Response of Merkel cell polyomavirus-positive Merkel cell carcinoma xenografts to a survivin inhibitor

Merkel cell carcinoma (MCC) is a neuroendocrine skin cancer associated with high mortality. Merkel cell polyomavirus (MCV), discovered in 2008, is associated with ∼80% of MCC. The MCV large tumor (LT) oncoprotein upregulates the cellular oncoprotein survivin through its conserved retinoblastoma protein-binding motif. We confirm here that YM155, a survivin suppressor, is cytotoxic to MCV-positive MCC cells in vitro at nanomolar levels. Mouse survival was significantly improved for NOD-Scid-Gamma mice treated with YM155 in a dose and duration dependent manner for 3 of 4 MCV-positive MCC xenografts. One MCV-positive MCC xenograft (MS-1) failed to significantly respond to YM155, which corresponds with in vitro dose-response activity. Combination treatment of YM155 with other chemotherapeutics resulted in additive but not synergistic cell killing of MCC cell lines in vitro. These results suggest that survivin targeting is a promising therapeutic approach for most but not all MCV-positive MCCs. © 2013 Dresang et al

Idiosyncratic deals for older workers: increased heterogeneity among older workers enhance the need for i-Deals

The rapid aging of the workforce throughout the Western world and parts of Asia, including Japan and China, poses many challenges on contemporary organizations (European Commission, 2010 ; Wang & Shultz, 2010 ). The Babyboom generation, consisting of workers born between 1945 and 1965, constitutes a large part of the current workforce. Due to decreased fertility rates, there are fewer younger workers entering the labor market, as a consequence of which the percentage of older workers is rapidly increasing (Truxillo & Fraccaroli, 2013 ). Consequently, organizations are increasingly aware that the employee population is changing, and that strategies to employ, motivate, and retain workers have to be adapted accordingly. It is no longer suffi cient for organizations to focus on employing younger workers (e.g., through designing traineeships for graduates), because the infl ux of younger workers in the labor market is stagnating, which is in particular present in certain sectors, such as technical occupations and health care (Polat, Bal, & Jansen, 2012 ). Hence, organizations increasingly will have to rely on older workers, and try to retain older workers, and motivate them to stay longer in the workforce. Similarly, governments across Europe are also increasing offi cial retirement ages, and making it fi nancially less attractive for older workers to retire early (European Commission)

Conditioned task-set competition:Neural mechanisms of emotional interference in depression

Depression has been associated with increased response times at the incongruent, neutral, and negative-word trials of the classical and emotional Stroop tasks (Epp et al., 2012). Response time slow-down effects at incongruent and negative-word trials of the Stroop tasks were reported to correlate with depressive severity, indicating strong relevance of the effects to the symptomatology. The current study proposes a novel integrative computational model of neural mechanisms of both the classical and the emotional Stroop effects, drawing on the previous prominent theoretical explanations of performance at the classical Stroop task (Cohen et al., 1990; Herd et al., 2006), and in addition suggesting that negative emotional words represent conditioned stimuli for future negative outcomes. The model is shown to explain the classical Stroop effect and the slow (between-trial) emotional Stroop effect with biologically-plausible mechanisms, providing an advantage over the previous theoretical accounts (Matthews and Harley, 1996; Wyble et al., 2008). Simulation results suggested a candidate mechanism responsible for the pattern of depressive performance at the classical and the emotional Stroop tasks. Hyperactivity of the amygdala, together with increased inhibitory influence of the amygdala over dopaminergic neurotransmission, could be at the origin of the performance deficits

The effects of surface fossil magnetic fields on massive star evolution: IV. Grids of models at Solar, LMC, and SMC metallicities

Magnetic fields can drastically change predictions of evolutionary models of massive stars via mass-loss quenching, magnetic braking, and efficient angular momentum transport, which we aim to quantify in this work. We use the MESA software instrument to compute an extensive main-sequence grid of stellar structure and evolution models, as well as isochrones, accounting for the effects attributed to a surface fossil magnetic field. The grid is densely populated in initial mass (3–60 M⊙), surface equatorial magnetic field strength (0–50 kG), and metallicity (representative of the Solar neighbourhood and the Magellanic Clouds). We use two magnetic braking and two chemical mixing schemes and compare the model predictions for slowly rotating, nitrogen-enriched (‘Group 2’) stars with observations in the Large Magellanic Cloud. We quantify a range of initial field strengths that allow for producing Group 2 stars and find that typical values (up to a few kG) lead to solutions. Between the subgrids, we find notable departures in surface abundances and evolutionary paths. In our magnetic models, chemical mixing is always less efficient compared to non-magnetic models due to the rapid spin-down. We identify that quasi-chemically homogeneous main sequence evolution by efficient mixing could be prevented by fossil magnetic fields. We recommend comparing this grid of evolutionary models with spectropolarimetric and spectroscopic observations with the goals of (i) revisiting the derived stellar parameters of known magnetic stars, and (ii) observationally constraining the uncertain magnetic braking and chemical mixing schemes

Antibody Repertoires in Humanized NOD-scid-IL2Rγnull Mice and Human B Cells Reveals Human-Like Diversification and Tolerance Checkpoints in the Mouse

Immunodeficient mice reconstituted with human hematopoietic stem cells enable the in vivo study of human hematopoiesis. In particular, NOD-scid-IL2Rγnull engrafted mice have been shown to have reasonable levels of T and B cell repopulation and can mount T-cell dependent responses; however, antigen-specific B-cell responses in this model are generally poor. We explored whether developmental defects in the immunoglobulin gene repertoire might be partly responsible for the low level of antibody responses in this model. Roche 454 sequencing was used to obtain over 685,000 reads from cDNA encoding immunoglobulin heavy (IGH) and light (IGK and IGL) genes isolated from immature, naïve, or total splenic B cells in engrafted NOD-scid-IL2Rγnull mice, and compared with over 940,000 reads from peripheral B cells of two healthy volunteers. We find that while naïve B-cell repertoires in humanized mice are chiefly indistinguishable from those in human blood B cells, and display highly correlated patterns of immunoglobulin gene segment use, the complementarity-determining region H3 (CDR-H3) repertoires are nevertheless extremely diverse and are specific for each individual. Despite this diversity, preferential DH-JH pairings repeatedly occur within the CDR-H3 interval that are strikingly similar across all repertoires examined, implying a genetic constraint imposed on repertoire generation. Moreover, CDR-H3 length, charged amino-acid content, and hydropathy are indistinguishable between humans and humanized mice, with no evidence of global autoimmune signatures. Importantly, however, a statistically greater usage of the inherently autoreactive IGHV4-34 and IGKV4-1 genes was observed in the newly formed immature B cells relative to naïve B or total splenic B cells in the humanized mice, a finding consistent with the deletion of autoreactive B cells in humans. Overall, our results provide evidence that key features of the primary repertoire are shaped by genetic factors intrinsic to human B cells and are principally unaltered by differences between mouse and human stromal microenvironments

Local Orientation and the Evolution of Foraging: Changes in Decision Making Can Eliminate Evolutionary Trade-offs

Information processing is a major aspect of the evolution of animal behavior. In foraging, responsiveness to local feeding opportunities can generate patterns of behavior which reflect or “recognize patterns” in the environment beyond the perception of individuals. Theory on the evolution of behavior generally neglects such opportunity-based adaptation. Using a spatial individual-based model we study the role of opportunity-based adaptation in the evolution of foraging, and how it depends on local decision making. We compare two model variants which differ in the individual decision making that can evolve (restricted and extended model), and study the evolution of simple foraging behavior in environments where food is distributed either uniformly or in patches. We find that opportunity-based adaptation and the pattern recognition it generates, plays an important role in foraging success, particularly in patchy environments where one of the main challenges is “staying in patches”. In the restricted model this is achieved by genetic adaptation of move and search behavior, in light of a trade-off on within- and between-patch behavior. In the extended model this trade-off does not arise because decision making capabilities allow for differentiated behavioral patterns. As a consequence, it becomes possible for properties of movement to be specialized for detection of patches with more food, a larger scale information processing not present in the restricted model. Our results show that changes in decision making abilities can alter what kinds of pattern recognition are possible, eliminate an evolutionary trade-off and change the adaptive landscape

Multiple Determinants of Whole and Regional Brain Volume among Terrestrial Carnivorans

Mammalian brain volumes vary considerably, even after controlling for body size. Although several hypotheses have been proposed to explain this variation, most research in mammals on the evolution of encephalization has focused on primates, leaving the generality of these explanations uncertain. Furthermore, much research still addresses only one hypothesis at a time, despite the demonstrated importance of considering multiple factors simultaneously. We used phylogenetic comparative methods to investigate simultaneously the importance of several factors previously hypothesized to be important in neural evolution among mammalian carnivores, including social complexity, forelimb use, home range size, diet, life history, phylogeny, and recent evolutionary changes in body size. We also tested hypotheses suggesting roles for these variables in determining the relative volume of four brain regions measured using computed tomography. Our data suggest that, in contrast to brain size in primates, carnivoran brain size may lag behind body size over evolutionary time. Moreover, carnivore species that primarily consume vertebrates have the largest brains. Although we found no support for a role of social complexity in overall encephalization, relative cerebrum volume correlated positively with sociality. Finally, our results support negative relationships among different brain regions after accounting for overall endocranial volume, suggesting that increased size of one brain regions is often accompanied by reduced size in other regions rather than overall brain expansion

Type I interferon/IRF7 axis instigates chemotherapy-induced immunological dormancy in breast cancer

Neoadjuvant and adjuvant chemotherapies provide survival benefits to breast cancer patients, in particular in estrogen receptor negative (ER-) cancers, by reducing rates of recurrences. It is assumed that the benefits of (neo)adjuvant chemotherapy are due to the killing of disseminated, residual cancer cells, however, there is no formal evidence for it. Here, we provide experimental evidence that ER- breast cancer cells that survived high-dose Doxorubicin and Methotrexate based chemotherapies elicit a state of immunological dormancy. Hallmark of this dormant phenotype is the sustained activation of the IRF7/IFN-beta/IFNAR axis subsisting beyond chemotherapy treatment. Upregulation of IRF7 in treated cancer cells promoted resistance to chemotherapy, reduced cell growth and induced switching of the response from a myeloid derived suppressor cell-dominated immune response to a CD4(+)/CD8(+) T cell-dependent anti-tumor response. IRF7 silencing in tumor cells or systemic blocking of IFNAR reversed the state of dormancy, while spontaneous escape from dormancy was associated with loss of IFN-beta production. Presence of IFN-beta in the circulation of ER- breast cancer patients treated with neoadjuvant Epirubicin chemotherapy correlated with a significantly longer distant metastasis-free survival. These findings establish chemotherapy-induced immunological dormancy in ER- breast cancer as a novel concept for (neo)adjuvant chemotherapy activity, and implicate sustained activation of the IRF7/IFN-beta/IFNAR pathway in this effect. Further, IFN-beta emerges as a potential predictive biomarker and therapeutic molecule to improve outcome of ER- breast cancer patients treated with (neo)adjuvant chemotherapy.Peer reviewe