The German Cancer Research Center (known as the Deutsches Krebsforschungszentrum or simply DKFZ in German), is a national cancer research center based in Heidelberg, Germany. It is a member of the Helmholtz Association of German Research Centres, the largest scientific organization in Germany.
Faithful DNA replication is essential for genome stability, yet replication forks face constant stress. The Bloom syndrome helicase (BLM) safeguards fork integrity, but excessive BLM activity can itself induce replication stress. We identify SLX4IP as a genome-wide regulator that restrains BLM to maintain replication fork stability. SLX4IP localizes broadly across chromatin with recruitment enhanced under replication stress. Loss of SLX4IP slows replication forks, remodels the replisome, and generates post-replicative single-stranded DNA gaps that are accompanied by elevated nuclear ADP ribose, reflecting compromised replication integrity. These defects are driven by dysregulated BLM activity, establishing SLX4IP as a negative regulator of BLM-dependent replication stress. At ALT telomeres, SLX4IP deficiency triggers ATR signaling, telomere fragility, and accumulation of ALT-associated PML bodies. Here, SLX4IP functions in parallel with FANCM to restrain BLM at ALT telomeres, with co-depletion of SLX4IP and FANCM causing synthetic lethality in ALT-positive cells, a phenotype fully rescued by BLM loss. Together, our results define SLX4IP as a critical genome-wide regulator of replication fork integrity and reveal SLX4IP as a potential vulnerability in ALT-positive cancers.
Skin aging is driven by intrinsic and extrinsic factors. Epigenetic alterations are one primary hallmark of aging and powerful biomarkers of biological skin age. To investigate epigenetic skin aging mechanisms and their regulation as a skin longevity approach across diverse ethnicities and phototypes, we assessed epidermal methylomes from white, African, and Asian donors. We collected epidermis samples from 17 multi-ethnic donors with diverse phototypes using a newly established tape-stripping method followed by array-based DNA methylation profiling to investigate the robustness of DNA methylation clocks across diverse ethnic backgrounds. Additionally, we conducted a clinical study with 60 participants representing Fitzpatrick phototypes I–VI. Diverse clinical parameters and biological skin age of the volunteers were determined at baseline and after applying a serum containing the natural epigenetic inhibitor dihydromyricetin (DHM) for 8 weeks to investigate skin longevity effects across phototypes. Data analysis revealed that age-dependent DNA hypermethylation is conserved across populations and affects genes essential for keratinocyte vitality and longevity. A newly developed epidermal methylation clock accurately predicted biological age in multi-ethnic cohorts, confirming the robustness of epigenetic age estimation across phototypes. Topical application of a DHM-containing serum significantly reduced epidermal DNA methylation age. Epigenetic rejuvenation was associated with clinical improvements, including reduced skin roughness and wrinkle visibility and occupancy, and increased dermal echogenicity. Together, these findings establish that epigenetic aging signatures are conserved across ethnicities and that targeted modulation using a DHM-containing topical formulation can reverse biological skin age while improving structural and visible signs of aging. This work provides the clinical evidence supporting epigenetic rejuvenation as a viable strategy for skin longevity across diverse populations.
Abstract Oil is frequently used as a solvent to inject lipophilic substances into the peritoneum of laboratory animals. Although mineral oil causes chronic peritoneal inflammation, little is known whether other oils are better suited. We show that olive, peanut, corn, or mineral oil causes xanthogranulomatous inflammation with depletion of resident peritoneal macrophages. However, there were striking differences in the severity of the inflammatory response. Peanut and mineral oil caused severe chronic inflammation with persistent neutrophil and monocyte recruitment, expansion of the vasculature, and fibrosis. Corn and olive oil provoked no or only mild signs of chronic inflammation. Mechanistically, the vegetal oils were taken up by macrophages leading to foam cell formation and induction of cell death. Olive oil triggered caspase-3 cleavage and apoptosis, which facilitate the resolution of inflammation. Peanut oil and, to a lesser degree, corn oil, triggered caspase-1 activation and macrophage pyroptosis, which impair the resolution of inflammation. As such, intraperitoneal oil administration can interfere with the outcome of subsequent experiments. As a proof of principle, intraperitoneal peanut oil injection was compared with its oral delivery in a thioglycolate-induced peritonitis model. The chronic peritoneal inflammation due to peanut oil injection impeded the proper recruitment of macrophages and the resolution of inflammation in this peritonitis model. In summary, the data indicate that it is advisable to deliver lipophilic substances, like tamoxifen, by oral gavage instead of intraperitoneal injection. Implications: This work contributes to the reproducibility of animal research by helping to understand some of the undesired effects observed in animal experiments.
Abstract Background Diagnostic pathways based on PSA, digital rectal examination (DRE), and systematic biopsy (SB) may miss clinically significant prostate cancer (csPCa) and lead to overdiagnosis of indolent disease. Multiparametric MRI (mpMRI) and MRI-targeted biopsy (TB) improve detection of csPCa; however, the additional diagnostic value of routine SB in biopsy-naïve men with suspicious MRI findings remains controversial. Methods PRIMA is a randomized, prospective, multicenter non-inferiority diagnostic accuracy trial in eight German hospitals. Biopsy-naïve men aged 50–75 years with PSA ≥ 3 ng/ml and/or suspicious DRE undergo mpMRI (PI-RADS v2.1, PI-QUAL v2). Men with PI-RADS 4–5 or PI-RADS 3 with PSA density > 0.15 are randomized 1:1 to TB only (Arm A) or TB + SB (Arm B). Persistent PI-RADS 4–5 lesions with negative biopsy undergo MRI in-bore biopsy. Outcomes Co-primary endpoints are csPCa (ISUP ≥ 2) detection and detection of clinically insignificant cancer (ISUP 1). Secondary endpoints include patient-reported outcomes (EORTC-QLQ-C30, EPIC-26, VAS), biopsy-related complications, biopsy approach, MRI in-bore yield, AI/radiomics validation and follow-up cancer incidence. Sample size One thousand nine hundred eight men were allocated to achieve 1590 analyzable patients (> 80% power; non-inferiority margin δ = 13%). Discussion PRIMA will provide high-level evidence whether systematic biopsy can be safely omitted in MRI-positive biopsy-naïve men, potentially reducing diagnostic morbidity and overtreatment. Trial registration ClinicalTrials.gov NCT04993508. Registered on 2 December 2022.
BackgroundChildren remain underrepresented in clinical research, despite regulatory frameworks like the EU Paediatric Regulation and Paediatric Investigation Plans (PIPs). The 2024 Declaration of Helsinki revision now recognises excluding vulnerable populations from research as a potential ethical concern. The Clinical Trial Regulation (EU) No 536/2014 aims to harmonise clinical trial application assessment procedures through a coordinated process involving a Reporting Member State (RMS) and Member States Concerned (MSCs).AimsTo determine if harmonisation is occurring, we conducted the first systematic analysis of Phase I/II paediatric trial application assessments across Member States (MS) in the European Union (EU) focusing on assessment variability, evidence requirements, PIP integration, and adolescent inclusion practices in adult trials.MethodsIn the context of a fellowship at the European Medicines Agency, non-public data of 160 paediatric Clinical Trial Applications (CTAs) submitted through the Clinical Trial Information System (January 2022-July 2024) were screened, with inclusion of 55 Phase I/II trials in the main analysis (selected for their focus on innovative treatments and complex risk-benefit assessments). For each CTA, requests for information (consisting of considerations stated by the RMS and MSCs), assessment reports, sponsor responses, and PIP documentation were reviewed. The number of considerations in the requests for information per MS was analysed with median values calculated. Also, considerations were systemically categorised and assessment patterns between RMS and MSC roles were compared. It was examined how PIPs were integrated into assessments and approaches to adolescent inclusion in adult trials was analysed through systematic review of MS considerations.ResultsOf the 160 paediatric CTAs screened, 145 received authorisation, 10 were not authorised, and 5 were withdrawn. Among the 145 authorised CTAs, 61 were Phase I/II trials, 55 of which were included in the main analysis. Analysis of these applications revealed significant heterogeneity in both the number and type of considerations raised across MS, with the median number of considerations per CTA ranging from 5.5 to 26 across MSs (p = 0.025), with particularly marked variation when MSs acted as MSCs compared to RMSs-where additional considerations ranged from zero to 25 per CTA on top of those raised by the RMS. In 36% (20/55), MSs raised concerns about insufficient (pre-)clinical evidence pointing to divergent interpretations of evidence requirements. The degree to which PIPs were integrated into CTA assessments varied considerably-ranging from strict adherence to PIP elements to minimal consideration. In 92% (11/12), MSs showed reluctance to include adolescents in adult Phase I/II trials.ConclusionsDespite the CTR's harmonisation goals, substantial variations persist in assessment practices across MSs, particularly regarding evidence requirements, PIP integration, and adolescent inclusion in adult trials. These variations directly impact equitable access to clinical trials for children across the EU. Urgent regulatory guidance is needed to align interpretation of evidence standards, clarify the role of PIPs in CTA evaluation, and support evidence-based approaches to adolescent inclusion in adult trials.
