The statistical procedures as outlined by the European Medicines Agency (EMA) and United States Food and Drug Administration (FDA) guidelines for bioequivalence testing of highly variable drugs ...(HVDs) are complex. Additionally, the sample size is affected by clinical study designs or practical real-world problems, such as dropout rate or study budget. To overcome these difficulties, we propose a model-based approach for the selection of a study design with a sample size that satisfies the bioequivalence criteria using simulation studies based on a pharmacokinetic (PK) model. The designed approach was implemented using a simulation procedure considering some conventionally measured factors, such as geometric mean ratio and within-subject coefficient of variation, with various PK information important in determining bioequivalence. All simulation results were assessed according to the EMA and FDA guidelines. Furthermore, power calculations from simulation results were interpreted with regard to PK characteristics and compared among 2 × 2, 3 × 3, and 2 × 4 crossover designs to determine the efficient design considering appropriate sample size and duration of the clinical study. The proposed approach can be applied to bioequivalence studies of all drugs. However, the current study was targeted at HVDs, which are highly likely to require detailed decision making for sample size and study design.
Most therapeutic drug monitoring (TDM) packages are based on the maximum a posteriori (MAP) estimation. In this study, HMCtdm, a new TDM package, was developed using a Hamiltonian Monte Carlo (HMC) ...simulation. The estimation process of HMCtdm for the drugs amikacin, vancomycin, theophylline, and phenytoin was based on the R package Torsten. The prior pharmacokinetic (PK) models of the drugs were derived from the Abbottbase
pharmacokinetics systems (PKS) program. The performance of HMCtdm for each drug was assessed through internal and external validations. The internal validation results of the HMCtdm were compared with those of a MAP-based estimation. The developed open-source HMCtdm package is user friendly. The validation results were reviewed and interpreted using the mean percentage error and root mean squared error. The successful transplantation of the prior PK structures (used in PKS) was confirmed by comparing the validation results with a MAP estimation. An open-source HMC-based TDM package was also successfully developed in this study, and its performance was evaluated. This package can be operated by users unfamiliar with C++ and can be further developed for various applications.
TIGIT is an immune checkpoint receptor that is expressed on subsets of activated T cells and natural killer (NK) cells. Several ligands for TIGIT, including poliovirus receptor (PVR), are expressed ...on cancer cells and mediate inhibitory signaling to suppress antitumor activities of the immune cells. Many studies support that the TIGIT signaling is a potential target for cancer immunotherapy. We developed an IgG4-type monoclonal antibody against human TIGIT, designated as MG1131, using a phage display library of single-chain variable fragments (scFvs). MG1131 interacts with TIGIT much more tightly than PVR does. The crystal structure of a scFv version of MG1131 bound to TIGIT was determined, showing that MG1131 could block the PVR-TIGIT interaction and thus the immunosuppressive signaling of TIGIT. Consistently, MG1131 is bound to TIGIT-expressing cells and interferes with PVR binding to these cells. Moreover, MG1131 increased NK cell-mediated tumor killing activities, inhibited immunosuppressive activity of regulatory T (Treg) cells from healthy donors, and restored interferon-γ secretion from peripheral blood mononuclear cells derived from multiple myeloma patients. MG1131 also increased T cell infiltration to the tumor site and inhibited tumor growth in mice. Collectively, these data indicate that MG1131 modulates the effector functions of T cells and NK cells positively and Treg cells negatively.
Members of the ROK family of proteins are mostly transcriptional regulators and kinases that generally relate to the control of primary metabolism, whereby its member glucose kinase acts as the ...central control protein in carbon control in Streptomyces. Here, we show that deletion of SCO6008 (rok7B7) strongly affects carbon catabolite repression (CCR), growth, and antibiotic production in Streptomyces coelicolor. Deletion of SCO7543 also affected antibiotic production, while no major changes were observed after deletion of the rok family genes SCO0794, SCO1060, SCO2846, SCO6566, or SCO6600. Global expression profiling of the rok7B7 mutant by proteomics and microarray analysis revealed strong upregulation of the xylose transporter operon xylFGH, which lies immediately downstream of rok7B7, consistent with the improved growth and delayed development of the mutant on xylose. The enhanced CCR, which was especially obvious on rich or xylose-containing media, correlated with elevated expression of glucose kinase and of the glucose transporter GlcP. In liquid-grown cultures, expression of the biosynthetic enzymes for production of prodigionines, siderophores, and calcium-dependent antibiotic (CDA) was enhanced in the mutant, and overproduction of prodigionines was corroborated by matrix-assisted laser desorption ionization–time-of-flight analysis. These data present Rok7B7 as a pleiotropic regulator of growth, CCR, and antibiotic production in Streptomyces.
Previously, we reported that the hot water extract of
leaves (WHS) and its active component, hydrangenol, possess in vitro and in vivo effects on skin wrinkles and moisturization. We conducted a ...randomized, double-blind, placebo-controlled trial to clinically evaluate the effect of WHS on human skin. Participants (
= 151) were randomly assigned to receive either WHS 300 mg, WHS 600 mg, or placebo, once daily for 12 weeks. Skin wrinkle, hydration, elasticity, texture, and roughness parameters were assessed at baseline and after 4, 8, and 12 weeks. Compared to the placebo, skin wrinkles were significantly reduced in both WHS groups after 8 and 12 weeks. In both WHS groups, five parameters (R1-R5) of skin wrinkles significantly improved and skin hydration was significantly enhanced when compared to the placebo group after 12 weeks. Compared with the placebo, three parameters of skin elasticity, including overall elasticity (R2), net elasticity (R5), and ratio of elastic recovery to total deformation (R7), improved after 12 weeks of oral WHS (600 mg) administration. Changes in skin texture and roughness were significantly reduced in both WHS groups. No WHS-related adverse reactions were reported. Hence, WHS could be used as a health supplement for skin anti-aging.
As mesothelin is overexpressed in various types of cancer, it is an attractive target for therapeutic antibodies. T-cell bispecific antibodies bind to target cells and engage T cells via binding to ...CD3, resulting in target cell killing by T-cell activation. However, the affinity of the CD3-binding arm may influence CD3-mediated plasma clearance or antibody trapping in T-cell-containing tissues. This may then affect the biodistribution of bispecific antibodies. In this study, we used scFab and knob-into-hole technologies to construct novel IgG-based 1 + 1 MG1122-A and 2 + 1 MG1122-B bispecific antibodies against mesothelin and CD3ε. MG1122-B was designed to be bivalent to mesothelin and monovalent to CD3ε, using a 2 + 1 head-to-tail format. Activities of the two antibodies were evaluated in mesothelin-positive tumor cells in vitro and xenograft models in vivo. Although both antibodies exhibited target cell killing efficacy and produced regression of xenograft tumors with CD8+ T-cell infiltration, the antitumor efficacy of MG1122-B was significantly higher. MG1122-B may improve tumor targeting because of its bivalency for tumor antigen. It may also reduce systemic toxicity by limiting the activation of circulating T cells. Thus, MG1122-B may be useful for treating mesothelin-positive solid tumors.
Detecting local spatial clusters for count data is an important task in spatial epidemiology. Two broad approaches—moving window and disease mapping methods—have been suggested in some of the ...literature to find clusters. However, the existing methods employ somewhat arbitrarily chosen tuning parameters, and the local clustering results are sensitive to the choices. In this paper, we propose a penalized likelihood method to overcome the limitations of existing local spatial clustering approaches for count data. We start with a Poisson regression model to accommodate any type of covariates, and formulate the clustering problem as a penalized likelihood estimation problem to find change points of intercepts in two-dimensional space. The cost of developing a new algorithm is minimized by modifying an existing least absolute shrinkage and selection operator algorithm. The computational details on the modifications are shown, and the proposed method is illustrated with Seoul tuberculosis data.
As a loudspeaker's physical size decreases, its ability to reproduce low frequencies is hindered. In this paper we propose a method of creating virtual bass using an efficient frequency tracking ...algorithm. The proposed algorithm has low computational complexity but excellent performance. The results of computer simulations and subjective tests are presented to validate the algorithm .
이미 corrected Akaike`s information criterion(AICc)가 AIC에 비해 우수한 이론적 성질을 가진 것으로 알려져 있으나, 현재 실제 자료분석에서 최적의 예측 모형을 선택하기 위해 가장 널리 사용되는 정보기준은 여전히 Akaike`s information criterion(AIC)이다. 이것은 AICc를 사용함으로써 실제 ...우리가 어떠한 종류의 이점을 얻을 수 있는 가에 대해 논의하고 있는 연구가 부족해서이다. 우리는 이 논문에서 수치 연구를 통해 AIC와 AICc의 성능을 비교하고 AICc 의 사용이 가져오는 장점에 대해 확인을 할 것이다. 또한, 포아송 또는 이항 분포 자료 분석에서 과대산포(overdispersion) 현상이 나타난 경우 사용하는 quasi Akaike`s information criterion(QAIC)와 corrected quasi Akaike`s information criterion(QAICc) 성능에 대해서도 시뮬레이션을 통해 비교해보고자 한다.
Corrected Akaike`s information criterion (AICc) is known to have better finite sample properties. However, Akaike`s information criterion (AIC) is still widely used to select an optimal prediction model among several candidate models due to of a lack of research on benefits obtained using AICc. In this paper, we compare the performance of AIC and AICc through numerical simulations and confirm the advantage of using AICc. In addition, we also consider the performance of quasi Akaike`s information criterion (QAIC) and the corrected quasi Akaike`s information criterion (QAICc) for binomial and Poisson data under overdispersion phenomenon.
Bacterial integration host factors (IHFs) play important roles in site-specific recombination, DNA replication, transcription, genome organization and bacterial pathogenesis. In
Streptomyces ...coelicolor
, there are three putative IHFs: SCO1480, SCO2950 and SCO5556. SCO1480 or
Streptomyces
IHF (sIHF) was previously identified as a transcription factor that binds to the promoter region of
redD
, the pathway-specific regulatory gene for the undecylprodigiosin biosynthetic gene cluster. Here we show that production of the pigmented antibiotics actinorhodin and undecylprodigiosin is strongly enhanced in
sihf
null mutants, while sporulation was strongly inhibited, with an on average 25% increase in spore size. Furthermore, the
sihf
mutant spores showed strongly reduced viability, with high sensitivity to heat and live/dead staining revealing a high proportion of empty spores, while enhanced expression of sIHF increased viability. This suggests a major role for sIHF in controlling viability, perhaps via the control of DNA replication and/or segregation. Proteomic analysis of the
sihf
null mutant identified several differentially expressed transcriptional regulators, indicating that sIHF may have an extensive response regulon. These data surprisingly reveal that a basic architectural element conserved in many actinobacteria such as mycobacteria, corynebacteria, streptomycetes and rhodococci may act as a global regulator of secondary metabolism and cell development.
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