Effective combination treatment of GD2-expressing neuroblastoma and Ewing's sarcoma using anti-GD2 ch14.18/CHO antibody with Vγ9Vδ2+ γδT cells

Gamma delta T lymphocytes (γδT cells) have pleiotropic properties including innate cytotoxicity, which make them attractive effectors for cancer immunotherapy. Combination treatment with zoledronic acid and IL-2 can activate and expand the most common subset of blood γδT, which express the Vγ9Vδ2 T cell receptor (TCR) (Vδ2 T cells). Vγ9Vδ2 T cells are equipped for antibody-dependent cell-mediated cytotoxicity (ADCC) through expression of the low-affinity FcγR CD16. GD2 is a highly ranked tumor associated antigen for immunotherapy due to bright expression on the cell surface, absent expression on normal tissues and availability of therapeutic antibodies with known efficacy in neuroblastoma. To explore the hypothesis that zoledronic acid, IL-2 and anti-GD2 antibodies will synergize in a therapeutic combination, we evaluated in vitro cytotoxicity and tumor growth inhibition in the GD2 expressing cancers neuroblastoma and Ewing's sarcoma. Vδ2 T cells exert ADCC against GD2-expressing Ewing's sarcoma and neuroblastoma cell lines, an effect which correlates with the brightness of GD2 expression. In an immunodeficient mouse model of small established GD2-expressing Ewing's sarcoma or neuroblastoma tumors, the combination of adoptively transferred Vδ2+ T cells, expanded in vitro with zoledronic acid and IL-2, with anti-GD2 antibody ch14.18/CHO, and with systemic zoledronic acid, significantly suppressed tumor growth compared to antibody or γδT cell-free controls. Combination treatment using ch14.18/CHO, zoledronic acid and IL-2 is more effective than their use in isolation. The already-established safety profiles of these agents make testing of the combination in GD2 positive cancers such as neuroblastoma or Ewing's sarcoma both rational and feasible

Mitigating amphibian chytridiomycoses in nature

Amphibians across the planet face the threat of population decline and extirpation caused by the disease chytridiomycosis. Despite consensus that the fungal pathogens responsible for the disease are conservation issues, strategies to mitigate their impacts in the natural world are, at best, nascent. Reducing risk associated with the movement of amphibians, non-amphibian vectors and other sources of infection remains the first line of defence and a primary objective when mitigating the threat of disease in wildlife. Amphibian-associated chytridiomycete fungi and chytridiomycosis are already widespread, though, and we therefore focus on discussing options for mitigating the threats once disease emergence has occurred in wild amphibian populations. All strategies have shortcomings that need to be overcome before implementation, including stronger efforts towards understanding and addressing ethical and legal considerations. Even if these issues can be dealt with, all currently available approaches, or those under discussion, are unlikely to yield the desired conservation outcome of disease mitigation. The decision process for establishing mitigation strategies requires integrated thinking that assesses disease mitigation options critically and embeds them within more comprehensive strategies for the conservation of amphibian populations, communities and ecosystems

Dispositional mindfulness and reward motivated eating: The role of emotion regulation and mental habit

Evidence regarding the effectiveness of mindfulness based interventions (MBIs) for eating disorders, weight management and food craving is emerging and further studies are required to understand the underlying mechanisms of MBIs in these domains. The current study was designed to establish the role of specific mechanisms underlying the putative relationship between mindfulness and reward motivated eating. We predicted that mindfulness would be negatively related to features of reward motivated eating and that this association would be mediated by emotion regulation and habitual negative self-thinking. A cross-sectional survey measuring uncontrolled and emotional eating, mindfulness, emotion regulation and habitual negative self-thinking was completed by female and male meditators and non-meditators (N = 632). Lower levels of dispositional mindfulness were associated with difficulties in emotion regulation, habitual negative self-thinking and both emotional and uncontrolled eating. Difficulties in emotion regulation significantly mediated the mindfulness-uncontrolled eating relationship. Habitual negative self-thinking significantly mediated the mindfulness-emotional eating relationship. Participants with meditation experience reported greater levels of dispositional mindfulness, fewer difficulties with emotion regulation and habitual negative self-thinking and reduced uncontrolled eating tendencies, compared to non-meditators. The findings suggest that MBIs designed to change reward motivated eating and weight control should focus on emotion regulation and mental habits as underlying mechanisms

Information Dynamics in Living Systems: Prokaryotes, Eukaryotes, and Cancer

BACKGROUND: Living systems use information and energy to maintain stable entropy while far from thermodynamic equilibrium. The underlying first principles have not been established. FINDINGS: We propose that stable entropy in living systems, in the absence of thermodynamic equilibrium, requires an information extremum (maximum or minimum), which is invariant to first order perturbations. Proliferation and death represent key feedback mechanisms that promote stability even in a non-equilibrium state. A system moves to low or high information depending on its energy status, as the benefit of information in maintaining and increasing order is balanced against its energy cost. Prokaryotes, which lack specialized energy-producing organelles (mitochondria), are energy-limited and constrained to an information minimum. Acquisition of mitochondria is viewed as a critical evolutionary step that, by allowing eukaryotes to achieve a sufficiently high energy state, permitted a phase transition to an information maximum. This state, in contrast to the prokaryote minima, allowed evolution of complex, multicellular organisms. A special case is a malignant cell, which is modeled as a phase transition from a maximum to minimum information state. The minimum leads to a predicted power-law governing the in situ growth that is confirmed by studies measuring growth of small breast cancers. CONCLUSIONS: We find living systems achieve a stable entropic state by maintaining an extreme level of information. The evolutionary divergence of prokaryotes and eukaryotes resulted from acquisition of specialized energy organelles that allowed transition from information minima to maxima, respectively. Carcinogenesis represents a reverse transition: of an information maximum to minimum. The progressive information loss is evident in accumulating mutations, disordered morphology, and functional decline characteristics of human cancers. The findings suggest energy restriction is a critical first step that triggers the genetic mutations that drive somatic evolution of the malignant phenotype

Principles of crystal growth of intermetallic and oxide compounds from molten solutions

We present a tutorial on the principles of crystal growth of intermetallic and oxide compounds from molten solutions, with an emphasis on the fundamental principles governing the underlying phase equilibria and phase diagrams of multicomponent systems.Comment: 43 pages, 24 figures; Philosophical Magazine, 201

Targeted prevention of common mental health disorders in university students: randomised controlled trial of a transdiagnostic trait-focused web-based intervention

Background: A large proportion of university students show symptoms of common mental disorders, such as depression, anxiety, substance use disorders and eating disorders. Novel interventions are required that target underlying factors of multiple disorders.<p></p> Aims: To evaluate the efficacy of a transdiagnostic trait-focused web-based intervention aimed at reducing symptoms of common mental disorders in university students.<p></p> Method: Students were recruited online (n = 1047, age: M = 21.8, SD = 4.2) and categorised into being at high or low risk for mental disorders based on their personality traits. Participants were allocated to a cognitive-behavioural trait-focused (n = 519) or a control intervention (n = 528) using computerised simple randomisation. Both interventions were fully automated and delivered online (trial registration: ISRCTN14342225). Participants were blinded and outcomes were self-assessed at baseline, at 6 weeks and at 12 weeks after registration. Primary outcomes were current depression and anxiety, assessed on the Patient Health Questionnaire (PHQ9) and Generalised Anxiety Disorder Scale (GAD7). Secondary outcome measures focused on alcohol use, disordered eating, and other outcomes.<p></p> Results: Students at high risk were successfully identified using personality indicators and reported poorer mental health. A total of 520 students completed the 6-week follow-up and 401 students completed the 12-week follow-up. Attrition was high across intervention groups, but comparable to other web-based interventions. Mixed effects analyses revealed that at 12-week follow up the trait-focused intervention reduced depression scores by 3.58 (p<.001, 95%CI [5.19, 1.98]) and anxiety scores by 2.87 (p = .018, 95%CI [1.31, 4.43]) in students at high risk. In high-risk students, between group effect sizes were 0.58 (depression) and 0.42 (anxiety). In addition, self-esteem was improved. No changes were observed regarding the use of alcohol or disordered eating.<p></p> Conclusions This study suggests that a transdiagnostic web-based intervention for university students targeting underlying personality risk factors may be a promising way of preventing common mental disorders with a low-intensity intervention

The evolution of methods for establishing evolutionary timescales

The fossil record is well known to be incomplete. Read literally, it provides a distorted view of the history of species divergence and extinction, because different species have different propensities to fossilize, the amount of rock fluctuates over geological timescales, as does the nature of the environments that it preserves. Even so, patterns in the fossil evidence allow us to assess the incompleteness of the fossil record. While the molecular clock can be used to extend the time estimates from fossil species to lineages not represented in the fossil record, fossils are the only source of information concerning absolute (geological) times in molecular dating analysis. We review different ways of incorporating fossil evidence in modern clock dating analyses, including node-calibrations where lineage divergence times are constrained using probability densities and tip-calibrations where fossil species at the tips of the tree are assigned dates from dated rock strata. While node-calibrations are often constructed by a crude assessment of the fossil evidence and thus involves arbitrariness, tip-calibrations may be too sensitive to the prior on divergence times or the branching process and influenced unduly affected by well-known problems of morphological character evolution, such as environmental influence on morphological phenotypes, correlation among traits, and convergent evolution in disparate species. We discuss the utility of time information from fossils in phylogeny estimation and the search for ancestors in the fossil record. This article is part of the themed issue ‘Dating species divergences using rocks and clocks’

Populations of a Susceptible Amphibian Species Can Grow despite the Presence of a Pathogenic Chytrid Fungus

Disease can be an important driver of host population dynamics and epizootics can cause severe host population declines. Batrachochytrium dendrobatidis (Bd), the pathogen causing amphibian chytridiomycosis, may occur epizootically or enzootically and can harm amphibian populations in many ways. While effects of Bd epizootics are well documented, the effects of enzootic Bd have rarely been described. We used a state-space model that accounts for observation error to test whether population trends of a species highly susceptible to Bd, the midwife toad Alytes obstetricans, are negatively affected by the enzootic presence of the pathogen. Unexpectedly, Bd had no negative effect on population growth rates from 2002–2008. This suggests that negative effects of disease on individuals do not necessarily translate into negative effects at the population level. Populations of amphibian species that are susceptible to the emerging disease chytridiomycosis can persist despite the enzootic presence of the pathogen under current environmental conditions

F-theory on Genus-One Fibrations

We argue that M-theory compactified on an arbitrary genus-one fibration, that is, an elliptic fibration which need not have a section, always has an F-theory limit when the area of the genus-one fiber approaches zero. Such genus-one fibrations can be easily constructed as toric hypersurfaces, and various $SU(5)\times U(1)^n$ and $E_6$ models are presented as examples. To each genus-one fibration one can associate a $\tau$-function on the base as well as an $SL(2,\mathbb{Z})$ representation which together define the IIB axio-dilaton and 7-brane content of the theory. The set of genus-one fibrations with the same $\tau$-function and $SL(2,\mathbb{Z})$ representation, known as the Tate-Shafarevich group, supplies an important degree of freedom in the corresponding F-theory model which has not been studied carefully until now. Six-dimensional anomaly cancellation as well as Witten's zero-mode count on wrapped branes both imply corrections to the usual F-theory dictionary for some of these models. In particular, neutral hypermultiplets which are localized at codimension-two fibers can arise. (All previous known examples of localized hypermultiplets were charged under the gauge group of the theory.) Finally, in the absence of a section some novel monodromies of Kodaira fibers are allowed which lead to new breaking patterns of non-Abelian gauge groups.Comment: 53 pages, 9 figures, 6 tables. v2: references adde

Asking questions can help: development and preliminary evaluation of a question prompt list for palliative care patients

Question prompt lists (QPLs) have been shown to be an inexpensive and effective communication tool for patients in oncology consultations. We aimed to develop and pilot a QPL for palliative care (PC) patients. In order to identify suitable questions for inclusion in the QPL, we conducted focus groups and individual interviews with 19 patients, 24 carers and 22 PC health professionals. A further 21 health professionals reviewed the draft document. The draft QPL was piloted in 23 patients. In total, 112 questions were identified and grouped into eight categories. All participants felt that the QPL, in booklet form, could be a useful tool. Out of 23 patients in the pilot study, 22 agreed that the QPL was helpful, contained useful questions, was easy to understand and would be useful in the future. State anxiety (STAI) decreased after receiving the booklet and seeing the doctor in 16 out of 19 patients (overall anxiety decreased by a median of 8, IQR 1-13). Participants in the pilot study endorsed the inclusion of end-of-life issues in the QPL, despite some reservations expressed about this by health professionals in the individual interviews. We have identified a specific QPL that might facilitate useful dialogue between PC patients and their doctor. The QPL has strong support from patients, their carers and relevant health professionals