The IGF system plays critical roles in somatic growth in an endocrine fashion (somatomedin hypothesis) as well as proliferation and differentiation of normal and malignant cells in a paracrine/autocrine fashion. IGFBP-3 is known to modulate the actions of IGFs in circulation as well as the immediate extracellular environment. Interestingly, apart from the ability to inhibit or enhance IGF actions, IGFBP-3 also exhibits very clear, distinct biological effects independent of the IGF/IGF-I receptor axis. Over the past decade it has become widely appreciated that IGF/IGF-IR-independent actions of IGFBP-3 (antiproliferative and proapoptotic effects) contribute to improving the pathophysiology of a variety of human diseases, such as cancer, diabetes, and malnutrition. Recent studies have implicated interaction of IGFBP-3 with a variety of proteins or signaling cascades critical to cell cycle control and apoptosis; however, the actual mechanism of IGFBP-3 action is still unclear. This review reinforces the concept in support of the IGF/IGF-IR axis-independent actions of IGFBP-3 and delineates potential underlying mechanisms involved and subsequent biological significance, focusing in particular on functional binding partners and the clinical significance of IGFBP-3 in the assessment of cancer risk.

Insulin-like growth factor-binding protein-3 (IGFBP-3

No abstract

The dramatic effects of the anti-IgE mAb omalizumab to lower free IgE levels and FcεRI levels on basophils contrast with more modest clinical effects. Accordingly, whether IgE modulates FcεRI levels and FcεRI-dependent mediator release in vitro on human skin mast cells (MCTC type) that had matured in vivo is of interest. IgE reversibly enhanced FcεRI levels on MCTC cells in a dose- and time-dependent manner (up-regulation t1/2 of 4–5 days with 1–3 μg/ml IgE), without affecting cell proliferation. A molar ratio of omalizumab to IgE of 0.9 at baseline prevented receptor up-regulation by 50%, whereas adding omalizumab to MCTC cells already with IgE-enhanced FcεRI levels at molar ratios of 5, 12.5, and 31 reduced FcεRI levels to baseline with respective t1/2 values of 8.7, 6.3, and 4.8 days. MCTC cells with IgE-enhanced FcεRI levels were more sensitive to stimulation with a low dose of anti-FcεRI mAb in terms of degranulation and production of PGD2, GM-CSF, IL-6, IL-13, and TNF-α. Reducing up-regulated FcεRI levels with omalizumab also reduced mediator release to a low dose of anti-FcεRI mAb to baseline by 3–4 wk. Thus, reducing free IgE should decrease the hypersensitivity of allergic individuals to low naturally occurring concentrations of allergens.

No abstract

No abstract

Early investigations into the insulin-like growth factor (IGF)-independent actions of insulin-like growth factor-binding protein (IGFBP)-3 have implicated a large array of signaling proteins with links to cell cycle control and apoptosis. However, the actual mechanism of IGFBP-3 action is still unclear. In an effort to clearly understand the mechanism of IGF-independent IGFBP-3 actions, a proteomic approach to identify the actual proteins involved in interaction with IGFBP-3 from different cell compartments, the phosphorylation status of IGFBP-3 under different physiologic conditions and the proteins upregulated by IGFBP-3 are briefly reviewed. The IGF system is a well-recognized key player in diseases such as cancer, diabetes and malnutrition. It is only after the signaling pathways of the IGF-independent actions of IGFBP-3 are clearly understood that the system can be manipulated to affect these disorders.

Affinity chromatographic methods for purifying antibodies are reviewed. Topics reviewed include (a) the matrices used in the preparation of the affinity supports; (b) the chemistries commonly used to attach affinity ligands directly on hydroxyl-carrying supports and indirectly through the use of bifunctional agents to crosslink the affinity ligands to the supports; (c) methods for detecting ligand leakage; (d) macromolecular affinity ligands; (e) low molecular weight peptidyl affinity ligands; (f) low molecular weight non-peptidyl affinity ligands; (g) optimal conditions for achieving improved product yield; and (h) optimal elution systems that minimize the denaturation of the purified antibodies.