Tailoring Targeted Therapy to Individual Patients: Lessons to be Learnt from the Development of Mitomycin C

The modern era of targeted therapeutics offers the potential to tailor therapy to individual patients whose tumours express a specific target. Previous attempts to forecast tumour response to conventional chemotherapeutics based on similar principles have however been disappointing. Mitomycin C (MMC), for example, is a bioreductive drug that requires metabolic activation by cellular reductases for activity. The enzyme NAD(P)H:Quinone oxidoreductase-1 (NQO1) can reduce MMC to DNA damaging species but attempts to establish the relationship between tumour response to MMC and NQO1 expression have generated conflicting reports of good and poor correlations. Several other reductases are known to activate MMC. This, in conjunction with the fact that various physiological and biochemical factors influence therapeutic response, suggests that the mechanism of action of MMC is too complex to allow tumour response to be predicted on the basis of a single enzyme. Alternative approaches using more complex biological and pharmacological systems that reflect the spectrum of reductases present within the tumour have been developed and it remains to be seen whether or not the predictive value of these approaches is enhanced. With regards to targeted therapeutics, the experience with MMC suggests that prediction of tumour response based on analysis of a single target may be too simplistic. Multiple mechanisms of action and the influence of tumour microenvironment on cell biology and drug delivery are likely to influence the final outcome of therapy. The challenge for the future progression of this field is to develop assays that reflect the overall biological and pharmacological processes involved in drug activation whilst retaining the simplicity and robustness required for routine chemosensitivity testing in a clinical setting

Design, Synthesis and biological evaluation of novel acridine-polyamine conjugates against prostate cancer

Prostate cancer is the most common cause of cancer death in men, aged 85 and over. Androgen receptor, a single polypeptide with three functional domains is very important during initiation and progression of the disease. In this study, a DNA intercalating agent, acridine is linked to the testosterone via a polyamine linker to obtain a compound with trifunctional characteristics, where the acridine intercalates the DNA, the polyamine linker binds the phosphoryl groups of the DNA backbone and the testosterone moiety binds into the AR ligand binding domain, with which its DNA binding domain is bound already to the DNA. This trifunctional compound and related derivatives have been synthesized and tested against androgen dependent- and androgen independent- prostate cancer cell lines and they have demonstrated to be cytotoxic at the micromolar concentrations

GMM Estimation of Autoregressive Roots Near Unity with Panel Data

This paper investigates a generalized method of moments (GMM) approach to the estimation of autoregressive roots near unity with panel data. The two moment conditions studied are obtained by constructing bias corrections to the score functions under OLS and GLS detrending, respectively. It is shown that the moment condition under GLS detrending corresponds to taking the projected score on the Bhattacharya basis, linking the approach to recent work on projected score methods for models with infinite numbers of nuisance parameters (Waterman and Lindsay, 1998). Assuming that the localizing parameter makes a nonpositive value, we establish consistency of the GMM estimator and find its limiting distribution. A notable new finding is that the GMM estimator has convergence rate n^{1/6}, slower than root{n}, when the true localizing parameter is zero (i.e., when there is a panel unit root) and the deterministic trends in the panel are linear. These results, which rely on boundary point asymptotics, point to the continued difficulty of distinguishing unit roots from local alternatives, even when there is an infinity of additional data.Bias, boundary point asymptotics, GMM estimation, local to unity, moment conditions, nuisance parameters, panel data, pooled regression, projected score

Breakup of meteoroids in the Venusian atmosphere and its effects on crater formation

Early results of the Magellan mission to Venus show that almost all of the observed impact craters appear to be unaffected by erosion, burial, and tectonic deformation. Therefore it is reasonable to assume that the observed paucity of small craters in the cumulative size-frequency distribution (SFD) relative to the simple power laws observed on airless planets is most likely due to atmospheric effects on the incoming meteoroids. A model was developed earlier for travel and breakup of a meteoroid in an atmosphere, but this model was never used to estimate a SFD. An attempt is made to match the cumulative SFD and the number and size distribution of multiple-floored craters and crater fields using this model

From videocassette to video stream: Issues involved in re‐purposing an existing educational video

Conventional video recordings can be converted into video streams but the process can be complex and problematic. The authors’ experience of re‐purposing an existing video, Back Care for Health Professionals, for streaming is used to illustrate what was involved and to highlight the important issues. Financial, legal, technical and pedagogic issues are examined

The antigenic determinants and regulation of delayed hypersensitivity to staphylococcus aureus in mice

Imperial Users onl

GMM Estimation of Autoregressive Roots Near Unity with Panel Data

This paper investigates a generalized method of moments (GMM) approach to the estimation of autoregressive roots near unity with panel data and incidental deterministic trends. Such models arise in empirical econometric studies of firm size and in dynamic panel data modeling with weak instruments. The two moment conditions in the GMM approach are obtained by constructing bias corrections to the score functions under OLS and GLS detrending, respectively. It is shown that the moment condition under GLS detrending corresponds to taking the projected score on the Bhattacharya basis, linking the approach to recent work on projected score methods for models with infinite numbers of nuisance parameters (Waterman and Lindsay, 1998). Assuming that the localizing parameter takes a nonpositive value, we establish consistency of the GMM estimator and find its limiting distribution. A notable new finding is that the GMM estimator has convergence rate n/{1/6}, slower than /n, when the true localizing parameter is zero (i.e., when there is a panel unit root) and the deterministic trends in the panel are linear. These results, which rely on boundary point asymptotics, point to the continued difficulty of distinguishing unit roots from local alternatives, even when there is an infinity of additional data.Bias, boundary point asymptotics, GMM estimation, local to unity, moment conditions, nuisance parameters, panel data, pooled regression, projected score

World News

A group of environmental experts warned that four infrastructure projects in the Amazon have caused a rush of deforestation even before building has begun. The report on the world’s largest tropical forest, by international environmental experts charged with advising Brazil and rich countries donating to a program which has channeled $350 million to conserving the Amazon, came after data in June showed the Amazon deforestation rate jumped 40 percent last year. Profitable soy farming is seen as a special threat. Roughly 15 percent of the Amazon - an area larger than western Europe of continuous tropical forest that is home to up to 30 percent of the world’s animal and plant species - has so far been cut down