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Progress in the systemic control of osteosarcoma has been limited over the past decades thus indicating the urgent clinical need for the development of novel treatment strategies. Therefore, we have recently developed new preclinical models to study promising novel agents for the treatment of pediatric osteosarcoma. The checkpoint kinase (chk) inhibitor prexasertib (LY2606368) and its salt form (LSN2940930) have recently been shown to be active in adult and pediatric malignancies, including sarcoma. We have now tested the potency of prexasertib in clonogenic survival assays in two new lines of primary patient‐derived osteosarcoma cells and in two established osteosarcoma cell lines as a single agent and in combination with cisplatin and the poly ADP‐ribose polymerase (PARP) inhibitor talazoparib. Prexasertib alone results in strongly reduced clonogenic survival at low nanomolar concentrations and acts by affecting cell cycle progression, induction of apoptosis and induction of double‐stranded DNA breakage at concentrations that are well below clinically tolerable and safe plasma concentrations. In combination with cisplatin and talazoparib, prexasertib acts in a synergistic fashion. Chk1 inhibition by prexasertib and its combination with the DNA damaging agent cisplatin and the PARP‐inhibitor talazoparib thus emerges as a potential new treatment option for pediatric osteosarcoma which will now have to be tested in preclinical primary patient derived in vivo models and clinical studies., What's new? Treatment options and outcomes for osteosarcoma have changed very little in decades. New treatment strategies are thus urgently needed. In this study, the authors found that the checkpoint inhibitor ‘prexasertib’ increased apoptosis and DNA damage in patient‐derived osteosarcoma cells, at very low concentrations. In addition, when combined with cisplatin and talazoparib, prexasertib acted in a synergistic fashion. This drug thus represents a promising therapeutic candidate for further preclinical and clinical development in osteosarcoma.

On the bow shock in front of Earth flows current due to the curl of interplanetary magnetic field across the shock. It is uncertain whether the bow shock current closes on the magnetopause, into th...

Chemotherapeutic agents are part of the standard treatment algorithms for many malignancies; however, their application and dosage are limited by their toxic effects to normal tissues. Chemotherapy-induced toxicities can be long-lasting and may be incompletely reversible; therefore, causative therapies for chemotherapy-dependent side effects are needed, especially considering the increasing survival rates of treated cancer patients. Mesenchymal stem cells (MSCs) have been shown to exhibit regenerative abilities for various forms of tissue damage. Preclinical data suggest that MSCs may also help to alleviate tissue lesions caused by chemotherapeutic agents, mainly by establishing a protective microenvironment for functional cells. Due to the systemic administration of most anticancer agents, the effects of these drugs on the MSCs themselves are of crucial importance to use stem cell-based approaches for the treatment of chemotherapy-induced tissue toxicities. Here, we present a concise review of the published data regarding the influence of various classes of chemotherapeutic agents on the survival, stem cell characteristics and physiological functions of MSCs. Molecular mechanisms underlying the effects are outlined, and resulting challenges of MSC-based treatments for chemotherapy-induced tissue injuries are discussed.

This paper explores the role of tax policy in shaping incentives for executive effort (labor supply) and rent seeking within the firm. We develop a theoretical model that distinguishes between effort and rent‐seeking responses to income taxes, and provides a framework to estimate a lower bound for the rent‐seeking response. Using executive compensation and governance data, we find that rent seeking represents an important component of the response to changes in tax rates, especially among executives in firms with the worst corporate governance. (JEL D31, G30, H21)

This paper hypothesizes that fiscal policy is one important factor determining whether or not environmentally and socially sustainable economic growth is possible. We postulate that tax policies affect the incentives to make the economy more or less dependent on natural resources and the environment as factors of production. So-called pro-growth tax policies consisting of a low tax burden, low direct taxes but high indirect ones, affect the composition of factor endowment, often inducing overinvestment in physical capital and underinvestment in human capital, including education and health. These policies in part explain a structure of production heavily dependent on natural-resource-based and environmentally dirty industries. Moreover, these tax policies induce high levels of inequality, which ultimately may render economic growth socially and politically unsustainable. This analysis has important implications for Chile and for other developing countries, especially in Latin America, which are highly dependent on natural resources and have highly unequal income distributions. Copyright © 2016 John Wiley & Sons, Ltd and ERP Environment

Carbon ion radiation is a promising new form of radiotherapy for cancer, but the central question about the biologic effects of charged particle radiation is yet incompletely understood. Key to this question is the understanding of the interaction of ions with DNA in the cell's nucleus. Induction and repair of DNA lesions including double-strand breaks (DSBs) are decisive for the cell. Several DSB repair markers have been used to investigate these processes microscopically, but the limited resolution of conventional microscopy is insufficient to provide structural insights. We have applied superresolution microscopy to overcome these limitations and analyze the fine structure of DSB repair foci. We found that the conventionally detected foci of the widely used DSB marker γH2AX (Ø 700-1000 nm) were composed of elongated subfoci with a size of ∼100 nm consisting of even smaller subfocus elements (Ø 40-60 nm). The structural organization of the subfoci suggests that they could represent the local chromatin structure of elementary DSB repair units at the DSB damage sites. Subfocus clusters may indicate induction of densely spaced DSBs, which are thought to be associated with the high biologic effectiveness of carbon ions. Superresolution microscopy might emerge as a powerful tool to improve our knowledge of interactions of ionizing radiation with cells.-Lopez Perez, R., Best, G., Nicolay, N. H., Greubel, C., Rossberger, S., Reindl, J., Dollinger, G., Weber, K.-J., Cremer, C., Huber, P. E. Superresolution light microscopy shows nanostructure of carbon ion radiation-induced DNA double-strand break repair foci.

A generalized Leontief cost function was used to investigate energy and non-energy input substitution possibilities and output scale effects on factor demand in Canadian agriculture. Results suggest that (1) substitution possibilities exist between energy and non-energy inputs, and energy and energy-based inputs appear to be complements; (2) labor is the best substitute for energy inputs, followed by land and other intermediate inputs; and (3) the output scale has significant effect in reducing production costs and decreasing the responsiveness of input to price changes. These findings indicate that an effective energy conservation measure would be the encouragement of production practices oriented to use more labor and land intensive techniques rather than using more agricultural chemicals for reducing cultivation practices. On a utilise une fonction de cout Leontief generalisee pour examiner d'une part les possibilities de substituer entrees energetiques el non energetiques et d'autre part les effets d'echelle de sortie sur la demande factorielle dans l'agriculture canadienne. Les resultats suggerent que: (1) il est possible de substituer entrees energetiques et non energetiques; les entrees energetiques et celles basees sur l'energie semblent complementaires, (2) la main-d'oeuvre est le meilleur substitut aux entrees energetiques; viennent ensuite la terre et autres entrees intermediares, et (3) l'echelle de sortie joue un role determinant dans la reduction des couts de production et dans une sensibilite plus petite des entrees aux changements de prix. Ces decouvertes indiquent qu'une mesure efficace pour conserver l'energie serait, plutol que d'utiliser davantage de produits chimiques agricoles, d'encourager les pratiques de production basee sur la main-d'oeuvre et l'utilisation intensive de la terre.

Retirement and succession considerations of family farm operators in Maryland are considered in this paper. Retirement decisions are found to be mainly determined by personal considerations, and only secondary importance is given to succession considerations. However, the relative importance of succession considerations is positively related to the importance of the farm enterprise relative to other income-generating activities of the family. The conclusion is that retirement and succession decisions in family farms are not separable.

Is a reduced share of agriculture in the economy an obstacle for the agricultural sector to play an important role in poverty alleviation? What is the key channel, if any, by which agriculture is benefiting the poor in Chile that would be worthwhile to promote in other countries? By answering these questions we expand the literature on poverty and composition of growth by proposing a methodology that allows to disentangle the mechanisms by which agricultural growth can be poverty reducing. We find that in Chile agriculture plays a large role in reducing poverty, and most of this effect is channeled through the labor market.

A common factor that explains why agriculture causes too much environmental degradation, grows too slowly, and has been ineffective in reducing rural poverty is the generalized tendency by governments to under invest in public goods despite the high rates of return to such investments. A large share of rural public expenditures is deviated to private goods (mostly subsidies to the wealthy), which generally have low or even negative rates of return. Behind such an obviously aberrant choice are political economy forces; a highly unequal political lobby market leads to government policies that are biased in favor of economic elites and detrimental for both the environment and rural development. Globalization may affect this important distortion on the allocation of government expenditures in various ways. One such way is by restricting the ability of governments to repress the political mobilization of the poor to counter the almost unchallenged power of the elites in the lobby market. This may contribute toward creating conditions that are more consistent with sustainable and socially equitable development.

In most patients with atrial fibrillation (AF) and stroke, there is thrombotic embolization from the left atrial appendage (LAA). Percutaneous closure of the LAA is a novel alternative for the treatment of patients with AF at a high risk of stroke, in whom long-term anticoagulation therapy is not possible or not desired. This study details the initial experience with the Amplatzer Cardiac Plug (ACP) in humans.Investigator-initiated retrospective preregistry data collection to evaluate procedural feasibility and safety up to 24 hr after implantation of the ACP, a nitinol device designed for percutaneous trans-septal implantation in LAA of patients with paroxysmal, permanent, or persistent AF.In 137 of 143 patients, LAA occlusion was attempted, and successfully performed in 132 (96%). There were serious complications in 10 (7.0%) patients (three patients with ischemic stroke; two patients experienced device embolization, both percutaneously recaptured; and five patients with clinically significant pericardial effusions). Minor complications were insignificant pericardial effusions in four, transient myocardial ischemia in two, and loss of the implant in the venous system in one patient.The implantation of the ACP device is a feasible method for percutaneous occlusion of the LAA.

This study is concerned with the measurement of factor demand responses and other production characteristics of the food processing industry in Canada. An important feature of the study is that it allows for non-competitive behaviour of the industry and thus permits an estimation of the degree of oligopoly power. The major results of the study are that the hypothesis of (output) price-taking behaviour is statistically rejected and that the average degree of oligopoly power is significant. Moreover, the industry appears to be quite responsive to changes in the factor price structure. Labour and energy are the most responsive inputs while raw food materials and capital show substantially less sensitivity to price variations.

This paper reports on the estimation of a dynamic model of the food manufacturing industry in Canada. Its major objectives are to analyze the determinants of investments and the production structure of the industry. An important finding of the study is that the hypothesis of instantaneous capital adjustment to changing market conditions is statistically rejected. Capital stock adjustment to optimal levels takes approximately two and one-third years. Another result is that although the industry is responsive to price changes, a general pattern of inelastic factor demand and output supply prevails in the short run, intermediate run, and even in the long run.

Hertel's major point is that some of my estimates (Lopez) would violate "predicted outcomes based on economic theory." These outcomes correspond to the so-called "normal" case as discussed by Hicks and others. Two types of "normal" outcomes are violated by my results, namely the gross input complementarity condition and the requirement that gross or Marshallian own-price elasticities need to be larger (in absolute values) than compensated or Hicksian elasticities. The gross complementarity condition does not follow from the theory of the profit-maximizing firm. It rather arises from assumptions regarding second derivatives of the production or transformation functions (i.e., cross-second derivatives among inputs are positive). The second set of conditions does follow from the theory of the firm, and its violation may suggest inconsistency between the estimated results and the underlying model. Therefore, these two sets of conditions are based on fundamentally different sources: the former depends on superimposed assumptions about the production technology on the profit maximization model, while the latter is inherent to the model. Hence, the evaluation of estimated elasticities using the first set of conditions is a dubious procedure since there is no a priori reason to assume that the technological assumptions underlying these conditions are of general validity, particularly in the multi-input, multi-output context.' Rather, the more reasonable approach would be to use empirical estimates to verify the degree of generality of such assumptions. With respect to the second set of conditions, I believe that they constitute sensible criteria for the evaluation of empirical estimates that are based on the profit-maximizing model. Their violation may reflect that the profit-maximizing model is inadequate, data problems, aggregation problems, etc. In my estimates this condition is not satisfied by the "land and structures" input when its own-price elasticities are evaluated at mean values of the variables. As discussed in the 1984 article (p. 364) the "land and structures" input is likely to suffer from measurement problems. It appears that the adjustments for "land and structure" quality were insufficient mainly due to the lack of data on qualitative aspects of structures. It is also interesting to indicate, however, that this condition is not violated at all sample points. In fact, when the elasticities are evaluated at about 25% of the sample points, the own gross-price elasticities of "land and structures" are greater in absolute value than the compensated elasticities, as the profit-maximization hypothesis implies.