A good imitation: Aryl‐1‐indanyl ketones are found to be highly efficient, reversible, cell‐penetrating inhibitors of the human peptidyl prolyl cis/trans isomerase Pin1. Owing to their structure 1, ...they are assumed to mimic the transition state 2 of the enzymatically catalyzed rotation about the imidic peptide bond preceding a proline residue.
Geschickt imitiert: Aryl‐1‐indanylketone erweisen sich als hocheffiziente, reversible und zellgängige Inhibitoren der humanen Peptidyl‐Prolyl‐cis/trans‐Isomerase Pin1. Aufgrund ihrer Struktur 1 wird ...angenommen, dass sie den Übergangszustand 2 der enzymatisch katalysierten Rotation um die imidische Peptidbindung vor dem Prolin nachahmen.
Primary chemotherapy in breast cancer poses a dilemma with regard to adjuvant locoregional radiotherapy, as guidelines for locoregional radiotherapy were originally based on pathology results of ...primary surgery. We aimed to evaluate the oncological safety of de-escalated locoregional radiotherapy in patients with cT1–2N1 breast cancer treated with primary chemotherapy, according to a predefined, consensus-based study guideline.
In this prospective registry study (RAPCHEM, BOOG 2010–03), patients referred to one of 17 participating radiation oncology centres in the Netherlands between Jan 1, 2011, and Jan 1, 2015, with cT1–2N1 breast cancer (one to three suspicious nodes on imaging before primary chemotherapy, of which at least one had been pathologically confirmed), and who were treated with primary chemotherapy and surgery of the breast and axilla were included in the study. The study guideline comprised three risk groups for locoregional recurrence, with corresponding locoregional radiotherapy recommendations: no chest wall radiotherapy and no regional radiotherapy in the low-risk group, only local radiotherapy in the intermediate-risk group, and locoregional radiotherapy in the high-risk group. Radiotherapy consisted of a biologically equivalent dose of 25 fractions of 2 Gy, with or without a boost. During the study period, the generally applied radiotherapy technique in the Netherlands was forward-planned or inverse-planned intensity modulated radiotherapy. 5-year follow-up was assessed, taking into account adherence to the study guideline, with locoregional recurrence rate as primary endpoint. We hypothesised that 5-year locoregional recurrence rate would be less than 4% (upper-limit 95% CI 7·8%). This study was registered at ClinicalTrials.gov, NCT01279304, and is completed.
838 patients were eligible for 5-year follow-up analyses: 291 in the low-risk group, 370 in the intermediate-risk group, and 177 in the high-risk group. The 5-year locoregional recurrence rate in all patients was 2·2% (95% CI 1·4–3·4). The 5-year locoregional recurrence rate was 2·1% (0·9–4·3) in the low-risk group, 2·2% (1·0–4·1) in the intermediate-risk group, and 2·3% (0·8–5·5) in the high-risk group. If the study guideline was followed, the locoregional recurrence rate was 2·3% (0·8–5·3) for the low-risk group, 1·0% (0·2–3·4) for the intermediate-risk group, and 1·4% (0·3–4·5) for the high-risk group.
In this study, the 5-year locoregional recurrence rate was less than 4%, which supports our hypothesis that it is oncologically safe to de-escalate locoregional radiotherapy based on locoregional recurrence risk, in selected patients with cT1–2N1 breast cancer treated with primary chemotherapy, according to this predefined, consensus-based study guideline.
Dutch Cancer Society.
For the Dutch translation of the abstract see Supplementary Materials section.
Large‐scale groundwater models are required to estimate groundwater availability and to inform water management strategies on the national scale. However, parameterization of large‐scale groundwater ...models covering areas of major river basins and more is challenging due to the lack of observational data and the mismatch between the scales of modeling and measurements. In this work, we propose to bridge the scale gap and derive regional hydraulic parameters by spectral analysis of groundwater level fluctuations. We hypothesize that specific locations in aquifers can reveal regional parameters of the hydraulic system. We first generate ensembles of synthetic but realistic aquifers which systematically differ in complexity. Applying Liang and Zhang’s (2013), https://doi.org/10.1016/j.jhydrol.2012.11.044, semi‐analytical solution for the spectrum of hydraulic head time series, we identify for each ensemble member and at different locations representative aquifer parameters. Next, we extend our study to investigate the use of spectral analysis in more complex numerical models and in real settings. Our analyses indicate that the variance of inferred effective transmissivity and storativity values for stochastic aquifer ensembles is small for observation points which are far away from the Dirichlet boundary. Moreover, the head time series has to cover a period which is roughly 10 times as long as the characteristic time of the aquifer. In deterministic aquifer models we infer equivalent, regionally valid parameters. A sensitivity analysis further reveals that as long as the aquifer length and the position of the groundwater measurement location is roughly known, the parameters can be robustly estimated.
Plain Language Summary
We build large‐scale (regional) computer models of the subsurface flow conditions in order to quantify the long‐term shift in groundwater storage and response on the national level under changing climatic conditions and increasing human water demands. These models must be fed with hydrogeological parameters obtained from subsurface observation wells, drilling logs, and hydraulic tests in conjunction with (hydro)geological and geostatistical methods. In some regions these wells are sparsely distributed and derived parameters are representative only for small areas. We hypothesize that groundwater level records can reveal regional aquifer information when analyzed in the spectral domain. In order to bridge that scale gap and because groundwater level time series are generally available, we propose to infer regional parameters by analyzing the frequency content (spectrum) of long groundwater level time series. The required parameters were determined using mathematical formulations of the theoretical spectrum for simplified settings. We tested the methodology in computer models with limited complexity and found that the groundwater level time series indeed contain regional information if the time of observation is sufficiently long. Lastly, we apply the spectral analysis to real groundwater data to test the capability of the method to infer regional aquifer parameters in real aquifers.
Key Points
We successfully tested the spectral analysis of groundwater level fluctuations in numerical models and obtained regional aquifer parameters
In a sensitivity analysis of the spectral analysis using field data, the storativity and the response times could be robustly estimated
The application of the suggested methodology to the field data from a catchment in central Germany produced plausible results
Cross-sectional studies have shown that obesity is associated with lower intestinal cholesterol absorption and higher endogenous cholesterol synthesis. These metabolic characteristics have also been ...observed in patients with type 2 diabetes, metabolic syndrome, steatosis or cholestasis. The number of intervention studies evaluating the effect of weight loss on these metabolic characteristics is, however, limited, while the role of the different fat compartments has not been studied into detail. In a randomized trial, abdominally obese men (N = 54) followed a 6-week very low caloric (VLCD) diet, followed by a 2 week weight-maintenance period. Non-cholesterol sterols were measured at baseline and after 8 weeks, and compared to levels in lean participants (N = 25). After weight loss, total cholesterol (TC)-standardized cholestanol levels increased by 0.18 µmol/mmol (p < 0.001), while those of campesterol and lathosterol decreased by 0.25 µmol/mmol (p < 0.05) and 0.39 µmol/mmol (p < 0.001), respectively. Moreover, after weight loss, TC-standardized lathosterol and cholestanol levels were comparable to those of lean men. Increases in TC-standardized cholestanol after weight loss were significantly associated with changes in waist circumference (p < 0.01), weight (p < 0.001), BMI (p < 0.001) and visceral fat (p < 0.01), but not with subcutaneous and intrahepatic lipids. In addition, cross-sectional analysis showed that visceral fat fully mediated the association between BMI and TC-standardized cholestanol levels. Intrahepatic lipid content was a partial mediator for the association between BMI and TC-standardized lathosterol levels. In conclusion, diet-induced weight loss decreased cholesterol synthesis and increased cholesterol absorption. The increase in TC-standardized cholestanol levels was not only related to weight loss, but also to a decrease in visceral fat volume. Whether these metabolic changes ameliorate other metabolic risk factors needs further study.
Substantial progress has been made in characterising the risk associated with exposure to allergens in food. However, absence of agreement on what risk is tolerable has made it difficult to set ...quantitative limits to manage that risk and protect allergic consumers effectively. This paper reviews scientific progress in the area and the diverse status of allergen management approaches and lack of common standards across different jurisdictions, including within the EU. This lack of regulation largely explains why allergic consumers find Precautionary Allergen Labelling confusing and cannot rely on it. We reviewed approaches to setting quantitative limits for a broad range of food safety hazards to identify the reasoning leading to their adoption. This revealed a diversity of approaches from pragmatic to risk-based, but we could not find clear evidence of the process leading to the decision on risk acceptability. We propose a framework built around the criteria suggested by Murphy and Gardoni (2008) for approaches to defining tolerable risks. Applying these criteria to food allergy, we concluded that sufficient knowledge exists to implement the framework, including sufficient expertise across the whole range of stakeholders to allow opinions to be heard and respected, and a consensus to be achieved.
•Quantitative limits for unintended allergen presence have in general not been defined across and within jurisdictions.•Inability to define what risk is tolerable is a major obstacle to defining those limits.•Diverse approaches (pragmatic to risk-based) have been adopted to define quantitative limits for other food safety hazards.•How tolerability decisions were reached in the case of those hazards is unclear.•We propose a framework for transparent decisions on risk tolerability, founded on full participation of stakeholders.
Hepatocellular carcinoma (HCC) is the most common primary malignant liver tumor and a leading cause of cancer-related deaths worldwide. However, current diagnostic tools are often invasive and ...technically limited. In the last decade, non-invasive liquid biopsies have transformed the field of clinical oncology, showcasing the potential of various liquid-biopsy derived analytes, including extracellular vesicles (EVs), to diagnose and monitor HCC progression and metastatic spreading, serving as promising novel biomarkers. A prospective single-center cohort study including 37 HCC patients and 20 patients with non-malignant liver disease (NMLD), as a control group, was conducted. Serum EVs of both groups were analyzed before and after liver surgery. The study utilized microbead-based magnetic particle sorting and flow cytometry to detect 37 characteristic surface proteins of EVs. Furthermore, HCC patients who experienced tumor recurrence (R-HCC) within 12 months after surgery were compared to HCC patients without recurrence (NR-HCC). EVs of R-HCC patients (n = 12/20) showed significantly lower levels of CD31 compared to EVs of NR-HCC patients (p = 0.0033). EVs of NMLD-group showed significantly higher expressions of CD41b than EVs of HCC group (p = 0.0286). The study determined significant short-term changes in CD19 dynamics in EVs of the NMLD-group, with preoperative values being significantly higher than postoperative values (p = 0.0065). This finding of our pilot study suggests EVs could play a role as potential targets for the development of diagnostic and therapeutic approaches for the early and non-invasive detection of HCC recurrence. Further, more in-depth analysis of the specific EV markers are needed to corroborate their potential role as diagnostic and therapeutic targets for HCC.
Neddylation has been implicated in various cellular pathways and in the pathophysiology of numerous diseases. We identified four individuals with bi-allelic variants in NAE1, which encodes the ...neddylation E1 enzyme. Pathogenicity was supported by decreased NAE1 abundance and overlapping clinical and cellular phenotypes. To delineate how cellular consequences of NAE1 deficiency would lead to the clinical phenotype, we focused primarily on the rarest phenotypic features, based on the assumption that these would best reflect the pathophysiology at stake. Two of the rarest features, neuronal loss and lymphopenia worsening during infections, suggest that NAE1 is required during cellular stress caused by infections to protect against cell death. In support, we found that stressing the proteasome system with MG132—requiring upregulation of neddylation to restore proteasomal function and proteasomal stress—led to increased cell death in fibroblasts of individuals with NAE1 genetic variants. Additionally, we found decreased lymphocyte counts after CD3/CD28 stimulation and decreased NF-κB translocation in individuals with NAE1 variants. The rarest phenotypic feature—delayed closure of the ischiopubic rami—correlated with significant downregulation of RUN2X and SOX9 expression in transcriptomic data of fibroblasts. Both genes are involved in the pathophysiology of ischiopubic hypoplasia. Thus, we show that NAE1 plays a major role in (skeletal) development and cellular homeostasis during stress. Our approach suggests that a focus on rare phenotypic features is able to provide significant pathophysiological insights in diseases caused by mutations in genes with pleiotropic effects.
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The authors describe four individuals with bi-allelic variants in NAE1, which encodes the NEDD8-activating enzyme E1 regulatory subunit and is essential for neddylation. By focusing on the biology underlying the rarest observed clinical features, they unveil the importance of neddylation for skeletal development and for maintaining cellular integrity during stress.
Large-cell transformation (LCT) of mycosis fungoides (MF) has been associated with a higher risk of relapse and progression and, consequently, restricted prognosis. Its molecular pathogenesis has not ...been elucidated yet.
In order to address molecular mechanisms of LCT, we performed hybrid capture panel-based sequencing of skin biopsies from 10 patients suffering from MF with LCT versus 17 patients without LCT including follow-up biopsies during clinical course, respectively (51 samples in total). The analyzed patients were attributed to three different groups based on the presence of LCT and clinical behavior.
While indolent MF cases without LCT did not show pathogenic driver mutations, a high rate of oncogenic alterations was detected in patients with LCT and aggressive clinical courses. Various genes of different oncogenic signaling pathways, including the MAPK and JAK-STAT signaling pathways, as well as epigenetic modifiers were affected. A high inter-individual and distinctive intra-individual mutation diversity was observed. Oncogenic RAS mutations were exclusively detected in patients with LCT.
Our data demonstrate that LCT transition of MF is associated with increased frequency of somatic mutations in cancer-associated genes. In particular, the activation of RAS signaling-together with epigenetic dysregulation-may crucially contribute to the molecular pathogenesis of the LCT phenotype, thus conveying its adverse clinical behavior.
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