Targeting the Insulin-Like Growth Factor Pathway in Rhabdomyosarcomas: Rationale and Future Perspectives

Rhabdomyosarcomas (RMS) are a heterogeneous group of tumors that share features of skeletal myogenesis and represent the most common pediatric soft tissue sarcoma. Even though significant advances have been achieved in RMS treatment, prognosis remains very poor for many patients. Several elements of the Insulin-like Growth Factor (IGF) pathway are involved in sarcomas, including RMS. The IGF2 ligand is highly expressed in most, if not all, RMS, and frequent overexpression of the receptor IGF1R is also found. This is confirmed here through mining expression profiling data of a large series of RMS samples. IGF signaling is implicated in the genesis, growth, proliferation, and metastasis of RMS. Blockade of this pathway is therefore a potential therapeutic strategy for the treatment of RMS. In this paper we examine the biological rationale for targeting the IGF pathway in RMS as well as the current associated preclinical and clinical experience

Temporal and Spatial Variation of Nitrogen in Wyoming Big Sagebrush

Sagebrush steppe systems represent one of North America’s greatest conservation challenges. Shrinking habitat and declining animal populations have prompted researchers to fill gaps in our understanding of the ecology of this system, particularly at a scale relevant to individual animals. What animals eat and why are fundamental questions linked to habitat quality and use. We investigated the temporal and spatial heterogeneity of the dietary quality of food to better understand habitat use by a sagebrush specialist, the pygmy rabbit (Brachylagus idahoensis). Within a foraging patch, pygmy rabbits selectively browse on individual Wyoming big sagebrush (Artemisia tridentata wyomingensis) that are high in nitrogen. Therefore, we hypothesized that variation in nitrogen would influence habitat use by pygmy rabbits at the patch scale. As a first step to test this hypothesis, we investigated the temporal and spatial variation in nitrogen content of patches of sagebrush within a study site in southcentral Idaho. Nitrogen concentration was determined using the Kjeldahl method. We used multivariate analysis of variance to test for differences in nitrogen content among three months within the winter season (November, January, and March) and between patches of sagebrush on mounds with deeper soils where pygmy rabbits burrow (on-mound) versus patches of sagebrush in shallower soils adjacent to mounds (off-mound). We found that nitrogen content of sagebrush was temporally and spatially dynamic. For both on- and off-mound plants, nitrogen content was significantly higher in March than November. Regardless of season, nitrogen content was significantly higher in plants on mounds compared to off-mound plants. Understanding the phenology and spatial heterogeneity of nitrogen content will help ecologists better assess diet quality and habitat quality within and among landscapes and seasons. Moreover, effective management and restoration efforts of sagebrush depend upon understanding patterns in nutrient availability to pygmy rabbits and other sagebrush specialists

Seasonal temperature acclimatization in a semi-fossorial mammal and the role of burrows as thermal refuges.

Small mammals in habitats with strong seasonal variation in the thermal environment often exhibit physiological and behavioral adaptations for coping with thermal extremes and reducing thermoregulatory costs. Burrows are especially important for providing thermal refuge when above-ground temperatures require high regulatory costs (e.g., water or energy) or exceed the physiological tolerances of an organism. Our objective was to explore the role of burrows as thermal refuges for a small endotherm, the pygmy rabbit (Brachylagus idahoensis), during the summer and winter by quantifying energetic costs associated with resting above and below ground. We used indirect calorimetry to determine the relationship between energy expenditure and ambient temperature over a range of temperatures that pygmy rabbits experience in their natural habitat. We also measured the temperature of above- and below-ground rest sites used by pygmy rabbits in eastern Idaho, USA, during summer and winter and estimated the seasonal thermoregulatory costs of resting in the two microsites. Although pygmy rabbits demonstrated seasonal physiological acclimatization, the burrow was an important thermal refuge, especially in winter. Thermoregulatory costs were lower inside the burrow than in above-ground rest sites for more than 50% of the winter season. In contrast, thermal heterogeneity provided by above-ground rest sites during summer reduced the role of burrows as a thermal refuge during all but the hottest periods of the afternoon. Our findings contribute to an understanding of the ecology of small mammals in seasonal environments and demonstrate the importance of burrows as thermal refuge for pygmy rabbits

Impact of fusion gene status versus histology on riskâ stratification for rhabdomyosarcoma: Retrospective analyses of patients on UK trials

BackgroundLongâ term toxicities from current treatments are a major issue in paediatric cancer. Previous studies, including our own, have shown prognostic value for the presence of PAX3/7â FOXO1 fusion genes in rhabdomyosarcoma (RMS). It is proposed to introduce PAX3/7â FOXO1 positivity as a component of risk stratification, rather than alveolar histology, in future clinical trials.ProcedureTo assess the potential impact of this reclassification, we have determined the changes to risk category assignment of 210 histologically reviewed patients treated in the UK from previous malignant mesenchymal tumour clinical trials for nonâ metastatic RMS based on identification of PAX3/7â FOXO1 by fluorescence in situ hybridisation and/or reverse transcription PCR.ResultsUsing fusion gene positivity in the current risk stratification would reassign 7% of patients to different European Paediatric Soft Tissue Sarcoma Study Group (EpSSG) risk groups. The next European trial would have 80% power to detect differences in eventâ free survival of 15% over 10 years and 20% over 5 years in reassigned patients. This would decrease treatment for over a quarter of patients with alveolar histology tumours that lack PAX3/7â FOXO1.ConclusionsFusion gene status used in stratification may result in significant numbers of patients benefitting from lower treatmentâ associated toxicity. Prospective testing to show this reassignment maintains current survival rates is now required and is shown to be feasible based on estimated recruitment to a future EpSSG trial. Together with developing novel therapeutic strategies for patients identified as higher risk, this may ultimately improve the outcome and quality of life for patients with RMS.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/137481/1/pbc26386_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/137481/2/pbc26386.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/137481/3/pbc26386-sup-0002-FigureS2.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/137481/4/pbc26386-sup-0001-FigureS1.pd

Understanding Tradeoffs Between Food and Predation Risks in a Specialist Mammalian Herbivore

Understanding habitat use by animals requires understanding the simultaneous tradeoffs between food and predation risk within a landscape. Quantifying the synergy between patches that provide quality food and those that are safe from predators at a scale relevant to a foraging animal could better reveal the parameters that influence habitat selection. To understand more thoroughly how animals select habitat components, we investigated tradeoffs between diet quality and predation risk in a species endemic to sagebrush Artemisia spp. communities in North America, the pygmy rabbitBrachylagus idahoensis. This species is a rare example of a specialist herbivore that relies almost entirely on sagebrush for food and cover. We hypothesized that pygmy rabbits would forage in areas with low food risk (free of plant secondary metabolites, PSMs) and low predation risk (high concealment). However, because of relatively high tolerance to PSMs in sagebrush by pygmy rabbits, we hypothesized that they would trade off the risk of PSM-containing food to select lower predation risk when risks co-occurred. We compared food intake of pygmy rabbits during three double-choice trials designed to examine tradeoffs by offering animals two levels of food risk (1,8-cineole, a PSM) and predation risk (concealment cover). Rabbits ate more food at feeding stations with PSM-free food and high concealment cover. However, interactions between PSMs and cover suggested that the value of PSM-free food could be reduced if concealment is low and the value of high concealment can decrease if food contains PSMs. Furthermore, foraging decisions by individual rabbits suggested variation in tolerance of food or predation risks

Fearscapes: Mapping Functional Properties of Cover for Prey with Terrestrial LiDAR

Heterogeneous vegetation structure can create a variable landscape of predation risk—a fearscape—that influences the use and selection of habitat by animals. Mapping the functional properties of vegetation that influence predation risk (e.g., concealment and visibility) across landscapes can be challenging. Traditional ground-based measures of predation risk are location specific and limited in spatial resolution. We demonstrate the benefits of terrestrial laser scanning (TLS) to map the properties of vegetation structure that shape fearscapes. We used TLS data to estimate the concealment of prey from multiple vantage points, representing predator sightlines, as well as the visibility of potential predators from the locations of prey. TLS provides a comprehensive data set that allows an exploration of how habitat changes may affect prey and predators. Together with other remotely sensed imagery, TLS could facilitate the scaling up of fearscape analyses to promote the management and restoration of landscapes

Modeling Trade-Offs Between Plant Fiber and Toxins: A Framework for Quantifying Risks Perceived by Foraging Herbivores

When selecting habitats, herbivores must weigh multiple risks, such as predation, starvation, toxicity, and thermal stress, forcing them to make fitness trade-offs. Here, we applied the method of paired comparisons (PC) to investigate how herbivores make trade-offs between habitat features that influence selection of food patches. The method of PC measures utility and the inverse of utility, relative risk, and makes trade-offs and indifferences explicit by forcing animals to make choices between two patches with different types of risks. Using a series of paired-choice experiments to titrate the equivalence curve and find the marginal rate of substitution for one risk over the other, we evaluated how toxin-tolerant (pygmy rabbit Brachylagus idahoensis) and fiber-tolerant (mountain cottontail rabbit Sylviagus nuttallii) herbivores differed in their hypothesized perceived risk of fiber and toxins in food. Pygmy rabbits were willing to consume nearly five times more of the toxin 1,8-cineole in their diets to avoid consuming higher levels of fiber than were mountain cottontails. Fiber posed a greater relative risk for pygmy rabbits than cottontails and cineole a greater risk for cottontails than pygmy rabbits. Our flexible modeling approach can be used to (1) quantify how animals evaluate and trade off multiple habitat attributes when the benefits and risks are difficult to quantify, and (2) integrate diverse risks that influence fitness and habitat selection into a single index of habitat value. This index potentially could be applied to landscapes to predict habitat selection across several scales

Age-related biological features of germ cell tumors.

Germ cell tumors (GCTs) are rare but clinically and pathologically diverse tumors that occur in an extensive range of age groups, from children to older adults and which include both seminomatous and nonseminomatous tumors. Current clinical management for both male and female teenagers and young adults (TYAs) with GCTs remains inconsistent, alternating between pediatric and adult multidisciplinary oncology teams, based on locally defined age cutoffs. Therefore, we reviewed available literature to determine the biological similarities and differences between GCTs in young children (0-12 years), TYAs (13-24 years), and older adults (>24 years). GCTs arising in pediatric and adult populations in general showed marked molecular biological differences within identical histological subtypes, whereas there was a distinct paucity of available data for GCTs in the TYA population. These findings highlight that clinical management based simply on chronological age may be inappropriate for TYA and suggests that the optimal future management of GCTs should consider specific molecular biological factors in addition to clinical parameters in the context of patient-specific age group rather than medical specialty.This is the accepted manuscript. The final version is available at http://onlinelibrary.wiley.com/doi/10.1002/gcc.22131/abstract

A perspective on polo-like kinase-1 inhibition for the treatment of rhabdomyosarcoma

Rhabdomyosarcomas are the most common pediatric soft tissue sarcoma and are a major cause of death from cancer in young patients requiring new treatment options to improve outcomes. High-risk patients include those with metastatic or relapsed disease and tumors with PAX3-FOXO1 fusion genes that encode a potent transcription factor that drives tumourigenesis through transcriptional reprogramming. Polo-Like Kinase-1 (PLK1) is a serine/threonine kinase that phosphorylates a wide range of target substrates and alters their activity. PLK1 functions as a pleiotropic master regulator of mitosis and regulates DNA replication after stress. Taken together with high levels of expression that correlate with poor outcomes in many cancers, including rhabdomyosarcomas, it is an attractive therapeutic target. This is supported in rhabdomyosarcoma models by characterization of molecular and phenotypic effects of reducing and inhibiting PLK1, including changes to the PAX3-FOXO1 fusion protein. However, as tumor re-growth has been observed, combination strategies are required. Here we review preclinical evidence and consider biological rationale for PLK1 inhibition in combination with drugs that promote apoptosis, interfere with activity of PAX3-FOXO1 and are synergistic with microtubule-destabilizing drugs such as vincristine. The preclinical effects of low doses of the PLK1 inhibitor volasertib in combination with vincristine, which is widely used in rhabdomyosarcoma treatment, show particular promise in light of recent clinical data in the pediatric setting that support achievable volasertib doses predicted to be effective. Further development of novel therapeutic strategies including PLK1 inhibition may ultimately benefit young patients with rhabdomyosarcoma and other cancers