Semiparametric analysis of time-to-event data and longitudinal data

Interval-censored failure time data are commonly observed in demographical, epi-demiological, financial, medical, and sociological studies. It is well-known that the proportional hazards model is one of the most used regression models for the anal-ysis of failure time data, and significant literature has been established for fitting it to interval-censored data. Many authors have discussed the problem when complete information on the covariates is available, or the missing is completely at random. Nevertheless, an established method for the situation where the missing is at random does not seem to exist. The first part of this dissertation discusses fitting the pro-portional hazards model to interval-censored failure time data when there may exist missing on covariates. A sieve maximum likelihood estimation approach is proposed with the use of I-splines to approximate the unknown cumulative baseline hazard function. For the implementation of the method, we develop an EM algorithm based on two-stage data augmentation. Furthermore, we show that the proposed estimators of regression parameters are consistent and asymptotically normal. Many authors have discussed the joint analysis of longitudinal data and time-to-event data, but most of the existing methods are the hazard-based approach for the failure time of interest. It is well-known that sometimes the mean residual life (MRL) model, which measures the remaining life expectancy, may be of more interest. To address this issue, the second and third parts of this dissertation consider an MRL-based method for the joint analysis, which gives a meaningful and informative alternative to the hazard-based approach. In the second part, we propose to utilize the proportional mean residual life (PMRL) function with latent random effect to jointly access the observed baseline prognostic factors and continuous longitudinal risk factor on the MRL function. The proposed method extends the conventional proportional mean residual model to accommodate a latent random effect that links the time to event with longitudinal measurement. For the parameter estimation, we propose an extended estimating equation approach. The simulation study shows that the performance of the proposed method is satisfactory. We then apply the proposed method to the ADNI study that reveals insights into critical factors that influence the progression time from MCI status to AD conversion. To further accommodate binary longitudinal outcome, in the third part, the pro-portional mean residual model and the generalized linear mixed model are employed to model the failure time of interest and the longitudinal variable, respectively. For estimation, a quasi-likelihood approach is developed with the use of Laplace approx-imation. A simulation study is conducted, and the proposed method is applied to a set of real data

A Review of the Antibacterial Activity of Chitosan and Its Application in Antibacterial Packaging

Chitosan can be used as an active antibacterial agent or film-forming substrate in foods, and has become a powerful substitute for synthetic plastic polymers because of its good biodegradability, film-forming capacity and antibacterial activity. However, chitosan films have several limitations such as poor water solubility and weak mechanical properties, which limit its application in antibacterial food packaging materials to a certain degree. The safety of applying the antibacterial activity of chitosan in foods has attracted much attention in recent years. In order to provide new ideas for further development and utilization of chitosan-based antibacterial composite materials, this paper expounds the antibacterial mechanism of chitosan and the methods to improve its antibacterial performance, and summarizes the current status of the application of chitosan-polysaccharide, protein or lipid composite films in food preservation

Salvianolic Acid A Attenuates Endoplasmic Reticulum Stress and Protects Against Cholestasis-Induced Liver Fibrosis via the SIRT1/HSF1 Pathway

Background: Endoplasmic reticulum stress (ER stress) plays a critical role in the pathogenesis of liver fibrosis; thus, it can be a potential therapeutic target of fibrosis. However, the mechanism of ER stress regulation in fibrosis, particularly through sirtuin 1 (SIRT1), remains unclear. The objective of this study was to investigate the effect of SIRT1-mediated inhibition of ER stress in bile duct ligation (BDL)-induced liver fibrosis, and to explore the effect of salvianolic acid A (SalA) on BDL-induced liver fibrosis through SIRT1/heat shock factor 1 (HSF1) signaling.Materials and Methods: We explored the effects of SalA on liver fibrosis and ER stress in BDL-induced liver fibrosis in rats and the human hepatic stellate cell line LX2 cells. The LX2 cells were treated with 20 ng of platelet-derived growth factor-BB homodimer (PDGF-BB) for 24 h, and then incubated in the absence or presence of SalA (25 μM) for 24 h.Results:In vivo, SalA treatment alleviated BDL-induced liver injury and ER stress. Importantly, SalA treatment increased HSF1 expression and activity using a SIRT1-dependent mechanism. In LX2 cells, PDGF-BB induced ER stress and fibrosis were blocked by HSF1 overexpression. Furthermore, SIRT1 siRNA abrogated the SalA-mediated promotion of HSF1 deacetylation and expression, suggesting that SalA-mediated protection occurs by SIRT1 targeting HSF1 for deacetylation.Conclusion: This is the first study to identify the SIRT1/HSF1 pathway as a key therapeutic target for controlling BDL-induced liver fibrosis and to show that SalA confers protection against BDL- and PDGF-BB-induced hepatic fibrosis and ER stress through SIRT1-mediated HSF1 deacetylation

Computerized electrocardiogram data transformation enables effective algorithmic differentiation of wide QRS complex tachycardias

BACKGROUND: Accurate automated wide QRS complex tachycardia (WCT) differentiation into ventricular tachycardia (VT) and supraventricular wide complex tachycardia (SWCT) can be accomplished using calculations derived from computerized electrocardiogram (ECG) data of paired WCT and baseline ECGs. OBJECTIVE: Develop and trial novel WCT differentiation approaches for patients with and without a corresponding baseline ECG. METHODS: We developed and trialed WCT differentiation models comprised of novel and previously described parameters derived from WCT and baseline ECG data. In Part 1, a derivation cohort was used to evaluate five different classification models: logistic regression (LR), artificial neural network (ANN), Random Forests [RF], support vector machine (SVM), and ensemble learning (EL). In Part 2, a separate validation cohort was used to prospectively evaluate the performance of two LR models using parameters generated from the WCT ECG alone (Solo Model) and paired WCT and baseline ECGs (Paired Model). RESULTS: Of the 421 patients of the derivation cohort (Part 1), a favorable area under the receiver operating characteristic curve (AUC) by all modeling subtypes: LR (0.96), ANN (0.96), RF (0.96), SVM (0.96), and EL (0.97). Of the 235 patients of the validation cohort (Part 2), the Solo Model and Paired Model achieved a favorable AUC for 103 patients with (Solo Model 0.87; Paired Model 0.95) and 132 patients without (Solo Model 0.84; Paired Model 0.95) a corroborating electrophysiology procedure or intracardiac device recording. CONCLUSION: Accurate WCT differentiation may be accomplished using computerized data of (i) the WCT ECG alone and (ii) paired WCT and baseline ECGs

The involvement of autophagy and cytoskeletal regulation in TDCIPP-induced SH-SY5Y cell differentiation

Exposure and toxicity to organophosphate-based flame retardants are an increasing health concern. Neurons appear to be particularly vulnerable to the effects of these chemicals. For example, in vitro studies have shown that tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) induces apoptosis and autophagy in neural cells. In the present study, we investigated the cell biological mechanisms of TDCIPP-induced neurotoxicity using undifferentiated human SH-SY5Y neuroblastoma cells as a model. Interestingly, TDCIPP treatment promoted differentiation in SH-SY5Y cells, which displayed various alterations including neurite elongation, an expansion of the numbers of neurite-bearing cells, and an increase in expression of cytoskeletal components normally enriched in neurons. Furthermore, the upregulation of microtubule-associated protein light chain 3, the degradation of p62/sequestosome 1, and the formation of autophagosomes occurred in treated cells, suggesting that TDCIPP exposure induces autophagy. However, pretreatment with the autophagy inhibitor 3-methyladenine suppressed TDCIPP-induced autophagy and reduced expression of the aforementioned cytoskeletal components. This correlated with a reduction in neurite outgrowth and numbers of neurite-bearing cells. Taken together, these results indicate that autophagy might promote TDCIPP-induced SH-SY5Y cell differentiation, which leads to an increase in expression of cytoskeletal components and neurite outgrowth. This study offers key insights into the mechanisms of neurotoxicity associated with this commonly used organophosphate. (C) 2017 Published by Elsevier B.V.</p

Tris (1, 3-dichloro-2-propyl) phosphate induces apoptosis and autophagy in SH-SY5Y cells: Involvement of ROS-mediated AMPK/mTOR/ULK1 pathways

Tris (1, 3-dichloro-2-propyl) phosphate (TDCIPP), an extensively used organophosphorus flame retardant, is frequently detected in the environment and biota. Recent studies have shown that TDCIPP has neurotoxic effects. We hypothesized that the neurotoxicity might occur via the induction of the apoptosis and autophagy pathways. In the present study, we investigated TDCIPP-induced apoptotic death and autophagy in SH-SY5Y cells. Treatment with TDCIPP induced increased reactive oxygen species (ROS) generation and cell apoptosis, as well as autophagy. The autophagy inhibitor 3-methyladenine (3-MA) markedly decreased the expression of the autophagy marker beclin-1, microtubule-associated protein light chain 3-II (LC310, p62/sequestosome 1 (SQSTM1) degradation, and promoted apoptosis. Conversely, the autophagy inducer rapamycin (Rapa) alleviated TDCIPP-induced apoptosis and markedly increased the expression of the autophagy markers. Pretreatment with N-acetyl cysteine (NAC) eliminated the increased ROS generation, resulting in increased cell viability. For further examination of the signaling pathways involved in TDCIPP-induced autophagy, compound C, a pharmacological inhibitor of adenosine monophosphate activated protein kinase (AMPK) was used. Western blotting showed that compound C markedly reduced the expression of phospho-AMPK (p-AMPK) and phospho Unc-51-like kinase 1 (p-ULK1), increased phospho mammalian target of rapamycin (p-mTOR) expression, and decreased beclin-1 and LC3II expression. These results suggested that the AMPK/mTOR/ULK1 signaling pathway was involved in TDCIPP-induced autophagy. The antioxidant NAC antagonized TDCIPP-induced activation of AMPK and autophagy. Taken together, our findings provide the first evidence that TDCIPP promotes apoptosis and autophagy simultaneously and that this process involves the ROS-mediated AlVIPK/mTOR/ULK1 pathways. Lastly, the induction of autophagy is a protective mechanism against TDCIPP-induced apoptosis. (C) 2016 Published by Elsevier Ltd.</p

Tris (1,3-dichloro-2-propyl) phosphate -induced apoptotic signaling pathways in SH-SY5Y neuroblastoma cells

Tris (1, 3-dichloro-2-propyl) phosphate (TDCIPP, also known as TDCPP), an extensively used flame retardant, is frequently detected in the environment and biota. Recent studies have shown that TDCIPP has neurotoxic effects. In this study, we determined the mechanisms of TDCIPP-induced neurotoxicity in human neuroblastoma (SH-SY5Y) cells. By using morphological examination, flow cytometry, and mitochondrial membrane potential (Delta Ym) measurement, we confirmed that exposure to TDCIPP caused apoptosis accompanied by the activation of apoptosis-related genes (e.g. Bax and Bc1-2) and caspase 3 protein in SH-SY5Y cells. Increased reactive oxygen species (ROS) formation and intracellular calcium ions ([Ca2+](i)) were also observed in TDCIPP-treated SH-SY5Y cells. Exposure to TDCIPP led to the activation of protein markers of endoplasmic reticulum (ER) stress, including eukaryotic translation initiation factor 2a subunit (p-EIF2a), activation transcription factor (ATF4), glucose-regulated protein (GRP78), and the proapoptotic factor C/EBP homologous protein (CHOP). To determine the role of the ER in apoptosis, phenyl butyric acid (PBA), an ER stress inhibitor, was applied. Treatment with PBA effectively attenuated TDCIPP-induced ER stress and protected against apoptotic death in SH-SY5Y cells by inhibition of Bax expression and promotion of Bcl-2 expression. Furthermore, we found that pretreatment of the cells with the ROS scavenger N-acetyl cysteine (NAC) inhibited the ER stress response and prevented apoptosis. The combination of PBA and NAC pretreatment could further prevent TDCIPP induced ER-stress and apoptotic death compared with PBA or NAC pretreatment alone. Thus, in the present study, we demonstrated that TDCIPP induces cytotoxicity through a ROS-dependent mechanism involving ER stress and activation of mitochondrial apoptotic pathways in SH-SY5Y cells. (C) 2016 Elsevier B.V. All rights reserved.</p