Defining the pathway to insulin-like growth factor system targeting in cancer

The insulin-like growth factors (IGEs; IGF-1 and IGF-2) play central roles in cell growth, differentiation, survival, transformation and metastasis. The biologic effects of the IGFs are mediated by the IGF-1 receptor (IGF-1R), a receptor tyrosine kinase with homology to the insulin receptor (IR). Dysregulation of the ICE system is well recognized as a key contributor to the progression of multiple cancers, with IGF-1R activation increasing the tumorigenic potential of breast, prostate, lung, colon and head and neck squamous cell carcinoma (HNSCC). Despite this relationship, targeting the IGF-1R has only recently undergone development as a molecular cancer therapeutic. As it has taken hold, we are witnessing a robust increase and interest in targeting the inhibition of IGF-1R signaling. This is accentuated by the list of over 30 drugs, including monoclonal antibodies (mAbs) and tyrosine kinase inhibitors (TKIs) that are under evaluation as single agents or in combination therapies 1]. The ICE-binding proteins (IGFBPs) represent the third component of the ICE system consisting of a class of six soluble secretory proteins. They represent a unique class of naturally occurring ICE-antagonists that bind to and sequester IGF-1 and IGF-2, inhibiting their access to the IGF-1R. Due to their dual targeting of the IGFs without affecting insulin action, the IGFBPs are an untapped ``third'' class of IGF-1R inhibitors. in this commentary, we highlight some of the significant aspects of and prospects for targeting the IGF-1R and describe what the future may hold. (C) 2010 Elsevier Inc. All rights reserved.

Over-expression and purification strategies for recombinant multi-protein oligomers: A case study of Mycobacterium tuberculosis sigma/anti-sigma factor protein complexes

The function of a protein in a cell often involves coordinated interactions with one or several regulatory partners. It is thus imperative to characterize a protein both in isolation as well as in the context of its complex with an interacting partner. High resolution structural information determined by X-ray crystallography and Nuclear Magnetic Resonance offer the best route to characterize protein complexes. These techniques, however, require highly purified and homogenous protein samples at high concentration. This requirement often presents a major hurdle for structural studies. Here we present a strategy based on co-expression and co-purification to obtain recombinant multi-protein complexes in the quantity and concentration range that can enable hitherto intractable structural projects. The feasibility of this strategy was examined using the sigma factor/anti-sigma factor protein complexes from Mycobacterium tuberculosis. The approach was successful across a wide range of sigma factors and their cognate interacting partners. It thus appears likely that the analysis of these complexes based on variations in expression constructs and procedures for the purification and characterization of these recombinant protein samples would be widely applicable for other multi-protein systems. (C) 2010 Elsevier Inc. All rights reserved.

Involvement of cytoskeletal structures in nerve-growth-factor-mediated induction of ornithine decarboxylase.

Induction of ornithine decarboxylase elicited in response to nerve-growth factor in target organs is greatly decreased by preincubation of these tissues with cytoskeletal poisons such as vinblastine, diamide, cytochalasin B and colchicine. These results are interpreted as evidence for the involvement of receptor-associated cytoskeletal structures in mediating the nerve-growth-factor-specific induction of ornithine decarboxylase.

Involvement of cytoskeletal structures in nerve-growth-factor-mediated induction of ornithine decarboxylase

Induction of ornithine decarboxylase elicited in response to nerve-growth factor in target organs is greatly decreased by preincubation of these tissues with cytoskeletal poisons such as vinblastine, diamide, cytochalasin B and colchicine. These results are interpreted as evidence for the involvement of receptor-associated cytoskeletal structures in mediating the nerve-growth-factor-specific induction of ornithine decarboxylase.

Dynamic Structure Factor of Sponge Phases

We predict the dynamic light scattering intensity S(q,t) for the L3 phase (anomalous isotropic phase) of dilute surfactant solutions. Our results are based on a Landau-Ginzburg approach, which was previously used to explain the observed static structure factor S(q, 0). In the extreme limit of small q, we find a monoexponential decay with marginal or irrelevant hydrodynamic interactions. In most other regimes the decay of S(q,t) is strongly nonexponential; in one case, it is purely algebraic at long times.

Cycloheximide enhances factor binding to the native 40S ribosomal subunit of Microsporum canis

Native and derived ribosomal particles from the mycelial cells of Microsporum canis grown in the presence and absence of cycloheximide were compared by CsCl equilibrium density gradient centrifugation. Since the buoyant densities of ribonucleoprotein complexes are dependent on the protein-RNA ratio, they reflect the composition of these particles. The native monosomes from cells grown in the presence and absence of cycloheximide had a buoyant density of 1.585 g/cc. The native 60S subunits showed a density of 1.540 g/cc from cells grown in both presence and absence of cycloheximide, while the derived subunits showed a density of 1.610 g/cc. The derived 40S subunits had a density of 1.550 g/cc while the native 40S showed a major species of density 1.535 g/cc with three other minor species ranging in densities from 1.450-1.390 g/cc. The mycelia grown in the presence of cycloheximide showed an increased proportion of native 40S subunits in the density range of 1.450-1.390 g/cc, indicating that the drug enhances factor binding to native ribosomal subunits in M. canis.

Measurement of complex optical flow with use of an augmented generalized gradient scheme

We present a method for measuring the local velocities and first-order variations in velocities in a timevarying image. The scheme is an extension of the generalized gradient model that encompasses the local variation of velocity within a local patch of the image. Motion within a patch is analyzed in parallel by 42 different spatiotemporal filters derived from 6 linearly independent spatiotemporal kernels. No constraints are imposed on the image structure, and there is no need for smoothness constraints on the velocity field. The aperture problem does not arise so long as there is some two-dimensional structure in the patch being analyzed. Among the advantages of the scheme is that there is no requirement to calculate second or higher derivatives of the image function. This makes the scheme robust in the presence of noise. The spatiotemporal kernels are of simple form, involving Gaussian functions, and are biologically plausible receptive fields. The validity of the scheme is demonstrated by application to both synthetic and real video images sequences and by direct comparison with another recently published scheme Biol. Cybern. 63, 185 (1990)] for the measurement of complex optical flow.

Higher twist and higher order contributions to the pion electromagnetic form factor

The O(m(pi)4/(m(u) + (d))2Q2) and O(alpha(S)2) corrections to the leading term of the perturbative QCD calculation of the pion electromagnetic form factor are examined numerically. Both sets of terms provide significant corrections for values of Q2 between 1 and 15 GeV2/c2.

Measurement of complex optical flow with use of an augmented generalized gradient scheme

We present a method for measuring the local velocities and first-order variations in velocities in a time-varying image. The scheme is an extension of the generalized gradient model that encompasses the local variation of velocity within a local patch of the image. Motion within a patch is analyzed in parallel by 42 different spatiotemporal filters derived from 6 linearly independent spatiotemporal kernels. No constraints are imposed on the image structure, and there is no need for smoothness constraints on the velocity field. The aperture problem does not arise so long as there is some two-dimensional structure in the patch being analyzed. Among the advantages of the scheme is that there is no requirement to calculate second or higher derivatives of the image function. This makes the scheme robust in the presence of noise. The spatiotemporal kernels are of simple form, involving Gaussian functions, and are biologically plausible receptive fields. The validity of the scheme is demonstrated by application to both synthetic and real video images sequences and by direct comparison with another recently published scheme [Biol. Cybern. 63, 185 (1990)] for the measurement of complex optical flow.

Analysis of a long thick orthotropic circular cylindrical shell panel

An exact three-dimensional elasticity solution has been obtained for an infinitely long, thick transversely isotropic circular cylindrical shell panel, simply supported along the longitudinal edges and subjected to a radial patch load. Using a set of three displacement functions, the boundary value problem is reduced to Bessel's differential equation. Numerical results are presented for different thickness to mean radius ratios and semicentral angles of the shell panel. Classical and first-order shear deformation orthotropic shell theories have been examined in comparison with the present elasticity solution.

Implications of the recent high statistics determination of the pion electromagnetic form factor in the timelike region

The recently evaluated two-pion contribution to the muon g - 2 and the phase of the pion electromagnetic form factor in the elastic region, known from pi pi scattering by Fermi-Watson theorem, are exploited by analytic techniques for finding correlations between the coefficients of the Taylor expansion at t = 0 and the values of the form factor at several points in the spacelike region. We do not use specific parametrizations, and the results are fully independent of the unknown phase in the inelastic region. Using for instance, from recent determinations, < r(pi)(2)> = (0.435 +/- 0.005) fm(2) and F(-1.6 GeV2) = 0.243(-0.014)(+0.022), we obtain the allowed ranges 3.75 GeV-4 less than or similar to c less than or similar to 3.98 GeV-4 and 9.91 GeV-6 less than or similar to d less than or similar to 10.46 GeV-6 for the curvature and the next Taylor coefficient, with a strong correlation between them. We also predict a large region in the complex plane where the form factor cannot have zeros.

Molecular organization of the gene encoding Xenopus laevis transforming growth factor-beta 5

Transforming growth factor-beta s (TGF-beta 5) are multifunctional polypeptides, known to influence proliferation and differentiation of many cell types. TGF-beta 5 cDNA was cloned from Xenopus laevis and this isoform is unique to the amphibians. Here, we report the isolation and characterization of the TGF-beta 5 genomic clones to determine the structure of TGF-beta 5 gene. The gene consists of seven exons and all intron-exon boundaries follow the GT-AG consensus. The organization of TGF-beta 5 gene was identical to that of the mammalian TGF-beta isoforms, with the exception of position of the first splice junction. We determined the size of TGF-beta 5 gene to be approximately 20 kb.