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Control of cellular identity requires coordination of developmental programs with environmental factors such as nutrient availability, suggesting that perturbing metabolism can alter cell state. Here, we find that nucleotide depletion and DNA replication stress drive differentiation in human and murine normal and transformed hematopoietic systems, including patient-derived acute myeloid leukemia (AML) xenografts. These cell state transitions begin during S phase and are independent of ATR/ATM checkpoint signaling, double-stranded DNA break formation, and changes in cell cycle length. In systems where differentiation is blocked by oncogenic transcription factor expression, replication stress activates primed regulatory loci and induces lineage-appropriate maturation genes despite the persistence of progenitor programs. Altering the baseline cell state by manipulating transcription factor expression causes replication stress to induce genes specific for alternative lineages. The ability of replication stress to selectively activate primed maturation programs across different contexts suggests a general mechanism by which changes in metabolism can promote lineage-appropriate cell state transitions.
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Diferenciação Celular , Replicação do DNA , Replicação do DNA/genética , Animais , Humanos , Diferenciação Celular/genética , Camundongos , Nucleotídeos/metabolismo , Nucleotídeos/genética , Linhagem da Célula/genética , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Leucemia Mieloide Aguda/metabolismo , Fase S/genética , Transdução de SinaisRESUMO
IKZF1 encodes the transcription factor IKAROS, a zinc finger DNA-binding protein with a key role in lymphoid lineage development. IKAROS plays a critical role in the development of lineage-restricted mature lymphocytes. Deletions within IKZF1 in B-cell acute lymphoblastic leukemia (B-ALL) lead to a loss of normal IKAROS function, conferring leukemic stem cell properties, including self-renewal and subsequent uncontrolled growth. IKZF1 deletions are associated with treatment resistance and inferior outcomes. Early identification of IKZF1 deletions in B-ALL may inform the intensification of therapy and other potential treatment strategies to improve outcomes in this high-risk leukemia.
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PURPOSE: Patients with relapsed or refractory T-cell acute lymphoblastic leukemia (T-ALL) or lymphoblastic lymphoma (T-LBL) have limited therapeutic options. Clinical use of genomic profiling provides an opportunity to identify targetable alterations to inform therapy. EXPERIMENTAL DESIGN: We describe a cohort of 14 pediatric patients with relapsed or refractory T-ALL enrolled on the Leukemia Precision-based Therapy (LEAP) Consortium trial (NCT02670525) and a patient with T-LBL, discovering alterations in platelet-derived growth factor receptor-α (PDGFRA) in 3 of these patients. We identified a novel mutation in PDGFRA, p.D842N, and used an integrated structural modeling and molecular biology approach to characterize mutations at D842 to guide therapeutic targeting. We conducted a preclinical study of avapritinib in a mouse patient-derived xenograft (PDX) model of FIP1L1-PDGFRA and PDGFRA p.D842N leukemia. RESULTS: Two patients with T-ALL in the LEAP cohort (14%) had targetable genomic alterations affecting PDGFRA, a FIP1-like 1 protein/PDGFRA (FIP1L1-PDGFRA) fusion and a novel mutation in PDGFRA, p.D842N. The D842N mutation resulted in PDGFRA activation and sensitivity to tested PDGFRA inhibitors. In a T-ALL PDX model, avapritinib treatment led to decreased leukemia burden, significantly prolonged survival, and even cured a subset of mice. Avapritinib treatment was well tolerated and yielded clinical benefit in a patient with refractory T-ALL. CONCLUSIONS: Refractory T-ALL has not been fully characterized. Alterations in PDGFRA or other targetable kinases may inform therapy for patients with refractory T-ALL who otherwise have limited treatment options. Clinical genomic profiling, in real time, is needed for fully informed therapeutic decision making.
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Leucemia-Linfoma Linfoblástico de Células Precursoras , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Humanos , Criança , Animais , Camundongos , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Mutação , Receptores Proteína Tirosina Quinases/genética , Linfócitos TRESUMO
Nelarabine, an antimetabolite prodrug, is approved as monotherapy for children and adults with relapsed and refractory T-cell acute lymphoblastic leukemia and lymphoma (R/R T-ALL/LBL), although it is often used in combination regimens. We sought to understand differences in efficacy and toxicity when nelarabine is administered alone or in combination. We retrospectively analyzed 44 consecutive patients with R/R T-ALL/LBL; 29 of whom were treated with combination therapy, most with cyclophosphamide and etoposide (23, 79%) and 15 with monotherapy. The median age was 19 years (range, 2-69), including 18 children (<18 years). After a median of 1 (range, 1-3) cycle of treatment, 24 patients (55%) achieved complete remission, 62% (18/29) with combination therapy and 40% (6/15) with monotherapy (P = .21). Most responders (21, 88%) pursued allogeneic stem cell transplant (alloSCT). Overall survival (OS) was 12.8 months (95% confidence interval, 6.93-not reached) in the entire cohort and was higher in the combination therapy than in the monotherapy group (24-month OS, 53% vs 8%; P = .003). The rate of neurotoxicity was similar between groups (27% vs 17%; P = .46) and grade 3/4 anemia and thrombocytopenia were more frequent in the combination group (76% vs 20%; P < .001% and 66% vs 27%; P = .014, respectively). In a multivariate analysis, nelarabine combination therapy and alloSCT post nelarabine were associated with improved OS (hazard ratio, 0.41; P = .04 and hazard ratio, 0.25; P = .008, respectively). In conclusion, compared with monotherapy, nelarabine combination therapy was well tolerated and associated with improved survival in pediatric and adult patients with R/R T-ALL/LBL.
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Linfoma , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Adulto , Humanos , Criança , Adulto Jovem , Estudos Retrospectivos , Linfócitos T/patologiaRESUMO
Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of multiorgan system dysfunction that is caused by hypercytokinemia and persistent activation of cytotoxic T lymphocytes and macrophages. A nearly ubiquitous finding and a diagnostic criterion of HLH is the presence of cytopenias in ≥ 2 cell lines. The mechanism of cytopenias in HLH is multifactorial but appears to be predominantly driven by suppression of hematopoiesis by pro-inflammatory cytokines and, to some extent, by consumptive hemophagocytosis. Recognition of cytopenias as a manifestation of HLH is an important consideration for patients with bone marrow failure of unclear etiology.
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COVID-19/patologia , Células Mieloides/patologia , SARS-CoV-2/patogenicidade , Síndrome de Resposta Inflamatória Sistêmica/patologia , COVID-19/sangue , COVID-19/virologia , Criança , Feminino , Humanos , Masculino , Células Mieloides/virologia , Prognóstico , Síndrome , Síndrome de Resposta Inflamatória Sistêmica/sangue , Síndrome de Resposta Inflamatória Sistêmica/virologiaRESUMO
Background Pediatric ACGME (Accreditation Council for Graduate Medical Education) requirements include demonstrated competence in umbilical line placement. Given a waning number of these procedures clinically available to residents, new methods of procedural teaching must be employed. We developed a simulation-based strategy, using adult-learning principles, to teach umbilical venous catheter (UVC) placement to pediatric residents. We also determined whether procedural teaching via simulation increased confidence and competence among pediatric residents in performing the procedure. Methods Out of 23 first-year pediatric residents, eight participated in the study. Participants completed a survey evaluating their self-perceived competence and confidence in umbilical line placement. Their simulated umbilical line placement was assessed using a standardized checklist. Residents were then trained on simulated line placement in small groups by neonatologists. Six months later, residents completed a post-training survey and were assessed while placing simulated lines. Statistical analysis was completed using a paired t-test for parametric data, Wilcoxon signed-rank sum test for non-parametric data, and McNemar's chi-squared test for categorical data. Spearman's correlation was used for ordinal variables and Pearson's correlation was used for continuous variables. Results Nine PGY-1 (post-graduate year-1) residents completed the pre-training survey and simulation, while eight residents completed the post-training survey and simulation. There was an increase in resident confidence in placing umbilical lines six months after completion of the training session (p = 0.015) even though there was no difference in the number of umbilical lines that residents had placed in the intervening time. The residents performed a greater number of steps correctly after the training compared to their performance before the training (p=0.001). There was a statistically significant positive correlation between resident confidence and the number of steps performed correctly (rs(14)= 0.649, p = 0.006). There was no correlation between confidence and the number of umbilical lines placed on live subjects. Conclusion A teaching strategy that allows pediatric residents to struggle to perform UVC placement in a simulated setting, before receiving expert instruction, is effective at increasing their confidence and competence, even in the absence of exposure to human subjects.
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BACKGROUND: Fever and neutropenia is a common reason for nonelective hospitalization of pediatric oncology patients. Herein we report nearly five years of experience with a clinical pathway designed to guide outpatient management for patients who had low-risk features. PROCEDURES: Through a multidisciplinary collaboration, we implemented a clinical pathway at our institution using established low-risk criteria to guide outpatient management of pediatric oncology patients. Comprehensive chart review of all febrile neutropenia episodes was conducted to characterize outcomes of patients with low-risk febrile neutropenia following clinical pathway implementation. RESULTS: Between April 1, 2013, and October 1, 2017, there were 169 cases of febrile neutropenia managed in our Pediatric Oncology Unit. Sixty-seven (40%) of these episodes were defined as low risk and managed either entirely in the outpatient setting (41 episodes, 24%) or with a step-down strategy involving a very brief inpatient stay (26 episodes, 15%). There were no intensive care unit admissions or deaths among the low-risk patients. Of those identified as low risk, seven patients (10%) required subsequent hospitalization during the follow-up period, two for inadequate oral intake, two for persistent fevers, one for cellulitis, one for seizure unrelated to the febrile episode, and one for a positive blood culture. CONCLUSIONS: Following implementation of a clinical pathway, the majority of patients designated as low risk were managed primarily in the outpatient setting without major morbidity or mortality, suggesting that carefully selected low-risk patients can be successfully treated with outpatient management and subsequent admission if warranted.
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Procedimentos Clínicos , Neutropenia Febril/terapia , Hospitalização , Pacientes Internados , Pacientes Ambulatoriais , Adolescente , Criança , Pré-Escolar , Feminino , Febre de Causa Desconhecida/terapia , Humanos , Masculino , Neoplasias/terapiaRESUMO
OBJECTIVE: The α4ß7 integrin monoclonal antibody vedolizumab is hypothesised to be gut selective. Effects of vedolizumab on immune responses to parenterally or enterally administered antigens were investigated. DESIGN: In this randomised, double-blind, placebo-controlled, phase I trial, healthy participants received a single intravenous dose of vedolizumab 750â mg (n=64) or placebo (n=63). After 4â days, participants began intramuscular hepatitis B vaccine (HBV; days 4, 32, 60) and oral cholera vaccine (OCV; days 4, 18) regimens. The study was designed to demonstrate a 15% non-inferiority margin for the between-group difference in the primary end point: percentage of participants with HBV seroconversion at day 74 (serum hepatitis B surface antigen (HBs) antibody titre ≥10â IU/L). OCV seroconversion at day 74 (>4-fold increase in serum cholera toxin (CT) antibodies) was a secondary end point. RESULTS: A total of 56 (90.3%) placebo-treated and 54 (88.5%) vedolizumab-treated participants responded to HBV. Geometric mean anti-HBs titres were similar for placebo (114.4â IU/L) and vedolizumab (129.6â IU/L) at day 74. A total of 60 (96.8%) placebo-treated and 52 (82.5%) vedolizumab-treated participants responded to OCV at day 74. Geometric mean anti-CT IgG levels were higher for placebo than for vedolizumab at day 74 (9210.08 vs. 3007.8â ELISA Units (EU)/mL) and day 32 (11629.3 vs. 1575.4â EU/mL). Anti-CT IgA results were similar. Adverse events were consistent with previous experience. One serious adverse event (spontaneous abortion) was reported for placebo. CONCLUSIONS: Vedolizumab did not alter the response to parenterally administered antigens but reduced the response to oral antigens, demonstrating its gut-selective mechanism of action. TRIAL REGISTRATION NUMBER: NCT Number: 01981616; EudraCT Number: 2011-001874-24.
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Anticorpos Monoclonais Humanizados/farmacologia , Formação de Anticorpos/efeitos dos fármacos , Trato Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/imunologia , Adulto , Método Duplo-Cego , Feminino , Vacinas contra Hepatite B/imunologia , Humanos , Imunização , Masculino , Adulto JovemRESUMO
Pancreatitis-associated protein (PAP) is a novel cytokine with putative anti-inflammatory effects. PAP gene expression has been found to be increased in the myocardium of rats with decompensated pressure-overload hypertrophy. A prospective pilot study was performed to test the hypotheses that PAP is elevated in ambulatory patients with heart failure (HF) and that concentrations correlate with the severity of disease. Blood samples were obtained from patients with HF (n = 70) and normal controls (n = 17). Patients with New York Heart Association class III and IV symptoms had a greater mean PAP than patients with class I and II symptoms (35.5 ± 4.0 vs 10.3 ± 1.0 µg/L, p <0.001) and normal controls (35.5 ± 4.0 vs 6.2 ± 0.5 µg/L, p <0.001). Receiver-operating characteristic curves revealed that PAP had similar sensitivity and specificity for HF admission at 6 months as B-type natriuretic peptide and equivalent predictive value for 12-month and 24-month all-cause mortality. On the basis of the receiver-operating characteristic curve analysis, patients were then grouped into those with a serum PAP <24 or ≥24 µg/L. Patients with PAP ≥24 µg/L had significantly worse renal function, greater B-type natriuretic peptide and C-reactive protein levels, higher pulmonary artery systolic pressure, and greater 6- and 24-month all-cause mortality (p <0.05). In conclusion, PAP levels correlate with disease severity in patients with HF and are a marker of cardiorenal syndrome, neurohormonal activation, and elevated filling pressures. PAP is a sensitive and specific marker for increased 6-month HF morbidity and 12- and 24-month all-cause mortality. These results justify the prospective evaluation of PAP as a novel prognostic marker for disease severity in patients with HF.