No abstract

Certain cancers exert unexplained remote effects on the nervous system. Small cell carcinoma (SCC) of the lung, a tumour capable of spike electrogenesis and which is of possible neural crest origin, is present in approximately 70% of patients with the Lambert-Eaton myasthenic syndrome (LEMS), a disorder characterized by fatigable muscle weakness. Patients with this syndrome have a defect in the (Ca2+-dependent) quantal release of acetylcholine from motor nerve terminals evoked by a nerve impulse or by high K+ (ref.5), and a decreased number of presynaptic active zone particles. The physiological and morphological features of the syndrome can be transferred to mice by the patients' IgG, consistent with an autoantibody interfering with the function of voltage-dependent Ca2+ channels. Here we demonstrate that K+-induced 45Ca2+ flux in a cultured human SCC line is significantly reduced by LEMS IgG, suggesting that in SCC-LEMS an autoantibody to tumour Ca2+-channel determinants is triggered; its cross-reaction with similar determinants at the motor nerve terminal could lead to the remote neurological syndrome.

We have developed a strategy for guiding the selection of human antibody fragments from phage display repertoires to a single epitope of an antigen, using rodent monoclonal antibodies as a template. Thus the heavy chain of a rodent antibody (MAb32) directed against human tumor necrosis factor alpha (TNF alpha) was cloned and paired as a template chain with a repertoire of human light chains for display as Fab fragments on filamentous phage. The phage were selected by binding to the antigen. The selected human light chains were in turn paired with a repertoire of human heavy chains displayed on phage, and the phage selected again. The isolated phage displaying human antibody fragments binding to TNF alpha also bound to a peptide comprising the N-terminal region of TNF alpha as with MAb32. One of the human Fab fragments was recloned for expression as a glycosylated human antibody in mammalian cells: Binding to TNF alpha could be competed with MAb32 or with anti-serum to the peptide, indicating the same epitope. The human antibody was found to have a binding affinity (Kd = 15 nM) similar to MAb32 (Kd = 26 nM). The process contrasts with existing means of "humanizing" rodent monoclonal antibodies in that the antibodies derived are completely human.

No abstract

Studies in numerous species provide evidence that diet during development can mediate physiological changes necessary for puberty. In cattle, several studies have reported inverse correlations between postweaning growth rate and age at puberty and heifer pregnancy rates. Thus, postweaning growth rate was determined to be an important factor affecting age of puberty, which in turn influences pregnancy rates. This and other research conducted during the late 1960s through the early 1980s indicated puberty occurs at a genetically predetermined size, and only when heifers reach their target BW can increased pregnancy rates be obtained. Guidelines were established indicating replacement heifers should achieve 60 to 65% of their expected mature BW by breeding. Traditional approaches for postweaning development of replacement heifers used during the last several decades have primarily focused on feeding heifers to achieve or exceed an appropriate target BW and thereby maximize heifer pregnancy rates. Intensive heifer development systems may maximize pregnancy rates, but not necessarily optimize profit or sustainability. Since inception of target BW guidelines, subsequent research demonstrated that the growth pattern heifers experience before achieving a critical target BW could be varied. Altering rate and timing of BW gain can result in compensatory growth periods, providing an opportunity to decrease feed costs. Recent research has demonstrated that feeding replacement heifers to traditional target BW increased development costs without improving reproduction or subsequent calf production relative to development systems in which heifers were developed to lighter target BW ranging from 50 to 57% of mature BW.