Malignant melanoma is the skin cancer with the most significant impact on man, carrying the highest risk of death from metastasis. Both incidence and mortality rates continue to rise each year, with no effective long-term treatment on the horizon. In part, this reflects lack of identification of critical genes involved and specific therapies targeted to correct these defects. We report that selective activation of the Akt3

Early detection is a crucial element for the timely diagnosis and successful treatment of all human cancers but is limited by the sensitivity of current imaging methodologies. We have synthesized and studied bioresorbable calcium phosphate nanoparticles (CPNPs) in which molecules of the near-infrared (NIR) emitting fluorophore, indocyanine green (ICG), are embedded. The ICG-CPNPs demonstrate exceptional colloidal and optical characteristics. Suspensions consisting of 16 nm average diameter particles are colloidally stable in physiological solutions (phosphate buffered 0.15 M saline (PBS), pH 7.4) with carboxylate or polyethylene glycol (PEG) surface functionality. ICG-doped CPNPs exhibit significantly greater intensity at the maximum emission wavelength relative to the free constituent fluorophore, consistent with the multiple molecules encapsulated per particle. The quantum efficiency per molecule of the ICG-CPNPs is 200% greater at 0.049 +/- 0.003 over the free fluorophore in PBS. Photostability based on fluorescence half-life of encapsulated ICG in PBS is 500% longer under typical clinical imaging conditions relative to the free dye. PEGylated ICG-CPNPs accumulate in solid, 5 mm diameter xenograft breast adenocarcinoma tumors via enhanced retention and permeability (EPR) within 24 h after systemic tail vein injection in a nude mouse model. Ex situ tissue imaging further verifies the facility of the ICG-CPNPs for deep-tissue imaging with NIR signals detectable from depths up to 3 cm in porcine muscle tissue. Our ex vivo and in vivo experiments verify the promise of the NIR CPNPs for diagnostic imaging in the early detection of solid tumors.

Diabetic retinopathy remains a frightening prospect to patients and frustrates physicians. Destruction of damaged retina by photocoagulation remains the primary treatment nearly 50 years after its introduction. The diabetes pandemic requires new approaches to understand the pathophysiology and improve the detection, prevention, and treatment of retinopathy. This perspective considers how the unique anatomy and physiology of the retina may predispose it to the metabolic stresses of diabetes. The roles of neural retinal alterations and impaired retinal insulin action in the pathogenesis of early retinopathy and the mechanisms of vision loss are emphasized. Potential means to overcome limitations of current animal models and diagnostic testing are also presented with the goal of accelerating therapies to manage retinopathy in the face of ongoing diabetes. Diabetes 55:2401-2411, 2006 D espite years of clinical and laboratory investigation, diabetic retinopathy remains the leading cause of vision impairment and blindness among working-age adults, yet the fundamental cause(s) remains uncertain. Retinal photocoagulation to reduce neovascularization and macular edema was developed in the 1950s and is still the standard of care (1). The number of people worldwide at risk of developing vision loss from diabetes is predicted to double over the next 30 years (2), so it is imperative to develop better means to identify, prevent, and treat retinopathy in its earliest stages rather than wait for the onset of vision-threatening lesions. Progress in these areas requires a new perspective on the problem that includes the roles of the neural retina, impaired insulin action, and inflammation. In this way, established neurobiological principles can inform us how diabetes impairs vision, and knowledge of metabolism, inflammation, and regenerative medicine may lead to new treatments.This perspective will discuss how the unique anatomy and physiology of the retina may render it vulnerable to the metabolic derangements of diabetes and lead to impaired vision. The intent of this unconventional approach is to encourage consideration of new opportunities for investigations that will advance the field. NORMAL RETINAL STRUCTURE AND PHYSIOLOGY Topographic and cellular organization of the retina.It is instructive to consider the functional organization of the retina (literally a network) to better understand the impact of diabetes (http://webvision.med.utah.edu). The retina is a transparent layer of neural tissue between the retinal pigmented epithelium and the vitreous body. Normal vision depends on intact cell-cell communication among the neuronal, glial, microglial, vascular, and pigmented epithelial cells of the retina. The fundamental functions of the retina are to capture photons, convert the photochemical energy into electrical energy, integrate the resulting action potentials, and transmit them to the occipital lobe of the brain, where they are deciphered and interpreted into recognizable images. The retina is partitioned from the syst...

Background: It remains a matter of debate whether autophagy contributes to apoptosis. Results: Atg5 and p62 are required for an intracellular death-inducing signaling complex (iDISC) formation on autophagosomal membranes for caspase-8 self-processing. Conclusion: Autophagosome serves as a platform for the intracellular activation of caspase-8. Significance: Induction of iDISC formation may shift cytoprotective autophagy to apoptosis for more effective cancer therapies.