50 years of radiation research: medicine

The advances brought about by research in radiation medicine over the past 50 years are presented. The era began with the atomic explosions in Hiroshima and Nagasaki and the establishment of the Atomic Bomb Casualty Commission to understand what damage was caused by exposure of a large population to radiation. A better understanding of the effects of whole-body exposure led to the development of whole-body radiation treatment techniques and to bone marrow transplantation in the treatment of leukemias. The field of diagnostic imaging was revolutionized by a series of inventions that included angiography, mammography, computed tomography, magnetic resonance imaging, magnetic resonance spectroscopy, and ultrasound imaging. The field of nuclear medicine came of age through new man-made radionuclides and the invention of scanning and imaging techniques including positron emission tomography. Radiotherapy, a minor sideline of radiology, developed into radiation oncology, an extremely important component of modern cancer therapy. The advances in clinical radiotherapy were made possible by discoveries and inventions in physics and engineering and by insights and discoveries in radiobiology. The result of the last 50 years of progress is a very powerful set of clinical tools.     

Using genetically engineered mice for radiation research

The laboratory mouse has been used for many decades as a model system for radiation research. Recent advances in genetic engineering now allow scientists to delete genes in specific cell types at different stages of development. The ability to manipulate genes in the mouse with spatial and temporal control opens new opportunities to investigate the role of genes in regulating the response of normal tissues and tumors to radiation. Currently, we are using the Cre-loxP system to delete genes, such as p53, in a cell-type specific manner in mice to study mechanisms of acute radiation injury and late effects of radiation. Our results demonstrate that p53 is required in the gastrointestinal (GI) epithelium to prevent radiation-induced GI syndrome and in endothelial and/or hematopoietic cells to prevent late effects of radiation. We have also used these genetic tools to generate primary tumors in mice to study tumor response to radiation therapy. These advances in genetic engineering provide a powerful model system to dissect both the mechanisms of normal tissue injury after irradiation and the mechanisms by which radiation cures cancer.     

Radiation-induced bystander effects: what are they, and how relevant are they to human radiation exposures?

The term radiation-induced bystander effect is used to describe radiation-induced biological changes that manifest in unirradiated cells remaining within an irradiated cell population. Despite their failure to fit into the framework of classical radiobiology, radiation-induced bystander effects have entered the mainstream and have become established in the radiobiology vocabulary as a bona fide radiation response. However, there is still no consensus on a precise definition of radiation-induced bystander effects, which currently encompasses a number of distinct signal-mediated effects. These effects are classified here into three classes: bystander effects, abscopal effects and cohort effects. In this review, the data have been evaluated to define, where possible, various features specific to radiation-induced bystander effects, including their timing, range, potency and dependence on dose, dose rate, radiation quality and cell type. The weight of evidence supporting these defining features is discussed in the context of bystander experimental systems that closely replicate realistic human exposure scenarios. Whether the manifestation of bystander effects in vivo is intrinsically limited to particular radiation exposure scenarios is considered. The conditions under which radiation-induced bystander effects are induced in vivo will ultimately determine their impact on radiation-induced carcinogenic risk.     

Current imaging paradigms in radiation oncology

The technological revolution in imaging during recent decades has transformed the way image-guided radiation therapy is performed. Anatomical imaging (plain radiography, computed tomography, magnetic resonance imaging) greatly improved the accuracy of delineating target structures and has formed the foundation of 3D-based radiation treatment. However, the treatment planning paradigm in radiation oncology is beginning to shift toward a more biological and molecular approach as advances in biochemistry, molecular biology, and technology have made functional imaging (positron emission tomography, nuclear magnetic resonance spectroscopy, optical imaging) of physiological processes in tumors more feasible and practical. This review provides an overview of the role of current imaging strategies in radiation oncology, with a focus on functional imaging modalities, as it relates to staging and molecular profiling (cellular proliferation, apoptosis, angiogenesis, hypoxia, receptor status) of tumors, defining radiation target volumes, and assessing therapeutic response. In addition, obstacles such as imaging-pathological validation, optimal timing of post-therapy scans, spatial and temporal evolution of tumors, and lack of clinical outcome studies are discussed that must be overcome before a new era of functional imaging-guided therapy becomes a clinical reality.     

Intravascular MR imaging and intravascular MR-guided interventions

Intravascular MR technology, using an intravascularly placed MR receiver probe to acquire high-resolution angiographic MR images (i.e. intravascular MR imaging) and to guide cardiovascular interventional therapies (i.e. intravascular MR-guided interventions), is a new, very attractive development in the field of MR imaging. The new technology offers unique advantages for cardiovascular imaging and interventions, including superior contrast capability and multiplanar imaging capabilities without the use of contrast agents and with no risk of ionizing radiation. Thecombination of intravascular MR techniques with other advanced MR imaging techniques, such as functional MR imaging, will open new avenues for the future comprehensive management of cardiovascular atherosclerotic disease. Further improvements in intravascular MR fluoroscopy with true real-time display, analogous to X-ray fluoroscopy, will dramatically establish the role of intravascular MR technology in modern medicine.     

Imaging neurodegeneration in Parkinson's disease

Neuroimaging techniques have evolved over the past several years giving us unprecedented information about the degenerative process in Parkinson's disease (PD) and other movement disorders. Functional imaging approaches such as positron emission tomography (PET) and single photon emission computerised tomography (SPECT) have been successfully employed to detect dopaminergic dysfunction in PD, even while at a preclinical stage, and to demonstrate the effects of therapies on function of intact dopaminergic neurons within the affected striatum. PET and SPECT can also monitor PD progression as reflected by changes in brain levodopa and glucose metabolism and dopamine transporter binding. Structural imaging approaches include magnetic resonance imaging (MRI) and transcranial sonography (TCS). Recent advances in voxel-based morphometry and diffusion-weighted MRI have provided exciting potential applications for the differential diagnosis of parkinsonian syndromes. Substantia nigra hyperechogenicity, detected with TCS, may provide a marker of susceptibility to PD, probably reflecting disturbances of iron metabolism, but does not appear to correlate well with disease severity or change with disease progression. In the future novel radiotracers may help us assess the involvement of non-dopaminergic brain pathways in the pathology of both motor and non-motor complications in PD.     

Intrinsic radiation sensitivity: cellular signaling is the key

The concept that the balance between DNA damage and repair determines intrinsic radiation sensitivity has dominated radiobiology for several decades. There is undeniably a cause- effect relationship between radiation-induced molecular alterations in the genomic DNA and cellular consequences. In the last decade, however, it has become obvious that the chromatin context affects the fate of damaged DNA and that cellular signaling is an important factor in defining intrinsic radiation sensitivity. Damaged DNA is the site of signal generation; however, alternative signaling at the plasma membrane is triggered: Reactive oxygen species (ROS) inactivate phosphatases and consequently cause activation of kinases localized at the plasma membrane; this includes ligand-independent activation of receptor kinases. Cells with an apparently functional DNA repair system may show increased radiation sensitivity due to deficiencies in specific kinases essential for repair activation and checkpoint control. Other signals that determine intrinsic radiosensitivity may affect proneness to apoptosis, the balance between DNA damage fixation and repair, and the translocation of proteins participating in the response to ionizing radiation. Interplay between the various signals decides the extent to which the repair of radiation-inflicted damage is supported or limited; in some cell types, this includes DNA-damage-independent processes guided by plasma membrane-generated signaling. Cellular signaling in the context of specific subcellular structures is the key to understanding how the molecular effects of radiation are expressed as biological consequences in various cell types. A systems approach should bring us closer to this end.     

Uncomfortable issues in radiation protection posed by low-dose radiobiology

This paper aims to stimulate discussion about the relevance for radiation protection of recent findings in low-dose radiobiology. Issues are raised which suggest that low-dose effects are much more complex than has been previously assumed. These include genomic instability, bystander effects, multiple stressor exposures and chronic exposures. To date, these have been accepted as being relevant issues, but there is no clear way to integrate knowledge about these effects into the existing radiation protection framework. A further issue which might actually lead to some fruitful approaches for human radiation protection is the need to develop a new framework for protecting non-human biota. The brainstorming that is being applied to develop effective and practical ways to protect ecosystems widens the debate from the narrow focus of human protection which is currently about protecting humans from radiation-induced cancers.     

Pathophysiological Responses in Rat and Mouse Models of Radiation-Induced Brain Injury

The brain is the major dose-limiting organ in patients undergoing radiotherapy for assorted conditions. Radiation-induced brain injury is common and mainly occurs in patients receiving radiotherapy for malignant head and neck tumors, arteriovenous malformations, or lung cancer-derived brain metastases. Nevertheless, the underlying mechanisms of radiation-induced brain injury are largely unknown. Although many treatment strategies are employed for affected individuals, the effects remain suboptimal. Accordingly, animal models are extremely important for elucidating pathogenic radiation-associated mechanisms and for developing more efficacious therapies. So far, models employing various animal species with different radiation dosages and fractions have been introduced to investigate the prevention, mechanisms, early detection, and management of radiation-induced brain injury. However, these models all have limitations, and none are widely accepted. This review summarizes the animal models currently set forth for studies of radiation-induced brain injury, especially rat and mouse, as well as radiation dosages, dose fractionation, and secondary pathophysiological responses.     

Long-term effects of radiation exposure among adult survivors of childhood cancer: results from the childhood cancer survivor study

In the last four decades, advances in therapies for primary cancers have improved overall survival for childhood cancer. Currently, almost 80% of children will survive beyond 5 years from diagnosis of their primary malignancy. These improved outcomes have resulted in a growing population of childhood cancer survivors. Radiation therapy, while an essential component of primary treatment for many childhood malignancies, has been associated with risk of long-term adverse outcomes. The Childhood Cancer Survivor Study (CCSS), a retrospective cohort of over 14,000 survivors of childhood cancer diagnosed between 1970 and 1986, has been an important resource to quantify associations between radiation therapy and risk of long-term adverse health and quality of life outcomes. Radiation therapy has been associated with increased risk for late mortality, development of second neoplasms, obesity, and pulmonary, cardiac and thyroid dysfunction as well as an increased overall risk for chronic health conditions. Importantly, the CCSS has provided more precise estimates for a number of dose-response relationships, including those for radiation therapy and development of subsequent malignant neoplasms of the central nervous system, thyroid and breast. Ongoing study of childhood cancer survivors is needed to establish long-term risks and to evaluate the impact of newer techniques such as conformal radiation therapy or proton-beam therapy.     

Micro-CT of rodents: State-of-the-art and future perspectives

Micron-scale computed tomography (micro-CT) is an essential tool for phenotyping and for elucidating diseases and their therapies. This work is focused on preclinical micro-CT imaging, reviewing relevant principles, technologies, and applications. Commonly, micro-CT provides high-resolution anatomic information, either on its own or in conjunction with lower-resolution functional imaging modalities such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT). More recently, however, advanced applications of micro-CT produce functional information by translating clinical applications to model systems (e.g. measuring cardiac functional metrics) and by pioneering new ones (e.g. measuring tumor vascular permeability with nanoparticle contrast agents). The primary limitations of micro-CT imaging are the associated radiation dose and relatively poor soft tissue contrast. We review several image reconstruction strategies based on iterative, statistical, and gradient sparsity regularization, demonstrating that high image quality is achievable with low radiation dose given ever more powerful computational resources. We also review two contrast mechanisms under intense development. The first is spectral contrast for quantitative material discrimination in combination with passive or actively targeted nanoparticle contrast agents. The second is phase contrast which measures refraction in biological tissues for improved contrast and potentially reduced radiation dose relative to standard absorption imaging. These technological advancements promise to develop micro-CT into a commonplace, functional and even molecular imaging modality.     

PET amyloid-beta imaging in preclinical Alzheimer's disease

Alzheimer's disease (AD) is the leading cause of dementia, accounting for 60-70% of all cases [Hebert et al., 2003, 1]. The need for effective therapies for AD is great. Current approaches, including cholinesterase inhibitors and N-methyl-d-aspartate (NMDA) receptor antagonists, are symptomatic treatments for AD but do not prevent disease progression. Many diagnostic and therapeutic approaches to AD are currently changing due to the knowledge that underlying pathology starts 10 to 20 years before clinical signs of dementia appear [Holtzman et al., 2011, 2]. New therapies which focus on prevention or delay of the onset or cognitive symptoms are needed. Recent advances in the identification of AD biomarkers now make it possible to detect AD pathology in the preclinical stage of the disease, in cognitively normal (CN) individuals; this biomarker data should be used in the selection of high-risk populations for clinical trials. In vivo visualization of AD neuropathology and biological, biochemical or physiological confirmation of the effects of treatment likely will substantially improve development of novel pharmaceuticals. Positron emission tomography (PET) is the leading neuroimaging tool to detect and provide quantitative measures of AD amyloid pathology in vivo at the early stages and follow its course longitudinally. This article is part of a Special Issue entitled: Imaging Brain Aging and Neurodegenerative disease.     

Optical coherence tomography: fundamental principles, instrumental designs and biomedical applications

The advances made in the last two decades in interference technologies, optical instrumentation, catheter technology, optical detectors, speed of data acquisition and processing as well as light sources have facilitated the transformation of optical coherence tomography from an optical method used mainly in research laboratories into a valuable tool applied in various areas of medicine and health sciences. This review paper highlights the place occupied by optical coherence tomography in relation to other imaging methods that are used in medical and life science areas such as ophthalmology, cardiology, dentistry and gastrointestinal endoscopy. Together with the basic principles that lay behind the imaging method itself, this review provides a summary of the functional differences between time-domain, spectral-domain and full-field optical coherence tomography, a presentation of specific methods for processing the data acquired by these systems, an introduction to the noise sources that plague the detected signal and the progress made in optical coherence tomography catheter technology over the last decade.     

New targets for the treatment of follicular lymphoma

The last two decades have witnessed striking advances in our understanding of the biological factors underlying the development of Follicular lymphoma (FL). Development of newer treatment approaches have improved the outlook for many individuals with these disorders; however, with these advances come new questions. Given the long-term survival of patients with FL, drugs with favourable side-effect profile and minimal long-term risks are desired. FL is incurable with current treatment modalities. It often runs an indolent course with multiple relapses and progressively shorter intervals of remission. The identification of new targets and development of novel targeted therapies is imperative to exploit the biology of FL while inherently preventing relapse and prolonging survival. This review summarizes the growing body of knowledge regarding novel therapeutic targets, enabling the concept of individualized targeted therapy for the treatment of FL.     

Animal models for radiation injury, protection and therapy

Current events throughout the world underscore the growing threat of different forms of terrorism, including radiological or nuclear attack. Pharmaceutical products and other approaches are needed to protect the civilian population from radiation and to treat those with radiation-induced injuries. In the event of an attack, radiation exposures will be heterogeneous in terms of both dose and quality, depending on the type of device used and each victim's location relative to the radiation source. Therefore, methods are needed to protect against and treat a wide range of early and slowly developing radiation-induced injuries. Equally important is the development of rapid and accurate biodosimetry methods for estimating radiation doses to individuals and guiding clinical treatment decisions. Acute effects of high-dose radiation include hematopoietic cell loss, immune suppression, mucosal damage (gastrointestinal and oral), and potential injury to other sites such as the lung, kidney and central nervous system (CNS). Long-term effects, as a result of both high- and low-dose radiation, include dysfunction or fibrosis in a wide range of organs and tissues and cancer. The availability of appropriate types of animal models, as well as adequate numbers of animals, is likely to be a major bottleneck in the development of new or improved radioprotectors, mitigators and therapeutic agents to prevent or treat radiation injuries and of biodosimetry methods to measure radiation doses to individuals.     

Non-targeted and delayed effects of exposure to ionizing radiation: II. Radiation-induced genomic instability and bystander effects in vivo,clastogenic factors and transgenerational effects

The goal of this review is to summarize the evidence for non-targeted and delayed effects of exposure to ionizing radiation in vivo. Currently, human health risks associated with radiation exposures are based primarily on the assumption that the detrimental effects of radiation occur in irradiated cells. Over the years a number of non-targeted effects of radiation exposure in vivo have been described that challenge this concept. These include radiation-induced genomic instability, bystander effects, clastogenic factors produced in plasma from irradiated individuals that can cause chromosomal damage when cultured with nonirradiated cells, and transgenerational effects of parental irradiation that can manifest in the progeny. These effects pose new challenges to evaluating the risk(s) associated with radiation exposure and understanding radiation-induced carcinogenesis.     

Introduction to the special issue on molecular imaging in radiation biology

Molecular imaging is an evolving science that is concerned with the development of novel imaging probes and biomarkers that can be used to non-invasively image molecular and cellular processes. This special issue approaches molecular imaging in the context of radiation research, focusing on biomarkers and imaging methods that provide measurable signals that can assist in the quantification of radiation-induced effects of living systems at the physical, chemical and biological levels. The potential to image molecular changes in response to a radiation insult opens new and exciting opportunities for a more profound understanding of radiation biology, with the possibility of translation of these techniques to radiotherapy practice. This special issue brings together 14 reviews dedicated to the use of molecular imaging in the field of radiation research. The initial three reviews are introductory overviews of the key molecular imaging modalities: magnetic resonance, nuclear and optical. This is followed by 11 reviews each focusing on a specialist area within the field of radiation research. These include: hypoxia and perfusion, tissue metabolism, normal tissue injury, cell death and viability, receptor targeting and nanotechnology, reporter genes, reactive oxygen species (ROS), and biological dosimetry. Over the preceding decade, molecular imaging brought significant new advances to our understanding of every area of radiation biology. This special issue shows us these advances and points to the vibrant future of our field armed with these new capabilities.     

Targeted molecular imaging of angiogenesis in PET and SPECT: a review

Over the past few decades, there have been significant advancements in the imaging techniques of positron emission tomography (PET) and single photon emission tomography (SPECT). These changes have allowed for the targeted imaging of cellular processes and the development of hybrid imaging systems (e.g., SPECT/CT and PET/CT), which provide both functional and structural images of biological systems. One area that has garnered particular attention is angiogenesis as it relates to ischemic heart disease and limb ischemia. Though the aforementioned techniques have benefits and consequences, they enable scientists and clinicians to identify regions that are vulnerable to or have been exposed to ischemic injury via non-invasive means. This literature review highlights the advancements in molecular imaging techniques and specific probes as they pertain to the process of angiogenesis in cardiovascular disease.     

Bioconjugated quantum dots for cancer research: Present status,prospects and remaining issues

Semiconductor quantum dots (QDs) are nanoparticles in which charge carriers are three dimensionally confined or quantum confined. The quantum confinement provides size-tunable absorption bands and emission color to QDs. Also, the photoluminescence (PL) of QDs is exceptionally bright and stable, making them potential candidates for biomedical imaging and therapeutic interventions. Although fluorescence imaging and photodynamic therapy (PDT) of cancer have many advantages over imaging using ionizing radiations and chemo and radiation therapies, advancement of PDT is limited due to the poor availability of photostable and NIR fluorophores and photosensitizing (PS) drugs. With the introduction of biocompatible and NIR QDs, fluorescence imaging and PDT of cancer have received new dimensions and drive. In this review, we summarize the prospects of QDs for imaging and PDT of cancer. Specifically, synthesis of visible and NIR QDs, targeting cancer cells with QDs, in vitro and in vivo cancer imaging, multimodality, preparation of QD-PS conjugates and their energy transfer, photosensitized production of reactive oxygen intermediates (ROI), and the prospects and remaining issues in the advancement of QD probes for imaging and PDT of cancer are summarized.