Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 48.351
Filtrar
1.
Nat Commun ; 12(1): 1850, 2021 03 25.
Artículo en Inglés | MEDLINE | ID: mdl-33767176

RESUMEN

Artificial intelligence and machine learning (ML) promise to transform cancer therapies by accurately predicting the most appropriate therapies to treat individual patients. Here, we present an approach, named Drug Ranking Using ML (DRUML), which uses omics data to produce ordered lists of >400 drugs based on their anti-proliferative efficacy in cancer cells. To reduce noise and increase predictive robustness, instead of individual features, DRUML uses internally normalized distance metrics of drug response as features for ML model generation. DRUML is trained using in-house proteomics and phosphoproteomics data derived from 48 cell lines, and it is verified with data comprised of 53 cellular models from 12 independent laboratories. We show that DRUML predicts drug responses in independent verification datasets with low error (mean squared error < 0.1 and mean Spearman's rank 0.7). In addition, we demonstrate that DRUML predictions of cytarabine sensitivity in clinical leukemia samples are prognostic of patient survival (Log rank p < 0.005). Our results indicate that DRUML accurately ranks anti-cancer drugs by their efficacy across a wide range of pathologies.


Asunto(s)
Antineoplásicos/uso terapéutico , Biología Computacional/métodos , Citarabina/uso terapéutico , Ensayos de Selección de Medicamentos Antitumorales/métodos , Leucemia/tratamiento farmacológico , Aprendizaje Automático , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Células Hep G2 , Humanos , Leucemia/mortalidad , Neoplasias/tratamiento farmacológico , Pronóstico , Proteómica/métodos
2.
Ciudad Autónoma de Buenos Aires; Comisión Nacional de Evaluación de Tecnologías de Salud; Marzo 2021. 30 p. (Informe de Evaluación de Tecnologías Sanitarias N°15, 15).
Monografía en Español | LILACS, BINACIS, ARGMSAL | ID: biblio-1151674

RESUMEN

El presente informe es producto del trabajo colaborativo de la Comisión Nacional de Evaluación de Tecnologías de Salud (CONETEC), dependiente del Ministerio de Salud de la Nación y creada por RM N° 623/2018. La CONETEC realiza evaluaciones y emite recomendaciones a la autoridad sanitaria sobre la incorporación, forma de uso, financiamiento y políticas de cobertura de las tecnologías sanitarias desde una perspectiva global del sistema de salud argentino. En sus evaluaciones y recomendaciones, la CONETEC tiene en cuenta criterios de calidad, seguridad, efectividad, eficiencia y equidad, evaluados bajo dimensiones éticas, médicas, económicas y sociales. Sus resultados son consensuados mediante discusiones públicas y ponderados a través de un marco de valor explícito, con la participación de todos los actores involucrados en el proceso de toma de decisiones en salud. Los informes y recomendaciones de esta comisión surgen de este proceso público, transparente y colaborativo, siendo de libre consulta y acceso para toda la sociedad.


Asunto(s)
Anciano , Leucemia/tratamiento farmacológico , Leucemia/epidemiología
3.
Arch. argent. pediatr ; 119(1): 44-50, feb. 2021. tab, ilus
Artículo en Inglés, Español | LILACS, BINACIS | ID: biblio-1147085

RESUMEN

Objetivo. Determinar la adherencia de pacientes oncológicos pediátricos a la medicación oral del mantenimiento y conocer sus creencias sobre la medicación.Población y métodos. Durante 2018-19, se recogió información de padres, adolescentes y oncólogos en seis hospitales públicos pediátricos de la Argentina. Se administraron cuestionarios de adherencia (Simplified Medication Adherence Questionnaire) y de creencias sobre la medicación (Beliefs About Medicines Questionnaire). Se consideró adherente a quien refirió tomar la medicación sin saltear dosis y respetando el tiempo de ayuno.Resultados. N = 203 pacientes. La adherencia informada por los padres fue del 75 %; la estimada por los oncólogos, del 82 %, y la referida por adolescentes, del 45 %. Las variables que mostraron asociación con la adherencia fueron solvencia económica, diagnóstico, hospital tratante, cantidad de hijos a cargo, tratamientos oncológicos realizados y existencia de obstáculos en el cumplimiento. Esta muestra no percibía los medicamentos como dañinos, pero consideró que se los utilizaba abusivamente. La mayoría percibía la necesidad de tomar la medicación antineoplásica para mantener/recuperar la salud, pero también expresó preocupaciones. La percepción sobre la medicación fue similar entre los padres y los adolescentes, y no se asoció con el nivel de adherencia.Conclusiones. La adherencia informada por los padres en esta muestra fue del 75 %. Los padres y los pacientes percibían la medicación como necesaria y manifestaron preocupaciones vinculadas al tratamiento


Objective. To determine the adherence to oral maintenance medication among pediatric cancer patients and know their beliefs about medications.Population and methods. Information was obtained from parents, adolescents, and oncologists from six public children's hospitals of Argentina during 2018 and 2019. Questionnaires on adherence (Simplified Medication Adherence Questionnaire) and beliefs about medication (Beliefs About Medicines Questionnaire) were administered. Patients were considered adherent if they referred taking their medication without missing a dose and complying with fasting time.Results. N = 203 patients. Parent-reported adherence was 75 %; adherence estimated by oncologists, 82 %; and that referred by adolescents, 45 %. The outcome measures associated with adherence were financial solvency, diagnosis, treating hospital, number of children under the care of the caregiver, cancer treatments received, and presence of barriers in compliance. Sample subjects did not perceive medications as harmful, but considered they were overused. Most subjects perceived the necessity to take antineoplastic agents to maintain or recover their health, but also expressed their concerns. The perception about medication was similar between parents and adolescents, and was not associated with the level of adherence.Conclusions. In this sample, parent-reported adherence was 75 %. Parents and patients perceived a necessity for medication and expressed their concerns about treatment.


Asunto(s)
Humanos , Masculino , Femenino , Lactante , Preescolar , Niño , Adolescente , Cumplimiento de la Medicación , Cumplimiento y Adherencia al Tratamiento , Antineoplásicos , Leucemia , Encuestas y Cuestionarios , Mantenimiento
4.
Artículo en Chino | MEDLINE | ID: mdl-33535343

RESUMEN

Objective: To analyze the diagnosis of 3 cases of leukemia applying for the diagnosis of occupational radiogenic neoplasms. Methods: Retrospective analysis the occupational history, the disease history and the probability of causation (PC value) information of 3 radiological workers. Results: Two cases' PC value of 95% confidence limit of were >50%, and they were diagnosed as radiogenic neoplasms. One case was <50% and diagnosed as nonoccupational radiogenic neoplasms. Conclusion: The probability of causation analysis has important guiding significance for the diagnosis of occupational radiogenic neoplasms. Radiological workers should improve their awareness of self-protection and reduce the occurrence of occupational diseases.


Asunto(s)
Leucemia , Enfermedades Profesionales , Exposición Profesional , Humanos , Leucemia/diagnóstico , Leucemia/epidemiología , Enfermedades Profesionales/diagnóstico , Enfermedades Profesionales/epidemiología , Probabilidad , Radiografía , Estudios Retrospectivos
5.
Ann Oncol ; 32(4): 478-487, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33626377

RESUMEN

BACKGROUND: We predicted cancer mortality statistics for 2021 for the European Union (EU) and its five most populous countries plus the UK. We also focused on pancreatic cancer and female lung cancer. MATERIALS AND METHODS: We obtained cancer death certifications and population data from the World Health Organization and Eurostat databases for 1970-2015. We predicted numbers of deaths and age-standardised (world population) rates for 2021 for total cancers and 10 major cancer sites, using a joinpoint regression model. We calculated the number of avoided deaths over the period 1989-2021. RESULTS: We predicted 1 267 000 cancer deaths for 2021 in the EU, corresponding to age-standardised rates of 130.4/100 000 men (-6.6% since 2015) and 81.0/100 000 for women (-4.5%). We estimated further falls in male lung cancer rates, but still trending upward in women by +6.5%, reaching 14.5/100 000 in 2021. The breast cancer predicted rate in the EU was 13.3/100 000 (-7.8%). The rates for stomach and leukaemias in both sexes and for bladder in males are predicted to fall by >10%; trends for other cancer sites were also favourable, except for the pancreas, which showed stable patterns in both sexes, with predicted rates of 8.1/100 000 in men and 5.6/100 000 in women. Rates for pancreatic cancer in EU men aged 25-49 and 50-64 years declined, respectively, by 10% and 1.8%, while for those aged 65+ years increased by 1.3%. Rates fell for young women only (-3.4%). Over 1989-2021, about 5 million cancer deaths were avoided in the EU27 compared with peak rates in 1988. CONCLUSION: Overall cancer mortality continues to fall in both sexes. However, specific focus is needed on pancreatic cancer, which shows a sizeable decline for young men only. Tobacco control remains a priority for the prevention of pancreatic and other tobacco-related cancers, which account for one-third of the total EU cancer deaths, especially in women, who showed less favourable trends.


Asunto(s)
Neoplasias de la Mama , Leucemia , Neoplasias Pulmonares , Neoplasias , Anciano , Europa (Continente)/epidemiología , Unión Europea , Femenino , Humanos , Neoplasias Pulmonares/epidemiología , Masculino , Mortalidad , Páncreas
6.
Mol Biol (Mosk) ; 55(1): 139-151, 2021.
Artículo en Ruso | MEDLINE | ID: mdl-33566033

RESUMEN

Dysfunction of genes that control mitosis and are responsible for the correct segregation of sister chromatids in anaphase is often accompanied by aneuploidy, which is frequently detected in leukemia. One of the components of the kinetochore complex, namely, the AF15q14/KNL1/CASC5 protein, is an important factor ensuring the correct binding of the pericentromeric region of chromosomes with the spindle microtubules. As shown recently, in some leukemias, the gene of this protein can be involved in the generation of the chromosomal translocation t(11;15)(q23;q14) or a variant of the chimeric MLL-AF15Q14 oncogene, which serves as a biomarker of poor prognosis. Despite the implication of mRNA of the CASC5 gene in oncogenesis of solid tumors, expression of this gene in hematopoietic neoplasms has not been studied. We analyzed expression levels of the CASC5 gene and the nearest regulatory genes, including WT1, APOBEC3A (A3A), and N-MYC. A pronounced decrease in CASC5 expression in bone marrow cells of primary leukemia patients compared with healthy donors was found. It was also shown that reduced expression of the CASC5 gene correlates with the detection of targeted mutations in patients composed two prognostic subgroups (favorable, unfavorable) with a significance level (p <0.05). It was noted that the change in the expression level of the CASC5 gene in acute myeloid leukemia is associated with overexpression of the genes WT1, A3A, and in some cases N-MYC and SPT16, which is consistent with the resistance to chemotherapy and leukemia progression. However, the question of which regulatory gene initiates leukemogenesis remains open.


Asunto(s)
Leucemia Mieloide Aguda , Leucemia , Proteínas de Ciclo Celular/genética , Citidina Desaminasa , Expresión Génica , Humanos , Leucemia/genética , Proteínas Asociadas a Microtúbulos/genética , Proteína de la Leucemia Mieloide-Linfoide , Proteínas , Translocación Genética
7.
Hastings Cent Rep ; 51(1): 4-5, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33630326

RESUMEN

The Covid-19 pandemic has created a clinical environment in which health care practitioners are experiencing moral distress in numerous and novel ways. In this narrative reflection, a pediatric palliative care physician explores how his hospital's strict visitation policy set the stage for moral distress when, in the early months of the pandemic, it prevented two parents from being together at the bedside of their dying child.


Asunto(s)
/epidemiología , Niño Hospitalizado , Política Organizacional , Padres/psicología , Visitas a Pacientes , /prevención & control , Niño , Humanos , Leucemia/terapia , Masculino
8.
Crit Rev Oncol Hematol ; 158: 103206, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-33388454

RESUMEN

Natural killer (NK) cells were originally considered to belong to the innate immune system to play a protective role against tumor cells and viral infections. In human, they can recognize self and non-self HLA class 1 as their ligand. So, analyzing the outcomes of allogeneic hematopoietic stem cell transplantation is a good opportunity to know the antitumor effects and regulatory effects of NK cells through HLA class 1 matching and mismatching of donor and recipient. In this review, I looked back on the main analysis results of the past transplants, summarized our reports consisting of many cases in a single ethnic, and showed that NK cells might work oppositely depending on the type of leukemia. New treatment strategies based on these concepts may offer individualized treatment options and ultimately increase offer the possibility of a cure for patients with leukemia.


Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Leucemia , Antígenos HLA , Humanos , Células Asesinas Naturales , Leucemia/terapia , Receptores KIR
9.
Anal Chem ; 93(4): 2669-2677, 2021 02 02.
Artículo en Inglés | MEDLINE | ID: mdl-33465307

RESUMEN

Existing data acquisition modes such as full-scan, data-dependent (DDA), and data-independent acquisition (DIA) often present limited capabilities in capturing metabolic information in liquid chromatography-mass spectrometry (LC-MS)-based metabolomics. In this work, we proposed a novel metabolomic data acquisition workflow that combines DDA and DIA analyses to achieve better metabolomic data quality, including enhanced metabolome coverage, tandem mass spectrometry (MS2) coverage, and MS2 quality. This workflow, named data-dependent-assisted data-independent acquisition (DaDIA), performs untargeted metabolomic analysis of individual biological samples using DIA mode and the pooled quality control (QC) samples using DDA mode. This combination takes advantage of the high-feature number and MS2 spectral coverage of the DIA data and the high MS2 spectral quality of the DDA data. To analyze the heterogeneous DDA and DIA data, we further developed a computational program, DaDIA.R, to automatically extract metabolic features and perform streamlined metabolite annotation of DaDIA data set. Using human urine samples, we demonstrated that the DaDIA workflow delivers remarkably improved data quality when compared to conventional DDA or DIA metabolomics. In particular, both the number of detected features and annotated metabolites were greatly increased. Further biological demonstration using a leukemia metabolomics study also proved that the DaDIA workflow can efficiently detect and annotate around 4 times more significant metabolites than DDA workflow with broad MS2 coverage and high MS2 spectral quality for downstream statistical analysis and biological interpretation. Overall, this work represents a critical development of data acquisition mode in untargeted metabolomics, which can greatly benefit untargeted metabolomics for a wide range of biological applications.


Asunto(s)
Exactitud de los Datos , Metabolómica/métodos , Programas Informáticos , Humanos , Leucemia/metabolismo , Metaboloma , Urinálisis , Flujo de Trabajo
10.
Medicine (Baltimore) ; 100(1): e24014, 2021 Jan 08.
Artículo en Inglés | MEDLINE | ID: mdl-33429764

RESUMEN

INTRODUCTION: As a hematopoietic carcinogen, benzene induces human leukemia through its active metabolites such as benzoquinone, which may cause oxidative damage to cancer-related nuclear genes by increasing reactive oxygen species (ROS). Mitochondrion is the main regulatory organelle of ROS, genetic abnormality of mitochondrion can impede its regulation of ROS, leading to more severe oxidative damage. Mutations have been related to certain types of cancer in several mitochondrial genes, but they have never been completely analyzed genome-wide in leukemia. PATIENT CONCERNS: The patient was a 52-year-old female who had chronic exposure to benzene for several years. Her symptoms mainly included recurrent dizziness, fatigue, and they had lasted for nearly 8 years and exacerbated in recent weeks before diagnosis. DIAGNOSIS: Samples of peripheral blood were taken from the patient using evacuated tubes with EDTA anticoagulant on the second day of her hospitalization. At the same time blood routine and BCR/ABL genes of leukemic phenotype were tested. Platelets were isolated for mitochondrial DNA (mtDNA) extraction. The genetic analysis of ATP synthase Fo subunit 8 (complex V), ATP synthase Fo subunit 6 (complex V), cytochrome c oxidase subunit 1 (complex IV), cytochrome c oxidase subunit 2 (complex IV), cytochrome c oxidase subunit 3, Cytb, NADH dehydrogenase subunit 1 (complex I) (ND) 1, ND2, ND3, ND4, ND5, ND6, 12S-RNA, 16S-RNA, tRNA-Cysteine, A, N, tRNA-Leucine, E, displacement loop in platelet mtDNA were performed. All the detected gene mutations were validated using the conventional Sanger sequencing method. INTERVENTIONS: The patient received imatinib, a small molecule kinase inhibitor, and symptomatic treatments. OUTCOMES: After 3 months treatment her blood routine test indicators were restored to normal. CONCLUSION: A total of 98 mutations were found, and 25 mutations were frame shift. The ND6 gene mutation rate was the highest among all mutation points. Frame shifts were identified in benzene-induced leukemia for the first time. Many mutations in the platelet mitochondrial genome were identified and considered to be potentially pathogenic in the female patient with benzene-induced leukemia. The mutation rate of platelet mitochondrial genome in the benzene-induced leukemia patient is relatively high, and the complete genome analysis is helpful to fully comprehend the disease characteristics.


Asunto(s)
Plaquetas/patología , Leucemia/etiología , Leucemia/genética , Mitocondrias/genética , Antineoplásicos/uso terapéutico , Benceno/efectos adversos , Exposición a Riesgos Ambientales/efectos adversos , Femenino , Genoma Mitocondrial/genética , Genoma Mitocondrial/fisiología , Humanos , Mesilato de Imatinib/uso terapéutico , Persona de Mediana Edad , Mitocondrias/fisiología
11.
Ann Hematol ; 100(2): 465-479, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-33386934

RESUMEN

Additional sex combs like 1 (ASXL1) mutations are one of the most common molecular biological abnormalities in patients with primary myelofibrosis (PMF), and the effect of these mutations on prognosis remains controversial. Hence, we conducted a meta-analysis to assess the prognostic value and clinical characteristics of ASXL1 mutations in PMF patients. Eligible studies were systematically searched from PubMed, Embase, and the Cochrane Library. We extracted the hazard ratios (HRs) and their 95% confidence intervals (CIs) of overall survival (OS) and leukemia-free survival (LFS), the number of patients transformed to acute leukemia, and clinical characteristics to carry out a meta-analysis by fixed effect model or random effect model according to the heterogeneity between studies. A total of 4501 PMF patients from 16 cohorts of 14 studies were included in this meta-analysis. The results revealed that ASXL1 mutations might predict a shorter OS (HR = 2.30, 95% CI: 1.79-2.94, P < 0.00001) and a higher probability of transformation to acute leukemia (LFS: HR = 1.77, 95% CI: 1.30-2.42, P = 0.0003; the rate of acute leukemia transformation: OR = 2.06, 95% CI: 1.50-2.83, P < 0.00001). Furthermore, ASXL1 mutations were correlated with patients older than 65 years old, male, a lower level of platelet counts, and a higher risk of the international prognostic score system. These findings indicate that ASXL1 mutations have a significant adverse impact on the prognosis of PMF patients and may contribute to risk stratification and prognostic assessment for PMF patients.


Asunto(s)
Carcinogénesis/genética , Leucemia , Mutación , Proteínas de Neoplasias/genética , Mielofibrosis Primaria , Proteínas Represoras/genética , Enfermedad Aguda , Factores de Edad , Anciano , Supervivencia sin Enfermedad , Femenino , Humanos , Leucemia/genética , Leucemia/mortalidad , Masculino , Mielofibrosis Primaria/genética , Mielofibrosis Primaria/mortalidad , Factores Sexuales , Tasa de Supervivencia
12.
Int J Mol Sci ; 22(3)2021 Jan 24.
Artículo en Inglés | MEDLINE | ID: mdl-33498945

RESUMEN

Thrombosis is a major cause of morbimortality in patients with chronic Philadelphia chromosome-negative myeloproliferative neoplasms (MPN). In the last decade, multiple lines of evidence support the role of leukocytes in thrombosis of MPN patients. Besides the increase in the number of cells, neutrophils and monocytes of MPN patients show a pro-coagulant activated phenotype. Once activated, neutrophils release structures composed of DNA, histones, and granular proteins, called extracellular neutrophil traps (NETs), which in addition to killing pathogens, provide an ideal matrix for platelet activation and coagulation mechanisms. Herein, we review the published literature related to the involvement of NETs in the pathogenesis of thrombosis in the setting of MPN; the effect that cytoreductive therapies and JAK inhibitors can have on markers of NETosis, and, finally, the novel therapeutic strategies targeting NETs to reduce the thrombotic complications in these patients.


Asunto(s)
Leucemia/complicaciones , Trastornos Mieloproliferativos/complicaciones , Neutrófilos , Trombosis/etiología , Animales , Humanos , Leucemia/inmunología , Trastornos Mieloproliferativos/inmunología , Trombosis/inmunología
13.
Nat Commun ; 12(1): 223, 2021 01 11.
Artículo en Inglés | MEDLINE | ID: mdl-33431820

RESUMEN

Enhancers are DNA sequences that enable complex temporal and tissue-specific regulation of genes in higher eukaryotes. Although it is not entirely clear how enhancer-promoter interactions can increase gene expression, this proximity has been observed in multiple systems at multiple loci and is thought to be essential for the maintenance of gene expression. Bromodomain and Extra-Terminal domain (BET) and Mediator proteins have been shown capable of forming phase condensates and are thought to be essential for super-enhancer function. Here, we show that targeting of cells with inhibitors of BET proteins or pharmacological degradation of BET protein Bromodomain-containing protein 4 (BRD4) has a strong impact on transcription but very little impact on enhancer-promoter interactions. Dissolving phase condensates reduces BRD4 and Mediator binding at enhancers and can also strongly affect gene transcription, without disrupting enhancer-promoter interactions. These results suggest that activation of transcription and maintenance of enhancer-promoter interactions are separable events. Our findings further indicate that enhancer-promoter interactions are not dependent on high levels of BRD4 and Mediator, and are likely maintained by a complex set of factors including additional activator complexes and, at some sites, CTCF and cohesin.


Asunto(s)
Elementos de Facilitación Genéticos , Regiones Promotoras Genéticas , Transcripción Genética , Factor de Unión a CCCTC/metabolismo , Carcinogénesis/efectos de los fármacos , Carcinogénesis/genética , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Cromatina/metabolismo , Proteínas Cromosómicas no Histona/metabolismo , Proteínas de Unión al ADN/metabolismo , Glicoles/farmacología , Histonas/metabolismo , Humanos , Leucemia/genética , Leucemia/patología , Modelos Genéticos , Unión Proteica/efectos de los fármacos , Proteínas Proto-Oncogénicas c-myc/genética , Transcripción Genética/efectos de los fármacos
14.
Virol J ; 18(1): 1, 2021 01 04.
Artículo en Inglés | MEDLINE | ID: mdl-33397387

RESUMEN

BACKGROUND: Virus neutralization by antibodies is an important prognostic factor in many viral diseases. To easily and rapidly measure titers of neutralizing antibodies in serum or plasma, we developed pseudovirion particles composed of the spike glycoprotein of SARS-CoV-2 incorporated onto murine leukemia virus capsids and a modified minimal murine leukemia virus genome encoding firefly luciferase. This assay design is intended for use in laboratories with biocontainment level 2 and therefore circumvents the need for the biocontainment level 3 that would be required for replication-competent SARS-CoV-2 virus. To validate the pseudovirion assay, we set up comparisons with other available antibody tests including those from Abbott, Euroimmun and Siemens, using archived, known samples. RESULTS: 11 out of 12 SARS-CoV-2-infected patient serum samples showed neutralizing activity against SARS-CoV-2-spike pseudotyped MLV viruses, with neutralizing titers-50 (NT50) that ranged from 1:25 to 1:1,417. Five historical samples from patients hospitalized for severe influenza infection in 2016 tested negative in the neutralization assay (NT50 < 25). Three serum samples with high neutralizing activity against SARS-CoV-2/MLV pseudoviruses showed no detectable neutralizing activity (NT50 < 25) against SARS-CoV-1/MLV pseudovirions. We also compared the semiquantitative Siemens SARS-CoV-2 IgG test, which measures binding of IgG to recombinantly expressed receptor binding domain of SARS-CoV-2 spike glycoprotein with the neutralization titers obtained in the pseudovirion assay and the results show high concordance between the two tests (R2 = 0.9344). CONCLUSIONS: SARS-CoV-2 spike/MLV pseudovirions provide a practical means of assessing neutralizing activity of antibodies in serum or plasma from infected patients under laboratory conditions consistent with biocontainment level 2. This assay offers promise also in evaluating immunogenicity of spike glycoprotein-based candidate vaccines in the near future.


Asunto(s)
/inmunología , Leucemia/inmunología , Pruebas de Neutralización/métodos , Glicoproteína de la Espiga del Coronavirus/inmunología , Virión/inmunología , /inmunología , Animales , Anticuerpos Neutralizantes/sangre , Anticuerpos Antivirales/sangre , Células HEK293 , Humanos , Inmunoglobulina G/sangre , Ratones
15.
Nat Struct Mol Biol ; 28(2): 190-201, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33479542

RESUMEN

NUP98 fusion proteins cause leukemia via unknown molecular mechanisms. All NUP98 fusion proteins share an intrinsically disordered region (IDR) in the NUP98 N terminus, featuring repeats of phenylalanine-glycine (FG), and C-terminal fusion partners often function in gene control. We investigated whether mechanisms of oncogenic transformation by NUP98 fusion proteins are hardwired in their protein interactomes. Affinity purification coupled to mass spectrometry (MS) and confocal imaging of five NUP98 fusion proteins expressed in human leukemia cells revealed that shared interactors were enriched for proteins involved in biomolecular condensation and that they colocalized with NUP98 fusion proteins in nuclear puncta. We developed biotinylated isoxazole-mediated condensome MS (biCon-MS) to show that NUP98 fusion proteins alter the global composition of biomolecular condensates. An artificial FG-repeat-containing fusion protein phenocopied the nuclear localization patterns of NUP98 fusion proteins and their capability to drive oncogenic gene expression programs. Thus, we propose that IDR-containing fusion proteins combine biomolecular condensation with transcriptional control to induce cancer.


Asunto(s)
Núcleo Celular/metabolismo , Proteínas de Homeodominio , Leucemia , Proteínas de Complejo Poro Nuclear , Proteínas de Fusión Oncogénica , Animales , Expresión Génica , Regulación Leucémica de la Expresión Génica , Células HEK293 , Células HL-60 , Proteínas de Homeodominio/química , Proteínas de Homeodominio/fisiología , Humanos , Leucemia/metabolismo , Leucemia/patología , Ratones , Células 3T3 NIH , Proteínas de Complejo Poro Nuclear/química , Proteínas de Complejo Poro Nuclear/fisiología , Proteínas de Fusión Oncogénica/química , Proteínas de Fusión Oncogénica/fisiología
16.
Phytomedicine ; 81: 153409, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33341310

RESUMEN

BACKGROUND: Sesquiterpene lactones having α-methylene-γ-lactone moiety are promising natural metabolites showing various biological activity. One of the major metabolites isolated from Pulicaria undulata, 2α-hydroxyalantolactone (PU-1), has not been investigated in detail yet. Multidrug resistance (MDR) represents a major obstacle for cancer chemotherapy and the capability of novel natural products to overcoming MDR is of great interest. PURPOSE: Exploring the molecular modes of action for potent natural product metabolites. METHODS: The resazurin reduction assay was employed to evaluate the cytotoxicity of PU-1 on sensitive and their corresponding drug-resistant cell lines (overexpressing P-glycoprotein, BCRP, ABCB5, ΔEGFR, or TP53 knockout). Gene expression profiling was performed by transcriptome-wide mRNA microarray in the human CCRF-CEM leukemic cells after treatment with PU-1. The top significantly up- or down-regulated genes were identified by Chipster program and analyzed using Ingenuity Pathway Analysis (IPA) software. Finally, flow cytometry and Western blotting were performed for cell cycle analyses and apoptosis detection. RESULTS: The sesquiterpene lactone, PU-1, showed potent cytotoxicity towards the drug-sensitive and -resistant cell lines. Transcriptome-wide mRNA expression profiling and pathway analysis pointed to genes involved in DNA damage response and G2/M cell cycle arrest. G2/M arrest was verified by flow cytometry and further confirmed by the upregulation of p21 and downregulation of p-CDC25C expression in Western blotting. Moreover, the suggested DNA damage checkpoint regulation was confirmed by immunofluorescence and Western blotting by upregulation of pS345 Chk1, p-H3 and γ-H2AX. Furthermore, PU-1 inhibited PI3K/AKT pathway, which is involved in signaling DNA damage and G2/M arrest. Cells ultimately induced apoptosis upon PU-1 treatment. CONCLUSIONS: PU-1 is a potent natural product inhibiting otherwise drug-resistant human tumor cell growth through DNA damage, G2/M cell cycle arrest and apoptosis.


Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Leucemia/tratamiento farmacológico , Pulicaria/química , Sesquiterpenos/farmacología , Antineoplásicos Fitogénicos/química , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Daño del ADN/efectos de los fármacos , Resistencia a Antineoplásicos/fisiología , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Leucemia/patología , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3/farmacología , Sesquiterpenos/química
18.
J Ethnopharmacol ; 266: 113458, 2021 Feb 10.
Artículo en Inglés | MEDLINE | ID: mdl-33039632

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Fumaria officinalis (Fumariaceae) is recorded in the Kurdish ethnobotany for various health problems. AIM OF THE STUDY: In this study, the cytotoxic activity of F. officinalis extracts on two leukemia and nine multiple myeloma (MM) cell lines was investigated. MATERIALS AND METHODS: The cytotoxic and ferroptotic activity were examined by resazurin reduction assay. Flow cytometry, immunoblotting assay and fluorescence microscopy were used to measure cell cycle distribution, apoptosis, induction of reactive oxygen species (ROS), loss integrity of mitochondrial membrane potential (MMP) and autophagy. LC-ESI/MS was used to identify chemical constituents present in F. officinalis. RESULTS: Chloroform (CF) and ethyl acetate (EF) fractions showed drastic cytotoxic effect on CCRF-CEM and CEM/ADR 5000 cells. NCI-H929 cell line exhibited higher sensitivity against CF, while EF demonstrated its higher cytotoxicity on OPM-2 cells with IC50 value 14.80 ± 1.70 and 28.13 ± 1.38 µg/mL respectively. Flow cytometric and morphological studies confirmed that CF and EF induced apoptosis in NCI-H929 cells by loss of MMP, generation of ROS and obvious morphological variations. In DNA histograms, up to 50% of the cells were accumulated by CF and 44% by EF in the sub-G0/G1 phase following 72 h treatment. EF induced autophagic cell death, while CF stimulated iron-dependent cell death. Moreover, two isoquinoline alkaloids and four flavonoids were identified in the active fractions. CONCLUSION: To our knowledge, this is the first report demonstrating the cytotoxicity of F. officinalis extracts in MM cell lines. CF and EF fractions inhibited MM cell proliferation through various modes of actions.


Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Fumaria/química , Leucemia/tratamiento farmacológico , Mieloma Múltiple/tratamiento farmacológico , Extractos Vegetales/farmacología , Antineoplásicos Fitogénicos/administración & dosificación , Antineoplásicos Fitogénicos/aislamiento & purificación , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Línea Celular Tumoral , Humanos , Concentración 50 Inhibidora , Leucemia/patología , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Mieloma Múltiple/patología , Extractos Vegetales/administración & dosificación , Especies Reactivas de Oxígeno/metabolismo
19.
J Formos Med Assoc ; 120(1 Pt 1): 226-233, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-32439247

RESUMEN

BACKGROUND/PURPOSE: Leukemia cutis (LC), by definition, is the infiltration of neoplastic leukocytes in the skin. The overall incidence of LC is rare. We aimed to investigate the association between clinical characteristics, classifications and prognosis among different types of LC in Taiwan. METHODS: We performed a retrospective analysis of forty-two patients with histopathology proven LC based on skin biopsies in a medical center in Southern Taiwan from 1997 to 2018. The study involved medical records of the patients, clinical manifestations, and outcomes according to different types of leukemia. RESULTS: This series consisted of 27 males and 15 females, and the mean age was 55.7 years old. The most common cutaneous features were papules (38%) and nodules (29%), followed by plaques (16%) and ulcers (10%). The most commonly affected sites were the trunk (33%) and extremities (31.5%), although generalized distribution (14%) was not rare. The prognosis of LC was very poor, 76.2% of patients (32/42) died during the follow-up, and the median survival time was 7.2 months (95% CI, 4.53-9.87 months). No statistical significance was found (P = 0.068 for survival curves) among different types of LC. CONCLUSION: This study was the first large-scale research in regarding to LC of Han Chinese. The commonest clinical presentations were papules and nodules, and the predilection sites were trunk and extremities. Besides, there was the high frequency of LC from AML and MDS in Taiwan. Clinicians should pay more attention to the leukemia patients with extramedullary manifestations due to poor survival outcomes.


Asunto(s)
Leucemia , Neoplasias Cutáneas , Femenino , Humanos , Leucemia/epidemiología , Infiltración Leucémica , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Piel , Taiwán/epidemiología
20.
Crit Rev Oncol Hematol ; 157: 103170, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33316638

RESUMEN

Resistance of extramedullary leukemia growth post-transplant prevents cure. Review of its behavior detailed in 585 published cases should lead to better treatment. Leukemic tumors were found up to 13 years after transplant, most in sites inaccessible to physical exam. In 83%, marrow was not in morphologic relapse; next relapse was most often extramedullary. Induction protocols alone produced few durable responses in acute leukemias and fatal marrow aplasia in 17 %. Overall, 120 patients survived over 2 years, 43 relapse-free up to 18 years, the majority after combined tumor-directed and systemic therapy. Overall median survival was 9 months. This review highlights how results can improve: by defining extent of leukemia involvement with scans before transplant, and emergently when leukemic tumor is found after, ablating tumor directly to abort metastasis, and determining dosing of systemic chemotherapy that protects, without ablating, donor marrow. Monitoring total body remission with body scans should increase transplant cures.


Asunto(s)
Leucemia , Biología , Médula Ósea , Trasplante de Médula Ósea , Humanos , Leucemia/terapia , Recurrencia
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA
...