bluuebunny/crossref_metadata_2025_split huggingface dataset:
Protein kinase inhibitors for targeting tumor‐initiating cells in uveal melanoma
Authors: Cabre Estivill E. , Pereira E. , Vinyals A. , Lorenzo D. , Varela M. , Piulats J.M. , Caminal J.M. , Fabra À. 
Published: September 2017

PurposeUveal Melanoma (UM) is the most common intraocular tumor in adults. Surgery and brachytherapies have improved survival rates, but up to 40% of patients develop liver metastases.Mutations in the Gαq family members GNAQ and GNA11 are present in 80% of UM tumors whereas BRAF mutations are much less common. Consequently, Protein Kinase signaling pathways are dysregulated and specific targets can be identified for precise therapeutic approach. On the other hand, it has been proposed that tumors contain a specialized subset of cells defined as tumor‐initiating cells (TICs) that may be responsible for de novo resistance to drugs and metastatic disease. Thus, targeting TICs may be imperative for achieving a cure.MethodsTo this end, we performed an in vitro screening using the Screen‐Well® Kinase Inhibitor Library (BML‐2832‐0100) on TIC‐enriched populations of UM cells harboring either GNAQ /GNA11 or BRAF mutations.ResultsThese UM‐TICs have the capacity to self‐renew and generate tumor spheres (melanospheres) in low‐adherent culture conditions. Furthermore, they display stem cell‐like features such as high expression of CD133, CD44, Nestin or ABCB5 specific markers. The metastatic ability of OMM‐2.5‐enriched TIC cells is currently explored in vivo after their orthotopic injection into the uvea of HL‐SCID mice. Our results revealed that metastatic and TIC‐enriched populations were more resistant to antiproliferative effects of kinase inhibitors. Several kinase inhibitors such as Tyrphostin 51 (EGFRi), DES (PKCi), DRB (CK2i) and ML‐9 (MLCKi) differentially affected growth and survival of TIC‐enriched population from parental cell line Mel270.ConclusionsTaken together, we showed that EGFR, MAPK, PKC and PI3K signaling pathways are activated in TICs and their respective inhibitors may represent attractive therapeutic candidates for metastatic UM.
Retinal involvement in mitochondrial diseases
Authors: Leroy B.P. 
Published: September 2017

PurposeTo describe the retinal phenotypes of mitochondrial conditions.MethodsA case presentation format will be used to illustrate different retinal conditions due to mitochondrial mutations. Both clinical and electrophysiological phenotypes as well as genotypes will be discussed.ResultsPhenotypes and genotypes of mitochondrial diseases leading to retinal involvement are very different. The degree of retinal involvement is very variable, both between families and within the same family.ConclusionsRetinal involvement of mitochondrial disease is very diverse. Specialised imaging, psychophysics and visual electrophysiology are important tools to estimate severity of involvement.
Patient management – genetic testing and practical considerations
Authors: Liskova P. , Kolarova H. , Kousal B. , Honzik T. 
Published: September 2017

SummaryMitochondrial diseases frequently manifest with ocular signs involving the optic nerves, extraocular muscles and retina; therefore, the ophthalmologist is, in many cases, the first specialist consulted. During the last decade, it has been shown that even disorders originally thought to be an isolated ocular entity may display a broad spectrum of overlapping phenotypes affecting multiple organs. This makes genetic counselling challenging. Ophthalmic examination using state of the art imaging, such as optical coherence tomography and autofluorescence, may identify subclinical disease, therefore ophthalmologists can play an important role in guiding further investigation and molecular testing. It is becoming apparent that clinical classification should be associated with the underlying genetic defect to improve our understanding of genotype‐phenotype correlation for these conditions. Supported by AZV 16‐32341A.
Artistic depictions of the eyes and blindness throughout history
Authors: Bullock J. 
Published: September 2017

SummarySight has always been the fundamental means by which we human beings relate to our environment and to each other. We use our eyesight to perceive, to understand, and to ascertain the truth. For thousands of years, artists have depicted the theme of blindness and have portrayed its transforming effects. The eyes of the blind are frequently illustrated no differently from those of other, presumably sighted, figures. In addition, since neither most artists nor observers are ophthalmologicly sophisticated, with rare exceptions, it is highly unusual for the artist to depict authentic ocular pathology. The various methods of artistic representation of blindness are given with numerous examples. While it is clear that the artistic renderings of blindness, depicted across various media of expression, are extremely varied, there have been some amazing constants throughout recorded history, even though medical understanding of, and our ability to restore, vision, has undergone almost incomprehensible change. Oscar Wilde said: “…art imitates life.” It is clear that the fear of blindness and the appreciation of our precious gift of sight, as depicted in art, have changed little over the ages.
Lifetime Study in mice: radiation‐induced cataract
Authors: Dalke C. , Kunze S. , Rößler U. , Neff F. , Greiter M. , Gomolka M. , Hornhardt S. , Garrett L. , Unger K. , Rosemann M. , Azimzadeh O. , Wurst W. , Zitzelsberger H. , Hölter S.M. , Tapio S. , Kulka U. , Atkinson M. , Graw J. 
Published: September 2017

SummaryWe did a lifetime study in irradiated and control mice with a follow up time until 24 months post irradiation with repeated in vivo analysis of the lens density and the retina.Mice of different genetic constitution (wild‐type, Ercc2+/‐) were acutely whole body irradiated with low doses of ionising radiation (0, 63, 125 and 500 mGy) and a low dose rate (63 mGy/min). Lens opacification was analysed monthly by Scheimpflug imaging and the retinal fundus and thickness was analysed by OCT. At different time points (4 and 24 hours, 12, 18 and 24 months post irradiation) mice were sacrificed and eyes were analysed by histology and immunohistochemistry.Mice of all groups, even the DNA repair helicase deficient mice (Ercc2+/−), did not develop clinically relevant radiation‐dependent lens opacities. Only an age‐dependent increase of lens density was identified. Consequently, no major morphological changes were visible in the eye histology of all mice. Immunohistochemical staining against DNaseIIb revealed no differences between the groups as well as 8‐OHG staining resulted in similar ROS levels in all irradiation groups. However, non‐irradiated Ercc2+/‐ mice showed an increased level of oxidative stress compared to wild‐type mice.
Surgical management of diabetic macular edema – Against
Authors: Chatziralli I. 
Published: September 2017

SummaryDiabetic macular edema (DME) is the leading cause of visual impairment in patients with diabetes mellitus. Disruption of the blood‐retinal‐barrier has been implicated to the pathogenesis of DME. In addition, vascular endothelial growth factor (VEGF) and other inflammatory mediators have been found to be major contributors to angiogenesis and to increased vascular permeability, leading to DME.Although surgical management of DME has been proposed as a treatment option, since it releases vitreous traction at the macula and improves oxygenation of the posterior segment, complications and persistence of macular edema postoperatively put this treatment modality in suspicion. In fact, eyes with refractory edema and no observable traction seem less likely to improve after surgical treatment. Moreover, in the majority of cases, there is no functional improvement, despite the encouraging anatomical results.Nowadays, anti‐VEGF agents still remain the standard of care in the management of DME, while intravitreal steroids gain interest as well. In cases, in which DME coexists with vitreoretinal interface pathology, pars plana vitrectomy in selected cases may be useful.
Global histone modifications predict the outcome of glaucoma surgery
Authors: Jeon S. , Park H.Y.L. , Kim J.H. , Jung Y. , Park C.K. 
Published: September 2017

PurposeConjunctival and subconjunctival fibrosis at the surgical site influences the outcome of glaucoma surgery. Since glaucoma surgery initiates a cascade of events that leads to up‐ or downregulation of various genes and the subsequent release of cytokines and growth factors, we analyzed global histone modifications at the site of glaucoma surgery and their relationship with the outcome of glaucoma surgery.Methods44 patients who were scheduled to undergo glaucoma surgery were enrolled in this study. A 4 × 4 mm section of Tenon's tissue with overlying conjunctiva was cut from the eye at the margin of the incision. Primary rabbit anti‐histone antibodies were applied in humidified chamber at the following dilutions: H3 K9 K14 K18 K23 K27Ac at 1:200, H4 K5 K8 K12 K16Ac at 1:200, H3 K4diMe at 1:800 (Abcam), and H4 R3diMe at 1:25 (Millipore). The sections were counterstained with Harris's haematoxylin, dehydrated, and mounted.ResultsUsing histochemical staining, we determined the number of cells that were positive for histone acetylation and demethylation of histones H3 and H4. The patients were divided into high‐ and low‐acetylated or ‐methylated groups accordingly. The low‐acetylation group for H3 K9 K14 K18 K23 K27 and H4 K5 K8 K12 K16 had poorer surgical outcomes based on Kaplan‐Meier plots. The preoperative intraocular pressure was significantly related to acetylation of both H3 K9 K14 K18 K23 K27 and H4 K5 K8 K12 K16 in univariate and multivariate regression analyses.ConclusionsOur findings suggest global histone modifications in the conjunctival and subconjunctival tissues predict glaucoma surgery outcomes. A low acetylation status indicated a poor prognosis for glaucoma surgery. Prognostication using histone modifications might have implications for epigenetic therapy to improve glaucoma surgery outcomes.
Early signs of microglial activation in mice retinas contralateral to experimental glaucoma: quantitative analysis of cells number, processes retraction and reorientation
Authors: de Hoz R. , RAMIREZ A.I. , Gonzalez‐Martin R. , Ajoy D. , Salazar J.J. , Salobrar‐Garcia E. , Rojas B. , Triviño A. , Ramirez J.M. 
Published: September 2017

PurposeTo quantify retinal microglia signs of activation after 24 h of unilateral laser‐induced ocular hypertension (OHT) in OHT‐eyes and their contralateral eyes.MethodsAlbino Swiss mice were divided into two groups, naïve (n = 6) and lasered (n = 6). Retinal whole‐mounts were immunolabeled with anti Iba‐1 to quantify the: i) number of microglial cells in the photoreceptor layer (PRL), outer plexiform layer (OPL) and inner plexiform layer (IPL); ii) the area of the retina occupied by Iba‐1 + in the nerve fiber layer‐ganglion cells layer (NFL‐GCL) and; iii) the arbor area of microglial cells in the OPL and IPL. iv) the number of microglial vertical processes connecting the OPL and PRL.ResultsIn OHT eyes and contralateral eyes had no significant differences in cell number with respect to naïve. OHT eyes presented a significant decrease in microglial arbor area in the OPL in comparison with control (p < 0.01) and in the IPL in comparison with control and contralateral eyes (p < 0.01 and p < 0.05 respectively). However the retinal area occupied by Iba‐1 + cells in the NFL‐GCL was significantly increased: i) in both contralateral and OHT eyes with respect to control (p < 0.01 in both instances); and ii) in OHT eyes with respect to contralateral eyes (p < 0.05). In contralateral untreated eyes, the number of microglial vertical processes connecting the OPL and PRL were significantly increased in comparison with control and OHT eyes (p < 0.01 and p < 0.05 respectively).ConclusionsAt 24 h, laser‐induced OHT produces a reactive non‐proliferative microgliotic response both in OHT eyes and in contralateral untreated eyes. Whether this response favors neuroprotection or neurodegeneration needs to be clarify.
Orbital recurrence of uveal melanoma after 45 years from enucleation
Authors: Hadjistilianou T. , Galluzzi P. , Toti P. , Menicacci F. , Menicacci C. , Daini R. , Pica A. , Zografos L. 
Published: September 2017

PurposeA 52‐year‐old woman who had undergone enucleation of the left eye at the age of 7 years for posterior uveal melanoma, had no further problems until 45 years later, when she developed a multifocal malignancy of the ipsilateral orbit.MethodsCase report.ResultsMRI documented the presence of nodular multiple masses in the anophthalmic socket suggesting possible metastatic disease. Hepatic examination and ultrasound evaluation, CT scan of the thorax and bone scintigraphy excluded other sites of metastatic lesions.She underwent excissional of the 3 distinct tumors, 2 inferiorly and one superiorly in the anophthalmic socket. After surgery she received proton beem radiotherapy in the anopthalmic socket for a total of 4.600rads.Histopathology documented malignant melanoma of the orbit characterized by epitheliod cells.ConclusionsThe long interval between recognition of the primary tumor and enucleation and the appearance of clinically manifest metastatic disease in the ipsilateral orbit is the longest reported in the literature to date.A similar case of metastatic choroidal melanoma to the contralateral orbit 40 years after enucleation has been reported by Coupland (1996).
Novel gene based therapies for inherited retinal dystrophies in pediatric patients
Authors: Stieger K. 
Published: September 2017

SummaryGene based therapies for inherited retinal dystrophies have improved dramatically over the past 10 years. Clinical trials in patients based on the adeno‐associated virus (AAV) mediated gene transfer of a correct cDNA copy of the mutant gene were started for several disorders, including early onset severe retinal dystrophy associated with mutations in the RPE65 gene, and juvenile retinoschisis due to mutations in the RS1 gene. Furthermore, optogenetic approaches and cell based therapies are on the verge to the clinical application. The highest expectations though have raised the recent development of genome editing strategies based on CRISPR‐Cas endonucleases, which together with a template DNA enable the correction of the mutant DNA sequence ex vivo or in vivo in photoreceptor cells. In this lecture, an overview will be given on the current state of the art in gene based therapies for pediatric patients, and limitations and potential solutions will be discussed.
The prevalence of asthenopia and its determinants in a population of university students
Authors: Yekta A.A. , Khabazkhoob M. , Hashemi H. , Ali S.B. , Ostadimoghaddam H. , Najafi A. , Heravian J. 
Published: September 2017

PurposeTo determine the prevalence of asthenopia and some of its determinants in a population of Iranian university studentsMethodsIn this cross‐sectional study, multi‐stage cluster sampling was applied in students of Kazerun's universities in south of Iran. After selecting the subjects, ophthalmic examinations and interview was conducted with each student. In line with previous studies, any person with at least one of the symptoms of eye pain, dry eyes, eye swelling, blurred vision, diplopia, foreign body sensation, photophobia, tearing and low visual acuity was considered to have asthenopia.ResultsOf 1462 selected subjects with a mean age of 22.8 ± 3.1 years, 73% of them were females. The prevalence of asthenopia was 71.2%, 40.6%, and 19.7% based on having 1, 2, and 3 symptoms, respectively. The prevalence of asthenopia was 73.3% in females and 65.5% in males (P = 0.004). The highest (81.5%) and lowest (58.4%) prevalence of asthenopia was seen in the age group 28–29 years and 30 years and above, respectively. The prevalence of asthenopia was higher in hyperopic subjects than myopic and emmetropic subjects (P < 0.001). The prevalence of asthenopia was 77.7% in astigmatic and 79.2% in anisometropic participants. The mean amplitude of accommodation was 9.7 ± 2.6 D and 10.28 ± 4.3 D in asthenopic and healthy subjects, respectively (P = 0.008). The mean near point of convergence was 7.2 ± 2.8 cm and 7.7 ± 3.9 cm in asthenopic and healthy subjects, respectively (P0 < 0.001).ConclusionsThe prevalence of asthenopia is markedly high in university students, may causes difficulty in reading and is important to address this condition in this age group.
Genetic causes of deaf‐blindness in sixteen Czech families
Authors: Kousal B. , Dudakova L. , Bujakowska K. , Liskova P. 
Published: September 2017

PurposeUsher syndrome (USH) is the most common cause of hereditary deaf‐blindness in humans with an estimated prevalence of 3‐6 per 100,000 inhabitants. USH is inherited as an autosomal recessive trait and is clinically divided into three types based on audiological profile and vestibular symptoms. The aim of the project was to phenotype the first cohort of Czech patients with USH (16 families, 21 affected individuals) and to perform investigation into the molecular genetic cause of their disease.MethodsSanger sequencing of 6 frequently mutated USH2A exons was performed as an initial step in probands suspected to suffer from USH type II. Unsolved cases were then investigated by a range of techniques including whole‐exome sequencing, targeted gene panel next generation sequencing and single‐nucleotide polymorphism (SNP) array for copy number variation analysis. Detected missense mutations were evaluated for pathogenicity by six in silico tools. Mutations were verified and their segregation within the families was performed by Sanger sequencing.ResultsIn total 17 different mutations evaluated as pathogenic were identified in 20 individuals (95%) from 15 families, of these c.1256G>A, c.13342_13347del, deletion of exons 33 and 34 in USH2A, c.871G>A in CDH23 and c.937C>T in USH1C were novel. A known c.11864G>A in USH2A was the most prevalent mutation observed, found either in a homozygous or compound heterozygous state in 9 families. SNP haplotype analysis supported the hypothesis of a founder effect. Investigation into the geographic origin suggested regional clustering of the c.11864G>A allele in Southeastern part of the Czech Republic.ConclusionsThe proposed research will help to elucidate factors involved in the etiopathogenesis of USH, which is important for prognosis, patient counseling, management, development and introduction of novel therapies.
Motile activity and cytoskeleton changes in uveal melanoma after proton beam radiation
Authors: Romanowska Dixon B. , Jasinska‐Konior K. , Sarna M. , Urbanska K. , Olko P. , Elas M. 
Published: September 2017

PurposeProton beam irradiation is known to invoke different biological response than photons.We compared the effect of proton beam irradiation and X‐rays on the survival and migratory properties of melanoma cells.MethodsMel270, human uveal melanoma cell line was treated with physical doses of 1‐5 Gy of proton beam (58 MeV) from Proteus C‐235 cyclotron or X‐rays (300 kV Phillips) at the dose rate of 1 Gy/min were given to suspended cells.ResultsInvasive potential of cells was slightly diminished after both types of radiation at 20 days post‐radiation and then returned to normal at 40 days. Wound healing ability was decreased after X‐rays. The beta‐1‐integrin level was decreased after both types of radiation in Mel270 cells, and vimentin, a marker of EMT was not changed. Less stress fibers were seen in cytoskeleton of Mel270 cells after radiation.ConclusionsLow doses of both types of radiation influenced the motile activity and cytoskeleton in Mel270 cells.
SS – OCT angiography in retinal dystrophies with macular edema or cysts
Authors: El Matri L. , Falfoul Y. , Hassairi A. , El Matri K. , Nafaa F. , Chebil A. 
Published: September 2017

PurposeTo analyze swept source optical coherence tomography angiography (SS – OCT‐A) findings in retinal dystrophies with macular edema or cysts.MethodsOptical coherence tomography angiography and structural OCT were performed using a Swept‐source DRI OCT Triton (Topcon, Corporation, Japan) for 3 patients with retinitis pigmentosa and macular edema, 3 patients with enhanced S‐cone syndrome and 1 patient with X‐linked retinoschisis.ResultsIn all patients, changes were more pronounced in the deep plexus where macular edema was more evident. Also, there was focal dislocation of the vascular network in correspondence with the serous intraretinal cysts. In patients with retinitis pigmentosa, capillary were visible at the top of the cysts. On the other hand, in case of X‐linked retinoschisis, we found wheel‐like cystoids cavities separated by apparently well‐vascularized walls with a good correspondence with structural en face OCT.ConclusionsOCT‐A may provide information of great interest in inherited retinal dystrophies with macular edema or cysts.It reveals particular alterations above all located at the level of the deep capillary plexus and the choriocapillaris. Such information may be useful for phenotyping each case and understanding pathogenesis of cysts development in each dystrophy helping their future therapeutic management.
The development and performance of a new patient derived tool to measure Dimensions in Treatment of Age‐related Macular Degeneration (DITAMD)
Authors: Jelin E. , Wisløff T. , Moe M.C. , Heiberg T. 
Published: September 2017

PurposeA growing aging population increases the number of patients treated for neovascular Age related Macular Degeneration (nAMD). Studies reporting the patient's perspective during treatment are limited. Our aim was to develop and test a tool for monitoring treatment burden and satisfaction among nAMD patients.MethodsDevelopment: Patients (n = 44), mean (SD) age 80.4 (8.2), 62.8% females, diagnosed with nAMD selected dimensions mattering most during treatment. Reported dimensions were analysed according to similar content, then coded. Test: Recently diagnosed patients (n = 178), with logMAR visual acuity in treated eye 0.43 (0.42), completed DITAMD after 3 months treatment on a Likert scale (1–5). A weight based on the identified importance in the development phase, had a sum score, range 0–10.ResultsDevelopment: Dimensions reported most frequently were included in DITAMD; receive treatment, information, waiting time, confidence, accommodating staff, follow up, planning, continuity, pain relief, injection technique, transportation, hygiene, early treatment access, involvement and visual aids. Test: Patients (n = 178) reported DITAMD score of 8.1 (0.9) suggesting satisfaction with treatment. The score was not significantly associated to age or gender. A subgroup of patients (n = 70) considered relevance (0–10) of the questionnaire; mean (SD) 8.3 (1.3), indicating high level of face validity. Satisfaction during treatment and perceived importance of the dimensions were compared with paired T‐test for each item, for some dimensions, satisfaction was significantly higher than importance. However, information about visual aids had significantly lower satisfaction the importance.ConclusionsDITAMD allows monitoring patient relevant experience during treatment of nAMD. The discrepancy between satisfaction and perceived importance should guide patient care.