Multiple existing studies have developed multivariate growth models with nonlinear functional forms to explore joint development where two longitudinal records are associated over time. However, multiple repeated outcomes are not necessarily synchronous. Accordingly, it is of interest to investigate an association between two repeated variables on different occasions, for example, how a short-term change of one variable affects a long-term change of the other(s). One statistical tool for such analyses is longitudinal mediation models. In this study, we extend latent growth mediation models with linear trajectories (Cheong et al., 2003) and develop two models to evaluate mediational processes where the bilinear spline (i.e., the linear-linear piecewise) growth model is utilized to capture the change patterns. We define the mediational process as either the baseline covariate or the change of covariate influencing the change of the mediator, which, in turn, affects the change of the outcome. We present the proposed models by simulation studies. Our simulation studies demonstrate that the proposed mediational models can provide unbiased and accurate point estimates with target coverage probabilities with a 95% confidence interval. To illustrate modeling procedures, we analyze empirical longitudinal records of multiple disciplinary subjects, including reading, mathematics, and science test scores, from Grade K to Grade 5. The empirical analyses demonstrate that the proposed model can estimate covariates' direct and indirect effects on the change of the outcome. Through the real-world data analyses, we also provide a set of feasible recommendations for empirical researchers. We also provide the corresponding code for the proposed models.

Background: In the CASPIAN trial, durvalumab + chemotherapy demonstrated significant improvements in overall survival compared with chemotherapy alone in patients with extensive-stage small cell lung cancer (SCLC). We aimed to assess the cost-effectiveness of durvalumab in patients with extensive-stage SCLC from the US healthcare system perspective. Patients and Methods: A comprehensive Markov model was adapted to evaluate cost and effectiveness of durvalumab combination versus platinum/etoposide alone in the first-line therapy of extensive-stage SCLC based on data from the CASPIAN study. The main endpoints included total costs, life years (LYs), quality-adjusted life-years (QALYs), and incremental cost-e-ectiveness ratios (ICERs). Model robustness was assessed with sensitivity analysis, and additional subgroup analyses were also performed. Results: Durvalumab + chemotherapy therapy resulted in an additional 0.27 LYs and 0.20 QALYs, resulting in an ICER of $464,711.90 per QALY versus the chemotherapy treatment. The cost of durvalumab has the greatest influence on this model. Subgroup analyses showed that the ICER remained higher than $150,000/QALY (the willingness-to-pay threshold in the United States) across all patient subgroups. Conclusions: Durvalumab in combination with platinum/etoposide is not a cost-effective option in the first-line treatment of patients with extensive-stage SCLC.

This study proposes transformation functions and matrices between coefficients in the original and reparameterized parameter spaces for an existing linear-linear piecewise model to derive the interpretable coefficients directly related to the underlying change pattern. Additionally, the study extends the existing model to allow individual measurement occasions and investigates predictors for individual differences in change patterns. We present the proposed methods with simulation studies and a real-world data analysis. Our simulation study demonstrates that the method can generally provide an unbiased and accurate point estimate and appropriate confidence interval coverage for each parameter. The empirical analysis shows that the model can estimate the growth factor coefficients and path coefficients directly related to the underlying developmental process, thereby providing meaningful interpretation.

Studies have shown that 2,5-hexanedione (2,5-HD) is the main active metabolite of n-hexane in the human body. The toxicity of n-hexane and 2,5-hexanedione has been extensively researched, but toxicity to the reproductive system, especially the impact on female reproductive function, has been less frequently reported. In this study, we exposed human ovarian granulosa cells to 0, 16, 64, and 256 μM 2,5-HD in vitro for 24 h. Through hematoxylin-eosin (HE) staining, Hoechst 33342 staining, transmission electron microscopy, and flow cytometry using FITC-Annexin V/PI double staining, 2,5-HD was demonstrated to cause significant apoptosis of human ovarian granulosa cells in a dose-dependent manner. As part of our continuing studies, we investigated the underlying apoptosis mechanism of human ovarian granulosa cells exposed to 0, 16, 64, and 256 μM 2,5-HD in vitro for 24 h. Real-time quantitative PCR and Western blot analysis were used to detect changes in the expression of the apoptosis-related BCL-2 family (BCL-2, BAX) and CASPASE family (CASPASE-3) with increasing 2,5-HD concentration. The results showed that with increasing 2,5-HD doses, the expression of BCL-2 decreased. However, a marked dose-dependent increase in the expression of BAX and active CASPASE-3 (p17) was observed in human ovarian granulosa cells. These results suggest that the mechanisms of 2,5-HD causing increased apoptosis in human ovarian granulosa cells might be through BCL-2, BAX, and CASPASE-3 signaling pathways.

The two major theories of glucocorticoid (GC)-induced osteonecrosis of the femoral head (ONFH) are apoptosis and ischaemia. The traditional theory implicates ischaemia as the main aetiological factor because the final common pathway of ONFH is interruption of blood supply to the bone. The most common causes of interruption of blood supply include fat embolism and coagulation disorders. GCs can directly or indirectly lead to coagulation disorders, producing a hypercoagulable state, followed by poor blood flow, ischaemia, and eventually ONFH. This review summarizes the existing knowledge on coagulation disorders in the context of GC-induced ONFH, including hypofibrinolysis and thrombophilia, endothelial cell dysfunction and damage, endothelial cell apoptosis, lipid metabolism, platelet activation, and the effect of anticoagulant treatment.

Formyl peptide receptors (FPRs) are G protein-coupled chemoattractant receptors expressed mainly in phagocytic leukocytes. High expression of FPRs has also been detected in several cancers but the functions of FPR1 in tumor invasion and metastasis is poorly understood. In this study, we investigated the expression of FPRs in primary human colorectal cancer (CRC) and analyzed the association of FPRs expression with clinicopathological parameters. The levels of FPRs mRNA, especially those of FPR1, were significantly higher in colorectal tumors than in distant normal tissues and adjacent non-tumor tissues. FPR1 mRNA expression was also associated with tumor serosal infiltration. FPR1 protein expression was both in the colorectal epitheliums and tumor infiltrating neutrophils/macrophages. Furthermore, the functions of FPR1 in tumor invasion and tissue repair were investigated using the CRC cell lines SW480 and HT29. Higher cell surface expression of FPR1 is associated with significantly increased migration in SW480 cells compared with HT29 cells that have less FPR1 membrane expression. Finally, genetic deletion of fpr1 increased the survival rate of the resulting knockout mice compared with wild type littermates in a mouse model of colitis-associated colorectal cancer. Our data demonstrate that FPR1 may play an important role in tumor cell invasion in CRC patients.

Methylation occurs commonly in UTUCs, may affect carcinogenic mechanisms, and is a well predictive factor for cancer-specific survival and bladder recurrence in UTUCs.

The mammalian target of rapamycin, mTOR, is a serine-threonine protein kinase downstream of the phosphatidylinositol 3-kinase (PI3K)-AKT axis. The pathway can regulate cell growth, proliferation, and survival by activating ribosomal kinases. Recent studies have implicated the mTOR signaling pathway in ovarian neoplasms, polycystic ovary syndrome (PCOS) and premature ovarian failure (POF). Preclinical investigations have demonstrated that the PI3K/AKT/mTOR pathway is frequently activated in the control of various ovarian functions. mTOR allows cancer cells to escape the normal biochemical system and regulates the balance between apoptosis and survival. Some recent studies have suggested that involvement of the mTOR signaling system is an important pathophysiological basis of PCOS. Overexpression of the mTOR pathway can impair the interaction of cumulus cells, lead to insulin resistance, and affect the growth of follicles directly. The roles of mTOR signaling in follicular development have been extensively studied in recent years; abnormalities in this process lead to a series of pathologies such as POF and infertility. To improve understanding of the role of the mTOR signaling pathway in the pathogenesis and development of ovarian diseases, here we review the roles of mTOR signaling in such diseases and discuss the corresponding therapeutic strategies that target this pathway. Clin. Anat. 31:891-898, 2018. © 2018 Wiley Periodicals, Inc.