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.

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.

Chronic suppression of testicular function by constant infusion of gonadotropin-releasing hormone agonist and testosterone supplementation in the bonnet monkey (Macaca radiata)

Objective: To study the efficacy of long-term buserelin acetate infusion to desensitize pituitary and block testicular function in adult male monkeys (Macaca radiata). Animals: Proven fertile male monkeys exhibiting normal testicular function. Protocol: Each of the control (n = 5) and experimental monkeys (n = 10) received a fresh miniosmotic pump every 21 days, whereas pumps in controls delivered vehicle of experimentals released 50-mu-g buserelin acetate every 24 hours. On day 170 (renewed every 60 days) a silastic capsule containing crystalline testosterone (T) was implanted in the experimental monkeys. At the end of 3 years, treatment was stopped, and recovery of testicular function and fertility monitored. Results: (1) Treatment resulted in marked reduction of nocturnal but not basal serum T; (2) the pituitary remained desensitized to buserelin acetate throughout the 3-year period; (3) animals were largely azoospermic with occasional oligospermia exhibited by two monkeys; and (4) withdrawal of treatment restored testicular function, with 70% of animals regaining fertility. Conclusion: Long-term infertility (but restorable) can be induced in male monkeys by constant infusion of buserelin acetate and T.

Effect of constant infusion of gonadotropin releasing hormone (GnRH) agonist Buserelin and antagonist CDB 2085 A using osmotic minipumps on testicular function in adult male bonnet monkey (Macaca radiata)

The effect of chronic infusion of gonadotropic hormone agonist Buserelin or antagonist CDB 2085 A for 15 weeks via alzet minipumps in adult male bonnet monkeys was studied. Infusion of Buserelin resulted in a decrease in the difference between serum testosterone values at 22.00 hours and 10.00 hours, decrease in responsiveness to injected Buserelin as judged by change in serum testosterone values from pre-injection values and decrease in sperm counts. Infusion of antagonist resulted in a decrease in the difference between serum testosterone values at 22.00 hours and 10.00 hours.

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.

Prediction of separation factor in foam separation of proteins

A phenomenological model has been developed for predicting separation factors obtained in concentrating protein solutions using batch-foam columns. The model considers the adsorption of surface active proteins onto the air-water interface of bubbles, and drainage of liquid from the foam, which are the two predominant processes responsible for separation in foam columns. The model has been verified with data collected on casein and bovine serum albumin (BSA) solutions, for which adsorption isotherms are available in the literature. It has been found that an increase in liquid pool height above the gas distributor and the time allowed for drainage result in a better separation. Further, taller foam columns yield poorer separation at constant time of drainage. The model successfully predicts the observed results. (C) 1997 Elsevier Science Ltd.

The TCP4 transcription factor of Arabidopsis blocks cell division in yeast at G1 -> S transition

The TCP transcription factors control important aspects of plant development. Members of class I TCP proteins promote cell cycle by regulating genes directly involved in cell proliferation. In contrast, members of class II TCP proteins repress cell division. While it has been postulated that class II proteins induce differentiation signal, their exact role on cell cycle has not been studied. Here, we report that TCP4, a class II TCP protein from Arabidopsis that repress cell proliferation in developing leaves, inhibits cell division by blocking G1 -> S transition in budding yeast. Cells expressing TCP4 protein with increased transcriptional activity fail to progress beyond G1 phase. By analyzing global transcriptional status of these cells, we show that expression of a number of cell cycle genes is altered. The possible mechanism of G1 -> S arrest is discussed. (C) 2011 Elsevier Inc. All rights reserved.

Hyper-activation of the TCP4 transcription factor in Arabidopsis thaliana accelerates multiple aspects of plant maturation

Plant organs are initiated as primordial outgrowths, and require controlled cell division and differentiation to achieve their final size and shape. Superimposed on this is another developmental program that orchestrates the switch from vegetative to reproductive to senescence stages in the life cycle. These require sequential function of heterochronic regulators. Little is known regarding the coordination between organ and organismal growth in plants. The TCP gene family encodes transcription factors that control diverse developmental traits, and a subgroup of class II TCP genes regulate leaf morphogenesis. Absence of these genes results in large, crinkly leaves due to excess division, mainly at margins. It has been suggested that these class II TCPs modulate the spatio-temporal control of differentiation in a growing leaf, rather than regulating cell proliferation per se. However, the link between class II TCP action and cell growth has not been established. As loss-of-function mutants of individual TCP genes in Arabidopsis are not very informative due to gene redundancy, we generated a transgenic line that expressed a hyper-activated form of TCP4 in its endogenous expression domain. This resulted in premature onset of maturation and decreased cell proliferation, leading to much smaller leaves, with cup-shaped lamina in extreme cases. Further, the transgenic line initiated leaves faster than wild-type and underwent precocious reproductive maturation due to a shortened adult vegetative phase. Early senescence and severe fertility defects were also observed. Thus, hyper-activation of TCP4 revealed its role in determining the timing of crucial developmental events, both at the organ and organism level.

Total Factor Productivity Growth and Output Growth in Indian Electronics Industry in the Liberalization Era: An Empirical Examination

This paper analyses the efficiency and productivity growth of Electronics industry, which is considered one of the vibrant and rapidly growing manufacturing industry sub-sectors of India in the liberalization era since 1991. The main objective of the paper is to examine the extent and growth of Total Factor Productivity (TFP) and its components namely, Technical Efficiency Change (TEC) and Technological Progress (TP) and its contribution to total output growth. In this study, the electronics industry is broadly classified into communication equipments, computer hardware, consumer electronics and other electronics, with the purpose of performing a comparative analysis of productivity growth for each of these sub-sectors for the time period 1993-2004. The paper found that the sub-sectors have improved in terms of economies of scale and contribution of capital.The change in technical efficiency and technological progress moved in reverse directions. Three of the four industry witnessed growth in the output primarily due to TFPG and the contribution of input growth to output growth had been negative/negligible, except for Computer hardware where contribution from both input growth and TFPG to output growth were prominent. The paper explored the possible reasons that addressed the issue of low technical efficiency and technological progress in the industry.

Total Factor Productivity in Indian Electronic Sector after Liberalisation: Sources and Outcomes

This paper analyses the efficiency and productivity growth of the Electronic Sector of India in the liberalization era since 1991. The study gives an insight into the process of the growth of one of the most upcoming sector of this decade. This sector has experienced a vast structural change along with the changing economic structures in India after liberalisation. With the opening up of this sector to foreign market and incoming of multinational companies, the environment has become highly competitive. The law that operates is that of Darwin’s ‘Survival of the fittest’. Existing industries experience a continuous threat of exit due to entrance of new potential entrants. Thus, it becomes inevitable for the existing industries in this sector to improve productivity growth for their survival. It is thus important to analyze how the industries in this sector have performed over the years and what are the factors that have contributed to the overall output growth.

A Unique Modification of the Eukaryotic Initiation Factor 5A Shows the Presence of the Complete Hypusine Pathway in Leishmania donovani

Deoxyhypusine hydroxylase (DOHH) catalyzes the final step in the post-translational synthesis of an unusual amino acid hypusine (N-(sic)-(4-amino-2-hydroxybutyl) lysine), which is present on only one cellular protein, eukaryotic initiation factor 5A (eIF5A). We present here the molecular and structural basis of the function of DOHH from the protozoan parasite, Leishmania donovani, which causes visceral leishmaniasis. The L. donovani DOHH gene is 981 bp and encodes a putative polypeptide of 326 amino acids. DOHH is a HEAT-repeat protein with eight tandem repeats of alpha-helical pairs. Four conserved histidine-glutamate sequences have been identified that may act as metal coordination sites. A similar to 42 kDa recombinant protein with a His-tag was obtained by heterologous expression of DOHH in Escherichia coli. Purified recombinant DOHH effectively catalyzed the hydroxylation of the intermediate, eIF5A-deoxyhypusine (eIF5A-Dhp), in vitro. L. donovani DOHH (LdDOHH) showed similar to 40.6% sequence identity with its human homolog. The alignment of L. donovani DOHH with the human homolog shows that there are two significant insertions in the former, corresponding to the alignment positions 159-162 (four amino acid residues) and 174-183 (ten amino acid residues) which are present in the variable loop connecting the N- and C-terminal halves of the protein, the latter being present near the substrate binding site. Deletion of the ten-amino-acid-long insertion decreased LdDOHH activity to 14% of the wild type recombinant LdDOHH. Metal chelators like ciclopirox olamine (CPX) and mimosine significantly inhibited the growth of L. donovani and DOHH activity in vitro. These inhibitors were more effective against the parasite enzyme than the human enzyme. This report, for the first time, confirms the presence of a complete hypusine pathway in a kinetoplastid unlike eubacteria and archaea. The structural differences between the L. donovani DOHH and the human homolog may be exploited for structure based design of selective inhibitors against the parasite.