Ion-pairing high-performance liquid chromatography-ultraviolet （HPLC-UV） methods were developed to determine two commonly used chelating agents, ethylenediaminetetraacetic acid （EDTA） in Abilify （a small molecule...Ion-pairing high-performance liquid chromatography-ultraviolet （HPLC-UV） methods were developed to determine two commonly used chelating agents, ethylenediaminetetraacetic acid （EDTA） in Abilify （a small molecule drug with aripiprazole as the active pharmaceutical ingredient） oral solution and die- thylenetriaminepentaacetic acid （DTPA） in Yervoy （a monoclonal antibody drug with ipilimumab as the active pharmaceutical ingredient） intravenous formulation. Since the analytes, EDTA and DTPA, do not contain chromophores, transition metal ions （Cu2＋, Fe3＋） which generate highly stable metallocom- plexes with the chelating agents were added into the sample preparation to enhance UV detection. The use of metallocomplexes with ion-pairing chromatography provides the ability to achieve the desired sensitivity and selectivity in the development of the method. Specifically, the sample preparation in- volving metallocomplex formation allowed sensitive UV detection. Copper was utilized for the de- termination of EDTA and iron was utilized for the determination of DTPA. In the case of EDTA, a gradient mobile phase separated the components of the formulation from the analyte. In the method for DTPA, the active drug substance, ipilimumab, was eluted in the void. In addition, the optimization of the concentration of the ion-pairing reagent was discussed as a means of enhancing the retention of the aminopolycarboxylic acids （APCAs） including EDTA and DTPA and the specificity of the method. The analytical method development was designed based on the chromatographic properties of the analytes, the nature of the sample matrix and the intended purpose of the method. Validation data were presented for the two methods. Finally, both methods were successfully utilized in determining the fate of the chelates.展开更多
This article describes cell signaling network of metastatic prostate cancer(PCa)to bone and visceral organs in the context of tumor microenvironment and for the development of novel therapeutics.The article focuses on...This article describes cell signaling network of metastatic prostate cancer(PCa)to bone and visceral organs in the context of tumor microenvironment and for the development of novel therapeutics.The article focuses on our recent progress in the understanding of:1)The plasticity and dynamics of tumorestroma interaction;2)The significance of epigenetic reprogramming in conferring cancer growth,invasion and metastasis;3)New insights on altered junctional communication affecting PCa bone and brain metastases;4)Novel strategies to overcome therapeutic resistance to hormonal antagonists and chemotherapy;5)Geneticbased therapy to co-target tumor and bone stroma;6)PCa-bone-immune cell interaction and TBX2-WNTprotein signaling in bone metastasis;7)The roles of monoamine oxidase and reactive oxygen species in PCa growth and bone metastasis;and 8)Characterization of imprinting cluster of microRNA,in tumorestroma interaction.This article provides new approaches and insights of PCa metastases with emphasis on basic science and potential for clinical translation.This article referenced the details of the various approaches and discoveries described herein in peer-reviewed publications.We dedicate this article in our fond memory of Dr.Donald S.Coffey who taught us the spirit of sharing and the importance of focusing basic science discoveries toward translational medicine.展开更多
Workplace stress is a common problem with broad effects in professional life. This study aimed to understand how workplace stressors affect job satisfaction among biologics development professionals. A cross-sectional...Workplace stress is a common problem with broad effects in professional life. This study aimed to understand how workplace stressors affect job satisfaction among biologics development professionals. A cross-sectional survey was conducted at a biologics development organization. Multiple linear regression analysis was performed using years of experience, ambiguity, job conflict, perceived control, social support, job demands, self-esteem, and self-rated workplace stress as independent variables and job satisfaction as dependent variable (response). The regression model indicated that the workplace stressors and their two-level interactions significantly predicted employees’ job satisfaction, which explained 89% of the variance in level of job satisfaction (R2 = 0.89, F(17, 16) = 7.251, p = 0.0001). The interaction between perceived control and job demand and interaction between self-rated stress and job conflict had the biggest effect size on job satisfaction. This model was further used in Monte Carlo simulation to predict the outcome of job satisfaction under different work conditions. The findings will help the management to develop strategies to improve employee job satisfaction.展开更多
In the present study, total membrane proteins from tumor cell lines including HepG2, Hep3 B2,H226, Ovcar3 and N87 were extracted and digested with γLys C and trypsin. The resulting peptide lysate were pre-fractionate...In the present study, total membrane proteins from tumor cell lines including HepG2, Hep3 B2,H226, Ovcar3 and N87 were extracted and digested with γLys C and trypsin. The resulting peptide lysate were pre-fractionated and subjected to untargeted quantitative proteomics analysis using a high resolution mass spectrometer. The mass spectra were processed by the Max Quant and the protein abundances were estimated using total peak area(TPA) method. A total of 6037 proteins were identified, and the analysis resulted in the identification of 2647 membrane proteins. Of those, tumor antigens and absorption,metabolism, disposition and elimination(ADME) proteins including UDP-glucuronosyltransferase,cytochrome P450, solute carriers and ATP-binding cassette transporters were detected and disclosed significant variations among the cell lines. The principal component analysis was performed for the cluster of cell lines. The results demonstrated that H226 is closely related with N87, while Hep3 B2 aligned with HepG2. The protein cluster of Ovcar3 was apart from that of other cell lines investigated. By providing for the first time quantitative untargeted proteomics analysis, the results delineated the expression profiles of membrane proteins. These findings provided a useful resource for selecting targets of choice for anticancer therapy through advancing data obtained from preclinical tumor cell line models to clinical outcomes.展开更多
Drug metabolism and pharmacokinetics(DMPK) is an important branch of pharmaceutical sciences.The nature of ADME(absorption,distribution,metabolism,excretion) and PK(pharmacokinetics) inquiries during drug discovery an...Drug metabolism and pharmacokinetics(DMPK) is an important branch of pharmaceutical sciences.The nature of ADME(absorption,distribution,metabolism,excretion) and PK(pharmacokinetics) inquiries during drug discovery and development has evolved in recent years from being largely descriptive to seeking a more quantitative and mechanistic understanding of the fate of drug candidates in biological systems.Tremendous progress has been made in the past decade,not only in the characterization of physiochemical properties of drugs that influence their ADME,target organ exposure,and toxicity,but also in the identification of design principles that can minimize drug-drug interaction(DDI) potentials and reduce the attritions.The importance of membrane transporters in drug disposition,efficacy,and safety,as well as the interplay with metabolic processes,has been increasingly recognized.Dramatic increases in investments on new modalities beyond traditional small and large molecule drugs,such as peptides,oligonucleotides,and antibody-drug conjugates,necessitated further innovations in bioanalytical and experimental tools for the characterization of their ADME properties.In this review,we highlight some of the most notable advances in the last decade,and provide future perspectives on potential major breakthroughs and innovations in the translation of DMPK science in various stages of drug discovery and development.展开更多
We propose a new two-/three-stage dose-finding design called Target Toxicity(TT)for phase Ⅰ clinical trials,where we link the decision rules in the dose-finding process with the conclusions from a hypothesis test.The...We propose a new two-/three-stage dose-finding design called Target Toxicity(TT)for phase Ⅰ clinical trials,where we link the decision rules in the dose-finding process with the conclusions from a hypothesis test.The power to detect excessive toxicity is also given.This solves the problem of why the minimal number of patients is needed for the selected dose level.Our method provides a statistical explanation of traditional‘3+3’design using frequentist framework.The proposed method is very flexible and it incorporates other interval-based decision rules through different parameter settings.We provide the decision tables to guide investigators when to decrease,increase or repeat a dose for next cohort of subjects.Simulation experiments were conducted to compare the performance of the proposed method with other dose-finding designs.A free open source R package tsdf is available on CRAN.It is dedicated to deriving two-/three-stage design decision tables and perform dose-finding simulations.展开更多
文摘Ion-pairing high-performance liquid chromatography-ultraviolet （HPLC-UV） methods were developed to determine two commonly used chelating agents, ethylenediaminetetraacetic acid （EDTA） in Abilify （a small molecule drug with aripiprazole as the active pharmaceutical ingredient） oral solution and die- thylenetriaminepentaacetic acid （DTPA） in Yervoy （a monoclonal antibody drug with ipilimumab as the active pharmaceutical ingredient） intravenous formulation. Since the analytes, EDTA and DTPA, do not contain chromophores, transition metal ions （Cu2＋, Fe3＋） which generate highly stable metallocom- plexes with the chelating agents were added into the sample preparation to enhance UV detection. The use of metallocomplexes with ion-pairing chromatography provides the ability to achieve the desired sensitivity and selectivity in the development of the method. Specifically, the sample preparation in- volving metallocomplex formation allowed sensitive UV detection. Copper was utilized for the de- termination of EDTA and iron was utilized for the determination of DTPA. In the case of EDTA, a gradient mobile phase separated the components of the formulation from the analyte. In the method for DTPA, the active drug substance, ipilimumab, was eluted in the void. In addition, the optimization of the concentration of the ion-pairing reagent was discussed as a means of enhancing the retention of the aminopolycarboxylic acids （APCAs） including EDTA and DTPA and the specificity of the method. The analytical method development was designed based on the chromatographic properties of the analytes, the nature of the sample matrix and the intended purpose of the method. Validation data were presented for the two methods. Finally, both methods were successfully utilized in determining the fate of the chelates.
基金The authors thank the financial support from NIH/National Cancer Institute grants(2P01CA098912)the editorial assistance from Gary Mawyer.
文摘This article describes cell signaling network of metastatic prostate cancer(PCa)to bone and visceral organs in the context of tumor microenvironment and for the development of novel therapeutics.The article focuses on our recent progress in the understanding of:1)The plasticity and dynamics of tumorestroma interaction;2)The significance of epigenetic reprogramming in conferring cancer growth,invasion and metastasis;3)New insights on altered junctional communication affecting PCa bone and brain metastases;4)Novel strategies to overcome therapeutic resistance to hormonal antagonists and chemotherapy;5)Geneticbased therapy to co-target tumor and bone stroma;6)PCa-bone-immune cell interaction and TBX2-WNTprotein signaling in bone metastasis;7)The roles of monoamine oxidase and reactive oxygen species in PCa growth and bone metastasis;and 8)Characterization of imprinting cluster of microRNA,in tumorestroma interaction.This article provides new approaches and insights of PCa metastases with emphasis on basic science and potential for clinical translation.This article referenced the details of the various approaches and discoveries described herein in peer-reviewed publications.We dedicate this article in our fond memory of Dr.Donald S.Coffey who taught us the spirit of sharing and the importance of focusing basic science discoveries toward translational medicine.
文摘Workplace stress is a common problem with broad effects in professional life. This study aimed to understand how workplace stressors affect job satisfaction among biologics development professionals. A cross-sectional survey was conducted at a biologics development organization. Multiple linear regression analysis was performed using years of experience, ambiguity, job conflict, perceived control, social support, job demands, self-esteem, and self-rated workplace stress as independent variables and job satisfaction as dependent variable (response). The regression model indicated that the workplace stressors and their two-level interactions significantly predicted employees’ job satisfaction, which explained 89% of the variance in level of job satisfaction (R2 = 0.89, F(17, 16) = 7.251, p = 0.0001). The interaction between perceived control and job demand and interaction between self-rated stress and job conflict had the biggest effect size on job satisfaction. This model was further used in Monte Carlo simulation to predict the outcome of job satisfaction under different work conditions. The findings will help the management to develop strategies to improve employee job satisfaction.
文摘In the present study, total membrane proteins from tumor cell lines including HepG2, Hep3 B2,H226, Ovcar3 and N87 were extracted and digested with γLys C and trypsin. The resulting peptide lysate were pre-fractionated and subjected to untargeted quantitative proteomics analysis using a high resolution mass spectrometer. The mass spectra were processed by the Max Quant and the protein abundances were estimated using total peak area(TPA) method. A total of 6037 proteins were identified, and the analysis resulted in the identification of 2647 membrane proteins. Of those, tumor antigens and absorption,metabolism, disposition and elimination(ADME) proteins including UDP-glucuronosyltransferase,cytochrome P450, solute carriers and ATP-binding cassette transporters were detected and disclosed significant variations among the cell lines. The principal component analysis was performed for the cluster of cell lines. The results demonstrated that H226 is closely related with N87, while Hep3 B2 aligned with HepG2. The protein cluster of Ovcar3 was apart from that of other cell lines investigated. By providing for the first time quantitative untargeted proteomics analysis, the results delineated the expression profiles of membrane proteins. These findings provided a useful resource for selecting targets of choice for anticancer therapy through advancing data obtained from preclinical tumor cell line models to clinical outcomes.
基金supported in part by grants from the National Institutes of Health (CA023074,CA092596,ES004940,ES006694,and ES020867,USA)。
文摘Drug metabolism and pharmacokinetics(DMPK) is an important branch of pharmaceutical sciences.The nature of ADME(absorption,distribution,metabolism,excretion) and PK(pharmacokinetics) inquiries during drug discovery and development has evolved in recent years from being largely descriptive to seeking a more quantitative and mechanistic understanding of the fate of drug candidates in biological systems.Tremendous progress has been made in the past decade,not only in the characterization of physiochemical properties of drugs that influence their ADME,target organ exposure,and toxicity,but also in the identification of design principles that can minimize drug-drug interaction(DDI) potentials and reduce the attritions.The importance of membrane transporters in drug disposition,efficacy,and safety,as well as the interplay with metabolic processes,has been increasingly recognized.Dramatic increases in investments on new modalities beyond traditional small and large molecule drugs,such as peptides,oligonucleotides,and antibody-drug conjugates,necessitated further innovations in bioanalytical and experimental tools for the characterization of their ADME properties.In this review,we highlight some of the most notable advances in the last decade,and provide future perspectives on potential major breakthroughs and innovations in the translation of DMPK science in various stages of drug discovery and development.
文摘We propose a new two-/three-stage dose-finding design called Target Toxicity(TT)for phase Ⅰ clinical trials,where we link the decision rules in the dose-finding process with the conclusions from a hypothesis test.The power to detect excessive toxicity is also given.This solves the problem of why the minimal number of patients is needed for the selected dose level.Our method provides a statistical explanation of traditional‘3+3’design using frequentist framework.The proposed method is very flexible and it incorporates other interval-based decision rules through different parameter settings.We provide the decision tables to guide investigators when to decrease,increase or repeat a dose for next cohort of subjects.Simulation experiments were conducted to compare the performance of the proposed method with other dose-finding designs.A free open source R package tsdf is available on CRAN.It is dedicated to deriving two-/three-stage design decision tables and perform dose-finding simulations.
