SignificancePhotoreceptor cell death resulting from retinal detachment (RD) causes significant visual loss. While the immune system is activated during RD, its role is still unclear. Microglia are resident immune cells in the retina and are thought to be either protective or deleterious in response to neuronal injury, suggesting context-dependent effects. Here, we demonstrate that microglia limit retinal damage during acute injury, since microglial ablation led to increased photoreceptor death. Microglial morphological–activation changes triggered their migration into injured tissue where they formed intimate connections with infiltrating immune cells and phagocytized injured photoreceptors. These findings provide insight into the microglial response and function during RD, indicating microglia promote photoreceptor survival during acute phase injury by removing potentially damaging cell debris.

Calcium/calmodulin-stimulated protein kinase II (CaMKII) is a multi-functional kinase that controls a range of cellular functions, including proliferation, differentiation and apoptosis. The biological properties of CaMKII are regulated by multi-site phosphorylation. However, the role that CaMKII phosphorylation plays in cancer cell metastasis has not been examined. We demonstrate herein that CaMKII expression and phosphorylation at T286 is increased in breast cancer when compared to normal breast tissue, and that increased CAMK2 mRNA is associated with poor breast cancer patient prognosis (worse overall and distant metastasis free survival). Additionally, we show that overexpression of WT, T286D and T286V forms of CaMKII in MDA-MB-231 and MCF-7 breast cancer cells increases invasion, migration and anchorage independent growth, and that overexpression of the T286D phosphomimic leads to a further increase in the invasive, migratory and anchorage independent growth capacity of these cells. Pharmacological inhibition of CaMKII decreases MDA-MB-231 migration and invasion. Furthermore, we demonstrate that overexpression of T286D, but not WT or T286V-CaMKII, leads to phosphorylation of FAK, STAT5a, and Akt. These results demonstrate a novel function for phosphorylation of CaMKII at T286 in the control of breast cancer metastasis, offering a promising target for the development of therapeutics to prevent breast cancer metastasis.

BackgroundPeroxisome proliferator activated receptor-alpha (PPARα) is a ubiquitously expressed nuclear receptor. The role of endogenous PPARα in retinal neuronal homeostasis is unknown. Retinal photoreceptors are the highest energy-consuming cells in the body, requiring abundant energy substrates. PPARα is a known regulator of lipid metabolism, and we hypothesized that it may regulate lipid use for oxidative phosphorylation in energetically demanding retinal neurons.ResultsWe found that endogenous PPARα is essential for the maintenance and survival of retinal neurons, with Pparα -/- mice developing retinal degeneration first detected at 8 weeks of age. Using extracellular flux analysis, we identified that PPARα mediates retinal utilization of lipids as an energy substrate, and that ablation of PPARα ultimately results in retinal bioenergetic deficiency and neurodegeneration. This may be due to PPARα regulation of lipid transporters, which facilitate the internalization of fatty acids into cell membranes and mitochondria for oxidation and ATP production.ConclusionWe identify an endogenous role for PPARα in retinal neuronal survival and lipid metabolism, and furthermore underscore the importance of fatty acid oxidation in photoreceptor survival. We also suggest PPARα as a putative therapeutic target for age-related macular degeneration, which may be due in part to decreased mitochondrial efficiency and subsequent energetic deficits.Electronic supplementary materialThe online version of this article (doi:10.1186/s12915-017-0451-x) contains supplementary material, which is available to authorized users.

Diabetic retinopathy (DR) is a common neurovascular complication of type 1 diabetes. Current therapeutics target neovascularization characteristic of end-stage disease, but are associated with significant adverse effects. Targeting early events of DR such as neurodegeneration may lead to safer and more effective approaches to treatment. Two independent prospective clinical trials unexpectedly identified that the PPARα agonist fenofibrate had unprecedented therapeutic effects in DR, but gave little insight into the physiological and molecular mechanisms of action. The objective of the present study was to evaluate potential neuroprotective effects of PPARα in DR, and subsequently to identify the responsible mechanism of action. Here we reveal that activation of PPARα had a robust protective effect on retinal function as shown by Optokinetic tracking in a rat model of type 1 diabetes, and also decreased retinal cell death, as demonstrated by a DNA fragmentation ELISA. Further, PPARα ablation exacerbated diabetes-induced decline of visual function as demonstrated by ERG analysis. We further found that PPARα improved mitochondrial efficiency in DR, and decreased ROS production and cell death in cultured retinal neurons. Oxidative stress biomarkers were elevated in diabetic Pparα-/- mice, suggesting increased oxidative stress. Mitochondrially mediated apoptosis and oxidative stress secondary to mitochondrial dysfunction contribute to neurodegeneration in DR. Taken together, these findings identify a robust neuroprotective effect for PPARα in DR, which may be due to improved mitochondrial function and subsequent alleviation of energetic deficits, oxidative stress and mitochondrially mediated apoptosis.

This review highlights that abnormalities in DNA repair mechanisms in AML cells are potential novel treatment targets for AML patients with disease that is resistant to current therapies.

Microglial activation and subsequent pathological neuroinflammation contribute to diabetic retinopathy (DR). However, the underlying mechanisms of microgliosis, and means to effectively suppress pathological microgliosis, remain incompletely understood. Peroxisome proliferator-activated receptor alpha (PPARα) is a transcription factor that regulates lipid metabolism. The present study aimed to determine if PPARα affects pathological microgliosis in DR. In global Pparα mice, retinal microglia exhibited decreased structural complexity and enlarged cell bodies, suggesting microglial activation. Microglia-specific conditional Pparα−/− (PCKO) mice showed decreased retinal thickness as revealed by optical coherence tomography. Under streptozotocin (STZ)-induced diabetes, diabetic PCKO mice exhibited decreased electroretinography response, while diabetes-induced retinal dysfunction was alleviated in diabetic microglia-specific Pparα-transgenic (PCTG) mice. Additionally, diabetes-induced retinal pericyte loss was exacerbated in diabetic PCKO mice and alleviated in diabetic PCTG mice. In cultured microglial cells with the diabetic stressor 4-HNE, metabolic flux analysis demonstrated that Pparα ablation caused a metabolic shift from oxidative phosphorylation to glycolysis. Pparα deficiency also increased microglial STING and TNF-α expression. Taken together, these findings revealed a critical role for PPARα in pathological microgliosis, neurodegeneration, and vascular damage in DR, providing insight into the underlying molecular mechanisms of microgliosis in this context and suggesting microglial PPARα as a potential therapeutic target.

Background Mammography technologists’ level of training, years of experience, and feedback on technique may play an important role in the breast cancer screening process. However, very little information on the mammography technologist workforce exists. Methods In 2013, we conducted a mailed survey to 912 mammography technologists working in 224 Mammography Quality Standards Act accredited facilities in North Carolina. Using standard survey methodology we developed and implemented a questionnaire focused on the education and training, work experiences, and workplace interactions of mammography technologists. We aggregated responses using survey weights to account for non-response. We describe and compare lead (administrative responsibilities) and non-lead (supervised by another technologist) mammography technologist characteristics, testing for differences using t-tests and chi-square tests. Results A total of 433 mammography technologists responded (survey response rate=47.5%; 95% confidence interval:44.2%-50.7%), including 128 lead and 305 non-lead technologists. Most mammography technologists were non-Hispanic, white, females and the average age was 48 years. Approximately 93% of lead and non-lead technologists had mammography specific training but <4% had sonography certification and 3% had MRI certification. Lead technologists reported more years performing screening mammography (p-value=0.02) and film mammography (p-value=0.03), more administrative hours (p-value<0.0001), and more workplace autonomy (p-value=0.002) than non-lead technologists. Non-lead technologists were more likely to report performing diagnostic mammograms (p-value=0.0004) or other breast imaging (p-value=0.001), discuss image quality with a peer (p-value=0.013), and have frequent face-to-face interaction with radiologists (p-value=0.03). Conclusion Our findings offer insights into mammography technologists’ training and work experiences, highlighting variability in technologist characteristics between lead and non-lead technologists.

IntroductionHepatocellular Carcinoma (HCC) is the sixth most frequent cancer and the second leading cause of cancer related death worldwide, with a poor five year survival and increasing incidence in the Western World. The family of oncogenic serine/threonine kinases comprises three members: Pim1, Pim2 and Pim3. While Pim1 has been the major focus in oncological research and therapeutic exploration so far, Pim2 is overexpressed in HCC as well and has been suggested to be relevant in HCC tumorigenesis.Material and methodssiRNA-mediated knockdown of Pim2 cells was determined on (mRNA) and protein level (Western blot). Biological effects of Pim2 knockdown in HCC were explored by investigating cell proliferation (WST-1-assay), cell cycle distribution (flow cytometry), apoptosis (flow cytometry, Caspase activity-assay), and colony formation (clonogenic assay). Changes in downstream signalling pathways leading to the observed biological effects after Pim2 knockdown were explored on mRNA as well as on protein level. The therapeutic potential of a Pim2 was assessed in an in vivo s.c. xenograft mouse model using polymeric nanoparticles based on polyethyleneimine (PEI) as siRNA-delivery platform for systemic treatment.Results and discussionsKnockdown of Pim2 using siRNAs lead to strong reduction in Pim2 mRNA and protein levels. This resulted in various cellular effects, including the inhibition of proliferation, increased apoptosis, as well as altered cell cycle distribution and reduced colony formation. On the molecular level, Pim2 knockdown led to changed expression and/or phosphorylation of key proteins involved in the regulation of cell cycle (cyclin B1) and apoptosis (Survivin, Bad). In the in vivo xenograft mouse model, systemic delivery of PEI/siPim2 nanoparticles resulted in profound tumor-inhibitory effects.ConclusionOur results highlight the relevance of the oncogenic serine/threonine kinase Pim2 in HCC. Counteracting its overexpression by siRNA therapeutics, or specifically inhibiting Pim2 on the protein level, might represent novel treatment strategies in HCC therapy.