Background:While improved screening rates have contributed to an overall decrease in the incidence of colorectal cancer(CRC),the incidence of early-age-onset CRC(EAO CRC;age<50 years)has increased.Here,we character...Background:While improved screening rates have contributed to an overall decrease in the incidence of colorectal cancer(CRC),the incidence of early-age-onset CRC(EAO CRC;age<50 years)has increased.Here,we characterize the genetic alterations and tumor microenvironment(TME)for EAO and later-age-onset(LAO)CRCs to identify relevant biological differences that might point to etiologic factors.Methods:A cohort of EAO(n=60)and LAO(n=93)CRC patients were evaluated for mutations by using targeted DNA sequencing and for TME differences by using immunohistochemistry and immunofluorescence.The Cancer Genome Atlas(TCGA)PanCancer Atlas colorectal adenocarcinoma cohort was evaluated for transcriptional changes between EAO(n=82)and LAO(n=510)patients.Results:KRAS and BRAF mutations were less frequent in EAO CRCs.Gene-set enrichment analysis of TCGA data revealed the downregulation of immune-related pathways in EAO CRCs.Both age cohorts had similar numbers of CD8^(+) tumor-infiltrating lymphocytes(TILs),although LAO patients had more CD4^(+) TILs and Th1-polarized CD4s.While significant associations between immune subsets and versican(VCAN),versikine,and alpha-smooth muscle actin(αSMA)were found,none of these trends differed between age cohorts.EAO patients trended towards greater VCAN accumulation in adjacent normal tissue,lower rates of VCAN proteolysis,and decreasedαSMA accumulation vs LAO patients.Conclusions:Overall,established EAO cancers are similar to LAO cancers in mutational profile and key TME features.High VCAN andαSMA expression in adjacent normal colon indicates a presence of factors that are associated with increased intestinal subclinical inflammation.Future mechanistic studies will be conducted to better understand the importance of these findings and related processes should be prioritized as potential etiologic factors for EAO tumorigenesis.展开更多
Androgen deprivation therapy(ADT)has been the standard of care for the last 75 years in metastatic hormone sensitive prostate cancer(PCa).However,this approach is rarely curative.Recent clinical trials have demonstrat...Androgen deprivation therapy(ADT)has been the standard of care for the last 75 years in metastatic hormone sensitive prostate cancer(PCa).However,this approach is rarely curative.Recent clinical trials have demonstrated that ADT combined with other agents,notably docetaxel and abiraterone,lead to improved survival.The mechanisms surrounding this improved cancer outcomes are incompletely defined.The response of cancer cells to ADT includes apoptosis and cell death,but a significant fraction remains viable.Our laboratory has demonstrated both in vitro and in vivo that cellular senescence occurs in a subset of these cells.Cellular senescence is a phenotype characterized by cell cycle arrest,senescenceassociated b-galactosidase(SA-b-gal),and a hypermetabolic state.Positive features of cellular senescence include growth arrest and immune stimulation,although persistence may release cytokines and growth factors that are detrimental.Senescent tumor cells generate a catabolic state with increased glycolysis,protein turnover and other metabolic changes that represent targets for drugs,like metformin,to be applied in a synthetic lethal approach.This review examines the response to ADT and the putative role of cellular senescence as a biomarker and therapeutic target in this context.展开更多
AIM： To investigate the association between individual or combined use of non-steroidal anti-inflammatory drugs （NSAIDs） or statins and colorectal cancer risk.METHODS： In a population-based case-control study in w...AIM： To investigate the association between individual or combined use of non-steroidal anti-inflammatory drugs （NSAIDs） or statins and colorectal cancer risk.METHODS： In a population-based case-control study in women, we examined the association between NSAIDs and statin use and the risk of colorectal cancers. We further investigated whether the use of statins modifies the protective effect of NSAIDs. Female cases （n = 669）of colorectal cancer aged 50-74 years were identified from a storewide registry in Wisconsin during 1999-2001. Community control women （n = 1375） were randomly selected from lists of licensed drivers and Medicare beneficiaries. Medication use and risk factor information were gathered during a structured telephone interview. A multivariable logistic regression model was used to calculate odds ratio （OR） and 95% confidence interval （CI）.RESULTS： Overall, NSAIDs users had a 30% reduction in risk of colorectal cancer （95% CI： 0.56-0.88）. Statin use was not associated with colorectal cancer risk （OR = 1.17, 95% CI： 0.74-1.85）, regardless of structural type （lipophilic or hydrophilic）, duration of use, or recency. There was no evidence of an interaction between NSAIDs and statins and colorectal cancer risk （P-interaction = 0.28）.CONCLUSION： Although our results confirm the inverse association between NSAIDs use and colorectal cancer risk, they do not support a risk reduction in statin users, or an interaction effect of combined NSAIDs and statin use.展开更多
DNA methyltransferases(DNMTs)are an evolutionarily conserved family of DNA methylases,transferring a methyl group onto the fifth carbon of a cytosine residue.The mammalian DNMT family includes three major members that...DNA methyltransferases(DNMTs)are an evolutionarily conserved family of DNA methylases,transferring a methyl group onto the fifth carbon of a cytosine residue.The mammalian DNMT family includes three major members that have functional methylation activities,termed DNMT1,DNMT3A,and DNMT3B.DNMT3A and DNMT3B are responsible for methylation establishment,whereas DNMT1 maintains methylation during DNA replication.Accumulating evidence demonstrates that regulation of DNAmethylation by DNMTs is critical for normal hematopoiesis.Aberrant DNA methylation due to DNMT dysregulation and mutations is known as an important molecular event of hematological malignancies,such as DNMT3A mutations in acute myeloid leukemia.In this reviewwe first describe the basic methylation mechanisms of DNMTs and their functions in lymphocyte maturation and differentiation,We then discuss the current understanding of DNA methylation heterogeneity in leukemia and lymphoma to highlight the importance of studying DNA methylation targets.We also discuss DNMT mu-tations and pathogenic roles in human leukemia and lymphoma.We summarize the recent understanding of how DNMTs interact with transcription factors or cofactors to repress the expression of tumor suppressor genes.Firnally.we highlight current clinical studies using DNMT inhibitors for the treatment of these hematological malignancies.展开更多
Silica nanoparticles have been one of the most promising nanosystems for biomedical applications due to their facile surface chemistry and non-toxic nature. However, it is still challenging to effectively deliver them...Silica nanoparticles have been one of the most promising nanosystems for biomedical applications due to their facile surface chemistry and non-toxic nature. However, it is still challenging to effectively deliver them into tumor sites and noninvasively visualize their in vivo biodistribution with excellent sensitivity and accuracy for effective cancer diagnosis. In this study, we design a yolk/shell-structured silica nanosystem ^(64) Cu-NOTAQD@HMSN-PEG-TRC105, which can be employed for tumor vasculature targeting and dual-modality PET/optical imaging, leading to superior targeting specificity, excellentimaging capability and more reliable diagnostic outcomes.By combining vasculature targeting, pH-sensitive drug delivery, and dual-modality imaging into a single platform,as-designed yolk/shell-structured silica nanosystems may be employed for the future image-guided tumor-targeted drug delivery, to further enable cancer theranostics.展开更多
Photodynamic therapy(PDT)by near-infrared(NIR)irradiation is a promising technique for treating various cancers.Here,we reported the development of free-standing wafer-scale Au nanosheets(NSs)that exhibited an impress...Photodynamic therapy(PDT)by near-infrared(NIR)irradiation is a promising technique for treating various cancers.Here,we reported the development of free-standing wafer-scale Au nanosheets(NSs)that exhibited an impressive PDT effect.The Au NSs were synthesized by ionic layer epitaxy at the air-water interface with a uniform thickness in the range from 2 to 8.5 nm.These Au NSs were found very effective in generating singlet oxygen under NIR irradiation.In vitro cellular study showed that the Au NSs had very low cytotoxicity and high PDT efficiency due to their uniform 2D morphology.Au NSs could kill cancer cells after 5 min NIR irradiation with little heat generation.This performance is comparable to using 10 times mass loading of Au nanoparticles(NPs).This work suggests that two-dimensional(2D)Au NSs could be a new type of biocompatible nanomaterial for PDT of cancer with an extraordinary photon conversion and cancer cell killing efficiency.展开更多
Colorectal cancer(CRC)is the third most common and lethal cancer worldwide.1 Farnesoid X receptor(FXR)is a regulator of bile acid(BA)homeostasis and its expression is inversely correlated with the incidence of CRC.2,3...Colorectal cancer(CRC)is the third most common and lethal cancer worldwide.1 Farnesoid X receptor(FXR)is a regulator of bile acid(BA)homeostasis and its expression is inversely correlated with the incidence of CRC.2,3 Moreover,our recent study discovered that dietary factors and dysregulated Wnt signaling independently alter BA profiles,some of which antagonize intestinal FXR,such as Tauro-β-muricholic acid(T-βMCA)and deoxycholic acid(DCA).展开更多
Cancer patients are at increased risk for severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection and mortality.Like other viruses in the SARS family,SARS-CoV-2 employs two host proteins,angiotensin-conve...Cancer patients are at increased risk for severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection and mortality.Like other viruses in the SARS family,SARS-CoV-2 employs two host proteins,angiotensin-converting enzyme 2(ACE2)and transmembrane serine protease 2(TMPRSS2),for viral entry.1 Recent studies showed that many of the host proteins identified as potential targets for developing COVID therapies are dysregulated in cancer,2 prompting us to investigate whether human cancer cells are susceptible to SARS-CoV-2 infection,and whether chemotherapy could modulate a cancer patient's risk for infection.展开更多
Chimeric antigen receptor(CAR)T cell therapy is a form of adoptive cell therapy that has revolutionized the field of cancer immunotherapy.Owing to the unprecedented efficacy seen in the treatment of blood cancers,the ...Chimeric antigen receptor(CAR)T cell therapy is a form of adoptive cell therapy that has revolutionized the field of cancer immunotherapy.Owing to the unprecedented efficacy seen in the treatment of blood cancers,the FDA has now approved multiple CAR T cell products for the treatment of various hematologic malignancies.Despite the clinical success seen in hematologic malignancies,CAR T cell therapies have demonstrated only modest efficacy in the treatment of solid tumors.Thus,great efforts are underway to increase the treatment efficacy in solid tumors and further enhance the treatment of hematologic malignancies.However,irrespective of advancements in efficacy,there are still unmet needs for patients receiving CAR T cell therapies.CAR T cell therapies carry significant risks of potentially fatal toxicities,and few of these toxicities were predicted in the animal models used to advance these therapies to the clinic.Therefore,significant advancements are needed to help reduce the incidence and severity of these toxicities to ultimately enhance patient safety and quality of life.This review will provide a brief overview of some of the major toxicities associated with CAR T cell therapies and will discuss the various engineering strategies used to mitigate such toxicities in preclinical models and clinical studies.展开更多
Recent advances in immunotherapy,such as immune checkpoint inhibitors and chimeric antigen receptor(CAR)T-cell therapy,have transformed the landscape of cancer treatment.By leveraging the body’s own immune system,imm...Recent advances in immunotherapy,such as immune checkpoint inhibitors and chimeric antigen receptor(CAR)T-cell therapy,have transformed the landscape of cancer treatment.By leveraging the body’s own immune system,immunotherapy has expanded beyond cancer to address autoimmunity,fibrosis,and senescence.Nonetheless,there are still obstacles to overcome to further improve the efficacy of current immunotherapies.To that end,efforts have been made to elucidate the underlying mechanisms behind resistance to current immunotherapy regimens,alongside the exploration of novel therapeutic approaches to target and manipulate components of the immune system.展开更多
Dysregulation of p53 and phosphoinositide(PIP_(n)) signaling are both key drivers of oncogenesis and metastasis.Our recent findings reveal a previously unrecognized interaction between these pathways,converging in the...Dysregulation of p53 and phosphoinositide(PIP_(n)) signaling are both key drivers of oncogenesis and metastasis.Our recent findings reveal a previously unrecognized interaction between these pathways,converging in the nucleus to form a PIP_(n)-p53 signalosome that modulates nuclear AKT activation and downstream signaling,thereby influencing cancer cell survival and motility.This review examines recent insights into nuclear PIP_(n)signaling in the context of established roles for p53 in cell dynamics and migration while also deliberating current research on how nuclear PIP_(n)s interact with p53 to form signalosomes that affect cell motility.We emphasize the critical role of PIP_(n)in stabilizing p53 and activating de novo nuclear AKT signaling,which subsequently modulates key motility-related pathways.Understanding the unique operation and function of the PIP_(n)-p53 signalosome in nuclear phosphatidylinositol 3-kinase(PI3K)-AKT activation offers novel therapeutic strategies for controlling cancer metastasis by targeting pertinent interactions and events.展开更多
Arginine methylation is a common posttranslational modification that governs important cellular processes and impacts development,cell growth,proliferation,and differentiation.Arginine methylation is catalyzed by prot...Arginine methylation is a common posttranslational modification that governs important cellular processes and impacts development,cell growth,proliferation,and differentiation.Arginine methylation is catalyzed by protein arginine methyltransferases(PRMTs),which are classified as type I and type II enzymes responsible for the formation of asymmetric and symmetric dimethylarginine,respectively.PRMT5 is the main type II enzyme that catalyzes symmetric dimethylarginine of histone proteins to induce gene silencing by generating repressive histone marks,including H2AR3me2s,H3R8me2s,and H4R3me2s.PRMT5 can also methylate nonhistone proteins such as the transcription factors p53,E2F1 and p65.Modifications of these proteins by PRMT5 are involved in diverse cellular processes,including transcription,translation,DNA repair,RNA processing,and metabolism.A growing literature demonstrates that PRMT5 expression is upregulated in hematologic malignancies,including leukemia and lymphoma,where PRMT5 regulates gene expression to promote cancer cell proliferation.Targeting PRMT5 by specific inhibitors has emerged as a potential therapeutic strategy to treat these diseases.展开更多
Neutrophils have recently emerged as promising carriers for drug delivery due to their unique properties including rapid response toward inflammation,chemotaxis,and transmigration.When integrated with nanotechnology t...Neutrophils have recently emerged as promising carriers for drug delivery due to their unique properties including rapid response toward inflammation,chemotaxis,and transmigration.When integrated with nanotechnology that has enormous advantages in improving treatment efficacy and reducing side effects,neutrophil-based nano-drug delivery systems have expanded the repertoire of nanoparticles employed in precise therapeutic interventions by either coating nanoparticles with their membranes,loading nanoparticles inside living cells,or engineering chimeric antigen receptor(CAR)-neutrophils.These neutrophil-inspired therapies have shown superior biocompatibility,targeting ability,and therapeutic robustness.In this review,we summarized the benefits of combining neutrophils and nanotechnologies,the design principles and underlying mechanisms,and various applications in disease treatments.The challenges and prospects for neutrophil-based drug delivery systems were also discussed.展开更多
Activating the cyclic guanosine monophosphate-adenosine monophosphate synthase/stimulator of interferon genes(cGAS/STING)signaling has emerged as a promising anti-tumor strategy due to the important role of the pathwa...Activating the cyclic guanosine monophosphate-adenosine monophosphate synthase/stimulator of interferon genes(cGAS/STING)signaling has emerged as a promising anti-tumor strategy due to the important role of the pathway in innate and adaptive immunity,yet the selective delivery of STING agonists to tumors following systemic administration remains challenging.Herein,we develop a nano-STING agonist-decorated microrobot platform to achieve the enhanced anti-tumor effect.Fe ions and the STING agonist 2’3’-cyclic guanosine monophosphate-adenosine monophosphate(cGAMP)are co-encapsulated in the mitochondria-targeting nanoparticles(mTNPs),which can trigger the release of mitochondrial DNA(mtDNA)by Fenton reactioninduced mitochondria oxidative damage.The exogenous cGAMP and the endogenous mtDNA can work synergistically to induce potent cGAS/STING signaling activation.Furthermore,we decorate mTNPs onto Salmonella typhimurium VNP20009(VNP)bacteria to facilitate tumor accumulation and deep penetration.We demonstrate that the systemic administration of this microrobot activates both innate and adaptive immunity,improving the immunotherapeutic efficacy of the STING agonists.展开更多
Inflammatory bowel disease(IBD)is inflammatory intestinal disorders associated with dysregulated gut microbiota.Bacteriotherapy that leverages bacteria as therapeutics has shown tremendous promise in resolving gut dys...Inflammatory bowel disease(IBD)is inflammatory intestinal disorders associated with dysregulated gut microbiota.Bacteriotherapy that leverages bacteria as therapeutics has shown tremendous promise in resolving gut dysbiosis and reducing inflammatory mediators to treat IBD.Orally delivered probiotics,such as Escherichia coli Nissle 1917(EcN),can produce beneficial ingredients,competitively inhibit the proliferation of pathogens,and promote the restoration of gut microbiome homeostasis.However,environmental stresses(such as gastric acids)in the gastrointestinal(GI)tract pose an enormous challenge to the probiotics following oral administration,leading to decreases in viability and activity of probiotics.Meanwhile,the inferior mucoadhesive capability of probiotics results in low colonization efficacy,further compromising their therapeutic effect.Coating probiotics with functional biomaterials may protect them from elimination and prolong their retention in the GI tract.Here,we developed a facile double-layer electrostatic assembly technique to encapsulate EcN bacteria in protective layers of mucoadhesive chitosan(CS)and immunomodulatory hyaluronic acid(HA)to generate HA-CS-EcN.These biomaterials confer the coated EcN resistance to environmental assault and enhanced mucoadhesion in the GI tract.The probiotics equipped with the multifunctional shield can thus suppress inflammation and reshape the intestinal microenvironment to enhance therapeutic efficacy for the prevention and treatment of IBD.Collectively,this study presents a novel probiotic coating strategy to augment the outcome of bacteriotherapy to combat IBD.展开更多
Acute kidney injury(AKI)leads to unacceptably high mortality due to difficulties in timely intervention and less efficient renal delivery of therapeutic drugs.Here,a series of polyvinylpyrrolidone(PVP)-curcumin nanopa...Acute kidney injury(AKI)leads to unacceptably high mortality due to difficulties in timely intervention and less efficient renal delivery of therapeutic drugs.Here,a series of polyvinylpyrrolidone(PVP)-curcumin nanoparticles(PCurNP)are designed to meet the renal excretion threshold(~45 kDa),presenting a controllable delivery nanosystem for kidney targeting.Renal accumulation of the relatively small nanoparticles,^(89)Zr-PCurNP M10 with the diameter between 5 and 8 nm,is found to be 1.7 times and 1.8 times higher than the accumulation of^(89)Zr-PCurNP M29(20-50 nm)and M40(20-50 nm)as revealed by PET imaging.Furthermore,serum creatinine analysis,kidney tissues histology,and tubular injury scores revealed that PCurNP M10 efficiently treated cisplatin-induced AKI.Herein,PCurNP offers a novel and simple strategy for precise PET image-guided drug delivery of renal protective materials.展开更多
Immunotherapy remains more effective for hematologic tumors than for solid tumors.One of the main challenges to immunotherapy of solid tumors is the immunosuppressive microenvironment these tumors generate,which limit...Immunotherapy remains more effective for hematologic tumors than for solid tumors.One of the main challenges to immunotherapy of solid tumors is the immunosuppressive microenvironment these tumors generate,which limits the cytotoxic capabilities of immune effector cells(e.g.,cytotoxic T and natural killer cells).This microenvironment is characterized by hypoxia,nutrient starvation,accumulated waste products,and acidic pH.Tumor-hijacked cells,such as fibroblasts,macrophages,and T regulatory cells,also contribute to this inhospitable microenvironment for immune cells by secreting immunosuppressive cytokines that suppress the antitumor immune response and lead to immune evasion.Thus,there is a strong interest in developing new drugs and cell formulations that modulate the tumor microenvironment and reduce tumor cell immune evasion.Microphysiological systems(MPSs)are versatile tools that may accelerate the development and evaluation of these therapies,although specific examples showcasing the potential of MPSs remain rare.Advances in microtechnologies have led to the development of sophisticated microfluidic devices used to recapitulate tumor complexity.The resulting models,also known as microphysiological systems(MPSs),are versatile tools with which to decipher the molecular mechanisms driving immune cell antitumor cytotoxicity,immune cell exhaustion,and immune cell exclusion and to evaluate new targeted immunotherapies.Here,we review existing microphysiological platforms to study immuno-oncological applications and discuss challenges and opportunities in the field.展开更多
I mmunosuppressive therapies have meaningful effects on the treatment of multiple sclerosis(MS),a classical inflammatory autoimmune disease of the central nervous system.1 In mice with experimental autoimmune encephal...I mmunosuppressive therapies have meaningful effects on the treatment of multiple sclerosis(MS),a classical inflammatory autoimmune disease of the central nervous system.1 In mice with experimental autoimmune encephalomyelitis(EAE),a murine model of human MS,we showed that an adoptive transfer of GM-CSF and Interleukin-15 Fusion Transgene(GIFT15)-derived regulatory B cells(GIFT15 Bregs)sustained a durable remission of the disease.2,3 These regulatory B cells require the expression of MHC class II and IL-10 for suppressive activity.展开更多
Multifunctional yolk/shell-structured hybrid nanomaterials have attracted increasing interest as theranostic nanoplatforms for cancer imaging and therapy. However, because of the lack of suitable surface engineering a...Multifunctional yolk/shell-structured hybrid nanomaterials have attracted increasing interest as theranostic nanoplatforms for cancer imaging and therapy. However, because of the lack of suitable surface engineering and tumor targeting strategies, previous research has focused mainly on nanostructure design and synthesis with few successful examples showing active tumor targeting after systemic administration. In this study, we report the general synthetic strategy of chelator-free zirconium-89 （89Zr）-radiolabeled, TRC105 antibody-conjugated, silica-based yolk/sheU hybrid nanopartides for in vivo tumor vasculature targeting. Three types of inorganic nanoparticles with varying morphologies and sizes were selected as the internal cores, which were encapsulated into single hollow mesoporous silica nanosheUs to form the yolk/sheU-structured hybrid nanopartides. As a proof-of-concept, we demonstrated successful surface functionalization of the nanoparticles with polyethylene glycol, TRC105 antibody （specific for CD105/endoglin）, and ~Zr （a positron-emitting radioisotope）, and enhanced in vivo tumor vasculature-targeted positron emission tomography imaging in 4T1 murine breast tumor-bearing mice. This strategy could be applied to the synthesis of other types of yolk/shell theranostic nanoparticles for tumor- targeted imaging and drug delivery.展开更多
Androgen receptor(AR)is a major transcription factor that plays a role in inflammatory response including interleukin-6(IL6)signaling.1 While AR regulation through paracrine loop signaling in prostate tissue is well-s...Androgen receptor(AR)is a major transcription factor that plays a role in inflammatory response including interleukin-6(IL6)signaling.1 While AR regulation through paracrine loop signaling in prostate tissue is well-studied,its impact through an IL6 autocrine loop in the lung has not been wellstudied despite the organ's response to respiratory viral infection.Chemical inhibition and RNA knockdown of AR identified a bZIP transcription factor MAF to be a common target of inflammation using these perturbations in lung cells.展开更多
基金supported by the National Institutes of Health[R37 CA226526 and R01 CA272855 to D.A.D.,T32 CA009135 to K.A.J.,and P30 CA014520 Core Grant]。
文摘Background:While improved screening rates have contributed to an overall decrease in the incidence of colorectal cancer(CRC),the incidence of early-age-onset CRC(EAO CRC;age<50 years)has increased.Here,we characterize the genetic alterations and tumor microenvironment(TME)for EAO and later-age-onset(LAO)CRCs to identify relevant biological differences that might point to etiologic factors.Methods:A cohort of EAO(n=60)and LAO(n=93)CRC patients were evaluated for mutations by using targeted DNA sequencing and for TME differences by using immunohistochemistry and immunofluorescence.The Cancer Genome Atlas(TCGA)PanCancer Atlas colorectal adenocarcinoma cohort was evaluated for transcriptional changes between EAO(n=82)and LAO(n=510)patients.Results:KRAS and BRAF mutations were less frequent in EAO CRCs.Gene-set enrichment analysis of TCGA data revealed the downregulation of immune-related pathways in EAO CRCs.Both age cohorts had similar numbers of CD8^(+) tumor-infiltrating lymphocytes(TILs),although LAO patients had more CD4^(+) TILs and Th1-polarized CD4s.While significant associations between immune subsets and versican(VCAN),versikine,and alpha-smooth muscle actin(αSMA)were found,none of these trends differed between age cohorts.EAO patients trended towards greater VCAN accumulation in adjacent normal tissue,lower rates of VCAN proteolysis,and decreasedαSMA accumulation vs LAO patients.Conclusions:Overall,established EAO cancers are similar to LAO cancers in mutational profile and key TME features.High VCAN andαSMA expression in adjacent normal colon indicates a presence of factors that are associated with increased intestinal subclinical inflammation.Future mechanistic studies will be conducted to better understand the importance of these findings and related processes should be prioritized as potential etiologic factors for EAO tumorigenesis.
基金The study was supported by DOD Prostate Cancer Research Program PC150221,R.Stephenson Family Fund.
文摘Androgen deprivation therapy(ADT)has been the standard of care for the last 75 years in metastatic hormone sensitive prostate cancer(PCa).However,this approach is rarely curative.Recent clinical trials have demonstrated that ADT combined with other agents,notably docetaxel and abiraterone,lead to improved survival.The mechanisms surrounding this improved cancer outcomes are incompletely defined.The response of cancer cells to ADT includes apoptosis and cell death,but a significant fraction remains viable.Our laboratory has demonstrated both in vitro and in vivo that cellular senescence occurs in a subset of these cells.Cellular senescence is a phenotype characterized by cell cycle arrest,senescenceassociated b-galactosidase(SA-b-gal),and a hypermetabolic state.Positive features of cellular senescence include growth arrest and immune stimulation,although persistence may release cytokines and growth factors that are detrimental.Senescent tumor cells generate a catabolic state with increased glycolysis,protein turnover and other metabolic changes that represent targets for drugs,like metformin,to be applied in a synthetic lethal approach.This review examines the response to ADT and the putative role of cellular senescence as a biomarker and therapeutic target in this context.
文摘AIM： To investigate the association between individual or combined use of non-steroidal anti-inflammatory drugs （NSAIDs） or statins and colorectal cancer risk.METHODS： In a population-based case-control study in women, we examined the association between NSAIDs and statin use and the risk of colorectal cancers. We further investigated whether the use of statins modifies the protective effect of NSAIDs. Female cases （n = 669）of colorectal cancer aged 50-74 years were identified from a storewide registry in Wisconsin during 1999-2001. Community control women （n = 1375） were randomly selected from lists of licensed drivers and Medicare beneficiaries. Medication use and risk factor information were gathered during a structured telephone interview. A multivariable logistic regression model was used to calculate odds ratio （OR） and 95% confidence interval （CI）.RESULTS： Overall, NSAIDs users had a 30% reduction in risk of colorectal cancer （95% CI： 0.56-0.88）. Statin use was not associated with colorectal cancer risk （OR = 1.17, 95% CI： 0.74-1.85）, regardless of structural type （lipophilic or hydrophilic）, duration of use, or recency. There was no evidence of an interaction between NSAIDs and statins and colorectal cancer risk （P-interaction = 0.28）.CONCLUSION： Although our results confirm the inverse association between NSAIDs use and colorectal cancer risk, they do not support a risk reduction in statin users, or an interaction effect of combined NSAIDs and statin use.
基金the National lnstitutes of Health/National Cancer Institute(NlH/NCT)grant RO1 CA187299(L.R.)。
文摘DNA methyltransferases(DNMTs)are an evolutionarily conserved family of DNA methylases,transferring a methyl group onto the fifth carbon of a cytosine residue.The mammalian DNMT family includes three major members that have functional methylation activities,termed DNMT1,DNMT3A,and DNMT3B.DNMT3A and DNMT3B are responsible for methylation establishment,whereas DNMT1 maintains methylation during DNA replication.Accumulating evidence demonstrates that regulation of DNAmethylation by DNMTs is critical for normal hematopoiesis.Aberrant DNA methylation due to DNMT dysregulation and mutations is known as an important molecular event of hematological malignancies,such as DNMT3A mutations in acute myeloid leukemia.In this reviewwe first describe the basic methylation mechanisms of DNMTs and their functions in lymphocyte maturation and differentiation,We then discuss the current understanding of DNA methylation heterogeneity in leukemia and lymphoma to highlight the importance of studying DNA methylation targets.We also discuss DNMT mu-tations and pathogenic roles in human leukemia and lymphoma.We summarize the recent understanding of how DNMTs interact with transcription factors or cofactors to repress the expression of tumor suppressor genes.Firnally.we highlight current clinical studies using DNMT inhibitors for the treatment of these hematological malignancies.
基金supported,in part,by the University of Wisconsin–Madisonthe National Institutes of Health (P30CA014520 and T32CA009206)the American Cancer Society (125246-RSG-13-099-01-CCE)
文摘Silica nanoparticles have been one of the most promising nanosystems for biomedical applications due to their facile surface chemistry and non-toxic nature. However, it is still challenging to effectively deliver them into tumor sites and noninvasively visualize their in vivo biodistribution with excellent sensitivity and accuracy for effective cancer diagnosis. In this study, we design a yolk/shell-structured silica nanosystem ^(64) Cu-NOTAQD@HMSN-PEG-TRC105, which can be employed for tumor vasculature targeting and dual-modality PET/optical imaging, leading to superior targeting specificity, excellentimaging capability and more reliable diagnostic outcomes.By combining vasculature targeting, pH-sensitive drug delivery, and dual-modality imaging into a single platform,as-designed yolk/shell-structured silica nanosystems may be employed for the future image-guided tumor-targeted drug delivery, to further enable cancer theranostics.
基金This work was supported by the Army Research Office(No.W911NF-16-1-0198)the National Science Foundation(No.DMR-1709025)+2 种基金National Institutes of Health(Nos.R01EB0213360,1R21EB027857,and P30CA014520)Diffraction data was collected at ChemMatCARS Sector 15,which is principally supported by the Divisions of Chemistry and Materials Research,National Science Foundation,under grant number NSF/CHE-1834750Use of the Advanced Photon Source,an Office of Science User Facility operated for the U.S.Department of Energy(DOE)Office of Science by Argonne National Laboratory,was supported by the U.S.DOE(No.DEAC02-06CH11357).
文摘Photodynamic therapy(PDT)by near-infrared(NIR)irradiation is a promising technique for treating various cancers.Here,we reported the development of free-standing wafer-scale Au nanosheets(NSs)that exhibited an impressive PDT effect.The Au NSs were synthesized by ionic layer epitaxy at the air-water interface with a uniform thickness in the range from 2 to 8.5 nm.These Au NSs were found very effective in generating singlet oxygen under NIR irradiation.In vitro cellular study showed that the Au NSs had very low cytotoxicity and high PDT efficiency due to their uniform 2D morphology.Au NSs could kill cancer cells after 5 min NIR irradiation with little heat generation.This performance is comparable to using 10 times mass loading of Au nanoparticles(NPs).This work suggests that two-dimensional(2D)Au NSs could be a new type of biocompatible nanomaterial for PDT of cancer with an extraordinary photon conversion and cancer cell killing efficiency.
基金funded by UW-Madison startup grants for T.F.and is funded by American Cancer Society(ACS)Institutional Research Grant(IRG)(No.MSN228402).
文摘Colorectal cancer(CRC)is the third most common and lethal cancer worldwide.1 Farnesoid X receptor(FXR)is a regulator of bile acid(BA)homeostasis and its expression is inversely correlated with the incidence of CRC.2,3 Moreover,our recent study discovered that dietary factors and dysregulated Wnt signaling independently alter BA profiles,some of which antagonize intestinal FXR,such as Tauro-β-muricholic acid(T-βMCA)and deoxycholic acid(DCA).
基金This project was supported by grants from the National Institutes of Health(No.R01 CA236356 and R01 CA213293)to Wei XuUniversity of Wisconsin Carbone Cancer Center Support Grant(No.P30 CA014520)Dr.Shengjie Zhang received partial salary support from the National Natural Science Foundation of China(No.81502603).
文摘Cancer patients are at increased risk for severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection and mortality.Like other viruses in the SARS family,SARS-CoV-2 employs two host proteins,angiotensin-converting enzyme 2(ACE2)and transmembrane serine protease 2(TMPRSS2),for viral entry.1 Recent studies showed that many of the host proteins identified as potential targets for developing COVID therapies are dysregulated in cancer,2 prompting us to investigate whether human cancer cells are susceptible to SARS-CoV-2 infection,and whether chemotherapy could modulate a cancer patient's risk for infection.
基金American Cancer Society Research Scholar Grant,Grant/Award Number:RSG-23-1140821-01-ETMETAVIVOR Foundation Early Career Research Grant Award。
文摘Chimeric antigen receptor(CAR)T cell therapy is a form of adoptive cell therapy that has revolutionized the field of cancer immunotherapy.Owing to the unprecedented efficacy seen in the treatment of blood cancers,the FDA has now approved multiple CAR T cell products for the treatment of various hematologic malignancies.Despite the clinical success seen in hematologic malignancies,CAR T cell therapies have demonstrated only modest efficacy in the treatment of solid tumors.Thus,great efforts are underway to increase the treatment efficacy in solid tumors and further enhance the treatment of hematologic malignancies.However,irrespective of advancements in efficacy,there are still unmet needs for patients receiving CAR T cell therapies.CAR T cell therapies carry significant risks of potentially fatal toxicities,and few of these toxicities were predicted in the animal models used to advance these therapies to the clinic.Therefore,significant advancements are needed to help reduce the incidence and severity of these toxicities to ultimately enhance patient safety and quality of life.This review will provide a brief overview of some of the major toxicities associated with CAR T cell therapies and will discuss the various engineering strategies used to mitigate such toxicities in preclinical models and clinical studies.
文摘Recent advances in immunotherapy,such as immune checkpoint inhibitors and chimeric antigen receptor(CAR)T-cell therapy,have transformed the landscape of cancer treatment.By leveraging the body’s own immune system,immunotherapy has expanded beyond cancer to address autoimmunity,fibrosis,and senescence.Nonetheless,there are still obstacles to overcome to further improve the efficacy of current immunotherapies.To that end,efforts have been made to elucidate the underlying mechanisms behind resistance to current immunotherapy regimens,alongside the exploration of novel therapeutic approaches to target and manipulate components of the immune system.
基金supported by grants JCYJ20220818102611025 and RCYX20210706092040044 from the Science and Technology Foundation of Shenzhengrant 82071193 from the National Natural Science Foundation of China+4 种基金grant 0920220233 from the Guangdong Zhujiang Programsupported by grant JCYJ20240813094605008 from the Shenzhen Natural Science Foundationgrant D2301007 from the Shenzhen Medical Research Fundgrant 2023A1515110237 from the Guangdong Province Basic and Applied Basic Research Foundationgrant 32400577 from the National Natural Science Foundation of China。
文摘Dysregulation of p53 and phosphoinositide(PIP_(n)) signaling are both key drivers of oncogenesis and metastasis.Our recent findings reveal a previously unrecognized interaction between these pathways,converging in the nucleus to form a PIP_(n)-p53 signalosome that modulates nuclear AKT activation and downstream signaling,thereby influencing cancer cell survival and motility.This review examines recent insights into nuclear PIP_(n)signaling in the context of established roles for p53 in cell dynamics and migration while also deliberating current research on how nuclear PIP_(n)s interact with p53 to form signalosomes that affect cell motility.We emphasize the critical role of PIP_(n)in stabilizing p53 and activating de novo nuclear AKT signaling,which subsequently modulates key motility-related pathways.Understanding the unique operation and function of the PIP_(n)-p53 signalosome in nuclear phosphatidylinositol 3-kinase(PI3K)-AKT activation offers novel therapeutic strategies for controlling cancer metastasis by targeting pertinent interactions and events.
文摘Arginine methylation is a common posttranslational modification that governs important cellular processes and impacts development,cell growth,proliferation,and differentiation.Arginine methylation is catalyzed by protein arginine methyltransferases(PRMTs),which are classified as type I and type II enzymes responsible for the formation of asymmetric and symmetric dimethylarginine,respectively.PRMT5 is the main type II enzyme that catalyzes symmetric dimethylarginine of histone proteins to induce gene silencing by generating repressive histone marks,including H2AR3me2s,H3R8me2s,and H4R3me2s.PRMT5 can also methylate nonhistone proteins such as the transcription factors p53,E2F1 and p65.Modifications of these proteins by PRMT5 are involved in diverse cellular processes,including transcription,translation,DNA repair,RNA processing,and metabolism.A growing literature demonstrates that PRMT5 expression is upregulated in hematologic malignancies,including leukemia and lymphoma,where PRMT5 regulates gene expression to promote cancer cell proliferation.Targeting PRMT5 by specific inhibitors has emerged as a potential therapeutic strategy to treat these diseases.
基金supported,in part,by METAVIVOR Foundation Early Career Research Grant Award,American Cancer Society Research Scholar Grant(Grant number:RSG-23-1140821-01-ET)the University of Wisconsin Carbone Cancer Center Research Collaborative and the Pancreas Cancer Task Force,and the start-up package from the University of Wisconsin-Madison.
文摘Neutrophils have recently emerged as promising carriers for drug delivery due to their unique properties including rapid response toward inflammation,chemotaxis,and transmigration.When integrated with nanotechnology that has enormous advantages in improving treatment efficacy and reducing side effects,neutrophil-based nano-drug delivery systems have expanded the repertoire of nanoparticles employed in precise therapeutic interventions by either coating nanoparticles with their membranes,loading nanoparticles inside living cells,or engineering chimeric antigen receptor(CAR)-neutrophils.These neutrophil-inspired therapies have shown superior biocompatibility,targeting ability,and therapeutic robustness.In this review,we summarized the benefits of combining neutrophils and nanotechnologies,the design principles and underlying mechanisms,and various applications in disease treatments.The challenges and prospects for neutrophil-based drug delivery systems were also discussed.
基金This work was supported by the start-up package from the University of Wisconsin-Madison(to Q.Y.H.).
文摘Activating the cyclic guanosine monophosphate-adenosine monophosphate synthase/stimulator of interferon genes(cGAS/STING)signaling has emerged as a promising anti-tumor strategy due to the important role of the pathway in innate and adaptive immunity,yet the selective delivery of STING agonists to tumors following systemic administration remains challenging.Herein,we develop a nano-STING agonist-decorated microrobot platform to achieve the enhanced anti-tumor effect.Fe ions and the STING agonist 2’3’-cyclic guanosine monophosphate-adenosine monophosphate(cGAMP)are co-encapsulated in the mitochondria-targeting nanoparticles(mTNPs),which can trigger the release of mitochondrial DNA(mtDNA)by Fenton reactioninduced mitochondria oxidative damage.The exogenous cGAMP and the endogenous mtDNA can work synergistically to induce potent cGAS/STING signaling activation.Furthermore,we decorate mTNPs onto Salmonella typhimurium VNP20009(VNP)bacteria to facilitate tumor accumulation and deep penetration.We demonstrate that the systemic administration of this microrobot activates both innate and adaptive immunity,improving the immunotherapeutic efficacy of the STING agonists.
基金supported by the University of Wisconsin Carbone Cancer Center Research Collaborativethe Pancreas Cancer Task Force and the start-up package from the University of Wisconsin-Madison.
文摘Inflammatory bowel disease(IBD)is inflammatory intestinal disorders associated with dysregulated gut microbiota.Bacteriotherapy that leverages bacteria as therapeutics has shown tremendous promise in resolving gut dysbiosis and reducing inflammatory mediators to treat IBD.Orally delivered probiotics,such as Escherichia coli Nissle 1917(EcN),can produce beneficial ingredients,competitively inhibit the proliferation of pathogens,and promote the restoration of gut microbiome homeostasis.However,environmental stresses(such as gastric acids)in the gastrointestinal(GI)tract pose an enormous challenge to the probiotics following oral administration,leading to decreases in viability and activity of probiotics.Meanwhile,the inferior mucoadhesive capability of probiotics results in low colonization efficacy,further compromising their therapeutic effect.Coating probiotics with functional biomaterials may protect them from elimination and prolong their retention in the GI tract.Here,we developed a facile double-layer electrostatic assembly technique to encapsulate EcN bacteria in protective layers of mucoadhesive chitosan(CS)and immunomodulatory hyaluronic acid(HA)to generate HA-CS-EcN.These biomaterials confer the coated EcN resistance to environmental assault and enhanced mucoadhesion in the GI tract.The probiotics equipped with the multifunctional shield can thus suppress inflammation and reshape the intestinal microenvironment to enhance therapeutic efficacy for the prevention and treatment of IBD.Collectively,this study presents a novel probiotic coating strategy to augment the outcome of bacteriotherapy to combat IBD.
基金supported by the National Natural Science Foundation of China(81601605,21571147,82102121)the Postdoctoral Science Foundation of China(2016M600670)+2 种基金supported by the University of Wisconsin–Madison,the National Institutes of Health(NIBIB/NCI P30CA014520)the Natural Science Foundation of SZU(Grant No.827-000143)the Shenzhen Peacock Plan(KQTD2016053112051497).
文摘Acute kidney injury(AKI)leads to unacceptably high mortality due to difficulties in timely intervention and less efficient renal delivery of therapeutic drugs.Here,a series of polyvinylpyrrolidone(PVP)-curcumin nanoparticles(PCurNP)are designed to meet the renal excretion threshold(~45 kDa),presenting a controllable delivery nanosystem for kidney targeting.Renal accumulation of the relatively small nanoparticles,^(89)Zr-PCurNP M10 with the diameter between 5 and 8 nm,is found to be 1.7 times and 1.8 times higher than the accumulation of^(89)Zr-PCurNP M29(20-50 nm)and M40(20-50 nm)as revealed by PET imaging.Furthermore,serum creatinine analysis,kidney tissues histology,and tubular injury scores revealed that PCurNP M10 efficiently treated cisplatin-induced AKI.Herein,PCurNP offers a novel and simple strategy for precise PET image-guided drug delivery of renal protective materials.
基金supported by the UW SEED grant 101-4-534300-AAK3854 and the UW Carbone Cancer Centersupported by NIH/NCI F31 NRSA Individual Fellowship(F31CA247248)+2 种基金financial support from the“Moore4Medical”project funded by the ECSEL Joint Undertaking under grant agreement H2020-ECSEL-2019-IA-876190the PRIME project funded by the European Union's Horizon 2020 Research and Innovation Program under grant agreement No 829010 and Ministerio de Ciencia e Innovaciónla Agencia y del Fondo Europeo de Desarrollo Regional(project PID2021-126051OB-C41 funded by MCIN/AEI/https://doi.org/10.13039/501100011033/FEDER,UE).
文摘Immunotherapy remains more effective for hematologic tumors than for solid tumors.One of the main challenges to immunotherapy of solid tumors is the immunosuppressive microenvironment these tumors generate,which limits the cytotoxic capabilities of immune effector cells(e.g.,cytotoxic T and natural killer cells).This microenvironment is characterized by hypoxia,nutrient starvation,accumulated waste products,and acidic pH.Tumor-hijacked cells,such as fibroblasts,macrophages,and T regulatory cells,also contribute to this inhospitable microenvironment for immune cells by secreting immunosuppressive cytokines that suppress the antitumor immune response and lead to immune evasion.Thus,there is a strong interest in developing new drugs and cell formulations that modulate the tumor microenvironment and reduce tumor cell immune evasion.Microphysiological systems(MPSs)are versatile tools that may accelerate the development and evaluation of these therapies,although specific examples showcasing the potential of MPSs remain rare.Advances in microtechnologies have led to the development of sophisticated microfluidic devices used to recapitulate tumor complexity.The resulting models,also known as microphysiological systems(MPSs),are versatile tools with which to decipher the molecular mechanisms driving immune cell antitumor cytotoxicity,immune cell exhaustion,and immune cell exclusion and to evaluate new targeted immunotherapies.Here,we review existing microphysiological platforms to study immuno-oncological applications and discuss challenges and opportunities in the field.
基金This work was supported in part by R01AI093881(JG)and by a gift from Above&Beyond LLC.
文摘I mmunosuppressive therapies have meaningful effects on the treatment of multiple sclerosis(MS),a classical inflammatory autoimmune disease of the central nervous system.1 In mice with experimental autoimmune encephalomyelitis(EAE),a murine model of human MS,we showed that an adoptive transfer of GM-CSF and Interleukin-15 Fusion Transgene(GIFT15)-derived regulatory B cells(GIFT15 Bregs)sustained a durable remission of the disease.2,3 These regulatory B cells require the expression of MHC class II and IL-10 for suppressive activity.
文摘Multifunctional yolk/shell-structured hybrid nanomaterials have attracted increasing interest as theranostic nanoplatforms for cancer imaging and therapy. However, because of the lack of suitable surface engineering and tumor targeting strategies, previous research has focused mainly on nanostructure design and synthesis with few successful examples showing active tumor targeting after systemic administration. In this study, we report the general synthetic strategy of chelator-free zirconium-89 （89Zr）-radiolabeled, TRC105 antibody-conjugated, silica-based yolk/sheU hybrid nanopartides for in vivo tumor vasculature targeting. Three types of inorganic nanoparticles with varying morphologies and sizes were selected as the internal cores, which were encapsulated into single hollow mesoporous silica nanosheUs to form the yolk/sheU-structured hybrid nanopartides. As a proof-of-concept, we demonstrated successful surface functionalization of the nanoparticles with polyethylene glycol, TRC105 antibody （specific for CD105/endoglin）, and ~Zr （a positron-emitting radioisotope）, and enhanced in vivo tumor vasculature-targeted positron emission tomography imaging in 4T1 murine breast tumor-bearing mice. This strategy could be applied to the synthesis of other types of yolk/shell theranostic nanoparticles for tumor- targeted imaging and drug delivery.
基金funded in part by Astellas-Pfizer and was supported by the University of Wisconsin School of Medicine and Public Health and the University of Wisconsin Carbone Cancer Center Support Grant P30CA014520 and UW School of Medicine and Public Health(SMPH)and UWCCC grant to Gopal lyerAll lung cell lines except NCl-H3122 were received as research support as part of the ATCC Innovation Challenge.
文摘Androgen receptor(AR)is a major transcription factor that plays a role in inflammatory response including interleukin-6(IL6)signaling.1 While AR regulation through paracrine loop signaling in prostate tissue is well-studied,its impact through an IL6 autocrine loop in the lung has not been wellstudied despite the organ's response to respiratory viral infection.Chemical inhibition and RNA knockdown of AR identified a bZIP transcription factor MAF to be a common target of inflammation using these perturbations in lung cells.
