Immunobiology of pregnancy: from basic science to translational medicine

Embryo implantation failure and spontaneous abortions represent the main causes of infertility in developed countries. Unfortunately, incomplete knowledge of the multiple factors involved in implantation and fetal development keeps the success rate of medically assisted procreation techniques relatively low. According to recent literature, cellular and molecular mechanisms of ‘immunogenic tolerance’ towards the embryo are crucial to establish an ‘anti-inflammatory’ state permissive of a healthy pregnancy. In this review we dissect the role played by the immune system in the endometrial–embryo crosstalk, with a particular emphasis towards the fork-head-box-p3 (Foxp3⁺) CD4⁺CD25⁺ regulatory T (Treg) cells and discuss the most recent therapeutic advances in the context of early immune-mediated pregnancy loss.     

The role of basic science in evidence-based medicine

Proponents of Evidence-based medicine (EBM) do not provide a clear role for basic science in therapeutic decision making. Of what they do say about basic science, most of it is negative. Basic science resides on the lower tiers of EBM’s hierarchy of evidence. Therapeutic decisions, according to proponents of EBM, should be informed by evidence from randomised studies (and systematic reviews of randomised studies) rather than basic science. A framework of models explicates the links between the mechanisms of basic science, experimental inquiry, and observed data. Relying on the framework of models I show that basic science often plays a role not only in specifying experiments, but also analysing and interpreting the data that is provided. Further, and contradicting what is implied in EBM’s hierarchy of evidence, appeals to basic science are often required to apply clinical research to therapeutic questions.     

Complex biomedical systems: from basic science to translation

The Department of Biomedical Engineering (BME) of the University of Southern California (BME@USC) has a longstanding tradition of advancing biomedicine through the development and application of novel engineering ideas. More than 80 primary and affiliated faculty members conduct cutting-edge research in a wide variety of areas, such as neuroengineering, biosystems and biosignal analysis, medical devices (including biomicroelectromechanical systems (bioMEMS) and bionanotechnology), biomechanics, bioimaging, and imaging informatics. Currently, the department hosts six internationally recognized research centers: the Biomimetic MicroElectronic Systems Engineering Research Center (funded by the National Science Foundation), the Biomedical Simulations Resource [funded by the National Institutes of Health (NIH)], the Medical Ultrasonic Transducer Center (funded by NIH), the Center for Neural Engineering, the Center for Vision Science and Technology (funded by an NIH Bioengineering Research Partnership Grant), and the Center for Genomic and Phenomic Studies in Autism (funded by NIH). BME@USC ranks in the top tier of all U.S. BME departments in terms of research funding per faculty.     

The vitamin D story: a collaborative effort of basic science and clinical medicine

The discovery in 1919-1924 of vitamin D and its production in skin and foods by UV irradiation led to the elimination of rickets as a major medical problem. The identification and chemical preparation of vitamin D in the next decade provided large quantities of vitamin D to the physician for the treatment of a variety of metabolic bone diseases. Early in the 1960s, little was known about the function of vitamin D in causing mineralization of the skeleton, and hence in preventing the disease rickets in children and osteomalacia in adults. With the application of modern tools of biochemistry came the discovery that vitamin D must first be modified by 25-hydroxylation in the liver followed by 1 alpha-hydroxylation in the kidney to produce the vitamin D hormone 1 alpha,25-dihydroxyvitamin D3 [1,25-(OH)2D3]. This process is strongly feedback-regulated and is one of the major endocrine systems regulating plasma calcium and phosphorus concentrations. Furthermore, it is a major endocrine system regulating bone mass and state. With the chemical synthesis of 1,25-(OH)2D3 and many of its analogs has come the possibility of treating a number of metabolic bone diseases not previously managed adequately, such as vitamin D-resistant rickets, hypoparathyroidism, renal osteodystrophy, and osteoporosis. By using 1,25-(OH)2D3, considerable work has been carried out to understand how this hormone facilitates calcium transport across the intestinal membrane. Modern work is described on the molecular mechanism of action of the vitamin D hormone in eliciting the cellular responses that result in mineral homeostasis. The possible use of the vitamin D analogs to bring about differentiation of myelocytic-type leukemias and in the treatment of psoriasis has been an important new development. This paper will thus be a blend of basic science of the vitamin D system and the application of that information to the treatment of disease.     

Lysyl oxidase: from basic science to future cancer treatment

In this mini-review, we discuss the physiological and pathological roles of lysyl oxidase (LOX) and its family, LOX-like proteins (LOXL), in relation to prognosis of major cancers. The number of reports on LOX family is numerous. We have decided to review the articles that were recently published (i.e. past 5 years). Experimental techniques in molecular biology have advanced surprisingly in the past decade. Accordingly, the results of the studies are more reliable. Most studies reached the same conclusion; a higher LOX- or LOXL- expression is associated with a poor prognosis. Molecular experiments have already started aiming for clinical application, and the results are encouraging. Suppressing LOX or LOXL activities resulted in lower cell motility in collagen gel and, moreover, succeeded in reducing metastases in mice. LOX family members were originally recognized as molecules that cross-link collagen fibers in the extracellular matrix. Recent studies demonstrated that they are also involved in a phenomenon called Epithelial Mesenchymal Transition (EMT). This may affect cell movement and cancer cell invasiveness. LOX and LOXL2 are regulated by hypoxia, a major factor in the failure of cancer treatment. Here we discuss the molecular biology of the LOX family in relation to its role in tumor biology.     

Cancer genomics: from discovery science to personalized medicine

Recent advances in genome technologies and the ensuing outpouring of genomic information related to cancer have accelerated the convergence of discovery science and clinical medicine. Successful examples of translating cancer genomics into therapeutics and diagnostics reinforce its potential to make possible personalized cancer medicine. However, the bottlenecks along the path of converting a genome discovery into a tangible clinical endpoint are numerous and formidable. In this Perspective, we emphasize the importance of establishing the biological relevance of a cancer genomic discovery in realizing its clinical potential and discuss some of the major obstacles to moving from the bench to the bedside.     

Midbrain-derived neural stem cells: from basic science to therapeutic approaches

Neural stem cells (NSCs) are a subtype of tissue-specific progenitor cells capable of extended self-renewal and the ability to generate all major cell types of nervous tissue, such as neurons, astroglia and oligodendroglial cells. Recent studies suggest that salient patterning in anterior–posterior and dorsal–ventral axes occurs early, concomitantly with neural induction and therefore stem cells and restricted precursors exhibit regionalization. Fetal mesencephalic NSCs can be isolated and expanded in vitro for many months while retaining their potential to differentiate into glia and neurons, with a subset of neurons displaying all the major properties of mature functional dopaminergic neurons. Since Parkinsons disease (PD) is characterized by the loss of a specific type of dopaminergic cells, the prospect of replacing the missing or damaged cells is very attractive in PD. Thus, mesencephalic NSCs might serve as a new and continuous source of dopaminergic neurons for regenerative strategies in this neurodegenerative disorder. This review discusses new data concerning the cell biology and therapeutic potential of NSCs derived from the midbrain region of the central nervous system.The work of the authors was supported in part by the Interdisziplinäres Zentrum für klinische Forschung (IZKF) Ulm (Project D6) to A.S., the BMBF (Polish-German Cooperation in Neuroscience Program) to A.S., the Ministerium für Wissenschaft und Kultur Baden-Württemberg (Landesforschungsschwerpunkt Neurodegeneration und Neuroregeneration) to A.S., and the Landesstiftung Baden-Württemberg (Förderprogramm Adulte Stammzellen) to A.S. M.S. was supported by a fellowship from the IZKF Ulm     

HIV-1 Tat-based vaccines: from basic science to clinical trials

Vaccination against human immunodeficiency virus (HIV)-1 infection requires candidate antigen(s) (Ag) capable of inducing an effective, broad, and long-lasting immune response against HIV-1 despite mutation events leading to differences in virus clades. The HIV-1 Tat protein is more conserved than envelope proteins, is essential in the virus life cycle and is expressed very early upon virus entry. In addition, both humoral and cellular responses to Tat have been reported to correlate with a delayed progression to disease in both humans and monkeys. This suggested that Tat is an optimal target for vaccine development aimed at controlling virus replication and blocking disease onset. Here are reviewed the results of our studies including the effects of the Tat protein on monocyte-derived dendritic cells (MDDCs) that are key antigen-presenting cells (APCs), and the results from vaccination trials with both the Tat protein or tat DNA in monkeys. We provide evidence that the HIV-1 Tat protein is very efficiently taken up by MDDCs and promotes T helper (Th)-1 type immune responses against itself as well as other Ag. In addition, a Tat-based vaccine elicits an immune response capable of controlling primary infection of monkeys with the pathogenic SHIV89.6P at its early stages allowing the containment of virus spread. Based on these results and on data of Tat conservation and immune cross-recognition in field isolates from different clades, phase I clinical trials are being initiated in Italy for both preventive and therapeutic vaccination.     

Regime, phase and paradigm shifts: making community ecology the basic science for fisheries

Modern fishery science, which began in 1957 with Beverton and Holt, is ca. 50 years old. At its inception, fishery science was limited by a nineteenth century mechanistic worldview and by computational technology; thus, the relatively simple equations of population ecology became the fundamental ecological science underlying fisheries. The time has come for this to change and for community ecology to become the fundamental ecological science underlying fisheries. This point will be illustrated with two examples. First, when viewed from a community perspective, excess production must be considered in the context of biomass left for predators. We argue that this is a better measure of the effects of fisheries than spawning biomass per recruit. Second, we shall analyse a simple, but still multi-species, model for fishery management that considers the alternatives of harvest regulations, inshore marine protected areas and offshore marine protected areas. Population or community perspectives lead to very different predictions about the efficacy of reserves.     

The application of basic science to translational cancer research

A report on the inaugural symposium of the Hutchison/MRC Research Centre, Cambridge, UK, 24-25 October 2002.     

Evolutionary biology: a basic science for medicine in the 21st century

Evolutionary biology was a poorly developed discipline at the time of the Flexner Report and was not included in Flexner's recommendations for premedical or medical education. Since that time, however, the value of an evolutionary approach to medicine has become increasingly recognized. There are several ways in which an evolutionary perspective can enrich medical education and improve medical practice. Evolutionary considerations rationalize our continued susceptibility or vulnerability to disease; they call attention to the idea that the signs and symptoms of disease may be adaptations that prevent or limit the severity of disease; they help us understand the ways in which our interventions may affect the evolution of microbial pathogens and of cancer cells; and they provide a framework for thinking about population variation and risk factors for disease. Evolutionary biology should become a foundational science for the medical education of the future.     

Glutamate and related acidic excitatory neurotransmitters: from basic science to clinical application

There is convincing evidence that acidic amino acids, in particular L-glutamate, or substances containing them serve as the major excitatory neurotransmitters in the brain. At least three distinct receptors mediate the excitatory effects of this class of neurotransmitters. Pharmacological studies with agonists and antagonists of these receptors suggest that they may mediate the neurodegenerative consequences of Huntington's disease, status epilepticus, and hypoxemia, and that glutamate receptor antagonists have clinical potential as anticonvulsants, analgesics, and neuroprotective agents.     

Regenerative medicine research in China: from basic research to clinical practice

<正>I am very happy to write editorial for this Special Issue of Stem Cells and Regenerative Medicine in China in Science China Life Sciences.As we all know,stem cells and regenerative medicine research is the frontiers not only in China,but also in the world.In recent decades,rapid research progressing,strong governmental support and recruitment of highly trained scientists from abroad together with domestic outstanding researchers and clinicians have made it possible     

Zebrafish kidney development: basic science to translational research

The zebrafish has become a significant model system for studying renal organogenesis and disease, as well as for the quest for new therapeutics, because of the structural and functional simplicity of the embryonic kidney. Inroads to the nature and disease states of kidney-related ciliopathies and acute kidney injury (AKI) have been advanced by zebrafish studies. This model organism has been instrumental in the analysis of mutant gene function for human disease with respect to ciliopathies. Additionally, in the AKI field, recent work in the zebrafish has identified a bona fide adult zebrafish renal progenitor (stem) cell that is required for neo-nephrogenesis, both during the normal lifespan and in response to renal injury. Taken together, these studies solidify the zebrafish as a successful model system for studying the broad spectrum of ciliopathies and AKI that affect millions of humans worldwide, and point to a very promising future of zebrafish drug discovery. The emphasis of this review will be on the role of the zebrafish as a model for human kidney-related ciliopathies and AKI, and how our understanding of these complex pathologies is being furthered by this tiny teleost.     

The science of emotion as a multidisciplinary research paradigm

I discuss the emergence of a science of emotion and argue that research in this domain requires an appreciation of the organization of emotional processes at different levels as postulated by social neuroscience. Emotions cannot be understood without relying on a program of multidisciplinary research. Local multidisciplinarity cannot be achieved without a programmatic framework that takes three issues into account (1) the relationship of multiple levels of emotions and connected processes, (2) the mutually informative study of humans, animals, and artificial systems, and (3) the dynamic nature of emotions in a dynamic systems approach. Illustrations for my arguments are provided relating to facial expressions of humans.