Non-homologous DNA end joining in normal and cancer cells and its dependence on break structures

DNA double-strand breaks (DSBs) are a serious threat to the cell, for if not or miss-repaired, they can lead to chromosomal aberration, mutation and cancer. DSBs in human cells are repaired via non-homologous DNA end joining (NHEJ) and homologous recombination repair pathways. In the former process, the structure of DNA termini plays an important role, as does the genetic constitution of the cells, through being different in normal and pathological cells. In order to investigate the dependence of NHEJ on DSB structure in normal and cancer cells, we used linearized plasmids with various, complementary or non-complementary, single-stranded or blunt DNA termini, as well as whole-cell extract isolated from normal human lymphocytes, chronic myeloid leukemia K562 cells and lung cancer A549 cells. We observed a pronounced variability in the efficacy of NHEJ reaction depending on the type of ends. Plasmids with complementary and blunt termini were more efficiently repaired than the substrate with 3' protruding single-strand ends. The hierarchy of the effectiveness of NHEJ was on average, from the most effective to the least, A549/ normal lymphocytes/ K562. Our results suggest that the genetic constitution of the cells together with the substrate terminal structure may contribute to the efficacy of the NHEJ reaction. This should be taken into account on considering its applicability in cancer chemo- or radiotherapy by pharmacologically modulating NHEJ cellular responses

Accuracy of perfusion MRI with high spatial but low temporal resolution to assess invasive breast cancer response to neoadjuvant chemotherapy: a retrospective study

<p>Abstract</p> <p>Background</p> <p>To illustrate that Breast-MRI performed in high spatial resolution and low temporal resolution (1 minute) allows the measurement of kinetic parameters that can assess the final pathologic response to neoadjuvant chemotherapy in breast cancer.</p> <p>Methods</p> <p>Breast-MRI was performed in 24 women before and after treatment. Eight series of 1.11 minute-duration were acquired with a sub-millimeter spatial resolution. Transfer constant (K^trans) and leakage space (V_e) were calculated using measured and theoretical Arterial Input Function (AIF). Changes in kinetic parameters after treatment obtained with both AIFs were compared with final pathologic response graded in non-responder (< 50% therapeutic effect), partial-responder (> 50% therapeutic effect) and complete responder. Accuracies to identify non-responders were compared with receiver operating characteristic curves.</p> <p>Results</p> <p>With measured-AIF, changes in kinetic parameters measured after treatment were in agreement with the final pathological response. Changes in V_eand K^transwere significantly different between non-(N = 11), partial-(N = 7), and complete (N = 6) responders, (P = 0.0092 and P = 0.0398 respectively). A decrease in V_eof more than -72% and more than -84% for K^transresulted in 73% sensitivity for identifying non-responders (specificity 92% and 77% respectively). A decrease in V_eof more than -87% helped to identify complete responders (Sensitivity 89%, Specificity 83%). With theoretical-AIF, changes in kinetic parameters had lower accuracy.</p> <p>Conclusion</p> <p>There is a good agreement between pathological findings and changes in kinetic parameters obtained with breast-MRI in high spatial and low temporal resolution when measured-AIF is used. Further studies are necessary to confirm whether MRI contrast kinetic parameters can be used earlier as a response predictor to neoadjuvant chemotherapy.</p