DNA mismatch repair controls the mutagenicity of Polymerase ζ-dependent translesion synthesis at methylated guanines.

By replicating damaged nucleotides, error-prone DNA translesion synthesis (TLS) enables the completion of replication, albeit at the expense of fidelity. TLS of helix-distorting DNA lesions, that usually have reduced capacity of basepairing, comprises insertion opposite the lesion followed by extension, the latter in particular by polymerase ζ (Pol ζ). However, little is known about involvement of Pol ζ in TLS of non- or poorly-distorting, but miscoding, lesions such as O-methyldeoxyguanosine (O-medG).

Fitting a progressive three-state colorectal cancer model to interval-censored surveillance data under outcome-dependent sampling using a weighted likelihood approach.

To optimize colorectal cancer (CRC) surveillance, accurate information on the risk of developing CRC from premalignant lesions is essential. However, directly observing this risk is challenging since precursor lesions, i.e.

The effects of lifestyle interventions on disease activity and quality of life in patients with systemic lupus erythematosus: A systematic review.

Introduction: Systemic Lupus Erythematosus (SLE) is an autoimmune disease affecting multiple organs, characterized by flares and remission. Treatment aims to reduce flare severity and prevent long-term damage, but remission is often elusive, and patients may still experience flares and a reduced quality of life (QoL). This had led to a growing interest in non-pharmacological therapies to improve patient wellbeing.

Attainment of remission and low disease activity after treatment with belimumab in patients with systemic lupus erythematosus: a post-hoc analysis of pooled data from five randomised clinical trials.

Background: Disease remission or low disease activity are key treatment targets for patients with systemic lupus erythematosus (SLE). Pivotal trials of belimumab were conducted before the introduction of these targets. In this study, we aimed to pool data across trials to assess attainment of remission and low disease activity in a large, racially and culturally diverse patient population with SLE.

Gemcitabine therapeutically disrupts essential SIRT1-mediated p53 repression in atypical teratoid/rhabdoid tumors.

Atypical teratoid/rhabdoid tumors (ATRTs) are highly malignant embryonal tumors of the central nervous system with a dismal prognosis. Using a newly developed and validated patient-derived ATRT culture and xenograft model, alongside a panel of primary ATRT models, we found that ATRTs are selectively sensitive to the nucleoside analog gemcitabine. Gene expression and protein analyses indicate that gemcitabine treatment causes the degradation of sirtuin 1 (SIRT1), resulting in cell death through activation of nuclear factor κB (NF-κB) and p53.

Systematic Evaluation of Tyrosine Kinase Inhibitors as OATP1B1 Substrates Using a Competitive Counterflow Screen.

Unlabelled: Although the primary elimination pathway for most tyrosine kinase inhibitors (TKI) involves CYP3A4-mediated metabolism, the mechanism by which these agents are brought into hepatocytes remains unclear. In this study, we optimized and validated a competitive counterflow (CCF) assay to examine TKIs as substrates of the hepatic uptake transporter OATP1B1. The CCF method was based on the stimulated efflux of radiolabeled estradiol-17β-glucuronide under steady-state conditions in HEK293 cells engineered to overexpress OATP1B1.

Nutrient Status and Intakes of Adults with Phenylketonuria.

A phenylalanine-restricted diet, supplemented with protein substitutes (PSs), remains the cornerstone of phenylketonuria (PKU) management. However, adherence is challenging in adulthood, and data on the nutritional status of early and continuously treated adults with PKU (ETAwPKU) are scarce. A total of 34 ETAwPKU (16 females; mean ± SD, age: 28 ± 9 years, phenylalanine concentration: 847 ± 285 µmol/L) and 34 age- and sex-matched control subjects were compared regarding their blood nutrient status, self-reported dietary intake, and cognitive wellbeing.

Variability in Care Pathways for Hip Fracture Patients in The Netherlands.

: Integrated orthogeriatric care has demonstrated benefits in hip fracture management for older patients. Comprehensive care pathways are essential for effective integrated care delivery, yet local variability in care pathways persists. We assessed the current hip fracture care pathways in the Netherlands, focusing on the variability between these care pathways and the degree of implementation of orthogeriatric care.

School Health Promotion, the Body Mass Index z-Score, and Psychosocial Health in Primary Schools of the Netherlands.

Childhood overweight and psychosocial issues remain significant public health concerns. Schools worldwide implement health promotion programs to address these issues and to support the physical and psychosocial health of children. However, more insight is needed into the relation between these health-promoting programs and the Body Mass Index (BMI) z-score and psychosocial health of children, while taking into account how school factors might influence this relation.

Refining the scope of genetic influences on alcohol misuse through environmental stratification and gene-environment interaction.

Background: Gene-environment interaction (G × E) is likely an important influence shaping individual differences in alcohol misuse (AM), yet it has not been extensively studied in molecular genetic research. In this study, we use a series of genome-wide gene-environment interaction (GWEIS) and in silico annotation methods with the aim of improving gene identification and biological understanding of AM.

Methods: We carried out GWEIS for four AM phenotypes in the large UK Biobank sample (N = 360,314), with trauma exposure and socioeconomic status (SES) as moderators of the genetic effects.

P53-dependent hypusination of eIF5A affects mitochondrial translation and senescence immune surveillance.

Cellular senescence is characterized by a permanent growth arrest and is associated with tissue aging and cancer. Senescent cells secrete a number of different cytokines referred to as the senescence-associated secretory phenotype (SASP), which impacts the surrounding tissue and immune response. Here, we find that senescent cells exhibit higher rates of protein synthesis compared to proliferating cells and identify eIF5A as a crucial regulator of this process.

The Dual Mode of Antibacterial Action of the Synthetic Small Molecule DCAP Involves Lipid II Binding.

The synthetic small molecule DCAP is a chemically well-characterized compound with antibiotic activity against Gram-positive and Gram-negative bacteria, including drug-resistant pathogens. Until now, its mechanism of action was proposed to rely exclusively on targeting the bacterial membrane, thereby causing membrane depolarization, and increasing membrane permeability (Eun 2012, 134 (28), 11322-11325; Hurley 2015, 6, 466-471). Here, we show that the antibiotic activity of DCAP results from a dual mode of action that is more targeted and multifaceted than previously anticipated.

A long-term study of stable isotope ratios of fingernail keratin and amino acids in a mother-infant dyad.

Objective: To evaluate the potential of compound-specific isotope analysis of amino acids (CSIA-AA) for investigating infant feeding practices, we conducted a long-term study that compared infant and maternal amino acid (AA) nitrogen isotope ratios.

Materials And Methods: Fingernail samples were collected from a single mother-infant dyad over 19 months postpartum. Carbon and nitrogen stable isotope ratios were measured in the bulk keratin of the fingernail samples.

Frequency and Genetic Spectrum of Inherited Retinal Dystrophies in a Large Dutch Pediatric Cohort: The RD5000 Consortium.

Purpose: Gene-based therapies for inherited retinal dystrophies (IRDs) are upcoming. Treatment before substantial vision loss will optimize outcomes. It is crucial to identify common phenotypes and causative genes in children.

Short communications: Exploring temporal fluorescent changes in the composition of human semen stains.

Semen traces are considered important pieces of evidence in forensic investigations, especially those involving sexsual offenses. Recently, our research group developed a fluorescence-based technique to accurately determine the age of semen traces. However, the specific compounds resonsible for the fluoresescent behaviour of ageing semens remain unknown.

Early therapeutic drug monitoring helps to identify inflammatory bowel disease patients with a high risk to fail thiopurine treatment.

Aims: Conventional thiopurines (azathioprine and mercaptopurine) remain standard therapy to maintain steroid sparing remission in inflammatory bowel disease (IBD), but are regularly discontinued due to adverse drug reactions (ADRs). Measurement of the metabolites 6-thioguanine nucleotides (6-TGN), 6-methylmercaptopurine ribonucleotides (6-MMPR) and the 6-MMPR/6-TGN ratio, may predict the development of these ADRs. Our aim was to evaluate whether early thiopurine metabolite measurements were associated with clinical outcomes.

Examination of sex-specific interactions between gut microbiota and host metabolism after 12-week combined polyphenol supplementation in individuals with overweight or obesity.

Polyphenols exert beneficial effects on host metabolism, which may be mediated by the gut microbiota. We investigated sex-specific differences in microbiota composition and interactions with cardiometabolic parameters after polyphenol supplementation in individuals with overweight/obesity. In a double-blind, randomized, placebo-controlled trial, 19 women and 18 men with normal glucose tolerance and body mass index >25 kg/m received epigallocatechin-3-gallate and resveratrol (EGCG+RES, 282 + 80 mg/d) or placebo supplements for 12 weeks.

Feasibility of hand grip tests during and after hospitalization in geriatric patients: an observational study.

Background: Monitoring the recovery trajectory during and after hospitalization can be a valuable method to observe whether additional care is needed to optimize recovery. Hand grip strength tests are commonly used to measure an individual's physical condition. Eforto® is a system to monitor hand grip strength and grip work as measures of recovery.

The role of ultra-processed foods in plant-based diets: associations with human health and environmental sustainability.

Purpose: Investigate the associations of ultra-processed foods (UPF) in healthful (hPDI) and unhealthful (uPDI) plant-based diets with all-cause mortality, greenhouse gas emissions (GHGE), and blue water consumption (BWC).

Methods: Analyses were based on 35,030 participants (20-70 years; 74% females) from the EPIC-NL cohort who were followed up from 1993 to 1997 through 2014. Plant-based diet indices (hPDI and uPDI) and UPF consumption were calculated from a validated FFQ, assessed at baseline.