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Strainiene E, Binkis M, Urnikyte S, Stankevicius V, Sasnauskiene A, Kundrotas G, Kazlauskas A, Suziedelis K. Microenvironment dependent gene expression signatures in reprogrammed human colon normal and cancer cell lines. BMC Cancer 2018;18(1):222.Abstract
BACKGROUND: Since the first evidence suggesting existence of stem-like cancer cells, the process of cells reprogramming to the stem cell state remains as an attractive tool for cancer stemness research. Current knowledge in the field of cancer stemness, indicates that the microenvironment is a fundamental regulator of cell behavior. With regard to this, we investigated the changes of genome wide gene expression in reprogrammed human colon normal epithelial CRL-1831 and colon carcinoma DLD1 cell lines grown under more physiologically relevant three-dimensional (3D) cell culture microenvironment compared to 2D monolayer. METHODS: Whole genome gene expression changes were evaluated in both cell lines cultured under 3D conditions over a 2D monolayer by gene expression microarray analysis. To evaluate the biological significance of gene expression changes, we performed pathway enrichment analysis using the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Gene network analysis was used to study relationships between differentially expressed genes (DEGs) in functional categories by the GeneMANIA Cytoscape toolkit. RESULTS: In total, we identified 3228 and 2654 differentially expressed genes (DEGs) for colon normal and cancer reprogrammed cell lines, respectively. Furthermore, the expression of 1097 genes was commonly regulated in both cell lines. KEGG enrichment analysis revealed that in total 129 and 101 pathways for iPSC-CRL-1831 and for CSC-DLD1, respectively, were enriched. Next, we grouped these pathways into three functional categories: cancer transformation/metastasis, cell interaction, and stemness. β-catenin (CTNNB1) was confirmed as a hub gene of all three functional categories. CONCLUSIONS: Our present findings suggest common pathways between reprogrammed human colon normal epithelium (iPSC-CRL-1831) and adenocarcinoma (CSC-DLD1) cells grown under 3D microenvironment. In addition, we demonstrated that pathways important for cancer transformation and tumor metastatic activity are altered both in normal and cancer stem-like cells during the transfer from 2D to 3D culture conditions. Thus, we indicate the potential of cell culture models enriched in normal and cancer stem-like cells for the identification of new therapeutic targets in cancer treatment.
Chen X, Liu Y, Zhang Y, Kam WR, Pasquale LR, Sullivan DA. Impact of aromatase absence on murine intraocular pressure and retinal ganglion cells. Sci Rep 2018;8(1):3280.Abstract
We hypothesize that aromatase, an enzyme that regulates estrogen production, plays a significant role in the control of intraocular pressure (IOP) and retinal ganglion cells (RGCs). To begin to test our hypothesis, we examined the impact of aromatase absence, which completely eliminates estrogen synthesis, in male and female mice. Studies were performed with adult, age-matched wild type (WT) and aromatase knockout (ArKO) mice. IOP was measured in a masked fashion in both eyes of conscious mice at 12 and 24 weeks of age. Retinas were obtained and processed for RGC counting with a confocal microscope. IOP levels in both 12- and 24-week old female ArKO mice were significantly higher than those of age- and sex-matched WT controls. The mean increase in IOP was 7.9% in the 12-week-, and 19.7% in the 24-week-old mice, respectively. These changes were accompanied by significant 9% and 7% decreases in RGC numbers in the ArKO female mice, relative to controls, at 12- and 24-weeks, respectively. In contrast, aromatase deficiency did not lead to an increased IOP in male mice. There was a significant reduction in RGC counts in the 12-, but not 24-, week-old male ArKO mice, as compared to their age- and sex-matched WT controls. Overall, our findings show that aromatase inhibition in females is associated with elevated IOP and reduced RGC counts.
Wan MJ, Gilbert A, Kazlas M, Wu C, Mantagos IS, Hunter DG, Shah AS. The Effect of Botulinum Toxin Augmentation on Strabismus Surgery for Large-Angle Infantile Esotropia. Am J Ophthalmol 2018;189:160-165.Abstract
PURPOSE: To determine whether botulinum toxin augments the effect of strabismus surgery in pediatric patients with large-angle infantile esotropia. DESIGN: Retrospective, comparative, case series. METHODS: Setting: Tertiary-care pediatric hospital. STUDY POPULATION: Patients with large-angle infantile esotropia. INTERVENTION: Treatment with botulinum toxin-augmented bilateral medial rectus muscle recessions ("augmented-surgery group") or traditional bilateral medial rectus muscle recessions ("surgery-only group"). MAIN OUTCOME MEASURE: The effect of surgery on ocular alignment at 4 months, measured in prism diopters of change per mm of surgery (PD/mm). RESULTS: There were 14 patients in the augmented-surgery group and 16 patients in the surgery-only group. The mean effect on alignment was significantly greater in the augmented-surgery group compared to the surgery-only group at 4 months (5.7 ± 1.3 vs 4.0 ± 1.4 PD/mm, P = .002) and at 1 year (5.4 ± 1.2 vs 3.7 ± 1.2 PD/mm, P = .002). There was a partial loss of treatment effect between 4 months and 1 year in both groups, which was similar in magnitude (P = .57). On linear regression, there was a trend toward a positive correlation between botulinum toxin dose and treatment effect, but this was not statistically significant (P = .09). CONCLUSIONS: Botulinum toxin augments the surgical effect of medial rectus muscle recession. Botulinum toxin-augmented surgery may be an alternative to traditional options for large-angle infantile esotropia. A surgical dosing table is proposed for this technique.
Li W, Webster KA, LeBlanc ME, Tian H. Secretogranin III: a diabetic retinopathy-selective angiogenic factor. Cell Mol Life Sci 2018;75(4):635-647.Abstract
Secretogranin III (Scg3) is a member of the granin protein family that regulates the biogenesis of secretory granules. Scg3 was recently discovered as an angiogenic factor, expanding its functional role to extrinsic regulation. Unlike many other known angiogenic factors, the pro-angiogenic actions of Scg3 are restricted to pathological conditions. Among thousands of quantified endothelial ligands, Scg3 has the highest binding activity ratio to diabetic vs. healthy mouse retinas and lowest background binding to normal vessels. In contrast, vascular endothelial growth factor binds to and stimulates angiogenesis of both diabetic and control vasculature. Consistent with its role in pathological angiogenesis, Scg3-neutralizing antibodies alleviate retinal vascular leakage in mouse models of diabetic retinopathy and retinal neovascularization in oxygen-induced retinopathy mice. This review summarizes our current knowledge of Scg3 as a regulatory protein of secretory granules, highlights its new role as a highly disease-selective angiogenic factor, and envisions Scg3 inhibitors as "selective angiogenesis blockers" for targeted therapy.
Jakobiec FA, Ma L, Wolkow N, Cameron DJ, Maltry AC. Osseous and Adipocytic Differentiations in the Intraocular Lens and Vitreous. Am J Ophthalmol 2018;186:77-88.Abstract
PURPOSE: To analyze 3 unusual mesenchymal transformations within the eye: adipose or osseous metaplasia of the lens and adipose tissue in the vitreous cavity. DESIGN: Observational case series. METHODS: Reevaluation of clinicopathologic diagnoses and histopathologic findings in sections stained with hematoxylin-eosin, periodic acid-Schiff (PAS) reaction, and Masson trichrome method. RESULTS: The 3 cases of mesenchymal transformation occurred in microphthalmic eyes with persistent hyperplastic primary vitreous (more recently termed persistent fetal vasculature). In 1 case there was total lens replacement with lamellar bone; in another, total replacement of the crystalline lens by adipose tissue; and in a third, an anomalous pocket of adipose tissue in the central vitreous. Multifocal remnants of the lens capsule were seen in the osseous case but were absent from the adipocytic cases. The vitreous adipose tissue was surrounded by an elaborate capillary plexus with an empty, collapsed PAS-positive lens capsule in the pupillary region. Anterior pigmented neuroectodermal disorganization, dysgenesis of angle structures, and a hypoplastic or disorganized iris were also observed in the 3 cases. CONCLUSIONS: After review of the literature, it appears that lenticular osseous replacement occurs more often than adipocytic. In addition to vascularization of the lens through a capsular dehiscence, other causes are explored, including direct epithelial-mesenchymal transformations of the lens epithelium or, less likely, of the disorganized adjacent neuroectoderm. The focus of vitreous adipose tissue may represent a transformed luxated lens extruded from its capsule, which was left behind in the pupillary zone.
Cheng L, Wong LJ, Yan N, Han RC, Yu H, Guo C, Batsuuri K, Zinzuwadia A, Guan R, Cho K-S, Chen DF. Ezh2 does not mediate retinal ganglion cell homeostasis or their susceptibility to injury. PLoS One 2018;13(2):e0191853.Abstract
Epigenetic predisposition is thought to critically contribute to adult-onset disorders, such as retinal neurodegeneration. The histone methyltransferase, enhancer of zeste homolog 2 (Ezh2), is transiently expressed in the perinatal retina, particularly enriched in retinal ganglion cells (RGCs). We previously showed that embryonic deletion of Ezh2 from retinal progenitors led to progressive photoreceptor degeneration throughout life, demonstrating a role for embryonic predisposition of Ezh2-mediated repressive mark in maintaining the survival and function of photoreceptors in the adult. Enrichment of Ezh2 in RGCs leads to the question if Ezh2 also mediates gene expression and function in postnatal RGCs, and if its deficiency changes RGC susceptibility to cell death under injury or disease in the adult. To test this, we generated mice carrying targeted deletion of Ezh2 from RGC progenitors driven by Math5-Cre (mKO). mKO mice showed no detectable defect in RGC development, survival, or cell homeostasis as determined by physiological analysis, live imaging, histology, and immunohistochemistry. Moreover, RGCs of Ezh2 deficient mice revealed similar susceptibility against glaucomatous and acute optic nerve trauma-induced neurodegeneration compared to littermate floxed or wild-type control mice. In agreement with the above findings, analysis of RNA sequencing of RGCs purified from Ezh2 deficient mice revealed few gene changes that were related to RGC development, survival and function. These results, together with our previous report, support a cell lineage-specific mechanism of Ezh2-mediated gene repression, especially those critically involved in cellular function and homeostasis.
Utochkin IS, Wolfe JM. Visual search for changes in scenes creates long-term, incidental memory traces. Atten Percept Psychophys 2018;80(4):829-843.Abstract
Humans are very good at remembering large numbers of scenes over substantial periods of time. But how good are they at remembering changes to scenes? In this study, we tested scene memory and change detection two weeks after initial scene learning. In Experiments 1-3, scenes were learned incidentally during visual search for change. In Experiment 4, observers explicitly memorized scenes. At test, after two weeks observers were asked to discriminate old from new scenes, to recall a change that they had detected in the study phase, or to detect a newly introduced change in the memorization experiment. Next, they performed a change detection task, usually looking for the same change as in the study period. Scene recognition memory was found to be similar in all experiments, regardless of the study task. In Experiment 1, more difficult change detection produced better scene memory. Experiments 2 and 3 supported a "depth-of-processing" account for the effects of initial search and change detection on incidental memory for scenes. Of most interest, change detection was faster during the test phase than during the study phase, even when the observer had no explicit memory of having found that change previously. This result was replicated in two of our three change detection experiments. We conclude that scenes can be encoded incidentally as well as explicitly and that changes in those scenes can leave measurable traces even if they are not explicitly recalled.
Salongcay RP, Silva PS. The Role of Teleophthalmology in the Management of Diabetic Retinopathy. Asia Pac J Ophthalmol (Phila) 2018;Abstract
The emergence of diabetes as a global epidemic is accompanied by the rise in diabetes‑related retinal complications. Diabetic retinopathy, if left undetected and untreated, can lead to severe visual impairment and affect an individual's productivity and quality of life. Globally, diabetic retinopathy remains one of the leading causes of visual loss in the working‑age population. Teleophthalmology for diabetic retinopathy is an innovative means of retinal evaluation that allows identification of eyes at risk for visual loss, thereby preserving vision and decreasing the overall burden to the health care system. Numerous studies worldwide have found teleophthalmology to be a reliable and cost‑efficient alternative to traditional clinical examinations. It has reduced barriers to access to specialized eye care in both rural and urban communities. In teleophthalmology applications for diabetic retinopathy, it is critical that standardized protocols in image acquisition and evaluation are used to ensure low image ungradable rates and maintain the quality of images taken. Innovative imaging technology such as ultrawide field imaging has the potential to provide significant benefit with integration into teleophthalmology programs. Teleophthalmology programs for diabetic retinopathy rely on a comprehensive and multidisciplinary approach with partnerships across specialties and health care professionals to attain wider acceptability and allow evidence‑based eye care to reach a much broader population.
Keohane CE, Steele AD, Fetzer C, Khowsathit J, Van Tyne D, Moynié L, Gilmore MS, Karanicolas J, Sieber SA, Wuest WM. Promysalin Elicits Species-Selective Inhibition of Pseudomonas aeruginosa by Targeting Succinate Dehydrogenase. J Am Chem Soc 2018;140(5):1774-1782.Abstract
Natural products have served as an inspiration to scientists both for their complex three-dimensional architecture and exquisite biological activity. Promysalin is one such Pseudomonad secondary metabolite that exhibits narrow-spectrum antibacterial activity, originally isolated from the rhizosphere. We herein utilize affinity-based protein profiling (AfBPP) to identify succinate dehydrogenase (Sdh) as the biological target of the natural product. The target was further validated in silico, in vitro, in vivo, and through the selection, and sequencing, of a resistant mutant. Succinate dehydrogenase plays an essential role in primary metabolism of Pseudomonas aeruginosa as the only enzyme that is involved both in the tricarboxylic acid cycle (TCA) and in respiration via the electron transport chain. These findings add credence to other studies that suggest that the TCA cycle is an understudied target in the development of novel therapeutics to combat P. aeruginosa, a significant pathogen in clinical settings.
Bauer CM, Cattaneo Z, Merabet LB. Early blindness is associated with increased volume of the uncinate fasciculus. Eur J Neurosci 2018;47(5):427-432.Abstract
Growing evidence demonstrates dramatic structural and functional neuroplastic changes in individuals born with early-onset blindness. For example, cross-modal sensory processing at the level of the occipital cortex appears to be associated with adaptive behaviors in the blind. However, detailed studies examining the structural properties of key white matter pathways in other regions of the brain remain limited. Given that blind individuals rely heavily on their sense of hearing, we examined the structural properties of two important pathways involved with auditory processing, namely the uncinate and arcuate fasciculi. High angular resolution diffusion imaging (HARDI) tractography was used to examine structural parameters (i.e., tract volume and quantitative anisotropy, or QA) of these two fasciculi in a sample of 13 early blind individuals and 14 normally sighted controls. Compared to controls, early blind individuals showed a significant increase in the volume of the left uncinate fasciculus. A small area of increased QA was also observed halfway along the right arcuate fasciculus in the blind group. These findings contribute to our knowledge regarding the broad neuroplastic changes associated with profound early blindness.
King R, Struebing FL, Li Y, Wang J, Koch AA, Cooke Bailey JN, Gharahkhani P, Gharahkhani P, Gharahkhani P, Macgregor S, Allingham RR, Hauser MA, Wiggs JL, Geisert EE. Genomic locus modulating corneal thickness in the mouse identifies POU6F2 as a potential risk of developing glaucoma. PLoS Genet 2018;14(1):e1007145.Abstract
Central corneal thickness (CCT) is one of the most heritable ocular traits and it is also a phenotypic risk factor for primary open angle glaucoma (POAG). The present study uses the BXD Recombinant Inbred (RI) strains to identify novel quantitative trait loci (QTLs) modulating CCT in the mouse with the potential of identifying a molecular link between CCT and risk of developing POAG. The BXD RI strain set was used to define mammalian genomic loci modulating CCT, with a total of 818 corneas measured from 61 BXD RI strains (between 60-100 days of age). The mice were anesthetized and the eyes were positioned in front of the lens of the Phoenix Micron IV Image-Guided OCT system or the Bioptigen OCT system. CCT data for each strain was averaged and used to QTLs modulating this phenotype using the bioinformatics tools on GeneNetwork (www.genenetwork.org). The candidate genes and genomic loci identified in the mouse were then directly compared with the summary data from a human POAG genome wide association study (NEIGHBORHOOD) to determine if any genomic elements modulating mouse CCT are also risk factors for POAG.This analysis revealed one significant QTL on Chr 13 and a suggestive QTL on Chr 7. The significant locus on Chr 13 (13 to 19 Mb) was examined further to define candidate genes modulating this eye phenotype. For the Chr 13 QTL in the mouse, only one gene in the region (Pou6f2) contained nonsynonymous SNPs. Of these five nonsynonymous SNPs in Pou6f2, two resulted in changes in the amino acid proline which could result in altered secondary structure affecting protein function. The 7 Mb region under the mouse Chr 13 peak distributes over 2 chromosomes in the human: Chr 1 and Chr 7. These genomic loci were examined in the NEIGHBORHOOD database to determine if they are potential risk factors for human glaucoma identified using meta-data from human GWAS. The top 50 hits all resided within one gene (POU6F2), with the highest significance level of p = 10-6 for SNP rs76319873. POU6F2 is found in retinal ganglion cells and in corneal limbal stem cells. To test the effect of POU6F2 on CCT we examined the corneas of a Pou6f2-null mice and the corneas were thinner than those of wild-type littermates. In addition, these POU6F2 RGCs die early in the DBA/2J model of glaucoma than most RGCs. Using a mouse genetic reference panel, we identified a transcription factor, Pou6f2, that modulates CCT in the mouse. POU6F2 is also found in a subset of retinal ganglion cells and these RGCs are sensitive to injury.
Vazirani J, Nair D, Shanbhag S, Wurity S, Ranjan A, Sangwan V. Limbal Stem Cell Deficiency - Demography And Underlying Causes. Am J Ophthalmol 2018;Abstract
PURPOSE: To determine the demographic features of patients affected by limbal stem cell deficiency (LSCD), and to identify the underlying causes of LSCD DESIGN: Retrospective, multi-center case series SETTING: Two large tertiary care ophthalmology hospitals SUBJECTS: Patients with a diagnosis of LSCD presenting from January 1, 2005 to December 31, 2014 METHODS: Records of patients with a clinical diagnosis of LSCD were reviewed. Demographic details and clinical features at presentation, as well as the underlying cause of LSCD (if identified) were noted. Descriptive statistical analysis and chart preparation were done. MAIN OUTCOME MEASURES: Type of LSCD (unilateral or bilateral), age and sex of patients, extent of LSCD (clock hours of limbus involved) and underlying cause of LSCD RESULTS: We found 1331 patients with LSCD in the ten year period under study. Unilateral LSCD was more common (791 patients) than bilateral LSCD (540 patients). Out of 1331 patients, 875 (65.74%) were male. The median age of patients was 24 years. Extent of LSCD could be determined in 1849 eyes, of which 1239 eyes (67%) had total LSCD. The underlying cause of LSCD could be identified in 1512 eyes. In cases of unilateral LSCD, ocular surface burns was the commonest identifiable cause ( 83.73%). The leading identifiable causes of bilateral LSCD were ocular surface burns (29.95%), allergic conjunctivitis (29.48%), Stevens Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) (23.11%), aniridia (9.43%) and mucous membrane pemphigoid (3.54%). Lime ("chuna") injury was responsible for ocular surface burns in 352 (62.08%) out of 567 cases in which the agent was identified. CONCLUSIONS: In our study, unilateral LSCD was more common than bilateral LSCD. Young males were commonly affected, with a majority of eyes suffering from total LSCD. Overall, ocular surface burns are the leading cause of LSCD.Unilateral and bilateral LSCD had a markedly different distribution of causes, necessitating different approaches to management.
Stahl A, Krohne TU, Eter N, Oberacher-Velten I, Guthoff R, Meltendorf S, Ehrt O, Aisenbrey S, Roider J, Gerding H, Jandeck C, Smith LEH, Walz JM, for and in of Group CARDSERP (CARE-ROP) S. Comparing Alternative Ranibizumab Dosages for Safety and Efficacy in Retinopathy of Prematurity: A Randomized Clinical Trial. JAMA Pediatr 2018;172(3):278-286.Abstract
Importance: Anti-vascular endothelial growth factor (VEGF) therapies are a novel treatment option in retinopathy of prematurity (ROP). Data on dosing, efficacy, and safety are insufficient. Objective: To investigate lower doses of anti-VEGF therapy with ranibizumab, a substance with a significantly shorter systemic half-life than the standard treatment, bevacizumab. Design, Setting, and Participants: This randomized, multicenter, double-blind, investigator-initiated trial at 9 academic medical centers in Germany compared ranibizumab doses of 0.12 mg vs 0.20 mg in infants with bilateral aggressive posterior ROP; ROP stage 1 with plus disease, 2 with plus disease, or 3 with or without plus disease in zone I; or ROP stage 3 with plus disease in posterior zone II. Patients were recruited between September 2014 and August 2016. Twenty infants were screened and 19 were randomized. Interventions: All infants received 1 baseline ranibizumab injection per eye. Reinjections were allowed in case of ROP recurrence after at least 28 days. Main Outcomes and Measures: The primary end point was the number of infants who did not require rescue therapy at 24 weeks. Key secondary end points included time-to-event analyses, progression of physiologic vascularization, and plasma VEGF levels. Stages of ROP were photodocumented and reviewed by an expert committee. Results: Nineteen infants with ROP were enrolled (9 [47.4%] female; median [range] postmenstrual age at first treatment, 36.4 [34.7-39.7] weeks), 3 of whom died during the study (1 in the 0.12-mg group and 2 in the 0.20-mg group). Of the surviving infants, 8 (88.9%) (17 eyes [94.4%]) in the 0.12-mg group and 6 (85.7%) (13 eyes [92.9%]) in the 0.20-mg group did not require rescue therapy. Both ranibizumab doses were equally successful in controlling acute ROP (Cochran-Mantel-Haenszel analysis; odds ratio, 1.88; 95% CI, 0.26-13.49; P = .53). Physiologic intraretinal vascularization was superior in the 0.12-mg group. The VEGF plasma levels were not systematically altered in either group. Conclusions and Relevance: This pilot study demonstrates that ranibizumab is effective in controlling acute ROP and that 24% of the standard adult dose (0.12 mg) appears equally effective as 40% (0.20 mg). Superior vascularization of the peripheral retina with 0.12 mg of ranibizumab indicates that the lower dose may be favorable. Unchanged plasma VEGF levels point toward a limited systemic drug exposure after ranibizumab. Trial Registration: clinicaltrials.gov Identifier: NCT02134457 and clinicaltrialsregister.eu Identifier: 2013-002539-13.
Ma L, Jakobiec FA, Wolkow N, Dryja TP, Borodic GE. Multiple Eyelid Cysts (Apocrine and Eccrine Hidrocystomas, Trichilemmal Cyst, and Hybrid Cyst) in a Patient With a Prolactinoma. Ophthalmic Plast Reconstr Surg 2018;34(3):e83-e85.Abstract
A 53-year-old man presented with smooth-domed, variegated cysts (polycystic disease) of all 4 eyelids, worse on the left side. Some of the cysts were clear, while others were creamy-white colored. In addition, multiple, very fine vesicopapules were noted along the eyelid margins. Histopathologic examination revealed a trichilemmal cyst, several pure apocrine hidrocystomas displaying multiple chambers, a hybrid cyst, and many small eccrine cysts of the deep dermis. The apocrine lesions, including the small ones at the eyelid margins, predominated. Smooth muscle actin sometimes positively stained outer myoepithelial cells in some of the apocrine cysts, which helped to distinguish them from eccrine cysts. Most noteworthy was the fact that the patient had been diagnosed with a prolactinoma 20 years earlier. There is only 1 previous report of multiple apocrine cysts and an antecedent prolactinoma in the dermatologic literature. This syndrome should be separated from that of Schöpf-Schulz-Passarge, which manifests multiple small eyelid apocrine cysts and other ectodermal dysplasias without any association with neoplasia, and from that of focal dermal hypoplasia (Goltz-Gorlin) syndrome with apocrine cysts but again without neoplasia.

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