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Although tyrosine kinase inhibitor (TKI) therapy has markedly improved the survival of people with chronic-phase chronic myeloid leukemia (CML), 20-30% of people still experienced therapy failure. Data from 1,955 consecutive subjects with chronic-phase CML diagnosed by the European LeukemiaNet (ELN) recommendations from 1 center receiving initial TKI imatinib or a second-generation (2G-) TKI therapy were interrogated to develop a clinical prediction model for TKI therapy failure. This model was subsequently validated in 3,454 subjects from 76 other centers. Using the predictive clinical co-variates associated with TKI therapy failure, we developed a model that stratified subjects into low-, intermediate- and high-risk subgroups with significantly different cumulative incidences of therapy failure (p < 0.001). There was good discrimination and calibration in the external validation dataset, and the performance was consistent with that of the training dataset. Our model had the better prediction discrimination than the Sokal and ELTS scores did, with the greater time-dependent area under the receiver-operator characteristic curve (AUROC) values and a better ability to re-defined the risk of therapy failure. Our model could help physicians estimate the likelihood of initial imatinib or 2G-TKI therapy failure in people with chronic-phase CML.
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BACKGROUND: There are limited data comprehensively comparing therapy responses and outcomes among nilotinib, dasatinib, flumatinib and imatinib for newly diagnosed chronic-phase chronic myeloid leukemia in a real-world setting. PATIENTS AND METHODS: Data from patients with chronic-phase CML receiving initial a second-generation tyrosine-kinase inhibitor (2G-TKI, nilotinib, dasatinib or flumatinib) or imatinib therapy from 77 Chinese centers were retrospectively interrogated. Propensity-score matching (PSM) analyses were performed to to compare therapy responses and outcomes among these 4 TKIs. RESULTS: 2,496 patients receiving initial nilotinib (n = 512), dasatinib (n = 134), flumatinib (n = 411) or imatinib (n = 1,439) therapy were retrospectively interrogated in this study. PSM analyses indicated that patients receiving initial nilotinib, dasatinib or flumatinib therapy had comparable cytogenetic and molecular responses (p = .28-.91) and survival outcomes including failure-free survival (FFS, p = .28-.43), progression-free survival (PFS, p = .19-.93) and overall survival (OS) (p values = .76-.78) but had significantly higher cumulative incidences of cytogenetic and molecular responses (all p values < .001) and higher probabilities of FFS (p < .001-.01) than those receiving imatinib therapy, despite comparable PFS (p = .18-.89) and OS (p = .23-.30). CONCLUSION: Nilotinib, dasatinib and flumatinib had comparable efficacy, and significantly higher therapy responses and higher FFS rates than imatinib in newly diagnosed CML patients. However, there were no significant differences in PFS and OS among these 4 TKIs. These real-world data may provide additional evidence for routine clinical assessments to identify more appropriate therapies.
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Dasatinib , Mesilato de Imatinib , Humanos , Femenino , Masculino , Estudios Retrospectivos , Persona de Mediana Edad , Dasatinib/uso terapéutico , Dasatinib/farmacología , Mesilato de Imatinib/uso terapéutico , Mesilato de Imatinib/farmacología , Adulto , Anciano , Pirimidinas/uso terapéutico , Leucemia Mieloide de Fase Crónica/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Resultado del Tratamiento , Adulto Joven , Adolescente , Benzamidas/uso terapéutico , Anciano de 80 o más Años , AminopiridinasRESUMEN
PURPOSE: The refractory nature and proneness to recurrence of lung cancer are related to the proliferation and differentiation of lung cancer stem cells (LCSCs). This paper aims to explore the effect of aquaporin-3 (AQP3) on the functions of LCSCs, and its molecular mechanism in regulating the differentiation and apoptosis of LCSCs through the Wnt/glycogen synthase kinase-3ß (GSK-3ß)/ß-catenin pathway. METHODS: The stem cells were selected and the cell lines with low expression of AQP3 were constructed, followed by transcriptome sequencing. LCSCs were transfected with empty lentivirus in the control group and transfected with AQP3 shRNA in the interference group, and the low expression of AQP3 was inhibited using the Wnt pathway inhibitor XAV939 in the interference+inhibitor group. The expressions of AQP3, Wnt/GSK-3ß/ß-catenin pathway genes, stemness genes, differentiation-related markers and apoptosis proteins in LCSCs were detected. RESULTS: In the interference group, the pathway genes were highly expressed. The genes in the interference group were enriched in the Wnt/GSK-3ß/ß-catenin pathway. In the interference group, the expressions of ß-catenin, GSK-3ß and signal transducer and activator of transcription 3 (STAT3) were significantly higher, while the expression of adenomatous polyposis coli (APC) was significantly lower (p<0.05). The expression of Wnt5α had no difference. In the interference group, the expressions of stemness-related genes were obviously higher, while the expression of CDK2 had no difference (p=0.471). The interference group had higher expressions of differentiation markers. CONCLUSION: AQP3 can reduce the differentiation and inhibit the apoptosis of LCSCs through reducing the expressions of Wnt/GSK-3ß/ß-catenin pathway-related genes such as ß-catenin, GSK-3ß and STAT3, thereby affecting the tumor progression.
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Acuaporina 3/metabolismo , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Células Madre Neoplásicas/metabolismo , Vía de Señalización Wnt , beta Catenina/metabolismo , Apoptosis/fisiología , Diferenciación Celular/fisiología , Proliferación Celular/fisiología , Humanos , Células Madre Neoplásicas/patologíaRESUMEN
This study was to investigate clinical features and prognosis of duplex primary malignant neoplasms involving chronic myeloid leukemia (CML-DPMNs). Clinical data of thirteen CML-DPMN patients who were admitted to the First Hospital of Jilin University from May 2008 to December 2018 were collected and retrospectively analyzed. Female patients (9/13) were predominant in this cohort study. Nine patients were metachronous DPMNs (metachronous duplex primary malignant neoplasms involving chronic myeloid leukemia) with 5 years median interval time from primary malignancy to secondary malignancy. The other 4 patients were diagnosed as synchronous CML-DPMNs. Seven of the metachronous duplex primary malignant neoplasms involving chronic myeloid leukemia suffered from CML following many years of comprehensive anti-cancer therapy. Two of CML-MDPMN patients had invasive ductal carcinoma of breast after many years of treatment with imatinib. There was no difference between treatment-related CML group and non-treatment-related CML group in regard as the gender, age, white blood cell count, hemoglobin level, platelet count, and risk level. The median overall survival time of these thirteen patients with CML-DPMNs was not reached. In conclusion, female patients are more likely to suffer from the CML-DPMNs in the present article. Overall survival time of patients with DPMNs involving CML could be promising if timely and effective treatment therapy is adopted.
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Neoplasias de la Mama , Mesilato de Imatinib/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva , Neoplasias Primarias Múltiples , Factores de Edad , Anticarcinógenos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , China/epidemiología , Femenino , Humanos , Incidencia , Leucemia Mielógena Crónica BCR-ABL Positiva/sangre , Leucemia Mielógena Crónica BCR-ABL Positiva/diagnóstico , Leucemia Mielógena Crónica BCR-ABL Positiva/epidemiología , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Masculino , Persona de Mediana Edad , Neoplasias Primarias Múltiples/sangre , Neoplasias Primarias Múltiples/diagnóstico , Neoplasias Primarias Múltiples/epidemiología , Neoplasias Primarias Múltiples/patología , Pronóstico , Estudios Retrospectivos , Factores de Riesgo , Factores Sexuales , Análisis de Supervivencia , Factores de TiempoRESUMEN
BACKGROUND: Nuclear factor-kappa B (NF-κB) is an important nuclear transcription factor in cells, involving in a series of processes such as cell proliferation, apoptosis, and differentiation. In this study, we explored the specific mechanism of NF-κB on the differentiation of osteoclasts. METHODS: MicroRNAs (miRNAs) expression microarray data GSE105027 related to osteoarthritis was obtained to screen out the differentially expressed miRNA. Phorbol-12-myristate-13-acetate (PMA) was used to induce THP-1 cells to differentiate into macrophages, followed by induction to osteoclasts using macrophage colony-stimulating factor (M-CSF) and receptor activator of NF-κB ligand (RANKL). ELISA and RT-qPCR were conducted to examine IL-6 and IL-1ß expression. The binding of NF-κB to the miR-1276 promoter region was demonstrated by ChIP assay, and targeting relationship between miR-1276 and MITF was verified by dual luciferase reporter assay. KK, iKBα, NF-kB, p-IKK, p-iKBα, p-NF-kB expression was analyzed by western blot. NF-κB and miR-1276 expression in osteoclasts was examined later. After gain- and less-of-function study, the effects on osteoclast differentiation were detected by TRAP-positive osteoclasts, TRAP activity, TRAP-5b content, F-Actin expression, as well as osteoclast differentiation marker genes expression. RESULTS: NF-κB was activated in osteoclasts, and down-regulation of NF-κB inhibited osteoclast differentiation. Next, miR-1276 was downregulated in osteoclasts after differentiation from monocytes. Meanwhile, NF-κB decreased the expression of miR-1276 by binding to the miR-1276 promoter, thereby elevating MITF expression, thereby promoting osteoclast differentiation. CONCLUSION: In summary, NF-κB promoted osteoclast differentiation through downregulating miR-1276 to upregulate MITF.
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Diferenciación Celular , Regulación hacia Abajo/genética , Factor de Transcripción Asociado a Microftalmía/metabolismo , FN-kappa B/metabolismo , Osteoclastos/citología , Osteoclastos/metabolismo , Secuencia de Bases , Diferenciación Celular/genética , Silenciador del Gen , Humanos , MicroARNs/genética , MicroARNs/metabolismo , Regiones Promotoras Genéticas/genética , Unión Proteica , Células THP-1RESUMEN
PURPOSE: To explore the effect of aquaporin-3 (AQP3) on the functions of lung cancer stem cells (LCSCs), and its molecular mechanism in regulating the differentiation and apoptosis of LCSCs through the Wnt/glycogen synthase kinase-3ß (GSK-3ß)/ß-catenin pathway. METHODS: The stem cells were selected and the cell lines with low expression of AQP3 were constructed, followed by transcriptome sequencing. LCSCs were transfected with empty lentivirus in control group and transfected with AQP3 shRNA in interference group, and the low expression of AQP3 was inhibited using the Wnt pathway inhibitor XAV939 in interference + inhibitor group. The expressions of AQP3, Wnt/GSK-3ß/ß-catenin pathway genes, stemness genes, differentiation-related markers and apoptosis proteins in LCSCs were detected. RESULTS: In interference group, the pathway genes were highly expressed. The genes in interference group were enriched in the Wnt/GSK-3ß/ß-catenin pathway. In interference group, the expressions of ß-catenin, GSK-3ß and signal transducer and activator of transcription 3 (STAT3) were significantly higher, while the expression of adenomatous polyposis coli (APC) was significantly lower (p<0.05). The expression of Wnt5α had no difference. In interference group, the expressions of stemness-related genes were obviously higher, while the expression of CDK2 had no difference (p=0.471). Interference group had higher expressions of differentiation markers. CONCLUSION: In conclusion, AQP3 can reduce the differentiation and inhibit the apoptosis of LCSCs through reducing the expressions of Wnt/GSK-3ß/ß-catenin pathway-related genes such as ß-catenin, GSK-3ß and STAT3, thereby affecting the tumor progression.
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Acuaporina 3/metabolismo , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Neoplasias Pulmonares/metabolismo , Vía de Señalización Wnt , beta Catenina/metabolismo , Apoptosis/fisiología , Diferenciación Celular/fisiología , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologíaRESUMEN
BACKGROUND: Luteolin (LUT) is a flavonoid found in vegetables and fruits that has diverse functions. Doxorubicin (DOX) is an anthracycline antibiotic that is frequently used for the treatment of various cancers. Unfortunately, the clinical efficacy of DOX is limited by its dose-related cardiotoxicity. In this study, we aimed to investigate the potential mechanism through which LUT attenuates cardiotoxicity in vivo. METHODS: We evaluated the body weight, heart weight, electrocardiogram, and pathological changes before and after administration of LUT. Moreover, the effects of LUT (50 mg/kg in the low dose group, 100 mg/kg in the high dose group) on biochemical parameters (brain natriuretic peptide, creatine kinase MB, cardiac troponin T, and dehydrogenation of lactate enzyme) and oxidative stress parameters (malondialdehyde and superoxide dismutase) were studied in the sera of cardiotoxicity model rats. We also identified the apoptotic mediators whose expression was induced by LUT by quantitative real-time reverse transcription-polymerase chain reaction (RT-qPCR) evaluation. In addition, we used network analysis to predict DOX-induced cardiotoxicity and protection afforded by LUT. Western blotting was used to detect the expression of associated proteins. RESULTS: LUT significantly improved DOX-induced cardiotoxicity in a dose-dependent fashion. LUT ameliorated DOX-induced weight loss and heart weight changes, as well as changes in biochemical parameters and oxidative stress parameters in heart injury model rats. LUT's protective effect was observed via regulation of the apoptotic markers Bcl-2, Bax, and caspase-3 mRNA and protein expression levels. Network analysis showed that the AKT/Bcl-2 signalling pathway was activated; specifically, the PH domain leucine-rich repeats protein phosphatase 1 (phlpp1) was involved in the AKT/Bcl-2 signal pathway. LUT inhibited the activity of phlpp1 leading to positive regulation of the AKT/Bcl-2 pathway, which attenuated doxorubicin-induced cardiotoxicity. CONCLUSIONS: These results demonstrate that LUT exerted protective effects against DOX-induced cardiotoxicity in vivo by alleviating oxidative stress, suppressing phlpp1 activity, and activating the AKT/Bcl-2 signalling pathway.
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RATIONALE: Concurrent calreticulin (CALR) mutation and BCR-ABL1 fusion are extremely rare in chronic myelogenous leukemia; to date, only 12 cases have been reported. PATIENT CONCERNS: A 57-year-old male who had an 11-year history of essential thrombocytosis presented to our hospital with leukocytosis and marked splenomegaly for 3 months. DIAGNOSES: Chronic myelogenous leukemia with myeloid fibrosis arising on the background of essential thrombocytosis harboring both BCR-ABL1 fusion and type-1 like CALR mutation. INTERVENTIONS: Imatinib was started at 300âmg daily and increased to 400âmg daily after 3 months; interferon was added after 12 months. OUTCOMES: Partial cytogenetic response was achieved after 3 months of imatinib therapy and complete cytogenetic response was achieved after 1 year of treatment. However, CALR mutation was still present with a stable mutational allele burden. LESSONS: In this case report and review of additional 12 cases with simultaneous presence of CALR-mutation and BCR-ABL1 fusion, we highlighted the importance of integrating clinical, morphological, and molecular genetic data for classifying atypical myeloid neoplasms.
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Calreticulina/genética , Proteínas de Fusión bcr-abl/genética , Genes abl , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Trombocitemia Esencial/genética , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Humanos , Mesilato de Imatinib/farmacología , Mesilato de Imatinib/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Trombocitemia Esencial/complicacionesRESUMEN
Feature selection in the framework of meta-analyses (meta feature selection), combines meta-analysis with a feature selection process and thus allows meta-analysis feature selection across multiple datasets. In the present study, a meta feature selection procedure that fitted a multiple Cox regression model to estimate the effect size of a gene in individual studies and to identify the overall effect of the gene using a meta-analysis model was proposed. The method was used to identify prognostic gene signatures for lung adenocarcinoma and lung squamous cell carcinoma. Furthermore, redundant gene elimination (RGE) is of crucial importance during feature selection, and is also essential for a meta feature selection process. The current study demonstrated that the proposed meta feature selection procedure with RGE outperforms that without RGE in terms of predictive ability, model parsimony and biological interpretation.
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Objectives: To analyze the efficacy and safety of decitabine combined with low/reduced-dose chemotherapy in newly diagnosed acute myeloid leukemia (AML) patients unfit for intensive therapy and to investigate the early prognostic indicators for these patients. Methods: The eligible patients treated with decitabine-based chemotherapy were retrospectively analyzed. Responses and long-term survival were calculated and their correlation with clinical characteristics was analyzed. Minimal residual disease (MRD) detected by flow cytometry (FCM) after the induction therapy was measured, and the association with prognosis was explored. Results: Fifty-five newly diagnosed AML patients were enrolled. The overall response rate (ORR) was 80.0%, with a complete remission (CR) rate of 63.64% and partial remission (PR) rate of 16.36%. Grade 4 hematological toxicity was common, and the incidence of infections was 83.64%, with 18.18% of patients suffered from severe infections. No serious bleeding or non-hematological adverse events occurred. Treatment-related mortality was 3.64%. The median overall survival (OS) and disease-free survival (DFS) were 17.0 (13.7-20.3) months and 17.0 (10.2-23.8) months, respectively. Multivariate analysis showed that an advanced age (≥ 60 years) and higher MRD (≥ 1.34%) after induction therapy were adverse prognostic factors for patients who had achieved CR. Conclusions: Decitabine-based chemotherapy may be a suitable therapeutic alternative for newly diagnosed AML patients who are unfit for intensive chemotherapy. An advanced age (≥ 60 years) and higher MRD (≥ 1.34%) were considered adverse prognostic factors.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Mieloide Aguda/patología , Aclarubicina/administración & dosificación , Adulto , Factores de Edad , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Citarabina/administración & dosificación , Daunorrubicina/administración & dosificación , Decitabina/administración & dosificación , Decitabina/efectos adversos , Supervivencia sin Enfermedad , Femenino , Citometría de Flujo , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Enfermedades Hematológicas/inducido químicamente , Homoharringtonina/administración & dosificación , Humanos , Quimioterapia de Inducción , Estimación de Kaplan-Meier , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Masculino , Persona de Mediana Edad , Neoplasia Residual , Pronóstico , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Imatinibbased targeted treatment is the standard therapy for chronic myeloid leukemia (CML); however, drug resistance is an inevitable issue for imatinibbased CML treatment. Imatinib resistance can be ascribed to BcrAbldependent and independent resistance. In the present study, peripheral blood samples were collected from imatinibsensitive (IS) and imatinibresistant (IR) CML patients and transcriptome sequencing was carried out. From the RNAseq data, a significantly altered IRrelated gene (IRG), ribonucleotide reductase regulatory subunit M2 (RRM2) was identified. Using realtime quantitative fluorescence PCR (qFPCR), we found that RRM2 was elevated in both IR CML patients and an IR cell line. Using reversetranscription PCR (RTPCR) and western blot analysis, we indicated that imatinib can increase RRM2 level in a dosedependent manner in IR cells. We also demonstrated that RRM2 is involved in the Bcl2/caspase cell apoptotic pathway and in the Akt cell signaling pathway, and therefore affects the cell survival following imatinib therapy. The present study, for the first time, indicates that RRM2 is responsible for drug resistance in imatinibbased therapy. Therefore, RRM2 gene can be considered as a potential therapeutic target in the clinical treatment of CML.
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Antineoplásicos/farmacología , Biomarcadores de Tumor/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Mesilato de Imatinib/farmacología , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Ribonucleósido Difosfato Reductasa/antagonistas & inhibidores , Adolescente , Adulto , Anciano , Apoptosis , Biomarcadores de Tumor/genética , Estudios de Casos y Controles , Proliferación Celular , Femenino , Estudios de Seguimiento , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/metabolismo , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Masculino , Persona de Mediana Edad , Pronóstico , Células Tumorales Cultivadas , Adulto JovenRESUMEN
RhoB, a member of the Ras homolog gene family and GTPase, regulates intracellular signaling pathways by interfacing with epidermal growth factor receptor (EGFR), Ras, and phosphatidylinositol 3-kinase (PI3K)/Akt to modulate responses in cellular structure and function. Notably, the EGFR, Ras, and PI3K/Akt pathways can lead to downregulation of RhoB, while simultaneously being associated with an increased propensity for tumorigenesis. Functionally, RhoB, part of the Rho GTPase family, regulates intracellular signaling pathways by interfacing with EGFR, RAS, and PI3K/Akt/mammalian target of rapamycin (mTOR), and MYC pathways to modulate responses in cellular structure and function. Notably, the EGFR, Ras, and PI3K/Akt pathways can lead to downregulation of RhoB, while simultaneously being associated with an increased propensity for tumorigenesis. RHOB expression has a complex regulatory backdrop consisting of multiple histone deacetyltransferase (HDACs 1 and 6) and microRNA (miR-19a, -21, and -223)-mediated mechanisms of modifying expression. The interwoven nature of RhoB's regulatory impact and cellular roles in regulating intracellular vesicle trafficking, cell motion, and the cell cycle lays the foundation for analyzing the link between loss of RhoB and tumorigenesis within the context of age-related decline in RhoB. RhoB appears to play a tissue-specific role in tumorigenesis, as such, uncovering and appreciating the potential for restoration of RHOB expression as a mechanism for cancer prevention or therapeutics serves as a practical application. An in-depth assessment of RhoB will serve as a springboard for investigating and characterizing this key component of numerous intracellular messaging and regulatory pathways that may hold the connection between aging and tumorigenesis.
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Janus nanoparticles (JNPs) have emerged in recent years as new compartmentalized colloids with two sides of different components, chemical properties or morphologies that have opened up a wide range of unique applications in biomedicine. Here, we explored a unique lactobionic acid (LA) modified metallic one-dimensional nanorod/metal organic framework (1D NR/MOF) JNP, the LA-gold NR/zeolitic imidazolate framework-8 (LA-AuNR/ZIF-8) JNP, for computed X-ray tomography (CT) image-guided liver cancer targeted synergistic chemo-photothermal theranostics. Taking advantage of the 1D nanostructure of the AuNRs, polyacrilic acid (PAA) was selectively attached to one side of the AuNRs for further growth of ZIF-8, and the exposed side of the AuNRs was modified with the targeting agent LA, thus realizing the drug loading and cancer specific targeting. In addition, the high contrast of Au makes the LA-AuNR/ZIF-8 JNPs suitable for CT image-guided cancer therapy. Furthermore, mice treated with doxorubicin (DOX) loaded LA-AuNR/ZIF-8 JNPs under near infrared (NIR) laser irradiation showed significant tumor inhibition, indicating the effective combination of pH and NIR stimuli response release, cancer specific targeting and synergistic chemotherapy and photothermal therapy.
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Antineoplásicos/farmacología , Disacáridos/farmacología , Neoplasias Hepáticas/terapia , Estructuras Metalorgánicas/farmacología , Fármacos Fotosensibilizantes/farmacología , Fototerapia , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Disacáridos/química , Ensayos de Selección de Medicamentos Antitumorales , Oro/química , Células Hep G2 , Humanos , Rayos Infrarrojos , Neoplasias Hepáticas/diagnóstico por imagen , Neoplasias Hepáticas Experimentales/diagnóstico por imagen , Neoplasias Hepáticas Experimentales/terapia , Células MCF-7 , Estructuras Metalorgánicas/síntesis química , Estructuras Metalorgánicas/química , Ratones , Ratones Endogámicos BALB C , Nanoestructuras/química , Fármacos Fotosensibilizantes/síntesis química , Fármacos Fotosensibilizantes/química , Tomografía Computarizada por Rayos X , Células Tumorales CultivadasRESUMEN
Circular RNA (CirRNA) is a type of noncoding RNA that has been shown to play a unique role in tumor development and other fields in recent years. In this study, we aimed to explore the biological role of hsa_circ_100290 in acute myeloid leukemia (AML). First, we found that the expression of hsa_circ_100290 was increased in human AML samples and cell lines. Down-regulation of hsa_circ_100290 significantly suppressed cell proliferation of AML cells. Silencing hsa_circ_100290 also dramatically induced cell cycle arrest and apoptosis. Bioinformatic prediction and luciferase assay revealed that hsa_circ_100290 and Rab10 were targeted by miR-203. Validation experiments verified that hsa_circ_100290 was co-expressed with Rab10 and was negatively correlated with miR-203 expression. Moreover, rescue experiments demonstrated that miR-203 inhibitor could reverse the role of hsa_circ_100290 knockdown on proliferation and apoptosis in AML cells. Overall, the present study identifies the crucial regulation of hsa_circ_100290 in AML cell proliferation and apoptosis via targeting the miR-203/Rab10 axis.
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Apoptosis/genética , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , MicroARNs/metabolismo , ARN/metabolismo , Secuencia de Bases , Médula Ósea/patología , Ciclo Celular/genética , Línea Celular Tumoral , Proliferación Celular/genética , Regulación hacia Abajo/genética , Regulación Neoplásica de la Expresión Génica , Humanos , MicroARNs/genética , ARN/genética , ARN Circular , Proteínas de Unión al GTP rab/metabolismoRESUMEN
The aim of this study was to profile the spectrum of genetic mutations in acute myeloid leukemia (AML) patients co-occurring with CEBPA double mutation (CEBPAdm). Between January 1, 2012, and June 30, 2017, 553 consecutive patients with de novo AML were screened for CEBPA mutations. Out of these, 81 patients classified as CEBPAdm were analyzed further by a sensitive next-generation sequencing assay for mutations in 112 candidate genes. Within the CEBPA gene itself, we found 164 mutations. The most common mutated sites were c.936_937insGAG (n = 11/164, 6.71%) and c.939_940insAAG (n = 11/164, 6.71%), followed by c.68dupC (n = 10/164, 6.10%). The most common co-occurring mutations were found in the CSF3R (n = 16/81, 19.75%), WT1 (n = 15/81, 18.52%), and GATA2 (n = 13/81, 16.05%) genes. Patients with CSF3R mutations had an inferior four-year relapse-free survival (RFS) than those with the wild-type gene (15.3% versus 46.8%, respectively; P = 0.021). Patients with WT1 mutations had an inferior five-year RFS compared with those without such mutations (0% versus 26.6%, respectively, P = 0.003). However, GATA2, CSF3R, WT1 mutations had no significant influence on the overall survival. There were some differences in the location of mutational hotspots within the CEBPA gene, as well as hotspots of other co-occurring genetic mutations, between AML patients from Chinese and Caucasian populations. Some co-occurring mutations may be potential candidates for refining the prognoses of AML patients with CEBPAdm in the Chinese population.
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To evaluate nutritional status in adult patients with acute leukemia (AL) using patient-generated subjective global assessment (PG-SGA) and to investigate the influence of nutritional status on prognosis.We observationally investigated 68 adult patients with newly diagnosed AL who received PG-SGA at the First Hospital of Jilin University between May 2013 and July 2015. Clinical features, chemotherapy regimens, biochemical indexes, body composition, complete remission (CR) rate, minimal residual disease (MRD), survival time, and side-effects of chemotherapy were compared between patients with and without severe malnutrition.Mean PG-SGA scores of the total patients were 6.1â±â4.0, and 19 of 68 (27.9%) patients had severe malnutrition (PG-SGA score ≥9). Patients with acute myeloid leukemia (AML) had higher scores than those with acute lymphocytic leukemia (ALL; Pâ=â.011) and high-risk patients had higher scores regardless of whether they had AML or ALL (AML, Pâ=â.012; ALL, Pâ=â.043). Univariate analysis showed that severe malnutrition was correlated with age (Pâ=â.041), transferrin (Pâ=â.042), Karnofsky Performance Status score (Pâ=â.006), and C-reactive protein (CRP) (Pâ=â.018). Multivariate analysis demonstrated that severe malnutrition was associated with CRP (hazard ratio [HR]â=â1.020, 95% confidence interval [CI]: 1.002-1.039, Pâ=â.026). No difference was found in CR rate (Pâ=â.831) between patients with and without malnutrition, but those who were severely malnourished had higher MRD (Pâ=â.048 in AML patients, Pâ=â.036 in ALL patients) and more gastrointestinal side-effects (Pâ=â.014). Severe malnutrition was also associated with inferior overall survival (HRâ=â0.243, 95% CI: 0.063-0.945, Pâ=â.041) but not with event-free survival (HRâ=â0.808, 95% CI: 0.338-1.934, Pâ=â.663).Severe malnutrition defined by PG-SGA in adult patients with de novo AL may result in poor outcome.
Asunto(s)
Autoevaluación Diagnóstica , Leucemia Mieloide Aguda/complicaciones , Desnutrición/diagnóstico , Desnutrición/etiología , Evaluación Nutricional , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicaciones , Adulto , Estudios de Cohortes , Estudios de Factibilidad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estado Nutricional , Estudios Retrospectivos , Índice de Severidad de la EnfermedadRESUMEN
The aim of this study was to investigate the clinical characteristics and efficacy of chronic myeloid leukemia (CML) onset with extreme thrombocytosis. A total of 121 newly diagnosed and untreated CML patients in chronic phase with complete clinical information from the First Hospital of Jilin University, from January 2010 to December 2014 were retrospectively recruited. Based on the platelet (PLT) count, 22 patients were assigned into CML with thrombocytosis (CML-T) group (PLT >1,000×109/L) and 65 patients were classified into CML without extreme thrombocytosis (CML-N) group (PLT ≤1,000×109/L). Fifty-four point five percent of patients in the CML-T group were female, which was higher than that in the CML-N group (27.7%) (P=0.022). Except for gender, there was no significant difference for clinical information of patients between the two groups. For Sokal and Hasford scoring systems, the percentage of patients at high risk in the CML-T group were higher than those in the CML-N group, 95.5% vs 52.3% (P=0.000) and 68.2% vs 41.5% (P=0.031), respectively; however, there was no significant difference for European Treatment and Outcome Study (EUTOS) score system between the two groups (P=0.213). In terms of major molecular response (MMR) rate, the percent of patients with MMR in CML-T group was lower than that in CML-N group at 36 months after tyrosine kinase inhibitor therapy (P=0.037). Up until December 2016, the median of event-free survival was 21 months in the CML-T group, however, that was not reached in the CML-N group (P=0.027). The majority of CML patients with extreme thrombocytosis were females, and compared to patients in the CML-N group, the percentage of high risk patients based on the Sokal and Hasford scoring systems was higher in the CML-T group, and the median event-free survival of patients was shorter.
RESUMEN
Breast cancer is the most common carcinoma among Chinese women. Interferon α (IFNα) has been used to treat various types of cancer, including breast cancer, but its antitumor activity is relative low, which significantly hinders its clinical application. In this study, we utilized a Ph.D.-12 peptide library screening system to identify a short peptide that specifically binds to MCF-7 breast cancer cells. By fusing the MCF-7 binding peptide (MBP) to the C-terminus of IFNα, we constructed an engineered IFNα-MBP fusion molecule (IMBP), and applied this novel fusion protein to the treatment of breast cancer. We found that IMBP exhibited significantly higher activity than wild-type IFNα in inhibiting cell growth and inducing cell apoptosis. Additionally, IMBP potentiated the therapeutic efficacy of doxorubicin-based breast cancer chemotherapy via the activation of cell cycle arrest and cell apoptosis pathway genes including p53, p21, CDK2, cyclin A, caspase 9, Bcl-2 and Bax. The enhanced activity of the synthetic IMBP was also associated with the activation of signal transducer and activation of transcription 1 (STAT1) pathway target genes (STAT1, IFIT1, IFITM1 and MX1). This study evaluated the potential value of the synthetic IMBP as a novel anti-breast cancer agent.