The development of a cellular model of nephrosis to evaluate nephrotoxic biomarkers

Nephrotoxicity is one of the major causes for compound failure late in the drug development process. Pharmaceutical companies are interested in identifying biomarkers of nephrotoxicity which can be used to identify potential toxic compounds earlier in the development process and hence reduce the overall time and costs involved in bringing a drug to market. I developed a cellular model of nephrosis, in NRK cells, using the well characterized nephrotoxicant compound puromycin aminonuceloside (PAN). Using this cellular model I examined the expression of kidney specific genes. Two podocyte specific proteins, podoplanin and podocalyxin were found to be specifically down-regulated. Podoplanin showed an almost universal 65% reduction in the level of gene expression after PAN treatment. Podocalyxin showed a dose-dependent reduction in expression, which reached a peak of 85% reduced expression at the highest PAN dose tested. A cell aggregation assay was developed to quantify the effect of PAN induced nephrosis on the cell adhesion properties of the NRK cells. It was found that PAN nephrosis had a significant effect on the cells ability to aggregate and to remain adhesive. However cells which lost the ability to adhere were still found to be viable. Integrin a3 protein expression was found not be altered in response to PAN treatment as determined by immunofluorescence microscopy however Laminin β2 was found to form aggregates in response to PAN treatment. The actin cytoskeleton was also found to be severely disrupted as a result of PAN induced nephrosis. Based on these studies podocalyxin has been identified as a potential genetic biomarker of nephrosis, however further study of podocalyxin expression in other models of nephrosis is required before podocalyxin can be routinely used as a predictor of nephrotoxicity

Dublin City University video track experiments for TREC 2003

In this paper, we describe our experiments for both the News Story Segmentation task and Interactive Search task for TRECVID 2003. Our News Story Segmentation task involved the use of a Support Vector Machine (SVM) to combine evidence from audio-visual analysis tools in order to generate a listing of news stories from a given news programme. Our Search task experiment compared a video retrieval system based on text, image and relevance feedback with a text-only video retrieval system in order to identify which was more effective. In order to do so we developed two variations of our Físchlár video retrieval system and conducted user testing in a controlled lab environment. In this paper we outline our work on both of these two tasks

Prostate Cancer: Is It a Battle Lost to Age?

Age is often considered an important non-modifiable risk factor for a number of diseases, including prostate cancer. Some prominent risk factors of prostate cancer include familial history, ethnicity and age. In this review, various genetic and physiological characteristics affected due to advancing age will be analysed and correlated with their direct effect on prostate cancer

A quinazoline-based HDAC inhibitor affects gene expression pathways involved in cholesterol biosynthesis and mevalonate in prostate cancer cells

Chronic inflammation can lead to the development of cancers and resolution of inflammation is an ongoing challenge.</p

Identification of potential anticancer activities of novel ganoderma lucidum extracts using gene expression and pathway network analysis

Ganoderma lucidum (lingzhi) has been used for the general promotion of health in Asia for many centuries. The common method of consumption is to boil lingzhi in water and then drink the liquid. In this study, we examined the potential anticancer activities of G. lucidum submerged in two commonly consumed forms of alcohol in East Asia: malt whiskey and rice wine. The anticancer effect of G. lucidum, using whiskey and rice wine-based extraction methods, has not been previously reported. The growth inhibition of G. lucidum whiskey and rice wine extracts on the prostate cancer cell lines, PC3 and DU145, was determined. Using Affymetrix gene expression assays, several biologically active pathways associated with the anticancer activities of G. lucidum extracts were identified. Using gene expression analysis (real-time polymerase chain reaction [RT-PCR]) and protein analysis (Western blotting), we confirmed the expression of key genes and their associated proteins that were initially identified with Affymetrix gene expression analysis

TRECVID 2004 experiments in Dublin City University

In this paper, we describe our experiments for TRECVID 2004 for the Search task. In the interactive search task, we developed two versions of a video search/browse system based on the Físchlár Digital Video System: one with text- and image-based searching (System A); the other with only image (System B). These two systems produced eight interactive runs. In addition we submitted ten fully automatic supplemental runs and two manual runs. A.1, Submitted Runs: • DCUTREC13a_{1,3,5,7} for System A, four interactive runs based on text and image evidence. • DCUTREC13b_{2,4,6,8} for System B, also four interactive runs based on image evidence alone. • DCUTV2004_9, a manual run based on filtering faces from an underlying text search engine for certain queries. • DCUTV2004_10, a manual run based on manually generated queries processed automatically. • DCU_AUTOLM{1,2,3,4,5,6,7}, seven fully automatic runs based on language models operating over ASR text transcripts and visual features. • DCUauto_{01,02,03}, three fully automatic runs based on exploring the benefits of multiple sources of text evidence and automatic query expansion. A.2, In the interactive experiment it was confirmed that text and image based retrieval outperforms an image-only system. In the fully automatic runs, DCUauto_{01,02,03}, it was found that integrating ASR, CC and OCR text into the text ranking outperforms using ASR text alone. Furthermore, applying automatic query expansion to the initial results of ASR, CC, OCR text further increases performance (MAP), though not at high rank positions. For the language model-based fully automatic runs, DCU_AUTOLM{1,2,3,4,5,6,7}, we found that interpolated language models perform marginally better than other tested language models and that combining image and textual (ASR) evidence was found to marginally increase performance (MAP) over textual models alone. For our two manual runs we found that employing a face filter disimproved MAP when compared to employing textual evidence alone and that manually generated textual queries improved MAP over fully automatic runs, though the improvement was marginal. A.3, Our conclusions from our fully automatic text based runs suggest that integrating ASR, CC and OCR text into the retrieval mechanism boost retrieval performance over ASR alone. In addition, a text-only Language Modelling approach such as DCU_AUTOLM1 will outperform our best conventional text search system. From our interactive runs we conclude that textual evidence is an important lever for locating relevant content quickly, but that image evidence, if used by experienced users can aid retrieval performance. A.4, We learned that incorporating multiple text sources improves over ASR alone and that an LM approach which integrates shot text, neighbouring shots and entire video contents provides even better retrieval performance. These findings will influence how we integrate textual evidence into future Video IR systems. It was also found that a system based on image evidence alone can perform reasonably and given good query images can aid retrieval performance

Effect of Sulforaphane on NOD2 via NF-κB: implications for Crohn’s disease

BACKGROUND: Sulforaphane has well established anti-cancer properties and more recently anti-inflammatory properties have also been determined. Sulforaphane has been shown to inhibit PRR-mediated pro-inflammatory signalling by either directly targeting the receptor or their downstream signalling molecules such as the transcription factor, NF-κB. These results raise the possibility that PRR-mediated inflammation could be suppressed by specific dietary bioactives. We examined whether sulforaphane could suppress NF-κB via the NOD2 pathway. METHODS: Human embryonic kidney 293T (HEK293T) cells were stably transfected with NOD2 variants and the NF-κB reporter, pNifty2-SEAP. The cells were co-treated with sulforaphane and MDP and secreted alkaline phosphatase (SEAP) production was determined. RESULTS: We found that sulforaphane was able to significantly suppress the ligand-induced NF-κB activity at physiologically relevant concentrations, achievable via the consumption of broccoli within the diet. CONCLUSIONS: These results demonstrate that the anti-inflammatory role of sulforaphane is not restricted to LPS-induced inflammatory signalling. These data add to the growing evidence that PRR activation can be inhibited by specific phytochemicals and thus suggests that diet could be a way of controlling inflammation. This is particularly important for a disease like Crohn’s disease where diet can play a key role in relieving or exacerbating symptoms

An update on the role of gut microbiota in chronic inflammatory diseases, and potential therapeutic targets

Introduction: The human microbiome plays a critical role in human health, having metabolic, protective, and trophic functions, depending upon its’ exact composition. This composition is affected by a number of factors, including the genetic background of the individual, early life factors (including method of birth, length of breastfeeding) and nature of the diet and other environmental exposures (including cigarette smoking) and general life habits. It plays a key role in the control of inflammation, and in turn, its’ composition is significantly influenced by inflammation. Areas covered: We consider metabolic, protective, and trophic functions of the microbiome and influences through the lifespan from post-partum effects, to diet later in life in healthy older adults, the effects of aging on both its’ composition, and influence on health and potential therapeutic targets that may have anti-inflammatory effects. Expert commentary: The future will see the growth of more effective therapies targeting the microbiome particularly with respect to the use of specific nutrients and diets personalized to the individual

Environmental factors and risk of aggressive prostate cancer among a population of New Zealand men - a genotypic approach

Prostate cancer is one of the most significant health concerns for men worldwide. Numerous researchers carrying out molecular diagnostics have indicated that genetic interactions with biological and behavioral factors play an important role in the overall risk and prognosis of this disease. Single nucleotide polymorphisms (SNPs) are increasingly becoming strong biomarker candidates to identify susceptibility to prostate cancer. We carried out a gene × environment interaction analysis linked to aggressive and non-aggressive prostate cancer (PCa) with a number of SNPs. By using this method, we identified the susceptible alleles in a New Zealand population, and examined the interaction with environmental factors. We have identified a number of SNPs that have risk associations both with and without environmental interaction. The results indicate that certain SNPs are associated with disease vulnerability based on behavioral factors. The list of genes with SNPs identified as being associated with the risk of PCa in a New Zealand population is provided in the graphical abstrac