In vivo Loss of Expression of Argininosuccinate Synthetase in Malignant Pleural Mesothelioma is a Biomarker for Susceptibility to Arginine Depletion.

Purpose: Malignant pleural mesothelioma (MPM) is an increasing health burden on many societies worldwide and, being generally resistant to conventional treatment, has a poor prognosis with a median survival of <1 year. Novel therapies based on the biology of this tumor seek to activate a proapoptotic cellular pathway. In this study, we investigated the expression and biological significance of argininosuccinate synthetase (AS), a rate-limiting enzyme in arginine production. Experimental Design: Initially, we documented down-regulation of AS mRNA in three of seven MPM cell lines and absence of AS protein in four of seven MPM cell lines. We confirmed that the 9q34 locus, the site of the AS gene, was intact using a 1-Mb comparative genomic hybridization array; however, there was aberrant promoter CpG methylation in cell lines lacking AS expression, consistent with epigenetic regulation of transcription. To investigate the use of AS negativity as a therapeutic target, arginine was removed from the culture medium of the MPM cell lines. Results: In keeping with the cell line data, 63% (52 of 82) of patients had tumors displaying reduced or absent AS protein, as assessed using a tissue microarray. Cell viability declined markedly in the AS-negative cell lines 2591 and MSTO but not in the AS-positive cell line, 28. This response was apparent by day 4 and maintained by day 9 in vitro. Arginine depletion induced BAX conformation change and mitochondrial inner membrane depolarization selectively in AS-negative MPM cells. Conclusions: In summary, we have identified AS negativity as a frequent event in MPM in vivo, leading to susceptibility to cytotoxicity following restriction of arginine. A phase II clinical trial is planned to evaluate the role of arginine depletion in patients with AS-negative MPM

Developing practice in breastfeeding

This paper reports on an approach to practice development in breastfeeding as part of a national programme of work to address inequalities in maternal and child nutrition. The production and dissemination of evidence and guidelines is necessary but not sufficient on its own to effect change in practice, particularly when dealing with complex public health issues. In the case of breastfeeding, review evidence and national guidance have shown that multifaceted changes are essential if policy aspirations are to be realized. The objectives of the programme described here were to (1) inform and enable practice development in breastfeeding in low-income areas; (2) evaluate the impact of approaches used; and (3) develop robust approaches and appropriate material for use nationally. A conceptual framework was established, and a six-stage process is outlined. The recruitment of four sentinel sites across whole health economies, involving professionals and the voluntary sector, was an essential component of the programme. The strength of the model is that it provides a structured, cross-sectoral approach to practice development in public health. A key challenge is to identify whose responsibility it is to resource practice development when a number of disciplines and sectors are involved. This question needs to be addressed if public health guidance is to be of sustained benefit