The proteasome,an evolutionarily conserved proteolytic complex comprising the 20S core particle and 19S regulatory particles,performs both shared and distinct functions across various tissues and organs.Spermatogenesi...The proteasome,an evolutionarily conserved proteolytic complex comprising the 20S core particle and 19S regulatory particles,performs both shared and distinct functions across various tissues and organs.Spermatogenesis,a highly complex developmental process,relies on proteasome activity at multiple stages to regulate protein turnover.In this study,we selected the 20S subunit PSMA1 and 19S regulatory subunit PSMD2 to investigate the potential functions of the proteasome in spermatogenesis.Using Psma1-EGFP and Psmd2-mCherry knock-in mouse models,we confirmed the expression of both subunits in all spermatogenic cell types,with pronounced presence in early germ cell development.To further clarify their functional significance,we specifically knocked out Psma1 and Psmd2 in germ cells.Deletion of either PSMA1 or PSMD2 led to disrupted spermatogenesis,characterized by the complete absence of sperm in the epididymis.Subsequent analysis indicated that loss of these proteasome components impaired meiotic initiation.Psma1 and Psmd2 knockout germ cells showed accumulation of DMRT1,a key regulator of mitosis-to-meiosis transition,leading to a reduction in STRA8 levels and consequent disruption of meiosis initiation.This study sheds light on the molecular mechanisms that govern meiotic initiation and identifies potential genes associated with male infertility.展开更多
Prostate cancer (PCa) is the second most common type of cancer among men worldwide and one of the leading causes of cancer-related deaths. According to data from the World Health Organization (WHO), this cancer causes...Prostate cancer (PCa) is the second most common type of cancer among men worldwide and one of the leading causes of cancer-related deaths. According to data from the World Health Organization (WHO), this cancer causes hundreds of thousands of new cases and tens of thousands of male deaths globally each year. The incidence of PCa varies across different regions and populations, generally being higher in developed countries. This disparity may be attributed to lifestyle factors and the widespread availability of screening and diagnostic technologies. Prostate-specific membrane antigen (PSMA) is a membrane-bound enzyme predominantly expressed in prostate tissue and PCa cells, with lower expression in normal tissues. This high expression makes PSMA a critical target for the diagnosis and treatment of PCa, particularly in the field of molecular imaging and radiopharmaceutical therapy. Recently, various studies have emerged on radiopharmaceuticals developed based on PSMA ligands, which can be used to specifically identify and locate PCa cells. Research on the radiomics of these novel drugs has also been updated. This article will discuss the role and limitations of PSMA PET in the diagnosis and management of PCa treatment.展开更多
Prostate cancer is the second most common cancer in men,accounting for 14.1%of new cancer cases in 2020.The aggressiveness of prostate cancer is highly variable,depending on its grade and stage at the time of diagnosi...Prostate cancer is the second most common cancer in men,accounting for 14.1%of new cancer cases in 2020.The aggressiveness of prostate cancer is highly variable,depending on its grade and stage at the time of diagnosis.Despite recent advances in prostate cancer treatment,some patients still experience recurrence or even progression after undergoing radical treatment.Accurate initial staging and monitoring for recurrence determine patient management,which in turn affect patient prognosis and survival.Classical imaging has limitations in the diagnosis and treatment of prostate cancer,but the use of novel molecular probes has improved the detection rate,specificity,and accuracy of prostate cancer detection.Molecular probe-based imaging modalities allow the visualization and quantitative measurement of biological processes at the molecular and cellular levels in living systems.An increased understanding of tumor biology of prostate cancer and the discovery of new tumor biomarkers have allowed the exploration of additional molecular probe targets.The development of novel ligands and advances in nano-based delivery technologies have accelerated the research and development of molecular probes.Here,we summarize the use of molecular probes in positron emission tomography(PET),single-photon emission computed tomography(SPECT),magnetic resonance imaging(MRI),optical imaging,and ultrasound imaging,and provide a brief overview of important target molecules in prostate cancer.展开更多
Objectives:Due to systematic side effects,there is a growing interest in nanoparticle formulation of anticancer drugs.Here,we aimed to synthesize poly(styrene-alt-maleic anhydride)cross-linked by melamine(PSMA/Me)and ...Objectives:Due to systematic side effects,there is a growing interest in nanoparticle formulation of anticancer drugs.Here,we aimed to synthesize poly(styrene-alt-maleic anhydride)cross-linked by melamine(PSMA/Me)and coated with magnetite nanoparticles(MNPs)PSMA/Me/Fe_(3)O_(4).In addition,we aimed to load paclitaxel(PTX)into PSMA/Me/Fe_(3)O_(4)for drug delivery and anticancer investigations.Methods:Novel PSMA/Me was synthesized via free radical copolymerization,coated with Fe_(3)O_(4),and then used as a transporter for PTX delivery.Fabricated copolymer was characterized using SEM,TGA,and XRD techniques.Drug release rate and loading efficiency were investigated.Human ovarian cancer cells(Skov-3)and breast cancer cells(MCF-7 cells)were incubated with the serial concentration of either free PTX or PSMA/Me/Fe_(3)O_(4)/PTX for cell viability and IC_(50)analysis for 24 and 48 h.Results:Characterization methods confirmed PSMA/Me copolymer formation.The results showed a significant encapsulation efficiency of 83%.The drug release analysis exhibited that PSMA/Me/Fe_(3)O_(4)/PTX may be considered pH-sensitive nanocarriers.PSMA/Me/Fe_(3)O_(4)/PTX reduced cell viability both dose and time-dependently(p<0.05).IC50 values of PSMA/Me/Fe_(3)O_(4)/PTX were low when compared to free PTX either 24 or 48 h post-treatment.Conclusions:Our results indicated that PSMA/Me/Fe_(3)O_(4)/PTX was more cytotoxic than PTX in both cancer cells.Findings indicated the potential of PSMA/Me/Fe_(3)O_(4)/PTX as an anticancer nanocarrier system.展开更多
Introduction: 68Ga-PSMA-11 is considered the gold standard in detection of micro and oligometastases in advanced prostate cancer, being used for therapeutic planning, as well as, potentially, for evaluating response t...Introduction: 68Ga-PSMA-11 is considered the gold standard in detection of micro and oligometastases in advanced prostate cancer, being used for therapeutic planning, as well as, potentially, for evaluating response to treatment. The development of ready-to-use lyophilized kit of PSMA-11 adds quality and safety to the routine use of this radiopharmaceutical and represents a pharmacotechnical challenge as it must preserve the integrity and specificity of the ligand. Methods: PSMA-11 kit formulation was proposed, considering radiolabeling parameters and the preservation of the peptide during the lyophilization process, using mannitol as an excipient. Critical temperature characterization studies were carried out using DSC equipment and the freeze-drying process was developed. The direct radiolabeling conditions were evaluated and standardized using 68Ge/68Ga generator eluate from two different manufacturers (ITG and Eckert & Ziegler). The radiochemical purity was evaluated by TLC and HPLC. Biological evaluation was carried out with lyophilized PSMA-11 to demonstrate the integrity of the peptide and preservation of biological activity after the lyophilization process. Results: Based on critical temperature characterization studies, the freeze-drying cycle was designed to reach a freezing temperature of around −40˚C and primary drying at 2˚C. Using 20 mg of mannitol, an intact and elegant lyophilized cake was obtained. PSMA-11 lyophilized kit was directly labeled with 68Ga eluate from 68Ge/68Ga GMP generators (ITG and Eckert & Ziegler) resulting in % RP > 95% at pH 4.0 to 4.5. The results obtained from in vitro and in vivo biological competition studies confirmed the preservation of PSMA-11 affinity for the receptor after lyophilization. Conclusion: A lyophilized formulation (Kit) of PSMA-11 was successfully obtained, which preserved the integrity and biological activity of the peptide and guaranteed radiolabeling efficiency.展开更多
Optimal therapeutic and diagnostic efficacy is essential for healthcare's global mission of advancing oncologic drug development.Accurate diagnosis and detection are crucial prerequisites for effective risk strati...Optimal therapeutic and diagnostic efficacy is essential for healthcare's global mission of advancing oncologic drug development.Accurate diagnosis and detection are crucial prerequisites for effective risk stratification and person-alized patient care in clinical oncology.A paradigm shift is emerging with the promise of multi-receptor-targeting compounds.While existing detection and staging methods have demonstrated some success,the traditional approach of monotherapy is being reevaluated to enhance therapeutic effectiveness.Het-erodimeric site-specific agents are a versatile solution by targeting two distinct biomarkers with a single theranostic agent.This review describes the inno-vation of dual-targeting compounds,examining their design strategies,thera-peutic implications,and the promising path they present for addressing complex diseases.展开更多
基金supported by the National Science Fund for Distinguished Young Scholars (81925015)Science and Technology Project of Guangzhou (2023A03J0886,2023A03J0871)National Natural Science Foundation of China (82030039,32400709)。
文摘The proteasome,an evolutionarily conserved proteolytic complex comprising the 20S core particle and 19S regulatory particles,performs both shared and distinct functions across various tissues and organs.Spermatogenesis,a highly complex developmental process,relies on proteasome activity at multiple stages to regulate protein turnover.In this study,we selected the 20S subunit PSMA1 and 19S regulatory subunit PSMD2 to investigate the potential functions of the proteasome in spermatogenesis.Using Psma1-EGFP and Psmd2-mCherry knock-in mouse models,we confirmed the expression of both subunits in all spermatogenic cell types,with pronounced presence in early germ cell development.To further clarify their functional significance,we specifically knocked out Psma1 and Psmd2 in germ cells.Deletion of either PSMA1 or PSMD2 led to disrupted spermatogenesis,characterized by the complete absence of sperm in the epididymis.Subsequent analysis indicated that loss of these proteasome components impaired meiotic initiation.Psma1 and Psmd2 knockout germ cells showed accumulation of DMRT1,a key regulator of mitosis-to-meiosis transition,leading to a reduction in STRA8 levels and consequent disruption of meiosis initiation.This study sheds light on the molecular mechanisms that govern meiotic initiation and identifies potential genes associated with male infertility.
文摘Prostate cancer (PCa) is the second most common type of cancer among men worldwide and one of the leading causes of cancer-related deaths. According to data from the World Health Organization (WHO), this cancer causes hundreds of thousands of new cases and tens of thousands of male deaths globally each year. The incidence of PCa varies across different regions and populations, generally being higher in developed countries. This disparity may be attributed to lifestyle factors and the widespread availability of screening and diagnostic technologies. Prostate-specific membrane antigen (PSMA) is a membrane-bound enzyme predominantly expressed in prostate tissue and PCa cells, with lower expression in normal tissues. This high expression makes PSMA a critical target for the diagnosis and treatment of PCa, particularly in the field of molecular imaging and radiopharmaceutical therapy. Recently, various studies have emerged on radiopharmaceuticals developed based on PSMA ligands, which can be used to specifically identify and locate PCa cells. Research on the radiomics of these novel drugs has also been updated. This article will discuss the role and limitations of PSMA PET in the diagnosis and management of PCa treatment.
基金supported by the Medical Health Science and Technology Project of Zhejiang Provincial Health Com-mission(No.2022RC146)the Zhejiang Provincial Natural Science Foundation of China(No.LQ22H050003).
文摘Prostate cancer is the second most common cancer in men,accounting for 14.1%of new cancer cases in 2020.The aggressiveness of prostate cancer is highly variable,depending on its grade and stage at the time of diagnosis.Despite recent advances in prostate cancer treatment,some patients still experience recurrence or even progression after undergoing radical treatment.Accurate initial staging and monitoring for recurrence determine patient management,which in turn affect patient prognosis and survival.Classical imaging has limitations in the diagnosis and treatment of prostate cancer,but the use of novel molecular probes has improved the detection rate,specificity,and accuracy of prostate cancer detection.Molecular probe-based imaging modalities allow the visualization and quantitative measurement of biological processes at the molecular and cellular levels in living systems.An increased understanding of tumor biology of prostate cancer and the discovery of new tumor biomarkers have allowed the exploration of additional molecular probe targets.The development of novel ligands and advances in nano-based delivery technologies have accelerated the research and development of molecular probes.Here,we summarize the use of molecular probes in positron emission tomography(PET),single-photon emission computed tomography(SPECT),magnetic resonance imaging(MRI),optical imaging,and ultrasound imaging,and provide a brief overview of important target molecules in prostate cancer.
文摘Objectives:Due to systematic side effects,there is a growing interest in nanoparticle formulation of anticancer drugs.Here,we aimed to synthesize poly(styrene-alt-maleic anhydride)cross-linked by melamine(PSMA/Me)and coated with magnetite nanoparticles(MNPs)PSMA/Me/Fe_(3)O_(4).In addition,we aimed to load paclitaxel(PTX)into PSMA/Me/Fe_(3)O_(4)for drug delivery and anticancer investigations.Methods:Novel PSMA/Me was synthesized via free radical copolymerization,coated with Fe_(3)O_(4),and then used as a transporter for PTX delivery.Fabricated copolymer was characterized using SEM,TGA,and XRD techniques.Drug release rate and loading efficiency were investigated.Human ovarian cancer cells(Skov-3)and breast cancer cells(MCF-7 cells)were incubated with the serial concentration of either free PTX or PSMA/Me/Fe_(3)O_(4)/PTX for cell viability and IC_(50)analysis for 24 and 48 h.Results:Characterization methods confirmed PSMA/Me copolymer formation.The results showed a significant encapsulation efficiency of 83%.The drug release analysis exhibited that PSMA/Me/Fe_(3)O_(4)/PTX may be considered pH-sensitive nanocarriers.PSMA/Me/Fe_(3)O_(4)/PTX reduced cell viability both dose and time-dependently(p<0.05).IC50 values of PSMA/Me/Fe_(3)O_(4)/PTX were low when compared to free PTX either 24 or 48 h post-treatment.Conclusions:Our results indicated that PSMA/Me/Fe_(3)O_(4)/PTX was more cytotoxic than PTX in both cancer cells.Findings indicated the potential of PSMA/Me/Fe_(3)O_(4)/PTX as an anticancer nanocarrier system.
文摘Introduction: 68Ga-PSMA-11 is considered the gold standard in detection of micro and oligometastases in advanced prostate cancer, being used for therapeutic planning, as well as, potentially, for evaluating response to treatment. The development of ready-to-use lyophilized kit of PSMA-11 adds quality and safety to the routine use of this radiopharmaceutical and represents a pharmacotechnical challenge as it must preserve the integrity and specificity of the ligand. Methods: PSMA-11 kit formulation was proposed, considering radiolabeling parameters and the preservation of the peptide during the lyophilization process, using mannitol as an excipient. Critical temperature characterization studies were carried out using DSC equipment and the freeze-drying process was developed. The direct radiolabeling conditions were evaluated and standardized using 68Ge/68Ga generator eluate from two different manufacturers (ITG and Eckert & Ziegler). The radiochemical purity was evaluated by TLC and HPLC. Biological evaluation was carried out with lyophilized PSMA-11 to demonstrate the integrity of the peptide and preservation of biological activity after the lyophilization process. Results: Based on critical temperature characterization studies, the freeze-drying cycle was designed to reach a freezing temperature of around −40˚C and primary drying at 2˚C. Using 20 mg of mannitol, an intact and elegant lyophilized cake was obtained. PSMA-11 lyophilized kit was directly labeled with 68Ga eluate from 68Ge/68Ga GMP generators (ITG and Eckert & Ziegler) resulting in % RP > 95% at pH 4.0 to 4.5. The results obtained from in vitro and in vivo biological competition studies confirmed the preservation of PSMA-11 affinity for the receptor after lyophilization. Conclusion: A lyophilized formulation (Kit) of PSMA-11 was successfully obtained, which preserved the integrity and biological activity of the peptide and guaranteed radiolabeling efficiency.
基金NIH Research Evaluation and Commercilization Hub,Grant/Award Number:1U01HL152410USVA Medical Research Service,Grant/Award Number:I01 BX00096409National Institutes of Health,Grant/Award Numbers:R01CA269221,R01CA225837。
文摘Optimal therapeutic and diagnostic efficacy is essential for healthcare's global mission of advancing oncologic drug development.Accurate diagnosis and detection are crucial prerequisites for effective risk stratification and person-alized patient care in clinical oncology.A paradigm shift is emerging with the promise of multi-receptor-targeting compounds.While existing detection and staging methods have demonstrated some success,the traditional approach of monotherapy is being reevaluated to enhance therapeutic effectiveness.Het-erodimeric site-specific agents are a versatile solution by targeting two distinct biomarkers with a single theranostic agent.This review describes the inno-vation of dual-targeting compounds,examining their design strategies,thera-peutic implications,and the promising path they present for addressing complex diseases.
