Integrated Pharmacodynamic Analysis Identifies Two Metabolic Adaption Pathways to Metformin in Breast Cancer.

Late-phase clinical trials investigating metformin as a cancer therapy are underway. However, there remains controversy as to the mode of action of metformin in tumors at clinical doses. We conducted a clinical study integrating measurement of markers of systemic metabolism, dynamic FDG-PET-CT, transcriptomics, and metabolomics at paired time points to profile the bioactivity of metformin in primary breast cancer. We show metformin reduces the levels of mitochondrial metabolites, activates multiple mitochondrial metabolic pathways, and increases 18-FDG flux in tumors. Two tumor groups are identified with distinct metabolic responses, an OXPHOS transcriptional response (OTR) group for which there is an increase in OXPHOS gene transcription and an FDG response group with increased 18-FDG uptake. Increase in proliferation, as measured by a validated proliferation signature, suggested that patients in the OTR group were resistant to metformin treatment. We conclude that mitochondrial response to metformin in primary breast cancer may define anti-tumor effect

International Construction Measurement Standards: Global Consistency in Presenting Construction Costs

This publication presents an international cost classification system for infrastructure projects. It aims to provide global consistency in classifying, defining, measuring, analysing and presenting the cost of infrastructure projects

On Smooth Time-Dependent Orbifolds and Null Singularities

We study string theory on a non-singular time-dependent orbifold of flat space, known as the `null-brane'. The orbifold group, which involves only space-like identifications, is obtained by a combined action of a null Lorentz transformation and a constant shift in an extra direction. In the limit where the shift goes to zero, the geometry of this orbifold reproduces an orbifold with a light-like singularity, which was recently studied by Liu, Moore and Seiberg (hep-th/0204168). We find that the backreaction on the geometry due to a test particle can be made arbitrarily small, and that there are scattering processes which can be studied in the approximation of a constant background. We quantize strings on this orbifold and calculate the torus partition function. We construct a basis of states on the smooth orbifold whose tree level string interactions are nonsingular. We discuss the existence of physical modes in the singular orbifold which resolve the singularity. We also describe another way of making the singular orbifold smooth which involves a sandwich pp-wave.Comment: 24 pages, one figur