YAP2 transcriptional regulator drives a multitude of cellular processes, including the newly discovered Hippo tumor suppressor pathway, by virtue of the ability of its WW domains to bind and recruit PPXY-containing ligands to specific subcellular compartments. Herein, we employ an array of biophysical tools to investigate allosteric communication between the WW tandem domains of YAP2. Our data show that the WW tandem domains of YAP2 negatively cooperate when binding to their cognate ligands. Moreover, the molecular origin of such negative cooperativity lies in an unfavorable entropic contribution to the overall free energy relative to ligand binding to isolated WW domains. Consistent with this notion, the WW tandem domains adopt a fixed spatial orientation such that the WW1 domain curves outwards and stacks onto the binding groove of WW2 domain, thereby sterically hindering ligand binding to both itself and its tandem partner. Although ligand binding to both WW domains disrupts such interdomain stacking interaction, they reorient themselves and adopt an alternative fixed spatial orientation in the liganded state by virtue of their ability to engage laterally so as to allow their binding grooves to point outwards and away from each other. In short, while the ability of WW tandem domains to aid ligand binding is well-documented, our demonstration that they may also be subject to negative binding cooperativity represents a paradigm shift in our understanding of the molecular action of this ubiquitous family of protein modules.
Background
This study sought to determine the oncologic impact of delays to surgery, radiotherapy, and completion of therapy in patients with head and neck squamous cell carcinoma.
Methods
The impact of biopsy to surgery (BTS) time, surgery to start of radiation time (STSR), and radiation treatment time (RTT) on locoregional recurrence (LRR), distant metastases (DMs), and cancer‐specific mortality (CSM) was examined. The cumulative incidences (CI) of LRR, DMs, and CSM were examined using Fine–Gray testing.
Results
A total of 277 patients treated with surgery and adjuvant radiotherapy were analyzed. On multivariable testing, BTS >50 days was associated with DM (P = .03), whereas RTT and STSR were not. RTT >43 days was associated with LRR (P = .02) in patients with non‐p16‐positive‐oropharynx cancer.
Conclusions
An increase in DM appears to be the mechanism by which prolonged time to treatment initiation leads to worse overall survival. Prolonged RTT has the greatest impact on patients with non‐p16 positive oropharynx cancers.
Elevated interleukin-6 (IL-6) levels may correlate with disease severity in COVID-19. We analyzed whether there was an association between elevated IL-6 levels and major adverse cardiac events (MACE) and/or mortality in COVID-19 patients. A retrospective chart review was performed on COVID-19 patients among four hospitals in one health system from March to May 2020, extracting information on baseline characteristics, MACE (i.e., myocardial infarction, stroke, deep venous thrombosis/pulmonary embolism, or shock requiring vasopressor support), mortality, and IL-6 levels. Of the 496 patients hospitalized with COVID-19, 191 patients had an IL-6 level drawn and 68% had elevated IL-6 levels. The elevated IL-6 population had higher odds of developing a MACE compared to the normal IL-6 population (
P
< 0.0001, odds ratio [OR] = 5.91, 95% confidence interval [CI] = 2.65–14.11). The elevated IL-6 population also had higher mortality rates (28.2% vs 5%,
P
= 0.0001, OR = 7.47, 95% CI = 2.19–39.32) and an increased incidence of a MACE and/or mortality (58.78% vs 20.00%,
P
< 0.0001, OR = 5.7, 95% CI 2.65–12.83) compared to the normal IL-6 population. Elevated IL-6 levels in COVID-19 patients may be associated with MACE and/or mortality. Monitoring IL-6 levels in COVID-19 patients may help risk-stratify patients.
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