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PURPOSE: To assess the association between plasma procalcitonin concentration at hospital admission and the risk of 50-day in-hospital mortality among patients with community-acquired bloodstream infections. METHODS: We carried out a retrospective, observational cohort study with all consecutive patients with bacteriologically confirmed community-acquired bloodstream infections hospitalized between 2006 and 2012. We aimed to assess the association between plasma procalcitonin at admission and 50-day in-hospital mortality. Patients were included in the analysis if they had undergone a blood culture test within 48 hours of hospitalization with a concomitant procalcitonin assay (time < 12 hours between the two tests). Inclusion in the study began on the day of hospital admission, and each patient was followed until death, discharge from the hospital, or last known follow-up in the 50 days following hospital admission. The endpoint was the occurrence of all-cause in-hospital mortality during the 50 days following hospital admission. RESULTS: During the 7-year study period, 1593 patients were admitted to one of the healthcare facilities of the University Hospital of Nancy from home or through the emergency department and had positive blood cultures and concomitant procalcitonin assays. Among the patients, 452 met the selection criteria and were analyzed. In ROC analysis, procalcitonin at baseline was significantly associated with 50-day in-hospital mortality, with an optimal threshold > 4.24 ng/mL. A baseline procalcitonin > 4.24 ng/mL was independently associated with an increased risk of in-hospital mortality (multivariable logistic regression: odds ratio, 2.58; 95% CI, 1.57-4.25; P = 0.0002; Cox proportional hazard regression: hazard ratio, 2.01; 95% CI, 1.30-3.11; P = 0.002). In sensitivity analyses, baseline procalcitonin quartiles were independently associated with 50-day in-hospital mortality (multivariable logistic regression: odds ratio, 1.47; 95% CI, 1.17-1.85; P = 0.001; Cox proportional hazard regression: hazard ratio, 1.31; 95% CI, 1.07-1.60; P = 0.008). The independent associations between baseline procalcitonin and the risk of 50-day in-hospital mortality were maintained after adjusting for C-reactive protein and sepsis status at admission. CONCLUSION: Our data provide the first evidence of the usefulness of plasma procalcitonin at admission as a risk-stratifying biomarker for predicting 50-day in-hospital mortality among patients with community-acquired bloodstream infections.
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Arsenic exposure is correlated with atherosclerosis in epidemiological studies and in animal models. We have previously shown that arsenic exposure enhanced the atherosclerotic plaque size, increased the plaque lipid content, and decreased the plaque smooth muscle cell and collagen contents in the apolipoprotein E knockout (apoE-/-) mice. However, the percentage of plaque-resident macrophages, the primary drivers of atherosclerosis remained unchanged. Therefore, we hypothesized that although arsenic does not change the quantity of macrophages, it alters the macrophage transcriptome towards a proatherogenic state. To test this hypothesis, we used bone marrow-derived macrophages, polarized them to either interferon-γ (IFN-É£) stimulated, proinflammatory or interleukin-4 (IL-4) stimulated, alternatively activated macrophages in the presence or absence of 0.67 µM (50 ppb) arsenic and performed RNA sequencing. Arsenic exposure altered the gene expression of the macrophages in a subtype-specific manner. Most differentially expressed genes (88%) were altered specifically in either IFN-É£- or IL-4-stimulated macrophages, whereas in the remaining 12% of genes that changed in both cell types, did so in opposite directions. In IL-4-stimulated macrophages, arsenic significantly downregulated the genes involved in cholesterol biosynthesis and the chemokines CCL17/CCL22, whereas in IFN-É£-stimulated macrophages, the genes associated with the liver X receptor (LXR) pathway were downregulated by arsenic. Using a bone marrow transplant experiment, we validated that the deletion of LXRα from the hematopoietic compartment rescued arsenic-enhanced atherosclerosis in the apoE-/- mouse model. Together, these data suggest that arsenic modulates subtype-specific transcriptomic changes in macrophages and further emphasize the need to define macrophage heterogeneity in atherosclerotic plaques in order to evaluate the proatherogenic role of arsenic.
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Arsénico , Aterosclerosis , Placa Aterosclerótica , Animales , Ratones , Arsénico/metabolismo , Interferón gamma/genética , Interferón gamma/metabolismo , Interleucina-4/genética , Interleucina-4/metabolismo , Ratones Noqueados , Aterosclerosis/inducido químicamente , Aterosclerosis/genética , Aterosclerosis/metabolismo , Placa Aterosclerótica/metabolismo , Macrófagos/metabolismo , Expresión Génica , Apolipoproteínas E/genética , Ratones Endogámicos C57BLRESUMEN
BACKGROUND: Patients with chronic inflammatory conditions are at an increased risk of developing atherothrombotic events. We aimed to assess the 1-year prognosis after myocardial infarction (MI) in patients with inflammatory bowel disease (IBD). METHODS: From the PMSI (Program de Medicalisation des Systèmes d'informatique) database, 246 out of 39,835 consecutive MI patients, hospitalized between 2012 and 2017, were diagnosed with IBD and followed up for 1 year after discharge. A matched cohort was built matching each MI patient with IBD to patient without IBD using age and sex (n = 1,470, matching ratio 1:5). RESULTS: Compared with MI patients without IBD, MI patients with IBD were younger (aged 69 vs. 70.8 years, p = 0.04) with a higher rate of increased body mass index (BMI) (21.5% vs 15%, p = 0.004), previously diagnosed ischemic cardiopathy (18.3% vs 12.6%, p < 0.0008) and chronic renal disease (8.9% vs 5.6%, p = 0.02). In our age- and sex-matched cohort, we found that all-cause mortality (9% vs 8.3, p = 0.729), stroke (0.8% vs 0.6%, p = 0.656) and hospitalization resulting from heart failure (3ool, .3% vs 3.5%, p = 0.846) did not significantly differ between the IBD and non-IBD groups within the first year after initial admission whereas the risk of recurrent MI was increased by 50% (2.9% vs 1.9%, p = 0.33) in the IBD group without reaching statistical significance. Moreover, a significant increase in the blood transfusion rate at the 1-year follow-up was observed in MI patients with IBD compared with MI patients without IBD (15.1% vs 9.4%, p < 0.001). CONCLUSION: Our findings suggest that both residual MI risk and bleeding events should be carefully monitored in MI patients diagnosed with chronic inflammation such as that observed in IBD.
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Síndrome Coronario Agudo , Enfermedades Inflamatorias del Intestino , Infarto del Miocardio , Síndrome Coronario Agudo/complicaciones , Síndrome Coronario Agudo/diagnóstico , Síndrome Coronario Agudo/epidemiología , Humanos , Enfermedades Inflamatorias del Intestino/complicaciones , Enfermedades Inflamatorias del Intestino/diagnóstico , Enfermedades Inflamatorias del Intestino/epidemiología , Infarto del Miocardio/diagnóstico , Estudios Retrospectivos , Factores de RiesgoRESUMEN
Introduction: This observational CMR study aims to characterize left-ventricular (LV) damage, which may be specifically attributed to COVID-19 and is distant in time from the acute phase, through serial CMR performed during the first year in patients with no prior cardiac disease. Methods: This study included consecutive patients without any prior history of cardiac disease but with a peak troponin-Ic > 50 ng/ml at the time of the first COVID-wave. All had a CMR in the first months after the acute phase, and some had an additional CMR at the end of the first year to monitor LV function, remodeling, and abnormalities evocative of myositis and myocarditis - i.e., increased T1/T2 relaxation times, increased extracellular volume (ECV), and delayed contrast enhancement. Results: Nineteen consecutively admitted COVID-19 patients (17 men, median age 66 [57-71] years) were included. Eight (42%) had hypertension, six (32%) were obese, and 16 (84%) had suffered an acute respiratory distress syndrome. The 1st CMR, recorded at a median 3.2 [interquartile range: 2.6-3.9] months from the troponin peak, showed (1) LV concentric remodeling in 12 patients (63%), (2) myocardial tissue abnormalities in 11 (58%), including 9 increased myocardial ECVs, and (3) 14 (74%) increased ECVs from shoulder skeletal muscles. The 2nd CMR, obtained at 11.1 [11.0-11.7] months from the troponin peak in 13 patients, showed unchanged LV function and remodeling but a return to normal or below the normal range for all ECVs of the myocardium and skeletal muscles. Conclusion: Many patients with no history of cardiac disease but for whom an increase in blood troponin-Ic ascertained COVID-19 induced myocardial damage exhibited signs of persistent extracellular edema at a median 3-months from the troponin peak, affecting the myocardium and skeletal muscles, which resolved within a one-year time frame. Associations with long-COVID symptoms need to be investigated on a larger scale now. Clinical Trial Registration: NCT04753762 on the ClinicalTrials.gov site.
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BACKGROUND: Pharmaceutical analysis of the prescription has to prop up the quality of patients' medication management in a context of medication's risk acculturation. But this activity remains highly variable. Medication-related clinical decision support may succeed in reducing adverse drug events and healthcare costs. PURPOSE: This study aims to present AVICENNE as a real time medication-related clinical decision support (rt-CDS) applied to pharmaceutical analysis and its ability to detect Drug related problems (DRP) consecutively resolved by pharmacists. Basic procedures A Medication-related rt-CDS is created by integrating the software PharmaClass® (Keenturtle), 5 health data streams on the patient and Pharmaceutical algorithms (PA). PA are created by modeling the pharmaceutical experiment about DRP and the thread of their criticality. They are partially encoded as computerized rules in Pharmaclass® allowing alerts' issue. An observational prospective study is conducted during 9-months among 1000 beds in 2 health facilities. The first step is to identify alerts as DRP; their resolution follows with clear guidelines worked out for the pharmaceutical analysis. A basis on predictive positive values (PPV) of the PA is being built today helping to know the performance of DRP detection and resolution. Main findings 71 PA are encoded as rules into Pharmaclass®: 40 targeted serious adverse drug events. 1508 alerts are analyzed by pharmacists. Among them 921 DRPs were characterized and 540 pharmaceutical interventions transmitted of which 219 were accepted by prescribers. Three PPV are defined depending on software, pharmacist and patient. Principal conclusion Clinical pharmacy societies should host, share and update a national corpus of PA and exploit its educational interest.
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Sistemas de Apoyo a Decisiones Clínicas , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Algoritmos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/prevención & control , Humanos , Preparaciones Farmacéuticas , Farmacéuticos , Estudios ProspectivosRESUMEN
The World Health Organisation recommends monitoring the circulation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We investigated anti-SARS-CoV-2 total immunoglobulin (IgT) antibody seroprevalence and in vitro sero-neutralization in Nancy, France, in spring 2020. Individuals were randomly sampled from electoral lists and invited with household members over 5 years old to be tested for anti-SARS-CoV-2 (IgT, i.e., IgA/IgG/IgM) antibodies by ELISA (Bio-rad); the sero-neutralization activity was evaluated on Vero CCL-81 cells. Among 2006 individuals, the raw seroprevalence was 2.1% (95% confidence interval 1.5 to 2.9), was highest for 20- to 34-year-old participants (4.7% (2.3 to 8.4)), within than out of socially deprived area (2.5% vs. 1%, p = 0.02) and with than without intra-family infection (p < 10-6). Moreover, 25% of participants presented at least one COVID-19 symptom associated with SARS-CoV-2 positivity (p < 10-13), with highly discriminant anosmia or ageusia (odds ratio 27.8 [13.9 to 54.5]); 16.3% (6.8 to 30.7) of seropositive individuals were asymptomatic. Positive sero-neutralization was demonstrated in vitro for 31/43 seropositive subjects. Regarding the very low seroprevalence, a preventive effect of the lockdown in March 2020 can be assumed for the summer, but a second COVID-19 wave, as expected, could be subsequently observed in this poorly immunized population.
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Anticuerpos Antivirales/sangre , COVID-19/epidemiología , COVID-19/inmunología , SARS-CoV-2/inmunología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Prueba Serológica para COVID-19 , Niño , Preescolar , Control de Enfermedades Transmisibles , Estudios Transversales , Femenino , Francia/epidemiología , Humanos , Inmunoglobulina G/sangre , Inmunoglobulina M/sangre , Masculino , Persona de Mediana Edad , Pruebas de Neutralización , Estudios Seroepidemiológicos , Población Suburbana/estadística & datos numéricos , Adulto JovenRESUMEN
Vascular anomalies, including local and peripheral thrombosis, are a hallmark of glioblastoma (GBM) and an aftermath of deregulation of the cancer cell genome and epigenome. Although the molecular effectors of these changes are poorly understood, the upregulation of podoplanin (PDPN) by cancer cells has recently been linked to an increased risk for venous thromboembolism (VTE) in GBM patients. Therefore, regulation of this platelet-activating protein by transforming events in cancer cells is of considerable interest. We used single-cell and bulk transcriptome data mining, as well as cellular and xenograft models in mice, to analyze the nature of cells expressing PDPN, as well as their impact on the activation of the coagulation system and platelets. We report that PDPN is expressed by distinct (mesenchymal) GBM cell subpopulations and downregulated by oncogenic mutations of EGFR and IDH1 genes, along with changes in chromatin modifications (enhancer of zeste homolog 2) and DNA methylation. Glioma cells exteriorize their PDPN and/or tissue factor (TF) as cargo of exosome-like extracellular vesicles (EVs) shed from cells in vitro and in vivo. Injection of glioma-derived podoplanin carrying extracelluar vesicles (PDPN-EVs) activates platelets, whereas tissue factor carrying extracellular vesicles (TF-EVs) activate the clotting cascade. Similarly, an increase in platelet activation (platelet factor 4) or coagulation (D-dimer) markers occurs in mice harboring the corresponding glioma xenografts expressing PDPN or TF, respectively. Coexpression of PDPN and TF by GBM cells cooperatively affects tumor microthrombosis. Thus, in GBM, distinct cellular subsets drive multiple facets of cancer-associated thrombosis and may represent targets for phenotype- and cell type-based diagnosis and antithrombotic intervention.
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Vesículas Extracelulares , Glioblastoma , Glioma , Trombosis , Animales , Humanos , Ratones , Tromboplastina/genéticaRESUMEN
Histone H3.3 glycine 34 to arginine/valine (G34R/V) mutations drive deadly gliomas and show exquisite regional and temporal specificity, suggesting a developmental context permissive to their effects. Here we show that 50% of G34R/V tumors (n = 95) bear activating PDGFRA mutations that display strong selection pressure at recurrence. Although considered gliomas, G34R/V tumors actually arise in GSX2/DLX-expressing interneuron progenitors, where G34R/V mutations impair neuronal differentiation. The lineage of origin may facilitate PDGFRA co-option through a chromatin loop connecting PDGFRA to GSX2 regulatory elements, promoting PDGFRA overexpression and mutation. At the single-cell level, G34R/V tumors harbor dual neuronal/astroglial identity and lack oligodendroglial programs, actively repressed by GSX2/DLX-mediated cell fate specification. G34R/V may become dispensable for tumor maintenance, whereas mutant-PDGFRA is potently oncogenic. Collectively, our results open novel research avenues in deadly tumors. G34R/V gliomas are neuronal malignancies where interneuron progenitors are stalled in differentiation by G34R/V mutations and malignant gliogenesis is promoted by co-option of a potentially targetable pathway, PDGFRA signaling.
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Neoplasias Encefálicas/genética , Carcinogénesis/genética , Glioma/genética , Histonas/genética , Interneuronas/metabolismo , Mutación/genética , Células-Madre Neurales/metabolismo , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/genética , Animales , Astrocitos/metabolismo , Astrocitos/patología , Neoplasias Encefálicas/patología , Carcinogénesis/patología , Linaje de la Célula , Reprogramación Celular/genética , Cromatina/metabolismo , Embrión de Mamíferos/metabolismo , Epigénesis Genética , Regulación Neoplásica de la Expresión Génica , Silenciador del Gen , Glioma/patología , Histonas/metabolismo , Lisina/metabolismo , Ratones Endogámicos C57BL , Modelos Biológicos , Clasificación del Tumor , Oligodendroglía/metabolismo , Regiones Promotoras Genéticas/genética , Prosencéfalo/embriología , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Transcripción Genética , Transcriptoma/genéticaRESUMEN
Glycine 34-to-tryptophan (G34W) substitutions in H3.3 arise in approximately 90% of giant cell tumor of bone (GCT). Here, we show H3.3 G34W is necessary for tumor formation. By profiling the epigenome, transcriptome, and secreted proteome of patient samples and tumor-derived cells CRISPR-Cas9-edited for H3.3 G34W, we show that H3.3K36me3 loss on mutant H3.3 alters the deposition of the repressive H3K27me3 mark from intergenic to genic regions, beyond areas of H3.3 deposition. This promotes redistribution of other chromatin marks and aberrant transcription, altering cell fate in mesenchymal progenitors and hindering differentiation. Single-cell transcriptomics reveals that H3.3 G34W stromal cells recapitulate a neoplastic trajectory from a SPP1+ osteoblast-like progenitor population toward an ACTA2+ myofibroblast-like population, which secretes extracellular matrix ligands predicted to recruit and activate osteoclasts. Our findings suggest that H3.3 G34W leads to GCT by sustaining a transformed state in osteoblast-like progenitors, which promotes neoplastic growth, pathologic recruitment of giant osteoclasts, and bone destruction. SIGNIFICANCE: This study shows that H3.3 G34W drives GCT tumorigenesis through aberrant epigenetic remodeling, altering differentiation trajectories in mesenchymal progenitors. H3.3 G34W promotes in neoplastic stromal cells an osteoblast-like progenitor state that enables undue interactions with the tumor microenvironment, driving GCT pathogenesis. These epigenetic changes may be amenable to therapeutic targeting in GCT.See related commentary by Licht, p. 1794.This article is highlighted in the In This Issue feature, p. 1775.
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Neoplasias Óseas/genética , Tumor Óseo de Células Gigantes/genética , Células Madre Mesenquimatosas/metabolismo , Osteoblastos/metabolismo , Diferenciación Celular , HumanosRESUMEN
Events at a receptor ectodomain affect the intracellular domain conformation, activating signal transduction (out-to-in conformational effects). We investigated the reverse direction (in-to-out) where the intracellular domain may impact on ectodomain conformation. The primary sequences of naturally occurring TrkC receptor isoforms (TrkC-FL and TrkC.T1) only differ at the intracellular domain. However, owing to their differential association with Protein Disulfide Isomerase the isoforms have different disulfide bonding and conformations at the ectodomain. Conformations were exploited to develop artificial ligands, mAbs, and small molecules, with isoform-specific binding and biased activation. Consistent, the physiological ligands NT-3 and PTP-sigma bind both isoforms, but NT-3 activates all signaling pathways, whereas PTP-sigma activates biased signals. Our data support an "in-to-out" model controlling receptor ectodomain conformation, a strategy that enables heterogeneity in receptors, ligands, and bioactivity. These concepts may be extended to the many wild-type or oncogenic receptors with known isoforms.
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Childhood brain tumors have suspected prenatal origins. To identify vulnerable developmental states, we generated a single-cell transcriptome atlas of >65,000 cells from embryonal pons and forebrain, two major tumor locations. We derived signatures for 191 distinct cell populations and defined the regional cellular diversity and differentiation dynamics. Projection of bulk tumor transcriptomes onto this dataset shows that WNT medulloblastomas match the rhombic lip-derived mossy fiber neuronal lineage and embryonal tumors with multilayered rosettes fully recapitulate a neuronal lineage, while group 2a/b atypical teratoid/rhabdoid tumors may originate outside the neuroectoderm. Importantly, single-cell tumor profiles reveal highly defined cell hierarchies that mirror transcriptional programs of the corresponding normal lineages. Our findings identify impaired differentiation of specific neural progenitors as a common mechanism underlying these pediatric cancers and provide a rational framework for future modeling and therapeutic interventions.
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Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Encéfalo/embriología , Regulación del Desarrollo de la Expresión Génica , Animales , Encéfalo/patología , Línea Celular Tumoral , Humanos , Lactante , Meduloblastoma/genética , Meduloblastoma/patología , Ratones , Neoplasias de Células Germinales y Embrionarias/genética , Neoplasias de Células Germinales y Embrionarias/patología , Fibras Nerviosas/patología , Fibras Nerviosas/fisiología , Prosencéfalo/citología , Prosencéfalo/embriología , Tumor Rabdoide/genética , Tumor Rabdoide/patología , Análisis de la Célula IndividualRESUMEN
Our ability to manage acute myeloid leukemia (AML) is limited by our incomplete understanding of the epigenetic disruption central to leukemogenesis, including improper histone methylation. Here we examine 16 histone H3 genes in 434 primary AML samples and identify Q69H, A26P, R2Q, R8H and K27M/I mutations (1.6%), with higher incidence in secondary AML (9%). These mutations occur in pre-leukemic hematopoietic stem cells (HSCs) and exist in the major leukemic clones in patients. They increase the frequency of functional HSCs, alter differentiation, and amplify leukemic aggressiveness. These effects are dependent on the specific mutation. H3K27 mutation increases the expression of genes involved in erythrocyte and myeloid differentiation with altered H3K27 tri-methylation and K27 acetylation. The functional impact of histone mutations is independent of RUNX1 mutation, although they at times co-occur. This study establishes that H3 mutations are drivers of human pre-cancerous stem cell expansion and important early events in leukemogenesis.
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Epigenómica , Regulación Leucémica de la Expresión Génica/fisiología , Histonas/metabolismo , Leucemia Mieloide Aguda/metabolismo , Animales , Animales Modificados Genéticamente , Antineoplásicos/farmacología , Secuencia de Bases , Células de la Médula Ósea , Diferenciación Celular , Transformación Celular Neoplásica , ADN/genética , Drosophila melanogaster/genética , Regulación Leucémica de la Expresión Génica/efectos de los fármacos , Hematopoyesis/fisiología , Células Madre Hematopoyéticas/metabolismo , Humanos , Ratones , Mutación , Neoplasias ExperimentalesRESUMEN
High-grade gliomas defined by histone 3 K27M driver mutations exhibit global loss of H3K27 trimethylation and reciprocal gain of H3K27 acetylation, respectively shaping repressive and active chromatin landscapes. We generated tumor-derived isogenic models bearing this mutation and show that it leads to pervasive H3K27ac deposition across the genome. In turn, active enhancers and promoters are not created de novo and instead reflect the epigenomic landscape of the cell of origin. H3K27ac is enriched at repeat elements, resulting in their increased expression, which in turn can be further amplified by DNA demethylation and histone deacetylase inhibitors providing an exquisite therapeutic vulnerability. These agents may therefore modulate anti-tumor immune responses as a therapeutic modality for this untreatable disease.
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Neoplasias Encefálicas/metabolismo , Glioma/metabolismo , Histonas/genética , Histonas/metabolismo , Acetilación , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/genética , Línea Celular Tumoral , Cromatina/metabolismo , Elementos de Facilitación Genéticos/efectos de los fármacos , Epigenómica/métodos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Glioma/tratamiento farmacológico , Glioma/genética , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/uso terapéutico , Humanos , MutaciónRESUMEN
Lys-27-Met mutations in histone 3 genes (H3K27M) characterize a subgroup of deadly gliomas and decrease genome-wide H3K27 trimethylation. Here we use primary H3K27M tumor lines and isogenic CRISPR-edited controls to assess H3K27M effects in vitro and in vivo. We find that whereas H3K27me3 and H3K27me2 are normally deposited by PRC2 across broad regions, their deposition is severely reduced in H3.3K27M cells. H3K27me3 is unable to spread from large unmethylated CpG islands, while H3K27me2 can be deposited outside these PRC2 high-affinity sites but to levels corresponding to H3K27me3 deposition in wild-type cells. Our findings indicate that PRC2 recruitment and propagation on chromatin are seemingly unaffected by K27M, which mostly impairs spread of the repressive marks it catalyzes, especially H3K27me3. Genome-wide loss of H3K27me3 and me2 deposition has limited transcriptomic consequences, preferentially affecting lowly-expressed genes regulating neurogenesis. Removal of H3K27M restores H3K27me2/me3 spread, impairs cell proliferation, and completely abolishes their capacity to form tumors in mice.
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Neoplasias Encefálicas/genética , Cromatina/metabolismo , Glioblastoma/genética , Histonas/genética , Complejo Represivo Polycomb 2/metabolismo , Adolescente , Anciano , Animales , Neoplasias Encefálicas/patología , Sistemas CRISPR-Cas , Carcinogénesis/genética , Línea Celular Tumoral , Proliferación Celular/genética , Niño , Islas de CpG/genética , Metilación de ADN/genética , Epigénesis Genética , Femenino , Edición Génica/métodos , Regulación Neoplásica de la Expresión Génica , Glioblastoma/patología , Células HEK293 , Código de Histonas/genética , Histonas/metabolismo , Humanos , Lisina/genética , Masculino , Metionina/genética , Ratones , Ratones Endogámicos NOD , Ratones SCID , Mutación , Neurogénesis/genética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Tungsten is an emerging environmental toxicant associated with several pediatric leukemia clusters, although a causal association has not been established. Our previous work demonstrated that tungsten exposure resulted in an accumulation of pre-B cells in the bone marrow, the same cell type that accumulates in pediatric acute lymphoblastic leukemia (ALL). To better understand the relevant molecular mechanisms, we performed RNA-sequencing on flow sorted pre-B cells from control and tungsten-exposed mice. Tungsten decreased the expression of multiple genes critical for B cell development, including members of the interleukin-7 receptor (IL-7R) and pre-B cell receptor signaling pathways, such as Jak1, Stat5a, Pax5, Syk, and Ikzf3. These results were confirmed in an in vitro model of B cell differentiation, where tungsten arrested differentiation at the pro-B cell stage and inhibited proliferation. These changes were associated with decreased expression of multiple genes in the IL-7R signaling pathway and decreased percentage of IL-7R, phosphorylated STAT5 double-positive cells. Supplementation with IL-7 or overexpression of Pax5, the transcription factor downstream of IL-7R, rescued the tungsten-induced differentiation block. Together, these data support the hypothesis that IL-7R/Pax5 signaling axis is critical to tungsten-mediated effects on pre-B cell development. Importantly, many of these molecules are modulated in ALL.
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Linfocitos B/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Factor de Transcripción PAX5/metabolismo , Receptores de Interleucina-7/metabolismo , Compuestos de Tungsteno/toxicidad , Animales , Linfocitos B/metabolismo , Linfocitos B/patología , Regulación hacia Abajo , Expresión Génica/efectos de los fármacos , Masculino , Ratones Endogámicos C57BL , Factor de Transcripción PAX5/genética , Receptores de Interleucina-7/genética , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genéticaRESUMEN
BACKGROUND: Recurrent specific mutations in evolutionarily conserved histone 3 (H3) variants drive pediatric high-grade gliomas (HGGs), but little is known about their downstream effects. The aim of this study was to identify genes involved in the detrimental effects of mutant H3.3-K27M, the main genetic driver in lethal midline HGG, in a transgenic Drosophila model. METHODS: Mutant and wild-type histone H3.3-expressing flies were generated using a φC31-based integration system. Genetic modifier screens were performed by crossing H3.3-K27M expressing driver strains and 194 fly lines expressing short hairpin RNA targeting genes selected based on their potential role in the detrimental effects of mutant H3. Expression of the human orthologues of genes with functional relevance in the fly model was validated in H3-K27M mutant HGG. RESULTS: Ubiquitous and midline glia-specific expression of H3.3-K27M but not wild-type H3.3 caused pupal lethality, morphological alterations, and decreased H3K27me3. Knockdown of 17 candidate genes shifted the lethal phenotype to later stages of development. These included histone modifying and chromatin remodeling genes as well as genes regulating cell differentiation and proliferation. Notably, several of these genes were overexpressed in mutant H3-K27M mutated HGG. CONCLUSIONS: Rapid screening, identification, and validation of relevant targets in "oncohistone" mediated pathogenesis have proven a challenge and a barrier to providing novel therapies. Our results provide further evidence on the role of chromatin modifiers in the genesis of H3.3-K27M. Notably, they validate Drosophila as a model system for rapid identification of relevant genes functionally involved in the detrimental effects of H3.3-K27M mutagenesis.
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Biomarcadores de Tumor/genética , Drosophila melanogaster/crecimiento & desarrollo , Drosophila melanogaster/genética , Glioma/genética , Histonas/genética , Mutación , ARN Interferente Pequeño/genética , Animales , Drosophila melanogaster/metabolismo , Glioma/patología , Secuenciación de Nucleótidos de Alto Rendimiento , Ensayos Analíticos de Alto Rendimiento , HumanosRESUMEN
Big data methodologies, made possible with the increasing generation and availability of digital data and enhanced analytical capabilities, have produced new insights to improve outcomes in many disciplines. Application of big data in the health-care sector is in its early stages, although the potential for leveraging underutilized data to gain a better understanding of disease and improve quality of care is enormous. Owing to the intrinsic characteristics of inflammatory bowel disease (IBD) and the management dilemmas that it imposes, the implementation of big data research strategies not only can complement current research efforts but also could represent the only way to disentangle the complexity of the disease. In this Review, we explore important potential applications of big data in IBD research, including predictive models of disease course and response to therapy, characterization of disease heterogeneity, drug safety and development, precision medicine and cost-effectiveness of care. We also discuss the strengths and limitations of potential data sources that big data analytics could draw from in the field of IBD, including electronic health records, clinical trial data, e-health applications and genomic, transcriptomic, proteomic, metabolomic and microbiomic data.
Asunto(s)
Macrodatos , Enfermedades Inflamatorias del Intestino , Toma de Decisiones Clínicas/métodos , Análisis Costo-Beneficio , Humanos , Enfermedades Inflamatorias del Intestino/diagnóstico , Enfermedades Inflamatorias del Intestino/economía , Enfermedades Inflamatorias del Intestino/etiología , Enfermedades Inflamatorias del Intestino/terapia , Medicina de Precisión/economía , Medicina de Precisión/métodos , Pronóstico , Estados UnidosRESUMEN
BACKGROUND: Systemic congestion, evaluated by estimated plasma volume status (ePVS), is associated with in-hospital mortality in acute heart failure (AHF). However, the diagnostic and prognostic value of ePVS in patients with acute dyspnea has been insufficiently studied. OBJECTIVES: To assess the association between the first ePVS calculated from blood samples on admission in the emergency department (ED) and discharge diagnosis of AHF and in-hospital mortality in patients admitted for acute dyspnea. METHODS: The study included 1369 patients admitted for dyspnea in the ED in 2015. ePVS was calculated from hematocrit and hemoglobin values at admission. Comparisons of baseline characteristics according to ePVS tertiles were carried out and then associations between ePVS and the two outcomes "AHF diagnosis" and "intra-hospital mortality" were assessed using a logistic regression model. RESULTS: 36.6% had a BNP > 400 pg/mL and median ePVS was 4.58 dL/g [3.96-5.55]. Overall in-hospital mortality was 11.1% (n = 149). In multivariable analysis, the third ePVS tertile (> 5.12 dL/g) had a significantly increased risk of having AHF (OR = 1.64 [1.16-2.33], p = 0.005). In-hospital mortality rose across ePVS tertiles (8.4-13.8% p < 0.01). ePVS greater than the first or second tertile threshold (respectively, 4.17 dL/g and 5.12 dL/g) were both significantly associated with a higher risk of in-hospital mortality (OR for 2nd/3rd tertile = 2.06 [1.25-3.38], p = 0.004 and OR for 3rd tertile = 1.54 [1.01-2.36], p = 0.04). CONCLUSION: Higher ePVS values determined from first blood sample at admission are associated with a higher probability of AHF and in-hospital mortality in patients admitted in the ED for acute dyspnea.