APOBEC cytidine deaminase activity is a major source of hypermutation in cancer. But previous studies have shown that the TC context signature of these enzymes is not observed in sizable fractions of cancers with overexpression of APOBEC, suggesting that cooperating factors that contribute to this mutagenesis should be identified. The fragile histidine triad protein (Fhit) is a tumor suppressor and DNA caretaker that is deleted or silenced in >50% of cancers. Loss of Fhit protein activity causes replication stress through reduced Thymidine Kinase 1 expression, increased DNA breaks, and global genome instability in normal and cancer cells. Using data from The Cancer Genome Atlas (TCGA), we show that FHIT-low/APOBEC3B-high expressing lung adenocarcinomas display significantly increased numbers of APOBEC signature mutations. Tumor samples in this cohort with normal FHIT expression do not exhibit APOBEC hypermutation, despite having high APOBEC3B expression. In vitro, silencing Fhit expression elevates APOBEC3B-directed C > T mutations in the TP53 gene. Furthermore, inhibition of Fhit loss-induced DNA damage via thymidine supplementation decreases the TP53 mutation burden in FHIT-low/APOBEC3B-high cells. We conclude that APOBEC3B overexpression and Fhit-loss induced DNA damage are independent events that, when occurring together, result in a significantly increased frequency of APOBEC-induced mutations that drive cancer progression.

FHIT is a genome caretaker gene that is silenced in >50% of cancers. Loss of Fhit protein expression promotes accumulation of DNA damage, affects apoptosis and epithelial-mesenchymal transition, though molecular mechanisms underlying these alterations have not been fully elucidated. Initiation of genome instability directly follows Fhit loss and the associated reduced Thymidine Kinase 1 (TK1) protein expression. The effects on TK1 of Fhit knockdown and Fhit induction in the current study confirmed the role of Fhit in regulating TK1 expression. Changes in Fhit expression did not impact TK1 protein turnover or transcription from the TK1 promoter, nor steady-state levels of TK1 mRNA or turnover. Polysome profile analysis showed that up-regulated Fhit expression resulted in decreased TK1 RNA in non-translating messenger ribonucleoproteins and increased ribosome density on TK1 mRNA. Fhit does not bind RNA but its expression increased luciferase expression from a transgene bearing the TK1 5’-UTR. Fhit has been reported to act as a scavenger decapping enzyme, and a similar result with a mutant (H96) that binds but does not cleave nucleoside 5’,5’-triphosphates suggests the impact on TK1 translation is due to its ability to modulate the intracellular level of cap-like molecules. Consistent with this, cells expressing Fhit mutants with reduced activity toward cap-like dinucleotides exhibit DNA damage resulting from TK1 deficiency, whereas cells expressing wild-type Fhit or the H96N mutant do not. The results have implications for the mechanism by which Fhit regulates TK1 mRNA, and more broadly, for its modulation of multiple functions as tumor suppressor/genome caretaker.

Objective: There are limited data evaluating the impact of preoperative albumin levels in patients undergoing vascular procedures. This study evaluated the relationship of preoperative albumin levels with outcome after lower extremity (LE) vascular procedures for peripheral artery disease (PAD). Methods: Patients with PAD admitted for elective LE procedures between September 2008 and December 2015 were selected from the Cerner Health Facts database using International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis and procedure codes and preoperative laboratory values. Multivariable logistic regression was used to examine the association of patient characteristics, procedure type, and low preoperative albumin levels (<3.5 g/dL) with seven critical postoperative outcomes. Results: Of 4087 patients who underwent LE procedures for PAD, 1288 (31.5%) had preoperative albumin levels <3.5 g/dL. Lower albumin levels were associated with older patients, female patients, those with tissue loss, and black patients (P < .05). On average, compared with patients with normal preoperative albumin levels ($3.5 g/dL), patients with low preoperative albumin levels experienced longer hospital stays (6.1 vs 2.4 days; P < .0001); higher rates of postprocedure infection (24.5% vs 5.6%; P < .0001), in-hospital mortality (2.5% vs 0.3%; P < .0001), and 30day readmission (15.5% vs 13.1%; P ¼ .04); and more acute problems and complications. Multivariable logistic regression found that patients with low preoperative albumin levels were 2.6 times as likely to have an infectious complication (odds ratio [OR], 2.64; 95% confidence interval [CI], 2.10-3.32), 5.2 times as likely to die in the hospital (OR, 5.16; 95% CI, 2.34-11.39), and 2.4 times as likely to experience renal failure (OR, 2.47; 95% CI, 1.77-3.46) and cardiac complications (OR, 2.43; 95% CI, 1.66-3.57). Conclusions: LE procedures are performed for a variety of indications; the majority of these are not related to critical limb ischemia and are elective. In patients with low preoperative albumin levels, we strongly recommend deferring elective LE procedures for PAD, given the association with death and severe complications postoperatively. If LE procedures are necessary because of the severity of PAD, the role of preoperative nutritional optimization should be considered before intervention.