Cancer is not a risk factor for severe COVID-19 in children, except in patients with recent allogeneic hematopoietic stem cell transplantation or comorbidities.

The EPICO (Spanish general registry of COVID-19 in children)-SEHOP (Spanish Society of Pediatric Hematology and Oncology) platform gathers data from children with SARS-CoV-2 in Spain, allowing comparison between children with cancer or allogeneic hematopoietic stem cell transplantation (alloHSCT) and those without. The infection is milder in the cancer/alloHSCT group than in children without comorbidities (7.1% vs. 14.7%), except in children with recent alloHSCT (less than 300 days), of which 35.7% experienced severe COVID-19. These data have been shared with the SEHOP members to support treatment and isolation policies akin to those for children without cancer, except for those with recent alloHSCT or additional comorbidities. This highlights the collaborative registries potential in managing pandemic emergencies.

Use of olive and sunflower protein hydrolysates for the physical and oxidative stabilization of fish oil-in-water emulsions.

BACKGROUND: Olive and sunflower seeds are by-products generated in large amounts by the plant oil industry. The technological and biological properties of plant-based substrates, especially protein hydrolysates, have increased their use as functional ingredients for food matrices. The present study evaluates the physical and oxidative stabilities of 50 g kg-1 fish oil-in-water emulsions where protein hydrolysates from olive and sunflower seeds were incorporated at 20 g kg-1 protein as natural emulsifiers. The goal was to investigate the effect of protein source (i.e. olive and sunflower seeds), enzyme (i.e. subtilisin and trypsin) and degree of hydrolysis (5%, 8% and 11%) on the ability of the hydrolysate to stabilize the emulsion and retard lipid oxidation over a 7-day storage period. RESULTS: The plant protein hydrolysates displayed different emulsifying and antioxidant capacities when incorporated into the fish oil-in-water emulsions. The hydrolysates with degrees of hydrolysis (DH) of 5%, especially those from sunflower seed meal, provided higher physical stability, regardless of the enzymatic treatment. For example, the average D [2, 3] values for the emulsions containing sunflower subtilisin hydrolysates at DH 5% only slightly increased from 1.21 ± 0.02 µm (day 0) to 2.01 ± 0.04 µm (day 7). Moreover, the emulsions stabilized with sunflower or olive seed hydrolysates at DH 5% were stable against lipid oxidation throughout the storage experiment, with no significant variation in the oxidation indices between days 0 and 4. CONCLUSION: The results of the present study support the use of sunflower seed hydrolysates at DH 5% as natural emulsifiers for fish oil-in-water emulsions, providing both physical and chemical stability against lipid oxidation. © 2024 Society of Chemical Industry.

Advanced optical imaging for the rational design of nanomedicines.

Despite the enormous potential of nanomedicines to shape the future of medicine, their clinical translation remains suboptimal. Translational challenges are present in every step of the development pipeline, from a lack of understanding of patient heterogeneity to insufficient insights on nanoparticle properties and their impact on material-cell interactions. Here, we discuss how the adoption of advanced optical microscopy techniques, such as super-resolution optical microscopies, correlative techniques, and high-content modalities, could aid the rational design of nanocarriers, by characterizing the cell, the nanomaterial, and their interaction with unprecedented spatial and/or temporal detail. In this nanomedicine arena, we will discuss how the implementation of these techniques, with their versatility and specificity, can yield high volumes of multi-parametric data; and how machine learning can aid the rapid advances in microscopy: from image acquisition to data interpretation.

Ingresos de (in)migrantes por COVID-19 en un hospital de Valencia: estudio longitudinal retrospectivo de historias clínica / COVID-19 income of (im)migrants in a valencian hospital: a retrospective longitudinal study of medical records

Fundamentos: Los determinantes sociales de la salud (DSS) corresponden a aquellas circunstancias en las que las personasnacen, crecen, trabajan, viven y envejecen, incluido el conjunto más amplio de fuerzas y sistemas que influyen sobre las condicionesde vida. Los DSS generan patrones de distribución de las enfermedades en las sociedades. No hay motivos para pensar que esto nose cumpla para la COVID-19. El objetivo de este trabajo fue analizar el curso temporal de los ingresos hospitalarios por la COVID-19durante 2020 según su país de origen.Métdodos: Se realizó un estudio longitudinal retrospectivo de historias clínicas de personas hospitalizadas en el Hospital DoctorPeset de Valencia. Los casos fueron divididos entre personas originarias de algún país de la Unión Europea (casos comunitarios) y delresto de países (casos extracomunitarios). Las diferencias entre grupos fueron analizadas mediante las pruebas de Chi cuadrado y Tde Student. Para estudiar la asociación entre mortalidad y el país de origen se realizó un modelo de regresión logística múltiple. Lasfuerzas de asociación entre el país de origen y las variables mortalidad y proporción de ingreso hospitalario se valoraron mediantela razón deOdds (OR). El valor de significancia estadística se estableció en un p-valor menor de 0,05.Resultados: El 22,4% fueron personas de origen extracomunitario. El 78,3% de ellos provenían de países latinoamericanos. Laedad media de los extracomunitarios fue aproximadamente diecisiete años menor (IC 95% 15,2-19,7; p-valor<0,01). El 40,2% de los comu-nitarios y el 14,6% de los extracomunitarios fue hospitalizado dentro de los primeros seis meses del año. La probabilidad de ingresardurante el segundo semestre fue tres veces mayor en las personas de origen extracomunitario (OR 3,7; IC95% 1,9-7,4, p-valor<0,01).Conclusiones: Es posible que durante la segunda mitad del año 2020 existiera una mayor probabilidad de contagio en lapoblación extranjera...(AU)

Backgorund: Social determinants of health (SDH) refer to the circumstances in which people are born, grow, work, live andage, including the wider set of forces and systems that influence living conditions. SDH produce patterns of disease distribution insocieties. There is no reason to believe that this is not the case for COVID-19. The aim of this study was to analyse the time course ofhospital admissions for COVID-19 in 2020 among individuals according to their country of origin.Methods: A retrospective longitudinal study was conducted using the medical records of individuals hospitalised at the Doctor PesetHospital in Valencia. The cases were divided into those from a European Union country (community cases) and those from other countries(non-community cases). Differences between groups were analysed using the chi-squared test and Student’s t-test. A multiple logisticregression model was used to examine the association between hospitalisation and mortality. The strength of associations betweencountry of origin and the variables of mortality and hospital admission rate were assessed using Odds Ratio (OR). A significance level ofp-value<0.05 was set.Results: 22.4% of the sample were people of non-Community origin. Of these, 78.3% were from Latin American countries. Themean age of the non-community individuals was approximately seventeen years younger (95% CI 15.2-19.7; p-value<0.01). Within thefirst six months of the year, 40.2% of community cases and 14.6% of non-community cases were hospitalised. The odds of hospitalisa-tion in the second half of the year were three times higher for non-community cases (OR 3.7; 95% CI 1.9-7.4, p-value<0.01).Conclusions: There may have been a higher likelihood of infection among the foreign population during the second half of2020. The social stratum occupied by migrants may lead to differential exposure, possibly related to the measures implemented tocontain the pandemic.(AU)

Mapping Antibody Domain Exposure on Nanoparticle Surfaces Using DNA-PAINT.

Decorating nanoparticles with antibodies (Ab) is a key strategy for targeted drug delivery and imaging. For this purpose, the orientation of the antibody on the nanoparticle is crucial to maximize fragment antibody-binding (Fab) exposure and thus antigen binding. Moreover, the exposure of the fragment crystallizable (Fc) domain may lead to the engagement of immune cells through one of the Fc receptors. Therefore, the choice of the chemistry for nanoparticle-antibody conjugation is key for the biological performance, and methods have been developed for orientation-selective functionalization. Despite the importance of this issue, there is a lack of direct methods to quantify the antibodies' orientation on the nanoparticle's surface. Here, we present a generic methodology that enables for multiplexed, simultaneous imaging of both Fab and Fc exposure on the surface of nanoparticles, based on super-resolution microscopy. Fab-specific Protein M and Fc-specific Protein G probes were conjugated to single stranded DNAs and two-color DNA-PAINT imaging was performed. Hereby, we quantitatively addressed the number of sites per particle and highlight the heterogeneity in the Ab orientation and compared the results with a geometrical computational model to validate data interpretation. Moreover, super-resolution microscopy can resolve particle size, allowing the study of how particle dimensions affect antibody coverage. We show that different conjugation strategies modulate the Fab and Fc exposure which can be tuned depending on the application of choice. Finally, we explored the biomedical importance of antibody domain exposure in antibody dependent cell mediated phagocytosis (ADCP). This method can be used universally to characterize antibody-conjugated nanoparticles, improving the understanding of relationships between structure and targeting capacities in targeted nanomedicine.

Identification of fluorescently-barcoded nanoparticles using machine learning.

Barcoding of nano- and micro-particles allows distinguishing multiple targets at the same time within a complex mixture and is emerging as a powerful tool to increase the throughput of many assays. Fluorescent barcoding is one of the most used strategies, where microparticles are labeled with dyes and classified based on fluorescence color, intensity, or other features. Microparticles are ideal targets due to their relative ease of detection, manufacturing, and higher homogeneity. Barcoding is considerably more challenging in the case of nanoparticles (NPs), where their small size results in a lower signal and greater heterogeneity. This is a significant limitation since many bioassays require the use of nano-sized carriers. In this study, we introduce a machine-learning-assisted workflow to write, read, and classify barcoded PLGA-PEG NPs at a single-particle level. This procedure is based on the encapsulation of fluorescent markers without modifying their physicochemical properties (writing), the optimization of their confocal imaging (reading), and the implementation of a machine learning-based barcode reader (classification). We found nanoparticle heterogeneity as one of the main factors that challenges barcode separation, and that information extracted from the dyes' nanoscale confinement effects (such as Förster Resonance Energy Transfer, FRET) can aid barcode identification. Moreover, we provide a guide to reaching the optimal trade-off between the number of simultaneous barcodes and classification accuracy supporting the use of this workflow for a variety of bioassays.

Two different brain networks underlying picture naming with familiar pre-existing native words and new vocabulary.

The present research used fMRI to longitudinally investigate the impact of learning new vocabulary on the activation pattern of the language control network by measuring BOLD signal changes during picture naming tasks with familiar pre-existing native words (old words) and new vocabulary. Nineteen healthy participants successfully learned new synonyms for already known Spanish words, and they performed a picture naming task using the old words and the new words immediately after learning and two weeks after learning. The results showed that naming with old words, compared to naming with newly learned words, produced activations in a cortical network involving frontal and parietal regions, whereas the opposite contrast showed activation in a broader cortical/subcortical network, including the SMA/ACC, the hippocampus, and the midbrain. These two networks are maintained two weeks after learning. These results suggest that the language control network can be separated into two functional circuits for diverse cognitive purposes.

Domesticating models: On the contingency of Covid-19 modelling in UK media and policy.

Our article traces the representation of pandemic modelling in UK print media from the emergence of Covid-19 to the early stages of implementing the first UK-wide lockdown in late March 2020. Covid modelling, it is widely assumed, has shaped policy decisions and public responses to the pandemic in unprecedented ways. We analyse how the UK print media has configured modelling as a significant evidence tool in the representation of the pandemic. Interrogating assumptions about infectious disease modelling, we ask why models became the trusted tool of choice for knowing and responding to the Covid pandemic in the UK. Our analysis has yielded four different periods in the evolution of intersecting policy and media frames. Initially, modellers, policymakers and media alike emphasized uncertainty about available data, and hence the speculative character of modelled projections, thus justifying a 'wait and see' approach to government intervention. With growing public pressure for government action, policy and media frames were adjusted to emphasize the importance of timing interventions for best effect, with modelling evidence mobilized to justify inaction. This gave way to a period of crisis, as the press increasingly questioned the reliability of the existing models and policies, leading modellers and policy makers to dramatically revise their projections. Finally, with the imposition of the first UK lockdown, policy and media frames were brought back into alignment with one another, in a process of domestication through which the language of modelling became a basic resource for the discussion of the epidemic. Our epistemological microhistory thus challenges general accounts of the impacts of pandemic modelling and instead emphasizes contingency and interpretative flexibility.

Evaluation of the Anti-Leishmania mexicana and -Trypanosoma brucei Activity and Mode of Action of 4,4'-(Arylmethylene)bis(3-methyl-1-phenyl-1H-pyrazol-5-ol).

Trypanosomiasis and leishmaniasis are neglected infections caused by trypanosomatid parasites. The first-line treatments have many adverse effects, high costs, and are prone to resistance development, hence the necessity for new chemotherapeutic options. In line with this, twenty five 4,4'-(arylmethylene)bis(1H-pyrazol-5-ols) derivatives were synthesized and evaluated in vitro for their anti-trypanosomatid activity. Ten and five compounds from this series showed IC50 ≤ 10 µM against the promastigote and the bloodstream stage of Leishmania mexicana and Trypanosoma brucei brucei, respectively. Overall, derivatives with pyrazole rings substituted with electron-withdrawing groups proved more active than those with electron-donating groups. The hits proved moderately selective towards L. mexicana and T. brucei (selectivity index, SI, compared to murine macrophages = 5−26). The exception was one derivative displaying an SI (>111−189) against T. brucei that surpassed, by >6-fold, the selectivity of the clinical drug nifurtimox (SI = 13−28.5). Despite sharing a common scaffold, the hits differed in their mechanism of action, with halogenated derivatives inducing a rapid and marked intracellular oxidative milieu in infective T. brucei. Notably, most of the hits presented better absorption, distribution, metabolism, and excretion (ADME) properties than the reference drugs. Several of the bioactive molecules herein identified represent a promising starting point for further improvement of their trypanosomatid potency and selectivity.

Rare Diseases: Needs and Impact for Patients and Families: A Cross-Sectional Study in the Valencian Region, Spain.

Families with rare diseases (RDs) have unmet needs that are often overlooked by health professionals. Describing these needs and the impact of the disease could improve their medical care. A total of 163 surveys were obtained from patients visiting primary care centres in the Valencian Region (Spain), during 2015-2017, with a confirmed or suspected diagnosis of RD. Of the 84.7% with a confirmed diagnosis, 50.4% had a diagnostic delay exceeding one year, and it was more prevalent among adults (62.2%). Families with paediatric patients were in a worse economic situation, with lower incomes and higher monthly disease-related expenses (€300 on average). These expenses were incurred by 66.5% of families and were mainly for medication (40.3%). Among them, 58.5% reported not being able to afford adjuvant therapies. The disease had an impact on 73.1% of families, especially on their routine and emotional state. Expenses, needs, and impacts were more frequent among families of patients with a history of hospitalisation or deterioration. Patients with delayed diagnosis had a higher consumption of drugs prior to diagnosis. People affected by RDs in the Valencian Region need therapies to improve their autonomy and emotional state. Health professionals should be aware of these needs.

Mediastinal Recurrence of Uterine Cervix Cancer on 18F-FDG PET/CT.

ABSTRACT: We report the case of a 64-year-old woman with a mediastinal relapse of a uterine cervix cancer with positive human papillomavirus, an unusual site of recurrence. She consulted because of solid and liquid dysphagia of sudden appearance. Endoscopic study and non-contrast-enhanced CT showed intraluminal esophageal stenosis with a retrograde esophageal distension. 18F-FDG PET/CT demonstrated an infiltrating hypermetabolic lesion in posterior mediastinum, middle and lower esophagus, and stomach, with no signs of local or regional relapse of the uterine neoplasm.

Prevalencia de hipoglucemia grave en una cohorte de pacientes con diabetes tipo 1 / Prevalence of severe hypoglycemia in a cohort of patients with type 1 diabetes

INTRODUCCIÓN: La hipoglucemia es el principal factor limitante para alcanzar los objetivos de control glucémico en pacientes con diabetes tipo 1. La hipoglucemia grave conlleva riesgo de daño, e incluso de muerte. Tener hipoglucemias repetidas se relaciona con la aparición de hipoglucemias inadvertidas, las cuales incrementan el riesgo de hipoglucemias graves. Algunos metaanálisis recientes estiman una prevalencia del 35% de hipoglucemia grave en pacientes con diabetes tipo 1. OBJETIVO: Conocer la prevalencia de hipoglucemia grave en una cohorte de pacientes con diabetes tipo 1 y evaluar la dependencia entre las variables hipoglucemia grave e inadvertida evaluada mediante el test de Clarke. PACIENTES Y MÉTODOS: Se ha estudiado una cohorte de pacientes con diabetes tipo 1 para analizar la edad, sexo, tiempo de evolución de diabetes, tratamiento (múltiples dosis o infusión subcutánea continua de insulina), autocontrol glucémico, HbA1c, episodios de hipoglucemia grave sin pérdida de conciencia, episodios de hipoglucemia grave con pérdida de conciencia e hipoglucemias inadvertidas. RESULTADOS: El 39,8% de los pacientes presentaron hipoglucemias graves sin pérdida de conciencia (últimos 6 meses) y el 11,4%, con pérdida de conciencia (últimos 12 meses). El 40,9% presentaban hipoglucemias inadvertidas y se descartó la independencia entre estas y las hipoglucemias graves. La presencia de hipoglucemias graves con pérdida de conciencia se asoció a mayor edad y mayor tiempo de evolución; las hipoglucemias inadvertidas, con una mayor edad y una menor HbA1c. CONCLUSIÓN: Se confirma el elevado porcentaje de pacientes con diabetes tipo 1 afectos de hipoglucemia grave e inadvertida

INTRODUCTION: Hypoglycemia is the major limiting factor in the glycemic management of type 1 diabetes. Severe hypoglycemia puts patients at risk of injury and death. Recurrent hypoglycemia leads to impaired awareness of hypoglycemia and this increases the risk of severe hypoglycemia. Recent studies have reported rates for severe hypoglycemia of 35% in type 1 diabetic patients. OBJECTIVES: To assess the prevalence of severe hypoglycemia in type 1 diabetes mellitus patients and to evaluate the relationship between this and impaired awareness of hypoglycemia according to the Clarke test. PATIENTS AND METHODS: The following data were collected from a cohort of type 1 diabetic patients: age, gender, duration of type 1 diabetes, treatment (multiple daily insulin injection or continuous subcutaneous insulin infusion), glycemia self-control, HbA1c, episodes of severe hypoglycemia and impaired awareness of hypoglycemia. RESULTS: Of the participants, 39.8% had had at least one episode of severe hypoglycemia (in the previous 6 months), 11.4% with loss of consciousness (in the previous 12 months). According to the Clark test, 40.9% had impaired awareness of hypoglycemia. Older age and longer duration of diabetes were associated with a higher prevalence of severe hypoglycemia with unconsciousness; older age and a lower level of HbA1c were associated with impaired awareness of hypoglycemia. CONCLUSIONS: Our study allows us to confirm the high rate of severe hypoglycemia and impaired awareness of hypoglycemia in patients with type 1 diabetes

The Experience With Health Care of Patients With Inflammatory Arthritis: A Cross-sectional Survey Using the Instrument to Evaluate the Experience of Patients With Chronic Diseases.

BACKGROUND: Patients' experience with health care is becoming a key component for the provision of a patient-centered health care model. The aim of this study was to assess the experience with health care of patients with inflammatory arthritis and patient- and health care-related factors. METHODS: Patients responded to an anonymous survey provided by their treating clinical teams. The survey comprised the validated 12-item IEXPAC (Instrument to Evaluate the EXperience of PAtients with Chronic diseases) tool and demographic variables and health care-related characteristics that may affect patients' experience. RESULTS: A total of 359 of 625 surveys were returned (response rate, 57.4%). Overall, patient responses were positive (>60% gave "always/mostly" answers) for statements assessing the interaction between patients and health care professionals or patient self-management following health care professional guidance. However, positive patient responses for items regarding patient interaction with the health care system via the internet or with other patients were less than 13%. Only 25.6% of patients who had been hospitalized reported receiving a follow-up call or visit following discharge. In the bivariate analysis, experience scores were higher (better experience) in men, those seen by fewer specialists or by the same physician, and in patients treated with a fewer number of drugs or with subcutaneous/intravenous drugs. Multivariate analyses identified regular follow-up by the same physician and treatment with subcutaneous/intravenous drugs as variables associated with a better patient experience. CONCLUSIONS: This study identifies areas of care for patients with inflammatory arthritis with the potential to improve patients' experience and highlights the importance of patient-physician relationships and comprehensive patient care.

Prevalence of severe hypoglycemia in a cohort of patients with type 1 diabetes. / Prevalencia de hipoglucemia grave en una cohorte de pacientes con diabetes tipo 1.

INTRODUCTION: Hypoglycemia is the major limiting factor in the glycemic management of type 1 diabetes. Severe hypoglycemia puts patients at risk of injury and death. Recurrent hypoglycemia leads to impaired awareness of hypoglycemia and this increases the risk of severe hypoglycemia. Recent studies have reported rates for severe hypoglycemia of 35% in type 1 diabetic patients. OBJECTIVES: To assess the prevalence of severe hypoglycemia in type 1 diabetes mellitus patients and to evaluate the relationship between this and impaired awareness of hypoglycemia according to the Clarke test. PATIENTS AND METHODS: The following data were collected from a cohort of type 1 diabetic patients: age, gender, duration of type 1 diabetes, treatment (multiple daily insulin injection or continuous subcutaneous insulin infusion), glycemia self-control, HbA1c, episodes of severe hypoglycemia and impaired awareness of hypoglycemia. RESULTS: Of the participants, 39.8% had had at least one episode of severe hypoglycemia (in the previous 6 months), 11.4% with loss of consciousness (in the previous 12 months). According to the Clark test, 40.9% had impaired awareness of hypoglycemia. Older age and longer duration of diabetes were associated with a higher prevalence of severe hypoglycemia with unconsciousness; older age and a lower level of HbA1c were associated with impaired awareness of hypoglycemia. CONCLUSIONS: Our study allows us to confirm the high rate of severe hypoglycemia and impaired awareness of hypoglycemia in patients with type 1 diabetes.

Metastatic pulmonary dissemination as differential diagnosis of COVID-19 disease.

A 13-year-old boy presented to hospital with 3-day self-limited fever, followed by dry cough, persistent asthenia and impaired general condition of 2 weeks' duration. Blood analyses showed a severe inflammatory status and chest X-ray images were consistent with bilateral COVID-19 pneumonia. He developed an acute respiratory failure that required paediatric intensive care admission and non-invasive ventilation. A targeted COVID-19 treatment was initiated with hydroxicloroquine, corticosteroids, enoxaparine and a single dose of tocilizumab. Repeated serological tests and real-time reverse transcription PCR for SARS-CoV-2 were negative. Other infectious pathogens were also ruled out. Thoracic high resolution CT showed an intense bilateral pulmonary dissemination with lytic vertebral bone lesions. After diagnostic investigations, Ewing's sarcoma with metastatic pulmonary dissemination was diagnosed. Nowadays, in the context of SARS-CoV-2 community pandemic, we cannot forget that COVID-19 clinical presentation is not specific and other entities can mimic its clinical features.

TDP2 suppresses genomic instability induced by androgens in the epithelial cells of prostate glands.

Androgens stimulate the proliferation of epithelial cells in the prostate by activating topoisomerase 2 (TOP2) and regulating the transcription of target genes. TOP2 resolves the entanglement of genomic DNA by transiently generating double-strand breaks (DSBs), where TOP2 homodimers covalently bind to 5' DSB ends, called TOP2-DNA cleavage complexes (TOP2ccs). When TOP2 fails to rejoin TOP2ccs generating stalled TOP2ccs, tyrosyl DNA phosphodiesterase-2 (TDP2) removes 5' TOP2 adducts from stalled TOP2ccs prior to the ligation of the DSBs by nonhomologous end joining (NHEJ), the dominant DSB repair pathway in G0 /G1 phases. We previously showed that estrogens frequently generate stalled TOP2ccs in G0 /G1 phases. Here, we show that physiological concentrations of androgens induce several DSBs in individual human prostate cancer cells during G1 phase, and loss of TDP2 causes a five times higher number of androgen-induced chromosome breaks in mitotic chromosome spreads. Intraperitoneally injected androgens induce several DSBs in individual epithelial cells of the prostate in TDP2-deficient mice, even at 20 hr postinjection. In conclusion, physiological concentrations of androgens have very strong genotoxicity, most likely by generating stalled TOP2ccs.

Endogenous topoisomerase II-mediated DNA breaks drive thymic cancer predisposition linked to ATM deficiency.

The ATM kinase is a master regulator of the DNA damage response to double-strand breaks (DSBs) and a well-established tumour suppressor whose loss is the cause of the neurodegenerative and cancer-prone syndrome Ataxia-Telangiectasia (A-T). A-T patients and Atm-/- mouse models are particularly predisposed to develop lymphoid cancers derived from deficient repair of RAG-induced DSBs during V(D)J recombination. Here, we unexpectedly find that specifically disturbing the repair of DSBs produced by DNA topoisomerase II (TOP2) by genetically removing the highly specialised repair enzyme TDP2 increases the incidence of thymic tumours in Atm-/- mice. Furthermore, we find that TOP2 strongly colocalizes with RAG, both genome-wide and at V(D)J recombination sites, resulting in an increased endogenous chromosomal fragility of these regions. Thus, our findings demonstrate a strong causal relationship between endogenous TOP2-induced DSBs and cancer development, confirming these lesions as major drivers of ATM-deficient lymphoid malignancies, and potentially other conditions and cancer types.