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Purpose:Prostate-specific membrane antigen (PSMA) is an attractive target for radionuclide therapy of metastatic castration-resistant prostate cancer (mCRPC). PSMA-targeted alpha therapy (TAT) has shown early signs of activity in patients with prostate cancer refractory to beta radiation. We describe a novel, antibody-based TAT, the PSMA-targeted thorium-227 conjugate PSMA-TTC (BAY 2315497) consisting of the alpha-particle emitter thorium-227 complexed by a 3,2-HOPO chelator covalently linked to a fully human PSMA-targeting antibody.Experimental Design:PSMA-TTC was characterized for affinity, mode of action, and cytotoxic activity in vitro. Biodistribution, pharmacokinetics, and antitumor efficacy were investigated in vivo using cell line and patient-derived xenograft (PDX) models of prostate cancer.Results:PSMA-TTC was selectively internalized into PSMA-positive cells and potently induced DNA damage, cell-cycle arrest, and apoptosis in vitro. Decrease in cell viability was observed dependent on the cellular PSMA expression levels. In vivo, PSMA-TTC showed strong antitumor efficacy with T/C values of 0.01 to 0.31 after a single injection at 300 to 500 kBq/kg in subcutaneous cell line and PDX models, including models resistant to standard-of-care drugs such as enzalutamide. Furthermore, inhibition of both cancer and cancer-induced abnormal bone growth was observed in a model mimicking prostate cancer metastasized to bone. Specific tumor uptake and efficacy were demonstrated using various PSMA-TTC doses and dosing schedules. Induction of DNA double-strand breaks was identified as a key mode of action for PSMA-TTC both in vitro and in vivo.Conclusions:The strong preclinical antitumor activity of PSMA-TTC supports its clinical evaluation, and a phase I trial is ongoing in mCRPC patients (NCT03724747).

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Purpose:Targeted thorium-227 conjugates (TTC) represent a new class of molecules for targeted alpha therapy (TAT). Covalent attachment of a 3,2-HOPO chelator to an antibody enables specific complexation and delivery of the alpha particle emitter thorium-227 to tumor cells. Because of the high energy and short penetration range, TAT efficiently induces double-strand DNA breaks (DSB) preferentially in the tumor cell with limited damage to the surrounding tissue. We present herein the preclinical evaluation of a mesothelin (MSLN)-targeted thorium-227 conjugate, BAY 2287411. MSLN is a GPI-anchored membrane glycoprotein overexpressed in mesothelioma, ovarian, pancreatic, lung, and breast cancers with limited expression in healthy tissue.Experimental Design:The binding activity and radiostability of BAY 2287411 were confirmed bioanalytically. The mode-of-action and antitumor potency of BAY 2287411 were investigated in vitro and in vivo in cell line and patient-derived xenograft models of breast, colorectal, lung, ovarian, and pancreatic cancer.Results:BAY 2287411 induced DSBs, apoptotic markers, and oxidative stress, leading to reduced cellular viability. Furthermore, upregulation of immunogenic cell death markers was observed. BAY 2287411 was well-tolerated and demonstrated significant antitumor efficacy when administered via single or multiple dosing regimens in vivo. In addition, significant survival benefit was observed in a disseminated lung cancer model. Biodistribution studies showed specific uptake and retention of BAY 2287411 in tumors and enabled the development of a mechanistic pharmacokinetic/pharmacodynamic model to describe the preclinical data.Conclusions:These promising preclinical results supported the transition of BAY 2287411 into a clinical phase I program in mesothelioma and ovarian cancer patients (NCT03507452).

Supplementary Table 1

Supplementary Methods

Achieving the goals of the Paris Agreement and of climate neutrality by 2050 in the European Union will require mobilizing financial investments towards clean energy innovation. This study examines the role of internal finance (cash flows and cash holdings) and financing constraints for innovation in energy technologies. We construct a dataset for 1,300 European firms combining balance-sheet information and patenting activities in renewable (REN) and fossil-fuel (FF) technologies and estimate the sensitivity of patenting activities to firms’ internal finance. We use count estimation techniques and control for a large set of firm-specific characteristics and market developments in REN and FF technologies. We find that patenting activities of firms specialized in REN innovation are significantly more sensitive to a shock in cash flows than firms specializing in FF innovation. Hence, our results emphasize that innovative firms in clean energy may be particularly vulnerable to financing constraints. We discuss the implications of these results for energy transition policies aiming to redirect finance towards clean energy R&D.

Purpose Fibroblast growth factor receptor 2 (FGFR2) has been previously reported to be overexpressed in several types of cancer, whereas the expression in normal tissue is considered to be moderate to low. Thus, FGFR2 is regarded as an attractive tumor antigen for targeted alpha therapy. This study reports the evaluation of an FGFR2-targeted thorium-227 conjugate (FGFR2-TTC, BAY 2304058) comprising an anti-FGFR2 antibody, a chelator moiety covalently conjugated to the antibody, and the alpha particle–emitting radionuclide thorium-227. FGFR2-TTC was assessed as a monotherapy and in combination with the DNA damage response inhibitor ATRi BAY 1895344. Methods and Materials The in vitro cytotoxicity and mechanism of action were evaluated by determining cell viability, the DNA damage response marker γH2A.X, and cell cycle analyses. The in vivo efficacy was determined using human tumor xenograft models in nude mice. Results In vitro mechanistic assays demonstrated upregulation of γH2A.X and induction of cell cycle arrest in several FGFR2-expressing cancer cell lines after treatment with FGFR2-TTC. In vivo, FGFR2-TTC significantly inhibited tumor growth at a dose of 500 kBq/kg in the xenograft models NCI-H716, SNU-16, and MFM-223. By combining FGFR2-TTC with the ATR inhibitor BAY 1895344, an increased potency was observed in vitro, as were elevated levels of γH2A.X and inhibition of FGFR2-TTC–mediated cell cycle arrest. In the MFM-223 tumor xenograft model, combination of the ATRi BAY 1895344 with FGFR2-TTC resulted in significant tumor growth inhibition at doses at which the single agents had no effect. Conclusions The data provide a mechanism-based rationale for combining the FGFR2-TTC with the ATRi BAY 1895344 as a new therapeutic approach for treatment of FGFR2-positive tumors from different cancer indications.

This study considers the existence of a decline of academic skills in the summer – the so-called “summer slide” – in the context of a relatively short, six-week summer holiday. It further proposes that the extent of this decline will be moderated by home-based practice, and that this practice itself is a function of student and context-level factors. To investigate these issues, a pre-post (summer) study on mental arithmetic was conducted in the summer of 2018 among 932 Dutch grade 2 children. The results demonstrate a sizeable summer learning loss, finding a 0.26 s.d. decline in performance post vs pre-summer. The effect is significantly ameliorated through observed practice on an online educational platform (Squla), but not through self-reported practice. In contrast, perceived competence, gender, and socio-economic status correlate with self-reported practice, but not with observed practice. We discuss the implications of these results for existing and future research in the literature.

Purpose: Prostate-specific membrane antigen (PSMA) is an attractive target for radionuclide therapy of metastatic castration-resistant prostate cancer (mCRPC). PSMA-targeted alpha therapy (TAT) has shown early signs of activity in patients with prostate cancer refractory to beta radiation. We describe a novel, antibody-based TAT, the PSMA-targeted thorium-227 conjugate PSMA-TTC (BAY 2315497) consisting of the alpha-particle emitter thorium-227 complexed by a 3,2-HOPO chelator covalently linked to a fully human PSMA-targeting antibody. Experimental Design: PSMA-TTC was characterized for affinity, mode of action, and cytotoxic activity in vitro. Biodistribution, pharmacokinetics, and antitumor efficacy were investigated in vivo using cell line and patient-derived xenograft (PDX) models of prostate cancer. Results: PSMA-TTC was selectively internalized into PSMA-positive cells and potently induced DNA damage, cell-cycle arrest, and apoptosis in vitro. Decrease in cell viability was observed dependent on the cellular PSMA expression levels. In vivo, PSMA-TTC showed strong antitumor efficacy with T/C values of 0.01 to 0.31 after a single injection at 300 to 500 kBq/kg in subcutaneous cell line and PDX models, including models resistant to standard-of-care drugs such as enzalutamide. Furthermore, inhibition of both cancer and cancer-induced abnormal bone growth was observed in a model mimicking prostate cancer metastasized to bone. Specific tumor uptake and efficacy were demonstrated using various PSMA-TTC doses and dosing schedules. Induction of DNA double-strand breaks was identified as a key mode of action for PSMA-TTC both in vitro and in vivo. Conclusions: The strong preclinical antitumor activity of PSMA-TTC supports its clinical evaluation, and a phase I trial is ongoing in mCRPC patients (NCT03724747).

The solution chemistry of a chelator developed for 227Th targeted alpha therapy was probed. The compound of interest is an octadentate ligand comprising four N-methyl-3-hydroxy-pyridine-2-one metal-binding units, two tertiary amine groups, and one carboxylate arm appended for bioconjugation. The seven p Ka values of the ligand and the stability constants of complexes formed with Th(IV), Hf(IV), Zr(IV), Gd(III), Eu(III), Al(III), and Fe(III) were determined. The ligand exhibits extreme thermodynamic selectivity toward tetravalent metal ions with a ca. 20 orders of magnitude difference between the formation constant of the Th(IV) species formed at physiological pH, namely [ThL]-, and that of its Eu(III) analogue. Likewise, log β110 values of 41.7 ± 0.3 and 26.9 ± 0.3 (T = 25 °C) were measured for [ThL]- and [FeIIIL]2-, respectively, highlighting the high affinity and selectivity of the ligand for Th ions over potentially competing endogenous metals. Single crystal X-ray analysis of the Fe(III) complex revealed a dinuclear 2:2 metal:chelator complex crystallizing in the space group P1. The formation of this dimeric species is likely favored by several intramolecular hydrogen bonds and the protonation state of the chelator in acidic media. LIII edge EXAFS data on the Th(IV) complexes of both the ligand and a monoclonal antibody conjugate revealed the expected mononuclear 1:1 metal:chelator coordination environment. This was also confirmed by high resolution mass spectrometry. Finally, kinetic experiments demonstrated that labeling the bioconjugated ligand with Th(IV) could be achieved and completed after 1 h at room temperature, reinforcing the high suitability of this chelator for 227Th targeted alpha therapy.

Purpose: Targeted thorium-227 conjugates (TTC) represent a new class of molecules for targeted alpha therapy (TAT). Covalent attachment of a 3,2-HOPO chelator to an antibody enables specific complexation and delivery of the alpha particle emitter thorium-227 to tumor cells. Because of the high energy and short penetration range, TAT efficiently induces double-strand DNA breaks (DSB) preferentially in the tumor cell with limited damage to the surrounding tissue. We present herein the preclinical evaluation of a mesothelin (MSLN)-targeted thorium-227 conjugate, BAY 2287411. MSLN is a GPI-anchored membrane glycoprotein overexpressed in mesothelioma, ovarian, pancreatic, lung, and breast cancers with limited expression in healthy tissue. Experimental Design: The binding activity and radiostability of BAY 2287411 were confirmed bioanalytically. The mode-of-action and antitumor potency of BAY 2287411 were investigated in vitro and in vivo in cell line and patient-derived xenograft models of breast, colorectal, lung, ovarian, and pancreatic cancer. Results: BAY 2287411 induced DSBs, apoptotic markers, and oxidative stress, leading to reduced cellular viability. Furthermore, upregulation of immunogenic cell death markers was observed. BAY 2287411 was well-tolerated and demonstrated significant antitumor efficacy when administered via single or multiple dosing regimens in vivo. In addition, significant survival benefit was observed in a disseminated lung cancer model. Biodistribution studies showed specific uptake and retention of BAY 2287411 in tumors and enabled the development of a mechanistic pharmacokinetic/pharmacodynamic model to describe the preclinical data. Conclusions: These promising preclinical results supported the transition of BAY 2287411 into a clinical phase I program in mesothelioma and ovarian cancer patients (NCT03507452).

In this paper we provide an analysis of directed technical change in the sector of electricity generation. We rely on patent data in fossil-fuel (FF) and renewable energy (REN) technologies for 5471 European firms over the 1978–2006 period. The novelty of our approach is in the focus on firm׳s heterogeneity in driving technological change. We make a distinction between small specialized firms, which innovate in only one type of technology, and large mixed firms, which innovate in both technologies, to analyse how REN patents can replace FF ones at the sector level both through a shift in innovation activities within existing firms and through firms׳ entry and exit. We use zero-inflated count data estimation techniques to identify the factors that affect specialized versus mixed firms׳ patenting behaviour both at the intensive (i.e., levels of innovation) and extensive (i.e., technological entry) margins. We further investigate the implications of our firm-level estimations for reducing the gap between REN and FF innovation at the aggregate level. We establish two key findings: (1) a decrease in the FF-REN technology gap mainly comes about through technological entry of specialized REN firms following an increase in REN market size; (2) increases in FF prices, FF market size, and FF knowledge stocks all increase the technology gap by increasing mixed firms FF innovation rates. An important implication of our results is that policies aimed at increasing REN innovation should focus on helping small firms to start and sustain innovation in the long-run.

We analyze the conditions determining optimal technology seeking strategies for leader and laggard firms. We extend existing theories by differentiating leaders and laggards in terms of absorptive capacity and intra-firm technology transfer skills, next to productivity levels. In addition, both Foreign Direct Investment (FDI) as well as exports function as two alternative technology seeking strategies. Our theoretical results demonstrate that for a wide range of parameter settings, leaders optimally seek technology through FDI, whereas laggards do so through exports. Confronting these findings with some original exploratory industry-level analysis complemented by insights derived from case studies, we find broad overall support for our theoretical predictions.Highlights► We model optimal technology seeking strategies of leading and lagging firms in international duopoly. ► We find that laggards optimally engage in exports and leaders in FDI for a wide range of different parameter settings and assumptions. ► Exploratory case studies and some novel econometric analysis support the implications of our model. ► Our results bridge the gap between the established theory in this literature and some recent contrasting empirical evidence.

This paper utilizes new Dutch transaction-level data on international trade to investigate the microeconomic patterns of Dutch exports. First, we show that self-selection based on ex-ante productivity drives firms’ export decisions, which we subsequently relate to various sources of fixed market-entry costs: governance and regulatory quality, the extent of corruption, and cultural proximity. Second, we provide evidence that firms learn to export by trial and error, so as to obtain experience in exporting and to gather knowledge about the potential of foreign markets. Such experimentation appears to be reflected in the volatility of a firm’s export product portfolio. More volatility is associated with a higher survival rate in the export market. Finally, we draw conclusions on the potential implications for trade policy.

Many international business (IB) studies have used foreign direct investment (FDI) stocks to measure the aggregate value-adding activity of multinational enterprises (MNE) affiliates in host countries. We argue that FDI stocks are a biased measure of that activity, because the degree to which they overestimate or underestimate affiliate activity varies systematically with host-country characteristics. First, most FDI into countries that serve as tax havens generate no actual productive activity; thus FDI stocks in such countries overestimate affiliate activity. Second, FDI stocks do not include locally raised external funds, funds widely used in countries with well-developed financial markets or volatile exchange rates, resulting in an underestimation of affiliate activity in such countries. Finally, the extent to which FDI translates into affiliate activity increases with affiliate labor productivity, so in countries where labor is more productive, FDI stocks also result in an underestimation of affiliate activity. We test these hypotheses by first regressing affiliate value-added and affiliate sales on FDI stocks to calculate a country-specific mismatch, and then by regressing this mismatch on a host country's tax haven status, level of financial market development, exchange rate volatility, and affiliate labor productivity. All hypotheses are supported, implying that FDI stocks are a biased measure of MNE affiliate activity, and hence that the results of FDI-data-based studies of such activity need to be reconsidered. © 2010 Academy of International Business All rights reserved. ispartof: Journal of International Business Studies vol:41 issue:9 pages:1444-1459 status: published

Smeets R. and Wei Y. Productivity effects of United States multinational enterprises: the roles of market orientation and regional integration, Regional Studies. This paper considers the role of market orientation and regional integration in foreign direct investment (FDI) productivity effects. Using data of United States multinational enterprises operating in eight industries and thirteen Organisation for Economic Co-operation and Development (OECD) countries during 1987-2003, the productivity effects of local market-oriented FDI versus export-oriented FDI are compared, with the latter being split into FDI oriented at the parent and that at parties in third countries. Their productivity effects are also considered within two regional agreements: the Canadian-United States Free Trade Agreement (CUSFTA) and the European Union. Robust positive horizontal effects of parent firm-oriented FDI and third-country-oriented FDI are found, with notable differences in the effects of these FDI types between CUSFTA and the European Union. [image omitted] Smeets R. et Wei Y. Les effets productivite des societes multinationales aux Ue: le role de l'orientation marche et de l'integration regionale, Regional Studies. Cet article cherche a evaluer le role de l'orientation marche et de l'integration regionale dans les effets productivite de l'IDE. A partir des donnees sur les societes multinationales aux E-U installees dans huit industries et treize pays-membres de l'OCDE entre 1987 et 2003, on compare les effets productivite de l'IDE oriente vers le marche local a l'IDE a vocation exportatrice, ce dernier etant divise entre l'IDE oriente vers la maison-mere et celui qui est oriente vers des partenaires situees dans des pays tiers. On considere aussi leurs effets productivite dans deux zones regionales: a savoir, la CUSFTA (la zone du libre-echange entre le Canada et les Etats-Unis) et l'Ue. Il s'avere des effets horizontaux positifs soutenus quant a l'IDE oriente vers la maison-mere et les pays tiers, y compris d'importantes differences des effets de ces categories d'IDE entre la CUSFTA et l'Ue. Retombees IDE Orientation marche Integration regionale Smeets R. und Wei Y. Produktivitatseffekte multinationaler Unternehmen in den USA: die Rolle der Marktorientierung und regionalen Integration, Regional Studies. In diesem Beitrag untersuchen wir die Rolle der Marktorientierung und regionalen Integration auf die Produktivitatseffekte auslandischer Direktinvestitionen. Anhand der Daten US-amerikanischer multinationaler Unternehmen, die zwischen 1987 und 2003 in acht Branchen und 13 OECD-Staaten tatig waren, vergleichen wir die Produktivitatseffekte von am lokalen Markt orientierten Auslandsdirektinvestitionen mit denen von exportorientierten Auslandsdirektinvestitionen, wobei in der zweiten Kategorie zwischen Investitionen, die sich an der Muttergesellschaft orientieren, und Investitionen, die sich an Parteien in Drittlandern orientieren, unterschieden wurde. Ebenso untersuchen wir die Auswirkungen auf die Produktivitat innerhalb von zwei Regionalabkommen: dem CUSFTA und der EU. Wir finden robuste positive horizontale Auswirkungen auf die muttergesellschafts- und drittlandorientierten Auslandsdirektinvestitionen, wobei sich im Vergleich zwischen CUSFTA und EU deutliche Unterschiede hinsichtlich der Auswirkungen dieser Arten von Auslandsdirektinvestitionen zeigen. Ubertragungen durch Auslandsdirektinvestitionen Marktorientierung Regionale Integration Smeets R. y Wei Y.Efectos de productividad de empresas multinacionales de los Estados Unidos: los roles de la oientacion mercantil y la integracion regional, Regional Studies. En este articulo analizamos el papel de la orientacion mercantil y la integracion regional en los efectos de productividad de la Inversion Directa Extranjera (IDE). Con ayuda de datos de empresas multinacionales estadounidenses que operaron en 8 industrias y 13 paises de la OCDE durante 1987-2003, comparamos los efectos de la productividad de la IDE en mercados locales con la IDE en mercados de exportacion, esta ultima dividida entre la IDE para sociedades matrices y partidos en paises terceros. Asimismo consideramos sus efectos de productividad en el marco de dos acuerdos regionales: el CUSFTA (Tratado de Libre Comercio entre Canada y Estados Unidos) y la UE. Observamos solidos efectos horizontales positivos de la IDE en sociedades matrices y la IDE en paises terceros, con notables diferencias en los efectos de estos tipos de IDE entre el CUSFTA y la UE. Desbordamientos de la IDE Orientacion mercantil Integracion regional.

I Introduction RECENT INTEREST IN THE RELATIONSHIP between culture and economic development (Landes 1998; Fukuyama 1995; Knack and Keefer 1997; Zak and Knack 2001) has triggered the cultural dimension of entrepreneurship research (Shane 2003; Wennekers et al. 2005). The idea of an entrepreneurial culture being an important driving force of economic development is mainly based on anecdotal evidence, but seems to become more and more accepted. The basic reference that can be found in most papers dealing with entrepreneurship, economic development, and societal differences between countries is McClelland's The Achieving Society (1961). McClelland found a strong positive correlation between measures of need for achievement (N achievement) imagery in school textbooks and the rate of economic growth. He showed that such a relationship exists in two samples of 23 and 41 countries by relating 1925 and 1955 scores, respectively, on N achievement to subsequent economic growth. The intuitively attractive result, that economic growth partly results from the (entrepreneurial) ambition of human beings, has gradually become generally accepted. Most papers on entrepreneurship and economic development refer to McClelland's Achieving Society in their introduction as a common point of departure. (1) This is not to say that McClelland has not been criticized. His thesis has come under attack by a number of scholars from a range of disciplines, especially in the early 1960s (Rubin 1963; Schatz 1965, 1971). More recently, Pryor (2005) has demonstrated that a robust relationship between economic growth and national values in general does not exist. Empirical reestimations of McClelland's thesis do exist, but they are limited in scope and scale. Previous reestimations concern simple correlations between N achievement and economic data, or regressions including none or only a limited number of control variables. Since the 1960s, however, economic growth theory has expanded. Modern growth theory (Barro 1991; Barro and Sala-I-Martin 1995; Aghion and Howitt 1998) has resulted in a "standard" empirical growth model. This type of empirical growth regression typically includes initial level of welfare and proxies for human and physical capital (mostly the school enrollment ratio and the investment ratio). These growth models are also referred to as Barro regressions (after Barro 1991). The contribution we make in this article is confined to an empirical reestimation of McClelland's thesis and the development of an agenda for future research in this area. Building upon modern growth theory, we develop a basic empirical growth model and test if N achievement is related to economic growth. By providing a more advanced reestimation of McClelland's thesis, we complement existing literature in an important way. This is useful, as the increased interest in the cultural drivers of economic development, including entrepreneurship, has resulted in a revival of interest among economists in McClelland's work. Bibliometric analysis shows that McClelland's work has been cited in economics journals, especially in the late 1970s and early 1980s. (2) Whereas the early (critical) responses referring to The Achieving Society were mainly book reviews, starting in the late 1970s, McClelland's analysis became widespread among scholars interested in crossing the disciplinary boundaries of economics, especially sociopsychology. Not surprisingly, the three journals that contain the most citations to The Achieving Society are Economic Development and Cultural Change (first place, with 18 citations), Journal of Economic Psychology (in second, with 10 citations), and American Journal of Economics and Sociology (third, with 8 citations). Most recently, Small Business Economics, a journal focusing on entrepreneurship, also has contained a significant number of citations to McClelland. The picture that emerges is one in which McClelland's work keeps on generating interest for those working on entrepreneurship. …

Contains fulltext : 157205.pdf (Publisher’s version ) (Closed access) In this paper we investigate the impact of increased Intellectual Property Rights (IPR) protection on the productivity effects that MNE affiliates exert on local host-country firms. Conceptually, we argue that IPR protection has two opposing effects: On the one hand, it weakens the productivity effects through reduced knowledge spillovers and increased monopoly power of MNE affiliates. On the other hand, it strengthens productivity effects through increased knowledge sharing (with local suppliers) and higher quality products and processes produced and used by MNE affiliates. Given these opposing forces, the net outcome is an empirical matter. Using a sample of 81,299 local firms in 17 countries, we find that increased IPR protection strengthens backward (to supplier) productivity effects and weakens forward (to customer) productivity effects. These moderating effects of IPR protection are only observed in industries that strongly rely on patents to protect intellectual property. The results suggest that increased IPR protection leads to increased knowledge sharing with local suppliers, yet also to increased monopoly power over local (corporate) customers. 28 augustus 2015

This paper investigates the determinants of directed technical change at the Firm level in the electricity generation sector. We use firm-level data on patents filed in renewable (REN) and fossil fuel (FF) technologies by 5,261 european firms over the period 1978-2006. We investigate how energy prices, market size and knowledge stocks affect firms' incentives to innovate in one technology relative to another and how these factors may thereby induce a shift from FF to REN technology in the electricity generation sector. We separately study small specialized firms, which innovate in only one type of technology during our sample period, and large mixed firms, which innovate in both technologies. We also separate the extensive margin innovation decision (i.e. whether to conduct innovation) from the intensive margin decision (i.e. how much to innovate). Overall, we find that all three factors - energy prices, market sizes and past knowledge stocks - matter to redirect innovation towards REN and away from FF technologies. Yet, we find that these factors have a larger impact on closing the technology gap through the entry (and exit) of small specialized firms, rather than through large mixed firms' innovation. An implication of our results is that firm dynamics are of direct policy interest to induce the replacement of FF by REN technologies in the electricity generation sector.

This study investigates if firms' involvement in patent litigation as alleged infringers hinders their innovation. I develop a simple model that predicts a decrease in innovation following patent litigation. I investigate the model's implications in a sample of publicly listed US firms, using a combination of propensity score matching and difference-in-differences estimation. I find a negative impact of patent litigation on corporate R&D intensity - in the range of 2.6-4.7%-points - in small firms (with less than 500 employees), that are involved in extensive patent lawsuits (captured by the number of legal documents filed).

This paper investigates the determinants of directed technical change at the firm level in the electricity generation sector. We use firm-level data on patents filed in renewable (REN) and fossil fuel (FF) technologies by 5,261 European firms over the period 1978-2006. We investigate how energy prices, market size and knowledge stocks affect firms' incentives to innovate in one technology relative to another and how these factors may thereby induce a shift from FF to REN technology in the electricity generation sector. We separately study small specialized firms, which innovate in only one type of technology during our sample period, and large mixed firms, which innovate in both technologies. We also separate the extensive margin innovation decision (i.e. whether to conduct innovation) from the intensive margin decision (i.e. how much to innovate). Overall, we find that all three factors -- energy prices, market sizes and past knowledge stocks -- matter to redirect innovation towards REN and away from FF technologies. Yet, we find that these factors have a larger impact on closing the technology gap through the entry (and exit) of small specialized firms, rather than through large mixed firms' innovation. An implication of our results is that firm dynamics are of direct policy interest to induce the replacement of FF by REN technologies in the electricity generation sector.

Mesothelin (MSLN) is a 40 kDa membrane-anchored glycoprotein, involved in mediating cell-cell adhesion, metastatic spread, promotion of cell proliferation and resistance to apoptosis. Overexpression of MSLN is most prominent in mesothelioma, ovarian, lung, triple-negative breast (TNBC) and pancreatic cancers, while in healthy tissue, MSLN is confined mainly to the mesothelial cells of the peritoneum and pericardium. Several MSLN-targeting approaches are currently being investigated, including antibody drug conjugates. We describe herein a high energy, alpha-particle emitting MSLN Targeted Thorium Conjugate (MSLN-TTC). Thorium-227 (227Th) has a half-life of 18.7 days and decays via emission of an alpha particle to radium-223 (half-life 11.4 days), a calcium-mimetic used in the treatment of CRPC [1]. The MSLN-TTC comprises an anti-mesothelin monoclonal antibody covalently linked via an amide bond to a chelator moiety possessing high affinity for thorium-227. We present data from in vitro cytotoxicity assays demonstrating selective cell killing on MSLN positive cell-lines as well as in vivo efficacy in a mouse orthotopic bone xenograft model using NCI-H226 luciferase labeled cells. Experimental procedures: MSLN-TTC was prepared in high radiochemical yields and purity. In vitro cytotoxicity experiments were performed on the mesothelin-positive cell lines Ovcar-3 (ovarian), NCI-H226 (lung mesothelioma) and mesothelin-transfected HT29 (HT29MSLN/colorectal) cells. An in vivo model was established by orthotopic intratibial inoculation of luciferase-transfected NCI-H226 cells in athymic mice. Development of bone disease was monitored by luciferase activity and the extent of bone lesions determined by x-ray imaging and microCT. Results: MSLN-TTC induced specific in vitro cytotoxicity via induction of DNA double strand breaks as determined by phosphorylated histone protein H2AX. MSLN-TTC demonstrated statistical significant in vivo potency administered as a single dose of either 250 or 500 kBq/ kg in the orthotopic bone xenograft model. Animals treated with MSLN-TTC showed a) significantly reduced disease in the bone metastatic lesions b) decreased metastatic disease in the lungs and c) significant reduction in osteolytic/ osteoblastic bone lesions as evidenced by X-Ray and microCT compared to the vehicle control group. Furthermore, no significant loss in body weight was observed during the course of the study demonstrating that the MSLN-TTC was well tolerated. The data presented support the further investigation of the MSLN-TTC in bone metastatic disease. References: 1. Henriksen, G., et al., Targeting of osseous sites with alpha-emitting 223Ra: comparison with the beta-emitter 89Sr in mice. J Nucl Med, 2003. 44(2): p. 252-9. Citation Format: Urs B. Hagemann, Else-Marie Hagelin, Katrine Wickstroem, Kristine Sponheim, Roger Smeets, Jenny Karlsson, Roger M. Bjerke, Mari I. Suominen, Yvonne Konkol, Jenni Bernoulli, Jukka Rissanen, Jussi Halleen, Liv-Ingrid Oedegaardstuen, Alan Cuthbertson. A novel high energy alpha-pharmaceutical: In vitro and in vivo potency of a mesothelin-targeted thorium-227 conjugate (TTC) in a model of bone disease. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 591.

This paper has two aims. First, we uncover some salient components of fixed export costs, which play a crucial role in recent heterogeneous firms models of international trade. Second, we investigate whether the importance of these fixed export costs varies with the size of a firm’s export product portfolio. We find that a destination country’s institutional quality, such as the quality of regulation or the extent of corruption, form important impediments to a firm’s export decision, lowering the export probability to up to 10%-points. Moreover, relative to single-product firms, multi-product firms experience additional export probability decreases of around 2%-points.

Even though the Netherlands was the world’s sixth largest exporter in 2009, the majority of Dutch firms does not engage in international trade at all, possibly because they are unable to cover the costs to enter specific foreign markets. What are these costs that limited the internationalisation of Dutch firms? Using detailed and unique transaction-level data on export patterns of about 1,200 large Dutch firms in the years 2006-2007, this research opens the black box of market entry costs. First, we find that more productive firms are both more likely to engage in exports (extensive margin) and to export larger volumes abroad (intensive margin). Second, next to the common determinants of export volumes, such as market size, transport and trade costs, we find that poorly developed foreign institutions and regulations form important impediments to firms’ export decisions, but not to their subsequent export volume decisions. We also find some evidence that such effects on the export decision are relatively large in small markets, whereas export volumes react more to changes in trade and transport costs in large markets.

Recent surveys of the empirical literature have concluded that the evidence is mixed on the magnitude, direction, and even existence of knowledge spillovers from foreign direct investment (FDI). This article reviews the recent theoretical and empirical literature that responds to these inconclusive results and considers three main issues: spillover channels, mediating factors, and FDI heterogeneity. Studies that take into account individual spillover channels find robust evidence of knowledge spillovers from FDI. Studies on the importance of mediating factors and FDI heterogeneity are less conclusive and could benefit from greater convergence in methodologies and greater specificity in the spillover channels of interest. More generally, many studies do not properly distinguish between knowledge spillovers and knowledge transfers, and empirical studies seem to greatly outnumber theoretical studies. Copyright The Author 2008. Published by Oxford University Press on behalf of the International Bank for Reconstruction and Development / the world bank . All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org, Oxford University Press.

In this paper, we contribute to the literature investigating the impact of FDI on host country economic growth by distinguishing between the growth effects of horizontal (market seeking) FDI and vertical (efficiency seeking) FDI. Using a new database, we estimate the growth effects of vertical and horizontal US MNE activity into 44 host countries over the period 1983–2003, also using traditional total FDI figures as a benchmark. Controlling for endogeneity and absorptive capacity effects, we find that horizontal and vertical FDI have positive and significant growth effects in developed countries. Moreover, our results indicate a superior growth effect of horizontal FDI over vertical FDI. In line with existing literature, we find no significant effects of horizontal or vertical FDI in developing countries.

Contains fulltext : 45672.pdf (Publisher’s version ) (Closed access) Previous literature on openness has mainly dealt with the consequences of openness. In this paper, however, we are interested in the cultural determinants of openness. Conducting a cross-country analysis incorporating 53 countries over the period 1959–1997, we find that several aspects of national culture have an impact on openness. Specifically, we find positive effects of individualism and negative effects of uncertainty avoidance and power distance on openness. These findings point to the importance of taking cultural influences into account in future research on openness. Interestingly, the cultural effects were found to become stronger over time and to smoothen out in the end of the study period. This result is in line with the idea that the effect of culture may be expressed most clearly in situations where freedom of choice for policy makers is greatest. When this freedom is restricted, because of scarcity reasons or because there is a dominant view on best practice, the possibility of cultural preferences to influence policy decisions seems to be smaller. 26 p.

We study the impact of patent litigation on the patenting propensity of individual inventor-owners, i.e. inventors that also own their patents. We firt develop a theoretical framework in which inve...

We study the settlement and non-settlement outcomes of foreign and US patent holders in US patent litigation. We argue that foreign patent holders may be systematically more likely to settle, and l...

Knowledge generation and innovation are the cornerstones of every modern developed economy. Not only do they bring benefits to the firms engaging in them, they also induce positive externalities (o...

This study investigates the extent to which domestic and foreign R&D workers (i.e. “inventors”) employed by multinationals (MNEs) are complements or substitutes to each other. We argue that this re...