The effect of low-dose proteasome inhibition on pre-existing atherosclerosis in LDL receptor-deficient mice

Dysfunction of the ubiquitin-proteasome system (UPS) has been implicated in atherosclerosis development. However, the nature of UPS dysfunction has been proposed to be specific to certain stages of atherosclerosis development, which has implications for proteasome inhibition as a potential treatment option. Recently, low-dose proteasome inhibition with bortezomib has been shown to attenuate early atherosclerosis in low-density lipoprotein receptor-deficient (LDLR(-/-)) mice. The present study investigates the effect of low-dose proteasome inhibition with bortezomib on pre-existing advanced atherosclerosis in LDLR(-/-) mice. We found that bortezomib treatment of LDLR(-/-) mice with pre-existing atherosclerosis does not alter lesion burden. Additionally, macrophage infiltration of aortic root plaques, total plasma cholesterol levels, and pro-inflammatory serum markers were not influenced by bortezomib. However, plaques of bortezomib-treated mice exhibited larger necrotic core areas and a significant thinning of the fibrous cap, indicating a more unstable plaque phenotype. Taking recent studies on favorable effects of proteasome inhibition in early atherogenesis into consideration, our data support the hypothesis of stage-dependent effects of proteasome inhibition in atherosclerosis

Immunotherapeutic targeting of membrane Hsp70-expressing tumors using recombinant human granzyme B

Background: We have previously reported that human recombinant granzyme B (grB) mediates apoptosis in membrane heat shock protein 70 (Hsp70)-positive tumor cells in a perforin-independent manner

Stakeholder ownership: a theoretical framework for cross national understanding and analyses of stakeholder involvement in issues of substance use, problem use and addiction

This project contributes to understanding of the role of different stakeholder groups in the formulation and implementation of policy in the addictions field in Austria, Denmark, Finland, Italy, Poland and the UK. It comprises a number of case studies which draw on a range of theoretical frameworks to examine stakeholder dynamics at international, national and local levels. Mainly qualitative methods were used: interviews, policy and documentation analyses, webcrawler network analysis, and simple surveys; one case study was based on a survey only. The case studies fall into four main categories: three focus on controversial issues in drug treatment policy and practice – opioid substitution treatment, drug consumption rooms, and heroin assisted treatment; three look at stakeholder activity in alcohol control and public health; one pilot case study considers the potential role of researchers in the development of a scientific network around gambling; and one looks at the role of nurses in implementing brief interventions. In addition, themes explored across case studies included the role of evidence and stakeholder activity, drug users as stakeholders, and the role of external stakeholders on national policy. Professional stakeholders at implementation level and families and drug users as stakeholders are also considered. The case studies revealed that, in many instances, the addictions field is characterised by tensions between groups, by entrenched relationships between some addiction-specific stakeholder groups and powerful political stakeholders, and by the dominance of some forms of evidence over other forms of knowledge. Science and scientists are only influential in policy terms if their scientific findings ‘fit’ with the wider political context. Nevertheless, at least within the European context, there are opportunities for new stakeholder groups to emerge and gain policy salience and there are opportunities for stakeholders to challenge prevailing frames of understanding the addictions and prevailing modes of responding to problems of substance misuse and addiction

Membrane Hsp70 — a novel target for the isolation of circulating tumor cells after epithelial-to-mesenchymal transition

The presence of circulating tumor cells (CTCs) in the peripheral blood is a pre-requisite for progression, invasion, and metastatic spread of cancer. Consequently, the enumeration and molecular characterization of CTCs from the peripheral blood of patients with solid tumors before, during and after treatment serves as a valuable tool for categorizing disease, evaluating prognosis and for predicting and monitoring therapeutic responsiveness. Many of the techniques for isolating CTCs are based on the expression of epithelial cell surface adhesion molecule (EpCAM, CD326) on tumor cells. However, the transition of adherent epithelial cells to migratory mesenchymal cells (epithelial-to-mesenchymal transition, EMT)—an essential element of the metastatic process—is frequently associated with a loss of expression of epithelial cell markers, including EpCAM. A highly relevant proportion of mesenchymal CTCs cannot therefore be isolated using techniques that are based on the “capture” of cells expressing EpCAM. Herein, we provide evidence that a monoclonal antibody (mAb) directed against a membrane-bound form of Hsp70 (mHsp70)—cmHsp70.1—can be used for the isolation of viable CTCs from peripheral blood of tumor patients of different entities in a more quantitative manner. In contrast to EpCAM, the expression of mHsp70 remains stably upregulated on migratory, mesenchymal CTCs, metastases and cells that have been triggered to undergo EMT. Therefore, we propose that approaches for isolating CTCs based on the capture of cells that express mHsp70 using the cmHsp70.1 mAb are superior to those based on EpCAM expression

X-ray Nanodiffraction on a Single SiGe Quantum Dot inside a Functioning Field-Effect Transistor

For advanced electronic, optoelectronic, or mechanical nanoscale devices a detailed understanding of their structural properties and in particular the strain state within their active region is of utmost importance. We demonstrate that X-ray nanodiffraction represents an excellent tool to investigate the internal structure of such devices in a nondestructive way by using a focused synchotron X-ray beam with a diameter of 400 nm. We show results on the strain fields in and around a single SiGe island, which serves as stressor for the Si-channel in a fully functioning Si-metal-oxide semiconductor field-effect transistor

Stress Vulnerability And Alcohol Use And Consequences: From Human Laboratory Studies To Clinical Outcomes

It is well known that vulnerability to stress is a risk factor for alcohol use disorder (AUD). Chronic alcohol use can result in neuroadaptations in cortico-striatal pathways and hypothalamic pituitary adrenal (HPA) axis function that are manifested in altered behavioral and cognitive control functions contributing to alcohol craving, compulsive motivation, consumption and consequences. This symposium brings together studies utilizing novel approaches to help improve our understanding of stress – past, acute and chronic - on alcohol seeking and consumption and related outcomes using a combination of human laboratory models, neuroimaging and clinical measures. Examining factors that determine vulnerability as well as resilience to stress are of particular interest in the study of AUD because, in addition to increasing our understanding of the risk factors for AUD, such knowledge can be used to develop more effective treatments. Dr. Stangl presented a novel human experimental model that demonstrates, for the first time, stress-induced increases in alcohol self-administration in binge drinkers using a guided imagery paradigm combined with intravenous alcohol self-administration (IV-ASA). Dr. Blaine presented data demonstrating that glucocorticoid response to stress drives compulsive alcohol motivation and intake in binge/heavy drinkers. Dr. Plawecki presented data examining sex differences in the effect of two distinct stress paradigms – mood induction and abstinence – on IV-ASA in moderate drinkers. Dr. Schwandt presented clinical data providing a new perspective on the relationship between childhood trauma and AUD by suggesting possible underlying mechanisms that confer resilience, rather than vulnerability, to severe early life stress exposure

Influence of Pacing Mode and Rate on Peripheral Levels of Atrial Natriuretic Peptide (ANP)

The effect of acute modifications of pacing mode and rate on plasma ANP levels was evaluated. ANP was determined in ten resting patients with ODD pacemokers due to binodal disease or intermittent second- and third-degree AV block. At 82/minute pacing rate the ANP plasma levels (normal range 2 to 30 fmol/mL) corresponded to those under AAI (4.05 ± 2.10 fmol/mL) and DDD (4.18 ± 2.02 fmol/mL) pacing, but increased significantly (P < 0.05) during VVI pacing (6.96 ± 3.70 fmol/mL). Acceleration of DDD stimulation frequency from 82 to 113/minutes led to significant increases of ANP levels by the factor of three in all chosen AV delays. The lowest ANP plasma levels were measured of 175 msec AV delay under 82/minute pacing rate in DDD mode. Under 113/minutes the differences of ANP concentration after variations of AV delays were less pronounced. The influences of altered atrial pressure and tension on ANP release are discussed to account for changes in ANP plasma levels following different modes and rates of pacemaker stimulation.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75366/1/j.1540-8159.1989.tb01862.x.pd

The Graz seismo-electromagnetic VLF facility

Abstract. In this paper we describe the Graz seismo-electromagnetic very low frequency (VLF) facility, as part of the European VLF receiver network, together with the scientific objectives and results from two years operation. After a brief technical summary of the present system – with heritage from a predecessor facility – i.e. hardware, software, operational modes and environmental influences, we discuss results from statistical data and scientific events related to terrestrial VLF propagation over Europe