Multidisciplinary clinical approach to cancer patients with immune-related adverse events induced by checkpoint inhibitors

Immune-oncology is a major breakthrough in cancer treatment and has become the standard of care for a wide variety of solid organ malignancies. Unfortunately, manipulation of the immune system with checkpoint inhibitors may result in an immune-based attack of normal tissues which can lead to treatment discontinuation. These immune-related adverse events (irAEs) are diverse and affect several organs, constituting a new clinical challenge in the management of cancer patients. The complexity of this scenario requires a multidisciplinary approach that allows the early identification, diagnosis and treatment of specific irAE, ruling out other non-related adverse events. Hospital Clinic has a multidisciplinary team seeking to develop a coordinated strategy to facilitate the access of patients with suspected irAEs to specialised care resulting in harmonised management that guarantees the best patient care. The aim of the manuscript was to describe the current evidence on the management of irAEs reflecting a coordinated multidisciplinary approach to face this clinical challenge regardless of the immunotherapy indication

The Suppressive Effects of 1,25-dihydroxyvitamin D3 and Vitamin D Receptor on Brown Adipocyte Differentiation and Mitochondrial Respiration

The vitamin D system plays a role in metabolism regulation. It has been reported that 1,25(OH)2D3 [1,25-dihydroxyvitamin D] suppresses 3T3-L1 adipocyte differentiation. Vitamin D receptor (VDR) knockout mice showed increased energy expenditure whereas mice with adipose-specific VDR over expression showed decreased energy expenditure. Brown adipose tissue (BAT), which functions in non-shivering thermogenesis by uncoupling ATP synthesis from oxidation, plays important roles in energy expenditure. However, the effects of 1,25(OH)2D3 on brown adipocyte differentiation and mitochondrial respiration have not been studied. Reported here is the mRNA expression of VDR, UCP1, and CYP27B1 (1α[alpha]- hydroxylase) in two mice models of obesity; and the down regulation of mRNA of VDR, CYP24A1 (24-hyrdoxylase), and CYP27B1 during brown adipocyte differentiation in vitro. 1,25(OH)2D3 dose-dependently suppressed brown adipocyte differentiation, as revealed by oil red O (ORO) stained cell morphology, ORO absorbance, and brown adipocyte marker gene expression. Moreover, cellular bioenergetics measurements showed that 1,25(OH)2D3 suppressed isoproterenol-stimulated oxygen consumption rates (OCR), maximal OCR and OCR from proton leak, but had no effects on ATP-generating OCR and spare respiration capacity in brown adipocytes. Consistently, over-expression of VDR also suppressed brown adipocyte differentiation. Furthermore, both 1,25(OH)2D3 and VDR over expression suppressed PPARγ[gamma] transactivation in brown preadipocytes. Taken together, the results demonstrate the suppressive effects of 1,25(OH)2D3/VDR signaling on brown adipocyte differentiation and mitochondrial respiration and suggest a role of 1,25(OH)2D3/VDR signaling in regulating BAT function for obesity treatment and prevention

AGRICULTURE AND THE ENVIRONMENT

The distinctive nature of environmental quality problems in agriculturean industry based on the extraction of highly variable natural resources under stochastic conditionshas important implications for policy design. First, we examine the source of environmental quality problems and the strength of incentives for resource stewardship that may incidentally induce farmers to protect environmental quality. In turn, we examine environmental policy design under two features that are pervasive in agriculture: (1) heterogeneity caused by resource variability and (2) uncertainty. Next, we examine the effects of interactions between agricultural, environmental, and resource policies. Finally, we review important areas for further research.Environmental Economics and Policy,

A Risk Benefit Analysis of Mariculture as a means to Reduce the Impacts of Terrestrial Production of Food and Energy

The Scottish Aquaculture Research Forum (SARF) and WWF-UK commissioned this study to investigate whether the pressure on land and freshwater for future food and energy resources, and impacts on the climate, related to greenhouse gas (GHG) emissions, may be reduced through expansion of global mariculture. The study has undertaken a high level assessment of the ‘environmental footprint’ of global mariculture and terrestrial-based food and energy production systems through the collation and assessment of available Life Cycle Assessments (LCA) for key food products (beef, pork, chicken, freshwater finfish, marine finfish, shellfish and crustacean species) and biomass (terrestrial and algal) for energy production. The outputs of the footprint comparison were then used to assess the risks and benefits of increasing global mariculture, through the development of projected future scenarios in which mariculture contributes differing proportions of projected future food requirements. The analysis also qualitatively considered the socio-economic and wider environmental risks and benefits (e.g. in relation to ecosystem services) of global mariculture expansion, where expansion may occur geographically and whether future technological developments may help mitigate against identified impacts. The study identifies the key uncertainties and limitations of the risk/benefit analysis and makes prioritised recommendations on how these limitations can be addressed and the analysis developed for more regional or site-specific assessments

Targeting the formyl peptide receptor 1 for treatment of glioblastoma

Background and Aims Gliomas account for over half of all primary brain tumours and have a very poor prognosis, with a median survival of less than two years. There is an urgent and unmet clinical need to develop new therapies against glioma. Recent reports have indicated the overexpression of FPR1 in gliomas particularly in high grade gliomas. The aim of this project was to identify and synthesise small molecule FPR1 antagonists, and to demonstrate a proof of principle in preclinical in vitro and in vivo models that small molecule FPR1 antagonism can retard expansion of glioma. Methods A number of small molecule FPR1 antagonists were identified by in silico design, or from the literature and then were prepared using chemical synthesis. FPR1 antagonists were evaluated in vitro for their ability to abrogate FPR1-induced cellular responses in a range of models including calcium mobilisation, cell migration, and invasion. The efficacy of FPR1 antagonist ICT12035 in vivo was assessed in a U-87 MG subcutaneous xenograft model. Results Virtual high throughput screening using a homology model of FPR1 led to the identification of two small molecule FPR1 antagonists. At the same time chemical synthesis of two other antagonists, ICT5100 and ICT12035 as well as their analogues were carried out. The FPR1 antagonists were assessed in calcium flux assay which gave an insight into their structure-activity relationship. Further investigation of both ICT5100 and ICT12035 demonstrated that both small molecule FPR1 antagonists were effective at abrogating FPR1-induced calcium mobilisation, migration, and invasion in U- 87 MG in vitro models in a dose-dependent manner. ICT12035 is a particularly selective and potent inhibitor of FPR1 with an IC50 of 37.7 nM in calcium flux assay. Additionally, it was shown that the FPR1 antagonist ICT12035 was able to arrest the growth rate of U-87 MG xenografted tumours in mice. Conclusion The results demonstrate that targeting FPR1 by a small molecule antagonist such as ICT12035, could provide a potential new therapy for the treatment of glioblastoma.Yorkshire Cancer Researc

SLEMS : a knowledge based approach to soil loss estimation and modelling

ThesisThesis (M.Sc.E.), University of New Brunswick, 199