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Purpose: The CD38 cell surface antigen is expressed in diverse hematologic malignancies including multiple myeloma, B-cell non-Hodgkin lymphoma (NHL), B-cell chronic lymphocytic leukemia, B-cell acute lymphoblastic leukemia (ALL), and T-cell ALL. Here, we assessed the antitumor activity of the anti-CD38 antibody SAR650984.Experimental Design: Activity of SAR650984 was examined on lymphoma, leukemia and multiple myeloma cell lines, primary multiple myeloma samples, and multiple myeloma xenograft models in immunodeficient mice.Results: We identified a humanized anti-CD38 antibody with strong proapoptotic activity independent of cross-linking agents, and potent effector functions including complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity, and antibody-dependent cellular phagocytosis (ADCP), equivalent in vitro to rituximab in CD20 þ and CD38 þ models. This unique antibody, termed SAR650984, inhibited the ADP-ribosyl cyclase activity of CD38, likely through an allosteric antagonism as suggested by 3D structure analysis of the complex. In vivo, SAR650984 was active in diverse NHL, ALL, and multiple myeloma CD38 þ tumor xenograft models. SAR650984 demonstrated single-agent activity comparable with rituximab or cyclophosphamide in Daudi or SU-DHL-8 lymphoma xenograft models with induction of the proapoptotic marker cleaved capase-7. In addition, SAR650984 had more potent antitumor activity than bortezomib in NCI-H929 and Molp-8 multiple myeloma xenograft studies.

This review will focus on investigations of the auditory evoked neuromagnetic field component, the M100, detectable in the magnetoencephalogram recorded during presentation of auditory stimuli, approximately 100 milliseconds after stimulus onset. In particular, the dependence of M100 latency on attributes of the stimulus, such as intensity, pitch and timbre will be discussed, along with evidence relating M100 latency observations to perceptual features of the stimuli. Comparison with investigation of the analogous electrical potential component, the N1, will be made. Parametric development of stimuli from pure tones through complex tones to speech elements will be made, allowing the influence of spectral pitch, virtual pitch and perceptual categorization to be delineated and suggesting implications for the role of such latency observations in the study of speech processing. The final section will deal with potential clinical applications offered by M100 latency measurements, as objective indices of normal and abnormal cortical processing.

Autism, a pervasive developmental disorder with profound deficits in social relatedness, impairments in language and communication, and symptoms involving repetitive behaviors and restricted interests, is thought to be gene-dependent. 1-3 The well-replicated, but as yet unexplained, platelet hyperserotonemia of autism 4,5 has focused attention on the possible role of the neurotransmitter serotonin (5-hydroxytryptamine, 5-HT). Reports of other 5-HT-related abnormalities in autism 6,7 and the utility of serotonergic agents in partially ameliorating symptoms in some individuals with autism 8 have also served to increase interest in the possible involvement of 5-HT in the etiology and pathophysiology of autism. The important roles of 5-HT in neurodevelopment 9,10 and the rich serotonergic innervation of limbic areas critically involved in social and affiliative behaviors 11 have provided additional, more theoretical, bases for the 5-HT hypothesis.A wide range of 5-HT-related genes can be considered as possible candidate genes in autism. However, the 5-HT transporter gene (HTT, locus SLC6A4), encoding both the neuronal and platelet transporter, 12 is of particular interest for several reasons. Reports of a positive correlation between rates of platelet 5-HT transport and platelet levels of 5-HT 13,14 suggest that the transporter may play a part in the platelet hyperserotonemia of autism. The beneficial effects of agents that block neuronal serotonin transport 8 also focus attention on the possible role of the transporter in the pathophysiology of autism. Additionally, the reported association of a HTT promoter polymorphism with anxiety in the general population, 15 coupled with reports of higher stress responsivity in autism and an increased incidence of anxiety disorder in the families of individuals with autism, 16,17 has further stimulated interest in the HTT in autism. Most intriguing have been discrepant studies reporting preferential transmission of different alleles of the biallelic promoter region polymorphism in individuals with autism. 18,19 The promoter variant consists of a 44 base-pair deletion/insertion in a repeat region of the promoter. The deletion or short (s) allele occurs with a frequency of approximately 43%, while the long (l) form has an allele frequency of 57% in samples of predominately northern European ancestry. 15,20 It is noteworthy that the polymorphism is of apparent functional significance; native lymphoblastoid cell lines with sl or ss genotypes were reported to have approximately onehalf the rates of 5-HT transport, transporter expression, and HTT mRNA levels as those with the ll genotype. 15 After genotyping the HTT promoter alleles in a group of 69 French families with autistic children, the transmission of the alleles was examined to determine their influence on risk or susceptibility to autism. A possible modifying role of the HTT on the behavioral phenotypic expression of autism was also studied. This possibility was examined by comparing allelic transmission across severity sub...

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The human motor cortex exhibits transient bursts of high frequency gamma oscillations in the 60-90 Hz range during movement. It has been proposed that gamma oscillations generally reflect local intracortical activity. However, movement-evoked gamma is observed simultaneously in both cortical and subcortical (basal ganglia) structures and thus appears to reflect long-range cortical-subcortical interactions. Recent evidence suggests that gamma oscillations do not simply reflect sensory reafference, but have a facilitative role in movement initiation. Here we summarize contributions of MEG to our understanding of movement-evoked gamma oscillations, including evidence that transient gamma bursts during the performance of specific movements constitutes a stereotyped spectral and temporal pattern within individuals-a gamma "fingerprint"-that is highly stable over time. Although their functional significance remains to be fully understood, movement-evoked gamma oscillations may represent frequency specific tuning within cortical-subcortical networks that can be monitored non-invasively using MEG during a variety of motor tasks, and may provide important information regarding cortical dynamics of ongoing motor control.

The phosphoglucosamine mutase (GlmM) from Escherichia coli, specifically required for the interconversion of glucosamine-6-phosphate and glucosamine-1-phosphate (an essential step in the pathway for cell-wall peptidoglycan and lipopolysaccharide biosyntheses) was purified to homogeneity and its kinetic properties were investigated. The enzyme was active in a phosphorylated form and catalysed its reaction according to a classical ping-pong bi-bi mechanism. The dephosphorylated and phosphorylated forms of GlmM could be separated by HPLC and coupled MS showed that only one phosphate was covalently linked to the active site of the enzyme. The site of phosphorylation was clearly identified as Ser102 in the 445-amino acid polypeptide. GlmM was also capable of catalysing the interconversion of glucose-1-phosphate and glucose-6-phosphate isomers, although at a much lower (1400-fold) rate. Interestingly, the mutational change of the Ser100 to a threonine residue resulted in a 20-fold increase of the nonspecific phosphoglucomutase activity of GlmM, suggesting that the presence of either a serine or a threonine at this position in the consensus sequence of hexosephosphate mutases could be one of the factors that determines the specificity of these enzymes for either sugar-phosphate or amino sugar-phosphate substrates.

Plasma levels of the hypothalamo-pituitary-adrenal axis hormones beta-endorphin (BE), adrenocorticotropin hormone (ACTH), and cortisol were measured in autistic (N = 48), mentally retarded/cognitively impaired (MR/CI, N = 16), and normal control (N = 26) individuals. Comparison of log transformed data from the three groups revealed that levels of BE and ACTH were significantly higher (p < .05) in the autistic individuals than in normal controls. The higher means in the autistic group were due to significantly higher plasma levels of BE and ACTH, indices of acute stress response, in the more severely affected individuals. The data support the idea that individuals with severe autism have a heightened response to acute stressors rather than chronic hyperarousal or elevated basal stress response system functioning.