Oslo University Hospital, Radiumhospitalet (Norwegian: Oslo universitetssykehus, Radiumhospitalet) is one of the four campuses of Oslo University Hospital in Oslo, Norway, and is dedicated to cancer treatment. This part of the hospital is the most specialized hospital in Norway for cancer therapy and research on cancer. The Norwegian Radium Hospital was an independent hospital from May 21, 1932 to 2005, when it merged with Rikshospitalet. The hospital was founded with Severin Andreas Heyerdahl as chief physician and director, and Hans L. C. Huitfeldt as chairman of the board. From 1983 to the merge with Rikshospitalet in 2005 Jan Vincents Johannessen was CEO.The Radium Hospital merged in 2005 with Rikshospitalet to create Rikshospitalet-Radiumhospitalet HF. On January 1, 2009, Rikshospitalet merged with Ullevål University Hospital and Aker University Hospital to create Oslo University Hospital.
Germline defects in mismatch repair (MMR) genes are known to significantly increase the risk of developing certain types of cancers, notably colorectal and endometrial cancers. These conditions are characterized under Lynch syndrome. Accurate diagnosis of this predisposition, along with meaningful predictive testing for family members, necessitates the identification of pathogenic variants. However, classifying small coding genetic variants identified in cancer patients is very challenging, specifically in the case of PMS2 variants, since PMS2 pathogenic variants display a lower penetrance and less severe phenotype and therefore a lower tumor burden in affected families. We have assembled clinical data on four PMS2 missense variants of uncertain significance (VUS) identified in 23 patients (p.(Asp286Gly), p.(Asn335Ser), p.(Ile679Thr) and p.(Arg799Trp)). For these variants, functional testing was performed (RNA splicing, protein stability and catalytic activity). Since many protein ortholog sequences and accurate predictive models from AlphaFold2 are available, we also included a systematic analysis of residue conservation and structural role (ConStruct assessment). Overall, our findings indicate that p.(Asp286Gly) and p.(Arg799Trp) behave similarly to wild-type PMS2 and are thus probably neutral. In contrast, p.(Asn335Ser) and p.(Ile679Thr) conferred defects in protein expression or MMR activity. These could be explained by the relevant roles of these amino acids in MLH1-PMS2-N-terminal dimerization (p.Asn335) and C-terminal dimerization (p.Ile679). Our data thus suggest that p.(Asp286Gly) and p.(Arg799Trp) are benign, while the tumor risk in the other two variants remains to be established. Taken together, we suggest roadmaps for the individualized evaluation of difficult uncertain variants by comprising information from all available sources.
Heritable mutations in male germ cells pose a critical risk to human health and future generations, however standardized methods for assessing germ cell genotoxicity remain limited. We refined the in vivo alkaline comet assay (proof-of-concept (Dirven et al. 2023); protocol (Olsen et al. 2024)) to detect DNA damage in testicular germ cells, with selective addressment of haploid spermatids and primary spermatocytes. Measurements of DNA damage (% Tail DNA) and DNA content (total fluorescence intensity) in individual comets were combined with visual comet identification to distinguish testicular comet populations based on differences in DNA content and appearance. To verify the method's functionality and reliability, DNA damage was assessed in rats exposed to the direct-acting, well-characterized genotoxicants X-rays and ethyl methanesulfonate across distinct testicular cell populations, alongside liver and blood. To minimize experimental variation, the protocol included stringent standardization of animal handling, tissue processing, and comet assay procedures. Both X-rays and EMS induced significant DNA damage in testicular germ cells, with comparable responses across testicular cell types and similar (X-rays) or higher levels observed in somatic tissues. The low inter-animal variability observed supports the robustness of the method. Importantly, inclusion of testicular germ cells in OECD test guideline 489 would provide a valuable tool for hazard identification and mutagenicity classification of chemicals under the Globally Harmonized System of Classification and Labelling of Chemicals. This versatile, sensitive, and resource-efficient assay enhances the assessment of male-mediated genetic risks and supports regulatory efforts to protect reproductive health and safeguard the genetic integrity of future generations through the use of safer chemicals.
Prostate cancer, among the most prevalent cancer types globally, exhibits marked heterogeneity and varying disease progression and clinical outcomes. Improved molecular subtyping is needed for patient stratification. Since prostate cancer has relatively few somatic point mutations, whole-transcriptome data instead offers a rich and relevant source of molecular data. We analyzed bulk tissue transcriptomes from four cohorts to characterize primary prostate cancer’s cell type composition. A deconvolution of cell types was performed based on gene expression profiles. Patients with available multi-sample regional data from different tumor foci were analyzed for intrapatient heterogeneity. Three cell type composition subtypes were defined: T cells enriched (TCE), epithelial cells enriched (EPCE), and tumor-associated stromal cells enriched (TASCE). A machine learning model was developed to classify these subtypes and validated in three independent cohorts. The subtyping demonstrated a high correlation with established clinicopathological parameters (e.g., Gleason score, p-value < 0.05), and the classifier showed a promising ability to predict biochemical recurrence. Moreover, our analysis revealed that interfocal heterogeneity in patients with multifocal cancer significantly surpassed intrafocal heterogeneity (p-value < 0.05). In conclusion, this study provides a novel prostate cancer subgrouping based on cell type composition, with the TASCE subtype significantly associated with high biochemical recurrence risk.
Despite decades of research identifying the core autophagy-related (ATG) gene products that execute macroautophagy (hereafter autophagy), a systems-level understanding of how the broader genome dynamically tunes this process remains limited. Most studies rely on bulk assays that capture cumulative degradation at a single time point, making it difficult to resolve how autophagy is activated, sustained, and terminated over time. In addition, approaches to quantify temporal response kinetics across thousands of genotypes in parallel at the population level have been lacking, hindering predictive modeling and the development of precise pharmacological strategies to modulate autophagy.
