Structure-Based Optimization of Covalent, Small-Molecule Stabilizers of the 14-3-3σ/ERα Protein-Protein Interaction from Nonselective Fragments

The stabilization of protein-protein interactions (PPIs) has emerged as a promising strategy in chemical biology and drug discovery. The identification of suitable starting points for stabilizing native PPIs and their subsequent elaboration into selective and potent molecular glues lacks structure-guided optimization strategies. We have previously identified a disulfide fragment that stabilized the hub protein 14-3-3σ bound to several of its clients, including ERα and C-RAF. Here, we show the structure-based optimization of the nonselective fragment toward selective and highly potent small-molecule stabilizers of the 14-3-3σ/ERα complex. The more elaborated molecular glues, for example, show no stabilization of 14-3-3σ/C-RAF up to 150 μM compound. Orthogonal biophysical assays, including mass spectrometry and fluorescence anisotropy, were used to establish structure-activity relationships. The binding modes of 37 compounds were elucidated with X-ray crystallography, which further assisted the concomitant structure-guided optimization. By targeting specific amino acids in the 14-3-3σ/ERα interface and locking the conformation with a spirocycle, the optimized covalent stabilizer 181 achieved potency, cooperativity, and selectivity similar to the natural product Fusicoccin-A. This case study showcases the value of addressing the structure, kinetics, and cooperativity for molecular glue development. </p

The (ir)relevance of the abandoned criterion II for the diagnosis of serrated polyposis syndrome:a retrospective cohort study

The World Health Organization (WHO) recently updated the diagnostic criteria for serrated polyposis syndrome (SPS). One of the three previous diagnostic criteria (criterion II 2010) is now abandoned: ≥ 1 serrated polyp (SP) proximal to the sigmoid in a first-degree relative (FDR) of a patient with SPS. Individuals fulfilling this abandoned criterion now receive the same surveillance recommendations as all FDRs of patients with SPS. We aimed to compare the incidence of advanced neoplasia (AN) in FDRs with vs. without fulfillment of the abandoned criterion II 2010. We retrospectively recruited FDRs of patients with SPS who underwent a colonoscopy, and stratified them according to fulfilment of criterion II 2010 at baseline. Our primary and secondary outcomes were AN incidence during surveillance and at baseline, respectively. We included 224 FDRs of patients with SPS, of whom 36 (16%) fulfilled criterion II 2010 at baseline. One hundred and five underwent surveillance after baseline. Criterion II 2010-positive FDRs were at increased risk of AN, both during surveillance (hazard ratio 8.94, 95% CI 2.15–37.1, p =.003) as well as at baseline (adjusted odds-ratio 9.30, 95% CI 3.7–23.3, p <.001). FDRs of patients with SPS that underwent colonoscopy and fulfilled the abandoned criterion II 2010 for SPS diagnosis were at increased risk of AN at baseline and during surveillance in this small, retrospective cohort study. Our results should be interpreted with caution but suggest that adherence to surveillance recommendations for all FDRs of patients with SPS is important, especially for those that would have fulfilled the now abandoned criterion II 2010

The cost-effectiveness of the RSI QuickScan intervention programme for computer workers: Results of an economic evaluation alongside a randomised controlled trial

<p>Abstract</p> <p>Background</p> <p>The costs of arm, shoulder and neck symptoms are high. In order to decrease these costs employers implement interventions aimed at reducing these symptoms. One frequently used intervention is the RSI QuickScan intervention programme. It establishes a risk profile of the target population and subsequently advises interventions following a decision tree based on that risk profile. The purpose of this study was to perform an economic evaluation, from both the societal and companies' perspective, of the RSI QuickScan intervention programme for computer workers. In this study, effectiveness was defined at three levels: exposure to risk factors, prevalence of arm, shoulder and neck symptoms, and days of sick leave.</p> <p>Methods</p> <p>The economic evaluation was conducted alongside a randomised controlled trial (RCT). Participating computer workers from 7 companies (N = 638) were assigned to either the intervention group (N = 320) or the usual care group (N = 318) by means of cluster randomisation (N = 50). The intervention consisted of a tailor-made programme, based on a previously established risk profile. At baseline, 6 and 12 month follow-up, the participants completed the RSI QuickScan questionnaire. Analyses to estimate the effect of the intervention were done according to the intention-to-treat principle. To compare costs between groups, confidence intervals for cost differences were computed by bias-corrected and accelerated bootstrapping.</p> <p>Results</p> <p>The mean intervention costs, paid by the employer, were 59 euro per participant in the intervention and 28 euro in the usual care group. Mean total health care and non-health care costs per participant were 108 euro in both groups. As to the cost-effectiveness, improvement in received information on healthy computer use as well as in their work posture and movement was observed at higher costs. With regard to the other risk factors, symptoms and sick leave, only small and non-significant effects were found.</p> <p>Conclusions</p> <p>In this study, the RSI QuickScan intervention programme did not prove to be cost-effective from the both the societal and companies' perspective and, therefore, this study does not provide a financial reason for implementing this intervention. However, with a relatively small investment, the programme did increase the number of workers who received information on healthy computer use and improved their work posture and movement.</p> <p>Trial registration</p> <p>Trial registration number: NTR1117</p

Factors Associated with Revision Surgery after Internal Fixation of Hip Fractures

Background: Femoral neck fractures are associated with high rates of revision surgery after management with internal fixation. Using data from the Fixation using Alternative Implants for the Treatment of Hip fractures (FAITH) trial evaluating methods of internal fixation in patients with femoral neck fractures, we investigated associations between baseline and surgical factors and the need for revision surgery to promote healing, relieve pain, treat infection or improve function over 24 months postsurgery. Additionally, we investigated factors associated with (1) hardware removal and (2) implant exchange from cancellous screws (CS) or sliding hip screw (SHS) to total hip arthroplasty, hemiarthroplasty, or another internal fixation device. Methods: We identified 15 potential factors a priori that may be associated with revision surgery, 7 with hardware removal, and 14 with implant exchange. We used multivariable Cox proportional hazards analyses in our investigation. Results: Factors associated with increased risk of revision surgery included: female sex, [hazard ratio (HR) 1.79, 95% confidence interval (CI) 1.25-2.50; P = 0.001], higher body mass index (fo

UvA-DARE (Digital Academic Repository) Link to publication Citation for published version (APA)

Abstract. This is the debut of the Dutch Nao Team in the Standard Platform League. The team is a recreation of the Dutch Aibo Team, which was active in the predecessor of the SPL (2004)(2005)(2006). This year participation is mainly intended to gain experience. As basis for the competition the code release of B-Human is used, with two modifications. The first modification is improved kicking behavior to accommedate the new ball. The second modificition is two use both Nao camera&apos;s (one for ball control and one for localization)

Structure-Based Optimization of Covalent, Small-Molecule Stabilizers of the 14-3-3σ/ERα Protein-Protein Interaction from Nonselective Fragments.

The stabilization of protein-protein interactions (PPIs) has emerged as a promising strategy in chemical biology and drug discovery. The identification of suitable starting points for stabilizing native PPIs and their subsequent elaboration into selective and potent molecular glues lacks structure-guided optimization strategies. We have previously identified a disulfide fragment that stabilized the hub protein 14-3-3σ bound to several of its clients, including ERα and C-RAF. Here, we show the structure-based optimization of the nonselective fragment toward selective and highly potent small-molecule stabilizers of the 14-3-3σ/ERα complex. The more elaborated molecular glues, for example, show no stabilization of 14-3-3σ/C-RAF up to 150 μM compound. Orthogonal biophysical assays, including mass spectrometry and fluorescence anisotropy, were used to establish structure-activity relationships. The binding modes of 37 compounds were elucidated with X-ray crystallography, which further assisted the concomitant structure-guided optimization. By targeting specific amino acids in the 14-3-3σ/ERα interface and locking the conformation with a spirocycle, the optimized covalent stabilizer 181 achieved potency, cooperativity, and selectivity similar to the natural product Fusicoccin-A. This case study showcases the value of addressing the structure, kinetics, and cooperativity for molecular glue development

Hospital Variation in Feeding Jejunostomy Policy for Minimally Invasive Esophagectomy: A Nationwide Cohort Study

The purpose of this study was to investigate hospital variation in the placement, surgical techniques, and safety of feeding jejunostomies (FJ) during minimally invasive esophagectomy (MIE) in the Netherlands. This nationwide cohort study analyzed patients registered in the Dutch Upper Gastrointestinal Cancer Audit (DUCA) that underwent MIE for cancer. Hospital variation in FJ placement rates were investigated using case-mix corrected funnel plots. Short-term outcomes were compared between patients with and without FJ using multilevel multivariable logistic regression analysis. The incidence of FJ-related complications was described and compared between hospitals performing routine and non-routine placement (≥90%–p < 0.001). Significant hospital variation in the use of FJs after MIE exists in the Netherlands. No effect of FJs on complications was observed. FJs can be placed safely, with lower FJ-related complication rates, in centers performing routine placement