UV-induced melanoma mouse model dependent on endothelin 3 over-expression

Melanoma is one of the most aggressive types of cancer. It originates from the transformation of melanocytes present in the epidermal/dermal junction of the human skin. It is commonly accepted that melanomagenesis is influenced by the interaction of environmental factors, genetic factors, as well as tumor-host interactions. DNA photoproducts induced by UV radiation are, in normal cells, repaired by the nucleotide excision repair (NER) pathway. The prominent role of NER in cancer resistance is well exemplified by patients with Xeroderma Pigmentosum (XP). This disease results from mutations in the components of the NER pathway, such as XPA and XPC proteins. In humans, NER pathway disruption leads to the development of skin cancers, including melanoma. Similar to humans afflicted with XP, Xpa and Xpc deficient mice show high sensibility to UV light, leading to skin cancer development, except melanoma. The Endothelin 3 (Edn3) signaling pathway is essential for proliferation, survival and migration of melanocyte precursor cells. Excessive production of Edn3 leads to the accumulation of large numbers of melanocytes in the mouse skin, where they are not normally found. In humans, Edn3 signaling pathway has also been implicated in melanoma progression and its metastatic potential. The goal of this study was the development of the first UV-induced melanoma mouse model dependent on the over-expression of Edn3 in the skin. The UV-induced melanoma mouse model reported here is distinguishable from all previous published models by two features: melanocytes are not transformed a priori and melanomagenesis arises only upon neonatal UV exposure. In this model, melanomagenesis depends on the presence of Edn3 in the skin. Disruption of the NER pathway due to the lack of Xpa or Xpc proteins was not essential for melanomagenesis; however, it enhanced melanoma penetrance and decreased melanoma latency after one single neonatal erythemal UV dose. Exposure to a second dose of UV at six weeks of age did not change time of appearance or penetrance of melanomas in this mouse model. Thus, a combination of neonatal UV exposure with excessive Edn3 in the tumor microenvironment is sufficient for melanomagenesis in mice; furthermore, NER deficiency exacerbates this process.^

UV-Induced Melanoma Mouse Model Dependent on Endothelin 3 Over-Expression

Melanoma is one of the most aggressive types of cancer. It originates from the transformation of melanocytes present in the epidermal/dermal junction of the human skin. It is commonly accepted that melanomagenesis is influenced by the interaction of environmental factors, genetic factors, as well as tumor-host interactions. DNA photoproducts induced by UV radiation are, in normal cells, repaired by the nucleotide excision repair (NER) pathway. The prominent role of NER in cancer resistance is well exemplified by patients with Xeroderma Pigmentosum (XP). This disease results from mutations in the components of the NER pathway, such as XPA and XPC proteins. In humans, NER pathway disruption leads to the development of skin cancers, including melanoma. Similar to humans afflicted with XP, Xpa and Xpc deficient mice show high sensibility to UV light, leading to skin cancer development, except melanoma. The Endothelin 3 (Edn3) signaling pathway is essential for proliferation, survival and migration of melanocyte precursor cells. Excessive production of Edn3 leads to the accumulation of large numbers of melanocytes in the mouse skin, where they are not normally found. In humans, Edn3 signaling pathway has also been implicated in melanoma progression and its metastatic potential. The goal of this study was the development of the first UV-induced melanoma mouse model dependent on the over-expression of Edn3 in the skin. The UV-induced melanoma mouse model reported here is distinguishable from all previous published models by two features: melanocytes are not transformed a priori and melanomagenesis arises only upon neonatal UV exposure. In this model, melanomagenesis depends on the presence of Edn3 in the skin. Disruption of the NER pathway due to the lack of Xpa or Xpc proteins was not essential for melanomagenesis; however, it enhanced melanoma penetrance and decreased melanoma latency after one single neonatal erythemal UV dose. Exposure to a second dose of UV at six weeks of age did not change time of appearance or penetrance of melanomas in this mouse model. Thus, a combination of neonatal UV exposure with excessive Edn3 in the tumor microenvironment is sufficient for melanomagenesis in mice; furthermore, NER deficiency exacerbates this process.

Federal tax deductibility for local taxes and its effect on local revenue policies

This dissertation analyzes whether and how changes in federal tax policy affect local tax policies, specifically, the elimination of the federal deductibility of state and local taxes for individual taxpayers by the Tax Reform Act of 1986 (TRA86) in 59 California cities. Two methods are used in the study: a survey of local revenue officials and a time event time-series/cross sectional sales tax reliance study.^ The reliance study uses a covariance model to pool cross-section and time-series observations. The results of the reliance study indicate a statistically significant overall decline in sales tax reliance after 1986. The results of the survey indicate that local policy makers generally do not believe that federal deductibility is an important factor when considering raising local sales taxes. Further analysis shows that local revenue officials claiming federal deductibility is not an important factor are associated mostly with cities that registered no significant decline in sales tax reliance after 1986. Similarly, local revenue officials claiming federal deductibility is an important factor when considering local tax policy are associated mostly with cities that suffered a significant decline in sales tax reliance after 1986.^ Of that group, further analysis shows that the declines in sales tax reliance are associated mostly with cities located in the southwestern part of the state. When compared to other cities in the state, an analysis of variance reveals that there are a series of statistically significant factors associated with southwestern cities which may contribute to the decline in sales tax reliance following the enactment of the Tax Reform Act of 1986. ^

The effect of cross -age tutoring routines on the tutor's perception of self as reader

Perception of self as a non-reader has been identified as one of the factors why poor readers disengage from the reading process (Strang, 1967; Rosow, 1992), thus impeding progress. Perception and informational processes influence judgments of personal efficacy (Bandura, 1997). The student's sense of reading efficacy that influence effort expenditure and ultimately achievement, is often overlooked (Athey, 1985; Pajares, 1996). Academic routines within educational programs are implemented without adequate information on whether routines promote or impede efficacy growth. Cross-age tutoring, a process known to improve participants' academic achievement, motivation, and provide opportunities for authentic reading practice, has been successfully incorporated into reading instruction designs (Allen, 1976; Cohen, Kulik & Kulik, 1982; Labbo & Teale, 1990; Riessman, 1993). This study investigated the impact teacher-designed routines within a cross-age tutoring model, have on the tutor's sense of reading self-efficacy. ^ The Reader Self-Perception Scale (Henk & Melnick, 1992) was administered, pre- and post-treatment, to 118 fifth grade students. Preceding the initial survey administration intact classes were randomly assigned to 1 of 3 commonly utilized cross-age tutoring routines or designated as the non-treatment population. The data derived from the Reader Self-Perception Scale was analyzed using an analysis of covariance (ANCOVA). Results indicated that participation as a cross-age tutor does not significantly increase the tutor's perception of self as reader in 1 or more of the 4 modes of information influencing self-efficacy as compared to the non-treatment group. ^ The results of this study suggests that although a weekly tutoring session that delivers educationally credible routines impacts achievement and motivation, efficacy effect was not evident. Possible explanation and recommendations for future studies are proposed. ^

Interdependencies in corporate development: Relationship between strategic alliance and acquisition activities

A substantial amount of work in the field of strategic management has attempted to explain the antecedents and outcomes of organizational learning. Though multinational corporations simultaneously engage in various types of tasks, activities, and strategies on a regular basis, the transfer of organizational learning in a multi-task context has largely remained under-explored in the literature. To inform our understanding in this area, this dissertation aimed at synthesizing findings from two parallel research streams of corporate development activities: strategic alliances and acquisitions. Structured in the form of two empirical studies, this dissertation examines: 1) the strategic outcomes of alliance experience of previously allying partners in terms of subsequent acquisition attempts, and 2) the performance implications of prior alliance experience for acquisitions. The first study draws on the relational view of inter-organizational governance to explain how various deal-specific and dyadic characteristics of a partnership relate to partnering firms' post-alliance acquisition attempts. This model theorizes on a variety of relational mechanisms to build a cohesive theory of inter-organizational exchanges in a multi-task setting where strategic alliances ultimately lead to a firm's decision to commit further resources. The second study applies organizational learning theory, and specifically examines whether frequency, recency, and relatedness of different dimensions of prior alliances, beyond the dyad-level experience, relate to an acquirer's superior post-acquisition performance. The hypotheses of the studies are tested using logistic and ordinary least square regressions, respectively. Results analyzed from a sample of cross-border alliance and acquisition deals attempted (for study I) and/or completed (for study II) during the period of 1991 to 2011 generally support the theory that relational exchange determines acquiring firms' post alliance acquisition behavior and that organizational routines and learning from prior alliances influence a future acquirer's financial performance. Overall, the empirical findings support our overarching theory of interdependency, and confirm the transfer effect of learning across these alternate, yet related corporate strategies of alliance and acquisition.^

Synthesis of multisubstituted halo -olefins via Pd-catalyzed cross -coupling reactions. Applications in nucleoside chemistry

The enzyme S-adenosyl-L-homocysteine (AdoHcy) hydrolase effects hydrolytic cleavage of AdoHcy to adenosine (Ado) and L-homocysteine (Hcy). The cellular levels of AdoHcy and Hcy are critical because AdoHcy is a potent feedback inhibitor of crucial transmethylation enzymes. Also, elevated plasma levels of Hcy in humans have been shown to be a risk factor in coronary artery disease. ^ On the basis of the previous finding that AdoHcy hydrolase is able to add the enzyme-sequestered water molecule across the 5',6'-double bond of (halo or dihalohomovinyl)-adenosines causing covalent binding inhibition, we designed and synthesized AdoHcy analogues with the 5',6'-olefin motif incorporated in place of the carbon-5' and sulfur atoms. From the available synthetic methods we chose two independent approaches: the first approach was based on the construction of a new C5'-C6' double bond via metathesis reactions, and the second approach was based on the formation of a new C6'-C7' single bond via Pd-catalyzed cross-couplings. Cross-metathesis of the suitably protected 5'-deoxy-5'-methyleneadenosine with racemic 2-amino-5-hexenoate in the presence of Hoveyda-Grubb's catalyst followed by standard deprotection afforded the desired analogue as 5' E isomer of the inseparable mixture of 9'R/S diastereomers. Metathesis of chiral homoallylglycine [(2S)-amino-5-hexenoate] produced AdoHcy analogue with established stereochemistry E at C5'atom and S at C9' atom. The 5'-bromovinyl analogue was synthesized using the bromination-dehydrobromination strategy with pyridinium tribromide and DBU. ^ Since literature reports on the Pd-catalyzed monoalkylation of dihaloalkenes (Csp2-Csp3 coupling) were scarce, we were prompted to undertake model studies on Pd-catalyzed coupling between vinyl dihalides and alkyl organometallics. The 1-fluoro-1-haloalkenes were found to undergo Negishi couplings with alkylzinc bromides to give multisubstituted fluoroalkenes. The alkylation was trans-selective affording pure Z-fluoroalkenes. The highest yields were obtained with PdCl 2(dppb) catalyst, but the best stereochemical outcome was obtained with less reactive Pd(PPh3)4. Couplings of 1,1-dichloro-and 1,1-dibromoalkenes with organozinc reagents resulted in the formation of monocoupled 1-halovinyl product. ^

Foreign-born CEOs, country-specific skills, selection, and strategic consequences

In this dissertation, I first suggest an extension of the managerial rents model and more specifically the managerial skills typology that it offers. Building on research in international business, I propose adding country-specific skills (CSS) to this typology in addition to firm-specific, industry-specific, and generic skills. I define CSS as managers' abilities that are applicable and specific to a particular national institutional context. Such skills are distinct from the other three types identified and are likely to influence managers' performance and the performance of their firms. So if CSS are distinct skills, what are the implications for strategy and international business research? In an attempt to respond to this question, I conduct two empirical essays in which I examine the implications of this refinement of the typology of managerial skills for CEO selection and firms' mergers and acquisitions (M&A;) strategy. In the first empirical essay, I puzzle at the fact that although CSS constitute a barrier to high-level executive mobility across countries, there have been a growing number of foreign-born CEOs being appointed across the globe. Why are these individuals being selected for the post of CEO? Using information on the appointment of foreign-born and national CEOs from 2005 to 2010 among global 500 companies, I show that internationalization pressures help explain their selection and that two types of firms are likely to appoint foreign leaders: highly internationalized firms and firms that are likely to internationalize. In the second empirical essay, I examine the strategic implications of country-specific skills. Employing the same sample as the one used in the first empirical essay, I demonstrate that given that their mindset is likely to be less focused on firms' home market, foreign-born CEOs may be prone to institute more changes in firms' cross-border M&A; strategy than their domestic counterparts. I also theorize on the moderating influence of CEOs' insiderness.

What does board capital really bring to the table? Exploring the effect of directors' human and social capital on effective governance during international expansion

What constitutes effective corporate governance? Which director characteristics render boards effective at positively influencing firm-level performance outcomes? This dissertation examines these questions by taking a multilevel, multidisciplinary approach to corporate governance. I explore the individual-, team-, and firm- level factors that enable directors to serve effectively as strategic resources during international expansion. I argue that directors' international experience improves their ability to serve as effective strategic consultants and resource providers to firms during the complex internationalization process. However, unlike prior research, which tends to assume that directors with the potential to provide important resources uniformly do so, I acknowledge contextual factors (i.e. board cohesiveness, strategic relevance of directors' experience) that affect their propensity to actually influence outcomes. I explore these issues in three essays: one review essay and two empirical essays.^ In the first empirical essay, I integrate resource dependence theory with insights from social-psychological research to explore the influence of board capital on firms' cross-border M&A performance. Using a sample of cross-border M&As completed by S&P 500 firms from 2004-2009, I find evidence that directors' depth of international experience is associated with superior pre-deal outcomes. This suggests that boards' deep, market-specific knowledge is valuable during the target selection phase. I further find that directors' breadth of international experience is associated with superior post-deal performance, suggesting that these directors' global mindset helps firms in the post-M&A integration phase. I also find that these relationships are positively moderated by board cohesiveness, measured by boards' internal social ties.^ In the second empirical essay, I explore the boundary conditions of international board capital by examining how the characteristics of firms' internationalization strategy moderate the relationship between board capital and firm performance. Using a panel of 377 S&P 500 firms observed from 2004-2011, I find that boards' depth of international experience and social capital are more important during early stages of internationalization, when firms tend to lack market knowledge and legitimacy in the host markets. On the other hand, I find that breadth of international experience has a stronger relationship with performance when firms' have higher scope of internationalization, when information-processing demands are higher.^

Synthesis of multisubstituted halo-olefins via Pd-catalyzed cross-coupling reactions : applications in nucleoside chemistry

The enzyme S-adenosyl-L-homocysteine (AdoHey) hydrolase effects hydrolytic cleavage of AdoHcy to adenosine (Ado) and L-homocysteine (Hcy). The cellular levels of AdoHcy and Hcy are critical because AdoHcy is a potent feedback inhibitor of crucial transmethylation enzymes. Also, elevated plasma levels of Hcy in humans have been shown to be a risk factor in coronary artery disease. On the basis of the previous finding that AdoHcy hydrolase is able to add the enzyme-sequestered water molecule across the 5',6'-double bond of (halo or dihalohomovinyl)-adenosines causing covalent binding inhibition, we designed and synthesized AdoHcy analogues with the 5',6'-olefin motif incorporated in place of the carbon-5' and sulfur atoms. From the available synthetic methods we chose two independent approaches: the first approach was based on the construction of a new C5'- C6' double bond via metathesis reactions, and the second approach was based on the formation of a new C6'-C7' single bond via Pd-catalyzed cross-couplings. Cross-metathesis of the suitably protected 5'-deoxy-5'-methyleneadenosine with racemic 2-amino-5-hexenoate in the presence of Hoveyda-Grubb's catalyst followed by standard deprotection afforded the desired analogue as 5'E isomer of the inseparable mixture of 9'RIS diastereomers. Metathesis of chiral homoallylglycine [(2S)-amino-5-hexenoate] produced AdoHcy analogue with established stereochemistry E at C5'atom and S at C9' atom. The 5'-bromovinyl analogue was synthesized using the brominationdehydrobromination strategy with pyridinium tribromide and DBU. Since literature reports on the Pd-catalyzed monoalkylation of dihaloalkenes (Csp2-Csp3 coupling) were scarce, we were prompted to undertake model studies on Pdcatalyzed coupling between vinyl dihalides and alkyl organometallics. The 1-fluoro-1- haloalkenes were found to undergo Negishi couplings with alkylzinc bromides to give multisubstituted fluoroalkenes. The alkylation was trans-selective affording pure Zfluoroalkenes. The highest yields were obtained with PdCl 2(dppb) catalyst, but the best stereochemical outcome was obtained with less reactive Pd(PPh3)4 . Couplings of 1,1- dichloro-and 1,1-dibromoalkenes with organozinc reagents resulted in the formation of monocoupled 1-halovinyl product.

What Does Board Capital Really Bring to the Table? Exploring the Effect of Directors’ Human and Social Capital on Effective Governance During International Expansion

What constitutes effective corporate governance? Which director characteristics render boards effective at positively influencing firm-level performance outcomes? This dissertation examines these questions by taking a multilevel, multidisciplinary approach to corporate governance. I explore the individual-, team-, and firm- level factors that enable directors to serve effectively as strategic resources during international expansion. I argue that directors’ international experience improves their ability to serve as effective strategic consultants and resource providers to firms during the complex internationalization process. However, unlike prior research, which tends to assume that directors with the potential to provide important resources uniformly do so, I acknowledge contextual factors (i.e. board cohesiveness, strategic relevance of directors’ experience) that affect their propensity to actually influence outcomes. I explore these issues in three essays: one review essay and two empirical essays. In the first empirical essay, I integrate resource dependence theory with insights from social-psychological research to explore the influence of board capital on firms’ cross-border M&A performance. Using a sample of cross-border M&As completed by S&P 500 firms from 2004-2009, I find evidence that directors’ depth of international experience is associated with superior pre-deal outcomes. This suggests that boards’ deep, market-specific knowledge is valuable during the target selection phase. I further find that directors’ breadth of international experience is associated with superior post-deal performance, suggesting that these directors’ global mindset helps firms in the post-M&A integration phase. I also find that these relationships are positively moderated by board cohesiveness, measured by boards’ internal social ties. In the second empirical essay, I explore the boundary conditions of international board capital by examining how the characteristics of firms’ internationalization strategy moderate the relationship between board capital and firm performance. Using a panel of 377 S&P 500 firms observed from 2004-2011, I find that boards’ depth of international experience and social capital are more important during early stages of internationalization, when firms tend to lack market knowledge and legitimacy in the host markets. On the other hand, I find that breadth of international experience has a stronger relationship with performance when firms’ have higher scope of internationalization, when information-processing demands are higher.

Interdependencies in Corporate Development: Relationship between Strategic Alliance and Acquisition Activities

A substantial amount of work in the field of strategic management has attempted to explain the antecedents and outcomes of organizational learning. Though multinational corporations simultaneously engage in various types of tasks, activities, and strategies on a regular basis, the transfer of organizational learning in a multi-task context has largely remained under-explored in the literature. To inform our understanding in this area, this dissertation aimed at synthesizing findings from two parallel research streams of corporate development activities: strategic alliances and acquisitions. Structured in the form of two empirical studies, this dissertation examines: 1) the strategic outcomes of alliance experience of previously allying partners in terms of subsequent acquisition attempts, and 2) the performance implications of prior alliance experience for acquisitions. The first study draws on the relational view of inter-organizational governance to explain how various deal-specific and dyadic characteristics of a partnership relate to partnering firms’ post-alliance acquisition attempts. This model theorizes on a variety of relational mechanisms to build a cohesive theory of inter-organizational exchanges in a multi-task setting where strategic alliances ultimately lead to a firm’s decision to commit further resources. The second study applies organizational learning theory, and specifically examines whether frequency, recency, and relatedness of different dimensions of prior alliances, beyond the dyad-level experience, relate to an acquirer’s superior post-acquisition performance. The hypotheses of the studies are tested using logistic and ordinary least square regressions, respectively. Results analyzed from a sample of cross-border alliance and acquisition deals attempted (for study I) and/or completed (for study II) during the period of 1991 to 2011 generally support the theory that relational exchange determines acquiring firms’ post alliance acquisition behavior and that organizational routines and learning from prior alliances influence a future acquirer’s financial performance. Overall, the empirical findings support our overarching theory of interdependency, and confirm the transfer effect of learning across these alternate, yet related corporate strategies of alliance and acquisition.

Foreign-born CEOs, Country-Specific Skills, Selection, and Strategic Consequences

In this dissertation, I first suggest an extension of the managerial rents model and more specifically the managerial skills typology that it offers. Building on research in international business, I propose adding country-specific skills (CSS) to this typology in addition to firm-specific, industry-specific, and generic skills. I define CSS as managers’ abilities that are applicable and specific to a particular national institutional context. Such skills are distinct from the other three types identified and are likely to influence managers’ performance and the performance of their firms. So if CSS are distinct skills, what are the implications for strategy and international business research? In an attempt to respond to this question, I conduct two empirical essays in which I examine the implications of this refinement of the typology of managerial skills for CEO selection and firms’ mergers and acquisitions (M&A) strategy. In the first empirical essay, I puzzle at the fact that although CSS constitute a barrier to high-level executive mobility across countries, there have been a growing number of foreign-born CEOs being appointed across the globe. Why are these individuals being selected for the post of CEO? Using information on the appointment of foreign-born and national CEOs from 2005 to 2010 among global 500 companies, I show that internationalization pressures help explain their selection and that two types of firms are likely to appoint foreign leaders: highly internationalized firms and firms that are likely to internationalize. In the second empirical essay, I examine the strategic implications of country-specific skills. Employing the same sample as the one used in the first empirical essay, I demonstrate that given that their mindset is likely to be less focused on firms’ home market, foreign-born CEOs may be prone to institute more changes in firms’ cross-border M&A strategy than their domestic counterparts. I also theorize on the moderating influence of CEOs’ insiderness.