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Context: Thyroid eye disease (TED) is an autoimmune disease characterized by orbital inflammation and tissue remodeling. TED pathogenesis is poorly understood but is linked to autoantibodies to thyroid-stimulating hormone receptor (TSHR) and insulin-like growth factor 1 receptor (IGF-1R). Objective: To explore the potential involvement of viral infections in TED pathogenesis. Methods: Using NCBI BLAST, we compared human TSHR and IGF-1R proteins to various viral proteomes, including Papillomaviridae , Paramyxoviridae , Herpesviridae , Enterovirus , Polyomaviridae , and Rhabdoviridae . Enzyme-linked immunoassays (ELISAs) were performed on orbital adipose tissue samples from 22 TED patients and controls to quantify antiviral antibody titers. Demographics and clinical data were reviewed. Results: Homology analysis revealed conserved motifs between TSHR and IGF-1R with several viral proteins, particularly the human papillomavirus 18 (HPV18) L1 capsid protein. Basic demographic and clinical information between the cohorts were comparable. ELISAs showed statistically significant differences in the average HPV18 L1 IgG normalized optical density levels among tissues of control ( M = 0.9387, SD = 0.3548), chronic TED ( M = 2.305, SD = 1.064), and active acute TED ( M = 4.087, SD = 2.034) patients. These elevated HPV18 L1 IgG titers did not statistically correlate with TSH, T4, or TSI levels, and were elevated in TED patients irrespective of treatment with teprotumumab, indicating a direct immunological response to HPV. Conclusions: This study presents the first molecular evidence linking HPV and TED, highlighting molecular mimicry between HPV capsid protein and key autoimmunity targets in TED. This suggests an immunological link contributing to TED's pathogenesis, opening new avenues for understanding and managing the disease.
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PURPOSE: To determine the morphology and postoperative outcomes of pediatric cataracts with thin (leptophakic) lenses. DESIGN: Retrospective comparative clinical cohort study. METHODS: We identified the records of pediatric patients who had undergone cataract surgery between 2018 and 2023 and lens thickness less than 2 standard deviations of age-stratified normal eyes in the general population. Matching controls were identified based on sex, age at surgery, and intraocular lens implant status. Data abstracted include axial length, anterior chamber depth, lens thickness, visual acuity, intraocular pressure, and surgical details. RESULTS: A total of 13 eyes from 7 patients were identified to be leptophakic, 8 of which had matching controls. Compared with the control eyes, leptophakic eyes had thinner lenses (2.74 ± 0.39 mm vs 4.82 ± 1.01 mm, P < .01) with comparable anterior chamber depth (3.28 ± 0.76 mm vs 2.98 ± 1.28 mm, P = .13) and axial lengths (19.17 ± 2.61 mm vs 20.76 ± 1.76 mm, P = .20). Following cataract surgery, visual acuity improved for both the leptophakic and control cohorts within 2.5 months postoperatively (-0.68 ± 0.37 logMAR vs -0.06 ± 0.42 logMAR, P = .03) and at 1-2 years postoperatively (-1.58 ± 1.03 logMAR vs -0.60 ± 0.49 logMAR, P = .22) without any glaucoma-related adverse events. Of note, 5 of 13 leptophakic eyes (38%) were found to have posterior capsular ruptures intraoperatively. CONCLUSIONS: Leptophakic eyes demonstrated similar intraoperative and short-term postoperative outcomes when compared to control eyes, although vigilance for posterior capsular defects and ruptures may be necessary.
Subject(s)
Leg Dermatoses , Myxedema , Humans , Myxedema/metabolism , Myxedema/therapy , Insulin-Like Peptides , Up-Regulation , Leg Dermatoses/therapyABSTRACT
Randomized controlled trials have demonstrated mortality benefits for several medication classes in patients with heart failure (HF), especially with reduced ejection fraction (EF). However, the benefit of these traditional HF therapies in patients with HF from cardiac amyloidosis is unclear. our study aimed to evaluate the safety and efficacy of traditional HF therapies in patients with cardiac amyloidosis and HF with reduced EF or HF with mid-range EF (HFmrEF). We conducted a single-center retrospective study. Patients were included if they were diagnosed with cardiac amyloidosis and HF with reduced EF or HF with mid-range EF between January 2012 and 2022. The primary outcomes of interest were medication use patterns (for ß blockers [BB], angiotensin-converting enzyme inhibitors [ACEI], angiotensin receptor blockers [ARBs], angiotensin receptor neprilysin inhibitors [ARNI], and mineralocorticoid receptor antagonists [MRAs]); potential medication side effects (symptomatic bradycardia, fatigue, hypotension, lightheadedness, and syncope); hospitalization; and death. The associations of BB, ACEI/ARB/ARNI, and MRA use with clinical outcomes were evaluated using Kaplan-Meier and Cox proportional hazards regression. A total of 82 patients met study criteria. At time of cardiac amyloidosis diagnosis, 63.4% were on a BB, 51.2% were on an ACEI/ARB/ARNI, and 43.9% were on an MRA. At last follow-up, 51.2% were on a BB, 35.4% were on an ACEI/ARB/ARNI, and 43.9% were on an MRA. There were no statistically significant differences in rates of potential medication side effects in patients on the medication class compared with those who were not. There was no association with hospitalization or mortality for baseline or follow-up BB, ACEI/ARB/ARNI, or MRA use. In conclusion, BBs, ACEI/ARB/ARNIs, and MRAs may be safely used in this population. However, their use does not appear to improve mortality or hospitalization.
Subject(s)
Heart Failure , Ventricular Dysfunction, Left , Humans , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Angiotensin Receptor Antagonists/adverse effects , Retrospective Studies , Stroke Volume , Heart Failure/complications , Heart Failure/drug therapy , Heart Failure/chemically induced , Ventricular Dysfunction, Left/chemically induced , Adrenergic beta-Antagonists/therapeutic use , Adrenergic beta-Antagonists/pharmacology , Mineralocorticoid Receptor Antagonists/therapeutic use , Mineralocorticoid Receptor Antagonists/pharmacologyABSTRACT
Although primary tumors of the lacrimal gland are rare, adenoid cystic carcinoma (ACC) is the most common and lethal epithelial lacrimal gland malignancy. Traditional management of lacrimal gland adenoid cystic carcinoma (LGACC) involves the removal of the eye and surrounding socket contents, followed by chemoradiation. Even with this radical treatment, the 10-year survival rate for LGACC is 20% given the propensity for recurrence and metastasis. Due to the rarity of LGACC, its pathobiology is not well-understood, leading to difficulties in diagnosis, treatment, and effective management. Here, we integrate bulk RNA sequencing (RNA-seq) and spatial transcriptomics to identify a specific LGACC gene signature that can inform novel targeted therapies. Of the 3499 differentially expressed genes identified by bulk RNA-seq, the results of our spatial transcriptomic analysis reveal 15 upregulated and 12 downregulated genes that specifically arise from LGACC cells, whereas fibroblasts, reactive fibrotic tissue, and nervous and skeletal muscle account for the remaining bulk RNA-seq signature. In light of the analysis, we identified a transitional state cell or stem cell cluster. The results of the pathway analysis identified the upregulation of PI3K-Akt signaling, IL-17 signaling, and multiple other cancer pathways. This study provides insights into the molecular and cellular landscape of LGACC, which can inform new, targeted therapies to improve patient outcomes.
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Condyloma acuminatum with synchronous squamous cell carcinoma in situ (CIS) rarely occurs in the bladder. In developed countries, bladder squamous cell carcinoma (SCC) is uncommon. Among the various noninvasive squamous bladder lesions, there is significant morphological overlap, which further complicates accurate diagnosis. Immunosuppression and human papilloma virus increase the risk of bladder condyloma acuminatum, which has a strong association with bladder SCC. Herein, we describe a case of a 79-year-old man with a history of end-stage renal disease with kidney transplantation and anal SCC who presented with bladder squamous cell CIS arising in the background of condyloma acuminatum.
Subject(s)
Carcinoma, Squamous Cell , Condylomata Acuminata , Kidney Transplantation , Urinary Bladder Neoplasms , Male , Humans , Aged , Urinary Bladder , Kidney Transplantation/adverse effects , Urinary Bladder Neoplasms/diagnosis , Urinary Bladder Neoplasms/surgery , Urinary Bladder Neoplasms/complications , Carcinoma, Squamous Cell/diagnosis , Carcinoma, Squamous Cell/surgery , Condylomata Acuminata/diagnosis , Condylomata Acuminata/surgery , Condylomata Acuminata/pathologyABSTRACT
A 69-year-old woman with a history of a left orbital mass presented to the emergency room with progressive breakthrough pain in her left orbit despite medical therapy. On examination, there was extraocular motility restriction with diplopia upon left supraduction. Computed tomography (CT) scan of the orbits revealed soft tissue thickening of the left medial and superior periorbita and left lacrimal fossa; bony erosion of the left frontal bone, left orbital roof, and left lamina papyracea; and bilateral mass-like enlargement of the extraocular muscles. An orbitotomy with incisional biopsy was performed, and histopathological examination revealed non-caseating granulomatous inflammation consistent with sarcoidosis. Chest imaging demonstrated no sequela of pulmonary sarcoidosis, and her serum angiotensin converting enzyme (ACE) level was within normal range. She was treated with high-dose oral steroids with resolution of her symptoms. Her pain returned at the conclusion of the steroid taper, and it was controlled with chronic subcutaneous methotrexate and adalimumab injections.
Subject(s)
Orbital Diseases , Sarcoidosis , Female , Humans , Aged , Orbit/pathology , Sarcoidosis/diagnostic imaging , Sarcoidosis/drug therapy , Orbital Diseases/diagnostic imaging , Orbital Diseases/drug therapy , Oculomotor Muscles/pathology , Granuloma/pathologyABSTRACT
A rare occurrence of an atypical case of multiple evanescent white dot syndrome (MEWDS) in a 75-year-old man without viral prodrome or white dots on fundus that presented with acute, severe left eye visual loss, which returned to baseline without treatment in several weeks. Multimodal imaging, including fluorescein angiography (FA), fundus autofluorescence (FAF), indocyanine green angiography (ICG), and optical coherence tomography (OCT) demonstrated classical presentation of MEWDS with wreath-like lesions and inflammatory foci in the retinal pigment epithelium that correlated among modalities. Possible underlying systemic disorders were ruled out through extended work up. To the best of our knowledge, this is the first report to show atypical MEWDS in an elderly man with classic changes on FA, FAF, ICG, and OCT.
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Retinoblastoma is the most common eye cancer in children and is fatal if left untreated. Over the past three decades, chemotherapy has become the mainstay of eye-sparing treatment. Nevertheless, chemoresistance continues to represent a major challenge leading to ocular and systemic toxicity, vision loss, and treatment failure. Unfortunately, the mechanisms leading to chemoresistance remain incompletely understood. Here, we engineered low-passage human retinoblastoma cells to study the early molecular mechanisms leading to resistance to carboplatin, one of the most widely used agents for treating retinoblastoma. Using single-cell next-generation RNA sequencing (scRNA-seq) and single-cell barcoding technologies, we found that carboplatin induced rapid transcriptomic reprogramming associated with the upregulation of PI3K-AKT pathway targets, including ABC transporters and metabolic regulators. Several of these targets are amenable to pharmacologic inhibition, which may reduce the emergence of chemoresistance. We provide evidence to support this hypothesis using a third-generation inhibitor of the ABCB1 transporter.
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Purpose: Müller glia (MG) in the retina of Xenopus laevis (African clawed frog) reprogram to a transiently amplifying retinal progenitor state after an injury. These progenitors then give rise to new retinal neurons. In contrast, mammalian MG have a restricted neurogenic capacity and undergo reactive gliosis after injury. This study sought to establish MG cell lines from the regeneration-competent frog and the regeneration-deficient mouse. Methods: MG were isolated from postnatal day 5 GLAST-CreERT; Rbfl/fl mice and from adult (3-5 years post-metamorphic) X laevis. Serial adherent subculture resulted in spontaneously immortalized cells and the establishment of two MG cell lines: murine retinal glia 17 (RG17) and Xenopus glia 69 (XG69). They were characterized for MG gene and protein expression by qPCR, immunostaining, and Western blot. Purinergic signaling was assessed with calcium imaging. Pharmacological perturbations with 2'-3'-O-(4-benzoylbenzoyl) adenosine 5'-triphosphate (BzATP) and KN-62 were performed on RG17 cells. Results: RG17 and XG69 cells express several MG markers and retain purinergic signaling. Pharmacological perturbations of intracellular calcium responses with BzATP and KN-62 suggest that the ionotropic purinergic receptor P2X7 is present and functional in RG17 cells. Stimulation of XG69 cells with adenosine triphosphate-induced calcium responses in a dose-dependent manner. Conclusions: We report the characterization of RG17 and XG69, two novel MG cell lines from species with significantly disparate retinal regenerative capabilities. Translational Relevance: RG17 and XG69 cell line models will aid comparative studies between species endowed with varied regenerative capacity and will facilitate the development of new cell-based strategies for treating retinal degenerative diseases.
Subject(s)
Ependymoglial Cells , Retinal Neurons , Animals , Ependymoglial Cells/metabolism , Mammals , Mice , Neuroglia/metabolism , Retina , Xenopus laevisABSTRACT
Osteogenesis imperfecta (OI) is a rare connective tissue disorder with clinical and genetic heterogeneity. The cardinal features of OI are bone fragility and low bone mineral density (BMD). Pathogenic variants in COL1A1 and COL1A2 genes, which encode the proα-1(I) and proα-2(I) chains of Type 1 collagen, are the most common causes of OI. Mutations disrupting the carboxy-terminal propeptide cleavage site of the proα-1(I) and proα-2(I) chains have recently been reported as rare causes of OI with paradoxically normal to high BMD. This report describes a father and daughter with OI who are heterozygous for a novel likely pathogenic variant at the carboxy-terminal propeptide cleavage site of COL1A1 (NM_000088.4): c.3656A>G; (p.Asp1219Gly). We describe their intrafamilial phenotypic variability and overlapping features with other COL1A1-related disorders.
Subject(s)
Osteogenesis Imperfecta , Collagen Type I/genetics , Collagen Type I, alpha 1 Chain , Heterozygote , Humans , Mutation , Osteogenesis Imperfecta/geneticsABSTRACT
PURPOSE: To investigate the effects of mitomycin-C (MMC) and 5-fluorouracil (5-FU) on the viability, proliferation, and migratory capacity of cultured ocular adnexal sebaceous carcinoma (SC) cells. DESIGN: Laboratory investigation. METHODS: Human SC cell lines (Bascom Palmer 50 and 52 [BP50 and BP52]) and human limbal stem cells (LSCs) were treated with various concentrations of MMC and 5-FU. Cytotoxicity was assessed with the tetrazolium MTT colorimetric viability assay on normal corneal vs tumor cells. Growth curves and scratch assays were performed to characterize the effects of these chemotherapeutic agents on SC proliferation and migration, respectively. RESULTS: MMC decreased BP52 cell viability in a dose-dependent manner with a half-maximal effective dose (EC50) of 11.8 µM after 72 hours. SC viability decreased >50% at 80 mM 5-FU after 72 hours. MMC reduced LSC viability in a dose-dependent manner with an EC50 value of 3.24 µM, and 5-FU decreased LSC viability >50% at 160 µM. MMC decreased SC cell proliferation and migration in a dose-dependent manner. 5-FU displayed antiproliferative effects but did not affect cell migration at concentrations below 1000 µM. CONCLUSIONS: Our in vitro data corroborate clinical observations that MMC is efficacious for treating ocular adnexal SC, albeit at the expense of LSC viability. Our findings also demonstrate that topical 5-FU exhibits antiproliferative effects that supersede its cancer-killing and antimigratory effects on cultured SC cells.
Subject(s)
Carcinoma , Eye Neoplasms , Cell Survival , Cells, Cultured , Fluorouracil/pharmacology , Humans , Mitomycin/pharmacologyABSTRACT
A 69-year-old man with myelofibrosis presented with a two-day history of left periorbital swelling, blurred vision, and non-radiating dull orbital pain. On examination, there was restricted left-sided extraocular motility with conjunctival injection, chemosis, and periorbital edema. Magnetic resonance imaging demonstrated left-sided pre- and post-septal fat stranding concerning for orbital cellulitis. Two weeks before symptom onset, the patient began fedratinib therapy for myelofibrosis but discontinued this medication upon hospital admission. After restarting fedratinib, he presented with similar right-sided ophthalmic signs. A review of his medication history revealed a temporal relationship between symptom onset and fedratinib use. After medication discontinuation, his symptoms improved rapidly.
Subject(s)
Orbital Cellulitis , Primary Myelofibrosis , Aged , Humans , Inflammation/drug therapy , Male , Orbital Cellulitis/diagnosis , Primary Myelofibrosis/diagnosis , Primary Myelofibrosis/drug therapy , Pyrrolidines/therapeutic use , SulfonamidesABSTRACT
PURPOSE: Based on the differential gene expression analysis for predictive biomarkers with RNA-Sequencing data from Fuchs endothelial corneal dystrophy (FECD) patients, we are aiming to evaluate the efficacy of Library of Integrated Network-based Cellular Signatures (LINCS) perturbagen prediction software to identify novel pharmacotherapeutic targets that can revert the pathogenic gene expression signatures and reverse disease phenotype in FECD. METHODS: A publicly available RNA-seq dataset was used to compare corneal endothelial specimens from controls and patients with FECD. Based on the differential gene expression analysis for predictive biomarkers, we evaluated the efficacy of LINCS perturbagen prediction software to identify novel therapeutic targets that can revert the pathogenic gene expression signatures and reverse disease phenotypes in FECD. RESULTS: The RNA-seq dataset of the corneal endothelial cells from FECD patients revealed the differential gene expression signatures of FECD. Many of the differential expressed genes are related to canonical pathways of the FECD pathogenesis, such as extracellular matrix reorganization and immunological response. The expression levels of genes VSIG2, IL18, and ITGB8 were significantly increased in FECD compared with control. Meanwhile, the expression levels of CNGA3, SMOX, and CERS1 were significantly lower in the FECD than in control. We employed LINCS L1000 Characteristic Direction Signature Search Engine (L1000-CDS2) to investigate pathway-based molecular treatment. L1000-CDS2 predicted that small molecule drugs such as histone deacetylase (HDAC) inhibitors might be a potential candidate to reverse the pathological gene expression signature in FECD. CONCLUSIONS: Based on differential gene expression signatures, several candidate drugs have been identified to reverse the disease phenotypes in FECD. Gene expression signature with LINCS small molecule prediction software can discover novel preclinical drug candidates for FECD.
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Purpose: Sebaceous carcinoma (SC) is a malignant eyelid tumor of the ocular adnexa that is primarily treated via surgical excision. Few therapies exist in advanced cases, and medical therapy is limited because of our incomplete understanding of SC biology. Herein, we describe a technique to culture human ocular adnexal SC for use as an in vitro model. Methods: Human ocular adnexal SC tumor cells were isolated from a patient undergoing orbital exenteration surgery and named Bascom Palmer 50 (BP50). They were cultured in Dulbecco's modified Eagle medium/nutrient mixture F-12 supplemented with 10% fetal bovine serum and antibiotics and were maintained at 37°C in humidified 5% CO2. The cells were characterized by immunohistochemistry, exome sequencing, and short tandem repeats analysis. In vitro drug screening against mitomycin-C (MMC) was performed using a cell viability assay. Results: BP50 grew past 40 passages with a doubling time of 52.3 hours. Immunocytochemical staining revealed expression of SC-associated markers adipophilin, epithelial membrane antigen, p53, and androgen receptor. Whole exome sequencing showed a significant carryover in somatic mutations between the tumor tissue and corresponding cell line, revealing genetic markers consistent with SC. MMC affected cell viability in a dose-dependent manner. Conclusions: BP50 displays characteristics of ocular adnexal SC and therefore may facilitate improved understanding of SC biology and the high throughput assessment of novel therapeutic compounds and new drug combinatorial approaches targeted for this disease. Translational Relevance: Drug screening with MMC against these cells shows in vitro evidence to support its continued clinical use in SC.
Subject(s)
Adenocarcinoma, Sebaceous , Eye Neoplasms , Eyelid Neoplasms , Sebaceous Gland Neoplasms , Cell Line , Eye Neoplasms/drug therapy , Eyelid Neoplasms/drug therapy , HumansABSTRACT
A 65-year-old woman presented with a 6-week history of redness, eyelid swelling, and discharge in the right eye. Slit lamp examination revealed right medial canthal erythema with cicatricial lower lid ectropion, retraction, and inferior punctal obliteration. The patient was previously diagnosed with a medial canthal basal cell carcinoma 1.5 years ago, but opted for self-treatment with black salve, a commonly used naturopathic "cure" for skin cancer. Each application resulted in increasingly severe periorbital inflammation with eventual eschar formation. Over time, this led to cicatricial band formation over the medial canthus. After biopsy confirmation of residual basal cell carcinoma within the cicatricial tissues, the patient underwent Mohs surgery followed by multistaged reconstruction. Herein, we report a case of patient whose use of an unproven naturopathic "cure" led to persistent periorbital inflammation, persistence of malignancy, and significant tissue destruction.
Subject(s)
Carcinoma, Basal Cell , Ectropion , Sanguinaria , Aged , Carcinoma, Basal Cell/surgery , Ectropion/surgery , Eyelids/surgery , Female , Humans , Mohs SurgeryABSTRACT
A 9-year-old girl presented with a 3-day history of progressive proptosis accompanied by transient discomfort and blurry vision in the OD. MRI revealed a heterogeneously enhancing intraconal lesion that partially encased and displaced the optic nerve. There was no intraocular or intracranial involvement, nor were there signs of distant metastasis. Histopathologic evaluation and immunohistochemistry were consistent with orbital medulloepithelioma. The patient received 4 cycles of chemoradiation per a retinoblastoma protocol. Repeat MRI scans showed significant tumor regression, and further surgical debulking was performed. There has been no evidence of recurrence for over 14 months. Herein, the authors describe an eye-sparing, multimodal treatment of a rare case of localized orbital medulloepithelioma.
Subject(s)
Neuroectodermal Tumors, Primitive , Retinal Neoplasms , Retinoblastoma , Child , Female , Humans , Neoadjuvant Therapy , Neoplasm Recurrence, Local , Neuroectodermal Tumors, Primitive/diagnosis , Neuroectodermal Tumors, Primitive/therapyABSTRACT
A 68-year-old man with a history of type 2 diabetes mellitus and kidney transplantation on chronic immunosuppression presented with right-sided proptosis and vision loss. He was hospitalized 4 months prior for invasive sinus aspergillosis. MRI revealed abnormal enhancement in the right orbital apex, inferior medial right orbit, anterior cranial fossa floor, and anterior aspect of the falx cerebri. The patient was successfully managed with extensive sinus surgery, bifrontal craniotomy with resection of dura, cribriform plate resection, and a right orbital apex exenteration. The globe and anterior orbital structures were preserved to cover the large surgical sinodural-orbital defect and avoid complex reconstructive surgery. Orbital perfusion was maintained by exploiting the robust anastomoses between branches of external carotid and ophthalmic artery.
Subject(s)
Diabetes Mellitus, Type 2 , Aged , Craniotomy , Humans , Male , Orbit/diagnostic imaging , Orbit/surgery , Orbit Evisceration , PerfusionABSTRACT
Purpose: To evaluate the efficacy of Library of Integrated Network-based Cellular Signatures (LINCS) perturbagen prediction software to identify small molecules that revert pathologic gene signature and alter disease phenotype in orbital adipose stem cells (OASCs) derived from patients with thyroid-associated orbitopathy (TAO). Methods: Differentially expressed genes identified via RNA sequencing were inputted into LINCS L1000 Characteristic Direction Signature Search Engine (L1000CDS2) to predict candidate small molecules to reverse pathologic gene expression. TAO OASC cell lines were treated in vitro with six identified small molecules (Torin-2, PX12, withaferin A, isoliquiritigenin, mitoxantrone, and MLN8054), and expression of key adipogenic and differentially expressed genes was measured with quantitative polymerase chain reaction after 7 days of treatment. OASCs were differentiated into adipocytes, treated for 15 days, and stained with Oil Red O (OD 490 nm) to evaluate adipogenic changes. Results: The expression of key differentially expressed genes (IRX1, HOXB2, S100B, and KCNA4) and adipogenic genes (peroxisome proliferator activated receptor-γ, FABP4) was significantly decreased in TAO OASCs after treatment (P < .05). In treated TAO adipocytes (n = 3), all six tested small molecules yielded significant decrease (P < .05) in Oil Red O staining. In treated non-TAO adipocytes (n = 3), only three of the drugs yielded a significant decrease in Oil Red O staining. Conclusions: Combining disease expression signatures with LINCS small molecule prediction software can identify promising preclinical drug candidates for TAO. Translational Relevance: These findings may offer insight into future potential therapeutic options for TAO and demonstrate a streamlined model to predict drug candidates for other diseases.
Subject(s)
Graves Ophthalmopathy , Adipocytes , Adipogenesis/genetics , Adipose Tissue , Gene Expression , Graves Ophthalmopathy/drug therapy , Homeodomain Proteins , Humans , Transcription FactorsABSTRACT
Traumatic optic neuropathy (TON) can occur following blunt trauma to the orbit and can lead to permanent vision loss. In this study, we investigated the effectiveness of elamipretide (MTP-131), a small mitochondrially-targeted tetrapeptide, in conjunction with etanercept, a tumor necrosis factor (TNF) inhibitor, as neuroprotective agents of retinal ganglion cells (RGCs) after optic nerve trauma with sonication-induced TON (SI-TON) in mice. Treatment with intravitreal MTP-131 and subcutaneous etanercept and MTP-131 showed a 21% increase (p < 0.01) in RGC survival rate compared to PBS-treated control eyes. Subcutaneous etanercept and MTP-131 had an 11% increase (p < 0.05) in RGC survival compared to controls. Subcutaneous etanercept only group showed 20% increase (p < 0.01) in RGC survival compared to controls, while subcutaneous MTP-131 alone showed a 17% increase (p < 0.01). Surprisingly, we did not observe a synergistic effect between the two drugs in the group receiving both etanercept and MTP-131. One possible explanation for the absence of a synergistic effect is that MTP-131 and etanercept may be acting on different portions of the same pathway.