Phase I Study Of The Poly(ADP-Ribose) Polymerase Inhibitor, AG014699, In Combination With Temozolomide in Patients with Advanced Solid Tumors

Purpose: One mechanism of tumor resistance to cytotoxic therapy is repair of damaged DNA. Poly(ADP-ribose) polymerase (PARP)-1 is a nuclear enzyme involved in base excision repair, one of the five major repair pathways. PARP inhibitors are emerging as a new class of agents that can potentiate chemotherapy and radiotherapy. The article reports safety, efficacy, pharmacokinetic, and pharmacodynamic results of the first-in-class trial of a PARP inhibitor, AG014699, combined with temozolomide in adults with advanced malignancy.

Experimental Design: Initially, patients with solid tumors received escalating doses of AG014699 with 100 mg/m2/d temozolomide × 5 every 28 days to establish the PARP inhibitory dose (PID). Subsequently, AG014699 dose was fixed at PID and temozolomide escalated to maximum tolerated dose or 200 mg/m2 in metastatic melanoma patients whose tumors were biopsied. AG014699 and temozolomide pharmacokinetics, PARP activity, DNA strand single-strand breaks, response, and toxicity were evaluated.

Results: Thirty-three patients were enrolled. PARP inhibition was seen at all doses; PID was 12 mg/m2 based on 74% to 97% inhibition of peripheral blood lymphocyte PARP activity. Recommended doses were 12 mg/m2 AG014699 and 200 mg/m2 temozolomide. Mean tumor PARP inhibition at 5 h was 92% (range, 46-97%). No toxicity attributable to AG014699 alone was observed. AG014699 showed linear pharmacokinetics with no interaction with temozolomide. All patients treated at PID showed increases in DNA single-strand breaks and encouraging evidence of activity was seen.

Conclusions: The combination of AG014699 and temozolomide is well tolerated, pharmacodynamic assessments showing proof of principle of the mode of action of this new class of agents.

Host-based P2P flow identification and use in real-time

Data identification is a key task for any Internet Service Provider (ISP) or network administrator. As port fluctuation and encryption become more common in P2P traffic wishing to avoid identification, new strategies must be developed to detect and classify such flows. This paper introduces a new method of separating P2P and standard web traffic that can be applied as part of a data mining process, based on the activity of the hosts on the network. Unlike other research, our method is aimed at classifying individual flows rather than just identifying P2P hosts or ports. Heuristics are analysed and a classification system proposed. The accuracy of the system is then tested using real network traffic from a core internet router showing over 99% accuracy in some cases. We expand on this proposed strategy to investigate its application to real-time, early classification problems. New proposals are made and the results of real-time experiments compared to those obtained in the data mining research. To the best of our knowledge this is the first research to use host based flow identification to determine a flows application within the early stages of the connection.

Advanced glycation end product (AGE) accumulation on Bruch's membrane: links to age-related RPE dysfunction.

PURPOSE: Advanced glycation end products (AGEs) accumulate during aging and have been observed in postmortem eyes within the retinal pigment epithelium (RPE), Bruch's membrane, and subcellular deposits (drusen). AGEs have been associated with age-related dysfunction of the RPE-in particular with development and progression to age-related macular degeneration (AMD). In the present study the impact of AGEs at the RPE-Bruch's membrane interface was evaluated, to establish how these modifications may contribute to age-related disease. METHODS: AGEs on Bruch's membrane were evaluated using immunohistochemistry. A clinically relevant in vitro model of substrate AGE accumulation was established to mimic Bruch's membrane ageing. Responses of ARPE-19 growing on AGE-modified basement membrane (AGE-BM) for 1 month were investigated by using a microarray approach and validated by quantitative (q)RT-PCR. In addition to identified AGE-related mRNA alterations, lysosomal enzyme activity and lipofuscin accumulation were also studied in ARPE-19 grown on AGE-BM. RESULTS: Autofluorescent and glycolaldehyde-derived AGEs were observed in clinical specimens on Bruch's membrane and choroidal extracellular matrix. In vitro analysis identified a range of dysregulated mRNAs in ARPE-19 exposed to AGE-BM. Altered ARPE-19 degradative enzyme mRNA expression was observed on exposure to AGE-BM. AGE-BM caused a significant reduction in cathepsin-D activity in ARPE-19 (P

The EU’s Biopolitical Governance of Advanced Therapy Medicinal Products

This paper focuses on the specific example of the newly operational Regulation on Advanced Therapy Medicinal Products to explore the potential for biopolitics, an arena in which biocitizens can demand and contest the exercise of EU power over life. The paper shows how the discourses producing, organizing and orchestrating citizen participation in the EU’s governance of advanced therapies from above figure a ‘deficit model’ of citizens in need of education inter alia through their membership of patients’ associations who have membership of the Committee on Advanced Therapies established by the Regulation. Biocitizens are shown to be incorporated to service the EU’s legitimacy needs. The paper then warns against assuming biocitizens’ (self-) reflexivity ensures they do not reiterate and reinforce their construction within the ‘deficit model’ by unwittingly deploying the terms of their subjection. After which the paper highlights some elements that provide a rhetorical and operational opening for participation, and which therefore can be used by biocitizens to reconstruct their engagement with EU governance from below, the wider governance of advanced therapies, as well as in their self-governance.

Raman spectroscopy of advanced glycation end products (AGEs), possible markers for progressive retinal dysfunction

Raman microscopy is used to investigate the spectral features of selected compounds known to be involved in the development of the eye disease age-related macular degeneration (AMD). Diagnostic features were identified in synthetic samples of these compounds and in a biological matrix. The study demonstrates the potential of Raman microscopy for the development of diagnostic markers of the onset of AMD. Copyright (C) 2008 John Wiley & Sons, Ltd.

The experience of cancer cachexia: A qualitative study of advanced cancer patients and their family members

Background
Cachexia in advanced malignancy is a debilitating syndrome which contributes to approximately two million deaths worldwide annually. In spite of advances in understanding the biomedical aspects of cancer cachexia, little attention has been paid to exploring its holistic impact on patients and those who care for them.

Objective
The aim of this paper is to describe the lived experience of cachexia from the perspective of patients with cancer and their family members.

Design
An interpretative phenomenological approach was employed.

Setting and participants
A purposive sampling strategy recruited 15 patients and 12 family members from the Regional Cancer Centre in Northern Ireland.

Method
Each participant was interviewed during 2004/2005 using an unstructured interview. All interviews were recorded and transcribed verbatim. Analysis combined a two stage approach using thematic and interpretative phenomenological analysis.

Results
Analysis generated six superordinate themes that reflected the complex dynamics of the cachexia experience. Themes were: physiological changes in appetite; visuality of cachexia; weight loss interpreted as a bad sign; response from health care professionals; conflict over food; and coping responses.

Conclusions
Findings confirmed that cancer cachexia has far reaching implications for patients and their families, extending beyond physical problems into psychological, social and emotional issues. This insight is a critical first step in the development of more responsive care for these clients.

The role of advanced glycation end products in retinal ageing and disease

The retina is exposed to a lifetime of potentially damaging environmental and physiological factors that make the component cells exquisitely sensitive to age-related processes. Retinal ageing is complex and a raft of abnormalities can accumulate in all layers of the retina. Some of this pathology serves as a sinister preamble to serious conditions such as age-related macular degeneration (AMD) which remains the leading cause of irreversible blindness in the Western world.

The formation of advanced glycation end products (AGEs) is a natural function of ageing but accumulation of these adducts also represents a key pathophysiological event in a range of important human diseases. AGEs act as mediators of neurodegeneration, induce irreversible changes in the extracellular matrix, vascular dysfunction and pro-inflammatory signalling. Since many cells and tissues of the eye are profoundly influenced by such processes, it is fitting that advanced glycation is now receiving considerable attention as a possible pathogenic factor in visual disorders.

This review presents the current evidence for a pathogenic role for AGEs and activation of the receptor for AGEs (RAGE) in initiation and progression of retinal disease. It draws upon the clinical and experimental literature and highlights the opportunities for further research that would definitively establish these adducts as important instigators of retinal disease. The therapeutic potential for novel agents that can ameliorate AGE formation of attenuate RAGE signalling in the retina is also discussed.

A new advanced glycation inhibitor, LR-90, prevents experimental diabetic retinopathy in rats

Background: Diabetic retinopathy is associated with accumulation of advanced glycation end products in the retinal microvasculature. LR-90 is an effective multistage inhibitor of advanced glycation with renoprotective and anti-inflammatory properties.

Inhibition of Advanced Glycation and Absence of Galectin-3 Prevent Blood-Retinal Barrier Dysfunction during Short-Term Diabetes

Breakdown of the inner blood-retinal barrier (iBRB) occurs early in diabetes and is central to the development of sight-threatening diabetic macular edema (DME) as retinopathy progresses. In the current study, we examined how advanced glycation end products (AGEs) forming early in diabetes could modulate vasopermeability factor expression in the diabetic retina and alter inter-endothelial cell tight junction (TJ) integrity leading to iBRB dysfunction. We also investigated the potential for an AGE inhibitor to prevent this acute pathology and examined a role of the AGE-binding protein galectin-3 (Gal-3) in AGE-mediated cell retinal pathophysiology. Diabetes was induced in C57/BL6 wild-type (WT) mice and in Gal-3(-/-) transgenic mice. Blood glucose was monitored and AGE levels were quantified by ELISA and immunohistochemistry. The diabetic groups were subdivided, and one group was treated with the AGE-inhibitor pyridoxamine (PM) while separate groups of WT and Gal-3(-/-) mice were maintained as nondiabetic controls. iBRB integrity was assessed by Evans blue assay alongside visualisation of TJ protein complexes via occludin-1 immunolocalization in retinal flat mounts. Retinal expression levels of the vasopermeability factor VEGF were quantified using real-time RT-PCR and ELISA. WT diabetic mice showed significant AGE -immunoreactivity in the retinal microvasculature and also showed significant iBRB breakdown (P < .005). These diabetics had higher VEGF mRNA and protein expression in comparison to controls (P < .01). PM-treated diabetics had normal iBRB function and significantly reduced diabetes-mediated VEGF expression. Diabetic retinal vessels showed disrupted TJ integrity when compared to controls, while PM-treated diabetics demonstrated near-normal configuration. Gal-3(-/-) mice showed significantly less diabetes-mediated iBRB dysfunction, junctional disruption, and VEGF expression changes than their WT counterparts. The data suggests an AGE-mediated disruption of iBRB via upregulation of VEGF in the diabetic retina, possibly modulating disruption of TJ integrity, even after acute diabetes. Prevention of AGE formation or genetic deletion of Gal-3 can effectively prevent these acute diabetic retinopathy changes.