Challenges in assessing the sunscreen-melanoma association

Source at https://doi.org/10.1002/ijc.31997.Whether sunscreen use affects melanoma risk has been widely studied with contradictory results. To answer this question we performed a systematic review of all published studies, accounting for sources of heterogeneity and bias. We searched for original articles investigating the sunscreen‐melanoma association in humans to February 28, 2018. We then used random‐effects meta‐analysis to combine estimates of the association, stratified by study design. Stratified meta‐analysis and meta‐regression were used to identify sources of heterogeneity. We included 21,069 melanoma cases from 28 studies published 1979–2018: 23 case–control (11 hospital‐based, 12 population‐based), 1 ecological, 3 cohort and 1 randomised controlled trial (RCT). There was marked heterogeneity across study designs and among case–control studies but adjustment for confounding by sun exposure, sunburns and phenotype systematically moved estimates toward decreased melanoma risk among sunscreen users. Ever‐ vs. never‐use of sunscreen was inversely associated with melanoma in hospital‐based case–control studies (adjusted odds ratio (OR) = 0.57, 95%confidence interval (CI) 0.37–0.87, Pheterogeneity Pheterogeneity Pheterogeneity = 0.236). The association differed by latitude (Pinteraction = 0.042), region (Pinteraction = 0.008), adjustment for naevi/freckling (Pinteraction = 0.035), and proportion of never‐sunscreen‐users (Pinteraction = 0·012). Evidence from observational studies on sunscreen use and melanoma risk was weak and heterogeneous, consistent with the challenges of controlling for innate confounding by indication. The only RCT showed a protective effect of sunscreen

Effects of macromolecular crowding on intracellular diffusion from a single particle perspective

Compared to biochemical reactions taking place in relatively well-defined aqueous solutions in vitro, the corresponding reactions happening in vivo occur in extremely complex environments containing only 60–70% water by volume, with the remainder consisting of an undefined array of bio-molecules. In a biological setting, such extremely complex and volume-occupied solution environments are termed ‘crowded’. Through a range of intermolecular forces and pseudo-forces, this complex background environment may cause biochemical reactions to behave differently to their in vitro counterparts. In this review, we seek to highlight how the complex background environment of the cell can affect the diffusion of substances within it. Engaging the subject from the perspective of a single particle’s motion, we place the focus of our review on two areas: (1) experimental procedures for conducting single particle tracking experiments within cells along with methods for extracting information from these experiments; (2) theoretical factors affecting the translational diffusion of single molecules within crowded two-dimensional membrane and three-dimensional solution environments. We conclude by discussing a number of recent publications relating to intracellular diffusion in light of the reviewed material

Progressive Visceral Leishmaniasis Is Driven by Dominant Parasite-induced STAT6 Activation and STAT6-dependent Host Arginase 1 Expression

The clinicopathological features of the hamster model of visceral leishmaniasis (VL) closely mimic active human disease. Studies in humans and hamsters indicate that the inability to control parasite replication in VL could be related to ineffective classical macrophage activation. Therefore, we hypothesized that the pathogenesis of VL might be driven by a program of alternative macrophage activation. Indeed, the infected hamster spleen showed low NOS2 but high arg1 enzyme activity and protein and mRNA expression (p<0.001) and increased polyamine synthesis (p<0.05). Increased arginase activity was also evident in macrophages isolated from the spleens of infected hamsters (p<0.05), and arg1 expression was induced by L. donovani in primary hamster peritoneal macrophages (p<0.001) and fibroblasts (p<0.01), and in a hamster fibroblast cell line (p<0.05), without synthesis of endogenous IL-4 or IL-13 or exposure to exogenous cytokines. miRNAi-mediated selective knockdown of hamster arginase 1 (arg1) in BHK cells led to increased generation of nitric oxide and reduced parasite burden (p<0.005). Since many of the genes involved in alternative macrophage activation are regulated by Signal Transducer and Activator of Transcription-6 (STAT6), and because the parasite-induced expression of arg1 occurred in the absence of exogenous IL-4, we considered the possibility that L. donovani was directly activating STAT6. Indeed, exposure of hamster fibroblasts or macrophages to L. donovani resulted in dose-dependent STAT6 activation, even without the addition of exogenous cytokines. Knockdown of hamster STAT6 in BHK cells with miRNAi resulted in reduced arg1 mRNA expression and enhanced control of parasite replication (p<0.0001). Collectively these data indicate that L. donovani infection induces macrophage STAT6 activation and STAT6-dependent arg1 expression, which do not require but are amplified by type 2 cytokines, and which contribute to impaired control of infection