Cancer intelligence acquired (CIA): tumor glycosylation and sialylation codes dismantling antitumor defense

Aberrant glycosylation is a key feature of malignant transformation and reflects epigenetic and genetic anomalies among the multitude of molecules involved in glycan biosynthesis. Although glycan biosynthesis is not template bound, altered tumor glycosylation is not random, but associated with common glycosylation patterns. Evidence suggests that acquisition of distinct glycosylation patterns evolves from a ‘microevolutionary’ process conferring advantages in terms of tumor growth, tumor dissemination, and immune escape. Such glycosylation modifications also involve xeno- and hypersialylation. Xeno-autoantigens such as Neu5Gc-gangliosides provide potential targets for immunotherapy. Hypersialylation may display ‘enhanced self’ to escape immunosurveillance and involves several not mutually exclusive inhibitory pathways that all rely on protein–glycan interactions. A better understanding of tumor ‘glycan codes’ as deciphered by lectins, such as siglecs, selectins, C-type lectins and galectins, may lead to novel treatment strategies, not only in cancer, but also in autoimmune disease or transplantation.

Salicylic Acid, a Plant Defense Hormone, Is Specifically Secreted by a Molluscan Herbivore

Slugs and snails are important herbivores in many ecosystems. They differ from other herbivores by their characteristic mucus trail. As the mucus is secreted at the interface between the plants and the herbivores, its chemical composition may play an essential role in plant responses to slug and snail attack. Based on our current knowledge about host-manipulation strategies employed by pathogens and insects, we hypothesized that mollusks may excrete phytohormone-like substances into their mucus. We therefore screened locomotion mucus from thirteen molluscan herbivores for the presence of the plant defense hormones jasmonic acid (JA), salicylic acid (SA) and abscisic acid (ABA). We found that the locomotion mucus of one slug, Deroceras reticulatum, contained significant amounts of SA, a plant hormone that is known to induce resistance to pathogens and to suppress plant immunity against herbivores. None of the other slugs and snails contained SA or any other hormone in their locomotion mucus. When the mucus of D. reticulatum was applied to wounded leaves of A. thaliana, the promotor of the SA-responsive gene pathogenesis related 1 (PR1) was activated, demonstrating the potential of the mucus to regulate plant defenses. We discuss the potential ecological, agricultural and medical implications of this finding.

The underestimated role of roots in defense against leaf attackers

Plants have evolved intricate strategies to withstand attacks by herbivores and pathogens. Although it is known that plants change their primary and secondary metabolism in leaves to resist and tolerate aboveground attack, there is little awareness of the role of roots in these processes. This is surprising given that plant roots are responsible for the synthesis of plant toxins, play an active role in environmental sensing and defense signaling, and serve as dynamic storage organs to allow regrowth. Hence, studying roots is essential for a solid understanding of resistance and tolerance to leaf-feeding insects and pathogens. Here, we highlight this function of roots in plant resistance to aboveground attackers, with a special focus on systemic signaling and insect herbivores

Circumvention of cellular defense responses to DNA -directed nucleoside analogues by the protein kinase inhibitor, UCN-01

DNA-directed nucleoside analogues, such as ara-C, fludarabine, and gemcitabine, are antimetabolites effective in the treatment of a variety of cancers. However, resistance to nucleoside analogue-based chemotherapy in treatments is still a major problem in therapy. Therefore, it is essential to develop rationales for optimizing the use of nucleoside analogues in combination with other anticancer drugs or modalities such as radiation. The present study focuses on establishing mechanism-based combination strategy to overcome resistance to nucleoside analogues. ^ I hypothesized that the cytostatic concentrations of nucleoside analogues may cause S-phase arrest by activating an S-phase checkpoint that consists of a series of kinases. This may allow cells to repair damaged DNA over time and spare cytotoxicity. Thus, the ability of cells to enact an S-phase arrest in response to incorporation of potentially lethal amounts of nucleoside analogue may serve as a mechanism of resistance to S-phase-specific agents. As a corollary, the addition of a kinase inhibitor, such as UCN-01, may dysregulate the checkpoint response and abrogate the survival of S-phase-arrested cells by suppression of the survival signaling pathways. Using gemcitabine as a model of S-phase-specific nucleoside analogues in human acute myelogenous leukemia ML-1 cells, I demonstrated that cells arrested in S-phase in response to cytostatic conditions. Proliferation continued after washing the cells into drug-free medium, suggesting S-phase arrest served as a resistance mechanism of cancer cells to spare cytotoxicity of nucleoside analogues. However, nontoxic concentrations of UCN-01 rapidly killed S-phase-arrested cells by apoptosis. Furthermore, the molecular mechanism for UCN-01-induced apoptosis in S-phase-arrested cells was through inhibition of survival pathways associated with these cells. In this regard, suppression of the PI 3-kinase-Akt-Bad survival pathway as well as the NF-κB signaling pathway were associated with induction of apoptosis in S-phase-arrested cells by UCN-01, whereas the Ras-Raf-MEK-ERK pathway appeared not involved. This study has provided the rationales and strategies for optimizing the design of effective combination therapies to overcome resistance to nucleoside analogues. In fact, a clinical trial of the combination of ara-C with UCN-01 to treat relapsed or refractory AML patients has been initiated at U.T.M.D. Anderson Cancer Center. ^

Purification and Characterization of AsES Protein A Subtilisin Secreted by Acremonium Strictum is a Novel Plant Defense Elicitor.

In this work, the purification and characterization of an extracellular elicitor protein, designated AsES, produced by an avirulent isolate of the strawberry pathogen Acremonium strictum, are reported. The defense eliciting activity present in culture filtrates was recovered and purified by ultrafiltration (cutoff, 30 kDa), anionic exchange (Q-Sepharose, pH 7.5), and hydrophobic interaction (phenyl-Sepharose) chromatographies. Two-dimensional SDS-PAGE of the purified active fraction revealed a single spot of 34 kDa and pI 8.8. HPLC (C2/C18) and MS/MS analysis confirmed purification to homogeneity. Foliar spray with AsES provided a total systemic protection against anthracnose disease in strawberry, accompanied by the expression of defense-related genes (i.e. PR1 and Chi2-1). Accumulation of reactive oxygen species (e.g. H2O2 and O2̇̄) and callose was also observed in Arabidopsis. By using degenerate primers designed from the partial amino acid sequences and rapid amplification reactions of cDNA ends, the complete AsES-coding cDNA of 1167 nucleotides was obtained. The deduced amino acid sequence showed significant identity with fungal serine proteinases of the subtilisin family, indicating that AsES is synthesized as a larger precursor containing a 15-residue secretory signal peptide and a 90-residue peptidase inhibitor I9 domain in addition to the 283-residue mature protein. AsES exhibited proteolytic activity in vitro, and its resistance eliciting activity was eliminated when inhibited with PMSF, suggesting that its proteolytic activity is required to induce the defense response. This is, to our knowledge, the first report of a fungal subtilisin that shows eliciting activity in plants. This finding could contribute to develop disease biocontrol strategies in plants by activating its innate immunity.

The political economy of poverty alleviation strategies. The initiative for heavily indebted poor countries in Bolivia: More of the same

In the year 2000, approximately 1.1 billion people lived in extreme poverty while developed countries spent US$600 billion a year on defense. The Heavily Indebted Poor Countries (HIPC) Initiative is a recent component of a larger poverty reduction strategy supported by the International Financial Institutions, as well as many developed and developing countries. By implementing lessons of the past fifty years, this program attempts to diminish misery around the globe. As such, it provides debt relief while seeking to enable the poorest countries to simultaneously attain sustainable debt and promote human development. Interest in poverty reduction around the globe reemerged in the 1990s. This study contributes directly to this recent effort by presenting a nuanced approach that builds on the stepping-stones generated by other poverty scholars. To fulfill its goal, this investigation applies a political economy framework. Within this framework, the author conducts an actor-specific analysis. This dissertation addresses the following question: How do domestic and international actors respond to the implementation of poverty alleviation strategies? The author assumes actors desire to maximize their utility calculation and suggests these calculations are based on the player's motivations and external influences. Based on their motivations, the external influences, and the initiative's guidelines, each actor develops a set of expectations. To fulfill those expectations, stake holders utilize one or several strategies. Finally, the actors' ability to achieve their expectations determines each player's assessment of the initiative. The framework described is applied in an in-depth, actor-specific analysis of the HIPC in Bolivia. Bolivia's National Revolution represents the country's first attempt at reducing poverty. Since then, all governments have taken specific steps to combat poverty at the local and national levels. The Initiative for Heavily Indebted Poor Countries (HIPC) is one of the most recent macro strategies of this kind. The case study demonstrated that three factors (national ownership, effective sponsorship and the local context) determine the success levels of poverty reduction strategies from abroad. In addition, the investigation clearly shows that poverty reduction is not the sole motivation in the implementation of poverty alleviation strategies. All actors, however, share the dream of poverty reduction.

Political strategy, leadership, and policy entrepreneurship in Japanese defense policy and politics: A comparison of three prime ministerships

Since the end of the Cold War, Japan's defense policy and politics has gone through significant changes. Throughout the post cold war period, US-Japan alliance managers, politicians with differing visions and preferences, scholars, think tanks, and the actions of foreign governments have all played significant roles in influencing these changes. Along with these actors, the Japanese prime minister has played an important, if sometimes subtle, role in the realm of defense policy and politics. Japanese prime ministers, though significantly weaker than many heads of state, nevertheless play an important role in policy by empowering different actors (bureaucratic actors, independent commissions, or civil actors), through personal diplomacy, through agenda-setting, and through symbolic acts of state. The power of the prime minister to influence policy processes, however, has frequently varied by prime minister. My dissertation investigates how different political strategies and entrepreneurial insights by the prime minister have influenced defense policy and politics since the end of the Cold War. In addition, it seeks to explain how the quality of political strategy and entrepreneurial insight employed by different prime ministers was important in the success of different approaches to defense. My dissertation employs a comparative case study approach to examine how different prime ministerial strategies have mattered in the realm of Japanese defense policy and politics. Three prime ministers have been chosen: Prime Minister Hashimoto Ryutaro (1996-1998); Prime Minister Koizumi Junichiro (2001-2006); and Prime Minister Hatoyama Yukio (2009-2010). These prime ministers have been chosen to provide maximum contrast on issues of policy preference, cabinet management, choice of partners, and overall strategy. As my dissertation finds, the quality of political strategy has been an important aspect of Japan's defense transformation. Successful strategies have frequently used the knowledge and accumulated personal networks of bureaucrats, supplemented bureaucratic initiatives with top-down personal diplomacy, and used a revitalized US-Japan strategic relationship as a political resource for a stronger prime ministership. Though alternative approaches, such as those that have looked to displace the influence of bureaucrats and the US in defense policy, have been less successful, this dissertation also finds theoretical evidence that alternatives may exist.

Different Wars Require Different Strategies: Separating the “War on Drugs” from the “War on Drug [Traffickers]”

Using the securitization framework to highlight the arguments that facilitated the “War on Drugs”, this paper highlights a separate war against drug traffickers. Facilitated by ideology through the rhetoric promoted by the “War on Drugs,” the fear of communist expansion and democratic contraction, the “War on Drug Traffickers” was implemented, requiring its own strategy separate from the “War on Drugs.” This is an important distinction because the play on words changes the perception of the issue from one of drug addiction to one of weak institutions and insurgent/terrorist threat to those institutions. Furthermore, one cannot propose strategy to win, lose, or retreat in a war that one has been unable to identify properly. And while the all-encompassing “War on Drugs” has motivated tremendous discourse on its failure and possible solutions to remedy its failure, the generalizations made as a result of the inability to distinguish between the policies behind drug addiction and the militarized policies behind drug trafficking have discounted the effect of violence perpetrated by the state, the rationale for the state perpetrating that violence, and the dependence that the state has on foreign actors to perpetrate such violence. This makes it impossible to not only propose effective strategy but also to persuade states that participate in the “War on Drug Traffickers” to adopt the proposed strategy.

Turkish Security Policymaking on Nuclear Issues: Conceptualizing Advanced Cooperative Security Strategies

Turkey is a non-nuclear member of a nuclear alliance in a region where nuclear proliferation is of particular concern. As the only North Atlantic Treaty Organization (NATO) member that has a border with the Middle East, Turkish officials argue that Turkey cannot solely rely on NATO guarantees in addressing the regional security challenges. However, Turkey has not been able to formulate a security policy that reconciles its quest for independence, its NATO membership, the bilateral relationship with the United States, and regional engagement in the Middle East. This dissertation assesses the strategic implications of Turkey’s perceptions of the U.S./NATO nuclear and conventional deterrence on nuclear issues. It explores three case studies by the process tracing of Turkish policymakers’ nuclear-related decisions on U.S. tactical nuclear weapons deployed in Europe, national air and missile defense, and Iran’s nuclear program. The study finds that the principles of Turkish security policymaking do not incorporate a fundamentally different reasoning on nuclear issues than conventional deterrence. Nuclear weapons and their delivery systems do not have a defining role in Turkish security and defense strategy. The decisions are mainly guided by non-nuclear considerations such as Alliance politics, modernization of the domestic defense industry, and regional influence. The dissertation argues that Turkey could formulate more effective and less risky security policies on nuclear issues by emphasizing the cooperative security approaches within the NATO Alliance over confrontational measures. The findings of this dissertation reveal that a major transformation of Turkish security policymaking is required to end the crisis of confidence with NATO, redefinition of the strategic partnership with the US, and a more cautious approach toward the Middle East. The dissertation argues that Turkey should promote proactive measures to reduce, contain, and counter risks before they develop into real threats, as well as contribute to developing consensual confidence-building measures to reduce uncertainty.

Political Strategy, Leadership, and Policy Entrepreneurship in Japanese Defense Policy and Politics: A Comparison of Three Prime Ministerships

Since the end of the Cold War, Japan’s defense policy and politics has gone through significant changes. Throughout the post cold war period, US-Japan alliance managers, politicians with differing visions and preferences, scholars, think tanks, and the actions of foreign governments have all played significant roles in influencing these changes. Along with these actors, the Japanese prime minister has played an important, if sometimes subtle, role in the realm of defense policy and politics. Japanese prime ministers, though significantly weaker than many heads of state, nevertheless play an important role in policy by empowering different actors (bureaucratic actors, independent commissions, or civil actors), through personal diplomacy, through agenda-setting, and through symbolic acts of state. The power of the prime minister to influence policy processes, however, has frequently varied by prime minister. My dissertation investigates how different political strategies and entrepreneurial insights by the prime minister have influenced defense policy and politics since the end of the Cold War. In addition, it seeks to explain how the quality of political strategy and entrepreneurial insight employed by different prime ministers was important in the success of different approaches to defense. My dissertation employs a comparative case study approach to examine how different prime ministerial strategies have mattered in the realm of Japanese defense policy and politics. Three prime ministers have been chosen: Prime Minister Hashimoto Ryutaro (1996-1998); Prime Minister Koizumi Junichiro (2001-2006); and Prime Minister Hatoyama Yukio (2009-2010). These prime ministers have been chosen to provide maximum contrast on issues of policy preference, cabinet management, choice of partners, and overall strategy. As my dissertation finds, the quality of political strategy has been an important aspect of Japan’s defense transformation. Successful strategies have frequently used the knowledge and accumulated personal networks of bureaucrats, supplemented bureaucratic initiatives with top-down personal diplomacy, and used a revitalized US-Japan strategic relationship as a political resource for a stronger prime ministership. Though alternative approaches, such as those that have looked to displace the influence of bureaucrats and the US in defense policy, have been less successful, this dissertation also finds theoretical evidence that alternatives may exist.