Exposure to complex environmental mixtures leads to dynamic and evolving exposomes under different environ-mental conditions,presenting significant challenges to humans and other organisms.Therefore,on the demand of r...Exposure to complex environmental mixtures leads to dynamic and evolving exposomes under different environ-mental conditions,presenting significant challenges to humans and other organisms.Therefore,on the demand of risk management of complex mixture exposure,the determination of the overall toxicity and the key components that drive the observed toxic effects is the prerequisite.展开更多
We live in a chemical-intensive world where the number and volume of substances on the market continue to rise.1 Exposure to cocktails of these chemicals can be associated with adverse effects on human health and ecos...We live in a chemical-intensive world where the number and volume of substances on the market continue to rise.1 Exposure to cocktails of these chemicals can be associated with adverse effects on human health and ecosystems.2 Yet identifying the key toxic drivers within these complex mixtures remains a core challenge in environ-mental chemistry and toxicology owing to the immense complexity of real-world samples and the largely unknown identity of many bioactive chemicals.3,4 Although approaches such as large-scale pollutant quantification coupled with mixture modeling,effect-directed analysis(EDA),6 and protein pull-down assays7 have expanded our toolkit,they typically involve complex,multistep workflows with limited efficacy.Each method has its strengths and weaknesses.How to strategically increase the success and efficiency in identifying the toxic drivers?Here,we summarize key considerations based on recent methodological advances and suggest an integrative conceptual framework for addressing these challenges.展开更多
Simultaneously targeting key pathogenic drivers and remodeling of the tumor microenvironment represents a critical therapeutic strategy for relapsed or refractory(r/r)multiple myeloma(MM)and lymphoma.Purinostat mesyla...Simultaneously targeting key pathogenic drivers and remodeling of the tumor microenvironment represents a critical therapeutic strategy for relapsed or refractory(r/r)multiple myeloma(MM)and lymphoma.Purinostat mesylate(PM),a highly selective HDAC I/II binhibitor,exhibits excellent antitumor activity in MM and lymphoma cell lines and mouse models,outperforming the pan-HDAC inhibitor panobinostat or first-line/second-line multi-drug combinations.Different from panobinostat,bulk RNA-seq analysis revealed that PM suppressed essential tumor survival factors and triggered inflammation and interferon responses.The scRNA-seq of 5TMM models further indicated that PM enhanced antitumor immunity by boosting monocyte-and T cell-mediated immune responses.In a phase I trial(NCT05526313;N=29)of PM at doses up to 15 mg/m2,treatment-related Grade≥3 adverse events predominantly comprised hematologic toxicities:thrombocytopenia(75.9%),neutropenia(55.2%),leukopenia(41.4%),and lymphopenia(31.0%),with no dose-limiting toxicities observed.PM monotherapy achieved a disease control rate of 72.7%(8/11)and an objective response rate(ORR)of 9.1%(1/11)in r/r MM.Notably,r/r lymphoma patients showed an ORR of 61.6%(11/18),particularly reaching 63.6%(7/11)with 6 complete responses in diffuse large B-cell lymphoma(DLBCL).Treatment responders exhibited enhanced immune activation,with elevated CD3+CD8+T cells and increased cytokine levels,such as IFN-γand CXCL10.Overall,PM is safe and moderately effective in MM,but highly effective in lymphoma.Additionally,PM combined with pomalidomide and dexamethasone showed strong synergistic activity in r/r MM treatment.These findings support further openlabel,multicenter phase Ib/IIa trials of PM combination therapy with immunomodulators for r/r MM,as well as phase II monotherapy trials for r/r DLBCL and r/r T-cell lymphoma.展开更多
A recent phase I trial published in Nature by Braun et al.1 showed data on personalized cancer vaccination(PCV)in patients with high-risk,resected clear cell renal cell carcinoma(ccRCC)targeting neoantigens including ...A recent phase I trial published in Nature by Braun et al.1 showed data on personalized cancer vaccination(PCV)in patients with high-risk,resected clear cell renal cell carcinoma(ccRCC)targeting neoantigens including to key RCC driver somatic mutations and resulting in antitumour immunity.Notably,recurrence was not observed in any of the nine patients at median follow-up of 40.2 months,as well as dose-limiting toxicities,which renders neoantigen-targeting PCV as promising RCC therapy in the adjuvant setting.展开更多
基金supported by the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB0750300)the National Natural Science Foundation of China(22325606,22241604,52170106).
文摘Exposure to complex environmental mixtures leads to dynamic and evolving exposomes under different environ-mental conditions,presenting significant challenges to humans and other organisms.Therefore,on the demand of risk management of complex mixture exposure,the determination of the overall toxicity and the key components that drive the observed toxic effects is the prerequisite.
基金supported by the National Natural Science Foundation of China(22306003).
文摘We live in a chemical-intensive world where the number and volume of substances on the market continue to rise.1 Exposure to cocktails of these chemicals can be associated with adverse effects on human health and ecosystems.2 Yet identifying the key toxic drivers within these complex mixtures remains a core challenge in environ-mental chemistry and toxicology owing to the immense complexity of real-world samples and the largely unknown identity of many bioactive chemicals.3,4 Although approaches such as large-scale pollutant quantification coupled with mixture modeling,effect-directed analysis(EDA),6 and protein pull-down assays7 have expanded our toolkit,they typically involve complex,multistep workflows with limited efficacy.Each method has its strengths and weaknesses.How to strategically increase the success and efficiency in identifying the toxic drivers?Here,we summarize key considerations based on recent methodological advances and suggest an integrative conceptual framework for addressing these challenges.
基金funded by the Sichuan Province“14th Five-Year Plan”Life and Health Major Science and Technology Project(2022ZDZX0027)Key Project of Chengdu(2021-YF08-00002-GX)+3 种基金the Incubation Program for Clinical Trials of West China Hospital(19HXFH030)the National Natural Science Foundation of China(82104211)the 1.3.5 Project for Disciplines of Excellence,West China Hospital,Sichuan University(ZYGD23020,ZYJC21007)National Key Research and Development Program of China(2022YFC2502600,2022YFC2502603).
文摘Simultaneously targeting key pathogenic drivers and remodeling of the tumor microenvironment represents a critical therapeutic strategy for relapsed or refractory(r/r)multiple myeloma(MM)and lymphoma.Purinostat mesylate(PM),a highly selective HDAC I/II binhibitor,exhibits excellent antitumor activity in MM and lymphoma cell lines and mouse models,outperforming the pan-HDAC inhibitor panobinostat or first-line/second-line multi-drug combinations.Different from panobinostat,bulk RNA-seq analysis revealed that PM suppressed essential tumor survival factors and triggered inflammation and interferon responses.The scRNA-seq of 5TMM models further indicated that PM enhanced antitumor immunity by boosting monocyte-and T cell-mediated immune responses.In a phase I trial(NCT05526313;N=29)of PM at doses up to 15 mg/m2,treatment-related Grade≥3 adverse events predominantly comprised hematologic toxicities:thrombocytopenia(75.9%),neutropenia(55.2%),leukopenia(41.4%),and lymphopenia(31.0%),with no dose-limiting toxicities observed.PM monotherapy achieved a disease control rate of 72.7%(8/11)and an objective response rate(ORR)of 9.1%(1/11)in r/r MM.Notably,r/r lymphoma patients showed an ORR of 61.6%(11/18),particularly reaching 63.6%(7/11)with 6 complete responses in diffuse large B-cell lymphoma(DLBCL).Treatment responders exhibited enhanced immune activation,with elevated CD3+CD8+T cells and increased cytokine levels,such as IFN-γand CXCL10.Overall,PM is safe and moderately effective in MM,but highly effective in lymphoma.Additionally,PM combined with pomalidomide and dexamethasone showed strong synergistic activity in r/r MM treatment.These findings support further openlabel,multicenter phase Ib/IIa trials of PM combination therapy with immunomodulators for r/r MM,as well as phase II monotherapy trials for r/r DLBCL and r/r T-cell lymphoma.
基金supported by the Robert Bosch Stiftung(Stuttgart,Germany),the Deutsche Forschungsgemeinschaft(DFG,German Research Foundation)under Germany's Excellence Strategy-EXC 2180—390900677the DFG research grants SCHW858/6-1,SCHA1729/2-1 and GRK2816/1.
文摘A recent phase I trial published in Nature by Braun et al.1 showed data on personalized cancer vaccination(PCV)in patients with high-risk,resected clear cell renal cell carcinoma(ccRCC)targeting neoantigens including to key RCC driver somatic mutations and resulting in antitumour immunity.Notably,recurrence was not observed in any of the nine patients at median follow-up of 40.2 months,as well as dose-limiting toxicities,which renders neoantigen-targeting PCV as promising RCC therapy in the adjuvant setting.
