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OBJECTIVES: To assess the effects of digital patient decision-support tools for atrial fibrillation (AF) treatment decisions in adults with AF. STUDY DESIGN: Systematic review and meta-analysis. ELIGIBILITY CRITERIA: Eligible randomised controlled trials (RCTs) evaluated digital patient decision-support tools for AF treatment decisions in adults with AF. INFORMATION SOURCES: We searched MEDLINE, EMBASE and Scopus from 2005 to 2023.Risk-of-bias (RoB) assessment: We assessed RoB using the Cochrane Risk of Bias Tool 2 for RCTs and cluster RCT and the ROBINS-I tool for quasi-experimental studies. SYNTHESIS OF RESULTS: We used random effects meta-analysis to synthesise decisional conflict and patient knowledge outcomes reported in RCTs. We performed narrative synthesis for all outcomes. The main outcomes of interest were decisional conflict and patient knowledge. RESULTS: 13 articles, reporting on 11 studies (4 RCTs, 1 cluster RCT and 6 quasi-experimental) met the inclusion criteria. There were 2714 participants across all studies (2372 in RCTs), of which 26% were women and the mean age was 71 years. Socioeconomically disadvantaged groups were poorly represented in the included studies. Seven studies (n=2508) focused on non-valvular AF and the mean CHAD2DS2-VASc across studies was 3.2 and for HAS-BLED 1.9. All tools focused on decisions regarding thromboembolic stroke prevention and most enabled calculation of individualised stroke risk. Tools were heterogeneous in features and functions; four tools were patient decision aids. The readability of content was reported in one study. Meta-analyses showed a reduction in decisional conflict (4 RCTs (n=2167); standardised mean difference -0.19; 95% CI -0.30 to -0.08; p=0.001; I2=26.5%; moderate certainty evidence) corresponding to a decrease in 12.4 units on a scale of 0 to 100 (95% CI -19.5 to -5.2) and improvement in patient knowledge (2 RCTs (n=1057); risk difference 0.72, 95% CI 0.68, 0.76, p<0.001; I2=0%; low certainty evidence) favouring digital patient decision-support tools compared with usual care. Four of the 11 tools were publicly available and 3 had been implemented in healthcare delivery. CONCLUSIONS: In the context of stroke prevention in AF, digital patient decision-support tools likely reduce decisional conflict and may result in little to no change in patient knowledge, compared with usual care. Future studies should leverage digital capabilities for increased personalisation and interactivity of the tools, with better consideration of health literacy and equity aspects. Additional robust trials and implementation studies are warranted. PROSPERO REGISTRATION NUMBER: CRD42020218025.
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Immunotherapy with chimeric antigen receptor T cells for pediatric solid and brain tumors is constrained by available targetable antigens. Cancer-specific exons present a promising reservoir of targets; however, these have not been explored and validated systematically in a pan-cancer fashion. To identify cancer specific exon targets, here we analyze 1532 RNA-seq datasets from 16 types of pediatric solid and brain tumors for comparison with normal tissues using a newly developed workflow. We find 2933 exons in 157 genes encoding proteins of the surfaceome or matrisome with high cancer specificity either at the gene (n = 148) or the alternatively spliced isoform (n = 9) level. Expression of selected alternatively spliced targets, including the EDB domain of fibronectin 1, and gene targets, such as COL11A1, are validated in pediatric patient derived xenograft tumors. We generate T cells expressing chimeric antigen receptors specific for the EDB domain or COL11A1 and demonstrate that these have antitumor activity. The full target list, explorable via an interactive web portal ( https://cseminer.stjude.org/ ), provides a rich resource for developing immunotherapy of pediatric solid and brain tumors using gene or AS targets with high expression specificity in cancer.
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Neoplasias Encefálicas , Exones , Receptores Quiméricos de Antígenos , Humanos , Neoplasias Encefálicas/inmunología , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/genética , Animales , Exones/genética , Niño , Receptores Quiméricos de Antígenos/genética , Receptores Quiméricos de Antígenos/inmunología , Receptores Quiméricos de Antígenos/metabolismo , Ratones , Inmunoterapia/métodos , Empalme Alternativo , Fibronectinas/genética , Fibronectinas/metabolismo , Fibronectinas/inmunología , Ensayos Antitumor por Modelo de Xenoinjerto , Regulación Neoplásica de la Expresión Génica , RNA-Seq , Linfocitos T/inmunología , Linfocitos T/metabolismo , Línea Celular Tumoral , Inmunoterapia Adoptiva/métodosRESUMEN
Anaplastic large cell lymphoma (ALCL) is a mature T-cell lymphoma that accounts for for 10-15% of childhood lymphomas. Despite the observation that more than 90% of pediatric cases harbor the anaplastic lymphoma kinase (ALK) rearrangement resulting in aberrant ALK kinase expression, there is significant clinical, morphologic, and biological heterogeneity. To gain insights into the genomic aberrations and molecular heterogeneity within ALK-positive ALCL(ALK+ ALCL), we analyzed 46 pediatric ALK+ ALCLs by whole-exome sequencing, RNA-sequencing, and DNA methylation profiling. Whole-exome sequencing found on average 25 SNV/Indel events per sample with recurring genetic events in regulators of DNA damage (TP53, MDM4), transcription (JUNB), and epigenetic regulators (TET1, KMT2B, KMT2A, KMT2C, KMT2E). Gene expression and methylation profiling consistently subclassified ALK+ ALCLs into two groups characterized by diferential ALK expression levels. The ALK-low group showed enrichment of pathways associated with immune response, cytokine signaling, and a hypermethylated predominant pattern compared to the ALK- high group, which had more frequent copy number changes, and was enriched with pathways associated with cell growth, proliferation, metabolic pathways, and. Taken together, these findings suggest that there is molecular heterogeneity within pediatric ALK+ALCL, predicting distinct biological mechanisms that may provide novel insights into disease pathogenesis and represent prognostic markers.
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Signaling through Notch receptors intrinsically regulates tumor cell development and growth. Here, we studied the role of the Notch ligand Jagged2 on immune evasion in non-small cell lung cancer (NSCLC). Higher expression of JAG2 in NSCLC negatively correlated with survival. In NSCLC pre-clinical models, deletion of Jag2, but not Jag1, in cancer cells attenuated tumor growth and activated protective anti-tumor T cell responses. Jag2-/- lung tumors exhibited higher frequencies of macrophages that expressed immunostimulatory mediators and triggered T cell-dependent anti-tumor immunity. Mechanistically, Jag2 ablation promoted Nr4a-mediated induction of Notch ligands DLL1/4 on cancer cells. DLL1/4-initiated Notch1/2 signaling in macrophages induced the expression of transcription factor IRF4 and macrophage immunostimulatory functionality. IRF4 expression was required for the anti-tumor effects of Jag2 deletion in lung tumors. Antibody targeting of Jagged2 inhibited tumor growth and activated IRF4-driven macrophage-mediated anti-tumor immunity. Thus, Jagged2 orchestrates immunosuppressive systems in NSCLC that can be overcome to incite macrophage-mediated anti-tumor immunity.
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Carcinoma de Pulmón de Células no Pequeñas , Factores Reguladores del Interferón , Proteína Jagged-2 , Neoplasias Pulmonares , Ratones Noqueados , Macrófagos Asociados a Tumores , Animales , Humanos , Ratones , Proteínas de Unión al Calcio/metabolismo , Proteínas de Unión al Calcio/genética , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Línea Celular Tumoral , Factores Reguladores del Interferón/metabolismo , Factores Reguladores del Interferón/genética , Proteína Jagged-1/metabolismo , Proteína Jagged-1/genética , Proteína Jagged-2/metabolismo , Proteína Jagged-2/genética , Proteína Jagged-2/inmunología , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/genética , Macrófagos/inmunología , Macrófagos/metabolismo , Ratones Endogámicos C57BL , Receptor Notch1/metabolismo , Receptor Notch1/genética , Receptores Notch/metabolismo , Transducción de Señal , Escape del Tumor/inmunología , Macrófagos Asociados a Tumores/inmunología , Macrófagos Asociados a Tumores/metabolismoRESUMEN
INTRODUCTION: Novel therapeutic strategies are urgently needed for Mycobacterium avium complex pulmonary disease (MAC-PD). Human mesenchymal stromal cells (MSCs) can directly inhibit MAC growth, but their effect on intracellular bacilli is unknown. We investigated the ability of human MSCs to reduce bacterial replication and inflammation in MAC-infected macrophages and in a murine model of MAC-PD. METHODS: Human monocyte-derived macrophages (MDMs) were infected with M. avium Chester strain and treated with human bone marrow-derived MSCs. Intracellular and extracellular colony-forming units (CFUs) were counted at 72 hours. Six-week-old female balb/c mice were infected by nebulisation of M. avium Chester. Mice were treated with 1×106 intravenous human MSCs or saline control at 21 and 28 days post-infection. Lungs, liver and spleen were harvested 42 days post-infection for bacterial counts. Cytokines were quantified by ELISA. RESULTS: MSCs reduced intracellular bacteria in MDMs over 72 hours (median 35% reduction, p=0.027). MSC treatment increased extracellular concentrations of prostaglandin E2 (PGE2) (median 10.1-fold rise, p=0.002) and reduced tumour necrosis factor-α (median 28% reduction, p=0.025). Blocking MSC PGE2 production by cyclo-oxygenase-2 (COX-2) inhibition with celecoxib abrogated the antimicrobial effect, while this was restored by adding exogenous PGE2. MSC-treated mice had lower pulmonary CFUs (median 18% reduction, p=0.012), but no significant change in spleen or liver CFUs compared with controls. CONCLUSION: MSCs can modulate inflammation and reduce intracellular M. avium growth in human macrophages via COX-2/PGE2 signalling and inhibit pulmonary bacterial replication in a murine model of chronic MAC-PD.
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Modelos Animales de Enfermedad , Células Madre Mesenquimatosas , Ratones Endogámicos BALB C , Infección por Mycobacterium avium-intracellulare , Animales , Ratones , Femenino , Humanos , Infección por Mycobacterium avium-intracellulare/microbiología , Complejo Mycobacterium avium , Trasplante de Células Madre Mesenquimatosas/métodos , Macrófagos/microbiología , Dinoprostona/metabolismo , Sulfonamidas/farmacología , Mycobacterium aviumRESUMEN
Host defences to infection are based upon an integrated system of physical and biochemical barriers, innate and adaptive immunity. Weakness in any of these defensive elements leads to increased susceptibility to specific pathogens. Understanding how medical therapies disrupt host defences is key to the successful prevention, diagnosis and management of respiratory infection in the immunocompromised host.
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Inmunosupresores , Infecciones del Sistema Respiratorio , Humanos , Inmunosupresores/uso terapéutico , Inmunoterapia , Infecciones del Sistema Respiratorio/tratamiento farmacológico , Inmunidad Adaptativa , Huésped InmunocomprometidoRESUMEN
Super enhancers (SE), large genomic elements that activate transcription and drive cell identity, have been found with cancer-specific gene regulation in human cancers. Recent studies reported the importance of understanding the cooperation and function of SE internal components, i.e., the constituent enhancers (CE). However, there are no pan-cancer studies to identify cancer-specific SE signatures at the constituent level. Here, by revisiting pan-cancer SE activities with H3K27Ac ChIP-seq datasets, we report fingerprint SE signatures for 28 cancer types in the NCI-60 cell panel. We implement a mixture model to discriminate active CEs from inactive CEs by taking into consideration ChIP-seq variabilities between cancer samples and across CEs. We demonstrate that the model-based estimation of CE states provides improved functional interpretation of SE-associated regulation. We identify cancer-specific CEs by balancing their active prevalence with their capability of encoding cancer type identities. We further demonstrate that cancer-specific CEs have the strongest per-base enhancer activities in independent enhancer sequencing assays, suggesting their importance in understanding critical SE signatures. We summarize fingerprint SEs based on the cancer-specific statuses of their component CEs and build an easy-to-use R package to facilitate the query, exploration, and visualization of fingerprint SEs across cancers.
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Neoplasias , Súper Potenciadores , Humanos , Epigenómica , Elementos de Facilitación Genéticos/genética , Regulación de la Expresión Génica , Neoplasias/genéticaRESUMEN
Immunotherapy with CAR T cells for pediatric solid and brain tumors is constrained by available targetable antigens. Cancer-specific exons (CSE) present a promising reservoir of targets; however, these have not been explored and validated systematically in a pan-cancer fashion. To identify CSE targets, we analyzed 1,532 RNA-seq datasets from 16 types of pediatric solid and brain tumors for comparison with normal tissues using a newly developed workflow. We found 2,933 exons in 157 genes encoding proteins of the surfaceome or matrisome with high cancer specificity either at the gene (n=148) or the alternatively spliced (AS) isoform (n=9) level. Expression of selected AS targets, including the EDB domain of FN1 (EDB), and gene targets, such as COL11A1, were validated in pediatric PDX tumors. We generated CAR T cells specific to EDB or COL11A1 and demonstrated that COL11A1-CAR T-cells have potent antitumor activity. The full target list, explorable via an interactive web portal (https://cseminer.stjude.org/), provides a rich resource for developing immunotherapy of pediatric solid and brain tumors using gene or AS targets with high expression specificity in cancer.
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Developing synchronous bilateral Wilms tumor suggests an underlying (epi)genetic predisposition. Here, we evaluate this predisposition in 68 patients using whole exome or genome sequencing (n = 85 tumors from 61 patients with matched germline blood DNA), RNA-seq (n = 99 tumors), and DNA methylation analysis (n = 61 peripheral blood, n = 29 non-diseased kidney, n = 99 tumors). We determine the predominant events for bilateral Wilms tumor predisposition: 1)pre-zygotic germline genetic variants readily detectable in blood DNA [WT1 (14.8%), NYNRIN (6.6%), TRIM28 (5%), and BRCA-related genes (5%)] or 2)post-zygotic epigenetic hypermethylation at 11p15.5 H19/ICR1 that may require analysis of multiple tissue types for diagnosis. Of 99 total tumor specimens, 16 (16.1%) have 11p15.5 normal retention of imprinting, 25 (25.2%) have 11p15.5 copy neutral loss of heterozygosity, and 58 (58.6%) have 11p15.5 H19/ICR1 epigenetic hypermethylation (loss of imprinting). Here, we ascertain the epigenetic and genetic modes of bilateral Wilms tumor predisposition.
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Neoplasias Renales , Tumor de Wilms , Niño , Humanos , Tumor de Wilms/genética , Tumor de Wilms/patología , Genotipo , Metilación de ADN/genética , ADN , Neoplasias Renales/genética , Neoplasias Renales/patología , Epigénesis Genética , Impresión GenómicaRESUMEN
The Australian Cardiovascular Alliance (ACvA), the Cardiac Society of Australia and New Zealand (CSANZ) and the National Heart Foundation of Australia (NHFA) recently joined forces to bring the cardiovascular and stroke community together to convene and document a national discussion and propose a national CVD Implementation and Policy agenda and action plan. This includes prevention and screening, acute care and secondary prevention.
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Enfermedades Cardiovasculares , Humanos , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/prevención & control , Australia/epidemiología , Políticas , Nueva Zelanda/epidemiologíaRESUMEN
Pediatric acute megakaryoblastic leukemia (AMKL) is an aggressive blood cancer associated with poor therapeutic response and high mortality. Here we describe the development of CBFA2T3-GLIS2-driven mouse models of AMKL that recapitulate the phenotypic and transcriptional signatures of the human disease. We show that an activating Ras mutation that occurs in human AMKL increases the penetrance and decreases the latency of CBF2AT3-GLIS2-driven AMKL. CBFA2T3-GLIS2 and GLIS2 modulate similar transcriptional networks. We identify the dominant oncogenic properties of GLIS2 that trigger AMKL in cooperation with oncogenic Ras. We find that both CBFA2T3-GLIS2 and GLIS2 alter the expression of a number of BH3-only proteins, causing AMKL cell sensitivity to the BCL2 inhibitor navitoclax both in vitro and in vivo, suggesting a potential therapeutic option for pediatric patients suffering from CBFA2T3-GLIS2-driven AMKL.
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Leucemia Megacarioblástica Aguda , Animales , Ratones , Niño , Humanos , Leucemia Megacarioblástica Aguda/tratamiento farmacológico , Leucemia Megacarioblástica Aguda/genética , Compuestos de Anilina , Sulfonamidas , Proteínas de Fusión Oncogénica/metabolismo , Proteínas RepresorasRESUMEN
Several coastal ecosystems-most notably mangroves and tidal marshes-exhibit biogenic feedbacks that are facilitating adjustment to relative sea-level rise (RSLR), including the sequestration of carbon and the trapping of mineral sediment1. The stability of reef-top habitats under RSLR is similarly linked to reef-derived sediment accumulation and the vertical accretion of protective coral reefs2. The persistence of these ecosystems under high rates of RSLR is contested3. Here we show that the probability of vertical adjustment to RSLR inferred from palaeo-stratigraphic observations aligns with contemporary in situ survey measurements. A deficit between tidal marsh and mangrove adjustment and RSLR is likely at 4 mm yr-1 and highly likely at 7 mm yr-1 of RSLR. As rates of RSLR exceed 7 mm yr-1, the probability that reef islands destabilize through increased shoreline erosion and wave over-topping increases. Increased global warming from 1.5 °C to 2.0 °C would double the area of mapped tidal marsh exposed to 4 mm yr-1 of RSLR by between 2080 and 2100. With 3 °C of warming, nearly all the world's mangrove forests and coral reef islands and almost 40% of mapped tidal marshes are estimated to be exposed to RSLR of at least 7 mm yr-1. Meeting the Paris agreement targets would minimize disruption to coastal ecosystems.
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Calentamiento Global , Temperatura , Humedales , Avicennia/fisiología , Secuestro de Carbono , Arrecifes de Coral , Calentamiento Global/prevención & control , Calentamiento Global/estadística & datos numéricos , AnimalesRESUMEN
Penile squamous cell carcinoma (PSCC) is a rare malignancy in most parts of the world and the underlying mechanisms of this disease have not been fully investigated. About 30-50% of cases are associated with high-risk human papillomavirus (HPV) infection, which may have prognostic value. When PSCC becomes resistant to upfront therapies there are limited options, thus further research is needed in this venue. The extracellular domain-facing protein profile on the cell surface (i.e., the surfaceome) is a key area for biomarker and drug target discovery. This research employs computational methods combined with cell line translatomic (n = 5) and RNA-seq transcriptomic data from patient-derived tumors (n = 18) to characterize the PSCC surfaceome, evaluate the composition dependency on HPV infection, and explore the prognostic impact of identified surfaceome candidates. Immunohistochemistry (IHC) was used to validate the localization of select surfaceome markers. This analysis characterized a diverse surfaceome within patient tumors with 25% and 18% of the surfaceome represented by the functional classes of receptors and transporters, respectively. Significant differences in protein classes were noted by HPV status, with the most change being seen in transporter proteins (25%). IHC confirmed the robust surface expression of select surfaceome targets in the top 85% of expression and a superfamily immunoglobulin protein called BSG/CD147 was prognostic of survival. This study provides the first description of the PSCC surfaceome and its relation to HPV infection and sets a foundation for novel biomarker and drug target discovery in this rare cancer.
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Pathway-level survival analysis offers the opportunity to examine molecular pathways and immune signatures that influence patient outcomes. However, available survival analysis algorithms are limited in pathway-level function and lack a streamlined analytical process. Here we present a comprehensive pathway-level survival analysis suite, PATH-SURVEYOR, which includes a Shiny user interface with extensive features for systematic exploration of pathways and covariates in a Cox proportional-hazard model. Moreover, our framework offers an integrative strategy for performing Hazard Ratio ranked Gene Set Enrichment Analysis and pathway clustering. As an example, we applied our tool in a combined cohort of melanoma patients treated with checkpoint inhibition (ICI) and identified several immune populations and biomarkers predictive of ICI efficacy. We also analyzed gene expression data of pediatric acute myeloid leukemia (AML) and performed an inverse association of drug targets with the patient's clinical endpoint. Our analysis derived several drug targets in high-risk KMT2A-fusion-positive patients, which were then validated in AML cell lines in the Genomics of Drug Sensitivity database. Altogether, the tool offers a comprehensive suite for pathway-level survival analysis and a user interface for exploring drug targets, molecular features, and immune populations at different resolutions.
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Leucemia Mieloide Aguda , Melanoma , Niño , Humanos , Reposicionamiento de Medicamentos , Oncología Médica , Melanoma/tratamiento farmacológico , Melanoma/genética , Algoritmos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genéticaRESUMEN
INTRODUCTION: Emergency department (ED) overcrowding is a global problem and a threat to the quality and safety of emergency care. Providing timely and safe emergency care therein is challenging. To address this in New South Wales (NSW), Australia, the Emergency nurse Protocol Initiating Care-Sydney Triage to Admission Risk Tool (EPIC-START) was developed. EPIC-START is a model of care incorporating EPIC protocols, the START patient admission prediction tool, and a clinical deterioration tool to support ED flow, timely care, and patient safety. The aim of this study is to evaluate the impact of EPIC-START implementation across 30 EDs on patient, implementation, and health service outcomes. METHODS AND ANALYSIS: This study protocol adopts an effectiveness-implementation hybrid design (Med Care 50: 217-226, 2012) and uses a stepped-wedge cluster randomised control trial of EPIC-START, including uptake and sustainability, within 30 EDs across four NSW local health districts spanning rural, regional, and metropolitan settings. Each cluster will be randomised independently of the research team to 1 of 4 dates until all EDs have been exposed to the intervention. Quantitative and qualitative evaluations will be conducted on data from medical records and routinely collected data, and patient, nursing, and medical staff pre- and post-surveys. ETHICS AND DISSEMINATION: Ethical approval for the research was received from the Sydney Local Health District Research Ethics Committee (Reference Number 2022/ETH01940) on 14 December 2022. TRIAL REGISTRATION: Australian and New Zealand Clinical trial, ACTRN12622001480774p. Registered on 27 October 2022.
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Oncogenic fusions formed through chromosomal rearrangements are hallmarks of childhood cancer that define cancer subtype, predict outcome, persist through treatment, and can be ideal therapeutic targets. However, mechanistic understanding of the etiology of oncogenic fusions remains elusive. Here we report a comprehensive detection of 272 oncogenic fusion gene pairs by using tumor transcriptome sequencing data from 5190 childhood cancer patients. We identify diverse factors, including translation frame, protein domain, splicing, and gene length, that shape the formation of oncogenic fusions. Our mathematical modeling reveals a strong link between differential selection pressure and clinical outcome in CBFB-MYH11. We discover 4 oncogenic fusions, including RUNX1-RUNX1T1, TCF3-PBX1, CBFA2T3-GLIS2, and KMT2A-AFDN, with promoter-hijacking-like features that may offer alternative strategies for therapeutic targeting. We uncover extensive alternative splicing in oncogenic fusions including KMT2A-MLLT3, KMT2A-MLLT10, C11orf95-RELA, NUP98-NSD1, KMT2A-AFDN and ETV6-RUNX1. We discover neo splice sites in 18 oncogenic fusion gene pairs and demonstrate that such splice sites confer therapeutic vulnerability for etiology-based genome editing. Our study reveals general principles on the etiology of oncogenic fusions in childhood cancer and suggests profound clinical implications including etiology-based risk stratification and genome-editing-based therapeutics.
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Subunidad alfa 2 del Factor de Unión al Sitio Principal , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Niño , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Fusión de Oncogenes , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Transcriptoma , Causalidad , Proteínas de Fusión Oncogénica/genéticaRESUMEN
The networks of transcription factors (TFs) that control intestinal-resident memory CD8+ T (TRM) cells, including multipotency and effector programs, are poorly understood. In this work, we investigated the role of the TF Bcl11b in TRM cells during infection with Listeria monocytogenes using mice with post-activation, conditional deletion of Bcl11b in CD8+ T cells. Conditional deletion of Bcl11b resulted in increased numbers of intestinal TRM cells and their precursors as well as decreased splenic effector and circulating memory cells and precursors. Loss of circulating memory cells was in part due to increased intestinal homing of Bcl11b-/- circulating precursors, with no major alterations in their programs. Bcl11b-/- TRM cells had altered transcriptional programs, with diminished expression of multipotent/multifunctional (MP/MF) program genes, including Tcf7, and up-regulation of the effector program genes, including Prdm1. Bcl11b also limits the expression of Ahr, another TF with a role in intestinal CD8+ TRM cell differentiation. Deregulation of TRM programs translated into a poor recall response despite TRM cell accumulation in the intestine. Reduced expression of MP/MF program genes in Bcl11b-/- TRM cells was linked to decreased chromatin accessibility and a reduction in activating histone marks at these loci. In contrast, the effector program genes displayed increased activating epigenetic status. These findings demonstrate that Bcl11b is a frontrunner in the tissue residency program of intestinal memory cells upstream of Tcf1 and Blimp1, promoting multipotency and restricting the effector program.
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Linfocitos T CD8-positivos , Factores de Transcripción , Ratones , Animales , Linfocitos T CD8-positivos/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Diferenciación Celular , Intestinos , Proteínas Supresoras de Tumor/metabolismo , Proteínas Represoras/genética , Proteínas Represoras/metabolismoRESUMEN
Pathway-level survival analysis offers the opportunity to examine molecular pathways and immune signatures that influence patient outcomes. However, available survival analysis algorithms are limited in pathway-level function and lack a streamlined analytical process. Here we present a comprehensive pathway-level survival analysis suite, DRPPM-PATH-SURVEIOR, which includes a Shiny user interface with extensive features for systematic exploration of pathways and covariates in a Cox proportional-hazard model. Moreover, our framework offers an integrative strategy for performing Hazard Ratio ranked Gene Set Enrichment Analysis (GSEA) and pathway clustering. As an example, we applied our tool in a combined cohort of melanoma patients treated with checkpoint inhibition (ICI) and identified several immune populations and biomarkers predictive of ICI efficacy. We also analyzed gene expression data of pediatric acute myeloid leukemia (AML) and performed an inverse association of drug targets with the patient's clinical endpoint. Our analysis derived several drug targets in high-risk KMT2A-fusion-positive patients, which were then validated in AML cell lines in the Genomics of Drug Sensitivity database. Altogether, the tool offers a comprehensive suite for pathway-level survival analysis and a user interface for exploring drug targets, molecular features, and immune populations at different resolutions.
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This study comprehensively evaluated the landscape of genetic and epigenetic events that predispose to synchronous bilateral Wilms tumor (BWT). We performed whole exome or whole genome sequencing, total-strand RNA-seq, and DNA methylation analysis using germline and/or tumor samples from 68 patients with BWT from St. Jude Children's Research Hospital and the Children's Oncology Group. We found that 25/61 (41%) of patients evaluated harbored pathogenic or likely pathogenic germline variants, with WT1 (14.8%), NYNRIN (6.6%), TRIM28 (5%) and the BRCA-related genes (5%) BRCA1, BRCA2, and PALB2 being most common. Germline WT1 variants were strongly associated with somatic paternal uniparental disomy encompassing the 11p15.5 and 11p13/WT1 loci and subsequent acquired pathogenic CTNNB1 variants. Somatic coding variants or genome-wide copy number alterations were almost never shared between paired synchronous BWT, suggesting that the acquisition of independent somatic variants leads to tumor formation in the context of germline or early embryonic, post-zygotic initiating events. In contrast, 11p15.5 status (loss of heterozygosity, loss or retention of imprinting) was shared among paired synchronous BWT in all but one case. The predominant molecular events for BWT predisposition include pathogenic germline variants or post-zygotic epigenetic hypermethylation at the 11p15.5 H19/ICR1 locus (loss of imprinting). This study demonstrates that post-zygotic somatic mosaicism for 11p15.5 hypermethylation/loss of imprinting is the single most common initiating molecular event predisposing to BWT. Evidence of somatic mosaicism for 11p15.5 loss of imprinting was detected in leukocytes of a cohort of BWT patients and long-term survivors, but not in unilateral Wilms tumor patients and long-term survivors or controls, further supporting the hypothesis that post-zygotic 11p15.5 alterations occurred in the mesoderm of patients who go on to develop BWT. Due to the preponderance of BWT patients with demonstrable germline or early embryonic tumor predisposition, BWT exhibits a unique biology when compared to unilateral Wilms tumor and therefore warrants continued refinement of its own treatment-relevant biomarkers which in turn may inform directed treatment strategies in the future.