TCR-transgenic lymphocytes specific for HMMR/Rhamm limit tumor outgrowth in vivo

The hyaluronan-mediated motility receptor (HMMR/Rhamm) is overexpressed in numerous tumor types, including acute lymphoid leukemia and acute myeloid leukemia (AML). Several studies have reported the existence of T-cell responses directed against HMMR in AML patients that are linked to better clinical outcome. Therefore, we explored the use of HMMR-specific TCRs for transgenic expression in lymphocytes and their in vivo impact on HMMR(+) solid tumors and disseminated leukemia. We obtained TCRs via an in vitro priming approach in combination with CD137-mediated enrichment. Recipient lymphocytes expressing transgenic TCR revealed the specific tumor recognition pattern seen with the original T cells. Adoptive transfer experiments using a humanized xenograft mouse model resulted in significantly retarded solid tumor outgrowth, which was enhanced using IL-15-conditioned, TCR-transgenic effector memory cells. These cells also showed an increased potency to retard the outgrowth of disseminated AML, and this was further improved using CD8-enriched effector memory cells. To define a safe clinical setting for HMMR-TCR gene therapy, we analyzed transgenic T-cell recognition of hematopoietic stem cells (HSCs) and found on-target killing of HLA-A2(+) HSCs. Our findings clearly limit the use of HMMR-TCR therapy to MHC- mismatched HSC transplantation, in which HLA-A2 differences can be used to restrict recognition to patient HSCs and leukemia.     

Expectations and violations: Delineating the neural network of proactive inhibitory control

The ability to stop a prepared response (reactive inhibition) appears to depend on the degree to which stopping is expected (proactive inhibition). Functional MRI studies have shown that activation during proactive and reactive inhibition overlaps, suggesting that the whole neural network for reactive inhibition becomes already activated in anticipation of stopping. However, these studies measured proactive inhibition as the effect of stop‐signal probability on activation during go trials. Therefore, activation could reflect expectation of a stop‐signal (evoked by the stop‐signal probability cue), but also violation of this expectation because stop‐signals do not occur on go trials. We addressed this problem, using a stop‐signal task in which the stop‐signal probability cue and the go‐signal were separated in time. Hence, we could separate activation during the cue, reflecting expectation of the stop‐signal, from activation during the go‐signal, reflecting expectation of the stop‐signal or violation of that expectation. During the cue, the striatum, the supplementary motor complex (SMC), and the midbrain activated. During the go‐signal, the right inferior parietal cortex (IPC) and the right inferior frontal cortex (IFC) activated. These findings suggest that the neural network previously associated with proactive inhibition can be subdivided into two components. One component, including the striatum, the SMC, and the midbrain, activated during the cue, implicating this network in proactive inhibition. Another component, consisting of the right IPC and the right IFC, activated during the go‐signal. Rather than being involved in proactive inhibition, this network appears to be involved in processes associated with violation of expectations. Hum Brain Mapp 34:2015–2024, 2013. © 2011 Wiley Periodicals, Inc.     

Removal of Protein‐Bound,Hydrophobic Uremic Toxins by a Combined Fractionated Plasma Separation and Adsorption Technique

Protein‐bound uremic toxins, such as phenylacetic acid, indoxyl sulfate, and p‐cresyl sulfate, contribute substantially to the progression of chronic kidney disease (CKD) and cardiovascular disease (CVD). However, based on their protein binding, these hydrophobic uremic toxins are poorly cleared during conventional dialysis and thus accumulate in CKD‐5D patients. Therefore, we investigated whether hydrophobic and cationic adsorbers are more effective for removal of protein‐bound, hydrophobic uremic toxins than conventional high‐flux hemodialyzer. Five CKD‐5D patients were treated using the fractionated plasma separation, adsorption, and dialysis (FPAD) system for 5 h. A control group of five CKD patients was treated with conventional high‐flux hemodialysis. Plasma concentrations of phenylacetic acid, indoxyl sulfate, and p‐cresyl sulfate were measured. Removal rates of FPAD treatment in comparison to conventional high‐flux hemodialysis were increased by 130% for phenylacetic acid, 187% for indoxyl sulfate, and 127% for p‐cresol. FPAD treatment was tolerated well in terms of clinically relevant biochemical parameters. However, patients suffered from mild nausea 2 h after the start of the treatment, which persisted until the end of treatment. Due to the high impact of protein‐bound, hydrophobic uremic toxins on progression of CKD and CVD in CKD‐5D patients, the use of an adsorber in combination with dialysis membranes may be a new therapeutic option to increase the removal rate of these uremic toxins. However, larger, long‐term prospective clinical trials are needed to demonstrate the impact on clinical outcome.     

Differences and commonalities in the judgment of causality in physical and social contexts: An fMRI study

Understanding cause and effect is a fundamental aspect of human cognition. When shown videos of simple two-dimensional shapes colliding, humans experience one object causing the other to move, e.g., one billiard-like ball seeming to hit and move the other. The impression of causality can also occur when people attribute social interactions to moving objects. Whether the judgment of social and physical causality engages distinct or shared neural networks is not known. In a functional magnetic imaging (fMRI) study, participants were presented with two types of dynamic videos: a blue ball colliding with a red ball (P; physical condition) and a blue ball (“Mr. Blue”) passing a red ball (“Mrs. Red”) without making contact (S; social condition). Participants judged causal relationships (C) or movement direction (D; control task) in both video types, resulting in four conditions (PC; SC; PD; SD). We found common neural activations for physical and social causality judgments (SC>SD)∩(PC>PD) in the right middle/inferior frontal gyrus, right inferior parietal lobule, the right supplementary motor area, and bilateral insulae. For social causal judgments (SC>PC), we found distinct neural activity in the right temporo-parietal junction (rTPJ). These results provide evidence for a common neural network underlying judgments of causality that apply to both physical and social situations. The results also indicate that social causality judgments recruit additional neural resources in an area critical for determining animacy and intentionality.     

Neuroimaging in children, adolescents and young adults with psychological trauma

Childhood psychological trauma is a strong predictor of psychopathology. Preclinical research points to the influence of this type of trauma on brain development. However, the effects of psychological trauma on the developing human brain are less known and a challenging question is whether the effects can be reversed or even prevented. The aim of this review is to give an overview of neuroimaging studies in traumatized juveniles and young adults up till 2012. Neuroimaging studies in children and adolescents with traumatic experiences were found to be scarce. Most studies were performed by a small number of research groups in the United States and examined structural abnormalities. The reduction in hippocampal volume reported in adults with PTSD could not be confirmed in juveniles. The most consistent finding in children and adolescents, who experienced psychological trauma are structural abnormalities of the corpus callosum. We could not identify any studies investigating treatment effects. Neuroimaging studies in traumatized children and adolescents clearly lag behind studies in traumatized adults as well as studies on ADHD and autism.     

Long‐term course of substantia nigra hyperechogenicity in Parkinson's disease

A hyperechogenicity of the (SN+) in transcranial sonography corroborates the diagnosis of idiopathic Parkinson's disease (iPD). Although it is thought to represent a biomarker of the disease that is independent of disease severity and progression, differing results have been reported describing a positive correlation of the size and advancing clinical stage. In 50 parkinsonian patients, transcranial ultrasound and clinical examination was performed twice with a mean time interval of 6.4 years. SN+ did not change in size significantly between the first and second examination, whereas clinical parkinsonian symptoms—as determined by the motor part of the UPDRS—significantly worsened (P < 0.001). We found a highly significant intraindividual correlation in SN+ sizes between both examinations (P < 0.001). The size of SN+ did not correlate with the UPDRS part III at the time of first or second ultrasound examination. Progression of motor symptoms between the first and second investigation did not correlate with the size of SN+ at baseline. Furthermore, even in the subgroup of patients with an interval of ≥8 years between examinations, there was no significant change in SN+ size. SN+ represents a largely stable biomarker in iPD and does not reflect disease progression. The size of SN+ does not predict the further course of the disease. © 2012 Movement Disorder Society