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1.
J Transl Med ; 19(1): 388, 2021 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-34507566

RESUMO

BACKGROUND: Acute myeloid leukemia (AML) is the most common acute leukemia in adults, with a median age of 68 in clinical diagnosis. About 60% patients are over 60 years old. There are various treatment options for AML patients. But for elderly patients, the complete remission rates are disappointing due to genetic, molecular, and age-related factors. Development of next-generation sequencing technologies makes it possible to seek individual strategies for patients in different ages. This study analyzed transcriptome profiles in platelets of AML patients in different ages for the first time. METHODS: Platelet RNA sequencing in AML of ten elderly and seven young patients were performed with Illumina TruSeq Stranded mRNA library Prep Kit and Illumina HiSeq4000 sequencing instrument. With the FASTQ sequencing data obtained, statistical analyses between elderly with young AML patients were analyzed by R program. GO and KEGG enrichment analyses were performed via R package clusterProfiler. TOP 10 down-regulated/up-regulated genes in elderly patients compared to young patients were selected with the threshold of |L2FC| > 2 and padj ≤ 0.0001. The down-regulated gene ATF4 was chosen by GSEA analysis and ROC analysis with AUC > 0.95. RESULTS: We found 3059 genes with differential transcript levels (GDTLs) in AML patients of different age. Among them, 2048 genes are down-regulated and 651 genes are up-regulated in elderly patients. We found that gene transcript profiles in elderly patients is obviously different from those in young patients, including a collection of down-regulated genes related to proteins processing in endoplasmic reticulum and immunity. We further identified that genes of pathway in cancer and mitogen activated protein kinase (MAPK) pathway, involved in natural immunity and metabolism, are significantly down-regulated in elderly patients. Among all screened genes with decreased transcript levels, we believe that activating transcription factor 4 (ATF4) is a biomarker indicating different chemotherapy strategies for elderly patients. CONCLUSIONS: In summary, gene transcript profiles are different in platelets of elderly and young AML patients. And ATF4 can be a useful biomarker indicating different chemotherapy strategies for AML patients with different ages.


Assuntos
Leucemia Mieloide Aguda , Transcriptoma , Adulto , Idoso , Plaquetas , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Pessoa de Meia-Idade , Análise de Sequência de RNA , Transcriptoma/genética
2.
Rinsho Ketsueki ; 62(8): 954-966, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-34497236

RESUMO

Mutations in the FMS-like tyrosine kinase 3 (FLT3) gene represent the most common genetic alteration in acute myeloid leukemia (AML), identified in approximately one third of patients newly diagnosed with AML. FLT3 internal tandem duplication mutations (FLT3-ITD) are associated with increased relapse and inferior overall survival. Multiple inhibitors of FLT3 signaling have been developed in the last few years with variable kinase-inhibitory properties, pharmacokinetics, and toxicity profiles. At present, two FLT3 inhibitors (gilteritinib and quizartinib) have been approved as monotherapies for relapsed/refractory FLT3-mutated AML in Japan, and many more drugs are currently being researched in clinical trials as monotherapies or in combination with conventional chemotherapy or hypomethylating agents and in various settings, including front line, relapsed/refractory disease, and maintenance therapy after consolidation chemotherapy or allogeneic stem cell transplantation. Despite significant advances, some issues need to be overcome, including the resistance to FLT3 inhibitors and controversies regarding the role of FLT3 inhibitors in maintenance therapies and the role of allogeneic stem cell transplantation in FLT3-mutated AML.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Mutação , Inibidores de Proteínas Quinases/uso terapêutico , Recidiva , Tirosina Quinase 3 Semelhante a fms/genética
3.
Rinsho Ketsueki ; 62(8): 967-977, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-34497237

RESUMO

The etiology and pathogenesis of acute myeloid leukemia (AML) have been elucidated at chromosomal and genetic levels. The classification and prognosis for its treatment has clearly involved specific chromosomal aberrations and genetic mutations. The recent comprehensive genomic analysis represented by next-generation sequencers has led to discovering new genetic mutations in AML. These findings have not only been applied clinically as prognostic factors and MRD markers but also contributed to the development of new molecular-targeting drugs. Many new drugs have already been approved in the USA and Europe, and new stratified treatments have tried to incorporate them. With the advent of venetoclax, treatment strategies, especially for patients with poor prognosis and who are unfit, have been substantially revised, and the maintenance therapy for AML is also being reevaluated in accordance to the National Comprehensive Cancer Network guidelines. This article will review the current status of AML treatment in Japan and according to Western guidelines.


Assuntos
Leucemia Mieloide Aguda , Aberrações Cromossômicas , Genômica , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Mutação , Prognóstico
4.
Rinsho Ketsueki ; 62(8): 978-987, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-34497238

RESUMO

Recurrence in acute myeloid leukemia (AML) is a major barrier in patients who achieve complete remission after induction of remission and consolidation therapy and desire long-term survival. Allogeneic hematopoietic stem cell transplantation lowers recurrence risk in patients; however, recurrence is common even after transplantation. Many maintenance therapies for AML aim to lower recurrence risk; therefore, research has focused on identifying drugs with a tolerable adverse-effect profile. Thus far, many trials of cytotoxic anticancer drugs used in maintenance therapy have showed no improvement in survival rates. In contrast, recent studies on immunomodulation, epigenetics, molecular-targeted drugs, etc. have demonstrated promising results. Therefore, we plan to review various maintenance therapies, such as immunotherapy, demethylating agents, and targeted therapies (including fms-like tyrosine kinase 3 inhibitors in particular) based on the current evidence. Moreover, we describe a new strategy that incorporates the assessment of measurable minimal residual disease.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Preparações Farmacêuticas , Humanos , Japão , Leucemia Mieloide Aguda/tratamento farmacológico , Uso Off-Label , Indução de Remissão
5.
Elife ; 102021 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-34350827

RESUMO

For an emerging disease like COVID-19, systems immunology tools may quickly identify and quantitatively characterize cells associated with disease progression or clinical response. With repeated sampling, immune monitoring creates a real-time portrait of the cells reacting to a novel virus before disease-specific knowledge and tools are established. However, single cell analysis tools can struggle to reveal rare cells that are under 0.1% of the population. Here, the machine learning workflow Tracking Responders EXpanding (T-REX) was created to identify changes in both rare and common cells across human immune monitoring settings. T-REX identified cells with highly similar phenotypes that localized to hotspots of significant change during rhinovirus and SARS-CoV-2 infections. Specialized MHCII tetramer reagents that mark rhinovirus-specific CD4+ cells were left out during analysis and then used to test whether T-REX identified biologically significant cells. T-REX identified rhinovirus-specific CD4+ T cells based on phenotypically homogeneous cells expanding by ≥95% following infection. T-REX successfully identified hotspots of virus-specific T cells by comparing infection (day 7) to either pre-infection (day 0) or post-infection (day 28) samples. Plotting the direction and degree of change for each individual donor provided a useful summary view and revealed patterns of immune system behavior across immune monitoring settings. For example, the magnitude and direction of change in some COVID-19 patients was comparable to blast crisis acute myeloid leukemia patients undergoing a complete response to chemotherapy. Other COVID-19 patients instead displayed an immune trajectory like that seen in rhinovirus infection or checkpoint inhibitor therapy for melanoma. The T-REX algorithm thus rapidly identifies and characterizes mechanistically significant cells and places emerging diseases into a systems immunology context for comparison to well-studied immune changes.


Assuntos
COVID-19/imunologia , Leucemia Mieloide Aguda/imunologia , Melanoma/imunologia , Infecções por Picornaviridae/imunologia , Aprendizado de Máquina não Supervisionado , Adolescente , Adulto , Algoritmos , Linfócitos T CD4-Positivos/imunologia , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Melanoma/tratamento farmacológico , Neoplasias , Rhinovirus/isolamento & purificação , SARS-CoV-2/isolamento & purificação , Adulto Jovem
6.
Neoplasma ; 68(4): 832-841, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34348467

RESUMO

Phosphatase of regenerating liver-3 (PRL-3) is recognized as a novel independent crucial driver for AML progression. Thus, the specific inhibitor of PRL-3 would be a potential therapeutic agent to AML in clinics, but there are not enough preclinical applications reported yet. Here we evaluated the cytotoxicity of PRL-3 inhibitor, BR-1, against AML cells ML-1 and MOLM-13. Meanwhile, the effect of BR-1 on the biological characteristics of AML cells and the underlying mechanism was investigated along with the combination of BR-1 and sorafenib on the AML cell viability. Our results show that BR-1 promotes apoptosis by inactivation of the JAK/STAT5 and PI3K/AKT pathways, while inhibits cell proliferation through arresting cell cycle in the S phase. In addition, a combination of BR-1 with sorafenib can further improve the therapeutic effect on AML. Thus, our results demonstrated that BR-1 would be a novel and potent therapeutic agent to AML, and its combination with other anti-AML drugs would be a promising strategy for AML therapy.


Assuntos
Leucemia Mieloide Aguda , Fosfatidilinositol 3-Quinases , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Fígado , Sorafenibe
7.
Rinsho Ketsueki ; 62(7): 721-726, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-34349054

RESUMO

A 38-year-old woman was referred to our hospital because of fever, general malaise, and abnormal blood count. The white blood cell count was 19,500/µl, with 72% lymphoblast. Bone marrow examination showed increased cellularity with 94% lymphoblast. Flow cytometry revealed the following T-cell lineages: cyCD3 (+), CD5 (+), CD7 (+), and CD34 (+). Chromosome analysis revealed hypodiploidy. The patient was diagnosed with early T-cell precursor lymphoblastic leukemia (ETP-ALL). After two cycles of induction chemotherapy, she achieved complete remission, but the disease relapsed after one cycle of consolidation therapy. At the time of relapse, leukemic cells were myeloperoxidase positive and showed a loss of T-cell surface antigen, suggesting that a lineage switch occurred. The patient did not respond to the second induction therapy. She subsequently received 3+7 (idarubicin+cytarabine) for acute myeloid leukemia (AML), but she deceased due to refractory leukemia. At the time of relapse, genome sequencing was performed and mutations of NRAS, TP53, and MLLT-PICALM fusion genes were revealed. Here, we report a case of ETP-ALL who relapsed with a lineage switch to AML in concordance with refractory disease.


Assuntos
Leucemia Mieloide Aguda , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Citarabina/uso terapêutico , Feminino , Humanos , Quimioterapia de Indução , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Recidiva
8.
Rinsho Ketsueki ; 62(7): 774-780, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-34349062

RESUMO

Genetic complexity and heterogeneity have made drug discovery difficult in human malignancies. In the past few years, we aimed to find vulnerabilities in therapy-resistant and refractory acute myeloid leukemia (AML) through integrative analyses of genomic data, clinical information, and results from in vivo/in vitro cell biological assays. Through analyses, we found that the cells of patients with AML show distinct sensitivity/resistance to small inhibiting molecules for anti-apoptosis and cell cycle/division. In particular, AML cells harboring the IDH1/2 mutations were highly sensitive to BCL-2 inhibition, while inhibition of IAP proteins resulted in efficient elimination of AML cells with varied FLT3, NRAS, and CBL mutations. Linking AML-initiating events with appropriate therapeutic strategies through cellular and genomic analyses might be further translated into nonmyeloid malignancies and solid tumors in the future.


Assuntos
Leucemia Mieloide Aguda , Transcriptoma , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Mutação , Prognóstico , Tirosina Quinase 3 Semelhante a fms/genética
9.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 29(4): 1011-1018, 2021 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-34362476

RESUMO

OBJECTIVE: To the clinical characteristics and prognostic value of the patients with complete deletion of TET_JBP domain (ΔJBP) in TET2 acute myeloid leukemia (AML). METHODS: Next Generation Sequencing technology was used to determine the mutations of 34 AML-related genes (including TET2 gene). The I-TASSER tool was used to predict the tertiary structure of the full-length TET2 protein and TET_JBP structure deletion. RESULTS: Among 38 AML patients with TET2 mutations, 22(57.9%) showed truncation mutations, of which 16 (72.7%) produced TET2ΔJBP truncation mutants. Protein structure prediction showed that the deletion of TET_JBP domain lead to the significant changes of tertiary structure in TET2 protein. Compared with the patients in non-ΔJBP group, the age of patients in ΔJBP group were older (63 vs 54 years old, P=0.047), and the occurrence rate of CEBPA double mutation (CEBPAdm) were more frequency (31.3% vs 0, P=0.009), the complete remission (CR) rate after induction chemotherapy(37.5% vs 81.8%, P=0.008) were lower, the median EFS (5 vs 19 months, P=0.000) and median OS (16 vs 22 months, P=0.041) were shorter. Univariate analysis showed that platelets <50×109/L (P=0.004) and CEBPAdm (P=0.001) were related to the shorter OS of the patients. Further COX multivariate analysis showed that CEBPAdm is an independent prognostic factors of OS in TET2ΔJBP patients (P=0.010). In addition, ΔJBP patients with CEBPAdm showed lower hemoglobin levels (62 vs 75g/L, P=0.030) and lower median OS (9 months vs 18 months, P=0.000) than the patients without CEBPAdm. CONCLUSION: AML patients with TET2ΔJBP truncation mutant shows lower CR rate, shorter EFS and OS after induction chemotherapy, which may be related to the poor prognosis, and co-mutation with CEBPAdm, which is the independent prognostic factors of OS in AML patients with TET2ΔJBP.


Assuntos
Leucemia Mieloide Aguda , Proteínas de Ligação a DNA/genética , Humanos , Quimioterapia de Indução , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Pessoa de Meia-Idade , Mutação , Prognóstico , Proteínas Proto-Oncogênicas/genética , Indução de Remissão
10.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 29(4): 1071-1079, 2021 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-34362484

RESUMO

OBJECTIVE: To compare the efficacy and safety of different doses of daunorubicin combined with a standard dose of cytarabine as induction chemotherapy in newly diagnosed primary acute myeloid leukemia (AML) patients. METHODS: The clinical data and outcome were retrospectively analyzed in 86 newly diagnosed primary AML patients who were under 65 years old and treated with daunorubicin combined with cytarabine (DA regimen) at West China Hospital of Sichuan University from January 2017 to June 2019. Patients were divided into 2 groups based on the dose of daunorubicin they received, 35 cases in the escalated-dose group ï¼»75 mg/(m2·d)ï¼½ and 51 cases in the standard-dose group ï¼»60 mg/(m2·d)ï¼½. And then the effects of different doses of daunorubicin on complete remission (CR) rate, minimal residual disease (MRD)-negative CR rate, relapse-free survival (RFS), overall survival (OS), and adverse events were analyzed. RESULTS: Median follow-up time of all the patients was 15 months. The CR rate and MRD- CR rate of the escalated-dose group was 88.5% and 71.4%, respectively, which were higher than 64.7% and 41.2% of the standard-dose group (P=0.029, P=0.008). The estimated 2-year RFS of the escalated-dose group was 68.4%, which was higher than 38.5% of the standard-dose group (P=0.015), but estimated 2-year OS showed no statistically significant difference (77.1% vs 66.7%, P=0.059), as well as grade 3-4 adverse events. The escalated dose of daunorubicin had prolonged RFS (13 months vs not reached, P=0.022) and OS (23 months vs not reached, P=0.029) in the FLT3-ITD- AML patients. CONCLUSION: The escalated dose of daunorubicin can induce higher complete remission rate, deeper remission and longer duration of remission without increasing adverse events in newly diagnosed primary AML patients.


Assuntos
Daunorrubicina , Leucemia Mieloide Aguda , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica , Citarabina/uso terapêutico , Humanos , Quimioterapia de Indução , Leucemia Mieloide Aguda/tratamento farmacológico , Indução de Remissão , Estudos Retrospectivos
11.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 29(4): 1080-1084, 2021 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-34362485

RESUMO

OBJECTIVE: To investigate the clinical characteristics and prognosis of patients with acute myeloid leukemia(AML) combined with paroxysmal nocturnal hemoglobinuria(PNH). METHODS: The clinical data of 13 AML combined with PNH patients treated in our hospital from January 2017 to May 2019 were collected and retrospective analyzed. The complete remission(CR) rate for induction chemotherapy was analyzed. The level of PNH+ cell before and after chemotherapy were tested by Paired t test. Kaplan-Meier method and multi-factorial Cox regression model were used to analyze the influencing factors of prognosis. RESULTS: Among the 13 patients, 11 (84.6%) cases were CR after first induction chemotherapy. The median overall survival(OS) time was 17 months(0-30 months), the median progression-free survival(PFS) time was 16 months(2-26 months). There were no significant difference in the number of PNH+ cell before and after chemotherapy (P>0.05). Multivariate Cox regression analysis showed that age,sex,the level of hemoglobin, platelet were not related to the OS of the patients(P>0.05), the level of WBC, LDH and risk stratification at first diagnosed were related to the OS of the patients(P<0.05). Kaplan-Meier survival analysis showed that the OS rate of AML combined with PNH patients with leukocyte lower than 10×109/L at first diagnosed was better than that of the patients with leukocyte higher than 10×109/L (P=0.0261). The OS rate of patients with low or standard risk was better than the patients with high risk group(P=0.0010). CONCLUSION: The patients of AML combined with PNH have higher CR rate after the first induction chemotherapy. The level of WBC and LDH at first diagnosed are the factors that affecting the OS of the patients. The OS of patients with WBC lower than 10×109/L, at first diagnosed low and medium risk are better than the other patients.


Assuntos
Hemoglobinúria Paroxística , Leucemia Mieloide Aguda , Humanos , Quimioterapia de Indução , Leucemia Mieloide Aguda/tratamento farmacológico , Prognóstico , Indução de Remissão , Estudos Retrospectivos
12.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 29(4): 1355-1359, 2021 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-34362530

RESUMO

CXCL12/CXCR4 axis composed of chemokine CXCL12 and its specific ligand CXCR4 can regulate and control the adhesion of leukemia cells to protective bone marrow niche, promote cell survival, and resist apoptosis induced by signal transduction inhibitors and chemotherapeutic drugs. Therefore, CXCL12 /CXCR4 axis has become a new target for the treatment of acute myeloid leukemia. At present, CXCR4 inhibitors that have been developed are in different clinical trials, showing good anti-leukemia effect. In this review, the research advance of CXCR4 inhibitors in the treatment of acute myeloid leukemia is summarized briefly.


Assuntos
Antineoplásicos , Leucemia Mieloide Aguda , Antineoplásicos/uso terapêutico , Apoptose , Medula Óssea , Quimiocina CXCL12/farmacologia , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Receptores CXCR4 , Transdução de Sinais
13.
Int J Mol Sci ; 22(15)2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34360855

RESUMO

The FMS-like tyrosine kinase 3 (FLT3) gene is mutated in one-third of patients with de novo acute myeloid leukemia (AML). Mutated FLT3 variants are constitutively active kinases signaling via AKT kinase, MAP kinases, and STAT5. FLT3 inhibitors have been approved for the treatment of FLT3-mutated AML. However, treatment response to FLT3 inhibitors may be short-lived, and resistance may emerge. Compounds targeting STAT5 may enhance and prolong effects of FLT3 inhibitors in this subset of patients with FLT3-mutated AML. Here STAT5-inhibitor AC-4-130, FLT3 inhibitor midostaurin (PKC412), BMI-1 inhibitor PTC596, MEK-inhibitor trametinib, MCL1-inhibitor S63845, and BCL-2 inhibitor venetoclax were assessed as single agents and in combination for their ability to induce apoptosis and cell death in leukemic cells grown in the absence or presence of bone marrow stroma. Synergistic effects on cell viability were detected in both FLT3-mutated and FLT3-wild-type AML cells treated with AC-4-130 in combination with the MCL1 inhibitor S63845. AML patient samples with a strong response to AC-4-130 and S63845 combination treatment were characterized by mutated FLT3 or mutated TET2 genes. Susceptibility of AML cells to AC-4-130, PTC596, trametinib, PKC412, and venetoclax was altered in the presence of HS-5 stroma. Only the MCL1 inhibitor S63845 induced cell death with equal efficacy in the absence or presence of bone marrow stroma. The combination of the STAT5-inhibitor AC-4-130 and the MCL1 inhibitor S63845 may be an effective treatment targeting FLT3-mutated or TET2-mutated AML.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Pirimidinas/uso terapêutico , Fator de Transcrição STAT5/antagonistas & inibidores , Tiofenos/uso terapêutico , Proteínas Supressoras de Tumor/antagonistas & inibidores , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/genética , Humanos , Proteínas Proto-Oncogênicas/genética , Tirosina Quinase 3 Semelhante a fms/genética
14.
Viruses ; 13(7)2021 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-34372571

RESUMO

Anti-cancer activity can be improved by engineering immune cells to express chimeric antigen receptors (CARs) that recognize tumor-associated antigens. Retroviral vector gene transfer strategies allow stable and durable transgene expression. Here, we used alpharetroviral vectors to modify NK-92 cells, a natural killer cell line, with a third-generation CAR designed to target the IL-3 receptor subunit alpha (CD123), which is strongly expressed on the surface of acute myeloid leukemia (AML) cells. Alpharetroviral vectors also contained a transgene cassette to allow constitutive expression of human IL-15 for increased NK cell persistence in vivo. The anti-AML activity of CAR-NK-92 cells was tested via in vitro cytotoxicity assays with the CD123+ AML cell line KG-1a and in vivo in a patient-derived xenotransplantation CD123+ AML model. Unmodified NK-92 cells or NK-92 cells modified with a truncated version of the CAR that lacked the signaling domain served as controls. Alpharetroviral vector-modified NK-92 cells stably expressed the transgenes and secreted IL-15. Anti-CD123-CAR-NK-92 cells exhibited enhanced anti-AML activity in vitro and in vivo as compared to control NK-92 cells. Our data (1) shows the importance of IL-15 expression for in vivo persistence of NK-92 cells, (2) supports continued investigation of anti-CD123-CAR-NK cells to target AML, and (3) points towards potential strategies to further improve CAR-NK anti-AML activity.


Assuntos
Imunoterapia Adotiva/métodos , Subunidade alfa de Receptor de Interleucina-3/imunologia , Leucemia Mieloide Aguda/tratamento farmacológico , Idoso , Alpharetrovirus/genética , Animais , Linhagem Celular Tumoral , Feminino , Terapia Genética , Vetores Genéticos/genética , Humanos , Subunidade alfa de Receptor de Interleucina-3/genética , Subunidade alfa de Receptor de Interleucina-3/metabolismo , Células Matadoras Naturais/imunologia , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/imunologia , Masculino , Camundongos , Camundongos Endogâmicos NOD , Cultura Primária de Células , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/imunologia , Transdução Genética , Transgenes , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Nutrients ; 13(8)2021 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-34444931

RESUMO

Over the centuries, humans have traditionally used garlic (Allium sativum L.) as a food ingredient (spice) and remedy for many diseases. To confirm this, many extensive studies recognized the therapeutic effects of garlic bulbs. More recently, black garlic (BG), made by heat-ageing white garlic bulbs, has increased its popularity in cuisine and traditional medicine around the world, but there is still limited information on its composition and potential beneficial effects. In this study, the metabolite profile of methanol extract of BG (BGE) was determined by high-performance liquid chromatography coupled to tandem mass spectrometry in high-resolution mode. Results allowed to establish that BGE major components were sulfur derivatives, saccharides, peptides, organic acids, a phenylpropanoid derivative, saponins, and compounds typical of glycerophospholipid metabolism. Characterization of the BGE action in cancer cells revealed that antioxidant, metabolic, and hepatoprotective effects occur upon treatment as well as induction of maturation of acute myeloid leukemia cells. These results are interesting from the impact point of view of BG consumption as a functional food for potential prevention of metabolic and tumor diseases.


Assuntos
Alho/química , Leucemia Mieloide Aguda/tratamento farmacológico , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Antioxidantes/farmacologia , Cromatografia Líquida de Alta Pressão/métodos , Humanos , Leucemia Mieloide Aguda/patologia , Peptídeos/análise , Raízes de Plantas/química , Polissacarídeos/análise , Saponinas/análise , Especiarias/análise , Enxofre/análise , Espectrometria de Massas em Tandem/métodos , Células U937
16.
BMJ Case Rep ; 14(8)2021 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-34417240

RESUMO

Sweet syndrome (SS), also referred as acute febrile neutrophilic dermatosis, is an inflammatory process characterised by the abrupt appearance of erythematous papules or nodules with predominant neutrophilic infiltration in the dermis. Fever and neutrophilia are common presenting features. However, extracellular manifestations, including ocular and musculoskeletal, may occur. SS is divided into three subtypes: classical (or idiopathic), malignancy associated and drug induced. Medication-induced subtype accounts for up to 26% of cases. In recent years, emerging evidence has showed that SS may also occur in neutropenic patients who underwent induction for acute myeloid leukemia (AML). The identification of FMS-like tyrosine kinase 3 (FLT3) gene mutation in approximately 30% of patients with AML has promoted the targeted therapy with FLT3-internal tandem duplication (ITD) inhibitors. Midostaurin, a recently Food and Drug Administration-approved medication for FLT3-ITD-positive AML, was reported once as cause for SS. We report a midostaurin-induced SS with neutropenia in a patient following induction chemotherapy of AML.


Assuntos
Leucemia Mieloide Aguda , Síndrome de Sweet , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Estaurosporina/efeitos adversos , Estaurosporina/análogos & derivados , Síndrome de Sweet/induzido quimicamente , Síndrome de Sweet/diagnóstico , Síndrome de Sweet/tratamento farmacológico , Estados Unidos , Tirosina Quinase 3 Semelhante a fms/genética
17.
Artigo em Inglês | MEDLINE | ID: mdl-34360486

RESUMO

A number of systemic diseases including hematological disorders have manifestations in the oral cavity region. These manifestations may often represent early signs of the underlying hematopoietic disease and occur frequently in leukemia. Despite the fact that leukemia has long been known to be associated with oral health deterioration, the available literature on this topic consists mostly of case reports, without data to conclude these. The aim of the study was to assess dentition state in leukemic patients during one cycle of chemotherapy and its correlation with blood parameters. The study included 102 adults treated because of leukemia at the Clinic of Haemato-Oncology and Bone Marrow Transplantation at the university hospital in Lublin, Poland. The sample group consisted of 51 women and 51 men aged 22 to 72 (54.07 ± 10.33) with following diagnoses: Acute myelogenous leukemia (AML)-55 patients (53.92%), Chronic lymphocytic leukemia (CLL)-17 patients (16.67%), Acute lymphoblastic leukemia (ALL)-16 patients (15.69%), Chronic myelogenous leukemia (CML)-10 patients (9.80%), Acute promyelocytic leukemia (APL) -3 patients (2.94%), Chronic hairy cell leukemia (HCL)-1 patient (0.98%). DMFT index was used to assess dentition state. After the cycle of chemotherapy, their dentition state changed in terms of decayed, missing and filled teeth and correlated with hematological parameters. Adult patients with leukemia have high dental treatment needs, and high number of missing teeth; thus, a comprehensive and fast dental treatment is necessary to avoid systemic complications and ensure better quality of life.


Assuntos
Leucemia Linfocítica Crônica de Células B , Leucemia Mielogênica Crônica BCR-ABL Positiva , Leucemia Mieloide Aguda , Adulto , Dentição , Feminino , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/epidemiologia , Masculino , Qualidade de Vida
18.
Ann Palliat Med ; 10(7): 7884-7893, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34353076

RESUMO

BACKGROUND: A meta-analysis was performed to examine the clinical efficacy of drugs in the treatment of acute myelogenous leukemia (AML). METHODS: combinations of terms of "acute myeloid leukemia", "fludara", "cytarabine", "cladribine", "aclacinomycin", "granulocyte colony-stimulating factor (G-CSF)", and "hyaluronic acid" were searched in Chinese databases. "acute myelogenous leukemia", "fludara", "cytarabine", "cladribine", "aclacinomycin", "granulocyte colony-stimulating factor", and "hyaluronic acid" were searched in English databases. Review Manager 5.3 was employed for the meta-analysis. RESULTS: Ultimately, 12 articles were included. Most of the articles had a low-risk bias, and were of medium or high quality. The complete remission rates were tested for heterogeneity [chi-square test (Chi2) =4.10, degrees of freedom (df)=10, I2=0%; P=0.94]. The fixed effect model analysis showed that the difference between experimental participants and controls was considerable [Z=13.15, odds ratio (OR) =12.82, 95% confidence interval (CI): (8.77, 18.76); P<0.01]. The overall effective rates were tested for heterogeneity (Chi2=1.58, df=7, I2=0%; P=0.98), and difference between experimental participants and controls was considerable [Z=10.70, OR =1.32, 95% CI: (7.32,17.89); P<0.01]. The overall adverse reaction rates were tested for heterogeneity (Chi2=0.42, df=5, I2=0%; P=0.99), and the difference between experimental participants and controls was considerable [Z=5.00, OR =0.38, 95% CI: (0.26, 0.55); P<0.01]. The circles of some studies in the funnel diagrams were symmetrical with the midline, the accuracy of included trials was high, the publications were not biased, and the final conclusions were reliable. CONCLUSIONS: This meta-analysis showed that drug treatments of AML can improve complete remission and total effective rates and reduce adverse reaction rates, and thus are worthy of clinical promotion.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Leucemia Mieloide Aguda , Citarabina/uso terapêutico , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Resultado do Tratamento
19.
Hematology ; 26(1): 577-587, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34384339

RESUMO

OBJECTIVES: Compared with the 3 + 7 regimen, the cladribine-containing regimen has led to improvements in the rate of complete remission (CR) in the treatment of newly diagnosed acute myeloid leukemia (AML) patients. We conducted a systematic review and meta-analysis to investigate the overall efficacy and safety of cladribine-containing regimens in the induction treatment of newly diagnosed AML patients. METHODS: Eligible studies were identified from the PubMed, EMBASE, and Cochrane Library databases. Efficacy was assessed by CR rate, disease-free survival (DFS), and overall survival (OS). Safety was evaluated based on the early death (ED) rate, days for neutrophils<0.5 × 109/L, days for platelets<50 × 109/L, and duration of hospital stay after treatment. RESULTS: A total of 14 clinical trials were included in this meta-analysis, enrolling a total of 1058 newly diagnosed AML patients. The pooled estimate with a 95% confidence interval (CI) for CR was 64% (95% CI: 58-70%). Compared with the control group, the CR rate of the cladribine-containing regimen was higher (OR was 1.92 (95% CI: 1.55-2.38)). The combined ED rate was estimated to be 10% (95% CI: 5-14%). Compared with the control group, the ED rate of the cladribine-containing regimen was not increased (OR was 1.09 (95% CI: 0.78-1.53)). CONCLUSION: This meta-analysis suggests that cladribine-containing regimens are likely to be effective and safe for induction treatment of newly diagnosed AML patients. However, large sample size and prospective controlled studies are needed to confirm our findings.


Assuntos
Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cladribina/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cladribina/efeitos adversos , Humanos , Quimioterapia de Indução , Leucemia Mieloide Aguda/diagnóstico , Resultado do Tratamento
20.
J Med Case Rep ; 15(1): 437, 2021 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-34446105

RESUMO

BACKGROUND: Xeroderma pigmentosum is a rare inherited disease characterized by extreme hypersensitivity to ultraviolet rays and predisposing to cutaneous malignancies that can appear in childhood. These manifestations are often associated with ocular lesions and sometimes with neurological disorders. The association of xeroderma pigmentosum with internal neoplasms such as acute myeloblastic leukemia is not reported with great frequency, which confirms the rarity of this occurrence. CASE REPORT: A 26-year-old Moroccan women, xeroderma pigmentosum patient, was diagnosed with acute myeloblastic leukemia with a complex karyotype. Due to the adverse risk of the xeroderma pigmentosum association with acute myeloblastic leukemia and the profile of acute myeloblastic leukemia with complex karyotype and monosomy 7, which constitute factors of poor prognosis, as well as the absence of studies conceding the tolerance of the chemotherapy by patients suffering from xeroderma pigmentosum, our patient was put under low-dose cytarabine protocol with granulocyte colony-stimulating factor. Unfortunately, she died on the tenth day of chemotherapy by acute pulmonary edema of cardiogenic pace complicated by tamponade. CONCLUSION: According to reports, it is the second case showing association of xeroderma pigmentosum with acute myeloblastic leukemia. The management of these patients remains a challenge. Studies focusing on xeroderma pigmentosum patients developing hematological malignancies are necessary to better understand the most appropriate strategies and precautions for this specific case.


Assuntos
Leucemia Mieloide Aguda , Neoplasias Cutâneas , Xeroderma Pigmentoso , Adulto , Citarabina/uso terapêutico , Feminino , Humanos , Leucemia Mieloide Aguda/complicações , Leucemia Mieloide Aguda/tratamento farmacológico , Xeroderma Pigmentoso/complicações
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