Everyone knows and seems to agree that melanocytes are there to generate melanin -an intriguing, but underestimated multipurpose molecule that is capable of doing far more than providing pigment and UV protection to skin (1). What about the cell that generates melanin, then? Is this dendritic, neural crestderived cell still serving useful (or even important) functions when no-one looks at the pigmentation of our skin and its appendages and when there is essentially no UV exposure? In other words, what do epidermal and hair follicle melanocytes do in their spare time -at night, under your bedcover? How much of the full portfolio of physiological melanocyte functions in mammalian skin has really been elucidated already? Does the presence or absence of melanoctyes matter for normal epidermal and ⁄ or hair follicle functions (beyond pigmentation and UV protection), and for skin immune responses? Do melanocytes even deserve as much credit for UV protection as conventional wisdom attributes to them? In which interactions do these promiscuous cells engage with their immediate epithelial environment and who is controlling whom? What lessons might be distilled from looking at lower vertebrate melanophores and at extracutaneous melanocytes in the endeavour to reveal the 'secret identity' of melanocytes? The current Controversies feature explores these far too infrequently posed, biologically and clinically important questions. Complementing a companion viewpoint essay on malignant melanocytes (2), this critical re-examination of melanocyte biology provides a cornucopia of old, but underappreciated concepts and novel ideas on the slowly emerging complexity of physiological melanocyte functions, and delineates important, thought-provoking questions that remain to be definitively answered by future research. Praeludium pigmentosumFor those uninformed, the skin is an inert plastic wrap nature provides to keep us in and everything else out. How mistaken they are! The skin, in particular the epidermis, is one of the most active of all tissues ⁄ organs.Nature wisely placed the capillary circulation in the dermis. The epidermis has no vascular circulation thereby minimizing the probability that toxic chemicals, bacteria or fungi that penetrate through the stratum corneum can diffuse into the blood stream. That does not leave the epidermis defenseless. The epidermis has proteins called defensins that have anti-microbial properties. There are Toll-like receptors that recognize invading organisms and incite a host response. Even more interesting, it is well known that keratinocytes are avidly phagocytic. They have the capacity to phagocytize the wandering, invasive fungi or bacteria and digest them. It is both interesting and important that a-MSH stimulates the ingestion of candida by keratinocytes. a-MSH has a wide array of activities, only one of which is to stimulate the synthesis of melanin. There are receptors for a-MSH on Langerhans cells and keratinocytes as well as melanocytes. It has the ability to suppress infla...

18 F-PSMA-1007 is a novel prostate-specific membrane antigen (PSMA)-based radiopharmaceutical for imaging prostate cancer (PCa). The aim of this study was to compare the diagnostic accuracy of 18 F-PSMA-1007 with 68 Ga-PSMA-11 PET/CT in the same patients presenting with newly diagnosed intermediate-or high-risk PCa. Methods: Sixteen patients with intermediate-or high-risk PCa underwent 18 F-PSMA-1007 and 68 Ga-PSMA-11 PET/CT within 15 d. PET findings were compared between the 2 radiotracers and with reference-standard pathologic specimens obtained from radical prostatectomy. The Cohen κ-coefficient was used to assess the concordance between 18 F-PSMA-1007 and 68 Ga-PSMA-11 for detection of intraprostatic lesions. The McNemar test was used to assess agreement between intraprostatic PET/CT findings and histopathologic findings. Sensitivity, specificity, positive predictive value, and negative predictive value were reported for each radiotracer. SUV max was measured for all lesions, and tumor-to-background activity was calculated. Areas under receiver-operating-characteristic curves were calculated for discriminating diseased from nondiseased prostate segments, and optimal SUV cutoffs were calculated using the Youden index for each radiotracer. Results: PSMA-avid lesions in the prostate were identified in all 16 patients with an almost perfect concordance between the 2 tracers (κ ranged from 0.871 to 1). Aside from the dominant intraprostatic lesion, similarly detected by both radiotracers, a second less intense positive focus was detected in 4 patients only with 18 F-PSMA-1007. Three of these secondary foci were confirmed as Gleason grade 3 lesions, whereas the fourth was shown on pathologic examination to represent chronic prostatitis. Conclusion: This pilot study showed that both 18 F-PSMA-1007 and 68 Ga-PSMA-11 identify all dominant prostatic lesions in patients with intermediateor high-risk PCa at staging. 18 F-PSMA-1007, however, may detect additional low-grade lesions of limited clinical relevance.

Overexpressed extracellular matrix (ECM) in pancreatic ductal adenocarcinoma (PDAC) limits drug penetration into the tumor and is associated with poor prognosis. Here, we demonstrate that a pretreatment based on a proteolytic-enzyme nanoparticle system disassembles the dense PDAC collagen stroma and increases drug penetration into the pancreatic tumor. More specifically, the collagozome, a 100 nm liposome encapsulating collagenase, was rationally designed to protect the collagenase from premature deactivation and prolonged its release rate at the target site. Collagen is the main component of the PDAC stroma, reaching 12.8 ± 2.3% vol in diseased mice pancreases, compared to 1.4 ± 0.4% in healthy mice. Upon intravenous injection of the collagozome, ∼1% of the injected dose reached the pancreas over 8 h, reducing the level of fibrotic tissue to 5.6 ± 0.8%. The collagozome pretreatment allowed increased drug penetration into the pancreas and improved PDAC treatment. PDAC tumors, pretreated with the collagozome followed by paclitaxel micelles, were 87% smaller than tumors pretreated with empty liposomes followed by paclitaxel micelles. Interestingly, degrading the ECM did not increase the number of circulating tumor cells or metastasis. This strategy holds promise for degrading the extracellular stroma in other diseases as well, such as liver fibrosis, enhancing tissue permeability before drug administration.