Neutrophils,the most abundant leukocytes in human blood,are essential fighter immune cells against microbial infection.Based on the finding that neutrophils can either restrict or promote cancer progression,tumor-asso...Neutrophils,the most abundant leukocytes in human blood,are essential fighter immune cells against microbial infection.Based on the finding that neutrophils can either restrict or promote cancer progression,tumor-associated neutrophils(TAN)are classified into anti-tumor N1 and pro-tumor N2 subsets.One of the major mechanisms underlying the tumor-promoting function of N2-TANs is suppression of adaptive immune cells,in particular,cytotoxic T lymphocytes.Currently,no established methodologies are available that can unequivocally distinguish immunosuppressive TANs and granulocytic/polymorphonuclear myeloid-derived suppressor cells(G/PMN-MDSC).In view of the critical role of PMN-MDSCs in immune evasion and resistance to cancer immunotherapy,as established from data obtained with diverse cancer models,therapeutic strategies targeting these cells have been actively developed to enhance the efficacy of immunotherapy.Here,we have reviewed the available literature on strategies targeting PMN-MDSCs and summarized the findings into four categories:(1)depletion of existing PMN-MDSCs,(2)blockade of the development of PMNMDSCs,(3)blockade of PMN-MDSC recruitment,(4)inhibition of immunosuppressive function.Owing to their high mobility to inflamed organs and ability to trespass the blood-brain barrier,neutrophils are outstanding candidate carriers in nanoparticle-based therapies.Another attractive application of neutrophils in cancer therapy is the use of neutrophil membrane-derived nanovesicles as a surrogate of extracellular vesicles for more efficient and scalable drug delivery.In the second part of the review,we have highlighted recent advances in the field of neutrophil-based cancer drug delivery.Overall,we believe that neutrophil-based therapeutics are a rapidly growing area of cancer therapy with significant potential benefits.展开更多
The complex and variable nature of traumatic spinal cord inju- ry （SCI） presents a unique challenge for translational research. SCI is not bound by any demographic nor is it limited to specific injury biomechanics.
Although immunotherapy has revolutionized cancer treatment and achieved remarkable success across many different cancer types,only a subset of patients shows meaningful clinical responses.In particular,advanced prosta...Although immunotherapy has revolutionized cancer treatment and achieved remarkable success across many different cancer types,only a subset of patients shows meaningful clinical responses.In particular,advanced prostate cancer exhibits overwhelming de novo resistance to immune checkpoint blockade therapy.This is primarily due to the immunosuppressive tumor microenvironment of prostate cancer.Therefore,it is paramount to understand how prostate cancer cell-intrinsic mechanisms promote immune evasion and foster an immunosuppressive microenvironment.Here,we review recent findings that reveal the roles of the genetic alterations,androgen receptor signaling,cancer cell plasticity,and oncogenic pathways in shaping the immunosuppressive microenvironment and thereby driving immunotherapy resistance.Based on preclinical and clinical observations,a variety of therapeutic strategies are being developed that may illuminate new paths to enhance immunotherapy efficacy in prostate cancer.展开更多
The androgen receptor(AR)plays a critical role in the development and progression of prostate cancer by regulating key cellular pro-cesses such as cell proliferation and apoptosis.Although traditional AR-targeted ther...The androgen receptor(AR)plays a critical role in the development and progression of prostate cancer by regulating key cellular pro-cesses such as cell proliferation and apoptosis.Although traditional AR-targeted therapies have shown initial success,acquired resis-tance remains a significant clinical challenge,often driven by AR alterations and somatic gene mutations associated with homologous recombination deficiency(HRD).Approximately 20%of advanced prostate cancer cases exhibit HRD,resulting in substantial genomic instability and complicating treatment.Fortunately,Food and Drug Administration–approved poly(ADP-ribose)polymerase inhibitors,in-cluding olaparib and rucaparib,exploit synthetic lethality to target prostate cancer with HRD,and additional drugs targeting DNA dam-age response(DDR)proteins are under development.Emerging evidence suggests that AR activity enhances DDR gene expression,with multiple DDR proteins localized near androgen-regulated regions,highlighting a close interaction between AR and DDR pathways.Consequently,recent preclinical and clinical studies have investigated combining AR-targeted therapies with treatments that induce DNA damage,such as radiation therapy,or inhibit DNA repair mechanisms.This review discusses AR's role in cellular processes,the interplay between AR and DDR,and recent advances in prostate cancer treatment strategies.展开更多
The pregnane X receptor(PXR) plays an important and diverse role in mediating xenobiotic induction of drug-metabolizing enzymes and transporters.Several protein isoforms of PXR exist,and they have differential transcr...The pregnane X receptor(PXR) plays an important and diverse role in mediating xenobiotic induction of drug-metabolizing enzymes and transporters.Several protein isoforms of PXR exist,and they have differential transcriptional activity upon target genes; transcript variants 3(PXR3) and 4(PXR4) do not induce target gene expression,whereas transcript variants 1(PXR1) and 2(PXR2) respond to agonist by activating target gene expression.PXR protein variants also display differences in protein–protein interactions; PXR1 interacts with p53,whereas PXR3 does not.Furthermore,the transcript variants of PXR that encode these protein isoforms are differentially regulated by methylation and deletions in the respective promoters of the variants,and their expression differs in various human cancers and also in cancerous tissue compared to adjacent normal tissues.PXR1 and PXR4 m RNA are downregulated by methylation in cancerous tissue and have divergent effects on cellular proliferation when ectopically overexpressed.Additional detailed and comparative mechanistic studies are required to predict the effect of PXR transcript variant expression on carcinogenesis,therapeutic response,and the development of toxicity.展开更多
Cytochrome P450(CYP)enzymes function to catalyze a wide range of reactions,many of which are critically important for drug response.Members of the human cytochrome P4503A(CYP3A)family are particularly important in dru...Cytochrome P450(CYP)enzymes function to catalyze a wide range of reactions,many of which are critically important for drug response.Members of the human cytochrome P4503A(CYP3A)family are particularly important in drug clearance,and they collectively metabolize more than half of all currently prescribed medications.The ability of these enzymes to bind a large and structurally diverse set of compounds increases the chances of their modulating or facilitating drug metabolism in unfavorable ways.Emerging evidence suggests that individual enzymes in the CYP3A family play discrete and important roles in catalysis and disease progression.Here we review the similarities and differences among CYP3A enzymes with regard to substrate recognition,metabolism,modulation by small molecules,and biological consequence,highlighting some of those with clinical significance.We also present structural perspectives to further characterize the basis of these comparisons.展开更多
基金partly supported by a graduate fellowship from China Scholarship Council(Grant No.201708340071)partly supported by a Career Catalyst Research Grant(Grant No.18548293)from the Susan G.Komen Foundation+1 种基金a Cancer Research Grant from the Mary Kay Foundationa Research Grant from the Elsa U.Pardee Foundation。
文摘Neutrophils,the most abundant leukocytes in human blood,are essential fighter immune cells against microbial infection.Based on the finding that neutrophils can either restrict or promote cancer progression,tumor-associated neutrophils(TAN)are classified into anti-tumor N1 and pro-tumor N2 subsets.One of the major mechanisms underlying the tumor-promoting function of N2-TANs is suppression of adaptive immune cells,in particular,cytotoxic T lymphocytes.Currently,no established methodologies are available that can unequivocally distinguish immunosuppressive TANs and granulocytic/polymorphonuclear myeloid-derived suppressor cells(G/PMN-MDSC).In view of the critical role of PMN-MDSCs in immune evasion and resistance to cancer immunotherapy,as established from data obtained with diverse cancer models,therapeutic strategies targeting these cells have been actively developed to enhance the efficacy of immunotherapy.Here,we have reviewed the available literature on strategies targeting PMN-MDSCs and summarized the findings into four categories:(1)depletion of existing PMN-MDSCs,(2)blockade of the development of PMNMDSCs,(3)blockade of PMN-MDSC recruitment,(4)inhibition of immunosuppressive function.Owing to their high mobility to inflamed organs and ability to trespass the blood-brain barrier,neutrophils are outstanding candidate carriers in nanoparticle-based therapies.Another attractive application of neutrophils in cancer therapy is the use of neutrophil membrane-derived nanovesicles as a surrogate of extracellular vesicles for more efficient and scalable drug delivery.In the second part of the review,we have highlighted recent advances in the field of neutrophil-based cancer drug delivery.Overall,we believe that neutrophil-based therapeutics are a rapidly growing area of cancer therapy with significant potential benefits.
文摘The complex and variable nature of traumatic spinal cord inju- ry （SCI） presents a unique challenge for translational research. SCI is not bound by any demographic nor is it limited to specific injury biomechanics.
基金This work was supported by the National Institutes of Health grant R01CA248033(to Xin L)Department of Defense CDMRP PCRP grants W81XWH2010312(to Xin L)+3 种基金W81XWH2010332(to Xin L)an Investigator-Initiated Research Grant from American Institute for Cancer Research(to Xin L),Indiana CTSI pilot grants(to Xin L)through the NIH NCATS CTSA grant ULITR002529an Exceptional Project Award Grant from Breast Cancer Alliance(to Xin L)CCV and IITP grants from Walther Cancer Foundation(to YZ and LD).
文摘Although immunotherapy has revolutionized cancer treatment and achieved remarkable success across many different cancer types,only a subset of patients shows meaningful clinical responses.In particular,advanced prostate cancer exhibits overwhelming de novo resistance to immune checkpoint blockade therapy.This is primarily due to the immunosuppressive tumor microenvironment of prostate cancer.Therefore,it is paramount to understand how prostate cancer cell-intrinsic mechanisms promote immune evasion and foster an immunosuppressive microenvironment.Here,we review recent findings that reveal the roles of the genetic alterations,androgen receptor signaling,cancer cell plasticity,and oncogenic pathways in shaping the immunosuppressive microenvironment and thereby driving immunotherapy resistance.Based on preclinical and clinical observations,a variety of therapeutic strategies are being developed that may illuminate new paths to enhance immunotherapy efficacy in prostate cancer.
基金supported by the Indiana CTSI Core Pilot Funding(FY24CTSIE)the Startup Funding of JL from the University of Notre Dame(START097S).
文摘The androgen receptor(AR)plays a critical role in the development and progression of prostate cancer by regulating key cellular pro-cesses such as cell proliferation and apoptosis.Although traditional AR-targeted therapies have shown initial success,acquired resis-tance remains a significant clinical challenge,often driven by AR alterations and somatic gene mutations associated with homologous recombination deficiency(HRD).Approximately 20%of advanced prostate cancer cases exhibit HRD,resulting in substantial genomic instability and complicating treatment.Fortunately,Food and Drug Administration–approved poly(ADP-ribose)polymerase inhibitors,in-cluding olaparib and rucaparib,exploit synthetic lethality to target prostate cancer with HRD,and additional drugs targeting DNA dam-age response(DDR)proteins are under development.Emerging evidence suggests that AR activity enhances DDR gene expression,with multiple DDR proteins localized near androgen-regulated regions,highlighting a close interaction between AR and DDR pathways.Consequently,recent preclinical and clinical studies have investigated combining AR-targeted therapies with treatments that induce DNA damage,such as radiation therapy,or inhibit DNA repair mechanisms.This review discusses AR's role in cellular processes,the interplay between AR and DDR,and recent advances in prostate cancer treatment strategies.
基金supported by the American Lebanese Syrian Associated Charities (ALSAC),St.Jude Children0s Research Hospitalthe U.S. National Institutes of Health (Grants GM086415,GM110034,GM118041 and P30-CA21765)
文摘The pregnane X receptor(PXR) plays an important and diverse role in mediating xenobiotic induction of drug-metabolizing enzymes and transporters.Several protein isoforms of PXR exist,and they have differential transcriptional activity upon target genes; transcript variants 3(PXR3) and 4(PXR4) do not induce target gene expression,whereas transcript variants 1(PXR1) and 2(PXR2) respond to agonist by activating target gene expression.PXR protein variants also display differences in protein–protein interactions; PXR1 interacts with p53,whereas PXR3 does not.Furthermore,the transcript variants of PXR that encode these protein isoforms are differentially regulated by methylation and deletions in the respective promoters of the variants,and their expression differs in various human cancers and also in cancerous tissue compared to adjacent normal tissues.PXR1 and PXR4 m RNA are downregulated by methylation in cancerous tissue and have divergent effects on cellular proliferation when ectopically overexpressed.Additional detailed and comparative mechanistic studies are required to predict the effect of PXR transcript variant expression on carcinogenesis,therapeutic response,and the development of toxicity.
基金supported,in part,by ALSAC and by the National Institutes of Health grants R35-GM118041 and P30-CA21765.
文摘Cytochrome P450(CYP)enzymes function to catalyze a wide range of reactions,many of which are critically important for drug response.Members of the human cytochrome P4503A(CYP3A)family are particularly important in drug clearance,and they collectively metabolize more than half of all currently prescribed medications.The ability of these enzymes to bind a large and structurally diverse set of compounds increases the chances of their modulating or facilitating drug metabolism in unfavorable ways.Emerging evidence suggests that individual enzymes in the CYP3A family play discrete and important roles in catalysis and disease progression.Here we review the similarities and differences among CYP3A enzymes with regard to substrate recognition,metabolism,modulation by small molecules,and biological consequence,highlighting some of those with clinical significance.We also present structural perspectives to further characterize the basis of these comparisons.
