A combined experimental and computational framework to evaluate the behavior of therapeutic cells for peripheral nerve regeneration

Recent studies have explored the potential of tissue-mimetic scaffolds in encouraging nerve regeneration. One of the major determinants of the regenerative success of cellular nerve repair constructs is the local microenvironment, particularly native low oxygen conditions which can affect implanted cell survival and functional performance. In vivo, cells reside in a range of environmental conditions due to the spatial gradients of nutrient concentrations that are established. Here we evaluate in vitro the differences in cellular behaviour that such conditions induce, including key biological features such as oxygen metabolism, glucose consumption, cell death, and VEGF secretion. Experimental measurements are used to devise and parameterise a mathematical model that describes the behaviour of the cells. The proposed model effectively describes the interactions between cells and their microenvironment and could in the future be extended, allowing researchers to compare the behaviour of different therapeutic cells. Such a combinatorial approach could be used to accelerate the clinical translation of nerve repair constructs by identifying which critical design features should be optimised when fabricating engineered nerve repair conduits. This article is protected by copyright. All rights reserved

Genome Wide CRISPR/Cas9 Screen Identifies the Coagulation Factor IX (F9) as a Regulator of Senescence

[Abstract] During this last decade, the development of prosenescence therapies has become an attractive strategy as cellular senescence acts as a barrier against tumour progression. In this context, CDK4/6 inhibitors induce senescence and reduce tumour growth in breast cancer patients. However, even though cancer cells are arrested after CDK4/6 inhibitor treatment, genes regulating senescence in this context are still unknown limiting their antitumour activity. Here, using a functional genome-wide CRISPR/Cas9 genetic screen we found several genes that participate in the proliferation arrest induced by CDK4/6 inhibitors. We find that downregulation of the coagulation factor IX (F9) using sgRNA and shRNA prevents the cell cycle arrest and senescent-like phenotype induced in MCF7 breast tumour cells upon Palbociclib treatment. These results were confirmed using another breast cancer cell line, T47D, and with an alternative CDK4/6 inhibitor, Abemaciclib, and further tested in a panel of 22 cancer cells. While F9 knockout prevents the induction of senescence, treatment with a recombinant F9 protein was sufficient to induce a cell cycle arrest and senescence-like state in MCF7 tumour cells. Besides, endogenous F9 is upregulated in different human primary cells cultures undergoing senescence. Importantly, bioinformatics analysis of cancer datasets suggest a role for F9 in human tumours. Altogether, these data collectively propose key genes involved in CDK4/6 inhibitor response that will be useful to design new therapeutic strategies in personalised medicine in order to increase their efficiency, stratify patients and avoid drug resistance.This paper was funded by the BBSRC (BB/P000223/1), the MRC (MR/K501372/1), The Royal Society (RG170399) and Barts Charity (MGU0497 and G-002158) grants to A.O. M.M. was funded by PI19/00145, IN607B2020/12 and 858014. J.F.L. is funded by Xunta de Galicia (ED481B 2017/117). M.B. was funded by MRC (MR/K501372/1). T.P.M. was funded by a QMUL PhD programme and T.D.N.’s lab is currently funded by a Barts Charity project grant (MGU0534). P.C.F. is currently funded by GAIN (IN606C 2021/006) Xunta de GaliciaReino Unido. Biotechnology and Biological Sciences Research Council; BB/P000223/1Reino Unido. Medical Research Council; MR/K501372/1Reino Unido. Royal Society; RG170399Barts Charity (Londres); MGU0497Barts Charity (Londres); G-002158Xunta de Galicia; IN607B2020/12Xunta de Galicia; ED481B 2017/117Barts Charity (Londres); MGU0534Xunta de Galicia; IN606C 2021/00

How do I know if I’ve improved my continental scale flood early warning system?

Flood early warning systems mitigate damages and loss of life and are an economically efficient way of enhancing disaster resilience. The use of continental scale flood early warning systems is rapidly growing. The European Flood Awareness System (EFAS) is a pan-European flood early warning system forced by a multi-model ensemble of numerical weather predictions. Responses to scientific and technical changes can be complex in these computationally expensive continental scale systems, and improvements need to be tested by evaluating runs of the whole system. It is demonstrated here that forecast skill is not correlated with the value of warnings. In order to tell if the system has been improved an evaluation strategy is required that considers both forecast skill and warning value. The combination of a multi-forcing ensemble of EFAS flood forecasts is evaluated with a new skill-value strategy. The full multi-forcing ensemble is recommended for operational forecasting, but, there are spatial variations in the optimal forecast combination. Results indicate that optimizing forecasts based on value rather than skill alters the optimal forcing combination and the forecast performance. Also indicated is that model diversity and ensemble size are both important in achieving best overall performance. The use of several evaluation measures that consider both skill and value is strongly recommended when considering improvements to early warning systems

Euro+Med-Checklist Notulae, 14

Abstract: This is the fourteenth of a series of miscellaneous contributions, by various authors, where hitherto unpublished data relevant to both the Med-Checklist and the Euro+Med (or Sisyphus) projects are presented. This instalment deals with the families Apocynaceae, Compositae, Crassulaceae, Cyperaceae, Euphorbiaceae, Gramineae, Leguminosae, Nyctaginaceae, Onagraceae, Orobanchaceae, Rubiaceae, Solanaceae and Umbelliferae. It includes new country and area records and taxonomic and distributional considerations for taxa in Acalypha, Bupleurum, Carex, Datura, Epilobium, Eragrostis, Galium, Leontodon, Mirabilis, Nerium, Orobanche, Phelipanche, Rhinanthus, Saccharum, Sedum, Trifolium, Tripleurospermum and Willemetia. Citation For the whole article: Raab-Straube E. von & Raus Th. (ed.) 2021: Euro+Med-Checklist Notulae, 14.-Willdenowia 51: 355-369. For a single contribution (example): Bergmeier E. 2021: Leontodon longirostris (Finch & P. D. Sell) Talavera-Pp. 356-357 in: Raab-Straube E. von & Raus Th. (ed.), Euro+Med-Checklist Notulae, 14.-Willdenowia 51: 355-369. https://doi.org/10.3372/wi.51.51304 Version of record first published online on 30 November 2021 ahead of inclusion in December 2021 issue

Core outcome sets in dermatology: report from the second meeting of the International Cochrane Skin Group Core Outcome Set Initiative

Results of clinical trials are the most important information source for generating external clinical evidence. The use of different outcomes across trials, which investigate similar interventions for similar patient groups, significantly limits the interpretation, comparability and clinical application of trial results. Core outcome sets (COSs) aim to overcome this limitation. A COS is an agreed standardized collection of outcomes that should be measured and reported in all clinical trials for a specific clinical condition. The Core Outcome Set Initiative within the Cochrane Skin Group (CSG-COUSIN) supports the development of core outcomes in dermatology. In the second CSG-COUSIN meeting held in 2017, 11 COS development groups working on skin diseases presented their current work. The presentations and discussions identified the following overarching methodological challenges for COS development in dermatology: it is not always easy to define the disease focus of a COS; the optimal method for outcome domain identification and level of detail needed to specify such domains is challenging to many; decision rules within Delphi surveys need to be improved; appropriate ways of patient involvement are not always clear. In addition, there appear to be outcome domains that may be relevant as potential core outcome domains for the majority of skin diseases. The close collaboration between methodologists in the Core Outcome Set Initiative and the international Cochrane Skin Group has major advantages for trialists, systematic reviewers and COS developers

Efficacy and Safety of Intravitreal Gene Therapy for Leber Hereditary Optic Neuropathy Treated within 6 Months of Disease Onset

Purpose: To evaluate the efficacy of a single intravitreal injection of rAAV2/2-ND4 in subjects with visual loss from Leber hereditary optic neuropathy (LHON). Design: RESCUE is a multicenter, randomized, double-masked, sham-controlled, phase 3 clinical trial. Participants: Subjects with the m.11778G>A mitochondrial DNA mutation and vision loss ≤6 months from onset in 1 or both eyes were included. Methods: Each subject's right eye was randomly assigned (1:1) to treatment with rAAV2/2-ND4 (single injection of 9 × 1010 viral genomes in 90 μl) or to sham injection. The left eye received the treatment not allocated to the right eye. Main Outcome Measures: The primary end point was the difference of the change from baseline in best-corrected visual acuity (BCVA) between rAAV2/2-ND4–treated and sham-treated eyes at week 48. Other outcome measures included contrast sensitivity, Humphrey visual field perimetry, retinal anatomic measures, and quality of life. Follow-up extended to week 96. Results: Efficacy analysis included 38 subjects. Mean age was 36.8 years, and 82% were male. Mean duration of vision loss at time of treatment was 3.6 months and 3.9 months in the rAAV2/2-ND4–treated eyes and sham-treated eyes, respectively. Mean baseline logarithm of the minimum angle of resolution (logMAR) BCVA (standard deviation) was 1.31 (0.52) in rAAV2/2-ND4–treated eyes and 1.26 (0.62) in sham-treated eyes, with a range from −0.20 to 2.51. At week 48, the difference of the change in BCVA from baseline between rAAV2/2-ND4–treated and sham-treated eyes was −0.01 logMAR (P = 0.89); the primary end point of a −0.3 logMAR (15-letter) difference was not met. The mean BCVA for both groups deteriorated over the initial weeks, reaching the worst levels at week 24, followed by a plateau phase until week 48, and then an improvement of +10 and +9 Early Treatment Diabetic Retinopathy Study letters equivalent from the plateau level in the rAAV2/2-ND4–treated and sham-treated eyes, respectively. Conclusions: At 96 weeks after unilateral injection of rAAV2/2-ND4, LHON subjects carrying the m.11778G>A mutation treated within 6 months after vision loss achieved comparable visual outcomes in the injected and uninjected eyes