STI-571 (imatinib mesylate) enhances the apoptotic efficacy of pyrrolo-1,5-benzoxazepine-6, a novel microtubule-targeting agent, in both STI-571-sensitive and -resistant Bcr-Abl-positive human chronic myeloid leukemia cells

Interactions between the Bcr-Abl kinase inhibitor STI-571 (imatinib mesylate) and a novel microtubule-targeting agent (MTA), pyrrolo-1,5-benzoxazepine (PBOX)-6, were investigated in STI-571-sensitive and -resistant human chronic myeloid leukemia (CML) cells. Cotreatment of PBOX-6 with STI-571 induced significantly more apoptosis in Bcr-Abl-positive CML cell lines (K562 and LAMA-84) than either drug alone (P < 0.01). Cell cycle analysis of propidium iodide-stained cells showed that STI-571 significantly reduced PBOX-6-induced G2M arrest and polyploid formation with a concomitant increase in apoptosis. Similar results were obtained in K562 CML cells using lead MTAs (paclitaxel and nocodazole) in combination with STI-571. Potentiation of PBOX-6-induced apoptosis by STI-571 was specific to Bcr-Abl-positive leukemia cells with no cytoxic effects observed on normal peripheral blood cells. The combined treatment of STI-571 and PBOX-6 was associated with the down-regulation of Bcr-Abl and repression of proteins involved in Bcr-Abl transformation, namely the antiapoptotic proteins Bcl-x(L) and Mcl-1. Importantly, PBOX-6/STI-571 combinations were also effective in STI-571-resistant cells. Together, these findings highlight the potential clinical benefits in simultaneously targeting the microtubules and the Bcr-Abl oncoprotein in STI-571-sensitive and -resistant CML cells.

Calcium signaling in ocular arterioles

Local control of blood flow to the photoreceptors and associated neurons in the retina is largely achieved through changes in tone within the choroidal and retinal arterioles. This is primarily achieved through changes in [Ca2+] within the smooth muscle of these vessels, which regulates cell contraction and vascular constriction. Here we review some aspects of the cell physiology involved in these Ca2+-signaling processes, with particular emphasis on the molecular mechanisms involved. Ca2+-influx across the plasma membrane can occur via a variety of Ca2+-channels, including voltage-operated, store-operated, and receptor-operated channels. Ca2+ may also be released from intracellular stores via RyR-, or IP3R-gated channels in the SR membrane. Using high-speed confocal Ca2+-imaging, we have also demonstrated that the resulting signals are far from homogeneous, with spontaneous activity in retinal arterioles being characterized by both localized Ca2+-sparks and more global Ca2+-waves and oscillations. These signals may be specifically and differentially targeted, for example, to Ca2+-sensitive ion channels (stimulus-excitation coupling), or pathways regulating contraction (stimulus-contraction coupling). Exploring the role of changes in such targeting in disease states will provide exciting opportunities for future research.

Myc-dependent purine biosynthesis affects nucleolar stress and therapy response in prostate cancer

The androgen receptor is a key transcription factor contributing to the development of all stages of prostate cancer (PCa). In addition, other transcription factors have been associated with poor prognosis in PCa, amongst which c-Myc (MYC) is a well-established oncogene in many other cancers. We have previously reported that the AR promotes glycolysis and anabolic metabolism; many of these metabolic pathways are also MYC-regulated in other cancers. In this study, we report that in PCa cells de novo purine biosynthesis and the subsequent conversion to XMP is tightly regulated by MYC and independent of AR activity. We characterized two enzymes, PAICS and IMPDH2, within the pathway as PCa biomarkers in tissue samples and report increased efficacy of established anti-androgens in combination with a clinically approved IMPDH inhibitor, mycophenolic acid (MPA). Treatment with MPA led to a significant reduction in cellular guanosine triphosphate (GTP) levels accompanied by nucleolar stress and p53 stabilization. In conclusion, targeting purine biosynthesis provides an opportunity to perturb PCa metabolism and enhance tumour suppressive stress responses.

'Grooming' and the Sexual Abuse of Children:Institutional, Internet and Familial Dimensions

‘Grooming’ and the Sexual Abuse of Children: Institutional, Internet and Familial Dimensions critically examines the official and popular discourses on grooming, predominantly framed within the context of on-line sexual exploitation and abuse committed by strangers, and institutional child abuse committed by those in positions of trust.

Set against the broader theoretical framework of risk, security and governance, this book argues that due to the difficulties of drawing clear boundaries between innocuous and harmful motivations towards children, pre-emptive risk-based criminal law and policy are inherently limited in preventing, targeting and criminalising ‘grooming’ behaviour prior to the manifestation of actual harm. Through examination of grooming against the complexities of the onset of sexual offending against children and its actual role in this process, the author broadens existing discourses by providing a fuller, more nuanced conceptualisation of grooming, including its role in intra-familial and extra-familial contexts. There is also timely discussion of new and emerging forms of grooming, such as ‘street’ or ‘localised’ grooming, as typified by recent cases in Rochdale and Oldham, and ‘peer-to-peer’ grooming.

The first inter-disciplinary, thematic, and empirical investigation of grooming in a multi-jurisdictional context, ‘Grooming’ and the Sexual Abuse of Children draws on extensive empirical research in the form of over fifty interviews with professionals, working in the fields of sex offender risk assessment, management or treatment, as well as child protection or victim support in the four jurisdictions of the United Kingdom and the Republic of Ireland. Impeccably presented and meticulously considered, this book will be of interest to criminologists and those working and studying in the field of policing and criminal justice studies, as well as policy makers and practitioners in the areas of child protection and sex offender management.

Analysis of Bayesian classification-based approaches for Android malware detection

Mobile malware has been growing in scale and complexity spurred by the unabated uptake of smartphones worldwide. Android is fast becoming the most popular mobile platform resulting in sharp increase in malware targeting the platform. Additionally, Android malware is evolving rapidly to evade detection by traditional signature-based scanning. Despite current detection measures in place, timely discovery of new malware is still a critical issue. This calls for novel approaches to mitigate the growing threat of zero-day Android malware. Hence, the authors develop and analyse proactive machine-learning approaches based on Bayesian classification aimed at uncovering unknown Android malware via static analysis. The study, which is based on a large malware sample set of majority of the existing families, demonstrates detection capabilities with high accuracy. Empirical results and comparative analysis are presented offering useful insight towards development of effective static-analytic Bayesian classification-based solutions for detecting unknown Android malware.

A New Android Malware Detection Method Using Bayesian Classification

Mobile malware has been growing in scale and complexity as smartphone usage continues to rise. Android has surpassed other mobile platforms as the most popular whilst also witnessing a dramatic increase in malware targeting the platform. A worrying trend that is emerging is the increasing sophistication of Android malware to evade detection by traditional signature-based scanners. As such, Android app marketplaces remain at risk of hosting malicious apps that could evade detection before being downloaded by unsuspecting users. Hence, in this paper we present an effective approach to alleviate this problem based on Bayesian classification models obtained from static code analysis. The models are built from a collection of code and app characteristics that provide indicators of potential malicious activities. The models are evaluated with real malware samples in the wild and results of experiments are presented to demonstrate the effectiveness of the proposed approach.

High accuracy android malware detection using ensemble learning

With over 50 billion downloads and more than 1.3 million apps in Google’s official market, Android has continued to gain popularity amongst smartphone users worldwide. At the same time there has been a rise in malware targeting the platform, with more recent strains employing highly sophisticated detection avoidance techniques. As traditional signature based methods become less potent in detecting unknown malware, alternatives are needed for timely zero-day discovery. Thus this paper proposes an approach that utilizes ensemble learning for Android malware detection. It combines advantages of static analysis with the efficiency and performance of ensemble machine learning to improve Android malware detection accuracy. The machine learning models are built using a large repository of malware samples and benign apps from a leading antivirus vendor. Experimental results and analysis presented shows that the proposed method which uses a large feature space to leverage the power of ensemble learning is capable of 97.3 % to 99% detection accuracy with very low false positive rates.

Targeting death receptors in bladder, prostate and renal cancer

PURPOSE: We describe key components of normal and aberrant death receptor pathways, the association of these abnormalities with tumorigenesis in bladder, prostate and renal cancer, and their potential application in novel therapeutic strategies targeted toward patients with cancer.

MATERIALS AND METHODS: A MEDLINE literature search of the key words death receptors, TRAIL (tumor necrosis factor related apoptosis inducing ligand), FAS, bladder, prostate, renal and cancer was done to obtain information for review. A brief overview of the TRAIL and FAS death receptor pathways, and their relationship to apoptosis is described. Mechanisms that lead to nonfunction of these pathways and how they may contribute to tumorigenesis are linked. Current efforts to target death receptor pathways as a therapeutic strategy are highlighted.

RESULTS: Activation of tumor cell expressing death receptors by cytotoxic immune cells is the main mechanism by which the immune system eliminates malignant cells. Death receptor triggering induces a caspase cascade, leading to tumor cell apoptosis. Receptor gene mutation or hypermethylation, decoy receptor or splice variant over expression, and downstream inhibitor interference are examples of the ways that normal pathway functioning is lost in cancers of the bladder and prostate. Targeting death receptors directly through synthetic ligand administration and blocking downstream inhibitor molecules with siRNA or antisense oligonucleotides represent novel therapeutic strategies under development.

CONCLUSIONS: Research into the death receptor pathways has demonstrated the key role that pathway aberrations have in the initiation and progression of malignancies of the bladder, prostate and kidney. This new understanding has resulted in exciting approaches to restore the functionality of these pathways as a novel therapeutic strategy.

Targeting social need in a divided society: an evaluation of a community-based adult education initiative

This article examines the impact of a community-based adult education initiative designed to target social need in Northern Ireland. Set against a backdrop of extreme civil unrest and disadvantageous socio-economic conditions a cohort of adults was identified to participate in a personal and social development programme. The initiative was funded from Peace and Reconciliation resources made available to Northern Ireland by the European Union. High levels of unemployment and negativity about previous learning experiences were characteristic features among participants. An evaluation of the effectiveness of the programme was carried out and a follow-up qualitative survey ensued 6 months after the completion of the training. Results indicate that the learner-centred methodology was effective in providing a gateway to further education and training and enhancing participants' self-esteem, confidence, motivation, tolerance, social skills, community involvement and

Recent Advances in Antidiabetic Drug Therapies Targeting the Enteroinsular Axis

The enteroinsular axis (EIA) constitutes a physiological signalling system whereby intestinal endocrine cells secrete incretin hormones following feeding that potentiate insulin secretion and contribute to the regulation of blood glucose homeostasis. The two key hormones responsible are named glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Recent years have witnessed sustained development of antidiabetic therapies that exploit the EIA. Current clinical compounds divide neatly into two classes. One concerns analogues or mimetics of GLP-1, such as exenatide (Byetta) or liraglutide (NN2211). The other group comprises the gliptins (e. g. sitagliptin and vildagliptin) which boost endogenous incretin activity by inhibiting the enzyme dipeptidyl peptidase 4 (DPP 4) that degrades both GLP-1 and GIP. Ongoing research indicates that further incretin and gliptin compounds will become available for clinical use in the near future, offering comparable or improved efficacy. For incretin analogues there is the prospect of prolonged duration of action and alternative routes of administration. This review focuses on recent advances in pre-clinical research and their translation into clinical studies to provide future therapies for type 2 diabetes targeting the EIA.