No abstract

Base excision repair (BER), which is initiated by DNA N-glycosylase proteins, is the frontline for repairing potentially mutagenic DNA base damage. The NTHL1 glycosylase, which excises DNA base damage caused by reactive oxygen species, is thought to be a tumor suppressor. However, in addition to NTHL1 loss-of-function mutations, our analysis of cancer genomic datasets reveals that NTHL1 frequently undergoes amplification or upregulation in some cancers. Whether NTHL1 overexpression could contribute to cancer phenotypes has not yet been explored. To address the functional consequences of NTHL1 overexpression, we employed transient overexpression. Both NTHL1 and a catalytically-dead NTHL1 (CATmut) induce DNA damage and genomic instability in non-transformed human bronchial epithelial cells (HBEC) when overexpressed. Strikingly, overexpression of either NTHL1 or CATmut causes replication stress signaling and a decrease in homologous recombination (HR). HBEC cells that overexpress NTHL1 or CATmut acquire the ability to grow in soft agar and exhibit loss of contact inhibition, suggesting that a mechanism independent of NTHL1 catalytic activity contributes to acquisition of cancer-related cellular phenotypes. We provide evidence that NTHL1 interacts with the multifunctional DNA repair protein XPG suggesting that interference with HR is a possible mechanism that contributes to acquisition of early cellular hallmarks of cancer.

Background: Total ankle arthroplasty (TAA) utilization is increasing in the United States. As the incidence of this procedure grows, it is important for providers to understand the future projections for ankle arthroplasty and more importantly revision total ankle arthroplasty (rTAA). Methods: The National Inpatient Sample (USA) was queried from 2005 to 2017 for all TAA and rTAA. Poisson and linear regression analysis was performed to project annual incidence of TAA and rTAA to 2030, with subgroup analyses on septic rTAA. Results: There were 5315 TAAs performed in 2017, a 564% ( P < .001) increase when compared with the TAAs performed in 2005. From 2017 to 2030, the incidence of TAAs is projected to increase from 110% to 796% ( P < .001). There were 1170 rTAAs performed in 2017, a 155% ( P < .001) increase when compared with rTAAs performed in 2005. There was a 256% increase in the incidence of septic rTAAs from 2005 to 2017 with a projected increase between 22% and 120% by 2030. Conclusions: The incidence of both TAAs and rTAAs is projected to significantly increase over the next decade. Given the known risk factors of TAA and rTAA, these findings reinforce the need for thoughtful consideration when selecting patients for TAA.

Thrombotic thrombocytopenic purpura (TTP) is an uncommon and potentially lethal microangiopathy that carries a >90% mortality rate if not treated urgently and appropriately. Postoperative TTP after orthopaedic procedures is particularly rare with only four case reports existing in the literature. We present the case of postoperative TTP in a 57-year-old female who underwent elective total hip arthroplasty. We believe this case adds to the limited literature surrounding the topic. While rare, TTP after orthopaedic procedures poses a real and potentially fatal condition if not managed appropriately. Therefore, it is essential for orthopaedic surgeons to be cognizant of postoperative TTP for timely diagnosis and treatment.