Functional inhibition of RECQL5 helicase elicits non-homologous end joining response and sensitivity of breast cancers to PARP inhibitor.

Poly (ADPRibose) Polymerase inhibitor (PARPi) are clinically approved for the treatment of BRCA-mutated hereditary breast and ovarian cancers with homologous recombination (HR) deficiency, based on synthetic lethality concept. However, ∼90% of breast cancers are BRCA-wild type; they repair PARPi mediated damage through HR, leading to intrinsic de novo resistance. Hence, there is an unmet need of exploring novel targets in HR-proficient aggressive breast cancers for PARPi treatment. RECQL5 physically interacts and disrupts RAD51 from pre-synaptic filaments, aiding HR resolution, replication fork protection and preventing illegitimate recombination. In the current investigation, we show that targeted inhibition of HR by stabilization of RAD51-RECQL5 complex by a pharmacological inhibitor of RECQL5 (4a; 1,3,4-oxadiazole derivative) in the presence of PARPi [talazoparib (BMN673)] leads to abolition of functional HR with uncontrolled activation of NHEJ repair. This was assessed by GFP based NHEJ reporter assay, KU80 recruitment and in vitro NHEJ based plasmid ligation assay. Concomitant treatment with talazoparib and 4a generates copious amounts of replication stress, prolonged cell cycle arrest, extensive double strand breaks (DSBs) and mitotic catastrophe, leading to sensitization of HR-proficient breast cancers. Suppression of NHEJ activity abolishes 4a-mediated sensitization of breast cancers to PARPi treatment. Imperatively, 4a was ineffective against normal mammary epithelial cells, which expresses low RECQL5 vis-à-vis breast cancer cells. Moreover, functional inhibition of RECQL5 suppresses metastatic potential of breast cancer cells in response to PARPi. Together, we identified RECQL5 as a novel pharmacological target for expanding PARPi based treatment horizon for HR-proficient cancers.

Prevalence and Patterns of Refractive Errors in Children and Young Adults in an Urban Region in South India: the Hyderabad Eye Study.

PURPOSE: To determine the prevalence of refractive error (RE) and associated risk factors for myopic refractive errors in children and young adults from the urban region of Hyderabad, South India. METHODS: Four thousand sixty-five (4,065) participants aged 6-22 years were enrolled and examined in this cross-sectional study conducted from October 2013 to January 2015. Participants were enrolled from a random sample of schools and universities in regions representative of urban Hyderabad. RE was determined using cycloplegic autorefraction. The association of demographic factors such as age, gender, and socio-economic category (SEC) (low/mid/high) with myopia was explored with logistic regression with robust standard error. RESULTS: Of the total participants, 2,259 were children aged 6-15 years and 1,806 were adolescents and young adults aged 16-22 years. Overall prevalence of myopia, high myopia (≤ -5.00D and ≤ -6.00 D), hyperopia, emmetropia, and astigmatism was 29.8% (95% CI: 26.0% to 33.6%, n = 1,216), 2.9% (95% CI: 1.9% to 3.9%, n = 120), 1.1% (95%CI: 0.7% to 1.5%, n = 46), 14.7% (95% CI: 12.4% to 17.0%, n = 599), 46.9% (95% CI: 43.7% to 50.1%, n = 1913) and 8.6% (95% CI: 7.4% to 9.9%, n = 352) respectively. A strong correlation existed between age and prevalence of myopia (R2 = 0.88, p < .001) and high myopia (R2 = 0.71, p < .001). Children from schools of low SEC (34.7%) had higher prevalence of myopia compared to the mid SEC (16.8%) (p = .043). CONCLUSION: Myopia was the most prevalent refractive error and increased with age in this urban population. More myopia was observed in schools of low SEC.

Exploring non-adherence to contact lens wear schedule: Subjective assessments and patient related factors in children wearing single vision and myopia control contact lenses.

PURPOSE: To determine factors associated with non-adherence to contact lens wear schedule involving single vision and myopia control contact lenses in children. METHODS: Data from 379 children enrolled in a prospective, double masked, randomized clinical trial, aged 8-13 years, cycloplegic spherical equivalent of -0.75 to -3.50D and wearing either: single vision silicone hydrogel (SiH) CL (control lens); two anti-myopia SiH CL that incorporated relative plus in the central and periphery in a stepped manner (test lens I and II); and two extended depth of focus hydrogel CL (test lens III and IV) was considered. A questionnaire was administered to the participants at every scheduled visit and gathered information on days of wear/week and subjective assessments of ocular comfort and visual quality on an analog scale of 1-10.Participants were categorized as "Adherent" when lens wear was ≥ 6 days/week or "Non-adherent" when lens wear ≤ 5 days/week. Categorized adherence data was summarized as a percentage across visits for each CL type. Differences between the two groups were analyzed using linear mixed model. RESULTS: For the control lens, 79.6 % participants were adherent as compared to 63.7%-74.6% with test lenses (p=0.026). Non-adherence was greater in those that discontinued (p<0.001). Subjective ratings of visual quality for static and dynamic tasks were lower with non-adherent wearers and more variable between visits. Ocular comfort was also poorer in non-adherent wearers irrespective of lens material or lens design. Male gender, lower baseline myopia, lower high contrast visual acuity and esophoria were associated with a higher risk of non-adherence. CONCLUSIONS: The study identified a wide range of factors associated with non-adherence to lens wear schedule. Paying specific attention to these factors when evaluating patients for CL wear and taking steps to ensure satisfaction in lens wear may promote longer term continuation of wear.

Posterior segment conditions associated with myopia and high myopia.

Myopia, and especially high myopia, is associated with a number of posterior segment changes that are considered to be mostly a consequence of the increased axial elongation. This can result in mechanical strain, attendant vascular changes, stretching and thinning of tissues, and atrophy/deformation of tissues in later or more advanced stages. Such myopia-related changes are observed as changes and/or abnormalities in the vitreous, choroid, retina and peripheral retina, sclera and/or optic disc. Although many of these changes are benign, at times they may be associated with significant vision impairment that either requires active intervention or may suggest future progression of the disease. This review systematically addresses the posterior segment conditions seen in myopic eyes, describes the features associated with the condition and details management pathways.

Tessellated fundus appearance and its association with myopic refractive error.

The appearance of tessellated fundus in an eye may act as a marker in identifying visual performance, degree of myopia or risk of progression of myopia in a given eye. A systematic literature search using key words was performed using PubMed, Web of Science and Google Scholar and of the 832 studies identified, 10 full-length articles, which met the inclusion criteria, were considered for review. The primary outcome measures were association of tessellated fundus with: (i) visual acuity, (ii) refractive error, (iii) axial length, (iv) choroidal thickness and (v) future progression of myopia when compared to either no myopic maculopathy, or more severe myopic maculopathy. There was no significant difference in the visual acuity noted between eyes with normal fundus and tessellated fundus appearance. Compared to eyes with tessellated fundus, eyes with more severe myopic maculopathy had a four-line decrease in best-corrected visual acuity, more myopia (mean difference 2.75 D, range 0.28-5.78 D) and a longer axial length (mean difference 2 mm, range 2.29 to 1.71 mm). Eyes with tessellated fundus generally exhibited a significant decrease in choroidal thickness compared to eyes with no maculopathy. In mostly older individuals, eyes with tessellated fundus had a better outcome with respect to visual acuity, degree of myopia and axial length compared to other severe myopic maculopathies, but had a worse outcome for choroidal thickness and degree of myopia, compared to eyes with no myopic maculopathy. The features such as reduced choroidal thickness combined with a predilection to infra-temporal and parapapillary regions may indicate regions of stress that are prone to more stretching/atrophic changes. This systematic review demonstrated an association of tessellated fundus with visual acuity, refractive error, axial length and choroidal thickness and hence emphasises the documentation of the presence and location of tessellated fundus appearance that may help in predicting the progression of myopia.

Profile of off-axis higher order aberrations and its variation with time among various refractive error groups.

Peripheral higher order aberrations (HOA) of 646 children at 30° temporal, nasal and inferior visual field were measured under cycloplegia (5 mm pupil diameter) using a commercially available Shack-Hartmann aberrometer in the Sydney Myopia Study [age, 12.7 ±â€¯0.4 years (mean ±â€¯standard deviation)] and five years later in the Sydney Adolescent Vascular and Eye Study. At baseline, 176 eyes were emmetropic, 95 were myopic and 375 were hyperopic. Coma, 3rd order and RMS of coma increased with eccentricity for all eyes and no difference was observed for 4th order and RMS of C(4,0) among refractive error groups. More positive C(4,0) was observed for hyperopic eyes at periphery. At follow up, 26% had 'myopic change' and 70% had 'no change' in refractive error. At follow-up, horizontal coma became more negative at nasal field and more positive at temporal field for all eyes. More positive C(4,0) for hyperopic eyes at baseline may indicate variation in optical characteristics of peripheral cornea and crystalline lens. An increase in horizontal coma with time, irrespective of refractive error change, may be attributed to variation in the shape factor of peripheral cornea and crystalline lens and/or misalignment of optical surfaces/components relative to the visual axis (angle kappa) as the eye grows in axial length.

Influence of higher order aberrations and retinal image quality in myopisation of emmetropic eyes.

Refractive error, higher order aberrations (HOA), axial length (AL), anterior chamber depth (ACD) and average corneal radius of curvature were measured after cycloplegia from 166 emmetropic participants at the Sydney Myopia Study (SMS, 2004-2005, age 12.63 ± 0.48 years). Measurements were repeated approximately 5 years later at the Sydney Adolescent Vascular and Eye Study (SAVES, 2009-2010, age 17.08 ± 0.67 years). The baseline spherical equivalent (M) did not differ significantly between the participants lost to follow-up (65%) and the participants enrolled in SAVES study (p = 0.932). Refractive error and HOA were measured using a Shack-Hartmann aberrometer for a pupil diameter of 5 mm and AL, ACD and average corneal curvature measured using IOL Master at both visits. Retinal image quality in terms of Visual Strehl ratio (VSOTF) for a 5 mm pupil diameter was determined using on-axis lower and HOA. General linear model was used to determine the association of HOA and retinal image quality with change in refraction. Of the 166 emmetropes, 41 (25%) had myopic change (change in M > -0.50 D) and 125 (75%) had no change in refraction (change in M between +0.49 D and -0.49 D). Change in C[4, 0] (p < 0.001, R² = 0.236), fourth order RMS (p = 0.003, R² = 0.097) and coma RMS (p = 0.004, R² = 0.056) from baseline were significantly correlated with change in refraction. More positive change in C[4, 0] was associated with lesser myopic change in refraction. The eyes with myopic change in refraction decreased in positive C[4, 0] (at baseline = +0.049 ± 0.05 µm, at follow-up = +0.024 ± 0.05 µm, p < 0.05). In comparison, eyes with no change increased in positive C[4, 0] (at baseline = +0.033 ± 0.04 µm, at follow-up = +0.047 ± 0.04 µm, p < 0.05). Thus in conclusion, no significant association was observed between HOA and retinal image quality at baseline and development and progression of myopia among emmetropic eyes. The change in spherical aberration (C[4, 0]) with myopic change is possibly associated with changes occurring in crystalline lens during ocular growth.

Prevalence of anisometropia and its association with refractive error and amblyopia in preschool children.

AIM: To determine the age and ethnicity-specific prevalence of anisometropia in Australian preschool-aged children and to assess in this population-based study the risk of anisometropia with increasing ametropia levels and risk of amblyopia with increasing anisometropia. METHODS: A total 2090 children (aged 6-72 months) completed detailed eye examinations in the Sydney Paediatric Eye Disease Study, including cycloplegic refraction, and were included. Refraction was measured using a Canon RK-F1 autorefractor, streak retinoscopy and/or the Retinomax K-Plus 2 autorefractor. Anisometropia was defined by the spherical equivalent (SE) difference, and plus cylinder difference for any cylindrical axis between eyes. RESULTS: The overall prevalence of SE and cylindrical anisometropia ≥1.0 D were 2.7% and 3.0%, for the overall sample and in children of European-Caucasian ethnicity, 3.2%, 1.9%; East-Asian 1.7%, 5.2%; South-Asian 2.5%, 3.6%; Middle-Eastern ethnicities 2.2%, 3.3%, respectively. Anisometropia prevalence was lower or similar to that in the Baltimore Pediatric Eye Disease Study, Multi-Ethnic Pediatric Eye Disease Study and the Strabismus, Amblyopia and Refractive error in Singapore study. Risk (OR) of anisometropic amblyopia with ≥1.0 D of SE and cylindrical anisometropia was 12.4 (CI 4.0 to 38.4) and 6.5 (CI 2.3 to 18.7), respectively. We found an increasing risk of anisometropia with higher myopia ≥-1.0 D, OR 61.6 (CI 21.3 to 308), hyperopia > +2.0 D, OR 13.6 (CI 2.9 to 63.6) and astigmatism ≥1.5 D, OR 30.0 (CI 14.5 to 58.1). CONCLUSIONS: In this preschool-age population-based sample, anisometropia was uncommon with inter-ethnic differences in cylindrical anisometropia prevalence. We also quantified the rising risk of amblyopia with increasing SE and cylindrical anisometropia, and present the specific levels of refractive error and associated increasing risk of anisometropia.

Total ocular, anterior corneal and lenticular higher order aberrations in hyperopic, myopic and emmetropic eyes.

Total ocular higher order aberrations and corneal topography of myopic, emmetropic and hyperopic eyes of 675 adolescents (16.9 ± 0.7 years) were measured after cycloplegia using COAS aberrometer and Medmont videokeratoscope. Corneal higher order aberrations were computed from the corneal topography maps and lenticular (internal) higher order aberrations derived by subtraction of corneal aberrations from total ocular aberrations. Aberrations were measured for a pupil diameter of 5mm. Multivariate analysis of variance followed by multiple regression analysis found significant difference in the fourth order aberrations (SA RMS, primary spherical aberration coefficient) between the refractive error groups. Hyperopic eyes (+0.083 ± 0.05 µm) had more positive total ocular primary spherical aberration compared to emmetropic (+0.036 ± 0.04 µm) and myopic eyes (low myopia=+0.038 ± 0.05 µm, moderate myopia=+0.026 ± 0.06 µm) (p<0.05). No difference was observed for the anterior corneal spherical aberration. Significantly less negative lenticular spherical aberration was observed for the hyperopic eyes (-0.038 ± 0.05 µm) than myopic (low myopia=-0.088 ± 0.04 µm, moderate myopia=-0.095 ± 0.05 µm) and emmetropic eyes (-0.081 ± 0.04 µm) (p<0.05). These findings suggest the existence of differences in the characteristics of the crystalline lens (asphericity, curvature and gradient refractive index) of hyperopic eyes versus other eyes.