ABSTRACT:Hypertension is the most common comorbidity in patients with chronic lymphocytic leukemia (CLL), but its impact on the disease course of CLL remains poorly understood. In this nationwide cohort study of Danish patients with incident CLL (2008-2022), we examined the association between hypertension and survival from CLL diagnosis and treatment, and compare with the general population. Cox proportional hazard regression was applied for survival analyses, and the Aalen-Johansen estimator for cumulated incidence. At diagnosis of CLL, the hypertension prevalence was 46% in the CLL cohort and 45% in the general population. Hypertension was associated with shorter overall survival (OS) following CLL diagnosis (hazard ratio [HR], 1.10; 95% confidence interval [CI], 1.00-1.20) and first-line treatment (HR, 1.48; 95% CI, 1.18-1.86), primarily driven by infections and cardiocerebrovascular causes of death. The difference was seen for patients aged <75 years both following diagnosis (HR, 1.43; 95% CI, 1.25-1.64) and first-line treatment (HR, 1.89; 95% CI, 1.34-2.66). For patients treated with Bruton tyrosine kinase inhibitors, we observed a trend toward poorer OS in patients with hypertension (HR, 1.97; 95% CI, 0.90-4.34). No interaction between CLL in general and hypertension was observed (HR, 0.89; 95% CI, 0.79-1.02), meaning that hypertension did not confer a higher additional risk in patients with CLL than in individuals without CLL. This study identifies an important subgroup of patients with CLL aged <75 years with coexisting hypertension who have a poorer prognosis. Our findings support encouraging patients to maintain regular contact with primary care and adhere to preventative health measures, as hypertension and related comorbidities remain important for survival even after CLL diagnosis.
We present the Chromatin Landscape and Structure to Expression Regressor (CLASTER), an epigenetic-based deep neural network that can integrate different data modalities describing the chromatin landscape and its 3D structure. CLASTER effectively translates them into nascent transcription levels measured at a kilobasepair resolution. The model provides a platform to understand the epigenetic drivers and learned rules of nascent transcription, and to predict the impact of in silico epigenetic perturbations. We conclude that the predominant locality of current machine learning approaches emerges as a signature of genomic organization, having broad implications for future modeling approaches.
This study explored relational experiences among young adults with cancer and their self-chosen caregivers (friends and partners) across the cancer trajectory. A national, multicentre qualitative study was conducted in oncology and haematology settings at all five Danish University Hospitals. Individual semi-structured interviews were undertaken with young adults with cancer (diagnosed when aged 18–39 years) and their self-chosen friends or partners as caregivers. Data were analysed using reflexive thematic analysis and reported in accordance with COREQ. Nine young adults with cancer (aged 23–36 years) and 13 informal caregivers (aged 22–34 years) participated (partners n = 7, friends n = 6). Three themes were identified: (1) Holding on to Normality in a Youth Life on Pause, young adult with cancer and caregiver dyads created “breathing spaces” through everyday routines while navigating disruptions in body, mood, and participation in youth contexts; (2) Navigating Help, Needs, and Boundaries, young adults with cancer and their caregiver balanced requesting and offering support, preferred concrete help, and engaged in mutual protection, with professional support rarely accessed; and (3) Shifting Roles in the Relationship, relationships evolved toward “love and logistics”, and support was organised in changing circles of closeness, with friends often occupying an “in-between” position. Cancer in young adulthood emerges as a relational phenomenon. Acknowledging partners and friends as caregivers, and fostering communication, boundary setting, and role negotiation, may reinforce dyadic coping processes and support the continuity of everyday life.
Telomeropathies and ribosomopathies share clinical features such as bone marrow failure, developmental defects and cancer predisposition, suggesting convergent pathogenic mechanisms, yet a broadly unifying molecular basis is lacking. Here we identify the telomeric shelterin component TIN2 as a key regulator of nucleolar function and rDNA stability, thereby linking these disease entities. Using a nucleolar DNA damage response (n-DDR) focused RNAi screen, we show that TIN2 is required for nucleolar DNA damage signalling, rDNA segregation into nucleolar caps, and maintenance of transcription of ribosomal RNA genes (rDNA) and protein synthesis. TIN2 depletion or Dyskeratosis congenita (DC)‑associated TIN2 mutations induce rDNA instability, nucleolar stress and p53‑dependent cell death. Strikingly, loss of additional DC proteins with canonical telomeric roles similarly perturbs the n-DDR. Hyper-PARylation, likely caused by dysregulation of RNAs, drives these defects, as PARP1 knockout restores n-DDR activation in TIN2-deficient cells. Our findings redefine DC as both a telomeric and a nucleolar/rDNA disorder and uncover a potentially targetable PARP‑dependent pathway.
Genetic screening for rare pathogenic variants facilitates early detection and prevention of disease manifestations in medically actionable disorders, but sequencing costs limit widespread use. We introduce DoBSeq, a low-cost, high-throughput screening framework for detecting rare, single-nucleotide variants and indels. The framework includes: extraction of DNA from dried blood spots used in neonatal screening, automation of two-dimensional DNA pooling and library preparation, high-depth targeted sequencing using a 582-gene custom panel, and a probabilistic model to assign rare pathogenic variants to individuals. Benchmarked against whole-genome sequencing across 582 genes in a batch of 576 individuals, the framework detected 95% of all variants and recovered all clinically relevant pathogenic single-nucleotide variants in American College of Medical Genetics and Genomics (ACMG) actionable genes. Applied to 2304 anonymised blood donors, it yielded variant frequencies consistent with existing population estimates. At a sample cost of 29 USD, including 11 USD running costs, this framework provides a cost-efficient approach to population-level genetic screening.
