Microcystin-leucine-arginine(MC-LR)is positively linked with multiple cancers in humans.However,the association between MC-LR and the risk and prognosis of prostate cancer has not been conducted in epidemiological stu...Microcystin-leucine-arginine(MC-LR)is positively linked with multiple cancers in humans.However,the association between MC-LR and the risk and prognosis of prostate cancer has not been conducted in epidemiological studies.No reported studies have linked MC-LR exposure to the poor prognosis of prostate cancer by conducting experimental studies.The content of MC-LR was detected in most of the aquatic food in wet markets and supermarkets in Nanjing and posed a health risk for consumers.MC-LR levels in both prostate cancer tissues and serum were significantly higher than controls.The adjusted odds ratio(OR)for prostate cancer risk by serum MC-LR was 1.75(95%CI:1.21-2.52)in the whole subjects,and a positive correlation between MC-LR and advanced tumor stage was observed.Survival curve analysis indicated patients with higher MC-LR levels in tissues exhibited poorer overall survival.Human,animal,and cell studies confirmed that MC-LR exposure increases the expression of estrogen receptor-α(ERα)and promotes epithelial-mesenchymal transition(EMT)in prostate cancer.Moreover,MC-LR-induced decreased E-cadherin levels,increased vimentin levels,and increased migratory and invasive capacities of prostate cancer cells were markedly suppressed upon ERαknockdown.MC-LR-induced xenograft tumor growth and lungmetastasis in BALB/c nude mice can be effectively alleviated with ERαknockdown.Our data demonstrated that MC-LR upregulated vimentin and downregulated E-cadherin through activating ERα,promoting migration and invasion of prostate cancer cells.Our findings highlight the role of MC-LR in prostate cancer,providing new perspectives to understand MC-LR-induced prostatic toxicity.展开更多
Prostate biopsy is the gold standard for diagnosing prostate cancer(PCa).Prostate targeted biopsy(TB)having a higher rate of detecting clinically significant PCa(csPCa)than traditional systematic biopsy(SB)is supporte...Prostate biopsy is the gold standard for diagnosing prostate cancer(PCa).Prostate targeted biopsy(TB)having a higher rate of detecting clinically significant PCa(csPCa)than traditional systematic biopsy(SB)is supported by high-quality evidence.However,the TB indications and strategies are controversial.The National Cancer Center/Cancer Hospital,Chinese Academy of Medical Sciences,invited a panel of recognized urology experts in PCa to address these topics at the Panjiayuan Consensus Conference 2022.The conference results on prostate TB are presented herein.The National Cancer Center/Cancer Hospital,Chinese Academy of Medical Sciences identified 10 key areas of prostate biopsy:(1)selection of imaging examination;(2)indications of TB;(3)transperineal and transrectal prostate biopsy;(4)TB pathways;(5)TB and SB;(6)three techniques of TB;(7)the number of TB cores needed for one lesion;(8)core number for SB;(9)free-hand TB;(10)future development of TB/prostate diagnosis.Thus,a panel of 25 recognized urologists and 2 radiologists from China were invited to attend this conference.The panel voted anonymously on 14 predetermined questions.Voting was based on the panelists'clinical practice and opinion,rather than high-level evidence.The voting outcomes were supported by the panel unequally,and details of the voting results were reported.The voting results can help clinicians to decide on biopsy timing and proper strategies,for which guidelines are sparse.We also focused on the future development of TB and SB,such as the combined pathway of TB and SB,techniques of TB,biopsy cores,free-hand TB,and prostate-specific membrane antigen positron emission tomography/computed tomography.展开更多
Background:LY01005(Goserelin acetate sustained-release microsphere injection)is a modified gonadotropin-releasing hormone(GnRH)agonist injected monthly.This phase III trial study aimed to evaluated the efficacy and sa...Background:LY01005(Goserelin acetate sustained-release microsphere injection)is a modified gonadotropin-releasing hormone(GnRH)agonist injected monthly.This phase III trial study aimed to evaluated the efficacy and safety of LY01005 in Chinese patients with prostate cancer.Methods:We conducted a randomized controlled,open-label,non-inferiority trial across 49 sites in China.This study included 290 patients with prostate cancer who received either LY01005 or goserelin implants every 28 days for three injections.The primary efficacy endpoints were the percentage of patients with testosterone suppression≤50 ng/dL at day 29 and the cumulative probability of testosterone≤50 ng/dL from day 29 to 85.Non-inferiority was prespecified at a margin of-10%.Secondary endpoints included significant castration(≤20 ng/dL),testosterone surge within 72 h following repeated dosing,and changes in luteinizing hormone,follicle-stimulating hormone,and prostate specific antigen levels.Results:On day 29,in the LY01005 and goserelin implant groups,testosterone concentrations fell below medical-castration levels in 99.3%(142/143)and 100%(140/140)of patients,respectively,with a difference of-0.7%(95%confidence interval[CI],-3.9%to 2.0%)between the two groups.The cumulative probabilities of maintaining castration from days 29 to 85 were 99.3%and 97.8%,respectively,with a between-group difference of 1.5%(95%CI,-1.3%to 4.4%).Both results met the criterion for non-inferiority.Secondary endpoints were similar between groups.Both treatments were well-tolerated.LY01005 was associated with fewer injection-site reactions than the goserelin implant(0%vs.1.4%[2/145]).Conclusion:LY01005 is as effective as goserelin implants in reducing testosterone to castration levels,with a similar safety profile.Trial registration:ClinicalTrials.gov,NCT04563936.展开更多
Background:Interleukin-15(IL-15)is a promising immunotherapeutic agent owing to its powerful immune-activating effects.However,the clinical benefits of these treatments are limited.Crosstalk between tumor cells and im...Background:Interleukin-15(IL-15)is a promising immunotherapeutic agent owing to its powerful immune-activating effects.However,the clinical benefits of these treatments are limited.Crosstalk between tumor cells and immune cells plays an important role in immune escape and immunotherapy drug resistance.Herein,this study aimed to obtain in-depth understanding of crosstalk in the tumor microenvironment for providing potential therapeutic strategies to prevent tumor progression.Methods:T-cell killing assays and co-culture models were developed to determine the role of crosstalk between macrophages and tumor cells in breast cancer resistant to IL-15.Western blotting,histological analysis,CRISPR-Cas9 knockout,multi-parameter flow cytometry,and tumor cell-macrophage co-injection mouse models were developed to examine the mechanism by which IL-15Rα^(+)tumor-associated macrophages(TAMs)regulate breast cancer cell resistance to IL-15.Results:We found thatmacrophages contributed to the resistance of tumor cells to IL-15,and tumor cells induced macrophages to express high levels of theαsubunit of the IL-15 receptor(IL-15Rα).Further investigation showed that IL-15Rα^(+)TAMs reduced the protein levels of chemokine CX3C chemokine ligand 1(CX3CL1)in tumor cells to inhibit the recruitment of CD8^(+)T cells by releasing the IL-15/IL-15Rαcomplex(IL-15Rc).Administration of an IL-15Rc blocking peptide markedly suppressed breast tumor growth and overcame the resistance of cancer cells to anti-programmed cell death protein 1(PD-1)antibody immunotherapy.Interestingly,Granulocyte-macrophage colony-stimulating factor(GMCSF)inducedγchain(γc)expression to promote tumor cell-macrophage crosstalk,which facilitated tumor resistance to IL-15.Additionally,we observed that the non-transcriptional regulatory function of hypoxia inducible factor-1alpha(HIF-1α)was essential for IL-15Rc to regulateCX3CL1 expression in tumor cells.Conclusions:The IL-15Rc-HIF-1α-CX3CL1 signaling pathway serves as a crosstalk between macrophages and tumor cells in the tumormicroenvironment of breast cancer.Targeting this pathway may provide a potential therapeutic strategy for enhancing the efficacy of cancer immunotherapy.展开更多
基金supported by the National Natural Science Foundation of China(Nos.31870492,31901182)the Natural Science Foundation of Jiangsu Province of China(No.BK20190316).
文摘Microcystin-leucine-arginine(MC-LR)is positively linked with multiple cancers in humans.However,the association between MC-LR and the risk and prognosis of prostate cancer has not been conducted in epidemiological studies.No reported studies have linked MC-LR exposure to the poor prognosis of prostate cancer by conducting experimental studies.The content of MC-LR was detected in most of the aquatic food in wet markets and supermarkets in Nanjing and posed a health risk for consumers.MC-LR levels in both prostate cancer tissues and serum were significantly higher than controls.The adjusted odds ratio(OR)for prostate cancer risk by serum MC-LR was 1.75(95%CI:1.21-2.52)in the whole subjects,and a positive correlation between MC-LR and advanced tumor stage was observed.Survival curve analysis indicated patients with higher MC-LR levels in tissues exhibited poorer overall survival.Human,animal,and cell studies confirmed that MC-LR exposure increases the expression of estrogen receptor-α(ERα)and promotes epithelial-mesenchymal transition(EMT)in prostate cancer.Moreover,MC-LR-induced decreased E-cadherin levels,increased vimentin levels,and increased migratory and invasive capacities of prostate cancer cells were markedly suppressed upon ERαknockdown.MC-LR-induced xenograft tumor growth and lungmetastasis in BALB/c nude mice can be effectively alleviated with ERαknockdown.Our data demonstrated that MC-LR upregulated vimentin and downregulated E-cadherin through activating ERα,promoting migration and invasion of prostate cancer cells.Our findings highlight the role of MC-LR in prostate cancer,providing new perspectives to understand MC-LR-induced prostatic toxicity.
基金Capital's Funds for Health Improvement and Research,Grant/Award Number:2022-3-40714。
文摘Prostate biopsy is the gold standard for diagnosing prostate cancer(PCa).Prostate targeted biopsy(TB)having a higher rate of detecting clinically significant PCa(csPCa)than traditional systematic biopsy(SB)is supported by high-quality evidence.However,the TB indications and strategies are controversial.The National Cancer Center/Cancer Hospital,Chinese Academy of Medical Sciences,invited a panel of recognized urology experts in PCa to address these topics at the Panjiayuan Consensus Conference 2022.The conference results on prostate TB are presented herein.The National Cancer Center/Cancer Hospital,Chinese Academy of Medical Sciences identified 10 key areas of prostate biopsy:(1)selection of imaging examination;(2)indications of TB;(3)transperineal and transrectal prostate biopsy;(4)TB pathways;(5)TB and SB;(6)three techniques of TB;(7)the number of TB cores needed for one lesion;(8)core number for SB;(9)free-hand TB;(10)future development of TB/prostate diagnosis.Thus,a panel of 25 recognized urologists and 2 radiologists from China were invited to attend this conference.The panel voted anonymously on 14 predetermined questions.Voting was based on the panelists'clinical practice and opinion,rather than high-level evidence.The voting outcomes were supported by the panel unequally,and details of the voting results were reported.The voting results can help clinicians to decide on biopsy timing and proper strategies,for which guidelines are sparse.We also focused on the future development of TB and SB,such as the combined pathway of TB and SB,techniques of TB,biopsy cores,free-hand TB,and prostate-specific membrane antigen positron emission tomography/computed tomography.
文摘Background:LY01005(Goserelin acetate sustained-release microsphere injection)is a modified gonadotropin-releasing hormone(GnRH)agonist injected monthly.This phase III trial study aimed to evaluated the efficacy and safety of LY01005 in Chinese patients with prostate cancer.Methods:We conducted a randomized controlled,open-label,non-inferiority trial across 49 sites in China.This study included 290 patients with prostate cancer who received either LY01005 or goserelin implants every 28 days for three injections.The primary efficacy endpoints were the percentage of patients with testosterone suppression≤50 ng/dL at day 29 and the cumulative probability of testosterone≤50 ng/dL from day 29 to 85.Non-inferiority was prespecified at a margin of-10%.Secondary endpoints included significant castration(≤20 ng/dL),testosterone surge within 72 h following repeated dosing,and changes in luteinizing hormone,follicle-stimulating hormone,and prostate specific antigen levels.Results:On day 29,in the LY01005 and goserelin implant groups,testosterone concentrations fell below medical-castration levels in 99.3%(142/143)and 100%(140/140)of patients,respectively,with a difference of-0.7%(95%confidence interval[CI],-3.9%to 2.0%)between the two groups.The cumulative probabilities of maintaining castration from days 29 to 85 were 99.3%and 97.8%,respectively,with a between-group difference of 1.5%(95%CI,-1.3%to 4.4%).Both results met the criterion for non-inferiority.Secondary endpoints were similar between groups.Both treatments were well-tolerated.LY01005 was associated with fewer injection-site reactions than the goserelin implant(0%vs.1.4%[2/145]).Conclusion:LY01005 is as effective as goserelin implants in reducing testosterone to castration levels,with a similar safety profile.Trial registration:ClinicalTrials.gov,NCT04563936.
基金National Key Research and Development Plan,Grant/Award Number:2017YFA0506000Guangdong Basic and Applied Basic Research Foundation,Grant/Award Number:2021B1515120016+1 种基金National Natural Science Foundation of China,Grant/Award Number:82072822the Key Research and Development Program of Jiangsu Province,China-Social Development Projects,Grant/Award Number:BE2020687。
文摘Background:Interleukin-15(IL-15)is a promising immunotherapeutic agent owing to its powerful immune-activating effects.However,the clinical benefits of these treatments are limited.Crosstalk between tumor cells and immune cells plays an important role in immune escape and immunotherapy drug resistance.Herein,this study aimed to obtain in-depth understanding of crosstalk in the tumor microenvironment for providing potential therapeutic strategies to prevent tumor progression.Methods:T-cell killing assays and co-culture models were developed to determine the role of crosstalk between macrophages and tumor cells in breast cancer resistant to IL-15.Western blotting,histological analysis,CRISPR-Cas9 knockout,multi-parameter flow cytometry,and tumor cell-macrophage co-injection mouse models were developed to examine the mechanism by which IL-15Rα^(+)tumor-associated macrophages(TAMs)regulate breast cancer cell resistance to IL-15.Results:We found thatmacrophages contributed to the resistance of tumor cells to IL-15,and tumor cells induced macrophages to express high levels of theαsubunit of the IL-15 receptor(IL-15Rα).Further investigation showed that IL-15Rα^(+)TAMs reduced the protein levels of chemokine CX3C chemokine ligand 1(CX3CL1)in tumor cells to inhibit the recruitment of CD8^(+)T cells by releasing the IL-15/IL-15Rαcomplex(IL-15Rc).Administration of an IL-15Rc blocking peptide markedly suppressed breast tumor growth and overcame the resistance of cancer cells to anti-programmed cell death protein 1(PD-1)antibody immunotherapy.Interestingly,Granulocyte-macrophage colony-stimulating factor(GMCSF)inducedγchain(γc)expression to promote tumor cell-macrophage crosstalk,which facilitated tumor resistance to IL-15.Additionally,we observed that the non-transcriptional regulatory function of hypoxia inducible factor-1alpha(HIF-1α)was essential for IL-15Rc to regulateCX3CL1 expression in tumor cells.Conclusions:The IL-15Rc-HIF-1α-CX3CL1 signaling pathway serves as a crosstalk between macrophages and tumor cells in the tumormicroenvironment of breast cancer.Targeting this pathway may provide a potential therapeutic strategy for enhancing the efficacy of cancer immunotherapy.