Primary analysis of a phase II open-label trial of INCB039110, a selective JAK1 inhibitor, in patients with myelofibrosis.

Combined Janus kinase 1 (JAK1) and JAK2 inhibition therapy effectively reduces splenomegaly and symptom burden related to myelofibrosis but is associated with dose-dependent anemia and thrombocytopenia. In this open-label phase II study, we evaluated the efficacy and safety of three dose levels of INCB039110, a potent and selective oral JAK1 inhibitor, in patients with intermediate- or high-risk myelofibrosis and a platelet count ≥50×109/L. Of 10, 45, and 32 patients enrolled in the 100 mg twice-daily, 200 mg twice-daily, and 600 mg once-daily cohorts, respectively, 50.0%, 64.4%, and 68.8% completed week 24. A ≥50% reduction in total symptom score was achieved by 35.7% and 28.6% of patients in the 200 mg twice-daily cohort and 32.3% and 35.5% in the 600 mg once-daily cohort at week 12 (primary end point) and 24, respectively. By contrast, two patients (20%) in the 100 mg twice-daily cohort had ≥50% total symptom score reduction at weeks 12 and 24. For the 200 mg twice-daily and 600 mg once-daily cohorts, the median spleen volume reductions at week 12 were 14.2% and 17.4%, respectively. Furthermore, 21/39 (53.8%) patients who required red blood cell transfusions during the 12 weeks preceding treatment initiation achieved a ≥50% reduction in the number of red blood cell units transfused during study weeks 1-24. Only one patient discontinued for grade 3 thrombocytopenia. Non-hematologic adverse events were largely grade 1 or 2; the most common was fatigue. Treatment with INCB039110 resulted in clinically meaningful symptom relief, modest spleen volume reduction, and limited myelosuppression.

Disruption of PARP1 function inhibits base excision repair of a sub-set of DNA lesions.

The repair of endogenously induced DNA damage is essential to maintain genomic integrity. It has been shown that XRCC1 and PARP1 are involved in the repair of base lesions and SSBs, although the exact mode of action has yet to be determined. Here we show that XRCC1 is involved in the repair of base lesions and SSBs independent of the cell cycle. However, the rate of repair of damage requiring XRCC1 does reflect the damage complexity. The repair of induced DNA damage occurs by PARP1-dependent and PARP1-independent sub-pathways of BER. It is suggested that the repair of SSBs and purine base damage is by a sub-pathway of BER that requires both XRCC1 and PARP1. Repair of pyrimidine base damage may require XRCC1 but does not require PARP1 activity. Therefore, although BER of simple lesions occurs rapidly, pathway choice and the involvement of PARP1 are highly dependent on the types of lesion induced.

Novel Smad proteins localize to IR-induced double-strand breaks: interplay between TGFß and ATM pathways.

Cellular damage from ionizing radiation (IR) is in part due to DNA damage and reactive oxygen species, which activate DNA damage response (DDR) and cytokine signaling pathways, including the ataxia telangiectasia mutated (ATM) and transforming growth factor (TGF)ß/Smad pathways. Using classic double-strand breaks (DSBs) markers, we studied the roles of Smad proteins in DDR and the crosstalk between TGFß and ATM pathways. We observed co-localization of phospho-Smad2 (pSmad2) and Smad7 with DSB repair proteins following low and high linear energy transfer (LET) radiation in human fibroblasts and epithelial cells. The decays of both foci were similar to that of γH2AX foci. Irradiation with high LET particles induced pSmad2 and Smad7 foci tracks indicating the particle trajectory through cells. pSmad2 foci were absent in S phase cells, while Smad7 foci were present in all phases of cell cycle. pSmad2 (but not Smad7) foci were completely abolished when ATM was depleted or inactivated. In contrast, a TGFß receptor 1 (TGFßR1) inhibitor abrogated Smad7, but not pSmad2 foci at DSBs sites. In summary, we suggest that Smad2 and Smad7 contribute to IR-induced DSB signaling in an ATM or TGFßR1-dependent manner, respectively.

Effects of (5'S)-5',8-cyclo-2'-deoxyadenosine on the base excision repair of oxidatively generated clustered DNA damage. A biochemical and theoretical study.

The presence of 5',8-cyclo-2'-deoxyadenosine (5'S)-cdA induces modifications in the geometry of the DNA duplex in the 5'-end direction of the strand and in the 3'-end direction of the complementary strand. As a consequence, the enzymes are probably not able to adjust their active sites in this rigid structure. Additionally, clustered DNA damage sites, a signature of ionising radiation, pose a severe challenge to a cell's repair machinery, particularly base excision repair (BER). To date, clusters containing a DNA base lesion, (5'S)-cdA, which is repaired by nucleotide excision repair, have not been explored. We have therefore investigated whether bistranded clusters containing (5'S)-cdA influence the repairability of an opposed AP site lesion, which is repaired by BER. Using synthetic oligonucleotides containing a bistranded cluster with (5'S)-cdA and an AP site at different interlesion separations, we have shown that in the presence of (5'S)-cdA on the 5'-end side, repair of the AP site by the BER machinery is retarded when the AP site is ≤8 bases from the (5'S)-cdA. However, if (5'S)-cdA is located on the 3'-end side with respect to the AP site, the effect on its repair is much weaker and totally disappears for distances ≥8 bases.

Reduced repair capacity of a DNA clustered damage site comprised of 8-oxo-7,8-dihydro-2'-deoxyguanosine and 2-deoxyribonolactone results in an increased mutagenic potential of these lesions.

A signature of ionizing radiation is the induction of DNA clustered damaged sites. Non-double strand break (DSB) clustered damage has been shown to compromise the base excision repair pathway, extending the lifetimes of the lesions within the cluster, compared to isolated lesions. This increases the likelihood the lesions persist to replication and thus increasing the mutagenic potential of the lesions within the cluster. Lesions formed by ionizing radiation include 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGuo) and 2-deoxyribonolactone (dL). dL poses an additional challenge to the cell as it is not repaired by the short-patch base excision repair pathway. Here we show recalcitrant dL repair is reflected in mutations observed when DNA containing it and a proximal 8-oxodGuo is replicated in Escherichia coli. 8-oxodGuo in close proximity to dL on the opposing DNA strand results in an enhanced frequency of mutation of the lesions within the cluster and a 20 base sequence flanking the clustered damage site in an E. coli based plasmid assay. In vitro repair of a dL lesion is reduced when compared to the repair of an abasic (AP) site and a tetrahydrofuran (THF), and this is due mainly to a reduction in the activity of polymerase ß, leading to retarded FEN1 and ligase 1 activities. This study has given insights in to the biological effects of clusters containing dL.

The dynamics of Ku70/80 and DNA-PKcs at DSBs induced by ionizing radiation is dependent on the complexity of damage.

DNA double-strand breaks (DSBs) are biologically one of the most important cellular lesions and possess varying degrees of chemical complexity. The notion that the repairability of more chemically complex DSBs is inefficient led to the concept that the extent of DSB complexity underlies the severity of the biological consequences. The repair of DSBs by non-homologous end joining (NHEJ) has been extensively studied but it remains unknown whether more complex DSBs require a different sub-set of NHEJ protein for their repair compared with simple DSBs. To address this, we have induced DSBs in fluorescently tagged mammalian cells (Ku80-EGFP, DNA-PKcs-YFP or XRCC4-GFP, key proteins in NHEJ) using ultra-soft X-rays (USX) or multi-photon near infrared (NIR) laser irradiation. We have shown in real-time that simple DSBs, induced by USX or NIR microbeam irradiation, are repaired rapidly involving Ku70/80 and XRCC4/Ligase IV/XLF. In contrast, DSBs with greater chemical complexity are repaired slowly involving not only Ku70/80 and XRCC4/Ligase IV/XLF but also DNA-PKcs. Ataxia telangiectasia-mutated inhibition only retards repair of the more chemically complex DSBs which require DNA-PKcs. In summary, the repair of DSBs by NHEJ is highly regulated with pathway choice and kinetics of repair dependent on the chemical complexity of the DSB.

DNA damage induced by nitric oxide during ionizing radiation is enhanced at replication.

Nitric oxide (NO) is a very effective radiosensitizer of hypoxic mammalian cells, at least as efficient as oxygen in enhancing cell death in vitro. NO may induce cell death through the formation of base lesions which are difficult to repair, and if they occur within complex clustered damage common to ionizing radiation, they may lead to replication-induced DNA strand breaks. It has previously been shown that 8-azaguanine and xanthine result from the reaction of guanine radicals with nitric oxide. We have now shown that adenine radicals also react with NO to form hypoxanthine and 8-azaadenine. Cells irradiated in exponential growth in the presence of NO are twice as radiosensitive compared to those irradiated in anoxia alone, whereas confluent cells are less radiosensitive to (•)NO. In addition, the numbers of DNA double strand breaks observed as γH2AX staining following radiosensitization by NO, are higher in exponential cells than in confluent cells. DNA damage, detected as 53BP1 foci, is also higher in HF-19 cells expressing Cyclin A, a marker for cells in S and G2 phases of the cell cycle, following radiosensitization by NO. RAD51 foci are highest in V79-4 cells irradiated in the presence of NO compared to in anoxia, 24h after radiolysis. This work presents evidence that radiosensitization of cells by NO is in part through the formation of specific DNA damage, difficult to repair, which in dividing cells may induce the formation of stalled replication forks and as a consequence replication-induced DNA strand breaks which may lead to cell death.

Spatiotemporal dynamics of DNA repair proteins following laser microbeam induced DNA damage - when is a DSB not a DSB?

The formation of DNA lesions poses a constant threat to cellular stability. Repair of endogenously and exogenously produced lesions has therefore been extensively studied, although the spatiotemporal dynamics of the repair processes has yet to be fully understood. One of the most recent advances to study the kinetics of DNA repair has been the development of laser microbeams to induce and visualize recruitment and loss of repair proteins to base damage in live mammalian cells. However, a number of studies have produced contradictory results that are likely caused by the different laser systems used reflecting in part the wavelength dependence of the damage induced. Additionally, the repair kinetics of laser microbeam induced DNA lesions have generally lacked consideration of the structural and chemical complexity of the DNA damage sites, which are known to greatly influence their reparability. In this review, we highlight the key considerations when embarking on laser microbeam experiments and interpreting the real time data from laser microbeam irradiations. We compare the repair kinetics from live cell imaging with biochemical and direct quantitative cellular measurements for DNA repair.

Significance of DNA polymerase I in in vivo processing of clustered DNA damage.

We examined the biological consequences of bi-stranded clustered damage sites, consisting of a combination of DNA lesions, such as a 1-nucleotide gap (GAP), an apurinic/apyrimidinic (AP) site, and an 8-oxo-7,8-dihydroguanine (8-oxoG), using a bacterial plasmid-based assay. Following transformation with the plasmid containing bi-stranded clustered damage sites into the wild type strain of Escherichia coli, transformation frequencies were significantly lower for the bi-stranded clustered GAP/AP lesions (separated by 1bp) than for either a single GAP or a single AP site. When the two lesions were separated by 10-20bp, the transformation efficiencies were comparable with those of the single lesions. This recovery of transformation efficiency for separated lesions requires DNA polymerase I (Pol I) activity. Analogously, the mutation frequency was found to depend on the distance separating lesions in a bi-stranded cluster containing a GAP and an 8-oxoG, and Pol I was found to play an important role in minimising mutations induced as a result of clustered lesions. The mutagenic potential of 8-oxoG within the bi-stranded lesions does not depend on whether it is situated on the leading or lagging strand. These results indicate that the biological consequences of clustered DNA damage strongly depend on the extent of repair of the strand breaks as well as the DNA polymerase in lesion-avoidance pathways during replication.

Hierarchy of lesion processing governs the repair, double-strand break formation and mutability of three-lesion clustered DNA damage.

Ionising radiation induces clustered DNA damage sites which pose a severe challenge to the cell's repair machinery, particularly base excision repair. To date, most studies have focussed on two-lesion clusters. We have designed synthetic oligonucleotides to give a variety of three-lesion clusters containing abasic sites and 8-oxo-7, 8-dihydroguanine to investigate if the hierarchy of lesion processing dictates whether the cluster is cytotoxic or mutagenic. Clusters containing two tandem 8-oxoG lesions opposing an AP site showed retardation of repair of the AP site with nuclear extract and an elevated mutation frequency after transformation into wild-type or mutY Escherichia coli. Clusters containing bistranded AP sites with a vicinal 8-oxoG form DSBs with nuclear extract, as confirmed in vivo by transformation into wild-type E. coli. Using ung1 E. coli, we propose that DSBs arise via lesion processing rather than stalled replication in cycling cells. This study provides evidence that it is not only the prompt formation of DSBs that has implications on cell survival but also the conversion of non-DSB clusters into DSBs during processing and attempted repair. The inaccurate repair of such clusters has biological significance due to the ultimate risk of tumourigenesis or as potential cytotoxic lesions in tumour cells.

Influence of ionizing radiation and cell density on the kinetics of autocrine destruction and intercellular induction of apoptosis in precancerous cells.

Intercellular induction of apoptosis (IIA) represents a well-defined signaling model by which precancerous cells are selectively eradicated through reactive oxygen/nitrogen species and cytokine signaling from neighbour normal cells. Previously, we demonstrated that the IIA process could be enhanced by exposure of normal cells to very low doses of ionizing radiation as a result of perturbing the intercellular signaling. In this study, we investigate the kinetic behaviour of both autocrine destruction (AD) and IIA as a function of cell density of both precancerous and normal cells using an insert co-culture system and how exposure of normal cells to ionizing radiation influence the kinetics of apoptosis induction in precancerous cells. Increasing the seeding density of transformed cells shifts the kinetics of AD towards earlier times with the response plateauing only at high seeding densities. Likewise, when co-culturing precancerous cells with normal cells, increasing the seeding density of either normal or precancerous cells also shifts the kinetics of IIA response towards earlier times and plateau only at higher seeding densities. Irradiation of normal cells prior to co-culture further enhances the kinetics of IIA response, with the degree of enhancement dependent on the relative cell densities. These results demonstrate the pivotal role of the cell seeding density of normal and precancerous cells in modulating both AD and IIA. These results further support the proposition that ionizing radiation could result in an enhancement in the rate of removal of precancerous cells through the IIA process.

Defining healthcare never events to effect system change: A protocol for systematic review.

INTRODUCTION: A never event is the most egregious of patient safety incidents. It refers to events that should theoretically never happen, such amputating the wrong limb. The term "never event" is used around the world by a variety of medical and patient safety organizations and is synonymous with sentinel events and serious reportable events. Unfortunately, there is little consensus about which events, in particular, are never events. These differing lists hinder potential collaboration or large-scale analyses. A recent systematic review by Hegarty et al. (2020) identified the need for a standardized definition for serious reportable events. The objective of our systematic review is to build on this by identifying which events are consistently or frequently identified as never events in order to isolate those which are core never events. MATERIALS AND METHODS: A systematic review will be conducted using Medline, Medline in Process, Scopus, PsychINFO, Embase via OVID, and CINAHL via EBSCO databases, as well as grey literature. We will include articles of any study design that discuss never events or one of its synonymous terms in the context of medical care. Four independent reviewers will conduct the title and abstract as well as the full-text screening, and 2 reviewers will abstract data. Data will be analyzed using narrative synthesis. Results will be categorized by year and geographic location, and by other factors determined during full-text screening. DISCUSSION AND CONCLUSION: The lack of consensus regarding never events hinders progress in reducing their occurrence. Differing data sources makes comparison challenging, and limits the ability for patient safety groups to work collaboratively and share learnings with others. Identifying a core set of never events will serve as a first step to focus our efforts to reduce these harmful incidents.

Improving Inclusivity in Robotics Design: An Exploration of Methods for Upstream Co-Creation.

Disabled people are often involved in robotics research as potential users of technologies which address specific needs. However, their more generalised lived expertise is not usually included when planning the overall design trajectory of robots for health and social care purposes. This risks losing valuable insight into the lived experience of disabled people, and impinges on their right to be involved in the shaping of their future care. This project draws upon the expertise of an interdisciplinary team to explore methodologies for involving people with disabilities in the early design of care robots in a way that enables incorporation of their broader values, experiences and expectations. We developed a comparative set of focus group workshops using Community Philosophy, LEGO® Serious Play® and Design Thinking to explore how people with a range of different physical impairments used these techniques to envision a "useful robot". The outputs were then workshopped with a group of roboticists and designers to explore how they interacted with the thematic map produced. Through this process, we aimed to understand how people living with disability think robots might improve their lives and consider new ways of bringing the fullness of lived experience into earlier stages of robot design. Secondary aims were to assess whether and how co-creative methodologies might produce actionable information for designers (or why not), and to deepen the exchange of social scientific and technical knowledge about feasible trajectories for robotics in health-social care. Our analysis indicated that using these methods in a sequential process of workshops with disabled people and incorporating engineers and other stakeholders at the Design Thinking stage could potentially produce technologically actionable results to inform follow-on proposals.

Delayed repair of radiation induced clustered DNA damage: friend or foe?

A signature of ionizing radiation exposure is the induction of DNA clustered damaged sites, defined as two or more lesions within one to two helical turns of DNA by passage of a single radiation track. Clustered damage is made up of double strand breaks (DSB) with associated base lesions or abasic (AP) sites, and non-DSB clusters comprised of base lesions, AP sites and single strand breaks. This review will concentrate on the experimental findings of the processing of non-DSB clustered damaged sites. It has been shown that non-DSB clustered damaged sites compromise the base excision repair pathway leading to the lifetime extension of the lesions within the cluster, compared to isolated lesions, thus the likelihood that the lesions persist to replication and induce mutation is increased. In addition certain non-DSB clustered damaged sites are processed within the cell to form additional DSB. The use of E. coli to demonstrate that clustering of DNA lesions is the major cause of the detrimental consequences of ionizing radiation is also discussed. The delayed repair of non-DSB clustered damaged sites in humans can be seen as a "friend", leading to cell killing in tumour cells or as a "foe", resulting in the formation of mutations and genetic instability in normal tissue.

Processing of thymine glycol in a clustered DNA damage site: mutagenic or cytotoxic.

Localized clustering of damage is a hallmark of certain DNA-damaging agents, particularly ionizing radiation. The potential for genetic change arising from the effects of clustered damage sites containing combinations of AP sites, 8-oxo-7,8-dihydroguanine (8-oxoG) or 5,6-dihydrothymine is high. To date clusters containing a DNA base lesion that is a strong block to replicative polymerases, have not been explored. Since thymine glycol (Tg) is non-mutagenic but a strong block to replicative polymerases, we have investigated whether clusters containing Tg are highly mutagenic or lead to potentially cytotoxic lesions, when closely opposed to either 8-oxoG or an AP site. Using a bacterial plasmid-based assay and repair assays using cell extracts or purified proteins, we have shown that DNA double-strand breaks (DSBs) arise when Tg is opposite to an AP site, either through attempted base excision repair or at replication. In contrast, 8-oxoG opposite to Tg in a cluster 'protects' against DSB formation but does enhance the mutation frequency at the site of 8-oxoG relative to that at a single 8-oxoG, due to the decisive role of endonucleases in the initial stages of processing Tg/8-oxoG clusters, removing Tg to give an intermediate with an abasic site or single-strand break.

Factors affecting residency rank-listing: a Maxdiff survey of graduating Canadian medical students.

BACKGROUND: In Canada, graduating medical students consider many factors, including geographic, social, and academic, when ranking residency programs through the Canadian Residency Matching Service (CaRMS). The relative significance of these factors is poorly studied in Canada. It is also unknown how students differentiate between their top program choices. This survey study addresses the influence of various factors on applicant decision making. METHODS: Graduating medical students from all six Ontario medical schools were invited to participate in an online survey available for three weeks prior to the CaRMS match day in 2010. Max-Diff discrete choice scaling, multiple choice, and drop-list style questions were employed. The Max-Diff data was analyzed using a scaled simple count method. Data for how students distinguish between top programs was analyzed as percentages. Comparisons were made between male and female applicants as well as between family medicine and specialist applicants; statistical significance was determined by the Mann-Whitney test. RESULTS: In total, 339 of 819 (41.4%) eligible students responded. The variety of clinical experiences and resident morale were weighed heavily in choosing a residency program; whereas financial incentives and parental leave attitudes had low influence. Major reasons that applicants selected their first choice program over their second choice included the distance to relatives and desirability of the city. Both genders had similar priorities when selecting programs. Family medicine applicants rated the variety of clinical experiences more importantly; whereas specialty applicants emphasized academic factors more. CONCLUSIONS: Graduating medical students consider program characteristics such as the variety of clinical experiences and resident morale heavily in terms of overall priority. However, differentiation between their top two choice programs is often dependent on social/geographic factors. The results of this survey will contribute to a better understanding of the CaRMS decision making process for both junior medical students and residency program directors.

Interplay of two major repair pathways in the processing of complex double-strand DNA breaks.

Radiation-induced complex double-strand breaks (DSBs) characterised by base lesions, abasic sites or single-strand breaks in close proximity to the break termini, are believed to be a major cause of the biological effects of ionising radiation exposure. It has been hypothesised that complex DSBs pose problems for the repair machinery of the cell. Using a biochemical approach, we have investigated the challenge to two major repair processes: base excision repair and ligation of DSB ends. Double-stranded oligonucleotides were synthesised with 8-oxo-7,8-dihydroguanine (8-oxoG) at defined positions relative to readily ligatable 3'-hydroxy or 5'-phosphate termini. The break termini interfere with removal of 8-oxoG during base excision repair as elucidated from the severely reduced efficiency of 8-oxoG removal by OGG1 with AP endonuclease-1 when in close proximity to break termini. NEIL-1, however, can partially restore processing of complex DSBs in an AP endonuclease-1 independent manner. The influence of 8-oxoG on ligation shows delayed rejoining if 8-oxoG is positioned two to three bases from the 3'-hydroxy or six bases from the 5'-phosphate termini. When two 8-oxoG lesions are positioned across the break junction ligation is severely retarded. This reduced efficiency of repair indicates that complex DSBs are likely to persist longer than simple DSBs in cells, and as a consequence are more significant in contributing to the biological effects of ionising radiation.

Induction of DNA strand breaks, base lesions and clustered damage sites in hydrated plasmid DNA films by ultrasoft X rays around the phosphorus K edge.

To characterize the DNA damage induced by K-shell ionization of phosphorus atom in DNA backbone on the level of hydration, the yields of DNA strand breaks and base lesions arising from the interaction of ultrasoft X rays with energies around the phosphorus K edge were determined using dry and fully hydrated pUC18 plasmid DNA samples. Base lesions and bistranded clustered DNA damage sites were revealed by postirradiation treatment with the base excision repair proteins endonuclease III (Nth) and formamidopyrimidine-DNA glycosylase (Fpg). The yield of prompt single-strand breaks (SSBs) with dry DNA irradiated at the phosphorus K resonance energy (2153 eV) is about one-third that below the phosphorus K edge (2147 eV). The yields of prompt double-strand breaks (DSBs) were found to be less dependent on the X-ray energy, with the yields being about two times lower when irradiated at 2153 eV. Heat-labile sites were not produced in detectable amounts. The yields of base lesions were dependent on the energy of the X rays, especially when the DNA was fully hydrated. Bistranded clustered DNA damage sites, revealed enzymatically as additional DSBs, were produced in dry as well as in hydrated DNA with all three energies of X rays. The yields of these enzyme-sensitive sites were also lower when irradiated at the phosphorus K resonance energy. On the other hand, the yields of prompt SSBs and enzyme-sensitive sites for the two off-resonance energies were, larger than those determined previously for gamma radiation. The results indicate that the photoelectric effect caused by X rays and dense ionization and excitation events along the tracks of low-energy secondary electrons are more effective at inducing SSBs and enzyme-sensitive sites. The complex types of damage, prompt and enzymatically induced DSBs, are preferentially induced by phosphorus K resonance at 2153 eV rather than simple SSBs and isolated base lesions, particularly in hydrated conditions. It is concluded that not only the phosphorus K resonance and resulting emission of low-energy LMM-Auger electrons ( approximately 120 eV) but also the level of hydration plays an important role in the induction of complex damage in plasmid DNA.

Redox dependence of the reaction of alpha-alkoxyalkyl radicals with a series of oxidants.

Oxygen and oxidants enhance the sensitivity of cells to radiation. To understand this effect at the mechanistic level, the redox dependences for the reactivity of weakly reducing alpha-monoalkoxyalkyl radicals of 1,4-dioxane and tetrahydrofuran with a series of oxidants, for example, quinones, viologens, and nitro-arenes, with one-electron reduction potentials E71 values ranging from -80 to -640 mV, have been determined using the technique of pulse radiolysis. The second-order rate constants for these reactions with the alpha-monoalkoxyalkyl radicals of 1,4-dioxane and tetrahydrofuran are in the range (0.03-1.5) x 109 and (1.0-6.6) x 109 dm3 mol(-1) s(-1), respectively. The reactions of the alpha-alkoxyalkyl radicals of 1,4-dioxane with quinones and viologens involve an outer-sphere electron transfer, in contrast to a reaction with the nitro-arenes to give adducts. The resulting long-lived nitroaromatic adduct radicals were found to react with the reductant, TMPD, probably leading to the formation of hydroxylamine-type products. In cells, adducts formed on reaction of deoxyribose sugar radical with oxidants and subsequent reactions with reductants may contribute to the mechanisms involved in radiosensitization by oxygen and those oxidants that interact through adduct formation.

Radiation chemistry comes before radiation biology.

PURPOSE: This article seeks to illustrate some contributions of radiation chemistry to radiobiology and related science, and to draw attention to examples where radiation chemistry is central to our knowledge of specific aspects. Radiation chemistry is a mature branch of radiation science which is continually evolving and finding wider applications. This is particularly apparent in the study of the roles of free radicals in biology generally, and radiation biology specifically. The chemical viewpoint helps unite the spatial and temporal insight coming from radiation physics with the diversity of biological responses. While historically, the main application of radiation chemistry of relevance to radiation biology has been investigations of the free-radical processes leading to radiation-induced DNA damage and its chemical characterization, two features of radiation chemistry point to its wider importance. First, its emphasis on quantification and characterization at the molecular level helps provide links between DNA damage, biochemical repair processes, and mutagenicity and radiosensitivity. Second, its central pillar of chemical kinetics aids understanding of the roles of 'reactive oxygen species' in cell signalling and diverse biological effects more generally, and application of radiation chemistry in the development of drugs to enhance radiotherapy and as hypoxia-specific cytotoxins or diagnostic agents. The illustrations of the broader applications of radiation chemistry in this article focus on their relevance to radiation biology and demonstrate the importance of synergy in the radiation sciences. CONCLUSIONS: The past contributions of radiation chemistry to radiation biology are evident, but there remains considerable potential to help advance future biological understanding using the knowledge and techniques of radiation chemistry.