Legitimate Target Research Articles

New Drugs and Targets for Asthma and Chronic Obstructive Pulmonary Disease (CDPD)

This book, edited by Professor Peter Barnes and Dr Trevor Hansel, is a follow-up to an earlier volume on this subject by the same editors in 2001 published by Karger Press under the auspices of the Progress in Respiratory Disease series. The current volume provides a timely update on the wide number of drugs under evaluation for the treatment of asthma and chronic obstructive pulmonary disease (COPD), both diseases having continuing clear unmet medical needs. This volume is very comprehensive and draws on the expertise of authors working as scientists and/or clinicians in both the academic and the industrial world. The book is beautifully illustrated (80 figures and 46 tables, of which 67 are in full colour) and, as stated in the Foreword by Professor Bolliger, presents cutting-edge data, including ‘publications of up to 2010’ and in some chapters useful information on patents around some of the newer targets under investigation where there is not yet a comprehensive literature; as such, this volume is even more than a series of state-of-the-art reviews. Professor Barnes and Dr Hansel are to be congratulated on providing a volume that will undoubtedly become a very useful resource for the many people working in this field, covering as it does everything from early-stage projects still at the laboratory level through to drugs very close to becoming prescription drugs for the treatment of asthma and/or COPD. All of the chapters are well organized, clearly written and organized into appropriate sections within the book, so that particular drug classes can be readily located. The chapters are supported by high-quality and useful figures, which ensure that the material covered is readily accessible and not lost in dense prose. It is very difficult to identify an area of drug development not covered in this volume, which of course reflects the editors' wide knowledge of the considerable research activities going on in this field; however, if I had to make one constructive suggestion to improve future volumes, it would have been helpful to have had a chapter reviewing the enormous amount of research going on in this field with improving drug delivery to the lungs. The increasing variety of novel approaches to the delivery of drugs to the lungs is sometimes bewildering, even to people in the field, and certainly just about all of the drugs Barnes and Hansel review in this volume will ultimately be administered by this topical route. Additionally, it is also now increasingly being recognized that COPD in particular has many systemic (nonpulmonary) manifestations that are probably legitimate targets for drug treatment in order to improve the overall quality of life of patients suffering from this disorder. This research effort has already identified drugs being used for indications other than the treatment of lung disease that have value in the treatment of patients with COPD, e.g. statins. There is likely to be much more pharmacological research activity in the coming decade in finding treatments for these systemic manifestations, and indeed some drugs already used for the treatment of COPD are known to have useful systemic effects, e.g. theophylline, and the newest drug class recently approved for the treatment of COPD is an orally administered drug (roflumilast N-oxide). Despite the wide array of targets reviewed in this volume edited by Hansel and Barnes, it is clear that future ‘drug hunters’ in the field of respiratory diseases will need to think outside of their comfort zone.

Exploring the self-directed anger of the stigmatized

Does social identification protect or harm targets of discrimination? Two studies ( N = 52, N = 94) tested the prediction that perceived legitimacy moderates the impact of social identification on negative responses to discrimination. Results confirm that when discrimination is perceived as illegitimate, identification is negatively related to self-directed anger ( buffering effect) because identification provides a feeling of in-group support. However, when discrimination is perceived as legitimate, identification is positively related to self-directed anger ( exacerbating effect) because the internalized social identity is perceived as legitimate target for the negative treatment. Legitimacy is measured and manipulated among different low-status groups. The legitimization and internalization of discrimination driven by self-directed anger are discussed.

Hepatitis C Virus NS5A Protein Interacts with Phosphatidylinositol 4-Kinase Type IIIα and Regulates Viral Propagation

Hepatitis C Virus (HCV) nonstructural 5A (NS5A) is a pleiotropic protein involved in viral RNA replication and modulation of the cellular physiology in HCV-infected cells. To elucidate the mechanisms of the HCV life cycle, we identified cellular factors interacting with the NS5A protein in HCV-infected cells. Huh7.5 cells were electroporated with HCV Jc1 RNA. Cellular factors associated with HCV NS5A were identified by immunoprecipitation with Dynabead-conjugated NS5A antibody and LC-MS/MS. Phosphatidylinositol 4-kinase type IIIα (PI4KIIIα) was identified as a binding partner for the NS5A protein. NS5A derived from both genotypes 1b and 2a interacted with PI4KIIIα. NS5A interacted with PI4KIIIα through amino acids 401-600 of PI4KIIIα and domain I of NS5A. Interference of the protein interaction between NS5A and PI4KIIIα decreased HCV propagation. Knockdown of PI4KIIIα significantly reduced HCV replication in Huh7 cells harboring the subgenomic replicon and in Huh7.5 cells infected with cell culture grown virus (HCVcc). Silencing of PI4KIIIα further inhibited HCV release into the tissue culture medium. NS5A may recruit PI4KIIIα to the HCV RNA replication complex. These data suggest that PI4KIIIα is an essential host factor that supports HCV proliferation and therefore PI4KIIIα may be a legitimate target for anti-HCV therapy.

P03-414 - Anger arousal and well being as markers of social functioning and quality of life in the aftermath of exposure to life threatening trauma

IntroductionSevere stress or exposure to life threatening trauma is known to affect social functioning and quality of life.ObjectivesTo study well-being and anger arousal as markers of social functioning and quality of life in a group of University students exposed to a suicide bomb attack on a University in Pakistan.AimsTo examine indicators of social functioning in order to higlight them as targets for therapeutic interventions.MethodsSubjects were assessed after one year of exposure to a life threatening incident on University campus. Subjects completed an assessment schedule incorporating World Health Organization's Well-Being Index and Novarco Anger Inventory (25 items).Results54 students completed the assessment. The mean age of the group was 24 years. All subjects had completed 14–16 years of education and were in full time education at the time of assessment. The Well Being Index Score range was 1–24 with 26 sujects scoring 13 or lower scores indicating poor quality of life. 29 subjects scored higer levels of anger arousal on 10 or more items of Novarco Anger Inventory indicating difficulties in social functioning. The overall group showed a statistically significant negative correlation between the Well-Being Index Scores and the number of Novarco Anger Inventory items scored in the two highest categories of anger arousal.ConclusionsThe results of the study highlight anger arousal and well-being as important markers of functioning in the aftermath of a stressful life event. The study confirms their usefulness as legitimate therapeutic targets for pharmacotherapy, psychotherapeutic, and social interventions.

602 and One Dead: On Contribution to Global Poverty and Liability to Defensive Force

Abstract: When suggesting that we—the affluent in the developed world—are legitimate targets of defensive force due to our contribution to global poverty one is likely to be countered by one of two strategies. The first denies that we contribute to global poverty. The second seems to affirm that we contribute, and even that we have stringent contribution‐based duties to address this poverty, but denies that such contribution makes forcible resistance permissible. Those in this second group employ several argumentative strategies.In this paper I investigate these strategies for denying the force‐related implication of contribution to poverty. I do not argue for political violence or for the permissibility of targeting the affluent, I merely investigate a conditional: if contribution to global poverty generates stringent duties to address it, then this contribution implies permission on the part of the victims to defend themselves with force, or for third parties to use force on their behalf.

Food and Drug Administration Commentary on Methodological Issues in Negative Symptom Trials

Food and Drug Administration Commentary on Methodological Issues in Negative Symptom Trials

On Contending with Unruly Neighbors in the Global Village: Viewing Information Systems as Both Weapon and Target

Abstract : While information technologies we employ in business, government, and society have dramatically enhanced our ability to conduct commerce, the vulnerabilities of these systems create potential dangers not often fully apprehended. As an example, criminal and terrorist groups have demonstrated a sophisticated understanding of how to adapt organizational forms and information technologies to advance their agendas, regardless of how contemptible these may be. In this article, we consider how these groups may view information technology and systems both as means by which they may more effectively organize themselves and as potential targets as they subvert the underlying societal assumptions regarding the technology itself. Topics such as these have implications for both IS research and practice because the changing nature of warfare means entities that may have until recently been seen as non-combatant are no longer viewed as such; any organization's online resources may be regarded and serviced as legitimate targets. This fact, coupled with the interconnectedness of the global economy, makes it imperative to understand the potential threat--whether this is acted on by criminals, terrorists, or even by hostile nation states--and place greater emphasis on defending vital systems against such attacks.

Possible Role of Epidermal Growth Factor Receptors in the Therapy of Pancreatic Cancer

Pancreatic cancer is considered an 'orphan' cancer because of its relative low incidence. Unfortunately, even with early diagnosis, mortality rates are high and it ranks eighth in the worldwide ranking of deaths due to cancer. The administration of chemotherapeutic agents for the treatment of advanced disease has failed, and current research focuses on the understanding of molecular pathways in order to investigate the role of targeted therapy. It has been known that the development and the progression of pancreatic cancer are caused by the activation of oncogenes, the inactivation of tumor suppressor genes, and the deregulation of many signaling pathways of various growth factors, among which the epidermal growth factor receptor (EGFR) plays an important role. Growth factor receptors and their ligands not only regulate normal cell processes, but have also been identified as key regulators of human cancer formation. EGFR has been found to be expressed and altered in pancreatic cancer and clearly plays a significant role in tumor development and progression, including cell proliferation, regulation of apoptotic cell death, angiogenesis, and metastatic spread. The amplitude and kinetics of growth factor signaling are determined mainly by a highly regulated endocytic process that sorts and directs activated receptors to degradation in lysosomes. Therefore, EGFR is a legitimate therapeutic target. The aim of this review is to outline the endocytic escape of EGFRs in cancer with special attention towards recent advances in various approaches adopted for EGFR targeting.

Gut microbiota: next frontier in understanding human health and development of biotherapeutics

The gut microbiota is a remarkable asset for human health. As a key element in the development and prevention of specific diseases, its study has yielded a new field of promising biotherapeutics. This review provides comprehensive and updated knowledge of the human gut microbiota, its implications in health and disease, and the potentials and limitations of its modification by currently available biotherapeutics to treat, prevent and/or restore human health, and future directions. Homeostasis of the gut microbiota maintains various functions which are vital to the maintenance of human health. Disruption of the intestinal ecosystem equilibrium (gut dysbiosis) is associated with a plethora of human diseases, including autoimmune and allergic diseases, colorectal cancer, metabolic diseases, and bacterial infections. Relevant underlying mechanisms by which specific intestinal bacteria populations might trigger the development of disease in susceptible hosts are being explored across the globe. Beneficial modulation of the gut microbiota using biotherapeutics, such as prebiotics, probiotics, and antibiotics, may favor health-promoting populations of bacteria and can be exploited in development of biotherapeutics. Other technologies, such as development of human gut models, bacterial screening, and delivery formulations eg, microencapsulated probiotics, may contribute significantly in the near future. Therefore, the human gut microbiota is a legitimate therapeutic target to treat and/or prevent various diseases. Development of a clear understanding of the technologies needed to exploit the gut microbiota is urgently required.

Reforming the Welfare State: Camden 1965-73

The housing projects built by the London Borough of Camden in the years 1965-73 belong arguably to the most substantial investigations into the architecture of social housing undertaken in the past half-century. Under borough architect Sydney Cook, Camden aimed to establish a new kind of housing architecture based, not on the Corbusian tabula rasa, but on a radical reinterpretation of traditional English urbanism. The outcome was a series of projects, including Fleet Road, Alexandra Road, Highgate New Town, Branch Hill and Maiden Lane, designed by members of Cook’s team, including Neave Brown, Peter Tábori and Gordon Benson and Alan Forsyth, as well as projects designed by up-and-coming private architects like Colquhoun & Miller, Edward Cullinan and Farrell Grimshaw. While it began in what Hobsbawm called the ‘golden age’ of postwar capitalism, the Cook years (1965-73) saw the onset of the crisis of the 1970s and with it the rise of the New Right and the Hard Left, both of which viewed the Camden housing projects as a legitimate target for attack. Based on archival research and interviews, the paper explores the ways in which the Cook projects both mediated and articulated the emergence of these fissures within the British welfare state.

Molecular mechanisms of sarcomere dysfunction in dilated and hypertrophic cardiomyopathy

The sarcomeres form the molecular motor of the cardiomyocyte and consist of a complex multi-protein of thick and thin filaments which are anchored to the cytoskeleton. The thick filament, composed of myosin and associated proteins, and the thin filament composed of actin, tropomyosin and the troponins develop actin–myosin crossbridges which cycle in response to calcium resulting in the sliding of the filaments and contraction. The thin filament is fixed to the cardiomyocyte cytoskeleton at the Z-disc, a complex of structural and regulatory proteins. A giant protein, titin, provides an external scaffold and regulates passive force in diastole. Both genetic disorders and acquired conditions may affect proteins of the sarcomere. Genetic disorders of the thick and thin filament proteins are the predominant cause of hypertrophic cardiomyopathy. These mutations lead to abnormal sarcomere function, often an enhanced sensitivity to calcium, and impaired relaxation. This may result in secondary changes in calcium cycling and amplification of hypertrophic signaling cascades. Correcting the abnormal function of the sarcomere as well as intervening in later stages of the pathophysiologic cascades may ameliorate disease. In dilated cardiomyopathy genetic abnormalities in the sarcomere, Z-disc, calcium regulatory and cytoskeletal proteins as well as the dystrophin complex may be causal for disease. In dilated cardiomyopathy, disturbances in post-translational modifications of the sarcomere may also play a prominent role. Experimental models indicate that altered phosphorylation of sarcomeric proteins may impair systolic and diastolic functions as well as the response to heart rate and afterload. Thus correcting these post-translational changes is a legitimate target for future therapeutic strategies for dilated cardiomyopathy.

Protein Tyrosine Phosphatase 1B Inhibitors: A Molecular Level Legitimate Approach for the Management of Diabetes Mellitus

Diabetes mellitus is a systemic disease responsible for morbidity in the western world and is gradually becoming prevalent in developing countries too. The prevalence of diabetes is rapidly increasing in industrialized countries and type 2 diabetes accounts for 90% of the disease. Insulin resistance is a major pathophysiological factor in the development of type 2 diabetes, occurring mainly in muscle, adipose tissues, and liver leading to reduced glucose uptake and utilization and increased glucose production. The prevalence and rising incidence of diabetes emphasized the need to explore new molecular targets and strategies to develop novel antihyperglycemic agents. Protein Tyrosine Phosphatase 1B (PTP 1B) has recently emerged as a promising molecular level legitimate therapeutic target in the effective management of type 2 diabetes. PTP 1B, a cytosolic nonreceptor PTPase, has been implicated as a negative regulator of insulin signal transduction. Therefore, PTP 1B inhibitors would increase insulin sensitivity by blocking the PTP 1B-mediated negative insulin signaling pathway and might be an attractive target for type 2 diabetes mellitus and obesity. With X-ray crystallography and NMR-based fragment screening, the binding interactions of several classes of inhibitors have been elucidated, which could help the design of future PTP 1B inhibitors. The drug discovery research in PTP 1B is a challenging area to work with and many pharmaceutical organizations and academic research laboratories are focusing their research toward the development of potential PTP 1B inhibitors which would prove to be a milestone for the management of diabetes.

Notch Signaling Proteins: Legitimate Targets for Cancer Therapy

Proteins and small peptides (growth factors and hormones) are key molecules in maintaining cellular homeostasis. To that end, Notch signaling pathway proteins are known to play critical roles in maintaining the balance between cell proliferation, differentiation and apoptosis, and thus it has been suggested that Notch may be responsible for the development and progression of human malignancies. Therefore, the Notch signaling pathway proteins may present novel therapeutic targets, which could have promising therapeutic impact on eradicating human malignancies. This review describes the role of Notch signaling pathway proteins in cancer and how its deregulation is involved in tumor development and progression leading to metastasis and the ultimate demise of patients diagnosed with cancer. Further, we summarize the role of several Notch inhibitors especially "natural agents" that could represent novel therapeutic strategies targeting Notch signaling toward better treatment outcome of patients diagnosed with cancer.

Shopping for answers from Marx and Spencer

Shopping for answers from Marx and Spencer

Special issues in injury prevention research: Developing the science of program implementation

Introduction Despite widespread application of the public health approach to injury prevention, there is an acknowledged limitation in the extent to which it facilitates translation of research evidence to injury prevention practice. Aim In this paper we clarify the ecoepidemiological principles that underpin the public health approach to injury control in order to support explicit efforts to address the multilevel component causes and improve the evidence base on which effective program implementation depends. Keypoints If injury causation is understood in terms of the ecoepidemiological model rather than the proximal risk factor model, then quantification of the context in which the event occurs is evidently as important as quantification of the energy exchange event itself. The ecoepidemiological model of injury causation recognises barriers and facilitators to injury prevention as component causes of population burden of injury and thus delineates these factors as legitimate targets for intervention. Injury prevention programs that are designed to specifically address the factors causally related to the program's implementation, as well as the contextual factors that determine the characteristics of the energy exchange event, are more likely to be implemented and more likely to result in effective uptake of recommended energy exchange countermeasures. Conclusion Interventions to reduce the burden of injury in the population should address the individual level factors that increase the risk of injury, but also the upstream factors that influence the extent to which there is widespread adoption by individuals of the recommended countermeasures.

Notch Signaling Proteins: Legitimate Targets for Cancer Therapy

Notch Signaling Proteins: Legitimate Targets for Cancer Therapy

Abstract 5043: Effects of a novel PI3 kinase/mTOR inhibitor on proliferation and pAKT signaling in canine lymphoma

Abstract PF-04691503 is a dual inhibitor of both PI3K and mTOR, inhibits PI3K signaling in cancer cell lines, and exhibits in vitro and in vivo anti-proliferative activity in PI3K-pathway driven cell lines. It is a nanomolar inhibitor of all 4 isoforms of the catalytic subunit of PI3K and of both TORC1 and TORC2. Anti-cancer activity of the inhibitor is hypothesized to be through inhibition of survival, proliferative, and anti-apoptotic processes. Phosphorylation of the protein kinase, Akt, is associated with activation of the phosphatidyl 3-kinase (PI-3K)/mammalian target of rapamycin (mTOR) signaling pathway, which plays a role in cell proliferation (Witzig and Kaufmann 2006). Recent studies by Gulmann et al (2005) showed increased pAKT in human lymphoma samples, and those of Rassidakis et al (2005) suggested that inhibition of Akt phosphorylation (pAKT) may be of value in the treatment of lymphoma. Using flow cytometry we report that cells obtained from 10 of 11 lymph node biopsies of dogs with lymphoma exhibit detectable pAKT using a phospho-Akt (Ser473) antibody, compared to an IgG isotype control or a competative phospho-Akt (Ser473) blocking peptide. Cells from normal canine lymph nodes do not exhibit detectable pAKT. The majority of the pAKT signal was generated from lymphoblasts present in the malignant, but not in the normal, lymph nodes. In separate studies, lymph node cells obtained from healthy dogs and dogs with lymphoma were stimulated in vitro with the mitogen, Con A. The novel PI3K/mTOR dual inhibitor, PF-04691503, produced dose dependent inhibition of proliferation as exemplified in a dog with T-cell lymphoma (EC50 = 18 nM)) and in a normal dog (EC50 = 53 nM)). No pAKT signal could be detected in peripheral blood mononuclear cells, from normal or lymphoma patients stimulated with hu-IGF-1 (the endogenous ligand for PI3), Con-A or LPS. These data suggest that PI-3 kinase and pAKT (1) are activated in canine lymphoma, (2) play a role in the lymphoproliferation associated with this disease, (3) represent legitimate targets for therapeutic intervention in lymphoma, and (4) can be studied ‘translationally’ in dogs as a model for humans. Gulmann C, Espina V, Petricoin E, et al. Proteomic analysis of apoptotic pathways reveals prognostic factors in follicular lymphoma. Clin Cancer Res 11:5847-5855, 2005. Rassidakis GZ, Feretzaki M, Atwell C, et al. Inhibition of Akt increases p27 Kip1 levels and induces cell cycle arrest in anaplastic large cell lymphoma. Blood 105:827-829, 2005. Witzig TE and Kaufmann SH. Inhibition of phosphatidyl 3-kinase (PI-3K)/mammalian target of rapamycin (mTOR) pathway in hematologic malignancies. Current Treatment Options in Oncology 7:285-294, 2006. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5043.

Impulsive Aggression in Attention-Deficit/Hyperactivity Disorder: Symptom Severity, Co-Morbidity, and Attention-Deficit/Hyperactivity Disorder Subtype

The aim of this study was to characterize aggression and its relationship to psychiatric co-morbidity, attention-deficit/hyperactivity disorder (ADHD) subtype, and ADHD symptom severity in clinically referred ADHD youngsters. We also wanted to ascertain whether reactive and impulsive aggression is more prevalent than proactive aggression in an ADHD sample. Consecutively referred ADHD children and adolescents (n = 268) and community controls (n = 100) were assessed systematically regarding demographics, psychiatric diagnosis, overt aggression severity, proactive and reactive aggression severity, and ADHD symptom severity using correlational analysis and analysis of covariance (ANCOVA). Across all aggression measures, ADHD children were more aggressive than community controls. ADHD children with nonanxiety co-morbid disorders were more aggressive than ADHD children without such co-morbidity. The number of co-morbid psychiatric diagnoses and ADHD symptom severity were significantly associated with aggression. ADHD youngsters demonstrated significantly more reactive than proactive forms of aggression across all co-morbid diagnoses. Aggression is common in clinically referred ADHD youngsters and should be identified as a legitimate target for psychopharmacological treatment in children and adolescents with moderate to severe ADHD and nonanxiety co-morbid diagnostic disorders.

Are Attitudes To Ageing and Wisdom Enhancement Legitimate Targets For CBT For Late Life Depression and Anxiety?

This paper provides a brief overview of demographic change and suggests that as people are living longer and healthier than previous generations, there is a need to consider how well psychotherapy models are suited to the new generation of elders. The paper also outlines the use of gerontological therapies as vehicles for change to enhance treatment outcome for CBT for late life depression and anxiety. In particular ageing experience and attitude is seen through the lens of a stress-diathesis and wisdom enhancement is considered as a legitimate target in the treatment of late life depression and anxiety.

Defining Terrorism for Public Policy Purposes: The Group-Target Definition

AbstractFor the sake of developing and evaluating public policy decisions aimed at combating terrorism, we need a precise public definition of terrorism that distinguishes terrorism from other forms of violence. Ordinary usage does not provide a basis for such a definition, and so it must be stipulative. I propose essentially pragmatic criteria for developing such a stipulative public definition. After noting that definitions previously proposed in the philosophical literature are inadequate based on these criteria, I propose an alternative, which I call the 'group-target' definition and which distinguishes terrorism from other forms of violence by the distinctive principle of discrimination used by terrorists to identify legitimate targets. I argue that this definition meets the criteria for a satisfactory public definition, and suggest that based on it there is good reason to suspect the adequacy of anti-terrorism policies that rely predominantly on forceful interdiction of terrorists.