Retinal vascular biomarkers for early detection and monitoring of Alzheimer’s disease

The earliest detectable change in Alzheimer’s disease (AD) is the buildup of amyloid plaque in the brain. Early detection of AD, prior to irreversible neurological damage, is important for the efficacy of current interventions as well as for the development of new treatments. Although PiB-PET imaging and CSF amyloid are the gold standards for early AD diagnosis, there are practical limitations for population screening. AD-related pathology occurs primarily in the brain, but some of the hallmarks of the disease have also been shown to occur in other tissues, including the retina, which is more accessible for imaging. Retinal vascular changes and degeneration have previously been reported in AD using optical coherence tomography and laser Doppler techniques. This report presents results from analysis of retinal photographs from AD and healthy control participants from the Australian Imaging, Biomarkers and Lifestyle (AIBL) Flagship Study of Ageing. This is the first study to investigate retinal blood vessel changes with respect to amyloid plaque burden in the brain. We demonstrate relationships between retinal vascular parameters, neocortical brain amyloid plaque burden and AD. A number of RVPs were found to be different in AD. Two of these RVPs, venular branching asymmetry factor and arteriolar length-to-diameter ratio, were also higher in healthy individuals with high plaque burden (P=0.01 and P=0.02 respectively, after false discovery rate adjustment). Retinal photographic analysis shows potential as an adjunct for early detection of AD or monitoring of AD-progression or response to treatments

Loss of PTEN stabilizes the lipid modifying enzyme cytosolic phospholipase A<inf>2</inf>a via AKT in prostate cancer cells

Aberrant increase in pAKT, due to a gain-of-function mutation of PI3K or lossof- function mutation or deletion of PTEN, occurs in prostate cancer and is associated with poor patient prognosis. Cytosolic phospholipase A2a (cPLA2a) is a lipid modifying enzyme by catalyzing the hydrolysis of membrane arachidonic acid. Arachidonic acid and its metabolites contribute to survival and proliferation of prostate cancer cells. We examined whether AKT plays a role in promoting cPLA2a action in prostate cancer cells. We found a concordant increase in pAKT and cPLA2a levels in prostate tissue of prostate epithelial-specific PTEN-knockout but not PTEN-wide type mice. Restoration of PTEN expression or inhibition of PI3K action decreased cPLA2a expression in PTENmutated or deleted prostate cancer cells. An increase in AKT by Myr-AKT elevated cPLA2a protein levels, which could be diminished by inhibition of AKT phosphorylation without noticeable change in total AKT levels. pAKT levels had no influence on cPLA2a at mRNA levels but reduced cPLA2a protein degradation. Anti-AKT antibody coimmunoprecipitated cPLA2a and vice versa. Hence, AKT plays a role in enhancing cPLA2a protein stability in PTEN-null prostate cancer cells, revealing a link between oncogenic pathway and lipid metabolism

The histone chaperone complex FACT promotes proliferative switch of G<inf>0</inf> cancer cells

© 2018 UICC Cancer cell repopulation through cell cycle re-entry by quiescent (G0) cell is thought to be an important mechanism behind treatment failure and cancer recurrence. Facilitates Chromatin Transcription (FACT) is involved in DNA repair, replication and transcription by eviction of histones or loosening their contact with DNA. While FACT expression is known to be high in a range of cancers, the biological significance of the aberrant increase is not clear. We found that in prostate and lung cancer cells FACT mRNA and protein levels were low at G0 compared to the proliferating state but replenished upon cell cycle re-entry. Silencing of FACT with Dox-inducible shRNA hindered cell cycle re-entry by G0 cancer cells, which could be rescued by ectopic expression of FACT. An increase in SKP2, c-MYC and PIRH2 and a decrease in p27 protein levels seen upon cell cycle re-entry were prevented or diminished when FACT was silenced. Further, using mVenus-p27K− infected cancer cells to measure p27 degradation capacity, we confirm that inhibition of FACT at release from quiescence suppressed the p27 degradation capacity resulting in an increased mVenus-p27K− signal. In conclusion, FACT plays an important role in promoting the transition from G0 to the proliferative state and can be a potential therapeutic target to prevent prostate and lung cancer from progression and recurrence