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Olberg, Sven,Green, Olga,Cai, Bin,Yang, Deshan,Rodriguez, Vivian,Zhang, Hao,Kim, Jin Sung,Parikh, Parag J.,Mutic, Sasa,Park, Justin C. BioMed Central 2018 Radiation oncology Vol.13 No.-
<P><B>Background</B></P><P>To simplify the adaptive treatment planning workflow while achieving the optimal tumor-dose coverage in pancreatic cancer patients undergoing daily adaptive magnetic resonance image guided radiation therapy (MR-IGRT).</P><P><B>Methods</B></P><P>In daily adaptive MR-IGRT, the plan objective function constructed during simulation is used for plan re-optimization throughout the course of treatment. In this study, we have constructed the initial objective functions using two methods for 16 pancreatic cancer patients treated with the ViewRay™ MR-IGRT system: 1) the conventional method that handles the stomach, duodenum, small bowel, and large bowel as separate organs at risk (OARs) and 2) the OAR grouping method. Using OAR grouping, a combined OAR structure that encompasses the portions of these four primary OARs within 3 cm of the planning target volume (PTV) is created. OAR grouping simulation plans were optimized such that the target coverage was comparable to the clinical simulation plan constructed in the conventional manner. In both cases, the initial objective function was then applied to each successive treatment fraction and the plan was re-optimized based on the patient’s daily anatomy. OAR grouping plans were compared to conventional plans at each fraction in terms of coverage of the PTV and the optimized PTV (PTV OPT), which is the result of the subtraction of overlapping OAR volumes with an additional margin from the PTV.</P><P><B>Results</B></P><P>Plan performance was enhanced across a majority of fractions using OAR grouping. The percentage of the volume of the PTV covered by 95% of the prescribed dose (D<SUB>95</SUB>) was improved by an average of 3.87 ± 4.29% while D<SUB>95</SUB> coverage of the PTV OPT increased by 3.98 ± 4.97%. Finally, D<SUB>100</SUB> coverage of the PTV demonstrated an average increase of 6.47 ± 7.16% and a maximum improvement of 20.19%.</P><P><B>Conclusions</B></P><P>In this study, our proposed OAR grouping plans generally outperformed conventional plans, especially when the conventional simulation plan favored or disregarded an OAR through the assignment of distinct weighting parameters relative to the other critical structures. OAR grouping simplifies the MR-IGRT adaptive treatment planning workflow at simulation while demonstrating improved coverage compared to delivered pancreatic cancer treatment plans in daily adaptive radiation therapy.</P>
Detoxification: A Novel Function of BRCA1 in Tumor Suppression?
Kang, Hyo Jin,Hong, Young Bin,Kim, Hee Jeong,Rodriguez, Olga C.,Nath, Raghu G.,Tilli, Elena M.,Albanese, Christopher,Chung, Fung-Lung,Kwon, Sang Hoon,Bae, Insoo Oxford University Press 2011 Toxicological sciences Vol.122 No.1
<P>Our studies found that BRCA1 levels negatively correlate with DNA adducts induced by Benzo(a)pyrene (BaP). Pulse-chase experiments showed that the increase in BaP-induced DNA adducts in BRCA1 knockdown cells may not be associated with BRCA1’s function in nucleotide excision repair activity; rather, it may be associated with its function in modulating transcriptional regulation. BRCA1 knockdown in MCF-10A cells significantly attenuated the induction of CYP1A1 following BaP treatment indicating that the increase in BaP-induced adducts in BRCA1 knockdown cells is not CYP1A1 dependent. However, our study shows that BRCA1 defective cells may still be able to biotransform BaP by regulating other CYP enzymes, including CYP1B1. Knockdown of BRCA1 also severely affected the expression levels of two types of uridine diphosphate glucorunyltransferase (UGT1A1 and UGT1A9) and NRF2. Both UGTs are known as BaP-specific detoxification enzymes, and NRF2 is a master regulator of antioxidant and detoxification genes. Thus, we concluded that the increased amount of BaP-induced DNA adducts in BRCA1 knockdown cells is strongly associated with its loss of functional detoxification. Chromatin immunoprecipitation assay revealed that BRCA1 is recruited to the promoter/enhancer sequences of UGT1A1, UGT1A9, and NRF2. Regulation of UGT1A1 and UGT1A9 expression showed that the induction of DNA adducts by BaP is directly affected by their expression levels. Finally, overexpression of UGTs, NRF2, or ARNT significantly decreased the amount of BaP-induced adducts in BRCA1-deficient cells. Overall, our results suggest that BRCA1 protects cells by reducing the amount of BaP-induced DNA adducts possibly via transcriptional activation of detoxification gene expression.</P>