In clinical development,adequate and well-controlled randomised clinical trials are usually conducted to evaluate the safety and efficacy of test treatment under investigation.The purpose is to ensure that there is an...In clinical development,adequate and well-controlled randomised clinical trials are usually conducted to evaluate the safety and efficacy of test treatment under investigation.The purpose is to ensure that there is an accurate and reliable assessment of test treatment under study.In practice,however,some controversial issues inevitably appear despite the compliance of good clinical practice.These debatable issues include,but are not limited to,(1)appropriateness of hypotheses for clinical investigation,(2)feasibility of power calculation for sample size requirement,(3)integrity of randomisation/blinding,(4)strategy for clinical endpoint selection,(5)demonstrating effectiveness or ineffectiveness,(6)impact of protocol amendments and(7)independence of independent data monitoring committee.In this article,these controversial issues are discussed.The impact of these issues in evaluating the safety and efficacy of the test treatment under investigation is also assessed.Recommendations regarding possible resolutions to these issues are provided whenever possible.展开更多
BACKGROUND Cytomegalovirus(CMV)prophylaxis with valganciclovir and ganciclovir is associated with elevated neutropenia and leukopenia risk in kidney transplant recipients,although the impact of these events on healthc...BACKGROUND Cytomegalovirus(CMV)prophylaxis with valganciclovir and ganciclovir is associated with elevated neutropenia and leukopenia risk in kidney transplant recipients,although the impact of these events on healthcare resource utilization(HCRU)and clinical outcomes is unclear.AIM To quantify clinical events and HCRU associated with neutropenia and leukope-nia among adults receiving valganciclovir and/or ganciclovir post-kidney trans-plantation.METHODS Adult kidney transplant recipients receiving valganciclovir and/or ganciclovir prophylaxis were identified in the TriNetX database from 2012 to 2021.Patient characteristics were evaluated in the 1-year period pre-first transplant.HCRU and adjusted event rates per person-year were evaluated in follow-up year 1 and years 2-5 after first kidney transplantation among cohorts with vs without neutropenia and/or leukopenia.RESULTS Of 15398 identified patients,the average age was 52.39 years and 58.70%were male.Patients with neutropenia and/or leukopenia had greater risk of clinical events for CMV-related events,opportunistic infections,use of granulocyte colony stimulating factor,and hospitalizations(relative risk>1 in year 1 and years 2-5).Patients with vs without neutropenia and/or leukopenia had higher HCRU in year 1 and years 2-5 post kidney transplantation,including the mean number of inpatient admissions(year 1:3.47 vs 2.76;years 2-5:2.70 vs 2.29)and outpatient visits(48.97 vs 34.42;31.73 vs 15.59,respectively),as well as the mean number of labs(1654.55 vs 1182.27;622.37 vs 327.89).CONCLUSION Adults receiving valganciclovir and/or ganciclovir prophylaxis post-kidney transplantation had greater risk of neutropenia and/or leukopenia,which were associated with higher clinical event rates and HCRU up to 5 years post-transplantation.These findings suggest the need for alternative prophylaxis options with lower myelosup-pressive effects to improve patient outcomes.展开更多
BACKGROUND Although epidemiological data on non-alcoholic fatty liver disease in China are available,data on cardiometabolic risk factors have not been addressed under the metabolic dysfunction-associated steatotic li...BACKGROUND Although epidemiological data on non-alcoholic fatty liver disease in China are available,data on cardiometabolic risk factors have not been addressed under the metabolic dysfunction-associated steatotic liver disease(MASLD)consensus.AIM To synthesize the epidemiological characteristics of MASLD/metabolic dysfunction-associated steatohepatitis(MASH),especially their associated cardiometabolic risk factors in China.METHODS We searched EMBASE,MEDLINE,Central Cochrane,CNKI,and Wangfan for studies from January 1,2013 to December 31,2023.Studies involving individuals with MASLD/MASH in China that reported epidemiological outcomes were included.Meta-analysis was performed to assess the prevalence of MASLD/MASH.Exploratory outcomes included extrahepatic comorbidities and genetic variants related to MASLD.RESULTS In total,561 studies involving 6632718 participants were included in this analysis.The prevalence of MASLD and MASH and the annual incidence of MASLD were 30.4%[95%confidence interval(CI):29.4-31.3],6.7%(95%CI:2.2-13.4),and 37 cases per 1000 person-years(95%CI:28-47),respectively.In addition,the prevalence rates of MASLD in individuals with dyslipidemia,obesity,and hypertension were 59.9%(95%CI:52.6-67.0),53.9%(95%CI:47.9-59.9),and 44.3%(95%CI:41.1-47.6),respectively.The prevalence of lean MASLD(body mass index<24 kg/m2)was 12.0%(95%CI:10.0-14.0),and 21.7%of the total MASLD population in China had lean MASLD.CONCLUSION This study provides a comprehensive overview of the epidemiology and disease burden of MASLD/MASH in China,providing additional evidence for optimizing MASLD/MASH management in China and a reference for the global understanding of MASLD/MASH epidemiology.展开更多
A total of 23 new cancer medicines or indication expansions were approved by the U.S.Food and Drug Administration in 2012.Among these,12 are new molecular entities(NMEs)--new chemical or biological drugs approved for ...A total of 23 new cancer medicines or indication expansions were approved by the U.S.Food and Drug Administration in 2012.Among these,12 are new molecular entities(NMEs)--new chemical or biological drugs approved for the first time for oncologic use--and 10 of these NMEs are molecular targeted agents.Among the 10 targeted agents,4 are anti-angiogenesis agents and 2 are Bcr-Abl pathway inhibitors,targeting well established targets validated by previously approved agents such as bevacizumab(Avastin)or imatinib(Gleevec).Despite this progress,several questions remain:Do these newly approved agents provide sufficient treatment options to manage the broad spectrum of cancers we deal with in the clinic?Where will the next wave of new cancer drugs come from?Where should R&D efforts be invested to continue improve cancer treatment and management,especially for tumor types uniquely prevalent in China?This editorial and the review articles in this special issue of Chinese Journal of Cancer provide an in depth review of the progress and challenges in developing targeted cancer therapies,as well as an outlook of new research areas where near term breakthroughs are expected to overcome some of these challenges.展开更多
Monoclonal antibodies(mAbs)have become a major class of therapeutic agents providing effective alternatives to treating various human diseases.To date,15 mAbs have been approved by regulatory agencies in the world for...Monoclonal antibodies(mAbs)have become a major class of therapeutic agents providing effective alternatives to treating various human diseases.To date,15 mAbs have been approved by regulatory agencies in the world for clinical use in oncology indications.The selectivity and specificity,the unique pharmacokinetics,and the ability to engage and activate the host immune system differentiate these biologics from traditional small molecule anticancer drugs.mAb-based regimens have brought clinical benefits,including improvements in overall survival,to patients with a variety of cancers.Many challenges still remain,however,to fully realize the potential of these new medicines.With our further understanding of cancer biology,mechanism of antibody action,and advancement of antibody engineering technologies,many novel antibody formats or antibody-derived molecules are emerging as promising new generation therapeutics.Carefully designed and engineered,they retain the advantage of specificity and selectivity of original antibodies,but in the meantime acquire additional special features such as improved pharmacokinetics,increased selectivity,and enhanced anticancer efficacy.Promising clinical results are being generated with these newly improved antibody-based therapeutics.展开更多
We evaluated novel Chlamydial vaccines, consisting of major outer membrane protein (MOMP) alone or in combination with polymorphic membrane proteins D (PmpD) and G (PmpG) using a C57BL/6 mouse model. Native MOMP (nMOM...We evaluated novel Chlamydial vaccines, consisting of major outer membrane protein (MOMP) alone or in combination with polymorphic membrane proteins D (PmpD) and G (PmpG) using a C57BL/6 mouse model. Native MOMP (nMOMP) isolated from <em>C</em>. <em>muridarum</em> elementary bodies (EBs) and recombinant PmpD and PmpG proteins were adjuvanted with Monophosphoryl lipid A (MPLA), with either lipid nanoparticles (LNPs) or the cationic lipid dimethyldioctadecylammonium bromide (DDA). Antibody titers to <em>C</em>. <em>muridarum</em> nMOMP, and EBs were evaluated by ELISA, and T-cell responses were analyzed by intracellular cytokine staining (ICS). Protection from challenge was determined by qPCR. Vaccine immunized mice showed significantly higher antibody titers to nMOMP (P < 0.001) and <em>C</em>. <em>muridarum</em> EBs (P < 0.001), when compared to the adjuvant alone group. Antibody titers in vaccine groups with Monophosphoryl lipid A (MPLA) + LNP were higher as compared to the MPLA + DDA group (P < 0.001) except for (Cm nMOMP + PmpG + PmpD p73 + PmpD p82 + MPLA + DDA) vs (Cm nMOMP + PmpG + PmpD p73 + PmpD p82 + MPLA + LNP) for both <em>C</em>. <em>muridarum</em> EBs and PmpG. ICS analysis showed more robust CD4 + T-cell responses (IFN-<em>γ</em>/IL-2/TNF-a) in the DDA and LNP groups compared to the adjuvant alone group. The DDA + MPLA gave robust Th17 responses in comparison to MPLA and LNP group. Mice immunized with <em>Chlamydia</em> antigens also showed protection from <em>C</em>. <em>muridarum</em> challenge, by reduction in bacterial shedding for all groups (P < 0.003) compared to shedding from the adjuvant control. Both vaccine formulations generated robust immunological responses, and both were protective by reducing bacterial shedding after challenge. This data indicates equal protection can be achieved without the induction of Th17 responses.展开更多
AIM: to evaluate addition of boceprevir to peginterferon/ribavirin(PR) in Russian patients with chronic hepatitis C virus(HCV).METHODS: treatment-naive(t N) and treatmentexperienced(t E) patients(who had failed prior ...AIM: to evaluate addition of boceprevir to peginterferon/ribavirin(PR) in Russian patients with chronic hepatitis C virus(HCV).METHODS: treatment-naive(t N) and treatmentexperienced(t E) patients(who had failed prior treatment with PR for ≥ 12 wk) with chronic HCV genotype 1 infection were enrolled in this placebocontrolled, double-blind study. All patients initially received PR for 4 wk. Patients randomized to control treatment then received PR for an additional 44 wk. t N patients randomized to triple therapy received boceprevir(800 mg three times daily) plus PR for 24 wk and then further therapy according to treatment week 8(t W8) HCV RNA levels. t E patients received boceprevir plus PR for 32 wk and then further therapy according to t W8 HCV RNA levels. treatment was discontinued for t N patients with detectable HCV RNA at t W24 and t E patients with detectable HCV RNA at t W12 because of futility. the primary efficacy end point was sustained virologic response(SVR) defined as undetectable HCV RNA 24 wk after completing all study therapy.RESULTS: SVR was 74.8% in the boceprevir plus PR arm compared with 46.2% in the control arm, with a stratification-adjusted treatment difference of 29.2%(95%CI: 16.4-41.5; P < 0.0001). Rates of SVR were higher in the boceprevir arm in both t N and t E patient groups(t N 78.4% vs 56.3%; t E 69.4% vs 30.0%). Within t E patients, the rates of SVR were higher with boceprevir plus PR compared with PR, regardless of treatment failure type(null responder, partial responder, and relapser). Most patients receiving boceprevir plus PR in both t N(86%) and t E(71%) populations were eligible for reduced treatment duration. Anemia was increased in patients receiving boceprevir plus PR vs PR alone(47.2% vs 24.4%); there was a corresponding increase in ribavirin dose reduction and erythropoietin use. Among patients receiving boceprevir plus PR, SVR rates were similar in patients with anemia(< 10 g/d L) and those without anemia(71.2% vs 77.4%).CONCLUSION: Regulatory approval has been obtained for boceprevir plus PR in Russian patients with HCV genotype 1 infection based on the results of this study.展开更多
The novel coronavirus(COVID-19)pandemic that emerged from Wuhan city in December 2019 overwhelmed health systems and paralyzed economies around the world.It became the most important public health challenge facing man...The novel coronavirus(COVID-19)pandemic that emerged from Wuhan city in December 2019 overwhelmed health systems and paralyzed economies around the world.It became the most important public health challenge facing mankind since the 1918 Spanish flu pandemic.Various theoretical and empirical approaches have been designed and used to gain insight into the transmission dynamics and control of the pandemic.This study presents a primer for formulating,analysing and simulating mathematical models for understanding the dynamics of COVID-19.Specifically,we introduce simple compartmental,Kermack-McKendrick-type epidemic models with homogeneously-and heterogeneously-mixed populations,an endemic model for assessing the potential population-level impact of a hypothetical COVID-19 vaccine.We illustrate how some basic non-pharmaceutical interventions against COVID-19 can be incorporated into the epidemic model.A brief overview of other kinds of models that have been used to study the dynamics of COVID-19,such as agent-based,network and statistical models,is also presented.Possible extensions of the basic model,as well as open challenges associated with the formulation and theoretical analysis of models for COVID-19 dynamics,are suggested.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
Cancer treatment has witnessed the emergence of innovative stimuli-responsive nanotherapeutics aiming to overcome limitations associated with traditional drug delivery systems.Metal-organic frameworks(MOFs),a subset o...Cancer treatment has witnessed the emergence of innovative stimuli-responsive nanotherapeutics aiming to overcome limitations associated with traditional drug delivery systems.Metal-organic frameworks(MOFs),a subset of inorganic nanomaterials,are known for their porous structures and versatile applications in integrated cancer diagnosis and therapy.Their noteworthy features include customizable porosity,diverse chemical configurations,adjustable sizes and shapes,and the potential for surface functionalization.The study delved into conventional cancer therapies,provided an overview of MOFs,and discussed various MOF synthesis approaches.Furthermore,this review explored the development of stimuli-responsive MOFs to enhance targeted drug delivery and bioimaging,improving the overall efficacy of cancer treatment,and investigated the applications of stimuli-responsive multifunctional MOFs in nanostructures activated by factors influencing precise drug delivery and bioimaging in cancers.pH,light,ions,temperature,magnetic field,redox reactions,and ATP contribute to the precise control of drug delivery and bioimaging processes.Designed multifunctional MOFs exhibit characteristic changes in response to external and internal stimuli,proving advantageous for drug release and bioimaging.Surface-modified MOFs with responsive features demonstrate excellent biocompatibility with noncancerous cells,efficient drug-loading capabilities,and nanocarrier-mediated targeted drug delivery to cancerous cells.Therefore,the innovative strategy of inorganic nanoscale MOFs with responsive properties holds significant promise for targeted therapeutic drug delivery and imaging across diverse malignancies.The growing interest in stimuli-activated MOFs will open new opportunities in cancer theragnostic applications.展开更多
Missing data are unavoidable in longitudinal clinical trials,and outcomes are not always normally distributed.In the presence of outliers or heavy-tailed distributions,the conventional multiple imputation with the mix...Missing data are unavoidable in longitudinal clinical trials,and outcomes are not always normally distributed.In the presence of outliers or heavy-tailed distributions,the conventional multiple imputation with the mixed model with repeated measures analysis of the average treatment effect(ATE)based on the multivariate normal assumption may produce bias and power loss.Control-based imputation(CBI)is an approach for evaluating the treatment effect under the assumption that participants in both the test and control groups with missing outcome data have a similar outcome profile as those with an identical history in the control group.We develop a robust framework to handle non-normal outcomes under CBI without imposing any parametric modeling assumptions.Under the proposed framework,sequential weighted robust regressions are applied to protect the constructed imputation model against non-normality in the covariates and the response variables.Accompanied by the subsequent mean imputation and robust model analysis,the resulting ATE estimator has good theoretical properties in terms of consistency and asymptotic normality.Moreover,our proposed method guarantees the analysis model robustness of the ATE estimation in the sense that its asymptotic results remain intact even when the analysis model is misspecified.The superiority of the proposed robust method is demonstrated by comprehensive simulation studies and an AIDS clinical trial data application.展开更多
Graphene oxide(GO)and mesoporous silica nanoparticle(MSN)have been documented as advanced nanocarriers for drug delivery due to their unique and versatile properties.The design of GO-MSN nanocomposite offers a large s...Graphene oxide(GO)and mesoporous silica nanoparticle(MSN)have been documented as advanced nanocarriers for drug delivery due to their unique and versatile properties.The design of GO-MSN nanocomposite offers a large surface area,adjustable pore size,biocompatibility,and low cytotoxicity.The application of acyclovir(ACV)(BCS:III)is suffering from poor permeability,low bioavailability,etc.Hence,the use of GO-MSN nanocomposite for the delivery of ACV may overcome the limitations of ACV.Therefore,the present work aims to design the lipid-coated ACV-loaded GO-MSN(LC-ACV-GO-MSN)nanocomposites.In brief,the design of experiments(DoE,32 response surface methodology)approach was preferred for the development of GO-MSN nanocomposite.The loading of ACV in nanocomposite was done passive loading whereas the coating of lipids was done using a modified thin film hydration technique.At last,different spectral characterizations were performed.The output demonstrated that the entrapment efficiency of ACV-MSN and ACV-GO-MSN was 51.13%and 71.86%,respectively.Afterward,the designed LC-ACV-GO-MSN and ACV-GO-MSN nanocomposite shows 93.40%and 80.74%in vitro drug release,respectively.In conclusion,the design of LC-ACV-GO-MSN nanocomposite using optimized GO-MSN followed lipid coating offers the modified release.Therefore,in the future,LC-ACV-GO-MSN nanocomposite can be used for the delivery of ACV and other drug molecules with a high payload and enhanced release profile.We hope the current proof of concept may provide advantages over existing methods and emphasize the significance of protocells in cargo delivery systems.展开更多
文摘In clinical development,adequate and well-controlled randomised clinical trials are usually conducted to evaluate the safety and efficacy of test treatment under investigation.The purpose is to ensure that there is an accurate and reliable assessment of test treatment under study.In practice,however,some controversial issues inevitably appear despite the compliance of good clinical practice.These debatable issues include,but are not limited to,(1)appropriateness of hypotheses for clinical investigation,(2)feasibility of power calculation for sample size requirement,(3)integrity of randomisation/blinding,(4)strategy for clinical endpoint selection,(5)demonstrating effectiveness or ineffectiveness,(6)impact of protocol amendments and(7)independence of independent data monitoring committee.In this article,these controversial issues are discussed.The impact of these issues in evaluating the safety and efficacy of the test treatment under investigation is also assessed.Recommendations regarding possible resolutions to these issues are provided whenever possible.
文摘BACKGROUND Cytomegalovirus(CMV)prophylaxis with valganciclovir and ganciclovir is associated with elevated neutropenia and leukopenia risk in kidney transplant recipients,although the impact of these events on healthcare resource utilization(HCRU)and clinical outcomes is unclear.AIM To quantify clinical events and HCRU associated with neutropenia and leukope-nia among adults receiving valganciclovir and/or ganciclovir post-kidney trans-plantation.METHODS Adult kidney transplant recipients receiving valganciclovir and/or ganciclovir prophylaxis were identified in the TriNetX database from 2012 to 2021.Patient characteristics were evaluated in the 1-year period pre-first transplant.HCRU and adjusted event rates per person-year were evaluated in follow-up year 1 and years 2-5 after first kidney transplantation among cohorts with vs without neutropenia and/or leukopenia.RESULTS Of 15398 identified patients,the average age was 52.39 years and 58.70%were male.Patients with neutropenia and/or leukopenia had greater risk of clinical events for CMV-related events,opportunistic infections,use of granulocyte colony stimulating factor,and hospitalizations(relative risk>1 in year 1 and years 2-5).Patients with vs without neutropenia and/or leukopenia had higher HCRU in year 1 and years 2-5 post kidney transplantation,including the mean number of inpatient admissions(year 1:3.47 vs 2.76;years 2-5:2.70 vs 2.29)and outpatient visits(48.97 vs 34.42;31.73 vs 15.59,respectively),as well as the mean number of labs(1654.55 vs 1182.27;622.37 vs 327.89).CONCLUSION Adults receiving valganciclovir and/or ganciclovir prophylaxis post-kidney transplantation had greater risk of neutropenia and/or leukopenia,which were associated with higher clinical event rates and HCRU up to 5 years post-transplantation.These findings suggest the need for alternative prophylaxis options with lower myelosup-pressive effects to improve patient outcomes.
文摘BACKGROUND Although epidemiological data on non-alcoholic fatty liver disease in China are available,data on cardiometabolic risk factors have not been addressed under the metabolic dysfunction-associated steatotic liver disease(MASLD)consensus.AIM To synthesize the epidemiological characteristics of MASLD/metabolic dysfunction-associated steatohepatitis(MASH),especially their associated cardiometabolic risk factors in China.METHODS We searched EMBASE,MEDLINE,Central Cochrane,CNKI,and Wangfan for studies from January 1,2013 to December 31,2023.Studies involving individuals with MASLD/MASH in China that reported epidemiological outcomes were included.Meta-analysis was performed to assess the prevalence of MASLD/MASH.Exploratory outcomes included extrahepatic comorbidities and genetic variants related to MASLD.RESULTS In total,561 studies involving 6632718 participants were included in this analysis.The prevalence of MASLD and MASH and the annual incidence of MASLD were 30.4%[95%confidence interval(CI):29.4-31.3],6.7%(95%CI:2.2-13.4),and 37 cases per 1000 person-years(95%CI:28-47),respectively.In addition,the prevalence rates of MASLD in individuals with dyslipidemia,obesity,and hypertension were 59.9%(95%CI:52.6-67.0),53.9%(95%CI:47.9-59.9),and 44.3%(95%CI:41.1-47.6),respectively.The prevalence of lean MASLD(body mass index<24 kg/m2)was 12.0%(95%CI:10.0-14.0),and 21.7%of the total MASLD population in China had lean MASLD.CONCLUSION This study provides a comprehensive overview of the epidemiology and disease burden of MASLD/MASH in China,providing additional evidence for optimizing MASLD/MASH management in China and a reference for the global understanding of MASLD/MASH epidemiology.
文摘A total of 23 new cancer medicines or indication expansions were approved by the U.S.Food and Drug Administration in 2012.Among these,12 are new molecular entities(NMEs)--new chemical or biological drugs approved for the first time for oncologic use--and 10 of these NMEs are molecular targeted agents.Among the 10 targeted agents,4 are anti-angiogenesis agents and 2 are Bcr-Abl pathway inhibitors,targeting well established targets validated by previously approved agents such as bevacizumab(Avastin)or imatinib(Gleevec).Despite this progress,several questions remain:Do these newly approved agents provide sufficient treatment options to manage the broad spectrum of cancers we deal with in the clinic?Where will the next wave of new cancer drugs come from?Where should R&D efforts be invested to continue improve cancer treatment and management,especially for tumor types uniquely prevalent in China?This editorial and the review articles in this special issue of Chinese Journal of Cancer provide an in depth review of the progress and challenges in developing targeted cancer therapies,as well as an outlook of new research areas where near term breakthroughs are expected to overcome some of these challenges.
文摘Monoclonal antibodies(mAbs)have become a major class of therapeutic agents providing effective alternatives to treating various human diseases.To date,15 mAbs have been approved by regulatory agencies in the world for clinical use in oncology indications.The selectivity and specificity,the unique pharmacokinetics,and the ability to engage and activate the host immune system differentiate these biologics from traditional small molecule anticancer drugs.mAb-based regimens have brought clinical benefits,including improvements in overall survival,to patients with a variety of cancers.Many challenges still remain,however,to fully realize the potential of these new medicines.With our further understanding of cancer biology,mechanism of antibody action,and advancement of antibody engineering technologies,many novel antibody formats or antibody-derived molecules are emerging as promising new generation therapeutics.Carefully designed and engineered,they retain the advantage of specificity and selectivity of original antibodies,but in the meantime acquire additional special features such as improved pharmacokinetics,increased selectivity,and enhanced anticancer efficacy.Promising clinical results are being generated with these newly improved antibody-based therapeutics.
文摘We evaluated novel Chlamydial vaccines, consisting of major outer membrane protein (MOMP) alone or in combination with polymorphic membrane proteins D (PmpD) and G (PmpG) using a C57BL/6 mouse model. Native MOMP (nMOMP) isolated from <em>C</em>. <em>muridarum</em> elementary bodies (EBs) and recombinant PmpD and PmpG proteins were adjuvanted with Monophosphoryl lipid A (MPLA), with either lipid nanoparticles (LNPs) or the cationic lipid dimethyldioctadecylammonium bromide (DDA). Antibody titers to <em>C</em>. <em>muridarum</em> nMOMP, and EBs were evaluated by ELISA, and T-cell responses were analyzed by intracellular cytokine staining (ICS). Protection from challenge was determined by qPCR. Vaccine immunized mice showed significantly higher antibody titers to nMOMP (P < 0.001) and <em>C</em>. <em>muridarum</em> EBs (P < 0.001), when compared to the adjuvant alone group. Antibody titers in vaccine groups with Monophosphoryl lipid A (MPLA) + LNP were higher as compared to the MPLA + DDA group (P < 0.001) except for (Cm nMOMP + PmpG + PmpD p73 + PmpD p82 + MPLA + DDA) vs (Cm nMOMP + PmpG + PmpD p73 + PmpD p82 + MPLA + LNP) for both <em>C</em>. <em>muridarum</em> EBs and PmpG. ICS analysis showed more robust CD4 + T-cell responses (IFN-<em>γ</em>/IL-2/TNF-a) in the DDA and LNP groups compared to the adjuvant alone group. The DDA + MPLA gave robust Th17 responses in comparison to MPLA and LNP group. Mice immunized with <em>Chlamydia</em> antigens also showed protection from <em>C</em>. <em>muridarum</em> challenge, by reduction in bacterial shedding for all groups (P < 0.003) compared to shedding from the adjuvant control. Both vaccine formulations generated robust immunological responses, and both were protective by reducing bacterial shedding after challenge. This data indicates equal protection can be achieved without the induction of Th17 responses.
文摘AIM: to evaluate addition of boceprevir to peginterferon/ribavirin(PR) in Russian patients with chronic hepatitis C virus(HCV).METHODS: treatment-naive(t N) and treatmentexperienced(t E) patients(who had failed prior treatment with PR for ≥ 12 wk) with chronic HCV genotype 1 infection were enrolled in this placebocontrolled, double-blind study. All patients initially received PR for 4 wk. Patients randomized to control treatment then received PR for an additional 44 wk. t N patients randomized to triple therapy received boceprevir(800 mg three times daily) plus PR for 24 wk and then further therapy according to treatment week 8(t W8) HCV RNA levels. t E patients received boceprevir plus PR for 32 wk and then further therapy according to t W8 HCV RNA levels. treatment was discontinued for t N patients with detectable HCV RNA at t W24 and t E patients with detectable HCV RNA at t W12 because of futility. the primary efficacy end point was sustained virologic response(SVR) defined as undetectable HCV RNA 24 wk after completing all study therapy.RESULTS: SVR was 74.8% in the boceprevir plus PR arm compared with 46.2% in the control arm, with a stratification-adjusted treatment difference of 29.2%(95%CI: 16.4-41.5; P < 0.0001). Rates of SVR were higher in the boceprevir arm in both t N and t E patient groups(t N 78.4% vs 56.3%; t E 69.4% vs 30.0%). Within t E patients, the rates of SVR were higher with boceprevir plus PR compared with PR, regardless of treatment failure type(null responder, partial responder, and relapser). Most patients receiving boceprevir plus PR in both t N(86%) and t E(71%) populations were eligible for reduced treatment duration. Anemia was increased in patients receiving boceprevir plus PR vs PR alone(47.2% vs 24.4%); there was a corresponding increase in ribavirin dose reduction and erythropoietin use. Among patients receiving boceprevir plus PR, SVR rates were similar in patients with anemia(< 10 g/d L) and those without anemia(71.2% vs 77.4%).CONCLUSION: Regulatory approval has been obtained for boceprevir plus PR in Russian patients with HCV genotype 1 infection based on the results of this study.
基金One of the authors(ABG)acknowledge the support,in part,of the Simons Foundation(Award#585022)the National Science Foundation(Award#1917512)CNN acknowledges the support of the Simons Foundation(Award#627346).
文摘The novel coronavirus(COVID-19)pandemic that emerged from Wuhan city in December 2019 overwhelmed health systems and paralyzed economies around the world.It became the most important public health challenge facing mankind since the 1918 Spanish flu pandemic.Various theoretical and empirical approaches have been designed and used to gain insight into the transmission dynamics and control of the pandemic.This study presents a primer for formulating,analysing and simulating mathematical models for understanding the dynamics of COVID-19.Specifically,we introduce simple compartmental,Kermack-McKendrick-type epidemic models with homogeneously-and heterogeneously-mixed populations,an endemic model for assessing the potential population-level impact of a hypothetical COVID-19 vaccine.We illustrate how some basic non-pharmaceutical interventions against COVID-19 can be incorporated into the epidemic model.A brief overview of other kinds of models that have been used to study the dynamics of COVID-19,such as agent-based,network and statistical models,is also presented.Possible extensions of the basic model,as well as open challenges associated with the formulation and theoretical analysis of models for COVID-19 dynamics,are suggested.
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Cancer treatment has witnessed the emergence of innovative stimuli-responsive nanotherapeutics aiming to overcome limitations associated with traditional drug delivery systems.Metal-organic frameworks(MOFs),a subset of inorganic nanomaterials,are known for their porous structures and versatile applications in integrated cancer diagnosis and therapy.Their noteworthy features include customizable porosity,diverse chemical configurations,adjustable sizes and shapes,and the potential for surface functionalization.The study delved into conventional cancer therapies,provided an overview of MOFs,and discussed various MOF synthesis approaches.Furthermore,this review explored the development of stimuli-responsive MOFs to enhance targeted drug delivery and bioimaging,improving the overall efficacy of cancer treatment,and investigated the applications of stimuli-responsive multifunctional MOFs in nanostructures activated by factors influencing precise drug delivery and bioimaging in cancers.pH,light,ions,temperature,magnetic field,redox reactions,and ATP contribute to the precise control of drug delivery and bioimaging processes.Designed multifunctional MOFs exhibit characteristic changes in response to external and internal stimuli,proving advantageous for drug release and bioimaging.Surface-modified MOFs with responsive features demonstrate excellent biocompatibility with noncancerous cells,efficient drug-loading capabilities,and nanocarrier-mediated targeted drug delivery to cancerous cells.Therefore,the innovative strategy of inorganic nanoscale MOFs with responsive properties holds significant promise for targeted therapeutic drug delivery and imaging across diverse malignancies.The growing interest in stimuli-activated MOFs will open new opportunities in cancer theragnostic applications.
基金supported by the NSF(National Institutes of Health)[Grant Number DMS-1811245]NIA(National Science Foundation)[Grant Number 1R01AG066883]NIEHS[Grant Number 1R01ES031651].
文摘Missing data are unavoidable in longitudinal clinical trials,and outcomes are not always normally distributed.In the presence of outliers or heavy-tailed distributions,the conventional multiple imputation with the mixed model with repeated measures analysis of the average treatment effect(ATE)based on the multivariate normal assumption may produce bias and power loss.Control-based imputation(CBI)is an approach for evaluating the treatment effect under the assumption that participants in both the test and control groups with missing outcome data have a similar outcome profile as those with an identical history in the control group.We develop a robust framework to handle non-normal outcomes under CBI without imposing any parametric modeling assumptions.Under the proposed framework,sequential weighted robust regressions are applied to protect the constructed imputation model against non-normality in the covariates and the response variables.Accompanied by the subsequent mean imputation and robust model analysis,the resulting ATE estimator has good theoretical properties in terms of consistency and asymptotic normality.Moreover,our proposed method guarantees the analysis model robustness of the ATE estimation in the sense that its asymptotic results remain intact even when the analysis model is misspecified.The superiority of the proposed robust method is demonstrated by comprehensive simulation studies and an AIDS clinical trial data application.
基金The researchers affiliated with the Faculty of Pharmacy,Nootan Pharmacy College,Sankalchand Patel University,Visnagar 384315,Gujarat,India,express their satisfaction,attributing it to the essential resources available that facilitate their research endeavors.
文摘Graphene oxide(GO)and mesoporous silica nanoparticle(MSN)have been documented as advanced nanocarriers for drug delivery due to their unique and versatile properties.The design of GO-MSN nanocomposite offers a large surface area,adjustable pore size,biocompatibility,and low cytotoxicity.The application of acyclovir(ACV)(BCS:III)is suffering from poor permeability,low bioavailability,etc.Hence,the use of GO-MSN nanocomposite for the delivery of ACV may overcome the limitations of ACV.Therefore,the present work aims to design the lipid-coated ACV-loaded GO-MSN(LC-ACV-GO-MSN)nanocomposites.In brief,the design of experiments(DoE,32 response surface methodology)approach was preferred for the development of GO-MSN nanocomposite.The loading of ACV in nanocomposite was done passive loading whereas the coating of lipids was done using a modified thin film hydration technique.At last,different spectral characterizations were performed.The output demonstrated that the entrapment efficiency of ACV-MSN and ACV-GO-MSN was 51.13%and 71.86%,respectively.Afterward,the designed LC-ACV-GO-MSN and ACV-GO-MSN nanocomposite shows 93.40%and 80.74%in vitro drug release,respectively.In conclusion,the design of LC-ACV-GO-MSN nanocomposite using optimized GO-MSN followed lipid coating offers the modified release.Therefore,in the future,LC-ACV-GO-MSN nanocomposite can be used for the delivery of ACV and other drug molecules with a high payload and enhanced release profile.We hope the current proof of concept may provide advantages over existing methods and emphasize the significance of protocells in cargo delivery systems.
