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Item Defective Resection at DNA Double-Strand Breaks Leads to De Novo Telomere Formation and Enhances Gene Targeting(Public Library of Science, 2010-05-13) Chung, Woo-Hyun; Zhu, Zhu; Papusha, Alma; Malkova, Anna; Ira, Grzegorz; Biology, School of ScienceThe formation of single-stranded DNA (ssDNA) at double-strand break (DSB) ends is essential in repair by homologous recombination and is mediated by DNA helicases and nucleases. Here we estimated the length of ssDNA generated during DSB repair and analyzed the consequences of elimination of processive resection pathways mediated by Sgs1 helicase and Exo1 nuclease on DSB repair fidelity. In wild-type cells during allelic gene conversion, an average of 2–4 kb of ssDNA accumulates at each side of the break. Longer ssDNA is formed during ectopic recombination or break-induced replication (BIR), reflecting much slower repair kinetics. This relatively extensive resection may help determine sequences involved in homology search and prevent recombination within short DNA repeats next to the break. In sgs1Δ exo1Δ mutants that form only very short ssDNA, allelic gene conversion decreases 5-fold and DSBs are repaired by BIR or de novo telomere formation resulting in loss of heterozygosity. The absence of the telomerase inhibitor, PIF1, increases de novo telomere pathway usage to about 50%. Accumulation of Cdc13, a protein recruiting telomerase, at the break site increases in sgs1Δ exo1Δ, and the requirement of the Ku complex for new telomere formation is partially bypassed. In contrast to this decreased and alternative DSB repair, the efficiency and accuracy of gene targeting increases dramatically in sgs1Δ exo1Δ cells, suggesting that transformed DNA is very stable in these mutants. Altogether these data establish a new role for processive resection in the fidelity of DSB repair.Item Klatskin Tumor in the Light of ICD-O-3: A Population-Based Clinical Outcome Study Involving 1,144 Patients from the Surveillance, Epidemiology, and End Result (SEER) Database (2001-2012)(Cureus, 2021-10-21) Khan, Jaffar; Ullah, Asad; Matolo, Nathaniel; Waheed, Abdul; Nama, Noor; Khan, Tahir; Tareen, Bisma; Khan, Zarmina; Singh, Sohni G.; Cason, Frederick D.; Pathology and Laboratory Medicine, School of MedicineIntroduction: Klatskin tumors (KTs) occur at the confluence of the right and left extrahepatic ducts and are classified based on their anatomical and histological codes in the International Classification of Diseases for Oncology (ICD-O). The second edition of the ICD-O (ICD-O-2) allocated a distinctive histological code to KT, which also included intrahepatic cholangiocarcinoma (CC). This unclear coding may result in ambiguous reporting of the demographic and clinical features of KT. The current study aimed to investigate the demographic, clinical, and pathological factors affecting the prognosis and survival of KT in the light of the updated third edition of ICD-O, Ninth Revision (ICD-O-3). Methods: Data of 1,144 patients with KT from the Surveillance, Epidemiology, and End Result (SEER) database (2001-2012) were extracted. Patients with KT were analyzed for age, sex, race, stage, treatment, and long-term survival. The data were analyzed using chi-square tests, t-tests, and univariate and multivariate analyses. The Kaplan-Meier analysis was used to compare long-term survival between KT and subgroups of all biliary CCs. Results: Of all biliary CCs, KT comprised 9.35%, with a mean age of diagnosis of 73±13 years, and was more common in men (54.8%) and Caucasian patients (69.5%). Histologically, moderately differentiated tumors were the most common (38.9%) followed by poorly differentiated (35.7%), well-differentiated (23.3%), and undifferentiated tumors (2.2%) (p<0.001). Most tumors in the KT group were 2-4 cm in size (41.5%), while fewer were >4 cm (29.7%) and <2 cm (28.8%) (p<0.001). ICD-O-3 defined most KTs in extrahepatic location (53.5%), while the remainder were in other biliary locations (46.5%) (p<0.001). Most KT patients received no treatment (73%), and for those who were treated, the most frequent modality was radiation (52.7%), followed by surgery (28.1%), and both surgery and radiation (19.2%) (p<0.001). Mean survival time for KT patients treated with surgery was inferior to all CCs of the biliary tree (1.72±2.61 vs. 1.87±2.18 years) (p=0.047). Multivariate analysis identified regional metastasis (OR=2.8; 95% CI=2.6-3.0), distant metastasis (OR=2.1; 95% CI=1.9-2.4), lymph node positivity (OR=1.6; 95% CI=1.4-1.8), Caucasian race (OR=2.0; 95% CI=1.8-2.2), and male sex (OR=1.2; 95% CI=1.1-1.3) were independently associated with increased mortality for KT (p<0.001). Conclusion: The ICD-O-3 has permitted a greater understanding of KT. KT is a rare and lethal biliary malignancy that presents most often in Caucasian men in their seventh decade of life with moderately differentiated histology. Surgical resection does not provide any survival advantage compared to similarly treated biliary CCs. In addition, the combination of surgery and radiation appeared to provide no added survival benefits compared to other treatment modalities for KT.