2+)to form a binary coordination complex,where the strong metal-ligand interaction significantly promotes electron delocalization and elevates the reducibility of Mn center,favoring two sequential one-electron oxygen reduction reactions forming H_(2)O_(2),which can be further converted into highly oxidizing ·OH under the cocatalysis by Mn^(2+)and intracellular Fe^(2+).Additionally,as a twoelectron oxidation product of DA ligand,DA-oquinone is potent in exhausting cellular sulfhydryl and depleting reduced glutathione,inhibiting the intrinsic antioxidative mechanism of cancer cells,finally triggering severe oxidative damages in a synergistic manner.It is expected that such a strategy of nanotechnology-mediated metal-ligand coordination and subsequent nontoxicity-to-toxicity transition of DA in tumor may provide a promising prospect for future chemotherapy design.展开更多
Health care and medical care have always been dominant topics in human society.The field of precision medicine,iatrotechnics revolution and timely on-demand detection have continued to evolve in response to increasing...Health care and medical care have always been dominant topics in human society.The field of precision medicine,iatrotechnics revolution and timely on-demand detection have continued to evolve in response to increasing demands from the society.Furthermore,the emergence of innovative materials and their applications offer promising prospects for advancing global health.Polyoxometalates(POMs)are negatively-charged molecular metal oxides with well-defined structures,beautiful geometries and nanoscale sizes.Owing to their vast diversity in composition,structure,nuclearity and charge,they constitute a significant subcategory of inorganic clusters that contain bridging oxygen atoms between two or more metal ions.Nowadays,POMs based nanocomposites have been widely applied in the field of disease diagnosis,anticancer therapy and antibacterial therapy as new generation bioactive materials.In this review,the recent advances of POMs based nanocomposites in bioapplications are summarized and the future perspectives are discussed.展开更多
Background:Accumulating researchers have recognized mitophagy as a key player in tumors,but few studies have investigated its role in the tumor microenvironment(TME).Advances in the technology of single-cell RNA seque...Background:Accumulating researchers have recognized mitophagy as a key player in tumors,but few studies have investigated its role in the tumor microenvironment(TME).Advances in the technology of single-cell RNA sequencing(scRNA-seq)have allowed unveiling the concealed features of the TME at cellular resolution.This study aimed to elucidate the role of mitophagy within the TME of colorectal cancer(CRC)and to establish a mitophagy-mediated risk model.Methods:We assessed mitophagy-related pathway activities at both single-cell and tissue levels.Subsequently,an unsupervised clustering algorithm was employed to identify mitophagy-mediated subtypes.Furthermore,we developed a mitophagy-mediated risk signature(MMRS)using least absolute shrinkage and selection operator(LASSO)Cox analysis and constructed a MMRS model incorporating the risk score and clinical variables.Subsequently,we used quantitative reverse transcription polymerase chain reaction analysis to verify the expression of the screened genes.Results:We retrieved and annotated a total of 14,719 cells from eight samples in the scRNA-seq GSE132465 data set.The activities of mitophagy-related pathways were uniformly upregulated in cancer cells.Integrating with bulk RNA-seq data,we identified two mitophagy-mediated clusters(C1 and C2)with distinct characteristics and prognoses.C2 was identified as a mitophagy-high cluster.Then,we developed a five-gene MMRS via LASSO Cox analysis in The Cancer Genome Atlas(TCGA)cohort.We utilized the GSE39582 cohort to validate the efficacy of our model.The expression of CX3CL1 and INHBB was upregulated in CRC tissues.Conclusions:The present study identified two mitophagy-mediated CRC subtypes with distinct features.Our MMRS may provide potential therapeutic strategies for CRC.The findings of our work offer novel insights into the involvement of mitophagy in CRC.展开更多
The Wnt/β-catenin signaling is a conserved pathway that has a crucial role in embryonic and adult life.Dysregulation of the Wnt/β-catenin pathway has been associated with diseases including cancer,and components of ...The Wnt/β-catenin signaling is a conserved pathway that has a crucial role in embryonic and adult life.Dysregulation of the Wnt/β-catenin pathway has been associated with diseases including cancer,and components of the sisnaling have been proposed as innovative therapeutic targets,mainly for cancer therapy.The attention of the worldwide researchers paid to this issue is increasing,also in view of the therapeutic potential of these agents in diseases,such as Parkinson’s disease(PD),for which no cure is existing today.Much evidence indicates that abnormal Wnt/β-catenin signaling is involved in tumor immunology and the targeting of Wnt/β-catenin pathway has been also proposed as an attractive strategy to potentiate cancer immunotherapy.During the last decade,several products,including naturally occurring dietary agents as well as a wide variety of products from plant sources,including curcumin,quercetin,berberin,and ginsenosides,have been identified as potent modulators of the Wnt/β-catenin signaling and have gained interest as promising candidates for the development of chemopreventive or therapeutic drugs for cancer.In this review we make an overview of the nature-derived compounds reported to have antitumor activity by modulating the Wnt/β-catenin signaling,also focusing on extraction methods,chemical features,and bio-activity assays used for the screening of these compounds.展开更多
Globally, peptide-based anticancer therapies have drawn much attention. Marine organisms are a reservoir of anticancer peptides that await discovery. In this study, we aimed to identify cytotoxic oligopeptides from Sa...Globally, peptide-based anticancer therapies have drawn much attention. Marine organisms are a reservoir of anticancer peptides that await discovery. In this study, we aimed to identify cytotoxic oligopeptides from Sarcophyton glaucum. Peptides were purified from among the S. glaucum hydrolysates produced by alcalase, chymotrypsin, papain, and trypsin, guided by a methylthiazolyldiphenyl-tetrazolium bromide(MTT) assay on the human cervical cancer(HeLa) cell line for cytotoxicity evaluation. Purification techniques adopted were membrane ultrafiltration, gel filtration chromatography, solid phase extraction(SPE), and reversed-phase high-performance liquid chromatography(RP-HPLC). Purified peptides were identified by de novo peptide sequencing. From papain hydrolysate, three peptide sequences were identified: AGAPGG, AERQ, and RDTQ(428.45, 502.53, and 518.53 Da, respectively). Peptides synthesized from these sequences exhibited cytotoxicity on HeLa cells with median effect concentration(EC50) values of 8.6, 4.9, and 5.6 mmol/L, respectively, up to 5.8-fold stronger than the anticancer drug 5-fluorouracil. When tested at their respective EC50, AGAPGG, AERQ, and RDTQ showed only 16%, 25%, and 11% cytotoxicity to non-cancerous Hek293 cells, respectively. In conclusion, AERQ, AGAPGG, and RDTQ are promising candidates for future development as peptide-based anticancer drugs.展开更多
基金the European Research Council(ERC)under the European Union’s Horizon 2020 research and innovation programme(Grant Agreement No 678151-Project Acronym“TROJANANOHORSE”-ERC starting Grant)the Politecnico di Torino and the Moschini Spa Company through a seed funding of Proof-of-Concept Grant No.16417.
文摘Cancer has nowadays become one of the leading causes of death worldwide.Conventional anticancer approaches are associated with different limitations.Therefore,innovative methodologies are being investigated,and several researchers propose the use of remotely activated nanoparticles to trigger cancer cell death.The idea is to conjugate two different components,i.e.,an external physical input and nanoparticles.Both are given in a harmless dose that once combined together act synergistically to therapeutically treat the cell or tissue of interest,thus also limiting the negative outcomes for the surrounding tissues.Tuning both the properties of the nanomaterial and the involved triggering stimulus,it is possible furthermore to achieve not only a therapeutic effect,but also a powerful platform for imaging at the same time,obtaining a nano-theranostic application.In the present review,we highlight the role of nanoparticles as therapeutic or theranostic tools,thus excluding the cases where a molecular drug is activated.We thus present many examples where the highly cytotoxic power only derives from the active interaction between different physical inputs and nanoparticles.We perform a special focus on mechanical waves responding nanoparticles,in which remotely activated nanoparticles directly become therapeutic agents without the need of the administration of chemotherapeutics or sonosensitizing drugs.
基金supported by the National Natural Science Foundation of China(22174042 and 22374038)the Natural Science Foundation for Distinguished Young Scholars of Hunan Province(2021JJ10011)the Postgraduate Scientific Research Innovation Project of Hunan Province(CX20220390)。
文摘DNAzyme-based gene therapy faces some challenges including cell penetration,activity limitation,and co-delivery functions.Self-assembled DNA nanomedicine has attracted widespread attention due to its many advantages.It is urgent to develop a universal DNA degradation strategy for precise programmable drug release.Herein,we reported a self-catabolic DNAzyme nanospheres(SCNS),which could simultaneously achieve cell penetration,activity enhancement,and co-delivery functions.The SCNS were assembled through Y-DNA stepwise hybridization with each other,which were then loaded with aptamer(Apt),doxorubicin(Dox),and zinc oxide nanoparticles(ZnO NPs).The acid-triggered dissociation of ZnO NPs leads to the generation of Zn^(2+)ions cofactors for immediately self-catabolic DNAzyme nanospheres.After the disassembly of the SCNS,three types of anticancer treatments would be activated,which include Zn^(2+)involved reactive oxygen species(ROS),Dox-induced chemotherapy,and DNAzyme-based gene therapy.The experimental results show that the nanoplatform(Apt-SCNS-Dox-ZnO)has a good tumor-killing effect and minimal side effects.As a smart self-driven drug delivery nanoplatform,it is anticipated to displace extraordinary potential in biomedicine and bioengineering.
基金Supported by the Youth Project of National Natural Science Foundation of China(No.82104861)National Natural Science Foundation of China(Nos.U20A20408 and 82074450)+1 种基金Natural Science Foundation of Hunan Province of China(Nos.2021JJ40408,2021JJ40420)Hunan Provincial Department of Education General Project(No.20C1407)。
文摘The discovery of novel antitumor agents derived from natural plants is a principal objective of anticancer drug research.Frankincense,a widely recognized natural antitumor medicine,has undergone a systematic review encompassing its species,chemical constituents,and diverse pharmacological activities and mechanisms.The different species of frankincense include Boswellia serrata,Somali frankincense,Boswellia frereana,and Boswellia arabica.Various frankincense extracts and compounds exhibit antitumor,anti-inflammatory,and hepatoprotective properties and antioxidation,memory enhancement,and immunological regulation capabilities.They also have comprehensive effects on regulating flora.Frankincense and its principal chemical constituents have demonstrated promising chemoprophylactic and therapeutic abilities against tumors.This review provides a systematic summary of the mechanism of action underlying the antitumor effects of frankincense and its major constituents,thus laying the foundations for developing effective tumor-combating targets.
基金supported by China Medical University’s High-level Talents Research Start-up Fund(1210619010)Double First-Class Scientific Research Fund(3110210603).
文摘Current antitumor monotherapy has many limitations,highlighting the need for novel synergistic anticancer strategies.Ferroptosis is an iron-dependent form of nonapoptotic cell death that plays a pivotal regulatory role in tumorigenesis and treatment.Photodynamic therapy(PDT)causes irreversible chemical damage to target lesions and is widely used in antitumor therapy.However,PDT’s effectiveness is usually hindered by several obstacles,such as hypoxia,excess glutathione(GSH),and tumor resistance.Ferroptosis improves the anticancer efficacy of PDT by increasing oxygen and reactive oxygen species(ROS)or reducing GSH levels,and PDT also enhances ferroptosis induction due to the ROS effect in the tumor microenvironment(TME).Strategies based on nanoparticles(NPs)can subtly exploit the potential synergy of ferroptosis and PDT.This review explores recent advances and current challenges in the landscape of the underlyingmechanisms regulating ferroptosis and PDT,as well as nano delivery system-mediated synergistic anticancer activity.These include polymers,biomimetic materials,metal organic frameworks(MOFs),inorganics,and carrier-free NPs.Finally,we highlight future perspectives of this novel emerging paradigm in targeted cancer therapies.
基金supported by the National Basic Research Program of China(973 Program,No.2012CB933600)the National Natural Science Foundation of China(Nos.81771964 and 82072051)+4 种基金the Shanghai Municipal Natural Science Foundation(No.15ZR1408500)funded by the Special Project of Clinical Research of Health Industry of Shanghai Municipal Health Commission(No.201940178)the Scientific Research Project of Hongkou District Health Committee of Shanghai(No.2002-17)the Clinical Research Project of Wu Jieping Medical Foundation(No.320.6750.2020-18-2)the Research Project of Shanghai Fourth People’s Hospital(No.sykyqd 00701&00702).
文摘There are several limitations to the application of nanoparticles in the treatment of cancer,including their low drug loading,poor colloidal stability,insufficient tumor penetration,and uncontrolled release of the drug.Herein,gelatin/laponite(LP)/doxorubicin(GLD)nanoparticles are developed by crosslinking LP with gelatin for doxorubicin delivery.GLD shows high doxorubicin encapsulation efficacy(99%)and strong colloidal stability,as seen from the unchanged size over the past 21 days and reduced protein absorption by 48-fold compared with unmodified laponite/doxorubicin nanoparticles.When gelatin from 115 nm GLD reaches the tumor site,matrix metallopeptidase-2(MMP-2)from the tumor environment breaks it down to release smaller 40 nm LP nanoparticles for effective tumor cell endocytosis.As demonstrated by superior penetration in both in vitro three-dimensional(3D)tumor spheroids(138-fold increase compared to the free drug)and in vivo tumor models.The intracellular low pH and MMP-2 further cause doxorubicin release after endocytosis by tumor cells,leading to a higher inhibitory potential against cancer cells.The improved anticancer effectiveness and strong in vivo biocompatibility of GLD have been confirmed using a mouse tumor-bearing model.MMP-2/pH sequentially triggered anticancer drug delivery is made possible by the logical design of tumor-penetrating GLD,offering a useful method for anticancer therapy.
基金supported by the National Key R&D Program of China(Grant 2017YFA0506000 to Chunquan Sheng)National Natural Science Foundation of China(Grants 81725020 and 21738002 to Chunquan Sheng and 81872742 to Guoqiang Dong)the Innovation Program of Shanghai Municipal Education Commission(Grant 2019-01-07-00-07-E00073 to Chunquan Sheng,China)
文摘Necroptosis,a genetically programmed form of necrotic cell death,serves as an important pathway in human diseases.As a critical cell-killing mechanism,necroptosis is associated with cancer progression,metastasis,and immunosurveillance.Targeting necroptosis pathway by small molecule modulators is emerging as an effective approach in cancer therapy,which has the advantage to bypass the apoptosis-resistance and maintain antitumor immunity.Therefore,a better understanding of the mechanism of necroptosis and necroptosis modulators is necessary to develop novel strategies for cancer therapy.This review will summarize recent progress of the mechanisms and detecting methods of necroptosis.In particular,the relationship between necroptosis and cancer therapy and medicinal chemistry of necroptosis modulators will be focused on.
基金This study was supported by grants from the National Natural Science Foundation of China （No. 81172234） and the Fundamental Research Funds for the Central Universities of China.
文摘Objective： To gain insight into the mechanism by which sex-determining region of Y chromosome （SRY）-related high-mobility-group box 2 （SOX2） involved in carcinogenesis and cancer stem cells （CSCs）. Data Sources： The data used in this review were mainly published in English from 2000 to present obtained from PubMed. The search terms were ＂SOX2,＂ ＂cancer,＂ ＂tumor＂ or ＂CSCs.＂ Study Selection： Articles studying the mitochondria-related pathologic mechanism and treatment of glaucoma were selected and reviewed. Results： SOX2, a transcription factor that is the key in maintaining pluripotent properties of stem cells, is a member of SRV-related high-mobility group domain proteins. SOX2 participates in many biological processes, such as modulation of cell proliferation, regulation of cell death signaling, cell apoptosis, and most importantly, tumor formation and development. Although SOX2 has been implicated in the biology of various tumors and CSCs, the findings are highly controversial, and information regarding the underlying mechanism remains limited. Moreover, the mechanism by which SOX2 involved in carcinogenesis and tumor progression is rather unclear yet. Conclusions： Here, we review the important biological functions of SOX2 in different tumors and CSCs, and the function of SOX2 signaling in the pathobiology ofneoplasia, such as Wnt/β-catenin signaling pathway, Hippo signaling pathway, Survivin signaling pathway, P13K/Akt signaling pathway, and so on. Targeting towards SOX2 may be an effective therapeutic strategy for cancer therapy.
文摘Hepatocellular carcinoma(HCC)is the third leading cause of cancer death globally,with 15%of cases arising on a background of non-alcoholic fatty liver disease(NAFLD).NAFLD is a heterogenous condition ranging from fatty liver to cirrhosis and is itself a growing global problem,with estimated worldwide prevalence of 50%in 2040.Pathophysiology of NAFLD-HCC is not well understood,there are no dedicated screening programs,and there have been no clinical studies of anticancer treatments in this population specifically.However,the NAFLD-HCC population appears different than other aetiologies-patients tend to be older,diagnosed at more advanced stages,have more comorbidities,and overall worse prognosis.Understanding of best treatment options for this group of patients is an urgent unmet clinical need.This narrative review discusses NAFLD-HCC pathophysiology and systemic treatment,and offers suggestions for future directions in this therapy area.
文摘Epithelial-mesenchymal transition(EMT) has been linked with aggressive tumor biology and therapy resistance. It plays central role not only in the generation of cancer stem cells(CSCs) but also direct them across the multiple organ systems to promote tumor recurrence and metastasis. CSCs are reported to express stem cell genes as well as specific cell surfacemarkers and allow aberrant differentiation of progenies.It facilitates cancer cells to leave primary tumor, acquire migratory characteristics, grow into new environment and develop radio-chemo-resistance. Based on the current information, present review discusses and summarizes the recent advancements on the molecular mechanisms that derive epithelial plasticity and its major role in generating a subset of tumor cells with stemness properties and pathophysiological spread of tumor. This paper further highlights the critical need to examine the regulation of EMT and CSC pathways in identifying the novel probable therapeutic targets.These improved therapeutic strategies based on the co-administration of inhibitors of EMT, CSCs as well as differentiated tumor cells may provide improved antineoplastic response with no tumor relapse.
基金Supported by The Agreement between FIMA and the "UTE project CIMA"Red Temática de Investigación Cooperativa en Cáncer RD06 00200061 (to Berasain C and ávila MA)Ciberehd (to Prieto J) from Instituto de Salud Carlos Ⅲ,Grants FIS PI070392 and PI070402 from Ministerio de Sanidad y Con-sumo
文摘Pre-mRNA splicing is an essential step in the process of gene expression in eukaryotes and consists of the removal ofintrons and the linking of exons to generate mature mRNAs. This is a highly regulated mechanism that allows the alternative usage of exons, the retention ofintronic sequences and the generation of exonic sequences of variable length. Most human genes undergo splicing events, and disruptions of this process have been associated with a variety of diseases, including cancer. Hepatocellular carcinoma (HCC) is a molecularly heterogeneous type of tumor that usually develops in a cirrhotic liver. Alterations in pre-mRNA splicing of some genes have been observed in liver cancer, and although still scarce, the available data suggest that splicing defects may have a role in hepatocarcinogenesis. Here we briefly review the general mechanisms that regulatepre-mRNA splicing, and discuss some examples that illustrate how this process is impaired in liver tumorigenesis, and may contribute to HCC development. We believe that a more thorough examination of pre-mRNA splicing is still needed to accurately draw the molecular portrait of liver cancer. This will surely contribute to a better understanding of the disease and to the development of new effective therapies.
文摘G protein coupled receptors(GPCRs)have emerged as the most potential target for a number of drug discovery programs ranging from control of blood pressure,diabetes,cure for genetic diseases to treatment of cancer.A panel of different ligands including hormones,peptides,ions and small molecules is responsible for activation of these receptors.Molecular genetics has identified key GPCRs,whose mutations or altered expressions are linked with tumorgenicity.In this review,we discussed recent advances regarding the involvement of GPCRs in the development of cancers and approaches to manipulating the mechanism behind GPCRs involved tumor growth and metastasis to treat different types of human cancer.This review provides an insight into the current scenario of GPCR-targeted therapy,progress to date and the challenges in the development of anticancer drugs.
基金financially supported by the National Natural Science Foundation of China(Nos.21905021,U21A20308)Sichuan Science and Technology Support Program(Nos.2022NSFSC1269,2023NSF1977,2023NSFSC0637,2022ZYD0048,2021ZDYF3218,2021YFG0291,2021YFH0132)Sichuan Students’Platform for innovation and entrepreneurship training program(No.202210623013)。
文摘Applying the fluorescent carbon dots as smart materials in anticancer therapy is of great interest.However,carbon dots for multimodal synergistic anticancer therapy,especially for the triple modality,is rarely reported.Herein,we successfully synthesized OCDs by citric acid and(1R,2S)-2-amino-1,2-diphenylethan-1-ol,which show aggregation-induced emission property and two-photon fluorescence imaging.Meanwhile,OCDs are ideal photosensitizers for photothermal therapy under 808 nm and TypeⅠphotodynamic therapy with white light.Hydroxyl radicals,generated by TypeⅠphotodynamic therapy based on OCDs can transform protumoral M2 macrophages into antitumoral M1 macrophages,which exhibited immunotherapy ability.The synergism trimodal of OCDs results in potent anticancer efficacy,showing great potential in cancer therapy.
基金Supported by the 2018 Capital Health Development Research Key ProjectBeijing Municipal Commission of Health and Fanmily Planning(No.2018-1-4201)National Natural Science Foundation of China(No.81403250)
文摘In 2003, a 61-year old highly respected director of the Surgery Department of Dongfang Hospital Affiliated to Beijing University of Chinese Medicine was diagnosed as advanced lung cancer, moderately differentiated adenocarcinoma, coverinqmore than two thirds of the thoracic aorta, multiple mediastinal nodal metastases, pleural effusion ＂Only 3 months could be expected＂, a cruel fact came out after deliberation of many seasoned medical specialists. In the whole career of this surgery professor, he used the lancet as his weapon to save lives. But this time after weighing the pros and cons again and again, he required a ＂tender＂ plan with no lancet.
基金Tianjin Key Medical Discipline(Specialty)Construction Project,Grant/Award Number:TJYXZDXK-029ANational Natural Science Foundation of China,Grant/Award Numbers:82170327,82370332Research Impact Fund of the Hong Kong Metropolitan University,Grant/Award Number:RIF/2022/2.2。
文摘Cancer remains a major cause of mortality worldwide,and urological cancers are the most common cancers among men.Several therapeutic agents have been used to treat urological cancer,leading to improved survival for patients.However,this has been accompanied by an increase in the frequency of survivors with cardiovascular complications caused by anticancer medications.Here,we propose the novel discipline of uro-cardio-oncology,an evolving subspecialty focused on the complex interactions between cardiovascular disease and urological cancer.In this comprehensive review,we discuss the various cardiovascular toxicities induced by different classes of antineoplastic agents used to treat urological cancers,including androgen deprivation therapy,vascular endothelial growth factor receptor tyrosine kinase inhibitors,immune checkpoint inhibitors,and chemotherapeutics.In addition,we discuss possible mechanisms underlying the cardiovascular toxicity associated with anticancer therapy and outline strategies for the surveillance,diagnosis,and effective management of cardiovascular complications.Finally,we provide an analysis of future perspectives in this emerging specialty,identifying areas in need of further research.
基金supported by the National Natural Science Foundation of China(Grant Nos.51973218,51833010,51622307)the Youth Innovation Promotion Association of the Chinese Academy of Sciences。
文摘Combination therapy involves the simultaneous administration of compounds with varying mechanisms of action that can improve the efficacy of antitumor therapy and reduce toxicity.The most widely used combination regimen is chemotherapy combined with focused immunotherapy.This is implemented to induce the apoptosis of tumor cells and can activate immune responses,improving the clearance rate of primary lesions and maintaining the resistance to postoperative tumor recurrence and metastasis.Advances in micro/nanotechnology,nanomedicine and biomaterials have contributed to the development of enhanced local drug co-delivery systems for cancer treatment,improving tumor targeting and ameliorating severe systemic complications.Carrier materials can achieve the local long-term controllable release of multiple drugs,which not only avoids rapid drug diffusion from the pathological site,but can achieve synergistic effects at lower drug concentrations.Polymeric carriers display excellent biocompatibility and biodegradability;especially,some of them also have anti-tumor effects.The aim of this article was to review recent progress in the use of organic and polymeric materials for local tumor chemo-immunotherapy,which can be used as carriers for chemotherapeutic drugs,immune adjuvants and genes,including amphiphilic nanoparticles,nanocapsules,nano-disks,nano-polyplex particles,hydrogels and implantable materials.
基金the National Natural Science Foundation of China(grant no.21835007)Key Research Program of Frontier Sciences,Chinese Academy of Sciences(grant no.ZDBS-LY-SLH029)Shanghai Municipal Government S&T Project(grant no.17JC1404701).
文摘Great efforts have been made in investigating the neurotoxicity of dopamine(DA)in the presence of manganous ions.In contrast,here,we probe the possibility of DA-based cancer chemotherapy by leveraging intratumoral redox reactions of DA for producing cytotoxic species in situ.For this purpose,we have constructed a Mn-engineered,DA-loaded nanomedicine.Based on the unique size effect of the nanocarrier,this nanomedicine will not enter the central nervous system but can effectively accumulate in the tumor region,after which the nanocarrier can degrade to release Mn^(2+)and DA in response to the mild acidic intracelluar microenvironment of cancer cells.DA can chelate Mn^(2+)to form a binary coordination complex,where the strong metal-ligand interaction significantly promotes electron delocalization and elevates the reducibility of Mn center,favoring two sequential one-electron oxygen reduction reactions forming H_(2)O_(2),which can be further converted into highly oxidizing ·OH under the cocatalysis by Mn^(2+)and intracellular Fe^(2+).Additionally,as a twoelectron oxidation product of DA ligand,DA-oquinone is potent in exhausting cellular sulfhydryl and depleting reduced glutathione,inhibiting the intrinsic antioxidative mechanism of cancer cells,finally triggering severe oxidative damages in a synergistic manner.It is expected that such a strategy of nanotechnology-mediated metal-ligand coordination and subsequent nontoxicity-to-toxicity transition of DA in tumor may provide a promising prospect for future chemotherapy design.
基金financially supported by the National Natural Science Foundation of China (No.21801153)Academic promotion program of Shandong First Medical University (N0.2019LJ003)。
文摘Health care and medical care have always been dominant topics in human society.The field of precision medicine,iatrotechnics revolution and timely on-demand detection have continued to evolve in response to increasing demands from the society.Furthermore,the emergence of innovative materials and their applications offer promising prospects for advancing global health.Polyoxometalates(POMs)are negatively-charged molecular metal oxides with well-defined structures,beautiful geometries and nanoscale sizes.Owing to their vast diversity in composition,structure,nuclearity and charge,they constitute a significant subcategory of inorganic clusters that contain bridging oxygen atoms between two or more metal ions.Nowadays,POMs based nanocomposites have been widely applied in the field of disease diagnosis,anticancer therapy and antibacterial therapy as new generation bioactive materials.In this review,the recent advances of POMs based nanocomposites in bioapplications are summarized and the future perspectives are discussed.
基金supported by Traditional Chinese Medicine Bureau of Guangdong Province[grant no.20221092]the Sixth Affiliated Hospital of Sun Yat-sen University,1010 Clinical Research Project[grant no.1010PY(2020)-28].
文摘Background:Accumulating researchers have recognized mitophagy as a key player in tumors,but few studies have investigated its role in the tumor microenvironment(TME).Advances in the technology of single-cell RNA sequencing(scRNA-seq)have allowed unveiling the concealed features of the TME at cellular resolution.This study aimed to elucidate the role of mitophagy within the TME of colorectal cancer(CRC)and to establish a mitophagy-mediated risk model.Methods:We assessed mitophagy-related pathway activities at both single-cell and tissue levels.Subsequently,an unsupervised clustering algorithm was employed to identify mitophagy-mediated subtypes.Furthermore,we developed a mitophagy-mediated risk signature(MMRS)using least absolute shrinkage and selection operator(LASSO)Cox analysis and constructed a MMRS model incorporating the risk score and clinical variables.Subsequently,we used quantitative reverse transcription polymerase chain reaction analysis to verify the expression of the screened genes.Results:We retrieved and annotated a total of 14,719 cells from eight samples in the scRNA-seq GSE132465 data set.The activities of mitophagy-related pathways were uniformly upregulated in cancer cells.Integrating with bulk RNA-seq data,we identified two mitophagy-mediated clusters(C1 and C2)with distinct characteristics and prognoses.C2 was identified as a mitophagy-high cluster.Then,we developed a five-gene MMRS via LASSO Cox analysis in The Cancer Genome Atlas(TCGA)cohort.We utilized the GSE39582 cohort to validate the efficacy of our model.The expression of CX3CL1 and INHBB was upregulated in CRC tissues.Conclusions:The present study identified two mitophagy-mediated CRC subtypes with distinct features.Our MMRS may provide potential therapeutic strategies for CRC.The findings of our work offer novel insights into the involvement of mitophagy in CRC.
文摘The Wnt/β-catenin signaling is a conserved pathway that has a crucial role in embryonic and adult life.Dysregulation of the Wnt/β-catenin pathway has been associated with diseases including cancer,and components of the sisnaling have been proposed as innovative therapeutic targets,mainly for cancer therapy.The attention of the worldwide researchers paid to this issue is increasing,also in view of the therapeutic potential of these agents in diseases,such as Parkinson’s disease(PD),for which no cure is existing today.Much evidence indicates that abnormal Wnt/β-catenin signaling is involved in tumor immunology and the targeting of Wnt/β-catenin pathway has been also proposed as an attractive strategy to potentiate cancer immunotherapy.During the last decade,several products,including naturally occurring dietary agents as well as a wide variety of products from plant sources,including curcumin,quercetin,berberin,and ginsenosides,have been identified as potent modulators of the Wnt/β-catenin signaling and have gained interest as promising candidates for the development of chemopreventive or therapeutic drugs for cancer.In this review we make an overview of the nature-derived compounds reported to have antitumor activity by modulating the Wnt/β-catenin signaling,also focusing on extraction methods,chemical features,and bio-activity assays used for the screening of these compounds.
基金Project supported by the Fundamental Research Grant Scheme of the Ministry of Higher Education,Malaysia(FRGS/1/2013/ST04/UTAR/02/1)
文摘Globally, peptide-based anticancer therapies have drawn much attention. Marine organisms are a reservoir of anticancer peptides that await discovery. In this study, we aimed to identify cytotoxic oligopeptides from Sarcophyton glaucum. Peptides were purified from among the S. glaucum hydrolysates produced by alcalase, chymotrypsin, papain, and trypsin, guided by a methylthiazolyldiphenyl-tetrazolium bromide(MTT) assay on the human cervical cancer(HeLa) cell line for cytotoxicity evaluation. Purification techniques adopted were membrane ultrafiltration, gel filtration chromatography, solid phase extraction(SPE), and reversed-phase high-performance liquid chromatography(RP-HPLC). Purified peptides were identified by de novo peptide sequencing. From papain hydrolysate, three peptide sequences were identified: AGAPGG, AERQ, and RDTQ(428.45, 502.53, and 518.53 Da, respectively). Peptides synthesized from these sequences exhibited cytotoxicity on HeLa cells with median effect concentration(EC50) values of 8.6, 4.9, and 5.6 mmol/L, respectively, up to 5.8-fold stronger than the anticancer drug 5-fluorouracil. When tested at their respective EC50, AGAPGG, AERQ, and RDTQ showed only 16%, 25%, and 11% cytotoxicity to non-cancerous Hek293 cells, respectively. In conclusion, AERQ, AGAPGG, and RDTQ are promising candidates for future development as peptide-based anticancer drugs.
