Differential Effects of Pravastatin and Simvastatin on the Growth of Tumor Cells from Different Organ Sites

3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) inhibitors, commonly known as statins, may possess cancer preventive and therapeutic properties. Statins are effective suppressors of cholesterol synthesis with a well-established risk-benefit ratio in cardiovascular disease prevention. Mechanistically, targeting HMGCR activity primarily influences cholesterol biosynthesis and prenylation of signaling proteins. Pravastatin is a hydrophilic statin that is selectively taken up by a sodium-independent organic anion transporter protein-1B1 (OATP1B1) exclusively expressed in liver. Simvastatin is a hydrophobic statin that enters cells by other mechanisms. Poorly-differentiated and well-differentiated cancer cell lines were selected from various tissues and examined for their response to these two statins. Simvastatin inhibited the growth of most tumor cell lines more effectively than pravastatin in a dose dependent manner. Poorly-differentiated cancer cells were generally more responsive to simvastatin than well-differentiated cancer cells, and the levels of HMGCR expression did not consistently correlate with response to statin treatment. Pravastatin had a significant effect on normal hepatocytes due to facilitated uptake and a lesser effect on prostate PC3 and colon Caco-2 cancer cells since the OATP1B1 mRNA and protein were only found in the normal liver and hepatocytes. The inhibition of cell growth was accompanied by distinct alterations in mitochondrial networks and dramatic changes in cellular morphology related to cofilin regulation and loss of p-caveolin. Both statins, hydrophilic pravastatin and hypdrophobic simvastatin caused redistribution of OATP1B1 and HMGCR to perinuclear sites. In conclusion, the specific chemical properties of different classes of statins dictate mechanistic properties which may be relevant when evaluating biological responses to statins

TRAF4 is a novel phosphoinositide-binding protein modulating tight junctions and favoring cell migration

Tumor necrosis factor (TNF) receptor-associated factor 4 (TRAF4) is frequently overexpressed in carcinomas, suggesting a specific role in cancer. Although TRAF4 protein is predominantly found at tight junctions (TJs) in normal mammary epithelial cells (MECs), it accumulates in the cytoplasm of malignant MECs. How TRAF4 is recruited and functions at TJs is unclear. Here we show that TRAF4 possesses a novel phosphoinositide (PIP)-binding domain crucial for its recruitment to TJs. Of interest, this property is shared by the other members of the TRAF protein family. Indeed, the TRAF domain of all TRAF proteins (TRAF1 to TRAF6) is a bona fide PIP-binding domain. Molecular and structural analyses revealed that the TRAF domain of TRAF4 exists as a trimer that binds up to three lipids using basic residues exposed at its surface. Cellular studies indicated that TRAF4 acts as a negative regulator of TJ and increases cell migration. These functions are dependent from its ability to interact with PIPs. Our results suggest that TRAF4 overexpression might contribute to breast cancer progression by destabilizing TJs and favoring cell migration

Behavioral Sleep Intervention for Adolescents with Autism Spectrum Disorder: a Pilot Study

Objectives Sleep disturbances are a significant problem for individuals with autism spectrum disorder (ASD) across the lifespan; however, there is a paucity of research examining effective sleep interventions for adolescents with ASD. Although research has demonstrated individuals with ASD can be meaningfully engaged in their own intervention process, such engagement has not appeared in previous studies targeting sleep in adolescents with ASD. Methods This study investigated the feasibility of including pre-adolescents and adolescents (ages 9 to 14 years) with ASD as active intervention agents within comprehensive, individualized treatments for sleep problems. Participants had a range of intellectual functioning but all produced spoken language. Outcomes were evaluated using single-case designs. Results Data suggest intervention was effective in eliminating sleep disturbance for all participants. Improvements were maintained during 18- to 24-month follow-up. All three participants and their parents indicated a high degree of treatment satisfaction. Conclusions Findings illustrate the feasibility and potential benefit of including adolescents with ASD in the process of developing and implementing individualized behavioral interventions for sleep problems

Critical threshold size for overwintering sandeels (Ammodytes marinus)

Several ecologically and commercially important fish species spend the winter in a state of minimum feeding activity and at lower risk of predation. To enable this overwintering behaviour, energetic reserves are generated prior to winter to support winter metabolism. Maintenance metabolism in fish scales with body size and increases with temperature, and the two factors together determine a critical threshold size for passive overwintering below which the organism is unlikely to survive without feeding. This is because the energetic cost of metabolism exceeds maximum energy reserves. In the present study, we estimated the energetic cost of overwintering from a bioenergetic model. The model was parameterised using respirometry-based measurements of standard metabolic rate in buried A. tobianus (a close relative to A. marinus) at temperatures from 5.3 to 18.3 degrees C and validated with two independent long-term overwintering experiments. Maximum attainable energy reserves were estimated from published data on A. marinus in the North Sea. The critical threshold size in terms of length (L(th)) for A. marinus in the North Sea was estimated to be 9.5 cm. We then investigated two general predictions: (1) Fish smaller than L(th) display winter feeding activity, and (2) size at maturation of iteroparous species is larger than L(th) to ensure sufficient energy reserves to accommodate both the metabolic cost of passive overwintering and reproductive investments. Both predictions were found to be consistent with data on size at maturation and total body energy in December and February

EGF stimulates annexin 1-dependent inward vesiculation in a multivesicular endosome subpopulation

Here we show that EGF and EGF receptor (EGFR) are trafficked through a subpopulation of multivesicular endosomes/bodies (MVBs) that are distinct from morphologically identical vacuoles that label for the late endosomal marker lyso-bisphosphatidic acid (LBPA). EGF stimulation increases both MVB biogenesis and inward vesiculation within EGFR-containing MVBs. Deletion of annexin 1, a substrate of EGFR tyrosine kinase, abolishes the effect of EGF stimulation on inward vesiculation. This phenotype is reversible by transfection with wild-type but not Y21F phosphorylation mutant annexin 1. Deletion of annexin 1 has no effect on EGF-stimulated MVB biogenesis, suggesting that MVB biogenesis and inward vesiculation within MVB are mediated by separate mechanisms. Loss or depletion of annexin 1 has no effect on EGF degradation and causes only a small delay in EGFR degradation, indicating that annexin 1 operates downstream of Hrs- and ESCRT-mediated sorting and is required solely for EGF-stimulated inward vesiculation. Annexin 1 accumulates on internal vesicles of MVB after EGF-stimulated inward vesiculation, suggesting that it may be required for a late stage in inward vesiculation