Osteosarcoma,with poor survival after metastasis,is considered the most common primary bone cancer in adolescents.Notwithstanding the efforts of researchers,its five-year survival rate has only shown limited improveme...Osteosarcoma,with poor survival after metastasis,is considered the most common primary bone cancer in adolescents.Notwithstanding the efforts of researchers,its five-year survival rate has only shown limited improvement,suggesting that existing therapeutic strategies are insufficient to meet clinical needs.Notably,immunotherapy has shown certain advantages over traditional tumor treatments in inhibiting metastasis.Therefore,managing the immune microenvironment in osteosarcoma can provide novel and valuable insight into the multifaceted mechanisms underlying the heterogeneity and progression of the disease.Additionally,given the advances in nanomedicine,there exist many advanced nanoplatforms for enhanced osteosarcoma immunotherapy with satisfactory physiochemical characteristics.Here,we review the classification,characteristics,and functions of the key components of the immune microenvironment in osteosarcoma.This review also emphasizes the application,progress,and prospects of osteosarcoma immunotherapy and discusses several nanomedicine-based options to enhance the efficiency of osteosarcoma treatment.Furthermore,we examine the disadvantages of standard treatments and present future perspectives for osteosarcoma immunotherapy.展开更多
Hyaluronan and proteoglycan link protein 1(Hapln1)supports active cardiomyogenesis in zebrafish hearts,but its regulation in mammal cardiomyocytes is unclear.This study aimed to explore the potential regulation of Hap...Hyaluronan and proteoglycan link protein 1(Hapln1)supports active cardiomyogenesis in zebrafish hearts,but its regulation in mammal cardiomyocytes is unclear.This study aimed to explore the potential regulation of Hapln1 in the dedifferentiation and proliferation of cardiomyocytes and its therapeutic value in myocardial infarction with human induced pluripotent stem cell(hiPSC)-derived cardiomyocytes(CMs)and an adult mouse model of myocardial infarction.HiPSC-CMs and adult mice with myocardial infarction were used as in vitro and in vivo models,respectively.Previous single-cell RNA sequencing data were retrieved for bioinformatic exploration.The results showed that recombinant human Hapln1(rhHapln1)promotes the proliferation of hiPSC-CMs in a dose-dependent manner.As a physical binding protein of Hapln1,versican interacted with Nodal growth differentiation factor(NODAL)and growth differentiation factor 11(GDF11).GDF11,but not NODAL,was expressed by hiPSC-CMs.GDF11 expression was unaffected by rhHapln1 treatment.However,this molecule was required for rhHapln1-mediated activation of the transforming growth factor(TGF)-β/Drosophila mothers against decapentaplegic protein(SMAD)2/3 signaling in hiPSC-CMs,which stimulates cell dedifferentiation and proliferation.Recombinant mouse Hapln1(rmHapln1)could induce cardiac regeneration in the adult mouse model of myocardial infarction.In addition,rmHapln1 induced hiPSC-CM proliferation.In conclusion,Hapln1 can stimulate the dedifferentiation and proliferation of iPSC-derived cardiomyocytes by promoting versican-based GDF11 trapping and subsequent activation of the TGF-β/SMAD2/3 signaling pathway.Hapln1 might be an effective hiPSC-CM dedifferentiation and proliferation agent and a potential reagent for repairing damaged hearts.展开更多
Oral tyrosine kinase inhibitors(TKIs) against epidermal growth factor receptor(EGFR) family have been introduced into the clinic to treat human malignancies for decades. Despite superior properties of EGFR-TKIs as sma...Oral tyrosine kinase inhibitors(TKIs) against epidermal growth factor receptor(EGFR) family have been introduced into the clinic to treat human malignancies for decades. Despite superior properties of EGFR-TKIs as small molecule targeted drugs, their applications are still restricted due to their low solubility, capricious oral bioavailability, large requirement of daily dose, high binding tendency to plasma albumin and initial/acquired drug resistance. Nanotechnology is a promising tool to improve efficacy of these drugs. Through non-oral routes. Various nanotechnology-based delivery approaches have been developed for providing efficient delivery of EGFR-TKIs with a better pharmacokinetic profile and tissue-targeting ability. This review aims to indicate the advantage of nanocarriers for EGFR-TKIs delivery.展开更多
A calculation method for heats of formation (HOF, referred to as △Hf) based on the density functional theory (DFT) is presented in this work. Similar to Gaussian-3 theory, the atomic scheme is applied to calculate th...A calculation method for heats of formation (HOF, referred to as △Hf) based on the density functional theory (DFT) is presented in this work. Similar to Gaussian-3 theory, the atomic scheme is applied to calculate the heats of formation of the molecules. In this method, we have modified the formula for calculation of Gaussian-3 theory in several ways, including the correction for diffuse functions and the correction for higher polarization functions. These corrections are found to be significant. The average absolute deviation from experiment for the 164 calculated heats of formation is about 1.9 kcal·mol?1, while average absolute deviation from G3MP2 for the 149 (among the 164 molecules, 15 large-sized molecules can not be calculated at the G3MP2 level) calculated heats of formation is only about 1.9 kcal·mol?1. It indicates that the present method can be applied to predict the heats of formation of medium-sized and large-sized molecules, while the heats of formation of these molecules using Gaussian-3 theory are much difficult, even impossible, to calculate. That is, this method provides a choice in the calculation of △Hf for medium-sized and large-sized molecules.展开更多
Oral squamous cell carcinoma (OSCC) develops on the mucosal epithelium of the oral cavity. It accounts for approximately 90% oforal malignancies and impairs appearance, pronunciation, swallowing, and flavor perception...Oral squamous cell carcinoma (OSCC) develops on the mucosal epithelium of the oral cavity. It accounts for approximately 90% oforal malignancies and impairs appearance, pronunciation, swallowing, and flavor perception. In 2020, 377,713 OSCC cases werereported globally. According to the Global Cancer Observatory (GCO), the incidence of OSCC will rise by approximately 40% by2040, accompanied by a growth in mortality. Persistent exposure to various risk factors, including tobacco, alcohol, betel quid (BQ),and human papillomavirus (HPV), will lead to the development of oral potentially malignant disorders (OPMDs), which are oralmucosal lesions with an increased risk of developing into OSCC. Complex and multifactorial, the oncogenesis process involvesgenetic alteration, epigenetic modification, and a dysregulated tumor microenvironment. Although various therapeuticinterventions, such as chemotherapy, radiation, immunotherapy, and nanomedicine, have been proposed to prevent or treat OSCCand OPMDs, understanding the mechanism of malignancies will facilitate the identification of therapeutic and prognostic factors,thereby improving the efficacy of treatment for OSCC patients. This review summarizes the mechanisms involved in OSCC.Moreover, the current therapeutic interventions and prognostic methods for OSCC and OPMDs are discussed to facilitatecomprehension and provide several prospective outlooks for the fields.展开更多
As the major cell precursors in osteogenesis, mesenchymal stem cells(MSCs) are indispensable for bone homeostasis and development. However, the primary mechanisms regulating osteogenic differentiation are controversia...As the major cell precursors in osteogenesis, mesenchymal stem cells(MSCs) are indispensable for bone homeostasis and development. However, the primary mechanisms regulating osteogenic differentiation are controversial. Composed of multiple constituent enhancers, super enhancers(SEs) are powerful cis-regulatory elements that identify genes that ensure sequential differentiation. The present study demonstrated that SEs were indispensable for MSC osteogenesis and involved in osteoporosis development. Through integrated analysis, we identified the most common SE-targeted and osteoporosis-related osteogenic gene,ZBTB16. ZBTB16, positively regulated by SEs, promoted MSC osteogenesis but was expressed at lower levels in osteoporosis.Mechanistically, SEs recruited bromodomain containing 4(BRD4) at the site of ZBTB16, which then bound to RNA polymerase IIassociated protein 2(RPAP2) that transported RNA polymerase Ⅱ(POL Ⅱ) into the nucleus. The subsequent synergistic regulation of POL Ⅱ carboxyterminal domain(CTD) phosphorylation by BRD4 and RPAP2 initiated ZBTB16 transcriptional elongation, which facilitated MSC osteogenesis via the key osteogenic transcription factor SP7. Bone-targeting ZBTB16 overexpression had a therapeutic effect on the decreased bone density and remodeling capacity of Brd4^(fl/fl)Prx1-cre mice and osteoporosis(OP) models.Therefore, our study shows that SEs orchestrate the osteogenesis of MSCs by targeting ZBTB16 expression, which provides an attractive focus and therapeutic target for osteoporosis.展开更多
Ginsenoside Rg5 is a rare ginsenoside showing promising tumor-suppressive effects.This study aimed to explore its radio-sensitizing effects and the underlying mechanisms.Human lung adenocarcinoma cell lines A549 and C...Ginsenoside Rg5 is a rare ginsenoside showing promising tumor-suppressive effects.This study aimed to explore its radio-sensitizing effects and the underlying mechanisms.Human lung adenocarcinoma cell lines A549 and Calu-3 were used for in vitro and in vivo analysis.Bioinformatic molecular docking prediction and following validation by surface plasmon resonance(SPR)technology,cellular thermal shift assay(CETSA),and isothermal titration calorimetry(ITC)were conducted to explore the binding between ginsenoside Rg5 and 90 kD heat shock protein alpha(HSP90a).The effects of ginsenoside Rg5 on HSP90-cell division cycle 37(CDC37)interaction,the client protein stability,and the downstream regulations were further explored.Results showed that ginsenoside Rg5 could induce cell-cycle arrest at the G1 phase and enhance irradiationinduced cell apoptosis.It could bind to HSP90a with a high affinity,but the affinity was drastically decreased by HSP90a Y61A mutation.Co-immunoprecipitation(Co-IP)and ITC assays confirmed that ginsenoside Rg5 disrupts the HSP90-CDC37 interaction in a dose-dependent manner.It reduced irradiation-induced upregulation of the HSP90-CDC37 client proteins,including SRC,CDK4,RAF1,and ULK1 in A549 cell-derived xenograft(CDX)tumors.Ginsenoside Rg5 or MRT67307(an IKKε/TBK1 inhibitor)pretreatment suppressed irradiation-induced elevation of the LC3-II/b ratio and restored irradiation-induced downregulation of p62 expression.In A549 CDX tumors,ginsenoside Rg5 treatment suppressed LC3 expression and enhanced irradiation-induced DNA damage.In conclusion,ginsenoside Rg5 may be a potential radiosensitizer for lung adenocarcinoma.It interacts with HSP90a and reduces the binding between HSP90 and CDC37,thereby increasing the ubiquitin-mediated proteasomal degradation of the HSP90-CDC37 client proteins.展开更多
The utilization of enteroviruses engineered with reporter genes serves as a valuable tool for advancing our understanding of enterovirus biology and its applications,enabling the development of effective therapeutic a...The utilization of enteroviruses engineered with reporter genes serves as a valuable tool for advancing our understanding of enterovirus biology and its applications,enabling the development of effective therapeutic and preventive strategies.In this study,our initial attempts to introduce a NanoLuc luciferase(NLuc)reporter gene into recombinant enteroviruses were unsuccessful in rescuing viable progenies.We hypothesized that the size of the inserted tag might be a determining factor in the rescue of the virus.Therefore,we inserted the 11-amino-acid HiBiT tag into the genomes of enterovirus A71(EV-A71),coxsackievirus A10(CVA10),coxsackievirus A7(CVA7),coxsackievirus A16(CVA16),namely EV-A71-HiBiT,CVA16-HiBiT,CVA10-HiBiT,CVA7-HiBiT,and observed that the HiBiT-tagged viruses exhibited remarkably high rescue efficiency.Notably,the HiBiT-tagged enteroviruses displayed comparable characteristics to the wild-type viruses.A direct comparison between CVA16-NLuc and CVA16-HiBiT recombinant viruses revealed that the tiny HiBiT insertion had minimal impact on virus infectivity and replication kinetics.Moreover,these HiBiT-tagged enteroviruses demonstrated high genetic stability in different cell lines over multiple passages.In addition,the HiBiT-tagged viruses were successfully tested in antiviral drug assays,and the sensitivity of the viruses to drugs was not affected by the HiBiT tag.Ultimately,our findings provide definitive evidence that the integration of HiBiT into enteroviruses presents a universal,convenient,and invaluable method for advancing research in the realm of enterovirus virology.Furthermore,HiBiT-tagged enteroviruses exhibit great potential for diverse applications,including the development of antivirals and the elucidation of viral infection mechanisms.展开更多
Oral squamous cell carcinoma(OSCC)is known as one of the most malignant tumors with high recurrence and fatality rate.The poor tumor-targeting ability of traditional chemotherapeutic drugs has been a grand challenge f...Oral squamous cell carcinoma(OSCC)is known as one of the most malignant tumors with high recurrence and fatality rate.The poor tumor-targeting ability of traditional chemotherapeutic drugs has been a grand challenge for anti-OSCC therapy.Beyond that,a large quantity of tumor associated macrophages in OSCC tissues further diminish the anti-tumor effects of these drugs.Therefore,we produced a therapeutic nano drug delivery system(FA-PEG-PLA-JQ1)through encapsulating JQ1[a small-molecule inhibitor of bromodomain containing protein 4(BRD4)]into the folic acid(FA)-modified nanoparticle(PEG-PLA),which could prolong the half-life of JQ1 and target the tumor tissues.And then,JQ1 released from this nanoparticle could prevent OSCC growth inducing tumor cell apoptosis,inhibiting tumor angiogenesis and the polarization of M2 type macrophages.In conclusion,our date demonstrated the therapeutic benefits of FA-PEG-PLA-JQ1 against OSCC in vivo or in vitro,which could be a novel treatment strategy for OSCC in coming days.展开更多
Cancer remains a significant risk to human health.Nanomedicine is a new multidisciplinary field that is garnering a lot of interest and investigation.Nanomedicine shows great potential for cancer diagnosis and treatme...Cancer remains a significant risk to human health.Nanomedicine is a new multidisciplinary field that is garnering a lot of interest and investigation.Nanomedicine shows great potential for cancer diagnosis and treatment.Specifically engineered nanoparticles can be employed as contrast agents in cancer diagnostics to enable high sensitivity and high-resolution tumor detection by imaging examinations.Novel approaches for tumor labeling and detection are also made possible by the use of nanoprobes and nanobiosensors.The achievement of targeted medication delivery in cancer therapy can be accomplished through the rational design and manufacture of nanodrug carriers.Nanoparticles have the capability to effectively transport medications or gene fragments to tumor tissues via passive or active targeting processes,thus enhancing treatment outcomes while minimizing harm to healthy tissues.Simultaneously,nanoparticles can be employed in the context of radiation sensitization and photothermal therapy to enhance the therapeutic efficacy of malignant tumors.This review presents a literature overview and summary of how nanotechnology is used in the diagnosis and treatment of malignant tumors.According to oncological diseases originating from different systems of the body and combining the pathophysiological features of cancers at different sites,we review the most recent developments in nanotechnology applications.Finally,we briefly discuss the prospects and challenges of nanotechnology in cancer.展开更多
Ischemia/reperfusion(I/R) is a pathological process that occurs in numerous organs throughout the human body, and it is frequently associated with severe cellular damage and death. Recently it has emerged that ferropt...Ischemia/reperfusion(I/R) is a pathological process that occurs in numerous organs throughout the human body, and it is frequently associated with severe cellular damage and death. Recently it has emerged that ferroptosis, a new form of regulated cell death that is caused by iron-dependent lipid peroxidation, plays a significantly detrimental role in many I/R models. In this review, we aim to revise the pathological process of I/R and then explore the molecular pathogenesis of ferroptosis. Furthermore,we aim to evaluate the role that ferroptosis plays in I/R, providing evidence to support the targeting of ferroptosis in the I/R pathway may present as a therapeutic intervention to alleviate ischemia/reperfusion injury(IRI) associated cell damage and death.展开更多
BACKGROUND： The long-term use of nudeos（t）ide analogues causes drug resistance and mutations in the HBV reverse tran- scriptase （RT） region of the polymerase gene. The RT region overlaps the HBV surface gene （S ...BACKGROUND： The long-term use of nudeos（t）ide analogues causes drug resistance and mutations in the HBV reverse tran- scriptase （RT） region of the polymerase gene. The RT region overlaps the HBV surface gene （S gene） and therefore, the mutations in the RT region simultaneously modify S gene sequence. Certain mutations in the RT region bring about truncated S proteins because the corresponding changed S gene encodes a stop codon which results in the loss of a large portion of the C-terminal hydrophobic region of HBV surface protein. The rtA181T/sW172＊, rtM204I/sW196＊ and rtV191I/sW182＊ are the most frequently reported drug-resistant mutations with C-terminal truncation, these mutations have oncogenic potential. DATA SOURCES： PubMed and Web of Science were searched using terms： ＂hepatitis B virus＂, ＂HBV drug resistance mutation＂ ＂HBV surface protein＂ ＂HBV truncation＂, ＂hepatocellular carcinoma＂, ＂rtA181T/sW172＊＂, ＂rtM204I/sW196＊＂, ＂rtV191I/sW182＊＂, and relevant articles published in English in the past decades were reviewed. RESULTS： The rtA181T/sW172＊ and rtV191I/sW182＊ mutants occurred more frequently than the rtM204I/sW196＊ mutant both in chronic hepatitis B patients and the HBV-related hepatocellular carcinoma tissues. Although these mutations occur naturally, nudeos（t）ide analogues therapy is the main driving force. These mutations may exist alone or coexist with other HBV mutations. All these three mutants impair the virion secretion and result in HBV surface protein retention and serum HBV DNA level reduction. These mutations possess potential carcinogenic properties. The three mutations are resistant to more than one nucleos（t）ide analogue and therefore, it is difficult to treat the patients with the truncated mutations.CONCLUSIONS： Nucleos（t）ide analogues induce drug resistance and HBV S gene truncated mutations. These mutations have potential carcinogenesis.展开更多
Objective:Angiogenesis plays a vital role in tumor growth and metastasis.Here,we aimed to find novel efficient antiangiogenic molecules targeting vascular endothelial growth factor A(VEGFA)at the transcriptional level...Objective:Angiogenesis plays a vital role in tumor growth and metastasis.Here,we aimed to find novel efficient antiangiogenic molecules targeting vascular endothelial growth factor A(VEGFA)at the transcriptional level to treat triple-negative breast cancer(TNBC).Methods:We used a cell-based seryl tRNA synthetase(SerRS)promoter-driven dual-luciferase reporter system to screen an in-house library of 384 naturally occurring small molecules and their derivatives to find candidate molecules that could upregulate the expression of SerRS,a potent transcriptional repressor of VEGFA.The levels of SerRS and VEGFA were examined by quantitative RT-PCR(qRT-PCR),western blotting,and/or ELISAs in TNBC cells after candidate molecule administration.Zebrafish,the Matrigel plug angiogenesis assay in mice,the TNBC allograft,and xenograft mouse models were used to evaluate thein vivoanti-angiogenic and anti-cancer activities.Furthermore,the potential direct targets of the candidates were identified by proteomics and biochemical studies.Results:We found the most active compound was 3-(4-methoxyphenyl)quinolin-4(1H)-one(MEQ),an isoflavone derivative.In TNBC cells,MEQ treatment resulted in increased SerRS mRNA(P<0.001)and protein levels and downregulated VEGFA production.Both the vascular development of zebrafish and Matrigel plug angiogenesis in mice were inhibited by MEQ.MEQ also suppressed the angiogenesis in TNBC allografts and xenografts in mice,resulting in inhibited tumor growth and prolonged overall survival(P<0.05).Finally,we found that MEQ regulated SerRS transcription by interacting with MTA2(Metastasis Associated 1 Family Member 2).Conclusions:Our findings suggested that the MTA2/SerRS/VEGFA axis is a drug-treatable anti-angiogenic target,and MEQ is a promising anti-tumor molecule that merits further investigation for clinical applications.展开更多
Mesenchymal stem cells(MSCs) are a subset of multipotent stroma cells residing in various tissues of the body. Apart from supporting the hematopoietic stem cell niche, MSCs possess strong immunoregulatory ability and ...Mesenchymal stem cells(MSCs) are a subset of multipotent stroma cells residing in various tissues of the body. Apart from supporting the hematopoietic stem cell niche, MSCs possess strong immunoregulatory ability and multiple differentiation potentials. These powerful capacities allow the extensive application of MSCs in clinical practice as an effective treatment for diseases.Therefore, illuminating the functional mechanism of MSCs will help to improve their curative effect and promote their clinical use. Long noncoding RNA(LncRNA) is a novel class of noncoding RNA longer than 200 nt. Recently,multiple studies have demonstrated that LncRNA is widely involved in growth and development through controlling the fate of cells, including MSCs. In this review, we highlight the role of LncRNA in regulating the functions of MSCs and discuss their participation in the pathogenesis of diseases and clinical use in diagnosis and treatment.展开更多
Solute carriers(SLCs)are the largest family of transmembrane transporters that determine the exchange of various substances,including nutrients,ions,metabolites,and drugs across biological membranes.To date,the presen...Solute carriers(SLCs)are the largest family of transmembrane transporters that determine the exchange of various substances,including nutrients,ions,metabolites,and drugs across biological membranes.To date,the presence of about 287 SLC genes have been identified in the brain,among which mutations or the resultant dysfunctions of 71 SLC genes have been reported to be correlated with human brain disorders.Although increasing interest in SLCs have focused on drug development,SLCs are currently still under-explored as drug targets,especially in the brain.We summarize the main substrates and functions of SLCs that are expressed in the brain,with an emphasis on selected SLCs that are important physiologically,pathologically,and pharmacologically in the blood-brain barrier,astrocytes,and neurons.Evidence suggests that a fraction of SLCs are regulated along with the occurrences of brain disorders,among which epilepsy,neurodegenerative diseases,and autism are representative.Given the review of SLCs involved in the onset and procession of brain disorders,we hope these SLCs will be screened as promising drug targets to improve drug delivery to the brain.展开更多
Mesenchymal stem cells(MSCs)are multipotent stromal cells with great potential for clinical applications.However,little is known about their cell heterogeneity at a single-cell resolution,which severely impedes the de...Mesenchymal stem cells(MSCs)are multipotent stromal cells with great potential for clinical applications.However,little is known about their cell heterogeneity at a single-cell resolution,which severely impedes the development of MSC therapy.In this review,we focus on advances in the identification of novel surface markers and functional subpopulations of MSCs made by single-cell RNA sequencing and discuss their participation in the pathophysiology of stem cells and related diseases.The challenges and future directions of single-cell RNA sequencing in MSCs are also addressed in this review.展开更多
AIM:to study the prevalence of human papillomavirus(HPV) in esophageal carcinoma in tangshan,China,a high-incidence area.METHODS:Formalin-fixed,paraffin-embedded tissue specimens from 198 patients who were pathologica...AIM:to study the prevalence of human papillomavirus(HPV) in esophageal carcinoma in tangshan,China,a high-incidence area.METHODS:Formalin-fixed,paraffin-embedded tissue specimens from 198 patients who were pathologically diagnosed with esophageal squamous cell carcinoma from 2011 to 2013 were obtained from a pathology department in Tangshan.DNA was extracted from all198 specimens to detect HPV by polymerase chain reaction(PCR).β-globin PCR was performed to check the quality of the DNA extraction procedure.PCR was performed to detect a wide range of HPV types,and type-specific PCR was performed to detect HPV types16 and 18.Negative and positive controls were used for HPV 16 and 18 detection.RESULTS:the DNA extraction method in this study appeared to be more effective than other previously reported methods.After DNA extraction,more than98%of the tissue specimens had an acceptable result in the DNA qualification test(β-globin PCR).the overall prevalence of HPV in tumor tissues by GP6+/GP5+PCR was 79.79%,and the prevalence of HPV types16 and 18 was 40.40%and 47.47%,respectively.PCR demonstrated the presence of HPV,and direct sequencing confirmed the HPV genotypes.All HPVpositive PCR products were checked by DNA sequence analysis using DNAman and compared with the known HPV sequences listed in the basic Local Alignment Search tool database to evaluate the HPV types.this analysis confirmed the presence of HPV types 16 and18.CONCLUSION:DNA of high-risk HPV types 16 and 18is present in esophageal tumors,implicating HPV as a possible etiologic factor for esophageal squamous cell carcinoma.展开更多
Recent advances in neoantigen research have accelerated the development and regulatory approval of tumor immunotherapies,including cancer vaccines,adoptive cell therapy and antibody-based therapies,especially for soli...Recent advances in neoantigen research have accelerated the development and regulatory approval of tumor immunotherapies,including cancer vaccines,adoptive cell therapy and antibody-based therapies,especially for solid tumors.Neoantigens are newly formed antigens generated by tumor cells as a result of various tumor-specific alterations,such as genomic mutation,dysregulated RNA splicing,disordered post-translational modification,and integrated viral open reading frames.Neoantigens are recognized as non-self and trigger an immune response that is not subject to central and peripheral tolerance.The quick identification and prediction of tumor-specific neoantigens have been made possible by the advanced development of next-generation sequencing and bioinformatic technologies.Compared to tumor-associated antigens,the highly immunogenic and tumor-specific neoantigens provide emerging targets for personalized cancer immunotherapies,and serve as prospective predictors for tumor survival prognosis and immune checkpoint blockade responses.The development of cancer therapies will be aided by understanding the mechanism underlying neoantigen-induced anti-tumor immune response and by streamlining the process of neoantigen-based immunotherapies.This review provides an overview on the identification and characterization of neoantigens and outlines the clinical applications of prospective immunotherapeutic strategies based on neoantigens.We also explore their current status,inherent challenges,and clinical translation potential.展开更多
The chemokine ligand 13-chemokine receptor 5(CXCL13-CXCR5)axis has been characterized as a critical tumor-promoting signaling pathway in the tumor microenvironment(TME)in multiple types of solid tumors.In this study,w...The chemokine ligand 13-chemokine receptor 5(CXCL13-CXCR5)axis has been characterized as a critical tumor-promoting signaling pathway in the tumor microenvironment(TME)in multiple types of solid tumors.In this study,we analyzed the expression profile of CXCL13 in kidney clear cell carcinoma(KIRC)and its correlation with tumor-infiltrating immune cells(TIICs).A monoclonal antibody against CXCL13 with high affinity and purity was generated in our lab for western blot and immunohistochemistry(IHC).Bioinformatic analysis was performed based on bulk-seq data from the Cancer Genome Atlas(TCGA)-KIRC and single-cell RNA-seq data from scRNASeqDB and PanglaoDB.Results showed that high CXCL13 expression in TME was associated with shorter progression-free survival(PFS),disease-specific survival(DSS),and overall survival(OS).KIRC cell lines,as well as several other cancer cell lines,had negative CXCL13 expression.IHC staining from the Human Protein Atlas(HPA)and our tissue array indicated that CXCL13 might be mainly expressed by TIICs,but not KIRC tumor cells.CXCL13 expression was strongly and positively correlated withγδT cell abundance in TME.Besides,γδT cell infiltration was associated with poor survival of KIRC.Methylation 450k array data showed that CXCL13 promoter hypomethylation was common in TIICs.The methylation level of cg16361705 within the CXCL13 promoter might play an important role in modulating CXCL13 transcription.In conclusion,our study revealed that CXCL13 expression andγδT cell infiltration in TME is associated with unfavorable survival of KIRC.TIICs,most possiblyγδT cells,are the dominant source of CXCL13 in KIRC TME.展开更多
基金Guangdong Basic and Applied Basic Research Foundation(No.2019B030302012)National Key Research and Development Project(No.2020YFA0509400)+3 种基金National Natural Science Foundation of China(No.81821002,82130082)Excellent Young Scientists Fund of Natural Science Foundation of Henan Province(222300420072)Distinguished Young Scientists Fund of Henan Provincial Health Commission(YXKC2020025)1.3.5 project for disciplines of excellence,West China Hospital,Sichuan University(ZYJC21004 and ZYGD22007)。
文摘Osteosarcoma,with poor survival after metastasis,is considered the most common primary bone cancer in adolescents.Notwithstanding the efforts of researchers,its five-year survival rate has only shown limited improvement,suggesting that existing therapeutic strategies are insufficient to meet clinical needs.Notably,immunotherapy has shown certain advantages over traditional tumor treatments in inhibiting metastasis.Therefore,managing the immune microenvironment in osteosarcoma can provide novel and valuable insight into the multifaceted mechanisms underlying the heterogeneity and progression of the disease.Additionally,given the advances in nanomedicine,there exist many advanced nanoplatforms for enhanced osteosarcoma immunotherapy with satisfactory physiochemical characteristics.Here,we review the classification,characteristics,and functions of the key components of the immune microenvironment in osteosarcoma.This review also emphasizes the application,progress,and prospects of osteosarcoma immunotherapy and discusses several nanomedicine-based options to enhance the efficiency of osteosarcoma treatment.Furthermore,we examine the disadvantages of standard treatments and present future perspectives for osteosarcoma immunotherapy.
基金Shaanxi Province Natural Science Foundation,China(Grant No.:2021JM-568).
文摘Hyaluronan and proteoglycan link protein 1(Hapln1)supports active cardiomyogenesis in zebrafish hearts,but its regulation in mammal cardiomyocytes is unclear.This study aimed to explore the potential regulation of Hapln1 in the dedifferentiation and proliferation of cardiomyocytes and its therapeutic value in myocardial infarction with human induced pluripotent stem cell(hiPSC)-derived cardiomyocytes(CMs)and an adult mouse model of myocardial infarction.HiPSC-CMs and adult mice with myocardial infarction were used as in vitro and in vivo models,respectively.Previous single-cell RNA sequencing data were retrieved for bioinformatic exploration.The results showed that recombinant human Hapln1(rhHapln1)promotes the proliferation of hiPSC-CMs in a dose-dependent manner.As a physical binding protein of Hapln1,versican interacted with Nodal growth differentiation factor(NODAL)and growth differentiation factor 11(GDF11).GDF11,but not NODAL,was expressed by hiPSC-CMs.GDF11 expression was unaffected by rhHapln1 treatment.However,this molecule was required for rhHapln1-mediated activation of the transforming growth factor(TGF)-β/Drosophila mothers against decapentaplegic protein(SMAD)2/3 signaling in hiPSC-CMs,which stimulates cell dedifferentiation and proliferation.Recombinant mouse Hapln1(rmHapln1)could induce cardiac regeneration in the adult mouse model of myocardial infarction.In addition,rmHapln1 induced hiPSC-CM proliferation.In conclusion,Hapln1 can stimulate the dedifferentiation and proliferation of iPSC-derived cardiomyocytes by promoting versican-based GDF11 trapping and subsequent activation of the TGF-β/SMAD2/3 signaling pathway.Hapln1 might be an effective hiPSC-CM dedifferentiation and proliferation agent and a potential reagent for repairing damaged hearts.
基金financially supported by the National Natural Science Foundation (31525009 and 31771096)The National Key Research and Development Program of China (2017YFC1103502)+2 种基金Sichuan Innovative Research Team Program for Young Scientists (2016TD0004)Distinguished Young Scholars of Sichuan University (2011SCU04B18)1·3·5 project for disciplines of excellence, West China Hospital, Sichuan University.
文摘Oral tyrosine kinase inhibitors(TKIs) against epidermal growth factor receptor(EGFR) family have been introduced into the clinic to treat human malignancies for decades. Despite superior properties of EGFR-TKIs as small molecule targeted drugs, their applications are still restricted due to their low solubility, capricious oral bioavailability, large requirement of daily dose, high binding tendency to plasma albumin and initial/acquired drug resistance. Nanotechnology is a promising tool to improve efficacy of these drugs. Through non-oral routes. Various nanotechnology-based delivery approaches have been developed for providing efficient delivery of EGFR-TKIs with a better pharmacokinetic profile and tissue-targeting ability. This review aims to indicate the advantage of nanocarriers for EGFR-TKIs delivery.
文摘A calculation method for heats of formation (HOF, referred to as △Hf) based on the density functional theory (DFT) is presented in this work. Similar to Gaussian-3 theory, the atomic scheme is applied to calculate the heats of formation of the molecules. In this method, we have modified the formula for calculation of Gaussian-3 theory in several ways, including the correction for diffuse functions and the correction for higher polarization functions. These corrections are found to be significant. The average absolute deviation from experiment for the 164 calculated heats of formation is about 1.9 kcal·mol?1, while average absolute deviation from G3MP2 for the 149 (among the 164 molecules, 15 large-sized molecules can not be calculated at the G3MP2 level) calculated heats of formation is only about 1.9 kcal·mol?1. It indicates that the present method can be applied to predict the heats of formation of medium-sized and large-sized molecules, while the heats of formation of these molecules using Gaussian-3 theory are much difficult, even impossible, to calculate. That is, this method provides a choice in the calculation of △Hf for medium-sized and large-sized molecules.
基金supported by the National Key Research and Development Project of China (2020YFA0509400)Guangdong Basic and Applied Basic Research Foundation(2019B030302012)+1 种基金National Natural Science Foundation of China (81821002, 82130082)1·3·5 project for disciplines of excellence (ZYGD22007,ZYGC21004)
文摘Oral squamous cell carcinoma (OSCC) develops on the mucosal epithelium of the oral cavity. It accounts for approximately 90% oforal malignancies and impairs appearance, pronunciation, swallowing, and flavor perception. In 2020, 377,713 OSCC cases werereported globally. According to the Global Cancer Observatory (GCO), the incidence of OSCC will rise by approximately 40% by2040, accompanied by a growth in mortality. Persistent exposure to various risk factors, including tobacco, alcohol, betel quid (BQ),and human papillomavirus (HPV), will lead to the development of oral potentially malignant disorders (OPMDs), which are oralmucosal lesions with an increased risk of developing into OSCC. Complex and multifactorial, the oncogenesis process involvesgenetic alteration, epigenetic modification, and a dysregulated tumor microenvironment. Although various therapeuticinterventions, such as chemotherapy, radiation, immunotherapy, and nanomedicine, have been proposed to prevent or treat OSCCand OPMDs, understanding the mechanism of malignancies will facilitate the identification of therapeutic and prognostic factors,thereby improving the efficacy of treatment for OSCC patients. This review summarizes the mechanisms involved in OSCC.Moreover, the current therapeutic interventions and prognostic methods for OSCC and OPMDs are discussed to facilitatecomprehension and provide several prospective outlooks for the fields.
基金supported by the National Natural Science Foundation of China [82172385 to H.S., 82172349 to Y.W.]the Key-Area Research and Development Program of Guangdong Province [2019B020236001 to H.S.]+3 种基金the Shenzhen Key Medical Discipline Construction Fund [ZDSYS20190902092851024 to H.S.]the Natural Science Foundation of Guangdong Province [2020A1515010097 to Z.X.]the Shenzhen Outstanding Science and Technology Innovation Talents-Outstanding Youth Fund project [RCYX20210706092106042 to Z.X.]Funding for open access charge:Shenzhen Key Medical Discipline Construction Fund。
文摘As the major cell precursors in osteogenesis, mesenchymal stem cells(MSCs) are indispensable for bone homeostasis and development. However, the primary mechanisms regulating osteogenic differentiation are controversial. Composed of multiple constituent enhancers, super enhancers(SEs) are powerful cis-regulatory elements that identify genes that ensure sequential differentiation. The present study demonstrated that SEs were indispensable for MSC osteogenesis and involved in osteoporosis development. Through integrated analysis, we identified the most common SE-targeted and osteoporosis-related osteogenic gene,ZBTB16. ZBTB16, positively regulated by SEs, promoted MSC osteogenesis but was expressed at lower levels in osteoporosis.Mechanistically, SEs recruited bromodomain containing 4(BRD4) at the site of ZBTB16, which then bound to RNA polymerase IIassociated protein 2(RPAP2) that transported RNA polymerase Ⅱ(POL Ⅱ) into the nucleus. The subsequent synergistic regulation of POL Ⅱ carboxyterminal domain(CTD) phosphorylation by BRD4 and RPAP2 initiated ZBTB16 transcriptional elongation, which facilitated MSC osteogenesis via the key osteogenic transcription factor SP7. Bone-targeting ZBTB16 overexpression had a therapeutic effect on the decreased bone density and remodeling capacity of Brd4^(fl/fl)Prx1-cre mice and osteoporosis(OP) models.Therefore, our study shows that SEs orchestrate the osteogenesis of MSCs by targeting ZBTB16 expression, which provides an attractive focus and therapeutic target for osteoporosis.
基金supported by grants from the Project of Sichuan Science and Technology Department,China(Grant No.:2021YJ0010).
文摘Ginsenoside Rg5 is a rare ginsenoside showing promising tumor-suppressive effects.This study aimed to explore its radio-sensitizing effects and the underlying mechanisms.Human lung adenocarcinoma cell lines A549 and Calu-3 were used for in vitro and in vivo analysis.Bioinformatic molecular docking prediction and following validation by surface plasmon resonance(SPR)technology,cellular thermal shift assay(CETSA),and isothermal titration calorimetry(ITC)were conducted to explore the binding between ginsenoside Rg5 and 90 kD heat shock protein alpha(HSP90a).The effects of ginsenoside Rg5 on HSP90-cell division cycle 37(CDC37)interaction,the client protein stability,and the downstream regulations were further explored.Results showed that ginsenoside Rg5 could induce cell-cycle arrest at the G1 phase and enhance irradiationinduced cell apoptosis.It could bind to HSP90a with a high affinity,but the affinity was drastically decreased by HSP90a Y61A mutation.Co-immunoprecipitation(Co-IP)and ITC assays confirmed that ginsenoside Rg5 disrupts the HSP90-CDC37 interaction in a dose-dependent manner.It reduced irradiation-induced upregulation of the HSP90-CDC37 client proteins,including SRC,CDK4,RAF1,and ULK1 in A549 cell-derived xenograft(CDX)tumors.Ginsenoside Rg5 or MRT67307(an IKKε/TBK1 inhibitor)pretreatment suppressed irradiation-induced elevation of the LC3-II/b ratio and restored irradiation-induced downregulation of p62 expression.In A549 CDX tumors,ginsenoside Rg5 treatment suppressed LC3 expression and enhanced irradiation-induced DNA damage.In conclusion,ginsenoside Rg5 may be a potential radiosensitizer for lung adenocarcinoma.It interacts with HSP90a and reduces the binding between HSP90 and CDC37,thereby increasing the ubiquitin-mediated proteasomal degradation of the HSP90-CDC37 client proteins.
基金supported by the National Natural Science Foundation of China(grant nos.82002135 and 82172250).
文摘The utilization of enteroviruses engineered with reporter genes serves as a valuable tool for advancing our understanding of enterovirus biology and its applications,enabling the development of effective therapeutic and preventive strategies.In this study,our initial attempts to introduce a NanoLuc luciferase(NLuc)reporter gene into recombinant enteroviruses were unsuccessful in rescuing viable progenies.We hypothesized that the size of the inserted tag might be a determining factor in the rescue of the virus.Therefore,we inserted the 11-amino-acid HiBiT tag into the genomes of enterovirus A71(EV-A71),coxsackievirus A10(CVA10),coxsackievirus A7(CVA7),coxsackievirus A16(CVA16),namely EV-A71-HiBiT,CVA16-HiBiT,CVA10-HiBiT,CVA7-HiBiT,and observed that the HiBiT-tagged viruses exhibited remarkably high rescue efficiency.Notably,the HiBiT-tagged enteroviruses displayed comparable characteristics to the wild-type viruses.A direct comparison between CVA16-NLuc and CVA16-HiBiT recombinant viruses revealed that the tiny HiBiT insertion had minimal impact on virus infectivity and replication kinetics.Moreover,these HiBiT-tagged enteroviruses demonstrated high genetic stability in different cell lines over multiple passages.In addition,the HiBiT-tagged viruses were successfully tested in antiviral drug assays,and the sensitivity of the viruses to drugs was not affected by the HiBiT tag.Ultimately,our findings provide definitive evidence that the integration of HiBiT into enteroviruses presents a universal,convenient,and invaluable method for advancing research in the realm of enterovirus virology.Furthermore,HiBiT-tagged enteroviruses exhibit great potential for diverse applications,including the development of antivirals and the elucidation of viral infection mechanisms.
基金supported by the National Natural Science Foundation of China(Nos.32222046 and 82172630)the Key R&D Projects of the Science and Technology Department of Sichuan Province(No.2021YFS0235)the 1·3·5 Project for Disciplines of Excellence,West China Hospital,Sichuan University(Nos.ZYJC21022 and 2019HXFH017)。
文摘Oral squamous cell carcinoma(OSCC)is known as one of the most malignant tumors with high recurrence and fatality rate.The poor tumor-targeting ability of traditional chemotherapeutic drugs has been a grand challenge for anti-OSCC therapy.Beyond that,a large quantity of tumor associated macrophages in OSCC tissues further diminish the anti-tumor effects of these drugs.Therefore,we produced a therapeutic nano drug delivery system(FA-PEG-PLA-JQ1)through encapsulating JQ1[a small-molecule inhibitor of bromodomain containing protein 4(BRD4)]into the folic acid(FA)-modified nanoparticle(PEG-PLA),which could prolong the half-life of JQ1 and target the tumor tissues.And then,JQ1 released from this nanoparticle could prevent OSCC growth inducing tumor cell apoptosis,inhibiting tumor angiogenesis and the polarization of M2 type macrophages.In conclusion,our date demonstrated the therapeutic benefits of FA-PEG-PLA-JQ1 against OSCC in vivo or in vitro,which could be a novel treatment strategy for OSCC in coming days.
基金supported by the National Natural Science Foundation of China(Nos.82172643,32222046 and 32371545,China)the Sichuan Science and Technology Program(No.2023NSFSC1931,China)the 1·3·5 Project for Disciplines of Excellence,West China Hospital,Sichuan University(No.ZYJC21022,China).
文摘Cancer remains a significant risk to human health.Nanomedicine is a new multidisciplinary field that is garnering a lot of interest and investigation.Nanomedicine shows great potential for cancer diagnosis and treatment.Specifically engineered nanoparticles can be employed as contrast agents in cancer diagnostics to enable high sensitivity and high-resolution tumor detection by imaging examinations.Novel approaches for tumor labeling and detection are also made possible by the use of nanoprobes and nanobiosensors.The achievement of targeted medication delivery in cancer therapy can be accomplished through the rational design and manufacture of nanodrug carriers.Nanoparticles have the capability to effectively transport medications or gene fragments to tumor tissues via passive or active targeting processes,thus enhancing treatment outcomes while minimizing harm to healthy tissues.Simultaneously,nanoparticles can be employed in the context of radiation sensitization and photothermal therapy to enhance the therapeutic efficacy of malignant tumors.This review presents a literature overview and summary of how nanotechnology is used in the diagnosis and treatment of malignant tumors.According to oncological diseases originating from different systems of the body and combining the pathophysiological features of cancers at different sites,we review the most recent developments in nanotechnology applications.Finally,we briefly discuss the prospects and challenges of nanotechnology in cancer.
基金the Ministry of Science and Technology of China(2018YFC1312300)National Natural Science Foundation of China(81722016,81801182)+1 种基金Sichuan Science and Technology Program(2018JPT0037,2018SZ0190)China Postdoctoral Science Foundation(2017M623041)。
文摘Ischemia/reperfusion(I/R) is a pathological process that occurs in numerous organs throughout the human body, and it is frequently associated with severe cellular damage and death. Recently it has emerged that ferroptosis, a new form of regulated cell death that is caused by iron-dependent lipid peroxidation, plays a significantly detrimental role in many I/R models. In this review, we aim to revise the pathological process of I/R and then explore the molecular pathogenesis of ferroptosis. Furthermore,we aim to evaluate the role that ferroptosis plays in I/R, providing evidence to support the targeting of ferroptosis in the I/R pathway may present as a therapeutic intervention to alleviate ischemia/reperfusion injury(IRI) associated cell damage and death.
基金supported by a grant from the National Natural Science Foundation of China(81071363)
文摘BACKGROUND： The long-term use of nudeos（t）ide analogues causes drug resistance and mutations in the HBV reverse tran- scriptase （RT） region of the polymerase gene. The RT region overlaps the HBV surface gene （S gene） and therefore, the mutations in the RT region simultaneously modify S gene sequence. Certain mutations in the RT region bring about truncated S proteins because the corresponding changed S gene encodes a stop codon which results in the loss of a large portion of the C-terminal hydrophobic region of HBV surface protein. The rtA181T/sW172＊, rtM204I/sW196＊ and rtV191I/sW182＊ are the most frequently reported drug-resistant mutations with C-terminal truncation, these mutations have oncogenic potential. DATA SOURCES： PubMed and Web of Science were searched using terms： ＂hepatitis B virus＂, ＂HBV drug resistance mutation＂ ＂HBV surface protein＂ ＂HBV truncation＂, ＂hepatocellular carcinoma＂, ＂rtA181T/sW172＊＂, ＂rtM204I/sW196＊＂, ＂rtV191I/sW182＊＂, and relevant articles published in English in the past decades were reviewed. RESULTS： The rtA181T/sW172＊ and rtV191I/sW182＊ mutants occurred more frequently than the rtM204I/sW196＊ mutant both in chronic hepatitis B patients and the HBV-related hepatocellular carcinoma tissues. Although these mutations occur naturally, nudeos（t）ide analogues therapy is the main driving force. These mutations may exist alone or coexist with other HBV mutations. All these three mutants impair the virion secretion and result in HBV surface protein retention and serum HBV DNA level reduction. These mutations possess potential carcinogenic properties. The three mutations are resistant to more than one nucleos（t）ide analogue and therefore, it is difficult to treat the patients with the truncated mutations.CONCLUSIONS： Nucleos（t）ide analogues induce drug resistance and HBV S gene truncated mutations. These mutations have potential carcinogenesis.
基金This work was supported by grants from the National Natural Science Foundation of China(Grant Nos.81772974,81972882,and 81874297)the Bilateral Inter-Governmental S&T Cooperation Project from Ministry of Science and Technology of China(Grant No.2018YFE0114300)+2 种基金the 1.3.5 Project for Disciplines of Excellence,West China Hospital,Sichuan University.We thank Dr.Scott McKercher(The Scripps Research Institute,La Jolla,CA,USA)Dr.Phillip Bryant(Childrens Hospital of Philadelphia,PA,USA)Dr.Cameron R.McKay(Nankai University School of Medicine,Tianjin,China)for revising the manuscript.
文摘Objective:Angiogenesis plays a vital role in tumor growth and metastasis.Here,we aimed to find novel efficient antiangiogenic molecules targeting vascular endothelial growth factor A(VEGFA)at the transcriptional level to treat triple-negative breast cancer(TNBC).Methods:We used a cell-based seryl tRNA synthetase(SerRS)promoter-driven dual-luciferase reporter system to screen an in-house library of 384 naturally occurring small molecules and their derivatives to find candidate molecules that could upregulate the expression of SerRS,a potent transcriptional repressor of VEGFA.The levels of SerRS and VEGFA were examined by quantitative RT-PCR(qRT-PCR),western blotting,and/or ELISAs in TNBC cells after candidate molecule administration.Zebrafish,the Matrigel plug angiogenesis assay in mice,the TNBC allograft,and xenograft mouse models were used to evaluate thein vivoanti-angiogenic and anti-cancer activities.Furthermore,the potential direct targets of the candidates were identified by proteomics and biochemical studies.Results:We found the most active compound was 3-(4-methoxyphenyl)quinolin-4(1H)-one(MEQ),an isoflavone derivative.In TNBC cells,MEQ treatment resulted in increased SerRS mRNA(P<0.001)and protein levels and downregulated VEGFA production.Both the vascular development of zebrafish and Matrigel plug angiogenesis in mice were inhibited by MEQ.MEQ also suppressed the angiogenesis in TNBC allografts and xenografts in mice,resulting in inhibited tumor growth and prolonged overall survival(P<0.05).Finally,we found that MEQ regulated SerRS transcription by interacting with MTA2(Metastasis Associated 1 Family Member 2).Conclusions:Our findings suggested that the MTA2/SerRS/VEGFA axis is a drug-treatable anti-angiogenic target,and MEQ is a promising anti-tumor molecule that merits further investigation for clinical applications.
基金the National Natural Science Foundation of China,Nos.81672097,81672128,and 81702120
文摘Mesenchymal stem cells(MSCs) are a subset of multipotent stroma cells residing in various tissues of the body. Apart from supporting the hematopoietic stem cell niche, MSCs possess strong immunoregulatory ability and multiple differentiation potentials. These powerful capacities allow the extensive application of MSCs in clinical practice as an effective treatment for diseases.Therefore, illuminating the functional mechanism of MSCs will help to improve their curative effect and promote their clinical use. Long noncoding RNA(LncRNA) is a novel class of noncoding RNA longer than 200 nt. Recently,multiple studies have demonstrated that LncRNA is widely involved in growth and development through controlling the fate of cells, including MSCs. In this review, we highlight the role of LncRNA in regulating the functions of MSCs and discuss their participation in the pathogenesis of diseases and clinical use in diagnosis and treatment.
基金This work was supported by Nation Science and Technology Major Projects for Major New Drugs Innovation and Development(2018ZX09711003-004-002 to L.C.)Ministry of Science and Technology of China National Key R&D Programs(2018YFA0506903 to L.C.)National Natural Science Foundation of China grants(91857108 to L.C.).
文摘Solute carriers(SLCs)are the largest family of transmembrane transporters that determine the exchange of various substances,including nutrients,ions,metabolites,and drugs across biological membranes.To date,the presence of about 287 SLC genes have been identified in the brain,among which mutations or the resultant dysfunctions of 71 SLC genes have been reported to be correlated with human brain disorders.Although increasing interest in SLCs have focused on drug development,SLCs are currently still under-explored as drug targets,especially in the brain.We summarize the main substrates and functions of SLCs that are expressed in the brain,with an emphasis on selected SLCs that are important physiologically,pathologically,and pharmacologically in the blood-brain barrier,astrocytes,and neurons.Evidence suggests that a fraction of SLCs are regulated along with the occurrences of brain disorders,among which epilepsy,neurodegenerative diseases,and autism are representative.Given the review of SLCs involved in the onset and procession of brain disorders,we hope these SLCs will be screened as promising drug targets to improve drug delivery to the brain.
基金National Natural Science Foundation of China,No.81871750 and No.81971518the Fundamental Research Funds for the Central Universities,No.19ykpy01 and No.20ykpy04the Key Laboratory of Basic Research and Clinical Translation of Ankylosing Spondylitis,No.ZDSYS20190902092851024.
文摘Mesenchymal stem cells(MSCs)are multipotent stromal cells with great potential for clinical applications.However,little is known about their cell heterogeneity at a single-cell resolution,which severely impedes the development of MSC therapy.In this review,we focus on advances in the identification of novel surface markers and functional subpopulations of MSCs made by single-cell RNA sequencing and discuss their participation in the pathophysiology of stem cells and related diseases.The challenges and future directions of single-cell RNA sequencing in MSCs are also addressed in this review.
基金Supported by Chinese Center for Disease Control and Prevention and the State Key Laboratory for Infectious Disease Prevention and Control,No.2011SKLID103Beijing Key Laboratory of Environmental and Viral Oncology,College of Life Science and Bio-Engineering,Beijing University of Technology(Grant sponsor:State 863 projects,No.2012AA02A404,No2014ZX10005002 and No.PXM2014_014204_07_000046)
文摘AIM:to study the prevalence of human papillomavirus(HPV) in esophageal carcinoma in tangshan,China,a high-incidence area.METHODS:Formalin-fixed,paraffin-embedded tissue specimens from 198 patients who were pathologically diagnosed with esophageal squamous cell carcinoma from 2011 to 2013 were obtained from a pathology department in Tangshan.DNA was extracted from all198 specimens to detect HPV by polymerase chain reaction(PCR).β-globin PCR was performed to check the quality of the DNA extraction procedure.PCR was performed to detect a wide range of HPV types,and type-specific PCR was performed to detect HPV types16 and 18.Negative and positive controls were used for HPV 16 and 18 detection.RESULTS:the DNA extraction method in this study appeared to be more effective than other previously reported methods.After DNA extraction,more than98%of the tissue specimens had an acceptable result in the DNA qualification test(β-globin PCR).the overall prevalence of HPV in tumor tissues by GP6+/GP5+PCR was 79.79%,and the prevalence of HPV types16 and 18 was 40.40%and 47.47%,respectively.PCR demonstrated the presence of HPV,and direct sequencing confirmed the HPV genotypes.All HPVpositive PCR products were checked by DNA sequence analysis using DNAman and compared with the known HPV sequences listed in the basic Local Alignment Search tool database to evaluate the HPV types.this analysis confirmed the presence of HPV types 16 and18.CONCLUSION:DNA of high-risk HPV types 16 and 18is present in esophageal tumors,implicating HPV as a possible etiologic factor for esophageal squamous cell carcinoma.
基金This work was supported by grants from the National Key R&D Program of China(2020YFA0509400)Guangdong Basic and Applied Basic Research Foundation(2019B030302012)+2 种基金the National Natural Science Foundation of China(81821002,82130082,81790251,81972665,82173003,82102738 and 82103168)1·3·5 project for disciplines of excellence,West China Hospital,Sichuan University(ZYGD22007 and ZYJC21004)the Science and Technology Foundation of Shenzhen(JCYJ20200109113810154).BioRender was used to create the figures.
文摘Recent advances in neoantigen research have accelerated the development and regulatory approval of tumor immunotherapies,including cancer vaccines,adoptive cell therapy and antibody-based therapies,especially for solid tumors.Neoantigens are newly formed antigens generated by tumor cells as a result of various tumor-specific alterations,such as genomic mutation,dysregulated RNA splicing,disordered post-translational modification,and integrated viral open reading frames.Neoantigens are recognized as non-self and trigger an immune response that is not subject to central and peripheral tolerance.The quick identification and prediction of tumor-specific neoantigens have been made possible by the advanced development of next-generation sequencing and bioinformatic technologies.Compared to tumor-associated antigens,the highly immunogenic and tumor-specific neoantigens provide emerging targets for personalized cancer immunotherapies,and serve as prospective predictors for tumor survival prognosis and immune checkpoint blockade responses.The development of cancer therapies will be aided by understanding the mechanism underlying neoantigen-induced anti-tumor immune response and by streamlining the process of neoantigen-based immunotherapies.This review provides an overview on the identification and characterization of neoantigens and outlines the clinical applications of prospective immunotherapeutic strategies based on neoantigens.We also explore their current status,inherent challenges,and clinical translation potential.
基金funded by the National Science and Technology Major Project for Major New Drug Innovation and Development(2017ZX09302010).
文摘The chemokine ligand 13-chemokine receptor 5(CXCL13-CXCR5)axis has been characterized as a critical tumor-promoting signaling pathway in the tumor microenvironment(TME)in multiple types of solid tumors.In this study,we analyzed the expression profile of CXCL13 in kidney clear cell carcinoma(KIRC)and its correlation with tumor-infiltrating immune cells(TIICs).A monoclonal antibody against CXCL13 with high affinity and purity was generated in our lab for western blot and immunohistochemistry(IHC).Bioinformatic analysis was performed based on bulk-seq data from the Cancer Genome Atlas(TCGA)-KIRC and single-cell RNA-seq data from scRNASeqDB and PanglaoDB.Results showed that high CXCL13 expression in TME was associated with shorter progression-free survival(PFS),disease-specific survival(DSS),and overall survival(OS).KIRC cell lines,as well as several other cancer cell lines,had negative CXCL13 expression.IHC staining from the Human Protein Atlas(HPA)and our tissue array indicated that CXCL13 might be mainly expressed by TIICs,but not KIRC tumor cells.CXCL13 expression was strongly and positively correlated withγδT cell abundance in TME.Besides,γδT cell infiltration was associated with poor survival of KIRC.Methylation 450k array data showed that CXCL13 promoter hypomethylation was common in TIICs.The methylation level of cg16361705 within the CXCL13 promoter might play an important role in modulating CXCL13 transcription.In conclusion,our study revealed that CXCL13 expression andγδT cell infiltration in TME is associated with unfavorable survival of KIRC.TIICs,most possiblyγδT cells,are the dominant source of CXCL13 in KIRC TME.
