Gc protein-derived macrophage-activating factor decreases alpha-N-acetylgalactosaminidase levels in advanced cancer patients

α-N-acetylgalactosaminidase (nagalase) accumulates in the serum of cancer patients and its activity correlates with tumor burden, aggressiveness and clinical disease progression. The administration of GC protein-derived macrophage-activating factor (GcMAF) to cancer patients with elevated levels of nagalase has been associated with a decrease of serum nagalase activity and with significant clinical benefits. Here, we report the results of the administration of GcMAF to a heterogeneous cohort of patients with histologically diverse, advanced neoplasms, generally considered as “incurable” diseases. In most cases, GcMAF therapy was initiated at late stages of tumor progression. As this is an open-label, non-controlled, retrospective analysis, caution must be employed when establishing cause-effect relationships between the administration GcMAF and disease outcome. However, the response to GcMAF was generally robust and some trends emerged. All patients (n = 20) presented with elevated serum nagalase activity, well above normal values. All patients but one showed a significant decrease of serum nagalase activity upon weekly GcMAF injections. Decreased nagalase activity was associated with improved clinical conditions and no adverse side effects were reported. The observations reported here confirm and extend previous results and pave the way to further studies aimed at assessing the precise role and indications for GcMAF-based anticancer immunotherapy

Therapeutic effects of highly purified de-glycosylated GcMAF in the immunotherapy of patients with chronic diseases.

The de-Glycosylated vitamin D binding protein is a powerful Macrophage Activating Factor (GcMAF) that shows multiple biological effects that could be exploited in the immunotherapy of tumours, viral infections and autism. Here we report the observation of a series of clinical cases describing the results obtained administering highly purified GcMAF to patients with diverse types of chronic diseases. These are heterogeneous and refer to patients with different types of diseases at different stages. In some cases, patients underwent other complementary treatments such as stem cell infusion or administration of supplements. In patients harbouring tumours, GcMAF treatment was initiated at late stages of tumour progression. Therefore, since this is an open-label, non-controlled, retrospective analysis, caution must be employed when ascribing cause and effect to any treatment outcome. However, the response to GcMAF was robust and certain trends emerge evident. In all cases (n = 7), GcMAF subcutaneous injections were associated with improvement of clinical conditions. No adverse side effects were reported. The observation reported here confirm and extend the results previously presented by several Authors and open the way to further trials aimed at assessing the precise role and indications for GcMAF in the immunotherapy of chronic diseases

State updating and calibration period selection to improve dynamic monthly streamflow forecasts for an environmental flow management application

Monthly to seasonal streamflow forecasts provide useful information for a range of water resource management and planning applications. This work focuses on improving such forecasts by considering the following two aspects: (1) state updating to force the models to match observations from the start of the forecast period, and (2) selection of a shorter calibration period that is more representative of the forecast period, compared to a longer calibration period traditionally used. The analysis is undertaken in the context of using streamflow forecasts for environmental flow water management of an open channel drainage network in southern Australia. Forecasts of monthly streamflow are obtained using a conceptual rainfall–runoff model combined with a post-processor error model for uncertainty analysis. This model set-up is applied to two catchments, one with stronger evidence of non-stationarity than the other. A range of metrics are used to assess different aspects of predictive performance, including reliability, sharpness, bias and accuracy. The results indicate that, for most scenarios and metrics, state updating improves predictive performance for both observed rainfall and forecast rainfall sources. Using the shorter calibration period also improves predictive performance, particularly for the catchment with stronger evidence of non-stationarity. The results highlight that a traditional approach of using a long calibration period can degrade predictive performance when there is evidence of non-stationarity. The techniques presented can form the basis for operational monthly streamflow forecasting systems and provide support for environmental decision-making.Matthew S. Gibbs, David McInerney, Greer Humphrey, Mark A. Thyer, Holger R. Maier, Graeme C. Dandy and Dmitri Kavetsk

The MuTHRE Model for High Quality Sub-seasonal Streamflow Forecasts

Conference theme 'Digital Water.'Sub-seasonal streamflow forecasts, with lead times up to 30 days, can provide valuable information for water management, including reservoir operation to meet environmental flow, irrigation demands, and managing flood protection storage. A key aim is to produce “seamless” probabilistic forecasts, with high quality performance across the full range of lead times (1-30 days) and time scales (daily to monthly). This paper demonstrates that the Multi-Temporal Hydrological Residual Error (MuTHRE) model can address the challenge of “seamless” sub-seasonal forecasting. The MuTHRE model is designed to capture key features of hydrological errors, namely seasonality, dynamic biases due to hydrological non-stationarity, and extreme errors poorly represented by the common Gaussian distribution. The MuTHRE model is evaluated comprehensively over 11 catchments in the MurrayDarling Basin using multiple performance metrics, across a range of lead times, months and years, and at daily and monthly time scales. It is shown to provide “high” improvements, in terms of reliability for short lead times (up to 10 days), in dry months, and dry years. Forecast performance also improved in terms of sharpness. Importantly, improvements are consistent across multiple time scales (daily and monthly). This study highlights the benefits of modelling multiple temporal characteristics of hydrological errors, and demonstrates the power of the MuTHRE model for producing seamless sub-seasonal streamflow forecasts that can be utilized for a wide range of applications.David McInerney, Mark Thyer, Dmitri Kavetski, Richard Laugesen, Narendra Tuteja, and George Kuczer

A novel role for a major component of the vitamin D axis: vitamin D binding protein-derived macrophage activating factor induces human breast cancer cell apoptosis through stimulation of macrophages.

The role of vitamin D in maintaining health appears greater than originally thought, and the concept of the vitamin D axis underlines the complexity of the biological events controlled by biologically active vitamin D (1,25(OH)(2)D3), its two binding proteins that are the vitamin D receptor (VDR) and the vitamin D-binding protein-derived macrophage activating factor (GcMAF). In this study we demonstrate that GcMAF stimulates macrophages, which in turn attack human breast cancer cells, induce their apoptosis and eventually phagocytize them. These results are consistent with the observation that macrophages infiltrated implanted tumors in mice after GcMAF injections. In addition, we hypothesize that the last 23 hydrophobic amino acids of VDR, located at the inner part of the plasma membrane, interact with the first 23 hydrophobic amino acids of the GcMAF located at the external part of the plasma membrane. This al1ows 1,25(OH)(2)D3 and oleic acid to become sandwiched between the two vitamin D-binding proteins, thus postulating a novel molecular mode of interaction between GcMAF and VDR. Taken together, these results support and reinforce the hypothesis that GcMAF has multiple biological activities that could be responsible for its anti-cancer effects, possibly through molecular interaction with the VDR that in turn is responsible for a multitude of non-genomic as well as genomic effects

An assessment framework for classifying determinants of household water consumption and their priorities for research and practice

Achieving a thorough understanding of the determinants of household water consumption is crucial to support demand management strategies. Yet, existing research on household water consumption determinants is often limited to specific case studies, with findings that are difficult to generalize and not conclusive. Here, we contribute a framework for review, classification, and analysis of the literature on the determinants of household water consumption. Firstly, we identify a comprehensive set of 48 relevant publications, based on a systematic paper search. The framework firstly classifies household determinants into observable (physically seen/measured aspects of the house), latent (relates to the way occupants think/act/feel) and external (external to house and influence at regional level). Secondly, we undertake a trade-off analysis of different criteria that account for the representation of a potential water consumption determinant in the literature, its impact across heterogeneous case studies, and the effort required to collect information on it. The results of our trade-off analysis show that distinct groups of determinants exist, allowing for the formulation of four recommendation categories. These provide guidance for practitioners on which determinants to consider in practice and for researchers to prioritize in future research (Figure 1).A. Cominola, L. Preiss, M. Thyer, H. R. Maier, P. Prevos, R. Stewart, and A. Castellett

ENIGMA-anxiety working group: Rationale for and organization of large-scale neuroimaging studies of anxiety disorders

Anxiety disorders are highly prevalent and disabling but seem particularly tractable to investigation with translational neuroscience methodologies. Neuroimaging has informed our understanding of the neurobiology of anxiety disorders, but research has been limited by small sample sizes and low statistical power, as well as heterogenous imaging methodology. The ENIGMA‐Anxiety Working Group has brought together researchers from around the world, in a harmonized and coordinated effort to address these challenges and generate more robust and reproducible findings. This paper elaborates on the concepts and methods informing the work of the working group to date, and describes the initial approach of the four subgroups studying generalized anxiety disorder, panic disorder, social anxiety disorder, and specific phobia. At present, the ENIGMA‐Anxiety database contains information about more than 100 unique samples, from 16 countries and 59 institutes. Future directions include examining additional imaging modalities, integrating imaging and genetic data, and collaborating with other ENIGMA working groups. The ENIGMA consortium creates synergy at the intersection of global mental health and clinical neuroscience, and the ENIGMA‐Anxiety Working Group extends the promise of this approach to neuroimaging research on anxiety disorders

Randomised controlled feasibility trial of the Active Communication Education programme plus hearing aid provision versus hearing aid provision alone (ACE to HEAR): a study protocol

Introduction: Up to 30% of hearing aids fitted to new adult clients are reported to be of low benefit and used intermittently or not at all. Evidence suggests that additional interventions paired with service-delivery redesign may help improve hearing aid use and benefit. The range of interventions available is limited. In particular, the efficacy of interventions like the Active Communication Education (ACE) programme that focus on improving communication success with hearing-impaired people and significant others, has not previously been assessed. We propose that improved communication outcomes associated with the ACE intervention, lead to an increased perception of hearing aid value and more realistic expectations associated with hearing aid use and ownership, which are reported to be key barriers and facilitators for successful hearing aid use. This study will assess the feasibility of delivering ACE and undertaking a definitive randomised controlled trial to evaluate whether ACE would be a cost-effective and acceptable way of increasing quality of life through improving communication and hearing aid use in a public health service such as the National Health Service. Methods and analysis: This will be a randomised controlled, open feasibility trial with embedded economic and process evaluations delivered in audiology departments in two UK cities. We aim to recruit 84 patients (and up to 84 significant others) aged 18 years and over, who report moderate or less than moderate benefit from their new hearing aid. The feasibility of a large-scale study and the acceptability of the ACE intervention will be measured by recruitment rates, treatment retention, follow-up rates and qualitative interviews. Ethics and dissemination: Ethical approval granted by South East Coast-Surrey Research Ethics Committee (16/LO/2012). Dissemination of results will be via peer-reviewed research publications both online and in print, conference presentations, posters, patient forums and Trust bulletins. Trial registration number: ISRCTN28090877