[No abstract]

Exogenous collagen cross-linking has been investigated as method of reinforcing scleral biomechanics, with the goal of counteracting scleral weakening that occurs at the onset of myopia. This study uses whole globe inflation testing to investigate the biomechanical effect of treating posterior sclera with the collagen cross-linking agents methylglyoxal and genipin. Pairs of porcine eyes were treated in four ways. Three groups involved 1% methylglyoxal: two-hour (Group I) or thirty-minute (Group II) incubation of the whole globe, and thirty-minute incubation of only the posterior sclera of the intact eye (Group III). Group IV consisted of a thirty-minute incubation of the posterior sclera in 1% genipin. Following treatment, each eye was subjected to inflation testing under physiological pressure levels (0-150 mmHg); four strain markers on the posterior pole were tracked, providing displacement measurements in two directions. Results were used to derive load versus deformation behavior and to calculate stiffness at 0.25% strain (toe stiffness) and at peak strain (peak stiffness). Toe stiffness of Group I was 4.8 and 1.3 times greater than controls (sagittal and transverse directions, respectively: 5.23 ± 0.39 vs. 0.90 ± 0.08 mHg, P < 0.001; and 3.41 ± 0.19 vs. 1.51 ± 0.22 mHg, P < 0.01; values in mean ± SE). Group II was 7.4 and 4.3 times stiffer than controls (sagittal and transverse directions, respectively: 5.26 ± 0.49 vs. 0.63 ± 0.10 mHg, P < 0.02; and 3.44 ± 0.44 vs. 0.65 ± 0.07 mHg, P < 0.003). Group III was 3.6 and 3.4 times stiffer than controls (sagittal and transverse directions, respectively: 5.21 ± 0.39 vs. 1.13 ± 0.31 mHg, P < 0.01; and 4.94 ± 1.48 vs. 1.13 ± 0.25, P < 0.01), while Group IV was 8.2 and 2.8 times stiffer than controls (sagittal and transverse: 12.36 ± 1.96 vs. 1.35 ± 0.14 mHg, P < 0.01; and 12.45 ± 1.34 vs. 3.27 ± 0.50 mHg, P < 0.05). In all groups, there was no significant difference in peak stiffness after scleral cross-linking (SXL). At low strain, the posterior sclera was stiffer in both measured directions following methylglyoxal and genipin treatments, however at peak strain the treated sclera was not stiffer. Additionally, the saturation level of scleral stiffening by methylglyoxal can be reached within thirty minutes of treatment.

Background

Amyotrophic lateral sclerosis (ALS) is a complex, late-onset, neurodegenerative disease with a genetic contribution to disease liability. Genome-wide association studies (GWAS) have identified ten risk loci to date, including the TNIP1/GPX3 locus on chromosome five. Given association analysis data alone cannot determine the most plausible risk gene for this locus, we undertook a comprehensive suite of in silico, in vivo and in vitro studies to address this.

Methods

The Functional Mapping and Annotation (FUMA) pipeline and five tools (conditional and joint analysis (GCTA-COJO), Stratified Linkage Disequilibrium Score Regression (S-LDSC), Polygenic Priority Scoring (PoPS), Summary-based Mendelian Randomisation (SMR-HEIDI) and transcriptome-wide association study (TWAS) analyses) were used to perform bioinformatic integration of GWAS data (N_cases = 20,806, N_controls = 59,804) with 'omics reference datasets including the blood (eQTLgen consortium N = 31,684) and brain (N = 2581). This was followed up by specific expression studies in ALS case-control cohorts (microarray N_total = 942, protein N_total = 300) and gene knockdown (KD) studies of human neuronal iPSC cells and zebrafish-morpholinos (MO).

Results

SMR analyses implicated both TNIP1 and GPX3 (p < 1.15 × 10^-6), but there was no simple SNP/expression relationship. Integrating multiple datasets using PoPS supported GPX3 but not TNIP1. In vivo expression analyses from blood in ALS cases identified that lower GPX3 expression correlated with a more progressed disease (ALS functional rating score, p = 5.5 × 10^-3, adjusted R² = 0.042, B_effect = 27.4 ± 13.3 ng/ml/ALSFRS unit) with microarray and protein data suggesting lower expression with risk allele (recessive model p = 0.06, p = 0.02 respectively). Validation in vivo indicated gpx3 KD caused significant motor deficits in zebrafish-MO (mean difference vs. control ± 95% CI, vs. control, swim distance = 112 ± 28 mm, time = 1.29 ± 0.59 s, speed = 32.0 ± 2.53 mm/s, respectively, p for all < 0.0001), which were rescued with gpx3 expression, with no phenotype identified with tnip1 KD or gpx3 overexpression.

Conclusions

These results support GPX3 as a lead ALS risk gene in this locus, with more data needed to confirm/reject a role for TNIP1. This has implications for understanding disease mechanisms (GPX3 acts in the same pathway as SOD1, a well-established ALS-associated gene) and identifying new therapeutic approaches. Few previous examples of in-depth investigations of risk loci in ALS exist and a similar approach could be applied to investigate future expected GWAS findings.

The archetypal imaging characteristics of meningiomas are among the most stereotypic of all central nervous system (CNS) tumors. In the era of plain film and ventriculography, imaging was only performed if a mass was suspected, and their results were more suggestive than definitive. Following more than a century of technological development, we can now rely on imaging to non-invasively diagnose meningioma with great confidence and precisely delineate the locations of these tumors relative to their surrounding structures to inform treatment planning. Asymptomatic meningiomas may be identified and their growth monitored over time; moreover, imaging routinely serves as an essential tool to survey tumor burden at various stages during the course of treatment, thereby providing guidance on their effectiveness or the need for further intervention. Modern radiological techniques are expanding the power of imaging from tumor detection and monitoring to include extraction of biologic information from advanced analysis of radiological parameters. These contemporary approaches have led to promising attempts to predict tumor grade and, in turn, contribute prognostic data. In this supplement article, we review important current and future aspects of imaging in the diagnosis and management of meningioma, including conventional and advanced imaging techniques using CT, MRI, and nuclear medicine.

Meningiomas are the most common primary intracranial neoplasm. The current World Health Organization (WHO) classification categorizes meningiomas based on histopathological features, but emerging molecular data demonstrate the importance of genomic and epigenomic factors in the clinical behavior of these tumors. Treatment options for symptomatic meningiomas are limited to surgical resection where possible and adjuvant radiation therapy for tumors with concerning histopathological features or recurrent disease. At present, alternative adjuvant treatment options are not available in part due to limited historical biological analysis and clinical trial investigation on meningiomas. With advances in molecular and genomic techniques in the last decade, we have witnessed a surge of interest in understanding the genomic and epigenomic landscape of meningiomas. The field is now at the stage to adopt this molecular knowledge to refine meningioma classification and introduce molecular algorithms that can guide prediction and therapeutics for this tumor type. Animal models that recapitulate meningiomas faithfully are in critical need to test new therapeutics to facilitate rapid-cycle translation to clinical trials. Here we review the most up-to-date knowledge of molecular alterations that provide insight into meningioma behavior and are ready for application to clinical trial investigation, and highlight the landscape of available preclinical models in meningiomas.

Introduction

Meningioma is the most common primary intracranial tumour in adults. The majority are non-malignant, but a proportion behave more aggressively. Incidental/minimally symptomatic meningioma are often managed by serial imaging. Symptomatic meningioma, those that threaten neurovascular structures, or demonstrate radiological growth, are usually resected as first-line management strategy. For patients in poor clinical condition, or with inoperable, residual or recurrent disease, radiotherapy is often used as primary or adjuvant treatment. Effective pharmacotherapy treatments do not currently exist. There is heterogeneity in the outcomes measured and reported in meningioma clinical studies. Two 'Core Outcome Sets' (COS) will be developed: (COSMIC: Intervention) for use in meningioma clinical effectiveness trials and (COSMIC: Observation) for use in clinical studies of incidental/untreated meningioma.

Methods and analysis

Two systematic literature reviews and trial registry searches will identify outcomes measured and reported in published and ongoing (1) meningioma clinical effectiveness trials, and (2) clinical studies of incidental/untreated meningioma. Outcomes include those that are clinician reported, patient reported, caregiver reported and based on objective tests (eg, neurocognitive tests), as well as measures of progression and survival. Outcomes will be deduplicated and categorised to generate two long lists. The two long lists will be prioritised through two, two-round, international, modified eDelphi surveys including patients with meningioma, healthcare professionals, researchers and those in caring/supporting roles. The two final COS will be ratified through two 1-day online consensus meetings, with representation from all stakeholder groups.

Ethics and dissemination

Institutional review board (University of Liverpool) approval was obtained for the conduct of this study. Participant eConsent will be obtained prior to participation in the eDelphi surveys and consensus meetings. The two systematic literature reviews and two final COS will be published and freely available.

Trial registration number

COMET study ID 1508.