Publications by authors named "Christopher Bradley"

47 Publications

Intrinsic and extrinsic apoptosis responses in leukaemia cells following daunorubicin treatment.

BMC Cancer 2021 Apr 21;21(1):438. Epub 2021 Apr 21.

Department of Pharmacy and Biomedical Science, La Trobe Institute for Molecular Science (LIMS), La Trobe University, P.O. Box 199, Bendigo, VIC, 3552, Australia.

Background: Daunorubicin is used clinically in the treatment of myeloma, acute lymphatic and myelocytic leukaemia. The toxic lesions caused by daunorubicin induce various modes of cell death, including apoptosis. Apoptosis is highly regulated programmed cell death that can be initiated mainly via two pathways, through death receptors (extrinsic) or involvement of the mitochondria (intrinsic). Induction of apoptosis via these pathways has been alluded following treatment with daunorubicin, but never compared in acute lymphoblastic leukaemia over a time course.

Methods: This study investigated the mechanisms of daunorubicin induced apoptosis in the treatment of CCRF-CEM, MOLT-4 (acute T-lymphoblastic leukaemia) and SUP-B15 (acute B-lymphoblastic leukaemia) cells. Cells were treated with daunorubicin for 4 h, and then placed in recovery medium (without daunorubicin) for 4 h, 12 h and 24 h. Apoptotic response was analysing using annexin-V expression, caspase activity, mitochondrial membrane potential change and an array to detect 43 apoptotic proteins.

Results: Daunorubicin induced apoptosis in all leukemic cell lines, but with different levels and duration of response. Both apoptosis levels and caspase activity increased after four hours recovery then declined in CCRF-CEM and MOLT-4 cells. However, SUP-B15 cells displayed initially comparable levels but remained elevated over the 24 h assessment period. Changes in mitochondrial membrane potential occurred in both MOLT-4 and CCRF-CEM cells but not in SUP-B15 cells. Expression of apoptotic proteins, including Bcl-2, Bax, caspase 3 and FADD, indicated that daunorubicin potentially induced both extrinsic and intrinsic apoptosis in both CCRF-CEM and MOLT-4 cells, but only extrinsic apoptosis in SUP-B15 cells.

Conclusions: This study describes variations in sensitivities and timing of apoptotic responses in different leukaemia cell lines. These differences could be attributed to the lack of functional p53 in coordinating the cells response following cytotoxic treatment with daunorubicin, which appears to delay apoptosis and utilises alternative signalling mechanisms that need to be further explored.
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http://dx.doi.org/10.1186/s12885-021-08167-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8059319PMC
April 2021

Hydroxychloroquine/Azithromycin Therapy and QT Prolongation in Hospitalized Patients With COVID-19.

JACC Clin Electrophysiol 2021 01 5;7(1):16-25. Epub 2020 Aug 5.

Department of Cardiovascular Medicine, Oakland University William Beaumont School of Medicine and Beaumont Hospital, Royal Oak, Michigan, USA. Electronic address:

Objectives: This study aimed to characterize corrected QT (QTc) prolongation in a cohort of hospitalized patients with coronavirus disease-2019 (COVID-19) who were treated with hydroxychloroquine and azithromycin (HCQ/AZM).

Background: HCQ/AZM is being widely used to treat COVID-19 despite the known risk of QT interval prolongation and the unknown risk of arrhythmogenesis in this population.

Methods: A retrospective cohort of COVID-19 hospitalized patients treated with HCQ/AZM was reviewed. The QTc interval was calculated before drug administration and for the first 5 days following initiation. The primary endpoint was the magnitude of QTc prolongation, and factors associated with QTc prolongation. Secondary endpoints were incidences of sustained ventricular tachycardia or ventricular fibrillation and all-cause mortality.

Results: Among 415 patients who received concomitant HCQ/AZM, the mean QTc increased from 443 ± 25 ms to a maximum of 473 ± 40 ms (87 [21%] patients had a QTc ≥500 ms). Factors associated with QTc prolongation ≥500 ms were age (p < 0.001), body mass index <30 kg/m (p = 0.005), heart failure (p < 0.001), elevated creatinine (p = 0.005), and peak troponin (p < 0.001). The change in QTc was not associated with death over the short period of the study in a population in which mortality was already high (hazard ratio: 0.998; p = 0.607). No primary high-grade ventricular arrhythmias were observed.

Conclusions: An increase in QTc was seen in hospitalized patients with COVID-19 treated with HCQ/AZM. Several clinical factors were associated with greater QTc prolongation. Changes in QTc were not associated with increased risk of death.
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http://dx.doi.org/10.1016/j.jacep.2020.07.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7406234PMC
January 2021

Protocol driven periprocedural anticoagulation for left atrial ablation.

J Cardiovasc Electrophysiol 2021 Mar 2;32(3):639-646. Epub 2021 Feb 2.

Department of Cardiovascular Medicine, Oakland University William Beaumont School of Medicine, Royal Oak, Michigan, USA.

Introduction: A weight-based heparin dosing policy adjusted for preprocedural oral anticoagulation was implemented to reduce the likelihood of subtherapeutic dosing during left atrial catheter ablation procedures. We hypothesized that initiation of the protocol would result in a greater prevalence of therapeutic activated clotting time (ACT) values and decreased time to therapeutic ACT during left atrial ablation procedures.

Methods: A departmental protocol was initiated for which subjects received intravenous unfractionated heparin (UFH) to achieve and maintain a goal of ACT >300 s. Initial bolus dose was adjusted for pre-procedure oral anticoagulation and weight as follows: 50 units/kg for those receiving warfarin, 75 units/kg for those not anticoagulated, and 120 units/kg for those on direct oral anticoagulants (DOACs). A UFH infusion was initiated at 10% of the bolus per hour. One hundred consecutive left atrial ablation procedures treated with Protocol Guided heparin dosing were compared with a retrospective consecutive cohort of Usual Care heparin dosing.

Results: When the Usual Care and Protocol Guided cohorts were compared, significant findings were limited to those on pre-procedure DOAC. The initial UFH bolus increased from 99.3 ± 24.8 to 118.2 ± 22.8 units/kg (p < .001), the proportion of therapeutic ACT on the first draw after heparin administration increased from 57.7% to 76.6% (p = .010), and the time to therapeutic ACT after UFH administration decreased from 37.8 ± 19.8 to 30.2 ± 16.4 min (p = .032).

Conclusion: A weight-based protocol for periprocedural UFH administration resulted in a higher proportion of therapeutic ACT values and decreased the time to therapeutic ACT for those on pre-procedure DOAC.
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http://dx.doi.org/10.1111/jce.14892DOI Listing
March 2021

Effects on childhood infections of promoting safe and hygienic complementary-food handling practices through a community-based programme: A cluster randomised controlled trial in a rural area of The Gambia.

PLoS Med 2021 01 11;18(1):e1003260. Epub 2021 Jan 11.

London School of Hygiene & Tropical Medicine, London, United Kingdom.

Background: The Gambia has high rates of under-5 mortality from diarrhoea and pneumonia, peaking during complementary-feeding age. Community-based interventions may reduce complementary-food contamination and disease rates.

Methods And Findings: A public health intervention using critical control points and motivational drivers, delivered February-April 2015 in The Gambia, was evaluated in a cluster randomised controlled trial at 6- and 32-month follow-up in September-October 2015 and October-December 2017, respectively. After consent for trial participation and baseline data were collected, 30 villages (clusters) were randomly assigned to intervention or control, stratified by population size and geography. The intervention included a community-wide campaign on days 1, 2, 17, and 25, a reminder visit at 5 months, plus informal community-volunteer home visits. It promoted 5 key complementary-food and 1 key drinking-water safety and hygiene behaviours through performing arts, public meetings, and certifications delivered by a team from local health and village structures to all villagers who attended the activities, to which mothers of 6- to 24-month-old children were specifically invited. Control villages received a 1-day campaign on domestic-garden water use. The background characteristics of mother and clusters (villages) were balanced between the trial arms. Outcomes were measured at 6 and 32 months in a random sample of 21-26 mothers per cluster. There were no intervention or research team visits to villages between 6 and 32 months. The primary outcome was a composite outcome of the number of times key complementary-food behaviours were observed as a proportion of the number of opportunities to perform the behaviours during the observation period at 6 months. Secondary outcomes included the rate of each recommended behaviour; microbiological growth from complementary food and drinking water (6 months only); and reported acute respiratory infections, diarrhoea, and diarrhoea hospitalisation. Analysis was by intention-to-treat analysis adjusted by clustering. (Registration: PACTR201410000859336). We found that 394/571 (69%) of mothers with complementary-feeding children in the intervention villages were actively involved in the campaign. No villages withdrew, and there were no changes in the implementation of the intervention. The intervention improved behaviour adoption significantly. For the primary outcome, the rate was 662/4,351(incidence rate [IR] = 0.15) in control villages versus 2,861/4,378 (IR = 0.65) in intervention villages (adjusted incidence rate ratio [aIRR] = 4.44, 95% CI 3.62-5.44, p < 0.001), and at 32 months the aIRR was 1.17 (95% CI 1.07-1.29, p = 0.001). Secondary health outcomes also improved with the intervention: (1) mother-reported diarrhoea at 6 months, with adjusted relative risk (aRR) = 0.39 (95% CI 0.32-0.48, p < 0.001), and at 32 months, with aRR = 0.68 (95% CI 0.48-0.96, p = 0.027); (2) mother-reported diarrhoea hospitalisation at 6 months, with aRR = 0.35 (95% CI 0.19-0.66, p = 0.001), and at 32 months, with aRR = 0.38 (95% CI 0.18-0.80, p = 0.011); and (3) mother-reported acute respiratory tract infections at 6 months, with aRR = 0.67 (95% CI 0.53-0.86, p = 0.001), though at 32 months improvement was not significant (p = 0.200). No adverse events were reported. The main limitations were that only medium to small rural villages were involved. Obtaining laboratory cultures from food at 32 months was not possible, and no stool microorganisms were investigated.

Conclusions: We found that low-cost and culturally embedded behaviour change interventions were acceptable to communities and led to short- and long-term improvements in complementary-food safety and hygiene practices, and reported diarrhoea and acute respiratory tract infections.

Trial Registration: The trial was registered on the 17th October 2014 with the Pan African Clinical Trial Registry in South Africa with number (PACTR201410000859336) and 32-month follow-up as an amendment to the trial.
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http://dx.doi.org/10.1371/journal.pmed.1003260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7799804PMC
January 2021

The MRI colonic function test: Reproducibility of the Macrogol stimulus challenge.

Neurogastroenterol Motil 2020 11 16;32(11):e13942. Epub 2020 Jul 16.

National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK.

Background: Magnetic resonance imaging (MRI) of the colonic response to a macrogol challenge drink can be used to assess the mechanisms underlying severe constipation. We measured the intrasubject reproducibility of MRI measures of colonic function to aid their implementation as a possible clinical test.

Methods: Healthy participants attended for MRI on two occasions (identical protocols, minimum 1 week apart). They underwent a fasted scan and then consumed the macrogol drink. Subjects were scanned at 60 and 120 minutes, with maximum value reached used for comparison. The colonic volume, water content, mixing of colonic content and the movement of the colon walls were measured. Coefficients of variation and intraclass correlation coefficients (ICC) were calculated.

Results: Twelve participants completed the study: nine female, mean age 26 years (SD 5) and body mass index 24.8 kg/m (SD 3.2). All measures consistently increased above baseline following provocation with macrogol. The volume, water content and content mixing had good intrasubject reproducibility (ICC volume = 0.84, water content = 0.93, mixing = 0.79, P < .001). With the wall movement, the response to the challenge was generally large, but more variable between visits resulting in a lower ICC overall (ascending colon = 0.65, descending colon = 0.76, P < .001).

Conclusions: The colonic response to the macrogol stimulus as assessed by MRI is heterogeneous but large compared to baseline, with moderate to good reproducibility, making the test suitable to study potential pathologies underlying GI disorders such as constipation. More data are needed to better define the normal range for comparison with patient groups who may have both hypo- and hypermotile responses.
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http://dx.doi.org/10.1111/nmo.13942DOI Listing
November 2020

Woven Natural Fibre Reinforced Composite Materials for Medical Imaging.

Materials (Basel) 2020 Apr 4;13(7). Epub 2020 Apr 4.

School of Science and Technology, Nottingham Trent University, Nottingham NG11 8NS, UK.

Repeatable patient positioning is key to minimising the burden on planning radiotherapy treatment. There are very few materials commercially available which are suitable for use in all common imaging and treatment modalities such as magnetic resonance imaging (MRI), X-Ray computed tomography (CT) and radiotherapy. In this article, we present several such materials based on woven natural fibres embedded in a range of different resin materials which are suitable for such applications. By investigating a range of resins and natural fibre materials in combination and evaluating their performance in terms of MRI and X-Ray imaging, we show that a woven cotton material impregnated with a two-part epoxy resin provides a 15% improvement in passage of X-Rays and has no impact on the MRI signal (unlike the 40% MRI signal attenuation from carbon fibre), whilst also retaining a flexural modulus up to 71% of that of carbon fibre. These results demonstrate that natural fibre composites produced using such materials provide desirable properties for use in patient support and positioning devices for multi-modal imaging, without the need to significantly compromise on the strength of the material.
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http://dx.doi.org/10.3390/ma13071684DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7178646PMC
April 2020

Pulsed field ablation for pulmonary vein isolation in the treatment of atrial fibrillation.

J Cardiovasc Electrophysiol 2020 08 16;31(8):2136-2147. Epub 2020 May 16.

Department of Cardiovascular Medicine, Beaumont Hospital, Oakland University William Beaumont School of Medicine, Royal Oak, Michigan.

Pulsed-field ablation (PFA) is a promising new ablation modality for the treatment of atrial fibrillation. This energy form employs a train of microsecond duration high amplitude electrical pulses that ablate myocardium by electroporation of the sarcolemmal membrane without measurable tissue heating. The ablation pulse waveform has multiple variable components that can affect ablation efficacy, thus each proprietary system has unique properties that cannot be generalized to other systems. Success with PFA depends upon the proximity of the electrode to the target tissue, but not necessarily upon contact. A unique feature of PFA is tissue specificity. Myocardium is very susceptible to irreversible injury whereas the esophagus, phrenic nerves, pulmonary veins, and coronary arteries are relatively resistant to injury. The tissue specificity of PFA may result in a wide therapeutic range and improved safety profile during atrial fibrillation ablation. Vein isolation can be achieved very rapidly (seconds) promising that PFA may reduce procedure time to 1 hour or less. This attractive new technology promises to be a major advance in the field of atrial fibrillation ablation.
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http://dx.doi.org/10.1111/jce.14414DOI Listing
August 2020

Religious Attendance and the Social Support Trajectories of Older Mexican Americans.

J Cross Cult Gerontol 2019 Dec;34(4):403-416

Department of Sociology, Florida State University, Tallahassee, FL, 32306, USA.

In this paper, we directly assessed the extent to which the association between religious attendance and the social support trajectories of older Mexican Americans is due to selection (spurious) processes related to personality, health status, and health behavior. We employed seven waves of data from the Hispanic Established Populations for the Epidemiologic Study of the Elderly (1993-2010) to examine the association between religious attendance and perceived social support trajectories (n = 2479). We used growth mixture modeling to estimate latent classes of social support trajectories and multivariate multinomial logistic regression models to predict membership in the social support trajectory classes. Growth mixture estimates revealed three classes of social support trajectories: high, moderate, and low. Multinomial logistic regression estimates showed that the odds of membership in the low support trajectory class (versus the high social support trajectory class) were lower for respondents who attended religious services yearly, monthly, weekly, and more than weekly than for respondents who never attend religious services. Religious attendance could not distinguish between membership in the moderate and high support trajectory classes. These results persisted with adjustments for age, gender, immigrant status, language proficiency, education, income, religious affiliation, marital status, living arrangements, contact with family/friends, secular group memberships, self-esteem, smoking, heavy drinking, depression, cognitive functioning, and physical mobility. We conclude that the association between religious attendance and the social support trajectories of older Mexican Americans is primarily driven by processes related to social integration, not selection.
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http://dx.doi.org/10.1007/s10823-019-09386-4DOI Listing
December 2019

A randomized, controlled, double-blind crossover study on the effects of isoeffective and isovolumetric intravenous crystalloid and gelatin on blood volume, and renal and cardiac hemodynamics.

Clin Nutr 2020 07 16;39(7):2070-2079. Epub 2019 Oct 16.

Gastrointestinal Surgery, Nottingham Digestive Diseases Centre and National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, Queen's Medical Centre, Nottingham, NG7 2UH, UK; MRC Versus Arthritis Centre for Musculoskeletal Ageing Research, University of Nottingham, Queen's Medical Centre, Nottingham, NG7 2UH, UK. Electronic address:

Background & Aims: Blood volume expanding properties of colloids are superior to crystalloids. In addition to oncotic/osmotic properties, the electrolyte composition of infusions may have important effects on visceral perfusion, with infusions containing supraphysiological chloride causing hyperchloremic acidosis and decreased renal blood flow. In this non-inferiority study, a validated healthy human subject model was used to compare effects of colloid (4% succinylated gelatin) and crystalloid fluid regimens on blood volume, renal function, and cardiac output.

Methods: Healthy male participants were given infusions over 60 min > 7 days apart in a randomized, crossover manner. Reference arm (A): 1.5 L of Sterofundin ISO, isoeffective arm (B): 0.5 L of 4% Gelaspan®, isovolumetric arm (C): 0.5 L of 4% Gelaspan® and 1 L of Sterofundin ISO (all B. Braun, Melsungen, Germany). Participants were studied over 240 min. Changes in blood volume were calculated from changes in weight and hematocrit. Renal volume, renal artery blood flow (RABF), renal cortex perfusion and diffusion, and cardiac index were measured with magnetic resonance imaging.

Results: Ten of 12 males [mean (SE) age 23.9 (0.8) years] recruited, completed the study. Increase in body weight and extracellular fluid volume were significantly less after infusion B than infusions A and C, but changes in blood volume did not significantly differ between infusions. All infusions increased renal volume, with no significant differences between infusions. There was no significant difference in RABF across the infusion time course or between infusion types. Renal cortex perfusion decreased during the infusion (mean 18% decrease from baseline), with no significant difference between infusions. There was a trend for increased renal cortex diffusion (4.2% increase from baseline) for the crystalloid infusion. All infusions led to significant increases in cardiac index.

Conclusions: A smaller volume of colloid (4% succinylated gelatin) was as effective as a larger volume of crystalloid at expanding blood volume, increasing cardiac output and changing renal function. Significantly less interstitial space expansion occurred with the colloid.

Trial Registration: The protocol was registered with the European Union Drug Regulating Authorities Clinical Trials Database (https://eudract.ema.europa.eu) (EudraCT No. 2013-003260-32).
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http://dx.doi.org/10.1016/j.clnu.2019.09.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7359406PMC
July 2020

Determination of the DNA repair pathways utilised by acute lymphoblastic leukaemia cells following daunorubicin treatment.

BMC Res Notes 2019 Sep 24;12(1):625. Epub 2019 Sep 24.

Department of Pharmacy and Biomedical Sciences, La Trobe Institute for Molecular Sciences (LIMS), La Trobe University, P.O. Box 199, Bendigo, VIC, 3552, Australia.

Objective: DNA double strand breaks (DNA-DSBs) are among the most lethal DNA lesions leading to genomic instability and repaired by either homologous recombination (HR) or the non-homologous end joining (NHEJ) mechanisms. The purpose of this study was to assess the importance and the level of activation of non-homologous end joining (NHEJ) and homologous recombination (HR) DNA repair pathways in three cell lines, CCRF-CEM and MOLT-4 derived from T lymphocytes and SUP-B15 derived from B lymphocytes following treatment with chemotherapy agent daunorubicin.

Results: The Gamma histone H2AX (γH2AX) assay was used assess the effects of DNA-PK inhibitor NU7026 and RAD51 inhibitor RI-2 on repair of DNA-DSB following treatment with daunorubicin. In all cell lines, the NHEJ DNA repair pathway appeared more rapid and efficient. MOLT-4 and CCFR-CEM cells utilised both NHEJ and HR pathways for DNA-DSB repair. Whereas, SUP-B15 cells utilised only NHEJ for DSB repair, suggestive of a deficiency in HR repair pathways.
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http://dx.doi.org/10.1186/s13104-019-4663-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6760046PMC
September 2019

Workplace injury rates and firm-level turnover in Montana's oil and gas industry.

Am J Ind Med 2019 06 2;62(6):535-541. Epub 2019 May 2.

Workforce Services Division, Montana Department of Labor & Industry, Helena, MT.

Background: Do workers follow their self-interest by minimizing injury risk in their employment decision? If so, employers could use injury reduction as a recruitment and retention strategy. This study explores whether injury incidence is associated with turnover in Montana's Oil and Gas industry.

Methods: A panel data set of Unemployment Insurance and Workers' Compensation administrative records from 2010 to 2015 was used to model the relationship between turnover and injury claim rates at the firm level.

Results: Total turnover and injury rates were found to be positively related while injury rates and separation rates had no such association. Quarters in which the employer experienced a severe injury had a 3.3 percentage point increase in separation rates.

Discussion: The findings suggest that injured workers contribute to increased turnover, but coworker turnover does not increase with increased injury rates in the firm. Secondary findings suggest a relationship between recent hires and increased injury rates, although further investigation is required.
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http://dx.doi.org/10.1002/ajim.22983DOI Listing
June 2019

Time dependent response of daunorubicin on cytotoxicity, cell cycle and DNA repair in acute lymphoblastic leukaemia.

BMC Cancer 2019 Feb 27;19(1):179. Epub 2019 Feb 27.

Department of Pharmacy and Applied Sciences, La Trobe Institute for Molecular Science (LIMS), La Trobe University, P.O. Box 199, Bendigo, Victoria, Australia.

Background: Daunorubicin is commonly used in the treatment of acute lymphoblastic leukaemia (ALL). The aim of this study was to explore the kinetics of double strand break (DSB) formation of three ALL cell lines following exposure to daunorubicin and to investigate the effects of daunorubicin on the cell cycle and the protein kinases involved in specific checkpoints following DNA damage and recovery periods.

Methods: Three ALL cell lines CCRF-CEM and MOLT-4 derived from T lymphocytes and SUP-B15 derived from B lymphocytes were examined following 4 h treatment with daunorubicin chemotherapy and 4, 12 and 24 h recovery periods. Cell viability was measured via MTT (3-(4,5-dimethylthiazol-2-yl)-2-5 diphenyltetrazolium bromide) assay, reactive oxygen species (ROS) production by flow cytometry, double stranded DNA breaks by detecting γH2AX levels while stages of the cell cycle were detected following propidium iodide staining and flow cytometry. Western blotting was used to detect specific proteins while RNA was extracted from all cell lines and converted to cDNA to sequence Ataxia-telangiectasia mutated (ATM).

Results: Daunorubicin induced different degrees of toxicity in all cell lines and consistently generated reactive oxygen species. Daunorubicin was more potent at inducing DSB in MOLT-4 and CCRF-CEM cell lines while SUP-B15 cells showed delays in DSB repair and significantly more resistance to daunorubicin compared to the other cell lines as measured by γH2AX assay. Daunorubicin also causes cell cycle arrest in all three cell lines at different checkpoints at different times. These effects were not due to mutations in ATM as sequencing revealed none in any of the three cell lines. However, p53 was phosphorylated at serine 15 only in CCRF-CEM and MOLT-4 but not in SUP-B15 cells. The lack of active p53 may be correlated to the increase of SOD2 in SUP-B15 cells.

Conclusions: The delay in DSB repair and lower sensitivity to daunorubicin seen in the B lymphocyte derived SUP-B15 cells could be due to loss of function of p53 that may be correlated to increased expression of SOD2 and lower ROS production.
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http://dx.doi.org/10.1186/s12885-019-5377-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6391779PMC
February 2019

Inhibition of AKT signalling by benzoxazine derivative LTUR6 through the modulation of downstream kinases.

Invest New Drugs 2019 08 10;37(4):779-783. Epub 2019 Jan 10.

Faculty of Science Technology and Engineering, School of Pharmacy and Applied Science, Latrobe Institute of Molecular Sciences, La Trobe University, Bendigo, Australia.

Many compounds structurally similar to chromones have been developed to enhance the sensitizing effect of cancer cells to chemotherapeutic agents. Most of these compounds have been shown to promote this sensitization by targeting the repair pathways. One such compound is LTUR6, which enhances the sensitization of doxorubicin to colon cancer cells HT29, by inhibiting the phosphorylation of the double stranded break (DSB) repair enzyme AKT. The downstream regulatory targets of AKT that enhance doxorubicin mediated cytotoxicity in the presence of LTUR6 remains elusive. In this study, we performed comparative analyses of 43 kinase phosphorylation sites using the human phospho-kinase array proteome profiler. Results revealed altered expression levels of multiple proteins that regulated apoptotic signalling pathways. Increased activation of mTOR, RSK1/2/3, p38α and PRAS40 after combination treatment with LTUR6 and doxorubicin over doxorubicin alone was observed. This study provides a deeper insight into the key proteins involved and presents a novel molecular pathway.
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http://dx.doi.org/10.1007/s10637-019-00726-2DOI Listing
August 2019

Low Vision Enhancement with Head-mounted Video Display Systems: Are We There Yet?

Optom Vis Sci 2018 09;95(9):694-703

Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Significance: Head-mounted video display systems and image processing as a means of enhancing low vision are ideas that have been around for more than 20 years. Recent developments in virtual and augmented reality technology and software have opened up new research opportunities that will lead to benefits for low vision patients. Since the Visionics low vision enhancement system (LVES), the first head-mounted video display LVES, was engineered 20 years ago, various other devices have come and gone with a recent resurgence of the technology over the past few years. In this article, we discuss the history of the development of LVESs, describe the current state of available technology by outlining existing systems, and explore future innovation and research in this area. Although LVESs have now been around for more than two decades, there is still much that remains to be explored. With the growing popularity and availability of virtual reality and augmented reality technologies, we can now integrate these methods within low vision rehabilitation to conduct more research on customized contrast-enhancement strategies, image motion compensation, image-remapping strategies, and binocular disparity, all while incorporating eye-tracking capabilities. Future research should use this available technology and knowledge to learn more about the visual system in the low vision patient and extract this new information to create prescribable vision enhancement solutions for the visually impaired individual.
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http://dx.doi.org/10.1097/OPX.0000000000001278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6119088PMC
September 2018

Multi-organ assessment of compensated cirrhosis patients using quantitative magnetic resonance imaging.

J Hepatol 2018 Nov 8;69(5):1015-1024. Epub 2018 Jun 8.

NIHR Biomedical Research Centre, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK; Nottingham Digestive Diseases Centre, School of Medicine, University of Nottingham, Nottingham, UK. Electronic address:

Background & Aims: Advancing liver disease results in deleterious changes in a number of critical organs. The ability to measure structure, blood flow and tissue perfusion within multiple organs in a single scan has implications for determining the balance of benefit vs. harm for therapies. Our aim was to establish the feasibility of magnetic resonance imaging (MRI) to assess changes in Compensated Cirrhosis (CC), and relate this to disease severity and future liver-related outcomes (LROs).

Methods: A total of 60 patients with CC, 40 healthy volunteers and 7 patients with decompensated cirrhosis were recruited. In a single scan session, MRI measures comprised phase-contrast MRI vessel blood flow, arterial spin labelling tissue perfusion, T longitudinal relaxation time, heart rate, cardiac index, and volume assessment of the liver, spleen and kidneys. We explored the association between MRI parameters and disease severity, analysing differences in baseline MRI parameters in the 11 (18%) patients with CC who experienced future LROs.

Results: In the liver, compositional changes were reflected by increased T in progressive disease (p <0.001) and an increase in liver volume in CC (p = 0.006), with associated progressive reduction in liver (p <0.001) and splenic (p <0.001) perfusion. A significant reduction in renal cortex T and increase in cardiac index and superior mesenteric arterial blood flow was seen with increasing disease severity. Baseline liver T (p = 0.01), liver perfusion (p <0.01), and renal cortex T (p <0.01) were significantly different in patients with CC who subsequently developed negative LROs.

Conclusions: MRI enables the contemporaneous assessment of organs in liver cirrhosis in a single scan without the requirement for a contrast agent. MRI parameters of liver T renal T hepatic and splenic perfusion, and superior mesenteric arterial blood flow were related to the risk of LROs.

Lay Summary: This study assesses the changes to structure, blood flow and perfusion that occur in the key organs (liver, spleen and kidney) associated with severe liver disease (Compensated Cirrhosis), using magnetic resonance imaging. The magnetic resonance imaging measures which changed with disease severity and were related to negative liver-related clinical outcomes are described.
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http://dx.doi.org/10.1016/j.jhep.2018.05.037DOI Listing
November 2018

Multiparametric Renal Magnetic Resonance Imaging: Validation, Interventions, and Alterations in Chronic Kidney Disease.

Front Physiol 2017 14;8:696. Epub 2017 Sep 14.

Sir Peter Mansfield Imaging Centre, University of NottinghamNottingham, United Kingdom.

This paper outlines a multiparametric renal MRI acquisition and analysis protocol to allow non-invasive assessment of hemodynamics (renal artery blood flow and perfusion), oxygenation (BOLD T), and microstructure (diffusion, T mapping). We use our multiparametric renal MRI protocol to provide (1) a comprehensive set of MRI parameters [renal artery and vein blood flow, perfusion, T, T, diffusion (ADC, D, D, f), and total kidney volume] in a large cohort of healthy participants (127 participants with mean age of 41 ± 19 years) and show the MR field strength (1.5 T vs. 3 T) dependence of T and T relaxation times; (2) the repeatability of multiparametric MRI measures in 11 healthy participants; (3) changes in MRI measures in response to hypercapnic and hyperoxic modulations in six healthy participants; and (4) pilot data showing the application of the multiparametric protocol in 11 patients with Chronic Kidney Disease (CKD). Baseline measures were in-line with literature values, and as expected, T-values were longer at 3 T compared with 1.5 T, with increased T corticomedullary differentiation at 3 T. Conversely, T was longer at 1.5 T. Inter-scan coefficients of variation (CoVs) of T mapping and ADC were very good at <2.9%. Intra class correlations (ICCs) were high for cortex perfusion (0.801), cortex and medulla T (0.848 and 0.997 using SE-EPI), and renal artery flow (0.844). In response to hypercapnia, a decrease in cortex T was observed, whilst no significant effect of hyperoxia on T was found. In CKD patients, renal artery and vein blood flow, and renal perfusion was lower than for healthy participants. Renal cortex and medulla T was significantly higher in CKD patients compared to healthy participants, with corticomedullary T differentiation reduced in CKD patients compared to healthy participants. No significant difference was found in renal T. Multiparametric MRI is a powerful technique for the assessment of changes in structure, hemodynamics, and oxygenation in a single scan session. This protocol provides the potential to assess the pathophysiological mechanisms in various etiologies of renal disease, and to assess the efficacy of drug treatments.
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http://dx.doi.org/10.3389/fphys.2017.00696DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5603702PMC
September 2017

Role of a novel benzoxazine derivative in the chemosensitization of colon cancer.

Apoptosis 2017 08;22(8):988-1000

School of Pharmacy and Applied Science, Latrobe Institute of Molecular Sciences, La Trobe University, P.O. Box 199, Bendigo, VIC, 3552, Australia.

The concept to fight against tumour resistance is to use chemosensitizers that selectively sensitize tumour cells to chemotherapeutic drugs without affecting normal tissue. In this study, the chemosensitizing potential of a novel benzoxazine derivative in combination with Doxorubicin, a DNA damaging chemotherapeutic drug was evaluated. The results of this study showed that the compound LTUR6 is a potent chemosensitizer of Doxorubicin in colon cancer cell lines, HCT116 and HT29. It was also observed that LTUR6 delayed the resolution of Doxorubicin-induced γH2AX, a specific marker of unrepaired DNA DSB, and prolonged cell cycle arrest in both cell lines. This eventually led to DNA fragmentation, caspase activation and ultimately apoptosis in LTUR6 treated cell lines. Results of western blot analysis revealed that LTUR6 significantly inhibited the phosphorylation of DSB repair enzyme AKT, in response to Doxorubicin-induced DSB. We propose that the chemosensitization observed following inhibition of PI3K is likely due to the involvement of a number of downstream targets of AKT.
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http://dx.doi.org/10.1007/s10495-017-1380-4DOI Listing
August 2017

Accessing Valuable Ligand Supports for Transition Metals: A Modified, Intermediate Scale Preparation of 1,2,3,4,5-Pentamethylcyclopentadiene.

J Vis Exp 2017 03 20(121). Epub 2017 Mar 20.

Department of Science, Mount St. Mary's University;

A reliable, intermediate scale preparation of 1,2,3,4,5-pentamethylcyclopentadiene (Cp*H) is presented, based on modifications of existing protocols that derive from initial 2-bromo-2-butene lithiation followed by acid mediated dienol cyclization. The revised synthesis and purification of the ligand avoids the use of mechanical stirring while still permitting access to significant quantities (39 g) of Cp*H in good yield (58%). The procedure offers other additional benefits, including a more controlled quench of excess lithium during the production of the intermediate heptadienols and a simplified isolation of Cp*H of sufficient purity for metallation with transition metals. The ligand was subsequently used to synthesize [Cp*MCl2]2 complexes of both iridium and ruthenium to demonstrate the utility of the Cp*H prepared and purified by our method. The procedure outlined herein affords substantial quantities of a ubiquitous ancillary ligand support used in organometallic chemistry while minimizing the need for specialized laboratory equipment, thus providing a simpler and more accessible entry point into the chemistry of 1,2,3,4,5-pentamethylcyclopentadiene.
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http://dx.doi.org/10.3791/55366DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5409290PMC
March 2017

Roadmap for cardiovascular circulation model.

J Physiol 2016 12 29;594(23):6909-6928. Epub 2016 Sep 29.

Auckland Bioengineering Institute, University of Auckland, Auckland, New Zealand.

Computational models of many aspects of the mammalian cardiovascular circulation have been developed. Indeed, along with orthopaedics, this area of physiology is one that has attracted much interest from engineers, presumably because the equations governing blood flow in the vascular system are well understood and can be solved with well-established numerical techniques. Unfortunately, there have been only a few attempts to create a comprehensive public domain resource for cardiovascular researchers. In this paper we propose a roadmap for developing an open source cardiovascular circulation model. The model should be registered to the musculo-skeletal system. The computational infrastructure for the cardiovascular model should provide for near real-time computation of blood flow and pressure in all parts of the body. The model should deal with vascular beds in all tissues, and the computational infrastructure for the model should provide links into CellML models of cell function and tissue function. In this work we review the literature associated with 1D blood flow modelling in the cardiovascular system, discuss model encoding standards, software and a model repository. We then describe the coordinate systems used to define the vascular geometry, derive the equations and discuss the implementation of these coupled equations in the open source computational software OpenCMISS. Finally, some preliminary results are presented and plans outlined for the next steps in the development of the model, the computational software and the graphical user interface for accessing the model.
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http://dx.doi.org/10.1113/JP272660DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5134416PMC
December 2016

Non-invasive assessment of portal hypertension using quantitative magnetic resonance imaging.

J Hepatol 2016 12 27;65(6):1131-1139. Epub 2016 Jul 27.

National Institute for Health Research (NIHR) Nottingham Digestive Diseases Biomedical Research Unit, Nottingham University Hospitals NHS Trust and University of Nottingham, United Kingdom. Electronic address:

Background & Aims: Hepatic venous pressure gradient (HVPG) measurement is currently the only validated technique to accurately evaluate changes in portal pressure. In this study, we evaluate the use of non-contrast quantitative magnetic resonance imaging (MRI) as a surrogate measure of portal pressure.

Methods: Thirty patients undergoing HVPG measurement were prospectively recruited. MR parameters of longitudinal relaxation time (T), perfusion of the liver and spleen (by arterial spin labelling), and blood flow in the portal, splanchnic and collateral circulation (by phase contrast MRI) were assessed. We estimated the liver stiffness measurement (LSM) and enhanced liver fibrosis (ELF) score. The correlation of all non-invasive parameters with HVPG was evaluated.

Results: The mean (range) HVPG of the patients was 9.8 (1-22) mmHg, and 14 patients (48%) had clinically significant portal hypertension (CSPH, HVPG ⩾10mmHg). Liver T relaxation time, splenic artery and superior mesenteric artery velocity correlated significantly with HVPG. Using multiple linear regression, liver T and splenic artery velocity remained as the two parameters in the multivariate model significantly associated with HVPG (R=0.90, p<0.001). This correlation was maintained in patients with CSPH (R=0.85, p<0.001). A validation cohort (n=10) showed this linear model provided a good prediction of HVPG. LSM and ELF score correlated significantly with HVPG in the whole population but the correlation was absent in CSPH.

Conclusions: MR parameters related to both hepatic architecture and splanchnic haemodynamics correlate significantly with HVPG. This proposed model, confirmed in a validation cohort, could replace the invasive HVPG measurement.

Lay Summary: In patients with cirrhosis, the development and progression of portal hypertension is related to worse outcomes. However, the standard technique of assessing portal pressure is invasive and not widely used in clinical practice. Here, we have studied the use of non-invasive MRI in evaluating portal pressure. The MRI measures of liver architecture and blood flow in the splenic artery correlated well with portal pressure. Therefore, this non-invasive method can potentially be used to assess portal pressure in clinical trials and monitoring treatment in practice.
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http://dx.doi.org/10.1016/j.jhep.2016.07.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5123896PMC
December 2016

Cp*Co(IPr): synthesis and reactivity of an unsaturated Co(i) complex.

Chem Commun (Camb) 2016 Feb 5;52(12):2469-72. Epub 2015 Nov 5.

Department of Science, Mount St. Mary's University, Emmitsburg, MD 21727, USA.

Synthesis of coordinatively unsaturated Cp*Co(IPr) (2), is accomplished by addition of free N-heterocyclic carbene IPr to [(Cp*Co)2-μ-(η(4):η(4)-toluene)] (1). Stoichiometric reactivity is consistent with a 16 electron species, as 2 undergoes ligand addition/NHC displacement and reversible reaction with dihydrogen. Cp*Co(IPr) represents an elusive example of a stable Cp*CoL fragment.
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http://dx.doi.org/10.1039/c5cc06756aDOI Listing
February 2016

Using CellML with OpenCMISS to Simulate Multi-Scale Physiology.

Front Bioeng Biotechnol 2014 5;2:79. Epub 2015 Jan 5.

Auckland Bioengineering Institute, University of Auckland , Auckland , New Zealand.

OpenCMISS is an open-source modeling environment aimed, in particular, at the solution of bioengineering problems. OpenCMISS consists of two main parts: a computational library (OpenCMISS-Iron) and a field manipulation and visualization library (OpenCMISS-Zinc). OpenCMISS is designed for the solution of coupled multi-scale, multi-physics problems in a general-purpose parallel environment. CellML is an XML format designed to encode biophysically based systems of ordinary differential equations and both linear and non-linear algebraic equations. A primary design goal of CellML is to allow mathematical models to be encoded in a modular and reusable format to aid reproducibility and interoperability of modeling studies. In OpenCMISS, we make use of CellML models to enable users to configure various aspects of their multi-scale physiological models. This avoids the need for users to be familiar with the OpenCMISS internal code in order to perform customized computational experiments. Examples of this are: cellular electrophysiology models embedded in tissue electrical propagation models; material constitutive relationships for mechanical growth and deformation simulations; time-varying boundary conditions for various problem domains; and fluid constitutive relationships and lumped-parameter models. In this paper, we provide implementation details describing how CellML models are integrated into multi-scale physiological models in OpenCMISS. The external interface OpenCMISS presents to users is also described, including specific examples exemplifying the extensibility and usability these tools provide the physiological modeling and simulation community. We conclude with some thoughts on future extension of OpenCMISS to make use of other community developed information standards, such as FieldML, SED-ML, and BioSignalML. Plans for the integration of accelerator code (graphical processing unit and field programmable gate array) generated from CellML models is also discussed.
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http://dx.doi.org/10.3389/fbioe.2014.00079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4283644PMC
January 2015

Radiosensitizing activity of a novel Benzoxazine through the promotion of apoptosis and inhibition of DNA repair.

Invest New Drugs 2014 Jun 14;32(3):424-35. Epub 2014 Mar 14.

School of Pharmacy and Applied Science, La Trobe Institute of Molecular Sciences, La Trobe University, P.O. Box 199, Bendigo, VIC, 3552, Australia.

The DNA dependant protein kinase (DNA-PK) enzyme plays a major part in the repair of double stranded breaks induced by radiation and hence in the radio-resistance of tumour cells. Inhibitors of DNA-PK have been tested successfully in the past for their ability to sensitize cancer cells to the effects of radiation. Here we present a novel benzoxazine, 8-methyl-2-(morpholine-4yl)-7-(pyridine-3-methoxy)-4H-1,3-benzoxacine-4-one (LTU27) and analyse its ability to cause sensitization of lung cancer and colon cancer cells to radiation. There was a significant reduction in survival rate, increase in apoptosis and inhibition in autophosphorylation of DNA-PK and AKT1 after treating them concomitantly with both radiation and LTU27. The mechanism of action appears to be through inhibition of DNA-PK leading to delayed DNA repair and promotion of apoptosis.
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http://dx.doi.org/10.1007/s10637-014-0079-4DOI Listing
June 2014

Chemo-sensitisation of HeLa cells to etoposide by a benzoxazine in the absence of DNA-PK inhibition.

Invest New Drugs 2013 Dec 22;31(6):1466-75. Epub 2013 Sep 22.

La Trobe Institute of Molecular Science, La Trobe University, Bendigo, Australia.

The benzoaxines have been developed from structurally similar chromones as specific inhibitors of the PI3K family to sensitize cancer cells to the effects of chemotherapeutic agents; most have been shown to do this through specific inhibition of DNA-PK and DNA repair mechanisms. In this study we examined the benzoxazine, 2-((3-methoxybut-3en-2-yl)amino)-8methyl-4H-benzo[1,3]oxazin-4one (LTUSI54). This compound had no DNA-PK or PI3K inhibitory activity but still sensitized HeLa cells to the effects of Etoposide. LTUSI54 works synergistically with Etoposide to inhibit growth of HeLa cells and sub G1 analysis indicates that this is not due to an increase in apoptosis. LTUSI54 neither enhances DSB formation due to Etoposide nor does it delay the repair of such damage. Cell cycle analysis shows a clear G2 block with Etoposide alone while, in combination with LTUSI54 there is an additional S phase arrest. Phospho-kinase analysis indicated that LTUSI54 engages key regulators of cell cycle progression, specifically p38α, p53 and ERK 1/2. From our results we hypothesize that LTUSI54 is promoting the cell cycle arrest through activation of p38α pathways, independent of p53 mechanisms. This results in a decrease in p53 phosphorylation and hence, restricted apoptosis. Changes in cell number appear to be the result of p38α pathways disrupting cell cycle progression, at the S and G2 checkpoints. Further investigation into the finer mechanisms by which LTUSI54 effects cell cycle progression would be of great interest in assessing this compound as a chemosensitising agent.
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http://dx.doi.org/10.1007/s10637-013-0031-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3825418PMC
December 2013

Synthesis of a bis(indenyl) Co(I) anion: a reactive source of a 14 electron indenyl Co(I) equivalent.

Inorg Chem 2013 Mar 21;52(5):2446-57. Epub 2013 Feb 21.

Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, Texas 79409, United States.

Alkali metal reduction of (η(5)-C9H5-1,3-(SiMe3)2)2Co (1) in tetrahydrofuran (THF) permits isolation of the unusual and reactive 20 electron Co(I) anion [Na(THF)6][(η(5)-C9H5-1,3-(SiMe3)2)2Co] (2). Crystallographic characterization of both 1 and 2 provide support for the one electron reduction from Co(II) to Co(I). Reactivity studies of 2 are further consistent with a Co(I) equivalent, based on both one electron chemical oxidation to reform 1 and reaction with a variety of σ and π donors. Upon addition of pyridines or vinyltrimethylsilane to 2, known dimer [(C9H5-1,3-(SiMe3)2)2Co2] (3) is formed, likely through 16 electron (η(5)-C9H5-1,3-(SiMe3)2)Co(L) intermediates. Ethylene addition to 2 establishes an equilibrium between (η(5)-C9H5-1,3-(SiMe3)2)Co(η(2)-H2C═CH2)2 (8) and 2, suggestive of reversible ligand ejection from 2. Crossover experiments between a related metal indenide salt and 2 confirm ligand extrusion from the anion, even in the absence of strong supporting donors. Reaction of 2 with PMe3 results in formation of 3, (η(5)-C9H5-1,3-(SiMe3)2)Co(PMe3)2 (13), and a paramagnetic species, with the product ratios being highly dependent on the conditions of synthesis. Collectively, 2 demonstrates an alternative entry point into the chemistry of 14 electron Co(I) equivalents when compared to typical ligand loss from neutral 18 electron cyclopentadienyl cobalt bis(ligand) complexes, perhaps permitting generation of low electron count species more effective for small molecule activation.
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http://dx.doi.org/10.1021/ic302320wDOI Listing
March 2013

Synthesis, DNA-PK inhibition, anti-platelet activity studies of 2-(N-substituted-3-aminopyridine)-substituted-1,3-benzoxazines and DNA-PK and PI3K inhibition, homology modelling studies of 2-morpholino-(7,8-di and 8-substituted)-1,3-benzoxazines.

Eur J Med Chem 2012 Nov 5;57:85-101. Epub 2012 Sep 5.

School of Pharmacy and Applied Science, La Trobe University, P.O. Box 199, Bendigo, VIC 3552, Australia.

A number of new 2-(pyridin-3-ylamino)-4H-(substituted) benz[e]-1,3-oxazin-4-ones were synthesized 10a-g. These were then reacted with the hydro-halogen salt of 2, 3 and 4-(halo-methyl) pyridine in the presence of Cs(2)CO(3) to give eighteen new 2-(N-substituted (pyridin-3-ylmethyl) amino)-substituted-1,3-benzoxazines (compounds 11a-i, 13a-c, and 15a-f). X-ray crystallography was used to confirm that the 2-N-substituted structures 11 and 13 were formed rather than the 3-N-substitution analogues 12 and 14. Eleven of the new compounds were tested for their effect on collagen induced platelet aggregation and it was found that the most active inhibitory compound was 8-methyl-2-(pyridin-3-yl(pyridin-3-ylmethyl)amino)-7-(pyridin-3-ylmethoxy)-4H-benz[e]-1,3-oxazin-4-one 15e with an IC(50) of 10 ± 2 μM. DNA-dependent protein kinase (DNA-PK) inhibition data for 12 previously prepared 2-morpholino substituted-1,3-benzoxazines (compounds 19-31) were measured and showed high to moderate activity where the most active compound was compound 27 with an IC(50) of 0.28 μM. Furthermore DNA-PK inhibition data for six newly prepared 2-(N-substituted (pyridin-3-ylmethyl) amino)-substituted-1,3-benzoxazines (compounds 11b, 13a-b, 15a-b and 15e) and 8-methyl-7-(pyridin-3-ylmethoxy)-3-(pyridin-3-ylmethyl)-2H-benz[e]-1,3-oxazin-2,4(3H)-dione 17d were measured and moderate to low inhibitory activity was observed, with the most active of the compounds in this series being 8-methyl-2-(pyridin-3-yl(pyridin-3-ylmethyl)amino)-7-(pyridin-3-ylmethoxy)-4H-benz[e]-1,3-oxazin-4-one 15e with an IC(50) of 2.5 μM. PI3K inhibition studies revealed that compound 27 is highly potent (IC(50) for PI3Kα = 0.13 μM, PI3Kβ = 0.14 μM, PI3Kγ = 0.72 μM, PI3Kδ = 2.02 μM). Compound 22 with 7-[2-(4-methylpiperazin-1-yl)ethoxy] group shows greater inhibition of DNA-PK over PI3K. Docking of some 2-morpholino-substituted-1,3-benzoxazine compounds 19-31 within the binding pocket and structure-activity relationships (SAR) analyses were performed with results agreeing well with observed activities.
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http://dx.doi.org/10.1016/j.ejmech.2012.08.035DOI Listing
November 2012

sp2 C-H activation of dimethyl fumarate by a [(Cp*Co)2-μ-(η4 : η4-toluene)] complex.

Dalton Trans 2012 Jul 9;41(26):8190-7. Epub 2012 May 9.

Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX 79409-1061, USA.

The well-defined oxidative addition of the vinylic sp(2) C-H bond of dimethyl fumarate is mediated by the cobalt triple decker complex [(Cp*Co)(2)-μ-(η(4) : η(4)-toluene)] (1) at ambient temperature, affording the dinuclear, bridging cobalt hydride, fumaryl compound (2). The C-H activation product has been characterized by mass spectrometry, NMR spectroscopy, and X-ray crystallography. Computational studies of 2 support asymmetric bonding interactions between the two metal centres and the bridging hydride/fumaryl fragments. Monitoring the reaction of dimethyl fumarate with 1 by (1)H NMR spectroscopy allows observation of intermediate [Cp*Co(MeO(2)CCH=CHCO(2)Me)](n) (n = 1 or 2) (3). Addition of 4 equivalents of dimethyl fumarate to 1 results in rapid formation of the bis(ligand) adduct Cp*Co(η(2)-MeO(2)CCH=CHCO(2)Me)(2) (5). Reversibility of the C-H activation was probed by reaction of additional dimethyl fumarate with 2, suggesting ligand induced reductive elimination is possible under ambient conditions. Reaction between 2 and strong σ or π ligands, such as PMe(3) or CO, affords the corresponding Cp*Co(η(2)-MeO(2)CCH=CHCO(2)Me)(L) (L = PMe(3) (7); L = CO (8)) complexes when heated, demonstrating the ability of 2 to undergo two electron redox processes. Further evidence for reversible C-H activation is provided by the isomerization of dimethyl maleate to the corresponding fumarate using 2, suggesting the complex can serve as a source of Co(I) under the appropriate catalytic conditions.
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http://dx.doi.org/10.1039/c2dt30288hDOI Listing
July 2012

Development of more labile low electron count Co(I) sources: mild, catalytic functionalization of activated alkanes using a [(Cp*Co)2-μ-(η4:η4-arene)] complex.

Chem Commun (Camb) 2012 Jan 14;48(3):368-70. Epub 2011 Nov 14.

Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX, USA.

Catalytic transfer dehydrogenation of silyl protected amines, requiring sp(3) C-H bond activation, is mediated by a bridging arene complex of the type [(Cp*Co)(2)-μ-(η(4):η(4)-arene)] under mild conditions. Mechanistic and qualitative rate studies establish the compound as a more reactive Co(I) source when compared to other known Cp*Co(I) complexes.
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http://dx.doi.org/10.1039/c1cc15458cDOI Listing
January 2012

Synthesis, structural elucidation, DNA-PK inhibition, homology modelling and anti-platelet activity of morpholino-substituted-1,3-naphth-oxazines.

Bioorg Med Chem 2011 Jul 24;19(13):3983-94. Epub 2011 May 24.

School of Pharmacy and Applied Science, La Trobe University, Bendigo, Australia.

A number of new angular 2-morpholino-(substituted)-naphth-1,3-oxazines (compound 10b), linear 2-morpholino-(substituted)-naphth-1,3-oxazines (compounds 13b-c), linear 6, 7 and 9-O-substituted-2-morpholino-(substituted)-naphth-1,3-oxazines (compounds 17-22, 24, and 25) and angular compounds 14-16 and 23 were synthesised. The O-substituent was pyridin-2yl-methyl (15, 18, and 21) pyridin-3yl-methyl (16, 19, and 22) and 4-methylpipreazin-1-yl-ethoxy (23-25). Twelve compounds were tested for their inhibitory effect on collagen induced platelet aggregation and it was found that the most active compounds were compounds 19 and 22 with IC(50)=55±4 and 85±4 μM, respectively. Furthermore, the compounds were also assayed for their ability to inhibit DNA-dependent protein kinase (DNA-PK) activity. The most active compounds were 18 IC(50)=0.091 μM, 24 IC(50)=0.191 μM, and 22 IC(50)=0.331 μM. Homology modelling was used to build a 3D model of DNA-PK based on the X-ray structure of phosphatidylinositol 3-kinases (PI3Ks). Docking of synthesised compounds within the binding pocket and structure-activity relationships (SAR) analyses of the poses were performed and results agreed well with observed activity.
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http://dx.doi.org/10.1016/j.bmc.2011.05.032DOI Listing
July 2011

Synthesis, structural elucidation and DNA-dependant protein kinase and antiplatelet studies of 2-amino-[5, 6, 7, 8-mono and 7, 8-di-substituted]-1,3-benzoxazines.

Eur J Med Chem 2010 Nov 12;45(11):4934-46. Epub 2010 Aug 12.

School of Pharmacy and Applied Science, La Trobe University, P.O. Box 199, Bendigo 3552, Australia.

A number of new 2-amino-[5, 6, 7 and 8]-O-substituted 1,3-benzoxazines, and 2-amino 8-methyl-7-O-substituted-1,3-benzoxazines were synthesized. Thirty one new compounds were tested for their effect on collagen induced platelet aggregation and it was found that the most active compounds were 8-methyl-2-morpholin-4-yl-7-(pyridin-3-ylmethoxy)-4H-1,3-benzoxazin-4-one 9f and 8-methyl-2-morpholin-4-yl-7-(pyridin-4-ylmethoxy)-4H-1,3-benzoxazin-4-one 9j with IC(50) = 2 ± 1.5 and 4 ± 2 μM respectively. Inhibition of DNA-PK activity at concentrations of 1.6-4 μM were tested for 9 products 5i, 7a-e and 9b, 9f and 9j.
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http://dx.doi.org/10.1016/j.ejmech.2010.07.066DOI Listing
November 2010
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