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Repression of retrotransposition is crucial for the successful fitness of a mammalian organism. The domesticated transposon protein L1TD1, derived from LINE-1 (L1) ORF1p, is an RNA-binding protein that is expressed only in some cancers and early embryogenesis. In human embryonic stem cells, it is found to be essential for maintaining pluripotency. In cancer, L1TD1 expression is highly correlative with malignancy progression and as such considered a potential prognostic factor for tumors. However, its molecular role in cancer remains largely unknown. Our findings reveal that DNA hypomethylation induces the expression of L1TD1 in HAP1 human tumor cells. L1TD1 depletion significantly modulates both the proteome and transcriptome and thereby reduces cell viability. Notably, L1TD1 associates with L1 transcripts and interacts with L1 ORF1p protein, thereby facilitating L1 retrotransposition. Our data suggest that L1TD1 collaborates with its ancestral L1 ORF1p as an RNA chaperone, ensuring the efficient retrotransposition of L1 retrotransposons, rather than directly impacting the abundance of L1TD1 targets. In this way, L1TD1 might have an important role not only during early development but also in tumorigenesis.

Repression of retrotransposition is crucial for the successful fitness of a mammalian organism. The domesticated transposon protein L1TD1, derived from LINE-1 (L1) ORF1p, is an RNA-binding protein that is expressed only in some cancers and early embryogenesis. In human embryonic stem cells, it is found to be essential for maintaining pluripotency. In cancer, L1TD1 expression is highly correlative with malignancy progression and as such considered a potential prognostic factor for tumors. However, its molecular role in cancer remains largely unknown. Our findings reveal that DNA hypomethylation induces the expression of L1TD1 in HAP1 human tumor cells. L1TD1 depletion significantly modulates both the proteome and transcriptome and thereby reduces cell viability. Notably, L1TD1 associates with L1 transcripts and interacts with L1 ORF1p protein, thereby facilitating L1 retrotransposition. Our data suggest that L1TD1 collaborates with its ancestral L1 ORF1p as an RNA chaperone, ensuring the efficient retrotransposition of L1 retrotransposons, rather than directly impacting the abundance of L1TD1 targets. In this way, L1TD1 might have an important role not only during early development but also in tumorigenesis.

Repression of retrotransposition is crucial for the successful fitness of a mammalian organism. The domesticated transposon protein L1TD1, derived from LINE-1 ORF1p, is an RNA-binding protein that is expressed only in some cancers and early embryogenesis. In human embryonic stem cells it is found to be essential for maintaining pluripotency. In cancer, L1TD1 expression is highly correlative with malignancy progression and as such considered a potential prognostic factor for tumors. However, its molecular role in cancer remains largely unknown. Our findings reveal that DNA hypomethylation induces the expression of L1TD1 in HAP1 human tumor cells. L1TD1 depletion significantly modulates both the proteome and transcriptome and thereby reduces cell viability. Notably, L1TD1 associates with LINE-1 transcripts and interacts with LINE-1 ORF1p protein, thereby facilitating LINE-1 retrotransposition. Our data suggest that L1TD1 collaborates with its ancestral LINE-1 ORF1p as an RNA chaperone, ensuring the efficient retrotransposition of LINE-1 retrotransposons, rather than directly impacting the abundance of L1TD1 targets. In this way, L1TD1 might have an important role not only during early development but also in tumorigenesis.Competing Interest StatementThe authors have declared no competing interest.Footnotes* We have discussed in more detail our model shown in Figure S7C. We have changed Figure 3E. We have deleted the paragraph discussing a direct relationship of our findings to embryology in the Discussion.

Antiviral strategies to inhibit Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2) and the pathogenic consequences of COVID-19 are urgently required. Here, we demonstrate that the NRF2 antioxidant gene expression pathway is suppressed in biopsies obtained from COVID-19 patients. Further, we uncover that NRF2 agonists 4-octyl-itaconate (4-OI) and the clinically approved dimethyl fumarate (DMF) induce a cellular antiviral program that potently inhibits replication of SARS-CoV2 across cell lines. The inhibitory effect of 4-OI and DMF extends to the replication of several other pathogenic viruses including Herpes Simplex Virus-1 and-2, Vaccinia virus, and Zika virus through a type I interferon (IFN)-independent mechanism. In addition, 4-OI and DMF limit host inflammatory responses to SARS-CoV2 infection associated with airway COVID-19 pathology. In conclusion, NRF2 agonists 4-OI and DMF induce a distinct IFN-independent antiviral program that is broadly effective in limiting virus replication and in suppressing the pro-inflammatory responses of human pathogenic viruses, including SARS-CoV2. Viral infections usually cause disease through direct cytopathogenic effects and excessive inflammatory responses. Here, Olagnier et al. show that two NRF2 agonists, 4-OI and DMF, possess broad IFN-independent antiviral activity and decrease host inflammatory response to SARS-CoV-2 infection.

Recurrent mutations in SPOP -encoding a Cullin 3-based E3 ubiquitin ligase- in prostate cancer disrupt the recognition and degradation of ubiquitination substrates, including BET proteins. Consequently, stability of BET proteins is enhanced and this increases the resistance to BET inhibitors in SPOP -mutant prostate tumors. These results, together with those in Janouskova et al. and Zhang et al ., uncover a novel non genetic mechanism of resistance to BET inhibition involving cancer type-specific mutations in SPOP , and support the evaluation of SPOP mutations to inform the administration of BET inhibitors in the clinic. The bromodomain and extraterminal (BET) family of proteins comprises four members—BRD2, BRD3, BRD4 and the testis-specific isoform BRDT—that largely function as transcriptional coactivators 1 , 2 , 3 and play critical roles in various cellular processes, including the cell cycle, apoptosis, migration and invasion 4 , 5 . BET proteins enhance the oncogenic functions of major cancer drivers by elevating the expression of these drivers, such as c-Myc in leukemia 6 , 7 , or by promoting the transcriptional activities of oncogenic factors, such as AR and ERG in prostate cancer 8 . Pathologically, BET proteins are frequently overexpressed and are clinically linked to various types of human cancer 5 , 9 , 10 ; they are therefore being pursued as attractive therapeutic targets for selective inhibition in patients with cancer. To this end, a number of bromodomain inhibitors, including JQ1 and I-BET, have been developed 11 , 12 and have shown promising outcomes in early clinical trials. Although resistance to BET inhibitors has been documented in preclinical models 13 , 14 , 15 , the molecular mechanisms underlying acquired resistance are largely unknown. Here we report that cullin-3 SPOP earmarks BET proteins, including BRD2, BRD3 and BRD4, for ubiquitination-mediated degradation. Pathologically, prostate cancer–associated SPOP mutants fail to interact with and promote the degradation of BET proteins, leading to their elevated abundance in SPOP -mutant prostate cancer. As a result, prostate cancer cell lines and organoids derived from individuals harboring SPOP mutations are more resistant to BET-inhibitor-induced cell growth arrest and apoptosis. Therefore, our results elucidate the tumor-suppressor role of SPOP in prostate cancer in which it acts as a negative regulator of BET protein stability and also provide a molecular mechanism for resistance to BET inhibitors in individuals with prostate cancer bearing SPOP mutations.

Abstract Disclosure: J. Beck: None. E. Stasi: None. M. Christ-Crain: None. Background: Current guidelines recommend excluding hypothyroidism as a differential diagnosis for euvolemic hyponatremia1. However, there is a growing debate on hypothyroidism-induced hyponatremia, with poor evidence on its clinical significance. Especially data in severe hypothyroidism and myxedema is lacking. AIM To assess the prevalence of hyponatremia in patients with severe hypothyroidism and identify potential comorbidities associated with its development. DESIGN and METHODS Retrospective observational study, conducted at the University Hospital of Basel in Switzerland. Data were collected over a 10-year period (01/2014-11/2024) from in-and outpatients, who presented with free thyroxine (fT4) levels <8pmol/l with and without the diagnosis of myxedema, as documented in patients’ chart. Results: A total of 820 cases were analyzed, showing a mean sodium level of 138±5 mmol/l, TSH level of 56±62 mU/l and fT4 level of 5±2 pmol/l. The prevalence of hyponatremia in the cohort was 19% (n=155). No significant association was found between fT4 and sodium levels. Within this cohort, severe hypothyroidism, clinically defined by the treating physician, was identified in 45 cases (76% female, mean age of 63±15 years), including 12 cases of myxedema. The prevalence of hyponatremia in this subgroup was 22%, which was comparable to the overall cohort (p=0.7). Further characterization of the hyponatremic population showed a higher frequency of comorbidities compared to the normonatremic group, including malignancy (30% vs 9%), cardiovascular disease (60% vs 43%), heart failure (20% vs.14%), infectious disease (40% vs. 20%) and kidney disease (30% vs. 43%). Presence of malignancy was a significant predictor of lower sodium levels (-5mmol/l, p=0.04), while no significant correlation was found between fT4 levels and sodium levels (p=0.6) or development of hyponatremia (p=0.9). Also, the mortality rate within index hospitalization was higher in the hyponatremic group compared to the normonatremic group (20% vs 6%). Conclusion: Our analysis suggests that the prevalence of hyponatremia in severe hypothyroidism is comparable to the general hospitalized population, which is estimated to be around 20%2. Hyponatremia in our cohort cannot solely be explained by the presence of severe hypothyroidism. Instead, presence of comorbidities such as malignancy seem to play a major role in the development of hyponatremia in severe hypothyroidism. REFERENCES1 Spasovski et al, Clinical practice guideline on diagnosis and treatment of hyponatraemia, 2014, Eur.J. Endocrinol., doi.org/10.1530/EJE-13-10202Robert C. Hawkins, Age and gender as risk factors for hyponatremia and hypernatremia, 2003,Clinica Chimica Acta, doi:10.1016/j.cccn.2003.08.001 Presentation: Saturday, July 12, 2025

Background To support effective self-management after kidney transplantation, a holistic nurse-led self-management support intervention was developed using the Intervention Mapping approach. The primary aim was to evaluate the feasibility, acceptability and fidelity of the intervention for kidney transplant recipients and professionals. The secondary aim was to explore preliminary effects on outcomes. Methods A pilot study was conducted in 2015–2017 to evaluate the intervention. Nurse Practitioners (NP) guided recipients in assessing 14 life areas using the Self-Management Web. Participants were supported in developing self-regulation skills which can be applied to self-management of the illness. Strategies included goal setting, action planning, and promotion of motivation and self-efficacy. Adult recipients from an outpatient clinic of a Dutch University Hospital who underwent their transplant at least 1 month ago, were invited to participate. NPs, nephrologists and recipients were interviewed to assess feasibility, fidelity and implementation experience. Consultations were videoed and analysed to assess fidelity. To assess the preliminary effects, the intervention group completed baseline (T0) and follow-up (T1) questionnaires on self-management behavior, self-efficacy, quality of life and quality of care. A historical control group of kidney transplant recipients completed the same questionnaires at T1. Results Twenty-seven recipients agreed to participate in the intervention group, of which 24 completed the intervention and 16 completed baseline and follow-up surveys. The control group consisted of 33 recipients. Professionals and recipients appraised the open, holistic focus of the intervention as a welcome addition to standard care and felt that this helped to build a relationship of trust. Recipients also felt they became more competent in problem-solving skills. The within-group analysis showed no significant increase in patients’ self-management skills. The between-groups analysis showed significantly higher medication adherence among the intervention group ( P  = 0.03; G = 0.81). The within-groups analysis showed a significantly higher perceived quality of care ( P  = 0.02) in the intervention group. Conclusion This holistic nurse-led self-management support intervention was found to be feasible and acceptable by professionals and recipients alike. This pilot had a small sample therefore further research is needed into the potential effects on self-management behavior and well-being of transplant recipients. ISRCTN Trial Registry: ISRCTN15057632 (registered retrospectively on 20-07-2018).

Introduction The most common sensorineural disorder in humans is hearing impairment and approximately 60% of prelingual hearing disorders are genetic. Especially parents with a congenital deaf child want to know as early as possible whether their second born child has the same genetic defect or not. The aim of this study is to demonstrate that postnatal genetic umbilical cord analysis is both the earliest detection possibility and sufficient. Methods We included first born children with severe hearing impairment that underwent cochlear implantation. All included patients were analyzed genetically and exhibited mutations of either DFNB1 loci or SLC26A4 gene. Additionally, the umbilical cord of the sibling underwent genetic analysis to detect hereditary genetic mutations as early as possible. Results 49 newborn children out of 22 families were included in this study. Genetic analysis revealed clinical relevant mutations in all first born children and in four siblings via umbilical cord analysis. All patients who have been diagnosed with a relevant genetic mutation that caused severe hearing impairment underwent hearing rehabilitation via cochlear implant surgery. Conclusion This study demonstrates the sufficient and early as possible detection of known genetically hearing disorders via umbilical cord analysis. In case of a known familial genetic hearing disorder, it is advisable to analyze newborn siblings for the corresponding genetic defect as soon as possible, to be able to plan and initiate clinical care for the patient as early as possible. It is also extremely important for the parents to obtain clear information about the auditory status of the newborn.

Pediatric central nervous system (CNS) tumors represent the most common cause of cancer-related death in children aged 0–14 years. They differ from their adult counterparts, showing extensive clinical and molecular heterogeneity as well as a challenging histopathological spectrum that often impairs accurate diagnosis. Here, we use DNA methylation-based CNS tumor classification in combination with copy number, RNA-seq, and ChIP-seq analysis to characterize a newly identified CNS tumor type. In addition, we report histology, patient characteristics, and survival data in this tumor type. We describe a biologically distinct pediatric CNS tumor type ( n  = 31 cases) that is characterized by focal high-level amplification and resultant overexpression of either PLAGL1 or PLAGL2 , and an absence of recurrent genetic alterations characteristic of other pediatric CNS tumor types. Both genes act as transcription factors for a regulatory subset of imprinted genes (IGs), components of the Wnt/β-Catenin pathway, and the potential drug targets RET and CYP2W1 , which are also specifically overexpressed in this tumor type. A derived PLAGL-specific gene expression signature indicates dysregulation of imprinting control and differentiation/development. These tumors occurred throughout the neuroaxis including the cerebral hemispheres, cerebellum, and brainstem, and were predominantly composed of primitive embryonal-like cells lacking robust expression of markers of glial or neuronal differentiation (e.g., GFAP, OLIG2, and synaptophysin). Tumors with PLAGL1 amplification were typically diagnosed during adolescence (median age 10.5 years), whereas those with PLAGL2 amplification were diagnosed during early childhood (median age 2 years). The 10-year overall survival was 66% for PLAGL1 -amplified tumors, 25% for PLAGL2 -amplified tumors, 18% for male patients, and 82% for female patients. In summary, we describe a new type of biologically distinct CNS tumor characterized by PLAGL1/2 amplification that occurs predominantly in infants and toddlers ( PLAGL2 ) or adolescents ( PLAGL1 ) which we consider best classified as a CNS embryonal tumor and which is associated with intermediate survival. The cell of origin and optimal treatment strategies remain to be defined.

Abstract Disclosure: J. Beck: None. E. Kustos-Toth: None. L. Seeger: None. S. Monnerat: None. C. Bathelt: None. J. Refardt: None. M. Christ-Crain: None. Background: Hyponatremia is the most common electrolyte disorder in clinical practice and is associated with cognitive impairment. We have recently shown that correction of sodium levels can improve cognitive function1. Growing evidence suggests that serum brain-derived neurotrophic factor (BDNF) correlates with cognitive performance, playing a crucial role in learning, memory, and development of neurocognitive diseases, like dementia and depression. There is currently no data on serum BDNF levels in the context of hyponatremia. Aim: The primary objective of this study was to investigate the effect of hyponatremia correction on serum BDNF levels. Design and MethodsSecondary analysis of a prospective randomized, double-blind, crossover, placebo-controlled trial of 4-week empagliflozin 25mg/d vs placebo treatment in patients with syndrome of inappropriate antidiuresis (SIAD), conducted at the University Hospital Basel, Switzerland, from December 2017 to August 2021. Serum BDNF levels were assessed by quantitative enzyme-linked immunosorbent assay (ELISA). Statistical analyses were performed using R version 4.4.2. Results: A total of fourteen patients were included in the analysis (50% female, median age 72 years [65-77]. At baseline, the median sodium in the empagliflozin group was 131 mmol/l [128-132], which increased to 134 mmol/l [131-136] after treatment (p=0,008). In the placebo group, median sodium was 131mmol/l [130-132] at baseline and remained stable at 131 mmol/l [128-132] after treatment.In the total cohort, an increase in sodium was significantly associated with an increase in BDNF levels (1 mmol/l sodium increase led to a 0.3 ng/ml increase in BDNF levels, p = 0.04), which was more profound after empagliflozin treatment (p=0.004, compared to placebo p=0.3). In the multivariant model the treatment arm was no independent predictor of BDNF change. In patients without an increase in sodium, the median BDNF was 11,4ng/ml [10,2-18] at baseline compared to 10,9 ng/ml [8,7-15,7] after treatment. In patients with an increase in sodium, baseline median BDNF was 12,3 ng/ml [9,6-14,7] and increased to 15,2 ng/ml [11,8-19,3] after the treatment period. No association was observed between Montreal Cognitive Assessment (MoCA) scores and BDNF levels, regardless of treatment group. Conclusion: Our findings indicate that hyponatremia correction is associated with an increase in the serum cognitive marker BDNF, highlighting the importance of hyponatremia correction in cognitive health. Further studies are needed to confirm the role of BDNF upon hyponatremia treatment. References: 1 Refardt et al, JASN, doi.org/10.1681/ASN.2022050623 Presentation: Monday, July 14, 2025