Publications by authors named "Gabriel Velez"

47 Publications

Structure-based phylogeny identifies Avoralstat as a TMPRSS2 inhibitor that prevents SARS-CoV-2 infection in mice.

J Clin Invest 2021 Apr 12. Epub 2021 Apr 12.

Department of Ophthalmology, Stanford University, Palo Alto, United States of America.

Drugs targeting host proteins can act prophylactically to reduce viral burden early in disease and limit morbidity, even with antivirals and vaccination. Transmembrane serine protease 2 (TMPRSS2) is a human protease required for SARS-CoV-2 viral entry and may represent such a target. We hypothesized that drugs selected from proteins related by their tertiary structure, rather than their primary structure, were likely to interact with TMPRSS2. We created a structure-based phylogenetic computational tool named 3DPhyloFold to systematically identify structurally similar serine proteases with known therapeutic inhibitors and demonstrated effective inhibition of SARS-CoV-2 infection in vitro and in vivo. Several candidate compounds, Avoralstat, PCI-27483, Antipain, and Soybean-Trypsin-Inhibitor, inhibited TMPRSS2 in biochemical and cell infection assays. Avoralstat, a clinically tested Kallikrein-related B1 inhibitor, inhibited SARS-CoV-2 entry and replication in human airway epithelial cells. In an in vivo proof of principle, Avoralstat significantly reduced lung tissue titers and mitigated weight-loss when administered prophylactically to SARS-CoV-2 susceptible mice indicating its potential to be repositioned for COVID-19 prophylaxis in humans.
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http://dx.doi.org/10.1172/JCI147973DOI Listing
April 2021

Peptidomimetics Therapeutics for Retinal Disease.

Biomolecules 2021 Feb 24;11(3). Epub 2021 Feb 24.

Molecular Surgery Laboratory, Department of Ophthalmology, Byers Eye Institute, Stanford University, Palo Alto, CA 94304, USA.

Ocular disorders originating in the retina can result in a partial or total loss of vision, making drug delivery to the retina of vital importance. However, effectively delivering drugs to the retina remains a challenge for ophthalmologists due to various anatomical and physicochemical barriers in the eye. This review introduces diverse administration routes and the accordant pharmacokinetic profiles of ocular drugs to aid in the development of safe and efficient drug delivery systems to the retina with a focus on peptidomimetics as a growing class of retinal drugs, which have great therapeutic potential and a high degree of specificity. We also discuss the pharmacokinetic profiles of small molecule drugs due to their structural similarity to small peptidomimetics. Lastly, various formulation strategies are suggested to overcome pharmacokinetic hurdles such as solubility, retention time, enzymatic degradation, tissue targeting, and membrane permeability. This knowledge can be used to help design ocular delivery platforms for peptidomimetics, not only for the treatment of various retinal diseases, but also for the selection of potential peptidomimetic drug targets.
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http://dx.doi.org/10.3390/biom11030339DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7995992PMC
February 2021

Molecular Surgery: Proteomics of a Rare Genetic Disease Gives Insight into Common Causes of Blindness.

iScience 2020 Nov 13;23(11):101667. Epub 2020 Oct 13.

Omics Laboratory, Stanford University, Palo Alto, CA, USA.

Rare diseases are an emerging global health priority. Although individually rare, the prevalence of rare "orphan" diseases is high, affecting approximately 300 million people worldwide. Treatments for these conditions are often inadequate, leaving the disease to progress unabated. Here, we review the clinical features and pathophysiology of neovascular inflammatory vitreoretinopathy (NIV), a rare inflammatory retinal disease caused by mutations in the gene. Although the prevalence of NIV is low (1 in 1,000,000 people), the disease mimics more common causes of blindness (e.g. uveitis, retinitis pigmentosa, proliferative diabetic retinopathy, and proliferative vitreoretinopathy) at distinct clinical stages. There is no cure for NIV to date. We highlight how personalized proteomics helped identify potential stage-specific biomarkers and drug targets in liquid vitreous biopsies. The NIV vitreous proteome revealed enrichment of molecular pathways associated with common retinal pathologies and implicated superior targets for therapeutic drug repositioning. In addition, we review our pipeline for collecting, storing, and analyzing ophthalmic surgical samples. This approach can be adapted to treat a variety of rare genetic diseases.
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http://dx.doi.org/10.1016/j.isci.2020.101667DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7586135PMC
November 2020

Whole-Exome Sequencing of Patients With Posterior Segment Uveitis.

Am J Ophthalmol 2021 01 21;221:246-259. Epub 2020 Jul 21.

Molecular Surgery Laboratory, Stanford University, Palo Alto, California, USA; Department of Ophthalmology, Byers Eye Institute, Stanford University, Palo Alto, California, USA; Veterans Affairs, Palo Alto HCS, Palo Alto, California, USA. Electronic address:

Objective: To elucidate molecular risk factors for posterior segment uveitis using a functional genomics approach.

Design: Genetic association cohort study.

Methods: Setting: Single-center study at an academic referral center.

Study Population: 164 patients with clinically diagnosed uveitis of the posterior segment.

Main Outcome Measures: Exome sequencing was used to detect variants identified in 164 patients with posterior segment uveitis. A phenotype-driven analysis, protein structural modeling, and in silico calculations were then used to rank and predict the functional consequences of key variants.

Results: A total of 203 single nucleotide variants, in 23 genes across 164 patients, were included in this study. Both known and novel variants were identified in genes previously implicated in specific types of syndromic uveitis-such as NOD2 (Blau syndrome) and CAPN5 NIV (neovascular inflammatory vitreoretinopathy)-as well as variants in genes not previously linked to posterior segment uveitis. Based on a ranked list and protein-protein-interaction network, missense variants in NOD-like receptor family genes (NOD2, NLRC4, NLRP3, and NLRP1), CAPN5, and TYK2 were characterized via structural modeling and in silico calculations to predict how specific variants might alter protein structure and function. The majority of analyzed variants were notably different from wild type.

Conclusions: This study implicates new pathways and immune signaling proteins that may be associated with posterior segment uveitis susceptibility. A larger cohort and functional studies will help validate the pathogenicity of the mutations identified. In specific cases, whole-exome sequencing can help diagnose nonsyndromic uveitis in patients harboring known variants for syndromic inflammatory diseases.
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http://dx.doi.org/10.1016/j.ajo.2020.07.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7736069PMC
January 2021

Rethinking Responses to Youth Rebellion: Recent Growth and Development of Restorative Practices in Schools.

Curr Opin Psychol 2020 10 2;35:36-40. Epub 2020 Mar 2.

University of Utah, 380 South 1530 East, Rm. 502, Salt Lake City, UT, 84112, USA.

Adolescence has historically been framed as a time of rebellion and protest, with traditional responses in school applying punitive frameworks. In this article, we review recent psychological work on the restorative practices movement in schools as an alternative to how to respond to young people. This changing framework has implications for their development processes and can reframe some forms of rebellion as productive. We first more fully define what restorative justice entails and theoretical developments in this area. We then move to outlining interventions, programs, and associated outcomes. Finally, we end with future directions and research opportunities for psychologists.
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http://dx.doi.org/10.1016/j.copsyc.2020.02.011DOI Listing
October 2020

Proteomic analysis of intermediate uveitis suggests myeloid cell recruitment and implicates IL-23 as a therapeutic target.

Am J Ophthalmol Case Rep 2020 Jun 6;18:100646. Epub 2020 Mar 6.

Omics Laboratory, Stanford University, Palo Alto, CA, USA.

Purpose: To profile vitreous protein expression of intermediate uveitis (IU) patients.

Observations: We identified a mean of 363 ± 41 unique proteins (mean ± SD) in IU vitreous and 393 ± 69 unique proteins in control samples using liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis of liquid vitreous biopsies collected during pars plana vitrectomy. A total of 233 proteins were differentially expressed among control and IU samples, suggesting a protein signature that could distinguish the two groups. Pathway analysis identified 22 inflammatory mediators of the interleukin-12 (IL-12) signaling pathway in IU vitreous. Upstream regulator analysis identified downstream mediators of IL-23 and myeloid differentiation primary response protein (MYD88), both of which are involved in the recruitment and differentiation of myeloid cells. Taken together, our results suggest the recruitment of myeloid cells as an upstream pathway in the pathogenesis of IU.

Conclusions: This study provides insights into proteins that will serve as biomarkers and therapeutic targets for IU. These biomarkers will help design future clinical trials using rational molecular therapeutics.
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http://dx.doi.org/10.1016/j.ajoc.2020.100646DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7132169PMC
June 2020

Metabolite therapy guided by liquid biopsy proteomics delays retinal neurodegeneration.

EBioMedicine 2020 Feb 3;52:102636. Epub 2020 Feb 3.

Omics Laboratory, Department of Ophthalmology, Byers Eye Institute, Stanford University, Palo Alto, CA 94304, United States; Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304, United States. Electronic address:

Background: Neurodegenerative diseases are incurable disorders caused by progressive neuronal cell death. Retinitis pigmentosa (RP) is a blinding neurodegenerative disease that results in photoreceptor death and progresses to the loss of the entire retinal network. We previously found that proteomic analysis of the adjacent vitreous served as way to indirectly biopsy the retina and identify changes in the retinal proteome.

Methods: We analyzed protein expression in liquid vitreous biopsies from autosomal recessive (ar)RP patients with PDE6A mutations and arRP mice with Pde6ɑ mutations. Proteomic analysis of retina and vitreous samples identified molecular pathways affected at the onset of photoreceptor death. Based on affected molecular pathways, arRP mice were treated with a ketogenic diet or metabolites involved in fatty-acid synthesis, oxidative phosphorylation, and the tricarboxylic acid (TCA) cycle.

Findings: Dietary supplementation of a single metabolite, ɑ-ketoglutarate, increased docosahexaeonic acid levels, provided neuroprotection, and enhanced visual function in arRP mice. A ketogenic diet delayed photoreceptor cell loss, while vitamin B supplementation had a limited effect. Finally, desorption electrospray ionization mass spectrometry imaging (DESI-MSI) on ɑ-ketoglutarate-treated mice revealed restoration of metabolites that correlated with our proteomic findings: uridine, dihydrouridine, and thymidine (pyrimidine and purine metabolism), glutamine and glutamate (glutamine/glutamate conversion), and succinic and aconitic acid (TCA cycle).

Interpretation: This study demonstrates that replenishing TCA cycle metabolites via oral supplementation prolongs retinal function and provides a neuroprotective effect on the photoreceptor cells and inner retinal network.

Funding: NIH grants [R01EY026682, R01EY024665, R01EY025225, R01EY024698, R21AG050437, P30EY026877, 5P30EY019007, R01EY018213, F30EYE027986, T32GM007337, 5P30CA013696], NSF grant CHE-1734082.
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http://dx.doi.org/10.1016/j.ebiom.2020.102636DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7005447PMC
February 2020

Structural Insights into the Unique Activation Mechanisms of a Non-classical Calpain and Its Disease-Causing Variants.

Cell Rep 2020 01;30(3):881-892.e5

Omics Laboratory, Department of Ophthalmology, Byers Eye Institute, Stanford University, Palo Alto, CA 94304, USA; Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304, USA. Electronic address:

Increased calpain activity is linked to neuroinflammation including a heritable retinal disease caused by hyper-activating mutations in the calcium-activated calpain-5 (CAPN5) protease. Although structures for classical calpains are known, the structure of CAPN5, a non-classical calpain, remains undetermined. Here we report the 2.8 Å crystal structure of the human CAPN5 protease core (CAPN5-PC). Compared to classical calpains, CAPN5-PC requires high calcium concentrations for maximal activity. Structure-based phylogenetic analysis and multiple sequence alignment reveal that CAPN5-PC contains three elongated flexible loops compared to its classical counterparts. The presence of a disease-causing mutation (c.799G>A, p.Gly267Ser) on the unique PC2L2 loop reveals a function in this region for regulating enzymatic activity. This mechanism could be transferred to distant calpains, using synthetic calpain hybrids, suggesting an evolutionary mechanism for fine-tuning calpain function by modifying flexible loops. Further, the open (inactive) conformation of CAPN5-PC provides structural insight into CAPN5-specific residues that can guide inhibitor design.
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http://dx.doi.org/10.1016/j.celrep.2019.12.077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7001764PMC
January 2020

Novel REEP6 gene mutation associated with autosomal recessive retinitis pigmentosa.

Doc Ophthalmol 2020 02 19;140(1):67-75. Epub 2019 Sep 19.

Jonas Children's Vision Care, and Bernard & Shirlee Brown Glaucoma Laboratory, Columbia Stem Cell Initiative, Departments of Ophthalmology, Pathology and Cell Biology, Institute of Human Nutrition, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA.

Purpose: This study reports the ophthalmic and genetic findings of a Cameroonian patient with autosomal recessive retinitis pigmentosa (arRP) caused by a novel Receptor Expression Enhancing Protein 6 (REEP6) homozygous mutation.

Patient And Methods: A 33-year-old man underwent comprehensive ophthalmic examinations, including visual acuity measurements, dilated fundus imaging, electroretinography (ERG), and spectral-domain optical coherence tomography (SD-OCT). Short-wavelength fundus autofluorescence (SW-AF) and near-infrared fundus autofluorescence (NIR-AF) were also evaluated. Whole exome sequencing (WES) was used to identify potential pathogenic variants.

Results: Fundus examination revealed typical RP findings with additional temporal ten micron yellow dots. SD-OCT imaging revealed cystoid macular edema and perifoveal outer retinal atrophy with centrally preserved inner segment ellipsoid zone (EZ) bands. Hyperreflective spots were seen in the inner retinal layers. On SW-AF images, a hypoautofluorescent area in the perifoveal area was observed. NIR-AF imaging revealed an irregularly shaped hyperautofluorescent ring. His visual acuity was mildly affected. ERG showed undetectable rod responses and intact cone responses. Genetic testing via WES revealed a novel homozygous mutation (c.295G>A, p.Glu99Lys) in the gene encoding REEP6, which is predicted to alter the charge in the transmembrane helix.

Conclusions: This report is not only the first description of a Cameroonian patient with arRP associated with a REEP6 mutation, but also this particular genetic alteration. Substitution of p.Glu99Lys in REEP6 likely disrupts the interactions between REEP6 and the ER membrane. NIR-AF imaging may be particularly useful for assessing functional photoreceptor cells and show an "avocado" pattern of hyperautofluorescence in patients with the REEP6 mutation.
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http://dx.doi.org/10.1007/s10633-019-09719-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7310602PMC
February 2020

CAPN5 genetic inactivation phenotype supports therapeutic inhibition trials.

Hum Mutat 2019 12 26;40(12):2377-2392. Epub 2019 Aug 26.

Omics Laboratory, Byers Eye Institute, Department of Ophthalmology, Stanford University, Palo Alto, California.

Small molecule pharmacological inhibition of dominant human genetic disease is a feasible treatment that does not rely on the development of individual, patient-specific gene therapy vectors. However, the consequences of protein inhibition as a clinical therapeutic are not well-studied. In advance of human therapeutic trials for CAPN5 vitreoretinopathy, genetic inactivation can be used to infer the effect of protein inhibition in vivo. We created a photoreceptor-specific knockout (KO) mouse for Capn5 and compared the retinal phenotype to both wild-type and an existing Capn5 KO mouse model. In humans, CAPN5 loss-of-function (LOF) gene variants were ascertained in large exome databases from 60,706 unrelated subjects without severe disease phenotypes. Ocular examination of the retina of Capn5 KO mice by histology and electroretinography showed no significant abnormalities. In humans, there were 22 LOF CAPN5 variants located throughout the gene and in all major protein domains. Structural modeling of coding variants showed these LOF variants were nearby known disease-causing variants within the proteolytic core and in regions of high homology between human CAPN5 and 150 homologs, yet the LOF of CAPN5 was tolerated as opposed to gain-of-function disease-causing variants. These results indicate that localized inhibition of CAPN5 is a viable strategy for hyperactivating disease alleles.
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http://dx.doi.org/10.1002/humu.23894DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7493429PMC
December 2019

In trans variant calling reveals enrichment for compound heterozygous variants in genes involved in neuronal development and growth.

Genet Res (Camb) 2019 06 13;101:e8. Epub 2019 Jun 13.

Department of Pediatrics,The University of Iowa,Iowa City,IA,USA.

Compound heterozygotes occur when different variants at the same locus on both maternal and paternal chromosomes produce a recessive trait. Here we present the tool VarCount for the quantification of variants at the individual level. We used VarCount to characterize compound heterozygous coding variants in patients with epileptic encephalopathy and in the 1000 Genomes Project participants. The Epi4k data contains variants identified by whole exome sequencing in patients with either Lennox-Gastaut Syndrome (LGS) or infantile spasms (IS), as well as their parents. We queried the Epi4k dataset (264 trios) and the phased 1000 Genomes Project data (2504 participants) for recessive variants. To assess enrichment, transcript counts were compared between the Epi4k and 1000 Genomes Project participants using minor allele frequency (MAF) cutoffs of 0.5 and 1.0%, and including all ancestries or only probands of European ancestry. In the Epi4k participants, we found enrichment for rare, compound heterozygous variants in six genes, including three involved in neuronal growth and development - PRTG (p = 0.00086, 1% MAF, combined ancestries), TNC (p = 0.022, 1% MAF, combined ancestries) and MACF1 (p = 0.0245, 0.5% MAF, EU ancestry). Due to the total number of transcripts considered in these analyses, the enrichment detected was not significant after correction for multiple testing and higher powered or prospective studies are necessary to validate the candidacy of these genes. However, PRTG, TNC and MACF1 are potential novel recessive epilepsy genes and our results highlight that compound heterozygous variants should be considered in sporadic epilepsy.
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http://dx.doi.org/10.1017/S0016672319000065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7045018PMC
June 2019

Gain-of-function mutations in a member of the Src family kinases cause autoinflammatory bone disease in mice and humans.

Proc Natl Acad Sci U S A 2019 06 28;116(24):11872-11877. Epub 2019 May 28.

Institute of Experimental Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.

Autoinflammatory syndromes are characterized by dysregulation of the innate immune response with subsequent episodes of acute spontaneous inflammation. Chronic recurrent multifocal osteomyelitis (CRMO) is an autoinflammatory bone disorder that presents with bone pain and localized swelling. mice, isolated from a mutagenesis screen, exhibit a spontaneous inflammatory paw phenotype that includes sterile osteomyelitis and systemic reduced bone mineral density. To elucidate the molecular basis of the disease, positional cloning of the causative gene for was attempted. Using a candidate gene approach, a missense mutation in the C-terminal region of , a member of Src family tyrosine kinases (SFKs), was identified. For functional confirmation, additional mutations at the N terminus of were introduced in mice by CRISPR/Cas9-mediated genome editing. N-terminal deleterious mutations of abolished the inflammatory phenotype in mice, but in-frame and missense mutations in the same region continue to exhibit the phenotype. The fact that null mutant mice are morphologically normal suggests that the inflammation in this model depends on Fgr products. Furthermore, the levels of C-terminal negative regulatory phosphorylation of Fgr are distinctly reduced compared with that of wild-type Fgr. In addition, whole-exome sequencing of 99 CRMO patients including 88 trios (proband and parents) identified 13 patients with heterozygous coding sequence variants in , including two missense mutant proteins that affect kinase activity. Our results strongly indicate that gain-of-function mutations in are involved in sterile osteomyelitis, and thus targeting SFKs using specific inhibitors may allow for efficient treatment of the disease.
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http://dx.doi.org/10.1073/pnas.1819825116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6575637PMC
June 2019

Proteomic insight into the pathogenesis of CAPN5-vitreoretinopathy.

Sci Rep 2019 05 20;9(1):7608. Epub 2019 May 20.

Omics Laboratory, Stanford University, Palo Alto, CA, USA.

CAPN5 Neovascular Inflammatory Vitreoretinopathy (CAPN5-NIV; OMIM 193235) is a poorly-understood rare, progressive inflammatory intraocular disease with limited therapeutic options. To profile disease effector proteins in CAPN5-NIV patient vitreous, liquid vitreous biopsies were collected from two groups: eyes from control subjects (n = 4) with idiopathic macular holes (IMH) and eyes from test subjects (n = 12) with different stages of CAPN5-NIV. Samples were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Protein expression changes were evaluated by principal component analysis, 1-way ANOVA (significant p-value < 0.05), hierarchical clustering, gene ontology, and pathway representation. There were 216 differentially-expressed proteins (between CAPN5-NIV and control vitreous), including those unique to and abundant in each clinical stage. Gene ontology analysis revealed decreased synaptic signaling proteins in CAPN5-NIV vitreous compared to controls. Pathway analysis revealed that inflammatory mediators of the acute phase response and the complement cascade were highly-represented. The CAPN5-NIV vitreous proteome displayed characteristic enrichment of proteins and pathways previously-associated with non-infectious posterior uveitis, rhegmatogenous retinal detachment (RRD), age-related macular degeneration (AMD), proliferative diabetic retinopathy (PDR), and proliferative vitreoretinopathy (PVR). This study expands our knowledge of affected molecular pathways in CAPN5-NIV using unbiased, shotgun proteomic analysis rather than targeted detection platforms. The high-levels and representation of acute phase response proteins suggests a functional role for the innate immune system in CAPN5-NIV pathogenesis.
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http://dx.doi.org/10.1038/s41598-019-44031-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6527583PMC
May 2019

Mechanisms of neurodegeneration in a preclinical autosomal dominant retinitis pigmentosa knock-in model with a Rho mutation.

Cell Mol Life Sci 2019 Sep 11;76(18):3657-3665. Epub 2019 Apr 11.

Jonas Children's Vision Care and Bernard & Shirlee Brown Glaucoma Laboratory, Departments of Ophthalmology, Pathology, and Cell Biology, Columbia University, New York, NY, 10032, USA.

D190N, a missense mutation in rhodopsin, causes photoreceptor degeneration in patients with autosomal dominant retinitis pigmentosa (adRP). Two competing hypotheses have been developed to explain why D190N rod photoreceptors degenerate: (a) defective rhodopsin trafficking prevents proteins from correctly exiting the endoplasmic reticulum, leading to their accumulation, with deleterious effects or (b) elevated mutant rhodopsin expression and unabated signaling causes excitotoxicity. A knock-in D190N mouse model was engineered to delineate the mechanism of pathogenesis. Wild type (wt) and mutant rhodopsin appeared correctly localized in rod outer segments of D190N heterozygotes. Moreover, the rhodopsin glycosylation state in the mutants appeared similar to that in wt mice. Thus, it seems plausible that the injurious effect of the heterozygous mutation is not related to mistrafficking of the protein, but rather from constitutive rhodopsin activity and a greater propensity for chromophore isomerization even in the absence of light.
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http://dx.doi.org/10.1007/s00018-019-03090-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7144803PMC
September 2019

VCAN Canonical Splice Site Mutation is Associated With Vitreoretinal Degeneration and Disrupts an MMP Proteolytic Site.

Invest Ophthalmol Vis Sci 2019 01;60(1):282-293

Byers Eye Institute, Omics Laboratory, Department of Ophthalmology, Stanford University School of Medicine, Palo Alto, California, United States.

Purpose: To gain insight into the pathophysiology of vitreoretinal degeneration, the clinical course of three family members with Versican Vitreoretinopathy (VVR) is described, and a canonical splice site mutation in the gene encoding for versican (VCAN) protein was biochemically analyzed.

Methods: A retrospective chart review, human eye histopathology, Sanger DNA sequencing, protein structural modeling, and in vitro proteolysis assays were performed.

Results: The proband (II:1), mother (I:2), and younger sibling (II:2) suffered retinal degeneration with foveal sparing and retinal detachments with proliferative vitreoretinopathy, features that were confirmed on histopathologic analysis. All affected members carried a heterozygous adenine to guanine variant (c.4004-2A>G) predicted to result in exon 8 skipping or the deletion of 13 amino acids at the beginning of the GAGβ chain (VCAN p.1335-1347). This deleted region corresponded to a putative MMP cleavage site, validated using fluorescence resonance energy transfer (FRET)-based proteolysis assays. Proteomic network analysis identified 10 interacting partners in the human vitreous and retina linked to retinal detachment and degeneration.

Conclusions: VVR causes significant ocular disease, including retinal detachment and retinal dystrophy. The intronic VCAN mutation removes an MMP cleavage site, which alters versican structure and results in abnormal vitreous modeling. Disruption of a versican protein network may underlie clinicopathologic disease features and point to targeted therapies.
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http://dx.doi.org/10.1167/iovs.18-25624DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6735613PMC
January 2019

Fibrin Glue and Internal Limiting Membrane Abrasion for Optic Disc Pit Maculopathy.

Ophthalmic Surg Lasers Imaging Retina 2018 12;49(12):e271-e277

Background And Objective: To describe a novel surgical technique using pars plana vitrectomy (PPV), internal limiting membrane (ILM) abrasion, and intravitreal fibrin glue for the treatment of optic disc pit maculopathy.

Patients And Methods: Surgical case series technique with scanning electron microscopy (SEM) of human post-mortem eyes.

Results: Using SEM, the authors demonstrate the persistent adherence of vitreous fragments to the optic disc following induction of posterior vitreous detachment in human postmortem eyes. The authors describe a surgical technique using PPV, Tano Diamond Dusted Membrane Scraper for an ILM abrasion, intravitreal fibrin glue (Tisseel), and gas-air exchange to seal optic disc pits. The authors report successful long-term visual and anatomical outcomes in three patients.

Conclusions: Intravitreal fibrin glue, when combined with ILM abrasion, may be a viable treatment option for optic disc pit maculopathy with good short- and long-term visual acuity outcomes. SEM shows that ILM abrasion removes vitreous fragments, which are persistently adherent and may lead to failure with other interventional techniques. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:e271-e277.].
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http://dx.doi.org/10.3928/23258160-20181203-18DOI Listing
December 2018

SCAPER-associated nonsyndromic autosomal recessive retinitis pigmentosa.

Am J Med Genet A 2019 02 18;179(2):312-316. Epub 2018 Dec 18.

Department of Ophthalmology, New York-Presbyterian Hospital, New York, New York.

Mutations in the gene SCAPER (S-phase CyclinA Associated Protein residing in the Endoplasmic Reticulum) have recently been identified as causing syndromic autosomal recessive retinitis pigmentosa with the extraocular manifestations of intellectual disability and attention-deficit/hyperactivity disorder. We present the case of an 11-year-old boy that presented to our clinic with the complaint of decreased night vision. Clinical presentation, family history, and diagnostic imaging were congruent with the diagnosis of autosomal recessive retinitis pigmentosa. Genetic testing of the patient and both parents via whole-exome sequencing revealed the homozygous mutation c.2023-2A>G in SCAPER. Unique to our patient's presentation is the absence of intellectual disability and attention-deficit/hyperactivity disorder, suggesting that SCAPER-associated retinitis pigmentosa can also present without systemic manifestations.
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http://dx.doi.org/10.1002/ajmg.a.61001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6349500PMC
February 2019

ProSave: an application for restoring quantitative data to manipulated subsets of protein lists.

Source Code Biol Med 2018 12;13. Epub 2018 Nov 12.

1Omics Laboratory, Stanford University, Palo Alto, CA USA.

Background: In proteomics studies, liquid chromatography tandem mass spectrometry data (LC-MS/MS) is quantified by spectral counts or by some measure of ion abundance. Downstream comparative analysis of protein content (e.g. Venn diagrams and network analysis) typically does not include this quantitative data and critical information is often lost. To avoid loss of spectral count data in comparative proteomic analyses, it is critical to implement a tool that can rapidly retrieve this information.

Results: We developed ProSave, a free and user-friendly Java-based program that retrieves spectral count data from a curated list of proteins in a large proteomics dataset. ProSave allows for the management of LC-MS/MS datasets and rapidly retrieves spectral count information for a desired list of proteins.

Conclusions: ProSave is open source and freely available at https://github.com/MahajanLab/ProSave. The user manual, implementation notes, and description of methodology and examples are available on the site.
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http://dx.doi.org/10.1186/s13029-018-0070-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6233572PMC
November 2018

Personalized Proteomics for Precision Health: Identifying Biomarkers of Vitreoretinal Disease.

Transl Vis Sci Technol 2018 Sep 26;7(5):12. Epub 2018 Sep 26.

Omics Laboratory, Stanford University, Palo Alto, CA, USA.

Proteomic analysis is an attractive and powerful tool for characterizing the molecular profiles of diseased tissues, such as the vitreous. The complexity of data available for analysis ranges from single (e.g., enzyme-linked immunosorbent assay [ELISA]) to thousands (e.g., mass spectrometry) of proteins, and unlike genomic analysis, which is limited to denoting risk, proteomic methods take snapshots of a diseased vitreous to evaluate ongoing molecular processes in real time. The proteome of diseased ocular tissues was recently characterized, uncovering numerous biomarkers for vitreoretinal diseases and identifying protein targets for approved drugs, allowing for drug repositioning. These biomarkers merit more attention regarding their therapeutic potential and prospective validation, as well as their value as reproducible, sensitive, and specific diagnostic markers.

Translational Relevance: Personalized proteomics offers many advantages over alternative precision-health platforms for the diagnosis and treatment of vitreoretinal diseases, including identification of molecular constituents in the diseased tissue that can be targeted by available drugs.
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http://dx.doi.org/10.1167/tvst.7.5.12DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6159735PMC
September 2018

Missense mutation in SLIT2 associated with congenital myopia, anisometropia, connective tissue abnormalities, and obesity.

Orphanet J Rare Dis 2018 08 15;13(1):138. Epub 2018 Aug 15.

Jonas Children's Vision Care, and Bernard and Shirlee Brown Glaucoma Laboratory, New York, USA.

Background: SLIT2 is a protein ligand for the Roundabout (ROBO) receptor and was found to play a major role in repulsive midline axon guidance in central nervous system development. Based on studies utilizing knockout models, it has been postulated that SLIT2 is important for preventing inappropriate axonal routing during mammalian optic chiasm development.

Methods: Case report.

Results: Here, we report a case of congenital myopia, anisometropia, and obesity in a patient with a SLIT2 point mutation. Examination of the patient's skin biopsy revealed abnormalities in elastin and collagen fibrils that suggest an underlying connective tissue disorder. Structural modeling placed the novel mutation (p.D1407G) in the EGF-like domain 8 and was predicted to affect interactions with SLIT2 binding partners.

Conclusions: To the authors' knowledge, this is the first report of a SLIT2 variant in the context of these ocular findings.
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http://dx.doi.org/10.1186/s13023-018-0885-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6094464PMC
August 2018

Performance of a highly sensitive rapid diagnostic test (HS-RDT) for detecting malaria in peripheral and placental blood samples from pregnant women in Colombia.

PLoS One 2018 2;13(8):e0201769. Epub 2018 Aug 2.

Foundation for Innovative New Diagnostics (FIND), Geneva, Switzerland.

Background: Pregnancy poses specific challenges for the diagnosis of Plasmodium falciparum infection due to parasite sequestration in the placenta, which translates in low circulation levels in peripheral blood. The aim of this study is to assess the performance of a new highly sensitive rapid diagnostic test (HS-RDT) for the detection of malaria in peripheral and placental blood samples from pregnant women in Colombia.

Methods: This is a retrospective study using 737 peripheral and placental specimens collected from pregnant women in Colombian malaria-endemic regions. Light microscopy (LM), conventional rapid diagnostic tests (Pf/Pv RDT and Pf RDT), and HS-RDT testing were performed. Diagnostic accuracy endpoints of LM, HS-RDT and RDTs were compared with nested polymerase chain reaction (nPCR) as the reference test.

Results: In comparison with nPCR, the sensitivity of HS-RDT, Pf RDT, Pf/Pv RDT and LM to detect infection in peripheral samples was 85.7% (95% CI = 70.6-93.7), 82.8% (95% CI = 67.3-91.9), 77.1% (95% CI = 61.0-87.9) and 77.1% (95% CI = 61.0-87.9) respectively. The sensitivity to detect malaria in asymptomatic women, was higher with HS-RDT, where LM and Pf/Pv RDT missed half of infections detected by nPCR, but differences were not significant. Overall, specificity was similar for all tests (>99.0%). In placental blood, the prevalence of infection by P. falciparum by nPCR was 2.8% (8/286), by HS-RDT was 1% and by conventional RDTs (Pf RDT and Pf/Pv RDT) and LM was 0.7%. The HS-RDT detected placental infections in peripheral blood that were negative by LM and Pf/Pv RDT, however the number of positive placentas was low.

Conclusions: The sensitivity of HS-RDT to detect P. falciparum infections in peripheral and placental samples from pregnant women was slightly better compared to routinely used tests during ANC visits and at delivery. Although further studies are needed to guide recommendations on the use of the HS-RDT for malaria case management in pregnancy, this study shows the potential value of this test to diagnose malaria in pregnancy in low-transmission settings.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0201769PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6072118PMC
January 2019

Diagnostic accuracy of loop-mediated isothermal amplification (LAMP) for screening malaria in peripheral and placental blood samples from pregnant women in Colombia.

Malar J 2018 Jul 13;17(1):262. Epub 2018 Jul 13.

FIND, Geneva, Switzerland.

Background: Pregnant women frequently show low-density Plasmodium infections that require more sensitive methods for accurate diagnosis and early treatment of malaria. This is particularly relevant in low-malaria transmission areas, where intermittent preventive treatment is not recommended. Molecular methods, such as polymerase chain reaction (PCR) are highly sensitive, but require sophisticated equipment and advanced training. Instead, loop mediated isothermal amplification (LAMP) provides an opportunity for molecular detection of malaria infections in remote endemic areas, outside a reference laboratory. The aim of the study is to evaluate the performance of LAMP for the screening of malaria in pregnant women in Colombia.

Methods: This is a nested prospective study that uses data and samples from a larger cross-sectional project conducted from May 2016 to January 2017 in three Colombian endemic areas (El Bagre, Quibdó, and Tumaco). A total of 531 peripheral and placental samples from pregnant women self-presenting at local hospitals for antenatal care visits, at delivery or seeking medical care for suspected malaria were collected. Samples were analysed for Plasmodium parasites by light microscopy (LM), rapid diagnostic test (RDT) and LAMP. Diagnostic accuracy endpoints (sensitivity, specificity, predictive values, and kappa scores) of LM, RDT and LAMP were compared with nested PCR (nPCR) as the reference standard.

Results: In peripheral samples, LAMP showed an improved sensitivity (100.0%) when compared with LM 79.5% and RDT 76.9% (p < 0.01), particularly in afebrile women, for which LAMP sensitivity was two-times higher than LM and RDT. Overall agreement among LAMP and nPCR was high (kappa value = 1.0). Specificity was similar in all tests (100%). In placental blood, LAMP evidenced a four-fold improvement in sensitivity (88.9%) when compared with LM and RDT (22.2%), being the only method, together with nPCR, able to detect placental infections in peripheral blood.

Conclusions: LAMP is a simple, rapid and accurate molecular tool for detecting gestational and placental malaria, being able to overcome the limited sensitivity of LM and RDT. These findings could guide maternal health programs in low-transmission settings to integrate LAMP in their surveillance systems for the active detection of low-density infections and asymptomatic malaria cases.
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http://dx.doi.org/10.1186/s12936-018-2403-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6044080PMC
July 2018

Phenomenology and Intersectionality: Using PVEST as a Frame for Adolescent Identity Formation Amid Intersecting Ecological Systems of Inequality.

New Dir Child Adolesc Dev 2018 Jul 3. Epub 2018 Jul 3.

Beginning with Erikson, identity formation has often been framed as a salient developmental challenge for adolescents. Recent theoretical advances situate this identity formation as a central life course process involving ecological and social context associated with diverse experiences and characteristics. Some scholars have employed intersectionality as a call to study experiences of individuals who belong to multiple marginalized groups. In this article, we argue that developmental research would be served by a return to Crenshaw's formulation of intersectionality-that is, that marginalization involves systematic inequality and interlocking systems of oppression-as integrated with Spencer's phenomenological variant of ecological systems theory (PVEST). The latter was formulated as a needed critique of traditional developmental theories that generally ignored the problem of inequality as experienced through multiple layers of navigated contexts. Problematic ecological contexts can be understood through intersectionality's forefronting of complex structures and social positionality-that power dynamics and interconnected systems lead to differential outcomes within socially constructed categories like class, race, and gender. PVEST complements these insights through an attentiveness to phenomenological interpretations and responses-the "how" and "why" of the process. Therefore, we argue that adolescent outcomes should be understood both from the top and the bottom, including how youth interpret and cope with their vulnerability, based upon experiences of interlocking systems of oppression. The consequent synthesis should bolster the identification of pillar-like supports needed by youth and which afford effective assistance across respective socialization contexts.
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http://dx.doi.org/10.1002/cad.20247DOI Listing
July 2018

Extracellular superoxide dismutase (SOD3) regulates oxidative stress at the vitreoretinal interface.

Free Radic Biol Med 2018 08 22;124:408-419. Epub 2018 Jun 22.

Byers Eye Institute, Department of Ophthalmology, Stanford University, Palo Alto, CA, United States; Omics Laboratory, Stanford University, Palo Alto, CA, United States; Palo Alto Veterans Administration, Palo Alto, CA, United States. Electronic address:

Oxidative stress is a pathogenic feature in vitreoretinal disease. However, the ability of the inner retina to manage metabolic waste and oxidative stress is unknown. Proteomic analysis of antioxidants in the human vitreous, the extracellular matrix opposing the inner retina, identified superoxide dismutase-3 (SOD3) that localized to a unique matrix structure in the vitreous base and cortex. To determine the role of SOD3, Sod3 mice underwent histological and clinical phenotyping. Although the eyes were structurally normal, at the vitreoretinal interface Sod3 mice demonstrated higher levels of 3-nitrotyrosine, a key marker of oxidative stress. Pattern electroretinography also showed physiological signaling abnormalities within the inner retina. Vitreous biopsies and epiretinal membranes collected from patients with diabetic vitreoretinopathy (DVR) and a mouse model of DVR showed significantly higher levels of nitrates and/or 3-nitrotyrosine oxidative stress biomarkers suggestive of SOD3 dysfunction. This study analyzes the molecular pathways that regulate oxidative stress in human vitreous substructures. The absence or dysregulation of the SOD3 antioxidant at the vitreous base and cortex results in increased oxidative stress and tissue damage to the inner retina, which may underlie DVR pathogenesis and other vitreoretinal diseases.
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http://dx.doi.org/10.1016/j.freeradbiomed.2018.06.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6233711PMC
August 2018

A novel de novo mutation in a patient with inflammatory vitreoretinopathy, hearing loss, and developmental delay.

Cold Spring Harb Mol Case Stud 2018 06 1;4(3). Epub 2018 Jun 1.

Omics Laboratory, Stanford University, Palo Alto, California 94304, USA.

Mutations that activate the protease calpain-5 ( cause a nonsyndromic adult-onset autoinflammatory eye disease characterized by uveitis, altered synaptic signaling, retinal degeneration, neovascularization, and intraocular fibrosis. We describe a pediatric patient with severe inflammatory vitreoretinopathy accompanied by hearing loss and developmental delay associated with a novel, de novo missense mutation (c.865C>T, p.Arg289Trp) that shows greater hyperactivation of the calpain protease, indicating a genotype-phenotype correlation that links mutation severity to proteolytic activity and the possibility of earlier onset syndromic disease with auditory and neurological abnormalities.
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http://dx.doi.org/10.1101/mcs.a002519DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5983175PMC
June 2018

Proteomic analysis of the human retina reveals region-specific susceptibilities to metabolic- and oxidative stress-related diseases.

PLoS One 2018 21;13(2):e0193250. Epub 2018 Feb 21.

Omics Laboratory, Stanford University, Palo Alto, California, United States of America.

Differences in regional protein expression within the human retina may explain molecular predisposition of specific regions to ophthalmic diseases like age-related macular degeneration, cystoid macular edema, retinitis pigmentosa, and diabetic retinopathy. To quantify protein levels in the human retina and identify patterns of differentially-expressed proteins, we collected foveomacular, juxta-macular, and peripheral retina punch biopsies from healthy donor eyes and analyzed protein content by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Protein expression was analyzed with 1-way ANOVA, gene ontology, pathway representation, and network analysis. We identified a mean of 1,974 proteins in the foveomacular retina, 1,999 in the juxta-macular retina, and 1,779 in the peripheral retina. Six hundred ninety-seven differentially-expressed proteins included those unique to and abundant in each anatomic region. Proteins with higher expression in each region include: heat-shock protein 90-alpha (HSP90AA1), and pyruvate kinase (PKM) in the foveomacular retina; vimentin (VIM) and fructose-bisphosphate aldolase C (ALDOC); and guanine nucleotide-binding protein subunit beta-1 (GNB1) and guanine nucleotide-binding protein subunit alpha-1 (GNAT1) in the peripheral retina. Pathway analysis identified downstream mediators of the integrin signaling pathway to be highly represented in the foveomacular region (P = 6.48 e-06). Metabolic pathways were differentially expressed among all retinal regions. Gene ontology analysis showed that proteins related to antioxidant activity were higher in the juxta-macular and the peripheral retina, but present in lower amounts in the foveomacular retina. Our proteomic analysis suggests that certain retinal regions are susceptible to different forms of metabolic and oxidative stress. The findings give mechanistic insight into retina function, reveal important molecular processes, and prioritize new pathways for therapeutic targeting.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0193250PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5821407PMC
May 2018

The SAGE Model of Social Psychological Research.

Perspect Psychol Sci 2018 05 23;13(3):359-372. Epub 2018 Jan 23.

2 The Faraday Institute for Science and Religion, University of Cambridge.

We propose a SAGE model for social psychological research. Encapsulated in our acronym is a proposal to have a synthetic approach to social psychological research, in which qualitative methods are augmentative to quantitative ones, qualitative methods can be generative of new experimental hypotheses, and qualitative methods can capture experiences that evade experimental reductionism. We remind social psychological researchers that psychology was founded in multiple methods of investigation at multiple levels of analysis. We discuss historical examples and our own research as contemporary examples of how a SAGE model can operate in part or as an integrated whole. The implications of our model are discussed.
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http://dx.doi.org/10.1177/1745691617734863DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5946666PMC
May 2018

Therapeutic drug repositioning using personalized proteomics of liquid biopsies.

JCI Insight 2017 12 21;2(24). Epub 2017 Dec 21.

Omics Laboratory, Stanford University, Palo Alto, California, USA.

Background: In patients with limited response to conventional therapeutics, repositioning of already approved drugs can bring new, more effective options. Current drug repositioning methods, however, frequently rely on retrospective computational analyses and genetic testing - time consuming methods that delay application of repositioned drugs. Here, we show how proteomic analysis of liquid biopsies successfully guided treatment of neovascular inflammatory vitreoretinopathy (NIV), an inherited autoinflammatory disease with otherwise poor clinical outcomes.

Methods: Vitreous biopsies from NIV patients were profiled by an antibody array for expression of 200 cytokine-signaling proteins. Non-NIV controls were compared with NIV samples from various stages of disease progression. Patterns were identified by 1-way ANOVA, hierarchical clustering, and pathway analysis. Subjects treated with repositioned therapies were followed longitudinally.

Results: Proteomic profiles revealed molecular pathways in NIV pathologies and implicated superior and inferior targets for therapy. Anti-VEGF injections resolved vitreous hemorrhages without the need for vitrectomy surgery. Methotrexate injections reversed inflammatory cell reactions without the side effects of corticosteroids. Anti-IL-6 therapy prevented recurrent fibrosis and retinal detachment where all prior antiinflammatory interventions had failed. The cytokine array also showed that TNF-α levels were normal and that corticosteroid-sensitive pathways were absent in fibrotic NIV, helping explain prior failure of these conventional therapeutic approaches.

Conclusions: Personalized proteomics can uncover highly personalized therapies for autoinflammatory disease that can be timed with specific pathologic activities. This precision medicine strategy can also help prevent delivery of ineffective drugs. Importantly, proteomic profiling of liquid biopsies offers an endpoint analysis that can directly guide treatment using available drugs.
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http://dx.doi.org/10.1172/jci.insight.97818DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5752263PMC
December 2017

Personalized Proteomics in Proliferative Vitreoretinopathy Implicate Hematopoietic Cell Recruitment and mTOR as a Therapeutic Target.

Am J Ophthalmol 2018 02 13;186:152-163. Epub 2017 Dec 13.

Omics Laboratory, Stanford University, Palo Alto, California; Byers Eye Institute, Department of Ophthalmology, Stanford University, Palo Alto, California; Palo Alto Veterans Administration, Palo Alto, California. Electronic address:

Purpose: To profile vitreous cytokine expression of proliferative vitreoretinopathy (PVR) patients.

Design: Case-control study.

Methods: Liquid biopsies were collected from 2 groups: control subjects (n = 3) undergoing pars plana vitrectomy to remove an epiretinal membrane (ERM), and test subjects (n = 7) with varying degrees of PVR. A high-throughput cytokine screen measured expression of 200 cytokines. Cytokine expression patterns were prospectively validated in separate cohorts of control patients and those with PVR-A, PVR-B, and PVR-C (n = 10 for each group). Expression changes were evaluated by analysis of variance (significant P value < .05), hierarchical cluster algorithm, and pathway analysis, to identify candidate pathways for prospective studies.

Results: In PVR vitreous, 29 cytokines were upregulated compared to controls. Early PVR vitreous showed upregulation of T-cell markers, profibrotic cytokines, and cytokines downstream of mTOR activation (IL-2, IL-6, and IL-13), whereas in late PVR vitreous, cytokines driving monocyte responses and stem-cell recruitment (SDF-1) prevailed. Prospective validation confirmed the differential expression of specific cytokines from PVR-A to C.

Conclusions: Early PVR is characterized by activation of T cells and mTOR signaling, whereas advanced PVR is characterized by a chronic monocyte response. PVR might be treated by rational repositioning of existing drugs that target mTOR and IL-6. Our analysis demonstrates that successful therapeutic intervention will be highly dependent on the specific therapeutic target and the stage of PVR. This study provides insights into cytokines that will serve as biomarkers and therapeutic targets. These biomarkers will help design clinical trials that intervene at appropriate times.
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http://dx.doi.org/10.1016/j.ajo.2017.11.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5805631PMC
February 2018