A neuploidy (aberrant chromosome number) is a hallmark feature of human malignancies (1, 2) and has also been proposed as a necessary event for tumorigenesis (2). Although there have been many proposed hypotheses, there is no general agreement as to why aneuploidy is so highly prevalent in cancer cells, and how it contributes to tumor progression (3, 4). Importantly, if aneuploidy forms an underlying cause of human cancer, it has not been fully substantiated. The mechanisms of aneuploidy also remain a fundamental unresolved problem in cancer biology.To understand how aneuploidy might originate in mammalian tissues, we have focused on the elements that regulate chromosomal segregation, particularly those involved in sister chromatid cohesion and separation, because chromosome missegregation, for example during mitosis, can lead to aneuploidy. A key gene in our analysis is ESPL1, which encodes an endopeptidase called Separase that separates sister chromatids by cleaving cohesin Rad21/Mcd1/Scc1 during the metaphase to anaphase transition. The hypothesis we tested is that hormonal stimulation of the p53-null mouse mammary gland results in misexpression of the ESPL1 gene, thus promoting aneuploidy and breast cancer formation. Dysregulation of the mitotic machinery that helps maintain chromosomal stability in mammary cells can result in aneuploidy and subsequently, cancer formation. We focused on Separase for the following reasons that have important implications for breast cancer: (i) Separase plays a central role in promoting faithful chromosome segregation; (ii) our previous studies strongly indicated that hormonal stimulation of p53-null mice mammary gland results in overexpression of the ESPL1 and Separase protein, which may be a direct cause of aneuploidy (5); and (iii) siRNA-mediated knockdown of Separase and Separase deficient mouse embryonic fibroblasts results in genomic instability (6-8).An evolutionarily conserved protein complex called cohesin and an endopeptidase named Separase play pivotal roles in the accurate segregation of sister chromatids into two daughter cells. Cohesion along the length of the sister chromatids is formed during DNA replication in S phase. Cohesion along the chromosomal arms is removed during prophase and from centromeric regions at the metaphase-to-anaphase transition when Separase is activated after its inhibitory chaperone securin is degraded (9, 10).To understand how aberration in sister chromatid separation may contribute to chromosomal missegregation, we investigated the role of Separase overexpression in mouse mammary cells by using a mammary epithelial transplant model (11) as well as various biochemical and functional assays. Our results indicate that conditional overexpression of Separase alone in mammary epithelial cells with a p53 mutant background is sufficient to induce aneuploidy and tumorigenesis in vitro and in vivo. Results Conditional Expression of Mouse Separase (mSeparase) Results inAneuploidy in Mouse Mammary Epithelial Cells. To examine the direct effect of ...

Purpose:To evaluate the impact of low vision rehabilitation on functional vision of children with visual impairment.Materials and Methods:The LV Prasad–Functional Vision Questionnaire, designed specifically to measure functional performance of visually impaired children of developing countries, was used to assess the level of difficulty in performing various tasks pre and post visual rehabilitation in children with documented visual impairment. Chi-square test was used to assess the impact of rehabilitation intervention on functional vision performance; a P < 0.05 was considered significant.Results:LogMAR visual acuity prior to the introduction of low vision devices (LVDs) was 0.90 ± 0.05 for distance and for near it was 0.61 ± 0.05. After the intervention, the acuities improved significantly for distance (0.2 ± 0.27; P < 0.0001) and near (0.42 ± 0.17; P = 0.001). The most common reported difficulties were related to their academic activities like copying from the blackboard (80%), reading textbook at arm's length (77.2%), and writing along a straight line (77.2%). Absolute raw score of disability pre-LVD was 15.05 which improved to 7.58 post-LVD. An improvement in functional vision post visual rehabilitation was especially found in those activities related to their studying lifestyle like copying from the blackboard (P < 0.0001), reading textbook at arm's length (P < 0.0001), and writing along a straight line (P = 0.003).Conclusions:In our study group, there was a significant improvement in functional vision post visual rehabilitation, especially with those activities which are related to their academic output. It is important for these children to have an early visual rehabilitation to decrease the impairment associated with these decreased visual output and to enhance their learning abilities.

BackgroundPrevious studies show that clinical features at presentation, in retinoblastoma patients, like glaucoma and neovascularization of iris are associated with a higher incidence of high risk histopathology findings (HRF) in enucleated eyes. Herein, we analyze association between clinical features at time of enucleation and occurrence of HRF including invasion of anterior chamber, iris, ciliary body, choroid (massive), sclera, extrascleral tissue, optic nerve beyond lamina cribrosa, and optic nerve cut end, in a large series of eyes enucleated for retinoblastoma.ProcedureWe retrospectively studied demographic, clinical, and histopathology findings in all retinoblastoma patients who underwent primary enucleation at our center, over a 5 years duration. Statistical analysis was done to find any association between clinical features at presentation and the presence of HRF.ResultsThree hundred twenty‐six eyes were studied. Median age of presentation was 2 years. Glaucoma was the most common clinical finding at presentation apart from leucocoria. Out of 326 enucleated eyes, 28 (8.6%) had extrascleral and/or optic nerve transection invasion. Among remaining 298 eyes, with completely resected tumor, 115 (38.6%) had massive choroidal invasion, 54 (17%) had retrolaminar optic nerve invasion, and 24 (7%), 29 (9%), and 23(7%) had anterior chamber, iris, and ciliary body invasion, respectively. Age more than 2 years, lag period more than 3 months, hyphema, pseudohypopyon, staphyloma, and orbital cellulitis were associated with occurrence of three or more HRF on univariate analysis.ConclusionsClinical variables including older age, longer lag period, hyphema, pseudohypopyon, staphyloma, and orbital cellulitis were strongly associated with occurrence of HRF in this study. Pediatr Blood Cancer 2012; 58: 356–361. © 2011 Wiley Periodicals, Inc.

N Context.-In eyes enucleated for retinoblastoma, presence of histopathologic high-risk factors is associated with a higher risk of local recurrence and systemic metastasis.Objective.-To evaluate histopathologic features in children with retinoblastoma in our population and establish relationship between age, tumor differentiation, and high-risk features.Design.-Retrospective histopathologic analysis of 609 consecutively enucleated eyes for advanced intraocular retinoblastoma during a 10-year period. A nonparametric test was used to establish relationship between age, differentiation, and high-risk features.Results.-Poorly differentiated retinoblastoma presented in 80.3% and well-differentiated in 19.7% of eyes. Welldifferentiated tumors presented earlier (median 1.2 years) than poorly differentiated tumors (median 2.5 years) (P , .001). One hundred fourteen eyes (18.7%) had 1 and 138 (22.7%) had at least 2 high-risk histopathologic factors. Invasion of anterior chamber was found in 10.0%, iris in 10.7%, ciliary body in 6.7%, sclera in 13.7%, massive choroid in 24.6%, postlaminar optic nerve in 16.1%, resected margin of the optic nerve in 7.4%, and extrascleral tissue in 4.1% of eyes. Extensive necrosis was seen in 31.0% of eyes. Poorly differentiated tumors were significantly associated with presence of more than 1 highrisk histopathologic feature (P , .001) and extensive necrosis (P , .001).Conclusion.-Poorly differentiated tumors present at a later age and are associated with presence of multiple high-risk factors and extensive necrosis. In our population, high-risk histopathologic factors are present in a significant number of eyes. Because we have included only primarily enucleated eyes, this could truly represent the distribution of high-risk histopathologic factors in children with retinoblastoma. (Arch Pathol Lab Med. 2012;136:190-193; doi: 10.5858/ arpa.2010-0759-OA) R etinoblastoma is the most frequent primary malignant intraocular tumor in children and has an estimated annual incidence of 1 in 16 000 to 1 in 18 000 live births. 1With the present-day multidisciplinary therapeutic approach, ocular salvage is possible in group A through D intraocular tumors (International Retinoblastoma Classification). However, in group E tumors (and group D in unilateral cases), enucleation remains the modality of choice. Some histopathologic findings in enucleated eyes, designated as high-risk factors (HRFs), are associated with a greater risk of orbital recurrence and distant metastasis and need adjuvant therapy.There are few studies that have evaluated HRFs in eyes enucleated for advanced intraocular retinoblastoma from developing countries, and most of them have reported higher incidences compared with studies reported in the Western literature. [2][3][4][5] This has been attributed to delay in presentation and diagnosis, lack of specialized centers, and/or differences in biologic behavior of the tumors. 6-8Herein, we report the results of a retrospective histopathologic analysis conducted on a large series of ...

Background Cataracts are a major cause of childhood blindness globally. Although surgically treatable, it is unclear whether children would benefit from such interventions beyond the first few years of life, which are believed to constitute `critical' periods for visual development. Aims To study visual acuity outcomes after late treatment of early-onset cataracts and also to determine whether there are longitudinal changes in postoperative acuity. Methods We identified 53 children with dense cataracts with an onset within the first half-year after birth through a survey of over 20 000 rural children in India. All had accompanying nystagmus and were older than 8 years of age at the time of treatment. They underwent bilateral cataract surgery and intraocular lens implantation. We then assessed their best-corrected visual acuity 6 weeks and 6 months after surgery. Results 48 children from the pool of 53 showed improvement in their visual acuity after surgery. Our longitudinal assessments demonstrated further improvements in visual acuity for the majority of these children proceeding from the 6-week to 6-month assessment. Interestingly, older children in our subject pool did not differ significantly from the younger ones in the extent of improvement they exhibit. Conclusions and relevance Our results demonstrate that not only can significant vision be acquired until late in childhood, but that neural processes underlying even basic aspects of vision like resolution acuity remain malleable until at least adolescence. These data argue for the provision of cataract treatment to all children, irrespective of their age.