Introduction: Novel Frontiers in Cancer Metastasis

Clinical & Experimental Metastasis -     

Respecting the circle of life: one year outcomes from a randomized controlled comparison of an HIV risk reduction intervention for American Indian adolescents

Potential for widespread transmission of HIV/AIDS among American Indian (AI) adolescents exists, yet no evidence-based interventions (EBIs) have been adapted and evaluated with this population. Intensive psychoeducation may improve knowledge and decision-making which could potentially translate to reductions in HIV risk behaviors. A peer group randomized controlled comparison of an adapted EBI vs. control was delivered over an eight-day summer basketball camp in one reservation-based tribal community to adolescents ages 13–19. Outcome data were gathered immediately post-camp and at 6 and 12 months follow-up. Self-selected peer groups were randomized to intervention (n = 138) or control (n = 129) conditions for a total sample of 267 participants (56.2% female), mean age 15.1 years (SD = 1.7). Intervention participants had better condom use self-efficacy post-camp (Adjusted Mean Difference [AMD] = ?0.75, p < 0.005) and at 6 (AMD = ?0.44, p < 0.005) and 12 months (AMD = ?0.23, p < 0.05) follow-up. Intervention participants also had higher HIV prevention and transmission knowledge (post-camp: AMD = 0.07, p < 0.01; 6 months: AMD = 0.06, p < 0.01) were more likely to believe condoms prevent sexually transmitted infections (post-camp: RR = 1.41, p < 0.005; 6 months: RR = 1.34, p < 0.05), to talk with an adult about HIV/AIDS (post-camp: RR=1.78, p < 0.005; 6 months: RR = 1.14, p < 0.005), had higher partner negotiation efficacy related to substance use during sex (post-camp: AMD = 0.37, p < 0.01), and were more likely to intend to use a condom (post-camp: RR = 1.39, p < 0.01). The adapted intervention had short- and medium-term impacts on AI adolescent risk for HIV/AIDS, but attenuated at 12 months. Intervention delivery through a community-based camp is feasible and acceptable with strong retention. Additional study is needed to evaluate the adapted intervention's impact on sexual risk behaviors and if booster sessions and parent involvement translate to long-term impacts.     

Lysophosphatidylcholine‐induced cytotoxicity and protection by heparin in mouse brain bEND.3 endothelial cells

A pathological feature in atherosclerosis is the dysfunction and death of vascular endothelial cells (EC). Oxidized low‐density lipoprotein (LDL), known to accumulate in the atherosclerotic arterial walls, impairs endothelium‐dependent relaxation and causes EC apoptosis. A major bioactive ingredient of the oxidized LDL is lysophosphatidylcholine (LPC), which at higher concentrations causes apoptosis and necrosis in various EC. There is hitherto no report on LPC‐induced cytotoxicity in brain EC. In this work, we found that LPC caused cytosolic Ca²⁺ overload, mitochondrial membrane potential decrease, p38 activation, caspase 3 activation and eventually apoptotic death in mouse cerebral bEND.3 EC. In contrast to reported reactive oxygen species (ROS) generation by LPC in other EC, LPC did not trigger ROS formation in bEND.3 cells. Pharmacological inhibition of p38 alleviated LPC‐inflicted cell death. We examined whether heparin could be cytoprotective: although it could not suppress LPC‐triggered Ca²⁺ signal, p38 activation and mitochondrial membrane potential drop, it did suppress LPC‐induced caspase 3 activation and alleviate LPC‐inflicted cytotoxicity. Our data suggest LPC apoptotic death mechanisms in bEND.3 might involve mitochondrial membrane potential decrease and p38 activation. Heparin is protective against LPC cytotoxicity and might intervene steps between mitochondrial membrane potential drop/p38 activation and caspase 3 activation.     

Natural Variant of Collagen-Like Protein A in Serotype M3 Group A Streptococcus Increases Adherence and Decreases Invasive Potential

Group A Streptococcus (GAS) predominantly exists as a colonizer of the human oropharynx that occasionally breaches epithelial barriers to cause invasive diseases. Despite the frequency of GAS carriage, few investigations into the contributory molecular mechanisms exist. To this end, we identified a naturally occurring polymorphism in the gene encoding the streptococcal collagen-like protein A (SclA) in GAS carrier strains. All previously sequenced invasive serotype M3 GAS possess a premature stop codon in the sclA gene truncating the protein. The carrier polymorphism is predicted to restore SclA function and was infrequently identified by targeted DNA sequencing in invasive strains of the same serotype. We demonstrate that a strain with the carrier sclA allele expressed a full-length SclA protein, while the strain with the invasive sclA allele expressed a truncated variant. An isoallelic mutant invasive strain with the carrier sclA allele exhibited decreased virulence in a mouse model of invasive disease and decreased multiplication in human blood. Further, the isoallelic invasive strain with the carrier sclA allele persisted in the mouse nasopharynx and had increased adherence to cultured epithelial cells. Repair of the premature stop codon in the invasive sclA allele restored the ability to bind the extracellular matrix proteins laminin and cellular fibronectin. These data demonstrate that a mutation in GAS carrier strains increases adherence and decreases virulence and suggest selection against increased adherence in GAS invasive isolates.     

Respiratory muscle dysfunction in facioscapulohumeral muscular dystrophy

Sleep and Breathing -