Blockade of insulin-like growth factors increases efficacy of paclitaxel in metastatic breast cancer.

Breast cancer remains the leading cause of cancer death in women owing to metastasis and the development of resistance to established therapies. Macrophages are the most abundant immune cells in the breast tumor microenvironment and can both inhibit and support cancer progression. Thus, gaining a better understanding of how macrophages support cancer could lead to the development of more effective therapies. In this study, we find that breast cancer-associated macrophages express high levels of insulin-like growth factors 1 and 2 (IGFs) and are the main source of IGFs within both primary and metastatic tumors. In total, 75% of breast cancer patients show activation of insulin/IGF-1 receptor signaling and this correlates with increased macrophage infiltration and advanced tumor stage. In patients with invasive breast cancer, activation of Insulin/IGF-1 receptors increased to 87%. Blocking IGF in combination with paclitaxel, a chemotherapeutic agent commonly used to treat breast cancer, showed a significant reduction in tumor cell proliferation and lung metastasis in pre-clinical breast cancer models compared to paclitaxel monotherapy. Our findings provide the rationale for further developing the combination of paclitaxel with IGF blockers for the treatment of invasive breast cancer, and Insulin/IGF1R activation and IGF+ stroma cells as potential biomarker candidates for further evaluation

Adaptive robot training for the treatment of incoordination in Multiple Sclerosis

<p>Abstract</p> <p>Background</p> <p>Cerebellar symptoms are extremely disabling and are common in Multiple Sclerosis (MS) subjects. In this feasibility study, we developed and tested a robot therapy protocol, aimed at the rehabilitation of incoordination in MS subjects.</p> <p>Methods</p> <p>Eight subjects with clinically defined MS performed planar reaching movements while grasping the handle of a robotic manipulandum, which generated forces that either reduced (error-reducing, ER) or enhanced (error-enhancing, EE) the curvature of their movements, assessed at the beginning of each session. The protocol was designed to adapt to the individual subjects' impairments, as well as to improvements between sessions (if any). Each subject went through a total of eight training sessions. To compare the effect of the two variants of the training protocol (ER and EE), we used a cross-over design consisting of two blocks of sessions (four ER and four EE; 2 sessions/week), separated by a 2-weeks rest period. The order of application of ER and EE exercises was randomized across subjects. The primary outcome measure was the modification of the Nine Hole Peg Test (NHPT) score. Other clinical scales and movement kinematics were taken as secondary outcomes.</p> <p>Results</p> <p>Most subjects revealed a preserved ability to adapt to the robot-generated forces. No significant differences were observed in EE and ER training. However over sessions, subjects exhibited an average 24% decrease in their NHPT score. The other clinical scales showed small improvements for at least some of the subjects. After training, movements became smoother, and their curvature decreased significantly over sessions.</p> <p>Conclusions</p> <p>The results point to an improved coordination over sessions and suggest a potential benefit of a short-term, customized, and adaptive robot therapy for MS subjects.</p

Host-Species Transferrin Receptor 1 Orthologs Are Cellular Receptors for Nonpathogenic New World Clade B Arenaviruses

The ability of a New World (NW) clade B arenavirus to enter cells using human transferrin receptor 1 (TfR1) strictly correlates with its ability to cause hemorrhagic fever. Amapari (AMAV) and Tacaribe (TCRV), two nonpathogenic NW clade B arenaviruses that do not use human TfR1, are closely related to the NW arenaviruses that cause hemorrhagic fevers. Here we show that pseudotyped viruses bearing the surface glycoprotein (GP) of AMAV or TCRV can infect cells using the TfR1 orthologs of several mammalian species, including those of their respective natural hosts, the small rodent Neacomys spinosus and the fruit bat Artibeus jamaicensis. Mutation of one residue in human TfR1 makes it a functional receptor for TCRV, and mutation of four residues makes it a functional receptor for AMAV. Our data support an in vivo role for TfR1 in the replication of most, if not all, NW clade B arenaviruses, and suggest that with modest changes in their GPs the nonpathogenic arenaviruses could use human TfR1 and emerge as human pathogens

Integrated Ecosystem Assessment: Lake Ontario Water Management

BACKGROUND: Ecosystem management requires organizing, synthesizing, and projecting information at a large scale while simultaneously addressing public interests, dynamic ecological properties, and a continuum of physicochemical conditions. We compared the impacts of seven water level management plans for Lake Ontario on a set of environmental attributes of public relevance. METHODOLOGY AND FINDINGS: Our assessment method was developed with a set of established impact assessment tools (checklists, classifications, matrices, simulations, representative taxa, and performance relations) and the concept of archetypal geomorphic shoreline classes. We considered each environmental attribute and shoreline class in its typical and essential form and predicted how water level change would interact with defining properties. The analysis indicated that about half the shoreline of Lake Ontario is potentially sensitive to water level change with a small portion being highly sensitive. The current water management plan may be best for maintaining the environmental resources. In contrast, a natural water regime plan designed for greatest environmental benefits most often had adverse impacts, impacted most shoreline classes, and the largest portion of the lake coast. Plans that balanced multiple objectives and avoided hydrologic extremes were found to be similar relative to the environment, low on adverse impacts, and had many minor impacts across many shoreline classes. SIGNIFICANCE: The Lake Ontario ecosystem assessment provided information that can inform decisions about water management and the environment. No approach and set of methods will perfectly and unarguably accomplish integrated ecosystem assessment. For managing water levels in Lake Ontario, we found that there are no uniformly good and bad options for environmental conservation. The scientific challenge was selecting a set of tools and practices to present broad, relevant, unbiased, and accessible information to guide decision-making on a set of management options

Interactions between Predation and Resources Shape Zooplankton Population Dynamics

Identifying the relative importance of predation and resources in population dynamics has a long tradition in ecology, while interactions between them have been studied less intensively. In order to disentangle the effects of predation by juvenile fish, algal resource availability and their interactive effects on zooplankton population dynamics, we conducted an enclosure experiment where zooplankton were exposed to a gradient of predation of roach (Rutilus rutilus) at different algal concentrations. We show that zooplankton populations collapse under high predation pressure irrespective of resource availability, confirming that juvenile fish are able to severely reduce zooplankton prey when occurring in high densities. At lower predation pressure, however, the effect of predation depended on algal resource availability since high algal resource supply buffered against predation. Hence, we suggest that interactions between mass-hatching of fish, and the strong fluctuations in algal resources in spring have the potential to regulate zooplankton population dynamics. In a broader perspective, increasing spring temperatures due to global warming will most likely affect the timing of these processes and have consequences for the spring and summer zooplankton dynamics

Testing the Goodness of Supplementary Feeding to Enhance Population Viability in an Endangered Vulture

[Background]: Human-predator conflicts are directly or indirectly threatening many species with extinction. Thus, biologists are urged to find simple solutions to complex situations while avoiding unforeseen conservation outcomes. The provision of supplementary food at artificial feeding sites (AFS) is frequently used in the conservation of scavenger bird populations currently suffering from indirect poisoning, although no scientific studies on its effectiveness have been conducted.[Methodology/Principal Findings]: We used a long-term data set of 95 individually marked birds from the largest European core of the endangered bearded vulture (Gypaetus barbatus) to test the long-term effects of specific AFS for bearded vultures on their survival rates (by CMR models) and population dynamics (by Monte Carlo simulations) in an area where fatalities derived from illegal poisoning and the use of other toxics like veterinary drugs have increased over the last several years. Our data support the positive relationship between the use of AFS and survival. However, contrary to theoretical predictions (e.g. high and more stable adult survival among long-lived species), the use of AFS increased only survival of pre-adults. Moreover, AFS buffered the effects of illegal poisoning on this age-class, while adult survival decreased over years. Our simulations predicted a maximum value of extinction probability over a time horizon of 50 years. Population projections run with survival rates expected in scenarios without poisoning predicted the situation of least conservation concern, while including only AFS can maintain a large floater surplus that may delay population decline but fails to reduce poisoning risk among adults.[Conclusions/Significance]: Although AFS are not effective to save bearded vultures from an expected population decline, they delay population extinction and can be a useful tool for prolonging population viability while combating illegal and indirect poisoning. The eradication of different sources of poisoning is of top priority to ensure the long-term viability of this and many other species.Financial support for AM was obtained from the Departament of Medi Ambient i Habitatge of Generalitat de Catalunya and Ministry of Environment. MC was supported by an Excellence post-doctoral contract (Junta de Andalucía).Peer reviewe

Effects of long-term exposure to an electronic containment system on the behaviour and welfare of domestic cats

Free-roaming cats are exposed to a variety of risks, including involvement in road traffic accidents. One way of mitigating these risks is to contain cats, for example using an electronic boundary fence system that delivers an electric ‘correction’ via a collar if a cat ignores a warning cue and attempts to cross the boundary. However, concerns have been expressed over the welfare impact of such systems. Our aim was to determine if long-term exposure to an electronic containment system was associated with reduced cat welfare. We compared 46 owned domestic cats: 23 cats that had been contained by an electronic containment system for more than 12 months (AF group); and 23 cats with no containment system that were able to roam more widely (C group). We assessed the cats’ behavioural responses and welfare via four behavioural tests (unfamiliar person test; novel object test; sudden noise test; cognitive bias test) and an owner questionnaire. In the unfamiliar person test, C group lip-licked more than the AF group, whilst the AF group looked at, explored and interacted more with the unfamiliar person than C group. In the novel object test, the AF group looked at and explored the object more than C group. No significant differences were found between AF and C groups for the sudden noise or cognitive bias tests. Regarding the questionnaire, C group owners thought their cats showed more irritable behaviour and AF owners thought that their cats toileted inappropriately more often than C owners. Overall, AF cats were less neophobic than C cats and there was no evidence of significant differences between the populations in general affective state. These findings indicate that an electronic boundary fence with clear pre-warning cues does not impair the long term quality of life of cat

Studying the Underlying Event in Drell-Yan and High Transverse Momentum Jet Production at the Tevatron

We study the underlying event in proton-antiproton collisions by examining the behavior of charged particles (transverse momentum pT > 0.5 GeV/c, pseudorapidity |\eta| < 1) produced in association with large transverse momentum jets (~2.2 fb-1) or with Drell-Yan lepton-pairs (~2.7 fb-1) in the Z-boson mass region (70 < M(pair) < 110 GeV/c2) as measured by CDF at 1.96 TeV center-of-mass energy. We use the direction of the lepton-pair (in Drell-Yan production) or the leading jet (in high-pT jet production) in each event to define three regions of \eta-\phi space; toward, away, and transverse, where \phi is the azimuthal scattering angle. For Drell-Yan production (excluding the leptons) both the toward and transverse regions are very sensitive to the underlying event. In high-pT jet production the transverse region is very sensitive to the underlying event and is separated into a MAX and MIN transverse region, which helps separate the hard component (initial and final-state radiation) from the beam-beam remnant and multiple parton interaction components of the scattering. The data are corrected to the particle level to remove detector effects and are then compared with several QCD Monte-Carlo models. The goal of this analysis is to provide data that can be used to test and improve the QCD Monte-Carlo models of the underlying event that are used to simulate hadron-hadron collisions.Comment: Submitted to Phys.Rev.

Precision measurement of the top quark mass from dilepton events at CDF II

We report a measurement of the top quark mass, M_t, in the dilepton decay channel of $t\bar{t}\to b\ell'^{+}\nu_{\ell'}\bar{b}\ell^{-}\bar{\nu}_{\ell}$ using an integrated luminosity of 1.0 fb^{-1} of p\bar{p} collisions collected with the CDF II detector. We apply a method that convolutes a leading-order matrix element with detector resolution functions to form event-by-event likelihoods; we have enhanced the leading-order description to describe the effects of initial-state radiation. The joint likelihood is the product of the likelihoods from 78 candidate events in this sample, which yields a measurement of M_{t} = 164.5 \pm 3.9(\textrm{stat.}) \pm 3.9(\textrm{syst.}) \mathrm{GeV}/c^2, the most precise measurement of M_t in the dilepton channel.Comment: 7 pages, 2 figures, version includes changes made prior to publication by journa