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This study aimed to develop and validate a prognostic nomogram that combines clinical and sociodemographic factors of patients with newly diagnosed multiple myeloma (MM). A total of 257 newly diagnosed patients with MM from two independent medical centers in China were included in this retrospective cohort study. Univariate and multivariate Cox regression models were used to identify independent risk factors and to construct the nomogram. The predictive ability of the nomogram was evaluated using the areas under the curve (AUCs) and calibration curves. K-fold cross-validation was employed for internal validation of the nomogram performance. Moreover, a stratification system to determine risk level was generated based on the nomogram. Hemoglobulin, creatinine, rurality, and marital status were significantly associated with overall survival (OS) and were incorporated into the nomogram for OS prediction. The prognostic nomogram showed good discrimination and accuracy, and its predictive capability was superior to the International Staging System. The AUC values predicting the 1-, 3-, and 5-year OS probabilities of the nomogram were 0.775, 0.755, and 0.754, respectively. Subsequently, patients were classified into high- and low-risk subgroups based on the median total points of the nomogram; this risk stratification clearly distinguished between high- and low-risk MM patients with significantly different clinical outcomes (median OS: 27 months vs. 84 months). We established a novel prognostic prediction model by comprehensively incorporating clinical and sociodemographic variables, which can effectively predict the survival outcomes in patients with MM.
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Objective: This study aimed to comprehensively investigate the relationship between the survival differences and socioeconomic status (SES) in patients with multiple myeloma (MM) and construct a predictive nomogram to assess clinical outcomes of MM patients. Methods: The Surveillance, Epidemiology, and End Results (SEER) census tract-level SES database provides two specialized attributes: SES index and rurality. Using this database, 37,819 patients diagnosed with MM between January 2007 and December 2016 were enrolled. We evaluated the effects of SES index on overall survival (OS) and myeloma-specific survival (MSS) using Kaplan-Meier curves and Cox regression analyses. Thereafter, we included 126 patients with MM from two independent medical centers in China and divided them into training (Center 1) and validation (Center 2) cohorts. Univariate and multivariate Cox analyses were used in the training cohort to construct a nomogram for predicting clinical outcomes. Nomogram performance was assessed using the area under the curve (AUC) and calibration curves. Results: In the SEER cohort, lower SES was significantly associated with worse OS rates and MSS rates (both P < 0.001). Multivariate analysis confirmed SES as an independent predictor of survival. Subgroup analysis indicated an increasing linear trend in survival benefits in non-Hispanic White, married, insured, and urban populations with increasing SES (all P < 0.001). In the training cohort, albumin, creatinine, rurality, and SES were confirmed as independent prognostic indicators. A nomogram for OS prediction was developed using these four factors, and it showed satisfactory discrimination and calibration. The 18- and 36-month AUC values of the nomogram were 0.79 and 0.82, respectively. Based on the total nomogram points, patients were categorized into two risk levels with good separation. Conclusion: SES strongly influences survival disparities in patients with MM. Our nomogram consisting of clinical and sociodemographic characteristics can potentially predict survival outcomes.
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Multiple myeloma (MM) is an incurable plasma cell malignancy with a poor survival rate. Conventional chemotherapeutic agent-induced adverse events, including toxicity, neuropathy or drug resistance, significantly decrease the patients' quality of life and can even lead to interruption of treatment. Therefore, novel therapeutic drugs and strategies are urgently needed to improve MM therapy and patient outcomes. Here, we show that solamargine (SM), a steroidal alkaloid glycoside isolated from a Chinese herb Solanum nigrum L., exhibits promising anti-MM activity. In particular, SM suppressed the viability of MM cell lines (ARP-1 and NCI-H929) in a concentration- and time-dependent manner, inducing apoptosis in these cells. RNA-seq analysis showed that treatment with SM led to the upregulation of genes associated with cell death and autophagy in H929 cells. Further, we found that treatment with SM activated autophagy in the MM cells, as incubation with 3-Methyladenine, an inhibitor of autophagy, significantly alleviated SM-triggered apoptosis and inhibition of viability in MM cells. Interestingly, we also observed a synergistic effect between SM and bortezomib (BTZ), a common chemotherapeutic agent for MM, in both MM cells and human bone marrow CD138+ primary myeloma cells. We also confirmed the single-agent efficacy of SM and the synergistic effects between SM and BTZ in an MM xenograft mouse model. Collectively, these findings indicate that SM exerts an anti-MM effect, at least in part, by activating cell autophagy and reveal that SM alone or in combination with BTZ is a potential therapeutic strategy for treating MM.
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Antineoplásicos , Mieloma Múltiplo , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose , Autofagia , Bortezomib/farmacologia , Bortezomib/uso terapêutico , Linhagem Celular Tumoral , Humanos , Camundongos , Mieloma Múltiplo/patologia , Qualidade de Vida , Alcaloides de SolanáceasAssuntos
GTP Fosfo-Hidrolases/genética , Leucemia Neutrofílica Crônica/genética , Proteínas de Membrana/genética , Paraproteinemias/complicações , Derrame Pericárdico/complicações , Proteínas Repressoras/genética , Idoso , Humanos , Imunofenotipagem , Leucemia Neutrofílica Crônica/sangue , Leucemia Neutrofílica Crônica/complicações , Leucemia Neutrofílica Crônica/fisiopatologia , Masculino , Mutação , Esplenomegalia/diagnóstico por imagem , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: A variety of microRNAs (miRNAs) are aberrantly expressed in acute myeloid leukemia (AML), and these dysregulated miRNAs perform crucial roles in tumorigenesis and progression of AML. miR-628-3p (miR-628), one of the miRNAs dysregulated in multiple types of human cancers, exerts antitumor roles in different cancer types. However, no specific study has explored the expression pattern and role of miR-628 in AML. MATERIALS AND METHODS: In this study, RT-qPCR was performed to detect miR-628 expression in AML tissues and cell lines. CCK-8 assay, flow cytometry analysis and xenograft tumor experiment was carried out to determine the functions of miR-628 in AML cells. The possible mechanism underlying the activity of miR-628 in AML cells was also explored using a series of experiments. RESULTS: Our results revealed the downregulated expression of miR-628 in patients with AML and AML cell lines. Ectopic expression of miR-628 resulted in the inhibition of AML cell proliferation and induction of cell cycle arrest and apoptosis in vitro and attenuation of tumor growth in vivo. Insulin-like growth factor 1 receptor (IGF-1R) was identified as a direct target gene of miR-628 in AML cells. IGF-1R expression was upregulated in patients with AML and upregulation of IGF-1R expression inversely correlated with miR-628 level. Furthermore, IGF-1R knockdown imitated the tumor suppressive effect of miR-628 in AML cells. Restoration of IGF-1R expression abrogated the effects of miR-628 on the proliferation, cycle status, and apoptosis rate of AML cells. miR-628 inhibited the activation of phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/protein kinase B (Akt) pathway in AML cells both in vitro and in vivo through the inhibition of IGF-1R expression. CONCLUSION: Our results demonstrate that miR-628 exhibits antitumor effects in AML through the direct targeting of IGF-1R and regulation of PI3K/Akt pathway, suggestive of its potential role as a therapeutic target in patients with this aggressive hematological malignant tumor.
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The MECOM gene encoding a zinc finger protein that functions as a transcription factor, was located on chromosome 3q26, and rearrangements of MECOM often cause its overexpression in acute myeloid leukemia (AML). We identified H2AFY as a novel fusion gene partner of MECOM in an elderly male AML patient with cryptic 3q26 rearrangement using the whole transcriptome sequencing, who carried out abnormal karyotype of 46,XY,t(3;5)(q27;q31),add(14)(p11). We validated the existence of the unreported H2AFY-MECOM fusion gene by RT-PCR and Sanger DNA sequencing, and detected mutations of NRAS and BCOR in this patient. In addition, we found abnormally elevated expression of MECOM in this patient by quantitative-polymerase chain reaction (RQ-PCR). Further research is needed to investigate functional characterizations of this novel fusion in the development of AML.
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Histonas/genética , Leucemia Mieloide Aguda/genética , Proteína do Locus do Complexo MDS1 e EVI1/genética , Proteínas de Fusão Oncogênica/genética , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cromossomos Humanos Par 3 , Cromossomos Humanos Par 5 , Evolução Fatal , Rearranjo Gênico , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Humanos , Quimioterapia de Indução , Cariotipagem , Leucemia Mieloide Aguda/tratamento farmacológico , Masculino , Reação em Cadeia da Polimerase em Tempo Real , Análise de Sequência de DNA , Translocação GenéticaRESUMO
The stromal antigen 2 (STAG2) gene encodes a component of the cohesin complex that participates in the regulation of sister chromatid separation during mitosis. When activated, STAG2 may act as a 'caretaker' tumor suppressor gene. As it is unknown whether STAG2 gene is responsible for the occurrence and associated with the prognosis of acute myeloid leukemia (AML), the present study analyzed the relative expression levels of STAG2 in 127 de novo AML patients and 17 healthy volunteers using reverse transcription-quantitative polymerase chain reaction. In addition, AML patients were divided into three risk groups using cytogenetic and molecular genetic abnormalities to define their risk status. STAG2 gene expression was found to be significantly downregulated in de novo AML patients, when compared with the healthy controls; however, the expression was not significantly different in the various gender and age subgroups. Furthermore, no significant difference between risk groups was detected in AML patients. Thus, the STAG2 gene may serve an important role in AML development, but is not associated with prognosis in AML.
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Apoptose , Alcaloides , Células HL-60 , Harringtoninas , Mepesuccinato de Omacetaxina , Humanos , Quinolizinas , MatrinasRESUMO
Post-transplant lymphoproliferative disorders originating from T lymphocytes are a rare complication of allogeneic haematopoietic stem cell transplantation (allo-HSCT) that are not usually associated with Epstein-Barr virus infection. A male patient diagnosed at the age of 15 years with chronic myeloid leukaemia (in the chronic phase) was initially treated with oral hydroxyurea. The disease entered an accelerated phase when the patient was 22 years old. Complete remission was achieved after one course of homoharringtonine and cytarabine. The patient then underwent human leucocyte antigen-matched sibling donor allo-HSCT. Just over 6.5 years after the allo-HSCT, a second primary tumour was located in the distal femur and diagnosed as T-cell non-Hodgkin's lymphoma (stage IV, group B). This was treated with various chemotherapy and radiotherapy regimens, but the outcomes were poor and the disease progressed. The T-cell lymphoma invaded many sites, including the skeleton, spleen and skin, and the patient died within 8 months of the diagnosis. This current case report highlights the need for the early detection and prevention of subsequent primary malignancies after allo-HSCT.
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Transplante de Células-Tronco Hematopoéticas , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Linfoma de Células T/tratamento farmacológico , Linfoma de Células T/radioterapia , Adulto , Inibidores da Angiogênese/uso terapêutico , Antimetabólitos Antineoplásicos/uso terapêutico , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cisplatino/uso terapêutico , Citarabina/uso terapêutico , Dexametasona/uso terapêutico , Harringtoninas/uso terapêutico , Mepesuccinato de Omacetaxina , Humanos , Hidroxiureia/uso terapêutico , Linfoma de Células T/mortalidade , Masculino , Invasividade Neoplásica/patologia , Transplante HomólogoRESUMO
Acute promyelocytic leukemia (APL) is characterized by the generation of the PML-RARα fusion transcript as a result of a reciprocal chromosomal rearrangement, t(15;17)(q22;q12), with breakpoints within the PML gene and the RARα gene. In a small proportion of APL cases, RARα is fused with a number of alternative partner genes. The signal transducer and activator of transcription 5 beta (STAT5b) is one of the variant partners. Here, we describe one rare case with all-trans retinoic acid (ATRA) -unresponsive APL characterized by the STAT5b-RARα fusion transcript. Morphology and immunophenotypic analyses indicated the typical features of APL; however, cytogenetic analysis exhibited a normal karyotype, and importantly, results of interphase fluorescence in situ hybridization (FISH) or reverse transcriptase-polymerase chain reaction (RT-PCR) analysis indicated that PML-RARα expression was negative. FISH analysis with the RARα dual-color break-apart rearrangement probe indicated a submicroscopic deletion of the 3' end of one RARA gene. Indeed, the STAT5b-RARα fusion transcript was found in this case by array-based comparative genomic hybridization and nested RT-PCR. To the best of our knowledge, we report here only the sixth APL patient in the world with the STAT5b-RARα fusion transcript. Additional clinical studies concerning the prognosis, response to therapy, and pathogenesis of APL patients with STAT5b-RARα fusion are necessary.