Hypersensitivity of BRCA1 Heterozygote Lymphoblastoid cells to Gamma radiation and PARP inhibitors

PARP inhibitors can be used to induce synthetic lethality in cells with bi-allelic BRCA1 and BRCA2 mutations. However the effect of PARP inhibitors in combination with radiation on cells with mono-allelic mutations of BRCA1 and BRCA2 is unknown. We have examined the cell survival response of lymphoblastoid cells derived from normal individuals and those derived from carriers of BRCA1 and BRCA2 mutations, following exposure to ionising radiation and the PARP inhibitor Olaparib. Two lymphoblastoid cell lines from normal individuals and three with mono-allelic mutations in BRCA1 and BRCA2 were exposed to increasing doses of gamma radiation either alone or in combination with 5 μM Olaparib. Cell survival was measured using the MTT assay. Exposure to increasing doses of gamma radiation caused a reduction in cell survival of all cell types. The combined exposure to gamma radiation and 5 μM Olaparib did not enhance cell kill in normal or BRCA2 heterozygote lymphoblastoid cells but significantly enhanced cell kill in cells derived from BRCA1 carriers (P = 0.02). The treatment of cancer patients carrying mutations in the BRCA1 gene with radiotherapy and the PARP inhibitor Olaparib may significantly enhance radiation induced normal tissue toxicity in these patients.

Metals and linear alkylbenzene sulphonate as inhibitors of the algae Pseudokirchneriella subcapitata acid phosphatase activity.

Sewage sludge applied to soils as a fertilizer often contains metals and linear alkylbenzene sulphonate (LAS) as contaminants. These pollutants can be transported to the aquatic environment where they can alter the phosphatase activity in living organisms. The acid phosphatase of algae plays important roles in metabolism such as decomposing organic phosphate into free phosphate and autophagic digestive processes. The order of in vitro inhi- bition of Pseudokirchneriella subcapitata acid phosphatase at the highest concentration tested was LAS[Hg2? = Al 3?[Se4? = Pb2?[Cd2?. A non-competitive inhibi- tion mechanism was obtained for Hg2? (Ki = 0.040 mM) and a competitive inhibition for LAS (Ki = 0.007 mM). In vivo studies with treated algae cultures showed that the inhibition of specific activity was observed in algae exposed during 7 days, in contrast to short term (24 h) treatments with both these chemicals. Our results suggest that the inhibition parameters in vitro did not markedly differ between the two chemicals. On the other hand, in vivo evaluations showed strong differences between both pollu- tants regarding the concentration values and the degree of response.

Entry inhibitors and Carbosilane dendrimers are potent inhibitors of cell-associated HIV-2 infection

Poster presented at the 2015 Keystone Symposia Conference X5: HIV Vaccines. Banff, Alberta, Canada, 22-27 March 2015

Development of synthetic light-chain antibodies as novel and potent HIV fusion inhibitors

This is a non-final version of an article published in final form in AIDS. 2016 Jul 17;30(11):1691-701.

Design, synthesis and antiproliferative activity of hydroxyacetamide derivatives against HeLa cervical carcinoma cell and breast cancer cell line

Purpose: To design and develop a new series of histone deacetylase inhibitors (FP1 - FP12) and evaluate their inhibitory activity against hydroxyacetamide (HDAC) enzyme mixture-derived HeLa cervical carcinoma cell and MCF-7. Methods: The designed molecules (FP1 - FP12) were docked using AUTODOCK 1.4.6. FP3 and FP8 showed higher interaction comparable to the prototypical HDACI. The designed series of 2-[[(3- Phenyl/substituted Phenyl-[4-{(4-(substituted phenyl)ethylidine-2-Phenyl-1,3-Imidazol-5-One}](-4H- 1,2,4-triazol-5-yl)sulfanyl]-N-hydroxyacetamide derivatives (FP1-FP12) was synthesized by merging 2- [(4-amino-3-phenyl-4H- 1, 2, 4-triazol-5-yl) sulfanyl]-N-hydroxyacetamide and 2-{[4-amino-3-(2- hydroxyphenyl)-4H-1,2, 4-triazol-5-yl]sulfanyl}-N hydroxyacetamide derivatives with aromatic substituted oxazolone. The biological activity of the synthesized molecule (FP1-FP12) was evaluated against HDAC enzyme mixture-derived HeLa cervical carcinoma cell and breast cancer cell line (MCF-7). Results: HDAC inhibitory activity of FP10 showed higher IC50 (half-maximal concentration inhibitory activity) of 0.09 μM, whereas standard SAHA molecule showed IC50 of 0.057 μM. On the other hand, FP9 exhibited higher GI50 (50 % of maximal concentration that inhibited cell proliferation) of 22.8 μM against MCF-7 cell line, compared with the standard, adriamycin, with GI50 of (-) 50.2 μM. Conclusion: Synthesis, spectral characterization, and evaluation of HDAC inhibition activity and in vitro anticancer evaluation of novel hydroxyacetamide derivatives against MCF-7 cell line have been achieved. The findings indicate the emergence of potentialanticancer compounds.

Innovators or inhibitors? Accounting faculty resistance to new educational technologies in higher education

While technology affords new opportunities and benefits for educators in their teaching practice, a significant number of faculty are resistant to adopting new technologies. Unprompted, 93% of faculty interviewed in the Australian study to be discussed in this paper pointed to accounting educator resistance as a key barrier to technology adoption and use. Adopting the Technology Acceptance Model (TAM) as a framework, this paper argues that one of the greatest challenges facing business schools and Higher Education Institutions (HEIs) in the 21st century is not new technologies themselves, but the ability of educators to embrace educational technologies. Drawing on the qualitative data to emerge from interviews with accounting educators recognised as exemplary in their use of innovative technologies, this paper explores the reasons for lack of faculty uptake and argues for academics to become innovators rather than inhibitors. The findings offer a timely insight into a twenty-first century issue affecting HEIs and, specifically, accounting academics. While carried out in the Accounting discipline, the findings may be relatable and applicable to all disciplines. A suite of recommendations are proposed for institutions, business schools and academics to consider.

Multifunctional rare earth organic corrosion inhibitors

All rights reserved.Chromium (VI) compounds are commonly used in paint systems to provide corrosion protection, particularly for aerospace alloys. These compounds are toxic, carcinogenic and environmentally detrimental, therefore alternatives that are safe, environmentally benign and meet or exceed current levels of corrosion protection are vital. Multifunctional rare earth organic compounds incorporate known inhibitor species, achieving synergistic inhibition in corrosive environments. The mechanism, efficiency and surface interactions of these complexes are explored. The complexes were effective inhibitors for steel and aluminium alloys, through mixed inhibition. Advantages and limitations of these inhibitor complexes, along with applications and future research direction, are discussed.

Rare earth-based corrosion inhibitors

Corrosion inhibitors are an important method for minimizing corrosion; however traditional inhibitors such as chromates pose environmental problems. Rare earth metals provide an important, environmentally-friendly alternative. This book provides a comprehensive review of current research and examines how rare earth metals can be used to prevent corrosion and applied to protect metals in such industries as aerospace and construction. Chapter 1 begins by examining the important need to replace chromate, and then goes on to discuss the chemistry of the rare earth metals and their related compounds. Chapter 2 considers the techniques that can be used to identify corrosion inhibition mechanisms and to test the levels of protection offered to different metals by rare earth compounds. Subsequent chapters consider in more detail how rare earth elements can be used as corrosion inhibitors in different forms and for different metals. This includes discussion on the potential of rare earth elements for self-healing, tunable and multifunctional coatings. Finally, chapter 10 considers the cost and availability of the rare earths and the potential health and environmental risks associated with extracting them. Provides a review of current research and examines how rare earth metals can be used to prevent corrosion and applied to protect metals in such industries as aerospace and construction. Includes discussion on the potential of rare earth elements for self-healing, tunable and multifunctional coatings. Considers the cost and availability of the rare earths and the potential health and environmental risks associated with extracting them.

The epigenome as a therapeutic target for Parkinson's disease

Parkinson’s disease (PD) is a common, progressive neurodegenerative disease characterised by degeneration of nigrostriatal dopaminergic neurons, aggregation of α-synuclein and motor symptoms. Current dopamine-replacement strategies provide symptomatic relief, however their effectiveness wear off over time and their prolonged use leads to disabling side-effects in PD patients. There is therefore a critical need to develop new drugs and drug targets to protect dopaminergic neurons and their axons from degeneration in PD. Over recent years, there has been robust evidence generated showing that epigenetic dysregulation occurs in PD patients, and that epigenetic modulation is a promising therapeutic approach for PD. This article first discusses the present evidence implicating global, and dopaminergic neuron-specific, alterations in the methylome in PD, and the therapeutic potential of pharmacologically targeting the methylome. It then focuses on another mechanism of epigenetic regulation, histone acetylation, and describes how the histone acetyltransferase (HAT) and histone deacetylase (HDAC) enzymes that mediate this process are attractive therapeutic targets for PD. It discusses the use of activators and/or inhibitors of HDACs and HATs in models of PD, and how these approaches for the selective modulation of histone acetylation elicit neuroprotective effects. Finally, it outlines the potential of employing small molecule epigenetic modulators as neuroprotective therapies for PD, and the future research that will be required to determine and realise this therapeutic potential.

Kinetic modelling of in vitro data of PI3K, mTOR1, PTEN enzymes and on-target inhibitors Rapamycin, BEZ235, and LY294002

The phosphatidylinositide 3-kinases (PI3K) and mammalian target of rapamycin-1 (mTOR1) are two key targets for anti-cancer therapy. Predicting the response of the PI3K/AKT/mTOR1 signalling pathway to targeted therapy is made difficult because of network complexities. Systems biology models can help explore those complexities but the value of such models is dependent on accurate parameterisation. Motivated by a need to increase accuracy in kinetic parameter estimation, and therefore the predictive power of the model, we present a framework to integrate kinetic data from enzyme assays into a unified enzyme kinetic model. We present exemplar kinetic models of PI3K and mTOR1, calibrated on in vitro enzyme data and founded on Michaelis-Menten (MM) approximation. We describe the effects of an allosteric mTOR1 inhibitor (Rapamycin) and ATP-competitive inhibitors (BEZ2235 and LY294002) that show dual inhibition of mTOR1 and PI3K. We also model the kinetics of phosphatase and tensin homolog (PTEN), which modulates sensitivity of the PI3K/AKT/mTOR1 pathway to these drugs. Model validation with independent data sets allows investigation of enzyme function and drug dose dependencies in a wide range of experimental conditions. Modelling of the mTOR1 kinetics showed that Rapamycin has an IC50 independent of ATP concentration and that it is a selective inhibitor of mTOR1 substrates S6K1 and 4EBP1: it retains 40% of mTOR1 activity relative to 4EBP1 phosphorylation and inhibits completely S6K1 activity. For the dual ATP-competitive inhibitors of mTOR1 and PI3K, LY294002 and BEZ235, we derived the dependence of the IC50 on ATP concentration that allows prediction of the IC50 at different ATP concentrations in enzyme and cellular assays. Comparison of the drug effectiveness in enzyme and cellular assays showed that some features of these drugs arise from signalling modulation beyond the on-target action and MM approximation and require a systems-level consideration of the whole PI3K/PTEN/AKT/mTOR1 network in order to understand mechanisms of drug sensitivity and resistance in different cancer cell lines. We suggest that using these models in systems biology investigation of the PI3K/AKT/mTOR1 signalling in cancer cells can bridge the gap between direct drug target action and the therapeutic response to these drugs and their combinations.

The influence of HIV, HCV and inhibitors on the quality of life and behavior of the disease in patients with haemophilia: An observational study

Inhibitors are the main complication in the treatment of haemophilia. A high percentage of adult patients were infected in past decades by HIV and HCV through factor concentrates. This study compared the quality of life of patients with hemophilia (QoL) and illness behavior in adult patients with haemophilia according to the development of inhibitors and HIV or HCV co-infection. This is an observational clinical study. 69 adult patients with haemophilia participated. We used A36 Hemophilia-QoL and IBQ questionnaires to measure the QoL and illness behavior, respectively. The dependent variables were type and severity of haemophilia, type of treatment, development of inhibitors, HIV and HCV infection, or both. We observed significant differences in the perception of QoL and illness behavior in patients according to the development of inhibitor and coinfection with HIV-HCV. We obtained four groups: the first and second group, which comprise 67% of the sample, exhibit behavior patterns indicating good adaptation to the disease and good QoL. The other two groups, which comprise 33% of the sample show behavior that is not well adapted to the disease, and poor quality of life. The development of inhibitors itself does not influence the quality of life and illness behavior in patients with haemophilia. Patients infected with HIV or HCV do not have a worse illness behavior compared to those uninfected. The development of inhibitors and HIV-HCV co-infection has a negative impact on quality of life and illness behavior in patients with haemophilia.

New cholinesterase inhibitors for Alzheimer's disease: Structure Activity Studies (SARs) and molecular docking of isoquinolone and azepanone derivatives

A library of isoquinolinone and azepanone derivatives were screened for both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activity. The strategy adopted included (a) in vitro biological assays, against eel AChE (EeAChE) and equine serum BuChE (EqBuChE) in order to determine the compounds IC50 and their dose-response activity, consolidated by (b) molecular docking studies to evaluate the docking poses and interatomic interactions in the case of the hit compounds, validated by STD-NMR studies. Compound (1f) was identified as one of these hits with an IC50 of 89.5 mu M for EeAChE and 153.8 mu M for EqBuChE, (2a) was identified as a second hit with an IC50 of 108.4 mu M (EeAChE) and 277.8 mu M (EqBuChE). In order to gain insights into the binding mode and principle active site interactions of these molecules, (R)-(1f) along with 3 other analogues (also as the R-enantiomer) were docked into both RhAChE and hBuChE models. Galantamine was used as the benchmark. The docking study was validated by performing an STD-NMR study of (1f) with EeAChE using galantamine as the benchmark.

Structure-based virtual screening of hypothetical inhibitors of the enzyme longiborneol synthase: a potential target to reduce Fusarium head blight disease.

2016

Assessing the potential of inter-organisational shared services

Shared Services (SS) involves the convergence and streamlining of an organisation’s functions to ensure timely service delivery as effectively and efficiently as possible. As a management structure designed to promote value generation, cost savings and improved service delivery by leveraging on economies of scale, the idea of SS is driven by cost reduction and improvements in quality levels of service and efficiency. Current conventional wisdom is that the potential for SS is increasing due to the increasing costs of changing systems and business requirements for organisations and in implementing and running information systems. In addition, due to commoditisation of large information systems such as enterprise systems, many common, supporting functions across organisations are becoming more similar than not, leading to an increasing overlap in processes and fuelling the notion that it is possible for organisations to derive benefits from collaborating and sharing their common services through an inter-organisational shared services (IOSS) arrangement. While there is some research on traditional SS, very little research has been done on IOSS. In particular, it is unclear what are the potential drivers and inhibitors of IOSS. As the concepts of IOSS and SS are closely related to that of Outsourcing, and their distinction is sometimes blurred, this research has the first objective of seeking a clear conceptual understanding of the differences between SS and Outsourcing (in motivators, arrangements, benefits, disadvantages, etc) and based on this conceptual understanding, the second objective of this research is to develop a decision model (Shared Services Potential model) which would aid organisations in deciding which arrangement would be more appropriate for them to adopt in pursuit of process improvements for their operations. As the context of the study is on universities in higher education sharing administrative services common to or across them and with the assumption that such services were homogenous in nature, this thesis also reports on a case study. The case study involved face to face interviews from representatives of an Australian university to explore the potential for IOSS. Our key findings suggest that it is possible for universities to share services common across them as most of them were currently using the same systems although independently.