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ABSTRACT: In acute myeloid leukemia (AML), leukemia stem cells (LSCs) and leukemia progenitor cells (LPCs) interact with various cell types in the bone marrow (BM) microenvironment, regulating their expansion and differentiation. To study the interaction of CD4+ and CD8+ T cells in the BM with LSCs and LPCs, we analyzed their transcriptome and predicted cell-cell interactions by unbiased high-throughput correlation network analysis. We found that CD4+ T cells in the BM of patients with AML were activated and skewed toward T-helper (Th)1 polarization, whereas interleukin-9 (IL-9)-producing (Th9) CD4+ T cells were absent. In contrast to normal hematopoietic stem cells, LSCs produced IL-9, and the correlation modeling predicted IL9 in LSCs as a main hub gene that activates CD4+ T cells in AML. Functional validation revealed that IL-9 receptor signaling in CD4+ T cells leads to activation of the JAK-STAT pathway that induces the upregulation of KMT2A and KMT2C genes, resulting in methylation on histone H3 at lysine 4 to promote genome accessibility and transcriptional activation. This induced Th1-skewing, proliferation, and effector cytokine secretion, including interferon gamma (IFN-γ) and tumor necrosis factor α (TNF-α). IFN-γ and, to a lesser extent, TNF-α produced by activated CD4+ T cells induced the expansion of LSCs. In accordance with our findings, high IL9 expression in LSCs and high IL9R, TNF, and IFNG expression in BM-infiltrating CD4+ T cells correlated with worse overall survival in AML. Thus, IL-9 secreted by AML LSCs shapes a Th1-skewed immune environment that promotes their expansion by secreting IFN-γ and TNF-α.
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Linfocitos T CD4-Positivos , Interleucina-9 , Leucemia Mieloide Aguda , Células Madre Neoplásicas , Células TH1 , Interleucina-9/genética , Interleucina-9/metabolismo , Humanos , Leucemia Mieloide Aguda/inmunología , Leucemia Mieloide Aguda/patología , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Células Madre Neoplásicas/patología , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/inmunología , Células TH1/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Proliferación Celular , Proteína de la Leucemia Mieloide-Linfoide/genética , Proteína de la Leucemia Mieloide-Linfoide/metabolismo , Microambiente Tumoral/inmunología , Receptores de Interleucina-9/genética , Receptores de Interleucina-9/metabolismo , Interferón gamma/metabolismo , N-Metiltransferasa de Histona-Lisina/genéticaRESUMEN
Mutations in splicing factor (SF) genes SRSF2, U2AF1, SF3B1, and ZRSR2 are now considered adverse risk in the European LeukemiaNet 2022 acute myeloid leukemia (AML) risk stratification. The prognostic impact of SF mutations in AML has been predominantly derived from younger patients treated with intensive (INT) therapy. We evaluated 994 patients with newly diagnosed AML, including 266 (27%) with a SFmut. Median age was 67 years overall, with patients with SFmut being older at 72 years. SRSF2 (n = 140, 53%) was the most common SFmut. In patients treated with INT, median relapse-free survival (RFS) (9.6 vs 21.4 months, P = .04) and overall survival (OS) (15.9 vs 26.7 months, P = .06) were shorter for patients with SFmut than without SFwt, however this significance abrogated when evaluating patients who received venetoclax with INT therapy (RFS 15.4 vs 20.3 months, P = .36; OS 19.6 vs 30.7 months, P = .98). In patients treated with LI, median RFS (9.3 vs 7.7 months, P = .35) and OS (12.3 vs 8.5 months, P = .14) were similar for patients with and without SFmut , and outcomes improved in all groups with venetoclax. On multivariate analysis, SFmut did not affect hazards of relapse and death for INT arm but reduced both these hazards in LI arm. In a large AML data set with >60% of patients receiving venetoclax with LI/INT therapy, SFmut had no independent negative prognostic impact. Newer prognostic models that consider LI therapy and use of venetoclax among other factors are warranted.
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Leucemia Mieloide Aguda , Humanos , Anciano , Factores de Empalme de ARN/genética , Pronóstico , Factores de Empalme Serina-Arginina/genética , Factor de Empalme U2AF/genética , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , MutaciónRESUMEN
Asparaginase-based therapy is a cornerstone in acute lymphoblastic leukemia (ALL) treatment, capitalizing on the methylation status of the asparagine synthetase (ASNS) gene, which renders ALL cells reliant on extracellular asparagine. Contrastingly, ASNS expression in acute myeloid leukemia (AML) has not been thoroughly investigated, despite studies suggesting that AML with chromosome 7/7q deletions might have reduced ASNS levels. Here, we leverage reverse phase protein arrays to measure ASNS expression in 810 AML patients and assess its impact on outcomes. We find that AML with inv(16) has the lowest overall ASNS expression. While AML with deletion 7/7q had ASNS levels slightly lower than those of AML without deletion 7/7q, this observation was not significant. Low ASNS expression correlated with improved overall survival (46 versus 54 weeks, respectively, p = 0.011), whereas higher ASNS levels were associated with better response to venetoclax-based therapy. Protein correlation analysis demonstrated association between ASNS and proteins involved in methylation and DNA repair. In conclusion, while ASNS expression was not lower in patients with deletion 7/7q as initially predicted, ASNS levels were highly variable across AML patients. Further studies are needed to assess whether patients with low ASNS expression are susceptible to asparaginase-based therapy due to their inability to augment compensatory ASNS expression upon asparagine depletion.
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Aspartatoamoníaco Ligasa , Leucemia Mieloide Aguda , Proteómica , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/tratamiento farmacológico , Aspartatoamoníaco Ligasa/genética , Aspartatoamoníaco Ligasa/metabolismo , Femenino , Proteómica/métodos , Masculino , Persona de Mediana Edad , Adulto , Anciano , Deleción Cromosómica , Análisis por Matrices de Proteínas/métodos , Asparaginasa/uso terapéutico , Asparaginasa/genética , Cromosomas Humanos Par 7/genética , Adulto Joven , Ligasas de Carbono-Nitrógeno con Glutamina como Donante de Amida-NRESUMEN
Patients with relapsed acute myeloid leukemia (rAML) experience dismal outcomes. We performed a comprehensive analysis of patients with rAML to determine the genetic dynamics and survival predictive factors. We analyzed 875 patients with newly diagnosed AML who received intensive treatment (IT) or low-intensity treatment (LIT). Of these patients, 197 experienced subsequent rAML. Data was available for 164 patients, with a median time from CR/CRi to relapse of 6.5 months. Thirty-five of the 164 patients (21%) experienced relapse after allogeneic hematopoietic stem cell transplantation (alloSCT). At relapse mutations in genes involved in pathway signaling tended to disappear, whereas clonal hematopoiesis-related mutations or TP53 tended to persist. Patients with normal karyotypes tended to acquire cytogenetic abnormalities at relapse. Patients treated with IT had a higher emergence rate of TP53 mutations (16%), compared to patients treated with LIT (1%, P = 0.009). The overall response rates were 38% and 35% for patients treated with salvage IT or LIT, respectively. Seventeen patients (10%) underwent alloSCT after salvage therapy. The median overall survival (OS) duration after relapse was 5.3 months, with a 1-year OS rate of 17.6%. Complex karyotype (hazard ratio [HR] = 2.14, P < 0.001), a KMT2A rearrangement (HR = 3.52, P = 0.011), time in remission < 12 months (HR = 1.71, P = 0.011), and an elevated white blood cell count at relapse (HR = 2.38, P = 0.005) were independent risk factors for OS duration. More effective frontline and maintenance therapies are warranted to prevent rAML.
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Outcomes in older patients with acute myeloid leukemia (AML) have historically been poor. Given advances in low-intensity therapy (LIT) and stem cell transplantation (SCT), we performed a retrospective single-center study to evaluate the contemporary outcomes of this population. We reviewed all patients ≥60 years with newly diagnosed AML between 2012 and 2021 and analyzed treatment and SCT-related trends and outcomes. We identified 1073 patients with a median age of 71 years. Adverse clinical and cytomolecular findings were frequent within this cohort. In total, 16% of patients were treated with intensive chemotherapy, 51% with LIT alone, and 32% with LIT plus venetoclax. The composite complete remission rate with LIT plus venetoclax was 72%, which was higher than with LIT alone (48%, p < .0001) and comparable to intensive chemotherapy (74%, p = .6). The median overall survival (OS) with intensive chemotherapy, LIT, and LIT plus venetoclax was 20.1, 8.9, and 12.1 months, respectively. 18% of patients received SCT. SCT rates were 37%, 10%, and 22% in patients treated with intensive chemotherapy, LIT, and LIT plus venetoclax, respectively. The 2-year OS, relapse-free survival (RFS), cumulative incidence (CI) of relapse, and CI of treatment-related mortality with frontline SCT (n = 139) were 59%, 52%, 27%, and 22%, respectively. By landmark analysis, patients undergoing frontline SCT had superior OS (median 39.6 vs. 21.4 months, p < .0001) and RFS (30.9 vs. 12.1 months, p < .0001) compared with responding patients who did not. Outcomes in older patients with AML are improving with more effective LIT. Measures should be pursued to increase access to SCT in older patients.
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Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Humanos , Anciano , Supervivencia sin Enfermedad , Estudios Retrospectivos , Trasplante Homólogo , Leucemia Mieloide Aguda/tratamiento farmacológico , Trasplante de Células Madre , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
Recurrence of MRD in AML is associated with imminent relapse unless intervened upon. Change in chemotherapy regimen and/or immediate transplant improve outcomes.
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Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Neoplasia Residual , Pronóstico , RecurrenciaRESUMEN
Isocitrate dehydrogenase 1 or 2 (IDH1 or IDH2) mutations occur frequently in newly diagnosed (ND) acute myeloid leukemia (AML) often with co-occurring NPM1 mutations, which may influence treatment outcomes. Detailed analysis of IDH-mutated AML treated with venetoclax and influence of co-occurring NPM1 mutations remains unclear. This retrospective single-center cohort study evaluated clinical and molecular demographics,response and survival, and impact of co-occurring NPM1 mutations in patients with IDH1 or IDH2-mutated AML. 556 patients with IDH1, IDH2, and/or NPM1 mutated AML were included. Patients with IDH1mut AML (N = 119) were more likely to have older age, sAML, ELN-adverse risk disease, and adverse-risk cytogenetics compared to those with IDH2mut (N = 229) or IDHwt /NPM1mut AML (N = 208). In multivariate analysis, patients with IDH2mut (HR 0.61 [95%CI: 0.43-0.88], p value: .007) or IDHwt /NPM1mut (HR 0.65 [95% CI: 0.45-0.94], p value: .024) AML had a decreased risk of death versus IDH1mut AML. Venetoclax-based lower-intensity regimens partially abrogated the detrimental effect of IDH1mut with similar OS observed between IDH1mut /NPM1wt , IDH2mut /NPM1wt , and IDHwt /NPM1mut AML. With regards to the influence of IDHmut /NPM1mut cases, IC improved survival in IDH2mut /NPM1mut versus IDH2mut /NPM1wt AML (HR: 0.54 [95% CI: 0.2644-1.082], p value: .077), while venetoclax-based therapy improved survival in IDH1mut /NPM1mut versus IDH1mut /NPM1wt AML (HR: 0.094 [95% CI: 0.01-0.74], p value: .0056). Differing outcomes were observed in IDH1mut versus IDH2mut or NPM1mut AML which were influenced by co-occurring NPM1 mutations and partially abrogated with venetoclax-based therapy. Given the differing biology and survival in IDH1mut AML, investigations incorporating molecularly targeted therapies such as IDH inhibitors remain warranted in this subgroup.
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Isocitrato Deshidrogenasa , Leucemia Mieloide Aguda , Compuestos Bicíclicos Heterocíclicos con Puentes , Estudios de Cohortes , Humanos , Isocitrato Deshidrogenasa/genética , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Mutación , Nucleofosmina , Pronóstico , Estudios Retrospectivos , SulfonamidasRESUMEN
The p53-Mdm2 feedback loop is perceived to be critical for regulating stress-induced p53 activity and levels. However, this has never been tested in vivo. Using a genetically engineered mouse with mutated p53 response elements in the Mdm2 P2 promoter, we show that feedback loop-deficient Mdm2(P2/P2) mice are viable and aphenotypic and age normally. p53 degradation kinetics after DNA damage in radiosensitive tissues remains similar to wild-type controls. Nonetheless, DNA damage response is elevated in Mdm2(P2/P2) mice. Enhanced p53-dependent apoptosis sensitizes hematopoietic stem cells (HSCs), causing drastic myeloablation and lethality. These results suggest that while basal Mdm2 levels are sufficient to regulate p53 in most tissues under homeostatic conditions, the p53-Mdm2 feedback loop is critical for regulating p53 activity and sustaining HSC function after DNA damage. Therefore, transient disruption of p53-Mdm2 interaction could be explored as a potential adjuvant/therapeutic strategy for targeting stem cells in hematological malignancies.
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Daño del ADN/genética , Retroalimentación Fisiológica , Longevidad/genética , Proteínas Proto-Oncogénicas c-mdm2/genética , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Animales , Apoptosis/genética , Daño del ADN/efectos de la radiación , Técnicas de Sustitución del Gen , Células Madre Hematopoyéticas/efectos de la radiación , Ratones , Ratones Endogámicos C57BL , Mutación/genética , Regiones Promotoras Genéticas/genética , Unión Proteica/genética , Desnaturalización Proteica/efectos de la radiación , Estabilidad Proteica/efectos de la radiación , Tolerancia a Radiación/genética , Radiación Ionizante , Rayos UltravioletaRESUMEN
Introduction It has been established that underweight women with low gestational weight gain (GWG) are at a higher risk of having Small for Gestational Age (SGA) newborns. However, the association remains poorly studied in Middle Eastern societies exhibiting different ethnic groups, genetic predisposing factors along with differences in nutritional food intake during pregnancy. The aim of this study is to assess the risk of having a SGA newborn among underweight and normal weight BMI women while studying the role of GWG in this association. Methods This is a retrospective cross-sectional study of 62,351 singleton pregnancies from the National Collaborative Perinatal Neonatal Network between 2001 and 2009 from 27 hospitals across Lebanon. Women who had underweight and normal pre-pregnancy BMI were included. Results A total of 8.6% newborns were SGA and 6.6% of women were underweight. Among women with normal and underweight pre-pregnancy BMI, 8.6 and 12.4% had SGA births respectively. Overall, the adjusted OR of having SGA newborns was significantly higher among underweight women (OR = 1.448; 95%CI = 1.287-1.630) compared to normal pre-pregnancy BMI. Below normal weight gain significantly increased the odds of SGA for both normal and underweight pre-pregnancy BMI women, with adjusted ORs of 1.535 (95% CI = 1.418-1.661) and 1.970 (95%CI = 1.515-2.560) respectively. Discussion Higher risks of SGA newborns in underweight and normal BMI women with low GWG were observed. In addition, normal weight gain couldn't protect underweight women of having risk for SGA newborns. Hence, all pregnant women should be encouraged to maintain healthy BMI before pregnancy and attain adequate GWG.
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Recién Nacido Pequeño para la Edad Gestacional , Complicaciones del Embarazo/epidemiología , Mujeres Embarazadas/etnología , Delgadez/etnología , Adulto , Índice de Masa Corporal , Estudios Transversales , Femenino , Edad Gestacional , Humanos , Incidencia , Recién Nacido , Líbano/epidemiología , Masculino , Obesidad/epidemiología , Sobrepeso/epidemiología , Embarazo , Complicaciones del Embarazo/etiología , Estudios Retrospectivos , Factores de Riesgo , Delgadez/epidemiología , Aumento de Peso/etnologíaAsunto(s)
Leucemia Prolinfocítica de Células T/diagnóstico , Linfocitos/patología , Citometría de Flujo , Humanos , Leucemia Prolinfocítica de Células T/complicaciones , Leucemia Prolinfocítica de Células T/genética , Recuento de Leucocitos , Masculino , Persona de Mediana Edad , Proteínas Proto-Oncogénicas/genéticaAsunto(s)
Anticuerpos Biespecíficos , Leucemia-Linfoma Linfoblástico de Células Precursoras , Anticuerpos Biespecíficos/efectos adversos , Humanos , Inotuzumab Ozogamicina , Cromosoma Filadelfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genéticaRESUMEN
BACKGROUND: Iron overload is well documented in patients with ß-thalassemia major, and patients who have undergone hematopoietic stem cell transplantation (HSCT) remain at risk as a result of pre- and immediate post-HSCT transfusions. PROCEDURE: This is a prospective, randomized, 1-year clinical trial that compares the efficacy and safety of the once-daily oral iron chelator deferasirox versus phlebotomy for the treatment of iron overload in children with ß-thalassemia major following HSCT. RESULTS: Patients (aged 12.4 years) received deferasirox (n = 12, 10 mg/kg/day starting dose) or phlebotomy (n = 14, 6 ml/kg/2 weeks) for 1 year. In two and five patients, deferasirox dose was increased to 15 and 20 mg/kg/day, respectively. Magnetic resonance imaging (MRI)-assessed liver iron concentration (LIC) decreased with deferasirox (mean 12.5 ± 10.1 to 8.5 ± 9.3 mg Fe/g dry weight [dw]; P = 0.0005 vs. baseline) and phlebotomy (10.2 ± 6.8 to 8.3 ± 9.2 mg Fe/g dw; P = 0.05). LIC reductions were greater with deferasirox than with phlebotomy for patients with baseline serum ferritin 1,000 ng/ml or higher (-8.1 ± 1.5 vs. -3.5 ± 5.7 mg Fe/g dw; P = 0.048). Serum ferritin and non-transferrin-bound iron also decreased significantly. In two patients with severe cardiac siderosis, a clinically relevant improvement in myocardial T2* was seen, following phlebotomy and deferasirox therapy (n = 1 each). Adverse effects with deferasirox were skin rash, gastrointestinal upset, and increased liver function tests (all n = 1), while those for phlebotomy were difficulty with venous access (n = 4) and distress during procedure (n = 1). Parents of 13/14 children receiving phlebotomy wished to switch to deferasirox, with 1/14 being satisfied with phlebotomy. CONCLUSIONS: Deferasirox treatment or phlebotomy reduces iron burden in pediatric patients with ß- thalassemia major post-HSCT, with a manageable safety profile.
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Benzoatos/uso terapéutico , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Quelantes del Hierro/uso terapéutico , Sobrecarga de Hierro/terapia , Flebotomía/métodos , Triazoles/uso terapéutico , Talasemia beta/terapia , Adolescente , Niño , Preescolar , Terapia Combinada , Deferasirox , Femenino , Estudios de Seguimiento , Humanos , Sobrecarga de Hierro/diagnóstico , Sobrecarga de Hierro/etiología , Masculino , Pronóstico , Estudios ProspectivosRESUMEN
Hydroxyurea, blood transfusions, and hematopoietic stem cell transplantation represent the 3 disease-modifying therapies in children with sickle cell disease (SCD). Blood transfusions play an increasingly important role in both prevention and management of SCD complications in this age group. This review will focus on the indications of blood transfusion in children with SCD and modalities of its administration. It will also highlight the complications of this life-saving therapy and ways of optimizing transfusion to minimize its associated risks.
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Anemia de Células Falciformes/terapia , Transfusión Sanguínea , Anemia de Células Falciformes/complicaciones , Anemia de Células Falciformes/tratamiento farmacológico , Incompatibilidad de Grupos Sanguíneos/etiología , Incompatibilidad de Grupos Sanguíneos/inmunología , Transfusión Sanguínea/métodos , Viscosidad Sanguínea , Patógenos Transmitidos por la Sangre , Terapia Combinada , Recambio Total de Sangre , Predicción , Humanos , Quelantes del Hierro/uso terapéutico , Sobrecarga de Hierro/tratamiento farmacológico , Sobrecarga de Hierro/etiología , Sobrecarga de Hierro/prevención & control , Insuficiencia Multiorgánica/prevención & control , Esplenectomía , Accidente Cerebrovascular/etiología , Accidente Cerebrovascular/prevención & control , Reacción a la TransfusiónRESUMEN
BACKGROUND: Pre-pregnancy body mass index (BMI) and gestational weight gain (GWG) are reported to impact the preterm birth (PTB) rate and newborn size. Most studies have been conducted in developed countries, although PTB and adverse pregnancy outcomes are more frequent in the developing world. The aim of this study is to elucidate the association of pre-pregnancy BMI and GWG on the occurrence of PTB and sub-optimal fetal size in Lebanon. METHODS: This is a retrospective cohort study using a hospital-based register covering 35% of births in Lebanon between 2001 and 2012. Data were collected on 170 428 pregnancies from 32 hospitals using medical records and interviews. RESULTS: After adjusting for confounders, underweight women had increased odds of having very preterm [odds ratio (OR) 1.58, 95% confidence interval (CI) 1.16, 2.14], preterm (OR 1.42, 95% CI 1.28, 1.58), and small for gestational age (SGA) (OR 1.50, 95% CI 1.37, 1.63) neonates. When BMI was analysed with GWG, only SGA remained significant in underweight women with low GWG. For all BMI groups, low GWG was protective against large for gestational age (LGA) and high GWG increased the odds of LGA. GWG, both low (OR 1.25, 95% CI 1.15, 1.35) and high (OR 1.43, 95% CI 1.32, 1.55) increased the risk of PTB in normal weight women. The same result was obtained for overweight women. CONCLUSIONS: High GWG increased the risk of LGA for all groups and PTB in normal weight and overweight women, whereas low GWG increased the risk of SGA and PTB. Given that there are not many studies from middle income/developing countries on patterns of weight gain during pregnancy, findings from this study may help with pre-conception counselling with emphasis on the importance of an optimal pre-pregnancy BMI and appropriate weight gain during pregnancy.
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Índice de Masa Corporal , Recién Nacido Pequeño para la Edad Gestacional , Sobrepeso/epidemiología , Complicaciones del Embarazo/epidemiología , Mujeres Embarazadas , Nacimiento Prematuro/epidemiología , Delgadez/epidemiología , Adulto , Femenino , Humanos , Recién Nacido , Líbano/epidemiología , Oportunidad Relativa , Sobrepeso/complicaciones , Embarazo , Complicaciones del Embarazo/etiología , Resultado del Embarazo , Estudios Retrospectivos , Factores de Riesgo , Delgadez/complicaciones , Aumento de PesoRESUMEN
BACKGROUND: A caring, compassionate practitioner of the medical arts is the idealized version of what makes a good doctor. If asked to think of a painting of a doctor we most likely conjure an image of a physician sitting at a patient's bedside checking the pulse with a concerned look on his face. The reality is however that cynicism, among other negative attitudes, is becoming more prominent among physicians and medical staff. The causes and extent of cynicism likely vary among medical departments and different cultures. In this study, we aimed to assess attitudes of medical students and physicians in an Emergency Department (ED) in Lebanon that accommodates both local patients and is also known to attract patients from around the Middle East. METHODS: A total of 30 students, residents and attending physicians at the American University of Beirut Medical Center were invited to participate. All participants underwent semi-structured interviews that were recorded, transcribed and then analyzed for common themes. RESULTS: More negative emotions were expressed among participants than positive ones. Negative emotions were more frequently expressed among medical students, interns and residents than attending physicians. Cynicism in the ED was commonly reported however, maintenance of professionalism and adequate patient care were underscored. While empathy was recurrently found among participants, a trend towards a decrease in empathy with career progression was noted among attending physicians. Further, negative feelings towards patient families were prominent. Participants tended to categorize patients based on willingness to cooperate, gender, age, case acuity, ethnic origins and social status. CONCLUSIONS: Cynicism emerged as a prominent theme among medical students and staff in our study. However, participants were also empathetic. These attitudes were generally attributed to the peculiar stressors associated with the Lebanese culture, low acuity cases and "VIP" patients. It is crucial to explore methods in order to decrease cynicism and improve patient care. Also, the implications of these attitudes on patient care remain to be discovered.
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Actitud del Personal de Salud , Servicio de Urgencia en Hospital , Internado y Residencia , Cuerpo Médico de Hospitales/psicología , Relaciones Médico-Paciente , Estudiantes de Medicina/psicología , Adulto , Empatía , Femenino , Humanos , Entrevistas como Asunto , Líbano , Masculino , Negativismo , Investigación Cualitativa , Centros de Atención Terciaria , Recursos HumanosRESUMEN
BACKGROUND & AIMS: Aberrantly high expression of TRIM24 occurs in human cancers, including hepatocellular carcinoma. In contrast, TRIM24 in the mouse is reportedly a liver-specific tumour suppressor. To address this dichotomy and to uncover direct regulatory functions of TRIM24 in vivo, we developed a new mouse model that lacks expression of all Trim24 isoforms, as the previous model expressed normal levels of Trim24 lacking only exon 4. METHODS: To produce germline-deleted Trim24(dlE1) mice, deletion of the promoter and exon 1 of Trim24 was induced in Trim24(LoxP) mice by crossing with a zona pellucida 3-Cre line for global deletion. Liver-specific deletion (Trim24(hep)) was achieved by crossing with an albumin-Cre line. Phenotypic analyses were complemented by protein, gene-specific and global RNA expression analyses and quantitative chromatin immunoprecipitation. RESULTS: Global loss of Trim24 disrupted hepatic homeostasis in 100% of mice with highly significant, decreased expression of oxidation/reduction, steroid, fatty acid, and lipid metabolism genes, as well as increased expression of genes involved in unfolded protein response, endoplasmic reticulum stress and cell cycle pathways. Trim24(dlE1/dlE1) mice have markedly depleted visceral fat and, like Trim24(hep/hep) mice, spontaneously develop hepatic lipid-filled lesions, steatosis, hepatic injury, fibrosis and hepatocellular carcinoma. CONCLUSIONS: TRIM24, an epigenetic co-regulator of transcription, directly and indirectly represses hepatic lipid accumulation, inflammation, fibrosis and damage in the murine liver. Complete loss of Trim24 offers a model of human non-alcoholic fatty liver disease, steatosis, fibrosis and development of hepatocellular carcinoma in the absence of high-fat diet or obesity.
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Carcinoma Hepatocelular/genética , Hígado Graso/genética , Regulación Neoplásica de la Expresión Génica , Lípidos/análisis , Neoplasias Hepáticas Experimentales/genética , Proteínas Nucleares/genética , ARN Neoplásico/genética , Factores de Transcripción/genética , Animales , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Progresión de la Enfermedad , Hígado Graso/metabolismo , Hígado Graso/patología , Humanos , Hígado/metabolismo , Hígado/patología , Neoplasias Hepáticas Experimentales/metabolismo , Neoplasias Hepáticas Experimentales/patología , Ratones , Ratones Noqueados , Proteínas Nucleares/biosíntesis , Reacción en Cadena de la Polimerasa , Factores de Transcripción/biosíntesisRESUMEN
Consanguineous marriages constitute a significant fraction of marriages worldwide and confer a major public health concern on newborns. In addition to the risk of acquiring a recessive genetic disease, the offspring of consanguineous parents are plausibly at an increased risk of preterm birth, decreased anthropometric measurements, congenital defects and mortality. How consanguinity confers such an increased risk is still largely unknown. In this review, we discuss the effect of consanguinity on selected gestational outcomes by delineating the different studies that have led to such findings. We also investigate the different conclusions that have emerged regarding the effect of consanguinity on gestational outcomes.
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Tamaño Corporal/genética , Anomalías Congénitas/epidemiología , Consanguinidad , Mortalidad Infantil , Matrimonio/estadística & datos numéricos , Nacimiento Prematuro/epidemiología , Antropometría , Humanos , Lactante , Recién NacidoAsunto(s)
Alelos , Frecuencia de los Genes , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidad , Mutación , Proteínas Nucleares/genética , Adulto , Anciano , Costo de Enfermedad , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Nucleofosmina , Tasa de SupervivenciaRESUMEN
BACKGROUND: Acute myeloid leukemia (AML) is associated with a dismal prognosis. Immune checkpoint blockade (ICB) to induce antitumor activity in AML patients has yielded mixed results. Despite the pivotal role of B cells in antitumor immunity, a comprehensive assessment of B lymphocytes within AML's immunological microenvironment along with their interaction with ICB remains rather constrained. METHODS: We performed an extensive analysis that involved paired single-cell RNA and B-cell receptor (BCR) sequencing on 52 bone marrow aspirate samples. These samples included 6 from healthy bone marrow donors (normal), 24 from newly diagnosed AML patients (NewlyDx), and 22 from 8 relapsed or refractory AML patients (RelRef), who underwent assessment both before and after azacitidine/nivolumab treatment. RESULTS: We delineated nine distinct subtypes of B cell lineage in the bone marrow. AML patients exhibited reduced nascent B cell subgroups but increased differentiated B cells compared with healthy controls. The limited diversity of BCR profiles and extensive somatic hypermutation indicated antigen-driven affinity maturation within the tumor microenvironment of RelRef patients. We established a strong connection between the activation or stress status of naïve and memory B cells, as indicated by AP-1 activity, and their differentiation state. Remarkably, atypical memory B cells functioned as specialized antigen-presenting cells closely interacting with AML malignant cells, correlating with AML stemness and worse clinical outcomes. In the AML microenvironment, plasma cells demonstrated advanced differentiation and heightened activity. Notably, the clinical response to ICB was associated with B cell clonal expansion and plasma cell function. CONCLUSIONS: Our findings establish a comprehensive framework for profiling the phenotypic diversity of the B cell lineage in AML patients, while also assessing the implications of immunotherapy. This will serve as a valuable guide for future inquiries into AML treatment strategies.
Asunto(s)
Leucemia Mieloide Aguda , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Médula Ósea , Azacitidina/uso terapéutico , Perfilación de la Expresión Génica , Linfocitos B , Microambiente TumoralRESUMEN
Patients with leukemia experience profound immunosuppression both from their underlying disease as well as chemotherapeutic treatment. Little is known about the prevalence and clinical presentation of nontuberculous mycobacteria (NTM) in this patient population. We identified six cases of NTM infection from 29,743 leukemia patients who had acid-fast bacilli (AFB) cultures. Four cases had bloodstream infections and five had disseminated disease, including one who presented with an unusual case of diffuse cellulitis/myositis. All patients were lymphopenic at time of diagnosis, and two patients ultimately died from their NTM infection. NTM infections are a rare, but potentially life-threatening infection in patients with leukemia. Sending AFB cultures early is important to direct appropriate antimicrobial therapy and allow for future leukemia-directed therapy.