SummaryHuman UDP-glucuronosyltransferases (UGT) are the dominant phase II conjugative drug metabolism enzymes that also play a central role in the processing of a range of endobiotic compounds. UGTs catalyze the covalent addition of glucuronic acid sugar moieties to a host of therapeutics and environmental toxins, as well as to a variety of endogenous steroids and other signaling molecules. We report the 1.8 Å resolution apo crystal structure of the UDP-glucuronic acid binding domain of human UGT isoform 2B7 (UGT2B7), which catalyzes the conjugative elimination of opioid, antiviral, and anticancer drugs. This is the first crystal structure of any region of a mammalian UGT drug metabolism enzyme. Designed UGT2B7 mutants at residues predicted to interact with the UDP-glucuronic acid cofactor exhibited significantly impaired catalytic activity, with maximum effects observed for amino acids closest to the glucuronic acid sugar transferred to the acceptor molecule. Homology modeling of UGT2B7 with related plant flavonoid glucosyltransferases indicate that human UGTs share a common catalytic mechanism. Point mutations at predicted catalytic residues in UGT2B7 abrogated activity, strongly suggesting that human UGTs also utilize a serine hydrolase-like catalytic mechanism to facilitate glucuronic acid transfer.

The preventive SSI bundle was associated with a substantial reduction in SSIs after colorectal surgery. The increased costs associated with SSIs support that the bundle represents an effective approach to reduce health care costs.

Background Controversy exists over whether resection of the primary tumor in stage IV colorectal cancer with inoperable metastases improves patient outcomes. Objective To evaluate whether resection of the primary tumor without metastasectomy in patients with stage IV colorectal cancer is associated with improved overall survival compared to patients undergoing chemotherapy and/or radiation therapy alone. Design The 2003–2006 National Cancer Data Base was reviewed to identify patients with stage IV adenocarcinoma of the colon or rectum who underwent palliative treatment without curative intent, either in the form of surgical resection of the primary tumor without metastasectomy consisting of a colectomy or rectal resection with or without chemotherapy and/or radiation, or chemotherapy and/or radiation alone. Groups were compared for baseline characteristics. Overall survival was compared using Kaplan-Meier analysis before and after propensity matching with a 1:1 nearest neighbor algorithm. Results Of the 1446 patients included in the analysis, 231 (16%) underwent surgical resection of the primary tumor without metastasectomy. Surgical resection was associated with a significant survival benefit upon unadjusted analysis (median survival: 9.2 months vs 7.6 months, p<0.01). After propensity matching to adjust for non-random treatment selection, surgical resection continued to be associated with a significant survival benefit (median survival 9.2 months vs 7.3 months p<0.01). Limitations Potential for selection bias regarding which patients received surgical resection. Lack of data regarding indication for operation, specifically whether a patient was symptomatic or asymptomatic prior to resection. Inability to account for tumor size or grade among patients who did not receive surgical resection. Conclusions Surgical resection of the primary tumor without metastasectomy in patients with metastatic colorectal cancer is associated with improved survival as compared to chemotherapy/radiation therapy alone. Further research is necessary to determine which patients may benefit from this intervention.

Alterations in nuclear factor kappa B (NF-κB) essential modulator (NEMO; HUGO-approved symbol IKBKG) underlie most cases of ectodermal dysplasia with immune deficiency (EDI), a human disorder characterized by anhidrosis with diminished immunity. EDI has also been associated with a single heterozygous mutation at position Ser32 of the NF-κB inhibitor IκBα, one of two phosphorylation sites that are essential for targeting IκBα for proteasomal degradation and hence for activation of NF-κB. We report a novel heterozygous nonsense mutation in the IKBA (HUGO-approved symbol, NFKBIA) gene of a 1-year-old male child with EDI that introduces a premature termination codon at position Glu14. An in-frame methionine downstream of the nonsense mutation allows for reinitiation of translation. The resulting N-terminally truncated protein lacks both serine phosphorylation sites and inhibits NF-κB signaling by functioning as a dominant negative on NF-κB activity in lymphocytes and monocytes. These findings support the scanning model for translation initiation in eukaryotes and confirm the critical role of the NF-κB in the human immune response.

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Prognostic and epidemiologic study, level III.

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Objective Thoracoabdominal aortic aneurysm (TAAA) repair remains a significant challenge with considerable perioperative morbidity and mortality. A hybrid approach visceral debranching with endovascular aneurysm exclusion has been used to treat high-risk patients and therefore to allow repair in more patients. Limited data exist regarding long-term outcomes with this procedure as well as comparison to conventional open repair. This study describes our institutional algorithmic approach to TAAA repair using both open and hybrid techniques. Methods Hybrid and open TAAA repairs performed between July 2005 and August 2015 were identified from a prospectively maintained institutional aortic surgery database. Perioperative morbidity and mortality, freedom from reintervention, and long-term and aorta-specific survival were calculated and compared between the two groups. Results During the study period, 165 consecutive TAAA repairs were performed, including 84 open repairs and 81 hybrid repairs. Patients in the hybrid repair group were significantly older, were more frequently female, and had a generally greater comorbid disease burden, including significantly more chronic kidney disease. Despite the older and sicker cohort, there was no difference in in-hospital mortality between the two groups (9.9% hybrid vs 7.1% open; P = .59). Major morbidity rates differed by procedure, with patients undergoing open repair having a significantly higher rate of postoperative stroke (9.5% open vs 0% hybrid; P = .017), whereas patients undergoing hybrid repair had a higher rate of new permanent dialysis (14.8% hybrid vs 3.6% open; P = .043). There was no difference between groups in the rate of postoperative permanent paraplegia/paresis (8.3% open vs 7.4% hybrid; P = .294). There was a significantly increased rate of reintervention in the hybrid repair group (12.3% hybrid vs 1.2% open, P = .004), with all hybrid reinterventions performed because of endoleak. One-year survival was similar between groups at 69% in hybrid repairs vs 77% in open repairs. Long-term survival was worse in the hybrid group (5-year survival, 32% hybrid vs 56% open), although late survival appeared to be influenced mainly by comorbid disease burden, given the similar long-term aorta-specific survival between groups. Conclusions Use of an algorithmic approach whereby higher risk patients with TAAA are treated by a hybrid approach and lower risk patients with conventional open repair yields satisfactory short- and long-term outcomes. The availability of multiple options for TAAA repair within a single center likely allows repair in more patients with consequent decrease in the risk of aorta-related death, at the expense of increased reinterventions for endoleak.