Prediction of the response of cancer patients to different treatments and identification of biomarkers of drug response are two major goals of individualized medicine.Here,we developed a deep learning framework called...Prediction of the response of cancer patients to different treatments and identification of biomarkers of drug response are two major goals of individualized medicine.Here,we developed a deep learning framework called TINDL,completely trained on preclinical cancer cell lines(CCLs),to predict the response of cancer patients to different treatments.TINDL utilizes a tissue-informed normalization to account for the tissue type and cancer type of the tumors and to reduce the statistical discrepancies between CCLs and patient tumors.Moreover,by making the deep learning black box interpretable,this model identifies a small set of genes whose expression levels are predictive of drug response in the trained model,enabling identification of biomarkers of drug response.Using data from two large databases of CCLs and cancer tumors,we showed that this model can distinguish between sensitive and resistant tumors for 10(out of 14)drugs,outperforming various other machine learning models.In addition,our small interfering RNA(siRNA)knockdown experiments on 10 genes identified by this model for one of the drugs(tamoxifen)confirmed that tamoxifen sensitivity is substantially influenced by all of these genes in MCF7 cells,and seven of these genes in T47D cells.Furthermore,genes implicated for multiple drugs pointed to shared mechanism of action among drugs and suggested several important signaling pathways.In summary,this study provides a powerful deep learning framework for prediction of drug response and identification of biomarkers of drug response in cancer.The code can be accessed at https://github.com/ddhostallero/tindl.展开更多
Immune checkpoint blockade(ICB)therapy is a revolutionary approach to treat cancers,but still have limited clinical applications.Accumulating evidence pinpoints the immunosuppressive characteristics of the tumor micro...Immune checkpoint blockade(ICB)therapy is a revolutionary approach to treat cancers,but still have limited clinical applications.Accumulating evidence pinpoints the immunosuppressive characteristics of the tumor microenvironment(TME)as one major obstacle.The TME,characterized by acidity,hypoxia and elevated ROS levels,exerts its detrimental effects on infiltrating anti-tumor immune cells.Here,we developed a TME-responsive and immunotherapeutic catalase-loaded calcium carbonate nanoparticles(termed as CAT@CaCO_(3) NPs)as the simple yet versatile multi-modulator for TME remodeling.CaCO_(3) NPs can consume protons in the acidic TME to normalize the TME pH.CAT catalyzed the decomposition of ROS and thus generated O2.The released Ca^(2+)led to Ca^(2+)overload in the tumor cells which then triggered the release of damage-associated molecular patterns(DAMP)signals to initiate anti-tumor immune responses,including tumor antigen presentation by dendritic cells.Meanwhile,CAT@CaCO_(3) NPs-induced immunosupportive TME also promoted the polarization of the M2 tumor-associated macrophages to the M1 phenotype,further enhancing tumor antigen presentation.Consequently,T cell-mediated anti-tumor responses were activated,the efficacy of which was further boosted by aPD-1 immune checkpoint blockade.Our study demonstrated that local treatment of CAT@CaCO_(3) NPs and aPD-1 combination can effectively evoke local and systemic anti-tumor immune responses,inhibiting the growth of treated tumors and distant diseases.展开更多
Chemical warfare agents represent a severe threat to mankind and their efficient decontamination is a global necessity.However,traditional disposal strategies have limitations,including high energy consumption,use of ...Chemical warfare agents represent a severe threat to mankind and their efficient decontamination is a global necessity.However,traditional disposal strategies have limitations,including high energy consumption,use of aggressive reagents and generation of toxic byproducts.Here,inspired by the compartmentalized architecture and detoxification mechanism of bacterial microcompartments,we constructed oil-in-water Pickering emulsion droplets stabilized by hydrogen-bonded organic framework immobilized cascade enzymes for decontaminating mustard gas simulant(2-chloroethyl ethyl sulfide,CEES)under sweet conditions.Two exemplified droplet systems were developed with two-enzyme(glucose oxidase/chloroperoxidase)and threeenzyme(invertase/glucose oxidase/chloroperoxidase)cascades,both achieving over 6-fold enhancement in decontamination efficiency compared with free enzymes and>99% selectivity towards non-toxic sulfoxide.We found that the favored mass transfer of sugars and CEES from their respective phases to approach the cascade enzymes located at the droplet surface and the facilitated substrate channeling between proximally immobilized enzymes were key factors in augmenting the decontamination efficacy.More importantly,the robustness of immobilized enzymes enabled easy reproduction of both the droplet formation and detoxification performance over 10 cycles,following long-term storage and in far-field locations.展开更多
Cancer cells,in which the RAS and PI3K pathways are activated,produce high levels of reactive oxygen species(ROS),which cause oxidative DNA damage and ultimately cellular senescence.This process has been documented in...Cancer cells,in which the RAS and PI3K pathways are activated,produce high levels of reactive oxygen species(ROS),which cause oxidative DNA damage and ultimately cellular senescence.This process has been documented in tissue culture,mouse models,and human pre-cancerous lesions.In this context,cellular senescence functions as a tumour suppressor mechanism.Some rare cancer cells,however,manage to adapt to avoid senescence and continue to proliferate.One well-documented mode of adaptation involves increased production of antioxidants often associated with inactivation of the KEAP1 tumour suppressor gene and the resulting upregulation of the NRF2 transcription factor.In this review,we detail an alternative mode of adaptation to oxidative DNA damage induced by ROS:the increased activity of the base excision repair(BER)pathway,achieved through the enhanced expression of BER enzymes and DNA repair accessory factors.These proteins,exemplified here by the CUT domain proteins CUX1,CUX2,and SATB1,stimulate the activity of BER enzymes.The ensued accelerated repair of oxidative DNA damage enables cancer cells to avoid senescence despite high ROS levels.As a by-product of this adaptation,these cancer cells exhibit increased resistance to genotoxic treatments including ionizing radiation,temozolomide,and cisplatin.Moreover,considering the intrinsic error rate associated with DNA repair and translesion synthesis,the elevated number of oxidative DNA lesions caused by high ROS leads to the accumulation of mutations in the cancer cell population,thereby contributing to tumour heterogeneity and eventually to the acquisition of resistance,a major obstacle to clinical treatment.展开更多
基金supported by the New Frontiers in Research Fund(NFRF)of Government of Canada(Grant No.NFRFE-2019-01290 to Amin Emad and Junmei Cairns)the Natural Sciences and Engineering Research Council of Canada(NSERC)(Grant No.RGPIN-2019-04460 to Amin Emad)the McGill Initiative in Computational Medicine(MiCM)to Amin Emad.
文摘Prediction of the response of cancer patients to different treatments and identification of biomarkers of drug response are two major goals of individualized medicine.Here,we developed a deep learning framework called TINDL,completely trained on preclinical cancer cell lines(CCLs),to predict the response of cancer patients to different treatments.TINDL utilizes a tissue-informed normalization to account for the tissue type and cancer type of the tumors and to reduce the statistical discrepancies between CCLs and patient tumors.Moreover,by making the deep learning black box interpretable,this model identifies a small set of genes whose expression levels are predictive of drug response in the trained model,enabling identification of biomarkers of drug response.Using data from two large databases of CCLs and cancer tumors,we showed that this model can distinguish between sensitive and resistant tumors for 10(out of 14)drugs,outperforming various other machine learning models.In addition,our small interfering RNA(siRNA)knockdown experiments on 10 genes identified by this model for one of the drugs(tamoxifen)confirmed that tamoxifen sensitivity is substantially influenced by all of these genes in MCF7 cells,and seven of these genes in T47D cells.Furthermore,genes implicated for multiple drugs pointed to shared mechanism of action among drugs and suggested several important signaling pathways.In summary,this study provides a powerful deep learning framework for prediction of drug response and identification of biomarkers of drug response in cancer.The code can be accessed at https://github.com/ddhostallero/tindl.
基金supported by the start-up package from McGill University(to G.C.)CIHR grants(to G.C.)+2 种基金CCS-Challenge Grants(to G.C.)the Rolande and Marcel Gosselin Graduate Studentship,Dr.Victor KS Lui Studentship,Charlotte and Leo Karassik Foundation Oncology Ph.D.Fellowship from the Rosalind&Morris Goodman Cancer Institute as well as the BME recruitment awardThe authors thank Dr.Peter Siegel at McGill University for providing the 4T1 cell line.
文摘Immune checkpoint blockade(ICB)therapy is a revolutionary approach to treat cancers,but still have limited clinical applications.Accumulating evidence pinpoints the immunosuppressive characteristics of the tumor microenvironment(TME)as one major obstacle.The TME,characterized by acidity,hypoxia and elevated ROS levels,exerts its detrimental effects on infiltrating anti-tumor immune cells.Here,we developed a TME-responsive and immunotherapeutic catalase-loaded calcium carbonate nanoparticles(termed as CAT@CaCO_(3) NPs)as the simple yet versatile multi-modulator for TME remodeling.CaCO_(3) NPs can consume protons in the acidic TME to normalize the TME pH.CAT catalyzed the decomposition of ROS and thus generated O2.The released Ca^(2+)led to Ca^(2+)overload in the tumor cells which then triggered the release of damage-associated molecular patterns(DAMP)signals to initiate anti-tumor immune responses,including tumor antigen presentation by dendritic cells.Meanwhile,CAT@CaCO_(3) NPs-induced immunosupportive TME also promoted the polarization of the M2 tumor-associated macrophages to the M1 phenotype,further enhancing tumor antigen presentation.Consequently,T cell-mediated anti-tumor responses were activated,the efficacy of which was further boosted by aPD-1 immune checkpoint blockade.Our study demonstrated that local treatment of CAT@CaCO_(3) NPs and aPD-1 combination can effectively evoke local and systemic anti-tumor immune responses,inhibiting the growth of treated tumors and distant diseases.
基金supported by the National Key Research and Development Program of China(2020YFA0210800)the National Natural Science Foundation of China(22334004,22027805,22277011,22107019,22176035)the Major Project of Science and Technology of Fujian Province(2020HZ06006)。
文摘Chemical warfare agents represent a severe threat to mankind and their efficient decontamination is a global necessity.However,traditional disposal strategies have limitations,including high energy consumption,use of aggressive reagents and generation of toxic byproducts.Here,inspired by the compartmentalized architecture and detoxification mechanism of bacterial microcompartments,we constructed oil-in-water Pickering emulsion droplets stabilized by hydrogen-bonded organic framework immobilized cascade enzymes for decontaminating mustard gas simulant(2-chloroethyl ethyl sulfide,CEES)under sweet conditions.Two exemplified droplet systems were developed with two-enzyme(glucose oxidase/chloroperoxidase)and threeenzyme(invertase/glucose oxidase/chloroperoxidase)cascades,both achieving over 6-fold enhancement in decontamination efficiency compared with free enzymes and>99% selectivity towards non-toxic sulfoxide.We found that the favored mass transfer of sugars and CEES from their respective phases to approach the cascade enzymes located at the droplet surface and the facilitated substrate channeling between proximally immobilized enzymes were key factors in augmenting the decontamination efficacy.More importantly,the robustness of immobilized enzymes enabled easy reproduction of both the droplet formation and detoxification performance over 10 cycles,following long-term storage and in far-field locations.
基金supported by Canadian Institutes of Health Research(Grants MOP-326694 and MOP-391532)the National Science and Engineering Council(Grant RGPIN-2016-05155)to A.N.
文摘Cancer cells,in which the RAS and PI3K pathways are activated,produce high levels of reactive oxygen species(ROS),which cause oxidative DNA damage and ultimately cellular senescence.This process has been documented in tissue culture,mouse models,and human pre-cancerous lesions.In this context,cellular senescence functions as a tumour suppressor mechanism.Some rare cancer cells,however,manage to adapt to avoid senescence and continue to proliferate.One well-documented mode of adaptation involves increased production of antioxidants often associated with inactivation of the KEAP1 tumour suppressor gene and the resulting upregulation of the NRF2 transcription factor.In this review,we detail an alternative mode of adaptation to oxidative DNA damage induced by ROS:the increased activity of the base excision repair(BER)pathway,achieved through the enhanced expression of BER enzymes and DNA repair accessory factors.These proteins,exemplified here by the CUT domain proteins CUX1,CUX2,and SATB1,stimulate the activity of BER enzymes.The ensued accelerated repair of oxidative DNA damage enables cancer cells to avoid senescence despite high ROS levels.As a by-product of this adaptation,these cancer cells exhibit increased resistance to genotoxic treatments including ionizing radiation,temozolomide,and cisplatin.Moreover,considering the intrinsic error rate associated with DNA repair and translesion synthesis,the elevated number of oxidative DNA lesions caused by high ROS leads to the accumulation of mutations in the cancer cell population,thereby contributing to tumour heterogeneity and eventually to the acquisition of resistance,a major obstacle to clinical treatment.
