Retuning the Radio in Radiobiology.
Ontology highlight
ABSTRACT:
SUBMITTER: Chmura SJ
PROVIDER: S-EPMC6927860 | biostudies-literature | 2018 Apr
REPOSITORIES: biostudies-literature
Publications
Retuning the Radio in Radiobiology.
Chmura Steven J SJ Connell Philip P PP Weichselbaum Ralph R RR
Journal of the National Cancer Institute 20180401 4
Similar Datasets
Project description:Radiotherapy using accelerated charged particles is rapidly growing worldwide. About 85% of the cancer patients receiving particle therapy are irradiated with protons, which have physical advantages compared to X-rays but a similar biological response. In addition to the ballistic advantages, heavy ions present specific radiobiological features that can make them attractive for treating radioresistant, hypoxic tumors. An ideal heavy ion should have lower toxicity in the entrance channel (normal tissue) and be exquisitely effective in the target region (tumor). Carbon ions have been chosen because they represent the best combination in this direction. Normal tissue toxicities and second cancer risk are similar to those observed in conventional radiotherapy. In the target region, they have increased relative biological effectiveness and a reduced oxygen enhancement ratio compared to X-rays. Some radiobiological properties of densely ionizing carbon ions are so distinct from X-rays and protons that they can be considered as a different "drug" in oncology, and may elicit favorable responses such as an increased immune response and reduced angiogenesis and metastatic potential. The radiobiological properties of carbon ions should guide patient selection and treatment protocols to achieve optimal clinical results.
| S-EPMC7603235 | biostudies-literature
Project description:Innovation and progress in radiation oncology depend on discovery and insights realized through research in radiation biology. Radiobiology research has led to fundamental scientific insights, from the discovery of stem/progenitor cells to the definition of signal transduction pathways activated by ionizing radiation that are now recognized as integral to the DNA damage response (DDR). Radiobiological discoveries are guiding clinical trials that test radiation therapy combined with inhibitors of the DDR kinases DNA-dependent protein kinase (DNA-PK), ataxia telangiectasia mutated (ATM), ataxia telangiectasia related (ATR), and immune or cell cycle checkpoint inhibitors. To maintain scientific and clinical relevance, the field of radiation biology must overcome challenges in research workforce, training, and funding. The National Cancer Institute convened a workshop to discuss the role of radiobiology research and radiation biologists in the future scientific enterprise. Here, we review the discussions of current radiation oncology research approaches and areas of scientific focus considered important for rapid progress in radiation sciences and the continued contribution of radiobiology to radiation oncology and the broader biomedical research community.
| S-EPMC5928778 | biostudies-literature
Project description:The introduction of ionizing radiation in medicine revolutionized the diagnosis and treatment of disease and dramatically improved and continues to improve the quality of health care. Cardiovascular imaging and medical imaging in general, however, are associated with a range of radiobiologic effects, including, in rare instances, moderate to severe skin damage resulting from cardiac fluoroscopy. For the dose range associated with diagnostic imaging (corresponding to effective doses on the order of 10 mSv [1 rem]), the possible effects are stochastic in nature and largely theoretical. The most notable of these effects, of course, is the possible increase in cancer risk. The current review addresses radiobiology relevant to cardiovascular imaging, with particular emphasis on radiation induction of cancer, including consideration of the linear nonthreshold dose-response model and of alternative models such as radiation hormesis.
| S-EPMC5877470 | biostudies-literature
Project description:Rieske-type oxygenases are promising biocatalysts for the destruction of persistent pollutants or for the synthesis of fine chemicals. In this work, we explored pathways through which Rieske-type oxygenases evolve to expand their substrate range. BphAE(p4), a variant biphenyl dioxygenase generated from Burkholderia xenovorans LB400 BphAE(LB400) by the double substitution T335A/F336M, and BphAE(RR41), obtained by changing Asn(338), Ile(341), and Leu(409) of BphAE(p4) to Gln(338), Val(341), and Phe(409), metabolize dibenzofuran two and three times faster than BphAE(LB400), respectively. Steady-state kinetic measurements of single- and multiple-substitution mutants of BphAE(LB400) showed that the single T335A and the double N338Q/L409F substitutions contribute significantly to enhanced catalytic activity toward dibenzofuran. Analysis of crystal structures showed that the T335A substitution relieves constraints on a segment lining the catalytic cavity, allowing a significant displacement in response to dibenzofuran binding. The combined N338Q/L409F substitutions alter substrate-induced conformational changes of protein groups involved in subunit assembly and in the chemical steps of the reaction. This suggests a responsive induced fit mechanism that retunes the alignment of protein atoms involved in the chemical steps of the reaction. These enzymes can thus expand their substrate range through mutations that alter the constraints or plasticity of the catalytic cavity to accommodate new substrates or that alter the induced fit mechanism required to achieve proper alignment of reaction-critical atoms or groups.
| S-EPMC3149352 | biostudies-literature
Project description:Targeted alpha therapy (TAT) using alpha particle-emitting radionuclides is in the spotlight after the approval of 223RaCl2 for patients with metastatic castration-resistant prostate cancer and the development of several alpha emitter-based radiopharmaceuticals. It is acknowledged that alpha particles are highly cytotoxic because they produce complex DNA lesions. Hence, the nucleus is considered their critical target, and many studies did not report any effect in other subcellular compartments. Moreover, their physical features, including their range in tissues (<100 μm) and their linear energy transfer (50-230 keV/μm), are well-characterized. Theoretically, TAT is indicated for very small-volume, disseminated tumors (e.g., micrometastases, circulating tumor cells). Moreover, due to their high cytotoxicity, alpha particles should be preferred to beta particles and X-rays to overcome radiation resistance. However, clinical studies showed that TAT might be efficient also in quite large tumors, and biological effects have been observed also away from irradiated cells. These distant effects are called bystander effects when occurring at short distance (<1 mm), and systemic effects when occurring at much longer distance. Systemic effects implicate the immune system. These findings showed that cells can die without receiving any radiation dose, and that a more complex and integrated view of radiobiology is required. This includes the notion that the direct, bystander and systemic responses cannot be dissociated because DNA damage is intimately linked to bystander effects and immune response. Here, we provide a brief overview of the paradigms that need to be revisited.
| S-EPMC8353448 | biostudies-literature
Project description:Neutron therapy was developed from neutron radiobiology experiments, and had identified a higher cell kill per unit dose and an accompanying reduction in oxygen dependency. But experts such as Hal Gray were sceptical about clinical applications, for good reasons. Gray knew that the increase in relative biological effectiveness (RBE) with dose fall-off could produce marked clinical limitations. After many years of research, this treatment did not produce the expected gains in tumour control relative to normal tissue toxicity, as predicted by Gray. More detailed reasons for this are discussed in this paper. Neutrons do not have Bragg peaks and so did not selectively spare many tissues from radiation exposure; the constant neutron RBE tumour prescription values did not represent the probable higher RBE values in late-reacting tissues with low α/β values; the inevitable increase in RBE as dose falls along a beam would also contribute to greater toxicity than in a similar megavoltage photon beam. Some tissues such as the central nervous system white matter had the highest RBEs partly because of the higher percentage hydrogen content in lipid-containing molecules. All the above factors contributed to disappointing clinical results found in a series of randomised controlled studies at many treatment centres, although at the time they were performed, neutron therapy was in a catch-up phase with photon-based treatments. Their findings are summarised along with their technical aspects and fractionation choices. Better understanding of fast neutron experiments and therapy has been gained through relatively simple mathematical models-using the biological effective dose concept and incorporating the RBEmax and RBEmin parameters (the limits of RBE at low and high dose, respectively-as shown in the Appendix). The RBE itself can then vary between these limits according to the dose per fraction used. These approaches provide useful insights into the problems that can occur in proton and ion beam therapy and how they may be optimised. This is because neutron ionisations in living tissues are mainly caused by recoil protons of energy proportional to the neutron energy: these are close to the proton energies that occur close to the Bragg peak region. To some extent, neutron RBE studies contain the highest RBE ranges found within proton and ion beams near Bragg peaks. In retrospect, neutrons were a useful radiobiological tool that has continued to inform the scientific and clinical community about the essential radiobiological principles of all forms of high linear energy transfer therapy. Neutron radiobiology and its implications should be taught on training courses and studied closely by clinicians, physicists, and biologists engaged in particle beam therapies.
| S-EPMC7522468 | biostudies-literature
Project description:Mathematical models of chronic myeloid leukemia (CML) cell population dynamics are being developed to improve CML understanding and treatment. We review such models in light of relevant findings from radiobiology, emphasizing 3 points. First, the CML models almost all assert that the latency time, from CML initiation to diagnosis, is at most ?10 years. Meanwhile, current radiobiologic estimates, based on Japanese atomic bomb survivor data, indicate a substantially higher maximum, suggesting longer-term relapses and extra resistance mutations. Second, different CML models assume different numbers, between 400 and 10(6), of normal HSCs. Radiobiologic estimates favor values>10(6) for the number of normal cells (often assumed to be the HSCs) that are at risk for a CML-initiating BCR-ABL translocation. Moreover, there is some evidence for an HSC dead-band hypothesis, consistent with HSC numbers being very different across different healthy adults. Third, radiobiologists have found that sporadic (background, age-driven) chromosome translocation incidence increases with age during adulthood. BCR-ABL translocation incidence increasing with age would provide a hitherto underanalyzed contribution to observed background adult-onset CML incidence acceleration with age, and would cast some doubt on stage-number inferences from multistage carcinogenesis models in general.
| S-EPMC3362357 | biostudies-literature
Project description:Stereotactic ablative radiotherapy (SABR) is a novel radiation treatment method that delivers an intense dose of radiation to the treatment targets with high accuracy. The excellent local control and tolerance profile of SABR have made it become an important modality in cancer treatment. The radiobiology of SABR is a key factor in understanding and further optimizing the benefits of SABR. In this review, we have addressed several issues in the radiobiology of SABR from the perspective of clinical oncologists. The appropriateness of the linear-quadratic (LQ) model for SABR is controversial based on preclinical data, but it is a reliable tool from the perspective of clinical application because the biological effective dose (BED) calculated with it can represent the tumor control probability (TCP). Hypoxia is a common phenomenon in SABR in spite of the relatively small tumor size and has a negative effect on the efficacy of SABR. Preliminary studies indicate that a hypoxic radiosensitizer combined with SABR may be a feasible strategy, but so far there is not adequate evidence to support its application in routine practice. The vascular change of endothelial apoptosis and blood perfusion reduction in SABR may enhance the response of tumor cells to radiation. Combination of SABR with anti-angiogenesis therapy has shown promising efficacy and good tolerance in advanced cancers. SABR is more powerful in enhancing antitumor immunity and works better with immune checkpoint inhibitors (ICIs) than conventional fractionation radiotherapy. Combination of SABR with ICIs has become a practical option for cancer patients with metastases.
| S-EPMC7378931 | biostudies-literature
Project description:Current models of word-meaning access typically assume that lexical-semantic representations of ambiguous words (e.g., 'bark of the dog/tree') reach a relatively stable state in adulthood, with only the relative frequencies of meanings and immediate sentence context determining meaning preference. However, recent experience also affects interpretation: recently encountered word-meanings become more readily available (Rodd et al., 2016, 2013). Here, 3 experiments investigated how multiple encounters with word-meanings influence the subsequent interpretation of these ambiguous words. Participants heard ambiguous words contextually-disambiguated towards a particular meaning and, after a 20- to 30-min delay, interpretations of the words were tested in isolation. We replicate the finding that 1 encounter with an ambiguous word biased the later interpretation of this word towards the primed meaning for both subordinate (Experiments 1, 2, 3) and dominant meanings (Experiment 1). In addition, for the first time, we show cumulative effects of multiple repetitions of both the same and different meanings. The effect of a single subordinate exposure persisted after a subsequent encounter with the dominant meaning, compared to a dominant exposure alone (Experiment 1). Furthermore, 3 subordinate word-meaning repetitions provided an additional boost to priming compared to 1, although only when their presentation was spaced (Experiments 2, 3); massed repetitions provided no such boost (Experiments 1, 3). These findings indicate that comprehension is guided by the collective effect of multiple recently activated meanings and that the spacing of these activations is key to producing lasting updates to the lexical-semantic network. (PsycINFO Database Record
| S-EPMC6012009 | biostudies-literature
Project description:The auditory and motor neural systems are closely intertwined, enabling people to carry out tasks such as playing a musical instrument whose mapping between action and sound is extremely sophisticated. While the dorsal auditory stream has been shown to mediate these audio-motor transformations, little is known about how such mapping emerges with training. Here, we use longitudinal training on a cello as a model for brain plasticity during the acquisition of specific complex skills, including continuous and many-to-one audio-motor mapping, and we investigate individual differences in learning. We trained participants with no musical background to play on a specially designed MRI-compatible cello and scanned them before and after 1 and 4 wk of training. Activation of the auditory-to-motor dorsal cortical stream emerged rapidly during the training and was similarly activated during passive listening and cello performance of trained melodies. This network activation was independent of performance accuracy and therefore appears to be a prerequisite of music playing. In contrast, greater recruitment of regions involved in auditory encoding and motor control over the training was related to better musical proficiency. Additionally, pre-supplementary motor area activity and its connectivity with the auditory cortex during passive listening before training was predictive of final training success, revealing the integrative function of this network in auditory-motor information processing. Together, these results clarify the critical role of the dorsal stream and its interaction with auditory areas in complex audio-motor learning.
| S-EPMC6042146 | biostudies-literature