Additional benefit of combined therapy with melatonin and apoptotic adipose‐derived mesenchymal stem cell against sepsis‐induced kidney injury

This study tested whether combined therapy with melatonin and apoptotic adipose‐derived mesenchymal stem cells (A‐ADMSCs) offered additional benefit in ameliorating sepsis‐induced acute kidney injury. Adult male Sprague–Dawley rats (n = 65) were randomized equally into five groups: Sham controls (SC), sepsis induced by cecal‐ligation and puncture (CLP), CLP‐melatonin, CLP‐A‐ADMSC, and CLP‐melatonin‐A‐ADMSC. Circulating TNF‐α level at post‐CLP 6 hr was highest in CLP and lowest in SC groups, higher in CLP‐melatonin than in CLP‐A‐ADMSC and CLP‐melatonin‐A‐ADMSC groups (all P < 0.001). Immune reactivity as reflected in the number of splenic helper‐, cytoxic‐, and regulatory‐T cells at post‐CLP 72 hr exhibited the same pattern as that of circulating TNF‐α among all groups (P < 0.001). The histological scoring of kidney injury and the number of F4/80+ and CD14+ cells in kidney were highest in CLP and lowest in SC groups, higher in CLP‐melatonin than in CLP‐A‐ADMSC and CLP‐melatonin‐A‐ADMSC groups, and higher in CLP‐A‐ADMSC than in CLP‐melatonin‐A‐ADMSC groups (all P < 0.001). Changes in protein expressions of inflammatory (RANTES, TNF‐1α, NF‐κB, MMP‐9, MIP‐1, IL‐1β), apoptotic (cleaved caspase 3 and PARP, mitochondrial Bax), fibrotic (Smad3, TGF‐β) markers, reactive‐oxygen‐species (NOX‐1, NOX‐2), and oxidative stress displayed a pattern identical to that of kidney injury score among the five groups (all P < 0.001). Expressions of antioxidants (GR+, GPx+, HO‐1, NQO‐1+) were lowest in SC group and highest in CLP‐melatonin‐A‐ADMSC group, lower in CLP than in CLP‐melatonin and CLP‐A‐ADMSC groups, and lower in CLP‐melatonin‐ than in CLP‐A‐ADMSC‐tretaed animals (all P < 0.001). In conclusion, combined treatment with melatonin and A‐ADMSC was superior to A‐ADMSC alone in protecting the kidneys from sepsis‐induced injury.     

A Novel Bayesian Method for Efficacy Assessment in Animal Oncology Studies

In pre-clinical oncology studies, the investigator often compares efficacy of two or more treatments on tumor-bearing animals over a period of time. This is accomplished either through comparison of tumor volumes at various time points or overall survival. Due to ethical concerns, animals are euthanized before the end of the study whenever their tumor volumes reach a prespecified limit, the loss of bodyweight is beyond 20% or severely ulcerated tumors are observed. The traditional cross time-point tumor-size comparisons should not be performed when animals leave the study in a nonrandom nature. Survival analysis may alternatively be carried out to compare the time-to-euthanasia or natural death across treatment groups. As a result of government regulations, however, animal survival studies are hampered by small-sample sizes, often making statistical inference of survival data difficult. For example, it may be impossible to estimate median survival for an efficacious treatment group in which the majority of animals survive to the end of the study. Such cases create challenges to investigators who wish to rank-order the treatment effects, in effect picking the “winners” for further investigation. In this aricle, we list the benefits and shortcomings of popular methods and then propose a novel hypothesis test based directly on the survival probability to rank order the efficacy of treatments. The performance of the method is illustrated using a real-life example.