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Epstein-Barr virus (EBV) replication contributes to multiple human diseases, including infectious mononucleosis, nasopharyngeal carcinoma, B cell lymphomas, and oral hairy leukoplakia. We performed systematic quantitative analyses of temporal changes in host and EBV proteins during lytic replication to gain insights into virus-host interactions, using conditional Burkitt lymphoma models of type I and II EBV infection. We quantified profiles of >8,000 cellular and 69 EBV proteins, including >500 plasma membrane proteins, providing temporal views of the lytic B cell proteome and EBV virome. Our approach revealed EBV-induced remodeling of cell cycle, innate and adaptive immune pathways, including upregulation of the complement cascade and proteasomal degradation of the B cell receptor complex, conserved between EBV types I and II. Cross-comparison with proteomic analyses of human cytomegalovirus infection and of a Kaposi-sarcoma-associated herpesvirus immunoevasin identified host factors targeted by multiple herpesviruses. Our results provide an important resource for studies of EBV replication.

The Epstein-Barr virus (EBV) encoded oncoprotein Latent Membrane Protein 1 (LMP1) signals through two C-terminal tail domains to drive cell growth, survival and transformation. The LMP1 membrane-proximal TES1/CTAR1 domain recruits TRAFs to activate MAP kinase, non-canonical and canonical NF-kB pathways, and is critical for EBV-mediated B-cell transformation. TRAF1 is amongst the most highly TES1-induced target genes and is abundantly expressed in EBV-associated lymphoproliferative disorders. We found that TRAF1 expression enhanced LMP1 TES1 domain-mediated activation of the p38, JNK, ERK and canonical NF-kB pathways, but not non-canonical NF-kB pathway activity. To gain insights into how TRAF1 amplifies LMP1 TES1 MAP kinase and canonical NF-kB pathways, we performed proteomic analysis of TRAF1 complexes immuno-purified from cells uninduced or induced for LMP1 TES1 signaling. Unexpectedly, we found that LMP1 TES1 domain signaling induced an association between TRAF1 and the linear ubiquitin chain assembly complex (LUBAC), and stimulated linear (M1)-linked polyubiquitin chain attachment to TRAF1 complexes. LMP1 or TRAF1 complexes isolated from EBV-transformed lymphoblastoid B cell lines (LCLs) were highly modified by M1-linked polyubiqutin chains. The M1-ubiquitin binding proteins IKK-gamma/NEMO, A20 and ABIN1 each associate with TRAF1 in cells that express LMP1. TRAF2, but not the cIAP1 or cIAP2 ubiquitin ligases, plays a key role in LUBAC recruitment and M1-chain attachment to TRAF1 complexes, implicating the TRAF1:TRAF2 heterotrimer in LMP1 TES1-dependent LUBAC activation. Depletion of either TRAF1, or the LUBAC ubiquitin E3 ligase subunit HOIP, markedly impaired LCL growth. Likewise, LMP1 or TRAF1 complexes purified from LCLs were decorated by lysine 63 (K63)-linked polyubiqutin chains. LMP1 TES1 signaling induced K63-polyubiquitin chain attachment to TRAF1 complexes, and TRAF2 was identified as K63-Ub chain target. Co-localization of M1- and K63-linked polyubiquitin chains on LMP1 complexes may facilitate downstream canonical NF-kB pathway activation. Our results highlight LUBAC as a novel potential therapeutic target in EBV-associated lymphoproliferative disorders.

Autism is a complex childhood neurodevelopmental disorder with a strong genetic basis. Microdeletion or duplication of a approximately 500-700-kb genomic rearrangement on 16p11.2 that contains 24 genes represents the second most frequent chromosomal disorder associated with autism. The role of common and rare 16p11.2 sequence variants in autism etiology is unknown.To identify common 16p11.2 variants with a potential role in autism, we performed association studies using existing data generated from three microarray platforms: Affymetrix 5.0 (777 families), Illumina 550 K (943 families), and Affymetrix 500 K (60 families). No common variants were identified that were significantly associated with autism. To look for rare variants, we performed resequencing of coding and promoter regions for eight candidate genes selected based on their known expression patterns and functions. In total, we identified 26 novel variants in autism: 13 exonic (nine non-synonymous, three synonymous, and one untranslated region) and 13 promoter variants. We found a significant association between autism and a coding variant in the seizure-related gene SEZ6L2 (12/1106 autism vs. 3/1161 controls; p = 0.018). Sez6l2 expression in mouse embryos was restricted to the spinal cord and brain. SEZ6L2 expression in human fetal brain was highest in post-mitotic cortical layers, hippocampus, amygdala, and thalamus. Association analysis of SEZ6L2 in an independent sample set failed to replicate our initial findings.We have identified sequence variation in at least one candidate gene in 16p11.2 that may represent a novel genetic risk factor for autism. However, further studies are required to substantiate these preliminary findings.

Although the BCL6 transcriptional repressor is frequently expressed in human follicular lymphomas (FL), its biological role in this disease remains unknown. Herein, we comprehensively identify the set of gene promoters directly targeted by BCL6 in primary human FLs. We noted that BCL6 binds and represses NOTCH2 and NOTCH pathway genes. Moreover, BCL6 and NOTCH2 pathway gene expression is inversely correlated in FL. Notably, BCL6 upregulation is associated with repression of NOTCH2 and its target genes in primary human and murine germinal center (GC) cells. Repression of NOTCH2 is an essential function of BCL6 in FL and GC B cells because inducible expression of Notch2 abrogated GC formation in mice and killed FL cells. Indeed, BCL6-targeting compounds or gene silencing leads to the induction of NOTCH2 activity and compromises survival of FL cells, whereas NOTCH2 depletion or pathway antagonists rescue FL cells from such effects. Moreover, BCL6 inhibitors induced NOTCH2 expression and suppressed growth of human FL xenografts in vivo and primary human FL specimens ex vivo These studies suggest that established FLs are thus dependent on BCL6 through its suppression of NOTCH2Significance: We show that human FLs are dependent on BCL6, and primary human FLs can be killed using specific BCL6 inhibitors. Integrative genomics and functional studies of BCL6 in primary FL cells point toward a novel mechanism whereby BCL6 repression of NOTCH2 drives the survival and growth of FL cells as well as GC B cells, which are the FL cell of origin. Cancer Discov; 7(5); 506-21. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 443.

BackgroundAutism is a complex childhood neurodevelopmental disorder with a strong genetic basis. Microdeletion or duplication of a approximately 500-700-kb genomic rearrangement on 16p11.2 that contains 24 genes represents the second most frequent chromosomal disorder associated with autism. The role of common and rare 16p11.2 sequence variants in autism etiology is unknown.Methodology/principal findingsTo identify common 16p11.2 variants with a potential role in autism, we performed association studies using existing data generated from three microarray platforms: Affymetrix 5.0 (777 families), Illumina 550 K (943 families), and Affymetrix 500 K (60 families). No common variants were identified that were significantly associated with autism. To look for rare variants, we performed resequencing of coding and promoter regions for eight candidate genes selected based on their known expression patterns and functions. In total, we identified 26 novel variants in autism: 13 exonic (nine non-synonymous, three synonymous, and one untranslated region) and 13 promoter variants. We found a significant association between autism and a coding variant in the seizure-related gene SEZ6L2 (12/1106 autism vs. 3/1161 controls; p = 0.018). Sez6l2 expression in mouse embryos was restricted to the spinal cord and brain. SEZ6L2 expression in human fetal brain was highest in post-mitotic cortical layers, hippocampus, amygdala, and thalamus. Association analysis of SEZ6L2 in an independent sample set failed to replicate our initial findings.Conclusions/significanceWe have identified sequence variation in at least one candidate gene in 16p11.2 that may represent a novel genetic risk factor for autism. However, further studies are required to substantiate these preliminary findings.

Background: Cancer patients who are exposed to sepsis and had previous chemotherapy may have increased severity. Among chemotherapeutic agents, anthracyclines have been associated with cardiac toxicity. Like other chemotherapeutic agents, they may cause endothelial toxicity. The aim of this study was to evaluate the effect of anthracycline treatment on the outcome of cancer patients with sepsis. Methods: Data from cancer patients admitted to intensive care units (ICUs) for sepsis or septic shock were extracted from the Groupe de Recherche Respiratoire en Réanimation Onco-Hématologique database (1994–2015). Comparison between patients who received anthracycline and those who did not was performed using a propensity score, including confounding variables (age and underlying diseases). A competing risk adjusted for severity of illness (Sequential Organ Failure Assessment [SOFA] score) was used to analyze the duration of vasopressor requirement. Results: Among 2046 patients, 1070 (52.3%) patients who received anthracycline were compared with 976 (47.7%) who did not. The underlying disease was mostly acute hematological malignancy (49.2%). Sepsis, mostly pneumonia (47.7%), had developed 2 days (interquartile range [IQR]:1–4 days) prior to ICU admission. Most patients (n=1156/1980,58.4%) required vasopressors for 3 days (IQR: 2–6 days). Factors associated with the need for vasopressors were aplasia (hazard ratio [HR]=1.72, 95% confidence interval [CI]: 1.21 to 2.47, P=0.002) and day 1 respiratory SOFA score (HR=7.07, 95% CI: 2.75 to 22.1, P

In this study, we investigated relations between infants' understanding of intentional actions and measures of social responsiveness during a transitional period, 9- to 11-months. Infants (N = 52) were tested in visual habituation paradigms tapping their understanding of the relation between a person and the object of her attention. Measures of social responsiveness included orienting to the target of another's attention, point production, and supported joint attention in parent-child play. Infants' responses to the habituation events were related to their social responsiveness. Distinct factors for understanding actions and social responsiveness as relational were revealed. Infants who produced object-directed points were more likely to understand pointing as relational, and infants who engaged in high amounts of shared attention were more likely to understand gaze. Infants' tendency to orient in response to an adult's gaze shifts and points was unrelated to their understanding of gaze and pointing. These findings elucidate the ways in which social cognition and social responsiveness, although distinct, are related in development. (Contains 4 figures, 4 tables, and 5 footnotes.)

The governance of artisanal gold panning is characterized, in most African countries, by informal practices. The Bili-Uéré Hunting Domain (DCBU), the largest protected area in the Democratic Republic of Congo (60,000 km2), is threatened by artisanal gold mining, the governance of which deserves to be questioned. This article aims to demonstrate how local survival requirements limit the application of national legislation in the governance of gold panning in the said area. To achieve this, data collection mobilized a triple input of methodological instruments including documentation, discourse (individual and group interviews) and direct observation. At the end of the data analysis, the results show that the governance of gold panning in the DCBU is characterized by a coexistence between national regulations and informal practices. This coexistence is due to the local socio-economic needs of the stakeholders, abandoned by the State in its sovereign functions. The actors involved in the governance of gold panning have thus developed systems of relationships around the issues linked to this activity. These results prove that the question of gold panning governance in the DCBU is complex because the stakeholder games are defined at all levels, notably national, provincial and local. At each of these levels, gold panning is based on very structured local governance, governed by the predominance of informal rules. A holistic response from the State and other stakeholders is therefore necessary to reconcile socio-economic concerns with the application of mining and forestry regulations.

Despite increasing recognition of children's right to have a say about matters that affect them (Article 12, United Nations Convention on the Rights of the Child), this right is often denied in the context of child abuse research. This article explores the ways in which ethical decision-making can contribute to the denial of this right and the negative implications of this at both an individual and societal level.Ethical decision-making that stymies the conduct of abuse-focused research with children is usually justified with reference to protecting participants from risk of harm. Whilst in no way suggesting that this is not a critical consideration, the authors question the simplistic and deterministic ways in which this can be understood within ethical decision-making, and the unnecessarily risk-averse decisions that can ensue.Sharing examples from their cumulative 30 years' experience of engaging children and young people in abuse-focused research, the authors stress the need for a more holistic, nuanced and dynamic approach to assessing and managing risk of harm. This would consider risks of both inclusion and exclusion. Understanding that risk and harm are neither static nor universally experienced concepts, it would recognise the implausibility of the ‘do no harm’ guarantees often expected of social researchers. Instead, informed by rights-respecting and trauma-informed perspectives, it would focus on holistically promoting participant wellbeing in, and through, research. Key to this is permitting, and supporting, researchers to exercise contextually-informed, collaborative decision-making in the field; something the authors share their emerging practice framework for.

BackgroundIn the United States, transgender women are disproportionately impacted by HIV and prioritized in the national strategy to end the epidemic. Individual, interpersonal, and structural vulnerabilities underlie HIV acquisition among transgender women and fuel syndemic conditions, yet no nationwide cohort monitors their HIV and other health outcomes. ObjectiveOur objective is to develop a nationwide cohort to estimate HIV incidence, identify risk factors, and investigate syndemic conditions co-occurring with HIV vulnerability or acquisition among US transgender women. The study is informed by the Syndemics Framework and the Social Ecological Model, positing that stigma-related conditions are synergistically driven by shared multilevel vulnerabilities. MethodsTo address logistical and cost challenges while minimizing technology barriers and research distrust, we aim to establish a novel, hybrid community hub–supported digital cohort (N=3000). The digital cohort is the backbone of the study and is enhanced by hubs strategically located across the United States for increased engagement and in-person support. Study participants are English or Spanish speakers, are aged ≥18 years, identify as transgender women or along the transfeminine spectrum, reside in 1 of the 50 states or Puerto Rico, and do not have HIV (laboratory confirmed). Participants are followed for 24 months, with semiannual assessments. These include a questionnaire and laboratory-based HIV testing using self-collected specimens. Using residential zip codes, person-level data will be merged with contextual geolocated data, including population health measures and economic, housing, and other social and structural factors. Analyses will (1) evaluate the contribution of hub support to the digital cohort using descriptive statistics; (2) estimate and characterize syndemic patterns among transgender women using latent class analysis; (3) examine the role of contextual factors in driving syndemics and HIV prevention over time using multilevel regression models; (4) estimate HIV incidence in transgender women and examine the effect of syndemics and contextual factors on HIV incidence using Poisson regression models; and (5) develop dynamic, compartmental models of multilevel combination HIV prevention interventions among transgender women to simulate their impact on HIV incidence through 2030. ResultsEnrollment launched on March 15, 2023, with data collection phases occurring in spring and fall. As of February 24, 2024, a total of 3084 individuals were screened, and 996 (32.3%) met the inclusion criteria and enrolled into the cohort: 2.3% (23/996) enrolled at a hub, and 53.6% (534/996) enrolled through a community hub–supported strategy. Recruitment through purely digital methods contributed 61.5% (1895/3084) of those screened and 42.7% (425/996) of those enrolled in the cohort. ConclusionsStudy findings will inform the development of evidence-based interventions to reduce HIV acquisition and syndemic conditions among US transgender women and advance efforts to end the US HIV epidemic. Methodological findings will also have critical implications for the design of future innovative approaches to HIV research. International Registered Report Identifier (IRRID)DERR1-10.2196/59846

Autism spectrum disorders (ASDs) represent a group of childhood neurodevelopmental and neuropsychiatric disorders characterized by deficits in verbal communication, impairment of social interaction, and restricted and repetitive patterns of interests and behaviour. To identify common genetic risk factors underlying ASDs, here we present the results of genome-wide association studies on a cohort of 780 families (3,101 subjects) with affected children, and a second cohort of 1,204 affected subjects and 6,491 control subjects, all of whom were of European ancestry. Six single nucleotide polymorphisms between cadherin 10 (CDH10) and cadherin 9 (CDH9)-two genes encoding neuronal cell-adhesion molecules-revealed strong association signals, with the most significant SNP being rs4307059 (P = 3.4 X [10.sup.-8], odds ratio =1.19). These signals were replicated in two independent cohorts, with combined Pvalues ranging from 7.4 X [10.sup.-8] to 2.1 X [10.sup.-10]. Our results implicate neuronal cell-adhesion molecules in the pathogenesis of ASDs, and represent, to our knowledge, the first demonstration of genome-wide significant association of common variants with susceptibility to ASDs., ASDs encompass a range of clinically defined conditions, including autism and pervasive developmental disorder not otherwise specified, which are more common and severe, as well as Asperger's syndrome, which appears [...]

Autism spectrum disorders (ASDs) are childhood neurodevelopmental disorders with complex genetic origins(1-4). Previous studies focusing on candidate genes or genomic regions have identified several copy number variations (CNVs) that are associated with an increased risk of ASDs(5-9). Here we present the results from a whole-genome CNV study on a cohort of 859 ASD cases and 1,409 healthy children of European ancestry who were genotyped with 550,000 single nucleotide polymorphism markers, in an attempt to comprehensively identify CNVs conferring susceptibility to ASDs. Positive findings were evaluated in an independent cohort of 1,336 ASD cases and 1,110 controls of European ancestry. Besides previously reported ASD candidate genes, such as NRXNI (ref. 10) and CNTN4 (refs 11, 12), several new susceptibility genes encoding neuronal cell-adhesion molecules, including NLGNI and ASTN2, were enriched with CNVs in ASD cases compared to controls (P = 9.5 x [10.sup.-3]). Furthermore, CNVs within or surrounding genes involved in the ubiquitin pathways, including UBE3A, PARKZ RFWD2 and FBX040, were affected by CNVs not observed in controls (P= 3.3 x [10.sup.-3]). We also identified duplications 55 kilobases upstream of complementary DNA AK123120 (P=3.6 x [10.sup.-6]). Although these variants may be individually rare, they target genes involved in neuronal cell-adhesion or ubiquitin degradation, indicating that these two important gene networks expressed within the central nervous system may contribute to the genetic susceptibility of ASD., ASDs, including autism, are neurodevelopmental disorders characterized by impairments in social and communication skills, as well as stereotyped and repetitive behaviours and/or a restricted range of interests. Current prevalence estimates [...]

A two-stage genetic study is performed in which genomewide linkage and family-based association mapping is followed up by association and replication studies in an independent sample. It is concluded that a common variant in contactin-associated protein-like 2 (CNTNAP2) is associated with increased risk for autism in two independent family-based samples and exhibits a parent-of-origin bias.

Introduction The Building on Existing Tools to Improve Cancer and Chronic Disease Prevention and Screening in Primary Care (BETTER) programme trains allied health professionals working in primary care settings to develop personalised chronic disease ‘prevention prescriptions’ with patients. However, maintenance of health behaviour changes is difficult without ongoing support. Sustainable options to enhance the BETTER programme and ensure accessibility to underserved populations are needed. We designed the BETTER Women programme, which uses a digital app to match patients with a trained peer health coach (PHC) who provides ongoing support for health behaviour change after receipt of a BETTER prevention prescription in primary care.Methods and analysis We will conduct a type 1 hybrid implementation-effectiveness patient-randomised trial. Interested women aged 40–68 years will be recruited from three large, sociodemographically distinct primary care clinics (urban, suburban and rural). Patients will be randomised 1:1 to intervention or wait-list control after receipt of their BETTER prevention prescription. We will aim to recruit 204 patients per group (408 total). Effectiveness will be assessed by the primary outcome of targeted behaviours achieved for each participant at 6 months, consisting of three cancer screening tests (cervical, breast and colorectal) and four behavioural determinants of cancer and chronic disease (diet, smoking, alcohol use and physical activity). Data will be collected through patient survey and clinical chart review, measured at 3, 6 and 12 months. Implementation outcomes will be assessed through patient surveys and interviews with patients, peer health coaches and healthcare providers. An embedded economic evaluation will examine cost per quality-adjusted life-year and per additional health behavioural targets achieved.Ethics and dissemination This study has been approved by Women’s College Hospital Research Ethics Board (REB), the Royal Victoria Regional Health Centre REB and the University of Toronto REB. All participants will provide informed consent prior to enrolment. Participation is voluntary and withdrawal will have no impact on the usual care received from their primary care provider. The results of this trial will be published in peer-reviewed journals and shared via conference presentations. Deidentified datasets will be shared on request, after publication of results.Trial registration number NCT04746859.

Traumatic abdominal wall hernia is a rare presentation, most commonly reported in the context of motor vehicle accidents and associated with blunt abdominal injuries and handlebar injuries in the pediatric population. A 13-year-old boy presented with multiple traumatic injuries and hemodynamic instability after a high-speed motor vehicle accident. His injuries consisted of massive traumatic abdominal wall hernia (grade 4) with bowel injury and perforation, blunt aortic injury, a Chance fracture, hemopneumothorax, and a humeral shaft fracture. Initial surgical management included partial resection of the terminal ileum, sigmoid colon, and descending colon. Laparostomy was managed with negative pressure wound therapy. The patient underwent skin-only primary closure of the abdominal wall and required multiple returns to theatre for debridement, dressing changes, and repair of other injuries. Various surgical management options for abdominal wall closure were considered. In total, he underwent 36 procedures. The multiple injuries had competing management aims, which required close collaboration between specialist clinicians to form an individualized management plan. The severity and complexity of this injury was of a scale not previously experienced by many clinicians and benefited from intrahospital and interhospital specialist collaboration. The ideal aim of primary surgical repair was not possible in this case of a giant abdominal wall defect.

SARS-CoV-2 infection of immunocompromised individuals often leads to prolonged detection of viral RNA and infectious virus in nasal specimens, presumably due to the lack of induction of an appropriate adaptive immune response. Mutations identified in virus sequences obtained from persistently infected patients bear signatures of immune evasion and have some overlap with sequences present in variants of concern. We characterized virus isolates obtained greater than 100 days after the initial COVID-19 diagnosis from two COVID-19 patients undergoing immunosuppressive cancer therapy, wand compared them to an isolate from the start of the infection. Isolates from an individual who never mounted an antibody response specific to SARS-CoV-2 despite the administration of convalescent plasma showed slight reductions in plaque size and some showed temperature-dependent replication attenuation on human nasal epithelial cell culture compared to the virus that initiated infection. An isolate from another patient—who did mount a SARS-CoV-2 IgM response—showed temperature-dependent changes in plaque size as well as increased syncytia formation and escape from serum-neutralizing antibodies. Our results indicate that not all virus isolates from immunocompromised COVID-19 patients display clear signs of phenotypic change, but increased attention should be paid to monitoring virus evolution in this patient population.

Abstract We performed a cross‐sectional study to determine associations between cognition and MRI‐derived brain outcomes, with obesity, diabetes duration, and metabolic risk factors in 51 Pima American Indians with longstanding type 2 diabetes (T2d) (mean [SD] age: 48.4 [11.3] years, T2d duration: 20.1 [9.1] years). Participants had similar cognition (NIH Toolbox Cognition Battery composite: 45.3 [9.8], p = 0.64, n = 51) compared to normative data. T2d duration, but not other metabolic risk factors, associated with decreased cortical thickness (Point Estimate (PE): −0.0061, 95%CI: −0.0113, −0.0009, n = 45), gray matter volume (PE: −830.39, 95%CI: −1503.14, −157.64, n = 45), and increased white matter hyperintensity volume (PE: 0.0389, 95%CI: 0.0049, 0.0729, n = 45).

Abstract Introduction Adolescent girls and young women (AGYW) living with HIV experience poor HIV outcomes and high rates of unintended pregnancy. Little is known about which healthcare provisions can optimize their HIV‐related outcomes, particularly among AGYW mothers. Methods Eligible 12‐ to 24‐year‐old AGYW living with HIV from 61 health facilities in a South African district completed a survey in 2018–2019 (90% recruited). Analysing surveys and medical records from n = 774 participants, we investigated associations of multiple HIV‐related outcomes (past‐week adherence, consistent clinic attendance, uninterrupted treatment, no tuberculosis [TB] and viral suppression) with seven healthcare provisions: no antiretroviral therapy (ART) stockouts, kind and respectful providers, support groups, short travel time, short waiting time, confidentiality, and safe and affordable facilities. Further, we compared HIV‐related outcomes and healthcare provisions between mothers (n = 336) and nulliparous participants (n = 438). Analyses used multivariable regression models, accounting for multiple outcomes. Results HIV‐related outcomes were poor, especially among mothers. In multivariable analyses, two healthcare provisions were “accelerators,” associated with multiple improved outcomes, with similar results among mothers. Safe and affordable facilities, and kind and respectful staff were associated with higher predicted probabilities of HIV‐related outcomes (p

Abstract The aim of the Protocole National De Diagnostic et de Soins/French National Protocol for Diagnosis and Healthcare (PNDS) is to provide advice for health professionals on the optimum care provision and pathway for patients with glycogen storage disease type III (GSD III).The protocol aims at providing tools that make the diagnosis, defining the severity and different damages of the disease by detailing tests and explorations required for monitoring and diagnosis, better understanding the different aspects of the treatment, defining the modalities and organisation of the monitoring. This is a practical tool, to which health care professionals can refer. PNDS cannot, however, predict all specific cases, comorbidities, therapeutic particularities or hospital care protocols, and does not seek to serve as a substitute for the individual responsibility of the physician in front of his/her patient.

Human tumors progress in part by accumulating epigenetic alterations, which include gains and losses of DNA methylation in different parts of the cancer cell genome. Recent work has revealed a link between these two opposite alterations by showing that DNA hypomethylation in tumors can induce the expression of transcripts that overlap downstream gene promoters and thereby induce their hypermethylation. Preliminary in silico evidence prompted us to investigate if this mechanism applies to the locus harboring AGO1, a gene that plays a central role in miRNA biogenesis and RNA interference. Inspection of public RNA-Seq datasets and RT-qPCR experiments show that an alternative transcript starting 13.4 kb upstream of AGO1 (AGO1-V2) is expressed specifically in testicular germ cells, and becomes aberrantly activated in different types of tumors, particularly in tumors of the esophagus, stomach, and lung. This expression pattern classifies AGO1-V2 into the group of “Cancer-Germline” (CG) genes. Analysis of transcriptomic and methylomic datasets provided evidence that transcriptional activation of AGO1-V2 depends on DNA demethylation of its promoter region. Western blot experiments revealed that AGO1-V2 encodes a shortened isoform of AGO1, corresponding to a truncation of 75 aa in the N-terminal domain, and which we therefore referred to as “∆NAGO1”. Interestingly, significant correlations between hypomethylation/activation of AGO1-V2 and hypermethylation/repression of AGO1 were observed upon examination of tumor cell lines and tissue datasets. Overall, our study reveals the existence of a process of interdependent epigenetic alterations in the AGO1 locus, which promotes swapping between two AGO1 protein-coding mRNA isoforms in tumors.

ObjectiveTo assess the success rate of patent ductus arteriosus (PDA) transcatheter closure in preterm infants and to describe the nature of procedural adverse events and short-term clinical status.Study designAll the preterm infants with PDA transcatheter closure were evaluated retrospectively between July 2019 and March 2023 in a single level III neonatal intensive care unit in France. The procedure was performed in the catheterization laboratory using venous canulation. We retrospectively collected data about the patients' characteristics, procedural outcomes and complications.ResultsTwenty-five infants born between 23.4 and 32.0 weeks of gestational age (mean ± SD 26.3 ± 1.9 weeks) underwent transcatheter PDA closure. Their mean age and weight at the time of the procedure were 52 days (range 22–146 days) and 1,620 g (range 890–3,700 g), respectively. Successful closure was achieved in all but one patient. Procedure related complications were reported in 10 infants (40%), including 6 left pulmonary artery stenosis one of which required a balloon dilatation, two cardiac tamponades and two inferior vena cava thrombosis. Only two post-ligature syndromes occurred after the procedure. Two infants died one of which was related to the procedure.ConclusionTranscatheter closure of a PDA is a valid alternative to surgical ligation due to its high success rate and low incidence of post-ligature syndrome. Nevertheless, we also report rare, although serious complications.