Background:Triple-negative breast cancer(TNBC),characterized by its lack of traditional hormone receptors and HER2,presents a significant challenge in oncology due to its poor response to conventional therapies.Autoph...Background:Triple-negative breast cancer(TNBC),characterized by its lack of traditional hormone receptors and HER2,presents a significant challenge in oncology due to its poor response to conventional therapies.Autophagy is an important process for maintaining cellular homeostasis,and there are currently autophagy biomarkers that play an effective role in the clinical treatment of tumors.In contrast to targeting protein activity,intervention with proteinprotein interaction(PPI)can avoid unrelated crosstalk and regulate the autophagy process with minimal interference pathways.Methods:Here,we employed Naive Bayes,Decision Tree,and k-Nearest Neighbors to elucidate the complex PPI network associated with autophagy in TNBC,aiming to uncover novel therapeutic targets.Meanwhile,the candidate proteins interacting with Beclin 2 were initially screened in MDA-MB-231 cells using Beclin 2 as bait protein by immunoprecipitation-mass spectrometry assay,and the interaction relationship was verified by molecular docking and CO-IP experiments after intersection.Colony formation,cellular immunofluorescence,cell scratch and 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT)tests were used to predict the clinical therapeutic effects of manipulating candidate PPI.Results:By developing three PPI classification models and analyzing over 13,000 datasets,we identified 3733 previously unknown autophagy-related PPIs.Our network analysis revealed the central role of Beclin 2 in autophagy regulation,uncovering its interactions with 39 newly identified proteins.Notably,the CO-IP studies identified the substantial interaction between Beclin 2 and Ubiquilin 1,which was anticipated by our model and discovered in immunoprecipitation-mass spectrometry assay results.Subsequently,in vitro investigations showed that overexpressing Beclin 2 increased Ubiquilin 1,promoted autophagy-dependent cell death,and inhibited proliferation and metastasis in MDA-MB-231 cells.Conclusions:This study not only enhances our understanding of autophagy regulation in TNBC but also identifies the Beclin 2-Ubiquilin 1 axis as a promising target for precision therapy.These findings open new avenues for drug discovery and offer inspiration for more effective treatments for this aggressive cancer subtype.展开更多
Radioactive microspheres have demonstrated excellent therapeutic effects and good tolerance in the treatment of unresectable primary and secondary liver malignancies.This is attributed to precise embolization and pote...Radioactive microspheres have demonstrated excellent therapeutic effects and good tolerance in the treatment of unresectable primary and secondary liver malignancies.This is attributed to precise embolization and potent anti-tumor effect.However,certain limitations such as unstable loading,perfusion stasis,heterogeneous distribution,ectopic distribution,and insufficient dosage,restrict their clinical application.Herein,a novel personalized Y-90 carbon microsphere with high uniformity,high specific activity and high availability(^(90)Y-HUACM)is presented.It is synthesized through planar molecular complex adsorption and chemical deposition solidification.^(90)Y-HUACM exhibited controllable size,excellent biocompatibility,outstanding in vitro and in vivo stability.The radiolabeling efficiency of Y-90 exceeded 99%and the leaching rate of Y-90 is far below 0.1%.Furthermore,the excellent anti-tumor effect,nuclide loading stability,anti-reflux characteristics,precise embolization,and biosafety of^(90)Y-HUACM were validated in a rabbit VX2liver tumor model.In summary,this new,high-performance,and customizable radioactive microsphere provides a superior choice for selective internal radiation treatment of advanced liver cancer is expected to be rapidly applied in clinical practice.展开更多
Background:Non-small cell lung cancer(NSCLC)is often accompanied by brain metastasis(BM),and the prognosis of patients with BM is poor.This study assesses the prognostic impact of BM in NSCLC patients with epidermal g...Background:Non-small cell lung cancer(NSCLC)is often accompanied by brain metastasis(BM),and the prognosis of patients with BM is poor.This study assesses the prognostic impact of BM in NSCLC patients with epidermal growth factor receptor(EGFR)mutations.Methods:We retrospectively evaluated 692 advanced NSCLC patients with EGFR mutations treated with tyrosine kinase inhibitors(TKIs)at West China Hospital from 2015 to 2019.The overall survival rate(OS),progression-free survival rate(PFS),objective response rate(ORR),disease control rate(DCR),and clinical parameters of the BM and non-BM groups were compared.Univariable and multivariable regressions were performed to identify independent prognostic factors,followed by validation of a predictive nomogram using receiver operating characteristics and calibration curves.Immune infiltration in tumor tissues was assessed by immunostaining.Results:NSCLC patients with BM exhibited a higher frequency of other-site and multi-organ metastases than those without BM.The BM group demonstrated significantly worse OS(26.2 vs.39.1 months,p<0.001)and PFS(12.3 vs.18.8 months,p<0.001),although the DCR(p=0.831)and ORR(p=0.653)were similar in both groups.BM was identified as an independent predictor of poor prognosis.The nomogram performed well,achieving a C index of 0.73,with consistent calibration curves for predicted and actual prognoses.Additionally,fewer peripheral lymphocytes were observed in the BM group.Conclusions:BM is a significant risk factor for NSCLC patients,potentially linked to lymphocytopenia.展开更多
BACKGROUND Cancer-associated fibroblasts(CAFs),crucial components of the tumor microenvironment in primary and metastatic tumors,can impact the activity of cancer cells and contribute to their progression.Given their ...BACKGROUND Cancer-associated fibroblasts(CAFs),crucial components of the tumor microenvironment in primary and metastatic tumors,can impact the activity of cancer cells and contribute to their progression.Given their extensive interactions with cancer cells and other stromal cells,we aimed to evaluate the prognostic value of CAFs in patients with liver cancer(LC).AIM To investigate the association between CAF expression and clinicopathological characteristics as well as overall survival(OS)in patients with LC,including hepatocellular carcinoma(HCC)and intrahepatic cholangiocarcinoma(iCCA).METHODS We performed a meta-analysis of cohort studies with available data on the effects of CAF expression on both clinicopathological characteristics and OS via hazard ratios(HRs)and risk ratios with 95%confidence intervals(CIs).Studies were subgrouped on the basis of CAF markers and cancer type,and the subgroup effects of CAF expression on both HCC and iCCA were analyzed through meta-regression.The Newcastle-Ottawa Scale was used to evaluate the included studies to guarantee their quality and minimize the possibility of bias.RESULTS Nine trials were selected and included a total of 1518 patients.According to our primary meta-analysis,the expression of CAFs in LC patients was significantly associated with a decrease in OS(LC:HR:1.62;95%CI:1.34-1.97;P<0.001;HCC:HR:1.67;95%CI:1.34-2.07;P<0.001;iCCA:HR:1.47;95%CI:0.97-2.23;P=0.07);nevertheless,it was not significantly associated with almost all clinicopathologic characteristics,including tumor size,venous infiltration,alpha-fetoprotein level,and differentiation grade.According to the subgroup analysis of smooth muscle actin(SMA)markers in both HCC patients and iCCA patients,high CAF expression in HCC(HR:2.29;95%CI:1.01-5.22;P=0.048)and iCCA(HR:2.04;95%CI:1.09-3.81;P=0.025)patients was a significant indicator of poor OS.Moreover,the clinicopathological characteristics were also verified by the SMA marker,which had a nearly significant effect on the venous infiltration of iCCA(risk ratio:2.70;95%CI:0.97-7.49;P=0.057).CONCLUSION High CAF expression,evaluated by both mixed markers and SMAs,is significantly associated with poor OS in patients with LC,including both HCC patients and iCCA patients.However,further research is necessary since how CAF expression and clinicopathologic features are related is yet unknown.展开更多
In recent years,different drugs therapies for treatment pulmonary fibrosis(PF) have gained much attention due to development of drug delivery technology and urgent clinical needs.PF treatment existed a variety of curr...In recent years,different drugs therapies for treatment pulmonary fibrosis(PF) have gained much attention due to development of drug delivery technology and urgent clinical needs.PF treatment existed a variety of currently clinical problem but PF could be treated with different drugs potentially though drug delivery technology.This review systematically expounds its basic theory,various drug delivery technologies,and future development directions.In the introduction,the relationship between the pathological mechanism of PF and drug delivery,the basic principles of the drug delivery system and the biological barriers faced by pulmonary drug delivery are analyzed.This review details delivery of small molecule drug,macromolecular drug and cells,including chemical synthesis and natural small molecule drug delivery,as well as RNA and cell-based delivery.Finally,the challenges and perspectives of these drugs to treat PF delivery technologies are discussed and key aspects in the development of PF drugs are considered.We hoped that this review can provide comprehensive and in-depth theoretical reference and technical support for the drug treatment of PF.展开更多
Malignant pleural effusion(MPE) is a serious disease caused by malignant tumors with high morbidity and mortality.Chemotherapy,immunotherapy,and antiangiogenic therapy are common treatments for MPE at present.However,...Malignant pleural effusion(MPE) is a serious disease caused by malignant tumors with high morbidity and mortality.Chemotherapy,immunotherapy,and antiangiogenic therapy are common treatments for MPE at present.However,traditional chemotherapeutic drugs have many side effects and can easily lead to drug resistance in patients.The complex tumor microenvironment(TME) of MPE directly reduces the antitumor efficacy of immunotherapy.Fortunately,drug delivery systems(DDSs) based on biomaterials have the ability to overcome some of the drawbacks of conventional treatments by improving drug stability,increasing the accuracy of tumor cell targeting,reducing toxic side effects,and remodeling TME,ultimately improving drug efficacy.Therefore,the purpose of this review is to provide an overview and discussion of the latest progress in biomaterial-based DDSs for the treatment of MPE.We discuss the application of biomaterials in the treatment of MPE from multiple perspectives,including chemotherapy,immunotherapy,combination therapy,and pleurodesis,where microspheres,cell membrane-derived microparticles(MPs),micelles,nanoparticles,and liposomes,are involved.The application of these biomaterials has been proven to have great potential in the treatment of MPE,providing a new idea for follow-up research.展开更多
PEGylation,the controlled covalent conjugation of polyethylene glycol to therapeutics,enhances therapeutic efficacy through optimized pharmacokinetics.However,to date no high-molecular-weight PEGylated small-molecule ...PEGylation,the controlled covalent conjugation of polyethylene glycol to therapeutics,enhances therapeutic efficacy through optimized pharmacokinetics.However,to date no high-molecular-weight PEGylated small-molecule prodrugs have received regulatory approval.This technological gap can be partially attributed to the exponential proliferation of metabolic intermediates resulting from multi-payload conjugation strategies,which introduces unprecedented analytical complexities in metabolite profiling and pharmacokinetic characterization.To address this challenge,we developed a liquid chromatography-triple-quadrupole/time-of-flight mass spectrometry platform for PEG20k-(irinotecan)3,a Phase III clinical candidate.Our methodology employs payload stoichiometry-based chromatographic resolution for clustering isomeric PEG species.Complementarily,diagnostic product ions at m/z 699.83,569.27,and 587.28 enable systematic differentiation between double-loaded,single-loaded,and released irinotecan payload.This approach successfully identifies eight metabolic clusters spanning from PEG-conjugates,cleaved PEG segments,and released small-molecule species.Its demonstrated capacity to deconvolute complex metabolic profiles—through payload-stoichiometry based chromatographic resolution coupled with diagnostic ion analysis—positions this workflow as an attractive tool for accelerating the development of PEGylated small-molecule therapeutics.展开更多
Neural stem cells(NSCs)have the potential for self-renewal and multidirectional differentiation,and their transplantation has achieved good efficacy in a variety of diseases.However,only 1%-10%of transplanted NSCs sur...Neural stem cells(NSCs)have the potential for self-renewal and multidirectional differentiation,and their transplantation has achieved good efficacy in a variety of diseases.However,only 1%-10%of transplanted NSCs survive in the ischemic and hypoxic microenvironment of posthemorrhagic hydrocephalus.^(Sox2)is an important factor for NSCs to maintain proliferation.Therefore,^(Sox2)-overexpressing NSCs(NSC^(Sox2))may be more successful in improving neurological dysfunction after posthemorrhagic hydrocephalus.In this study,human NSC^(Sox2)was transplanted into a posthemorrhagic hydrocephalus mouse model,and retinoic acid was administered to further promote NSC differentiation.The results showed that NSC^(Sox2)attenuated the ventricular enlargement caused by posthemorrhagic hydrocephalus and improved neurological function.NSC^(Sox2)also promoted nerve regeneration,inhibited neuroinflammation and promoted M2 polarization(anti-inflammatory phenotype),thereby reducing cerebrospinal fluid secretion in choroid plexus.These findings suggest that NSC^(Sox2)rescued ventricular enlargement and neurological dysfunction induced by posthemorrhagic hydrocephalus through neural regeneration and modulation of inflammation.展开更多
AIM To evaluate the clinical outcomes of patients who underwent endoscopic submucosal tunnel dissection(ESTD) for esophageal squamous cell carcinoma(ESCC) and precancerous lesions.METHODS ESTD was performed in 289 pat...AIM To evaluate the clinical outcomes of patients who underwent endoscopic submucosal tunnel dissection(ESTD) for esophageal squamous cell carcinoma(ESCC) and precancerous lesions.METHODS ESTD was performed in 289 patients. The clinical outcomes of the patients and pathological features of the lesions were retrospectively reviewed.RESULTS A total of 311 lesions were included in the analysis. The en bloc rate, complete resection rate, and curative resection rate were 99.04%, 81.28%, and 78.46%, respectively. The ESTD procedure time was 102.4 ± 35.1 min, the mean hospitalization time was 10.3 ± 2.8 d, and the average expenditure was 3766.5 ± 846.5 dollars. The intraoperative bleeding rate was 6.43%, the postoperative bleeding rate was 1.61%, the perforation rate was 1.93%, and the postoperative infection rate was 9.65%. Esophageal stricture and positive margin were severe adverse events, with an incidence rate of 14.79% and 15.76%, respectively. No tumor recurrence occurred during the follow-up period. CONCLUSION ESTD for ESCC and precancerous lesions is feasible and relatively safe, but for large mucosal lesions, the rate of esophageal stricture and positive margin is high.展开更多
Alterations in the mesenchymal-epithelial transition factor(MET)gene are critical drivers of non-small cell lung cancer(NSCLC).In recent years advances in precision therapies targeting MET alterations have significant...Alterations in the mesenchymal-epithelial transition factor(MET)gene are critical drivers of non-small cell lung cancer(NSCLC).In recent years advances in precision therapies targeting MET alterations have significantly expanded treatment options for NSCLC patients.These alterations include MET exon 14 skipping mutations(MET exon 14 skipping),MET gene amplifications,MET point mutations(primarily kinase domain mutations),and MET protein overexpression.Accurate identification of these alterations and appropriate selection of patient populations and targeted therapies are essential for improving clinical outcomes.The East China Lung Cancer Group,Youth Committee(ECLUNG YOUNG,Yangtze River Delta Lung Cancer Cooperation Group)has synthesized insights from China’s innovative drug development landscape and clinical practice to formulate an expert consensus on the diagnosis and treatment of NSCLC patients with MET alterations.This consensus addresses key areas,such as optimal testing timing,testing methods,testing strategies,quality control measures,and treatment approaches.By offering standardized recommendations,this guidance aims to streamline diagnostic and therapeutic processes and enhance clinical decision-making for NSCLC with MET alterations.展开更多
OBJECTIVE To discover a small molecule targeting ULK1-modulated cell death of triple negative breast cancer and exploreits potential mechanisms.METHODS ULK1 expression was analyzed by The Cancer Genome Atlas(TCGA)anal...OBJECTIVE To discover a small molecule targeting ULK1-modulated cell death of triple negative breast cancer and exploreits potential mechanisms.METHODS ULK1 expression was analyzed by The Cancer Genome Atlas(TCGA)analysis and tissue microarray(TMA)analysis.ULK1agonist was designed by using in silico screening,as well as modified by chemical synthesis and screened by kinase and anti-proliferative activities.The amino acid residues that key to the activation site of LYN-1604 were determined by site-directed mutagenesis,as well as in vitro kinase assay and ADP-Glo kinase assay.The mechanisms of LYN-1604 induced cell death were investigated by fluorescence microscope,western blotting,flow cytometry analysis,immunocytochemistry,as well as si RNA and GFP-m RFP-LC3 plasmid transfections.Potential ULK1 interactors were discovered by performing comparative microarray analysis and the therapeutic effect of LYN-1604 was assessed by xenograft breast cancer mouse model.RESULTS We found that ULK1 was remarkably downregulated in breast cancer tissue samples,especial y in triple negative breast cancer(TNBC).32 candidate smal molecules were synthesized,and we discovered a small molecule named LYN-1604 as the best candidate ULK1agonist.Additionally,we identified that three amino acid residues(LYS50,LEU53 and TYR89)were key to the activation site of LYN-1604 and ULK1.Subsequently,we demonstrated that LYN-1604 could induce autophagy-associated cell death via ULK complex(ULK1-m ATG13-FIP200-ATG101)in MDA-MB-231 cells.We also found that LYN-1604 induced cell death involved in ATF3,RAD21 and caspase 3,accompanied with autophagy and apoptosis.Moreover,we demonstrated that LYN-1604 had a good therapeutic potential on TNBC by targeting ULK1-modulated cell death in vivo.CONCLUSION We discovered a small molecule(LYN-1604)has therapeutic potential by targeting ULK1-modulated cell death associated with autophagy and apoptosis of TNBC in vitro and in vivo,which could be utilized as a new anti-TNBC drug candidate.展开更多
Autophagy , an evolutionarily conserved lysosomal degradation process , has drawn an increasing amount of attention in recent years for its role in a variety of human diseases, such as cancer. Notably, autophagy plays...Autophagy , an evolutionarily conserved lysosomal degradation process , has drawn an increasing amount of attention in recent years for its role in a variety of human diseases, such as cancer. Notably, autophagy plays an important role in regulating several survival and death signaling pathways that determine cell fate in cancer. To date, substantial evidence has demonstrated that some key autophagic mediators, such as autophagy-related genes (ATGs), PI3K, mTOR, p53, and Beclin-1, may play crucial roles in modulating autophagic activity in cancer initiation and progression. Because autophagy-modulating agents such as rapamycin and chloroquine have already been used clinically to treat cancer, it is conceivable that targeting autophagic pathways may provide a new opportunity for discovery and development of more novel cancer therapeutics. With a deeper understanding of the regulatory mechanisms governing autophagy, we will have a better opportunity to facilitate the exploitation of autophagy as a target for therapeutic intervention in cancer. This review discusses the current status of targeting autophagic pathways as a potential cancer therapy.展开更多
BACKGROUND Recent evidence indicates that malignant ascites may be associated with the high malignancy and poor prognosis of gastric cancer(GC)with peritoneal metastasis(PM),but no robust consensus has been reached un...BACKGROUND Recent evidence indicates that malignant ascites may be associated with the high malignancy and poor prognosis of gastric cancer(GC)with peritoneal metastasis(PM),but no robust consensus has been reached until now.AIM To evaluate the prognostic significance of malignant ascites in GC patients with PM.METHODS Two independent authors conducted database searches.The searches were performed in the EMBASE,PubMed,and Cochrane Library databases,and the terms used to search included stomach neoplasms,GC,ascites,peritoneal effusion,survival,and survival analysis.Outcomes included overall survival and hazard ratios with 95%confidence intervals(CIs).Three pairs of comparisons for measuring survival were made:(1)Patients with ascites vs those without ascites;(2)Patients with massive ascites vs those with mild to moderate ascites;and(3)Patients with massive ascites vs those with no to moderate ascites.RESULTS Fourteen articles including fifteen studies were considered in the final analysis.Among them,nine studies assessed the difference in prognosis between patients with and without malignant ascites.A pooled HR of 1.63(95%CI:1.47-1.82,P<0.00001)indicated that GC patients with malignant ascites had a relatively poor prognosis compared to patients without ascites.We also found that the prognosis of GC patients with malignant ascites was related to the volume of ascites in the six other studies.CONCLUSION GC patients with malignant ascites tend to have a worse prognosis,and the volume of ascites has an impact on GC outcomes.展开更多
Cancer immunotherapy harnesses the immune system to attack tumors and has received extensive attention in recent years.Cancer vaccines as an important branch of immunotherapy are designed for delivering tumor antigens...Cancer immunotherapy harnesses the immune system to attack tumors and has received extensive attention in recent years.Cancer vaccines as an important branch of immunotherapy are designed for delivering tumor antigens to antigen-presenting cells(APCs)to stimulate a strong immune response to against tumors,representing a potentially therapeutic and prophylactic effect with the long-term anticancer benefits.Nevertheless,the disappointing outcomes of their clinical use might be attributed to dilemma in antigen selection,immunogenicity,lymph nodes(LNs)targeting ability,lysosomal escape ability,immune evasion,etc.Nanotechnology,aiming to overcome these barriers,has been utilized in cancer vaccine development for decades.Numerous preclinical and clinical studies demonstrate positive results in nanomaterials-based cancer vaccines with considerable improvement in the vaccine efficacy.In this review,we systematically introduced the characteristics of nanovaccines and highlighted the different types of nanomaterials used for cancer vaccine design.In addition,the opportunities and challenges of the emerging nanotechnology-based cancer vaccines were discussed.展开更多
As one of the most common metastatic sites of malignancies,bone has a unique microenvironment that allows metastatic tumor cells to grow and flourish.The fenestrated capillaries in the bone,bone matrix,and bone cells,...As one of the most common metastatic sites of malignancies,bone has a unique microenvironment that allows metastatic tumor cells to grow and flourish.The fenestrated capillaries in the bone,bone matrix,and bone cells,including osteoblasts and osteoclasts,together maintain the homeostasis of the bone microenvironment.In contrast,tumor-derived factors act on bone components,leading to subsequent bone resorption or excessive bone formation.The various pathways involved also provide multiple targets for therapeutic strategies against bone metastases.In this review,we summarize the current understanding of the mechanism of bone metastases.Based on the general process of bone metastases,we specifically highlight the complex crosstalk between tumor cells and the bone microenvironment and the current management of cancer bone metastases.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
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
Gambogic acid(GA) is a natural product with potent anticancer activity in vitro. However, poor water solubility and systematic toxicity limit the further clinical application of GA. Micellization of hydrophobic molecu...Gambogic acid(GA) is a natural product with potent anticancer activity in vitro. However, poor water solubility and systematic toxicity limit the further clinical application of GA. Micellization of hydrophobic molecule could effectively ameliorate aqueous dispersity of GA and induce better blood retention and tumor accumulation, hence lead to improved stability and therapeutic effect of GA. In this study, monomethyl poly(ethylene glycol)-poly(ε-caprolactone)-poly(trimethylene carbonate)(MPEG-P(CL-ran-TMC)) was used to encapsulate GA by a single-step solid dispersion method to form a GA encapsulated MPEG-P(CLran-TMC) micelles(GA micelles). GA micelles were characterized with a small particle size(44 ±1 nm),high drug loading content(26.28% ± 0.12%) and high-efficiency encapsulation(87.59% ± 0.41 %). Compared with free GA, GA micelles showed better dispersion in water, prolonged release behavior in vitro, and enhanced tumor cellular uptake. GA micelles could also effectively induce apoptosis in AsPC-1 cells.Compared with free GA, GA micelles exhibited superior antitumor efficacy and better apoptosis induced effect in a subcutaneous xenograft mouse model of AsPC-1 cells. In conclusion, GA micelles which showed high-efficiency anti-tumor effect in vitro and in vivo may serve as a candidate for pancreatic cancer therapy.展开更多
Colorectal cancer causes the third most common type of malignant tumors with high morbidity and mortality.Chemotherapy is currently one of the most effective and common treatments for colorectal cancer.However,the poo...Colorectal cancer causes the third most common type of malignant tumors with high morbidity and mortality.Chemotherapy is currently one of the most effective and common treatments for colorectal cancer.However,the poor water solubility of some chemotherapeutics,untargeted drug delivery,and the undesirable systemic side effects of conventional treatment remain the major issues for colorectal cancer chemotherapy.Fortunately,drug delivery systems(DDS)based on biomaterials have been widely investigated and found to be capable of resolving those issues with good performance.Therefore,the main goal of this review is to summarize and discuss the progress and potential advantages of different DDS for colorectal cancer chemotherapy.We not only reviewed the nanocarriers used to improve the solubility of chemotherapeutics,including liposomes,micelles,and nanoparticles,but also discussed targeted DDS based on specific ligand-receptor recognition and tumor microenvironmental stimulus responses.Furthermore,locally administered systems based on hydrogels and microspheres,which have been shown to increase drug accumulation at the tumor site while decreasing systemic toxicity,were also emphasized.DDS provides a good option for improving the efficacy of chemotherapy in the treatment of colorectal cancer.展开更多
Either cetuximab or bevacizumab can improve the survival of patients with metastastic colorectal cancer(mCRC)if administered combided with cytotoxic agents.However,the effect of two or more target agents in combinatio...Either cetuximab or bevacizumab can improve the survival of patients with metastastic colorectal cancer(mCRC)if administered combided with cytotoxic agents.However,the effect of two or more target agents in combination is uncertain in these patients.Here,we reported a patient with mCRC successfully treated by a combination of target agents after the failure of chemotherapy.The patient received palliative resection of primary tumor followed by 9 cycles of postoperative XELOX regimen,cytokine-induced killer cell(CIK)-based biotherapy,traditional Chinese medicine,particle implantation in the lung metastatic lesions.The tumor progressed 20 months after the standard treatments.Then,the regimen cetuximab,bevacizumab and cefitinib was applied.During the treatment with targeted agents,grade IV acne-like rash and relatively severe parionychia of the toes occurred.Both of them recovered smoothly.The PET-CT reexamination at 40 days after the target treatment showed that the metabolism of mediastinal lymph nodes basically recovered to a normal level.The combination of multiple targeted agents obtained a progression-free survival(PFS)of 11 months and the patient with a good quality of life during this period.展开更多
基金the National Natural Science Foundation of China(Nos.22307009,82374155,82073997,82104376)the Sichuan Science and Technology Program(Nos.2023NSFSC1108,2024NSFTD0023)+1 种基金the Postdoctoral Research Project of Sichuan Provincethe Xinglin Scholar Research Promotion Project of Chengdu University of TCM.
文摘Background:Triple-negative breast cancer(TNBC),characterized by its lack of traditional hormone receptors and HER2,presents a significant challenge in oncology due to its poor response to conventional therapies.Autophagy is an important process for maintaining cellular homeostasis,and there are currently autophagy biomarkers that play an effective role in the clinical treatment of tumors.In contrast to targeting protein activity,intervention with proteinprotein interaction(PPI)can avoid unrelated crosstalk and regulate the autophagy process with minimal interference pathways.Methods:Here,we employed Naive Bayes,Decision Tree,and k-Nearest Neighbors to elucidate the complex PPI network associated with autophagy in TNBC,aiming to uncover novel therapeutic targets.Meanwhile,the candidate proteins interacting with Beclin 2 were initially screened in MDA-MB-231 cells using Beclin 2 as bait protein by immunoprecipitation-mass spectrometry assay,and the interaction relationship was verified by molecular docking and CO-IP experiments after intersection.Colony formation,cellular immunofluorescence,cell scratch and 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT)tests were used to predict the clinical therapeutic effects of manipulating candidate PPI.Results:By developing three PPI classification models and analyzing over 13,000 datasets,we identified 3733 previously unknown autophagy-related PPIs.Our network analysis revealed the central role of Beclin 2 in autophagy regulation,uncovering its interactions with 39 newly identified proteins.Notably,the CO-IP studies identified the substantial interaction between Beclin 2 and Ubiquilin 1,which was anticipated by our model and discovered in immunoprecipitation-mass spectrometry assay results.Subsequently,in vitro investigations showed that overexpressing Beclin 2 increased Ubiquilin 1,promoted autophagy-dependent cell death,and inhibited proliferation and metastasis in MDA-MB-231 cells.Conclusions:This study not only enhances our understanding of autophagy regulation in TNBC but also identifies the Beclin 2-Ubiquilin 1 axis as a promising target for precision therapy.These findings open new avenues for drug discovery and offer inspiration for more effective treatments for this aggressive cancer subtype.
基金supported by the National Major Scientific and Technological Special Project for“Significant New Drugs Development”(No.2018ZX09201018–028)the nuclear energy development projects of China during the 13thFive Year Plan periodthe key research and development project of the Sichuan Provincial Department of Science and Technology(No.18ZDYF1466)。
文摘Radioactive microspheres have demonstrated excellent therapeutic effects and good tolerance in the treatment of unresectable primary and secondary liver malignancies.This is attributed to precise embolization and potent anti-tumor effect.However,certain limitations such as unstable loading,perfusion stasis,heterogeneous distribution,ectopic distribution,and insufficient dosage,restrict their clinical application.Herein,a novel personalized Y-90 carbon microsphere with high uniformity,high specific activity and high availability(^(90)Y-HUACM)is presented.It is synthesized through planar molecular complex adsorption and chemical deposition solidification.^(90)Y-HUACM exhibited controllable size,excellent biocompatibility,outstanding in vitro and in vivo stability.The radiolabeling efficiency of Y-90 exceeded 99%and the leaching rate of Y-90 is far below 0.1%.Furthermore,the excellent anti-tumor effect,nuclide loading stability,anti-reflux characteristics,precise embolization,and biosafety of^(90)Y-HUACM were validated in a rabbit VX2liver tumor model.In summary,this new,high-performance,and customizable radioactive microsphere provides a superior choice for selective internal radiation treatment of advanced liver cancer is expected to be rapidly applied in clinical practice.
基金supported by Sichuan Province Central Government Guide Local Science and Technology Development Project(No.2023ZYD0169).
文摘Background:Non-small cell lung cancer(NSCLC)is often accompanied by brain metastasis(BM),and the prognosis of patients with BM is poor.This study assesses the prognostic impact of BM in NSCLC patients with epidermal growth factor receptor(EGFR)mutations.Methods:We retrospectively evaluated 692 advanced NSCLC patients with EGFR mutations treated with tyrosine kinase inhibitors(TKIs)at West China Hospital from 2015 to 2019.The overall survival rate(OS),progression-free survival rate(PFS),objective response rate(ORR),disease control rate(DCR),and clinical parameters of the BM and non-BM groups were compared.Univariable and multivariable regressions were performed to identify independent prognostic factors,followed by validation of a predictive nomogram using receiver operating characteristics and calibration curves.Immune infiltration in tumor tissues was assessed by immunostaining.Results:NSCLC patients with BM exhibited a higher frequency of other-site and multi-organ metastases than those without BM.The BM group demonstrated significantly worse OS(26.2 vs.39.1 months,p<0.001)and PFS(12.3 vs.18.8 months,p<0.001),although the DCR(p=0.831)and ORR(p=0.653)were similar in both groups.BM was identified as an independent predictor of poor prognosis.The nomogram performed well,achieving a C index of 0.73,with consistent calibration curves for predicted and actual prognoses.Additionally,fewer peripheral lymphocytes were observed in the BM group.Conclusions:BM is a significant risk factor for NSCLC patients,potentially linked to lymphocytopenia.
基金Supported by the Sichuan Science and Technology Program,No.2024NSFSC1936.
文摘BACKGROUND Cancer-associated fibroblasts(CAFs),crucial components of the tumor microenvironment in primary and metastatic tumors,can impact the activity of cancer cells and contribute to their progression.Given their extensive interactions with cancer cells and other stromal cells,we aimed to evaluate the prognostic value of CAFs in patients with liver cancer(LC).AIM To investigate the association between CAF expression and clinicopathological characteristics as well as overall survival(OS)in patients with LC,including hepatocellular carcinoma(HCC)and intrahepatic cholangiocarcinoma(iCCA).METHODS We performed a meta-analysis of cohort studies with available data on the effects of CAF expression on both clinicopathological characteristics and OS via hazard ratios(HRs)and risk ratios with 95%confidence intervals(CIs).Studies were subgrouped on the basis of CAF markers and cancer type,and the subgroup effects of CAF expression on both HCC and iCCA were analyzed through meta-regression.The Newcastle-Ottawa Scale was used to evaluate the included studies to guarantee their quality and minimize the possibility of bias.RESULTS Nine trials were selected and included a total of 1518 patients.According to our primary meta-analysis,the expression of CAFs in LC patients was significantly associated with a decrease in OS(LC:HR:1.62;95%CI:1.34-1.97;P<0.001;HCC:HR:1.67;95%CI:1.34-2.07;P<0.001;iCCA:HR:1.47;95%CI:0.97-2.23;P=0.07);nevertheless,it was not significantly associated with almost all clinicopathologic characteristics,including tumor size,venous infiltration,alpha-fetoprotein level,and differentiation grade.According to the subgroup analysis of smooth muscle actin(SMA)markers in both HCC patients and iCCA patients,high CAF expression in HCC(HR:2.29;95%CI:1.01-5.22;P=0.048)and iCCA(HR:2.04;95%CI:1.09-3.81;P=0.025)patients was a significant indicator of poor OS.Moreover,the clinicopathological characteristics were also verified by the SMA marker,which had a nearly significant effect on the venous infiltration of iCCA(risk ratio:2.70;95%CI:0.97-7.49;P=0.057).CONCLUSION High CAF expression,evaluated by both mixed markers and SMAs,is significantly associated with poor OS in patients with LC,including both HCC patients and iCCA patients.However,further research is necessary since how CAF expression and clinicopathologic features are related is yet unknown.
基金funded by the National Natural Science Foundation of China (No.NSFC82400096)Science and Technology Department of Sichuan Province (No.2025ZNSFSC1538)Xihua University Internal Talent Introduction Project with Scientific Research Funding (No.ZX20250087)。
文摘In recent years,different drugs therapies for treatment pulmonary fibrosis(PF) have gained much attention due to development of drug delivery technology and urgent clinical needs.PF treatment existed a variety of currently clinical problem but PF could be treated with different drugs potentially though drug delivery technology.This review systematically expounds its basic theory,various drug delivery technologies,and future development directions.In the introduction,the relationship between the pathological mechanism of PF and drug delivery,the basic principles of the drug delivery system and the biological barriers faced by pulmonary drug delivery are analyzed.This review details delivery of small molecule drug,macromolecular drug and cells,including chemical synthesis and natural small molecule drug delivery,as well as RNA and cell-based delivery.Finally,the challenges and perspectives of these drugs to treat PF delivery technologies are discussed and key aspects in the development of PF drugs are considered.We hoped that this review can provide comprehensive and in-depth theoretical reference and technical support for the drug treatment of PF.
基金financial support from the Noncommunicable Chronic Diseases-National Science and Technology Major Project (Nos.2024ZD0522800,2024ZD0522803)the National Natural Science Foundation of China (Nos.U21A20417,31930067,31800797)+2 种基金the Natural Science Foundation of Sichuan Province (No.2024NSFSC0046)the Sichuan Science and Technology Program (No.2022YFS0333)the 1·3·5 Project for Disciplines of Excellence,West China Hospital,Sichuan University (No.ZYGD24003)。
文摘Malignant pleural effusion(MPE) is a serious disease caused by malignant tumors with high morbidity and mortality.Chemotherapy,immunotherapy,and antiangiogenic therapy are common treatments for MPE at present.However,traditional chemotherapeutic drugs have many side effects and can easily lead to drug resistance in patients.The complex tumor microenvironment(TME) of MPE directly reduces the antitumor efficacy of immunotherapy.Fortunately,drug delivery systems(DDSs) based on biomaterials have the ability to overcome some of the drawbacks of conventional treatments by improving drug stability,increasing the accuracy of tumor cell targeting,reducing toxic side effects,and remodeling TME,ultimately improving drug efficacy.Therefore,the purpose of this review is to provide an overview and discussion of the latest progress in biomaterial-based DDSs for the treatment of MPE.We discuss the application of biomaterials in the treatment of MPE from multiple perspectives,including chemotherapy,immunotherapy,combination therapy,and pleurodesis,where microspheres,cell membrane-derived microparticles(MPs),micelles,nanoparticles,and liposomes,are involved.The application of these biomaterials has been proven to have great potential in the treatment of MPE,providing a new idea for follow-up research.
基金support from the National Natural Science Foundation of China(Nos.82030107,82304443,82373944)the Hainan Provincial Natural Science Foundation of China(No.825QN288).
文摘PEGylation,the controlled covalent conjugation of polyethylene glycol to therapeutics,enhances therapeutic efficacy through optimized pharmacokinetics.However,to date no high-molecular-weight PEGylated small-molecule prodrugs have received regulatory approval.This technological gap can be partially attributed to the exponential proliferation of metabolic intermediates resulting from multi-payload conjugation strategies,which introduces unprecedented analytical complexities in metabolite profiling and pharmacokinetic characterization.To address this challenge,we developed a liquid chromatography-triple-quadrupole/time-of-flight mass spectrometry platform for PEG20k-(irinotecan)3,a Phase III clinical candidate.Our methodology employs payload stoichiometry-based chromatographic resolution for clustering isomeric PEG species.Complementarily,diagnostic product ions at m/z 699.83,569.27,and 587.28 enable systematic differentiation between double-loaded,single-loaded,and released irinotecan payload.This approach successfully identifies eight metabolic clusters spanning from PEG-conjugates,cleaved PEG segments,and released small-molecule species.Its demonstrated capacity to deconvolute complex metabolic profiles—through payload-stoichiometry based chromatographic resolution coupled with diagnostic ion analysis—positions this workflow as an attractive tool for accelerating the development of PEGylated small-molecule therapeutics.
基金supported by the National Natural Science Foundation of China,Nos.82473334(to LZ),82401629(to XL)the Major Scientific and Technological Achievements Transformation Project of Ningxia Hui Autonomous Region,No.2022CJE09013(to LZ)+4 种基金Mianyang Science and Technology Bureau(Mianyang Science and Technology Program),No.2023ZYDF097(to LZ)NHC Key Laboratory of Nuclear Technology Medical Transformation(Mianyang Central Hospital),No.2023HYX001(to LZ)Spinal Cord Diseases Clinical Medical Center of Yunnan Province,No.2024JSKFKT-16(to BG)the Natural Science Foundation of Sichuan Province,No.2024NSFSC1646(to XL)the China Postdoctoral Science Foundation,Nos.GZC20231811(to XL),2024T170601(to XL)and 2024M76228(to XL).
文摘Neural stem cells(NSCs)have the potential for self-renewal and multidirectional differentiation,and their transplantation has achieved good efficacy in a variety of diseases.However,only 1%-10%of transplanted NSCs survive in the ischemic and hypoxic microenvironment of posthemorrhagic hydrocephalus.^(Sox2)is an important factor for NSCs to maintain proliferation.Therefore,^(Sox2)-overexpressing NSCs(NSC^(Sox2))may be more successful in improving neurological dysfunction after posthemorrhagic hydrocephalus.In this study,human NSC^(Sox2)was transplanted into a posthemorrhagic hydrocephalus mouse model,and retinoic acid was administered to further promote NSC differentiation.The results showed that NSC^(Sox2)attenuated the ventricular enlargement caused by posthemorrhagic hydrocephalus and improved neurological function.NSC^(Sox2)also promoted nerve regeneration,inhibited neuroinflammation and promoted M2 polarization(anti-inflammatory phenotype),thereby reducing cerebrospinal fluid secretion in choroid plexus.These findings suggest that NSC^(Sox2)rescued ventricular enlargement and neurological dysfunction induced by posthemorrhagic hydrocephalus through neural regeneration and modulation of inflammation.
基金Supported by the Science and Technology Department of Sichuan Province for Scientific Research,No.2015SZ0123
文摘AIM To evaluate the clinical outcomes of patients who underwent endoscopic submucosal tunnel dissection(ESTD) for esophageal squamous cell carcinoma(ESCC) and precancerous lesions.METHODS ESTD was performed in 289 patients. The clinical outcomes of the patients and pathological features of the lesions were retrospectively reviewed.RESULTS A total of 311 lesions were included in the analysis. The en bloc rate, complete resection rate, and curative resection rate were 99.04%, 81.28%, and 78.46%, respectively. The ESTD procedure time was 102.4 ± 35.1 min, the mean hospitalization time was 10.3 ± 2.8 d, and the average expenditure was 3766.5 ± 846.5 dollars. The intraoperative bleeding rate was 6.43%, the postoperative bleeding rate was 1.61%, the perforation rate was 1.93%, and the postoperative infection rate was 9.65%. Esophageal stricture and positive margin were severe adverse events, with an incidence rate of 14.79% and 15.76%, respectively. No tumor recurrence occurred during the follow-up period. CONCLUSION ESTD for ESCC and precancerous lesions is feasible and relatively safe, but for large mucosal lesions, the rate of esophageal stricture and positive margin is high.
文摘Alterations in the mesenchymal-epithelial transition factor(MET)gene are critical drivers of non-small cell lung cancer(NSCLC).In recent years advances in precision therapies targeting MET alterations have significantly expanded treatment options for NSCLC patients.These alterations include MET exon 14 skipping mutations(MET exon 14 skipping),MET gene amplifications,MET point mutations(primarily kinase domain mutations),and MET protein overexpression.Accurate identification of these alterations and appropriate selection of patient populations and targeted therapies are essential for improving clinical outcomes.The East China Lung Cancer Group,Youth Committee(ECLUNG YOUNG,Yangtze River Delta Lung Cancer Cooperation Group)has synthesized insights from China’s innovative drug development landscape and clinical practice to formulate an expert consensus on the diagnosis and treatment of NSCLC patients with MET alterations.This consensus addresses key areas,such as optimal testing timing,testing methods,testing strategies,quality control measures,and treatment approaches.By offering standardized recommendations,this guidance aims to streamline diagnostic and therapeutic processes and enhance clinical decision-making for NSCLC with MET alterations.
基金supported by National Natural Science Foundation of China(81402496,81673455and 81602627)China Postdoctoral Special Science Foundation(2017T100704)China Postdoctoral Science Foundation(2015M580794)
文摘OBJECTIVE To discover a small molecule targeting ULK1-modulated cell death of triple negative breast cancer and exploreits potential mechanisms.METHODS ULK1 expression was analyzed by The Cancer Genome Atlas(TCGA)analysis and tissue microarray(TMA)analysis.ULK1agonist was designed by using in silico screening,as well as modified by chemical synthesis and screened by kinase and anti-proliferative activities.The amino acid residues that key to the activation site of LYN-1604 were determined by site-directed mutagenesis,as well as in vitro kinase assay and ADP-Glo kinase assay.The mechanisms of LYN-1604 induced cell death were investigated by fluorescence microscope,western blotting,flow cytometry analysis,immunocytochemistry,as well as si RNA and GFP-m RFP-LC3 plasmid transfections.Potential ULK1 interactors were discovered by performing comparative microarray analysis and the therapeutic effect of LYN-1604 was assessed by xenograft breast cancer mouse model.RESULTS We found that ULK1 was remarkably downregulated in breast cancer tissue samples,especial y in triple negative breast cancer(TNBC).32 candidate smal molecules were synthesized,and we discovered a small molecule named LYN-1604 as the best candidate ULK1agonist.Additionally,we identified that three amino acid residues(LYS50,LEU53 and TYR89)were key to the activation site of LYN-1604 and ULK1.Subsequently,we demonstrated that LYN-1604 could induce autophagy-associated cell death via ULK complex(ULK1-m ATG13-FIP200-ATG101)in MDA-MB-231 cells.We also found that LYN-1604 induced cell death involved in ATF3,RAD21 and caspase 3,accompanied with autophagy and apoptosis.Moreover,we demonstrated that LYN-1604 had a good therapeutic potential on TNBC by targeting ULK1-modulated cell death in vivo.CONCLUSION We discovered a small molecule(LYN-1604)has therapeutic potential by targeting ULK1-modulated cell death associated with autophagy and apoptosis of TNBC in vitro and in vivo,which could be utilized as a new anti-TNBC drug candidate.
文摘Autophagy , an evolutionarily conserved lysosomal degradation process , has drawn an increasing amount of attention in recent years for its role in a variety of human diseases, such as cancer. Notably, autophagy plays an important role in regulating several survival and death signaling pathways that determine cell fate in cancer. To date, substantial evidence has demonstrated that some key autophagic mediators, such as autophagy-related genes (ATGs), PI3K, mTOR, p53, and Beclin-1, may play crucial roles in modulating autophagic activity in cancer initiation and progression. Because autophagy-modulating agents such as rapamycin and chloroquine have already been used clinically to treat cancer, it is conceivable that targeting autophagic pathways may provide a new opportunity for discovery and development of more novel cancer therapeutics. With a deeper understanding of the regulatory mechanisms governing autophagy, we will have a better opportunity to facilitate the exploitation of autophagy as a target for therapeutic intervention in cancer. This review discusses the current status of targeting autophagic pathways as a potential cancer therapy.
基金Supported by the National Natural Science Foundation of China,No.81672577
文摘BACKGROUND Recent evidence indicates that malignant ascites may be associated with the high malignancy and poor prognosis of gastric cancer(GC)with peritoneal metastasis(PM),but no robust consensus has been reached until now.AIM To evaluate the prognostic significance of malignant ascites in GC patients with PM.METHODS Two independent authors conducted database searches.The searches were performed in the EMBASE,PubMed,and Cochrane Library databases,and the terms used to search included stomach neoplasms,GC,ascites,peritoneal effusion,survival,and survival analysis.Outcomes included overall survival and hazard ratios with 95%confidence intervals(CIs).Three pairs of comparisons for measuring survival were made:(1)Patients with ascites vs those without ascites;(2)Patients with massive ascites vs those with mild to moderate ascites;and(3)Patients with massive ascites vs those with no to moderate ascites.RESULTS Fourteen articles including fifteen studies were considered in the final analysis.Among them,nine studies assessed the difference in prognosis between patients with and without malignant ascites.A pooled HR of 1.63(95%CI:1.47-1.82,P<0.00001)indicated that GC patients with malignant ascites had a relatively poor prognosis compared to patients without ascites.We also found that the prognosis of GC patients with malignant ascites was related to the volume of ascites in the six other studies.CONCLUSION GC patients with malignant ascites tend to have a worse prognosis,and the volume of ascites has an impact on GC outcomes.
基金supported by the National Science Foundation for Excellent Young Scholars(No.32122052)National Natural Science Foundation Regional Innovation and Development(No.U19A2003).
文摘Cancer immunotherapy harnesses the immune system to attack tumors and has received extensive attention in recent years.Cancer vaccines as an important branch of immunotherapy are designed for delivering tumor antigens to antigen-presenting cells(APCs)to stimulate a strong immune response to against tumors,representing a potentially therapeutic and prophylactic effect with the long-term anticancer benefits.Nevertheless,the disappointing outcomes of their clinical use might be attributed to dilemma in antigen selection,immunogenicity,lymph nodes(LNs)targeting ability,lysosomal escape ability,immune evasion,etc.Nanotechnology,aiming to overcome these barriers,has been utilized in cancer vaccine development for decades.Numerous preclinical and clinical studies demonstrate positive results in nanomaterials-based cancer vaccines with considerable improvement in the vaccine efficacy.In this review,we systematically introduced the characteristics of nanovaccines and highlighted the different types of nanomaterials used for cancer vaccine design.In addition,the opportunities and challenges of the emerging nanotechnology-based cancer vaccines were discussed.
基金This work is supported by the National Natural Science Foundation of China(reference number:81602492)the National Key Research and Development Program of China(reference number:2016YFA0201402)the National Major Scientific and Technological Special Project for"Significant New Drugs Development"(reference number:2018ZX09733001).
文摘As one of the most common metastatic sites of malignancies,bone has a unique microenvironment that allows metastatic tumor cells to grow and flourish.The fenestrated capillaries in the bone,bone matrix,and bone cells,including osteoblasts and osteoclasts,together maintain the homeostasis of the bone microenvironment.In contrast,tumor-derived factors act on bone components,leading to subsequent bone resorption or excessive bone formation.The various pathways involved also provide multiple targets for therapeutic strategies against bone metastases.In this review,we summarize the current understanding of the mechanism of bone metastases.Based on the general process of bone metastases,we specifically highlight the complex crosstalk between tumor cells and the bone microenvironment and the current management of cancer bone metastases.
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.
基金supported by National Natural Science Foundation of China (No. 81822025)National Program for Support of Top-notch Young Professionals (No. W02070141)1.3.5 Project for Disciplines of Excellence, West China Hospital, Sichuan University
文摘Gambogic acid(GA) is a natural product with potent anticancer activity in vitro. However, poor water solubility and systematic toxicity limit the further clinical application of GA. Micellization of hydrophobic molecule could effectively ameliorate aqueous dispersity of GA and induce better blood retention and tumor accumulation, hence lead to improved stability and therapeutic effect of GA. In this study, monomethyl poly(ethylene glycol)-poly(ε-caprolactone)-poly(trimethylene carbonate)(MPEG-P(CL-ran-TMC)) was used to encapsulate GA by a single-step solid dispersion method to form a GA encapsulated MPEG-P(CLran-TMC) micelles(GA micelles). GA micelles were characterized with a small particle size(44 ±1 nm),high drug loading content(26.28% ± 0.12%) and high-efficiency encapsulation(87.59% ± 0.41 %). Compared with free GA, GA micelles showed better dispersion in water, prolonged release behavior in vitro, and enhanced tumor cellular uptake. GA micelles could also effectively induce apoptosis in AsPC-1 cells.Compared with free GA, GA micelles exhibited superior antitumor efficacy and better apoptosis induced effect in a subcutaneous xenograft mouse model of AsPC-1 cells. In conclusion, GA micelles which showed high-efficiency anti-tumor effect in vitro and in vivo may serve as a candidate for pancreatic cancer therapy.
基金financial support from the National Natural Science Foundation of China(Nos.U21A20417,31930067,and 31800797)the Sichuan Science and Technology Program(Nos.2022YFS0333 and 2022YFS0203)+1 种基金the 1·3·5 project for disciplines of excellence,West China Hospital,Sichuan University(No.ZYGD18002)the Post-Doctor Research Project,West China Hospital,Sichuan University(No.2018HXBH066)。
文摘Colorectal cancer causes the third most common type of malignant tumors with high morbidity and mortality.Chemotherapy is currently one of the most effective and common treatments for colorectal cancer.However,the poor water solubility of some chemotherapeutics,untargeted drug delivery,and the undesirable systemic side effects of conventional treatment remain the major issues for colorectal cancer chemotherapy.Fortunately,drug delivery systems(DDS)based on biomaterials have been widely investigated and found to be capable of resolving those issues with good performance.Therefore,the main goal of this review is to summarize and discuss the progress and potential advantages of different DDS for colorectal cancer chemotherapy.We not only reviewed the nanocarriers used to improve the solubility of chemotherapeutics,including liposomes,micelles,and nanoparticles,but also discussed targeted DDS based on specific ligand-receptor recognition and tumor microenvironmental stimulus responses.Furthermore,locally administered systems based on hydrogels and microspheres,which have been shown to increase drug accumulation at the tumor site while decreasing systemic toxicity,were also emphasized.DDS provides a good option for improving the efficacy of chemotherapy in the treatment of colorectal cancer.
基金Major Sci-Tech Project of"National Significant New Drug Creation"(No 2008ZX09312-002)
文摘Either cetuximab or bevacizumab can improve the survival of patients with metastastic colorectal cancer(mCRC)if administered combided with cytotoxic agents.However,the effect of two or more target agents in combination is uncertain in these patients.Here,we reported a patient with mCRC successfully treated by a combination of target agents after the failure of chemotherapy.The patient received palliative resection of primary tumor followed by 9 cycles of postoperative XELOX regimen,cytokine-induced killer cell(CIK)-based biotherapy,traditional Chinese medicine,particle implantation in the lung metastatic lesions.The tumor progressed 20 months after the standard treatments.Then,the regimen cetuximab,bevacizumab and cefitinib was applied.During the treatment with targeted agents,grade IV acne-like rash and relatively severe parionychia of the toes occurred.Both of them recovered smoothly.The PET-CT reexamination at 40 days after the target treatment showed that the metabolism of mediastinal lymph nodes basically recovered to a normal level.The combination of multiple targeted agents obtained a progression-free survival(PFS)of 11 months and the patient with a good quality of life during this period.
