The study evaluated the safety of humanised antibody A33 (huA33) in patients with colorectal carcinoma, determined the pharmacokinetics, tissue distribution and imaging characteristics of intravenously administered huA33 in these patients and determined the patient's immune response to IV huA33. (non-author abstract)
Background The enteric nervous system originates from neural crest cells that migrate into the embryonic foregut and then sequentially colonize the midgut and hindgut. Defects in neural crest migration result in regions of the gut that lack enteric ganglia, a condition in humans called Hirschsprung's disease. The high degree of phenotypic variability reported in Hirschsprung's disease suggests the involvement of modifier genes. Methods We used a two-locus complementation approach to screen for genetic interactions between L1cam and members of the endothelin signalling pathway. Immunohistochemistry was used to label PGP9.5+ enteric neurons and Sox10+ neural crest-derived cells in wholemount preparations of embryonic gut. Key Results Loss or haploinsufficiency of L1cam significantly increased the severity of aganglionosis in Et-3 and Ednrb null mutant embryos. Furthermore, the colonization of the developing gut by neural crest-derived cells was significantly delayed in L1cam−/y; Et-3−/− and L1cam−/y;Ednrbsl/sl embryos. Conclusions & Inferences We have identified the X-linked gene, L1cam, as the first modifier gene for members of the endothelin signalling pathway during development of the enteric nervous system. Mutations in L1CAM may act to modulate the severity of aganglionosis in some cases of Hirschsprung's disease.
Abstract The translocator protein (18 kDa; TSPO), formerly known as the peripheral benzodiazepine receptor, is an outer mitochondrial membrane protein that associates with the mitochondrial permeability transition pore to regulate both steroidogenesis and apoptosis. TSPO expression is induced in adult dorsal root ganglion (DRG) sensory neurons after peripheral nerve injury and a TSPO receptor ligand, Ro5‐4864, enhances DRG neurite growth in vitro and axonal regeneration in vivo . We have now found that TSPO is induced in neonatal motor neurons after peripheral nerve injury and have evaluated its involvement in neonatal and adult sensory and motor neuron survival, and in adult motor neuron regeneration. The TSPO ligand Ro5‐4864 rescued cultured neonatal DRG neurons from nerve growth factor withdrawal‐induced apoptosis and protected neonatal spinal cord motor neurons from death due to sciatic nerve axotomy. However, Ro5‐4864 had only a small neuroprotective effect on adult facial motor neurons after axotomy, did not delay onset or prolong survival in SOD1 mutant mice, and failed to protect adult DRG neurons from sciatic nerve injury‐induced death. In contrast, Ro5‐4864 substantially enhanced adult facial motor neuron nerve regeneration and restoration of function after facial nerve axotomy. These data indicate a selective sensitivity of neonatal sensory and motor neurons to survival in response to Ro5‐4864, which highlights that survival in injured immature neurons cannot necessarily predict success in adults. Furthermore, although Ro5‐4864 is only a very weak promoter of survival in adult neurons, it significantly enhances regeneration and functional recovery in adults.
The enteric nervous system (ENS) is derived from vagal and sacral neural crest cells (NCC) that delaminate from the neural tube and undergo extensive migration and proliferation in order to colonize the entire length of the gut and differentiate into many millions of neurons and glial cells. Although apoptotic programmed cell death is an essential physiological process during development of the majority of the vertebrate nervous system, apoptosis within early ENS development has not been comprehensively investigated. The aim of this study was to determine the presence and extent of apoptosis within the vagal NCC population that gives rise to most of the ENS in the chick embryo. We demonstrated that apoptotic cells, as shown by terminal deoxynucleotidyl transferase biotin-dUTP nick end labelling and active caspase-3 immunoreactivity, are present within an electroporated green fluorescent protein (GFP) and human natural killer-1 (HNK-1) immunopositive NCC population migrating from the vagal region of the neural tube to the developing foregut. Inhibition of caspase activity in vagal NCC, by electroporation with a dominant-negative form of caspase-9, increased the number of vagal NCC available for ENS formation, as shown by 3-dimensional reconstruction of serial GFP or HNK-1 labelled sections, and resulted in hyperganglionosis within the proximal foregut, as shown by NADPH-diaphorase whole gut staining. These findings suggest that apoptotic cell death may be a normal process within the precursor pool of pre-enteric NCC that migrates to the gut, and as such it may play a role in the control of ENS formation.
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