Atrial Natriuretic Peptide and Acute Changes in Central Blood Volume by Hyperthermia in Healthy Humans

BACKGROUND: Hyperthermia induces vasodilatation that reduces central blood volume (CBV), central venous pressure (CVP) and mean arterial pressure (MAP). Inhibition of atrial natriuretic peptide (ANP) could be a relevant homeostatic defense mechanism during hyperthermia with a decrease in CBV. The present study evaluated how changes in plasma ANP reflect the changes in CBV during hyperthermia. METHODS: Ten healthy subjects provided with a water perfused body suit increased body core temperature 1 °C. In situ labeled autologous red blood cells were used to measure the CBV with a gamma camera. Regions of interest were traced manually on the images of the whole body blood pool scans. Two measures of CBV were used: Heart/whole body ratio and thorax/whole body ratio. CVP and MAP were recorded. Arterial (ANP(art)) and venous plasma ANP were determined by radioimmunoassay. RESULTS: The ratio thorax/whole body and heart/whole body decreased 7 % and 11 %, respectively (p<0.001). MAP and CVP decreased during hyperthermia by 6.8 and 5.0 mmHg, respectively (p<0.05; p<0.001). Changes in both thorax/whole body (R=0.80; p<0.01) and heart/whole body ratios (R=0.78; p<0.01) were correlated with changes in ANP(art). However, there was no correlation between venous ANP and changes in CBV, nor between ANP(art) and MAP or CVP. CONCLUSION: Arterial but not venous plasma concentration of ANP, is correlated to changes in CBV, but not to pressures. We suggest that plasma ANP(art) may be used as a surrogate marker of acute CBV changes

A genetic basis for the variation in the vulnerability of cancer to DNA damage

Radiotherapy is not currently informed by the genetic composition of an individual patient's tumour. To identify genetic features regulating survival after DNA damage, here we conduct large-scale profiling of cellular survival after exposure to radiation in a diverse collection of 533 genetically annotated human tumour cell lines. We show that sensitivity to radiation is characterized by significant variation across and within lineages. We combine results from our platform with genomic features to identify parameters that predict radiation sensitivity. We identify somatic copy number alterations, gene mutations and the basal expression of individual genes and gene sets that correlate with the radiation survival, revealing new insights into the genetic basis of tumour cellular response to DNA damage. These results demonstrate the diversity of tumour cellular response to ionizing radiation and establish multiple lines of evidence that new genetic features regulating cellular response after DNA damage can be identified

TRIM24 links a non-canonical histone signature to breast cancer

Recognition of modified histone species by distinct structural domains within ‘reader’ proteins plays a critical role in the regulation of gene expression. Readers that simultaneously recognize histones with multiple marks allow transduction of complex chromatin modification patterns into specific biological outcomes. Here we report that chromatin regulator tripartite motif-containing 24 (TRIM24) functions in humans as a reader of dual histone marks by means of tandem plant homeodomain (PHD) and bromodomain (Bromo) regions. The three-dimensional structure of the PHD-Bromo region of TRIM24 revealed a single functional unit for combinatorial recognition of unmodified H3K4 (that is, histone H3 unmodified at lysine 4, H3K4me0) and acetylated H3K23 (histone H3 acetylated at lysine 23, H3K23ac) within the same histone tail. TRIM24 binds chromatin and oestrogen receptor to activate oestrogen-dependent genes associated with cellular proliferation and tumour development. Aberrant expression of TRIM24 negatively correlates with survival of breast cancer patients. The PHD-Bromo of TRIM24 provides a structural rationale for chromatin activation through a non-canonical histone signature, establishing a new route by which chromatin readers may influence cancer pathogenesis

Organizational learning via expatriate managers: Collective myopia as blocking mechanism

Qualitative case studies of two Japanese multinational department stores in Hong Kong are used to illustrate possible blocking mechanisms and collective myopia that hinder Japanese expatriate managers in acquiring double-loop organizational learning in their international assignments. Four major blocking mechanisms were identified - parent company community spirit, dozoku inhabitants, parent company\u27s translators and desire for normality. These blocking mechanisms were related to the Japanese head office\u27s culture, ideology and desire to control. They inhibited the expatriates from challenging established practices, procedures and norms, prevented them from becoming knowledgeable human agents, and hindered them from forming reflexivity. The expatriates, as a result, failed to learn from their international assignments. A conceptual model for expatriate learning and blocking mechanisms is drawn from the case examples, and implications for improving expatriate management to strengthen organizational learning are discussed. Copyright © 2005 SAGE Publications