Objective: Patients with BRAF-mutant colorectal cancer(CRC) have a poor prognosis. Molecular status is not currently used to select which drug to use in combination with radiotherapy. Our aim was to identify drugs tha...Objective: Patients with BRAF-mutant colorectal cancer(CRC) have a poor prognosis. Molecular status is not currently used to select which drug to use in combination with radiotherapy. Our aim was to identify drugs that radiosensitise CRC cells with known BRAF status.Methods: We screened 298 oncological drugs with and without ionising radiation in colorectal cancer cells isogenic for BRAF. Hits from rank product analysis were validated in a 16-cell line panel of human CRC cell lines, using clonogenic survival assays and xenograft models in vivo.Results: Most consistently identified hits were drugs targeting cell growth/proliferation or DNA damage repair. The most effective class of drugs that radiosensitised wild-type and mutant cell lines was PARP inhibitors. In clonogenic survival assays, talazoparib produced a radiation enhancement ratio of 1.9 in DLD1(BRAF-wildtype) cells and 1.8 in RKO(BRAF V600 E) cells. In DLD1 xenografts, talazoparib significantly increased the inhibitory effect of radiation on tumour growth(P ≤ 0.01).Conclusions: Our method for screening large drug libraries for radiosensitisation has identified PARP inhibitors as promising radiosensitisers of colorectal cancer cells with wild-type and mutant BRAF backgrounds.展开更多
Over 17 and 160 types of chemical modifications have been identified in DNA and RNA,respectively.The interest in understanding the various biological functions of DNA and RNA modifications has lead to the cutting-edge...Over 17 and 160 types of chemical modifications have been identified in DNA and RNA,respectively.The interest in understanding the various biological functions of DNA and RNA modifications has lead to the cutting-edged fields of epigenomics and epitranscriptomics.Developing chemical and biological tools to detect specific modifications in the genome or transcriptome has greatly facilitated their study.Here,we review the recent technological advances in this rapidly evolving field.We focus on high-throughput detection methods and biological findings for these modifications,and discuss questions to be addressed as well.We also summarize third-generation sequencing methods,which enable long-read and single-molecule sequencing of DNA and RNA modification.展开更多
In this special topic "Herbal small RNAs, novel precision medicine from Mother Nature", we present four original articles that study the entry of small RNAs derived from herbs used in traditional Chinese med...In this special topic "Herbal small RNAs, novel precision medicine from Mother Nature", we present four original articles that study the entry of small RNAs derived from herbs used in traditional Chinese medicine into mammalian cells and their function within human and mouse cells, and one review paper focusing on current trends in herb genomics (Du et al., 2017;Huang et al., 2018;Zhang et al., 2018;Li et al., 2019;Xin et al., 2018).展开更多
Cross-kingdom herbal mi RNA was first reported in 2012.Using a modified herbal extraction protocol,we obtained 73,677,287sequences by RNA-seq from 245 traditional Chinese Medicine(TCM),of which 20,758,257 were unique ...Cross-kingdom herbal mi RNA was first reported in 2012.Using a modified herbal extraction protocol,we obtained 73,677,287sequences by RNA-seq from 245 traditional Chinese Medicine(TCM),of which 20,758,257 were unique sequences.We constructed a Bencao(herbal)small RNA(s RNA)Atlas(http://bencao.bmicc.cn),annotated the sequences by sequence-based clustering,and created a nomenclature system for Bencao s RNAs.The profiles of 21,757 mi RNAs in the Atlas were highly consistent with those of plant mi RNAs in mi RBase.Using software tools,our results demonstrated that all human genes might be regulated by s RNAs from the Bencao s RNA Atlas,part of the predicted human target genes were experimentally validated,suggesting that Bencao s RNAs might be one of the main bioactive components of herbal medicines.We established roadmaps for oligonucleotide drugs development and optimization of TCM prescriptions.Moreover,the decoctosome,a lipo-nano particle consisting of 0.5%–2.5%of the decoction,demonstrated potent medical effects.We propose a Bencao(herbal)Index,including small-molecule compounds(SM),protein peptides(P),nucleic acid(N),non-nucleic and non-proteinogenic large-molecule compounds(LM)and elements from Mendeleev's periodic table(E),to quantitatively measure the medical effects of botanic medicine.The Bencao s RNA Atlas is a resource for developing gene-targeting oligonucleotide drugs and optimizing botanical medicine,and may provide potential remedies for the theory and practice of one medicine.展开更多
基金supported by Bowel Disease Research FoundationOxford Cancer Research Centre+4 种基金the National Institute for Health Research University College London Hospitals Biomedical Research Centrethe Cancer Research UK University College London Experimental Cancer Medicine CentreCRUK-UCL Centre Award (Grant No. C416/ A25145)the Cancer Research UK Centers Network Accelerator Award Grant (Grant No.A21993) to the ART-NET Consortiumthe NIHR Oxford Biomedical Research Centre
文摘Objective: Patients with BRAF-mutant colorectal cancer(CRC) have a poor prognosis. Molecular status is not currently used to select which drug to use in combination with radiotherapy. Our aim was to identify drugs that radiosensitise CRC cells with known BRAF status.Methods: We screened 298 oncological drugs with and without ionising radiation in colorectal cancer cells isogenic for BRAF. Hits from rank product analysis were validated in a 16-cell line panel of human CRC cell lines, using clonogenic survival assays and xenograft models in vivo.Results: Most consistently identified hits were drugs targeting cell growth/proliferation or DNA damage repair. The most effective class of drugs that radiosensitised wild-type and mutant cell lines was PARP inhibitors. In clonogenic survival assays, talazoparib produced a radiation enhancement ratio of 1.9 in DLD1(BRAF-wildtype) cells and 1.8 in RKO(BRAF V600 E) cells. In DLD1 xenografts, talazoparib significantly increased the inhibitory effect of radiation on tumour growth(P ≤ 0.01).Conclusions: Our method for screening large drug libraries for radiosensitisation has identified PARP inhibitors as promising radiosensitisers of colorectal cancer cells with wild-type and mutant BRAF backgrounds.
基金This work was supported by the National Natural Science Foundation of China(Grant No.31861143026 to C.Y.)the Ministry of Science and Technology of China(Grant Nos.2019YFA0110902 and 2019YFA08002501 to C.Y.)the Ludwig Institute for Cancer Research(C-X.S.),Cancer Research UK(C63763/A26394 and C63763/A27122 to C-X.S.)NIHR Oxford Biomedical Research Centre(to C-X.S.)and Emerson Collective(to C-X.S.).L-Y.Z.is supported by China Scholarship Council.The views expressed are those of the authors and not necessarily those of the NHS,the NIHR or the Department of Health.We apologize for not being able to cite all the publications related to this topic due to space constraints of the journal.
文摘Over 17 and 160 types of chemical modifications have been identified in DNA and RNA,respectively.The interest in understanding the various biological functions of DNA and RNA modifications has lead to the cutting-edged fields of epigenomics and epitranscriptomics.Developing chemical and biological tools to detect specific modifications in the genome or transcriptome has greatly facilitated their study.Here,we review the recent technological advances in this rapidly evolving field.We focus on high-throughput detection methods and biological findings for these modifications,and discuss questions to be addressed as well.We also summarize third-generation sequencing methods,which enable long-read and single-molecule sequencing of DNA and RNA modification.
文摘In this special topic "Herbal small RNAs, novel precision medicine from Mother Nature", we present four original articles that study the entry of small RNAs derived from herbs used in traditional Chinese medicine into mammalian cells and their function within human and mouse cells, and one review paper focusing on current trends in herb genomics (Du et al., 2017;Huang et al., 2018;Zhang et al., 2018;Li et al., 2019;Xin et al., 2018).
基金the National Natural Science Foundation of China(81788101,32100104)the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences(2021-I2M-1022)+1 种基金the CAMS Endowment Fund(2021-CAMS-JZ001)the Overseas Expertise Introduction Center for Discipline Innovation(“111 Center”)(BP0820029)。
文摘Cross-kingdom herbal mi RNA was first reported in 2012.Using a modified herbal extraction protocol,we obtained 73,677,287sequences by RNA-seq from 245 traditional Chinese Medicine(TCM),of which 20,758,257 were unique sequences.We constructed a Bencao(herbal)small RNA(s RNA)Atlas(http://bencao.bmicc.cn),annotated the sequences by sequence-based clustering,and created a nomenclature system for Bencao s RNAs.The profiles of 21,757 mi RNAs in the Atlas were highly consistent with those of plant mi RNAs in mi RBase.Using software tools,our results demonstrated that all human genes might be regulated by s RNAs from the Bencao s RNA Atlas,part of the predicted human target genes were experimentally validated,suggesting that Bencao s RNAs might be one of the main bioactive components of herbal medicines.We established roadmaps for oligonucleotide drugs development and optimization of TCM prescriptions.Moreover,the decoctosome,a lipo-nano particle consisting of 0.5%–2.5%of the decoction,demonstrated potent medical effects.We propose a Bencao(herbal)Index,including small-molecule compounds(SM),protein peptides(P),nucleic acid(N),non-nucleic and non-proteinogenic large-molecule compounds(LM)and elements from Mendeleev's periodic table(E),to quantitatively measure the medical effects of botanic medicine.The Bencao s RNA Atlas is a resource for developing gene-targeting oligonucleotide drugs and optimizing botanical medicine,and may provide potential remedies for the theory and practice of one medicine.
