A fully human anti-IL-7Rα antibody promotes antitumor activity against T-cell acute lymphoblastic leukemia.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological cancer for which treatment options often result in incomplete therapeutic efficacy and long-term side-effects. Interleukin 7 (IL-7) and its receptor IL-7Rα promote T-ALL development and mutational activation of IL-7Rα associates with very high risk in relapsed disease. Using combinatorial phage-display libraries and antibody reformatting, we generated a fully human IgG1 monoclonal antibody (named B12) against both wild-type and mutant human IL-7Rα, predicted to form a stable complex with IL-7Rα at a different site from IL-7. B12 impairs IL-7/IL-7R-mediated signaling, sensitizes T-ALL cells to treatment with dexamethasone and can induce cell death per se. The antibody also promotes antibody-dependent natural killer-mediated leukemia cytotoxicity in vitro and delays T-cell leukemia development in vivo, reducing tumor burden and promoting mouse survival. B12 is rapidly internalized and traffics to the lysosome, rendering it an attractive vehicle for targeted intracellular delivery of cytotoxic cargo. Consequently, we engineered a B12-MMAE antibody-drug conjugate and provide proof-of-concept evidence that it has increased leukemia cell killing abilities as compared with the naked antibody. Our studies serve as a stepping stone for the development of novel targeted therapies in T-ALL and other diseases where IL-7Rα has a pathological role

Metabolomics-Based Discovery of Diagnostic Biomarkers for Onchocerciasis

Onchocerciasis, caused by the filarial parasite Onchocerca volvulus, afflicts millions of people, causing such debilitating symptoms as blindness and acute dermatitis. There are no accurate, sensitive means of diagnosing O. volvulus infection. Clinical diagnostics are desperately needed in order to achieve the goals of controlling and eliminating onchocerciasis and neglected tropical diseases in general. In this study, a metabolomics approach is introduced for the discovery of small molecule biomarkers that can be used to diagnose O. volvulus infection. Blood samples from O. volvulus infected and uninfected individuals from different geographic regions were compared using liquid chromatography separation and mass spectrometry identification. Thousands of chromatographic mass features were statistically compared to discover 14 mass features that were significantly different between infected and uninfected individuals. Multivariate statistical analysis and machine learning algorithms demonstrated how these biomarkers could be used to differentiate between infected and uninfected individuals and indicate that the diagnostic may even be sensitive enough to assess the viability of worms. This study suggests a future potential of these biomarkers for use in a field-based onchocerciasis diagnostic and how such an approach could be expanded for the development of diagnostics for other neglected tropical diseases

Ocean Acidification Affects Prey Detection by a Predatory Reef Fish

Changes in olfactory-mediated behaviour caused by elevated CO2 levels in the ocean could affect recruitment to reef fish populations because larval fish become more vulnerable to predation. However, it is currently unclear how elevated CO2 will impact the other key part of the predator-prey interaction – the predators. We investigated the effects of elevated CO2 and reduced pH on olfactory preferences, activity levels and feeding behaviour of a common coral reef meso-predator, the brown dottyback (Pseudochromis fuscus). Predators were exposed to either current-day CO2 levels or one of two elevated CO2 levels (∼600 µatm or ∼950 µatm) that may occur by 2100 according to climate change predictions. Exposure to elevated CO2 and reduced pH caused a shift from preference to avoidance of the smell of injured prey, with CO2 treated predators spending approximately 20% less time in a water stream containing prey odour compared with controls. Furthermore, activity levels of fish was higher in the high CO2 treatment and feeding activity was lower for fish in the mid CO2 treatment; indicating that future conditions may potentially reduce the ability of the fish to respond rapidly to fluctuations in food availability. Elevated activity levels of predators in the high CO2 treatment, however, may compensate for reduced olfactory ability, as greater movement facilitated visual detection of food. Our findings show that, at least for the species tested to date, both parties in the predator-prey relationship may be affected by ocean acidification. Although impairment of olfactory-mediated behaviour of predators might reduce the risk of predation for larval fishes, the magnitude of the observed effects of elevated CO2 acidification appear to be more dramatic for prey compared to predators. Thus, it is unlikely that the altered behaviour of predators is sufficient to fully compensate for the effects of ocean acidification on prey mortality

Larval Connectivity in an Effective Network of Marine Protected Areas

Acceptance of marine protected areas (MPAs) as fishery and conservation tools has been hampered by lack of direct evidence that MPAs successfully seed unprotected areas with larvae of targeted species. For the first time, we present direct evidence of large-scale population connectivity within an existing and effective network of MPAs. A new parentage analysis identified four parent-offspring pairs from a large, exploited population of the coral-reef fish Zebrasoma flavescens in Hawai'i, revealing larval dispersal distances ranging from 15 to 184 km. In two cases, successful dispersal was from an MPA to unprotected sites. Given high adult abundances, the documentation of any parent-offspring pairs demonstrates that ecologically-relevant larval connectivity between reefs is substantial. All offspring settled at sites to the north of where they were spawned. Satellite altimetry and oceanographic models from relevant time periods indicated a cyclonic eddy that created prevailing northward currents between sites where parents and offspring were found. These findings empirically demonstrate the effectiveness of MPAs as useful conservation and management tools and further highlight the importance of coupling oceanographic, genetic, and ecological data to predict, validate and quantify larval connectivity among marine populations

Learning Temporal Patterns of Risk in a Predator-Diverse Environment

Predation plays a major role in shaping prey behaviour. Temporal patterns of predation risk have been shown to drive daily activity and foraging patterns in prey. Yet the ability to respond to temporal patterns of predation risk in environments inhabited by highly diverse predator communities, such as rainforests and coral reefs, has received surprisingly little attention. In this study, we investigated whether juvenile marine fish, Pomacentrus moluccensis (lemon damselfish), have the ability to learn to adjust the intensity of their antipredator response to match the daily temporal patterns of predation risk they experience. Groups of lemon damselfish were exposed to one of two predictable temporal risk patterns for six days. “Morning risk” treatment prey were exposed to the odour of Cephalopholis cyanostigma (rockcod) paired with conspecific chemical alarm cues (simulating a rockcod present and feeding) during the morning, and rockcod odour only in the evening (simulating a rockcod present but not feeding). “Evening risk” treatment prey had the two stimuli presented to them in the opposite order. When tested individually for their response to rockcod odour alone, lemon damselfish from the morning risk treatment responded with a greater antipredator response intensity in the morning than in the evening. In contrast, those lemon damselfish previously exposed to the evening risk treatment subsequently responded with a greater antipredator response when tested in the evening. The results of this experiment demonstrate that P. moluccensis have the ability to learn temporal patterns of predation risk and can adjust their foraging patterns to match the threat posed by predators at a given time of day. Our results provide the first experimental demonstration of a mechanism by which prey in a complex, multi-predator environment can learn and respond to daily patterns of predation risk

Environmental Factors Affecting Large-Bodied Coral Reef Fish Assemblages in the Mariana Archipelago

Large-bodied reef fishes represent an economically and ecologically important segment of the coral reef fish assemblage. Many of these individuals supply the bulk of the reproductive output for their population and have a disproportionate effect on their environment (e.g. as apex predators or bioeroding herbivores). Large-bodied reef fishes also tend to be at greatest risk of overfishing, and their loss can result in a myriad of either cascading (direct) or indirect trophic and other effects. While many studies have investigated habitat characteristics affecting populations of small-bodied reef fishes, few have explored the relationship between large-bodied species and their environment. Here, we describe the distribution of the large-bodied reef fishes in the Mariana Archipelago with an emphasis on the environmental factors associated with their distribution. Of the factors considered in this study, a negative association with human population density showed the highest relative influence on the distribution of large-bodied reef fishes; however, depth, water temperature, and distance to deep water also were important. These findings provide new information on the ecology of large-bodied reef fishes can inform discussions concerning essential fish habitat and ecosystem-based management for these species and highlight important knowledge gaps worthy of additional research

Immunohistochemical estimation of cell cycle phase in laryngeal neoplasia

We previously developed an immunohistochemical method for estimating cell cycle state and phase in tissue samples, including biopsies that are too small for flow cytometry. We have used our technique to examine whether primary abnormalities of the cell cycle exist in laryngeal neoplasia. Antibodies against the markers of cell cycle entry, minichromosome maintenance protein-2 (Mcm-2) and Ki67, and putative markers of cell cycle phase, cyclin D1 (G1-phase), cyclin A (S-phase), cyclin B1 (G2-phase) and phosphohistone H3 (Mitosis) were applied to paraffin-embedded sections of normal larynx (n=8), laryngeal dysplasia (n=10) and laryngeal squamous cell carcinoma (n=10). Cells expressing each marker were determined as a percentage of total cells, termed the labelling index (LI), and as a percentage of Mcm-2-positive cells, termed the labelling fraction (LF). The frequency of coexpression of each putative phase marker was investigated by confocal microscopy. There was a correlation between Mcm-2 and Ki67 LIs (ρ=0.93) but Mcm-2 LIs were consistently higher. All cells expressing a phase marker coexpressed Mcm-2, whereas Ki67 was not expressed in a proportion of these cells. The putative phase markers showed little coexpression. Labelling index values increased on progression from normal larynx through laryngeal dysplasia to squamous cell carcinoma for Mcm-2 (P=0.001), Ki67 (P=0.0002), cyclin D1 (P=0.015), cyclin A (P=0.0001) and cyclin B1 (P=0.0004). There was no evidence of an increase in the LF for any phase marker. Immunohistochemistry can be used to estimate cell cycle state and phase in laryngeal biopsies. Our data argues against primary cell cycle phase abnormalities in laryngeal neoplasia