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The COVID-19 pandemic is unceasingly spreading across the globe, and recently a highly transmissible Omicron SARS-CoV-2 variant (B.1.1.529) has been discovered in South Africa and Botswana. Rapid identification of this variant is essential for pandemic assessment and containment. However, variant identification is mainly being performed using expensive and time-consuming genomic sequencing. In this study we propose an alternative RT-qPCR approach for the detection of the Omicron BA.1 variant using a low-cost and rapid SYBR Green method. We have designed specific primers to confirm the deletion mutations in the spike (S Δ143-145) and the nucleocapsid (N Δ31-33) which are characteristics of this variant. For the evaluation, we used 120 clinical samples from patients with PCR-confirmed SARS-CoV-2 infections, and displaying an S-gene target failure (SGTF) when using TaqPath COVID-19 kit (Thermo Fisher Scientific, Waltham, USA) that included the ORF1ab, S, and N gene targets. Our results showed that all the 120 samples harbored S Δ143-145 and N Δ31-33, which was further confirmed by Whole genome sequencing (WGS) of 10 samples thereby validating our SYBR Green-based protocol. This protocol can be easily implemented to rapidly confirm the diagnosis of the Omicron BA.1 variant in COVID-19 patients and prevent its spread among populations, especially in countries with high prevalence of SGTF profile.

The aim was to compare the long-term surgical outcomes of visco-circumferential-suture-trabeculotomy (VCST) and rigid probe viscotrabeculotomy (VT) in patients with primary congenital glaucoma (PCG).The study was conducted on 84 (47 right) eyes of 49 (32 males) children PCG to the pediatric ophthalmology unit of Mansoura Ophthalmic Center of Mansoura University, Egypt between 2015 and 2018. An initial office examination was followed by an examination under general anesthesia to establish the diagnosis of PCG. The children were then scheduled for surgery and the eyes randomly assigned to VCST or VT. Follow-up visits were scheduled at the first day, first week, first, and third months and then every 3 months for 1 year.The mean±SD age of the study children at presentation was 4.8±2.1 and 4.9±1.7 months in the VCST and the VT groups, respectively (P=0.827). The mean±SD preoperative intraocular pressure (IOP) was 29.13±3.3 and 29.89±3.2 mm Hg in the VCST and VT groups, respectively (P=0.292) and 11.9±1.3 and 13.8±1.2 mm Hg at the end of 36 moths of follow-up (P0.001). The IOP at all follow-up time points (except at the third month, P=0.924) was statistically significantly less in the VCST group than in the VT group (at week 1, month 1, 6, 9, 12, 18, 24, 30, and 36 the P0.001). The cumulative probability of success was 100%, 95%, 90%, and 90%, respectively in VSCT and 100%, 72.7%, 97.7%, 90.9%, and 84% in VT at 12, 24, 30, and 36 months.Both VCST and VT were effective and safe for lowering the IOP in PCG with VCST providing a marginal advantage over VT.

To compare trabeculectomy with Ologen implant(Trab-Ologen) to combined viscotrabeculotomy-synechiolysis(VTS) in uncontrolled uveitic glaucoma (UG). A retrospective chart review of 47 patients subjected to VTS(24 eyes) or Trab-ologen(23 eyes) at Mansoura Ophthalmic Center between 2010 and 2016. The patients were evaluated on day 1, week 1, months 1, 3, 6, 12, 18, 24, 30, 36, 42, and 48. The mean ± standard deviation age of patients in the Trab-ologen and VST groups were 38.29 ± 12.5 and 38.91 ± 11.8 years (p = 0.86), respectively. Juvenile Idiopathic arthritis (controlled on methotrexate) was the most common associated systemic disease (3 patients in each group). The mean ± standard deviation of the intraocular pressure (IOP) and IOP-lowering medications preoperatively and at the end of follow up in the Trab-ologen and VST groups were 33.1 ± 2.6 mmHg, 33.2 ± 2.6 mmHg (p = 0.91), 3.4 ± 0.5, 3.4 ± 0.5 (0.90) and 15.4 ± 1.2 mmHg, 13.0 ± 0.9 mmHg (p

Purpose: To report the corneal tomographic characteristics of eyes that had surgery for controlled primary congenital glaucoma (PCG) and to compare it with an age-matched group of normal children. Methods: The study was conducted on 44 (24 right) eyes of 27 children (18 boys) who had surgery for PCG and 60 (31 right) eyes of 32 age-matched control children (9 boys). Children with PCG had a thorough ophthalmic examination and the demographic and medical and surgical history was retrieved from the patients' clinical chart records. After clinical examination, the study participants underwent Scheimpflug imaging using the Pentacam (Oculus Optikgeräte GmbH). Results: Both study and control children were approximately 9 years of age at the time of the study ( P = .39). The eyes with PCG had a spherical equivalent mean ± standard deviation of −4.70 ± 3.50 diopters (D). Eyes with PCG demonstrated a cylinder of −2.80 ± 2.10 D, flatter corneas than control eyes ( P = .0002 and .0012 for flat and steep keratometry, respectively), and statistically significantly higher astigmatism ( P = .011) and thinner corneas, both at pupil center ( P < .001) and thinnest location ( P < .001). There was a statistically significant negative correlation between the postoperative axial length (at the time of the scan) and each of the Scheimpflug parameters flat keratometry ( P = .002), steep keratometry ( P = .003), pachymetry at pupil center ( P = .01), and pachymetry at thinnest location ( P = .009). Conclusions: The eyes of patients with PCG have thinner, flatter, and more astigmatic corneas than the eyes of age-matched control children. [ J Pediatr Ophthalmol Strabismus . 2021;58(4):218–223.]

The aim of the study was to compare the effect of viscotrabeculotomy and the effect of trabeculectomy on the intraocular pressure (IOP) in cases of open angle glaucoma (OAG). Prospective comparative study. The study was conducted on 148 eyes of 148 patients (87 men) presenting with and operated upon for OAG at Mansoura Ophthalmic center of Mansoura University in Mansoura, Egypt from 2012 to 2016. Patients were randomized into viscotrabeculotomy and trabeculectomy groups. Postoperative follow up visits were scheduled at weeks 1 and 2 then months 1, 2, 3, 6, 9, 12, 15, 18, 21 and 24. Complications were noted and managed according to needs. The primary outcome measure was IOP. The study was conducted on 148 eyes (74 right) of 148 patients (87 men). The mean ± SD (range, median) age of the study patients was 50.1 ± 11.5 (20–67, 53) and 51.1 ± 10.0 (27–65, 54.5) years respectively. The mean ± SD (range, median) IOP of the study eyes on maximal tolerated IOP lowering therapy was 23.15 ± 2.31 (19–30, 23.0) and 23.64 ± 1.87 (20–28, 23.0) mmHg respectively and at the end of the 24 months of follow up was 14.91 ± 2.4 (12–23, 14) and 16.64 ± 2.8 (14–25, 16) mmHg respectively (p =

Com a chegada do Novo Coronavírus (SARS-CoV-2) e sua grande força de contaminação, assim como a inexistência de medicação e cura e até mesmo a falta de informações devido à exclusividade do caso, recomendações foram adotadas pela sociedade mundial, como o isolamento e distanciamento social, uso de máscaras e álcool em gel, práticas de higiene mais rigorosas, entre outras. A pandemia acarretou diversos desafios com impactos diretos e indiretos em todas as áreas, mas principalmente na saúde, sendo necessário avaliar as mudanças, consequências e necessidade de novos hábitos dentro dessa nova realidade. Com base nisto, esse trabalho tem como objetivo estudar sobre a importância dos hábitos de higiene no enfrentamento à COVID-19. Para atingir esse objetivo será realizado um criterioso levantamento bibliográfico utilizando obras publicadas nos últimos dois anos embasadas na temática apresentada. Com base nisso, expõe-se que estudo acontecerá por meio de uma revisão bibliográfica. Durante a pesquisa buscou-se por publicações que contemplasse a temática aqui exposta. As bases de dados utilizadas foram: Google Acadêmico, Scientific Electronic Library Online (Scielo) e Literatura Latino-Americana e do Caribe em Ciências da Saúde (Lilacs), utilizando os descritores: SARS-CoV-2, COVID-19, pandemia, higiene e Coronavírus. Por meio desses materiais estudados será possível fundamentar esse estudo. Pode-se concluir que os hábitos de higienização das mãos e objetos, o uso da máscara e também a limpeza dos sapatos ao voltar da rua, cuidado com as roupas e com a casa, e higiene com o próprio corpo continuarão sendo importantes medidas mesmo após o fim da pandemia, pois, com o surgimento das variantes e a obscuridade do conhecimento científico a respeito da transmissibilidade, e a infinidade da doença, os cuidados precisam ser mantidos para que haja o controle da mesma.

International audience; Rhabdomyosarcoma (RMS) is an aggressive childhood soft-tissue tumor, with propensity for local invasion and distant metastasis. Exosomes are secreted vesicles that mediate paracrine signaling by delivering functional proteins and miRNA to recipient cells. The transmembrane protein CD147, also known as Basigin or EMMPRIN, is enriched in various tumor cells, as well as in tumor-derived exosomes, and has been correlated with poor prognosis in several types of cancer, but has not been previously investigated in RMS. We investigated the effects of CD147 on RMS cell biology and paracrine signaling, specifically its contribution to invasion and metastatic phenotype. CD147 downregulation diminishes RMS cell invasion and inhibits anchorage-independent growth in vitro. While treatment of normal fibroblasts with RMS-derived exosomes results in a significant increase in proliferation, migration, and invasion, these effects are reversed when using exosomes from CD147-downregulated RMS cells. In human RMS tissue, CD147 was expressed exclusively in metastatic tumors. Altogether, our results demonstrate that CD147 contributes to RMS tumor cell aggressiveness, and is involved in modulating the microenvironment through RMS-secreted exosomes. Targeted inhibition of CD147 reduces its expression levels within the isolated exosomes and reduces the capacity of these exosomes to enhance cellular invasive properties.

Purpose To assess the long-term results of viscotrabeculotomy in infants with primary congenital glaucoma and to compare its outcome with conventional trabeculotomy. Patients and methods A prospective randomized comparative study included infants with primary congenital glaucoma younger than 2 years. Patients were divided into two groups: viscotrabeculotomy group and conventional trabeculotomy group. Preoperative and postoperative intraocular pressures, corneal diameter, intraoperative and postoperative complications, and success rates were compared between two groups. All the patients were followed up for 5 years. Results The study included 154 eyes of 92 infants distributed randomly among the two groups; 78 and 76 eyes in viscotrabeculotomy and conventional trabeculotomy groups, respectively. In both groups, there was a statistically significant intraocular pressure reduction at all time points of the follow-up periods compared to the preoperative values (p < 0.0001). At 5 years, viscotrabeculotomy group showed significant reduction of the mean postoperative intraocular pressure (49.47%) than conventional trabeculotomy group (48.64%) (p < 0.0001). Intraocular pressure was statistically lower in viscotrabeculotomy starting from 12th month and till the end of the follow-up. At 5 years, the total success rate of viscotrabeculotomy group was 89.74% compared to 85.53% in conventional trabeculotomy group without significant difference (p = 0.487). The postoperative mean values of the cup/disk ratio in viscotrabeculotomy group showed statistically lower values compared to conventional trabeculotomy group (p = 0.019). Postoperative hyphema was statistically higher in conventional trabeculotomy group (p Conclusion Viscotrabeculotomy and conventional trabeculotomy proved to be effective in cases of primary congenital glaucoma. Viscotrabeculotomy appeared to have prolonged stability in controlling the intraocular pressure with higher success rates and lower complications.

The beneficial effects of lipoic acid (LA) in cancer treatment have been well documented in the last decade. Indeed, LA exerts crucial antiproliferative effects by reducing breast cancer cell viability, cell cycle progression and the epithelial-to-mesenchymal transition (EMT). However, the mechanisms of action (MOA) underlying these antiproliferative effects remain to be elucidated. Recently, we demonstrated that LA decreases breast cancer cell proliferation by inhibiting IGF-1R maturation via the downregulation of the proprotein convertase furin. The aim of the present study was to investigate the MOA by which LA inhibits furin expression in estrogen receptor α (ERα) (+) and (−) breast cancer cell lines. We unveil that LA exerts a pro-oxidant effect on these cell lines, the resulting reactive oxygen species (ROS) generated being responsible for the reduction in the expression of the major (CREB) protein. This transcription factor is overexpressed in many types of cancers and regulates the expression of furin in breast cancer cells independently of ERα, as evidenced herein by the inhibition of furin expression following CREB silencing. Consequently, our findings expose for the first time the complete MOA of LA via the CREB/furin axis leading to inhibition of breast cancer cell proliferation.

Purposeto compare effect Ranibizumab and Aflibercept, for the treatment of macular edema secondary to non-ischemic central retinal vein occlusion CRVO in young adults.MethodsForty eyes of 40 young adult patients with macular edema due to CRVO were enrolled in this prospective double-armed clinical trial. The patients were randomized into 2 groups of 20 patients each. First group received intravitreal injection of Ranibizumab while second group received Aflibercept. All patients were subjected to measurement of Best corrected visual acuity BCVA, fluorescein angiography (FA) to detect retinal ischemia and Spectral domain OCT (SD-OCT) to measure macular edema at baseline and during 12-month follow up period. Intravitreal injections were three injections with a 1-month interval between injections.ResultsBCVA in group 1 had significant steady increase over time from baseline to 1 year [55.9 ± 10.3], p = 0.017). Group 2 had also significant steady increase over time from baseline to 1 year [60.8 ± 8.4], p = 0.035) with no significant difference between the 2 groups (p > 0.05). Regarding central subfield thickness CST, in the first group, statistically significant decrease in the CST over time from baseline to 1 year [295.1 ± 56 Um], p p > 0.05).ConclusionRanibizumab and aflibercept showed a comparable promising outcome in the management of macular edema secondary to nonischemic CRVO in patients aged Trial registration number : NCT05282420

Purpose To evaluate the surgical outcome of epicanthus and telecanthus correction by C-U medial canthoplasty with lateral canthoplasty in Blepharophimosis Syndrome. Patients and methods This was a retrospective single arm interventional study including 18 eyes of 9 patients with Blepharophimosis-ptosis-epicanthus inversus syndrome who presented to oculoplastic clinic, ophthalmology department, Qena university hospital in the period of between July 2020 to April 2021. All the patients had BPES with epicanthus and telecanthus. All cases were subjected to by C plasty with medial and lateral canthoplasty for correction of epicanthus and telecanthus correction followed by frontalis suspension surgery to correct the co-existing blepharoptosis. Results The study included 9 cases of BPES, 6 boys and 3 girls, the mean age was 5.4 ± 1.5 in the study group, all patients had a positive family history for BPES. After surgery, the mean IICD decreased from 38.44 mm preoperatively to 32.8 mm postoperatively, with a mean difference of 6.2 mm (P P Conclusion C-U medial canthoplasty with lateral canthoplasty in Blepharophimosis Syndrome was found to be an effective procedure in the correction of epicanthus and telecanthus.

Purpose: To compare viscotrabeculotomy with anterior chamber irrigation to Ahmed glaucoma valve implantation for secondary glaucoma following silicone oil removal. Methods: A prospective study was conducted on 43 vitrectomized pseudophakic eyes with persistent glaucoma after silicone oil removal. Patients were randomized to either viscotrabeculotomy with anterior chamber irrigation or Ahmed glaucoma valve implantation. All patients were examined on day 1, week 1, and months 1, 3, 6, 9, 12, 18, and 24 postoperatively. Postoperative complications were noted. Success was defined as an intraocular pressure between 6 and 20 mmHg and with an intraocular pressure reduction of >30% compared with the preoperative intraocular pressure. Results: There were 22 eyes in the viscotrabeculotomy with anterior chamber irrigation and 21 eyes in the Ahmed glaucoma valve implantation group. The mean preoperative and postoperative intraocular pressure in the viscotrabeculotomy with anterior chamber irrigation and Ahmed glaucoma valve implantation groups were 35.5 ± 2.6 mmHg and 35.5 ± 2.4 mmHg and 16.9 ± 0.7 mmHg and 17.9 ± 0.9 mmHg respectively (p˂0.0001). There was a statistically significant intraocular pressure reduction at all follow-up time points compared to preoperative values (p˂0.0001) in both groups. The unqualified success rate in the viscotrabeculotomy with anterior chamber irrigation and Ahmed glaucoma valve implantation groups were 72.73% and 61.9%, respectively. A minimal self-limited hyphema was the most common complication. Conclusions: Both viscotrabeculotomy with anterior chamber irrigation and Ahmed glaucoma valve implantation are effective in lowering the intraocular pressure in glaucoma after silicone oil removal with viscotrabeculotomy with anterior chamber irrigation providing greater reduction, higher success rates, and minimal complications. RESUMO Objetivo: Comparar a viscotrabeculotomia com irrigação da câmara anterior com o implante de válvula de glaucoma de Ahmed para glaucoma secundário após remoção de óleo de silicone. Métodos: Foi realizado um estudo prospectivo de 43 olhos pseudofácicos vitrectomizados com glaucoma persistente após a remoção de óleo de silicone. Os pacientes foram randomizados para viscotrabeculotomia com irrigação da câmara anterior ou implante de válvula de Ahmed. Todos os pacientes foram examinados no primeiro dia, na primeira semana e 1, 3, 6, 9, 12, 18 e 24 meses após a cirurgia. Observaram-se complicações pós-operatórias. O sucesso foi definido como uma pressão intraocular entre 6 e 20 mmHg e uma redução da pressão intraocular >30% em comparação com a pressão intraocular pré-operatória. Resultados: Foram designados 22 olhos para o grupo da viscotrabeculotomia com irrigação da câmara anterior e 21 olhos para o grupo do implante de válvula de Ahmed. A pressão intraocular média pré-operatória foi de 35,5 ± 2,6 mmHg para o grupo da viscotrabeculotomia com irrigação da câmara anterior e pós- e de 35,5 ± 2,4 mmHg no grupo do implante de válvula de Ahmed. e Os valores pós-operatórios foram de 16,9 ± 0,7 mmHg e 17,9 ± 0,9 mmHg para esses mesmos grupos, respectivamente (p

The oncogenic transcription factor ZNF217 orchestrates several molecular signaling networks to reprogram integrated circuits governing hallmark capabilities within cancer cells. High levels of ZNF217 expression provide advantages to a specific subset of cancer cells to reprogram tumor progression, drug resistance and cancer cell plasticity. ZNF217 expression level, thus, provides a powerful biomarker of poor prognosis and a predictive biomarker for anticancer therapies. Cancer epigenetic mechanisms are well known to support the acquisition of hallmark characteristics during oncogenesis. However, the complex interactions between ZNF217 and epigenetic processes have been poorly appreciated. Deregulated DNA methylation status at ZNF217 locus or an intricate cross-talk between ZNF217 and noncoding RNA networks could explain aberrant ZNF217 expression levels in a cancer cell context. On the other hand, the ZNF217 protein controls gene expression signatures and molecular signaling for tumor progression by tuning DNA methylation status at key promoters by interfering with noncoding RNAs or by refining the epitranscriptome. Altogether, this review focuses on the recent advances in the understanding of ZNF217 collaboration with epigenetics processes to orchestrate oncogenesis. We also discuss the exciting burgeoning translational medicine and candidate therapeutic strategies emerging from those recent findings connecting ZNF217 to epigenetic deregulation in cancer.

Purpose The aim of the current study was to compare visco-trabeculotomy (VT) with standard trabeculectomy with mitomycin C (Trab-MMC) in the treatment of quiescent neovascular glaucoma (NVG). Methods The study was conducted on 51 eyes of 51 patients presenting with NVG and treated at an Ophthalmic Center in Egypt between March 2014 and April 2017. All study eyes were subjected to a standard protocol of intravitreal injection of ranibizumab followed by panretinal photocoagulation. Eyes were then randomized to either VT or Trab-MMC. Study eyes were followed up for at least 18 months. Success was defined as an intraocular pressure of ≤21 mm Hg and without vision-threatening complications. Complications were noted. Results The mean ± SD (range, median) age of the study patients was 54.1 ± 6.4 (40-67, 54.5) and 52.4 ± 8.8 (38-66, 53) years in the VT (26 eyes) and Trab-MMC (25 eyes) groups, respectively (P = 0.45). The mean ± SD (range, median) intraocular pressure (IOP) of the study eyes was 45.19 ± 2.97 (39-52, 45.5) and 45.64 ± 3.56 (3-53, 45) mm Hg on maximal medical therapy in the VT and Trab-MMC groups, respectively (P = 0.61). At 18 months' follow-up, the mean ± SD (range, median) IOP of the study eyes was 18.19 ± 2.0 (16-23, 17) and 19.92 ± 2.6 (18-26, 19) mm Hg in the VT and Trab-MMC groups, respectively (P = 0.004). There was no difference in postoperative antiglaucoma medication between the 2 groups (P = 0.62). Complications included hyphema and Descemet split in the VT group and an IOP spike in the Trab-MMC group. Success rates were 84.6% and 80% in the VT and Trab-MMC groups, respectively (P = 0.726). Conclusions Both VT and Trab-MMC groups are effective in reducing the IOP in cases of NVG after control of neovascularization with anti-vascular endothelial growth factor and pan retinal photocoagulation.

PURPOSE To compare the outcome of the intraocular pressure (IOP) of Ahmed glaucoma valve (AGV) revision to visco-trabeculotomy (VT) in children's eyes with failed AGV. PATIENTS AND METHODS A prospective randomized study conducted on 41 children (41 eyes) with uncontrolled glaucoma with an AGV presenting to the pediatric ophthalmology clinic of Mansoura Ophthalmic Center between 2011 and 2016. Study eyes were randomized to AGV revision or VT. Success (true and qualified) (IOP

Mai A Mohammed,1 Mohamed Saad Morsy,1 Nashwa Shehata Zeater,2 Nader Bayoumi1 1Ophthalmology Department, Faculty of Medicine, Alexandria University, Alexandria, Egypt; 2Resident of Ophthalmology, Damanhour Eye Hospital, Damanhour, EgyptCorrespondence: Mai A Mohammed 36 Kamaleldin Salah, Semouha, Alexandria, EgyptTel +201221081590Fax +203 42 444 41Email mai.abdalnabi@yahoo.comBackground: To evaluate the VEP parameters in operated controlled primary congenital glaucoma (PCG) eyes and compare them to normal age similar children eyes.Methods: A cross-sectional comparative study conducted on 34 (19 right) eyes of 26 (19 males) children operated for PCG and 30 (17 right) eyes of 22 (12 males) age similar control children in a university-based practice. All study participants were subjected to a standard protocol of examination and electrophysiological testing (single flash VEP response, light adapted, pupils not dilated), reporting on the P2 implicit time, N1-P1 and N2-P2 (amplitude).Results: The mean±SD of the age of the study children and controls was 43.22± 33.2 and 55.68± 35.2 months respectively (p=0.217). The mean±SD IOP and cup/disc ratio of the study children were 18.4± 5.2 and 5.2± 3.3mmHg and 0.7± 0.2 and 0.3± 0.3 at presentation and at testing, respectively. The VEP testing was conducted after 21.5± 21.3 months of surgery for PCG. There was no statistically significant differences in P2, N1-P1 and N2-P2 between patients and controls (p=0.941, 0.916,0.945, respectively). There was no statistically significant correlation between most of the clinical characteristics of the study eyes and any of the studied VEP parameters.Conclusion: Operated controlled PCG eyes have VEP parameters that match their normal fellow children.Keywords: primary congenital glaucoma, visual evoked potentials, optic nerve, electrophysiology

Rana El Sabeh,1,2 Mélanie Bonnet,1 Katy Le Corf,1 Kevin Lang,1 Alain Kfoury,1 Bassam Badran,2 Nader Hussein,2 Francois Virard,1 Isabelle Treilleux,3 Muriel Le Romancer,1 Serge Lebecque,1 Serge Manie,1 Isabelle Coste,1,* Toufic Renno1,* 1Université de Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, France; 2Université Libanaise, PRASE, Hadath, Lebanon; 3Pathology Department, Centre Léon Bérard, Lyon, France*These authors contributed equally to this workCorrespondence: Toufic Renno; Isabelle CosteCentre de Recherche en Cancétologie de Lyon, 28 Rue Laennec, Lyon, 69373, FranceTel +33 4 691 666 29; +33 4 691 666 30Email toufic.renno@lyon.unicancer.fr ; isabelle.coste@lyon.unicancer.frIntroduction: Most Toll-like receptors and IL-1/IL-18 receptors activate a signaling cascade via the adaptor molecule MyD88, resulting in NF-κB activation and inflammatory cytokine and chemokine production. Females are less susceptible than males to inflammatory conditions, presumably due to protection by estrogen. The exact mechanism underlying this protection is unknown.Methods: MCF7 cells expressing wild-type or mutated LXXLL motif were used to determine MyD88/estrogen receptor (ER)-a interaction by immunoprecipitation and cell activation by ELISA and luciferase reporter assay. IL-1b and/or E2 were used to activate MCF7 cells expressing normal or knocked down levels of PRMT1. Finally, in situ proximity ligation assay with anti-MyD88 and anti-methylated ER-a (methER-a) antibodies was used to evaluate MyD88/methylated ER-a interaction in THP1 cells and histological sections.Results: We show that MyD88 interacts with a methylated, cytoplasmic form of estrogen receptor-alpha (methER-α). This interaction is required for NF-κB transcriptional activity and pro-inflammatory cytokine production, and is dissociated by estrogen. Importantly, we show a strong gender segregation in gametogenic reproductive organs, with MyD88/methER-α interactions found in testicular tissues and in ovarian tissues from menopausal women, but not in ovaries from women age 49 and less – suggesting a role for estrogen in disrupting this complex in situ.Discussion: Collectively, our results indicate that the formation of MyD88/methER-α complexes during inflammatory signaling and their disruption by estrogen may represent a mechanism that contributes to gender bias in inflammatory responses.Keywords: nuclear receptor, post-translational modification, inflammation, protein-protein-interaction

International audience; Breast cancer (BC) is one of the most common cancers in women worldwide. Even though the role of estrogen receptor alpha (ERα) is extensively documented in the development of breast tumors, other members of the nuclear receptor family have emerged as important players. Synthetic glucocorticoids (GCs) such as dexamethasone (dex) are commonly used in BC for their antiemetic, anti-inflammatory, as well as energy and appetite stimulating properties, and to manage the side effects of chemotherapy. However, dex triggers different effects depending on the BC subtype. The glucocorticoid receptor (GR) is also an important marker in BC, as high GR expression is correlated with a poor and good prognosis in ERα-negative and ERα-positive BCs, respectively. Indeed, though it drives the expression of pro-tumorigenic genes in ERα-negative BCs and is involved in resistance to chemotherapy and metastasis formation, dex inhibits estrogen-mediated cell proliferation in ERα-positive BCs. Recently, a new natural ligand for GR called OCDO was identified. OCDO is a cholesterol metabolite with oncogenic properties, triggering mammary cell proliferation in vitro and in vivo. In this review, we summarize recent data on GR signaling and its involvement in tumoral breast tissue, via its different ligands.

Purpose To report on the changes in the natural crystalline lens in primary congenital glaucoma (PCG) eyes that had undergone previous combined angle-filtering surgery with antimetabolites. Settings The pediatric ophthalmology unit of the ophthalmology department of Alexandria Main University Hospital. Design A retrospective chart review. Methods A retrospective chart review of patients presenting with and operated (by combined angle-filtering surgery with antimetabolites) for PCG in the period from 2005 to 2018. Any lens pathology was noted as well as the management and the outcome. Results The records of 422 children (613 eyes) were reviewed. Lens pathology was noted in 54 (8.8%) eyes. Abnormalities in lens clarity (cataract) were detected in 31 (56%) eyes, and abnormalities in lens position (subluxation) were detected in 24 (44%) eyes. Management options included observation (in 28 eyes), lensectomy for aphakia (in 14 eyes), lensectomy with in the bag intraocular lens (IOL) implantation (in 11 eyes), and lensectomy with iris-fixated IOL (in 1 eye). Elevation of intraocular pressure (IOP) occurred in only 4 eyes (of 26 operated eyes, 15.3%) after lens extraction. Conclusions Changes in the natural crystalline lens clarity and/or position occurred in 8.8% (54 of 613) of PCG eyes operated by combined angle-filtering surgery with antimetabolites. Lens extraction was a relatively safe procedure with only 15% (4 of 26) of eyes suffering an elevation of IOP after lens extraction.

To report the flash visual evoked potential (VEP) findings in children with primary congenital glaucoma (PCG) before and after successful surgical control of the intraocular pressure (IOP). The study enrolled children presenting with PCG to the Ophthalmology Department of Alexandria Main University Hospital in the period between June and December 2019. All study participants were subjected to a standard protocol of examination, to confirm the diagnosis of PCG. The child was then referred for flash VEP testing. Peaks were designated as negative and positive waves in a numerical sequence (N1, P1, N2, P2, N3 and P3). The child was then scheduled for surgery within 1 week of presentation. Postoperative VEP testing was scheduled as soon as feasible and was conducted in the same way as the preoperative VEP testing. The study was conducted on 11 (four right) eyes of eight (five males) children. The mean ± standard deviation of the age of the study children at presentation and at postoperative VEP testing was 3.5 ± 1.6 and 5.1 ± 3.0 months, respectively. The study eyes mean ± standard deviation IOP at presentation and at postoperative VEP testing was 23.0 ± 6.7 and 8.3 ± 2.4 mmHg, respectively (p

Rhabdomyosarcoma (RMS) is a highly malignant soft tissue sarcoma classified into two major histologic subtypes: embryonal (ERMS) and alveolar (ARMS). ARMS subtype is clinically more aggressive, and characterized by an oncogenic fusion protein PAX3-FOXO1 (P3F) that drives oncogenic cellular properties. To understand the role of the fusion oncoprotein in paracrine signaling, we focused on secreted exosomes, which have been demonstrated to contribute to metastasis in multiple tumor types. Advanced Proteomics-bioinformatics analysis of the protein cargo of exosomes isolated from C2C12 myoblasts transduced with P3F fusion gene revealed 52 deregulated proteins compared to control cells, with 26 enriched and 26 depleted proteins. Using both PANTHER gene classification and Ingenuity Pathway Analysis (IPA) software, we found that the main biological processes in which the 52 deregulated proteins are involved, include "catalytic activity," "binding," "metabolic process," and "cellular process." The pathways engaging the 26 enriched proteins include the "14-3-3 mediated signaling," "cell cycle," and "ERK5, VEGF, IGF1,and p70S6K signaling." Furthermore, the main nodes in which deregulated exosome proteins and miRNAs intersected revealed pathways conferring protection from stress and promoting plasticity. Based on the bioinformatics analysis and the altered exosome proteome profile, we performed biochemical functional analysis to study the diverse properties of these exosomes where angiogenesis, stemness, and anti-oxidative stress properties were validated using different platforms. P3F-modulated exosomes activated ERK, 4-EBP1, and MMP-2 in recipient cells, and enhanced angiogenesis and stemness. In addition, P3F led to lower cellular reactive oxygen species levels and enhanced resistance against oxidative stress; and treatment of stromal cells with P3F-modulated exosomes also conferred protection against exogenous oxidative stress. Our findings highlight the role of P3F fusion protein in modulating exosome cargo to confer a protective effect on recipient cells against oxidative stress and to promote plasticity and survival, potentially contributing to the known aggressive phenotype of the fusion gene-positive subtype of RMS.

Background: Pediatric ocular trauma may be a major source of lifelong visual morbidity and disability. Objective: To report on the different types of ocular injury in children in a tertiary referral center. Participants and settings: Children presenting with ocular trauma to the casualty department of the pediatric ophthalmology unit of Alexandria Main University Hospital in Alexandria, Egypt. Methods: The study was conducted from June to December 2018. Upon admission, thorough history was obtained from the attending person(s), and thorough ophthalmic examination was performed. Appropriate treatment was subsequently provided to every case (though not the scope of the current study). Results: A total of 146 children (from a total of 436 patients, 33.5%) (103 males, 70.5%) presented with various types of ocular injuries. The mean age ± standard deviation of the injured children was 98.1 ± 56.4 months. Study participants were almost equally distributed between within and outside of the city of the study locale, with a predominance of patients from urban areas in Alexandria (30%) and from rural areas outside of Alexandria (35.6%). Seventy percent of the care providers of the study children were manual workers. The places of the incidents were almost equally distributed between household (40%) and external environment with a slight predominance of the later (50%). Conclusions: Ocular injuries represent one-third of all ocular injuries in the study locale. Ocular injuries in children occur with an almost equal distribution in both urban and rural areas and in both household and external environments. Mechanical trauma was the most common cause of trauma.

Purpose: To compare releasable and regular sutures in combined angle and filtering surgery for primary congenital glaucoma. Methods: A prospective study was conducted on 39 eyes (26 right eyes) of 39 children (20 boys; 19 girls) who had primary congenital glaucoma treated with combined trabeculotomy-trabeculectomy with mitomycin C and scleral flap closure with regular or releasable sutures. Follow-up was 24 months. Success rates (defined as an intraocular pressure [IOP] < 16 mm Hg without hypotony-related complications and/or lack of IOP-related progression of the disease) were studied and complications were noted. Results: The mean age of the study participants was 6.7 ± 5.8 months (range: 1 to 24 months; median: 5 months) in the regular suture group (20 eyes) and 5.3 ± 2.8 months (range: 1 to 13 months; median: 5 months) in the releasable suture group (19 eyes). The initial glaucoma surgery was successful in 13 (65%) and 13 (68.4%) eyes in the regular suture and releasable suture groups, respectively. The mean IOP was 17.4 ± 7.3 and 16.0 ± 5.4 mm Hg ( P = .84) preoperatively and 8.0 ± 9.7 and 5.8 ± 3.6 mm Hg ( P = .40) at the end of follow-up in the regular suture and releasable suture groups, respectively. There was no statistically significant difference in the clinical parameters between the two groups. Complications included rhegmatogenous retinal detachment, cataract, and superior lens subluxation, with each complication developing in one eye. Conclusions: Releasable sutures were not more advantageous than regular sutures in combined trabeculotomy-trabeculectomy with mitomycin C surgery for primary congenital glaucoma. [ J Pediatr Ophthalmol Strabismus . 2017;54(5):295–301.]

Purpose Primary congenital glaucoma (PCG) accounts for 26–29% of childhood blindness in Egypt. The identification of disease causing mutations has not been extensively investigated. We aimed to examine the frequency of CYP1B1 and MYOC mutations in PCG Egyptian patients, and study a possible genotype/phenotype correlation. Methods Ninety-eight patients with PCG diagnosed at the Ophthalmology department of Alexandria Main University Hospital were enrolled. Demographic and phenotypic characteristics were recorded. Patients and 100 healthy subjects (control group) were screened for two mutations in CYP1B1 gene (G61E, R368H) and one mutation in MYOC gene (Gln48His) using polymerase chain reaction/restriction fragment length polymorphism (PCR/RFLP). Phenotypic characteristics pertaining to disease severity were compared. Results Nineteen patients (19%) with PCG were found positive for one or more of the mutations screened for. Seven patients (7%) were homozygous for the G61E mutation. Ten patients (10%) were heterozygous; 6 for the G61E mutation, 2 for the R368H mutation and 2 for the Gln48His mutation. Two patients (2%) were double heterozygotes harboring a R368H as well as a Gln48His mutation. The most common mutation observed was the G61E in 13 patients; 7 homozygotes and 6 heterozygotes for the mutation. The control group were negative for all mutations screened for. No significant correlations between the mutations and phenotype severity were detected. A statistically significant positive correlation however was found between the different mutations and each of the IOP and the cup/disk ratio. Conclusion The current study further endorses the role of CYP1B1 mutations in the etiology of PCG among Egyptian patients and is the first study to report MYOC gene mutation in Egyptian patients with PCG.

The beneficial effects of lipoic acid (LA) in cancer treatment have been well documented in the last decade. Indeed, LA exerts crucial antiproliferative effects by reducing breast cancer cell viability, cell cycle progression and the epithelial-to-mesenchymal transition (EMT). However, the mechanisms of action (MOA) underlying these antiproliferative effects remain to be elucidated. Recently, we demonstrated that LA decreases breast cancer cell proliferation by inhibiting IGF-1R maturation via the downregulation of the proprotein convertase furin. The aim of the present study was to investigate the MOA by which LA inhibits furin expression in estrogen receptor α (ERα) (+) and (-) breast cancer cell lines. We unveil that LA exerts a pro-oxidant effect on these cell lines, the resulting reactive oxygen species (ROS) generated being responsible for the reduction in the expression of the major (CREB) protein. This transcription factor is overexpressed in many types of cancers and regulates the expression of furin in breast cancer cells independently of ERα, as evidenced herein by the inhibition of furin expression following CREB silencing. Consequently, our findings expose for the first time the complete MOA of LA via the CREB/furin axis leading to inhibition of breast cancer cell proliferation.

To report on the corneal biomechanical characteristics, namely the corneal hysteresis (CH), corneal resistance factor (CRF), as well as the intraocular pressure (IOP) goldman compensated (IOPg), and the cornea compensated (IOPcc), using the ocular response analyzer (ORA) in different age groups in a cohort of normal individuals from the second decade to the seventh decade and beyond. The study was a cross-sectional survey conducted on 997 eyes of 508 normal individuals presenting for a routine ophthalmic examination at Alexandria Main University Hospital in Alexandria University, Alexandria, Egypt. The study subjects were age stratified into decades (10–20, 21–30, 31–40, 41–50, > 50) and the ORA parameters (CH, CRF, IOPg, IOPcc) reported and stratified. Correlations were sought between the ORA parameters and the age, gender, and laterality. The study was conducted on 997 (502 right) eyes of 508 (234 males) normal individuals. The mean ± SD ages of the study groups were 14.7 ± 3.2, 25.9 ± 3.0, 35.3 ± 2.8, 44.6 ± 2.9, and 61.1 ± 7.7 years. The mean ± SD of the CH in the study groups were 10.9 ± 2.4, 9.8 ± 1.5, 9.8 ± 1.4, 9.7 ± 1.7, and 9.5 ± 1.6 mmHg and of the CRF were 10.9 ± 2.4, 9.5 ± 1.7, 9.4 ± 1.8, 9.6 ± 1.9, and 9.6 ± 1.8 mmHg. A statistically significant negative correlation was found between age and each of CH and CRF. IOPcc demonstrated a fairly constant trend in the different age groups whereas IOPg demonstrated an initial decline followed by a gradual rise over time. The corneal biomechanical properties CH and CRF decrease with age. IOPg and IOPcc change minimally with age.

BackgroundBreast cancer is the second most common cancer in the world. Despite advances in therapies, the mechanisms of resistance remain the underlying cause of morbidity and mortality. Lipoic acid (LA) is an antioxidant and essential cofactor in oxidative metabolism. Its potential therapeutic effects have been well documented, but its mechanisms of action (MOA) are not fully understood.MethodsThe aim of this study is to validate the inhibitory LA effect on the proliferation of various breast cancer cell lines and to investigate the MOA that may be involved in this process. We tested LA effects by ex vivo studies on fresh human mammary tumour samples.ResultsWe demonstrate that LA inhibits the proliferation and Akt and ERK signalling pathways of several breast cancer cells. While searching for upstream dysregulations, we discovered the loss of expression of IGF-1R upon exposure to LA. This decrease is due to the downregulation of the convertase, furin, which is implicated in the maturation of IGF-1R. Moreover, ex vivo studies on human tumour samples showed that LA significantly decreases the expression of the proliferation marker Ki67.ConclusionLA exerts its anti-proliferative effect by inhibiting the maturation of IGF-1R via the downregulation of furin.

International audience; Vascular calcification (VC) is the pathological accumulation of calcium phosphate crystals in one of the layers of blood vessels, leading to loss of elasticity and causing severe calcification in vessels. Medial calcification is mostly seen in patients with chronic kidney disease (CKD) and diabetes. Identification of key enzymes and their actions during calcification will contribute to understand the onset of pathological calcification. Phospholipase D (PLD1, PLD2) is active at the earlier steps of mineralization in osteoblasts and chondrocytes. In this study, we aimed to determine their effects during high-phosphate treatment in mouse vascular smooth muscle cell line MOVAS, in the ex vivo model of the rat aorta, and in the in vivo model of adenine-induced CKD. We observed an early increase in PLD1 gene and protein expression along with the increase in the PLD activity in vascular muscle cell line, during calcification induced by ascorbic acid and beta-glycerophosphate. Inhibition of PLD1 by the selective inhibitor VU0155069, or the pan-PLD inhibitor, halopemide, prevented calcification. The mechanism of PLD activation is likely to be protein kinase C (PKC)-independent since bisindolylmaleimide X hydrochloride, a pan-PKC inhibitor, did not affect the PLD activity. In agreement, we found an increase in Pld1 gene expression and PLD activity in aortic explant cultures treated with high phosphate, whereas PLD inhibition by halopemide decreased calcification. Finally, an increase in both Pld1 and Pld2 expression occurred simultaneously with the appearance of VC in a rat model of CKD. Thus, PLD, especially PLD1, promotes VC in the context of CKD and could be an important target for preventing onset or progression of VC.

Purpose The aim of the study was to estimate the age-specific and sex-specific prevalence of age-related macular degeneration (AMD) among elderly patients attending Alexandria Main University Hospital. Study design A cross-sectional survey was conducted. Patients and methods Patients aged 55 years or older were randomly selected from those attending different outpatient clinics at Alexandria Main University Hospital. One thousand eyes of 532 patients were included in the study. They underwent full ophthalmic examination with fundus photography. The fundus photographs were graded into early and late AMD according to the International Age-Related Macular Epidemiological Study Group Classification system. Prevalence rates were calculated. Results The overall prevalence of AMD was 6.6%. The prevalence of early and late AMD was 5.3 and 2.4%, respectively. There was a significantly higher prevalence of early and late AMD among those aged at least 75 years as compared with other age groups. The prevalence of AMD among male participants was 9.2% compared with only 4.1% among female participants. When potential risk factors were analyzed, smokers and those suffering from hypertension were associated with a significantly higher prevalence of AMD than were nonsmokers or those without hypertension. Diabetes mellitus was not significantly associated with AMD. Conclusion In this study, the prevalence of early AMD in younger age groups was lower than that found in other population-based studies in western populations. The prevalence of AMD increased with age and was significantly higher among men and smokers.

Purpose To study primary congenital glaucoma characteristics and surgery in a University-based practice in Egypt. Patients and methods The present study was a retrospective chart review of 165 eyes of 112 children who presented and were operated upon between 2005 and 2012 at Alexandria Main University Hospital in Egypt. The charts were reviewed for demographics as well as clinical data. Postoperative data were retrieved till the end of the follow-up period. Complications were noted, and success rates were studied. Results The mean age±SD (range) of the study population at presentation was 6.1±4.4 (1–24) months, and of the follow-up period was 32.3±21.7 (6–78) months. The average (range) number of glaucoma procedures performed for each eye was 1.3 (1–4). The most common primary glaucoma surgical procedure performed was combined trabeculotomy–trabeculectomy with mitomycin C (143 procedures). The mean values (range) of preoperative intraocular pressure (on no intraocular pressure lowering therapy), corneal diameter and thickness, cup/disc ratio and axial length of the study eyes were 18.7±5.9 (5–36) mmHg, 12.8±0.9 (10–17) mm and 619.5±95.2 (433–784) μm, 0.6±0.2 (0–1) and 22.99±1.82 (17.0–30.59) mm, respectively, and postoperatively at last follow-up were 7.4±6.6 (0–46) mmHg, 13.0±0.9 (10–18) mm and 530.6±75.1 (425–823) μm, 0.3±0.3 (0–1) and 24.06±2.13 (20.55–30.75) mm, respectively. Cumulative success by Kaplan–Meier analysis was 0.97, 0.89, 0.83, 0.73 and 0.61 at 1, 2, 3, 4 and 5 years, respectively. Complications included corneal scarring, cataract, intraretinal haemorrhages, hypotony disc oedema, rhegmatogenous retinal detachment and endophthalmitis. Conclusion Combined trabeculotomy–trabeculectomy with mitomycin C is a successful treatment for primary congenital glaucoma. Meticulous, continuous and prolonged follow-up is mandatory for all operated cases to ensure long-term success.

Breast cancer is the most common cancer in women worldwide. Estrogen signaling pathways have been identified as efficient targets of breast cancer therapy, given their key role in promoting breast tumor growth. Agents blocking estrogen-mediated pathways are routinely used in clinical applications in patients displaying estrogen-sensitive breast cancer subtypes; however intrinsic or acquired resistance to treatment often occurs or develops, thus limiting their efficacy. This limitation has highlighted an imperative need to identify new predictive biomarkers. Recent findings have highlighted a role for the Liver Kinase B1 (LKB1) in breast cancer tumorigenesis. LKB1 is a serine/threonine kinase mutated in Peutz-Jeghers syndrome (PJS), implicated in many cellular processes including energy metabolism, cell polarization and cell cycle arrest and has also been shown to play an essential role as a tumor suppressor gene by negatively regulating the mTOR pathway. This review provides an overview of previous findings and ongoing research on LKB1, and substantiates the use of this kinase as a potential prognostic and predictive biomarker of breast cancer.

Mammalian phospholipase D (PLD) mostly hydrolyzes phosphatidylcholine producing phosphatidic acid. PLD activity was previously detected in different osteoblastic cell models, and was increased by several growth factors involved in bone homeostasis. To confirm possible actions of PLD isoforms during mineralization process, we analyzed their effects in osteoblastic cell models and during bone formation. PLD1 expression, along with PLD activity, increased during differentiation of primary osteoblasts and Saos-2 cells, and peaked at the onset of mineralization. Subsequently, both PLD1 expression and PLD activity decreased, suggesting that PLD1 function is regulated during osteoblast maturation. In contrast, PLD2 expression was not significantly affected during differentiation of osteoblasts. Overexpression of PLD1 in Saos-2 cells improved their mineralization potential. PLD inhibitor Halopemide or PLD1-selective inhibitor, led to a decrease in mineralization in both cell types. On the contrary, the selective inhibitor of PLD2, did not affect the mineralization process. Moreover, primary osteoblasts isolated from PLD1 knockout (KO) mice were significantly less efficient in mineralization as compared with those isolated from wild type (WT) or PLD2 KO mice. In contrast, bone formation, as monitored by high-resolution microcomputed tomography analysis, was not impaired in PLD1 KO nor in PLD2 KO mice, indicating that the lack of PLD1 or that of PLD2 did not affect the bone structure in adult mice. Taken together, our findings indicate that PLD activity, especially which of PLD1 isoform, may enhance the mineralization process in osteoblastic cells. Nonetheless, the lack of PLD1 or PLD2 do not seem to significantly affect bone formation in adult mice.

International audience; Protein arginine methyltransferase 5 (PRMT5) is the main enzyme responsible for the symmetrical dimethylation of arginine residues on target proteins in both the cytoplasm and the nucleus. Though its activity has been associated with tumor progression in various cancers, the expression pattern of this oncoprotein has been scarcely studied in breast cancer. In the current work, we analyzed its expression in a large cohort of breast cancer patients, revealing higher nuclear PRMT5 levels in ERα-positive tumors and an association with prolonged disease free and overall survival. Interestingly, high PRMT5 nuclear expression was also associated with higher nuclear liver kinase B1 (LKB1), suggesting that a functional relationship may occur. Consistently, several approaches provided evidence that PRMT5 and LKB1 interact directly in the cytoplasm of mammary epithelial cells. Moreover, although PRMT5 is not able to methylate LKB1, we found that PRMT5 is a bona fade substrate for LKB1. We identified T132, 139 and 144 residues, located in the TIM-Barrel domain of PRMT5, as target sites for LKB1 phosphorylation. The point mutation of PRMT5 T139/144 to A139/144 drastically decreased its methyltransferase activity, due probably to the loss of its interaction with regulatory proteins such as MEP50, pICln and RiOK1. In addition, modulation of LKB1 expression modified PRMT5 activity, highlighting a new regulatory mechanism that could have clinical implications.

Of 170 children who underwent 248 glaucoma procedures at a single center between 2005 and 2012, 13 eyes of 12 children (5.24%) developed decompression retinopathy, which resolved spontaneously, leaving no visible structural damage to the fundus structures. The mean age of children with hemorrhages was 39.2 ± 63.5 months; of those without, 8.0 ± 9.7 months. The fundus hemorrhages were peripapillary, subfoveal, dot-and-blot, and diffuse. Combined angle and filtering surgery with antimetabolite was the most common procedure performed in all eyes. There were no statistically significant differences between eyes with and without hemorrhages with respect to demographics or preoperative and operative characteristics. No definite ocular risk factor was identified for the occurrence of decompression retinopathy.

Purpose: To compare the effect of two exposure durations of mitomycin C in combined angle and filtering surgery for primary congenital glaucoma. Methods: This was a prospective study conducted in the Department of Ophthalmology at Alexandria Main University Hospital, Alexandria, Egypt, on 75 eyes with primary congenital glaucoma that underwent combined trabeculotomy–trabeculectomy with intraoperative mitomycin C application for 1 minute (MMC 1) or 2 minutes (MMC 2) and were followed up for 24 months. Success rates were studied and complications noted. Success was defined by a composite primary end point of an intraocular pressure (IOP) of less than 16 mm Hg under general anesthesia, without any IOP-lowering medications and with no hypotony-related complications and/or lack of IOP-related progression of the disease as evidenced by worsening of the ocular biometric characteristics. Results: The mean age of the study participants was 6.7 ± 4.1 months (range: 2 to 16 months; median: 6 months) in the MMC 1 group (35 eyes) and 7.7 ± 5.7 months (range: 1 to 32 months; median: 6.5 months) in the MMC 2 group (40 eyes). The initial surgery was successful in 32 (91.5%) and 31 (77.5%) eyes in the MMC 1 and MMC 2 groups, respectively. The mean IOP was 18.4 ± 5.1 and 18.1 ± 6.1 mm Hg preoperatively and 5.5 ± 3.5 and 4.8 ± 2.8 mm Hg at the end of follow-up in the MMC 1 and MMC 2 groups, respectively. There was no statistically significant difference in the clinical parameters between the two groups. Complications included cataracts in each group and hypotony optic disc edema in 3 eyes (7.5%) in the MMC 2 group. Conclusions: Both mitomycin C application durations were effective in combined trabeculotomy–trabeculectomy with mitomycin C for primary congenital glaucoma. The longer duration was not advantageous in disease control and there were no significant differences in complications. [ J Pediatr Ophthalmol Strabismus . 2018;55(3):164–170.]

Activating mutations in Neuroblastoma RAS viral oncogene homolog (NRAS) are found in 15–30% of melanomas and are associated with a poor prognosis. Although MAP kinase kinase (MEK) inhibitors used as single agents showed a limited clinical benefit in patients with NRAS-mutant melanoma due to their rather cytostatic effect and high toxicity, their combination with other inhibitors of pathways known to cooperate with MEK inhibition may maximise their antitumour activity. Similarly, in a context where p53 is largely inactivated in melanoma, hyperexpression of Microphthalmia associated transcription factor (MITF) and its downstream anti-apoptotic targets may be the cause of the restraint cytotoxic effects of MEK inhibitors. Indeed, drug combinations targeting both mutant BRAF and MITF or one of its important targets Bcl-2 were effective in mutant BRAF melanoma but had no effect on acquired resistance. Therefore, we aimed to further investigate the downstream MITF targets that can explain this anti-apoptotic effect and to evaluate in parallel the effect of p53 reactivation on the promotion of apoptosis under MEK inhibition in a panel of Q61 NRAS-mutant melanoma cells. First, we showed that MEK inhibition (pimasertib) led to a significant inhibition of cell proliferation but with a limited effect on apoptosis that could be explained by the systematic MITF upregulation. Mimicking the MITF effect via cyclic adenosine monophosphate activation conferred resistance to MEK inhibition and upregulated Bcl-2 expression. In addition, acquired resistance to MEK inhibition was associated with a strong activation of the anti-apoptotic signalling MITF/Bcl-2. More importantly, selective Bcl-2 inhibition by ABT-199 or Bcl-2 knockout using CRISPR/Cas9 system annihilated the acquired resistance and restored the sensitivity of NRAS-mutant melanoma cells to MEK inhibition. Strikingly and similarly, direct p53 reactivation (PRIMA-1 Met , APR-246) also broke resistance and synergised with MEK inhibition to induce massive apoptosis in NRAS-mutant melanoma cells with wild-type or mutant p53. Hence, our data identify MITF/Bcl-2 as a key mechanism underlying resistance of NRAS-mutant melanoma cells to apoptosis by MEK inhibitors and paves the way for a promising drug combination that could prevent or reverse anti-MEK resistance in this group of patients.

IFN-γ is a cytokine with important roles in the innate and adaptive immune responses. This cytokine is secreted by activated T cells, NK cells and macrophages. Studies on the regulation of human IFN-γ expression had been previously focused on the promoter region. Consequently, the role of microRNAs (miRs) in this regulation has not been investigated yet. As miR-24 and miR-181 were found to have potential target sites in IFN-γ mRNA 3'UTR, we assessed their impact on IFN-γ expression by co-stimulating PB CD4+ T cells with anti-CD3, anti-CD28, IL-12, and IL-18. This co-stimulation cocktail induced an abundant secretion of IFN-γ together with a down-regulation of miR-24, and miR-181. Existence of a link between these two phenomena was further substantiated by transfection and transduction assays that showed that these two miRs negatively regulate IFN-γ expression by directly binding to their target sites in the mRNA. Thus, identifying target sites for miR-24 and miR-181 in IFN-γ-3'UTR points to a novel regulatory mechanism of this crucial gene.

To ensure recognition of a broad variety of pathogens, the innate immune system has evolved, through a number of receptors, a strategy to recognize a limited number of conserved pathogen-associated molecular patterns. These receptors include the Toll-like receptors (TLRs), which are transmembrane receptors expressed in a variety of immune, but also epithelial and transformed cells (1). TLRs are connected to the cell signaling machinery via intracellular adaptor molecules. The first such adaptor molecule to be discovered was MyD88, which has an N-terminal death domain (DD), which recruits downstream signaling molecules (2). MyD88 is also an adaptor of the interleukin 1 receptor (IL-1R) family signaling. Activation of the TLR/IL-1R signaling pathway activates the major inflammatory transcription factor NF-kB by allowing its nuclear translocation. Inflammation is recognized as a promoter of carcinogenesis (3). Predictably, MyD88 was shown to play a role in tumorigenesis via TLR and IL-1 proinflammatory mechanisms (4). We have recently shown that MyD88 operates as an adaptor connecting inflammatory signaling pathways with the Ras oncogenic signaling pathway. Specifically, we showed that MyD88 is required for Ras-dependent cell signaling and transformation (5). Here we show in a panel of Ras-dependent colon cancer cell lines that, in addition to its role in tumor initiation, MyD88 plays an important role in the survival of Ras-transformed cells. We demonstrate that MyD88 is required for the expression of the major DNA repair enzyme ERCC1, and therefore for efficient DNA repair, and that knocking down MyD88 sensitizes colon cancer cells to genotoxic agents such as platinum salts in vitro and in vivo. These results indicate a novel and original link between inflammation, DNA repair, and cancer.

To study the additive value of deep sclerectomy to the procedure of combined trabeculotomy—trabeculectomy with mitomycin C (CTTM) for the treatment of primary congenital glaucoma. This study is a prospective, randomized case series. The study was conducted on 20 eyes of 20 children with primary congenital glaucoma presenting to the Department of Ophthalmology of the Alexandria Main University Hospital. Preoperative examination under anesthesia was followed by surgical intervention. Postoperative examinations were conducted immediately after surgery and at 1, 2, 3, 6, 9, and 12 months. Intraoperative and postoperative complications, as well as operative time, were recorded. The mean (±SD, range) age of the study patients in the CTTM group and in the combined trabeculotomy–trabeculectomy with mitomycin C with deep sclerectomy (CTTM-DS) group was 4.7 (±2.0, 2–8) and 7.0 (±3.8, 3–13) months, respectively. The mean (±SD, range) preoperative intraocular pressure (IOP) in the CTTM and CTTM-DS groups was 16.7 (4.3, 10–26) and 16.4 (8.4, 8–36), respectively, and these dropped at 12 months of follow-up to 4.9 (2.0, 2–8) and 5.6 (3.3, 2–10), respectively. The mean (±SD, range) of the duration of the operation in the CTTM and the CTTM-DS was 57 (±8, 50–71) min and 53 (±7, 42–64) min, respectively (P=0.428). Two eyes (20%) in the CTTM-DS group developed hypotony disc edema at the first 2 months and resolved spontaneously thereafter. No other complications were noted in either of the groups. The addition of deep sclerectomy to the procedure of CTTM in pediatric glaucoma surgery facilitates the finding of Schlemm’s canal, shortens the duration of surgery, and is not associated with any additional complications. Hence, the author recommends the addition of deep sclerectomy to CTTM surgery for primary congenital glaucoma.

Waardenburg anophthalmia syndrome, also known as microphthalmia with limb anomalies, ophthalmoacromelic syndrome, and anophthalmia-syndactyly, is a rare autosomal-recessive developmental disorder that has been mapped to 10p11.23. Here we show that this disease is heterogeneous by reporting on a consanguineous family, not linked to the 10p11.23 locus, whose two affected children have a homozygous mutation in SMOC1. Knockdown experiments of the zebrafish smoc1 revealed that smoc1 is important in eye development and that it is expressed in many organs, including brain and somites.

Purpose To investigate the role of ultrasound biomicroscopy (UBM) in the evaluation of anterior segment anatomy in cases of congenital and developmental cataract. Setting Alexandria Main University Hospital, Ophthalmology Department, Faculty of Medicine, Alexandria University, Alexandria, Egypt. Methods In this cross-sectional nonrandomized unmasked study, ultrasound biomicroscopy (UBM) was used to evaluate the anterior segment anatomy of 32 eyes of 21 children with congenital and developmental cataract. The parents were questioned for details of the children's history. An initial office examination was done to detect visual function, pupil color, lens morphology, corneal clarity, and presence of gross anterior segment anomaly. If the fundus was visible, it was examined in cooperative children after mydriasis. Under general anesthesia, each child was examined by UBM. Results The parameters detected by UBM included anterior chamber depth, lens thickness, zonular fiber length, ciliary process length, anterior chamber angle, and lens morphology. A-scan biometry was also performed to detect anterior chamber biometric characteristics. Conclusion Ultrasound biomicroscopy is a valuable tool for evaluating childhood cataracts and associated ocular anomalies as well as anterior segment biometric characteristics.

International audience; Multiple endocrine neoplasia type 1 (MEN1) results from the mutation of the predisposing gene, MEN1. Heterozygous Men1 mutant mice previously generated by several laboratories, including ours, mimic largely MEN1 pathology. Interestingly, our heterozygous Men1 mutant mice exhibit not only the endocrine tumours commonly seen in MEN1 patients, but also Leydig cell tumours (LCT) with high frequency, accompanied systematically by loss of the wild-type Men1 allele. As there exists a similarity of tumour phenotype between these mice and those mutated for the components of anti-Mullerian hormone (AMH)/bone morphogenic protein (BMP) pathway belonging to transforming growth factor-beta (TGF-beta) family, we investigated the expression and the activity of this pathway, known to have an important biological role in Leydig cells. Here, we report that the expression of AMH receptor type 2 is reduced in Men1 LCTs. Both immunostaining and western blot analyses also demonstrate a markedly decreased nuclear expression of Smad1, 3, 4 and 5 in the tumours. More interestingly, we show that the reconstituted menin expression in Men1-deficient Leydig cells derived from LCTs can significantly increase the transcriptional activity of a BMP pathway target promoter, XVent2. Furthermore, we found that the expression of p18, p27 and cyclin dependant kinase 4 (Cdk4), targets of TGF-beta pathways, is altered in the Leydig cell lesions. Our data provide the evidence of the deregulation of AMH/BMP and TGF-beta pathways in mouse Men1 LCTs, highlighting their involvement in tumorigenesis of Leydig cells due to Men1 inactivation.

Globe rupture is a common sight-threatening ophthalmic emergency. We present a twelve-year-old girl with ocular trauma by sharp object resulting in corneal laceration, hyphema, traumatic cataract and iris prolapse. This case illustrates the importance of early diagnosis, proper wound repair of ruptured globe as well as management of post-operative complications and value of early post-operative visual rehabilitation.

Purpose: To report the clinical and genetic study of a child with bilateral anophthalmia. Methods: A 14-year-old Egyptian boy, born from consanguineous parents, underwent a general and a full ophthalmological examination. Mutation screen of the A/M genes with recessive inheritance was done stepwise and DNA was analyzed by Sanger sequencing. Results: Bilateral anophthalmia, arachnodactyly of the feet and high arched palate were observed on general examination. The parents were first cousins and healthy. Sequencing analysis revealed a novel compound heterozygous mutation in one of the copy of exon 2 of VSX2 and a possible deletion of at least exon 2 on the other allele. Conclusions: A compound heterozygous VSX2 mutation associated with anophthalmia was identified in a patient from an Egyptian consanguineous family. This report brings the number of VSX2 mutation in anophthalmia/ microphthalmia (A/M) to 13. Functional consequences of the reported changes still need to be characterized, as well as the percentage of A/M caused by mutations in the VSX2 gene. This family also shows that despite consanguinity, heterozygous mutations can also happen and one should not restrict the molecular analysis to homozygous mutations.

Although the presence of nuclear estrogen receptor is widely used to guide breast cancer therapy, less attention has been paid to the receptor cytoplasmic signaling. Recently, we have shown that this pathway is operative in vivo and is activated in aggressive tumors representing a new potential target for breast cancer therapy. Here, we identified LKB1 as a partner of ERα and we explored its potential role in estrogen nongenomic signaling. The associations between LKB1 expression and the actors of this pathway, namely the methylated form of ERα (metERα), Src and PI3K, have been analyzed both in cultured cells and in 154 primary breast tumor samples. We found that LKB1 is a component of the cytoplasmic signaling complex in breast cell lines as well as in primary breast tumors. Moreover, an inverse correlation between the localization of LKB1 in nuclear and cytoplasmic compartments is observed. Importantly, high expression of cytoplasmic LKB1 is an independent marker of poor prognosis, associated with reduced overall survival (OS) and disease free survival (DFS). Conversely, the presence of nuclear LKB1 associates with increased OS and DFS. In conclusion, our results highlight that LKB1 expression in breast cancer appears to have opposite effects depending on its subcellular localization and may be used as a new prognostic biomarker.

Anophthalmia or microphthalmia (A/M), characterized by absent or small eye, can be unilateral or bilateral and represent developmental anomalies due to the mutations in several genes. Recently, mutations in aldehyde dehydrogenase family 1, member A3 (ALDH1A3) also known as retinaldehyde dehydrogenase 3, have been reported to cause A/M. Here, we screened a cohort of 75 patients with A/M and showed that mutations in ALDH1A3 occurred in six families. Based on this series, we estimate that mutations in ALDH1A3 represent a major cause of A/M in consanguineous families, and may be responsible for approximately 10% of the cases. Screening of this gene should be performed in a first line of investigation, together with SOX2. (C) 2014 Wiley Periodicals, Inc.

ERα functions are tightly controlled by numerous post-translational modifications including arginine methylation, which is required to mediate the extranuclear functions of the receptor. We report that upon oestrogenic stimulation, JMJD6, the only arginine demethylase described so far, interacts with and regulates methylated ERα (metERα) function. Moreover, by combining the silencing of JMJD6 with demethylation assays, we show that metERα is a new substrate for JMJD6. We propose that the demethylase activity of JMJD6 is a decisive regulator of the rapid physiological responses to oestrogen.

Although the presence of nuclear estrogen receptor is widely used to guide breast cancer therapy, less attention has been paid to the receptor cytoplasmic signaling. Recently, we have shown that this pathway is operative in vivo and is activated in aggressive tumors representing a new potential target for breast cancer therapy. Here, we identified LKB1 as a partner of ERα and we explored its potential role in estrogen nongenomic signaling. The associations between LKB1 expression and the actors of this pathway, namely the methylated form of ERα (metERα), Src and PI3K, have been analyzed both in cultured cells and in 154 primary breast tumor samples. We found that LKB1 is a component of the cytoplasmic signaling complex in breast cell lines as well as in primary breast tumors. Moreover, an inverse correlation between the localization of LKB1 in nuclear and cytoplasmic compartments is observed. Importantly, high expression of cytoplasmic LKB1 is an independent marker of poor prognosis, associated with reduced overall survival (OS) and disease free survival (DFS). Conversely, the presence of nuclear LKB1 associates with increased OS and DFS. In conclusion, our results highlight that LKB1 expression in breast cancer appears to have opposite effects depending on its subcellular localization and may be used as a new prognostic biomarker.