Suramin induces and enhances apoptosis in a model of hyperoxia-induced oligodendrocyte injury

Recent evidence suggests oxygen as a powerful trigger for cell death in the immature white matter, leading to periventricular leukomalacia (PVL) as a cause of adverse neurological outcome in survivors of preterm birth. This oligodendrocyte (OL) death is associated with oxidative stress, upregulation of apoptotic signaling factors (i.e., Fas, caspase-3) and decreased amounts of neurotrophins. In search of neuroprotective strategies we investigated whether the polysulfonated urea derivative suramin, recently identified as a potent inhibitor of Fas signaling, affords neuroprotection in an in vitro model of hyperoxia-induced injury to immature oligodendrocytes. Immature OLs (OLN-93) were subjected to 80% hyperoxia (48 h) in the presence or absence of suramin (0, 30, 60, 120 microM). Cell death was assessed by flow cytometry (Annexin V, caspase-3 activity assay) and immunohistochemistry for activated caspase-3. Immunoblotting for the death receptor Fas, cleaved caspase-8 and the phosphorylated isoform of the serine-threonin kinase Akt (pAkt) was performed. Suramin lead to OL apoptosis and potentiated hyperoxia-induced injury in a dose-dependent manner. Immunoblotting revealed increased Fas and caspase-8 expression by suramin treatment. This effect was significantly enhanced when suramin was combined with hyperoxia. Furthermore, pAkt levels decreased following suramin exposure, indicating interference with neurotrophin-dependent growth factor signaling. These data indicate that suramin causes apoptotic cell death and aggravates hyperoxia-induced cell death in immature OLs. Its mechanism of action includes an increase of previously described hyperoxia-induced expression of pro-apoptotic factors and deprivation of growth factor dependent signaling components.     

Two novel loci,COBL and SLC10A2, for Alzheimer's disease in African Americans

Introduction

African Americans' (AAs) late-onset Alzheimer's disease (LOAD) genetic risk profile is incompletely understood. Including clinical covariates in genetic analyses using informed conditioning might improve study power.

Gender-specific Differences in Clinicopathologic Outcomes Following Radical Cystectomy: An International Multi-institutional Study of More Than 8000 Patients

Background

The impact of gender on the staging and prognosis of urothelial carcinoma of the bladder (UCB) is insufficiently understood.

Objective

To assess gender-specific differences in pathologic factors and survival of UCB patients treated with radical cystectomy (RC).

Design, setting, and participants

Data from 8102 patients treated with RC (6497 men [80%] and 1605 women [20%]) for UCB between 1971 and 2012 were analyzed.

Outcome measurements and statistical analysis

Multivariable competing-risk regression analyses were performed to evaluate the relationship of gender on disease recurrence (DR) and cancer-specific mortality (CSM). We also tested the interaction of gender and tumor stage, nodal status, and lymphovascular invasion (LVI).

Results and limitations

Female patients were older at the time of RC (p = 0.033) and had higher rates of pathologic stage T3/T4 disease (p < 0.001). In univariable, but not in multivariable analysis, female gender was associated with a higher risk of DR (p = 0.022 and p = 0.11, respectively). Female gender was an independent predictor for CSM (p = 0.004). We did not find a significant interaction between gender and stage, nodal metastasis, or LVI (all p values >0.05).

Conclusions

We found female gender to be associated with a higher risk of CSM following RC. However, these findings do not appear to be explained by gender differences in pathologic stage, nodal status, or LVI. This gender disparity may be due to differences in care and/or the biology of UCB.     

Synaptic Plasticity in Mouse Models of Autism Spectrum Disorders

Analysis of synaptic plasticity together with behavioral and molecular studies have become a popular approach to model autism spectrum disorders in order to gain insight into the pathosphysiological mechanisms and to find therapeutic targets. Abnormalities of specific types of synaptic plasticity have been revealed in numerous genetically modified mice that have molecular construct validity to human autism spectrum disorders. Constrained by the feasibility of technique, the common regions analyzed in most studies are hippocampus and visual cortex. The relevance of the synaptic defects in these regions to the behavioral abnormalities of autistic like behaviors is still a subject of debate. Because the exact regions or circuits responsible for the core features of autistic behaviors in humans are still poorly understood, investigation using region-specific conditional mutant mice may help to provide the insight into the neuroanatomical basis of autism in the future.     

Genetic disruption of USP9X sensitizes colorectal cancer cells to 5-fluorouracil

The X-linked deubiquitinase USP9X affects the stability and activity of numerous regulatory proteins that influence cell survival. Recent studies suggest that decreased USP9X expression can confer a selective advantage onto developing cancer cells and thereby promotes disease progression. To examine the effect of USP9X on the cellular responses to anticancer therapies, we derived cancer cell lines in which the USP9X locus was disrupted by homologous recombination. The resulting USP9X-deficient cancer cells exhibited increased activation of apoptotic pathways and markedly decreased clonogenic survival in response to 5-fluorouracil, a chemotherapeutic drug that is widely used for treatment of gastrointestinal malignancies. These unexpected results suggest that cancers with low USP9X expression might be specifically sensitized to some conventional therapeutic agents.     

The Impact of Behavioral Intervention on Family Interactions at Mealtime in Pediatric Cystic Fibrosis

The current study evaluated the impact of a behavioral intervention (Be In Charge!), targeting caloric intake and weight gain in children with CF, on family interactions at mealtime. Forty-five families of children with cystic fibrosis (CF), ages 4 to 12 years, were randomized to Be In Charge! or nutrition education and assessed using the McMaster Mealtime Family Interaction Coding System. No differences were found in family functioning between the two interventions pre- to posttreatment or 1-year follow-up, except for Affect Management. A significantly greater percentage of families receiving Be In Charge! demonstrated improvement in Affect Management from pretreatment to 1-year follow-up. Implications for developing the next generation of behavioral interventions are discussed.     

The Influence of Parental Supervision on Medical Adherence in Adolescents With Cystic Fibrosis: Developmental Shifts From Pre to Late Adolescence

Previous research suggests that both parental supervision and adherence decrease in adolescence, as the drive for independence and autonomy emerge naturally during this developmental period. The current study evaluated relationships between patient-reported parental supervision and adherence in 103 preadolescents and adolescents with cystic fibrosis (CF). Activity patterns (medical and nonmedical) were measured using the daily phone diary (DPD) and adherence to nebulized medications was measured electronically. Age was strongly related to amount of supervision, with less supervision provided for older adolescents. Further, preadolescents and adolescents who spent more of their treatment time supervised by parents, particularly mothers, had better adherence.     

An Empirical Analysis of Indoor Tanners: Implications for Audience Segmentation in Campaigns

Tanning bed use before age 35 has been strongly associated with several types of skin cancer. The current study sought to advance an understanding of audience segmentation for indoor tanning among young women. Panhellenic sorority systems at two universities in the Southeastern United States participated in this study. A total of 1,481 young women took the survey; 421 (28%) had tanned indoors in the previous 12 months and were the focus of the analyses reported in this article. Results suggested two distinct tanner types: regular (n = 60) and irregular (n = 353) tanners. Regular tanners tanned more frequently (M = 36.2 vs. 8.6 times per year) and reported significantly higher positive outcome expectations (p < .001) and lower negative outcome expectations (p < .01) than irregular tanners, among other significant differences. Hierarchical logistic regression analysis revealed several significant (p < .001) predictors of regular tanning type, with tanning dependence emerging as the strongest predictor of this classification (OR = 2.25). Implications for developing anti-tanning messages directed at regular and irregular tanners are discussed.