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SUMMARY Id helix-loop-helix (HLH) proteins (Id1–4) bind E protein bHLH transcription factors, preventing them from forming active transcription complexes that drive changes in cell states. Id proteins are primarily expressed during development to inhibit differentiation, but they become re-expressed in adult tissues in diseases of the vasculature and cancer. We show that the genetic loss of Id1/Id3 reduces ocular neovascularization in mouse models of wet age-related macular degeneration (AMD) and retinopathy of prematurity (ROP). An in silico screen identifies AGX51, a small-molecule Id antagonist. AGX51 inhibits the Id1-E47 interaction, leading to ubiquitin-mediated degradation of Ids, cell growth arrest, and reduced viability. AGX51 is well-tolerated in mice and phenocopies the genetic loss of Id expression in AMD and ROP models by inhibiting retinal neovascularization. Thus, AGX51 is a first-in-class compound that antagonizes an interaction formerly considered undruggable and that may have utility in the management of multiple diseases.

BackgroundInsufficient sleep increases blood pressure. However, the effects of milder, highly prevalent but frequently neglected sleep disturbances, including poor sleep quality and insomnia, on vascular health in women are unclear. We investigated whether poor sleep patterns are associated with blood pressure and endothelial inflammation in a diverse sample of women.Methods and ResultsWomen who participated in the ongoing American Heart Association Go Red for Women Strategically Focused Research Network were studied (n=323, 57% minority, mean age=39±17 years, range=20–79 years). Sleep duration, sleep quality, and time to sleep onset were assessed using the Pittsburgh Sleep Quality Index (score ≥5=poor sleep quality). Risk for obstructive sleep apnea was evaluated using the Berlin questionnaire, and insomnia was assessed using the Insomnia Severity Index. In a subset of women who participated in the basic study (n=26), sleep duration was assessed objectively using actigraphy, and endothelial inflammation was assessed directly in harvested endothelial cells by measuring nuclear translocation of nuclear factor kappa B. Vascular reactivity was measured by brachial artery flow‐mediated dilation (n=26). Systolic and diastolic blood pressure were measured by trained personnel (n=323). Multivariable linear regressions were used to evaluate associations between sleep patterns and blood pressure, nuclear factor kappa B, and flow‐mediated dilation. Mean sleep duration was 6.8±1.3 hours/night in the population study and 7.5±1.1 hour/night in the basic study. In the population study sample, 50% had poor sleep quality versus 23% in the basic study, and 37% had some level of insomnia versus 15% in the basic study. Systolic blood pressure was associated directly with poor sleep quality, and diastolic blood pressure was of borderline significance with obstructive sleep apnea risk after adjusting for confounders (P=0.04 and P=0.08, respectively). Poor sleep quality was associated with endothelial nuclear factor kappa B activation (β=30.6; P=0.03). Insomnia and longer sleep onset latency were also associated with endothelial nuclear factor kappa B activation (β=27.6; P=0.002 and β=8.26; P=0.02, respectively). No evidence was found for an association between sleep and flow‐mediated dilation.ConclusionsThese findings provide direct evidence that common but frequently neglected sleep disturbances such as poor sleep quality and insomnia are associated with increased blood pressure and vascular inflammation even in the absence of inadequate sleep duration in women.Clinical Trial Registration URL: https://www.clinicaltrials.gov. Unique identifier: NCT02835261.

IMPORTANCE Patients with head and neck cancer receive care at academic comprehensive cancer programs (ACCPs), integrated network cancer programs (INCPs), comprehensive community cancer programs (CCCPs), and community cancer programs (CCPs). The type of treatment facility may be associated with overall survival.OBJECTIVE To examine whether type of treatment facility is associated with overall survival after a diagnosis of head and neck cancer. DESIGN, SETTING, AND PARTICIPANTSThis population-based retrospective cohort study included patients from the National Cancer Database, a prospectively maintained, hospital-based cancer registry of patients treated at more than 1500 US hospitals. Participants were diagnosed with malignant tumors of the EXPOSURES Treatment at facilities classified as ACCPs, INCPs, CCCPs, or CCPs. MAIN OUTCOMES AND MEASURES Overall survival after diagnosis and treatment of head and neck cancer was the primary outcome. The secondary outcome was the odds of receiving treatment at ACCPs and INCPs vs CCCPs and CCPs. Multivariable Cox proportional hazards regression and univariable and multivariable logistic regression models were used for analysis. RESULTS A total of 525 740 patients (368 821 men [70.2%]; mean [SD] age, 63.3 [14.0] years) were diagnosed with malignant tumors of the head and neck during the study period. Among them, 36 595 patients (7.0%) were treated at CCPs; 174 658 (33.2%), at CCCPs; 232 867 (44.3%), at ACCPs; and 57 857 (11.0%), at INCPs. The median survival for patients with aerodigestive cancers was 69.2 (95% CI, 68.6-69.8) months; salivary gland cancers, 107.2 (95% CI, 103.9-110.2) months; and skin cancers, 113.2 (95% CI, 111.4-114.6) months. Improved overall survival was associated with treatment at ACCPs (hazard ratio [HR], 0.89; 95% CI, 0.88-0.91), INCPs (HR, 0.94; 95% CI, 0.92-0.96), and CCCPs (HR, 0.94; 95% CI, 0.92-0.95) compared with CCPs. Compared with patients with private insurance, those with government insurance (odds ratio [OR], 1.35; 95% CI, 1.29-1.41), no insurance (OR, 1.12; 95% CI, 1.09-1.16), or Medicaid (OR, 1.17; 95% CI, 1.14-1.20) were more likely to receive treatment at ACCPs and INCPs, whereas patients with Medicare were less likely to receive treatment at ACCPs and INCPs (OR, 0.95; 95% CI, 0.94-0.97). Compared with white patients, black (OR, 1.55; 95% CI, 1.52-1.59) and Asian (OR, 1.56; 95% CI, 1.49-1.63) patients were more likely to receive care at ACCPs and INCPs. Compared with patients from lower-income areas, patients from high-incomeareas were more likely to receive treatment at ACCPs and INCPs (OR, 1.25; 95% CI, 1.22-1.28). (continued)

One important aspect of recovery and repair after spinal cord injury (SCI) lies in the complex cellular interactions at the injury site that leads to the formation of a lesion scar. EphA4, a promiscuous member of the EphA family of repulsive axon guidance receptors, is expressed by multiple cell types in the injured spinal cord, including astrocytes and neurons. We hypothesized that EphA4 contributes to aspects of cell-cell interactions at the injury site after SCI, thus modulating the formation of the astroglial-fibrotic scar. To test this hypothesis, we studied tissue responses to a thoracic dorsal hemisection SCI in an EphA4 mutant mouse line. We found that EphA4 expression, as assessed by β-galactosidase reporter gene activity, is associated primarily with astrocytes in the spinal cord, neurons in the cerebral cortex and, to a lesser extent, spinal neurons, before and after SCI. However, we did not observe any overt reduction of glial fibrillary acidic protein (GFAP) expression in the injured area of EphA4 mutants in comparison with controls following SCI. Furthermore, there was no evident disruption of the fibrotic scar, and the boundary between reactive astrocytes and meningeal fibroblasts appeared unaltered in the mutants, as were lesion size, neuronal survival and inflammation marker expression. Thus, genetic deletion of EphA4 does not significantly alter the astroglial response or the formation of the astroglial-fibrotic scar following a dorsal hemisection SCI in mice. In contrast to what has been proposed, these data do not support a major role for EphA4 in reactive astrogliosis following SCI.