The Asymmetric Binding of PGC-1α to the ERRα and ERRγ Nuclear Receptor Homodimers Involves a Similar Recognition Mechanism

Background: PGC-1a is a crucial regulator of cellular metabolism and energy homeostasis that functionally acts togetherwith the estrogen-related receptors (ERRa and ERRc) in the regulation of mitochondrial and metabolic gene networks.Dimerization of the ERRs is a pre-requisite for interactions with PGC-1a and other coactivators, eventually leading totransactivation. It was suggested recently (Devarakonda et al) that PGC-1a binds in a strikingly different manner to ERRcligand-binding domains (LBDs) compared to its mode of binding to ERRa and other nuclear receptors (NRs), where itinteracts directly with the two ERRc homodimer subunits.Methods/Principal Findings: Here, we show that PGC-1a receptor interacting domain (RID) binds in an almost identicalmanner to ERRa and ERRc homodimers. Microscale thermophoresis demonstrated that the interactions between PGC-1aRID and ERR LBDs involve a single receptor subunit through high-affinity, ERR-specific L3 and low-affinity L2 interactions.NMR studies further defined the limits of PGC-1a RID that interacts with ERRs. Consistent with these findings, the solutionstructures of PGC-1a/ERRa LBDs and PGC-1a/ERRc LBDs complexes share an identical architecture with an asymmetricbinding of PGC-1a to homodimeric ERR.Conclusions/Significance: These studies provide the molecular determinants for the specificity of interactions betweenPGC-1a and the ERRs, whereby negative cooperativity prevails in the binding of the coactivators to these receptors. Ourwork indicates that allosteric regulation may be a general mechanism controlling the binding of the coactivators tohomodimers

The impact of surgical delay on resectability of colorectal cancer: An international prospective cohort study

AimThe SARS-CoV-2 pandemic has provided a unique opportunity to explore the impact of surgical delays on cancer resectability. This study aimed to compare resectability for colorectal cancer patients undergoing delayed versus non-delayed surgery.MethodsThis was an international prospective cohort study of consecutive colorectal cancer patients with a decision for curative surgery (January-April 2020). Surgical delay was defined as an operation taking place more than 4 weeks after treatment decision, in a patient who did not receive neoadjuvant therapy. A subgroup analysis explored the effects of delay in elective patients only. The impact of longer delays was explored in a sensitivity analysis. The primary outcome was complete resection, defined as curative resection with an R0 margin.ResultsOverall, 5453 patients from 304 hospitals in 47 countries were included, of whom 6.6% (358/5453) did not receive their planned operation. Of the 4304 operated patients without neoadjuvant therapy, 40.5% (1744/4304) were delayed beyond 4 weeks. Delayed patients were more likely to be older, men, more comorbid, have higher body mass index and have rectal cancer and early stage disease. Delayed patients had higher unadjusted rates of complete resection (93.7% vs. 91.9%, P = 0.032) and lower rates of emergency surgery (4.5% vs. 22.5%, P ConclusionOne in 15 colorectal cancer patients did not receive their planned operation during the first wave of COVID-19. Surgical delay did not appear to compromise resectability, raising the hypothesis that any reduction in long-term survival attributable to delays is likely to be due to micro-metastatic disease