Mental disorders such as schizophrenia, bipolar illness, and depression have become the predominant chronic diseases of young people, accounting for approximately 40% of the medical burden for people aged 15–44 in the United States and Canada. Research is transforming our understanding of these disorders, as exemplified in the articles in this Review Series. Important, “disruptive” insights into pathophysiology are emerging from studies addressing these illnesses as brain disorders, developmental disorders, and complex genetic disorders — rather than only as psychological conflicts or chemical imbalances, as they were considered in the past. Current medications are not sufficient for most patients. A new and deep understanding of the pathophysiology of these disabling disorders is our best hope for a new generation of treatments that will help patients to recover.
Thomas R. Insel
Cytokines are a large family of more than 100 small proteins that function as short-range mediators involved in essentially all biological processes. They have been found to be important rate-limiting signals, and it is now known that blocking some cytokines, e.g., TNF-α, and cytokine receptors, such as human EGFR 1 (HER1) or HER2, yields effective therapeutics that address unmet needs. This Review Series surveys three chronic inflammatory disease areas and two forms of cancer and discusses the important role of cytokines and their receptors in these disease processes. Their role as potential therapeutic targets is also highlighted.
Advances in science and technology have transformed the health of the populations of the developed world, with substantial increases in life expectancy and reductions in morbidity. These advances have not, however, touched the lives of the poorest people of the world — the billions living in developing countries. This Review Series on global health highlights the key factors contributing to inequity in health across the globe and the scientific questions that remain unanswered but are critical to creating effective and appropriate health solutions. The gaps in knowledge identified in this series point the way for scientists to contribute to a changed world.
Carol A. Dahl, Tadataka Yamada
The marked disruption of the homeostasis of a physiological system, be it a cell, tissue, organ, or whole organism, is more commonly known as stress. In many ways, aging can be considered the ultimate stress. However, physiological systems are constantly exposed to more acute stresses. Advances in our understanding of the molecular response of several physiological systems to both physiologic and pathologic stress is discussed in this Review Series. It is hoped that such understanding will facilitate the development of approaches to ameliorate some of the limitations these stresses place on individuals. However, as pointed out in many of the articles, much remains to be learned before such approaches can be envisioned.
Andrew R. Marks
Small molecules and antibodies have revolutionized the treatment of malignant diseases and appear promising for the treatment of many others. Nonetheless, there are many candidate therapeutic targets that are not amenable to attack by the current generation of targeted therapies, and in a small but growing number of patients, resistance to initially successful treatments evolves. This Review Series on the medicinal promise of posttranscriptional gene silencing with small interfering RNA and other molecules capable of inducing RNA interference (RNAi) is motivated by the hypothesis that effectors of RNAi can be developed into effective drugs for treating malignancies as well as many other types of disease. As this Review Series points out, there is still much to do, but many in the field now hope that the time has finally arrived when “antisense” therapies will finally come of age and fulfill their promise as the magic bullets of the 21st century.
Alan M. Gewirtz
The discovery of the Philadelphia chromosome as a hallmark of chronic myelogenous leukemia in 1960 by Peter Nowell provided evidence for a genetic link to cancer. As with most seminal scientific observations, the description of the Philadelphia chromosome posed many more questions than were answered. This Review series includes contributions from individuals who performed critical experiments addressing some of the most important of these questions, reflecting the nearly 50 years of work inspired by Nowell’s initial finding. The legacy of the Philadelphia chromosome now serves as a paradigm for how basic science discoveries can lead to effective new approaches for the treatment of human disease.
Gary A. Koretzky
A major challenge for the immune system is to recognize and eliminate cells undergoing carcinogenesis. Immune defense against tumors is complex. It can be mediated early by the innate immune system (i.e., phagocytes, NK cells, NKT cells, cytokines, and complement proteins) and later by the adaptive immune system (i.e., B cells and T cells). The eight articles in this Review series on tumor immunology discuss the mechanisms underlying immune surveillance of tumors, the regulation of carcinogenesis by immune inflammatory mediators, current approaches to controlling tumor growth through immunotherapy, and novel targets of immunotherapy.
It is now well accepted that diabetes mellitus is one of the main threats to human health in the twenty-first century. The total number of people with diabetes worldwide was estimated at between 151 million and 171 million in 2000 and is projected to increase to 221 million in 2010 and to 366 million in 2030. Needless to say, the increase in the number of people with diabetes will be accompanied by an increase in the number of those with diabetic complications such as nephropathy, retinopathy, neuropathy, and atherosclerosis. The global mortality attributable to diabetes in the year 2000 was estimated at 2.9 million deaths, a number that will also increase. Given that type 2 diabetes accounts for more than 90% of cases of diabetes worldwide, it is important that we understand the pathogenesis of this condition and develop new approaches to its prevention and treatment.
Biological evolution has struggled to produce mechanisms that can limit blood loss following injury. In humans and other mammals, control of blood loss (hemostasis) is achieved through a combination of plasma proteins, most of which are made in the liver, and platelets, anucleate blood cells that are produced in the bone marrow by megakaryocytes. Much has been learned about the underlying mechanisms, but much remains to be determined. The articles in this series review current ideas about the production of megakaryocytes from undifferentiated hematopoietic precursors, the steps by which megakaryocytes produce platelets, and the molecular mechanisms within platelets that make hemostasis possible. The underlying theme that connects the articles is the intense investigation of a complex system that keeps humans from bleeding to death, but at the same time exposes us to increased risk of thrombosis and vascular disease.
Lawrence F. Brass
This series of Reviews on cell death explores the creation of new therapies for correcting excessive or deficient cell death in human disease. Signal transduction pathways controlling cell death and the molecular core machinery responsible for cellular self-destruction have been elucidated with unprecedented celerity during the last decade, leading to the design of novel strategies for blocking pathological cell loss or for killing unwanted cells. Thus, an increasing number of compounds targeting a diverse range of apoptosis-related molecules are being explored at the preclinical and clinical levels. Beyond the agents that are already FDA approved, a range of molecules targeting apoptosis-regulatory transcription factors, regulators of mitochondrial membrane permeabilization, and inhibitors or activators of cell death–related proteases are under close scrutiny for drug development.
Douglas R. Green, Guido Kroemer
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