Fluorescence imaging techniques represent essential tools in in vitro,preclinical,and clinical studies.In this study,an improved one-step hydrothermal method to synthesize citric acid(CA)modifiedα-NaYbF_(4):2%Er^(3+)...Fluorescence imaging techniques represent essential tools in in vitro,preclinical,and clinical studies.In this study,an improved one-step hydrothermal method to synthesize citric acid(CA)modifiedα-NaYbF_(4):2%Er^(3+)nanocrystals was proposed.The introduction of various doping ions into NaYbF_(4):2%Er^(3+)and the different valence states of the same ions affect both the crystal size and upconversion luminesce nce.There fore,we investigated the upconversion luminesce nce enha ncement of NaYbF_(4):2%Er^(3+)by ion doping and find that the upconversion luminescence intensity of the upconversion nanoparticles(UCNPs)co-doped with 5 mol%Fe^(2+)ions shows the greatest enhancement,especially for red emission at654 nm.Furthermore,HeLa cells incubated with UCNPs allow for imaging with strong red upconversion emission detectio n.Confocal laser scanning microscope(CLSM)fluorescent images of HeLa cells indicate that NaYbF_(4):2%Er/5%Fe^(2+)leads to a clear outline and improves visualization of the cell morphology.In addition,the CA coated NaYbF_(4):2%Er^(3+)/5%Fe^(2+)nanoparticles and NaYbF_(4):2%Er^(3+)/5%Fe^(2+)show low cytotoxicity in HeLa cells.Organ imaging reveals the efficiency of these UCNPs to analyze the lungs,liver,and spleen.Together,these results indicate that the Cit-NaYbF_(4):2%Er^(3+)/5%Fe^(2+)UCNPs are efficient nanoprobes for fluorescence molecular to mography.展开更多
Phenotypic screening has played an important role in discovering innovative small-molecule drugs and clinical candidates with unique molecular mechanisms of action.However,conducting cell-based high-throughput screeni...Phenotypic screening has played an important role in discovering innovative small-molecule drugs and clinical candidates with unique molecular mechanisms of action.However,conducting cell-based high-throughput screening from vast compound libraries is extremely time-consuming and expensive.Fortunately,deep learning has provided a new paradigm for identifying compounds with specific phenotypic properties.Herein,we developed a data-driven classification-generation cascade model to discover new chemotype antitumor drugs.Through wet-lab validation,WJ0976 and WJ0909 were identified as tetrahydrocarbazole derivatives and displayed potent broad-spectrum antitumor activity as well as growth inhibitory properties against multidrug-resistant cancer cells.Furthermore,the R-(−)-WJ0909(WJ0909B),demonstrated optimal antitumor efficacy in vitro and ex vivo patient-derived organoids(PDOs).Further investigations revealed that WJ0909B upregulates p53 expression and cause mitochondria-dependent endogenous apoptosis.Moreover,WJ0909B and the click-activated prodrug WJ0909B-TCO potently inhibited tumor growth in cell-derived xenograft models.This research highlights the significant potential of deep learning-guided approach to phenotypic drug discovery for anticancer drugs and the strategy of click-activated prodrug for targeted cancer therapy.展开更多
Constructing an optimal solid-electrolyte interphase(SEI)through electrolyte strategies is an effective approach to suppress lithium dendrites and improve deposition/stripping reversibility.Specifically,increasing the...Constructing an optimal solid-electrolyte interphase(SEI)through electrolyte strategies is an effective approach to suppress lithium dendrites and improve deposition/stripping reversibility.Specifically,increasing the proportion of anion coordination in the inner Li^(+)solvation sheath promotes the formation of an anion-derived SEI that features a high content of inorganic components favoring Li^(+)diffusion.However,whether this anion-rich structure can persist during cycling has not been dynamically investigated.In this work,we not only construct a favorable solvation structure but also study its evolution in both bulk and interface regions across varying temperatures.Additionally,we employ the unique“adsorption-attraction”mechanism of trifluoromethoxybenzene(PhOCF_(3))solvent to inhibit the undesirable transition from an“anion-rich”to“anion-deficient”structure at the anode interface,which is confirmed by 2D NMR and in situ infrared spectroscopy.In summary,this work explores the solvation structure in depth and proposes new perspectives on designing electrolytes for lithium metal batteries.展开更多
Prolonged activation of nuclear factor(NF)-кB signaling significantly contributes to the development of colorectal cancer(CRC).New therapeutic opportunities are emerging from targeting this distorted cell signaling t...Prolonged activation of nuclear factor(NF)-кB signaling significantly contributes to the development of colorectal cancer(CRC).New therapeutic opportunities are emerging from targeting this distorted cell signaling transduction.Here,we discovered the critical role of RING finger 138(RNF138)in CRC tumorigenesis through regulating the NF-кB signaling,which is independent of its Ubiquitin-E3 ligase activity involved in DNA damage response.RNF138^(−/−) mice were hyper-susceptible to the switch from colitis to aggressive malignancy,which coincided with sustained aberrant NF-кB signaling in the colonic cells.Furthermore,RNF138 suppresses the activation of NF-кB signaling pathway through preventing the translocation of NIK and IKK-Beta Binding Protein(NIBP)to the cytoplasm,which requires the ubiquitin interaction motif(UIM)domain.More importantly,we uncovered a significant correlation between poor prognosis and the downregulation of RNF138 associated with reinforced NF-кB signaling in clinical settings,raising the possibility of RNF138 dysregulation as an indicator for the therapeutic intervention targeting NF-кB signaling.Using the xenograft models built upon either RNF138-dificient CRC cells or the cells derived from the RNF138-dysregulated CRC patients,we demonstrated that the inhibition of NF-кB signaling effectively hampered tumor growth.Overall,our work defined the pathogenic role of aberrant NF-кB signaling due to RNF138 downregulation in the cascade events from the colitis switch to colonic neoplastic transformation and progression,and also highlights the possibility of targeting the NF-кB signaling in treating specific subtypes of CRC indicated by RNF138-ablation.展开更多
Many management strategies are available for pancreatic neuroendocrine neoplasms with liver metastases.However,a lack of biological,molecular,and genomic information and an absence of data from rigorous trials limit t...Many management strategies are available for pancreatic neuroendocrine neoplasms with liver metastases.However,a lack of biological,molecular,and genomic information and an absence of data from rigorous trials limit the validity of these strategies.This review presents the viewpoints from an international conference consisting of several expert working groups.The working groups reviewed a series of questions of particular interest to clinicians taking care of patients with pancreatic neuroendocrine neoplasms with liver metastases by reviewing the existing management strategies and literature,evaluating the evidence on which management decisions were based,developing internationally acceptable recommendations for clinical practice,and making recommendations for clinical and research endeavors.The review for each question will be followed by recommendations from the panel.展开更多
Neuroendocrine tumours(NETs)are rare cancers with positive somatostatin receptor 2(SSTR2)expression,and treatment strategies for NETs are not satisfactory.Nanomaterial-mediated therapy targeting SSTR2 in NETs is very ...Neuroendocrine tumours(NETs)are rare cancers with positive somatostatin receptor 2(SSTR2)expression,and treatment strategies for NETs are not satisfactory.Nanomaterial-mediated therapy targeting SSTR2 in NETs is very promising.This study firstly combined mesoporous silica-coated gold nanorods(AuNRs@mSiO_(2))and targeting-SSTR2 dodecane tetraacetic acidtyrosine3-octreotate(DOTA-TATE)into AuNRs@mSiO_(2)@DOTA-TATE to investigate NETs inhibition under near-infrared light.AuNRs@mSiO_(2)@DOTA-TATE showed good photothermal conversion efficiency.In vitro,under light irradiation,the cell viability significantly decreased with increasing AuNR@mSiO_(2)@DOTA-TATE concentration;in two successfully established neuroendocrine tumour organoids with SSTR2 expression,AuNRs@mSiO_(2)@DOTA-TATE with light inhibited tumours significantly better than AuNRs@mSiO_(2) with light.In vivo,the SSTR2-targeting ability and biodistribution of AuNRs@mSiO_(2)@DOTA-TATE were confirmed with AuNRs@mSiO_(2)@64Cu-DOTA-TATE under micro-positron emission tomography/computed tomography(micro-PET/CT);in the AuNRs@mSiO_(2)@DOTA-TATE with laser group,the tumour surface temperature increased rapidly,with tumour volumes similar to those in the octreotide group and significantly lower than those in other groups.There was no significant difference in mice body weight between the AuNRs@mSiO_(2)@DOTA-TATE with laser group and other groups.No significant inflammatory lesions or cell necrosis was found in the main organs.In summary,we presented a feasible strategy to construct AuNRs@mSiO_(2)@DOTA-TATE with good photothermal conversion efficiency,targetingSSTR2 ability,significant antitumour effects,and good biocompatibility,warranting further explorations of AuNRs@mSiO_(2)@DOTA-TATE for NETs therapy applications.展开更多
Liver metastasis remains the primary cause of mortality in patients with colon cancer. Identifying specific driver gene mutations that contribute to metastasis may offer viable therapeutic targets. To explore clonal e...Liver metastasis remains the primary cause of mortality in patients with colon cancer. Identifying specific driver gene mutations that contribute to metastasis may offer viable therapeutic targets. To explore clonal evolution and genetic heterogeneity within the metastasis, we conducted single-cell exome sequencing on 150 single cells isolated from the primary tumor, liver metastasis, and lymphatic metastasis from a stage IV colon cancer patient. The genetic landscape of the tumor samples revealed that both lymphatic and liver metastases originated from the same region of the primary tumor. Notably, the liver metastasis was derived directly from the primary tumor, bypassing the lymph nodes. Comparative analysis of the sequencing data for individual cell pairs within different tumors demonstrated that the genetic heterogeneity of both liver and lymphatic metastases was also greater than that of the primary tumor. This finding indicates that liver and lymphatic metastases arose from clusters of circulating tumor cell (CTC) of a polyclonal origin, rather than from a single cell from the primary tumor. Single-cell transcriptome analysis suggested that higher EMT score and CNV scores were associated with more polyclonal metastasis. Additionally, a mutation in the TRPS1 (Transcriptional repressor GATA binding 1) gene, TRPS1 R544Q, was enriched in the single cells from the liver metastasis. The mutation significantly increased CRC invasion and migration both in vitro and in vivo through the TRPS1R544Q/ZEB1 axis. Further TRPS1 mutations were detected in additional colon cancer cases, correlating with advanced-stage disease and inferior prognosis. These results reveal polyclonal seeding and TRPS1 mutation as potential mechanisms driving the development of liver metastases in colon cancer.展开更多
基金Project supported by the Natural Science Basic Research Program of Shaanxi Province(2021JZ-43)the Key Program for International Science and Technology Cooperation Projects of Shaanxi Province(2018KWZ-08)+2 种基金the National Key Research and Development Program of China(2019YFC1520904)the Scientific Research Plan of Shannxi Provincial Education Department,China(18JK0780)Ningxia Natural Fund(2023AAC03338)。
文摘Fluorescence imaging techniques represent essential tools in in vitro,preclinical,and clinical studies.In this study,an improved one-step hydrothermal method to synthesize citric acid(CA)modifiedα-NaYbF_(4):2%Er^(3+)nanocrystals was proposed.The introduction of various doping ions into NaYbF_(4):2%Er^(3+)and the different valence states of the same ions affect both the crystal size and upconversion luminesce nce.There fore,we investigated the upconversion luminesce nce enha ncement of NaYbF_(4):2%Er^(3+)by ion doping and find that the upconversion luminescence intensity of the upconversion nanoparticles(UCNPs)co-doped with 5 mol%Fe^(2+)ions shows the greatest enhancement,especially for red emission at654 nm.Furthermore,HeLa cells incubated with UCNPs allow for imaging with strong red upconversion emission detectio n.Confocal laser scanning microscope(CLSM)fluorescent images of HeLa cells indicate that NaYbF_(4):2%Er/5%Fe^(2+)leads to a clear outline and improves visualization of the cell morphology.In addition,the CA coated NaYbF_(4):2%Er^(3+)/5%Fe^(2+)nanoparticles and NaYbF_(4):2%Er^(3+)/5%Fe^(2+)show low cytotoxicity in HeLa cells.Organ imaging reveals the efficiency of these UCNPs to analyze the lungs,liver,and spleen.Together,these results indicate that the Cit-NaYbF_(4):2%Er^(3+)/5%Fe^(2+)UCNPs are efficient nanoprobes for fluorescence molecular to mography.
基金supported by CAMS Innovation Fund for Medical Sciences,China(No.2021-I2M-1-028 and No.2021-I2M-1-054,China)+6 种基金the National Natural Science Foundation of China,China(No.82303782,China)the China Postdoctoral Science Foundation,China(2024M763807,China)the 2024 China Industrial Technology Infrastructure Public Service Platform Project,China(GN2024-31-4700)The computing resources were supported by Biomedical High Performance Computing Platform,Chinese Academy of Medical Sciences,China.
文摘Phenotypic screening has played an important role in discovering innovative small-molecule drugs and clinical candidates with unique molecular mechanisms of action.However,conducting cell-based high-throughput screening from vast compound libraries is extremely time-consuming and expensive.Fortunately,deep learning has provided a new paradigm for identifying compounds with specific phenotypic properties.Herein,we developed a data-driven classification-generation cascade model to discover new chemotype antitumor drugs.Through wet-lab validation,WJ0976 and WJ0909 were identified as tetrahydrocarbazole derivatives and displayed potent broad-spectrum antitumor activity as well as growth inhibitory properties against multidrug-resistant cancer cells.Furthermore,the R-(−)-WJ0909(WJ0909B),demonstrated optimal antitumor efficacy in vitro and ex vivo patient-derived organoids(PDOs).Further investigations revealed that WJ0909B upregulates p53 expression and cause mitochondria-dependent endogenous apoptosis.Moreover,WJ0909B and the click-activated prodrug WJ0909B-TCO potently inhibited tumor growth in cell-derived xenograft models.This research highlights the significant potential of deep learning-guided approach to phenotypic drug discovery for anticancer drugs and the strategy of click-activated prodrug for targeted cancer therapy.
基金support from the National Key Research and Development Program of China(2021YFB2400300)the National Natural Science Foundation of China(21875198,21875195)+1 种基金the Fundamental Research Funds for the Central Universities(20720190040)the Key Project of Science and Technology of Xiamen(3502Z20201013).
文摘Constructing an optimal solid-electrolyte interphase(SEI)through electrolyte strategies is an effective approach to suppress lithium dendrites and improve deposition/stripping reversibility.Specifically,increasing the proportion of anion coordination in the inner Li^(+)solvation sheath promotes the formation of an anion-derived SEI that features a high content of inorganic components favoring Li^(+)diffusion.However,whether this anion-rich structure can persist during cycling has not been dynamically investigated.In this work,we not only construct a favorable solvation structure but also study its evolution in both bulk and interface regions across varying temperatures.Additionally,we employ the unique“adsorption-attraction”mechanism of trifluoromethoxybenzene(PhOCF_(3))solvent to inhibit the undesirable transition from an“anion-rich”to“anion-deficient”structure at the anode interface,which is confirmed by 2D NMR and in situ infrared spectroscopy.In summary,this work explores the solvation structure in depth and proposes new perspectives on designing electrolytes for lithium metal batteries.
基金supported by CAMS Innovation Fund for Medical Sciences(CIFMS,2021-I2M-1-066,2017-I2M-4-002 to H.Z.,2021-I2M-1-019 to W.S.,2021-1-I2M-014 to C.Z.L.)the National Natural Science Foundation of China(81972311,82141127 and 81672461 to H.Z.,81672472,and 31970794 to W.S.,81570780 to C.Z.L.,32000586 to K.L.)+4 种基金the Nonprofit Central Research Institute Fund of Chinese Academy of Medical Sciences(2019PT310026 to H.Z.)Sanming Project of Medicine in Shenzhen(SZSM202011010 to H.Z.)the National Key Research and Development Program of China(2018YFC1003500 to W.S.)the State Key Laboratory Special fund from the Ministry of Science(2060204 to W.S.)the State Key Project on Infection Diseases of China(2017ZX10201021-007-003 to H.Z.).
文摘Prolonged activation of nuclear factor(NF)-кB signaling significantly contributes to the development of colorectal cancer(CRC).New therapeutic opportunities are emerging from targeting this distorted cell signaling transduction.Here,we discovered the critical role of RING finger 138(RNF138)in CRC tumorigenesis through regulating the NF-кB signaling,which is independent of its Ubiquitin-E3 ligase activity involved in DNA damage response.RNF138^(−/−) mice were hyper-susceptible to the switch from colitis to aggressive malignancy,which coincided with sustained aberrant NF-кB signaling in the colonic cells.Furthermore,RNF138 suppresses the activation of NF-кB signaling pathway through preventing the translocation of NIK and IKK-Beta Binding Protein(NIBP)to the cytoplasm,which requires the ubiquitin interaction motif(UIM)domain.More importantly,we uncovered a significant correlation between poor prognosis and the downregulation of RNF138 associated with reinforced NF-кB signaling in clinical settings,raising the possibility of RNF138 dysregulation as an indicator for the therapeutic intervention targeting NF-кB signaling.Using the xenograft models built upon either RNF138-dificient CRC cells or the cells derived from the RNF138-dysregulated CRC patients,we demonstrated that the inhibition of NF-кB signaling effectively hampered tumor growth.Overall,our work defined the pathogenic role of aberrant NF-кB signaling due to RNF138 downregulation in the cascade events from the colitis switch to colonic neoplastic transformation and progression,and also highlights the possibility of targeting the NF-кB signaling in treating specific subtypes of CRC indicated by RNF138-ablation.
基金supported by the National Natural Science Foundation of China(Grant number,82141127).
文摘Many management strategies are available for pancreatic neuroendocrine neoplasms with liver metastases.However,a lack of biological,molecular,and genomic information and an absence of data from rigorous trials limit the validity of these strategies.This review presents the viewpoints from an international conference consisting of several expert working groups.The working groups reviewed a series of questions of particular interest to clinicians taking care of patients with pancreatic neuroendocrine neoplasms with liver metastases by reviewing the existing management strategies and literature,evaluating the evidence on which management decisions were based,developing internationally acceptable recommendations for clinical practice,and making recommendations for clinical and research endeavors.The review for each question will be followed by recommendations from the panel.
基金supported by CAMS Innovation Fund for Medical Sciences(CIFMS)(Nos.2021-I2M-1-066,2017-I2M-4-002,and 2021-I2M1-019)the National Natural Science Foundation of China(Nos.81972311,82141127,and 31970794)+3 种基金the State Key Project on Infection Diseases of China(No.2017ZX10201021-007-003)the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences(No.2019PT310026)Sanming Project of Medicine in Shenzhen(No.SZSM202011010)Independent research project of the State Key Laboratory of Tribology,and the State Key Laboratory Special fund from the Ministry of Science(No.2060204).
文摘Neuroendocrine tumours(NETs)are rare cancers with positive somatostatin receptor 2(SSTR2)expression,and treatment strategies for NETs are not satisfactory.Nanomaterial-mediated therapy targeting SSTR2 in NETs is very promising.This study firstly combined mesoporous silica-coated gold nanorods(AuNRs@mSiO_(2))and targeting-SSTR2 dodecane tetraacetic acidtyrosine3-octreotate(DOTA-TATE)into AuNRs@mSiO_(2)@DOTA-TATE to investigate NETs inhibition under near-infrared light.AuNRs@mSiO_(2)@DOTA-TATE showed good photothermal conversion efficiency.In vitro,under light irradiation,the cell viability significantly decreased with increasing AuNR@mSiO_(2)@DOTA-TATE concentration;in two successfully established neuroendocrine tumour organoids with SSTR2 expression,AuNRs@mSiO_(2)@DOTA-TATE with light inhibited tumours significantly better than AuNRs@mSiO_(2) with light.In vivo,the SSTR2-targeting ability and biodistribution of AuNRs@mSiO_(2)@DOTA-TATE were confirmed with AuNRs@mSiO_(2)@64Cu-DOTA-TATE under micro-positron emission tomography/computed tomography(micro-PET/CT);in the AuNRs@mSiO_(2)@DOTA-TATE with laser group,the tumour surface temperature increased rapidly,with tumour volumes similar to those in the octreotide group and significantly lower than those in other groups.There was no significant difference in mice body weight between the AuNRs@mSiO_(2)@DOTA-TATE with laser group and other groups.No significant inflammatory lesions or cell necrosis was found in the main organs.In summary,we presented a feasible strategy to construct AuNRs@mSiO_(2)@DOTA-TATE with good photothermal conversion efficiency,targetingSSTR2 ability,significant antitumour effects,and good biocompatibility,warranting further explorations of AuNRs@mSiO_(2)@DOTA-TATE for NETs therapy applications.
基金National Key Research and Development Program of China(2023YFC3403800)National Natural Science Foundation of China(81972311,82303782)+3 种基金special Funds of the National Natural Science Foundation of China(82141127)CAMS Innovation Fund for Medical Sciences(CIFMS)(2021-12M-066)Non-profit Central Research Institution Fund of Chinese Academy of Medical Science(2019PT310026)Sanming Project of Medicine in Shenzhen(SZSM202011010).
文摘Liver metastasis remains the primary cause of mortality in patients with colon cancer. Identifying specific driver gene mutations that contribute to metastasis may offer viable therapeutic targets. To explore clonal evolution and genetic heterogeneity within the metastasis, we conducted single-cell exome sequencing on 150 single cells isolated from the primary tumor, liver metastasis, and lymphatic metastasis from a stage IV colon cancer patient. The genetic landscape of the tumor samples revealed that both lymphatic and liver metastases originated from the same region of the primary tumor. Notably, the liver metastasis was derived directly from the primary tumor, bypassing the lymph nodes. Comparative analysis of the sequencing data for individual cell pairs within different tumors demonstrated that the genetic heterogeneity of both liver and lymphatic metastases was also greater than that of the primary tumor. This finding indicates that liver and lymphatic metastases arose from clusters of circulating tumor cell (CTC) of a polyclonal origin, rather than from a single cell from the primary tumor. Single-cell transcriptome analysis suggested that higher EMT score and CNV scores were associated with more polyclonal metastasis. Additionally, a mutation in the TRPS1 (Transcriptional repressor GATA binding 1) gene, TRPS1 R544Q, was enriched in the single cells from the liver metastasis. The mutation significantly increased CRC invasion and migration both in vitro and in vivo through the TRPS1R544Q/ZEB1 axis. Further TRPS1 mutations were detected in additional colon cancer cases, correlating with advanced-stage disease and inferior prognosis. These results reveal polyclonal seeding and TRPS1 mutation as potential mechanisms driving the development of liver metastases in colon cancer.
