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Experimental autoimmune uveitis (EAU) is the most commonly used animal model to study the progression of chronic uveitis and to test various therapies to treat the disease. However, to accurately evaluate the effectiveness of such treatments, a grading system that combines the latest imaging techniques with definitive quantitative grading thresholds is required. This study aimed to develop a comprehensive grading system that objectively evaluates EAU progression in C57BL/6J mice. EAU was induced following immunisation with interphotoreceptor retinoid-binding protein (IRBP) and pertussis toxin. Weekly fundus and optical coherence tomography (OCT) images were acquired over 12 weeks using a Micron IV imaging system. Each mouse was graded (between 0 to 4) based on changes seen on both the fundus (optic disc, retinal blood vessels and retinal tissue) and OCT (vitreous and retinal layers) images. A total EAU response (with a maximum score of 48) was calculated for each mouse based on the sum of the individual scores each week. Analysis of the clinical scores depicted a gradual increase in inflammatory signs including optic disc and vascular swelling, leukocyte infiltration in the vitreous, lesions in the retina and formation of granulomas and hyper-reflective foci in the retinal layers in EAU mice, with most signs reaching a plateau towards the end of the study period. Development of these signs into sight-threatening complications such as optic disc atrophy, structural damage to the retina and subretinal oedema were noted in 80–90% of mice suggesting consistent disease induction. Overall, a comprehensive and objective grading system encompassing all pathologies occurring in EAU mice was developed to enhance the preclinical evaluation of novel uveitis treatments.

The role of hypoxic tumour cells in resistance to radiotherapy, and in suppression of immune response, continues to endorse tumour hypoxia as a bona fide, yet largely untapped, drug target. Radiotherapy innovations such as stereotactic body radiotherapy herald new opportunities for classical oxygen-mimetic radiosensitisers. Only nimorazole is used clinically as a radiosensitiser, and there is a dearth of new radiosensitisers in development. In this report, we augment previous work to present new nitroimidazole alkylsulfonamides and we document their cytotoxicity and ability to radiosensitise anoxic tumour cells in vitro. We compare radiosensitisation with etanidazole and earlier nitroimidazole sulfonamide analogues and we identify 2-nitroimidazole and 5-nitroimidazole analogues with marked tumour radiosensitisation in ex vivo assays of surviving clonogens and with in vivo tumour growth inhibition.

Objective: Regulation of energy balance depends on pro-opiomelanocortin (POMC)-derived peptides and melanocortin-4 receptor (MC4R). Alpha-melanocyte stimulating hormone (α-MSH) is the predicted natural POMC-derived peptide that regulates energy balance. Desacetyl-α-MSH, the precursor for α-MSH, is present in brain and blood. Desacetyl-α-MSH is considered to be unimportant for regulating energy balance despite being more potent (compared with α-MSH) at activating the appetite-regulating MC4R in vitro. Thus, the physiological role for desacetyl-α-MSH is still unclear. Methods: We created a novel mouse model to determine whether desacetyl-α-MSH plays a role in regulating energy balance. We engineered a knock in targeted QKQR mutation in the POMC protein cleavage site that blocks the production of both desacetyl-α-MSH and α-MSH from adrenocorticotropin (ACTH1-39). Results: The mutant ACTH1-39 (ACTHQKQR) functions similar to native ACTH1-39 (ACTHKKRR) at the melanocortin 2 receptor (MC2R) in vivo and MC4R in vitro. Male and female homozygous mutant ACTH1-39 (Pomctm1/tm1) mice develop the characteristic melanocortin obesity phenotype. Replacement of either desacetyl-α-MSH or α-MSH over 14 days into Pomctm1/tm1 mouse brain significantly reverses excess body weight and fat mass gained compared to wild type (WT) (Pomcwt/wt) mice. Here, we identify both desacetyl-α-MSH and α-MSH peptides as regulators of energy balance and highlight a previously unappreciated physiological role for desacetyl-α-MSH. Conclusions: Based on these data we propose that there is potential to exploit the naturally occurring POMC-derived peptides to treat obesity but this relies on first understanding the specific function(s) for desacetyl-α-MSH and α-MSH. Keywords: POMC, Obesity, Desacetyl-α-MSH, α-MSH, Obese mouse model