Current Pharmaceutical Design - Volume 27, Issue 2, 2021
Volume 27, Issue 2, 2021
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Natural Products and Extracts as Xantine Oxidase Inhibitors - A Hope for Gout Disease?
Authors: Ilkay E. Orhan and Fatma S.S. DenizXanthine oxidase (EC 1.17.3.2) (XO) is one of the main enzymatic sources that create reactive oxygen species (ROS) in the living system. It is a dehydrogenase enzyme that performs electron transfer to nicotinamide adenine dinucleotide (NAD+), while oxidizing hypoxanthin, which is an intermediate compound in purine catabolism, first to xanthine and then to uric acid. XO turns into an oxidant enzyme that oxidizes thiol groups under certain stress conditions in the tissue. The last metabolic step, in which hypoxanthin turns into uric acid, is catalyzed by XO. Uric acid, considered a waste product, can cause kidney stones and gouty-type arthritis as it is crystallized, when present in high concentrations. Thus, XO inhibitors are one of the drug classes used against gout, a purine metabolism disease that causes urate crystal storage in the joint and its surroundings caused by hyperuricemia. Urate-lowering therapy includes XO inhibitors that reduce uric acid production as well as uricosuric drugs that increase urea excretion. Current drugs that obstruct uric acid synthesis through XO inhibition are allopurinol, febuxostat, and uricase. However, since the side effects, safety and tolerability problems of some current gout medications still exist, intensive research is ongoing to look for new, effective, and safer XO inhibitors of natural or synthetic origins for the treatment of the disease. In the present review, we aimed to assess in detail XO inhibitory capacities of pure natural compounds along with the extracts from plants and other natural sources via screening Pubmed, Web of Science (WoS), Scopus, and Google Academic. The data pointed out to the fact that natural products, particularly phenolics such as flavonoids (quercetin, apigenin, and scutellarein), tannins (agrimoniin and ellagitannin), chalcones (melanoxethin), triterpenes (ginsenoside Rd and ursolic acid), stilbenes (resveratrol and piceatannol), alkaloids (berberin and palmatin) have a great potential for new XO inhibitors capable of use against gout disease. In addition, not only plants but other biological sources such as microfungi, macrofungi, lichens, insects (silk worms, ants, etc) seem to be the promising sources of novel XO inhibitors.
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Mitochondrial-induced Epigenetic Modifications: From Biology to Clinical Translation
Authors: Jahnavi Sharma, Roshani Kumari, Arpit Bhargava, Rajnarayan Tiwari and Pradyumna K. MishraMitochondria are maternally inherited semi-autonomous organelles that play a central role in redox balance, energy metabolism, control of integrated stress responses, and cellular homeostasis. The molecular communication between mitochondria and the nucleus is intricate and bidirectional in nature. Though mitochondrial genome encodes for several key proteins involved in oxidative phosphorylation, several regulatory factors encoded by nuclear DNA are prominent contributors to mitochondrial biogenesis and function. The loss of synergy between this reciprocal control of anterograde (nuclear to mitochondrial) and retrograde (mitochondrial to nuclear) signaling, triggers epigenomic imbalance and affects mitochondrial function and global gene expressions. Recent expansions of our knowledge on mitochondrial epigenomics have offered novel perspectives for the study of several non-communicable diseases including cancer. As mitochondria are considered beacons for pharmacological interventions, new frontiers in targeted delivery approaches could provide opportunities for effective disease management and cure through reversible epigenetic reprogramming. This review focuses on recent progress in the area of mitochondrial-nuclear cross-talk and epigenetic regulation of mitochondrial DNA methylation, mitochondrial micro RNAs, and post-translational modification of mitochondrial nucleoid-associated proteins that hold major opportunities for targeted drug delivery and clinical translation.
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Mutations of mtDNA in some Vascular and Metabolic Diseases
Background: The present review article considers some chronic diseases of vascular and metabolic genesis, the causes of which may be mitochondrial dysfunction. Very often, in the long course of the disease, complications may occur, leading to myocardial infarction or ischemic stroke and, as a result, death. In particular, a large percentage of human deaths nowadays belongs to cardiovascular diseases, such as coronary heart disease (CHD), arterial hypertension, cardiomyopathies, and type 2 diabetes mellitus. Objective: The aim of the present review was the analysis of literature sources, devoted to an investigation of a link of mitochondrial DNA mutations with chronic diseases of vascular and metabolic genesis. Results: The analysis of literature indicates the association of the mitochondrial genome mutations with coronary heart disease, type 2 diabetes mellitus, hypertension, and various types of cardiomyopathies. Conclusion: The detected mutations can be used to analyze the predisposition to chronic diseases of vascular and metabolic genesis. They can also be used to create molecular-cell models necessary to evaluate the effectiveness of drugs developed for the treatment of these pathologies. MtDNA mutations associated with the absence of diseases of vascular and metabolic genesis could be potential candidates for gene therapy of the said diseases.
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Alkaloids of Peganum harmala: Anticancer Biomarkers with Promising Outcomes
Authors: Atefeh Jalali, Farid Dabaghian and Mohammad M. ZarshenasBackground: Cancer is a serious and growing global health issue worldwide. In the cancerous cells, the normal cell cycle has been disrupted via a series of irreversible changes. Recently, the investigations on herbal medicine and clarifying the phytochemicals potential in treat cancer has been increased. The combination of phytochemicals with conventional cancer treatment approaches can improve outcomes via advancing cell death, restraining cell proliferation and invasion, sensitizing cancerous cells, and promoting the immune system. Therefore, phytochemicals can be introduced as relevant complementary medicaments in cancer therapy. Peganum harmala L. (Zygophyllaceae) as a valuable medicinal herb, possesses various alkaloid ingredient. Objective: Pointing to the importance of new avenues for cancer management and P. harmala convincing effect in this field, this review strived to collect a frame to epitome possible scopes to develop novel medicines in cancer treatment. Methods: Keywords "Peganum harmala" and cancer, or chemotherapy, or anti-neoplasm were searched through the "Scopus" database up to 29th of February 2020. Papers linking to agriculture, chemistry, environmental, and genetics sciences were omitted and, papers centered on cancer were selected. Results and Discussion: In the current study, 42 related papers to cancer treatment and 22 papers on alkaloid bioactive components are collected from 72 papers. The β-carboline alkaloids derived from P. harmala, especially harmine, demonstrate notable anticancer properties by targeting apoptosis, autophagy, abnormal cell proliferation, angiogenesis, metastasis, and cytotoxicity. Based on the collected information, P. harmala holds significant anticancer activity. Considering the mechanism of the various anticancer drugs and their acting similarity to P. harmala, the alkaloids derived from this herb, particularly harmine, can introduce as a novel anticancer medicine solely or in adjuvant cancer therapy.
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The Impact of Immune Cell-derived Exosomes on Immune Response Initiation and Immune System Function
Exosomes are small extracellular vesicles that pass genetic material between various cells to modulate or alter their biological function. The role of exosomes is to communicate with the target cell for cell-to-cell communication. Their inherent characteristics of exosomes, such as adhesion molecules, allow targeting specifically to the receiving cell. Exosomes are involved in cell to cell communication in the immune system including antigen presentation, natural killer cells (NK cells) and T cell activation/polarisation, immune suppression and various anti-inflammatory processes. In this review, we have described various functions of exosomes secreted by the immune cells in initiating, activating and modulating immune responses; and highlight the distinct roles of exosomal surface proteins and exosomal cargo. Potential applications of exosomes such as distribution vehicles for immunotherapy are also discussed.
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Predictive Value of Sirtuins in Acute Myocardial Infarction - Bridging the Bench to the Clinical Practice
Acute myocardial infarction (AMI) is a non-transmissible condition with high prevalence, morbidity, and mortality. Different strategies for the management of AMI are employed worldwide, but its early diagnosis remains a major challenge. Many molecules have been proposed in recent years as predictive agents in the early detection of AMI, including troponin (C, T, and I), creatine kinase MB isoenzyme, myoglobin, heart-type fatty acid-binding protein, and a family of histone deacetylases with enzymatic activities named sirtuins. Sirtuins may be used as predictive or complementary treatment strategies and the results of recent preclinical studies are promising. However, human clinical trials and data are scarce, and many issues have been raised regarding the predictive values of sirtuins. The present review summarizes research on the predictive value of sirtuins in AMI. We also briefly summarize relevant clinical trials and discuss future perspectives and possible clinical applications.
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The Ligands of Translocator Protein: Design and Biological Properties
Authors: Grigory V. Mokrov, Olga A. Deeva and Tatiana A. GudashevaIn 2020, it is already 43 years since Braestrup and Squires discovered 18 kDa translocator protein (TSPO), known until 2006 as "peripheral benzodiazepine receptor". During this time, the functions of this receptor, which is located on the outer membrane of mitochondria, were studied in detail. One of the key functions of TSPO is the transfer of cholesterol from the outer to the inner mitochondrial membrane, which is the limiting stage in the synthesis of neurosteroids. TSPO is also involved in the transport of porphyrins, mitochondrial respiration, the opening of mitochondrial pores, apoptosis and cell proliferation. This review presents current information on the structure of TSPO, the mechanism of its participation in neurosteroidogenesis, as well as endogenous and synthetic TSPO ligands. Particular emphasis is placed on the analysis of approaches to the design of synthetic ligands and their neuropsychotropic activity in vitro and in vivo. The presented review demonstrates the promise of constructing new neuropsychotropic drugs in the series of TSPO ligands.
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Indolic Structure Metabolites as Potential Biomarkers of Non-infectious Diseases
Authors: Natalia V. Beloborodova, Ekaterina A. Chernevskaya and Maria L. GetsinaInterest in indolic structure metabolites, including a number of products of microbial biotransformation of the aromatic amino acid tryptophan, is increasingly growing. The review prepared by a team of authors is based on in-depthscrutiny of data available in PubMed, Scopus, Cyberleninka, Clinical Trials, and Cochrane Library, eventually narrowing the search to a set of keywords such as tryptophan metabolites; plasma metabolomics profiling; metabolomics fingerprinting; gas-, liquid chromatography mass spectrometry; serotonin; melatonin; tryptamine; indoxyl sulfate; indole-3-acetic acid; indole-3-propionic acid; 5-hydroxyindole-3-acetic acid; gut microbiota and microbial metabolites. It provides a summary that outlines the pattern of changes in the level of indolic structure metabolites in a number of diseases and deals with the data from the field of human microbiota metabolites. In modern experimental studies, including the use of gnotobiological (germ-free) animals, it has been convincingly proved that the formation of tryptophan metabolites such as indole-3-acetic acid, indole-3-propionic acid, tryptamine, and indoxyl sulfate is associated with gut bacteria. Attention to some concentration changes of indolic compounds is due to the fact that pronounced deviations and a significant decrease of these metabolites in the blood were found in a number of serious cardiovascular, brain or gastrointestinal diseases. The literature-based analysis allowed the authors to conclude that a constant (normal) level of the main metabolites of the indolic structure in the human body is maintained by a few strict anaerobic bacteria from the gut of a healthy body belonging to the species of Clostridium, Bacteroides, Peptostreptococcus, Eubacteria, etc. The authors focus on several metabolites of the indolic structure that can be called clinically significant in certain diseases, such as schizophrenia, depression, atherosclerosis, colorectal cancer, etc. Determining the level of indole metabolites in the blood can be used to diagnose and monitor the effectiveness of a comprehensive treatment approach.
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Developing Novel Anticancer Drugs for Targeted Populations: An Update
Authors: Tadesse B. Tafesse, Mohammed H. Bule, Fazlullah Khan, Mohammad Abdollahi and Mohsen AminiBackground: Due to higher failure rates, lengthy time and high cost of the traditional de novo drug discovery and development process, the rate of opportunity to get new, safe and efficacious drugs for the targeted population, including pediatric patients with cancer, becomes sluggish. Objectives: This paper discusses the development of novel anticancer drugs focusing on the identification and selection of targeted anticancer drug development for the targeted population. Methods: Information presented in this review was obtained from different databases, including PUBMED, SCOPUS, Web of Science, and EMBASE. Various keywords were used as search terms. Results: The pharmaceutical companies currently are executing drug repurposing as an alternative means to accelerate the drug development process that reduces the risk of failure, time and cost, which take 3-12 years with almost 25% overall probability of success as compared to de novo drug discovery and development process (10- 17 years) which has less than 10% probability of success. An alternative strategy to the traditional de novo drug discovery and development process, called drug repurposing, is also presented. Conclusion: Therefore, to continue with the progress of developing novel anticancer drugs for the targeted population, identification and selection of target to specific disease type is important. Considering the aspects of the age of the patient and the disease stages such as each cancer types are different when we study the disease at a molecular level. Drug repurposing technique becomes an influential alternative strategy to discover and develop novel anticancer drug candidates.
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High Sensitivity C-reactive Protein (hsCRP) and its Implications in Cardiovascular Outcomes
Authors: Andrea Denegri and Giuseppe BorianiAtherosclerosis and its fearsome complications represent the first cause of morbidity and mortality worldwide. Over the last two decades, several pieces of evidence have been accumulated, suggesting a central role of inflammation in atheroma development. High sensitivity C-reactive protein (hsCRP) is a well-established marker of cardiovascular (CV) disease; high levels of hsCRP have been associated with adverse CV outcome after acute coronary syndrome (ACS) and, despite some controversy, an active role for hsCRP in initiation and development of the atherosclerotic plaque has been also proposed. Randomized clinical trials focusing on hsCRP have been crucial in elucidating the anti-inflammatory effects of statin therapy. Thus, hsCRP has been progressively considered a real CV risk factor likewise to low-density lipoprotein cholesterol (LDL-C), expanding the concept of residual CV inflammatory risk. Subsequent research has been designed to investigate potential new targets of atherothrombotic protection. Despite the fact that the clinical usefulness of hsCRP is widely recognized, hsCRP may not represent the ideal target of specific anti-inflammatory therapies. Clinical investigations, therefore, have also focused on other inflammatory mediators, restricting hsCRP to an indicator rather than a therapeutic target. The aim of the present review is to provide an illustrative overview of the current knowledge of atherosclerosis and inflammation, highlighting the most representative clinical studies of lipid-lowering and antiinflammatory therapies focused on hsCRP in CV diseases.
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Do Mitochondrial DNA Mutations Play a Key Role in the Chronification of Sterile Inflammation? Special Focus on Atherosclerosis
Background: The aim of the elucidation of mechanisms implicated in the chronification of inflammation is to shed light on the pathogenesis of disorders that are responsible for the majority of the incidences of diseases and deaths, and also causes of ageing. Atherosclerosis is an example of the most significant inflammatory pathology. The inflammatory response of innate immunity is implicated in the development of atherosclerosis arising locally or focally. Modified low-density lipoprotein (LDL) was regarded as the trigger for this response. No atherosclerotic changes in the arterial wall occur due to the quick decrease in inflammation rate. Nonetheless, the atherosclerotic lesion formation can be a result of the chronification of local inflammation, which, in turn, is caused by alteration of the response of innate immunity. Objective: In this review, we discussed potential mechanisms of the altered response of the immunity in atherosclerosis with a particular emphasis on mitochondrial dysfunctions. Conclusion: A few mitochondrial dysfunctions can be caused by the mitochondrial DNA (mtDNA) mutations. Moreover, mtDNA mutations were found to affect the development of defective mitophagy. Modern investigations have demonstrated the controlling mitophagy function in response to the immune system. Therefore, we hypothesized that impaired mitophagy, as a consequence of mutations in mtDNA, can raise a disturbed innate immunity response, resulting in the chronification of inflammation in atherosclerosis.
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Pain Biomarkers in Cancer: An Overview
Background: Pain is a common symptom in oncologic patients and its management is generally guided with reference to pain individually perceived by patients and expressed through self-reported scales. However, the utility of these tools is limited as it strongly depends on patients’ opinions. For this reason, more objective instruments are desirable. Objective: In this overview, scientific articles indicating potential markers to be used for pain management in cancer were collected and discussed. Methods: Research was performed on principal electronic scientific databases by using the words “pain”, “cancer”, “markers” and “biomarkers” as the main keywords, and findings describing potential biomarkers for the management of cancer pain were reported. Results: Studies on pain markers not specific for cancer typology (inflammatory, genetic markers predicting response to analgesic drugs, neuroimaging markers) and pain markers for specific types of cancer (bone cancer, breast cancer, lung cancer, head and neck cancer, prostate cancer, cancer in pediatrics) have been presented and commented on. Conclusion: This overview supports the view of the involvement of inflammatory mediators in the mechanisms underlying cancer pain. Only a small amount of data from research up till today is available on markers that can help in the management of pain, except for pro-inflammatory cytokines and other inflammatory indexes such as C-reactive protein (CRP). However, biomarkers are a promising strategy useful to predict pain intensity and to objectively quantify analgesic response in guiding decisions regarding individual-tailored treatments for cancer patients.
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Can Molecular Biology Propose Reliable Biomarkers for Diagnosing Major Depression?
Background: Modern medicine has provided considerable knowledge of the pathophysiology of mental disorders at the body, systemic, organ and neurochemical levels of the biological organization of the body. Modern clinical diagnostics of depression have some problems, that is why psychiatric society makes use of diagnostics and taxonomy of different types of depression by implemention of modern molecular biomarkers in diagnostic procedures. But up to now, there are no reliable biomarkers of major depressive disorder (MDD) and other types of depression. Objective: The purpose of this review is to find fundamentals in pathological mechanisms of depression, which could be a basis for development of molecular and genetic biomarkers, being the most feasible for clinical use. Method: This review summarizes the published data using PubMed, Science Direct, Google Scholar and Scopus. Results: In this review, we summarized and discussed findings in molecular biology, genetics, neuroplasticity, neurotransmitters, and neuroimaging that could increase our understanding of the biological foundations of depression and show new directions for the development of reliable biomarkers. We did not find any molecular and genetic biomarker approved for the clinic. But the Genome-Wide Association Study method promises some progress in the development of biomarkers based on SNP in the future. Epigenetic factors also are a promising target for biomarkers. We have found some differences in the etiology of different types of atypical and melancholic depression. This knowledge could be the basis for development of biomarkers for clinical practice in diagnosis, prognosis and selection of treatment. Conclusion: Depression is not a monoetiological disease. Many pathological mechanisms are involved in depression, thus up to now, there is no approved and reliable biomarker for diagnosis, prognosis and correction of treatment of depression. The structural and functional complexity of the brain, the lack of invasive technology, poor correlations between genetic and clinical manifestation of depression, imperfect psychiatric classification and taxonomy of subtypes of disease are the main causes of this situation. One of the possible ways to come over this situation can be to pay attention to the trigger mechanism of disease and its subtypes. Researchers and clinicians should focus their efforts on searching the trigger mechanism of depression and different types of it . HPA axis can be a candidate for such trigger in depression caused by stress, because it influences the main branches of disease: neuroinflammation, activity of biogenic amines, oxidative and nitrosative stress, epigenetic factors, metabolomics, etc. But before we shall find any trigger mechanism, we need to create complex biomarkers reflecting genetic, epigenetic, metabolomics and other pathological changes in different types of depression. Recently the most encouraging results have been obtained from genetics and neuroimaging. Continuing research in these areas should be forced by using computational, statistical and systems biology approaches, which can allow to obtain more knowledge about the neurobiology of depression. In order to obtain clinically useful tests, search for biomarkers should use appropriate research methodologies with increasing samples and identifying more homogeneous groups of depressed patients.
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Steroid-resistant Nephrotic Syndrome in Children: A Mini-review on Genetic Mechanisms, Predictive Biomarkers and Pharmacotherapy Strategies
Authors: Hong-Li Guo, Ling Li, Ze-Yue Xu, Xia Jing, Ying Xia, Jin-Chun Qiu, Xing Ji, Feng Chen, Jing Xu and Fei ZhaoSteroid-resistant nephrotic syndrome (SRNS) constitutes the second most frequent cause of chronic kidney disease in childhood. The etiology of SRNS remains largely unknown and no standardized treatment exists. Recent advances in genomics have helped to build understanding of the molecular mechanisms and pathogenesis of the disease. The genetic polymorphisms in genes encoding proteins which are involved in the pharmacokinetics and pharmacodynamics of glucocorticoids (GCs) partially account for the different responses between patients with nephrotic syndrome. More importantly, single-gene causation in podocytes-associated proteins was found in approximately 30% of SRNS patients. Some potential biomarkers have been tested for their abilities to discriminate against pediatric patients who are sensitive to GCs treatment and patients who are resistant to the same therapy. This article reviews the recent findings on genetic mechanisms, predictive biomarkers and current therapies for SRNS with the goal to improve the management of children with this syndrome.
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Volumes & issues
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Volume 31 (2025)
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Volume (2025)
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Volume 30 (2024)
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Volume 29 (2023)
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Volume 28 (2022)
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Volume 27 (2021)
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Volume 26 (2020)
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Volume 25 (2019)
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Volume 24 (2018)
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Volume 23 (2017)
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Volume 22 (2016)
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Volume 21 (2015)
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Volume 20 (2014)
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Volume 19 (2013)
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Volume 18 (2012)
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Volume 17 (2011)
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Volume 16 (2010)
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Volume 15 (2009)
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Volume 14 (2008)
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Volume 13 (2007)
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Volume 12 (2006)
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Volume 11 (2005)
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Volume 10 (2004)
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Volume 9 (2003)
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Volume 8 (2002)
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Volume 7 (2001)
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Volume 6 (2000)
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