Review
Abstract
Disturbances in mechanisms that direct abnormal cells to undergo apoptosis frequently and critically contribute to tumorigenesis, yielding a logical target for potential therapeutic intervention. There is currently heightened interest in the extrinsic apoptosis pathway, with several proapoptotic receptor agonists (PARAs) in development. The PARAs include the ligand recombinant human Apo2L/TRAIL and agonistic mAbs. Mechanistic and preclinical data with Apo2L/TRAIL indicate exciting opportunities for synergy with conventional therapies and for combining PARAs with other molecularly targeted agents. Novel molecular biomarkers may help identify those patients most likely to benefit from PARA therapy.
Authors
Avi Ashkenazi, Roy S. Herbst
Abstract
The International HapMap Project was designed to create a genome-wide database of patterns of human genetic variation, with the expectation that these patterns would be useful for genetic association studies of common diseases. This expectation has been amply fulfilled with just the initial output of genome-wide association studies, identifying nearly 100 loci for nearly 40 common diseases and traits. These associations provided new insights into pathophysiology, suggesting previously unsuspected etiologic pathways for common diseases that will be of use in identifying new therapeutic targets and developing targeted interventions based on genetically defined risk. In addition, HapMap-based discoveries have shed new light on the impact of evolutionary pressures on the human genome, suggesting multiple loci important for adapting to disease-causing pathogens and new environments. In this review we examine the origin, development, and current status of the HapMap; its prospects for continued evolution; and its current and potential future impact on biomedical science.
Authors
Teri A. Manolio, Lisa D. Brooks, Francis S. Collins
Abstract
Williams-Beuren syndrome (WBS) is a microdeletion disorder caused by heterozygous loss of approximately 1.5-Mb pairs of DNA from chromosome 7. Patients with WBS have a characteristic constellation of medical and cognitive findings, with a hallmark feature of generalized arteriopathy presenting as stenoses of elastic arteries and hypertension. Human and mouse studies establish that defects in the elastin gene, leading to elastin haploinsufficiency, underlie the arteriopathy. In this review we describe potential links between elastin expression and arteriopathy, possible explanations for disease variability, and current treatment options and their limitations, and we propose several new directions for the development of nonsurgical preventative therapies based on insights from elastin biology.
Authors
Barbara R. Pober, Mark Johnson, Zsolt Urban
Abstract
There are still approximately 500 million cases of malaria and 1 million deaths from malaria each year. Yet recently, malaria incidence has been dramatically reduced in some parts of Africa by increasing deployment of anti-mosquito measures and new artemisinin-containing treatments, prompting renewed calls for global eradication. However, treatment and mosquito control currently depend on too few compounds and thus are vulnerable to the emergence of compound-resistant parasites and mosquitoes. As discussed in this Review, new drugs, vaccines, and insecticides, as well as improved surveillance methods, are research priorities. Insights into parasite biology, human immunity, and vector behavior will guide efforts to translate parasite and mosquito genome sequences into novel interventions.
Authors
Brian M. Greenwood, David A. Fidock, Dennis E. Kyle, Stefan H.I. Kappe, Pedro L. Alonso, Frank H. Collins, Patrick E. Duffy
Abstract
Contraceptives that are readily available and acceptable are required in many poorer countries to reduce population growth and in all countries to prevent maternal morbidity and mortality arising from unintended pregnancies. Most available methods use hormonal steroids or are variations of barrier methods. Reports from several fora over the last 12 years have emphasized the number of unwanted pregnancies and resultant abortions, which indicate an unmet need for safe, acceptable, and inexpensive contraceptive methods. This unmet need can be assuaged, in part, by development of new nonhormonal contraceptive methods. This Review addresses the contribution that the “omic” revolution can make to the identification of novel contraceptive targets, as well as the progress that has been made for different target molecules under development.
Authors
R. John Aitken, Mark A. Baker, Gustavo F. Doncel, Martin M. Matzuk, Christine K. Mauck, Michael J.K. Harper
Abstract
Kinetoplastids are a group of flagellated protozoans that include the species Trypanosoma and Leishmania, which are human pathogens with devastating health and economic effects. The sequencing of the genomes of some of these species has highlighted their genetic relatedness and underlined differences in the diseases that they cause. As we discuss in this Review, steady progress using a combination of molecular, genetic, immunologic, and clinical approaches has substantially increased understanding of these pathogens and important aspects of the diseases that they cause. Consequently, the paths for developing additional measures to control these “neglected diseases” are becoming increasingly clear, and we believe that the opportunities for developing the drugs, diagnostics, vaccines, and other tools necessary to expand the armamentarium to combat these diseases have never been better.
Authors
Ken Stuart, Reto Brun, Simon Croft, Alan Fairlamb, Ricardo E. Gürtler, Jim McKerrow, Steve Reed, Rick Tarleton
Abstract
Pneumonia is an illness, usually caused by infection, in which the lungs become inflamed and congested, reducing oxygen exchange and leading to cough and breathlessness. It affects individuals of all ages but occurs most frequently in children and the elderly. Among children, pneumonia is the most common cause of death worldwide. Historically, in developed countries, deaths from pneumonia have been reduced by improvements in living conditions, air quality, and nutrition. In the developing world today, many deaths from pneumonia are also preventable by immunization or access to simple, effective treatments. However, as we highlight here, there are critical gaps in our understanding of the epidemiology, etiology, and pathophysiology of pneumonia that, if filled, could accelerate the control of pneumonia and reduce early childhood mortality.
Authors
J. Anthony G. Scott, W. Abdullah Brooks, J.S. Malik Peiris, Douglas Holtzman, E. Kim Mulholland
Abstract
Latest estimates indicate that nutritional deficiencies account for 3 million child deaths each year in less-developed countries. Targeted nutritional interventions could therefore save millions of lives. However, such interventions require careful optimization to maximize benefit and avoid harm. Progress toward designing effective life-saving interventions is currently hampered by some serious gaps in our understanding of nutrient metabolism in humans. In this Personal Perspective, we highlight some of these gaps and make some proposals as to how improved research methods and technologies can be brought to bear on the problems of undernourished children in the developing world.
Authors
Andrew M. Prentice, M. Eric Gershwin, Ulrich E. Schaible, Gerald T. Keusch, Cesar G. Victora, Jeffrey I. Gordon
Abstract
The most up-to-date estimates demonstrate very heterogeneous spread of HIV-1, and more than 30 million people are now living with HIV-1 infection, most of them in sub-Saharan Africa. The efficiency of transmission of HIV-1 depends primarily on the concentration of the virus in the infectious host. Although treatment with antiviral agents has proven a very effective way to improve the health and survival of infected individuals, as we discuss here, the epidemic will continue to grow unless greatly improved prevention strategies can be developed and implemented. No prophylactic vaccine is on the horizon. However, several behavioral and structural strategies have made a difference — male circumcision provides substantial protection from sexually transmitted diseases, including HIV-1, and the application of antiretroviral agents for prevention holds great promise.
Authors
Myron S. Cohen, Nick Hellmann, Jay A. Levy, Kevin DeCock, Joep Lange
Abstract
Tuberculosis (TB) is a major threat to global health, recently exacerbated by the emergence of highly drug-resistant forms of the disease-causing pathogen and synergy with HIV/AIDS. In 2006, the Stop TB Partnership published “The global plan to stop TB: 2006–2015,” which set out a vision of halving the prevalence of and mortality caused by the disease by 2015, followed by eliminating the disease as a public health problem by 2050. This vision depends on the development of improved diagnostics, simpler treatment, and more effective vaccination. Recently, active translational research pipelines directed toward each of these goals have been established, but improved understanding of the fundamental biology of this complex disease will prove to be the key to radical advances in TB control.
Authors
Douglas B. Young, Mark D. Perkins, Ken Duncan, Clifton E. Barry III
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