Melanoma-associated Chondroitin Sulfate Proteoglycan (MCSP)-targeted delivery of soluble TRAIL potently inhibits melanoma outgrowth in vitro and in vivo

<p>Abstract</p> <p>Background</p> <p>Advanced melanoma is characterized by a pronounced resistance to therapy leading to a limited patient survival of ~6 - 9 months. Here, we report on a novel bifunctional therapeutic fusion protein, designated anti-MCSP:TRAIL, that is comprised of a melanoma-associated chondroitin sulfate proteoglycan (MCSP)-specific antibody fragment (scFv) fused to soluble human TRAIL. MCSP is a well-established target for melanoma immunotherapy and has recently been shown to provide important tumorigenic signals to melanoma cells. TRAIL is a highly promising tumoricidal cytokine with no or minimal toxicity towards normal cells. Anti-MCSP:TRAIL was designed to <b>1</b>. selectively accrete at the cell surface of MCSP-positive melanoma cells and inhibit MCSP tumorigenic signaling and <b>2</b>. activate apoptotic TRAIL-signaling.</p> <p>Results</p> <p>Treatment of a panel of MCSP-positive melanoma cell lines with anti-MCSP:TRAIL induced TRAIL-mediated apoptotic cell death within 16 h. Of note, treatment with anti-MCSP:sTRAIL was also characterized by a rapid dephosphorylation of key proteins, such as FAK, implicated in MCSP-mediated malignant behavior. Importantly, anti-MCSP:TRAIL treatment already inhibited anchorage-independent growth by 50% at low picomolar concentrations, whereas > 100 fold higher concentrations of non-targeted TRAIL failed to reduce colony formation. Daily i.v. treatment with a low dose of anti-MCSP:TRAIL (0.14 mg/kg) resulted in a significant growth retardation of established A375 M xenografts. Anti-MCSP:TRAIL activity was further synergized by co-treatment with rimcazole, a σ-ligand currently in clinical trials for the treatment of various cancers.</p> <p>Conclusions</p> <p>Anti-MCSP:TRAIL has promising pre-clinical anti-melanoma activity that appears to result from combined inhibition of tumorigenic MCSP-signaling and concordant activation of TRAIL-apoptotic signaling. Anti-MCSP:TRAIL alone, or in combination with rimcazole, may be of potential value for the treatment of malignant melanoma.</p

Repeated social defeat induces transient glial activation and brain hypometabolism:A positron emission tomography imaging study

Psychosocial stress is a risk factor for the development of depression. Recent evidence suggests that glial activation could contribute to the development of depressive-like behaviour. This study aimed to evaluate in vivo whether repeated social defeat (RSD) induces short- and long-term inflammatory and metabolic alterations in the brain through positron emission tomography (PET). Male Wistar rats ( n = 40) were exposed to RSD by dominant Long-Evans rats on five consecutive days. Behavioural and biochemical alterations were assessed at baseline, day 5/6 and day 24/25 after the RSD protocol. Glial activation (11C-PK11195 PET) and changes in brain metabolism (18F-FDG PET) were evaluated on day 6, 11 and 25 (short-term), and at 3 and 6 months (long-term). Defeated rats showed transient depressive- and anxiety-like behaviour, increased corticosterone and brain IL-1β levels, as well as glial activation and brain hypometabolism in the first month after RSD. During the third- and six-month follow-up, no between-group differences in any investigated parameter were found. Therefore, non-invasive PET imaging demonstrated that RSD induces transient glial activation and reduces brain glucose metabolism in rats. These imaging findings were associated with stress-induced behavioural changes and support the hypothesis that neuroinflammation could be a contributing factor in the development of depression

Patient safety incidents in radiology:frequency and distribution of incident types

Background Patient safety incidents may be a valuable source of information to learn from and to prevent future errors. Purpose To determine the distribution of patient safety incident types in radiology according to the International Classification for Patient Safety (ICPS), and to comprehensively review those incidents that were either harmful or serious in terms of risk of patient harm and reoccurrence. Material and Methods The most recent five-year database (2014-2019) of a radiology incident reporting system was evaluated. Results A total of 480 patient safety incidents were included. Top three ICPS incident types were clinical administration (119/480, 24.8%), resources/organizational management (112/480, 23.3%), and clinical process/procedure (91/480, 19.0%). Harm severities were none in 457 (95.2%) cases, mild in 14 (2.9%), moderate in 4 (0.8%), severe in 3 (0.6%), and unknown in one case. Subsequent Prevention Recovery Information System for Monitoring and Analysis (PRISMA) reviews were performed in 4 (0.8%) cases. The three patient safety incidents that caused severe harm (of which one underwent PRISMA review) involved resources/organizational management (n = 1), clinical process/procedure (n = 1), and medication/IV fluids (n = 1). Three other cases (with no harm in two cases and moderate harm in one case) that underwent PRISMA review involved resources/organizational management (n = 2) and medical device/equipment/property (n = 1). Conclusion Radiology-related patient safety incidents predominantly occur in three ICPS domains (clinical administration, resources/organizational management, and clinical process/procedure). Harmful/serious incidents are relatively rare. The standardly and transparently reported findings from this study may be used for healthcare quality improvement, benchmarking purposes, and as a primer for future studies

Positron Emission Tomography (PET) Imaging of Opioid Receptors

The opioid system consists of opioid receptors (which mediate the actions of opium), their endogenous ligands (the enkephalins, endorphins, endomorphins, dynorphin, and nociceptin), and the proteins involved in opioid production, transport, and degradation. PET tracers for the various opioid receptor subtypes are available, and changes in regional opioidergic activity have been assessed during both sensory and affective processing in healthy individuals and in various disease conditions such as chronic pain, neurodegeneration, epilepsy, eating disorders, and substance abuse. It is not always clear whether observed changes of tracer binding refl ect altered release of endogenous opioids or altered opioid receptor expression. Some radioligands for opioid receptors have suboptimal kinetics (i.e., slow dissociation from their target protein) or can induce undesired side effects even at low administered doses (sedation, respiratory arrest). There remains a need for PET tracers with improved properties, which can selectively visualize changes of the apparent density of a single opioid receptor subtype. Yet, PET offers the unique opportunity of quantifying opioid receptor- mediated signaling in the human central nervous system in vivo

Whiplash, Real or Not Real?: A Review and New Concept

Whiplash-associated disorder (WAD) describes a heterogeneous group of symptoms, which develops frequently after an unexpected rear-end car collision. In some of these patients, the symptoms persist for years. There is an ongoing scientific debate about the existence of tissue injury to support this disorder, due to the lack of findings with current diagnostic techniques and the prevalence of emotional traits as risk factors. The purpose of this chapter is to (1) overview the scientific data regarding the presence of an injury mechanism as a consequence of the whiplash trauma, (2) remark the unexpectedness of the accident as essential, and (3) present a new concept according to which WAD symptoms are the result of a mismatch between aberrant information from the cervical spinal cord and the information from the vestibular and visual systems, all of which are integrated in the mesencephalic periaqueductal gray and adjoining regions

Positron Emission Tomography (PET) Imaging of Opioid Receptors

The opioid system consists of opioid receptors (which mediate the actions of opium), their endogenous ligands (the enkephalins, endorphins, endomorphins, dynorphin, and nociceptin), and the proteins involved in opioid production, transport, and degradation. PET tracers for the various opioid receptor subtypes are available, and changes in regional opioidergic activity have been assessed during both sensory and affective processing in healthy individuals and in various disease conditions such as chronic pain, neurodegeneration, epilepsy, eating disorders, and substance abuse. It is not always clear whether observed changes of tracer binding refl ect altered release of endogenous opioids or altered opioid receptor expression. Some radioligands for opioid receptors have suboptimal kinetics (i.e., slow dissociation from their target protein) or can induce undesired side effects even at low administered doses (sedation, respiratory arrest). There remains a need for PET tracers with improved properties, which can selectively visualize changes of the apparent density of a single opioid receptor subtype. Yet, PET offers the unique opportunity of quantifying opioid receptor- mediated signaling in the human central nervous system in vivo

A Standardized Method for the Construction of Tracer Specific PET and SPECT Rat Brain Templates: Validation and Implementation of a Toolbox

High-resolution anatomical image data in preclinical brain PET and SPECT studies is often not available, and inter-modality spatial normalization to an MRI brain template is frequently performed. However, this procedure can be challenging for tracers where substantial anatomical structures present limited tracer uptake. Therefore, we constructed and validated strain- and tracer-specific rat brain templates in Paxinos space to allow intra-modal registration. PET [18F]FDG, [11C]flumazenil, [11C]MeDAS, [11C]PK11195 and [11C]raclopride, and SPECT [99mTc]HMPAO brain scans were acquired from healthy male rats. Tracer-specific templates were constructed by averaging the scans, and by spatial normalization to a widely used MRI-based template. The added value of tracer-specific templates was evaluated by quantification of the residual error between original and realigned voxels after random misalignments of the data set. Additionally, the impact of strain differences, disease uptake patterns (focal and diffuse lesion), and the effect of image and template size on the registration errors were explored. Mean registration errors were 0.70±0.32mm for [18F]FDG (n = 25), 0.23±0.10mm for [11C]flumazenil (n = 13), 0.88±0.20 mm for [11C]MeDAS (n = 15), 0.64±0.28mm for [11C]PK11195 (n = 19), 0.34±0.15mm for [11C]raclopride (n = 6), and 0.40±0.13mm for [99mTc]HMPAO (n = 15). These values were smallest with tracer-specific templates, when compared to the use of [18F]FDG as reference template (p&0.001). Additionally, registration errors were smallest with strain-specific templates (p&0.05), and when images and templates had the same size (p≤0.001). Moreover, highest registration errors were found for the focal lesion group (p&0.005) and the diffuse lesion group (p = n.s.). In the voxel-based analysis, the reported coordinates of the focal lesion model are consistent with the stereotaxic injection procedure. The use of PET/SPECT strain- and tracer-specific templates allows accurate registration of functional rat brain data, independent of disease specific uptake patterns and with registration error below spatial resolution of the cameras. The templates and the SAMIT package will be freely available for the research community.status: publishe

Nuclear Medicine Imaging in Concussive Head Injuries in Sports

Concussions in sports and during recreational activities are a major source of traumatic brain injury in our society. This is mainly relevant in adolescence and young adulthood, where the annual rate of diagnosed concussions is increasing from year to year. Contact sports (e.g., ice hockey, American football, or boxing) are especially exposed to repeated concussions. While most of the athletes recover fully from the trauma, some experience a variety of symptoms including headache, fatigue, dizziness, anxiety, abnormal balance and postural instability, impaired memory, or other cognitive deficits. Moreover, there is growing evidence regarding clinical and neuropathological consequences of repetitive concussions, which are also linked to an increased risk for depression and Alzheimer’s disease or the development of chronic traumatic encephalopathy. With little contribution of conventional structural imaging (computed tomography (CT) or magnetic resonance imaging (MRI)) to the evaluation of concussion, nuclear imaging techniques (i.e., positron emission tomography (PET) and single-photon emission computed tomography (SPECT)) are in a favorable position to provide reliable tools for a better understanding of the pathophysiology and the clinical evaluation of athletes suffering a concussion

Introduction on PET: Description of Basics and Principles

Positron emission tomography (or PET) is a non-destructive imaging technique in nuclear medicine with several unique properties: high sensitivity, low radiation dose, possibility to correct data for attenuation and scatter (thus quantitative), radioactive labeling of natural substances or drugs with high specific radioactivities so that these can be used as tracers to monitor the pharmacokinetics of the non-radioactive compounds. Limitations are the spatial resolution of commercially available PET cameras, resulting in blurring or non-visibility of objects smaller than 1 mm, and the short half-lives of the commonly used PET radionuclides (< 2 h). Because of the combination of positron emitters, specific radiopharmaceuticals and quantitative data analysis, PET is frequently used to study the pharmacokinetics and pharmacodynamics of test drugs non-invasively in humans

SPECT and PET in Eating Disorders

Medical imaging techniques like PET and SPECT have been applied for investigation of brain function in anorexia and bulimia nervosa. Regional abnormalities have been detected in cerebral blood flow, glucose metabolism, the availability of several neurotransmitter receptors (serotonin 1A and 2A, dopamine D2/D3, histamine H1, mu-opioid, and cannabinoid CB1), stimulant- induced dopamine release, and the density of serotonin transporters. Different subtypes of eating disorders appear to be associated with specific functional changes. It is hard to judge whether such changes are a consequence of chronic dietary restrictions or are caused by a putative anorexia (or bulimia) nervosa endophenotype. Many abnormalities (particularly those of glucose metabolism) appear to be reversible after restoration of weight or normal patterns of food intake and may represent consequences of purging or starvation. However, some changes of regional flow and neurotransmitter systems persist even after successful therapy which suggests that these reflect traits that are independent of the state of the illness. Changes of the serotonergic system (altered activity of 5-HT 1A and 5-HT 2A receptors and 5-HT transporters) may contribute to dysregulation of appetite, mood, and impulse control in eating disorders and may represent a trait which predisposes to the development of anxiety, obsessionality, and behavioral inhibition. Assessment of functional changes in the brain with PET or SPECT may have prognostic value and predict neuropsychological status after several years of therapy