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Manchester, United Kingdom

O'Connor J.P.B.,University of Manchester | Jayson G.C.,Paterson Institute for Cancer Research
Clinical Cancer Research | Year: 2012

The management of solid tumors has been transformed by the advent of VEGF pathway inhibitors. Early clinical evaluation of these drugs has used pharmacodynamic biomarkers derived from advanced imaging such as dynamic MRI, computed tomography (CT), and ultrasound to establish proof of principle. We have reviewed published studies that used these imaging techniques to determine whether the same biomarkers relate to survival in renal, hepatocellular, and brain tumors in patients treated with VEGF inhibitors. Data show that in renal cancer, pretreatment measurements of Ktrans and early pharmacodynamic reduction in tumor enhancement and density have prognostic significance in patients treated with VEGF inhibitors. A weaker, but significant, relationship is seen with subtle early size change (10% in one dimension) and survival. Data from high-grade glioma suggest that pretreatment fractional blood volume and Ktrans were prognostic of overall survival. However, lack of control data with other therapies prevents assessment of the predictive nature of these biomarkers, and such studies are urgently required. ©2012 AACR.

Gallagher J.T.,Paterson Institute for Cancer Research
Handbook of Experimental Pharmacology | Year: 2012

Heparan sulphate (HS), discovered in 1948 in heparin by-products, only emerged slowly from the shadow of heparin. Its inauspicious beginning was followed by the gradual realisation that HS was a separate entity with distinctive features. Both HS and heparin follow a common biosynthetic route but while heparin reaches full maturity, HS holds on to some of its youthful traits. The novel design and complex patterning of sulphation in HS enable it fulfil key roles in many, diverse biological processes. © 2012 Springer-Verlag Berlin Heidelberg.

Pines J.,Gurdon Institute | Hagan I.,Paterson Institute for Cancer Research
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2011

Orson Welles might have been a little unfair on the Swiss, after all cuckoo clocks were developed in the Schwartzwald, but, more importantly, Swiss democracy gives remarkably stable government with considerable decision-making at the local level. The alternative is the battling city-states of Renaissance Italy: culturally rich but chaotic at a higher level of organization. As our understanding of the cell cycle improves, it appears that the cell is organized more along the lines of Switzerland than Renaissance Italy, and one major challenge is to determine how local decisions are made and coordinated to produce the robust cell cycle mechanisms that we observe in the cell as a whole. © 2011 The Royal Society.

Gozdecka M.,Paterson Institute for Cancer Research | Breitwieser W.,Paterson Institute for Cancer Research
Biochemical Society Transactions | Year: 2012

MAPK (mitogen-activated protein kinase) pathways are among the most frequently deregulated signalling events in cancer. Among the critical targets of MAPK activities are members of the AP-1 (activator protein 1) transcription factor, a dimeric complex consisting of Jun, Fos, Maf and ATF (activating transcription factor) family DNA-binding proteins. Depending on the cellular context, the composition of the dimeric complexes determines the regulation of growth, survival or apoptosis. JNK (c-Jun N-terminal kinase), p38 and a number of Jun and Fos family proteins have been analysed for their involvement in oncogenic transformation and tumour formation. These data are also emerging for the ATF components of the AP-1 factor. The aim of the present review is to provide an overview of the functions of two ATF family proteins, ATF2 and ATF7, in mammalian development and their potential functions in tumour formation. ©The Authors Journal compilation ©2012 Biochemical Society.

Labib K.,Paterson Institute for Cancer Research | de Piccoli G.,Paterson Institute for Cancer Research
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2011

Checkpoints were originally identified as signalling pathways that delay mitosis in response to DNA damage or defects in chromosome replication, allowing time for DNA repair to occur. The ATR (ataxia- and rad-related) and ATM (ataxia-mutated) protein kinases are recruited to defective replication forks or to sites of DNA damage, and are thought to initiate the DNA damage response in all eukaryotes. In addition to delaying cell cycle progression, however, the S-phase checkpoint pathway also controls chromosome replication and DNA repair pathways in a highly complex fashion, in order to preserve genome integrity. Much of our understanding of this regulation has come from studies of yeasts, in which the best-characterized targets are the stimulation of ribonucleotide reductase activity by multiple mechanisms, and the inhibition of new initiation events at later origins of DNA replication. In addition, however, the S-phase checkpoint also plays a more enigmatic and apparently critical role in preserving the functional integrity of defective replication forks, by mechanisms that are still understood poorly. This review considers some of the key experiments that have led to our current understanding of this highly complex pathway. © 2011 The Royal Society.

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