ARF and p53 coordinate tumor suppression of an oncogenic IFN-β-STAT1-ISG15 signaling axis

SummaryThe ARF and p53 tumor suppressors are thought to act in a linear pathway to prevent cellular transformation in response to various oncogenic signals. Here, we show that loss of p53 leads to an increase in ARF protein levels, which function to limit the proliferation and tumorigenicity of p53-deficient cells by inhibiting an IFN-β-STAT1-ISG15 signaling axis. Human triple-negative breast cancer (TNBC) tumor samples with coinactivation of p53 and ARF exhibit high expression of both STAT1 and ISG15, and TNBC cell lines are sensitive to STAT1 depletion. We propose that loss of p53 function and subsequent ARF induction creates a selective pressure to inactivate ARF and propose that tumors harboring coinactivation of ARF and p53 would benefit from therapies targeted against STAT1 and ISG15 activation

Stress Coping of Patients with Substance use Disorder in Latvia

Stress is a part of our everyday life and it plays an important role in causing various diseases. Studies related to aetiology of using pshyhoactive substances have shown that stress is one of strongest factor that provokes the use of addictive substanceswhichemphasizes necessity of research aboutstress copingtypes for patients with addiction. Purpose of study is to examine stress coping among patients with substance use disorders in Latvia.2 research tools were used: a demographic questionnaire and “The Ways of coping scale” (Folkman& Lazarus, 1985). The results show that women use emotion-oriented stress coping. For women who have completed treatment, more specific ways of stress coping are accepting responsibility, escape-avoidance and positive reappraisal. Among men, the dominant stress coping strategy is problem-oriented stress coping. Male patients who have completed treatment use more accepting responsibility and planful problem solving.publishersversionPeer reviewe

Citizen science reveals widespread negative effects of roads on amphibian distributions

Landscape structure is important for shaping the abundance and distribution of amphibians, but prior studies of landscape effects have been species or ecosystem-specific. Using a large-scale, citizen science-generated database, we examined the effects of habitat composition, road disturbance, and habitat split (i.e. the isolation of wetland from forest by intervening land use) on the distribution and richness of frogs and toads in the eastern and central United States. Undergraduates from nine biology and environmental science courses collated occupancy data and characterized landscape structure at 1617 sampling locations from the North American Amphibian Monitoring Program. Our analysis revealed that anuran species richness and individual species distributions were consistently constrained by both road density and traffic volume. In contrast, developed land around wetlands had small, or even positive effects on anuran species richness and distributions after controlling for road effects. Effects of upland habitat composition varied among species, and habitat split had only weak effects on species richness or individual species distributions. Mechanisms underlying road effects on amphibians involve direct mortality, behavioral barriers to movement, and reduction in the quality of roadside habitats. Our results suggest that the negative effects of roads on amphibians occur across broad geographic regions, affecting even common species, and they underscore the importance of developing effective strategies to mitigate the impacts of roads on amphibian populations

Regional and scale-specific effects of land use on amphibian diversity [poster]

Background/Question/Methods Habitat loss and degradation influence amphibian distributions and are important drivers of population declines. Our previous research demonstrated that road disturbance, development and wetland area consistently influence amphibian richness across regions of the U.S. Here, we examined the relative importance of these factors in different regions and at multiple spatial scales. Understanding the scales at which habitat disturbance may be affecting amphibian distributions is important for conservation planning. Specifically, we asked: 1) Over what spatial scales do distinct landscape features affect amphibian richness? and 2) Do road types (non-rural and rural) have similar effects on amphibian richness? This is the second year of a collaborative, nationwide project involving 11 U.S. colleges integrated within undergraduate biology curricula. We summarized North American Amphibian Monitoring Program data in 13 Eastern and Central U.S states and used geographic information systems to extract landscape data for 471 survey locations. We developed models to quantify the influence of landscape variables on amphibian species richness and site occupancy across five concentric buffers ranging from 300m to 10,000m. Results/Conclusions Across spatial scales, development, road density and agriculture were the best predictors of amphibian richness and site occupancy by individual species. Across regions, we found that scale did not exert a large influence on how landscape features influenced amphibian richness as effects were largely comparable across buffers. However, development and percent impervious surface had stronger influence on richness at smaller spatial scales. Richness was lower at survey locations with higher densities of non-rural and rural roads, and non-rural road density had a larger negative effect at smaller scales. Within regions, landscape features driving patterns of species richness varied. The scales at which these factors were associated with richness were highly variable within regions, suggesting the scale effects may be region specific. Our project demonstrates that networks of undergraduate students can collaborate to compile and analyze large ecological data sets, while engaging students in authentic and inquiry-based learning in landscape-scale ecology

A Somatically Diversified Defense Factor, FREP3, Is a Determinant of Snail Resistance to Schistosome Infection

Schistosomiasis, a neglected tropical disease, owes its continued success to freshwater snails that support production of prolific numbers of human-infective cercariae. Encounters between schistosomes and snails do not always result in the snail becoming infected, in part because snails can mount immune responses that prevent schistosome development. Fibrinogen-related protein 3 (FREP3) has been previously associated with snail defense against digenetic trematode infection. It is a member of a large family of immune molecules with a unique structure consisting of one or two immunoglobulin superfamily domains connected to a fibrinogen domain; to date fibrinogen containing proteins with this arrangement are found only in gastropod molluscs. Furthermore, specific gastropod FREPs have been shown to undergo somatic diversification. Here we demonstrate that siRNA mediated knockdown of FREP3 results in a phenotypic loss of resistance to Schistosoma mansoni infection in 15 of 70 (21.4%) snails of the resistant BS-90 strain of Biomphalaria glabrata. In contrast, none of the 64 control BS-90 snails receiving a GFP siRNA construct and then exposed to S. mansoni became infected. Furthermore, resistance to S. mansoni was overcome in 22 of 48 snails (46%) by pre-exposure to another digenetic trematode, Echinostoma paraensei. Loss of resistance in this case was shown by microarray analysis to be associated with strong down-regulation of FREP3, and other candidate immune molecules. Although many factors are certainly involved in snail defense from trematode infection, this study identifies for the first time the involvement of a specific snail gene, FREP3, in the phenotype of resistance to the medically important parasite, S. mansoni. The results have implications for revealing the underlying mechanisms involved in dictating the range of snail strains used by S. mansoni, and, more generally, for better understanding the phenomena of host specificity and host switching. It also highlights the role of a diversified invertebrate immune molecule in defense against a human pathogen. It suggests new lines of investigation for understanding how susceptibility of snails in areas endemic for S. mansoni could be manipulated and diminished

An Integrated Disease/Pharmacokinetic/Pharmacodynamic Model Suggests Improved Interleukin-21 Regimens Validated Prospectively for Mouse Solid Cancers

Interleukin (IL)-21 is an attractive antitumor agent with potent immunomodulatory functions. Yet thus far, the cytokine has yielded only partial responses in solid cancer patients, and conditions for beneficial IL-21 immunotherapy remain elusive. The current work aims to identify clinically-relevant IL-21 regimens with enhanced efficacy, based on mathematical modeling of long-term antitumor responses. For this purpose, pharmacokinetic (PK) and pharmacodynamic (PD) data were acquired from a preclinical study applying systemic IL-21 therapy in murine solid cancers. We developed an integrated disease/PK/PD model for the IL-21 anticancer response, and calibrated it using selected “training” data. The accuracy of the model was verified retrospectively under diverse IL-21 treatment settings, by comparing its predictions to independent “validation” data in melanoma and renal cell carcinoma-challenged mice (R2>0.90). Simulations of the verified model surfaced important therapeutic insights: (1) Fractionating the standard daily regimen (50 µg/dose) into a twice daily schedule (25 µg/dose) is advantageous, yielding a significantly lower tumor mass (45% decrease); (2) A low-dose (12 µg/day) regimen exerts a response similar to that obtained under the 50 µg/day treatment, suggestive of an equally efficacious dose with potentially reduced toxicity. Subsequent experiments in melanoma-bearing mice corroborated both of these predictions with high precision (R2>0.89), thus validating the model also prospectively in vivo. Thus, the confirmed PK/PD model rationalizes IL-21 therapy, and pinpoints improved clinically-feasible treatment schedules. Our analysis demonstrates the value of employing mathematical modeling and in silico-guided design of solid tumor immunotherapy in the clinic