Toward experimental assessment of receptor occupancy: TGN1412 revisited

In March 2006, 6 healthy volunteers experienced serious adverse reactions during a first-in-human clinical trial of the superagonistic anti-CD28 mAb TGN1412. A first investigation excluded contaminations of the drug product or protocol irregularities as the root cause. Later, an expert scientific group convened in the United Kingdom to develop recommendations pertinent to minimizing risks of first-in-human clinical trials. The expert scientific group concluded from in silico calculations that at the initial dose of 0.1 mg/kg, which was adjusted on the basis of the no observed adverse effect level, approximately 86.2% to 90.9% CD28 receptor occupancy was obtained. Here we developed a flow cytometric method that revealed receptor occupancy of approximately 45% to 80% under the above conditions. Thus we present a method to experimentally determine receptor occupancy that can be taken as one parameter to define the minimal anticipated biological effect level as the basis for calculating safer starting doses for first-in-human clinical trials for products in which a potential risk has been identified. Additional measures are being discussed that will help to significantly improve safety of first-in-human clinical trials.     

Prior knowledge of illumination for 3D perception in the human brain

In perceiving 3D shape from ambiguous shading patterns, humans use the prior knowledge that the light is located above their head and slightly to the left. Although this observation has fascinated scientists and artists for a long time, the neural basis of this “light from above left” preference for the interpretation of 3D shape remains largely unexplored. Combining behavioral and functional MRI measurements coupled with multivoxel pattern analysis, we show that activations in early visual areas predict best the light source direction irrespective of the perceived shape, but activations in higher occipitotemporal and parietal areas predict better the perceived 3D shape irrespective of the light direction. These findings demonstrate that illumination is processed earlier than the representation of 3D shape in the visual system. In contrast to previous suggestions, we propose that prior knowledge about illumination is processed in a bottom-up manner and influences the interpretation of 3D structure at higher stages of processing.     

Illness representations and psychological adjustment of Greek couples dealing with a recently-diagnosed cancer: dyadic,interaction and perception-dissimilarity effects

The aim was to examine the impact of the dyadic, interaction and dissimilarity effects of the illness representations on the psychological health of recently diagnosed cancer patients and spouses in Greece. The sample consisted of 298 individuals nested in 149 couples. Effects were examined with the Actor–Partner Interdependence Model. Both actor (i.e., within person) and partner (i.e., between partners) effects were detected for both patients’ and spouses’ psychological symptoms. The negative association of patients’ psychological symptoms with their representations of illness coherence was weak at the higher and medium levels, and stronger at the lower levels of spouse corresponding representations. Patient–partner discrepancy in perceived illness consequences was associated with more psychological symptoms in patients. Adaptation to cancer is a dyadic process within the context of which patient and partner psychological well-being is affected by each other’s understanding of illness. Thus, the parallel examination of the illness representations of both partners is needed from the early phases of the illness trajectory.     

Object-selective responses in the human motion area MT/MST.

The perception of moving objects and our successful interaction with them entail that the visual system integrates shape and motion information about objects. However, neuroimaging studies have implicated different human brain regions in the analysis of visual motion (medial temporal cortex; MT/MST) and shape (lateral occipital complex; LOC), consistent with traditional approaches in visual processing that attribute shape and motion processing to anatomically and functionally separable neural mechanisms. Here we demonstrate object-selective fMRI responses (higher responses for intact than for scrambled images of objects) in MT/MST, and especially in a ventral subregion of MT/MST, suggesting that human brain regions involved mainly in the processing of visual motion are also engaged in the analysis of object shape.     

Complete screening for glucocerebrosidase mutations in Parkinson disease patients from Greece

Mutations in β-glucocerebrosidase gene (GBA) have been implicated in Parkinson disease (PD). A Greek cohort of 172 PD patients and 132 control individuals were screened for GBA mutations by complete sequencing of the gene's exons. Four mutations previously associated with Gaucher disease and/or Parkinson's disease (L445P, D409H, E326K, H255Q) were detected, as well as five newly identified variants (R329H, L268L, S271G, T428K, V460L), providing for the first time data regarding the frequency of GBA mutations among PD patients and controls, in the Greek population. H255Q was the most common GBA mutation among Greek PD patients (4/172). V460L was only found in control individuals (2/132). Overall, GBA mutations were significantly overrepresented in a subgroup of early onset PD patients, compared to controls (P = 0.019, OR = 4.2; 95%CI = 1.28–13.82), suggesting that GBA mutations may modify age of onset for PD.     

Suppression of serum antibody responses by pertussis toxin after respiratory tract colonization by Bordetella pertussis and identification of an immunodominant lipoprotein

Pertussis toxin (PT), a virulence factor secreted by Bordetella pertussis, contributes to respiratory tract infection and disease caused by this pathogen. By comparing a wild-type (WT) B. pertussis strain to a mutant strain with an in-frame deletion of the ptx genes encoding PT (DeltaPT), we recently found that the lack of PT confers a significant defect in respiratory tract colonization in mice after intranasal inoculation. In this study, we analyzed serum antibody responses in mice infected with the WT or DeltaPT strain and found that infection with the DeltaPT strain elicited greater responses to several B. pertussis antigens than did infection with the WT, despite the lower colonization level achieved by the DeltaPT strain. The same enhanced antibody response was observed after infection with a strain expressing an enzymatically inactive PT; but this response was not observed after infection with B. pertussis mutant strains lacking filamentous hemagglutinin or adenylate cyclase toxin, nor when purified PT was administered with the DeltaPT inoculum, indicating a specific role for PT activity in this immunosuppressive effect. In particular, there were consistent strong serum antibody responses to one or more low-molecular-weight antigens after infection with the DeltaPT strain. These antigens were Bvg independent, membrane localized, and also expressed by the closely related pathogens Bordetella parapertussis and Bordetella bronchiseptica. Two-dimensional gel electrophoresis and mass spectrometry were used to identify one of the immunodominant low-molecular-weight antigens as a protein with significant sequence homology to peptidoglycan-associated lipoprotein in several other gram-negative bacterial species. However, a serum antibody response to this protein alone did not protect mice against respiratory tract infection by B. pertussis.