Background:Macrovascular invasion(MaVI)occurs in nearly half of hepatocellular carcinoma(HCC)patients at diagnosis or during follow-up,which causes severe disease deterioration,and limits the possibility of surgical a...Background:Macrovascular invasion(MaVI)occurs in nearly half of hepatocellular carcinoma(HCC)patients at diagnosis or during follow-up,which causes severe disease deterioration,and limits the possibility of surgical approaches.This study aimed to investigate whether computed tomography(CT)-based radiomics analysis could help predict development of MaVI in HCC.Methods:A cohort of 226 patients diagnosed with HCC was enrolled from 5 hospitals with complete MaVI and prognosis follow-ups.CT-based radiomics signature was built via multi-strategy machine learning methods.Afterwards,MaVI-related clinical factors and radiomics signature were integrated to construct the final prediction model(CRIM,clinical-radiomics integrated model)via random forest modeling.Cox-regression analysis was used to select independent risk factors to predict the time of MaVI development.Kaplan-Meier analysis was conducted to stratify patients according to the time of MaVI development,progression-free survival(PFS),and overall survival(OS)based on the selected risk factors.Results:The radiomics signature showed significant improvement for MaVI prediction compared with conventional clinical/radiological predictors(P<0.001).CRIM could predict MaVI with satisfactory areas under the curve(AUC)of 0.986 and 0.979 in the training(n=154)and external validation(n=72)datasets,respectively.CRIM presented with excellent generalization with AUC of 0.956,1.000,and 1.000 in each external cohort that accepted disparate CT scanning protocol/manufactory.Peel9_fos_InterquartileRange[hazard ratio(HR)=1.98;P<0.001]was selected as the independent risk factor.The cox-regression model successfully stratified patients into the high-risk and low-risk groups regarding the time of MaVI development(P<0.001),PFS(P<0.001)and OS(P=0.002).Conclusions:The CT-based quantitative radiomics analysis could enable high accuracy prediction of subsequent MaVI development in HCC with prognostic implications.展开更多
BACKGROUND The treatment outcome of transarterial chemoembolization(TACE)in unresectable hepatocellular carcinoma(HCC)varies greatly due to the clinical heterogeneity of the patients.Therefore,several prognostic syste...BACKGROUND The treatment outcome of transarterial chemoembolization(TACE)in unresectable hepatocellular carcinoma(HCC)varies greatly due to the clinical heterogeneity of the patients.Therefore,several prognostic systems have been proposed for risk stratification and candidate identification for first TACE and repeated TACE(re-TACE).AIM To investigate the correlations between prognostic systems and radiological response,compare the predictive abilities,and integrate them in sequence for outcome prediction.METHODS This nationwide multicenter retrospective cohort consisted of 1107 unresectable HCC patients in 15 Chinese tertiary hospitals from January 2010 to May 2016.The Hepatoma Arterial-embolization Prognostic(HAP)score system and its modified versions(mHAP,mHAP2 and mHAP3),as well as the six-and-twelve criteria were compared in terms of their correlations with radiological response and overall survival(OS)prediction for first TACE.The same analyses were conducted in 912 patients receiving re-TACE to evaluate the ART(assessment for re-treatment with TACE)and ABCR(alpha-fetoprotein,Barcelona Clinic Liver Cancer,Child-Pugh and Response)systems for post re-TACE survival(PRTS).RESULTS All the prognostic systems were correlated with radiological response achieved by first TACE,and the six-and-twelve criteria exhibited the highest correlation(Spearman R=0.39,P=0.026)and consistency(Kappa=0.14,P=0.019),with optimal performance by area under the receiver operating characteristic curve of 0.71[95%confidence interval(CI):0.68-0.74].With regard to the prediction of OS,the mHAP3 system identified patients with a favorable outcome with the highest concordance(C)-index of 0.60(95%CI:0.57-0.62)and the best area under the receiver operating characteristic curve at any time point during follow-up;whereas,PRTS was well-predicted by the ABCR system with a C-index of 0.61(95%CI:0.59-0.63),rather than ART.Finally,combining the mHAP3 and ABCR systems identified candidates suitable for TACE with an improved median PRTS of 36.6 mo,compared with non-candidates with a median PRTS of 20.0 mo(logrank test P<0.001).CONCLUSION Radiological response to TACE is closely associated with tumor burden,but superior prognostic prediction could be achieved with the combination of mHAP3 and ABCR in patients with unresectable liver-confined HCC.展开更多
BACKGROUND Despite the promising prospects of using artificial intelligence and machine learning(ML)for disease classification and prediction purposes,the complexity and lack of explainability of this method make it d...BACKGROUND Despite the promising prospects of using artificial intelligence and machine learning(ML)for disease classification and prediction purposes,the complexity and lack of explainability of this method make it difficult to apply the constructed models in clinical practice.We developed and validated an interpretable ML model based on magnetic resonance imaging(MRI)radiomics and clinical features for the preoperative prediction of the pathological grades of hepatocellular carcinomas(HCCs).This model will help clinicians better understand the situation and develop personalized treatment plans.AIM To develop and validate an interpretable ML model for preoperative pathological grade prediction in HCC patients via a combination of multisequence MRI radiomics and clinical features.METHODS MRI and clinical data derived from 125 patients with HCCs confirmed by postoperative pathological examinations were retrospectively analyzed.The patients were randomly split into training and validation groups(7:3 ratio).Univariate and multivariate logistic regression analyses were performed to identify independent clinical predictors.The tumor lesions observed on axial fatsuppressed T2-weighted imaging(FS-T2WI),arterial phase(AP),and portal venous phase(PVP)images were delineated in a slice-by-slice manner using 3D-slicer to generate volumetric regions of interest,and radiomic features were extracted.Interclass correlation coefficients were calculated,and least absolute selection and shrinkage operator regression were conducted for feature selection purposes.Six predictive models were subsequently developed for pathological grade prediction:FS-T2WI,AP,PVP,integrated radiomics,clinical,and combined radiomics-clinical(RC)models.The effectiveness of these models was assessed by calculating their area under the receiver operating characteristic curve(AUC)values.The clinical applicability of the models was evaluated via decision curve analysis.Finally,the contributions of the different features contained in the model with optimal performance were interpreted via a SHapley Additive exPlanations analysis.RESULTS Among the 125 patients,87 were assigned to the training group,and 38 were assigned to the validation group.The maximum tumor diameter,hepatitis B virus status,and monocyte count were identified as independent predictors of pathological grade.Twelve optimal radiomic features were ultimately selected.The AUC values obtained for the FS-T2WI model,AP model,PVP model,radiomics model,clinical model,and combined RC model in the training group were 0.761[95%confidence interval(CI):0.562-0.857],0.870(95%CI:0.714-0.918),0.868(95%CI:0.714-0.959),0.917(95%CI:0.857-0.959),0.869(95%CI:0.643-0.973),and 0.941(95%CI:0.857-0.945),respectively;in the validation group,the AUC values were 0.724(95%CI:0.625-0.833),0.802(95%CI:0.686-1.000),0.797(95%CI:0.688-1.000),0.901(95%CI:0.833-0.906),0.865(95%CI:0.594-1.000),and 0.932(95%CI:0.812-1.000),respectively.The combined RC model demonstrated the best performance.Additionally,the decision curve analysis revealed that the combined RC model had satisfactory prediction efficiency,and the SHapley Additive exPlanations value analysis revealed that the“FS-T2WI-wavelet-HLL_gldm_Large Dependence High Gray Level Emphasis”feature contributed the most to the model,exhibiting a positive effect.CONCLUSION An interpretable ML model based on MRI radiomics provides a noninvasive tool for predicting the pathological grade of HCCs,which will help clinicians develop personalized treatment plans.展开更多
Pathogen infection is the main cause of human morbidity and death.Traditional antibiotics usually sterilize bacteria in chemical ways,which tends to develop serious antibiotic resistance.Cationic polymers exhibit good...Pathogen infection is the main cause of human morbidity and death.Traditional antibiotics usually sterilize bacteria in chemical ways,which tends to develop serious antibiotic resistance.Cationic polymers exhibit good bacterial inhibition with less resistance,but often face severe cytotoxicity toward normal cells.The optimization of polymeric antimicrobials for enhanced bactericidal capacity and improved biocompatibility is quite meaningful.In addition,photodynamic therapy(PDT)is a therapeutic modality with less susceptibility to develop resistance.Herein,a typical commercial polymeric antimicrobial,polyhexamethylene guanidine(PHMG)was selected for current proof-of-concept optimization due to its excellent bactericidal capacity but moderate biocompatibility.Eosin-Y(EoS)was copolymerized to afford EoS-labeled polymer conjugates,poly(2-(dimethylamino)ethyl methacrylate-co-eosin),P(DMAEMA-co-EoS),which was conjugated with PHMG to afford a novel polymeric antimicrobial,P(DMAEMA-co-EoS)-b-PHMG-b-P(DMAEMA-co-EoS),noted as PEoS-PHMG.It could efficiently kill broad-spectrum bacteria by physical damage and photodynamic therapy.Compared with PHMG,the bacterial inhibition of PEoS-PHMG was potentiated after the functionalization.Furthermore,PEoS-PHMG exhibited low cytotoxicity and minimal hemolysis,which was demonstrated by cell viability assays toward LO2 cells and RAW 264.7 cells as well as hemolytic assays against red blood cells.These results confirmed that the resultant PEoS-PHMG could act as promising alternative antibacterial materials with excellent broad-spectrum bacterial inhibition and favorable biocompatibility.展开更多
Background: The mechanisms by which acupuncture affects poststroke cognitive impairment (PSCI) remain unclear. Objective: To investigate brain functional network (BFN) changes in patients with PSCI after acupuncture t...Background: The mechanisms by which acupuncture affects poststroke cognitive impairment (PSCI) remain unclear. Objective: To investigate brain functional network (BFN) changes in patients with PSCI after acupuncture therapy. Methods: Twenty-two PSCI patients who underwent acupuncture therapy in our hospital were enrolled as research subjects. Another 14 people matched for age, sex, and education level were included in the normal control (HC) group. All the subjects underwent resting-state functional magnetic resonance imaging (rs-fMRI) scans;the PSCI patients underwent one scan before acupuncture therapy and another after. The network metric difference between PSCI patients and HCs was analyzed via the independent-sample t test, whereas the paired-sample t test was employed to analyze the network metric changes in PSCI patients before vs. after treatment. Results: Small-world network attributes were observed in both groups for sparsities between 0.1 and 0.28. Compared with the HC group, the PSCI group presented significantly lower values for the global topological properties (γ, Cp, and Eloc) of the brain;significantly greater values for the nodal attributes of betweenness centrality in the CUN. L and the HES. R, degree centrality in the SFGdor. L, PCG. L, IPL. L, and HES. R, and nodal local efficiency in the ORBsup. R, ORBsupmed. R, DCG. L, SMG. R, and TPOsup. L;and decreased degree centrality in the MFG. R, IFGoperc. R, and SOG. R. After treatment, PSCI patients presented increased degree centrality in the LING.L, LING.R, and IOG. L and nodal local efficiency in PHG. L, IOG. R, FFG. L, and the HES. L, and decreased betweenness centrality in the PCG. L and CUN. L, degree centrality in the ORBsupmed. R, and nodal local efficiency in ANG. R. Conclusion: Cognitive decline in PSCI patients may be related to BFN disorders;acupuncture therapy may modulate the topological properties of the BFNs of PSCI patients.展开更多
Introduction Liver cancer remains a global health challenge,and its incidence is increasing worldwide.It is estimated that by 2025,more than one million individuals will be affected by liver cancer annually[1,2].In re...Introduction Liver cancer remains a global health challenge,and its incidence is increasing worldwide.It is estimated that by 2025,more than one million individuals will be affected by liver cancer annually[1,2].In recent years,ablation has become a widely accepted treatment option for patients with primary and secondary liver malignancies[3].The commonly used ablation method for liver cancer is thermal ablation,including radiofrequency ablation.展开更多
With continuous advancements in interventional radiology,considerable progress has been made in transarterial therapies for hepatocellular carcinoma(HCC)in recent years,and an increasing number of research papers on t...With continuous advancements in interventional radiology,considerable progress has been made in transarterial therapies for hepatocellular carcinoma(HCC)in recent years,and an increasing number of research papers on transarterial therapies for HCC have been published.In this editorial,we comment on the article by Ma et al published in the recent issue of the World Journal of Gastrointestinal Oncology:“Efficacy and predictive factors of transarterial chemoembolization combined with lenvatinib plus programmed cell death protein-1 inhibition for unresectable HCC”.We focus specifically on the current research status and future directions of transarterial therapies.In the future,more studies are needed to determine the optimal transarterial local treatment for HCC.With the emergence of checkpoint immunotherapy modalities,it is expected that the results of trials of transarterial local therapy combined with systemic therapy will bring new hope to HCC patients.展开更多
BACKGROUND Malignant peripheral nerve sheath tumor(MPNST)is a type of spindle cell sarcoma originating from the peripheral nerve,which usually results in the corresponding nerve sign on magnetic resonance imaging(MRI)...BACKGROUND Malignant peripheral nerve sheath tumor(MPNST)is a type of spindle cell sarcoma originating from the peripheral nerve,which usually results in the corresponding nerve sign on magnetic resonance imaging(MRI).Patients with MPNST may also have neurofibromatosis type 1.CASE SUMMARY A 78-year-old male was admitted to the hospital due to a tumor in his left knee.He had a previous history of superficial spreading melanoma on the left thigh.Color Doppler ultrasonography showed a hypoechoic mass in the subcutaneous soft tissues of the medial left knee with an abundant rich blood flow.Computed tomography scanning did not show obvious signs of bone destruction,but the skin adjacent to the tumor was slightly thickened.MRI examination revealed that the hypervascular lesion was well-circumscribed,lobulated,invaded the surrounding soft tissues and demonstrated heterogeneous enhancement but lacked an entering and exiting nerve sign.The MRI result indicated the invasiveness of the tumor.The patient underwent a left knee joint mass expanded resection and the first histopathological examination showed a MPNST with positive surgical margins.Therefore,the second extended resection was performed,and the patient had a good outcome in the short term.CONCLUSION MRI is a useful technique for revealing the biological characteristics of MPNST and provides clinical support for evaluation of the surgical area before operation.展开更多
Primary hepatocellular carcinoma is one of the most common and deadliest malignant tumors in the world, and most patients are diagnosed after missing the optimal treatment period. TACE (Transcatheter arterial chemoemb...Primary hepatocellular carcinoma is one of the most common and deadliest malignant tumors in the world, and most patients are diagnosed after missing the optimal treatment period. TACE (Transcatheter arterial chemoembolization) is currently the preferred treatment for advanced HCC (Hepatocellular Carcinoma), as it can induce local ischemic necrosis of the tumor while reducing the systemic side effects of drugs by embolizing the tumor-feeding arteries. Lipiodol, with its unique comprehensive properties of imaging, drug loading, and embolization, has become a key component in the process of TACE. Therefore, analyzing the deposition of lipiodol in hepatic tumor tissues after TACE can effectively evaluate the treatment efficacy. This article summarizes and analyzes the metabolism of lipiodol in tumors and the clinical application of lipiodol deposition status in predicting patient prognosis, aiming to provide clearer diagnostic and treatment strategies for clinical doctors.展开更多
Arrhythmogenic right ventricular cardiomyopathy/dysplasia(ARVC/D)is characterized by progressive fibro-fatty replacement of cardiac myocytes in both ventricles,with the risk of heart failure and sudden death1,2.System...Arrhythmogenic right ventricular cardiomyopathy/dysplasia(ARVC/D)is characterized by progressive fibro-fatty replacement of cardiac myocytes in both ventricles,with the risk of heart failure and sudden death1,2.Systemic thromboembolism,including pulmonary embolism and cerebral infarction,was an essential risk of worsening prognosis of ARVC/D.展开更多
Objective: To explore regional homogeneity (ReHo) alterations after acupuncture treatment in poststroke cognitive impairment (PSCI) patients. Methods: Twenty-one PSCI patients who underwent acupuncture therapy in our ...Objective: To explore regional homogeneity (ReHo) alterations after acupuncture treatment in poststroke cognitive impairment (PSCI) patients. Methods: Twenty-one PSCI patients who underwent acupuncture therapy in our hospital and 12 matched healthy controls were enrolled in this study. All study subjects underwent resting-state functional magnetic resonance imaging (rs-fMRI);for PSCI patients, rs-fMRI scans were conducted before and after acupuncture therapy. Data preprocessing was performed using the DPARSF5.4 and SPM12 toolkits on the MATLAB 2022b platform. DPARSF5.4 was used to calculate the ReHo index of the preprocessed resting-state data. A two-sample t-test was used to compare the differences in ReHo between the PSCI patients group pretreatment and the control group (with sex and age as covariates), and a paired t-test was used to compare the differences in ReHo between the pretreatment and posttreatment groups of PSCI patients (without covariates). AAL_116_binary_mask.nii was used as the statistical mask, and the statistical results were corrected using family-wise error correction, with P Conclusion: PSCI patients exhibited abnormal ReHo in the resting state, and ReHo was significantly altered after acupuncture treatment. The results of this study suggest that ReHo might be a potential biomarker in the diagnosis and treatment of PSCI.展开更多
The newly emerged severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) has infected millions of people and caused tremendous morbidity and mortality worldwide. Effective treatment for coronavirus disease 2019(C...The newly emerged severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) has infected millions of people and caused tremendous morbidity and mortality worldwide. Effective treatment for coronavirus disease 2019(COVID-19) due to SARSCoV-2 infection is lacking, and different therapeutic strategies are under testing. Host humoral and cellular immunity to SARSCoV-2 infection is a critical determinant for patients’ outcomes. SARS-CoV-2 infection results in seroconversion and production of anti-SARS-CoV-2 antibodies. The antibodies may suppress viral replication through neutralization but might also participate in COVID-19 pathogenesis through a process termed antibody-dependent enhancement. Rapid progress has been made in the research of antibody response and therapy in COVID-19 patients, including characterization of the clinical features of antibody responses in different populations infected by SARS-CoV-2, treatment of COVID-19 patients with convalescent plasma and intravenous immunoglobin products, isolation and characterization of a large panel of monoclonal neutralizing antibodies and early clinical testing, as well as clinical results from several COVID-19 vaccine candidates. In this review, we summarize the recent progress and discuss the implications of these findings in vaccine development.展开更多
Acute myeloid leukaemia(AML) is the most common form of acute leukaemia in adults,with increasing incidence with age and a generally poor prognosis.Almost 20% of AML patients express mutant isocitrate dehydrogenase 2(...Acute myeloid leukaemia(AML) is the most common form of acute leukaemia in adults,with increasing incidence with age and a generally poor prognosis.Almost 20% of AML patients express mutant isocitrate dehydrogenase 2(mIDH2),which leads to the accumulation of the carcinogenic metabolite 2-hydroxyglutarate(2-HG),resulting in poor prognosis.Thus,global institutions have been working to develop mIDH2 inhibitors.SH1573 is a novel mIDH2 inhibitor that we independently designed and synthesised.We have conducted a comprehensive study on its pharmacodynamics,pharmacokinetics and safety.First,SH1573 exhibited a strong selective inhibition of mIDH2 R140 Q protein,which could effectively reduce the production of 2-HG in cell lines,serum and tumors of an animal model.It could also promote the differentiation of mutant AML cell lines and granulocytes in PDX models.Then,it was confirmed that SH1573 possessed characteristics of high bioavailability,good metabolic stability and wide tissue distribution.Finally,toxicological data showed that SH1573 had no effects on the respiratory system,cardiovascular system and nervous system,and was genetically safe.This research successfully promoted the approval of SH1573 for clinical trials(CTR20200247).All experiments demonstrated that,as a potential drug against mIDH2 R140 Q acute myeloid leukaemia,SH1573 was effective and safe.展开更多
Tumor microenvironment has been widely utilized for advanced drug delivery in recent years,among which hypoxia-responsive drug delivery systems have become the research hotspot.Although hypoxia-responsive micelles or ...Tumor microenvironment has been widely utilized for advanced drug delivery in recent years,among which hypoxia-responsive drug delivery systems have become the research hotspot.Although hypoxia-responsive micelles or polymersomes have been successfully developed,a type of hypoxia-degradable nanogel has rarely been reported and the advantages of hypoxia-degradable nanogel over other kinds of degradable nanogels in tumor drug delivery remain unclear.Herein,we reported the synthesis of a novel hypoxia-responsive crosslinker and the fabrication of a hypoxia-degradable zwitterionic poly(phosphorylcholine)-based(HPMPC)nanogel for tumor drug delivery.The obtained HPMPC nanogel showed ultra-long blood circulation and desirable immune compatibility,which leads to high and long-lasting accumulation in tumor tissue.Furthermore,HPMPC nanogel could rapidly degrade into oligomers of low molecule weight owing to the degradation of azo bond in hypoxic environment,which leads to the effective release of the loaded drug.Impressively,HPMPC nanogel showed superior tumor inhibition effect both in vitro and in vivo compared to the reduction-responsive phosphorylcholine-based nanogel,owing to the more complete drug release.Overall,the drug-loaded HPMPC nanogel exhibits a pronounced tumor inhibition effect in a humanized subcutaneous liver cancer model with negligible side effects,which showed great potential as nanocarrier for advanced tumor drug delivery.展开更多
N6-methyladenosine(m^(6)A),the most common and abundant epigenetic RNA modification,governs mRNA metabolism to determine cell differentiation,proliferation and response to stimulation.m^(6)A methyltransferase METTL3 h...N6-methyladenosine(m^(6)A),the most common and abundant epigenetic RNA modification,governs mRNA metabolism to determine cell differentiation,proliferation and response to stimulation.m^(6)A methyltransferase METTL3 has been reported to control T cell homeostasis and sustain the suppressive function of regulatory T cells(Tregs).However,the role of m^(6)A methyltransferase in other subtypes of T cells remains unknown.T helper cells 17(Th17)play a pivotal role in host defense and autoimmunity.Here,we found that the loss of METTL3 in T cells caused serious defect of Th17 cell differentiation,and impeded the development of experimental autoimmune encephalomyelitis(EAE).We generated Mettl3f/fIl17aCre mice and observed that METTL3 deficiency in Th17 cells significantly suppressed the development of EAE and displayed less Th17 cell infiltration into central nervous system(CNS).Importantly,we demonstrated that depletion of METTL3 attenuated IL-17A and CCR5 expression by facilitating SOCS3 mRNA stability in Th17 cells,leading to disrupted Th17 cell differentiation and infiltration,and eventually attenuating the process of EAE.Collectively,our results highlight that m^(6)A modification sustains Th17 cell function,which provides new insights into the regulatory network of Th17 cells,and also implies a potential therapeutic target for Th17 cell mediated autoimmune disease.展开更多
Arrhythmogenic cardiomyopathy(ACM),a fatal heart disease characterized by fibroadipocytic replacement of cardiac myocytes,accounts for 20%of sudden cardiac death and lacks effective treatment.It is often caused by mut...Arrhythmogenic cardiomyopathy(ACM),a fatal heart disease characterized by fibroadipocytic replacement of cardiac myocytes,accounts for 20%of sudden cardiac death and lacks effective treatment.It is often caused by mutations in desmosome proteins,with Desmoglein-2(DSG2)mutations as a common etiology.However,the mechanism underlying the accumulation of fibrofatty in ACM remains unknown,which impedes the development of curative treatment.Here we investigated the fat accumulation and the underlying mechanism in a mouse model of ACM induced by cardiac-specific knockout of Dsg2(CS-Dsg2^(-/-)).Heart failure and cardiac lipid accumulation were observed in CSDsg2^(-/-)mice.We demonstrated that these phenotypes were caused by decline of fatty acid(FA)β-oxidation resulted from impaired mammalian target of rapamycin(m TOR)signaling.Rapamycin worsened while overexpression of m TOR and 4EBP1 rescued the FAβ-oxidation pathway in CS-Dsg2^(-/-)mice.Reactivation of PPARa by fenofibrate or AAV9-Ppara significantly alleviated the lipid accumulation and restored cardiac function.Our results suggest that impaired m TOR-4EBP1-PPARa-dependent FAβ-oxidation contributes to myocardial lipid accumulation in ACM and PPARa may be a potential target for curative treatment of ACM.展开更多
Tumor cells undergoing immunogenic cell death (ICD) have emerged as an in situ therapeutic vaccine helping to activate a persistent anti-tumor response. Several chemotherapeutic agents have been demonstrated to induce...Tumor cells undergoing immunogenic cell death (ICD) have emerged as an in situ therapeutic vaccine helping to activate a persistent anti-tumor response. Several chemotherapeutic agents have been demonstrated to induce ICD, however accompanied with severe adverse effects in the clinic, weakening its immune responses. Herein, to elicit an intensive ICD while minimizing the systemic toxicity, we introduce a tumor targeting peptide modified bortezomib (BTZ) loading nanomedicine (i-NPBTZ) for the efficient delivery and controlled release of BTZ in tumors. This system is constructed by conjugating BTZ to PEGylated polyphenols via a pH-sensitive covalent boronate-phenol bond that allows them to self-assemble into nanovesicles in neutral condition with high drug loading efficiency. Once accumulated in acidic environment, BTZ-phenolic network is disassembled and thereby accelerates the release of BTZ from nanocarriers. The released BTZ selectively kill tumor cells with a concomitant evocation of tumor-specific cytotoxic T cells by triggering ICD in vivo. This can finally lead to an extended tumor ablation and prevention of distant metastasis in a syngeneic tumor mouse model, while reducing the systemic toxicity of BTZ. In general, our system offers a novel concept with clinical potential to exploit ICD for potentiating tumor immunotherapy and also provides an excellent example of the application of polymer-drug interaction for efficient drug delivery and controllable release.展开更多
Interleukin-27(IL-27),a heterodimeric cytokine,plays a protective role in diabetes.Ghrelin,a gastric hormone,provides a hunger signal to the central nervous system to stimulate food intake.The relationship between IL-...Interleukin-27(IL-27),a heterodimeric cytokine,plays a protective role in diabetes.Ghrelin,a gastric hormone,provides a hunger signal to the central nervous system to stimulate food intake.The relationship between IL-27 and ghrelin is still unexplored.Here we investigated that signal transducer and activator of transcription 3(STAT3)—mechanistic target of rapamycin(mTOR)signaling mediates the suppression of ghrelin induced by IL-27.Co-localization of interleukin 27 receptor subunit alpha(WSX-1)and ghrelin was observed in mouse and human gastric mucosa.Intracerebroventricular injection of IL-27 markedly suppressed ghrelin synthesis and secretion while stimulating STAT3-mTOR signaling in both C57 BL/6 J mice and high-fat diet-induced-obese mice.IL-27 inhibited the production of ghrelin in mHypoE-N42 cells.Inhibition of mTOR activity induced by mTOR siRNA or rapamycin blocked the suppression of ghrelin production induced by IL-27 in mHypoE-N42 cells.Stat 3 siRNA also abolished the inhibitory effect of IL-27 on ghrelin.IL-27 increased the interaction between STAT3 and mTOR in mHypoE-N42 cells.In conclusion,IL-27 suppresses ghrelin production through the STAT3-mTOR dependent mechanism.展开更多
A novel coronavirus disease 2019(COVID-19)emerged around December 2019 in Wuhan,China and has spread rapidly worldwide(Lu et al.,2020).Until March 27,2020,the Chinese health authorities had reported 82082 confirmed CO...A novel coronavirus disease 2019(COVID-19)emerged around December 2019 in Wuhan,China and has spread rapidly worldwide(Lu et al.,2020).Until March 27,2020,the Chinese health authorities had reported 82082 confirmed COVID-19 cases in China with 3298 deaths and 381443 confirmed cases with 20787 deaths outside China.The World Health Organization(WHO)named the virus SARS-CoV-2,which belongs to a distinct clade from the human severe acute respiratory syndrome CoV(SARS-CoV)and Middle East respiratory syndrome CoV(MERSCoV)(Zhu et al.,2020).展开更多
The microenvironment of hypoxia and immune-cold limits the therapeutic outcomes of immune checkpoint blockade(ICB)therapy in solid tumors.It is important and imperative to search new strategies to relieve tumor hypoxi...The microenvironment of hypoxia and immune-cold limits the therapeutic outcomes of immune checkpoint blockade(ICB)therapy in solid tumors.It is important and imperative to search new strategies to relieve tumor hypoxia and reverse immunosuppression of cold tumors.In this study,the oxygen(O_(2))self-replenishing nano-enabled coordination platform can be used to induce potent antitumor immune response in cold tumors.The nanoplatform can produce O_(2)by catalyzing hydrogen peroxide(H_(2)O_(2))in tumor site effectively,showing excellent photodynamic therapy(PDT)performance.Meanwhile,it can further trigger immunogenic cell death(ICD),enhance T cell infiltration,reverse immunosuppression,and reprogram the immune-cold tumor microenvironment.In vitro and in vivo results demonstrate that the nanoplatform has potential for eradicating tumors and long-term immunological memory effect.The nanoplatform opens up a strategy for reprograming the immunosuppressive microenvironment in cold tumors.展开更多
基金supported by grants from the National Key R&D Program of China(2017YFA0205200,2017YFC1308701,and 2017YFC1309100)National Natural Science Foundation of China(82001917,81930053,81227901,81771924,81501616,81571785,81771957,and 61671449)the Natural Science Foundation of Guangdong Province,China(2016A030311055 and 2016A030313770)。
文摘Background:Macrovascular invasion(MaVI)occurs in nearly half of hepatocellular carcinoma(HCC)patients at diagnosis or during follow-up,which causes severe disease deterioration,and limits the possibility of surgical approaches.This study aimed to investigate whether computed tomography(CT)-based radiomics analysis could help predict development of MaVI in HCC.Methods:A cohort of 226 patients diagnosed with HCC was enrolled from 5 hospitals with complete MaVI and prognosis follow-ups.CT-based radiomics signature was built via multi-strategy machine learning methods.Afterwards,MaVI-related clinical factors and radiomics signature were integrated to construct the final prediction model(CRIM,clinical-radiomics integrated model)via random forest modeling.Cox-regression analysis was used to select independent risk factors to predict the time of MaVI development.Kaplan-Meier analysis was conducted to stratify patients according to the time of MaVI development,progression-free survival(PFS),and overall survival(OS)based on the selected risk factors.Results:The radiomics signature showed significant improvement for MaVI prediction compared with conventional clinical/radiological predictors(P<0.001).CRIM could predict MaVI with satisfactory areas under the curve(AUC)of 0.986 and 0.979 in the training(n=154)and external validation(n=72)datasets,respectively.CRIM presented with excellent generalization with AUC of 0.956,1.000,and 1.000 in each external cohort that accepted disparate CT scanning protocol/manufactory.Peel9_fos_InterquartileRange[hazard ratio(HR)=1.98;P<0.001]was selected as the independent risk factor.The cox-regression model successfully stratified patients into the high-risk and low-risk groups regarding the time of MaVI development(P<0.001),PFS(P<0.001)and OS(P=0.002).Conclusions:The CT-based quantitative radiomics analysis could enable high accuracy prediction of subsequent MaVI development in HCC with prognostic implications.
文摘BACKGROUND The treatment outcome of transarterial chemoembolization(TACE)in unresectable hepatocellular carcinoma(HCC)varies greatly due to the clinical heterogeneity of the patients.Therefore,several prognostic systems have been proposed for risk stratification and candidate identification for first TACE and repeated TACE(re-TACE).AIM To investigate the correlations between prognostic systems and radiological response,compare the predictive abilities,and integrate them in sequence for outcome prediction.METHODS This nationwide multicenter retrospective cohort consisted of 1107 unresectable HCC patients in 15 Chinese tertiary hospitals from January 2010 to May 2016.The Hepatoma Arterial-embolization Prognostic(HAP)score system and its modified versions(mHAP,mHAP2 and mHAP3),as well as the six-and-twelve criteria were compared in terms of their correlations with radiological response and overall survival(OS)prediction for first TACE.The same analyses were conducted in 912 patients receiving re-TACE to evaluate the ART(assessment for re-treatment with TACE)and ABCR(alpha-fetoprotein,Barcelona Clinic Liver Cancer,Child-Pugh and Response)systems for post re-TACE survival(PRTS).RESULTS All the prognostic systems were correlated with radiological response achieved by first TACE,and the six-and-twelve criteria exhibited the highest correlation(Spearman R=0.39,P=0.026)and consistency(Kappa=0.14,P=0.019),with optimal performance by area under the receiver operating characteristic curve of 0.71[95%confidence interval(CI):0.68-0.74].With regard to the prediction of OS,the mHAP3 system identified patients with a favorable outcome with the highest concordance(C)-index of 0.60(95%CI:0.57-0.62)and the best area under the receiver operating characteristic curve at any time point during follow-up;whereas,PRTS was well-predicted by the ABCR system with a C-index of 0.61(95%CI:0.59-0.63),rather than ART.Finally,combining the mHAP3 and ABCR systems identified candidates suitable for TACE with an improved median PRTS of 36.6 mo,compared with non-candidates with a median PRTS of 20.0 mo(logrank test P<0.001).CONCLUSION Radiological response to TACE is closely associated with tumor burden,but superior prognostic prediction could be achieved with the combination of mHAP3 and ABCR in patients with unresectable liver-confined HCC.
文摘BACKGROUND Despite the promising prospects of using artificial intelligence and machine learning(ML)for disease classification and prediction purposes,the complexity and lack of explainability of this method make it difficult to apply the constructed models in clinical practice.We developed and validated an interpretable ML model based on magnetic resonance imaging(MRI)radiomics and clinical features for the preoperative prediction of the pathological grades of hepatocellular carcinomas(HCCs).This model will help clinicians better understand the situation and develop personalized treatment plans.AIM To develop and validate an interpretable ML model for preoperative pathological grade prediction in HCC patients via a combination of multisequence MRI radiomics and clinical features.METHODS MRI and clinical data derived from 125 patients with HCCs confirmed by postoperative pathological examinations were retrospectively analyzed.The patients were randomly split into training and validation groups(7:3 ratio).Univariate and multivariate logistic regression analyses were performed to identify independent clinical predictors.The tumor lesions observed on axial fatsuppressed T2-weighted imaging(FS-T2WI),arterial phase(AP),and portal venous phase(PVP)images were delineated in a slice-by-slice manner using 3D-slicer to generate volumetric regions of interest,and radiomic features were extracted.Interclass correlation coefficients were calculated,and least absolute selection and shrinkage operator regression were conducted for feature selection purposes.Six predictive models were subsequently developed for pathological grade prediction:FS-T2WI,AP,PVP,integrated radiomics,clinical,and combined radiomics-clinical(RC)models.The effectiveness of these models was assessed by calculating their area under the receiver operating characteristic curve(AUC)values.The clinical applicability of the models was evaluated via decision curve analysis.Finally,the contributions of the different features contained in the model with optimal performance were interpreted via a SHapley Additive exPlanations analysis.RESULTS Among the 125 patients,87 were assigned to the training group,and 38 were assigned to the validation group.The maximum tumor diameter,hepatitis B virus status,and monocyte count were identified as independent predictors of pathological grade.Twelve optimal radiomic features were ultimately selected.The AUC values obtained for the FS-T2WI model,AP model,PVP model,radiomics model,clinical model,and combined RC model in the training group were 0.761[95%confidence interval(CI):0.562-0.857],0.870(95%CI:0.714-0.918),0.868(95%CI:0.714-0.959),0.917(95%CI:0.857-0.959),0.869(95%CI:0.643-0.973),and 0.941(95%CI:0.857-0.945),respectively;in the validation group,the AUC values were 0.724(95%CI:0.625-0.833),0.802(95%CI:0.686-1.000),0.797(95%CI:0.688-1.000),0.901(95%CI:0.833-0.906),0.865(95%CI:0.594-1.000),and 0.932(95%CI:0.812-1.000),respectively.The combined RC model demonstrated the best performance.Additionally,the decision curve analysis revealed that the combined RC model had satisfactory prediction efficiency,and the SHapley Additive exPlanations value analysis revealed that the“FS-T2WI-wavelet-HLL_gldm_Large Dependence High Gray Level Emphasis”feature contributed the most to the model,exhibiting a positive effect.CONCLUSION An interpretable ML model based on MRI radiomics provides a noninvasive tool for predicting the pathological grade of HCCs,which will help clinicians develop personalized treatment plans.
基金supported by the Natural Science Foundation for Distinguished Young Scholars of Guangdong Province(No.2016A030306013)the Pearl River Young Talents Program of Science and Technology in Guangzhou(No.201906010047)the National Key Research and Development Program of China(No.2017YFA0205200)。
文摘Pathogen infection is the main cause of human morbidity and death.Traditional antibiotics usually sterilize bacteria in chemical ways,which tends to develop serious antibiotic resistance.Cationic polymers exhibit good bacterial inhibition with less resistance,but often face severe cytotoxicity toward normal cells.The optimization of polymeric antimicrobials for enhanced bactericidal capacity and improved biocompatibility is quite meaningful.In addition,photodynamic therapy(PDT)is a therapeutic modality with less susceptibility to develop resistance.Herein,a typical commercial polymeric antimicrobial,polyhexamethylene guanidine(PHMG)was selected for current proof-of-concept optimization due to its excellent bactericidal capacity but moderate biocompatibility.Eosin-Y(EoS)was copolymerized to afford EoS-labeled polymer conjugates,poly(2-(dimethylamino)ethyl methacrylate-co-eosin),P(DMAEMA-co-EoS),which was conjugated with PHMG to afford a novel polymeric antimicrobial,P(DMAEMA-co-EoS)-b-PHMG-b-P(DMAEMA-co-EoS),noted as PEoS-PHMG.It could efficiently kill broad-spectrum bacteria by physical damage and photodynamic therapy.Compared with PHMG,the bacterial inhibition of PEoS-PHMG was potentiated after the functionalization.Furthermore,PEoS-PHMG exhibited low cytotoxicity and minimal hemolysis,which was demonstrated by cell viability assays toward LO2 cells and RAW 264.7 cells as well as hemolytic assays against red blood cells.These results confirmed that the resultant PEoS-PHMG could act as promising alternative antibacterial materials with excellent broad-spectrum bacterial inhibition and favorable biocompatibility.
文摘Background: The mechanisms by which acupuncture affects poststroke cognitive impairment (PSCI) remain unclear. Objective: To investigate brain functional network (BFN) changes in patients with PSCI after acupuncture therapy. Methods: Twenty-two PSCI patients who underwent acupuncture therapy in our hospital were enrolled as research subjects. Another 14 people matched for age, sex, and education level were included in the normal control (HC) group. All the subjects underwent resting-state functional magnetic resonance imaging (rs-fMRI) scans;the PSCI patients underwent one scan before acupuncture therapy and another after. The network metric difference between PSCI patients and HCs was analyzed via the independent-sample t test, whereas the paired-sample t test was employed to analyze the network metric changes in PSCI patients before vs. after treatment. Results: Small-world network attributes were observed in both groups for sparsities between 0.1 and 0.28. Compared with the HC group, the PSCI group presented significantly lower values for the global topological properties (γ, Cp, and Eloc) of the brain;significantly greater values for the nodal attributes of betweenness centrality in the CUN. L and the HES. R, degree centrality in the SFGdor. L, PCG. L, IPL. L, and HES. R, and nodal local efficiency in the ORBsup. R, ORBsupmed. R, DCG. L, SMG. R, and TPOsup. L;and decreased degree centrality in the MFG. R, IFGoperc. R, and SOG. R. After treatment, PSCI patients presented increased degree centrality in the LING.L, LING.R, and IOG. L and nodal local efficiency in PHG. L, IOG. R, FFG. L, and the HES. L, and decreased betweenness centrality in the PCG. L and CUN. L, degree centrality in the ORBsupmed. R, and nodal local efficiency in ANG. R. Conclusion: Cognitive decline in PSCI patients may be related to BFN disorders;acupuncture therapy may modulate the topological properties of the BFNs of PSCI patients.
基金supported by grants from the Development Project of the National Major Scientific Research Instrument(82027803)National Natural Science Foundation of China(81971623 and 82171937)Key Project of the Natural Science Foundation of Zhejiang Province(LZ20H180001)。
文摘Introduction Liver cancer remains a global health challenge,and its incidence is increasing worldwide.It is estimated that by 2025,more than one million individuals will be affected by liver cancer annually[1,2].In recent years,ablation has become a widely accepted treatment option for patients with primary and secondary liver malignancies[3].The commonly used ablation method for liver cancer is thermal ablation,including radiofrequency ablation.
基金Project of City-University Science and Technology Strategic Cooperation of Nanchong City,No.20SXQT0324。
文摘With continuous advancements in interventional radiology,considerable progress has been made in transarterial therapies for hepatocellular carcinoma(HCC)in recent years,and an increasing number of research papers on transarterial therapies for HCC have been published.In this editorial,we comment on the article by Ma et al published in the recent issue of the World Journal of Gastrointestinal Oncology:“Efficacy and predictive factors of transarterial chemoembolization combined with lenvatinib plus programmed cell death protein-1 inhibition for unresectable HCC”.We focus specifically on the current research status and future directions of transarterial therapies.In the future,more studies are needed to determine the optimal transarterial local treatment for HCC.With the emergence of checkpoint immunotherapy modalities,it is expected that the results of trials of transarterial local therapy combined with systemic therapy will bring new hope to HCC patients.
文摘BACKGROUND Malignant peripheral nerve sheath tumor(MPNST)is a type of spindle cell sarcoma originating from the peripheral nerve,which usually results in the corresponding nerve sign on magnetic resonance imaging(MRI).Patients with MPNST may also have neurofibromatosis type 1.CASE SUMMARY A 78-year-old male was admitted to the hospital due to a tumor in his left knee.He had a previous history of superficial spreading melanoma on the left thigh.Color Doppler ultrasonography showed a hypoechoic mass in the subcutaneous soft tissues of the medial left knee with an abundant rich blood flow.Computed tomography scanning did not show obvious signs of bone destruction,but the skin adjacent to the tumor was slightly thickened.MRI examination revealed that the hypervascular lesion was well-circumscribed,lobulated,invaded the surrounding soft tissues and demonstrated heterogeneous enhancement but lacked an entering and exiting nerve sign.The MRI result indicated the invasiveness of the tumor.The patient underwent a left knee joint mass expanded resection and the first histopathological examination showed a MPNST with positive surgical margins.Therefore,the second extended resection was performed,and the patient had a good outcome in the short term.CONCLUSION MRI is a useful technique for revealing the biological characteristics of MPNST and provides clinical support for evaluation of the surgical area before operation.
文摘Primary hepatocellular carcinoma is one of the most common and deadliest malignant tumors in the world, and most patients are diagnosed after missing the optimal treatment period. TACE (Transcatheter arterial chemoembolization) is currently the preferred treatment for advanced HCC (Hepatocellular Carcinoma), as it can induce local ischemic necrosis of the tumor while reducing the systemic side effects of drugs by embolizing the tumor-feeding arteries. Lipiodol, with its unique comprehensive properties of imaging, drug loading, and embolization, has become a key component in the process of TACE. Therefore, analyzing the deposition of lipiodol in hepatic tumor tissues after TACE can effectively evaluate the treatment efficacy. This article summarizes and analyzes the metabolism of lipiodol in tumors and the clinical application of lipiodol deposition status in predicting patient prognosis, aiming to provide clearer diagnostic and treatment strategies for clinical doctors.
文摘Arrhythmogenic right ventricular cardiomyopathy/dysplasia(ARVC/D)is characterized by progressive fibro-fatty replacement of cardiac myocytes in both ventricles,with the risk of heart failure and sudden death1,2.Systemic thromboembolism,including pulmonary embolism and cerebral infarction,was an essential risk of worsening prognosis of ARVC/D.
文摘Objective: To explore regional homogeneity (ReHo) alterations after acupuncture treatment in poststroke cognitive impairment (PSCI) patients. Methods: Twenty-one PSCI patients who underwent acupuncture therapy in our hospital and 12 matched healthy controls were enrolled in this study. All study subjects underwent resting-state functional magnetic resonance imaging (rs-fMRI);for PSCI patients, rs-fMRI scans were conducted before and after acupuncture therapy. Data preprocessing was performed using the DPARSF5.4 and SPM12 toolkits on the MATLAB 2022b platform. DPARSF5.4 was used to calculate the ReHo index of the preprocessed resting-state data. A two-sample t-test was used to compare the differences in ReHo between the PSCI patients group pretreatment and the control group (with sex and age as covariates), and a paired t-test was used to compare the differences in ReHo between the pretreatment and posttreatment groups of PSCI patients (without covariates). AAL_116_binary_mask.nii was used as the statistical mask, and the statistical results were corrected using family-wise error correction, with P Conclusion: PSCI patients exhibited abnormal ReHo in the resting state, and ReHo was significantly altered after acupuncture treatment. The results of this study suggest that ReHo might be a potential biomarker in the diagnosis and treatment of PSCI.
基金supported by the National Key Research and Development Program of China(2017YFA0205200)the National Natural Science Foundation of China(81571785,81771957,81901857,81801811)+2 种基金Natural Science Foundation of Guangdong Province,China(2018A030313074)to Dr.Ligong Luthe Zhuhai Municipal Science and Technology Foundation(ZH22046301200004PWC)to Dr.Shi-You Lithe Sunny Li Family fund to You-Wen He。
文摘The newly emerged severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) has infected millions of people and caused tremendous morbidity and mortality worldwide. Effective treatment for coronavirus disease 2019(COVID-19) due to SARSCoV-2 infection is lacking, and different therapeutic strategies are under testing. Host humoral and cellular immunity to SARSCoV-2 infection is a critical determinant for patients’ outcomes. SARS-CoV-2 infection results in seroconversion and production of anti-SARS-CoV-2 antibodies. The antibodies may suppress viral replication through neutralization but might also participate in COVID-19 pathogenesis through a process termed antibody-dependent enhancement. Rapid progress has been made in the research of antibody response and therapy in COVID-19 patients, including characterization of the clinical features of antibody responses in different populations infected by SARS-CoV-2, treatment of COVID-19 patients with convalescent plasma and intravenous immunoglobin products, isolation and characterization of a large panel of monoclonal neutralizing antibodies and early clinical testing, as well as clinical results from several COVID-19 vaccine candidates. In this review, we summarize the recent progress and discuss the implications of these findings in vaccine development.
基金supported by National Key Research and Development Program of China(No.2017YFA0205200)National Natural Science Foundation of China(Nos.81773766 and 81903845)+1 种基金the Natural Science Foundation of Jiangsu Province(BK20161458,China)the“Double First-Class”University project(No.CPU2018GY38,China)。
文摘Acute myeloid leukaemia(AML) is the most common form of acute leukaemia in adults,with increasing incidence with age and a generally poor prognosis.Almost 20% of AML patients express mutant isocitrate dehydrogenase 2(mIDH2),which leads to the accumulation of the carcinogenic metabolite 2-hydroxyglutarate(2-HG),resulting in poor prognosis.Thus,global institutions have been working to develop mIDH2 inhibitors.SH1573 is a novel mIDH2 inhibitor that we independently designed and synthesised.We have conducted a comprehensive study on its pharmacodynamics,pharmacokinetics and safety.First,SH1573 exhibited a strong selective inhibition of mIDH2 R140 Q protein,which could effectively reduce the production of 2-HG in cell lines,serum and tumors of an animal model.It could also promote the differentiation of mutant AML cell lines and granulocytes in PDX models.Then,it was confirmed that SH1573 possessed characteristics of high bioavailability,good metabolic stability and wide tissue distribution.Finally,toxicological data showed that SH1573 had no effects on the respiratory system,cardiovascular system and nervous system,and was genetically safe.This research successfully promoted the approval of SH1573 for clinical trials(CTR20200247).All experiments demonstrated that,as a potential drug against mIDH2 R140 Q acute myeloid leukaemia,SH1573 was effective and safe.
基金financially supported by the National Key Research and Development Program of China(No.2017YFA0205200)the National Natural Science Foundation of China(Grant No.81903165 and 81901857)the Chinese Postdoctoral Foundation(Grant No.2019M663361,China)
文摘Tumor microenvironment has been widely utilized for advanced drug delivery in recent years,among which hypoxia-responsive drug delivery systems have become the research hotspot.Although hypoxia-responsive micelles or polymersomes have been successfully developed,a type of hypoxia-degradable nanogel has rarely been reported and the advantages of hypoxia-degradable nanogel over other kinds of degradable nanogels in tumor drug delivery remain unclear.Herein,we reported the synthesis of a novel hypoxia-responsive crosslinker and the fabrication of a hypoxia-degradable zwitterionic poly(phosphorylcholine)-based(HPMPC)nanogel for tumor drug delivery.The obtained HPMPC nanogel showed ultra-long blood circulation and desirable immune compatibility,which leads to high and long-lasting accumulation in tumor tissue.Furthermore,HPMPC nanogel could rapidly degrade into oligomers of low molecule weight owing to the degradation of azo bond in hypoxic environment,which leads to the effective release of the loaded drug.Impressively,HPMPC nanogel showed superior tumor inhibition effect both in vitro and in vivo compared to the reduction-responsive phosphorylcholine-based nanogel,owing to the more complete drug release.Overall,the drug-loaded HPMPC nanogel exhibits a pronounced tumor inhibition effect in a humanized subcutaneous liver cancer model with negligible side effects,which showed great potential as nanocarrier for advanced tumor drug delivery.
基金supported by the National Natural Science Foundation of China(82230067,82061148013,91842105,81821001)Shanghai Science and Technology Committee(20JC1417400,201409005500)+3 种基金the National Key Research and Development Program of China(2018YFA0508000)the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB29030101)the CAS Project for Young Scientists in Basic Research(YSBR-074)the Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment(2021B1212040004).
文摘N6-methyladenosine(m^(6)A),the most common and abundant epigenetic RNA modification,governs mRNA metabolism to determine cell differentiation,proliferation and response to stimulation.m^(6)A methyltransferase METTL3 has been reported to control T cell homeostasis and sustain the suppressive function of regulatory T cells(Tregs).However,the role of m^(6)A methyltransferase in other subtypes of T cells remains unknown.T helper cells 17(Th17)play a pivotal role in host defense and autoimmunity.Here,we found that the loss of METTL3 in T cells caused serious defect of Th17 cell differentiation,and impeded the development of experimental autoimmune encephalomyelitis(EAE).We generated Mettl3f/fIl17aCre mice and observed that METTL3 deficiency in Th17 cells significantly suppressed the development of EAE and displayed less Th17 cell infiltration into central nervous system(CNS).Importantly,we demonstrated that depletion of METTL3 attenuated IL-17A and CCR5 expression by facilitating SOCS3 mRNA stability in Th17 cells,leading to disrupted Th17 cell differentiation and infiltration,and eventually attenuating the process of EAE.Collectively,our results highlight that m^(6)A modification sustains Th17 cell function,which provides new insights into the regulatory network of Th17 cells,and also implies a potential therapeutic target for Th17 cell mediated autoimmune disease.
基金supported by grants from the National Natural Science Foundation of China(82170818,81770794,31401001)the Fundamental Research Funds for the Central Universities(21620423,China)the Science and Technology Project of Zhuhai(20191210E030072,China)。
文摘Arrhythmogenic cardiomyopathy(ACM),a fatal heart disease characterized by fibroadipocytic replacement of cardiac myocytes,accounts for 20%of sudden cardiac death and lacks effective treatment.It is often caused by mutations in desmosome proteins,with Desmoglein-2(DSG2)mutations as a common etiology.However,the mechanism underlying the accumulation of fibrofatty in ACM remains unknown,which impedes the development of curative treatment.Here we investigated the fat accumulation and the underlying mechanism in a mouse model of ACM induced by cardiac-specific knockout of Dsg2(CS-Dsg2^(-/-)).Heart failure and cardiac lipid accumulation were observed in CSDsg2^(-/-)mice.We demonstrated that these phenotypes were caused by decline of fatty acid(FA)β-oxidation resulted from impaired mammalian target of rapamycin(m TOR)signaling.Rapamycin worsened while overexpression of m TOR and 4EBP1 rescued the FAβ-oxidation pathway in CS-Dsg2^(-/-)mice.Reactivation of PPARa by fenofibrate or AAV9-Ppara significantly alleviated the lipid accumulation and restored cardiac function.Our results suggest that impaired m TOR-4EBP1-PPARa-dependent FAβ-oxidation contributes to myocardial lipid accumulation in ACM and PPARa may be a potential target for curative treatment of ACM.
基金This work was supported by the National Key R&D Program of China(Nos.2017YFA0205200 and 2020YFA0710700)the National Natural Science Foundation of China(Nos.81771957,51903105,51961145109,and 51773191)+1 种基金the China Postdoctoral Science Foundation(Nos.2019TQ0400 and 2019M663362)All animals received are in compliance with the guidelines outlined in the Guide for the Care and Use of Laboratory Animals,and all procedures were approved by the University of Science and Technology of China Animal Care and Use Committee(No.USTCACUC1801006).
文摘Tumor cells undergoing immunogenic cell death (ICD) have emerged as an in situ therapeutic vaccine helping to activate a persistent anti-tumor response. Several chemotherapeutic agents have been demonstrated to induce ICD, however accompanied with severe adverse effects in the clinic, weakening its immune responses. Herein, to elicit an intensive ICD while minimizing the systemic toxicity, we introduce a tumor targeting peptide modified bortezomib (BTZ) loading nanomedicine (i-NPBTZ) for the efficient delivery and controlled release of BTZ in tumors. This system is constructed by conjugating BTZ to PEGylated polyphenols via a pH-sensitive covalent boronate-phenol bond that allows them to self-assemble into nanovesicles in neutral condition with high drug loading efficiency. Once accumulated in acidic environment, BTZ-phenolic network is disassembled and thereby accelerates the release of BTZ from nanocarriers. The released BTZ selectively kill tumor cells with a concomitant evocation of tumor-specific cytotoxic T cells by triggering ICD in vivo. This can finally lead to an extended tumor ablation and prevention of distant metastasis in a syngeneic tumor mouse model, while reducing the systemic toxicity of BTZ. In general, our system offers a novel concept with clinical potential to exploit ICD for potentiating tumor immunotherapy and also provides an excellent example of the application of polymer-drug interaction for efficient drug delivery and controllable release.
基金supported by grants from the National Natural Science Foundation of China(81770794 and 314010010)the Special Grants from the Guangzhou Pearl River Young Talents of Science and Technology(201610010079,China)the Fundamental Research Funds for the Central Universities(21617457,China)
文摘Interleukin-27(IL-27),a heterodimeric cytokine,plays a protective role in diabetes.Ghrelin,a gastric hormone,provides a hunger signal to the central nervous system to stimulate food intake.The relationship between IL-27 and ghrelin is still unexplored.Here we investigated that signal transducer and activator of transcription 3(STAT3)—mechanistic target of rapamycin(mTOR)signaling mediates the suppression of ghrelin induced by IL-27.Co-localization of interleukin 27 receptor subunit alpha(WSX-1)and ghrelin was observed in mouse and human gastric mucosa.Intracerebroventricular injection of IL-27 markedly suppressed ghrelin synthesis and secretion while stimulating STAT3-mTOR signaling in both C57 BL/6 J mice and high-fat diet-induced-obese mice.IL-27 inhibited the production of ghrelin in mHypoE-N42 cells.Inhibition of mTOR activity induced by mTOR siRNA or rapamycin blocked the suppression of ghrelin production induced by IL-27 in mHypoE-N42 cells.Stat 3 siRNA also abolished the inhibitory effect of IL-27 on ghrelin.IL-27 increased the interaction between STAT3 and mTOR in mHypoE-N42 cells.In conclusion,IL-27 suppresses ghrelin production through the STAT3-mTOR dependent mechanism.
基金This work was supported by the Natural Science Foundation of Guangdong Province(2018A030313652)the National Mega Project on Major Infectious Disease Prevention(2017ZX10103011).
文摘A novel coronavirus disease 2019(COVID-19)emerged around December 2019 in Wuhan,China and has spread rapidly worldwide(Lu et al.,2020).Until March 27,2020,the Chinese health authorities had reported 82082 confirmed COVID-19 cases in China with 3298 deaths and 381443 confirmed cases with 20787 deaths outside China.The World Health Organization(WHO)named the virus SARS-CoV-2,which belongs to a distinct clade from the human severe acute respiratory syndrome CoV(SARS-CoV)and Middle East respiratory syndrome CoV(MERSCoV)(Zhu et al.,2020).
基金This work is supported by the National Natural Science Foundation of China(Nos.52103164,and 52173142)Guangdong Basic and Applied Basic Research Foundation(Nos.2021A1515220033 and 2020A1515111059)the Fundamental Research Funds for the Central Universities(No.JUSRP123079).
文摘The microenvironment of hypoxia and immune-cold limits the therapeutic outcomes of immune checkpoint blockade(ICB)therapy in solid tumors.It is important and imperative to search new strategies to relieve tumor hypoxia and reverse immunosuppression of cold tumors.In this study,the oxygen(O_(2))self-replenishing nano-enabled coordination platform can be used to induce potent antitumor immune response in cold tumors.The nanoplatform can produce O_(2)by catalyzing hydrogen peroxide(H_(2)O_(2))in tumor site effectively,showing excellent photodynamic therapy(PDT)performance.Meanwhile,it can further trigger immunogenic cell death(ICD),enhance T cell infiltration,reverse immunosuppression,and reprogram the immune-cold tumor microenvironment.In vitro and in vivo results demonstrate that the nanoplatform has potential for eradicating tumors and long-term immunological memory effect.The nanoplatform opens up a strategy for reprograming the immunosuppressive microenvironment in cold tumors.
