Nonribosomal peptide synthetases:Engineering, characterization and biotechnological potential

Non-ribosomale peptide synthetases (NRPS) zijn uitzonderlijk grote, modulaire en complexe moleculaire systemen, die verantwoordelijk zijn voor de productie van belangrijke bioactieve stoffen, zoals antibiotica, anti-kanker medicijnen, pigmenten, enzovoorts. Ondanks dat het steeds makkelijker wordt dit soort enzymen te identificeren en (gedeeltelijk) te classificeren, is het nog steeds ongelofelijk complex om het volledige potentieel van NRPS te benutten. Sinds de ontdekking van de eerste antibiotica, is er een toenemende interesse voor de ontwikkeling van tools voor het ontrafelen en engineering van NRPS. In onze huidige wereld, waarin we geconfronteerd worden met een globale antibiotica-resistentie crisis, is het van essentieel belang dat nieuwe antibiotica ontdekt en ontwikkeld worden. Dit proefschrift beschrijft naast specifieke nieuwe tools en strategieën voor de ontwikkeling en engineering van NRPS, ook in het algemeen de fundamentele aanpak van huidige bottlenecks in de ontwikkeling van nieuwe antibiotica. De gecombineerde kennis en strategieën, omschreven in dit proefschrift, zouden niet alleen kunnen worden gebruikt voor de adaptatie van al bestaande antibiotica voor nieuwe toepassingen, maar zouden ook kunnen leiden tot alternatieve routes in de ontwikkeling van een volgende, meer robuuste generatie antibiotica, hopelijk toepasbaar als moderne geneesmiddelen

Discontinuation of Palliative Brain Radiotherapy in Patients with Brain Metastases: A Case-Control Study.

Background: Discontinuation of radiotherapy is rarely discussed in the scientific literature. The goal of this study was, therefore, to estimate the frequency of and reasons for treatment discontinuations in patients receiving radiotherapy for brain metastases from solid tumors and to identify factors predicting said discontinuations. Methods: All patients treated for brain metastases from solid tumors between 2010 and 2020 at our institution were retrospectively reviewed. In addition to collecting relevant patient characteristics, the Recursive Partitioning Analysis (RPA) and disease-specific Graded Prognostic Assessment (GPA) groups for each patient were calculated to assess the performance of these scores in predicting treatment discontinuations. Results: Out of 468 patients who underwent cranial radiotherapy, 35 treatments (7.5%) were discontinued. The most frequent reason was clinical deterioration, which was documented in 26 (74.3%) of discontinued treatments. Patients whose radiotherapy was discontinued had, on average, more leptomeningeal disease (20.0% vs. 12.6%), worse ECOG performance status (mean ECOG performance status 1.86 vs. 1.39), and more uncontrolled extracranial metastases (85.3% vs. 70.8%). The frequencies of treatment discontinuation increased with worse prognosis and differed significantly across RPA groups (p = 0.037) but not across GPA groups (p = 0.612). Conclusions: Treatment discontinuation occurred in 7.5% of cases, mostly due to clinical deterioration. Poor performance status, as well as more advanced disease and, in turn, poor prognosis, were associated with higher discontinuation rates

Five Fractions versus Seven Fractions SBRT for Intermediate- and High-Risk Prostate Cancer: A Propensity Score Matched Pair Analysis.

PURPOSE To compare two stereotactic body radiotherapy (SBRT) regimens in patients with intermediate- or high-risk prostate cancer with regards toxicity and efficacy. METHODS/MATERIAL We retrospectively collected data from 198 patients treated with SBRT for prostate cancer at two different institutions. Patients received either 35-36.25 Gy in five fractions (group A) using Cyberknife robotic platform or 42.7 Gy in seven fractions (group B) using a C-arm LINAC (image-guided). Propensity score matching was done (2:1 nearest neighbor matching without replacement), resulting in 120 patients (80 patients for group A, 40 patients for group B). Toxicity, PSA nadir, biochemical failure and disease-free survival (DFS) were analyzed. RESULTS Median follow up of all patients was 13 months (range 1-91 months). Overall, 23.3% of patients had ≥G2 acute GU toxicity (21.1% group A versus 30% group B (p = 0.222)) and 6.6% of patients ≥G2 GI toxicity (2.5% versus 15% (p = 0.010)). There was one acute G3 GU toxicity in arm A and one acute G4 rectal bleeding in group B (anticoagulated patient). Regarding late toxicity, 14.1% of patients had ≥G2 late GU toxicity (17.4% versus 6.6% (p = 0.159)) and 5.0% of patients had ≥G2 late GI toxicity (1.4% versus 13.3% (p = 0.013)). There was one G3 late GU toxicity in arm B and two G3 late GI toxicities, one in each arm. Relative median PSA reduction was 92.4% (-53.9-99.9%) from baseline PSA (93.7% (-53.9-99.9%) in group A versus 87.7% (39.8-99.9%) in group B (p = 0.043). In total, 4.2% of patients had biochemical relapse, 5.0% in group A and 2.5% in group B (p = 0.518). One-year DFS in the overall cohort was 97.3%, 98.8% in group A and 94.3% in group B (p = 0.318). CONCLUSION Both SBRT regimens have acceptable acute and late toxicity and good efficacy. There are significantly more GI toxicities in the seven-fraction regimen. Longer follow-up is warranted for better comparison of long-term efficacy

Re-irradiation to the prostate using stereotactic body radiotherapy (SBRT) after initial definitive radiotherapy - A systematic review and meta-analysis of recent trials.

BACKGROUND There is increasing data on re-irradiation to the prostate using stereotactic body radiotherapy (SBRT) after definitive radiotherapy for prostate cancer, with increasing evidence on prostate re-irradiation using a C-arm LINAC or an MR LINAC in recent years. We therefore conducted this systematic review and meta-analysis on prostate re-irradiation including studies published from 2020 to 2023, to serve as an update on existing meta-analysis. METHODS We searched the PubMed and Embase databases in October 2023 with queries including combinations of "repeat", "radiotherapy", "prostate", "re-irradiation", "reirradiation", "re treatment", "SBRT", "retreatment". Publication date was set to be from 2020 to 2023. There was no limitation regarding language. We adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations. After data extraction, heterogeneity testing was done by calculating the I2. A random effects model with a restricted maximum likelihood estimator was used to estimate the combined effect. Funnel plot asymmetry was assessed visually and using Egger's test to estimate the presence of publication and/or small study bias. RESULTS 14 publications were included in the systematic review. The rates of acute ≥ grade 2 (G2) genitourinary (GU) and gastrointestinal (GI) toxicities reported in the included studies ranged from 0.0-30.0 % and 0.0-25.0 % respectively. For late ≥ G2 GU and GI toxicity, the ranges are 4.0-51.8 % and 0.0-25.0 %. The pooled rate of acute GU and GI toxicity ≥ G2 were 13 % (95 % CI: 7-18 %) and 2 % (95 % CI: 0-4 %). For late GU and GI toxicity ≥ G2 the pooled rates were 25 % (95 % CI: 14-35 %) and 5 % (95 % CI: 1-9 %). The pooled 2-year biochemical recurrence-free survival was 72 % (95 % CI: 64-92 %). CONCLUSIONS SBRT in the re-irradiation of radiorecurrent prostate cancer is safe and effective. Further prospective data are warranted

Impact of Surgical Training on Incidence of Surgical Site Infection

Background: Despite availability of other training forms, tutorial assistance cannot be entirely replaced in surgical education. Concerns exist that tutorial assistance may lead to an increased rate of surgical site infection (SSI). The purpose of the present study was to investigate whether the risk of SSI is higher after surgery with tutorial assistance than after surgery performed autonomously by a fully trained surgeon. Methods: All consecutive visceral, vascular, and traumatological inpatient procedures at a Swiss University Hospital were prospectively recorded during a 24-month period, and the patients were followed for 12months to ascertain the occurrence of SSI. Using univariable and multivariable logistic regressions, we assessed the association of tutorial assistance surgery with SSI in 6,103 interventions. Results: Autonomously performed surgery was associated with SSI in univariable analysis (5.36% SSI vs. 3.81% for tutorial assistance, p=0.006). In multivariable analysis, the odds of SSI for tutorial assistance was no longer significantly lower (Odds Ratio [OR]=0.82; 95% Confidence Interval [CI]: 0.62-1.09; p=0.163). Conclusions: Surgical training does not lead to higher SSI rate if trainees are adequately supervised and interventions are carefully selected. Although other forms of training are useful, tutorial assistance in the operating room continues to be the mainstay of surgical educatio

Applications of Machine Learning in Palliative Care: A Systematic Review

Objective: To summarize the available literature on using machine learning (ML) for palliative care practice as well as research and to assess the adherence of the published studies to the most important ML best practices. Methods: The MEDLINE database was searched for the use of ML in palliative care practice or research, and the records were screened according to PRISMA guidelines. Results: In total, 22 publications using machine learning for mortality prediction (n = 15), data annotation (n = 5), predicting morbidity under palliative therapy (n = 1), and predicting response to palliative therapy (n = 1) were included. Publications used a variety of supervised or unsupervised models, but mostly tree-based classifiers and neural networks. Two publications had code uploaded to a public repository, and one publication uploaded the dataset. Conclusions: Machine learning in palliative care is mainly used to predict mortality. Similarly to other applications of ML, external test sets and prospective validations are the exception