Purpose To evaluate and quantify visual function metrics to be used as predictors of AMD progression and visual acuity (VA) loss in patients with early and intermediate AMD. Design Baseline data of observational, cross-sectional, prospective study. Methods 101 patients were enrolled at Duke Eye Center: 80 patients with AMD age-related eye disease study (AREDS) stage 2 (N=33) and stage 3 (N=47) and 21 age-matched, normal controls. A dilated retinal examination, macular pigment optical density measurements, and several functional assessments: best-corrected VA, mesopic microperimety with eye tracking (MAIA), dark adaptometry (AdaptDx), low luminance VA (LLVA) (standard using log 2.0 neutral density filter and computerized method) and cone contrast test (CCT) (Innova Systems Inc) were performed. Low luminance deficit (LLD) was defined as the difference in numbers of letters read at standard vs. low luminance. Group comparisons were performed to evaluate differences between the control and the AREDS 2 and AREDS 3 groups using two-sided significance tests. Results Functional measures that significantly distinguished between normal and AREDS3 were standard and computerized (0.5 cd/m2) LLVA, percent reduced threshold and average threshold on microperimetry, CCTs, and rod intercept on dark adaptation (p < 0.05). The AREDS 3 group demonstrated deficits in microperimetry reduced threshhold, computerized LLD2 and dark adaptation rod intercept (p < 0.05) relative to AREDS 2. Conclusions and Relevance Our study suggests that LLVA, MAIA microperimetry, CCT and dark adaptation may serve as functional measures of AMD progression.

Evasion of apoptosis allows many cancers to resist chemotherapy. Apoptosis is mediated by the serial activation of caspase family proteins. These proteases are often activated upon the release of cytochrome c from the mitochondria, which is promoted by the proapoptotic Bcl-2 family protein, Bax. This function of Bax is enhanced by the MOAP-1 (modulator of apoptosis protein 1) protein in response to DNA damage. Previously, we reported that MOAP-1 is targeted for ubiquitylation and degradation by the APC/CCdh1 ubiquitin ligase. In this study, we identify the HECT (homologous to the E6-AP carboxyl terminus) family E3 ubiquitin ligase, UBR5, as a novel ubiquitin ligase for MOAP-1. We demonstrate that UBR5 interacts physically with MOAP-1, ubiquitylates MOAP-1 in vitro and inhibits MOAP-1 stability in cultured cells. In addition, we show that Dyrk2 kinase, a reported UBR5 interactor, cooperates with UBR5 in mediating MOAP-1 ubiquitylation. Importantly, we found that cisplatin-resistant ovarian cancer cell lines exhibit lower levels of MOAP-1 accumulation than their sensitive counterparts upon cisplatin treatment, consistent with the previously reported role of MOAP-1 in modulating cisplatin-induced apoptosis. Accordingly, UBR5 knockdown increased MOAP-1 expression, enhanced Bax activation and sensitized otherwise resistant cells to cisplatin-induced apoptosis. Furthermore, UBR5 expression was higher in ovarian cancers from cisplatin-resistant patients than from cisplatin-responsive patients. These results show that UBR5 downregulates proapoptotic MOAP-1 and suggest that UBR5 can confer cisplatin resistance in ovarian cancer. Thus UBR5 may be an attractive therapeutic target for ovarian cancer treatment.

SUMMARY Notwithstanding the positive clinical impact of endocrine therapies in estrogen receptor-alpha (ERα)-positive breast cancer, de novo and acquired resistance limits the therapeutic lifespan of existing drugs. Taking the position that resistance is nearly inevitable, we undertook a study to identify and exploit targetable vulnerabilities that were manifest in endocrine therapy-resistant disease. Using cellular and mouse models of endocrine therapy-sensitive and endocrine therapy-resistant breast cancer, together with contemporary discovery platforms, we identified a targetable pathway that is composed of the transcription factors FOXA1 and GRHL2, a coregulated target gene, the membrane receptor LYPD3, and the LYPD3 ligand, AGR2. Inhibition of the activity of this pathway using blocking antibodies directed against LYPD3 or AGR2 inhibits the growth of endocrine therapy-resistant tumors in mice, providing the rationale for near-term clinical development of humanized antibodies directed against these proteins.

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