RAD51D splice variants and cancer-associated mutations reveal XRCC2 interaction to be critical for homologous recombination.

The proficiency of cancer cells to repair DNA double-strand breaks (DSBs) by homologous recombination (HR) is a key determinant in predicting response to targeted therapies such as PARP inhibitors. The RAD51 paralogs work as multimeric complexes and act downstream of BRCA1 to facilitate HR. Numerous epidemiological studies have linked RAD51 paralog mutations with hereditary cancer predisposition. Despite their substantial links to cancer, RAD51 paralog HR function has remained elusive. Here we identify isoform 1 as the functional isoform of RAD51D, whereas isoform 4 which has a large N-terminal deletion (including the Walker A motif), and isoform 6 which includes an alternate exon in the N-terminus, are non-functional. To determine the importance of this N-terminal region, we investigated the impact of cancer-associated mutations and SNPs in this variable RAD51D N-terminal region using yeast-2-hybrid and yeast-3-hybrid assays to screen for altered protein-protein interactions. We identified two cancer-associated mutations close to or within the Walker A motif (G96C and G107 V, respectively) that independently disrupt RAD51D interaction with XRCC2. We validated our yeast interaction data in human U2OS cells by co-immunoprecipitation and determined the impact of these mutations on HR-proficiency using a sister chromatid recombination reporter assay in a RAD51D knock-out cell line. Our investigation reveals that the interaction of RAD51D with XRCC2 is required for DSB repair. By characterizing the impact of cancer-associated mutations on RAD51D interactions, we aim to develop predictive models for therapeutic sensitivity and resistance in patients who harbor similar mutations in RAD51D.

Correction to: Evolution of a Novel Robotic Training Curriculum in a Complex General Surgical Oncology Fellowship.

In the XML of the original article, L. Mark Knab's first name was tagged incorrectly.

Evolution of a Novel Robotic Training Curriculum in a Complex General Surgical Oncology Fellowship.

BACKGROUND: Robotic surgery is increasingly being used for complex oncologic operations, although currently there is no standardized curriculum in place for surgical oncologists. We describe the evolution of a proficiency-based robotic training program implemented for surgical oncology fellows, and demonstrate the outcomes of the program. METHODS: A 5-step robotic curriculum began integration in July 2013. Fellows from July 2013 to August 2017 were included. An education portfolio was created for each fellow, including pre-fellowship experience, fellowship experience with data from robotic curriculum and operative experience, and post-fellowship practice information. RESULTS: Of 30 fellows, 20% completed a prior fellowship, 97% trained at an academic residency, 57% had prior robotic training (median 5 h), and 43% had performed robotic surgery (median 0 cases). In fellowship, on average, fellows spent 5 h on the virtual reality curriculum and performed 19 biotissue anastomoses. For total surgeries, fellows operating from the console increased over time (p = 0.005). For pancreas, the average percentage of robotic pancreaticoduodenectomy (PD) steps completed increased (p < 0.011), as did the number of PDs in which the fellow completed the entire resection (p = 0.013). Fellows were 10 times more likely to complete the entire distal than PD from the console (p < 0.01). Post-fellowship, 83% of fellows obtained an academic position, 88% utilized robotics, and 91% performed pancreatic surgery. CONCLUSIONS: With dedicated training, fellows can safely primarily perform complex gastrointestinal robotic surgeries and, after graduation, take jobs incorporating this skill set. In this era of scrutiny on cost and outcomes, specialized training programs offer a safe integration option for complex technical skills.