Background:Cancer-targeted T-cell receptor T(TCR-T)cells hold promise in treating cancers such as hematological malignancies and breast cancers.However,approaches to obtain cancer-reactive TCR-T cells have been unsucc...Background:Cancer-targeted T-cell receptor T(TCR-T)cells hold promise in treating cancers such as hematological malignancies and breast cancers.However,approaches to obtain cancer-reactive TCR-T cells have been unsuccessful.Methods:Here,we developed a novel strategy to screen for cancer-targeted TCR-T cells using a special humanized mouse model with person-specific immune fingerprints.Rare steady-state circulating hematopoietic stem and progenitor cells were expanded via three-dimensional culture of steady-state peripheral blood mononuclear cells,and then the expanded cells were applied to establish humanized mice.The human immune system was evaluated according to the kinetics of dendritic cells,monocytes,T-cell subsets,and cytokines.To fully stimulate the immune response and to obtain B-cell precursor NAML-6-and triple-negative breast cancer MDA-MB-231-targeted TCR-T cells,we used the inactivated cells above to treat humanized mice twice a day every 7 days.Then,human T cells were processed for TCRβ-chain(TRB)sequencing analysis.After the repertoires had been constructed,features such as the fraction,diversity,and immune signature were investigated.Results:The results demonstrated an increase in diversity and clonality of T cells after treatment.The preferential usage and features of TRBV,TRBJ,and the V–J combination were also changed.The stress also induced highly clonal Science and Technology,Grant/Award Number:2021C03010;Zhejiang Provincial Natural Science Foundation of China,Grant/Award Numbers:LTGY24H080003,LY21H080004 expansion.Tumor burden and survival analysis demonstrated that stress induction could significantly inhibit the growth of subsequently transfused live tumor cells and prolong the survival of the humanized mice.Conclusions:We constructed a personalized humanized mouse model to screen cancer-targeted TCR-T pools.Our platform provides an effective source of cancer-targeted TCR-T cells and allows for the design of patient-specific engineered T cells.It therefore has the potential to greatly benefit cancer treatment.展开更多
Since the beginning of 2017, Chinese Journal of Cancer has published a series of important questions in cancer research and clinical oncology, which sparkle diverse thoughts, interesting communications, and potential ...Since the beginning of 2017, Chinese Journal of Cancer has published a series of important questions in cancer research and clinical oncology, which sparkle diverse thoughts, interesting communications, and potential collaborations among researchers all over the world. In this article, 9 more questions are presented as followed. Question 67. How could we overcome the resistance of hepatocellular carcinoma against chemotherapeutics? Question 68. Is pursuit of non-covalent small-molecule binders of RAS proteins viable as a strategy of cancer drug discovery? Question 69. In what oligomeric structures do RAS proteins signal? Question 70. How can we achieve non-invasive early detection and diagnosis of lung cancer? Question 71. Does genetic information influence the volatolome enabling diagnosis of lung cancer with genetic mutations via cell headspace or breath analysis? Question 72. Is heavy ion beam radiotherapy e ective to kill cancer stem cells? Question 73. Is there any diversity among di erent types of cancer in terms of sensitivity to heavy ion beam radiotherapy? Question 74. Can targeted alpha-particle therapy augment the e ect of carbon ion radiotherapy on malignancies? Question 75. How does chromosomal instability drive tumor progression?展开更多
Zwitterionic polymers are known to interact with cells and have been shown to reveal cancer cell specificity.In this work,the importance of the chemistry of the polymer backbone for the cellular specificity of amino-a...Zwitterionic polymers are known to interact with cells and have been shown to reveal cancer cell specificity.In this work,the importance of the chemistry of the polymer backbone for the cellular specificity of amino-acid-derived polyzwitterions is demonstrated.A series of glutamic acid(Glu)-based vinyl monomers(i.e.,an acrylate,a methacrylate,an acrylamide,and a methacrylamide)were prepared and used for reversible addition-fragmentation chain-transfer(RAFT)polymerisation,yielding defined polymers with narrow size distribution(Ð<1.3).All Glu-functionalised,zwitterionic polymers revealed high cytocompatibility;however,differences in cellular association and specificity were observed.In particular,the methacrylamide-derived polymers showed high association with both,breast cancer cells and non-cancerous dendritic cells and,consequently,lack specificity.In contrast,high specificity to only breast cancer cells was observed for polyacrylates,-methacrylates,and-acrylamides.Detailed analysis of the polymers revealed differences in hydrophobicity,zeta potential,and potential side chain hydrolysis,which are impacted by the polymer backbone and might be responsible for the altered the cell association of these polymers.It is shown that a slightly negative net charge is preferred over a neutral charge to retain cell specificity.This was also confirmed by association experiments in the presence of competitive amino acid transporter substrates.The affinity of slightly negatively charged Glu-derived polymers to the xCT Glu/cystine cell membrane antiporter was found to be higher than that of neutrally charged polymers.Our results emphasise the importance of the polymer backbone for the design of cell-specific polymers.This study further highlights the potential to tailor amino-acid-derived zwitterionic materials beyond their side chain functionality.展开更多
Exploiting a tissue diagnosis method to abstain the involuted operating and consume valuable reagents while realizing high-speed and inexpensive pathological grading technology to supply a better scheme for cancer the...Exploiting a tissue diagnosis method to abstain the involuted operating and consume valuable reagents while realizing high-speed and inexpensive pathological grading technology to supply a better scheme for cancer therapy is a significant method of cancers detection. A promising immuno-fluorescence strategy was rationally designed and synthesized by loading ruthenium complex into cervical cancer-targeted DNA-cage, which was well used to realize high-speed and inexpensive diagnosis of clinical cervical cancer tumor tissues avoiding the traditional multi-stage process, thus demonstrating high application potential in clinical pathological grading and surgical judgment. Moreover, it has been finding that Apts-DNA@Ru can enrichment in the tumor region, interestingly, no enrichment in normal cervical cancer tissue. It has the potential to realize the integration of in vivo diagnose and further synchronous treatment in the near future. Thence, this study demonstrates a strategy for integration of cancer-targeted DNA-cage and fluorescent Ru POP as alternative IHC reagents for next-generation more rapid convenient cancer detection.展开更多
Wortmannin, a known inhibitor of phosphoinositide 3-kinases(PI3 Ks), their low selectivity and high toxicity is still problematic and less is known about their effects on PI3 Ks in cellular systems. Hence, we have syn...Wortmannin, a known inhibitor of phosphoinositide 3-kinases(PI3 Ks), their low selectivity and high toxicity is still problematic and less is known about their effects on PI3 Ks in cellular systems. Hence, we have synthesized a series of multifunctional wortmannin probes with the ability to self-activate, by installing a clickable handle at C11 site, and secondary amine and cancer-targeting moiety at C20 site respectively. MTT assay first confirmed that self-activating probes have better inhibition potency and biotin enhanced their cancer cell uptake. Further experiments showed most of probes can target PI3 K/Akt/mTOR pathway with prolonged turn-over time. Protein profiling and pull-down results were observed that the derivatives not only labelled four PI3 Ks with selectivity, but also engaged in covalent interactions with numerous cellular proteins which could be the major reason of their high toxicity.展开更多
基金National Natural Science Foundation of China,Grant/Award Numbers:82130003,81970158,82000180Zhejiang Provincial Key R&D Projects of Department of Science and Technology,Grant/Award Number:2021C03010Zhejiang Provincial Natural Science Foundation of China,Grant/Award Numbers:LTGY24H080003,LY21H080004。
文摘Background:Cancer-targeted T-cell receptor T(TCR-T)cells hold promise in treating cancers such as hematological malignancies and breast cancers.However,approaches to obtain cancer-reactive TCR-T cells have been unsuccessful.Methods:Here,we developed a novel strategy to screen for cancer-targeted TCR-T cells using a special humanized mouse model with person-specific immune fingerprints.Rare steady-state circulating hematopoietic stem and progenitor cells were expanded via three-dimensional culture of steady-state peripheral blood mononuclear cells,and then the expanded cells were applied to establish humanized mice.The human immune system was evaluated according to the kinetics of dendritic cells,monocytes,T-cell subsets,and cytokines.To fully stimulate the immune response and to obtain B-cell precursor NAML-6-and triple-negative breast cancer MDA-MB-231-targeted TCR-T cells,we used the inactivated cells above to treat humanized mice twice a day every 7 days.Then,human T cells were processed for TCRβ-chain(TRB)sequencing analysis.After the repertoires had been constructed,features such as the fraction,diversity,and immune signature were investigated.Results:The results demonstrated an increase in diversity and clonality of T cells after treatment.The preferential usage and features of TRBV,TRBJ,and the V–J combination were also changed.The stress also induced highly clonal Science and Technology,Grant/Award Number:2021C03010;Zhejiang Provincial Natural Science Foundation of China,Grant/Award Numbers:LTGY24H080003,LY21H080004 expansion.Tumor burden and survival analysis demonstrated that stress induction could significantly inhibit the growth of subsequently transfused live tumor cells and prolong the survival of the humanized mice.Conclusions:We constructed a personalized humanized mouse model to screen cancer-targeted TCR-T pools.Our platform provides an effective source of cancer-targeted TCR-T cells and allows for the design of patient-specific engineered T cells.It therefore has the potential to greatly benefit cancer treatment.
文摘Since the beginning of 2017, Chinese Journal of Cancer has published a series of important questions in cancer research and clinical oncology, which sparkle diverse thoughts, interesting communications, and potential collaborations among researchers all over the world. In this article, 9 more questions are presented as followed. Question 67. How could we overcome the resistance of hepatocellular carcinoma against chemotherapeutics? Question 68. Is pursuit of non-covalent small-molecule binders of RAS proteins viable as a strategy of cancer drug discovery? Question 69. In what oligomeric structures do RAS proteins signal? Question 70. How can we achieve non-invasive early detection and diagnosis of lung cancer? Question 71. Does genetic information influence the volatolome enabling diagnosis of lung cancer with genetic mutations via cell headspace or breath analysis? Question 72. Is heavy ion beam radiotherapy e ective to kill cancer stem cells? Question 73. Is there any diversity among di erent types of cancer in terms of sensitivity to heavy ion beam radiotherapy? Question 74. Can targeted alpha-particle therapy augment the e ect of carbon ion radiotherapy on malignancies? Question 75. How does chromosomal instability drive tumor progression?
文摘Zwitterionic polymers are known to interact with cells and have been shown to reveal cancer cell specificity.In this work,the importance of the chemistry of the polymer backbone for the cellular specificity of amino-acid-derived polyzwitterions is demonstrated.A series of glutamic acid(Glu)-based vinyl monomers(i.e.,an acrylate,a methacrylate,an acrylamide,and a methacrylamide)were prepared and used for reversible addition-fragmentation chain-transfer(RAFT)polymerisation,yielding defined polymers with narrow size distribution(Ð<1.3).All Glu-functionalised,zwitterionic polymers revealed high cytocompatibility;however,differences in cellular association and specificity were observed.In particular,the methacrylamide-derived polymers showed high association with both,breast cancer cells and non-cancerous dendritic cells and,consequently,lack specificity.In contrast,high specificity to only breast cancer cells was observed for polyacrylates,-methacrylates,and-acrylamides.Detailed analysis of the polymers revealed differences in hydrophobicity,zeta potential,and potential side chain hydrolysis,which are impacted by the polymer backbone and might be responsible for the altered the cell association of these polymers.It is shown that a slightly negative net charge is preferred over a neutral charge to retain cell specificity.This was also confirmed by association experiments in the presence of competitive amino acid transporter substrates.The affinity of slightly negatively charged Glu-derived polymers to the xCT Glu/cystine cell membrane antiporter was found to be higher than that of neutrally charged polymers.Our results emphasise the importance of the polymer backbone for the design of cell-specific polymers.This study further highlights the potential to tailor amino-acid-derived zwitterionic materials beyond their side chain functionality.
基金supported by the National Key R&D Programs of China (No.2017YFC1103603)National Natural Science Foundation of China (No.21877049)+4 种基金Major Program for Tackling Key Problems of Industrial Technology in Guangzhou (No.201902020013)Dedicated Fund for Promoting High-Quality Marine Economic Development in Guangdong Province (Nos.GDOE2019-A31,2020-035)Guangzhou Key Laboratory of Molecular and Functional Imaging for Clinical Translation (No.201905010003)Innovation Team Project in Guangdong Colleges and Universities (No.2019KCXTD008)the Cultivation of Guangdong College Students’ Scientific and Technological Innovation – ‘‘Climbing Program’’ Special Funds (No.pdjh2019b0065)。
文摘Exploiting a tissue diagnosis method to abstain the involuted operating and consume valuable reagents while realizing high-speed and inexpensive pathological grading technology to supply a better scheme for cancer therapy is a significant method of cancers detection. A promising immuno-fluorescence strategy was rationally designed and synthesized by loading ruthenium complex into cervical cancer-targeted DNA-cage, which was well used to realize high-speed and inexpensive diagnosis of clinical cervical cancer tumor tissues avoiding the traditional multi-stage process, thus demonstrating high application potential in clinical pathological grading and surgical judgment. Moreover, it has been finding that Apts-DNA@Ru can enrichment in the tumor region, interestingly, no enrichment in normal cervical cancer tissue. It has the potential to realize the integration of in vivo diagnose and further synchronous treatment in the near future. Thence, this study demonstrates a strategy for integration of cancer-targeted DNA-cage and fluorescent Ru POP as alternative IHC reagents for next-generation more rapid convenient cancer detection.
基金financially supported by the Natural Science Foundation of Zhejiang Province (Nos. LQ16B020003, LY17B060009)the National Natural Science Foundation of China (Nos. 21708034, 21472172, 81672508, 61505076)Jiangsu Provincial Foundation for Distinguished Young Scholars (No. BK20170041)
文摘Wortmannin, a known inhibitor of phosphoinositide 3-kinases(PI3 Ks), their low selectivity and high toxicity is still problematic and less is known about their effects on PI3 Ks in cellular systems. Hence, we have synthesized a series of multifunctional wortmannin probes with the ability to self-activate, by installing a clickable handle at C11 site, and secondary amine and cancer-targeting moiety at C20 site respectively. MTT assay first confirmed that self-activating probes have better inhibition potency and biotin enhanced their cancer cell uptake. Further experiments showed most of probes can target PI3 K/Akt/mTOR pathway with prolonged turn-over time. Protein profiling and pull-down results were observed that the derivatives not only labelled four PI3 Ks with selectivity, but also engaged in covalent interactions with numerous cellular proteins which could be the major reason of their high toxicity.
