Animal Models of Barrett's Esophagus and Esophageal Adenocarcinoma–Past,Present, and Future

Esophageal adenocarcinoma is the fastest rising cancer in the United States. It develops from long‐standing gastroesophageal reflux disease which affects >20% of the general population. It carries a very poor prognosis with 5‐year survival <20%. The disease is known to sequentially progress from reflux esophagitis to a metaplastic precursor, Barrett''s esophagus and then onto dysplasia and esophageal adenocarcinoma. However, only few patients with reflux develop Barrett''s esophagus and only a minority of these turn malignant. The reason for this heterogeneity in clinical progression is unknown. To improve patient management, molecular changes which facilitate disease progression must be identified. Animal models can provide a comprehensive functional and anatomic platform for such a study. Rats and mice have been the most widely studied but disease homology with humans has been questioned. No animal model naturally simulates the inflammation to adenocarcinoma progression as in humans, with all models requiring surgical bypass or destruction of existing antireflux mechanisms. Valuable properties of individual models could be utilized to holistically evaluate disease progression. In this review paper, we critically examined the current animal models of Barrett''s esophagus, their differences and homologies with human disease and how they have shaped our current understanding of Barrett''s carcinogenesis.     

Neutralization of Mitochondrial Superoxide by Superoxide Dismutase 2 Promotes Bacterial Clearance and Regulates Phagocyte Numbers in Zebrafish

Mitochondria are known primarily as the location of the electron transport chain and energy production in cells. More recently, mitochondria have been shown to be signaling centers for apoptosis and inflammation. Reactive oxygen species (ROS) generated as by-products of the electron transport chain within mitochondria significantly impact cellular signaling pathways. Because of the toxic nature of ROS, mitochondria possess an antioxidant enzyme, superoxide dismutase 2 (SOD2), to neutralize ROS. If mitochondrial antioxidant enzymes are overwhelmed during severe infections, mitochondrial dysfunction can occur and lead to multiorgan failure or death. Pseudomonas aeruginosa is an opportunistic pathogen that can infect immunocompromised patients. Infochemicals and exotoxins associated with P. aeruginosa are capable of causing mitochondrial dysfunction. In this work, we describe the roles of SOD2 and mitochondrial ROS regulation in the zebrafish innate immune response to P. aeruginosa infection. sod2 is upregulated in mammalian macrophages and neutrophils in response to lipopolysaccharide in vitro, and sod2 knockdown in zebrafish results in an increased bacterial burden. Further investigation revealed that phagocyte numbers are compromised in Sod2-deficient zebrafish. Addition of the mitochondrion-targeted ROS-scavenging chemical MitoTEMPO rescues neutrophil numbers and reduces the bacterial burden in Sod2-deficient zebrafish. Our work highlights the importance of mitochondrial ROS regulation by SOD2 in the context of innate immunity and supports the use of mitochondrion-targeted ROS scavengers as potential adjuvant therapies during severe infections.     

Stitching the fabric back together: child fostering attitudes in the transition to a chronic HIV epidemic

There are an estimated 56 million orphans and vulnerable children across sub-Saharan Africa. Communities typically care for orphan children through informal caring arrangements – either within or outside of kinship networks. Within Kenya, an estimated 250,000 children live on the streets. There is less research related to fostering attitudes of this special population than orphans and vulnerable children generally. Important research over the past decade has illuminated multiple ways in which children are made more vulnerable because of HIV, including parental death and street-migration from HIV-affected households. As HIV transitions from a terminal illness to a chronic, manageable one, research is also required to establish how parents living with HIV can be an asset to children. In this study, we assess whether mothers living with HIV were very willing to foster biologically-related children, and street-involved children, how these fostering attitudes differed from mothers not living with HIV, and whether differences in fostering attitudes by reported HIV status were mediated by social support, family functioning and general self-rated health. Approximately 40% of mothers living with HIV were very willing to provide long-term foster care to biologically-related or street-involved children. This was less than the percentage of mothers not living with HIV, who were very willing to foster biologically-related children (61%) or street-involved children (58%). Significant portions of these differences were explained by social support, family functioning and general self-rated health. Multi-sectoral approaches are suggested by these findings in order to improve the child-fostering capacity of mothers living with HIV. Improving social support, family functioning and general self-rated health among HIV-infected mothers may not only provide protective benefits for the mothers and their children, but also expand the community’s capacity to care for orphan and vulnerable children.