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Background Uveal melanoma is a rare form of cancer with high mortality. The incidence of metastases is attributed to early seeding of micrometastases from the eye to distant organs, primarily the liver. Once these seeded clusters of dormant tumor cells grow into larger radiologically detectable macrometastases, median patient survival is about 1 year. Melatonin is an important hormone for synchronizing circadian rhythms. It is also involved in other aspects of human physiology and may offer therapeutic benefits for a variety of diseases including cancer. Methods Articles involving the physiological effects of melatonin, pharmacokinetics, and previous use in cancer studies were acquired using a comprehensive literature search in the Medline (PubMed) and Web of Science databases. In total, 147 publications were selected and included in the review. Results Melatonin has been observed to suppress the growth of cancer cells, inhibit metastatic spread, enhance immune system functions, and act as an anti-inflammatory in both in vitro and in vivo models. Melatonin may also enhance the efficacy of cancer treatments such as immuno- and chemotherapy. Numerous studies have shown promising results for oral melatonin supplementation in patients with other forms of cancer including cutaneous malignant melanoma. Cell line and animal studies support a hypothesis in which similar benefits may exist for uveal melanoma. Conclusions Given its low cost, good safety profile, and limited side effects, there may be potential for the use of melatonin as an adjuvant oncostatic treatment. Future avenues of research could include clinical trials to evaluate the effect of melatonin in prevention of macrometastases of uveal melanoma.

Neuroinflammation is recognized as a key component of neurodegenerative disease. In glaucoma, a common neurodegenerative disease and the leading cause of irreversible blindness, the evidence for neuroinflammation in patients is lacking. Animal models have demonstrated significant pro-inflammatory activation of resident glia in the retina, as well as influx of blood-derived monocytes and pro-inflammatory factors. Confirmation of this in human donor tissue has been challenging due to a lack of well-preserved and well-characterized post-mortem tissue. To address this we utilize archived, wax embedded eyes fixed immediately following enucleation from living glaucoma patients. We compared glaucoma to control eyes (enucleated for uveal melanoma where the tumor did not impact the central retina or optic nerve). We performed immunolabelling for neurodegenerative and glial markers (CD45, CD163, IBA1, GFAP, Vimentin) which were quantified by high-resolution light microscopy and image analysis in FIJI. Glaucoma eyes demonstrated significant neural loss consistent with advanced neurodegeneration. IBA1 and GFAP were significantly increased in the retina and optic nerve head of the glaucomatous eyes indicating that significant neuroinflammation had occurred which support findings in animal models. Inflammation is a treatable symptom of many diseases and as such, identification of earlier inflammatory processes in glaucoma could be important for potential future treatment options.

Transcriptional profiling of acute leukemia, specifically by RNA-sequencing or whole transcriptome sequencing (WTS), has provided fundamental insights into its underlying disease biology and allows unbiased detection of oncogenic gene fusions, as well as of gene expression signatures that can be used for improved disease classification. While used as a research tool for many years, RNA-sequencing is becoming increasingly used in clinical diagnostics. Here, we highlight key transcriptomic studies of acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) that have improved our biological understanding of these heterogeneous malignant disorders and have paved the way for translation into clinical diagnostics. Recent single-cell transcriptomic studies of ALL and AML, which provide new insights into the cellular ecosystem of acute leukemia and point to future clinical utility, are also reviewed. Finally, we discuss current challenges that need to be overcome for a more wide-spread adoption of RNA-sequencing in clinical diagnostics and how this technology significantly can aid the identification of genetic alterations in current guidelines and of newly emerging disease entities, some of which are critical to identify because of the availability of targeted therapies, thereby paving the way for improved precision medicine of acute leukemia.

Aquaporins play a crucial role in water homeostasis in the human body, and recently the physiological importance of aquaporins as glycerol channels have been demonstrated. The aquaglyceroporins (AQP3, AQP7, AQP9 and AQP10) represent key glycerol channels, enabling glycerol flux across the membranes of cells. Adipocytes are the major source of glycerol and during lipolysis, glycerol is released to be metabolized by other tissues through a well-orchestrated process. Here we show that both AQP3 and AQP7 bind to the lipid droplet protein perilipin 1 (PLIN1), suggesting that PLIN1 is involved in the coordination of the subcellular translocation of aquaglyceroporins in human adipocytes. Moreover, in addition to aquaglyceroporins, we discovered by transcriptome sequencing that AQP1 is expressed in human primary adipocytes. AQP1 is mainly a water channel and thus is thought to be involved in the response to hyper-osmotic stress by efflux of water during hyperglycemia. Thus, this data suggests a contribution of both orthodox aquaporin and aquaglyceroporin in human adipocytes to maintain the homeostasis of glycerol and water during fasting and feeding.

SUMMARY Acute myeloid leukemia (AML) is defined by an accumulation of immature myeloid blasts in the bone marrow. To identify key dependencies of AML stem cells in vivo, here we use a CRISPR-Cas9 screen targeting cell surface genes in a syngeneic MLL-AF9 AML mouse model and show that CXCR4 is a top cell surface regulator of AML cell growth and survival. Deletion of Cxcr4 in AML cells eradicates leukemia cells in vivo without impairing their homing to the bone marrow. In contrast, the CXCR4 ligand CXCL12 is dispensable for leukemia development in recipient mice. Moreover, expression of mutated Cxcr4 variants reveals that CXCR4 signaling is essential for leukemia cells. Notably, loss of CXCR4 signaling in leukemia cells leads to oxidative stress and differentiation in vivo. Taken together, our results identify CXCR4 signaling as essential for AML stem cells by protecting them from differentiation independent of CXCL12 stimulation., In Brief In an in vivo CRISPR screen, Ramakrishnan et al. identify CXCR4 as a critical regulator of AML stem cells. Although the CXCR4 ligand CXCL12 is dispensable for leukemia development, CXCR4 signaling is essential for AML cells because it protects them from differentiation., Graphical Abstract