Expression of a single chemokine receptor gene, CCR7, increased B16 cell metastasis to draining lymph nodes, suggesting that cancer cells may co-opt normal mechanisms of lymph node homing during metastasis.

Purpose We investigate whether ocular and person-based characteristics are associated with dark adaptation (DA) measured using the AdaptRx™ device (Apeliotus Technologies, Atlanta, GA). Design Cross-sectional, single-center, observational study. Participants 116 participants >50 years with a range in age-related macular degeneration (AMD) severity. Methods Participants underwent best-corrected visual acuity (BCVA) testing, ophthalmoscopic examination and multimodal imaging. Presence of reticular pseudodrusen (RPD) was assessed by masked grading of fundus images and confirmed with OCT. Eyes were also graded for AMD features (drusen, pigmentary changes, late AMD) to generate a person-based AMD severity groups. One eye was designated the study eye for DA testing using the AdaptRx™ device. Nonparametric statistical testing was performed on all comparisons. Main Outcome Measure The primary outcome of this study was the rod-intercept time (RIT) which is defined as the time for a participant's visual sensitivity to recover to a stimulus intensity of 5 × 10−3 cd/m2 (a decrease of 3 log units), or until a maximum test duration of 40 minutes was reached. Results A total of 116 study eyes in 116 participants (mean age=75.4±9.4 years, 58% female) were analyzed. Increased RIT was significantly associated with increasing age (r=0.34, p=0.0002), decreasing BCVA (r=−0.54, p<0.0001), pseudophakia (p=0.03), decreasing subfoveal choroidal thickness (r=−0.27, p=0.003). Study eyes with RPD (15/116, 13%) had a significantly greater mean RIT compared to eyes without RPD in any AMD severity group (p<0.02 for all comparisons) with 80% reaching the DA test ceiling. Conclusion Impairments in DA increase with age, worse visual acuity, presence of RPD, AMD severity and decreased subfoveal choroidal thickness. Analysis of covariance found the multivariable model that best fit our data included age, AMD group, and presence of RPD (R2=0.56) with the presence of RPD conferring the largest parameter estimate.

Background Impaired signaling in the IFN-γ/IL-12 pathway causes susceptibility to severe disseminated infections with mycobacteria and dimorphic yeasts. Dominant gain-of-function mutations in signal transducer and activator of transcription 1 (STAT1) have been associated with chronic mucocutaneous candidiasis. Objective We sought to identify the molecular defect in patients with disseminated dimorphic yeast infections. Methods PBMCs, EBV-transformed B cells, and transfected U3A cell lines were studied for IFN-γ/IL-12 pathway function. STAT1 was sequenced in probands and available relatives. Interferon-induced STAT1 phosphorylation, transcriptional responses, protein-protein interactions, target gene activation, and function were investigated. Results We identified 5 patients with disseminated Coccidioides immitis or Histoplasma capsulatum with heterozygous missense mutations in the STAT1 coiled-coil or DNA-binding domains. These are dominant gain-of-function mutations causing enhanced STAT1 phosphorylation, delayed dephosphorylation, enhanced DNA binding and transactivation, and enhanced interaction with protein inhibitor of activated STAT1. The mutations caused enhanced IFN-γ–induced gene expression, but we found impaired responses to IFN-γ restimulation. Conclusion Gain-of-function mutations in STAT1 predispose to invasive, severe, disseminated dimorphic yeast infections, likely through aberrant regulation of IFN-γ–mediated inflammation.

This study evaluated the safety and tolerability of ocular RS1 adeno-associated virus (AAV8-RS1) gene augmentation therapy to the retina of participants with X-linked retinoschisis (XLRS). XLRS is a monogenic trait affecting only males, caused by mutations in the RS1 gene. Retinoschisin protein is secreted principally in the outer retina, and its absence results in retinal cavities, synaptic dysfunction, reduced visual acuity, and susceptibility to retinal detachment. This phase I/IIa single-center, prospective, open-label, three-dose-escalation clinical trial administered vector to nine participants with pathogenic RS1 mutations. The eye of each participant with worse acuity (≤63 letters; Snellen 20/63) received the AAV8-RS1 gene vector by intravitreal injection. Three participants were assigned to each of three dosage groups: 1e9 vector genomes (vg)/eye, 1e10 vg/eye, and 1e11 vg/eye. The investigational product was generally well tolerated in all but one individual. Ocular events included dose-related inflammation that resolved with topical and oral corticosteroids. Systemic antibodies against AAV8 increased in a dose-related fashion, but no antibodies against RS1 were observed. Retinal cavities closed transiently in one participant. Additional doses and immunosuppressive regimens are being explored to pursue evidence of safety and efficacy (ClinicalTrials.gov: NCT02317887).