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Eltrombopag combined with immunosuppressive therapy (IST) was superior to IST alone for severe aplastic anemia (SAA) in the previous studies. But in China, horse antithymocyte globulin (hATG) is not available, instead, we use rabbit ATG (rATG). Here, we compared the efficacy and safety of IST (rATG combined with cyclosporine) combined with or without eltrombopag for the first-line treatment of SAA and very severe aplastic anemia (VSAA). A total of 371 patients in ten institutions in China from April 1, 2017 to December 1, 2022 were enrolled. The overall response (OR) rate at 3 months (54.2% vs. 41%; P = 0.046), the complete response (CR) (31.3% vs. 19.4%; P = 0.041) and OR (78.3% vs. 51.1%; P < 0.0001) rates at 6 months were significantly higher with IST combined with eltrombopag than with IST alone in SAA patients. While in VSAA patients, the addition of eltrombopag to IST only increased the CR rate at 6 months (29.8% vs. 9.43%; P = 0.010). Liver injury increased significantly in groups treated with IST combined with eltrombopag (P < 0.05). Serious treatment-related toxicities were similar (P > 0.05). In patients with SAA, 3-year failure-free survival (FFS) of eltrombopag combined with IST group was significantly higher than that of IST group (70.7 ± 5.3% vs. 50.3 ± 3.9%; P = 0.007). In patients with VSAA, the addition of eltrombopag significantly improved 3-year overall survival (OS) (82.2 ± 5.7% vs. 57.3 ± 7.2%; P = 0.020). Our findings suggested that IST combined with eltrombopag could improve the hematological recovery of newly diagnosed SAA without increasing severe toxicities. But in VSAA, the addition of eltrombopag seemed to show no other improvement to efficacy except the CR rate at 6 months.
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Anemia Aplástica , Soro Antilinfocitário , Benzoatos , Hidrazinas , Imunossupressores , Pirazóis , Anemia Aplástica/tratamento farmacológico , Anemia Aplástica/mortalidade , Benzoatos/uso terapêutico , Pirazóis/uso terapêutico , Pirazóis/efeitos adversos , Humanos , Hidrazinas/uso terapêutico , Hidrazinas/administração & dosagem , Hidrazinas/efeitos adversos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Adolescente , Imunossupressores/uso terapêutico , Soro Antilinfocitário/uso terapêutico , Soro Antilinfocitário/administração & dosagem , Adulto Jovem , Idoso , Estudos Retrospectivos , Quimioterapia Combinada , Criança , Resultado do Tratamento , Índice de Gravidade de Doença , Pré-Escolar , Ciclosporina/uso terapêutico , Ciclosporina/administração & dosagem , China/epidemiologia , Taxa de SobrevidaRESUMO
Crovalimab is a novel C5 complement inhibitor that enables rapid and sustained C5 inhibition with subcutaneous, low-volume self-administration every 4 weeks. COMMODORE 2 (NCT04434092) is a global, randomized, open-label, multicenter, phase 3 trial evaluating the non-inferiority of crovalimab versus eculizumab in patients with paroxysmal nocturnal hemoglobinuria not previously treated with C5 inhibition. C5 inhibitor-naive patients with lactate dehydrogenase (LDH) ≥2 × upper limit of normal (ULN) were randomized 2:1 to crovalimab or eculizumab. Co-primary efficacy endpoints were proportion of patients with hemolysis control (centrally assessed LDH ≤1.5 × ULN) and proportion with transfusion avoidance. Secondary efficacy endpoints were proportions of patients with breakthrough hemolysis, stabilized hemoglobin, and change in FACIT-Fatigue score. The primary treatment period was 24 weeks. Two hundred and four patients were randomized (135 crovalimab; 69 eculizumab). Crovalimab was non-inferior to eculizumab in the co-primary endpoints of hemolysis control (79.3% vs. 79.0%; odds ratio, 1.0 [95% CI, 0.6, 1.8]) and transfusion avoidance (65.7% vs. 68.1%; weighted difference, -2.8 [-15.7, 11.1]), and in the secondary efficacy endpoints of breakthrough hemolysis (10.4% vs. 14.5%; weighted difference, -3.9 [-14.8, 5.3]) and hemoglobin stabilization (63.4% vs. 60.9%; weighted difference, 2.2 [-11.4, 16.3]). A clinically meaningful improvement in FACIT-Fatigue score occurred in both arms. Complete terminal complement activity inhibition was generally maintained with crovalimab. The safety profiles of crovalimab and eculizumab were similar with no meningococcal infections. Most patients who switched from eculizumab to crovalimab after the primary treatment period preferred crovalimab. These data demonstrate the positive benefit-risk profile of crovalimab.
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Anticorpos Monoclonais Humanizados , Inativadores do Complemento , Hemoglobinúria Paroxística , Humanos , Hemoglobinúria Paroxística/tratamento farmacológico , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/administração & dosagem , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Inativadores do Complemento/uso terapêutico , Inativadores do Complemento/efeitos adversos , Hemólise/efeitos dos fármacos , Complemento C5/antagonistas & inibidores , IdosoRESUMO
The role of mammalian target of rapamycin and its suppressor sirolimus in the regulation of hematopoietic stem and progenitor cells (HSPCs) is controversial. We show here that sirolimus enhanced regeneration of HSPCs in mice exposed to sublethal total body irradiation (TBI) and other regenerative stressors. Sorted Lin- CD150+ bone marrow cells from sirolimus-treated TBI mice had increased expression of c-Kit and other hematopoietic genes. HSPCs from sirolimus-treated TBI mice were functionally competent when tested by competitive engraftment in vivo. Postradiation regeneration of HSPCs in mice treated with sirolimus was accompanied by decreased γ-H2AX levels detected by flow cytometry and increased expression of DNA repair genes by quantitative polymerase chain reaction. Reduction of cell death and DNA damage post-radiation by sirolimus was associated with enhanced clearance of cellular reactive oxygen species (ROS) in HSPCs. Increased HSPC recovery with sirolimus was also observed in mice injected with hematoxic agents, busulfan and 5-fluorouracil. In contrast, sirolimus showed no effect on HSPCs in normal mice at steady state, but stimulated HSPC expansion in mice carrying the Wv mutation at the c-Kit locus. In human to mouse xenotransplantation, sirolimus enhanced engraftment of irradiated human CD34+ cells. In summary, our results are consistent with sirolimus' acceleration of HSPC recovery in response to hematopoietic stress, associated with reduced DNA damage and ROS. Sirolimus might have clinical application for the treatment and prevention of hematopoietic injury.
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Transplante de Células-Tronco Hematopoéticas/métodos , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/fisiologia , Imunossupressores/farmacologia , Sirolimo/farmacologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Sobrevivência Celular/efeitos da radiação , Fluoruracila/toxicidade , Células-Tronco Hematopoéticas/efeitos da radiação , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Células-Tronco/efeitos dos fármacos , Células-Tronco/fisiologia , Células-Tronco/efeitos da radiação , Irradiação Corporal Total/efeitos adversosRESUMO
BACKGROUND: Long non-coding RNAs (lncRNAs), a vital component of functional regulators, are involved in various human cancers development, including diffuse large B-cell lymphoma (DLBCL). In particular, lncRNA HAGLROS has been reported to be associated with several types of cancer in humans. Nevertheless, the role of HAGLROS in DLBCL has yet to be described. METHODS: The HAGLROS expression patterns and its relationship with clinicopathological features and survival were investigated in DLBCL patients. CCK-8 and transwell assays were used to analyze the cell proliferation, migration, and invasion capacities. AGO2-RIP, dual-luciferase assay, RT-qPCR, and rescue experiments were fulfilled to measure the physical interaction between HAGLROS and miR-100. Xenograft assay was conducted to test tumor growth ability. RESULTS: HAGLROS was upregulated in DLBCL tissues and cells, and closely associated with advanced clinicopathological features. Upregulation of HAGLROS resulted in poor survival outcomes in DLBCL patients. In addition, HAGLROS knockdown inhibited the proliferation, migration, and invasion of DLBCL cells in vitro. Further experiments revealed that HAGLROS negatively regulated the expression of miR-100 in DLBCL, and the expression of miR-100 and HAGLROS showed an inverse correlation in DLBCL tissues. HAGLROS functioned as a competing endogenous RNA for miR-100 in DLBCL cells, and miR-100 overexpression abolished the oncogenic effects of HAGLROS upregulation on DLBCL progression. Besides, in-vivo assays revealed that HAGLROS knockdown suppressed tumor growth in nude mice. CONCLUSION: HAGLROS overexpression contributes to DLBCL development and poor prognosis via targeting miR-100, which could be a potential prognostic biomarker and therapeutic target for DLBCL patients.
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Linfoma Difuso de Grandes Células B , MicroRNAs/genética , RNA Longo não Codificante/genética , Adulto , Idoso , Animais , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Feminino , Humanos , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/mortalidade , Linfoma Difuso de Grandes Células B/patologia , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Adulto JovemRESUMO
BACKGROUND: Liquid-liquid phase separation (LLPS) within the nucleus is directly linked to driving gene expression through transcriptional complexes. Histone lysine methyltransferase 2D (KMT2D) is widely present in many cancers. It is known to epigenetically stimulate the expression of genes associated with tumorigenesis and metastasis. Our analyses show that KMT2D possesses two distinct low-complexity domains (LCDs) capable of driving the assembly of membrane-less condensates. The dependence of the mechanisms underlying monomethylation of H3K4 on the LLPS microenvironment derived from KMT2D LCDs is unclear in tumor. METHODS: KMT2D LCD-depletion cells were used to investigate tumor cell proliferation, apoptosis, and migration. We identified some core proteins, including WDR5, RBBP5, and ASH2L, which are involved in the KMT2D-associated catalytic complex in KMT2D LCD-deficient cells to further elucidate the mechanism that decreases monomethylation of H3K4. We also evaluated the viability of KMT2D LCD-deficient cells in vivo. Finally, using 1,6-hexanediol (HD), an inhibitor of LLPS, we determined cell activities associated with KMT2D function in wild-type PANC-1 cells. RESULTS: Without the LLPS microenvironment in KMT2D LCD-deficient cells or wild-type PANC-1 cells treated with HD, the WDR5 protein was significantly less stable and the protein-protein interactions between the components of the KMT2D-enzyme complex were attenuated, impairing the formation of the complex. Moreover, with the decrease in H3K4me1 level at enhancers, transcription factors such as LIFR and KLF4 were markedly downregulated, effectively inhibiting tumor progression. In xenograft tumor models, PANC-1 cells lacking the KMT2D LCDs showed effectively suppressed tumor growth compared to normal cells. CONCLUSIONS: Our data indicate that the two low-complexity domains of the KMT2D protein could form a stable LLPS microenvironment, promoting the KMT2D catalysis of H3K4 monomethylation through stabilization of the WDR5 protein and KMT2D-enzyme complex. Therefore, finding ways to regulate the LLPS microenvironment will be benefitial for new cancer treatment strategies.
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Proteínas de Ligação a DNA/genética , Histonas/genética , Proteínas de Neoplasias/genética , Neoplasias Pancreáticas/genética , Domínios Proteicos/genética , Transcrição Gênica/genética , Animais , Carcinogênese/genética , Linhagem Celular , Proliferação de Células/genética , Feminino , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Pancreáticas/patologia , Mapas de Interação de Proteínas/genética , Fatores de Transcrição/genéticaRESUMO
Interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) have been implicated historically in the immune pathophysiology of aplastic anemia (AA) and other bone marrow (BM) failure syndromes. We recently defined the essential roles of IFN-γ produced by donor T cells and the IFN-γ receptor in the host in murine immune-mediated BM failure models. TNF-α has been assumed to function similarly to IFN-γ. We used our murine models and mice genetically deficient in TNF-α or TNF-α receptors (TNF-αRs) to establish an analogous mechanism. Unexpectedly, infusion of TNF-α-/- donor lymph node (LN) cells into CByB6F1 recipients or injection of FVB LN cells into TNF-αR-/- recipients both induced BM failure, with concurrent marked increases in plasma IFN-γ and TNF-α levels. Surprisingly, in TNF-α-/- recipients, BM damage was attenuated, suggesting that TNF-α of host origin was essential for immune destruction of hematopoiesis. Depletion of host macrophages before LN injection reduced T-cell IFN-γ levels and reduced BM damage, whereas injection of recombinant TNF-α into FVB-LN cell-infused TNF-α-/- recipients increased T-cell IFN-γ expression and accelerated BM damage. Furthermore, infusion of TNF-αR-/- donor LN cells into CByB6F1 recipients reduced BM T-cell infiltration, suppressed T-cell IFN-γ production, and alleviated BM destruction. Thus, TNF-α from host macrophages and TNF-αR expressed on donor effector T cells were critical in the pathogenesis of murine immune-mediated BM failure, acting by modulation of IFN-γ secretion. In AA patients, TNF-α-producing macrophages in the BM were more frequent than in healthy controls, suggesting the involvement of this cytokine and these cells in human disease.
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Anemia Aplástica/imunologia , Doenças da Medula Óssea/imunologia , Hemoglobinúria Paroxística/imunologia , Macrófagos/imunologia , Linfócitos T/imunologia , Fator de Necrose Tumoral alfa/imunologia , Aloenxertos , Anemia Aplástica/genética , Anemia Aplástica/patologia , Anemia Aplástica/terapia , Animais , Doenças da Medula Óssea/genética , Doenças da Medula Óssea/patologia , Doenças da Medula Óssea/terapia , Transtornos da Insuficiência da Medula Óssea , Transplante de Medula Óssea , Hemoglobinúria Paroxística/genética , Hemoglobinúria Paroxística/patologia , Hemoglobinúria Paroxística/terapia , Humanos , Interferon gama/genética , Interferon gama/imunologia , Macrófagos/patologia , Camundongos , Camundongos Knockout , Linfócitos T/patologia , Fator de Necrose Tumoral alfa/genéticaRESUMO
BACKGROUND: Aberrant expression of long non-coding RNAs (lncRNAs) is closely associated with development and prognosis of human cancers. LncRNA SNHG16 is reportedly involved in human cancer; however, its roles in multiple myeloma (MM) remain unclear. METHODS: In this study, we investigated the function and molecular mechanisms of SNHG16 in MM. MM cells were transfected with si-SNHG16 or si-NC. SNHG16 expression levels was measured by qRT-PCR. Cell proliferation was monitored using the MTS. Flow cytometry assay was performed to measure the cell cycle and apoptosis. Luciferase reporter assay were performed to confirm the sponged miRNAs of SNHG16. RESULTS: SNHG16 expression was up-regulated in MM tissues. SNHG16 knockdown suppressed cell proliferation, arrested cell cycle transition from G1 to S phase, and promoted the apoptosis of MM cells. Moreover, SNHG16 knockdown promoted cleaved-Caspase-3, cleaved-Caspase-9, Foxa3a, and Bax expression, while markedly inhibiting CCND1, Bcl-2, Cyclin D1, PI3K, and p-AKT expression in MM cells. miR-342-3p was a direct target of SNHG16. SNHG16 knockdown significantly increased miR-342-3p expression in MM cells. Overexpression miR-342-3p markedly suppressed cell proliferation, arrested cell cycle transition from G1 to S phase, and promoted apoptosis of MM cells. Overexpression of miR-342-3p markedly promoted cleaved-Caspase-3/-9, Foxa3a, and Bax expression, and inhibited CCND1, Bcl-2, Cyclin D1, PI3K, and p-AKT expression in MM cells. Additionally, repression of miR-342-3p could rescue the effect of SNHG16 knockdown on MM cell proliferation, cycle arrest, apoptosis, and related protein expression. CONCLUSION: Knockdown of lncRNA SNHG16 suppresses MM cell proliferation by sponging miR-342-3p, implicating SNHG16 as a novel therapeutic target for MM.
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Oligoclonal expansion of CD8+ CD28- lymphocytes has been considered indirect evidence for a pathogenic immune response in acquired aplastic anemia. A subset of CD8+ CD28- cells with CD57 expression, termed effector memory cells, is expanded in several immune-mediated diseases and may have a role in immune surveillance. We hypothesized that effector memory CD8+CD28-CD57+ cells may drive aberrant oligoclonal expansion in aplastic anemia. We found CD8+CD57+ cells frequently expanded in the blood of aplastic anemia patients, with oligoclonal characteristics by flow cytometric Vß usage analysis: skewing in 1-5 Vß families and frequencies of immunodominant clones ranging from 1.98% to 66.5%. Oligoclonal characteristics were also observed in total CD8+ cells from aplastic anemia patients with CD8+CD57+ cell expansion by T-cell receptor deep sequencing, as well as the presence of 1-3 immunodominant clones. Oligoclonality was confirmed by T-cell receptor repertoire deep sequencing of enriched CD8+CD57+ cells, which also showed decreased diversity compared to total CD4+ and CD8+ cell pools. From analysis of complementarity-determining region 3 sequences in the CD8+ cell pool, a total of 29 sequences were shared between patients and controls, but these sequences were highly expressed in aplastic anemia subjects and also present in their immunodominant clones. In summary, expansion of effector memory CD8+ T cells is frequent in aplastic anemia and mirrors Vß oligoclonal expansion. Flow cytometric Vß usage analysis combined with deep sequencing technologies allows high resolution characterization of the T-cell receptor repertoire, and might represent a useful tool in the diagnosis and periodic evaluation of aplastic anemia patients. (Registered at clinicaltrials.gov identifiers: 00001620, 01623167, 00001397, 00071045, 00081523, 00961064).
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Anemia Aplástica/imunologia , Antígenos CD57/imunologia , Linfócitos T CD8-Positivos/imunologia , Células Clonais/imunologia , Regiões Determinantes de Complementaridade/imunologia , Memória Imunológica/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Anemia Aplástica/genética , Anemia Aplástica/patologia , Antígenos CD57/genética , Linfócitos T CD8-Positivos/metabolismo , Estudos de Casos e Controles , Células Clonais/metabolismo , Células Clonais/patologia , Regiões Determinantes de Complementaridade/genética , Citometria de Fluxo/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Memória Imunológica/genética , Receptores de Antígenos de Linfócitos T alfa-beta/genéticaRESUMO
Acquired aplastic anemia, the prototypical bone marrow failure disease, is characterized by pancytopenia and marrow hypoplasia. Most aplastic anemia patients respond to immunosuppressive therapy, usually with anti-thymocyte globulin and cyclosporine, but some relapse on cyclosporine withdrawal or require long-term administration of cyclosporine to maintain blood counts. In this study, we tested efficacy of rapamycin as a new or alternative treatment in mouse models of immune-mediated bone marrow failure. Rapamycin ameliorated pancytopenia, improved bone marrow cellularity, and extended animal survival in a manner comparable to the standard dose of cyclosporine. Rapamycin effectively reduced Th1 inflammatory cytokines interferon-γ and tumor necrosis factor-α, increased the Th2 cytokine interleukin-10, stimulated expansion of functional regulatory T cells, eliminated effector CD8+ T cells (notably T cells specific to target cells bearing minor histocompatibility antigen H60), and preserved hematopoietic stem and progenitor cells. Rapamycin, but not cyclosporine, reduced the proportion of memory and effector T cells and maintained a pool of naïve T cells. Cyclosporine increased cytoplasmic nuclear factor of activated T-cells-1 following T-cell receptor stimulation, whereas rapamycin suppressed phosphorylation of two key signaling molecules in the mammalian target of rapamycin pathway, S6 kinase and protein kinase B. In summary, rapamycin was an effective therapy in mouse models of immune-mediated bone marrow failure, acting through different mechanisms to cyclosporine. Its specific expansion of regulatory T cells and elimination of clonogenic CD8+ effectors support its potential clinical utility in the treatment of aplastic anemia.
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Anemia Aplástica/imunologia , Anemia Aplástica/patologia , Doenças da Medula Óssea/imunologia , Doenças da Medula Óssea/patologia , Medula Óssea/imunologia , Medula Óssea/patologia , Hemoglobinúria Paroxística/imunologia , Hemoglobinúria Paroxística/patologia , Imunossupressores/farmacologia , Sirolimo/farmacologia , Anemia Aplástica/tratamento farmacológico , Anemia Aplástica/metabolismo , Anemia Aplástica/mortalidade , Animais , Medula Óssea/efeitos dos fármacos , Doenças da Medula Óssea/tratamento farmacológico , Doenças da Medula Óssea/mortalidade , Transtornos da Insuficiência da Medula Óssea , Modelos Animais de Doenças , Epitopos de Linfócito T/imunologia , Hemoglobinúria Paroxística/tratamento farmacológico , Hemoglobinúria Paroxística/mortalidade , Memória Imunológica , Camundongos , Pancitopenia/imunologia , Pancitopenia/patologia , Transdução de Sinais , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Resultado do TratamentoRESUMO
OBJECTIVE: This retrospective study was designed to determine the efficacy and safety of low-dose bortezomib and dexamethasone (lBD) in elderly Chinese patients with WaldenstrÓ§m macroglobulinemia (WM). METHODS: Ten patients with WM aged over 60 years received first-line treatment with lBD. RESULTS: The median age was 70 years (range, 61-77 years). The overall response rate was 80%, including 1 patient who achieved a complete response, 1 patient with very good partial response, and 6 patients with a partial response. Median time to response was 1.8 months after treatment with lBD. Six (60%) patients achieved a partial response, including 2 (20%) patients who had a more than 75% reduction in serum immunoglobulin M levels. A rapid reduction in paraprotein was observed in three patients who received plasmapheresis. After a median follow-up period of 36 months, all patients were still alive and six had no disease progression. The estimated median time to progression was 39 months (range, 15-60 months). The most common adverse events were anemia, thrombocytopenia, neuropathy, and neutropenia. Peripheral neuropathy was the most common non-hematological toxicity in six (60%) patients, but did not result in the discontinuation of bortezomib. CONCLUSIONS: Our findings show that lBD is an effective and tolerable treatment regimen for elderly patients with WM.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Macroglobulinemia de Waldenstrom/tratamento farmacológico , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Biomarcadores , Bortezomib/administração & dosagem , Dexametasona/administração & dosagem , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento , Macroglobulinemia de Waldenstrom/diagnóstico , Macroglobulinemia de Waldenstrom/mortalidadeRESUMO
Matched-related donor hematopoietic stem cell transplantation (HSCT) remains the preferred first-line option for severe aplastic anemia (SAA) patients aged <40 years even in the era of eltrombopag (EPAG). However, there has not been any direct comparison between immunosuppressive therapy (IST) plus EPAG (IST + EPAG) and haploidentical HSCT (Haplo-HSCT) as first-line therapy. This study prospectively compared the efficacy, safety and health-related quality of life (HRQoL) of Haplo-HSCT (n = 147) and IST + EPAG (n = 121) as first-line treatment for patients with SAA. The results showed that 86.3% of patients in the Haplo-HSCT group and 24.1% of patients in the IST + EPAG group achieved normal complete blood count (CBC) (P < 0.001) after 6 months of treatment. The time to achieve transfusion independence and absolute neutrophil count ≥ 1.0 × 109/L were shorter in the Haplo-HSCT group than in the IST + EPAG group (P < 0.05). In the IST + EPAG and Haplo-HSCT, 3-year overall survival (OS) was 92.4 ± 2.4% and 82.8 ± 3.1% (P = 0.017), whereas 3-year failure-free survival (FFS) was 69.4 ± 4.2% and 81.6 ± 3.2% (P = 0.002), respectively. Similar results were observed in patients with <40 years of age. Among patients with ≥40 years of age, there was no difference in 3-year OS (88.6 ± 4.8% vs. 82.4 ± 8.1%, P = 0.517) between the IST + EPAG and Haplo-HSCT groups, whereas 3-year FFS was lower in the IST + EPAG (58.7 ± 7.5% vs. 82.4 ± 8.1%, P = 0.043). Subgroup analysis for populations aged <40 years indicated that SAA benefited more from IST + EPAG, and very SAA (vSAA) benefited more from Haplo-HSCT. Patients treated with haplo-HSCT scored significantly better in the HRQoL than treated with IST + EPAG (P < 0.0001). Multivariate analysis showed that first-line Haplo-HSCT was associated with normal CBC at 6 months, better FFS and led to a better HRQoL (P < 0.001). In summary, the IST + EPAG achieved better OS for <40 years SAA patients, while the Haplo-HSCT accelerated hematopoietic recovery and HRQoL, achieved better FFS even for those <40 years vSAA and ≥40 years patients.
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A 67-year-old woman presented with fever, purpura, and confusion. A preliminary diagnosis of thrombotic thrombocytopenic purpura (TTP) was made on the basis of clinical presentation and lab findings, such as reduced platelet count, increased bilirubin, and so on. She was treated with therapeutic plasma exchange (TPE) and methylprednisolone. During the treatment, peripheral blood monocytosis (monocyte 4 × 10(9)/L) was noticed. The monocytes were CD56 positive. A putative diagnosis of chronic myelomonocytic leukemia (CMML) was proposed. Three months later, the diagnosis of CMML was established on the basis of persistent monocytosis. All other potential causes were considered (e.g., quinine exposure, diarrhea) and excluded. This case highlights the needs to consider hematological malignancy such as CMML in patients with TTP.
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Leucemia Mielomonocítica Crônica/complicações , Leucemia Mielomonocítica Crônica/diagnóstico , Púrpura Trombocitopênica Trombótica/diagnóstico , Púrpura Trombocitopênica Trombótica/etiologia , Idoso , Evolução Fatal , Feminino , Glucocorticoides/uso terapêutico , Humanos , Leucemia Mielomonocítica Crônica/tratamento farmacológico , Metilprednisolona/uso terapêutico , Troca Plasmática , Púrpura Trombocitopênica Trombótica/epidemiologia , RecidivaRESUMO
Background: The emergence of dexamethasone (Dex) resistance limits its efficacy. Side population (SP) cells in MM have strong tumorigenicity. Nevertheless, the detailed effect by which SP cells regulate Dex resistance in MP cells has not been completely verified and needs to be further investigated. Methods: SP and MP cells were sorted from RPMI-8226. mRNA expression and cell viability were analyzed using quantitative real-time PCR (qRT-PCR) and MTS assays, respectively. The presence of exosomal lncRNA SNHG16 was verified by transmission electron microscopy, differential ultracentrifugation, and qRT-PCR. Protein expression levels were measured using western blotting. Gain or loss function analyses were performed to demonstrate the role of SNHG16 in the Dex resistance of MP cells. Results: Dex resistance of SP cells was remarkably stronger than that of MP cells. Compared with MP cells, the survival rate and Dex resistance of MP cells cotreated with SP cell-derived exosomes were increased. SNHG16 expression was significantly enhanced in SP cell-derived exosomes compared to MP cell-derived exosomes. SNHG16 expression was remarkably increased in MP cells transfected with OE-SNHG16 vectors, and Dex resistance of MP cells was enhanced. When SNHG16 was silenced in SP cells, the SNHG16 expression was downregulated in both SP cells and SP cell-derived exosomes. SNHG16 expression and Dex resistance were both remarkably downregulated in MP cells treated with SP-si-SNHG16-exosomes compared to MP cells treated with SP-si-NC-exosomes. Conclusion: MM SP cells promote Dex resistance in MP cells through exosome metastasis of SNHG16.
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INTRODUCTION: Multiple myeloma (MM) is a fatal hematological malignancy and does not have adequate prognostic indicators. Previous studies indicate that CEP72 is closely related to tumorigenesis and tumor progression. However, the expression and function of CEP72 in multiple myeloma have yet to be elucidated. METHODS: In this study, we explored the correlation between CEP72 expression and clinicopathological characteristics as well as the impacts of CEP72 expression on the survival of MM patients. In addition, PPI, GSEA and Chemotherapy drug resistance analysis identified the possible mechanism. RESULTS: CEP72 is overexpressed in both MM patients and MM cell lines. Clinically, patients in the CEP72high subgroup were significantly older than those in the CEP72low subgroup (p = 0.003). Up-regulation of CEP72 was related to poor overall survival and event-free survival. PPI network showed that CEP72 was related to PCM1, KIZ, OFD1, etc. GSEA analysis showed that CEP72 was enriched in cell cycle, oocyte meiosis, protein export, lysosome and N-glycan biosynthesis pathways. Drug resistance analysis indicated that there was a positive correlation between the CEP72 expression and the IC50 values of 6-mercaptopurine, 8-chloro-adenosine, clofarabine, fludarabine and allopurinol. CONCLUSION: High CEP72 expression was a poor prognostic factor in patients diagnosed with multiple myeloma.
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Mieloma Múltiplo , Humanos , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/genética , Prognóstico , Proteínas Associadas aos Microtúbulos , Proteínas de Ciclo CelularRESUMO
OBJECTIVE: To compare the efficacy of eltrombopag combined with cyclosporine A (CsA) and CsA alone in patients with transfusion-dependent non-severe aplastic anemia (TD-NSAA). METHODS: The clinical data of 76 patients with treatment-naive TD-NSAA in Ningde Municipal Hospital of Ningde Normal University and Affiliated Hospital of Nantong University from December 2017 to June 2021 were retrospectively analyzed. Among them, 45 cases were treated with eltrombopag combined with CsA, and 31 patients with compatible baseline characters were treated with CsA alone. The efficacy of patients between the two groups was compared, and the factors affecting the curative effects were also analyzed. RESULTS: There were significant differences in hematological response (HR) and complete response(CR) rates between the two groups at 3, 6, 12 months, and follow-up endpoint of treatment (P<0.05). With the prolongation of eltrombopag treatment time, the curative effect increased gradually, and the patients achieved more CR and HR rates by the end of the follow-up period. Simultaneously, with the increase in the maximum stable dose of eltrombopag, the HR rate increased gradually. The megakaryocyte count in eltrombopag group was higher than that in control at 6 and 12 months (P<0.05). Compared with the control group, the median time of platelet transfusion independence in eltrombopag group was more shorter (P=0.018), and the median platelets transfusion volume was lower (P=0.009). At 3, 6, 12 months after eltrombopag, the change of platelet in eltrombopag group was higher than that in the control group (P<0.05). Analysis of related factors affecting the efficacy showed that sex, age, iron overload, platelet count before treatment had no effect on the efficacy, and the median maximum stable dosage and the administration period for eltrombopag were related to the curative effect. The patients of eltrombopag group experienced adverse events of varying degrees, but the reactions were mild and mostly tolerated. CONCLUSION: Eltrombopag can effectively improve the hematopoietic response and promote platelet recovery for TD-NSAA patients with relatively more residual hematopoietic cells, and it is safe and well tolerated.
Assuntos
Anemia Aplástica , Humanos , Anemia Aplástica/terapia , Estudos Retrospectivos , Resultado do Tratamento , Ciclosporina/uso terapêutico , Terapia de Imunossupressão , Imunossupressores/uso terapêuticoRESUMO
OBJECTIVES: POEMS syndrome is a rare disorder which has been increasingly recognized. The clonal origin is controversial. Some people argue that POEMS syndrome originates from abnormal plasma cell clones. So, treatment frequently targets the plasma cell clone. Nevertheless, others believe that both plasma cells and B cells can be the potential culprit in POEMS syndrome. METHODS: A 65-year-old male came to the emergency department of our hospital with the complaints of bilateral soles numbness and weight loss for half a year, abdominal distension for half a month, and chest tightness and shortness of breath for one day. He was then diagnosed as POEMS syndrome complicated with monoclonal B-cell lymphocytosis (non-CLL type). A standard bendamustine plus rituximab (BR) regimen combined with low dose of lenalidomide was administered. RESULTS: After four cycles of treatment, the ascites of the patient was absent and the neurological symptom disappeared. The renal function, the IgA level, and the VEGF level all returned to normal. DISCUSSION: POEMS syndrome, a multi-system disorder, is easily misdiagnosed. The clonal origin of POEMS syndrome is controversial and needs further study. For now, there are no approved treatment regimens. Treatments mainly target the plasma cell clone. This case suggested that other therapy besides anti-plasma cell treatment may also be effective in POEMS syndrome. CONCLUSION: We report a patient with POEMS syndrome who achieved complete response after treatment with the combination of a standard BR regimen and low dose of lenalidomide. POEMS syndrome's pathological mechanisms and therapies warrant further studies.
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Síndrome POEMS , Idoso , Humanos , Masculino , Lenalidomida/uso terapêutico , Síndrome POEMS/terapia , Síndrome POEMS/tratamento farmacológico , Indução de Remissão , Fator A de Crescimento do Endotélio Vascular/uso terapêutico , Linfócitos BRESUMO
Bone marrow-derived mesenchymal stem cell (BMSC) is one crucial component of the multiple myeloma (MM) microenvironment and supports the malignant progression of MM. Whether BMSCs act on MM cells via exosomes has not been well characterized. Herein, we used microarrays to screen out differentially expressed miRNAs in BMSCs from patients with MM (MM-MSCs) or benign diseases (BD-MSCs). We found that miR-483-5p was highly expressed in MM-MSCs, which may be transported through exosomes from MM-MSCs to MM cells to increase miR-483-5p expression in them. We then investigated the role and mechanism of miR-483-5p in the aggressive progression of MM in vitro. We verified that miR-483-5p promoted MM cell proliferation and reduced apoptosis. Then we predicted and validated that TIMP2, a tumor suppressor gene, is the downstream target of miR-483-5p in MM. In summary, our study indicated that MM-MSCs promote MM malignant progression via the release of exosomes and regulation of miR-483-5p/TIMP2 axis, suggesting an essential role of BMSCs derived exosomal miRNA in MM and a potential marker for MM diagnosis and therapy.
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OBJECTIVE: To construct a mouse model of Glanzmann's thrombasthenia (GT) with ITGA2B c.2659 C>T (p.Q887X) nonsense mutation by CRISPR/Cas9 technology, and then further explore the expression and function of glycoprotein αIIbß3 on the surface of platelet membrane. METHODS: The donor oligonucleotide and gRNA vector were designed and synthesized according to the ITGA2B gene sequence. The gRNA and Cas9 mRNA were injected into fertilized eggs with donor oligonucleotide and then sent back to the oviduct of surrogate mouse. Positive F0 mice were confirmed by PCR genotyping and sequence analysis after birth. The F1 generation of heterozygous GT mice were obtained by PCR and sequencing from F0 bred with WT mice, and then homozygous GT mice and WT mice were obtained by mating with each other. The phenotype of the model was then further verified by detecting tail hemorrhage time, saphenous vein bleeding time, platelet aggregation, expression and function of αIIbß3 on the surface of platelet. RESULTS: The bleeding time of GT mice was significantly longer than that of WT mice (P<0.01). Induced by collagen, thrombin, and adenosine diphosphate (ADP), platelet aggregation in GT mice was significantly inhibited (P<0.01, P<0.01, P<0.05). Flow cytometry analysis showed that the expression of αIIbß3 on the platelet surface of GT mice decreased significantly compared with WT mice (P<0.01), and binding amounts of activated platelets to fibrinogen were significantly reduced after thrombin stimulation (P<0.01). The spreading area of platelet on fibrinogen in GT mice was significantly smaller than that in WT mice (P<0.05). CONCLUSION: A GT mouse model with ITGA2B c.2659 C>T (p.Q887X) nonsense mutation has been established successfully by CRISPR/Cas9 technology. The aggregation function of platelet in this model is defective, which is consistent with GT performance.
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Códon sem Sentido , Integrina alfa2 , Trombastenia , Animais , Sistemas CRISPR-Cas , Modelos Animais de Doenças , Fibrinogênio/genética , Humanos , Integrina alfa2/genética , Camundongos , Oligonucleotídeos , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/genética , RNA Guia de Cinetoplastídeos , Trombastenia/diagnóstico , Trombastenia/genética , Trombina/genéticaRESUMO
BACKGROUND: Interferon regulatory factor-1 (IRF-1) plays a critical role in the injury to stem and progenitor regions associated with aberrant interferon-gamma (IFN-γ) in aplastic anemia (AA). The present study aimed to investigate the effects of IFN-γ on murine myeloid precursor cells (32D cells) with wild-type and inactive-type protein kinase B (Akt) after IRF-1 gene silencing. METHODS: With treatment of four concentrations of IFN-γ, the 32D cell viability and inhibition rate were assayed by middle-time-spray (MTS). The apoptosis rate was determined by flow cytometry, and the expression of the phosphorylated signal transducer and activator of transcription 3 (p-Stat3) and the phosphorylated signal transducer and activator of transcription 5 (p-Stat5) was analyzed by Western blot. RESULTS: The results from real time PCR (RT-PCR) assays suggested that the relative expression level of IRF-1-mRNA in the knockdown group (KD) was lower than that of in the negative control (NC) and blank control (Ctrl). In addition, the silencing efficiency was >70%, which was further validated by Western blotting. At 48 h, the rate of proliferation of 32D cells of wild-type Akt was significantly higher than that of inactive-type Akt (0.918±0.005 vs. 0.503±0.003, P=0.008), while the apoptosis rate in wild-type was significantly lower than that of inactive Akt (1.46%±0.41% vs. 2.98%±0.32%, P=0.006). After reducing the expression of IRF-1 gene, the promotion of hematopoiesis was recovered, resulting from the high concentration of IFN-γ achieved by reducing the expression of p-Stat5 via the Akt signaling pathway. CONCLUSIONS: Taken together, these results suggested that IRF-1 plays a critical role in the pro-apoptotic effect of IFN-γ on the proliferation of hematopoietic progenitor cells. These findings could contribute to understanding the mechanisms underlying the conversion from IFN-γ-mediated inhibition to promotion of hematopoiesis.
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BACKGROUND: Immune-related hemocytopenia (IRH) is a type of autoimmune disease that targets bone marrow hematopoietic cells. This study investigated the influence of atorvastatin on the functional aspects of bone marrow endothelial progenitor cells (BM EPCs) in IRH patients. METHODS: BM EPCs were isolated from 15 patients with IRH and 20 normal controls. The isolated BM EPCs were characterized by flow cytometry. Cell counting kit-8, flow cytometry, and Transwell migration assays were used to determine the proliferation, apoptosis, and migration of BM EPCs, respectively. Protein levels were determined by western blot assay. RESULTS: The BM EPCs isolated from IRH patients showed reduced proliferation, increased apoptosis, and attenuated migratory ability compared to those from normal controls. Western blot analysis showed that the protein level of p-p38 was significantly increased, while that of Phosphorylated protein kinase B (p-AKT) was significantly decreased in the BM EPCs from IRH patients, compared to BM EPCs from healthy subjects. Cell proliferation and migration were significantly enhanced by atorvastatin, recombinant human thrombopoietin, and SB20358 compared to the untreated BM EPCs from IRH patients. Atorvastatin, Recombinant human thrombopoietin (TPO), and SB20358 treatment significantly suppressed the protein levels of p-p38 protein, but increased those of p-AKT in BM EPCS from IRH patients. CONCLUSIONS: In summary, atorvastatin increases the number and function of BM EPCs in IRH patients by regulating the p38 and AKT signaling pathways.