Ziwei Liao - Academia.edu (original) (raw)

Papers by Ziwei Liao

Research paper thumbnail of Analysis of N-of-1 trials using Bayesian distributed lag model with autocorrelated errors

An N-of-1 trial is a multi-period crossover trial performed in a single individual, with a primar... more An N-of-1 trial is a multi-period crossover trial performed in a single individual, with a primary goal to estimate treatment effect on the individual instead of population-level mean responses. As in a conventional crossover trial, it is critical to understand carryover effects of the treatment in an N-of-1 trial, especially when no washout periods between treatment periods are instituted to reduce trial duration. To deal with this issue in situations where high volume of measurements is made during the study, we introduce a novel Bayesian distributed lag model that facilitates the estimation of carryover effects, while accounting for temporal correlations using an autoregressive model. Specifically, we propose a prior variance-covariance structure on the lag coefficients to address collinearity caused by the fact that treatment exposures are typically identical on successive days. A connection between the proposed Bayesian model and penalized regression is noted. Simulation result...

Research paper thumbnail of Bayesian Modeling in Personalized Medicine with Applications to N-of-1 Trials

The ultimate goal of personalized or precision medicine is to identify the best treatment for eac... more The ultimate goal of personalized or precision medicine is to identify the best treatment for each patient. An N-of-1 trial is a multiple-period crossover trial performed within a single individual, which focuses on individual outcome instead of population or group mean responses. As in a conventional crossover trial, it is critical to understand carryover effects of the treatment in an N-of-1 trial, especially in situations where there are no washout periods between treatment periods and high volume of measurements are made during the study. Existing statistical methods for analyzing N-of-1 trials include nonparametric tests, mixed effect models and autoregressive models. These methods may fail to simultaneously handle measurements autocorrelation and adjust for potential carryover effects. Distributed lag model is a regression model that uses lagged predictors to model the lag structure of exposure effects. In the dissertation, we first introduce a novel Bayesian distributed lag model that facilitates the estimation of carryover effects for single N-of-1 trial, while accounting for temporal correlations using an autoregressive model. In the second part, we extend the single N-of-1 trial model to multiple N-of-1 trials scenarios. In the third part, we again focus on single N-of-1 trials. But instead of modeling comparison with one treatment and one placebo (or active control), multiple treatments and one placebo (or active control) is considered.

Research paper thumbnail of Rolling continual reassessment method with overdose control: An efficient and safe dose escalation design

Contemporary Clinical Trials

Research paper thumbnail of A composite score to assess the burden of periodontal diseases and tooth loss

Journal of Periodontology

Research paper thumbnail of The organism of pleuro-pneumonia

Journal of Comparative Pathology and Therapeutics

Research paper thumbnail of UPA-sensitive ACPP-conjugated nanoparticles for multi-targeting therapy of brain glioma

Biomaterials, 2015

Now it is well evidenced that tumor growth is a comprehensive result of multiple pathways, and gl... more Now it is well evidenced that tumor growth is a comprehensive result of multiple pathways, and glioma parenchyma cells and stroma cells are closely associated and mutually compensatory. Therefore, drug delivery strategies targeting both of them simultaneously might obtain more promising therapeutic benefits. In the present study, we developed a multi-targeting drug delivery system modified with uPA-activated cell-penetrating peptide (ACPP) for the treatment of brain glioma (ANP). In vitro experiments demonstrated nanoparticles (NP) decorated with cell-penetrating peptide (CPP) or ACPP could significantly improve nanoparticles uptake by C6 glioma cells and nanoparticles penetration into glioma spheroids as compared with traditional NP and thus enhanced the therapeutic effects of its payload when paclitaxel (PTX) was loaded. In vivo imaging experiment revealed that ANP accumulated more specifically in brain glioma site than NP decorated with or without CPP. Brain slides further showed...

Research paper thumbnail of Enhancement of microbial hydroxylation of 13-ethyl-gon-4-ene-3,17-dione by Metarhizium anisopliae using nano-liposome technique

Journal of Industrial Microbiology & Biotechnology, 2014

The introduction of 11α-hydroxy to 13-ethyl-gon-4-ene-3,17-dione (GD) by microbial transformation... more The introduction of 11α-hydroxy to 13-ethyl-gon-4-ene-3,17-dione (GD) by microbial transformation is a key step in the synthesis of oral contraceptive desogestrel, while low substrate solubility and uptake into cells are tough problems influencing biotransformation efficiency greatly. Nano-liposome technique was used in the hydroxylation of GD by Metarhizium anisopliae. The substrate GD was processed to be GD-loaded nano-liposomes (GNLs) with high stability and encapsulation efficiency, and then applied in microbial hydroxylation by M. anisopliae. The results proved that the yield of the main product 11α-hydroxy-13-ethyl-gon-4-ene-3,17-dione (HGD) tripled compared to regular solvent dimethylformamide dispersion method at 2 g/l of substrate feeding concentration, and the HGD conversion rate showed no obvious reduction when the substrate feeding concentration increased from 2 to 6 g/l, which indicated the improvement of GNL addition method on biotransformation. Furthermore, the main b...

Research paper thumbnail of EGFP–EGF1-conjugated nanoparticles for targeting both neovascular and glioma cells in therapy of brain glioma

Biomaterials, 2014

As neovascular and glioma cells were closely associated and might be mutually promoted in glioma ... more As neovascular and glioma cells were closely associated and might be mutually promoted in glioma growth, a dual-targeting strategy targeting to both neovascular and glioma cells would be more promising as compared with those targeting one of them. In this study, we reported a drug delivery system where nanoparticles were decorated with EGFPeEGF1 (ENP), a fusion protein derived from factor VII with special affinity for tissue factor (TF) over-expressed in glioma tissues, to facilitate anti-glioma delivery of paclitaxel (PTX) by targeting both neovascular and glioma cells. In vitro protein binding assay demonstrated that EGFPeEGF1 bound well to C6 cells and perturbed human umbilical vein endothelial cells (HUVEC) with a concentration-dependent manner but not to unperturbed HUVEC. EGFPeEGF1eTF interaction significantly enhanced nanoparticles uptake by perturbed HUVEC and glioma C6 cells as well as nanoparticles penetration in C6 glioma spheroids, and thus improved the cytotoxicity of their payload in both monolayer cells and glioma spheroids models. In vivo imaging of glioma-bearing mice demonstrated the specific accumulation of ENP in glioma tissues. In vivo distribution of nanoparticles intuitively showed ENP mainly sited in both extravascular glioma cells and neovascular cells. Pharmacodynamic results revealed that PTX-loaded ENP (ENPePTX) significantly prolonged the median survival time of glioma-bearing mice compared with that of any other group. TUNEL assay and H&E staining showed that ENPePTX treatment induced significantly more cell apoptosis and tumor necrosis compared with other treatments. In conclusion, the results of this contribution demonstrated the great potential of EGFP eEGF1-functionalized nanoparticles for dual-targeting therapy of brain glioma.

Research paper thumbnail of Targeting fibronectins of glioma extracellular matrix by CLT1 peptide-conjugated nanoparticles

Biomaterials, 2014

The abundant extracellular matrix (ECM) in the glioma microenvironment play a critical role in th... more The abundant extracellular matrix (ECM) in the glioma microenvironment play a critical role in the maintenance of glioma morphology, glioma cells differentiation and proliferation, but little has been done to understand the feasibility of ECM as the therapeutic target for glioma therapy. In this study, a drug delivery system targeting fibronectins (FNs), a prevailing component in the ECM of many solid tumors, was constructed for glioma therapy based on the interaction between the abundant FNs in glioma tissues and the FNs-targeting moiety CLT1 peptide. CLT1 peptide was successfully conjugated to PEG-PLA nanoparticles (CNP). FNs were demonstrated to be highly expressed in the ECM of glioma spheroids in vitro and glioma tissues in vivo. CLT1 modification favored targeting nanoparticles penetration into the core of glioma spheroids and consequently induced more severe inhibitive effects on glioma spheroids growth than traditional NP. In vivo imaging, ex vivo imaging and glioma tissue slides showed that CNP enhanced nanoparticles retention in glioma site, distributed more extensively and more deeply into glioma tissues than that of conventional NP, and mainly located in glioma cells rather than in extracellular matrix as conventional NP. Pharmacodynamics outcomes revealed that the median survival time of glioma-bearing mice models treated with paclitaxel-loaded CNP (CNP-PTX) was significantly prolonged when compared with that of any other group. TUNEL assay demonstrated that more extensive cell apoptosis was induced by CNP-PTX treatment compared with other treatments. Altogether, these promising results indicated that this ECM-targeting drug delivery system enhanced retention and glioma cell uptake of nanoparticles and might have a great potential for glioma therapy in clinical applications.

Research paper thumbnail of LDLR-mediated peptide-22-conjugated nanoparticles for dual-targeting therapy of brain glioma

Biomaterials, 2013

Chemotherapy for brain glioma has been of limited benefit due to the inability of drugs to penetr... more Chemotherapy for brain glioma has been of limited benefit due to the inability of drugs to penetrate the blood-brain barrier (BBB) and non-selective drug accumulation in the entire brain. To obviate these limitations, dual-targeting paclitaxel-loaded nanoparticles were developed by decoration with peptide-22 (PNP-PTX), a peptide with special affinity for low-density lipoprotein receptor (LDLR), to transport the drug across the BBB, and then target brain tumour cells. Enzyme-linked immune sorbent assay (ELISA) revealed that LDLR was over-expressed in C6 cells and brain capillary endothelial cells (BCECs), but low LDLR expression was observed in H92c(2-1) cells. Nanoparticle uptake demonstrated that peptide-22-decorated nanoparticles significantly increased the cellular uptake of nanoparticles by C6 cells and BCECs but not by H92c(2-1) cells, and excess free peptide-22 significantly inhibited the cellular uptake of PNP by C6 cells and BCECs. Cellular uptake mechanism experiments showed that PNP uptake by both BCECs and C6 cells was energy-dependant and caveolae- and clathrin-mediated endocytosis pathway other than macropinocytosis were involved. Dual-targeting effects in an in vitro BBB model showed that peptide-22 decoration on nanoparticles loaded with paclitaxel significantly increased the transport ratio of PTX across the BBB and induced apoptosis of C6 glioma cells below the BBB, and these effects were significantly inhibited by excess free peptide-22. Ex vivo and in vivo fluorescence imaging indicated that PNP labelled with a near-infrared dye could permeate the BBB and accumulate more in the glioma site than unmodified NP. Glioma section observed by fluorescence microscopy further demonstrated PNP distributed more extensively in both glioma bulk and infiltrative region around than unmodified NP. Pharmacodynamics results revealed that the median survival time of glioma-bearing mice administered with dual-targeting PNP-PTX was significantly prolonged compared with that of any other group. TUNEL assay and H&E staining showed that PNP-PTX treatment induced significantly more cell apoptosis and tumour necrosis compared with other treatments. Taken together, these promising results suggested that the dual-targeting drug delivery system might have great potential for glioma therapy in clinical applications.

Research paper thumbnail of Analysis of N-of-1 trials using Bayesian distributed lag model with autocorrelated errors

An N-of-1 trial is a multi-period crossover trial performed in a single individual, with a primar... more An N-of-1 trial is a multi-period crossover trial performed in a single individual, with a primary goal to estimate treatment effect on the individual instead of population-level mean responses. As in a conventional crossover trial, it is critical to understand carryover effects of the treatment in an N-of-1 trial, especially when no washout periods between treatment periods are instituted to reduce trial duration. To deal with this issue in situations where high volume of measurements is made during the study, we introduce a novel Bayesian distributed lag model that facilitates the estimation of carryover effects, while accounting for temporal correlations using an autoregressive model. Specifically, we propose a prior variance-covariance structure on the lag coefficients to address collinearity caused by the fact that treatment exposures are typically identical on successive days. A connection between the proposed Bayesian model and penalized regression is noted. Simulation result...

Research paper thumbnail of Bayesian Modeling in Personalized Medicine with Applications to N-of-1 Trials

The ultimate goal of personalized or precision medicine is to identify the best treatment for eac... more The ultimate goal of personalized or precision medicine is to identify the best treatment for each patient. An N-of-1 trial is a multiple-period crossover trial performed within a single individual, which focuses on individual outcome instead of population or group mean responses. As in a conventional crossover trial, it is critical to understand carryover effects of the treatment in an N-of-1 trial, especially in situations where there are no washout periods between treatment periods and high volume of measurements are made during the study. Existing statistical methods for analyzing N-of-1 trials include nonparametric tests, mixed effect models and autoregressive models. These methods may fail to simultaneously handle measurements autocorrelation and adjust for potential carryover effects. Distributed lag model is a regression model that uses lagged predictors to model the lag structure of exposure effects. In the dissertation, we first introduce a novel Bayesian distributed lag model that facilitates the estimation of carryover effects for single N-of-1 trial, while accounting for temporal correlations using an autoregressive model. In the second part, we extend the single N-of-1 trial model to multiple N-of-1 trials scenarios. In the third part, we again focus on single N-of-1 trials. But instead of modeling comparison with one treatment and one placebo (or active control), multiple treatments and one placebo (or active control) is considered.

Research paper thumbnail of Rolling continual reassessment method with overdose control: An efficient and safe dose escalation design

Contemporary Clinical Trials

Research paper thumbnail of A composite score to assess the burden of periodontal diseases and tooth loss

Journal of Periodontology

Research paper thumbnail of The organism of pleuro-pneumonia

Journal of Comparative Pathology and Therapeutics

Research paper thumbnail of UPA-sensitive ACPP-conjugated nanoparticles for multi-targeting therapy of brain glioma

Biomaterials, 2015

Now it is well evidenced that tumor growth is a comprehensive result of multiple pathways, and gl... more Now it is well evidenced that tumor growth is a comprehensive result of multiple pathways, and glioma parenchyma cells and stroma cells are closely associated and mutually compensatory. Therefore, drug delivery strategies targeting both of them simultaneously might obtain more promising therapeutic benefits. In the present study, we developed a multi-targeting drug delivery system modified with uPA-activated cell-penetrating peptide (ACPP) for the treatment of brain glioma (ANP). In vitro experiments demonstrated nanoparticles (NP) decorated with cell-penetrating peptide (CPP) or ACPP could significantly improve nanoparticles uptake by C6 glioma cells and nanoparticles penetration into glioma spheroids as compared with traditional NP and thus enhanced the therapeutic effects of its payload when paclitaxel (PTX) was loaded. In vivo imaging experiment revealed that ANP accumulated more specifically in brain glioma site than NP decorated with or without CPP. Brain slides further showed...

Research paper thumbnail of Enhancement of microbial hydroxylation of 13-ethyl-gon-4-ene-3,17-dione by Metarhizium anisopliae using nano-liposome technique

Journal of Industrial Microbiology & Biotechnology, 2014

The introduction of 11α-hydroxy to 13-ethyl-gon-4-ene-3,17-dione (GD) by microbial transformation... more The introduction of 11α-hydroxy to 13-ethyl-gon-4-ene-3,17-dione (GD) by microbial transformation is a key step in the synthesis of oral contraceptive desogestrel, while low substrate solubility and uptake into cells are tough problems influencing biotransformation efficiency greatly. Nano-liposome technique was used in the hydroxylation of GD by Metarhizium anisopliae. The substrate GD was processed to be GD-loaded nano-liposomes (GNLs) with high stability and encapsulation efficiency, and then applied in microbial hydroxylation by M. anisopliae. The results proved that the yield of the main product 11α-hydroxy-13-ethyl-gon-4-ene-3,17-dione (HGD) tripled compared to regular solvent dimethylformamide dispersion method at 2 g/l of substrate feeding concentration, and the HGD conversion rate showed no obvious reduction when the substrate feeding concentration increased from 2 to 6 g/l, which indicated the improvement of GNL addition method on biotransformation. Furthermore, the main b...

Research paper thumbnail of EGFP–EGF1-conjugated nanoparticles for targeting both neovascular and glioma cells in therapy of brain glioma

Biomaterials, 2014

As neovascular and glioma cells were closely associated and might be mutually promoted in glioma ... more As neovascular and glioma cells were closely associated and might be mutually promoted in glioma growth, a dual-targeting strategy targeting to both neovascular and glioma cells would be more promising as compared with those targeting one of them. In this study, we reported a drug delivery system where nanoparticles were decorated with EGFPeEGF1 (ENP), a fusion protein derived from factor VII with special affinity for tissue factor (TF) over-expressed in glioma tissues, to facilitate anti-glioma delivery of paclitaxel (PTX) by targeting both neovascular and glioma cells. In vitro protein binding assay demonstrated that EGFPeEGF1 bound well to C6 cells and perturbed human umbilical vein endothelial cells (HUVEC) with a concentration-dependent manner but not to unperturbed HUVEC. EGFPeEGF1eTF interaction significantly enhanced nanoparticles uptake by perturbed HUVEC and glioma C6 cells as well as nanoparticles penetration in C6 glioma spheroids, and thus improved the cytotoxicity of their payload in both monolayer cells and glioma spheroids models. In vivo imaging of glioma-bearing mice demonstrated the specific accumulation of ENP in glioma tissues. In vivo distribution of nanoparticles intuitively showed ENP mainly sited in both extravascular glioma cells and neovascular cells. Pharmacodynamic results revealed that PTX-loaded ENP (ENPePTX) significantly prolonged the median survival time of glioma-bearing mice compared with that of any other group. TUNEL assay and H&E staining showed that ENPePTX treatment induced significantly more cell apoptosis and tumor necrosis compared with other treatments. In conclusion, the results of this contribution demonstrated the great potential of EGFP eEGF1-functionalized nanoparticles for dual-targeting therapy of brain glioma.

Research paper thumbnail of Targeting fibronectins of glioma extracellular matrix by CLT1 peptide-conjugated nanoparticles

Biomaterials, 2014

The abundant extracellular matrix (ECM) in the glioma microenvironment play a critical role in th... more The abundant extracellular matrix (ECM) in the glioma microenvironment play a critical role in the maintenance of glioma morphology, glioma cells differentiation and proliferation, but little has been done to understand the feasibility of ECM as the therapeutic target for glioma therapy. In this study, a drug delivery system targeting fibronectins (FNs), a prevailing component in the ECM of many solid tumors, was constructed for glioma therapy based on the interaction between the abundant FNs in glioma tissues and the FNs-targeting moiety CLT1 peptide. CLT1 peptide was successfully conjugated to PEG-PLA nanoparticles (CNP). FNs were demonstrated to be highly expressed in the ECM of glioma spheroids in vitro and glioma tissues in vivo. CLT1 modification favored targeting nanoparticles penetration into the core of glioma spheroids and consequently induced more severe inhibitive effects on glioma spheroids growth than traditional NP. In vivo imaging, ex vivo imaging and glioma tissue slides showed that CNP enhanced nanoparticles retention in glioma site, distributed more extensively and more deeply into glioma tissues than that of conventional NP, and mainly located in glioma cells rather than in extracellular matrix as conventional NP. Pharmacodynamics outcomes revealed that the median survival time of glioma-bearing mice models treated with paclitaxel-loaded CNP (CNP-PTX) was significantly prolonged when compared with that of any other group. TUNEL assay demonstrated that more extensive cell apoptosis was induced by CNP-PTX treatment compared with other treatments. Altogether, these promising results indicated that this ECM-targeting drug delivery system enhanced retention and glioma cell uptake of nanoparticles and might have a great potential for glioma therapy in clinical applications.

Research paper thumbnail of LDLR-mediated peptide-22-conjugated nanoparticles for dual-targeting therapy of brain glioma

Biomaterials, 2013

Chemotherapy for brain glioma has been of limited benefit due to the inability of drugs to penetr... more Chemotherapy for brain glioma has been of limited benefit due to the inability of drugs to penetrate the blood-brain barrier (BBB) and non-selective drug accumulation in the entire brain. To obviate these limitations, dual-targeting paclitaxel-loaded nanoparticles were developed by decoration with peptide-22 (PNP-PTX), a peptide with special affinity for low-density lipoprotein receptor (LDLR), to transport the drug across the BBB, and then target brain tumour cells. Enzyme-linked immune sorbent assay (ELISA) revealed that LDLR was over-expressed in C6 cells and brain capillary endothelial cells (BCECs), but low LDLR expression was observed in H92c(2-1) cells. Nanoparticle uptake demonstrated that peptide-22-decorated nanoparticles significantly increased the cellular uptake of nanoparticles by C6 cells and BCECs but not by H92c(2-1) cells, and excess free peptide-22 significantly inhibited the cellular uptake of PNP by C6 cells and BCECs. Cellular uptake mechanism experiments showed that PNP uptake by both BCECs and C6 cells was energy-dependant and caveolae- and clathrin-mediated endocytosis pathway other than macropinocytosis were involved. Dual-targeting effects in an in vitro BBB model showed that peptide-22 decoration on nanoparticles loaded with paclitaxel significantly increased the transport ratio of PTX across the BBB and induced apoptosis of C6 glioma cells below the BBB, and these effects were significantly inhibited by excess free peptide-22. Ex vivo and in vivo fluorescence imaging indicated that PNP labelled with a near-infrared dye could permeate the BBB and accumulate more in the glioma site than unmodified NP. Glioma section observed by fluorescence microscopy further demonstrated PNP distributed more extensively in both glioma bulk and infiltrative region around than unmodified NP. Pharmacodynamics results revealed that the median survival time of glioma-bearing mice administered with dual-targeting PNP-PTX was significantly prolonged compared with that of any other group. TUNEL assay and H&E staining showed that PNP-PTX treatment induced significantly more cell apoptosis and tumour necrosis compared with other treatments. Taken together, these promising results suggested that the dual-targeting drug delivery system might have great potential for glioma therapy in clinical applications.