Walter and Eliza Hall Institute of Medical Research

About: Walter and Eliza Hall Institute of Medical Research is a nonprofit organization based out in Melbourne, Victoria, Australia. It is known for research contribution in the topics: Antigen & Immune system. The organization has 5012 authors who have published 10620 publications receiving 873561 citations.

Optimizing the noise versus bias trade-off for Illumina whole genome expression BeadChips

Abstract: Five strategies for pre-processing intensities from Illumina expression BeadChips are assessed from the point of view of precision and bias. The strategies include a popular variance stabilizing transformation and model-based background corrections that either use or ignore the control probes. Four calibration data sets are used to evaluate precision, bias and false discovery rate (FDR). The original algorithms are shown to have operating characteristics that are not easily comparable. Some tend to minimize noise while others minimize bias. Each original algorithm is shown to have an innate intensity offset, by which unlogged intensities are bounded away from zero, and the size of this offset determines its position on the noise–bias spectrum. By adding extra offsets, a continuum of related algorithms with different noise–bias trade-offs is generated, allowing direct comparison of the performance of the strategies on equivalent terms. Adding a positive offset is shown to decrease the FDR of each original algorithm. The potential of each strategy to generate an algorithm with an optimal noise–bias trade-off is explored by finding the offset that minimizes its FDR. The use of control probes as part of the background correction and normalization strategy is shown to achieve the lowest FDR for a given bias.

Central administration of leptin to ovariectomized ewes inhibits food intake without affecting the secretion of hormones from the pituitary gland: evidence for a dissociation of effects on appetite and neuroendocrine function.

Abstract: We have studied the effect of leptin on food intake and neuroendocrine function in ovariectomized ewes. Groups (n = 5) received intracerebroventricular infusions of either vehicle or leptin (20 microg/h) for 3 days and were blood sampled over 6 h on days -1, 2, and for 3 h on day 3 relative to the onset of the infusion. The animals were then killed to measure hypothalamic neuropeptide Y expression by in situ hybridization. Plasma samples were assayed for metabolic parameters and pituitary hormones. Food intake was reduced by leptin, but did not change in controls. Leptin treatment elevated plasma lactate and nonesterified fatty acids, but did not affect glucose or insulin levels, indicating a state of negative energy balance that was met by the mobilization of body stores. Pulse analysis showed that the secretion of LH and GH was not affected by leptin treatment, nor were the mean plasma concentrations of FSH, PRL, or cortisol. Expression of messenger RNA for neuropeptide Y in the arcuate nucleus was reduced by the infusion of leptin, primarily due to reduced expression per cell rather than a reduction in the number of cells observed. Thus, the action of leptin to inhibit food intake is dissociated from neuroendocrine function. These results suggest that the metabolic effects of leptin are mediated via neuronal systems that possess leptin receptors rather than via endocrine effects.

A phase I clinical trial with monoclonal antibody ch806 targeting transitional state and mutant epidermal growth factor receptors

Abstract: An array of cell-surface antigens expressed by human cancers have been identified as targets for antibody-based therapies. The great majority of these antibodies do not have specificity for cancer but recognize antigens expressed on a range of normal cell types (differentiation antigens). Over the past two decades, our group has analyzed thousands of mouse monoclonal antibodies for cancer specificity and identified a battery of antibodies with limited representation on normal human cells. The most tumor-specific of these antibodies is 806, an antibody that detects a unique epitope on the epidermal growth factor receptor (EGFR) that is exposed only on overexpressed, mutant, or ligand-activated forms of the receptor in cancer. In vitro immunohistochemical specificity analysis shows little or no detectable 806 reactivity with normal tissues, even those with high levels of wild-type (wt)EGFR expression. Preclinical studies have demonstrated that 806 specifically targets a subset of EGFR expressed on tumor cells, and has significant anti-tumor effects on human tumor xenografts, primarily through abrogation of signaling pathways. The present clinical study was designed to examine the in vivo specificity of a chimeric form of mAb 806 (ch806) in a tumor targeting/biodistribution/pharmacokinetic analysis in patients with diverse tumor types. ch806 showed excellent targeting of tumor sites in all patients, no evidence of normal tissue uptake, and no significant toxicity. These in vitro and in vivo characteristics of ch806 distinguish it from all other antibodies targeting EGFR.