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2.
Prague Med Rep ; 123(3): 199-205, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36107449

RESUMO

Angiomyolipomas (AMLs) are mesenchymal tumours derived from perivascular epithelioid cells. Although AMLs are generally known as benign and extremely rare epithelioid variants of AML, they may be potentially aggressive. Here we present an adrenal epithelioid AML and the literature review. A 64-year-old female patient was diagnosed with a left adrenal mass detected incidentally on ultrasonography. Preoperative abdominal CT (computed tomography) showed a 95×68 mm heterogeneous contrast enhancement mass lesion in the left adrenal gland. The lesion was hormone inactive in the endocrinological evaluation, and left laparoscopic adrenalectomy was performed. The patient was discharged on the 2nd postoperative day. Pathology was reported as epithelioid subtype AML. The patient has no local recurrence or metastasis in the 18-month follow-up period and imaging. Adrenal epithelioid AML is an extremely rare and potentially aggressive variant. According to the literature, open or laparoscopic adrenalectomy seems to be suitable option for disease management.


Assuntos
Angiomiolipoma , Leucemia Mieloide Aguda , Glândulas Suprarrenais/patologia , Adrenalectomia , Angiomiolipoma/diagnóstico , Angiomiolipoma/patologia , Angiomiolipoma/cirurgia , Feminino , Hormônios , Humanos , Leucemia Mieloide Aguda/cirurgia , Pessoa de Meia-Idade
4.
Clin J Oncol Nurs ; 26(5): 569-573, 2022 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-36108218

RESUMO

Although many studies highlight the benefits of incorporating telehealth into oncology care, few have investigated how it could reduce geographic barriers to care for patients with acute myeloid leukemia living in rural commu.


Assuntos
Leucemia Mieloide Aguda , Telemedicina , Humanos , Leucemia Mieloide Aguda/terapia , North Carolina , População Rural
5.
Blood Cancer J ; 12(9): 131, 2022 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-36068213

RESUMO

The benefit of three-drug induction chemotherapy over a two-drug induction has not been evaluated in pediatric acute myeloid leukemia (AML). We, therefore, conducted a randomized controlled trial to ascertain the benefit of a three-drug induction regimen. Patients aged 1-18 years with newly diagnosed AML were randomized to two cycles of induction chemotherapy with daunorubicin and ara-C (DA) or two cycles of ara-C, daunorubicin, and etoposide (ADE). After induction, patients in both arms received consolidation with two cycles of high-dose ara-C. The study's primary objective was to compare the event-free survival (EFS) between the two arms. The secondary objectives included comparing the composite complete remission (cCR) rates, overall survival (OS), and toxicities. The study randomized 149 patients, 77 in the DA and 72 in the ADE arm. The median age was 8.7 years, and 92 (62%) patients were males. The median follow-up was 50.9 months. The cCR rate in the DA and ADE arm were 82% and 79% (p = 0.68) after the second induction. There were 13 (17%) induction deaths in the DA arm and 12 (17%) in the ADE arm (p = 0.97). The 5-year EFS in the DA and ADE arm was 34.4% and 34.5%, respectively (p = 0.66). The 5-year OS in the DA and ADE arms was 41.4% and 42.09%, respectively (p = 0.74). There were no significant differences in toxicities between the regimens. There was no statistically significant difference in EFS, OS, CR, or toxicity between ADE and DA regimens in pediatric AML. The trial was registered with the Clinical Trial Registry of India (Reference number: CTRI/2014/11/005202).


Assuntos
Quimioterapia de Indução , Leucemia Mieloide Aguda , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Criança , Citarabina/uso terapêutico , Daunorrubicina/efeitos adversos , Feminino , Humanos , Masculino , Indução de Remissão
6.
Clin Epigenetics ; 14(1): 113, 2022 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-36089606

RESUMO

Azacytidine (AzaC) and decitabine (AzadC) are cytosine analogs that covalently trap DNA methyltransferases, which place the important epigenetic mark 5-methyl-2'-deoxycytidine by methylating 2'-deoxycytidine (dC) at the C5 position. AzaC and AzadC are used in the clinic as antimetabolites to treat myelodysplastic syndrome and acute myeloid leukemia and are explored against other types of cancer. Although their principal mechanism of action is known, the downstream effects of AzaC and AzadC treatment are not well understood and the cellular prerequisites that determine sensitivity toward AzaC and AzadC remain elusive. Here, we investigated the effects and phenotype of AzaC and AzadC exposure on the acute myeloid leukemia cell line MOLM-13. We found that while AzaC and AzadC share many effects on the cellular level, including decreased global DNA methylation, increased formation of DNA double-strand breaks, transcriptional downregulation of important oncogenes and similar changes on the proteome level, AzaC failed in contrast to AzadC to induce apoptosis efficiently in MOLM-13. The only cellular marker that correlated with this clear phenotypical outcome was the level of hydroxy-methyl-dC, an additional epigenetic mark that is placed by TET enzymes and repressed in cancer cells. Whereas AzadC increased hmdC substantially in MOLM-13, AzaC treatment did not result in any increase at all. This suggests that hmdC levels in cancer cells should be monitored as a response toward AzaC and AzadC and considered as a biomarker to judge whether AzaC or AzadC treatment leads to cell death in leukemic cells.


Assuntos
Azacitidina , Leucemia Mieloide Aguda , Azacitidina/farmacologia , Linhagem Celular , DNA , Metilação de DNA , Decitabina/farmacologia , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico
7.
Hematology ; 27(1): 1003-1009, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36117408

RESUMO

BACKGROUND: Besides the traditional roles of HBA1 and HBB, recent findings suggest that hemoglobin genes may have roles in other contexts. OBJECTIVE: In the present study, we aim to investigate a possible tumor-suppressor role of HBA1 and HBB in acute myeloid leukemia. METHODS: Quantitative real-time PCR (RT-qPCR) was performed to detect the expression levels of HBA1 and HBB in acute myeloid leukemia patients and AML cell lines. The transfected cells were analyzed for Cell Counting Kit-8 (CCK-8), apoptosis, and cell cycle assay. RESULTS: HBA1 and HBB genes were significantly decreased in acute myeloid leukemia patients and AML cell lines. Furthermore, in vitro approaches showed that overexpression of HBA1 and HBB inhibited proliferation, induced cell apoptosis, and blocked cell cycle process at the G2/M phase in K562 cells. CONCLUSION: Our data indicated that HBA1 and HBB genes may be potential tumor-suppressor genes in acute myeloid leukemia.


Assuntos
Leucemia Mieloide Aguda , Sincalida , Proliferação de Células/genética , Hemoglobina A Glicada , Humanos , Células K562 , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo
8.
Cancer Cell ; 40(9): 917-919, 2022 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-36055227

RESUMO

In a recent Nature Medicine study, Zeng and colleagues integrate both genomic and stem cell models of acute myeloid leukemia (AML) by deconvoluting cellular hierarchies of more than 1,000 AML samples. This work introduces a framework capable of predicting drug responses to targeted therapies in future clinical trials.


Assuntos
Leucemia Mieloide Aguda , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Células-Tronco Neoplásicas
9.
BMC Oral Health ; 22(1): 386, 2022 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-36064398

RESUMO

BACKGROUND: Langerhans cell histiocytosis (LCH) is a heterogeneous neoplastic disorder that is rarely seen in patients aged 60 years and older. It is reported that elderly patients with LCH have a higher chance of having malignancies. In the oral cavity, patients with LCH can present with mucosal ulcers and extensive osteolysis, making it difficult for clinicians to make a proper diagnosis. CASE PRESENTATION: We reported an 82-year-old Chinese woman with oral symptoms as the first presentation of LCH, and eventually developed acute myeloid leukemia (AML). She suffered diffuse ulcers involving the entire gingival mucosa and the left half hard palate, and had lost several teeth. Genomic DNA sequencing of the cells from LCH revealed multiple mutations in TET2, BRAF, SRSF2, NRAS, MAP2K4 and so on. The patient declined the BRAFV600E inhibitor (Vemurafenib). Although a dramatic improvement of the oral ulcers was achieved after symptomatic treatment, the patient developed acute myeloid leukemia (AML) and died. CONCLUSIONS: This report presented the diagnostic difficulties of LCH with oral manifestations and highlighted the importance of radiological assessments and laboratory tests. Moreover, many of the mutations detected in our LCH patient are frequently seen in AML, suggesting that AML and LCH cells in this patient share the same origin.


Assuntos
Histiocitose de Células de Langerhans , Leucemia Mieloide Aguda , Idoso , Idoso de 80 Anos ou mais , Feminino , Histiocitose de Células de Langerhans/complicações , Histiocitose de Células de Langerhans/diagnóstico , Histiocitose de Células de Langerhans/genética , Humanos , Leucemia Mieloide Aguda/complicações , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Pessoa de Meia-Idade , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Úlcera
10.
Hematology ; 27(1): 1046-1055, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36094501

RESUMO

BACKGROUND: Acute myeloid leukemia (AML) is one of the most common malignant myeloid diseases in adults with a dismal prognosis. We aimed to explore the effects of circNFIX on the proliferation and apoptosis of AML cells. METHODS: The expressions of circNFIX, miR-876-3p and tripartite motif (TRIM) 31 in the bone marrow specimens of AML patients and AML cell lines were detected by qRT-PCR or western blot. Cell proliferation was evaluated by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and 5-ethynyl-29-deoxyuridine (EdU) assays. Cell cycle and apoptosis were analyzed by flow cytometry. Western blot was used to detect protein expression. The relationship between miR-876-3p and circNFIX or TRIM31 was identified by dual-luciferase reporter assay or RNA pull-down assay. RESULTS: The expression level of circNFIX was significantly increased in the bone marrow samples of AML patients and AML cells when compared with normal controls. CircNFIX silencing inhibited AML cell proliferation and promoted apoptosis. Inhibition of miR-876-3p reversed the effect of circNFIX knockdown on AML cell progression. In addition, circNFIX indirectly regulated TRIM31 through miR-876-3p. Further, TRIM31 overexpression counteracted the effect of circNFIX silencing on AML cell proliferation and apoptosis. CONCLUSION: CircNFIX knockdown could suppress the proliferation and induce the apoptosis of AML cells by targeting the miR-876-3p/TRIM31 axis.


Assuntos
Leucemia Mieloide Aguda , MicroRNAs , Adulto , Apoptose/genética , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Humanos , Leucemia Mieloide Aguda/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Proteínas com Motivo Tripartido/genética , Ubiquitina-Proteína Ligases
11.
JCI Insight ; 7(17)2022 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-36073548

RESUMO

Heterozygous mutations in FLT3ITD, TET2, and DNMT3A are associated with hematologic malignancies in humans. In patients, cooccurrence of mutations in FLT3ITD combined with TET2 (TF) or FLT3ITD combined with DNMT3A (DF) are frequent. However, in some rare complex acute myeloid leukemia (AML), all 3 mutations cooccur - i.e., FLT3ITD, TET2, and DNMT3A (TFD). Whether the presence of these mutations in combination result in quantitative or qualitative differences in disease manifestation has not been investigated. We generated mice expressing heterozygous Flt3ITD and concomitant for either heterozygous loss of Tet2 (TF) or Dnmt3a (DF) or both (TFD). TF and DF mice did not induce disease early on, in spite of similar changes in gene expression; during the same time frame, an aggressive form of transplantable leukemia was observed in TFD mice, which was mostly associated with quantitative but not qualitative differences in gene expression relative to TF or DF mice. The gene expression signature of TFD mice showed remarkable similarity to the human TFD gene signature at the single-cell RNA level. Importantly, TFD-driven AML responded to a combination of drugs that target Flt3ITD, inflammation, and methylation in a mouse model, as well as in a PDX model of AML bearing 3 mutations.


Assuntos
DNA Metiltransferase 3A , Proteínas de Ligação a DNA , Dioxigenases , Leucemia Mieloide Aguda , Tirosina Quinase 3 Semelhante a fms , Animais , DNA Metiltransferase 3A/genética , Proteínas de Ligação a DNA/genética , Dioxigenases/genética , Humanos , Leucemia Mieloide Aguda/genética , Camundongos , Proteínas Proto-Oncogênicas/genética , Tirosina Quinase 3 Semelhante a fms/genética
12.
Front Immunol ; 13: 980911, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36081495

RESUMO

Acute myelocytic leukemia (AML) is a malignancy of the stem cell precursors of the myeloid lineage. CD4+ and CD8+ T cells play pivotal roles in influencing AML progression but are functionally suppressed in the bone marrow microenvironment. We aimed to find hub genes related to T cell exhaustion and suppression, thereby providing evidence for immunotherapy. In this study, gene transcriptome expression data from TCGA and TARGET databases were utilized to find key genes. Firstly, CIBERSORT immune cell infiltration algorithm and WGCNA method were used to identify CD4+ and CD8+ T cells-related genes. Univariate and multivariate cox regression analyses were then introduced to construct the overall survival prognosis model and included hub genes. The ESTIMATE and ssGSEA scoring methods were used to analyze the correlation between the hub genes and immune activity. Single-cell transcriptome analysis was applied to detect the immune cells expressing hub genes, hence, to detect exact mechanisms. Consequently, FLT3LG and IFITM3P6 were determined to be positively correlated with patients' overall survival and microenvironment immune activity. Further study suggested FLT3-FLT3LG and IFITM3P6-miR-6748-3p-CBX7 signaling axes were involved in CD4+ and CD8+ T cells activation. This may be one of the mechanisms of T cells suppression in AML.


Assuntos
Medula Óssea , Leucemia Mieloide Aguda , Medula Óssea/metabolismo , Células da Medula Óssea/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Fatores de Crescimento de Células Hematopoéticas , Humanos , Leucemia Mieloide Aguda/patologia , Complexo Repressor Polycomb 1/metabolismo , Prognóstico , Microambiente Tumoral
13.
Hematology ; 27(1): 1088-1100, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36102723

RESUMO

Acute myeloid leukemia (AML) is a malignant clonal disease characterized by abnormal proliferation of immature myeloid cells and bone marrow failure. Regulatory T cells (Treg) play a suppressive role in the anti-tumor immune response in the tumor microenvironment. Screening biomarkers based on Treg immune-related genes may help to predict the prognosis and the efficacy of immunotherapy of AML.Gene expression profiles of AML (non-M3) were obtained from the TCGA and GEO databases. Gene module related to Treg was extracted using CIBERSORT and WGCNA algorithms. Univariate Cox regression and LASSO analyses were performed to identify hub genes and constructed the immune prognostic model. Molecular and immunological features associated with risk signature were explored, and TIDE was used to predict the efficacy of immunotherapy.A risk signature was constructed based on the five IRGs (IFI27L1, YIPF6, PARVB, TRIM32 and RHOBTB3). The risk signature could be served as an independent prognostic factor of AML. Patients in the high-risk group had a poorer OS than those in the low-risk group. In addition, patients in the high-risk group had higher TP53 mutation rate, higher infiltration of Treg, higher immune escape potential and less benefit from ICI therapy compared to low-risk group.Our study constructed a prognostic index based on five Treg-related biomarkers, which help to facilitate the differentiation of immunological and molecular characteristics of AML, predict patient prognosis and provide a reference for predicting benefits from ICI therapy.


Assuntos
Leucemia Mieloide Aguda , Linfócitos T Reguladores , Biomarcadores , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Prognóstico , Linfócitos T Reguladores/patologia , Microambiente Tumoral
14.
Saudi Med J ; 43(9): 1068, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36104048
15.
PLoS Comput Biol ; 18(9): e1010439, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36099249

RESUMO

The over-expression of the Bcl-2 protein is a common feature of many solid cancers and hematological malignancies, and it is typically associated with poor prognosis and resistance to chemotherapy. Bcl-2-specific inhibitors, such as venetoclax, have recently been approved for the treatment of chronic lymphocytic leukemia and small lymphocytic lymphoma, and they are showing promise in clinical trials as a targeted therapy for patients with relapsed or refractory acute myeloid leukemia (AML). However, successful treatment of AML with Bcl-2-specific inhibitors is often followed by the rapid development of drug resistance. An emerging paradigm for overcoming drug resistance in cancer treatment is through the targeting of mitochondrial energetics and metabolism. In AML in particular, it was recently observed that inhibition of mitochondrial translation via administration of the antibiotic tedizolid significantly affects mitochondrial bioenergetics, activating the integrated stress response (ISR) and subsequently sensitizing drug-resistant AML cells to venetoclax. Here we develop an integrative systems biology approach to acquire a deeper understanding of the molecular mechanisms behind this process, and in particular, of the specific role of the ISR in the commitment of cells to apoptosis. Our multi-scale mathematical model couples the ISR to the intrinsic apoptosis pathway in venetoclax-resistant AML cells, includes the metabolic effects of treatment, and integrates RNA, protein level, and cellular viability data. Using the mathematical model, we identify the dominant mechanisms by which ISR activation helps to overcome venetoclax resistance, and we study the temporal sequencing of combination treatment to determine the most efficient and robust combination treatment protocol.


Assuntos
Antineoplásicos , Leucemia Linfocítica Crônica de Células B , Leucemia Mieloide Aguda , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Sulfonamidas , Biologia de Sistemas
16.
Hematology ; 27(1): 994-1002, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36066283

RESUMO

INTRODUCTION: Several studies have confirmed that mutations in the Wilms tumor 1 (WT1) gene occur in adult acute myeloid leukemia (AML). However, few data are available regarding the incidence of WT1 mutations in CEBPAmut AML and their impact. METHODS: We retrospectively analyzed the frequency and clinical impact of WT1 mutations in 220 newly diagnosed AML patients with CEBPA mutations(CEBPAmut). Chromosome karyotype analysis was performed by R or G banding method and further confirmed either by fluorescence in situ hybridization (FISH) and/or by multiple reverse transcription polymerase chain reaction (multiple RT-PCR). Mutations were detected with a panel of 112mutational genes using next-generation sequencing (NGS). RESULTS: Overall, 30 WT1 mutations were detected in 29 of the 220 CEBPAmut AML patients (13.18%) screened. These mutations clustered overwhelmingly in exon 7 (n=16). WT1 mutations were found to be significantly more frequent in AML patients with double-mutated CEBPA (CEBPAdm) than in AML patients with single-mutated CEBPA (17.36%vs. 8.08%, P = 0.043). Among WT1-mutated patients, the most common co-mutation was FLT3-ITD (n = 7, 24.14%), followed by NRAS (n = 5, 17.24%), CSF3R (n = 4, 13.79%), GATA2 (n = 4, 13.79%), and KIT (n = 4, 13.79%). The most frequent functional pathway was signaling pathways inas many as 62.07% of cases. Notably,the concomitant mutations in epigenetic regulatorswere inversely correlated with WT1 mutations(P = 0.003). CEBPAdm AML patients with WT1 mutations had inferior relapse-free survival, event-free survival and overall survival compared with patients CEBPAdm AML without WT1 mutations (P = 0.002, 0.004, and 0.010, respectively). CONCLUSION: Our data showed that WT1 mutations are frequently identified in CEBPAmut AML, especially in CEBPAdm AML. CEBPAmut AML patients with WT1 mutations show distinct spectrum of comutations. In the context of CEBPAdm AML, WT1 mutations predict a poor prognosis.


Assuntos
Leucemia Mieloide Aguda , Proteínas Estimuladoras de Ligação a CCAAT/genética , Humanos , Hibridização in Situ Fluorescente , Leucemia Mieloide Aguda/patologia , Mutação , Prognóstico , Estudos Retrospectivos , Proteínas WT1/genética
17.
Int J Mol Sci ; 23(17)2022 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-36076988

RESUMO

Toll-like receptors (TLRs), NOD-like receptors (NLRs), and RIG-I-like receptors (RLRs) are major elements of the innate immune system that recognize pathogen-associated molecular patterns. Single-nucleotide polymorphisms (SNPs) in the TLR, NLR, and RLR genes may lead to an imbalance in the production of pro- and anti-inflammatory cytokines, changes in susceptibility to infections, the development of diseases, and carcinogenesis. Acute myeloid leukemia (AML) is a bone marrow malignancy characterized by uncontrolled proliferation of transformed myeloid precursors. We retrospectively analyzed 90 AML patients. We investigated the effect of fifteen SNPs located in the genes coding for RLR1 (rs9695310, rs10738889, rs10813831), NOD1 (rs2075820, rs6958571), NOD2 (rs2066845, rs2066847, rs2066844), TLR3 (rs5743305, rs3775296, 3775291), TLR4 (rs4986791, rs4986790), and TLR9 (rs187084, rs5743836). We observed that TLR4 rs4986791, TLR9 rs5743836, and NOD2 rs2066847 were associated with CRP levels, while RLR-1 rs10738889 was associated with LDH level. Furthermore, we found TLR3 rs5743305 AA to be more common in patients with infections. We also found TLR9 rs187084 C to be associated with more favorable risk, and RLR-1 rs9695310 GG with higher age at diagnosis. In conclusion, the current study showed that SNPs in the genes encoding TLRs, NLRs, and RLRs may be potential biomarkers in patients with AML.


Assuntos
Leucemia Mieloide Aguda , Proteínas NLR , Humanos , Leucemia Mieloide Aguda/genética , Proteínas NLR/genética , Polimorfismo de Nucleotídeo Único , Estudos Retrospectivos , Receptor 3 Toll-Like/genética , Receptor 4 Toll-Like/genética , Receptor Toll-Like 9/genética , Receptores Toll-Like/genética
18.
Int J Mol Sci ; 23(17)2022 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-36077202

RESUMO

Non-viral delivery of therapeutic nucleic acids (NA), including siRNA, has potential in the treatment of diseases with high unmet clinical needs such as acute myeloid leukaemia (AML). While cationic biomaterials are frequently used to complex the nucleic acids into nanoparticles, attenuation of charge density is desirable to decrease in vivo toxicity. Here, an anionic amphiphilic CD was synthesised and the structure was confirmed by Fourier-transform infrared spectroscopy (FT-IR), Nuclear Magnetic Resonance (NMR), and high-resolution mass spectrometry (HRMS). A cationic amphiphilic cyclodextrin (CD) was initially used to complex the siRNA and then co-formulated with the anionic amphiphilic CD. Characterisation of the co-formulated NPs indicated a significant reduction in charge from 34 ± 7 mV to 24 ± 6 mV (p < 0.05) and polydispersity index 0.46 ± 0.1 to 0.16 ± 0.04 (p < 0.05), compared to the cationic CD NPs. Size was similar, 161-164 nm, for both formulations. FACS and confocal microscopy, using AML cells (HL-60), indicated a similar level of cellular uptake (60% after 6 h) followed by endosomal escape. The nano co-formulation significantly reduced the charge while maintaining gene silencing (21%). Results indicate that blending of anionic and cationic amphiphilic CDs can produce bespoke NPs with optimised physicochemical properties and potential for enhanced in vivo performance in cancer treatment.


Assuntos
Ciclodextrinas , Leucemia Mieloide Aguda , Nanopartículas , Ânions , Cátions , Ciclodextrinas/química , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Nanopartículas/química , RNA Interferente Pequeno/química , RNA Interferente Pequeno/genética , Espectroscopia de Infravermelho com Transformada de Fourier
19.
Int J Mol Sci ; 23(17)2022 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-36077220

RESUMO

Topoisomerase inhibitors are widely used in cancer chemotherapy. However, one of the potential long-term adverse effects of such therapy is acute leukemia. A key feature of such therapy-induced acute myeloid leukemia (t-AML) is recurrent chromosomal translocations involving AML1 (RUNX1) or MLL (KMT2A) genes. The formation of chromosomal translocation depends on the spatial proximity of translocation partners and the mobility of the DNA ends. It is unclear which of these two factors might be decisive for recurrent t-AML translocations. Here, we used fluorescence in situ hybridization (FISH) and chromosome conformation capture followed by sequencing (4C-seq) to investigate double-strand DNA break formation and the mobility of broken ends upon etoposide treatment, as well as contacts between translocation partner genes. We detected the separation of the parts of the broken AML1 gene, as well as the increased mobility of these separated parts. 4C-seq analysis showed no evident contacts of AML1 and MLL with loci, implicated in recurrent t-AML translocations, either before or after etoposide treatment. We suggest that separation of the break ends and their increased non-targeted mobility-but not spatial predisposition of the rearrangement partners-plays a major role in the formation of these translocations.


Assuntos
Leucemia Mieloide Aguda , Translocação Genética , DNA , Quebras de DNA de Cadeia Dupla , Etoposídeo/efeitos adversos , Humanos , Hibridização in Situ Fluorescente , Leucemia Mieloide Aguda/genética , Inibidores da Topoisomerase II/efeitos adversos
20.
Cells ; 11(17)2022 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-36078163

RESUMO

FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplication (FLT3-ITD) mutations occur in about 25% of all acute myeloid leukemia (AML) patients and confer a poor prognosis. FLT3 inhibitors have been developed to treat patients with FLT3-mutated AML and have shown promise, though the acquisition of resistance occurs, highlighting the need for combination therapies to prolong the response to FLT3 inhibitors. In this study, we investigated the selective Mcl-1 inhibitor AZD5991 in combination with the FLT3 inhibitors gilteritinib and MRX-2843. The combinations synergistically induce apoptosis in AML cell lines and primary patient samples. The FLT3 inhibitors downregulate c-Myc transcripts through the suppression of the MEK/ERK and JAK2/STAT5 pathways, resulting in the decrease in c-Myc protein. This suppression of c-Myc plays an important role in the antileukemic activity of AZD5991. Interestingly, the suppression of c-Myc enhances AZD5991-inudced cytochrome c release and the subsequent induction of apoptosis. AZD5991 enhances the antileukemic activity of the FLT3 inhibitors gilteritinib and MRX-2843 against FLT3-mutated AML in vitro, warranting further development.


Assuntos
Leucemia Mieloide Aguda , Tirosina Quinase 3 Semelhante a fms , Compostos de Anilina , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Pirazinas/farmacologia , Tirosina Quinase 3 Semelhante a fms/genética
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