Skyrmion lattice formation and destruction mechanisms probed with TR-SANS.

Magnetic skyrmions are topologically protected, nanoscale whirls of the spin configuration that tend to form hexagonally ordered arrays. As a topologically non-trivial structure, the nucleation and annihilation of the skyrmion, as well as the interaction between skyrmions, varies from conventional magnetic systems. Recent works have suggested that the ordering kinetics in these materials occur over millisecond or longer timescales, which is unusually slow for magnetic dynamics. The current work investigates the skyrmion ordering kinetics, particularly during lattice formation and destruction, using time-resolved small angle neutron scattering (TR-SANS). Evaluating the time-resolved structure and intensity of the neutron diffraction pattern reveals the evolving real-space structure of the skyrmion lattice and the timeframe of the formation. Measurements were performed on three prototypical skyrmion materials: MnSi, (Fe,Co)Si, and Cu2OSeO3. To probe lattice formation and destruction kinetics, the systems were prepared in the stable skyrmion state, and then a square-wave magnetic field modulation was applied. The measurements show that the skyrmions quickly form ordered domains, with a significant distribution in lattice parameters, which then converge to the final structure; the results confirm the slow kinetics, with formation times between 10 ms and 99 ms. Comparisons are made between the measured formation times and the fundamental material properties, suggesting the ordering temperature, saturation magnetization and magnetocrystalline anisotropy may be driving the timeframes. Micromagnetic simulations were also performed and support a scaling of the kinetics with sample volume, a behavior which is caused by the reconciling of misaligned domains.

Large magnetic anisotropy of a decorated spin-chain system K2Co3(MoO4)3(OH)2.

The magnetic structure of K2Co3(MoO4)3(OH)2 is studied in detail. The material has a half-sawtooth one-dimensional (1-D) structure containing two unique Co2+ ions, one in the chain backbone and one on the apex of the sawtooth creating a series of isosceles triangles along the b-axis. These triangles can be a source of magnetic frustration. The ability to grow large single crystals enables detailed magnetic measurements with the crystals oriented in a magnetic field along the respective axes. It has a Curie-Weiss temperature θCW of 5.3(2) K with an effective magnetic moment of 4.8(3)µB/Co. The material is highly anisotropic with a sharp antiferromagnetic ordering transition at 7 K with a metamagnetic transition at 2 kOe. Neutron diffraction was used to determine the magnetic structure and revealed a magnetic structure with canted spins along the backbone of the chain while spins along the sawtooth caps maintained a colinear orientation, arranging antiferromagnetically relative to the backbone spins. The parallel chains arrange antiferromagnetically relative to each other along the c-axis and ferromagnetically along the a-axis.

White matter, cognition and psychotic-like experiences in UK Biobank.

BACKGROUND: Psychotic-like experiences (PLEs) are risk factors for the development of psychiatric conditions like schizophrenia, particularly if associated with distress. As PLEs have been related to alterations in both white matter and cognition, we investigated whether cognition (g-factor and processing speed) mediates the relationship between white matter and PLEs. METHODS: We investigated two independent samples (6170 and 19 891) from the UK Biobank, through path analysis. For both samples, measures of whole-brain fractional anisotropy (gFA) and mean diffusivity (gMD), as indications of white matter microstructure, were derived from probabilistic tractography. For the smaller sample, variables whole-brain white matter network efficiency and microstructure were also derived from structural connectome data. RESULTS: The mediation of cognition on the relationships between white matter properties and PLEs was non-significant. However, lower gFA was associated with having PLEs in combination with distress in the full available sample (standardized ß = -0.053, p = 0.011). Additionally, lower gFA/higher gMD was associated with lower g-factor (standardized ß = 0.049, p < 0.001; standardized ß = -0.027, p = 0.003), and partially mediated by processing speed with a proportion mediated of 7% (p = < 0.001) for gFA and 11% (p < 0.001) for gMD. CONCLUSIONS: We show that lower global white matter microstructure is associated with having PLEs in combination with distress, which suggests a direction of future research that could help clarify how and why individuals progress from subclinical to clinical psychotic symptoms. Furthermore, we replicated that processing speed mediates the relationship between white matter microstructure and g-factor.

Genetic ablation of the preptin-coding portion of Igf2 impairs pancreatic function in female mice.

Preptin is a 34-amino acid peptide derived from the E-peptide of pro-insulin-like growth factor 2 and is co-secreted with insulin from ß-cells. Little is understood about the effects of endogenous preptin on whole body glucose metabolism. We developed a novel mouse model in which the preptin portion of Igf2 was genetically ablated in all tissues, hereafter referred to as preptin knockout (KO), and tested the hypothesis that the removal of preptin will lead to a decreased insulin response to a metabolic challenge. Preptin KO and wild-type (WT) mice underwent weekly fasting blood glucose measurements, intraperitoneal insulin tolerance tests (ITT) at 9, 29, and 44 wk of age, and an oral glucose tolerance test (GTT) at 45 wk of age. Preptin KO mice of both sexes had similar Igf2 exon 2-3 mRNA expression in the liver and kidney compared with WT mice, but Igf2 exon 3-4 (preptin) expression was not detectable. Western blot analysis of neonatal serum indicated that processing of pro-IGF2 translated from the KO allele may be altered. Preptin KO mice had similar body weight, body composition, ß-cell area, and fasted glucose concentrations compared with WT mice in both sexes up to 47 wk of age. Female KO mice had a diminished ability to mount an insulin response following glucose stimulation in vivo. This effect was absent in male KO mice. Although preptin is not essential for glucose homeostasis, when combined with previous in vitro and ex vivo findings, these data show that preptin positively impacts ß-cell function.NEW & NOTEWORTHY This is the first study to describe a model in which the preptin-coding portion of the Igf2 gene has been genetically ablated in mice. The mice do not show reduced size at birth associated with Igf2 knockout suggesting that IGF2 functionality is maintained, yet we demonstrate a change in the processing of mature Igf2. Female knockout mice have diminished glucose-stimulated insulin secretion, whereas the insulin response in males is not different to wild type.

Genomic loci associated with performance limiting equine overriding spinous processes (kissing spines).

Commonly known as "Kissing Spines" (KS), the pathological mechanisms underlying impingement and overriding of spinous processes (ORSPs) in horses are poorly understood. Thoroughbreds, Warmbloods, and stock-type breeds, including Paint Horses and Quarter Horses are at increased risk for developing clinical signs of KS. A total of 155 stock-type and Warmblood horses presented at collaborating veterinary clinics and hospitals were examined using a strict clinical and radiographical phenotyping scheme to grade each horse from 0 for unaffected controls to 4 for severe KS. Following genotyping with the Illumina Equine SNP70 array (Illumina, Inc.) a Genome Wide Association Study (GWAS) using 61,229 filtered individual Single Nucleotide Polymorphisms (SNPs) was performed to the KS grade phenotype. Two significantly associated SNPs (BIEC2-668062 and BIEC2-668013) on chromosome 25 defined a ~1.4 Gb candidate region containing approximately 17 coding genes (EquCab3) and 195 ENSEMBL annotated variants. Investigation of the best associated SNP (BIEC2-668062) on chr25 demonstrates a significant correlation with an increase in one KS grade, on average, per A allele in this population. A significant effect of breed group, age, height or sex was not observed in this population. These preliminary results demonstrate the potential for KS diagnosis and preventative measures for WB/ST individuals supported by increased genetic risk for more severe KS grade. We propose further research including other affected breeds and evaluating causative variants, as well as the effect of BIEC2-668062 in these populations.

Three major dimensions of human brain cortical ageing in relation to cognitive decline across the eighth decade of life.

Different brain regions can be grouped together, based on cross-sectional correlations among their cortical characteristics; this patterning has been used to make inferences about ageing processes. However, cross-sectional brain data conflate information on ageing with patterns that are present throughout life. We characterised brain cortical ageing across the eighth decade of life in a longitudinal ageing cohort, at ages ~73, ~76, and ~79 years, with a total of 1376 MRI scans. Volumetric changes among cortical regions of interest (ROIs) were more strongly correlated (average r = 0.805, SD = 0.252) than were cross-sectional volumes of the same ROIs (average r = 0.350, SD = 0.178). We identified a broad, cortex-wide, dimension of atrophy that explained 66% of the variance in longitudinal changes across the cortex. Our modelling also discovered more specific fronto-temporal and occipito-parietal dimensions that were orthogonal to the general factor and together explained an additional 20% of the variance. The general factor was associated with declines in general cognitive ability (r = 0.431, p < 0.001) and in the domains of visuospatial ability (r = 0.415, p = 0.002), processing speed (r = 0.383, p < 0.001) and memory (r = 0.372, p < 0.001). Individual differences in brain cortical atrophy with ageing are manifest across three broad dimensions of the cerebral cortex, the most general of which is linked with cognitive declines across domains. Longitudinal approaches are invaluable for distinguishing lifelong patterns of brain-behaviour associations from patterns that are specific to aging.

A data-centric approach to generative modelling for 3D-printed steel.

The emergence of additive manufacture (AM) for metallic material enables components of near arbitrary complexity to be produced. This has potential to disrupt traditional engineering approaches. However, metallic AM components exhibit greater levels of variation in their geometric and mechanical properties compared to standard components, which is not yet well understood. This uncertainty poses a fundamental barrier to potential users of the material, since extensive post-manufacture testing is currently required to ensure safety standards are met. Taking an interdisciplinary approach that combines probabilistic mechanics and uncertainty quantification, we demonstrate that intrinsic variation in AM steel can be well described by a generative statistical model that enables the quality of a design to be predicted before manufacture. Specifically, the geometric variation in the material can be described by an anisotropic spatial random field with oscillatory covariance structure, and the mechanical behaviour by a stochastic anisotropic elasto-plastic material model. The fitted generative model is validated on a held-out experimental dataset and our results underscore the need to combine both statistical and physics-based modelling in the characterization of new AM steel products.

Psychotic-like experiences, polygenic risk scores for schizophrenia, and structural properties of the salience, default mode, and central-executive networks in healthy participants from UK Biobank.

Schizophrenia is a highly heritable disorder with considerable phenotypic heterogeneity. Hallmark psychotic symptoms can be considered as existing on a continuum from non-clinical to clinical populations. Assessing genetic risk and psychotic-like experiences (PLEs) in non-clinical populations and their associated neurobiological underpinnings can offer valuable insights into symptom-associated brain mechanisms without the potential confounds of the effects of schizophrenia and its treatment. We leveraged a large population-based cohort (UKBiobank, N = 3875) including information on PLEs (obtained from the Mental Health Questionnaire (MHQ); UKBiobank Category: 144; N auditory hallucinations = 55, N visual hallucinations = 79, N persecutory delusions = 16, N delusions of reference = 13), polygenic risk scores for schizophrenia (PRSSZ) and multi-modal brain imaging in combination with network neuroscience. Morphometric (cortical thickness, volume) and water diffusion (fractional anisotropy) properties of the regions and pathways belonging to the salience, default-mode, and central-executive networks were computed. We hypothesized that these anatomical concomitants of functional dysconnectivity would be negatively associated with PRSSZ and PLEs. PRSSZ was significantly associated with a latent measure of cortical thickness across the salience network (r = -0.069, p = 0.010) and PLEs showed a number of significant associations, both negative and positive, with properties of the salience and default mode networks (involving the insular cortex, supramarginal gyrus, and pars orbitalis, pFDR < 0.050); with the cortical thickness of the insula largely mediating the relationship between PRSSZ and auditory hallucinations. Generally, these results are consistent with the hypothesis that higher genetic liability for schizophrenia is related to subtle disruptions in brain structure and may predispose to PLEs even among healthy participants. In addition, our study suggests that networks engaged during auditory hallucinations show structural associations with PLEs in the general population.

Shear heating reconciles thermal models with the metamorphic rock record of subduction.

Some commonly referenced thermal-mechanical models of current subduction zones imply temperatures that are 100-500 °C colder at 30-80-km depth than pressure-temperature conditions determined thermobarometrically from exhumed metamorphic rocks. Accurately inferring subduction zone thermal structure, whether from models or rocks, is crucial for predicting metamorphic reactions and associated fluid release, subarc melting conditions, rheologies, and fault-slip phenomena. Here, we compile surface heat flow data from subduction zones worldwide and show that values are higher than can be explained for a frictionless subduction interface often assumed for modeling. An additional heat source--likely shear heating--is required to explain these forearc heat flow values. A friction coefficient of at least 0.03 and possibly as high as 0.1 in some cases explains these data, and we recommend a provisional average value of 0.05 ± 0.015 for modeling. Even small coefficients of friction can contribute several hundred degrees of heating at depths of 30-80 km. Adding such shear stresses to thermal models quantitatively reproduces the pressure-temperature conditions recorded by exhumed metamorphic rocks. Comparatively higher temperatures generally drive rock dehydration and densification, so, at a given depth, hotter rocks are denser than colder rocks, and harder to exhume through buoyancy mechanisms. Consequently--conversely to previous proposals--exhumed metamorphic rocks might overrepresent old-cold subduction where rocks at the slab interface are wetter and more buoyant than in young-hot subduction zones.

'When you are homeless, you are not thinking about your medication, but your food, shelter or heat for the night': behavioural determinants of homeless patients' adherence to prescribed medicines.

OBJECTIVES: This study aimed to explore behavioural determinants of homeless patients' adherence to prescribed medicines using Theoretical Domains Framework (TDF). STUDY DESIGN: A qualitative study using semi-structured, face-to-face interviews. METHODS: Participants were recruited from a homelessness primary healthcare centre in Aberdeen, United Kingdom (UK). Face-to-face interviews were audio-recorded and transcribed verbatim. Thematic analysis of the interview data was conducted using the Framework Approach based on the Theoretical Domains Framework. National Health Service ethical and Research and Development (R&D) approval was obtained. RESULTS: Twenty-five patients were interviewed, at which point data saturation was achieved. A total of 13 out of 14 Theoretical Domains Framework domains were identified that explained the determinants of adherence or non-adherence to prescribed medicines. These included: 'beliefs about consequences' (e.g. non-adherence leading to poor health); 'goals' of therapy (e.g. being a 'normal' person with particular reference to methadone adherence); and 'environmental context and resources' (e.g. stolen medicines and the lack of secure storage). Obtaining food and shelter was higher priority than access and adherence to prescribed medicines while being homeless. CONCLUSIONS: Behavioural determinants of non-adherence identified in this study were mostly related to participants' homelessness and associated lifestyle. Results are relevant to developing behaviour change interventions targeting non-adherent homeless patients and to the education of healthcare professionals serving this vulnerable population.

Multiplex PCR and Microarray for Detection of Swine Respiratory Pathogens.

Porcine respiratory disease complex (PRDC) is one of the most important health concerns for pig producers and can involve multiple viral and bacterial pathogens. No simple, single-reaction diagnostic test currently exists for the simultaneous detection of major pathogens commonly associated with PRDC. Furthermore, the detection of most of the bacterial pathogens implicated in PRDC currently requires time-consuming culture-based methods that can take several days to obtain results. In this study, a novel prototype automated microarray that integrates and automates all steps of post-PCR microarray processing for the simultaneous detection and typing of eight bacteria and viruses commonly associated with PRDC is described along with associated multiplex reverse transcriptase PCR. The user-friendly assay detected and differentiated between four viruses [porcine reproductive and respiratory syndrome virus (PRRSV), influenza A virus, porcine circovirus type 2, porcine respiratory corona virus], four bacteria (Mycoplasma hyopneumoniae, Pasteurella multocida, Salmonella enterica serovar Choleraesuis, Streptococcus suis), and further differentiated between type 1 and type 2 PRRSV as well as toxigenic and non-toxigenic P. multocida. The assay accurately identified and typed a panel of 34 strains representing the eight targeted pathogens and was negative when tested with 34 relevant and/or closely related non-target bacterial and viral species. All targets were also identified singly or in combination in a panel of clinical lung samples and/or experimentally inoculated biological material.

Os odontoideum in wolcott-rallison syndrome: a case series of 4 patients.

Wolcott-Rallison Syndrome is the commonest cause of neonatal diabetes in consanguineous families. It is associated with liver dysfunction, epiphyseal dysplasia, and developmental delay. It is caused by mutations in eukaryotic translation initiation factor 2-α kinase 3 (EIF2AK3).We report 4 children with WRS and Os Odontoideum resulting in significant neurological compromise. This cervical spine abnormality has not previously been described in this syndrome. This additional evidence broadens the clinical spectrum of this syndrome and confirms the role of EIF2AK3 in skeletal development. Furthermore, Os Odontoideum needs to be actively screened for in WRS patients to prevent neurological and respiratory compromise.

Insulated Isothermal Reverse Transcriptase PCR (iiRT-PCR) for Rapid and Sensitive Detection of Classical Swine Fever Virus.

Classical swine fever (CSF) is an OIE-listed disease that can have a severe impact on the swine industry. User-friendly, sensitive, rapid diagnostic tests that utilize low-cost field-deployable instruments for CSF diagnosis can be useful for disease surveillance and outbreak monitoring. In this study, we describe validation of a new probe-based insulated isothermal reverse transcriptase PCR (iiRT-PCR) assay for rapid detection of classical swine fever virus (CSFV) on a compact, user-friendly device (POCKIT(™) Nucleic Acid Analyzer) that does not need data interpretation by the user. The assay accurately detected CSFV RNA from a diverse panel of 33 CSFV strains representing all three genotypes plus an additional in vitro-transcribed RNA from cloned sequences representing a vaccine strain. No cross-reactivity was observed with a panel of 18 viruses associated with livestock including eight other pestivirus strains (bovine viral diarrhoea virus type 1 and type 2, border disease virus, HoBi atypical pestivirus), African swine fever virus, swine vesicular disease virus, swine influenza virus, porcine respiratory and reproductive syndrome virus, porcine circovirus 1, porcine circovirus 2, porcine respiratory coronavirus, vesicular exanthema of swine virus, bovine herpes virus type 1 and vesicular stomatitis virus. The iiRT-PCR assay accurately detected CSFV as early as 2 days post-inoculation in RNA extracted from serum samples of experimentally infected pigs, before appearance of clinical signs. The limit of detection (LOD95% ) calculated by probit regression analysis was 23 copies per reaction. The assay has a sample to answer turnaround time of less than an hour using extracted RNA or diluted or low volume of neat serum. The user-friendly, compact device that automatically analyses and displays results could potentially be a useful tool for surveillance and monitoring of CSF in a disease outbreak.

Temozolomide in the management of dopamine agonist-resistant prolactinomas.

BACKGROUND: The majority of prolactinomas respond to dopamine agonist therapy, but a proportion are resistant, requiring other treatments including surgery and/or radiotherapy. Temozolomide is an oral chemotherapy agent, which has been used as a salvage therapy to treat aggressive pituitary adenomas and carcinomas, including prolactinomas, unresponsive to all conventional treatment. CASE SERIES: We report three patients where temozolomide was used in the treatment of refractory prolactinomas. Case 1 describes a patient with a highly invasive prolactinoma, resistant to all conventional therapy, which responded dramatically to temozolomide used as a salvage treatment. In case 2, temozolomide was used after incomplete surgical resection to relieve chiasmal compression and avoid chiasm exposure to radiotherapy. In case 3, temozolomide enabled radiotherapy to be deferred in a 16-year old with a resistant prolactinoma. In all three cases, the tumours were negative by immunostaining for methylguanine methyltransferase (MGMT). LITERATURE REVIEW AND DISCUSSION: A review of the published literature reveals 51 reported cases of temozolomide treatment for pituitary tumours, including 20 prolactinomas. Fifteen of the 20 prolactinomas showed a good response to temozolomide. Our analysis demonstrates a strong association between MGMT-negative staining and a good response to temozolomide (OR 9.35, P = 0.0030). Current clinical practice is to use temozolomide as a salvage therapy after all conventional modalities of treatment have failed. We suggest that, in selected cases, consideration should be given to using temozolomide earlier in the treatment algorithm.

Uterine artery blood flow remains unchanged in pregnant mares in response to short-term administration of pentoxifylline.

The objective of this study was to use Doppler ultrasound technology to determine whether pentoxifylline administration increased uterine blood flow in normal pregnant pony mares. Thirteen pregnant pony mares between 18 and 190 d of gestation (mean ± SEM, 101 ± 55) were utilized for the study during two trial periods. In each trial, pentoxifylline (17 mg/kg by mouth every 12h, diluted in syrup) was administered to half of the mares for 3 d, while the other mares were treated with syrup only. Doppler measurements were obtained from the right and left uterine arteries from each mare for 2 d prior to treatment and throughout the treatment period. The mean Resistivity Index (RI), Pulsatility Index (PI), Uterine Artery Diameter (D), and Total Arterial Blood Flow (TABF) from each day were compared over time and between groups. Administration of pentoxifylline did not alter uterine blood flow parameters compared with controls (values for all treatment days combined were RI: 0.517 ± 0.014 vs 0.543 ± 0.016; PI: 0.876 ± 0.048 vs 0.927 ± 0.057; D: 0.388 ± 0.018 vs 0.379 ± 0.023 cm; and TABF: 35.26 ± 7.38 vs 30.73 ± 5.29 mL/min). Uterine blood flow increased over the course of the 5 d study, irrespective of treatment, and was higher in mares of greater gestational age than in early gestational mares (RI: r(2) = 0.35; PI: r(2) = 0.37; D: r(2) = 0.66; and TABF: r(2) = 0.67 - P < 0.00001). We concluded that any immediate benefits of pentoxifylline administration in the pregnant mare were not mediated through enhanced uterine artery blood flow.

B-mode and Doppler ultrasonography in pony mares with experimentally induced ascending placentitis.

REASONS FOR PERFORMING STUDY: Early, accurate diagnosis of ascending placentitis in mares remains a key challenge for successful treatment of the disease. Doppler ultrasonography has shown promise as a tool to diagnose pregnancy abnormalities and is becoming more available to equine clinicians. However, to date, no studies have prospectively compared this technique to standard B-mode measurement of the combined thickness of the uterus and placenta (CTUP). OBJECTIVES: The objective of the current study was to compare Doppler and B-mode ultrasonography for the detection of experimentally-induced ascending placentitis in mares. METHODS: Eleven healthy pony mares in late gestation were used in this study. Placentitis was induced in 6 mares between Days 280 and 295, while 5 mares served as negative controls. All mares were intensively monitored until delivery. Fetal heart rate, CTUP, uterine artery blood flow (resistance index, pulsatility index, arterial diameter and total arterial blood flow) and physical examination findings were recorded at each examination. Mares with an increased CTUP above published values were treated in accordance with published recommendations. Foals and fetal membranes were examined at birth. Ultrasonographic parameters were compared between groups using ANOVA. Foal viability and histological presence of placentitis were compared using a Fisher's exact test. RESULTS: The CTUP was increased above normal in 5 of 6 inoculated mares within 3 days after inoculation (P = 0.05). The sixth inoculated mare was excluded from subsequent data analysis. Uterine artery blood flow, physical examination findings and fetal heart rate were not different between groups. Gradual increases in CTUP, arterial diameter and total arterial blood flow were detected with increasing gestational age in the control mares (P = 0.02, P = 0.00001 and P = 0.00001, respectively). CONCLUSION: The CTUP, but not uterine blood flow, was different between groups (P = 0.00001). Recorded CTUP values for control pony mares were similar to previously published values for light breed horses.

Metastasis suppressors: basic and translational advances.

Tumor metastasis is a main contributor to death in cancer patients. In the last years, a new class of molecules that reduces the metastatic propensity has been identified: metastasis suppressors. These proteins regulate multiple steps in the metastatic cascade, including cell invasion, survival in the vascular and lymphatic circulation, and colonization of distant organ sites. As a consequence, they are very important therapeutic targets. This review discusses our current understanding of metastasis suppressors and how this knowledge might be useful to improve the treatment of cancer patients.

Identification of a potent anti-IL-15 antibody with opposing mechanisms of action in vitro and in vivo.

BACKGROUND AND PURPOSE: Interleukin-15 (IL-15) is important in the activation and proliferation of lymphocytic cell populations and is implicated in inflammatory disease. We report the characterization of a novel monoclonal antibody DISC0280 which is specific for human IL-15. EXPERIMENTAL APPROACH: DISC0280 was characterized in a direct binding assay of IL-15 with IL-15 receptor α (IL-15Rα) and by its ability to alter IL-15 mediated proliferation of a range of cell lines (cytotoxic T lymphocyte line-2, M-07e, KIT225). A pharmacodynamic model injecting male C57/BL6 mice with IL-15 or IL-15/IL-15Rα, with or without DISC0280, and assessing changes in lymphocytic cell populations and serum cytokines was utilized. KEY RESULTS: DISC0280 inhibited the binding of IL-15 to IL-15Rα and also potently inhibits IL-15 dependent proliferation of cells expressing IL-15Rα, shared interleukin 2/ interleukin 15 receptor ß chain (IL-15Rß) and common gamma chain (γ(c) ). DISC0280 also inhibited the IL-15 dependent proliferation of M-07e cells that only express IL-15Rß/γ(c) subunits. Human IL-15 injected into mice caused an increase in NK1.1(+) and CD3(+) cells in the spleen and peripheral blood and these effects were unexpectedly potentiated by giving DISC0280 with human IL-15. This increase in cells caused by DISC0280/IL-15 co-administration was greater than that observed when IL-15 was administered complexed with soluble IL-15Rα. CONCLUSIONS AND IMPLICATIONS: The ability of DISC0280 to bind to the IL-15Rα-binding site on IL-15 allows trans-presentation of IL-15 by DISC0280 in vivo, similar to the trans-presentation by soluble IL-15Rα. DISC0280 may be therefore suitable as a clinical substitute for IL-15.

Glypican-3 reexpression regulates apoptosis in murine adenocarcinoma mammary cells modulating PI3K/Akt and p38MAPK signaling pathways.

Glypican-3 (GPC3) is a proteoglycan involved in proliferation and cell survival. Several reports demonstrated that GPC3 is downregulated in some tumors, such as breast cancer. Previously, we determined that GPC3 reexpression in the murine mammary adenocarcinoma LM3 cells induced an impairment of their invasive and metastatic capacities, associated with a decrease of their motility and an increase of their cell death. We demonstrated that GPC3 inhibits canonical Wnt signaling, as well as it activates non canonical pathway. Now, we identified signaling pathways responsible for the pro-apoptotic role of GPC3 in LM3 cells. We found for the first time that GPC3 inhibits the PI3K/Akt anti-apoptotic pathway while it stimulates the p38MAPK stress-activated one. We report a concomitant modulation of CDK inhibitors as well as of pro- and anti-apoptotic molecules. Our results provide new clues regarding the mechanism involved in the modulation induced by GPC3 of mammary tumor cell growth and survival.