The P2Y12 Receptor Antagonist Ticagrelor Reduces Lysosomal pH and Autofluorescence in Retinal Pigmented Epithelial Cells From the ABCA4-/- Mouse Model of Retinal Degeneration

The accumulation of partially degraded lipid waste in lysosomal-related organelles may contribute to pathology in many aging diseases. The presence of these lipofuscin granules is particularly evident in the autofluorescent lysosome-associated organelles of the retinal pigmented epithelial (RPE) cells, and may be related to early stages of age-related macular degeneration. While lysosomal enzymes degrade material optimally at acidic pH levels, lysosomal pH is elevated in RPE cells from the ABCA4-/- mouse model of Stargardt\u27s disease, an early onset retinal degeneration. Lowering lysosomal pH through cAMP-dependent pathways decreases accumulation of autofluorescent material in RPE cells in vitro, but identification of an appropriate receptor is crucial for manipulating this pathway in vivo. As the P2Y12 receptor for ADP is coupled to the inhibitory Gi protein, we asked whether blocking the P2Y12 receptor with ticagrelor could restore lysosomal acidity and reduce autofluorescence in compromised RPE cells from ABCA4-/- mice. Oral delivery of ticagrelor giving rise to clinically relevant exposure lowered lysosomal pH in these RPE cells. Ticagrelor also partially reduced autofluorescence in the RPE cells of ABCA4-/- mice. In vitro studies in ARPE-19 cells using more specific antagonists AR-C69931 and AR-C66096 confirmed the importance of the P2Y12 receptor for lowering lysosomal pH and reducing autofluorescence. These observations identify P2Y12 receptor blockade as a potential target to lower lysosomal pH and clear lysosomal waste in RPE cells. © 2018 Lu, Gómez, Lim, Guha, O\u27Brien-Jenkins, Coffey, Campagno, McCaughey, Laties, Carlsson and Mitchell

Wildlife ecological risk assessment in the 21st century: Promising technologies to assess toxicological effects

Despite advances in toxicity testing and the development of new approach methodologies (NAMs) for hazard assessment, the ecological risk assessment (ERA) framework for terrestrial wildlife (i.e., air‐breathing amphibians, reptiles, birds, and mammals) has remained unchanged for decades. While survival, growth, and reproductive endpoints derived from whole-animal toxicity tests are central to hazard assessment, nonstandard measures of biological effects at multiple levels of biological organization (e.g., molecular, cellular, tissue, organ, organism, population, community, ecosystem) have the potential to enhance the relevance of prospective and retrospective wildlife ERAs. Other factors (e.g., indirect effects of contaminants on food supplies and infectious disease processes) are influenced by toxicants at individual, population, and community levels, and need to be factored into chemically based risk assessments to enhance the “eco” component of ERAs. Regulatory and logistical challenges often relegate such nonstandard endpoints and indirect effects to post-registration evaluations of pesticides and industrial chemicals and contaminated site evaluations. While NAMs are being developed, to date, their applications in ERAs focused on wildlife have been limited. No single magic tool or model will address all uncertainties in hazard assessment. Modernizing wildlife ERAs will likely entail combinations of laboratory‐ and field‐derived data at multiple levels of biological organization, knowledge collection solutions (e.g., systematic review, adverse outcome pathway frameworks), and inferential methods that facilitate integrations and risk estimations focused on species, populations, interspecific extrapolations, and ecosystem services modeling, with less dependence on whole‐animal data and simple hazard ratios

Concurrent Intrathecal and Intravenous Nivolumab in Leptomeningeal Disease: Phase 1 Trial Interim Results

There is a critical need for effective treatments for leptomeningeal disease (LMD). Here, we report the interim analysis results of an ongoing single-arm, first-in-human phase 1/1b study of concurrent intrathecal (IT) and intravenous (IV) nivolumab in patients with melanoma and LMD. The primary endpoints are determination of safety and the recommended IT nivolumab dose. The secondary endpoint is overall survival (OS). Patients are treated with IT nivolumab alone in cycle 1 and IV nivolumab is included in subsequent cycles. We treated 25 patients with metastatic melanoma using 5, 10, 20 and 50 mg of IT nivolumab. There were no dose-limiting toxicities at any dose level. The recommended IT dose of nivolumab is 50 mg (with IV nivolumab 240 mg) every 2 weeks. Median OS was 4.9 months, with 44% and 26% OS rates at 26 and 52 weeks, respectively. These initial results suggest that concurrent IT and IV nivolumab is safe and feasible with potential efficacy in patients with melanoma LMD, including in patients who had previously received anti-PD1 therapy. Accrual to the study continues, including in patients with lung cancer. ClinicalTrials.gov registration: NCT03025256

Pliocene-Pleistocene Glaciomarine Sedimentation in Eastern Prydz Bay and Development of the Prydz Trough-Mouth Fan, ODP Sites 1166 and 1167, East Antarctica

Lithostratigraphy, grain sizes and down-hole logs of Site 1166 on the continental shelf, and Site 1167 on the upper slope, are analyzed to reconstruct glacial processes in eastern Prydz Bay and the development of the Prydz trough-mouth fan. In eastern Prydz Bay upper Pliocene-lower Pleistocene glaciomarine sediments occur interbedded with open-marine muds and grade upward into waterlaid tills and subglacial tills. Lower Pleistocene sediments of the trough-mouth fan consist of coarse-grained debrites interbedded with bottom-current deposits and hemipelagic muds, indicating repeated advances and retreats of the Lambert Glacier-Amery Ice Shelf system with respect to the shelf break. Systematic fluctuations in lithofacies and down-hole logs characterize the upper Pliocene-lower Pleistocene transition at Sites 1166 and 1167 and indicate that an ice stream advanced and retreated within the Prydz Channel until the mid Pleistocene. The record from Site 1167 shows that the grounding line of the Lambert Glacier did not extend to the shelf break after 0.78 Ma. Published ice-rafted debris records in the Southern Ocean show peak abundances in the Pliocene and the early Pleistocene, suggesting a link between the nature of the glacial drainage system as recorded by the trough-mouth fans and increased delivery of ice-rafted debris to the Southern Ocean

Effects of the HEET Garment in the Prevention of Hypothermia in a Porcine Model

Background Hypothermia is a common battlefield trauma occurrence. This study compared the effectiveness of the hypothermia, environmental, exposure, and trauma (HEET) garment (Trident Industries, Beaufort, SC) with and without thermal inserts with a control group of two wool blankets in the prevention of hypothermia in a treated hypovolemic porcine model. Materials and methods Five female swine (Sus scrofa-Yorkshire cross) were assigned to each of threegroups: HEET with thermal inserts (n=5); HEET without thermal inserts (n=5); or control (n=5). After the animals were anesthetized and stabilized for 30min, the swine were hemorrhaged to a mean arterial pressure (MAP) of 30mm Hg, simulating a battlefield injury. Hetastarch 6% (500mL) was rapidly administered, simulating initial field resuscitation. One hour later, the animals’ shed blood was reinfused, simulating transfusion at a field medical facility. The investigators moved the animal into a cooler set at 10 °C±0.5 °C. A pulmonary artery catheter was used to monitor core body temperature over a 6-h period. Results A repeated measures ANOVA and Tukey’s post hoc test were used to analyze the data. There was a significant difference between the groups. At the end of 6h, the mean core temperature for the HEET with inserts group was 32.69 °C±1.5; the HEET without inserts, 31.02 °C±1.8; and control, 34.78 °C±1.2 (P\u3c0.05). While all groups became hypothermic, thewool blanket group was most effective in maintaining body temperature closer to normothermia. Conclusion. The HEET garments with and without heaters are ineffective in preventing hypothermia