Chimeric antigen receptor T(CAR-T)cell therapy is the novel treatment strategy for hematological malignancies such as acute lymphoblastic leukemia(ALL),lymphoma and multiple myeloma.However,treatment-related toxicitie...Chimeric antigen receptor T(CAR-T)cell therapy is the novel treatment strategy for hematological malignancies such as acute lymphoblastic leukemia(ALL),lymphoma and multiple myeloma.However,treatment-related toxicities such as cytokine release syndrome(CRS)and immune effector cell-associated neurotoxicity syndrome(ICANS)have become significant hurdles to CAR-T treatment.Multiple strategies were established to alter the CAR structure on the genomic level to improve efficacy and reduce toxicities.Recently,the innovative gene-editing technology-clustered regularly interspaced short palindromic repeats(CRISPR)/CRISPR-associated nuclease9(Cas9)system,which particularly exhibits preponderance in knock-in and knockout at specific sites,is widely utilized to manufacture CAR-T products.The application of CRISPR/Cas9 to CAR-T cell therapy has shown promising clinical results with minimal toxicity.In this review,we summarized the past achievements of CRISPR/Cas9 in CAR-T therapy and focused on the potential CAR-T targets.展开更多
Seed-borne bacterial pathogens cause severe yield loss and biotoxin contamination in rice,leading to increasing concern on the global food supply and environmental safety.Plant native microbes play an important role i...Seed-borne bacterial pathogens cause severe yield loss and biotoxin contamination in rice,leading to increasing concern on the global food supply and environmental safety.Plant native microbes play an important role in defending against diseases,but their actions are often influ-enced by the chemical fungicides applied in the field.Here,Bacillus licheniformis mmj was isolated from rice spikelet,which uniquely showed not only fungicide-responsiveness but also broad-spectrum antimicrobial activity against major rice bacterial pathogens including Xanthomonas oryzae pv.oryzae,Burkholderia plantari and Burkholderia glumae.To understand the hallmark underlying the environmental adaptation and anti-microbial activity of B.licheniformis mmj,the genome sequence was determined by SMRT and subjected to bioinformatics analysis.Genome sequence analysis enabled the identification of a set of antimicrobial-resistance and antibacterial activity genes together with an array of harsh environment-adaptive genes.Moreover,B.licheniformis mmj metabolites were analyzed with gas chromatography coupled to triple quadrupole mass spectrometry,and the volatile components that were linked with the antimicrobial activity were preliminarily profiled.Collectively,the present findings reveal the genomic and metabolic landscapes underlying fungicide-responsive B.licheniformis,which offers a new opportunity to design harsh environment-adaptive biopesticides to cope with prevalent bacterial phytopathogens.展开更多
The Myc proto-oncogene family consists of three members,C-MYC,MYCN,and MYCL,which encodes the transcription factor c-Myc(hereafter Myc),N-Myc,and L-Myc,respectively.Myc protein orchestrates diverse physiological proce...The Myc proto-oncogene family consists of three members,C-MYC,MYCN,and MYCL,which encodes the transcription factor c-Myc(hereafter Myc),N-Myc,and L-Myc,respectively.Myc protein orchestrates diverse physiological processes,including cell proliferation,differentiation,survival,and apoptosis.Myc modulates about 15%of the global transcriptome,and its deregulation rewires the cellular signaling modules inside tumor cells,thereby acquiring selective advantages.The deregulation of Myc occurs in>70%of human cancers,and is related to poor prognosis;hence,hyperactivated Myc oncoprotein has been proposed as an ideal drug target for decades.Nevertheless,no specific drug is currently available to directly target Myc,mainly because of its"undruggable"properties:lack of enzymatic pocket for conventional small molecules to bind;inaccessibility for antibody due to the predominant nucleus localization of Myc.Although the topic of targeting Myc has actively been reviewed in the past decades,exciting new progresses in this field keep emerging.In this review,after a comprehensive summarization of valuable sources for potential druggable targets of Myc-driven cancer,we also peer into the promising future of utilizing macropinocytosis to deliver peptides like Omomyc or antibody agents to intracellular compartment for cancer treatment.展开更多
The recent discovery of circular RNAs(circRNAs)and characterization of their functional roles have opened a new avenue for understanding the biology of genomes.circ RNAs have been implicated to play important roles in...The recent discovery of circular RNAs(circRNAs)and characterization of their functional roles have opened a new avenue for understanding the biology of genomes.circ RNAs have been implicated to play important roles in a variety of biological processes,but their precise functions remain largely elusive.Currently,a few approaches are available for novel circRNA prediction,but almost all these methods are intended for animal genomes.Considering that the major differences between the organization of plant and mammal genomes cannot be neglected,a plant-specific method is needed to enhance the validity of plant circ RNA identification.In this study,we present Circ Plant,an integrated tool for the exploration of plant circRNAs,potentially acting as competing endogenous RNAs(ceRNAs),and their potential functions.With the incorporation of several unique plant-specific criteria,Circ Plant can accurately detect plant circRNAs from high-throughput RNA-seq data.Based on comparison tests on simulated and real RNA-seq datasets from Arabidopsis thaliana and Oryza sativa,we show that Circ Plant outperforms all evaluated competing tools in both accuracy and efficiency.Circ Plant is freely available at http://bis.zju.edu.cn/circplant.展开更多
Multiple myeloma(MM)is a common malignant hematological tumor in adults,which is characterized by clonal malignant proliferation of plasma cells in the bone marrow and secretion of a large number of abnormal monoclona...Multiple myeloma(MM)is a common malignant hematological tumor in adults,which is characterized by clonal malignant proliferation of plasma cells in the bone marrow and secretion of a large number of abnormal monoclonal immunoglobulins(M protein),leading to bone destruction,hypercalcemia,anemia,and renal insufficiency(Alexandrakis et al.,2015;Yang et al.,2018).Since a large number of new drugs,represented by proteasome inhibitors and immunomodulators,have been successfullyused to treat MM.展开更多
Synthetic lethal screening,which exploits the combination of mutations that result in cell death,is a promising method for identifying novel drug targets.This method provides a new avenue for targeting Uundruggable,9 ...Synthetic lethal screening,which exploits the combination of mutations that result in cell death,is a promising method for identifying novel drug targets.This method provides a new avenue for targeting Uundruggable,9 proteins,such as c-Myc.Here,we revisit current methods used to target c-Myc and discuss the important functional nodes related to c-Myc in non-oncogene addicted network,whose inhibition may cause a catastrophe for tumor cell destiny but not for normal cells.We further discuss strategies to identify these functional nodes in the context of synthetic lethality.We review the progress and shortcomings of this research field and look forward to opportunities offered by synthetic lethal screening to treat tumors potently.展开更多
The coronavirus disease 2019(COVID-19)is an emerging infectious disease caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2).Within a matter of months,this highly contagious novel virus has led to a g...The coronavirus disease 2019(COVID-19)is an emerging infectious disease caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2).Within a matter of months,this highly contagious novel virus has led to a global outbreak and is still spreading rapidly across continents.In patients with COVID-19,underlying chronic diseases and comorbidities are associated with dismal treatment outcomes.Owing to their immunosuppressive status,patients with hematological malignancies(HMs)are at an increased risk of infection and have a worse prognosis than patients without HMs.Accordingly,intensive attention should be paid to this cohort.In this review,we summarize and analyze specific clinical manifestations for patients with coexisting COVID-19 and HMs.Furthermore,we briefly de-scribe customized management strategies and interventions for this susceptible cohort.This review is intended to guide clinical practice.展开更多
Rare and undiagnosed diseases substantially decrease patient quality of life and have increasingly become a heavy burden on healthcare systems.Because of the challenges in disease-causing gene identification and mecha...Rare and undiagnosed diseases substantially decrease patient quality of life and have increasingly become a heavy burden on healthcare systems.Because of the challenges in disease-causing gene identification and mechanism elucidation,patients are often confronted with difficulty obtaining a precise diagnosis and treatment.Due to advances in sequencing and multiomics analysis approaches combined with patient-derived iPSC models and gene-editing platforms,substantial progress has been made in the diagnosis and treatment of rare and undiagnosed diseases.The aforementioned techniques also provide an operational basis for future precision medicine studies.In this review,we summarize recent progress in identifying disease-causing genes based on GWAS/WES/WGS-guided multiomics analysis approaches.In addition,we discuss recent advances in the elucidation of pathogenic mechanisms and treatment of diseases with state-of-the-art iPSC and organoid models,which are improved by cell maturation level and gene editing technology.The comprehensive strategies described above will generate a new paradigm of disease classification that will significantly promote the precision and efficiency of diagnosis and treatment for rare and undiagnosed diseases.展开更多
基金the National Natural Science Foundation of China(No.81230014,No.81470341,No.81520108002 and No.81500157)the Key Project of Science and Technology Department of Zhejiang Province(No.2018C03016-2)the Key Research and Development Program of Zhejiang Province(No.2019C03016).
文摘Chimeric antigen receptor T(CAR-T)cell therapy is the novel treatment strategy for hematological malignancies such as acute lymphoblastic leukemia(ALL),lymphoma and multiple myeloma.However,treatment-related toxicities such as cytokine release syndrome(CRS)and immune effector cell-associated neurotoxicity syndrome(ICANS)have become significant hurdles to CAR-T treatment.Multiple strategies were established to alter the CAR structure on the genomic level to improve efficacy and reduce toxicities.Recently,the innovative gene-editing technology-clustered regularly interspaced short palindromic repeats(CRISPR)/CRISPR-associated nuclease9(Cas9)system,which particularly exhibits preponderance in knock-in and knockout at specific sites,is widely utilized to manufacture CAR-T products.The application of CRISPR/Cas9 to CAR-T cell therapy has shown promising clinical results with minimal toxicity.In this review,we summarized the past achievements of CRISPR/Cas9 in CAR-T therapy and focused on the potential CAR-T targets.
基金supported by the National Key R&D Program of China(No.2021YFE0113700)the National Natural Science Foundation of China(No.32122074)+1 种基金the Fundamental Research Funds for the Central Universities(No.2021FZZX001-31)the Programme for High-Level Talents Cultivation of Zhejiang University,and the Strategic Research on‘Plant Microbiome and Agroecosystem Health'(No.2020ZL008,Cao Guangbiao High Science and Technology Foundationof Zhejiang University),China。
文摘Seed-borne bacterial pathogens cause severe yield loss and biotoxin contamination in rice,leading to increasing concern on the global food supply and environmental safety.Plant native microbes play an important role in defending against diseases,but their actions are often influ-enced by the chemical fungicides applied in the field.Here,Bacillus licheniformis mmj was isolated from rice spikelet,which uniquely showed not only fungicide-responsiveness but also broad-spectrum antimicrobial activity against major rice bacterial pathogens including Xanthomonas oryzae pv.oryzae,Burkholderia plantari and Burkholderia glumae.To understand the hallmark underlying the environmental adaptation and anti-microbial activity of B.licheniformis mmj,the genome sequence was determined by SMRT and subjected to bioinformatics analysis.Genome sequence analysis enabled the identification of a set of antimicrobial-resistance and antibacterial activity genes together with an array of harsh environment-adaptive genes.Moreover,B.licheniformis mmj metabolites were analyzed with gas chromatography coupled to triple quadrupole mass spectrometry,and the volatile components that were linked with the antimicrobial activity were preliminarily profiled.Collectively,the present findings reveal the genomic and metabolic landscapes underlying fungicide-responsive B.licheniformis,which offers a new opportunity to design harsh environment-adaptive biopesticides to cope with prevalent bacterial phytopathogens.
基金This work is supported by National Cancer Institute 2R01CA139158Lymphoma SPORE Career Enhancement and Development Research Program Grants(W.H.)+2 种基金National Natural Science Foundation of China 31970555(Y.G.)Fundamental Research Funds for the Central Universities 2020FZZX001-09National Natural Science Foundation of China 32070630(J.Z.).
文摘The Myc proto-oncogene family consists of three members,C-MYC,MYCN,and MYCL,which encodes the transcription factor c-Myc(hereafter Myc),N-Myc,and L-Myc,respectively.Myc protein orchestrates diverse physiological processes,including cell proliferation,differentiation,survival,and apoptosis.Myc modulates about 15%of the global transcriptome,and its deregulation rewires the cellular signaling modules inside tumor cells,thereby acquiring selective advantages.The deregulation of Myc occurs in>70%of human cancers,and is related to poor prognosis;hence,hyperactivated Myc oncoprotein has been proposed as an ideal drug target for decades.Nevertheless,no specific drug is currently available to directly target Myc,mainly because of its"undruggable"properties:lack of enzymatic pocket for conventional small molecules to bind;inaccessibility for antibody due to the predominant nucleus localization of Myc.Although the topic of targeting Myc has actively been reviewed in the past decades,exciting new progresses in this field keep emerging.In this review,after a comprehensive summarization of valuable sources for potential druggable targets of Myc-driven cancer,we also peer into the promising future of utilizing macropinocytosis to deliver peptides like Omomyc or antibody agents to intracellular compartment for cancer treatment.
基金the National Key R&D Program of China(Grant Nos.2016YFA0501704 and 2018YFC0310602)the National Natural Science Foundation of China(Grant Nos.31771477 and 31571366)+1 种基金the Fundamental Research Funds for the Central Universities,Jiangsu Collaborative Innovation Center for Modern Crop Production,Chinathe 2018 Zhejiang University Academic Award for Outstanding Doctoral Candidates,China。
文摘The recent discovery of circular RNAs(circRNAs)and characterization of their functional roles have opened a new avenue for understanding the biology of genomes.circ RNAs have been implicated to play important roles in a variety of biological processes,but their precise functions remain largely elusive.Currently,a few approaches are available for novel circRNA prediction,but almost all these methods are intended for animal genomes.Considering that the major differences between the organization of plant and mammal genomes cannot be neglected,a plant-specific method is needed to enhance the validity of plant circ RNA identification.In this study,we present Circ Plant,an integrated tool for the exploration of plant circRNAs,potentially acting as competing endogenous RNAs(ceRNAs),and their potential functions.With the incorporation of several unique plant-specific criteria,Circ Plant can accurately detect plant circRNAs from high-throughput RNA-seq data.Based on comparison tests on simulated and real RNA-seq datasets from Arabidopsis thaliana and Oryza sativa,we show that Circ Plant outperforms all evaluated competing tools in both accuracy and efficiency.Circ Plant is freely available at http://bis.zju.edu.cn/circplant.
基金the National Natural Science Foundation of China(Nos.81800201 and 81872322)the Zhejiang Key Research and Development Project(No.2020C03014)the Key Project of Zhejiang Provincial Natural Science Foundation of China(No.LZ22H160009)。
文摘Multiple myeloma(MM)is a common malignant hematological tumor in adults,which is characterized by clonal malignant proliferation of plasma cells in the bone marrow and secretion of a large number of abnormal monoclonal immunoglobulins(M protein),leading to bone destruction,hypercalcemia,anemia,and renal insufficiency(Alexandrakis et al.,2015;Yang et al.,2018).Since a large number of new drugs,represented by proteasome inhibitors and immunomodulators,have been successfullyused to treat MM.
文摘Synthetic lethal screening,which exploits the combination of mutations that result in cell death,is a promising method for identifying novel drug targets.This method provides a new avenue for targeting Uundruggable,9 proteins,such as c-Myc.Here,we revisit current methods used to target c-Myc and discuss the important functional nodes related to c-Myc in non-oncogene addicted network,whose inhibition may cause a catastrophe for tumor cell destiny but not for normal cells.We further discuss strategies to identify these functional nodes in the context of synthetic lethality.We review the progress and shortcomings of this research field and look forward to opportunities offered by synthetic lethal screening to treat tumors potently.
基金Project supported by the National Natural Science Foundation of China(Nos.81770201 , 81730008)。
文摘The coronavirus disease 2019(COVID-19)is an emerging infectious disease caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2).Within a matter of months,this highly contagious novel virus has led to a global outbreak and is still spreading rapidly across continents.In patients with COVID-19,underlying chronic diseases and comorbidities are associated with dismal treatment outcomes.Owing to their immunosuppressive status,patients with hematological malignancies(HMs)are at an increased risk of infection and have a worse prognosis than patients without HMs.Accordingly,intensive attention should be paid to this cohort.In this review,we summarize and analyze specific clinical manifestations for patients with coexisting COVID-19 and HMs.Furthermore,we briefly de-scribe customized management strategies and interventions for this susceptible cohort.This review is intended to guide clinical practice.
基金the National Natural Science Foundation of China(31871453,91857116)the Natural Science Foundation of Jiangsu Province(BK20210150)+2 种基金the National Key Research and Development Program of China(2018YFC1005002,2018YFA0107100,2018YFA0107103)the Zhejiang Natural Science Foundation of China(LR19C120001)the Zhejiang Innovation Team Grant(2019R01004).
文摘Rare and undiagnosed diseases substantially decrease patient quality of life and have increasingly become a heavy burden on healthcare systems.Because of the challenges in disease-causing gene identification and mechanism elucidation,patients are often confronted with difficulty obtaining a precise diagnosis and treatment.Due to advances in sequencing and multiomics analysis approaches combined with patient-derived iPSC models and gene-editing platforms,substantial progress has been made in the diagnosis and treatment of rare and undiagnosed diseases.The aforementioned techniques also provide an operational basis for future precision medicine studies.In this review,we summarize recent progress in identifying disease-causing genes based on GWAS/WES/WGS-guided multiomics analysis approaches.In addition,we discuss recent advances in the elucidation of pathogenic mechanisms and treatment of diseases with state-of-the-art iPSC and organoid models,which are improved by cell maturation level and gene editing technology.The comprehensive strategies described above will generate a new paradigm of disease classification that will significantly promote the precision and efficiency of diagnosis and treatment for rare and undiagnosed diseases.
