Annual Review of Pharmacology and Toxicology - Volume 50, 2010
Volume 50, 2010
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Allosteric Receptors: From Electric Organ to Cognition
Vol. 50 (2010), pp. 1–38More LessThis autobiography covers the past 50 years beginning with the development of the concept of allosteric proteins and its application to pharmacological receptors. It continues with the identification of the nicotinic acetylcholine receptor, the discovery of its molecular organization, the structure of the acetylcholine-binding site and of the ion channel, and the demonstration of its allosteric transitions. The article then traces the origins of the concept of allosteric modulator and its consequences in pharmacology. It proceeds with the theory of selective stabilization of synapses and with experimental studies carried out on the contribution of the nicotinic receptor in the morphogenesis of the neuromuscular junction. The knowledge acquired with the nicotinic receptor is further exploited to reach higher levels of brain organization, and the contribution of nicotinic receptors to the action of nicotine on reward and cognition is explored, in particular, using a novel experimental strategy that combines nicotinic receptor genes knock-out and stereotaxic gene re-expression. Theoretical models of cognitive functions are proposed that link the molecular to the cognitive level. The report ends with a discussion on nicotinic receptors and the pharmacology of the future.
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Pharmacogenetics of Drug Dependence: Role of Gene Variations in Susceptibility and Treatment
Vol. 50 (2010), pp. 39–61More LessDrug dependency is a highly prevalent mental health disorder that imposes a significant burden on those directly affected, health care systems, and society in general. There is substantial heritability in the susceptibility to drug addiction, which indicates that there are genetic risk factors. Variation in the human genome is abundant and can directly affect drug dependency phenotypes, for example, by altering the function of a gene product or by altering gene expression. Pharmacogenetic studies can assess the effects of genetic variation on the risk for a particular phenotype (e.g., being an alcoholic). In addition, pharmacogenetic variability in treatment efficacy and adverse reactions can be investigated to identify particular genetic variants associated with altered responses. This review highlights examples of genetic variations that are important in the development and maintenance of specific drug dependencies as well as those that affect the response to treatment.
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Close Encounters of the Small Kind: Adverse Effects of Man-Made Materials Interfacing with the Nano-Cosmos of Biological Systems
Vol. 50 (2010), pp. 63–88More LessEngineered nanomaterials have unique physico-chemical properties that make them promising for many technological and biomedical applications, including tissue regeneration, drug and gene delivery, and in vivo monitoring of disease processes. However, with the burgeoning capabilities to manipulate structures at the nano-scale, intentional as well as unintentional human exposures to engineered nanomaterials are set to increase. Nanotoxicology is an emerging discipline focused on understanding the properties of engineered nanomaterials and their interactions with biological systems, and may be viewed as the study of the undesirable interference between man-made nanomaterials and cellular nanostructures or nanomachines. In this review, we discuss recognition of engineered nanomaterials by the immune system, our primary defense system against foreign invasion. Moreover, as oxidative stress is believed to be one of the major deleterious consequences of exposure to nanomaterials, we explore triggering of pro- and antioxidant pathways as well as biomarkers of oxidative stress. Finally, we highlight in vivo studies of the toxicological outcomes of engineered nanomaterials, including carbon nanotubes, with an emphasis on inflammation and genotoxic responses.
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GPCR Interacting Proteins (GIPs) in the Nervous System: Roles in Physiology and Pathologies
Vol. 50 (2010), pp. 89–109More LessG protein-coupled receptors (GPCRs) are key transmembrane recognition molecules for regulatory signals such as light, odors, taste hormones, and neurotransmitters. In addition to activating guanine nucleotide binding proteins (G proteins), GPCRs associate with a variety of GPCR-interacting proteins (GIPs). GIPs contain structural interacting domains that allow the formation of large functional complexes involved in G protein-dependent and -independent signaling. At the cellular level, other functions of GIPs include targeting of GPCRs to subcellular compartments and their trafficking to and from the plasma membrane. Recently, roles of GPCR-GIP interactions in central nervous system physiology and pathologies have been revealed. Here, we highlight the role of GIPs in some important neurological and psychiatric disorders, as well as their potential for the future development of therapeutic drugs.
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The c-MYC NHE III1: Function and Regulation
Vol. 50 (2010), pp. 111–129More Lessc-MYC is an important regulator of a wide array of cellular processes necessary for normal cell growth and differentiation, and its dysregulation is one of the hallmarks of many cancers. Consequently, understanding c-MYC transcriptional activation is critical for understanding developmental and cancer biology, as well as for the development of new anticancer drugs. The nuclease hypersensitive element (NHE) III1 region of the c-MYC promoter has been shown to be particularly important in regulating c-MYC expression. Specifically, the formation of a G-quadruplex structure appears to promote repression of c-MYC transcription. This review focuses on what is known about the formation of a G-quadruplex in the NHE III1 region of the c-MYC promoter, as well as on those factors that are known to modulate its formation. Last, we discuss the development of small molecules that stabilize or induce the formation of G-quadruplex structures and could potentially be used as anticancer agents.
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The RNA Polymerase I Transcription Machinery: An Emerging Target for the Treatment of Cancer
Vol. 50 (2010), pp. 131–156More LessThe RNA polymerase I (Pol I) transcription machinery in the nucleolus is the key convergence point that collects and integrates a vast array of information from cellular signaling cascades to regulate ribosome production that in turn guides cell growth and proliferation. Cancer cells commonly harbor mutations that inactivate tumor suppressors, hyperactivate oncogenes, and upregulate protein kinases, all of which promote Pol I transcription and drive cell proliferation. The intimate balance between Pol I transcription and growth-factor signaling is perturbed in cancer cells, indicating that upregulation of rRNA synthesis is mandatory for all tumors. Though the emerging picture of transcriptional regulation reveals an unexpected level of complexity, we are beginning to understand the multiple links between rRNA biogenesis and cancer. In this review, we discuss experimental data and potential strategies to downregulate rRNA synthesis and induce an antiproliferative response in cancer cells.
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LPA Receptors: Subtypes and Biological Actions
Vol. 50 (2010), pp. 157–186More LessLysophosphatidic acid (LPA) is a small, ubiquitous phospholipid that acts as an extracellular signaling molecule by binding to and activating at least five known G protein–coupled receptors (GPCRs): LPA1–LPA5. They are encoded by distinct genes named LPAR1–LPAR5 in humans and Lpar1–Lpar5 in mice. The biological roles of LPA are diverse and include developmental, physiological, and pathophysiological effects. This diversity is mediated by broad and overlapping expression patterns and multiple downstream signaling pathways activated by cognate LPA receptors. Studies using cloned receptors and genetic knockout mice have been instrumental in uncovering the significance of this signaling system, notably involving basic cellular processes as well as multiple organ systems such as the nervous system. This has further provided valuable proof-of-concept data to support LPA receptors and LPA metabolic enzymes as targets for the treatment of medically important diseases that include neuropsychiatric disorders, neuropathic pain, infertility, cardiovascular disease, inflammation, fibrosis, and cancer.
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The Role of Clock Genes in Pharmacology
Vol. 50 (2010), pp. 187–214More LessThe physiology of a wide variety of organisms is organized according to periodic environmental changes imposed by the earth's rotation. This way, a large number of physiological processes present diurnal rhythms regulated by an internal timing system called the circadian clock. As part of the rhythmicity in physiology, drug efficacy and toxicity can vary with time. Studies over the past four decades present diurnal oscillations in drug absorption, distribution, metabolism, and excretion. On the other hand, diurnal variations in the availability and sensitivity of drug targets have been correlated with time-dependent changes in drug effectiveness. In this review, we provide evidence supporting the regulation of drug kinetics and dynamics by the circadian clock. We also use the examples of hypertension and cancer to show current achievements and challenges in chronopharmacology.
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Toxicological Disruption of Signaling Homeostasis: Tyrosine Phosphatases as Targets
Vol. 50 (2010), pp. 215–235More LessThe protein tyrosine phosphatases (PTPs) consist of a diverse group of enzymes whose activity opposes that of the tyrosine kinases. As such, the PTPs have critical roles in maintaining signaling quiescence in resting cells and in restoring homeostasis by effecting signal termination. Interest in these enzymes has increased in recent years following the discovery that the activity of PTPs is modulated through redox mechanisms during signaling. The molecular features that enable redox regulation of PTPs during physiological signaling also render them highly susceptible to oxidative and electrophilic inactivation by a broad spectrum of structurally disparate xenobiotic compounds. The loss of PTP activity results in a profound disregulation of protein phosphotyrosine metabolism, leading to widespread and persistent activation of signaling cascades in the cell.
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Discovery and Development of Therapeutic Aptamers
Vol. 50 (2010), pp. 237–257More LessTherapeutic aptamers are single-stranded structured oligonucleotides that bind to protein targets with high affinity and specificity and modulate protein function. Aptamers are discovered by iterative rounds of selection for binding to the target protein, partitioning, and amplification of binding clones from a diverse starting library (SELEX). Postselection optimization of clones using chemical modification is directed at improving affinity, potency, and metabolic stability. A key attribute of therapeutic aptamers is the ability to tailor the pharmacokinetic profile by modulating the degree of metabolic stability and modulating renal clearance and rate of distribution by conjugation to various sizes of polyethylene glycol (PEG). In toxicology studies, therapeutic aptamers have been largely devoid of the previously reported oligonucleotide class effects of immune stimulation, complement activation, and anticoagulation; and the principal finding is the histologically visible accumulation of drug-related material in mononuclear phagocytes, a finding generally not considered an adverse effect. Good safety margins between the pharmacologically effective dose and toxicologically established no-adverse-effect levels have been observed consistently. There are presently seven aptamers either on the market or in clinical trials, but there is still much to be demonstrated in terms of chronic systemic use to fully realize the potential of this promising new class of drugs.
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RNA Targeting Therapeutics: Molecular Mechanisms of Antisense Oligonucleotides as a Therapeutic Platform
Vol. 50 (2010), pp. 259–293More LessDramatic advances in understanding of the roles RNA plays in normal health and disease have greatly expanded over the past 10 years and have made it clear that scientists are only beginning to comprehend the biology of RNAs. It is likely that RNA will become an increasingly important target for therapeutic intervention; therefore, it is important to develop strategies for therapeutically modulating RNA function. Antisense oligonucleotides are perhaps the most direct therapeutic strategy to approach RNA. Antisense oligonucleotides are designed to bind to the target RNA by well-characterized Watson-Crick base pairing, and once bound to the target RNA, modulate its function through a variety of postbinding events. This review focuses on the molecular mechanisms by which antisense oligonucleotides can be designed to modulate RNA function in mammalian cells and how synthetic oligonucleotides behave in the body.
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Metabotropic Glutamate Receptors: Physiology, Pharmacology, and Disease
Vol. 50 (2010), pp. 295–322More LessThe metabotropic glutamate receptors (mGluRs) are family C G-protein-coupled receptors that participate in the modulation of synaptic transmission and neuronal excitability throughout the central nervous system. The mGluRs bind glutamate within a large extracellular domain and transmit signals through the receptor protein to intracellular signaling partners. A great deal of progress has been made in determining the mechanisms by which mGluRs are activated, proteins with which they interact, and orthosteric and allosteric ligands that can modulate receptor activity. The widespread expression of mGluRs makes these receptors particularly attractive drug targets, and recent studies continue to validate the therapeutic utility of mGluR ligands in neurological and psychiatric disorders such as Alzheimer's disease, Parkinson's disease, anxiety, depression, and schizophrenia.
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Mechanisms of Cell Protection by Heme Oxygenase-1
Vol. 50 (2010), pp. 323–354More LessHeme oxygenases (HO) catabolize free heme, that is, iron (Fe) protoporphyrin (IX), into equimolar amounts of Fe2+, carbon monoxide (CO), and biliverdin. The stress-responsive HO-1 isoenzyme affords protection against programmed cell death. The mechanism underlying this cytoprotective effect relies on the ability of HO-1 to catabolize free heme and prevent it from sensitizing cells to undergo programmed cell death. This cytoprotective effect inhibits the pathogenesis of a variety of immune-mediated inflammatory diseases.
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Epac: Defining a New Mechanism for cAMP Action
Vol. 50 (2010), pp. 355–375More LesscAMP is a second messenger that is essential for relaying hormonal responses in many biological processes. The discovery of the cAMP target Epac explained various effects of cAMP that could not be attributed to the established targets PKA and cyclic nucleotide–gated ion channels. Epac1 and Epac2 function as guanine nucleotide exchange factors for the small G protein Rap. cAMP analogs that selectively activate Epac have helped to reveal a role for Epac in processes ranging from insulin secretion to cardiac contraction and vascular permeability. Advances in the understanding of the activation mechanism of Epac and its regulation by diverse anchoring mechanisms have helped to elucidate the means by which cAMP fulfills these functions via Epac.
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Circadian Timing in Cancer Treatments
Vol. 50 (2010), pp. 377–421More LessThe circadian timing system is composed of molecular clocks, which drive 24-h changes in xenobiotic metabolism and detoxification, cell cycle events, DNA repair, apoptosis, and angiogenesis. The cellular circadian clocks are coordinated by endogenous physiological rhythms, so that they tick in synchrony in the host tissues that can be damaged by anticancer agents. As a result, circadian timing can modify 2- to 10-fold the tolerability of anticancer medications in experimental models and in cancer patients. Improved efficacy is also seen when drugs are given near their respective times of best tolerability, due to (a) inherently poor circadian entrainment of tumors and (b) persistent circadian entrainment of healthy tissues. Conversely, host clocks are disrupted whenever anticancer drugs are administered at their most toxic time. On the other hand, circadian disruption accelerates experimental and clinical cancer processes. Gender, circadian physiology, clock genes, and cell cycle critically affect outcome on cancer chronotherapeutics. Mathematical and systems biology approaches currently develop and integrate theoretical, experimental, and technological tools in order to further optimize and personalize the circadian administration of cancer treatments.
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Economic Opportunities and Challenges for Pharmacogenomics
Vol. 50 (2010), pp. 423–437More LessEconomic evaluation provides health care decision makers with a powerful tool for resource allocation decisions because it offers a framework for comparing the costs and benefits of competing interventions or options. This paper reviews how economic analyses have been applied to the field of pharmacogenomics, both by the pharmaceutical industry to inform investment decisions and by payers to make coverage decisions. There is much anticipation that pharmacogenomic testing is likely to be cost-effective because it uses genomic information to improve drug effectiveness and reduce toxicity both in the drug development process and at the bedside. However, the demonstration of economic benefits first requires that pharmacogenomic testing show evidence of clinical effectiveness. This will only be achieved by greater participation of pharmacogenomics experts in comparative effectiveness research and additional emphasis on including costs in the determination of the relative value of pharmacogenomic testing to the health care system.
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Tissue Renin-Angiotensin-Aldosterone Systems: Targets for Pharmacological Therapy
Vol. 50 (2010), pp. 439–465More LessThe renin-angiotensin-aldosterone system is one of the most important systems in cardiovascular control and in the pathogenesis of cardiovascular diseases. Therefore, it is already a very successful drug target for the therapy of these diseases. However, angiotensins are generated not only in the plasma but also locally in tissues from precursors and substrates either locally expressed or imported from the circulation. In most areas of the brain, only locally generated angiotensins can exert effects on their receptors owing to the blood-brain barrier. Other tissue renin-angiotensin-aldosterone systems are found in cardiovascular organs such as kidney, heart, and vessels and play important roles in the function of these organs and in the deleterious actions of hypertension and diabetes on these tissues. Novel components with mostly opposite actions to the classical renin-angiotensin-aldosterone systems have been described and need functional characterization to evaluate their suitability as novel drug targets.
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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)