The Impact of p53 Dysfunction in ATR Inhibitor Cytotoxicity and Chemo- and Radiosensitisation.

Ataxia telangiectasia mutated and Rad3 related kinase (ATR) signals replication stress and DNA damage to S and G2 arrest and promotes DNA repair. Mutations in p53, critical for G1 checkpoint control, are common in cancer and predicted to confer vulnerability to ATR inhibitors. Reported data on the impact of p53 status are variable possibly because of the use of unmatched cells and surrogate endpoints of survival.

Common cancer-associated imbalances in the DNA damage response confer sensitivity to single agent ATR inhibition.

ATR is an attractive target in cancer therapy because it signals replication stress and DNA lesions for repair and to S/G2 checkpoints. Cancer-specific defects in the DNA damage response (DDR) may render cancer cells vulnerable to ATR inhibition alone. We determined the cytotoxicity of the ATR inhibitor VE-821 in isogenically matched cells with DDR imbalance.

Chk1 phosphorylated at serine345 is a predictor of early local recurrence and radio-resistance in breast cancer.

Radiation-induced DNA damage activates the DNA damage response (DDR). DDR up-regulation may predict radio-resistance and increase the risk of early local recurrence despite radiotherapy in early stage breast cancers. In 1755 early stage breast cancers, DDR signalling [ATM, ATR, total Ckh1, Chk1 phosphorylated at serine(345) (pChk1), Chk2, p53], base excision repair [PARP1, POLβ, XRCC1, FEN1, SMUG1], non-homologous end joining (Ku70/Ku80, DNA-PKcs) and homologous recombination [RAD51, BRCA1, γH2AX, BLM, WRN, RECQL5, PTEN] protein expression was correlated to time to early local recurrence.

Development of pharmacodynamic biomarkers for ATR inhibitors.

Background: ATR, which signals DNA damage to S/G2 cell cycle checkpoints and for repair, is an attractive target in cancer therapy. ATR inhibitors are being developed and a pharmacodynamic assay is needed to support clinical studies.

Methods: Phosphorylation of ATR targets, Chk1 and H2AX, was evaluated in MCF7 and K562 cells, human volunteer PBMCs and whole blood by Western blot, immunofluorescence microscopy and flow cytometry after DNA damage.

Implementing the National Hip Fracture Database: An audit of care.

Background: Hip fractures are common injuries in the elderly, with significant associated morbidity and mortality rates. The National Hip Fracture Database (NHFD) was implemented to audit care according to national standards thus improving its clinical and cost-effectiveness.

Patients And Methods: We retrospectively examined the care pathway for all hip fractures after its introduction at our centre over 1 year, with an audit of care according to the BOA-BGS 'Blue Book' guidelines.

Targeting the S and G2 checkpoint to treat cancer.

Cell survival following DNA damage depends on activating checkpoints to arrest proliferation. Most cancer cells have dysregulated G1 checkpoints making them dependent on their S and G2 checkpoints, which are activated by ATR/Chk1 signalling. Thus, inhibiting ATR or Chk1 should selectively sensitise cancer cells to DNA damage.

Radionuclide arthrogram with SPECT/CT for the evaluation of mechanical loosening of hip and knee prostheses.

Objective: To evaluate the value of SPECT/CT in radionuclide arthrogram (RNA) for the assessment of mechanical loosening of hip and knee prostheses.

Method: A retrospective audit of 117 RNA SPECT/CTs evaluated by a single reader--40 hips, (1 hemiarthroplasty) and 77 knees (12 unicompartmental). The detection of any radiotracer within the bone/prosthetic interface was deemed positive for loosening.

Unicondylar knee arthroplasty in a patient with poliomyelitis.

Osteoarthritis in patients who have had poliomyelitis creates a significant challenge. The loss, or reduction of power in the quadriceps, combined with recurvatum and often patella baja can cause problems when considering total knee arthroplasty. The authors present the first case report of a unicondylar knee arthroplasty in such a patient.

How accurate is Whiteside's line as a reference axis in total knee arthroplasty?

There is an increasing focus on the precision with which prostheses in the knee are inserted with advent of computer assisted surgery. Much attention has been paid to the differences between this and conventional alignment jig techniques. Both techniques however rely on accurate identification of bony morphology and utilising this information to correctly orientate the prosthesis.