Person: Willers, Henning
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Willers
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Henning
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Willers, Henning
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Publication Effects of Charged Particles on Human Tumor Cells(Frontiers Media S.A., 2016) Held, Kathryn; Kawamura, Hidemasa; Kaminuma, Takuya; Paz, Athena Evalour S.; Yoshida, Yukari; Liu, Qi; Willers, Henning; Takahashi, AkihisaThe use of charged particle therapy in cancer treatment is growing rapidly, in large part because the exquisite dose localization of charged particles allows for higher radiation doses to be given to tumor tissue while normal tissues are exposed to lower doses and decreased volumes of normal tissues are irradiated. In addition, charged particles heavier than protons have substantial potential clinical advantages because of their additional biological effects, including greater cell killing effectiveness, decreased radiation resistance of hypoxic cells in tumors, and reduced cell cycle dependence of radiation response. These biological advantages depend on many factors, such as endpoint, cell or tissue type, dose, dose rate or fractionation, charged particle type and energy, and oxygen concentration. This review summarizes the unique biological advantages of charged particle therapy and highlights recent research and areas of particular research needs, such as quantification of relative biological effectiveness (RBE) for various tumor types and radiation qualities, role of genetic background of tumor cells in determining response to charged particles, sensitivity of cancer stem-like cells to charged particles, role of charged particles in tumors with hypoxic fractions, and importance of fractionation, including use of hypofractionation, with charged particles.Publication A single-nucleotide polymorphism in the methylene tetrahydrofolate reductase (MTHFR) gene is associated with risk of radiation pneumonitis in lung cancer patients treated with thoracic radiation therapy(Wiley-Blackwell, 2011) Mak, Raymond; Alexander, Brian; Asomaning, Kofi; Suk Heist, Rebecca; Liu, Chen-yu; Su, Li; Zhai, Rihong; Ancukiewicz, Marek; Napolitano, Brian; Niemierko, Andrzej; Willers, Henning; Choi, Noah; Christiani, DavidBackground: To study the association between functional single nucleotide polymorphisms (SNPs) in candidate genes from oxidative stress pathways, and risk of radiation pneumonitis (RP) in patients treated with thoracic radiation therapy (RT) for locally advanced lung cancer (LC). Methods: We reviewed 136 patients treated with RT for LC between 2001 and 2007, and had prior genotyping of functional SNPs in oxidative stress genes including superoxide dismutase 2 (SOD2; rs4880) and methylenetetrahydrofolate reductase (MTHFR; rs1801131, rs1801133). RP events were retrospectively scored using the Common Terminology Criteria for Adverse Events, version 4.0. Cox proportional hazard regression was performed to identify clinical variables and genotypes associated with risk of grade ≥2 and grade ≥3 RP on univariate and multivariate analysis. P-values were corrected for multiple hypothesis testing. Results: With a median follow-up of 21.4 months, the incidence of ≥grade 2 RP was 29% and ≥grade 3 RP was 14%. On multivariate analysis, after adjusting for clinical factors such as concurrent chemotherapy, and consolidation docetaxel, and lung dosimetric parameters such as V20 and mean lung dose, MTHFR genotype (rs1801131; AA versus AC/CC) was significantly associated with risk of ≥grade 2 RP (Hazard ratio [HR]: 0.37; 95% confidence interval [CI]: 0.18-0.76; p=0.006, corrected p=0.018) and ≥grade 3 RP (HR: 0.21; 95% CI: 0.06-0.70; p=0.01; corrected p=0.03). SOD2 genotype was not associated with RP. Conclusions: Our study showed an association between MTHFR genotype and risk of clinically significant RP. Further study of MTHFR-related pathways may provide insight into the mechanisms behind RP.Publication Recombinational DNA Repair in Cancer and Normal Cells: The Challenge of Functional Analysis(Hindawi Publishing Corporation, 2002) Willers, Henning; Xia, Fen; Powell, Simon N.A major goal of current cancer research is to understand the functional consequences of mutations in recombinational DNA repair genes. The introduction of artificial recombination substrates into living cells has evolved into a powerful tool to perform functional analysis of DNA double strand break (DSB) repair. Here, we review the principles and practice of current plasmid assays with regard to the two major DSB repair pathways, homologous recombination and nonhomologous end-joining. A spectrum of assay types is available to assess repair in a wide variety of cell lines. However, several technical challenges still need to be overcome. Understanding the alterations of DSB repair in cancers will ultimately provide a rational basis for drug design that may selectively sensitize tumor cells to ionizing radiation and chemotherapy, thereby achieving therapeutic gain.Publication Hierarchy of Nonhomologous End-joining, Single-strand Annealing and Gene Conversion at Site-directed DNA Double-strand Breaks(Oxford University Press, 2008) Mansour, Wael Y.; Schumacher, Sabine; Rosskopf, Raphael; Rhein, Tim; Schmidt-Petersen, Filip; Gatzemeier, Fruszina; Haag, Friedrich; Borgmann, Kerstin; Willers, Henning; Dahm-Daphi, JochenIn mammalian cells, DNA double-strand breaks (DSBs) are repaired by three pathways, nonhomologous end-joining (NHEJ), gene conversion (GC) and single-strand annealing (SSA). These pathways are distinct with regard to repair efficiency and mutagenic potential and must be tightly controlled to preserve viability and genomic stability. Here, we employed chromosomal reporter constructs to characterize the hierarchy of NHEJ, GC and SSA at a single I-SceI-induced DSB in Chinese hamster ovary cells. We discovered that the use of GC and SSA was increased by 6- to 8-fold upon loss of Ku80 function, suggesting that NHEJ is dominant over the other two pathways. However, NHEJ efficiency was not altered if GC was impaired by Rad51 knockdown. Interestingly, when SSA was made available as an alternative mode for DSB repair, loss of Rad51 function led to an increase in SSA activity at the expense of NHEJ, implying that Rad51 may indirectly promote NHEJ by limiting SSA. We conclude that a repair hierarchy exists to limit the access of the most mutagenic mechanism, SSA, to the break site. Furthermore, the cellular choice of repair pathways is reversible and can be influenced at the level of effector proteins such as Ku80 or Rad51.Publication Distinct roles of XRCC4 and Ku80 in non-homologous end-joining of endonuclease- and ionizing radiation-induced DNA double-strand breaks(Oxford University Press, 2008) Schulte-Uentrop, Leonie; El-Awady, Raafat A.; Schliecker, Lena; Willers, Henning; Dahm-Daphi, JochenNon-homologous end-joining (NHEJ) of DNA double-strand breaks (DSBs) is mediated by two protein complexes comprising Ku80/Ku70/DNA-PKcs/Artemis and XRCC4/LigaseIV/XLF. Loss of Ku or XRCC4/LigaseIV function compromises the rejoining of radiation-induced DSBs and leads to defective V(D)J recombination. In this study, we sought to define how XRCC4 and Ku80 affect NHEJ of site-directed chromosomal DSBs in murine fibroblasts. We employed a recently developed reporter system based on the rejoining of I-SceI endonuclease-induced DSBs. We found that the frequency of NHEJ was reduced by more than 20-fold in XRCC4−/− compared to XRCC4+/+ cells, while a Ku80 knock-out reduced the rejoining efficiency by only 1.4-fold. In contrast, lack of either XRCC4 or Ku80 increased end degradation and shifted repair towards a mode that used longer terminal microhomologies for rejoining. However, both proteins proved to be essential for the repair of radiation-induced DSBs. The remarkably different phenotype of XRCC4- and Ku80-deficient cells with regard to the repair of enzyme-induced DSBs mirrors the embryonic lethality of XRCC4 knock-out mice as opposed to the viability of the Ku80 knock-out. Thus, I-SceI-induced breaks may resemble DSBs arising during normal DNA metabolism and mouse development. The removal of these breaks likely has different genetic requirements than the repair of radiation-induced DSBs.