Data on eye movements of glaucoma patients with asymmetrical visual field loss during free viewing.

This paper describes data from Asfaw at al. [1], which examined the eye movements of glaucoma patients (n=15) with pronounced asymmetrical vision loss (visual field loss worse in one eye). This allows for within-subject comparisons between the better and worse eye, thereby controlling for the effects of individual differences between patients. All patients had a clinical diagnosis of open angle glaucoma (OAG). Participants were asked to look at images of nature monocularly (free viewing; fellow eye patched) while gaze was recorded at 1000 Hz using a remote eye tracker (EyeLink 1000). Raw and processed eye tracking data are provided. In addition, clinical (visual acuity, contrast sensitivity and visual field) and demographic information (age, sex) are provided.

A structurally optimized FXR agonist, MET409, reduced liver fat content over 12 weeks in patients with non-alcoholic steatohepatitis.

BACKGROUND & AIMS: The benefits of farnesoid X receptor (FXR) agonists in patients with non-alcoholic steatohepatitis (NASH) have been validated, although improvements in efficacy and/or tolerability remain elusive. Herein, we aimed to assess the performance of a structurally optimized FXR agonist in patients with NASH. METHODS: In this 12-week, randomized, placebo-controlled study, we evaluated MET409 - a non-bile acid agonist with a unique chemical scaffold - in patients with NASH. Patients were randomized to receive either 80 mg (n = 20) or 50 mg (n = 19) of MET409, or placebo (n = 19). RESULTS: At Week 12, MET409 lowered liver fat content (LFC), with mean relative reductions of 55% (80 mg) and 38% (50 mg) vs. 6% in placebo (p <0.001). MET409 achieved ≥30% relative LFC reduction in 93% (80 mg) and 75% (50 mg) of patients vs. 11% in placebo (p <0.001) and normalized LFC (≤5%) in 29% (80 mg) and 31% (50 mg) of patients vs. 0% in placebo (p <0.05). An increase in alanine aminotransferase (ALT) was observed with MET409, confounding Week 12 changes from baseline (-25% for 80 mg, 28% for 50 mg). Nonetheless, MET409 achieved ≥30% relative ALT reduction in 50% (80 mg) and 31% (50 mg) of patients vs. 17% in placebo. MET409 was associated with on-target high-density lipoprotein cholesterol decreases (mean changes of -23.4% for 80 mg and -20.3% for 50 mg vs. 2.6% in placebo) and low-density lipoprotein cholesterol (LDL-C) increases (mean changes of 23.7% for 80 mg and 6.8% for 50 mg vs. -1.5% in placebo). Pruritus (mild-moderate) occurred in 16% (50 mg) and 40% (80 mg) of MET409-treated patients. CONCLUSION: MET409 lowered LFC over 12 weeks in patients with NASH and delivered a differentiated pruritus and LDL-C profile at 50 mg, providing the first clinical evidence that the risk-benefit profile of FXR agonists can be enhanced through structural optimization. LAY SUMMARY: Activation of the farnesoid X receptor (FXR) is a clinically validated approach for treating non-alcoholic steatohepatitis (NASH), although side effects such as itching or increases in low-density lipoprotein cholesterol are frequently dose-limiting. MET409, an FXR agonist with a unique chemical structure, led to significant liver fat reduction and delivered a favorable side effect profile after 12 weeks of treatment in patients with NASH. These results provide the first clinical evidence that the risk-benefit profile of FXR agonists can be enhanced.

Using eye movements to detect visual field loss: a pragmatic assessment using simulated scotoma.

Glaucoma is a leading cause of irreversible sight-loss and has been shown to affect natural eye-movements. These changes may provide a cheap and easy-to-obtain biomarker for improving disease detection. Here, we investigated whether these changes are large enough to be clinically useful. We used a gaze-contingent simulated visual field (VF) loss paradigm, in which participants experienced a variable magnitude of simulated VF loss based on longitudinal data from a real glaucoma patient (thereby controlling for other variables, such as age and general health). Fifty-five young participants with healthy vision were asked to view two short videos and three pictures, either with: (1) no VF loss, (2) moderate VF loss, or (3) advanced VF loss. Eye-movements were recorded using a remote eye tracker. Key eye-movement parameters were computed, including saccade amplitude, the spread of saccade endpoints (bivariate contour ellipse area), location of saccade landing positions, and similarity of fixations locations among participants (quantified using kernel density estimation). The simulated VF loss caused some statistically significant effects in the eye movement parameters. Yet, these effects were not capable of consistently identifying simulated VF loss, despite it being of a magnitude likely easily detectable by standard automated perimetry.

Measuring dynamic levels of self-perceived anxiety and concern during simulated mobility tasks in people with non-neovascular age-related macular degeneration.

BACKGROUND/AIMS: To assess response to real-world mobility scenarios in people with dry age-related macular degeneration (AMD) using a computer-based test. METHODS: Participants were shown 18 point-of-view computer-based movies simulating walking through real-world scenarios, and pressed a button during scenes which would cause them self-perceived anxiety or concern in their day-to-day life. Button pressure was recorded throughout. Pressure traces were generated, which aligned with each movie time point. Group averages based on AMD severity were generated. Bootstrapped confidence intervals (CIs) for responses by group were generated around traces. Traces were examined to discover events causing the greatest differences between groups. RESULTS: Participants had early/no AMD (n=8), intermediate AMD (n=7) or geographic atrophy (n=15 (GA)). Median (IQR) logMAR visual acuity was 0.04 (-0.04, 0.18), 0.26 (0.10, 0.40) and 0.32 (0.20, 0.56), respectively. Participants with intermediate AMD or GA recorded greater pressure than those with early and no AMD (Kruskal-Wallis, p=0.04). Four events involving navigating stairs and three under low luminance elicited greatest differences between groups (p<0.001). CONCLUSION: People with intermediate AMD or GA likely experience higher levels of concern associated with mobility. The test highlights areas of specific concern. Results should be useful in patient management and educating the public about the everyday effects of AMD.

Portable Perimetry Using Eye-Tracking on a Tablet Computer-A Feasibility Assessment.

PURPOSE: Visual field (VF) examination by standard automated perimetry (SAP) is an important method of clinical assessment. However, the complexity of the test, and its use of bulky, expensive equipment makes it impractical for case-finding. We propose and evaluate a new approach to paracentral VF assessment that combines an inexpensive eye-tracker with a portable tablet computer ("Eyecatcher"). METHODS: Twenty-four eyes from 12 glaucoma patients, and 12 eyes from six age-similar controls were examined. Participants were tested monocularly (once per eye), with both the novel Eyecatcher test and traditional SAP (HFA SITA standard 24-2). For Eyecatcher, the participant's task was to simply to look at a sequence of fixed-luminance dots, presented relative to the current point of fixation. Start and end fixations were used to determine locations where stimuli were seen/unseen, and to build a continuous map of sensitivity loss across a VF of approximately 20°. RESULTS: Eyecatcher was able to clearly separate patients from controls, and the results were consistent with those from traditional SAP. In particular, mean Eyecatcher scores were strongly correlated with mean deviation scores (r2 = 0.64, P < 0.001), and there was good concordance between corresponding VF locations (∼84%). Participants reported that Eyecatcher was more enjoyable, easier to perform, and less tiring than SAP (all P < 0.001). CONCLUSIONS: Portable perimetry using an inexpensive eye-tracker and a tablet computer is feasible, although possible means of improvement are suggested. TRANSLATIONAL RELEVANCE: Such a test could have significant utility as a case finding device.

Maximizing ER-α Degradation Maximizes Activity in a Tamoxifen-Resistant Breast Cancer Model: Identification of GDC-0927.

The further optimization of ER-α degradation efficacy of a series of ER modulators by refining side-chain substitution led to efficacious selective estrogen receptor degraders (SERDs). A fluoromethyl azetidine group was found to be preferred and resulted in the identification of bis-phenol chromene 17ha. In a tamoxifen-resistant breast cancer xenograft model, 17ha (ER-α degradation efficacy = 97%) demonstrated tumor regression, together with robust reduction of intratumoral ER-α levels. However, despite superior oral exposure, 5a (ER-α degradation efficacy = 91%) had inferior activity. This result suggests that optimizing ER-α degradation efficacy leads to compounds with robust effects in a model of tamoxifen-resistant breast cancer. Compound 17ha (GDC-0927) was evaluated in clinical trials in women with metastatic estrogen receptor-positive breast cancer.

Selective estrogen receptor degraders with novel structural motifs induce regression in a tamoxifen-resistant breast cancer xenograft.

Potent estrogen receptor ligands typically contain a phenolic hydrogen-bond donor. The indazole of the selective estrogen receptor degrader (SERD) ARN-810 is believed to mimic this. Disclosed herein is the discovery of ARN-810 analogs which lack this hydrogen-bond donor. These SERDs induced tumor regression in a tamoxifen-resistant breast cancer xenograft, demonstrating that the indazole NH is not necessary for robust ER-modulation and anti-tumor activity.

Identification of an Orally Bioavailable Chromene-Based Selective Estrogen Receptor Degrader (SERD) That Demonstrates Robust Activity in a Model of Tamoxifen-Resistant Breast Cancer.

About 75% of breast cancers are estrogen receptor alpha (ER-α) positive, and women typically initially respond well to antihormonal therapies such as tamoxifen and aromatase inhibitors, but resistance often emerges. Fulvestrant is a steroid-based, selective estrogen receptor degrader (SERD) that both antagonizes and degrades ER-α and shows some activity in patients who have progressed on antihormonal agents. However, fulvestrant must be administered by intramuscular injections that limit its efficacy. We describe the optimization of ER-α degradation efficacy of a chromene series of ER modulators resulting in highly potent and efficacious SERDs such as 14n. When examined in a xenograft model of tamoxifen-resistant breast cancer, 14n (ER-α degradation efficacy = 91%) demonstrated robust activity, while, despite superior oral exposure, 15g (ER-α degradation efficacy = 82%) was essentially inactive. This result suggests that optimizing ER-α degradation efficacy in the MCF-7 cell line leads to compounds with robust effects in models of tamoxifen-resistant breast cancer derived from an MCF-7 background.

Does Glaucoma Alter Eye Movements When Viewing Images of Natural Scenes? A Between-Eye Study.

Purpose: To investigate whether glaucoma produces measurable changes in eye movements. Methods: Fifteen glaucoma patients with asymmetric vision loss (difference in mean deviation [MD] > 6 dB between eyes) were asked to monocularly view 120 images of natural scenes, presented sequentially on a computer monitor. Each image was viewed twice-once each with the better and worse eye. Patients' eye movements were recorded with an Eyelink 1000 eye-tracker. Eye-movement parameters were computed and compared within participants (better eye versus worse eye). These parameters included a novel measure: saccadic reversal rate (SRR), as well as more traditional metrics such as saccade amplitude, fixation counts, fixation duration, and spread of fixation locations (bivariate contour ellipse area [BCEA]). In addition, the associations of these parameters with clinical measures of vision were investigated. Results: In the worse eye, saccade amplitude\(\def\upalpha{\unicode[Times]{x3B1}}\)\(\def\upbeta{\unicode[Times]{x3B2}}\)\(\def\upgamma{\unicode[Times]{x3B3}}\)\(\def\updelta{\unicode[Times]{x3B4}}\)\(\def\upvarepsilon{\unicode[Times]{x3B5}}\)\(\def\upzeta{\unicode[Times]{x3B6}}\)\(\def\upeta{\unicode[Times]{x3B7}}\)\(\def\uptheta{\unicode[Times]{x3B8}}\)\(\def\upiota{\unicode[Times]{x3B9}}\)\(\def\upkappa{\unicode[Times]{x3BA}}\)\(\def\uplambda{\unicode[Times]{x3BB}}\)\(\def\upmu{\unicode[Times]{x3BC}}\)\(\def\upnu{\unicode[Times]{x3BD}}\)\(\def\upxi{\unicode[Times]{x3BE}}\)\(\def\upomicron{\unicode[Times]{x3BF}}\)\(\def\uppi{\unicode[Times]{x3C0}}\)\(\def\uprho{\unicode[Times]{x3C1}}\)\(\def\upsigma{\unicode[Times]{x3C3}}\)\(\def\uptau{\unicode[Times]{x3C4}}\)\(\def\upupsilon{\unicode[Times]{x3C5}}\)\(\def\upphi{\unicode[Times]{x3C6}}\)\(\def\upchi{\unicode[Times]{x3C7}}\)\(\def\uppsy{\unicode[Times]{x3C8}}\)\(\def\upomega{\unicode[Times]{x3C9}}\)\(\def\bialpha{\boldsymbol{\alpha}}\)\(\def\bibeta{\boldsymbol{\beta}}\)\(\def\bigamma{\boldsymbol{\gamma}}\)\(\def\bidelta{\boldsymbol{\delta}}\)\(\def\bivarepsilon{\boldsymbol{\varepsilon}}\)\(\def\bizeta{\boldsymbol{\zeta}}\)\(\def\bieta{\boldsymbol{\eta}}\)\(\def\bitheta{\boldsymbol{\theta}}\)\(\def\biiota{\boldsymbol{\iota}}\)\(\def\bikappa{\boldsymbol{\kappa}}\)\(\def\bilambda{\boldsymbol{\lambda}}\)\(\def\bimu{\boldsymbol{\mu}}\)\(\def\binu{\boldsymbol{\nu}}\)\(\def\bixi{\boldsymbol{\xi}}\)\(\def\biomicron{\boldsymbol{\micron}}\)\(\def\bipi{\boldsymbol{\pi}}\)\(\def\birho{\boldsymbol{\rho}}\)\(\def\bisigma{\boldsymbol{\sigma}}\)\(\def\bitau{\boldsymbol{\tau}}\)\(\def\biupsilon{\boldsymbol{\upsilon}}\)\(\def\biphi{\boldsymbol{\phi}}\)\(\def\bichi{\boldsymbol{\chi}}\)\(\def\bipsy{\boldsymbol{\psy}}\)\(\def\biomega{\boldsymbol{\omega}}\)\(\def\bupalpha{\unicode[Times]{x1D6C2}}\)\(\def\bupbeta{\unicode[Times]{x1D6C3}}\)\(\def\bupgamma{\unicode[Times]{x1D6C4}}\)\(\def\bupdelta{\unicode[Times]{x1D6C5}}\)\(\def\bupepsilon{\unicode[Times]{x1D6C6}}\)\(\def\bupvarepsilon{\unicode[Times]{x1D6DC}}\)\(\def\bupzeta{\unicode[Times]{x1D6C7}}\)\(\def\bupeta{\unicode[Times]{x1D6C8}}\)\(\def\buptheta{\unicode[Times]{x1D6C9}}\)\(\def\bupiota{\unicode[Times]{x1D6CA}}\)\(\def\bupkappa{\unicode[Times]{x1D6CB}}\)\(\def\buplambda{\unicode[Times]{x1D6CC}}\)\(\def\bupmu{\unicode[Times]{x1D6CD}}\)\(\def\bupnu{\unicode[Times]{x1D6CE}}\)\(\def\bupxi{\unicode[Times]{x1D6CF}}\)\(\def\bupomicron{\unicode[Times]{x1D6D0}}\)\(\def\buppi{\unicode[Times]{x1D6D1}}\)\(\def\buprho{\unicode[Times]{x1D6D2}}\)\(\def\bupsigma{\unicode[Times]{x1D6D4}}\)\(\def\buptau{\unicode[Times]{x1D6D5}}\)\(\def\bupupsilon{\unicode[Times]{x1D6D6}}\)\(\def\bupphi{\unicode[Times]{x1D6D7}}\)\(\def\bupchi{\unicode[Times]{x1D6D8}}\)\(\def\buppsy{\unicode[Times]{x1D6D9}}\)\(\def\bupomega{\unicode[Times]{x1D6DA}}\)\(\def\bupvartheta{\unicode[Times]{x1D6DD}}\)\(\def\bGamma{\bf{\Gamma}}\)\(\def\bDelta{\bf{\Delta}}\)\(\def\bTheta{\bf{\Theta}}\)\(\def\bLambda{\bf{\Lambda}}\)\(\def\bXi{\bf{\Xi}}\)\(\def\bPi{\bf{\Pi}}\)\(\def\bSigma{\bf{\Sigma}}\)\(\def\bUpsilon{\bf{\Upsilon}}\)\(\def\bPhi{\bf{\Phi}}\)\(\def\bPsi{\bf{\Psi}}\)\(\def\bOmega{\bf{\Omega}}\)\(\def\iGamma{\unicode[Times]{x1D6E4}}\)\(\def\iDelta{\unicode[Times]{x1D6E5}}\)\(\def\iTheta{\unicode[Times]{x1D6E9}}\)\(\def\iLambda{\unicode[Times]{x1D6EC}}\)\(\def\iXi{\unicode[Times]{x1D6EF}}\)\(\def\iPi{\unicode[Times]{x1D6F1}}\)\(\def\iSigma{\unicode[Times]{x1D6F4}}\)\(\def\iUpsilon{\unicode[Times]{x1D6F6}}\)\(\def\iPhi{\unicode[Times]{x1D6F7}}\)\(\def\iPsi{\unicode[Times]{x1D6F9}}\)\(\def\iOmega{\unicode[Times]{x1D6FA}}\)\(\def\biGamma{\unicode[Times]{x1D71E}}\)\(\def\biDelta{\unicode[Times]{x1D71F}}\)\(\def\biTheta{\unicode[Times]{x1D723}}\)\(\def\biLambda{\unicode[Times]{x1D726}}\)\(\def\biXi{\unicode[Times]{x1D729}}\)\(\def\biPi{\unicode[Times]{x1D72B}}\)\(\def\biSigma{\unicode[Times]{x1D72E}}\)\(\def\biUpsilon{\unicode[Times]{x1D730}}\)\(\def\biPhi{\unicode[Times]{x1D731}}\)\(\def\biPsi{\unicode[Times]{x1D733}}\)\(\def\biOmega{\unicode[Times]{x1D734}}\)\((P = 0.012; - 13\% \)) and BCEA \((P = 0.005; - 16\% )\) were smaller, while SRR was greater (\(P = 0.018; + 16\% \)). There was a significant correlation between the intereye difference in BCEA, and differences in MD values (\({\rm{Spearman^{\prime} s}}\ r = 0.65;P = 0.01\)), while differences in SRR were associated with differences in visual acuity (\({\rm{Spearman^{\prime} s}}\ r = 0.64;P = 0.01\)). Furthermore, between-eye differences in BCEA were a significant predictor of between-eye differences in MD: for every 1-dB difference in MD, BCEA reduced by 6.2% (95% confidence interval, 1.6%-10.3%). Conclusions: Eye movements are altered by visual field loss, and these changes are related to changes in clinical measures. Eye movements recorded while passively viewing images could potentially be used as biomarkers for visual field damage.

Data on eye movements in people with glaucoma and peers with normal vision.

Eye movements of glaucoma patients have been shown to differ from age-similar control groups when performing everyday tasks, such as reading (Burton et al., 2012; Smith et al., 2014) [1], [2], visual search (Smith et al., 2012) [3], face recognition (Glen et al., 2013) [4], driving, and viewing static images (Smith et al., 2012) [5]. Described here is the dataset from a recent publication in which we compared the eye-movements of 44 glaucoma patients and 32 age-similar controls, while they watched a series of short video clips taken from television programs (Crabb et al., 2018) [6]. Gaze was recorded at 1000 Hz using a remote eye-tracker. We also provide demographic information and results from a clinical examination of vision for each participant.

The effect of non-neovascular age-related macular degeneration on face recognition performance.

PURPOSE: There is a well-established research base surrounding face recognition in patients with age-related macular degeneration (AMD). However, much of this existing research does not differentiate between results obtained for 'wet' AMD and 'dry' AMD. Here, we test the hypothesis that face recognition performance is worse in patients with dry AMD compared with visually healthy peers. METHODS: Patients (>60 years of age, logMAR binocular visual acuity 0.7 or better) with dry AMD of varying severity and visually healthy age-related peers (controls) completed a modified version of the Cambridge Face Memory Test (CFMT). Percentage of correctly identified faces was used as an outcome measure for performance for each participant. A 90% normative reference limit was generated from the distribution of CFMT scores recorded in the visually healthy controls. Scores for AMD participants were then specifically compared to this limit, and comparisons between average scores in the AMD severity groups were investigated. RESULTS: Thirty patients (median [interquartile range] age of 76 [70, 79] years) and 34 controls (median age of 70 [64, 75] years) were examined. Four, seventeen and nine patients were classified as having early, intermediate and late AMD (geographic atrophy) respectively. Five (17%) patients recorded a face recognition performance worse than the 90% limit (Fisher's exact test, p = 0.46) set by controls; four of these had geographic atrophy. Patients with geographic atrophy identified fewer faces on average (±SD) (61% ± 22%) than those with early and intermediate AMD (75 ± 11%) and controls (74% ± 11%). CONCLUSIONS: People with dry AMD may not suffer from problems with face recognition until the disease is in its later stages; those with late AMD (geographic atrophy) are likely to have difficulty recognising faces. The results from this study should influence the management and expectations of patients with dry AMD in both community practice and hospital clinics.

Searching for Objects in Everyday Scenes: Measuring Performance in People With Dry Age-Related Macular Degeneration.

Purpose: Treatment success in clinical trials for AMD would ideally be aligned to measurable performance in visual tasks rather than imperceptible changes on clinical charts. We test the hypothesis that patients with dry AMD perform worse than visually healthy peers on computer-based surrogates of "real-world" visual search tasks. Methods: A prospective case-control study was conducted in which patients with dry AMD performed a computer-based "real-world" visual search task. Participants searched for targets within images of everyday scenes while eye movements were recorded. Average search times across the images were recorded as a primary outcome measure. Comparisons were made against a 90% normative limit established in peers with healthy vision (controls). Eye movement parameters were examined as a secondary outcome measure. Results: Thirty-one patients and 33 controls with median (interquartile range) age of 75 (70-79) and 71 (66-75) years and logMAR binocular visual acuity 0.2 (0.18-0.31) and -0.06 (-0.12 to 0), respectively, were examined. Four, 18, and 9 patients were categorized as having early, intermediate, and late AMD, respectively. Nineteen (61%) patients exceeded the 90% normative limits for average search time; this was statistically significant (Fisher's exact test, P < 0.0001). On average, patients made smaller saccades than controls (P < 0.001). Conclusions: People with dry AMD, certainly those with advanced disease, are likely to have measurable difficulties beyond those observed in visually healthy peers on "real-world" search tasks. Further work might establish this type of task as a useful outcome measure for clinical trials.

'I didn't see that coming': simulated visual fields and driving hazard perception test performance.

BACKGROUND: Evidence is limited regarding specific types of visual field loss associated with unsafe driving. We use novel gaze-contingent software to examine the effect of simulated visual field loss on computer-based driving hazard detection with the specific aim of testing the impact of scotomata located to the right and left of fixation. METHODS: The 'hazard perception test' is a component of the UK driving licence examination, which measures speed of detecting 15 different hazards in a series of real-life driving films. We have developed a novel eye-tracking and computer set up capable of generating a realistic gaze-contingent scotoma simulation (GazeSS) overlaid on film content. Thirty drivers with healthy vision completed three versions of the hazard perception test in a repeated measures experiment. In two versions, GazeSS simulated a scotoma in the binocular field of view to the left or right of fixation. A third version was unmodified to establish baseline performance. RESULTS: Participants' mean baseline hazard perception test score was 51 ± 7 (out of 75). This reduced to 46 ± 9 and 46 ± 11 when completing the task with a binocular visual field defect located to the left and right of fixation, respectively. While the main effect of simulated visual field loss on performance was statistically significant (p = 0.007), there were no average differences in the experimental conditions where a scotoma was located in the binocular visual field to the right or left of fixation. CONCLUSION: Simulated visual field loss impairs driving hazard detection on a computer-based test. There was no statistically significant difference in average performance when the simulated scotoma was located to the right or left of fixation of the binocular visual field, but certain types of hazard caused more difficulties than others.

The selective estrogen receptor downregulator GDC-0810 is efficacious in diverse models of ER+ breast cancer.

ER-targeted therapeutics provide valuable treatment options for patients with ER+ breast cancer, however, current relapse and mortality rates emphasize the need for improved therapeutic strategies. The recent discovery of prevalent ESR1 mutations in relapsed tumors underscores a sustained reliance of advanced tumors on ERα signaling, and provides a strong rationale for continued targeting of ERα. Here we describe GDC-0810, a novel, non-steroidal, orally bioavailable selective ER downregulator (SERD), which was identified by prospectively optimizing ERα degradation, antagonism and pharmacokinetic properties. GDC-0810 induces a distinct ERα conformation, relative to that induced by currently approved therapeutics, suggesting a unique mechanism of action. GDC-0810 has robust in vitro and in vivo activity against a variety of human breast cancer cell lines and patient derived xenografts, including a tamoxifen-resistant model and those that harbor ERα mutations. GDC-0810 is currently being evaluated in Phase II clinical studies in women with ER+ breast cancer.

Optimization of an indazole series of selective estrogen receptor degraders: Tumor regression in a tamoxifen-resistant breast cancer xenograft.

Selective estrogen receptor degraders (SERDs) have shown promise for the treatment of ER+ breast cancer. Disclosed herein is the continued optimization of our indazole series of SERDs. Exploration of ER degradation and antagonism in vitro followed by in vivo antagonism and oral exposure culminated in the discovery of indazoles 47 and 56, which induce tumor regression in a tamoxifen-resistant breast cancer xenograft.

Patterns of Binocular Visual Field Loss Derived from Large-Scale Patient Data from Glaucoma Clinics.

PURPOSE: To estimate prevalence of visual field (VF) loss in superior and inferior hemifields in binocular VFs in a large sample of patients with bilateral glaucoma. DESIGN: Retrospective cohort study. PARTICIPANTS: Glaucoma patients and suspects attending 4 regionally different secondary-care eye clinics in the United Kingdom. METHODS: Binocular integrated visual fields (IVFs) using a best location method were constructed for 16 642 patients with bilateral VF loss. A significant VF defect was defined as 3 or more VF locations less than a certain sensitivity threshold, such as 20 dB. Patients were classified as having a VF defect in the inferior hemifield, superior hemifield, both hemifields, or neither hemifield. The criteria for number of locations and sensitivity threshold (in decibels) were varied across a large range of values. In addition, factor analysis was applied to the sensitivity values (in decibels) of the IVFs to determine common defect patterns in an automated fashion. MAIN OUTCOME MEASURES: Ratio of patients with binocular VF defects in the superior compared with the inferior areas of the IVF. RESULTS: Estimates of the ratio of patients having binocular VF defects in the superior compared with the inferior region of the IVF ranged from 2.1 (95% confidence interval, 2.1-2.4) to as high as 5.1 (95% confidence interval, 4.7-5.5), depending on the defect criteria used. Fewer than 10% of those patients exhibiting relatively early binocular VF loss had a defect confined to the inferior region only. Common patterns of binocular VF loss were dominated chiefly by superior hemifield defects. CONCLUSIONS: In a clinical population of patients with measurable VF loss in both eyes, superior-only binocular VF loss is more common than inferior-only loss. These estimates, derived from large collections of electronic medical records, are useful for interpreting findings about location of binocular VF loss impacting everyday activities and examining visual disability in glaucoma.

Identification of GDC-0810 (ARN-810), an Orally Bioavailable Selective Estrogen Receptor Degrader (SERD) that Demonstrates Robust Activity in Tamoxifen-Resistant Breast Cancer Xenografts.

Approximately 80% of breast cancers are estrogen receptor alpha (ER-α) positive, and although women typically initially respond well to antihormonal therapies such as tamoxifen and aromatase inhibitors, resistance often emerges. Although a variety of resistance mechanism may be at play in this state, there is evidence that in many cases the ER still plays a central role, including mutations in the ER leading to constitutively active receptor. Fulvestrant is a steroid-based, selective estrogen receptor degrader (SERD) that both antagonizes and degrades ER-α and is active in patients who have progressed on antihormonal agents. However, fulvestrant suffers from poor pharmaceutical properties and must be administered by intramuscular injections that limit the total amount of drug that can be administered and hence lead to the potential for incomplete receptor blockade. We describe the identification and characterization of a series of small-molecule, orally bioavailable SERDs which are potent antagonists and degraders of ER-α and in which the ER-α degrading properties were prospectively optimized. The lead compound 11l (GDC-0810 or ARN-810) demonstrates robust activity in models of tamoxifen-sensitive and tamoxifen-resistant breast cancer, and is currently in clinical trials in women with locally advanced or metastatic estrogen receptor-positive breast cancer.

Impact of superior and inferior visual field loss on hazard detection in a computer-based driving test.

PURPOSE: Binocular visual field (VF) loss is linked to driving impairment, guiding authorities to implement fitness to drive requirements for VFs. Yet, evidence is limited regarding the specific types of VF defect that impede driving. This study used a novel gaze-contingent display to test the hypothesis that superior VF loss impacts detection of driving hazards more than inferior loss. METHODS: The Hazard Perception Test (HPT) is a computer-based component of the UK examination for learner drivers. It measures the response rate for detecting hazards in a series of real-life driving films, yielding a score out of 75, calculated based on the efficiency of detecting 15 hazards. Thirty UK drivers with healthy vision completed three versions of the HPT in a random order. In two versions, a computer set-up incorporating an eye-tracker modified a simulated VF defect in the superior and inferior VFs, respectively, according to the users' real-time gaze as they completed the HPT. The other version was unmodified to measure the baseline performance. RESULTS: Participants' mean score at baseline was 49/75 (SD=9). Mean (SD) performance fell by 18% (40(11)) when viewing films with a superior defect and 12% with an inferior defect (43(10)). These average differences were statistically significant (p<0.001; 95% CI for mean difference=1-7) CONCLUSIONS: In this study, simulated VF defects impaired the ability to detect driving hazards relative to participants' normal performances, with superior defects having more impact than inferior defects. These results could help inform the design of fairer tests of the VF component for fitness to drive.

What's on TV? Detecting age-related neurodegenerative eye disease using eye movement scanpaths.

PURPOSE: We test the hypothesis that age-related neurodegenerative eye disease can be detected by examining patterns of eye movement recorded whilst a person naturally watches a movie. METHODS: Thirty-two elderly people with healthy vision (median age: 70, interquartile range [IQR] 64-75 years) and 44 patients with a clinical diagnosis of glaucoma (median age: 69, IQR 63-77 years) had standard vision examinations including automated perimetry. Disease severity was measured using a standard clinical measure (visual field mean deviation; MD). All study participants viewed three unmodified TV and film clips on a computer set up incorporating the Eyelink 1000 eyetracker (SR Research, Ontario, Canada). Eye movement scanpaths were plotted using novel methods that first filtered the data and then generated saccade density maps. Maps were then subjected to a feature extraction analysis using kernel principal component analysis (KPCA). Features from the KPCA were then classified using a standard machine based classifier trained and tested by a 10-fold cross validation which was repeated 100 times to estimate the confidence interval (CI) of classification sensitivity and specificity. RESULTS: Patients had a range of disease severity from early to advanced (median [IQR] right eye and left eye MD was -7 [-13 to -5] dB and -9 [-15 to -4] dB, respectively). Average sensitivity for correctly identifying a glaucoma patient at a fixed specificity of 90% was 79% (95% CI: 58-86%). The area under the Receiver Operating Characteristic curve was 0.84 (95% CI: 0.82-0.87). CONCLUSIONS: Huge data from scanpaths of eye movements recorded whilst people freely watch TV type films can be processed into maps that contain a signature of vision loss. In this proof of principle study we have demonstrated that a group of patients with age-related neurodegenerative eye disease can be reasonably well separated from a group of healthy peers by considering these eye movement signatures alone.