Self-Compassion as a Resource in the Self-Stigma Process of Overweight and Obese Individuals

ObjectiveSelf-stigma in overweight and obese individuals has strong associations with impairment in mental and global health. This study sought to explore self-compassion as a psychological resource in the self-stigma process.MethodsIn a 2012 representative German population survey of N = 1,158 overweight and obese individuals, self-compassion was examined as a mediator between self-stigma and mental and physical health outcomes, including BMI (kg/m²), using structural equation modeling and controlling for sociodemographic factors.ResultsPsychological variables were assessed using validated self-report questionnaires. Self-compassion partially mediated the relationships between self-stigma and depression, somatic symptoms, and health status / quality of life, lowering the predictive effect of self-stigma on the outcomes by approximately one-third. In contrast, self-compassion, because it was unrelated to BMI, did not mediate the association between self-stigma and BMI.ConclusionSelf-compassion has the potential to act as a buffer against the mental and global health detriments of self-stigma in overweight and obesity and could thus represent a target for interventions to reduce self-stigma and prevent these health impairments. In order to influence the association between self-stigma and BMI, self-compassion should conceptually be linked to weight management.Key Words: Stigma, Weight bias, Self-compassion, Depression, Somatic symptoms, Health, Quality of life     

The future of autoimmune liver diseases – Understanding pathogenesis and improving morbidity and mortality

Autoimmune liver diseases (AILD), namely autoimmune hepatitis (AIH), primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), are rare diseases. These days, patients with PBC almost never require liver transplantation. When treated early with ursodeoxycholic acid patients have a normal life expectancy if the disease is diagnosed at an early stage and the patients respond to treatment. Patients with AIH often go into remission with first‐line therapy including corticosteroids alone or in combination with azathioprine. Nevertheless, about one quarter of patients already developed cirrhosis at diagnosis. Those who do not respond to first line standard of care (SOC) have significant liver‐related morbidity and mortality. No approved second‐ or third‐line treatments are available and the drugs are selected based on limited case series and personal experience. Larger trials are needed to develop efficient therapies for difficult‐to‐treat AIH patients. No treatment has been found to alter the natural course of disease in patients with PSC except for liver transplantation. Identifying PSC patients at risk of developing cholangiocarcinoma (CCA) is another unmet need. Current research in all AILD including AIH, PBC and PSC, focuses on improving our understanding of the underlying disease process and identifying new therapeutic targets to decrease morbidity and mortality.     

Non-clinical pharmacokinetics and pharmacodynamics of rVIII-SingleChain,a novel recombinant single-chain factor VIII

Introduction

rVIII-SingleChain (CSL627), a novel recombinant coagulation factor VIII (FVIII), is under investigation in a phase I/III clinical programme (AFFINITY) for the treatment of haemophilia A. Non-clinical studies were conducted to investigate the pharmacokinetic/pharmacodynamic profile of rVIII-SingleChain in comparison with full-length recombinant FVIII.

Materials and Methods

Binding affinity of rVIII-SingleChain for von Willebrand factor was investigated by surface plasmon resonance analysis. The pharmacokinetic profile of rVIII-SingleChain was compared with a marketed full-length recombinant FVIII concentrate (Advate^®) in haemophilia A mice, von Willebrand factor knock-out mice, Crl:CD (SD) rats, rabbits and cynomolgus monkeys. Systemic FVIII activity or antigen levels were recorded. Procoagulant activity was measured in an FeCl₃-induced arterial occlusion model and by recording thrombin generation activity (ex vivo) after administration of 200–250 IU/kg rVIII-SingleChain or full-length FVIII to haemophilia A mice.

Results

rVIII-SingleChain displayed a high affinity for von Willebrand factor (K_D = 44 pM vs. 139 pM for full-length recombinant FVIII). In all animal species tested, rVIII-SingleChain had more favourable pharmacokinetic properties than full-length recombinant FVIII: clearance was decreased and area under the curve and terminal half-life were enhanced vs. full-length recombinant FVIII, while in vivo recovery and volume of distribution were equivalent. rVIII-SingleChain showed a prolonged thrombin generation potential and prolonged procoagulant activity vs. full-length recombinant FVIII in an FeCl₃-induced arterial occlusion model.

Conclusions

rVIII-SingleChain had a higher affinity for von Willebrand factor than full-length recombinant FVIII and displayed favourable pharmacokinetic/pharmacodynamic properties in non-clinical models.     

Phosphorylation-regulated axonal dependent transport of syntaxin 1 is mediated by a Kinesin-1 adapter

Presynaptic nerve terminals are formed from preassembled vesicles that are delivered to the prospective synapse by kinesin-mediated axonal transport. However, precisely how the various cargoes are linked to the motor proteins remains unclear. Here, we report a transport complex linking syntaxin 1a (Stx) and Munc18, two proteins functioning in synaptic vesicle exocytosis at the presynaptic plasma membrane, to the motor protein Kinesin-1 via the kinesin adaptor FEZ1. Mutation of the FEZ1 ortholog UNC-76 in Caenorhabditis elegans causes defects in the axonal transport of Stx. We also show that binding of FEZ1 to Kinesin-1 and Munc18 is regulated by phosphorylation, with a conserved site (serine 58) being essential for binding. When expressed in C. elegans, wild-type but not phosphorylation-deficient FEZ1 (S58A) restored axonal transport of Stx. We conclude that FEZ1 operates as a kinesin adaptor for the transport of Stx, with cargo loading and unloading being regulated by protein kinases.     

Mutated regions of nucleophosmin 1 elicit both CD4(+) and CD8(+) T-cell responses in patients with acute myeloid leukemia

Mutations in the nucleophosmin gene (NPM1(mut)) are one of the most frequent molecular alterations in acute myeloid leukemia (AML), and immune responses may contribute to the favorable prognosis of AML patients with NPM1(mut). In the present study, we were able to demonstrate both CD4(+) and CD8(+) T-cell responses against NPM1(mut). Ten peptides derived from wild-type NPM1 and NPM1(mut) were subjected to ELISPOT analysis in 33 healthy volunteers and 27 AML patients. Tetramer assays against the most interesting epitopes were performed and Cr(51)-release assays were used to show the cytotoxicity of peptide-specific T cells. Moreover, HLA-DR-binding epitopes were used to test the role of CD4(+) T cells in NPM1 immunogenicity. Two epitopes (epitopes #1 and #3) derived from NPM1(mut) induced CD8(+) T-cell responses. A total of 33% of the NPM1(mut) AML patients showed immune responses against epitope #1 and 44% against epitope #3. Specific lysis of leukemic blasts was detected. To obtain robust immune responses against tumor cells, the activation of CD4(+) T cells is crucial. Therefore, overlapping (OL) peptides were analyzed in ELISPOT assays and OL8 was able to activate both CD8(+) and CD4(+) T cells. The results of the present study show that NPM1(mut) induces specific T-cell responses of CD4(+) and CD8(+) T cells and therefore is a promising target for specific immunotherapies in AML.