Publications by authors named "Mark A Hill"

67 Publications

USP9X Is Required to Maintain Cell Survival in Response to High-LET Radiation.

Front Oncol 2021 1;11:671431. Epub 2021 Jul 1.

Cancer Research Centre, Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, United Kingdom.

Ionizing radiation (IR) principally acts through induction of DNA damage that promotes cell death, although the biological effects of IR are more broad ranging. In fact, the impact of IR of higher-linear energy transfer (LET) on cell biology is generally not well understood. Critically, therefore, the cellular enzymes and mechanisms responsible for enhancing cell survival following high-LET IR are unclear. To this effect, we have recently performed siRNA screening to identify deubiquitylating enzymes that control cell survival specifically in response to high-LET α-particles and protons, in comparison to low-LET X-rays and protons. From this screening, we have now thoroughly validated that depletion of the ubiquitin-specific protease 9X (USP9X) in HeLa and oropharyngeal squamous cell carcinoma (UMSCC74A) cells using small interfering RNA (siRNA), leads to significantly decreased survival of cells after high-LET radiation. We consequently investigated the mechanism through which this occurs, and demonstrate that an absence of USP9X has no impact on DNA damage repair post-irradiation nor on apoptosis, autophagy, or senescence. We discovered that USP9X is required to stabilize key proteins (CEP55 and CEP131) involved in centrosome and cilia formation and plays an important role in controlling pericentrin-rich foci, particularly in response to high-LET protons. This was also confirmed directly by demonstrating that depletion of CEP55/CEP131 led to both enhanced radiosensitivity of cells to high-LET protons and amplification of pericentrin-rich foci. Our evidence supports the importance of USP9X in maintaining centrosome function and biogenesis and which is crucial particularly in the cellular response to high-LET radiation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fonc.2021.671431DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8281306PMC
July 2021

Incorporating oxygenation levels in analytical DNA-damage models-quantifying the oxygen fixation mechanism.

Phys Med Biol 2021 Jul 9;66(14). Epub 2021 Jul 9.

University of Oxford, Department of Oncology, Oxford, United Kingdom.

To develop a framework to include oxygenation effects in radiation therapy treatment planning which is valid for all modalities, energy spectra and oxygen levels. The framework is based on predicting the difference in DNA-damage resulting from ionising radiation at variable oxygenation levels.Oxygen fixation is treated as a statistical process in a simplified model of complex and simple damage. We show that a linear transformation of the microscopic oxygen fixation process allows to extend this to all energies and modalities, resulting in a relatively simple rational polynomial expression. The model is expanded such that it can be applied for polyenergetic beams. The methodology is validated using Microdosimetric Monte Carlo Damage Simulation code (MCDS). This serves as a bootstrap to determine relevant parameters in the analytical expression, as MCDS is shown to be extensively verified with published empirical data. Double-strand break induction as calculated by this methodology is compared to published proton experiments. Finally, an example is worked out where the oxygen enhancement ratio (OER) is calculated at different positions in a clinically relevant spread out Bragg peak (SOBP) dose deposition in water. This dose deposition is obtained using a general Monte Carlo code (FLUKA) to determine dose deposition and locate fluence spectra.For all modalities (electrons, protons), the damage categorised as complex could be parameterised to within 0.3% of the value calculated using microdosimetric Monte Carlo. The proton beam implementation showed some variation in OERs which differed slightly depending on where the assessment was made; before the SOBP, mid-SOBP or at the distal edge. Environment oxygenation was seen to be the more important variable.An analytic expression calculating complex damage depending on modality, energy spectrum, and oxygenation levels was shown to be effective and can be readily incorporated in treatment planning software, to take into account the impact of variable oxygenation, forming a first step to an optimised treatment based on biological factors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1088/1361-6560/ac0b80DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8273901PMC
July 2021

Ongoing repair of migration-coupled DNA damage allows planarian adult stem cells to reach wound sites.

Elife 2021 Apr 23;10. Epub 2021 Apr 23.

Department of Zoology, University of Oxford, Oxford, United Kingdom.

Mechanical stress during cell migration may be a previously unappreciated source of genome instability, but the extent to which this happens in any animal in vivo remains unknown. We consider an in vivo system where the adult stem cells of planarian flatworms are required to migrate to a distal wound site. We observe a relationship between adult stem cell migration and ongoing DNA damage and repair during tissue regeneration. Migrating planarian stem cells undergo changes in nuclear shape and exhibit increased levels of DNA damage. Increased DNA damage levels reduce once stem cells reach the wound site. Stem cells in which DNA damage is induced prior to wounding take longer to initiate migration and migrating stem cell populations are more sensitive to further DNA damage than stationary stem cells. RNAi-mediated knockdown of DNA repair pathway components blocks normal stem cell migration, confirming that active DNA repair pathways are required to allow successful migration to a distal wound site. Together these findings provide evidence that levels of migration-coupled-DNA-damage are significant in adult stem cells and that ongoing migration requires DNA repair mechanisms. Our findings reveal that migration of normal stem cells in vivo represents an unappreciated source of damage, which could be a significant source of mutations in animals during development or during long-term tissue homeostasis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7554/eLife.63779DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8104965PMC
April 2021

Olaparib increases the therapeutic index of hemithoracic irradiation compared with hemithoracic irradiation alone in a mouse lung cancer model.

Br J Cancer 2021 May 19;124(11):1809-1819. Epub 2021 Mar 19.

CRUK & MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, UK.

Background: The radiosensitising effect of the poly(ADP-ribose) polymerase inhibitor olaparib on tumours has been reported. However, its effect on normal tissues in combination with radiation has not been well studied. Herein, we investigated the therapeutic index of olaparib combined with hemithoracic radiation in a urethane-induced mouse lung cancer model.

Methods: To assess tolerability, A/J mice were treated with olaparib plus whole thorax radiation (13 Gy), body weight changes were monitored and normal tissue effects were assessed by histology. In anti-tumour (intervention) studies, A/J mice were injected with urethane to induce lung tumours, and were then treated with olaparib alone, left thorax radiation alone or the combination of olaparib plus left thorax radiation at 8 weeks (early intervention) or 18 weeks (late intervention) after urethane injection. Anti-tumour efficacy and normal tissue effects were assessed by visual inspection, magnetic resonance imaging and histology.

Results: Enhanced body weight loss and oesophageal toxicity were observed when olaparib was combined with whole thorax but not hemithorax radiation. In both the early and late intervention studies, olaparib increased the anti-tumour effects of hemithoracic irradiation without increasing lung toxicity.

Conclusions: The addition of olaparib increased the therapeutic index of hemithoracic radiation in a mouse model of lung cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41416-021-01296-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8144220PMC
May 2021

The physical separation between the LET associated with the ultimate relative biological effect (RBE) and the maximum LET in a proton or ion beam.

Biomed Phys Eng Express 2020 07 7;6(5):055001. Epub 2020 Jul 7.

CRUK/MRC Oxford Institute for Radiation Oncology and Biology, University of Oxford, Gray Laboratory, Old Road Campus Research Building, Roosevelt Drive, Oxford, OX3 7DQ, United Kingdom.

Purpose: To identify the relative positions of the ultimate RBE, at a LET value of LET (where the LET-RBE turnover point occurs independently of dose), and of the maximum LET (LET) for a range of ions from protons to Iron ions.

Methods: For a range of relativistic velocities (β), the kinetic energies, LET values and ranges for each ion are obtained using SRIM software. For protons and helium ions, the LET changes with β are plotted and LET is compared with LET For all the ions studied the residual ranges of particles at LET and LET are subtracted to provide the physical separation (S) between LET and LET.

Results: Graphical methods are used to show the above parameters for protons and helium ions. For all the ions studied, LET occurs at kinetic energies which are higher than those at LET, so the ultimate maximal RBE occurs proximal to the Bragg peak for individual particles and not beyond it, as is commonly supposed. The distance S, between LET and LET, appears to increase linearly with the atomic charge value Z.

Conclusions: For the lighter elements, from protons to carbon ions, S is sufficiently small (less than the tolerance/accuracy of radiation treatments) and so will probably not influence therapeutic decisions or outcomes. For higher Z numbers such as Argon and Iron, larger S values of several centimetres occur, which may have implications not only in any proposed therapeutic beams but also at very low doses encountered in radiation protection where the few cells that are irradiated will typically be traversed by a single particle.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1088/2057-1976/ab9e13DOI Listing
July 2020

Induction of Genomic Instability in a Primary Human Fibroblast Cell Line Following Low-Dose Alpha-Particle Exposure and the Potential Role of Exosomes.

Biology (Basel) 2020 Dec 28;10(1). Epub 2020 Dec 28.

Department of Biological and Medical Sciences, Faculty of Health and Life Sciences, Oxford Brookes University, Oxford OX3 0BP, UK.

Purpose: To study the induction of genomic instability (GI) in the progeny of cell populations irradiated with low doses of alpha-particles and the potential role of exosome-encapsulated bystander signalling.

Methods: The induction of GI in HF19 normal fibroblast cells was assessed by determining the formation of micronuclei (MN) in binucleate cells along with using the alkaline comet assay to assess DNA damage.

Results: Low dose alpha-particle exposure (0.0001-1 Gy) was observed to produce a significant induction of micronuclei and DNA damage shortly after irradiation (assays performed at 5 and 1 h post exposure, respectively). This damage was not only still evident and statistically significant in all irradiated groups after 10 population doublings, but similar trends were observed after 20 population doublings. Exosomes from irradiated cells were also observed to enhance the level of DNA damage in non-irradiated bystander cells at early times.

Conclusion: very low doses of alpha-particles are capable of inducing GI in the progeny of irradiated cells even at doses where <1% of the cells are traversed, where the level of response was similar to that observed at doses where 100% of the cells were traversed. This may have important implications with respect to the evaluation of cancer risk associated with very low-dose alpha-particle exposure and deviation from a linear dose response.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/biology10010011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7824692PMC
December 2020

ReN VM spheroids in matrix: A neural progenitor three-dimensional in vitro model reveals DYRK1A inhibitors as potential regulators of radio-sensitivity.

Biochem Biophys Res Commun 2020 10 14;531(4):535-542. Epub 2020 Aug 14.

Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, OX3 7FZ, Oxford, England, UK. Electronic address:

Introduction: Pre-clinical testing of small molecules for therapeutic development across many pathologies relies on the use of in-vitro and in-vivo models. When designed and implemented well, these models serve to predict the clinical outcome as well as the toxicity of the evaluated therapies. The two-dimensional (2D) reductionist approach where cells are incubated in a mono-layer on hard plastic microtiter plates is relatively inexpensive but not physiologically relevant. In contrast, well developed and applied three dimensional (3D) in vitro models could be employed to bridge the gap between 2D in vitro primary screening and expensive in vivo rodent models by incorporating key features of the tissue microenvironment to explore differentiation, cortical development, cancers and various neuronal dysfunctions. These features include an extracellular matrix, co-culture, tension and perfusion and could replace several hundred rodents in the drug screening validation cascade.

Methods: Human neural progenitor cells from middle brain (ReN VM, Merck Millipore, UK) were expanded as instructed by the supplier (Merck Millipore, UK), and then seeded in 96-well low-attachment plates (Corning, UK) to form multicellular spheroids followed by adding a Matrigel layer to mimic extracellular matrix around neural stem cell niche. ReN VM cells were then differentiated via EGF and bFGF deprivation for 7 days and were imaged at day 7. Radiotherapy was mimicked via gamma-radiation at 2Gy in the absence and presence of selected DYRK1A inhibitors Harmine, INDY and Leucettine 41 (L41). Cell viability was measured by AlamarBlue assay. Immunofluorescence staining was used to assess cell pluripotency marker SOX2 and differentiation marker GFAP.

Results: After 7 days of differentiation, neuron early differentiation marker (GFAP, red) started to be expressed among the cells expressing neural stem cell marker SOX2 (green). Radiation treatment caused significant morphology change including the reduced viability of the spheroids. These spheroids also revealed sensitizing potential of DYRK1A inhibitors tested in this study, including Harmine, INDY and L41.

Discussion & Conclusions: Combined with the benefit of greatly reducing the issues associated with in vivo rodent models, including reducing numbers of animals used in a drug screening cascade, cost, ethics, and potential animal welfare burden, we feel the well-developed and applied 3D neural spheroid model presented in this study will provide a crucial tool to evaluate combinatorial therapies, optimal drug concentrations and treatment dosages.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbrc.2020.07.130DOI Listing
October 2020

Density compensated diodes for small field dosimetry: comprehensive testing and implications for design.

Phys Med Biol 2020 08 10;65(15):155011. Epub 2020 Aug 10.

Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, The Sherrington Building, Ashton Street, Liverpool L69 3BX, United Kingdom. Department of Physics, Clatterbridge Cancer Centre, Clatterbridge Road, Wirral CH63 4JY, United Kingdom. Department of Physics, University of Liverpool, Oliver Lodge Laboratory, Oxford Street, Liverpool L69 7ZE, United Kingdom.

Purpose: In small megavoltage photon fields, the accuracies of an unmodified PTW 60017-type diode dosimeter and six diodes modified by adding airgaps of thickness 0.6-1.6 mm and diameter 3.6 mm have been comprehensively characterized experimentally and computationally. The optimally thick airgap for density compensation was determined, and detectors were micro-CT imaged to investigate differences between experimentally measured radiation responses and those predicted computationally.

Methods: Detectors were tested on- and off-axis, at 5 and 15 cm depths in 6 and 15 MV fields ≥ 0.5 × 0.5 cm. Computational studies were carried out using the EGSnrc/BEAMnrc Monte Carlo radiation transport code. Experimentally, radiation was delivered using a Varian TrueBeam linac and doses absorbed by water were measured using Gafchromic EBT3 film and ionization chambers, and compared with diode readings. Detector response was characterized via the [Formula: see text] formalism, choosing a 4 × 4 cm reference field.

Results: For the unmodified 60017 diode, the maximum error in small field doses obtained from diode readings uncorrected by [Formula: see text] factors was determined as 11.9% computationally at +0.25 mm off-axis and 5 cm depth in a 15 MV 0.5 × 0.5 cm field, and 11.7% experimentally at -0.30 mm off-axis and 5 cm depth in the same field. A detector modified to include a 1.6 mm thick airgap performed best, with maximum computationally and experimentally determined errors of 2.2% and 4.1%. The 1.6 mm airgap deepened the modified dosimeter's effective point of measurement by 0.5 mm. For some detectors significant differences existed between responses in small fields determined computationally and experimentally, micro-CT imaging indicating that these differences were due to within-tolerance variations in the thickness of an epoxy resin layer.

Conclusions: The dosimetric performance of a 60017 diode detector was comprehensively improved throughout 6 and 15 MV small photon fields via density compensation. For this approach to work well with good detector-to-detector reproducibility, tolerances on dense component dimensions should be reduced to limit associated variations of response in small fields, or these components should be modified to have more water-like densities.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1088/1361-6560/ab91d9DOI Listing
August 2020

Radiation-induced Chromosome Instability: The Role of Dose and Dose Rate.

Genome Integr 2019 25;10. Epub 2019 Oct 25.

Department of Biological and Medical Sciences, Faculty of Health and Life Sciences, Oxford Brookes University, Oxford, England, UK.

Nontargeted effects include radiation-induced genomic instability (RIGI) which is observed in the progeny of cells exposed to ionizing radiation and can be manifested in different ways, including chromosomal instability and micronucleus (MN) formation. Since genomic instability is commonly observed in tumors and has a role in tumor progression, RIGI has the potential of being an important mechanism for radiation-induced cancer. The work presented explores the role of dose and dose rate on RIGI, determined using a MN assay, in normal primary human fibroblast (HF19) cells exposed to either 0.1 Gy or 1 Gy of X-rays delivered either as an acute (0.42 Gy/min) or protracted (0.0031 Gy/min) exposure. While the expected increase in MN was observed following the first mitosis of the irradiated cells compared to unirradiated controls, the results also demonstrate a significant increase in MN yields in the progeny of these cells at 10 and 20 population doublings following irradiation. Minimal difference was observed between the two doses used (0.1 and 1 Gy) and the dose rates (acute and protracted). Therefore, these nontargeted effects have the potential to be important for the low-dose and dose-rate exposure. The results also show an enhancement of the cellular levels of reactive oxygen species after 20 population doublings, which suggests that ionising radiation (IR) could potentially perturb the homeostasis of oxidative stress and so modify the background rate of endogenous DNA damage induction. In conclusion, the investigations have demonstrated that normal primary human fibroblast (HF19) cells are susceptible to the induction of early DNA damage and RIGI, not only after a high dose and high dose rate exposure to low linear energy transfer, but also following low dose, low dose rate exposures. The results suggest that the mechanism of radiation induced RIGI in HF19 cells can be correlated with the induction of reactive oxygen species levels following exposure to 0.1 and 1 Gy low-dose rate and high-dose rate x-ray irradiation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4103/genint.genint_5_19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6862263PMC
October 2019

Physical characteristics at the turnover-points of relative biological effect (RBE) with linear energy transfer (LET).

Phys Med Biol 2019 11 21;64(22):225010. Epub 2019 Nov 21.

Gray Laboratory, Oxford Institute for Radiation Oncology and Biology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford, OX3 7DG, United Kingdom. Author to whom any correspondence should be addressed.

This paper considers the kinematic physical characteristics of ionic beams for maximum relative bio-effectiveness (RBE). RBE studies, based on heterogenous cell survival studies at different laboratories and linear energy transfer (LET) conditions for proton, helium, carbon, neon and argon ions, have been further analysed to determine the LET values where RBE is maximal and the LET-RBE relationship has a turnover point. The SRIM stopping power software and other classical equations are used to determine the particle velocities, kinetic energies and their effective ionic charges at LET. The estimated mean LET values increase with atomic number (Z). Each LET has a unique relativistic velocity, β  =  v/c, the velocity v expressed as a fraction of the speed of light, (c), and which is non-linearly proportional to Z. For ions helium and heavier ions, these velocities indicate that the effective charge Z is around 0.99 of the full Z value at each LET, with remarkably stable velocities of 3-4 nm · fs per nucleon, or around 6-8 nm · fs per unit Z. For Z  =  1, (protons and deuterium) some values fall outside these ranges but the result depends on the mix of proton and deuterium used in experiments. An alternative index of βA/Z (A is the atomic mass number), suggests an average velocity of around 15 nm · fs for each particle at LET. These distances, traversed in the time of the radiochemical process initiation, are all within the dimensions of the nucleosome. Curve fitting of the data set provides a predictive equation for LET for any ion, as LET  =  30.4  +  [Formula: see text] (1  -  Exp[-0.61  √  (Z  -  1)]) when normalised to protons. These data can be extended to heavier ions such as silicon and iron and give values that are consistent with experimental data. Each ion probably has a unique LET value. Kinematic studies show maximum bio-effectiveness occurs at particle velocities where electron stripping remains at around 99% and where the velocity per nucleon is around 3-4 nm · fs. This study enhances the limited prior knowledge about the physical conditions of particle beams that provide maximum bio-effectiveness, with applications in particle radiotherapy, radiation protection and space travel.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1088/1361-6560/ab52a5DOI Listing
November 2019

Key characteristics of 86 agents known to cause cancer in humans.

J Toxicol Environ Health B Crit Rev 2019 22;22(7-8):244-263. Epub 2019 Oct 22.

McLaughlin Centre for Population Health Risk Assessment, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.

Since the inception of the International Agency for Research on Cancer (IARC) in the early 1970s, the has evaluated more than 1000 agents with respect to carcinogenic hazard; of these, up to and including Volume 119 of the , 120 agents met the criteria for classification as (Group 1). Volume 100 of the provided a review and update of Group 1 carcinogens. These agents were divided into six broad categories: (I) pharmaceuticals; (II) biological agents; (III) arsenic, metals, fibers, and dusts; (IV) radiation; (V) personal habits and indoor combustions; and (VI) chemical agents and related occupations. Data on biological mechanisms of action (MOA) were extracted from the to assemble a database on the basis of ten key characteristics attributed to human carcinogens. After some grouping of similar agents, the characteristic profiles were examined for 86 Group 1 agents for which mechanistic information was available in the up to and including Volume 106, based upon data derived from human , human , animal , and animal studies. The most prevalent key characteristic was "is genotoxic", followed by "alters cell proliferation, cell death, or nutrient supply" and "induces oxidative stress". Most agents exhibited several of the ten key characteristics, with an average of four characteristics per agent, a finding consistent with the notion that cancer development in humans involves multiple pathways. Information on the key characteristics was often available from multiple sources, with many agents demonstrating concordance between human and animal sources, particularly with respect to genotoxicity. Although a detailed comparison of the characteristics of different types of agents was not attempted here, the overall characteristic profiles for pharmaceutical agents and for chemical agents and related occupations appeared similar. Further in-depth analyses of this rich database of characteristics of human carcinogens are expected to provide additional insights into the MOA of human cancer development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/10937404.2019.1643536DOI Listing
May 2020

Cullin Ring Ubiquitin Ligases (CRLs) in Cancer: Responses to Ionizing Radiation (IR) Treatment.

Front Physiol 2019 1;10:1144. Epub 2019 Oct 1.

Medical Research Council Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, United Kingdom.

Treatment with ionizing radiation (IR) remains the cornerstone of therapy for multiple cancer types, including disseminated and aggressive diseases in the palliative setting. Radiotherapy efficacy could be improved in combination with drugs that regulate the ubiquitin-proteasome system (UPS), many of which are currently being tested in clinical trials. The UPS operates through the covalent attachment of ATP-activated ubiquitin molecules onto substrates following the transfer of ubiquitin from an E1, to an E2, and then to the substrate an E3 enzyme. The specificity of ubiquitin ligation is dictated by E3 ligases, which select substrates to be ubiquitylated. Among the E3s, cullin ring ubiquitin ligases (CRLs) represent prototypical multi-subunit E3s, which use the cullin subunit as a central assembling scaffold. CRLs have crucial roles in controlling the cell cycle, hypoxia signaling, reactive oxygen species clearance and DNA repair; pivotal factors regulating the cancer and normal tissue response to IR. Here, we summarize the findings on the involvement of CRLs in the response of cancer cells to IR, and we discuss the therapeutic approaches to target the CRLs which could be exploited in the clinic.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphys.2019.01144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6781834PMC
October 2019

Radiosensitivity of colorectal cancer to Y and the radiobiological implications for radioembolisation therapy.

Phys Med Biol 2019 07 5;64(13):135018. Epub 2019 Jul 5.

CRUK/MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, United Kingdom. Joint first authors. Author to whom any correspondence should be addressed.

Approximately 50% of all colorectal cancer (CRC) patients will develop metastasis to the liver. Y selective internal radiation therapy (SIRT) is an established treatment for metastatic CRC. There is still a fundamental lack of understanding regarding the radiobiology underlying the dose response. This study was designed to determine the radiosensitivity of two CRC cell lines (DLD-1 and HT-29) to Y β radiation exposure, and thus the relative effectiveness of Y SIRT in relation to external beam radiotherapy (EBRT). A Y-source dish was sandwiched between culture dishes to irradiate DLD-1 or HT-29 cells for a period of 6 d. Cell survival was determined by clonogenic assay. Dose absorbed per Y disintegration was calculated using the PENELOPE Monte Carlo code. PENELOPE simulations were benchmarked against relative dose measurements using EBT3 GAFchromic film. Statistical regression based on the linear-quadratic model was used to determine the radiosensitivity parameters [Formula: see text] and [Formula: see text] using R. These results were compared to radiosensitivity parameters determined for 6 MV clinical x-rays and Cs γ-ray exposure. Equivalent dose of EBRT in 2 Gy ([Formula: see text]) and 10 Gy ([Formula: see text]) fractions were derived for Y dose. HT-29 cells were more radioresistant than DLD-1 for all treatment modalities. Radiosensitivity parameters determined for 6 MV x-rays and Cs γ-ray were equivalent for both cell lines. The [Formula: see text] ratio for Y β -particle exposure was over an order of magnitude higher than the other two modalities due to protraction of dose delivery. Consequently, an Y SIRT absorbed dose of 60 Gy equates to an [Formula: see text] of 28.7 and 54.5 Gy and an [Formula: see text] of 17.6 and 19.3 Gy for DLD-1 and HT-29 cell lines, respectively. We derived radiosensitivity parameters for two CRC cell lines exposed to Y β -particles, 6 MV x-rays, and Cs γ-ray irradiation. These radiobiological parameters are critical to understanding the dose response of CRC lesions and ultimately informs the efficacy of Y SIRT relative to other radiation therapy modalities.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1088/1361-6560/ab23c4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6611228PMC
July 2019

Combinatorial Use of Chitosan Nanoparticles, Reversine, and Ionising Radiation on Breast Cancer Cells Associated with Mitosis Deregulation.

Biomolecules 2019 05 12;9(5). Epub 2019 May 12.

Department of Biological and Medical Sciences, Faculty of Health and Life Sciences, Oxford Brookes University, Gipsy Lane, Headington, Oxford OX3 0BP, UK.

Breast cancer is the most commonly occurring cancer in women worldwide and the second most common cancer overall. The development of new therapies to treat this devastating malignancy is needed urgently. Nanoparticles are one class of nanomaterial with multiple applications in medicine, ranging from their use as drug delivery systems and the promotion of changes in cell morphology to the control of gene transcription. Nanoparticles made of the natural polymer chitosan are easy to produce, have a very low immunogenic profile, and diffuse easily into cells. One hallmark feature of cancer, including breast tumours, is the genome instability caused by defects in the spindle-assembly checkpoint (SAC), the molecular signalling mechanism that ensures the timely and high-fidelity transmission of the genetic material to an offspring. In recent years, the use of nanoparticles to treat cancer cells has gained momentum. This is in part because nanoparticles made of different materials can sensitise cancer cells to chemotherapy and radiotherapy. These advances prompted us to study the potential sensitising effect of chitosan-based nanoparticles on breast cancer cells treated with reversine, which is a small molecule inhibitor of Mps1 and Aurora B that induces premature exit from mitosis, aneuploidy, and cell death, before and after exposure of the cancer cells to X-ray irradiation. Our measurements of metabolic activity as an indicator of cell viability, DNA damage by alkaline comet assay, and immunofluorescence using anti-P-H3 as a mitotic biomarker indicate that chitosan nanoparticles elicit cellular responses that affect mitosis and cell viability and can sensitise breast cancer cells to X-ray radiation (2Gy). We also show that such a sensitisation effect is not caused by direct damage to the DNA by the nanoparticles. Taken together, our data indicates that chitosan nanoparticles have potential application for the treatment of breast cancer as adjunct to radiotherapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/biom9050186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6571805PMC
May 2019

Characterisation of Deubiquitylating Enzymes in the Cellular Response to High-LET Ionizing Radiation and Complex DNA Damage.

Int J Radiat Oncol Biol Phys 2019 07 7;104(3):656-665. Epub 2019 Mar 7.

Cancer Research Centre, Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, United Kingdom. Electronic address:

Purpose: Ionizing radiation, particular high-linear energy transfer (LET) radiation, can induce complex DNA damage (CDD) wherein 2 or more DNA lesions are induced in close proximity, which contributes significantly to the cell killing effects. However, knowledge of the enzymes and mechanisms involved in coordinating the recognition and processing of CDD in cellular DNA are currently lacking.

Methods And Materials: A small interfering RNA screen of deubiquitylation enzymes was conducted in HeLa cells irradiated with high-LET α-particles or protons, versus low-LET protons and x-rays, and cell survival was monitored by clonogenic assays. Candidates whose depletion led to decreased cell survival specifically in response to high-LET radiation were validated in both HeLa and oropharyngeal squamous cell carcinoma (UMSCC74A) cells, and the association with CDD repair was confirmed using an enzyme modified neutral comet assay.

Results: Depletion of USP6 decreased cell survival specifically after high-LET α-particles and protons, but not low-LET protons or x-rays. USP6 depletion caused cell cycle arrest and a deficiency in CDD repair mediated through instability of poly(ADP-ribose) polymerase-1 (PARP-1) protein. Increased radiosensitivity of cells to high-LET protons as a consequence of defective CDD repair was furthermore mimicked using the PARP inhibitor olaparib, and through PARP-1 small interfering RNA.

Conclusions: USP6 controls cell survival in response to high-LET radiation by stabilizing PARP-1 protein levels, which is essential for CDD repair. We also describe synergy between CDD induced by high-LET protons and PARP inhibition, or PARP-1 depletion, in effective cancer cell killing.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijrobp.2019.02.053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6542414PMC
July 2019

Effects of variations in overall treatment time on the clonogenic survival of V79-4 cells: Implications for radiosurgery.

J Radiosurg SBRT 2019 ;6(1):1-9

Green Temple College, University of Oxford, Oxford UK.

The importance of effects related to the repair of sublethal radiation damage as treatment duration varies, partly a function of dose-rate, is a current controversy in clinical radiosurgery. Cell survival studies have been performed to verify the importance of this effect in relation to established models. Mammalian V79-4 cells were irradiated in vitro with γ-rays, either as an acute exposure in a few minutes, where the effects of sublethal irradiation damage repair over the period of exposure can be ignored, or as protracted exposures delivered over 15-120 min. Protraction was achieved either by introducing a variable time gap between two doses of 7 Gy, or as a continuous exposure at lower dose rates so that a range of doses were delivered in fixed times of 30, 60 or 120 min. For all doses there was a progressive reduction in efficacy with increasing overall treatment time. This was illustrated by the progressive increase in clonogenic cell survival with a resulting right shift of the survival curves. Cell survival curves for irradiations given either as an acute exposure (6.1 Gy/min), over fixed times (30, 60 and 120 min) or for a fixed low dose-rate (0.2 Gy/min) were well fitted by the Linear Quadratic (LQ) model giving an α/β ratio of 4.0 Gy and a single repair half-time of 31.5 min. The present results are consistent with published data with respect to the response of solid tumors and normal tissues, whose response to both continuous and fractionated irradiation is also well described by the LQ model. This suggests the need for dose compensation in radiosurgical treatments, and other forms of radiotherapy, where dose is delivered over a similar range of protracted overall treatment times, perhaps as a prerequisite to full biological effective dose treatment planning.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6355450PMC
January 2019

TRACKING DOWN ALPHA-PARTICLES: THE DESIGN, CHARACTERISATION AND TESTING OF A SHALLOW-ANGLED ALPHA-PARTICLE IRRADIATOR.

Radiat Prot Dosimetry 2019 May;183(1-2):264-269

CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Gray Laboratories, ORCRB Roosevelt Drive, Oxford OX3 7DQ, UK.

Human exposure to α-particles from radon and other radionuclides is associated with carcinogenesis, but if well controlled and targeted to cancer cells, α-particles may be used in radiotherapy. Thus, it is important to understand the biological effects of α-particles to predict cancer risk and optimise radiotherapy. To enable studies of α-particles in cells, we developed and characterised an α-particle automated irradiation rig that allows exposures at a shallow angle (70° to the normal) of cell monolayers in a 30 mm diameter dish to complement standard perpendicular irradiations. The measured incident energy of the α-particles was 3.3 ± 0.5 MeV (LET in water = 120 keV μm-1), with a maximum incident dose rate of 1.28 ± 0.02 Gy min-1, which for a 5 μm cell monolayer corresponds to a mean dose rate of 1.57 ± 0.02 Gy min-1 and a mean LET in water of 154 keV μm-1. The feasibility of resolving radiation-induced DNA double-strand breaks (DSB) foci along the track of α-particles was demonstrated using immunofluorescent labelling with γH2AX and 53BP1 in normal MRC-5 human lung cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/rpd/ncy300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6525335PMC
May 2019

Two Web Resources Linking Major Human Embryology Collections Worldwide.

Authors:
Mark A Hill

Cells Tissues Organs 2018 23;205(5-6):293-302. Epub 2019 Jan 23.

Anatomy, School of Medical Sciences, UNSW Sydney, Sydney, New South Wales, Australia,

Human embryology is a core subject for medicine and current research. While animal models of development now have significant online resources available, the vast majority of human embryonic material is locked up in historic collections. When accessed today, these collections are still contributing to our understanding of human development. This paper describes two online resources for studying human development that are unlocking these invaluable collections and providing related human developmental resources. The first of these is the online Embryology website (http://tiny.cc/Embryo) that links the human developmental timeline to historic and current research findings. Secondly is the Digital Embryology Consortium (https://human-embryology.org), an international research partnership to digitise, preserve, and make the major embryology histological collections available for researchers. By making this histological material more widely available to researchers with new methods of analysis, a better understanding of human development can be reached. This also opens the opportunity for new 3D reconstruction and virtual reality representation of these embryos.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000495619DOI Listing
August 2019

Cytotoxicity, dose-enhancement and radiosensitization of glioblastoma cells with rare earth nanoparticles.

Artif Cells Nanomed Biotechnol 2019 Dec;47(1):132-143

a Nuffield department of Women's and Reproductive Health , Women's Centre, John Radcliffe Hospital, University of Oxford , Oxford , UK.

Glioblastoma is a heterogeneous disease with multiple genotypic origins. Despite treatment protocols such as surgery, radiotherapy and chemotherapy, the prognosis for patients remains poor. This study investigates the cytotoxic and radiation dose-enhancing and radiosensitizing ability of five rare earth oxide nanoparticles, in two different immortalized mammalian cell lines; U-87 MG and Mo59K. Significant cytotoxicity was observed in U-87 MG cells when exposed to NdO and LaO Autophagy was also detected in cells after incubation with NdO Radiosensitization was observed in U-87 MG when incubated with GdO, CeO-Gd and NdO:Si. Importantly, these elements did not cause any intrinsic toxicity in the absence of irradiation and so could be considered biocompatible. The GdO and CeO-Gd nanoparticles were also seen to generate ROS in U-87 MG cells after irradiation. Furthermore, the Mo59K and U-87 MG cells responded very differently to exposure to the rare earth nanoparticles. This may indicate the importance of the genotype of cells in the successful use of rare earth oxides for treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/21691401.2018.1544564DOI Listing
December 2019

Early metal use and crematory practices in the American Southeast.

Proc Natl Acad Sci U S A 2018 08 30;115(33):E7672-E7679. Epub 2018 Jul 30.

Division of Anthropology, American Museum of Natural History, New York, NY 10024

Long-distance exchange of copper objects during the Archaic Period (ca. 8000-3000 cal B.P.) is a bellwether of emergent social complexity in the Eastern Woodlands. Originating from the Great Lakes, the Canadian Maritimes, and the Appalachian Mountains, Archaic-age copper is found in significant amounts as far south as Tennessee and in isolated pockets at major trade centers in Louisiana but is absent from most of the southeastern United States. Here we report the discovery of a copper band found with the cremated remains of at least seven individuals buried in the direct center of a Late Archaic shell ring located in coastal Georgia. Late Archaic shell rings are massive circular middens thought to be constructed, in part, during large-scale ritual gatherings and feasting events. The exotic copper and cremated remains are unique in coastal South Carolina and Georgia where Archaic-age cremations are conspicuously absent and no other Archaic copper objects have been reported. Elemental data produced through laser ablation inductively coupled plasma mass spectrometry shows the copper originated from the Great Lakes, effectively extending Archaic copper exchange almost 1,000 km beyond its traditional boundaries. Similarities in mortuary practices and the presence of copper originating from the Great Lakes reveal the presence of long-distance exchange relations spanning vast portions of the eastern United States and suggest an unexpected level of societal complexity at shell ring localities. These findings are consistent with the hypothesis that elite actors solidified their positions through ritual gatherings and the long-distance exchange of exotic objects during the Archaic.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.1808819115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6099914PMC
August 2018

High-resolution μCT of a mouse embryo using a compact laser-driven X-ray betatron source.

Proc Natl Acad Sci U S A 2018 06 5;115(25):6335-6340. Epub 2018 Jun 5.

The John Adams Institute for Accelerator Science, Blackett Laboratory, Imperial College London, London SW7 2AZ, United Kingdom.

In the field of X-ray microcomputed tomography (μCT) there is a growing need to reduce acquisition times at high spatial resolution (approximate micrometers) to facilitate in vivo and high-throughput operations. The state of the art represented by synchrotron light sources is not practical for certain applications, and therefore the development of high-brightness laboratory-scale sources is crucial. We present here imaging of a fixed embryonic mouse sample using a compact laser-plasma-based X-ray light source and compare the results to images obtained using a commercial X-ray μCT scanner. The radiation is generated by the betatron motion of electrons inside a dilute and transient plasma, which circumvents the flux limitations imposed by the solid or liquid anodes used in conventional electron-impact X-ray tubes. This X-ray source is pulsed (duration <30 fs), bright (>10 photons per pulse), small (diameter <1 μm), and has a critical energy >15 keV. Stable X-ray performance enabled tomographic imaging of equivalent quality to that of the μCT scanner, an important confirmation of the suitability of the laser-driven source for applications. The X-ray flux achievable with this approach scales with the laser repetition rate without compromising the source size, which will allow the recording of high-resolution μCT scans in minutes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.1802314115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6016801PMC
June 2018

Complex DNA Damage Induced by High Linear Energy Transfer Alpha-Particles and Protons Triggers a Specific Cellular DNA Damage Response.

Int J Radiat Oncol Biol Phys 2018 03 14;100(3):776-784. Epub 2017 Nov 14.

Cancer Research Centre, Department of Molecular and Clinical Cancer Medicine, University of Liverpool, United Kingdom. Electronic address:

Purpose: To investigate the precise mechanism of recognition and processing of ionizing radiation (IR)-induced complex DNA damage (CDD), where two or more DNA lesions are in close proximity, in cellular DNA which is packaged with histones to form chromatin.

Methods And Materials: HeLa and oropharyngeal squamous cell carcinoma (UMSCC74A and UMSCC6) cells were irradiated with high linear energy transfer (LET) α-particles or protons, versus low-LET protons and X rays. At various time points after irradiation, site-specific histone post-translational modifications were analyzed by quantitative Western blotting; DNA damage and repair were measured by different versions of the comet assay; and cell survival was determined using clonogenic assays.

Results: Site-specific histone post-translational modifications after low- and high-LET radiation, particularly proton irradiation, were screened, aiming to identify those responsive to CDD. We demonstrate that histone H2B ubiquitylated on lysine 120 (H2B) is specifically induced several hours after irradiation in response to high-LET α-particles and protons but not by low-LET protons or X rays/γ-radiation. This is associated with increased levels of CDD, which contributes to decreased cell survival. We further discovered that modulation of H2B is under the control of two E3 ubiquitin ligases, MSL2 and RNF20/RNF40 complex, whose depletion leads to defective processing and further persistence of CDD, and to additional decreased cell survival after irradiation.

Conclusion: This study demonstrates that the signaling and repair of CDD, particularly induced by high-LET IR is co-ordinated through the specific induction of H2B catalyzed by MSL2 and RNF20/40, a mechanism that contributes significantly to cell survival after irradiation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijrobp.2017.11.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5796827PMC
March 2018

Cardiac MR imaging genotoxicity?

Authors:
Mark A Hill

Eur Heart J 2018 01;39(4):313-315

CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Gray Laboratories, ORCRB Roosevelt Drive, Oxford, UK.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/eurheartj/ehx719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5837318PMC
January 2018

ESTRO ACROP: Technology for precision small animal radiotherapy research: Optimal use and challenges.

Radiother Oncol 2018 Mar 18;126(3):471-478. Epub 2017 Dec 18.

Division of Medical Radiation Physics, Department of Radiation Oncology and Christian Doppler Laboratory for Medical Radiation Research for Radiation Oncology, Medical University of Vienna, Austria.

Many radiotherapy research centers have recently installed novel research platforms enabling the investigation of the radiation response of tumors and normal tissues in small animal models, possibly in combination with other treatment modalities. Many more research institutes are expected to follow in the coming years. These novel platforms are capable of mimicking human radiotherapy more closely than older technology. To facilitate the optimal use of these novel integrated precision irradiators and various small animal imaging devices, and to maximize the impact of the associated research, the ESTRO committee on coordinating guidelines ACROP (Advisory Committee in Radiation Oncology Practice) has commissioned a report to review the state of the art of the technology used in this new field of research, and to issue recommendations. This report discusses the combination of precision irradiation systems, small animal imaging (CT, MRI, PET, SPECT, bioluminescence) systems, image registration, treatment planning, and data processing. It also provides guidelines for reporting on studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.radonc.2017.11.016DOI Listing
March 2018

Track to the future: historical perspective on the importance of radiation track structure and DNA as a radiobiological target.

Authors:
Mark A Hill

Int J Radiat Biol 2018 08 8;94(8):759-768. Epub 2017 Dec 8.

a CRUK/MRC Oxford Institute for Radiation Oncology , University of Oxford, Gray Laboratories, ORCRB Roosevelt Drive , Oxford , UK.

Purpose: Understanding the mechanisms behind induced biological response following exposure to ionizing radiation is not only important in assessing the risk associated with human exposure, but potentially can help identify ways of improving the efficacy of radiotherapy. Over the decades, there has been much discussion on what is the key biological target for radiation action and its associated size. It was already known in the 1930s that microscopic features of radiation significantly influenced biological outcomes. This resulted in the development of classic target theory, leading to field of microdosimetry and subsequently nanodosimetry, studying the inhomogeneity and stochastics of interactions, along with the identification of DNA as a key target.

Conclusions: Ultimately, the biological response has been found to be dependent on the radiation track structure (spatial and temporal distribution of ionization and excitation events). Clustering of energy deposition on the nanometer scale has been shown to play a critical role in determining biological response, producing not just simple isolated DNA lesions but also complex clustered lesions that are more difficult to repair. The frequency and complexity of these clustered damage sites are typically found to increase with increasing LET. However in order to fully understand the consequences, it is important to look at the relative distribution of these lesions over larger dimensions along the radiation track, up to the micrometer scale. Correlation of energy deposition events and resulting sites of DNA damage can ultimately result in complex gene mutations and complex chromosome rearrangements following repair, with the frequency and spectrum of the resulting rearrangements critically dependent on the spatial and temporal distribution of these sites and therefore the radiation track. Due to limitations in the techniques used to identify these rearrangements it is likely that the full complexity of the genetic rearrangements that occur has yet to be revealed. This paper discusses these issues from a historical perspective, with many of these historical studies still having relevance today. These can not only cast light on current studies but guide future studies, especially with the increasing range of biological techniques available. So, let us build on past knowledge to effectively explore the future.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/09553002.2017.1387304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6113897PMC
August 2018

Epithelial-mesenchymal transition transcription factors control pluripotent adult stem cell migration in planarians.

Development 2017 10 11;144(19):3440-3453. Epub 2017 Sep 11.

Department of Zoology, Tinbergen Building, South Parks Road, University of Oxford, Oxford OX1 3PS, UK

Migration of stem cells underpins the physiology of metazoan animals. For tissues to be maintained, stem cells and their progeny must migrate and differentiate in the correct positions. This need is even more acute after tissue damage by wounding or pathogenic infection. Inappropriate migration also underpins metastasis. Despite this, few mechanistic studies address stem cell migration during repair or homeostasis in adult tissues. Here, we present a shielded X-ray irradiation assay that allows us to follow stem cell migration in planarians. We demonstrate the use of this system to study the molecular control of stem cell migration and show that , and EMT transcription factor homologs are necessary for cell migration to wound sites and for the establishment of migratory cell morphology. We also observed that stem cells undergo homeostatic migration to anterior regions that lack local stem cells, in the absence of injury, maintaining tissue homeostasis. This requires the polarity determinant Our work establishes planarians as a suitable model for further in-depth study of the processes controlling stem cell migration .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1242/dev.154971DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5665486PMC
October 2017

Cerebrospinal Fluid Apolipoprotein E Levels in Delirium.

Dement Geriatr Cogn Dis Extra 2017 May-Aug;7(2):240-248. Epub 2017 Jul 11.

School of Medical Sciences, University of New South Wales, Sydney, New South Wales, Australia.

Background/aims: Delirium and the apolipoprotein E ε4 allele are risk factors for late-onset Alzheimer disease (LOAD), but the connection is unclear. We looked for an association.

Methods: Inpatients with delirium ( = 18) were compared with LOAD outpatients ( = 19), assaying blood and cerebrospinal fluid (CSF) using multiplex ELISA.

Results: The patients with delirium had a higher Confusion Assessment Method (CAM) score (5.6 ± 1.2 vs. 0.0 ± 0.0; < 0.001) and Delirium Index (13.1 ± 4.0 vs. 2.9 ± 1.2; = 0.001) but a lower Mini-Mental State Examination (MMSE) score (14.3 ± 6.8 vs. 20.8 ± 4.6; = 0.003). There was a reduction in absolute CSF apolipoprotein E level during delirium (median [interquartile range]: 9.55 μg/mL [5.65-15.05] vs. 16.86 μg/mL [14.82-20.88]; = 0.016) but no differences in apolipoprotein A1, B, C3, H, and J. There were no differences in blood apolipoprotein levels, and no correlations between blood and CSF apolipoprotein levels. CSF apolipoprotein E correlated negatively with the CAM score ( = -0.354; = 0.034) and Delirium Index ( = -0.341; = 0.042) but not with the Acute Physiology and Chronic Health Evaluation (APACHE) index, or the MMSE or Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE).

Conclusion: Reduced CSF apolipoprotein E levels during delirium may be a mechanistic link between two important risk factors for LOAD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000477847DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5567000PMC
July 2017

Improved outcome of I-mIBG treatment through combination with external beam radiotherapy in the SK-N-SH mouse model of neuroblastoma.

Radiother Oncol 2017 09 5;124(3):488-495. Epub 2017 Jun 5.

CRUK/MRC Oxford Institute for Radiation Oncology, Department of Oncology, Oxford University, UK. Electronic address:

Purpose: To assess the efficacy of different schedules for combining external beam radiotherapy (EBRT) with molecular radiotherapy (MRT) using I-mIBG in the management of neuroblastoma.

Materials And Methods: BALB/c nu/nu mice bearing SK-N-SH neuroblastoma xenografts were assigned to five treatment groups: I-mIBG 24h after EBRT, EBRT 6days after I-mIBG, EBRT alone, I-mIBG alone and control (untreated). A total of 56 mice were assigned to 3 studies. Study 1: Vessel permeability was evaluated using dynamic contrast-enhanced (DCE)-MRI (n=3). Study 2: Tumour uptake of I-mIBG in excised lesions was evaluated by γ-counting and autoradiography (n=28). Study 3: Tumour volume was assessed by longitudinal MR imaging and survival was analysed (n=25). Tumour dosimetry was performed using Monte Carlo simulations of absorbed fractions with the radiation transport code PENELOPE.

Results: Given alone, both I-mIBG and EBRT resulted in a seven-day delay in tumour regrowth. Following EBRT, vessel permeability was evaluated by DCE-MRI and showed an increase at 24h post irradiation that correlated with an increase in I-mIBG tumour uptake, absorbed dose and overall survival in the case of combined treatment. Similarly, EBRT administered seven days after MRT to coincide with tumour regrowth, significantly decreased the tumour volume and increased overall survival.

Conclusions: This study demonstrates that combining EBRT and MRT has an enhanced therapeutic effect and emphasizes the importance of treatment scheduling according to pathophysiological criteria such as tumour vessel permeability and tumour growth kinetics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.radonc.2017.05.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5636618PMC
September 2017
-->