Glaucoma, a leading cause of blindness, is characterized by optic nerve damage related to intraocular pressure (IOP), but its full etiology is unknown. Researchers at UAB have devised a custom device to measure scleral strain continuously around the eye under fixed levels of IOP, which here is used to assess how strain varies around the posterior pole, with IOP, and across glaucoma risk factors such as age. The hypothesis is that scleral strain decreases with age, which could alter biomechanics of the optic nerve head and cause damage that could eventually lead to glaucoma. To evaluate this hypothesis, we adapted Bayesian Functional Mixed Models to model these complex data consisting of correlated functions on spherical scleral surface, with nonparametric age effects allowed to vary in magnitude and smoothness across the scleral surface, multi-level random effect functions to capture within-subject correlation, and functional growth curve terms to capture serial correlation across IOPs that can vary around the scleral surface. Our method yields fully Bayesian inference on the scleral surface or any aggregation or transformation thereof, and reveals interesting insights into the biomechanical etiology of glaucoma. The general modeling framework described is very flexible and applicable to many complex, high-dimensional functional data.
Purpose: Consensus molecular subtyping (CMS) of colorectal cancer (CRC) has potential to reshape the CRC landscape. We developed and validated an assay that is applicable on formalin fixed paraffin embedded (FFPE) samples of CRC and implemented the assay in a CLIA-certified laboratory. Experimental design: We performed an in silico experiment to build an optimal CMS classifier using a training set of 1329 samples from 12 studies and validation set of 1329 samples from 14 studies. We constructed assay based on Nanostring codesets for the top 472 genes, and performed analyses on paired flash frozen (FF)/FFPE samples from 175 CRCs to adapt the classifier to FFPE using a subset of genes found to be concordant between FF and FFPE, and tested the classifier`s reproducibility, repeatability, and validated in a CLIA-certified laboratory. We assessed prognostic significance of CMS in 345 patients pooled across 3 clinical trials. Results: The best classifier was Weighted Support Vector Machine with high accuracy across platforms and gene lists (>0.95), and the 472-gene model outperforming existing classifiers. We constructed subsets of 99 and 200 genes with high FF/FFPE concordance, and adapted FFPE-based classifier that had strong classification accuracy (>80%) relative to "gold standard" CMS. The classifier was reproducible to sample type, RNA quality, and demonstrated poor prognosis for CMS1-3 and good prognosis for CMS2 in metastatic CRC (p<0.001). Conclusions: We developed and validated a CRC CMS assay that is ready for use in clinical trials, to assess prognosis in standard-of-care settings and explore as predictor of therapy response. Statement of translational relevance: In this manuscript, we have developed a gene expression assay for consensus molecular subtyping of colorectal cancer that shows prognostic relevance of CRC CMS. The assay is validated in CLIA-certified laboratory and is applicable for clinical trials in the current format. Research.
PurposeTo determine the relationship between peripapillary scleral strain change and cumulative differential IOP exposure in nonhuman primates (NHPs) with unilateral chronic ocular hypertension.MethodsPosterior scleral shells from 6 bilaterally normal and 10 unilateral chronic ocular hypertension NHPs were pressurized from 5 to 45 mm Hg, and the resulting full-field, three-dimensional, scleral surface deformations were acquired using laser speckle interferometry. Scleral tensile strain (local tissue deformation) was calculated by analytical differentiation of the displacement field; zero strain was assumed at 5 mm Hg. Maximum principal strain was used to represent the scleral strain, and strains were averaged over a 15°-wide (∼3.6-mm) circumpapillary region adjacent to the ONH. The relative difference in mean strain was calculated between fellow eyes and compared with the differential cumulative IOP exposure within NHPs during the study period. The relationship between the relative difference in scleral strain and the differential cumulative IOP exposure in fellow eyes was assessed using an F test and quadratic regression model.ResultsRelative differential scleral tensile strain was significantly associated with differential cumulative IOP exposure in contralateral eyes in the chronic ocular hypertension NHPs, with the bilaterally normal NHPs showing no significant strain difference between fellow eyes. The sclera in the chronic ocular hypertension eyes was more compliant than in their fellow eyes at low levels of differential cumulative IOP exposure, but stiffer at larger differential IOPs (P < 0.0001).ConclusionsThese cross-sectional findings suggest that longitudinal IOP-induced changes in scleral mechanical behavior are dependent on the magnitude of differential cumulative IOP exposure.
| BACKGROUNDPompe disease (PD), also known as acid maltase deficiency or glycogen storage disease type II, is a rare, autosomal recessive disease caused by the deficiency of lysosomal alpha-glucosidase (GAA). 1 GAA cleaves alpha-1,4 and alpha-1,6 linkages in glycogen under the acidic conditions of the lysosome. 2 In this lysosomal storage disorder, glycogen accumulation in affected tissue (e.g., skeletal and/or cardiac muscle) can result in progressive hypotonia, respiratory failure, and cardiomyopathy. The disease spectrum ranges from the severe, rapidly progressive infantile-onset Pompe disease (IOPD) to the slowly progressive, heterogeneous late-onset Pompe disease (LOPD). 3 Alglucosidase alfa, the enzyme replacement therapy (ERT), which is the current standard of care, improves lung function within the first few months of treatment, but lung function gradually returns to baseline at 36 months of treatment, with a slight decline after 36 months. 4 Similarly, in a prospective study conducted by Harlaar et al., 30 patients with LOPD who were treated with alglucosidase alfa had improved walking distances on the 6-minute walk test (6MWT) during the first 3 years of treatment. After the first 3 years, the patients experienced a decline; at the 10-year assessment, the average 6MWT distance was lower than the distance walked at the start of treatment. 5 Therefore, patients with LOPD have a substantial unmet medical need.Avalglucosidase alfa-ngpt (Nexviazyme) is a hydrolytic lysosomal glycogen-specific recombinant human α-glucosidase enzyme conjugated with multiple synthetic bis-mannose-6-phosphate (bis-M6P)-tetra-mannose glycans resulting in approximately 15 moles of M6P per mole of enzyme (15 M6P), which mediates binding to M6P receptors on the cell surface. In this article, we provide the summary of FDA's review of the Biologics License Application (BLA) for avalglucosidase alfa-ngpt, which was approved as an ERT for the treatment of patients 1 year of age and older with LOPD.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.