Annual Review of Pharmacology and Toxicology - Volume 56, 2016
Volume 56, 2016
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My Winding Road: From Microbiology to Toxicology and Environmental Health*
Vol. 56 (2016), pp. 1–17More LessI would certainly never have predicted that I would become the director of the National Institute of Environmental Health Sciences (NIEHS) and the National Toxicology Program (NTP) when I was a Jewish girl growing up in Teaneck, New Jersey. My family stressed the importance of education. Yet for a girl there were many not-so-subtle suggestions that the appropriate careers were in teaching or nursing, and the most important thing was to be a wife and mother. Well, I can't disagree with the latter, although I would have to add grandmother to that list of achievements. My parents were both college graduates, but my mom only taught high school English for one year before leaving the field to start our family. My dad returned from World War II and joined his brother in accounting. After my first sister was born, my father joined my mother's family jewelry business and helped to open a second retail store. My mother helped my dad out during the busy times—Christmas and wedding season—but otherwise focused on our growing family of three girls and one boy. This became increasingly challenging when it became clear that my little brother was severely retarded and would require extra care.
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Drugging Undruggable Molecular Cancer Targets
Vol. 56 (2016), pp. 23–40More LessCancer, more than any other human disease, now has a surfeit of potential molecular targets poised for therapeutic exploitation. Currently, a number of attractive and validated cancer targets remain outside of the reach of pharmacological regulation. Some have been described as undruggable, at least by traditional strategies. In this article, we outline the basis for the undruggable moniker, propose a reclassification of these targets as undrugged, and highlight three general classes of this imposing group as exemplars with some attendant strategies currently being explored to reclassify them. Expanding the spectrum of disease-relevant targets to pharmacological manipulation is central to reducing cancer morbidity and mortality.
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New Strategies in Cancer Nanomedicine
Vol. 56 (2016), pp. 41–57More LessWe review recent progress in cancer nanomedicine, including stimulus-responsive drug delivery systems and nanoparticles responding to light for phototherapy or tumor imaging. In addition, several new strategies to improve the circulation of nanoparticles in vivo, tumor penetration, and tumor targeting are discussed. The application of nanomedicine in cancer immunology, a relatively new type of cancer therapy, is also highlighted.
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Therapeutic Potential of T Cell Chimeric Antigen Receptors (CARs) in Cancer Treatment: Counteracting Off-Tumor Toxicities for Safe CAR T Cell Therapy
Gideon Gross, and Zelig EshharVol. 56 (2016), pp. 59–83More LessA chimeric antigen receptor (CAR) is a recombinant fusion protein combining an antibody-derived targeting fragment with signaling domains capable of activating T cells. Recent early-phase clinical trials have demonstrated the remarkable ability of CAR-modified T cells to eliminate B cell malignancies. This review describes the choice of target antigens and CAR manipulations to maximize antitumor specificity. Benefits and current limitations of CAR-modified T cells are discussed, with a special focus on the distribution of tumor antigens on normal tissues and the risk of on-target, off-tumor toxicities in the clinical setting. We present current methodologies for pre-evaluating these risks and review the strategies for counteracting potential off-tumor effects. Successful implementation of these approaches will improve the safety and efficacy of CAR T cell therapy and extend the range of cancer patients who may be treated.
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Toward a Better Understanding of the Complexity of Cancer Drug Resistance
Vol. 56 (2016), pp. 85–102More LessResistance to anticancer drugs is a complex process that results from alterations in drug targets; development of alternative pathways for growth activation; changes in cellular pharmacology, including increased drug efflux; regulatory changes that alter differentiation pathways or pathways for response to environmental adversity; and/or changes in the local physiology of the cancer, such as blood supply, tissue hydrodynamics, behavior of neighboring cells, and immune system response. All of these specific mechanisms are facilitated by the intrinsic hallmarks of cancer, such as tumor cell heterogeneity, redundancy of growth-promoting pathways, increased mutation rate and/or epigenetic alterations, and the dynamic variation of tumor behavior in time and space. Understanding the relative contribution of each of these factors is further complicated by the lack of adequate in vitro models that mimic clinical cancers. Several strategies to use current knowledge of drug resistance to improve treatment of cancer are suggested.
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RNA Interference (RNAi)-Based Therapeutics: Delivering on the Promise?
Vol. 56 (2016), pp. 103–122More LessA resurgence in clinical trials using RNA interference (RNAi) occurred in 2012. Although there were initial difficulties in achieving efficacious results with RNAi without toxic side effects, advances in delivery and improved chemistry made this resurgence possible. More than 20 RNAi-based therapeutics are currently in clinical trials, and several of these are Phase III trials. Continued positive results from these trials have helped bolster further attempts to develop clinically relevant RNAi therapies. With a wide variety of disease targets to choose from, the first RNAi therapeutic to be clinically approved is not far off. This review covers recently established and completed clinical trials.
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Approaches to Validate and Manipulate RNA Targets with Small Molecules in Cells
Vol. 56 (2016), pp. 123–140More LessRNA has become an increasingly important target for therapeutic interventions and for chemical probes that dissect and manipulate its cellular function. Emerging targets include human RNAs that have been shown to directly cause cancer, metabolic disorders, and genetic disease. In this review, we describe various routes to obtain bioactive compounds that target RNA, with a particular emphasis on the development of small molecules. We use these cases to describe approaches that are being developed for target validation, which include target-directed cleavage, classic pull-down experiments, and covalent cross-linking. Thus, tools are available to design small molecules to target RNA and to identify the cellular RNAs that are their targets.
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The Cellular Thermal Shift Assay: A Novel Biophysical Assay for In Situ Drug Target Engagement and Mechanistic Biomarker Studies
Vol. 56 (2016), pp. 141–161More LessA drug must engage its intended target to achieve its therapeutic effect. However, conclusively measuring target engagement (TE) in situ is challenging. This complicates preclinical development and is considered a key factor in the high rate of attrition in clinical trials. Here, we discuss a recently developed, label-free, biophysical assay, the cellular thermal shift assay (CETSA), which facilitates the direct assessment of TE in cells and tissues at various stages of drug development. CETSA also reveals biochemical events downstream of drug binding and therefore provides a promising means of establishing mechanistic biomarkers. The implementation of proteome-wide CETSA using quantitative mass spectrometry represents a novel strategy for defining off-target toxicity and polypharmacology and for identifying downstream mechanistic biomarkers. The first year of CETSA applications in the literature has focused on TE studies in cell culture systems and has confirmed the broad applicability of CETSA to many different target families. The next phase of CETSA applications will likely encompass comprehensive animal and patient studies, and CETSA will likely serve as a very valuable tool in many stages of preclinical and clinical drug development.
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Genome Editing: A New Approach to Human Therapeutics
Vol. 56 (2016), pp. 163–190More LessThe ability to manipulate the genome with precise spatial and nucleotide resolution (genome editing) has been a powerful research tool. In the past decade, the tools and expertise for using genome editing in human somatic cells and pluripotent cells have increased to such an extent that the approach is now being developed widely as a strategy to treat human disease. The fundamental process depends on creating a site-specific DNA double-strand break (DSB) in the genome and then allowing the cell's endogenous DSB repair machinery to fix the break such that precise nucleotide changes are made to the DNA sequence. With the development and discovery of several different nuclease platforms and increasing knowledge of the parameters affecting different genome editing outcomes, genome editing frequencies now reach therapeutic relevance for a wide variety of diseases. Moreover, there is a series of complementary approaches to assessing the safety and toxicity of any genome editing process, irrespective of the underlying nuclease used. Finally, the development of genome editing has raised the issue of whether it should be used to engineer the human germline. Although such an approach could clearly prevent the birth of people with devastating and destructive genetic diseases, questions remain about whether human society is morally responsible enough to use this tool.
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Structure-Driven Developments of 26S Proteasome Inhibitors
Vol. 56 (2016), pp. 191–209More LessThe 26S proteasome is a 2.5-MDa complex, and it operates at the executive end of the ubiquitin-proteasome pathway. It is a proven target for therapeutic agents for the treatment of some cancers and autoimmune diseases, and moreover, it has potential as a target of antibacterial agents. Most inhibitors, including all molecules approved for clinical use, target the 20S proteolytic core complex; its structure was determined two decades ago. Hitherto, efforts to develop inhibitors targeting the 19S regulatory particle subunits have been less successful. This is, in part, because the molecular architecture of this subcomplex has been, until recently, poorly understood, and high-resolution structures have been available only for a few subunits. In this review, we describe, from a structural perspective, the development of inhibitory molecules that target both the 20S and 19S subunits of the proteasome. We highlight the recent progress achieved in structure-based drug-discovery approaches, and we discuss the prospects for further improvement.
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Biobanking Comes of Age: The Transition to Biospecimen Science
Vol. 56 (2016), pp. 211–228More LessBiobanking involves the collection, processing, storage, and distribution of biological specimens and the policies and procedures necessary to accomplish those aims successfully. Although biobanking may also involve collections for environmental studies or museum archives, most efforts to standardize biobanking practices have been directed toward human biomedical research. Initially focused primarily on collecting samples for diagnostic purposes in pathology settings, biobanks have evolved into complex organizations engaged in advancing personalized (or precision) medicine and translational research. This evolution has involved the development of biobanking best practices and the transformation of a field driven by empirical approaches into the emerging area of biospecimen science. It has become increasingly important to develop evidence-based practices for collecting biospecimens and data that can be shared with confidence with international collaborators. Aside from these technical approaches, other factors play crucial roles, such as ethical and regulatory issues, business planning and sustainability, and approaches to data collection and sharing.
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Mitochondrial Biogenesis as a Pharmacological Target: A New Approach to Acute and Chronic Diseases
Vol. 56 (2016), pp. 229–249More LessMitochondrial dysfunction is a key pathophysiological component of many acute and chronic diseases. Maintenance of mitochondrial homeostasis through the balance of mitochondrial turnover, fission and fusion, and generation of new mitochondria via mitochondrial biogenesis is critical for tissue health. Pharmacological activation of mitochondrial biogenesis can enhance oxidative metabolism and tissue bioenergetics, and improve organ function in conditions characterized by mitochondrial dysfunction. However, owing to the complexity of mitochondrial assembly and maintenance, identification of specific activators of mitochondrial biogenesis has been difficult. This review provides an overview of the role of mitochondrial dysfunction in acute and chronic diseases, details the current state of therapeutics for the stimulation of mitochondrial biogenesis and their effects on disease outcomes, describes new screening methodologies to identify novel stimulators and noncanonical pathways of mitochondrial biogenesis, and discusses potential hurdles of mitochondrial biogenesis as a therapeutic strategy.
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Triclosan: A Widespread Environmental Toxicant with Many Biological Effects
Vol. 56 (2016), pp. 251–272More LessTriclosan (TCS) is a broad-spectrum antimicrobial agent that has been added to personal care products, including hand soaps and cosmetics, and impregnated in numerous different materials ranging from athletic clothing to food packaging. The constant disposal of TCS into the sewage system is creating a major environmental and public health hazard. Owing to its chemical properties of bioaccumulation and resistance to degradation, TCS is widely detected in various environmental compartments in concentrations ranging from nanograms to micrograms per liter. Epidemiology studies indicate that significant levels of TCS are detected in body fluids in all human age groups. We document here the emerging evidence—from in vitro and in vivo animal studies and environmental toxicology studies—demonstrating that TCS exerts adverse effects on different biological systems through various modes of action. Considering the fact that humans are simultaneously exposed to TCS and many TCS-like chemicals, we speculate that TCS-induced adverse effects may be relevant to human health.
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Systems Pharmacology Links GPCRs with Retinal Degenerative Disorders
Vol. 56 (2016), pp. 273–298More LessIn most biological systems, second messengers and their key regulatory and effector proteins form links between multiple cellular signaling pathways. Such signaling nodes can integrate the deleterious effects of genetic aberrations, environmental stressors, or both in complex diseases, leading to cell death by various mechanisms. Here we present a systems (network) pharmacology approach that, together with transcriptomics analyses, was used to identify different G protein–coupled receptors that experimentally protected against cellular stress and death caused by linked signaling mechanisms. We describe the application of this concept to degenerative and diabetic retinopathies in appropriate mouse models as an example. Systems pharmacology also provides an attractive framework for devising strategies to combat complex diseases by using (repurposing) US Food and Drug Administration–approved pharmacological agents.
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Existing and Future Drugs for the Treatment of the Dark Side of Addiction
Vol. 56 (2016), pp. 299–322More LessThe identification of a heuristic framework for the stages of the addiction cycle that are linked to neurocircuitry changes in pathophysiology includes the binge/intoxication stage, the withdrawal/negative affect stage, and the preoccupation/anticipation (craving) stage, which represent neuroadaptations in three neurocircuits (basal ganglia, extended amygdala, and frontal cortex, respectively). The identification of excellent and validated animal models, the development of human laboratory models, and an enormous surge in our understanding of neurocircuitry and neuropharmacological mechanisms have provided a revisionist view of addiction that emphasizes the loss of brain reward function and gain of stress function that drive negative reinforcement (the dark side of addiction) as a key to compulsive drug seeking. Reversing the dark side of addiction not only explains much of the existing successful pharmacotherapies for addiction but also points to vast new opportunities for future medications to alleviate this major source of human suffering.
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Can Humanized Mice Predict Drug “Behavior” in Humans?
Dan Xu, and Gary PeltzVol. 56 (2016), pp. 323–338More LessMost of what we know about a drug prior to human clinical studies is derived from animal testing. Because animals and humans have substantial differences in their physiology and in their drug metabolism pathways, we do not know very much about the pharmacokinetic and pharmacodynamic behavior of a drug in humans until after it is administered to many people. Hence, drug-induced liver injury has become a significant public health problem, and we have a very inefficient drug development process with a high failure rate. Because the human liver is at the heart of these problems, chimeric mice with humanized livers could be used to address these issues. We examine recent evidence indicating that drug testing in chimeric mice could provide better information about a drug's metabolism, disposition, and toxicity (i.e., its “behavior”) in humans and could aid in developing personalized medicine strategies, which would improve drug efficacy and safety.
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Targeting Prefrontal Cortical Systems for Drug Development: Potential Therapies for Cognitive Disorders
Amy F.T. Arnsten, and Min WangVol. 56 (2016), pp. 339–360More LessMedications to treat cognitive disorders are increasingly needed, yet researchers have had few successes in this challenging arena. Cognitive abilities in primates arise from highly evolved N-methyl-d-aspartate (NMDA) receptor circuits in layer III of the dorsolateral prefrontal cortex. These circuits have unique modulatory needs that can differ from the layer V neurons that predominate in rodents, but they offer multiple therapeutic targets. Cognitive improvement often requires low doses that enhance the pattern of information held in working memory, whereas higher doses can produce nonspecific changes that obscure information. Identifying appropriate doses for clinical trials may be helped by assessments in monkeys and by flexible, individualized dose designs. The use of guanfacine (Intuniv) for prefrontal cortical disorders was based on research in monkeys, supporting this approach. Coupling our knowledge of higher primate circuits with the powerful methods now available in drug design will help create effective treatments for cognitive disorders.
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MT1 and MT2 Melatonin Receptors: A Therapeutic Perspective
Vol. 56 (2016), pp. 361–383More LessMelatonin, or 5-methoxy-N-acetyltryptamine, is synthesized and released by the pineal gland and locally in the retina following a circadian rhythm, with low levels during the day and elevated levels at night. Melatonin activates two high-affinity G protein–coupled receptors, termed MT1 and MT2, to exert beneficial actions in sleep and circadian abnormality, mood disorders, learning and memory, neuroprotection, drug abuse, and cancer. Progress in understanding the role of melatonin receptors in the modulation of sleep and circadian rhythms has led to the discovery of a novel class of melatonin agonists for treating insomnia, circadian rhythms, mood disorders, and cancer. This review describes the pharmacological properties of a slow-release melatonin preparation (i.e., Circadin®) and synthetic ligands (i.e., agomelatine, ramelteon, tasimelteon), with emphasis on identifying specific therapeutic effects mediated through MT1 and MT2 receptor activation. Discovery of selective ligands targeting the MT1 or the MT2 melatonin receptors may promote the development of novel and more efficacious therapeutic agents.
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Structure, Function, and Drug Interactions of Neurotransmitter Transporters in the Postgenomic Era
Vol. 56 (2016), pp. 385–402More LessVesicular neurotransmitter transporters are responsible for the accumulation of neurotransmitters in secretory vesicles and play essential roles in chemical transmission. The SLC17 family contributes to sequestration of anionic neurotransmitters such as glutamate, aspartate, and nucleotides. Identification and subsequent cellular and molecular biological studies of SLC17 transporters unveiled the principles underlying the actions of these transporters. Recent progress in reconstitution methods in combination with postgenomic approaches has advanced studies on neurotransmitter transporters. This review summarizes the molecular properties of SLC17-type transporters and recent findings regarding the novel SLC18 transporter.
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Previous Volumes
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Volume 64 (2024)
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Volume 63 (2023)
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Volume 62 (2022)
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Volume 61 (2021)
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Volume 60 (2020)
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Volume 59 (2019)
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Volume 58 (2018)
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Volume 57 (2017)
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Volume 56 (2016)
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Volume 55 (2015)
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Volume 54 (2014)
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Volume 53 (2013)
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Volume 52 (2012)
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Volume 51 (2011)
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Volume 50 (2010)
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Volume 49 (2009)
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Volume 48 (2008)
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Volume 47 (2007)
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Volume 46 (2006)
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Volume 45 (2005)
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Volume 44 (2004)
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Volume 43 (2003)
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Volume 42 (2002)
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Volume 41 (2001)
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Volume 40 (2000)
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Volume 39 (1999)
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Volume 38 (1998)
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Volume 37 (1997)
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Volume 36 (1996)
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Volume 35 (1995)
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Volume 34 (1994)
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Volume 33 (1993)
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Volume 32 (1992)
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Volume 31 (1991)
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Volume 30 (1990)
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Volume 29 (1989)
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Volume 28 (1988)
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Volume 27 (1987)
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Volume 26 (1986)
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Volume 25 (1985)
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Volume 24 (1984)
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Volume 23 (1983)
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Volume 22 (1982)
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Volume 21 (1981)
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Volume 20 (1980)
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Volume 19 (1979)
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Volume 18 (1978)
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Volume 17 (1977)
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Volume 16 (1976)
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Volume 15 (1975)
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Volume 14 (1974)
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Volume 13 (1973)
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Volume 12 (1972)
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Volume 11 (1971)
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Volume 10 (1970)
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Volume 9 (1969)
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Volume 8 (1968)
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Volume 7 (1967)
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Volume 6 (1966)
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Volume 5 (1965)
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Volume 4 (1964)
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Volume 3 (1963)
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Volume 2 (1962)
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Volume 1 (1961)
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Volume 0 (1932)