Prion protein interaction with soil humic substances: environmental implications

Transmissible spongiform encephalopathies (TSE) are fatal neurodegenerative disorders caused by prions. Animal TSE include scrapie in sheep and goats, and chronic wasting disease (CWD) in cervids. Effective management of scrapie in many parts of the world, and of CWD in North American deer population is complicated by the persistence of prions in the environment. After shedding from diseased animals, prions persist in soil, withstanding biotic and abiotic degradation. As soil is a complex, multi-component system of both mineral and organic components, it is important to understand which soil compounds may interact with prions and thus contribute to disease transmission. Several studies have investigated the role of different soil minerals in prion adsorption and infectivity; we focused our attention on the interaction of soil organic components, the humic substances (HS), with recombinant prion protein (recPrP) material. We evaluated the kinetics of recPrP adsorption, providing a structural and biochemical characterization of chemical adducts using different experimental approaches. Here we show that HS act as potent anti-prion agents in prion infected neuronal cells and in the amyloid seeding assays: HS adsorb both recPrP and prions, thus sequestering them from the prion replication process. We interpreted our findings as highly relevant from an environmental point of view, as the adsorption of prions in HS may affect their availability and consequently hinder the environmental transmission of prion diseases in ruminants

Combined treatment of psoriasis with a new aromatic retinoid (Tigason) in low dosage orally and triamcinolone acetonide cream topically: a double-blind trial

In a multicentre double-blind trial the effect of three therapy regimens was studied for 6 weeks in ninety psoriasis patients: (1) aromatic retinoid (Ro 10-9359) orally (0.50-0.66 mg/kg body weight) and placebo cream topically; (2) aromatic retinoid (Ro 10-9359) (same dosage) with 0.1% triamcinolone acetonide and 5% salicylic acid in lanette wax cream; (3) placebo capsules with 0.1% triamcinolone acetonide and 5% salicylic acid in lanette wax cream. Regimen 1 had virtually no effect and regimen 2 gave better results than regimen 3 for almost all parameters, although statistical significance was reached for only some of them. The 6 week double-blind period was followed by an open study in which all patients were treated according to regimen 2. The clinical result could be maintained up to the end of the study (18 weeks), when more than 60% of the patients showed good to excellant (80-100%) improvement. Most of the side-effects of retinoid were mild and relatively rare. It is concluded that the combination of the aromatic retinoid (Ro 10-9359) given in low dosage orally with corticosteroids topically is as effective as therapy with the retinoid in high dosage alone, but with markedly less side-effect

NR4A3 fusion proteins trigger an axon guidance switch that marks the difference between EWSR1 and TAF15 translocated extraskeletal myxoid chondrosarcomas

Extraskeletal myxoid chondrosarcoma (EMC) is a rare sarcoma histotype with uncertain differentiation. EMC is hallmarked by the rearrangement of the NR4A3 gene, which in most cases fuses with EWSR1 or TAF15. TAF15-translocated EMC seem to feature a more aggressive course compared to EWSR1-positive EMCs, but whether the type of NR4A3 chimera impinges upon EMC biology is still largely undefined. To gain insights on this issue, a series of EMC samples (7 EWSR1-NR4A3 and 5 TAF15-NR4A3) were transcriptionally profiled. Our study unveiled that the two EMC variants display a distinct transcriptional profile and that the axon guidance pathway is a major discriminant. In particular, class 4\u20136 semaphorins and axonal guidance cues endowed with pro-tumorigenic activity were more expressed in TAF15-NR4A3 tumors; vice versa, class 3 semaphorins, considered to convey growth inhibitory signals, were more abundant in EWSR1-NR4A3 EMC. Intriguingly, the dichotomy in axon guidance signaling observed in the two tumor variants was recapitulated in in vitro cell models engineered to ectopically express EWSR1-NR4A3 or TAF15-NR4A3. Moreover, TAF15-NR4A3 cells displayed a more pronounced tumorigenic potential, as assessed by anchorage-independent growth. Overall, our results indicate that the type of NR4A3 chimera dictates an axon guidance switch and impacts on tumor cell biology. These findings may provide a framework for interpretation of the different clinical\u2013pathological features of the two EMC variants and lay down the bases for the development of novel patient stratification criteria and therapeutic approaches. \ua9 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland