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The development of divinylpyrimidine (DVP) reagents for the synthesis of antibody-drug conjugates (ADCs) with in vivo efficacy and tolerability is reported. Detailed structural characterisation of the synthesised ADCs was first conducted followed by in vitro and in vivo evaluation of the ADCs' ability to safely and selectively eradicate target-positive tumours.

The metabolic response to endotoxemia closely mimics those seen in sepsis. Here, we show that the urinary excretion of the metabolite 2-hydroxyglutarate (2HG) is dramatically suppressed following lipopolysaccharide (LPS) administration in vivo , and in human septic patients. We further show that enhanced activation of the enzymes responsible for 2-HG degradation, D- and L-2-HGDH, underlie this effect. To determine the role of supplementation with 2HG, we carried out co-administration of LPS and 2HG. This co-administration in mice modulates a number of aspects of physiological responses to LPS, and in particular, protects against LPS-induced hypothermia. Our results identify a novel role for 2HG in endotoxemia pathophysiology, and suggest that this metabolite may be a critical diagnostic and therapeutic target for sepsis., (Copyright © 2020 Fitzpatrick, Lambden, Macias, Puthucheary, Pietsch, Mendil, McPhail and Johnson.)

Purpose: Inherited pathogenic variants in genes encoding the metabolic enzymes succinate dehydrogenase (SDH) and fumarate hydratase predispose to tumor development through accumulation of oncometabolites (succinate and fumarate, respectively; ref. 1). Noninvasive in vivo detection of tumor succinate by proton magnetic resonance spectroscopy ( 1 H-MRS) has been reported in SDH-deficient tumors, but the potential utility of this approach in the management of patients with hereditary leiomyomatosis and renal cell cancer syndrome or Reed syndrome is unknown., Experimental Design: Magnetic resonance spectroscopy ( 1 H-MRS) was performed on three cases and correlated with germline genetic results and tumor IHC when available., Results: Here, we have demonstrated a proof of principle that 1 H-MRS can provide a noninvasive diagnosis of hereditary leiomyomatosis and renal cell cancer syndrome or Reed syndrome through detection of fumarate accumulation in vivo ., Conclusions: This study demonstrates that in vivo detection of fumarate could be employed as a functional biomarker., (©2019 American Association for Cancer Research.)

RNA methylation is emerging as a regulatory RNA modification that could have important roles in the control and coordination of gene transcription and protein translation. Herein, we describe an in vivo isotope-tracing methodology to demonstrate that the ribonucleoside 5-methylcytidine (m(5)C) is subject to oxidative processing in mammals, forming 5-hydroxymethylcytidine (hm(5)C) and 5-formylcytidine (f(5)C). Furthermore, we have identified hm(5)C in total RNA from all three domains of life and in polyA-enriched RNA fractions from mammalian cells. This suggests m(5)C oxidation is a conserved process that could have critical regulatory functions inside cells., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Introduction: Macular choroidal neovascularization (CNV) is a serious complication of high myopia, compromising the visual prognosis in young patients. The purpose of this study was to evaluate the safety and efficacy of first-line intravitreal ranibizumab in the treatment of myopic CNV., Patients and Methods: We conducted a single-center prospective, consecutive, interventional study of patients with subfoveal or juxtafoveal CNV secondary to pathologic myopia (PM) treated with intravitreal injection of ranibizumab in the Beni-Messous University Hospital from January 2009 to April 2010. Best-corrected visual acuity (BCVA), fundus examination, optical coherence tomography (OCT), and fluorescein angiography (FA) were performed at baseline and monthly for all patients. Indications for retreatment were persistence or recurrence of the neovascular activity., Results: The study included 40 eyes of 40 patients, 33 of whom were females (82.5%), with a mean age of 40.22 ± 10.81 years (range, 20-55 years), with visual acuity between 1/100 and 1/10. The mean spherical equivalent refractive error was -14.13 ± 4.65 diopters (range, -7 D to -23 D). The mean follow-up time was 8 months (range, 3-15 months). The mean number of intravitreal injections administered for each patient was 2.2 (range: 1-4). Follow-up ranged from 3 to 15 months (mean, 8 months). All patients maintained or improved their vision; the average gain in visual acuity was three lines (range: 1-9 lines). No injection complications or drug-related side effects were noted during the follow-up period., Discussion: Intravitreal ranibizumab to treat CNV complicated by high myopia seems to be associated with an improvement in VA and good tolerance. This study confirms the efficacy of first-line anti-VEGF, in particular, ranibizumab in this indication., Conclusion: In this series of eyes with limited follow-up, intravitreal ranibizumab was a safe and effective treatment for CNV secondary to PM, resulting in functional and anatomic improvement., (Copyright © 2010 Elsevier Masson SAS. All rights reserved.)