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Fms-like tyrosine kinase 3 (FLT3) mutations, present in over 30% of acute myeloid leukemia (AML) cases and dominated by FLT3-internal tandem duplication (FLT3-ITD), are associated with poor outcomes in patients with AML. While tyrosine kinase inhibitors (TKIs; e.g., gilteritinib) are effective, they face challenges such as drug resistance, relapse, and high costs. Here, we report that metformin, a cheap, safe, and widely used anti-diabetic agent, exhibits a striking synergistic effect with gilteritinib in treating FLT3-ITD AML. Metformin significantly sensitizes FLT3-ITD AML cells (including TKI-resistant ones) to gilteritinib. Metformin plus gilteritinib (low dose) dramatically suppresses leukemia progression and prolongs survival in FLT3-ITD AML mouse models. Mechanistically, the combinational treatment cooperatively suppresses polo-like kinase 1 (PLK1) expression and phosphorylation of FLT3/STAT5/ERK/mTOR. Clinical analysis also shows improved survival rates in patients with FLT3-ITD AML taking metformin. Thus, the metformin/gilteritinib combination represents a promising and cost-effective treatment for patients with FLT3-mutated AML, particularly for those with low income/affordability.
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Compuestos de Anilina , Proteínas de Ciclo Celular , Sinergismo Farmacológico , Leucemia Mieloide Aguda , Metformina , Mutación , Quinasa Tipo Polo 1 , Proteínas Serina-Treonina Quinasas , Proteínas Proto-Oncogénicas , Pirazinas , Transducción de Señal , Tirosina Quinasa 3 Similar a fms , Metformina/farmacología , Metformina/uso terapéutico , Tirosina Quinasa 3 Similar a fms/genética , Tirosina Quinasa 3 Similar a fms/metabolismo , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Humanos , Animales , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Transducción de Señal/efectos de los fármacos , Pirazinas/farmacología , Pirazinas/uso terapéutico , Compuestos de Anilina/farmacología , Compuestos de Anilina/uso terapéutico , Ratones , Mutación/genética , Línea Celular Tumoral , Tiofenos/farmacología , Tiofenos/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Factor de Transcripción STAT5/metabolismo , Factor de Transcripción STAT5/genética , Femenino , Ensayos Antitumor por Modelo de Xenoinjerto , Masculino , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
Dysregulated RNA modifications, stemming from the aberrant expression and/or malfunction of RNA modification regulators operating through various pathways, play pivotal roles in driving the progression of haematological malignancies. Among RNA modifications, N6-methyladenosine (m6A) RNA modification, the most abundant internal mRNA modification, stands out as the most extensively studied modification. This prominence underscores the crucial role of the layer of epitranscriptomic regulation in controlling haematopoietic cell fate and therefore the development of haematological malignancies. Additionally, other RNA modifications (non-m6A RNA modifications) have gained increasing attention for their essential roles in haematological malignancies. Although the roles of the m6A modification machinery in haematopoietic malignancies have been well reviewed thus far, such reviews are lacking for non-m6A RNA modifications. In this review, we mainly focus on the roles and implications of non-m6A RNA modifications, including N4-acetylcytidine, pseudouridylation, 5-methylcytosine, adenosine to inosine editing, 2'-O-methylation, N1-methyladenosine and N7-methylguanosine in haematopoietic malignancies. We summarise the regulatory enzymes and cellular functions of non-m6A RNA modifications, followed by the discussions of the recent studies on the biological roles and underlying mechanisms of non-m6A RNA modifications in haematological malignancies. We also highlight the potential of therapeutically targeting dysregulated non-m6A modifiers in blood cancer.
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Neoplasias Hematológicas , Humanos , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/metabolismo , Neoplasias Hematológicas/patología , Procesamiento Postranscripcional del ARN/genética , ARN/genética , ARN/metabolismo , Adenosina/análogos & derivados , Adenosina/metabolismo , Adenosina/genéticaRESUMEN
OBJECTIVE: To investigate the effect of TCP1 expression on the proliferation and the accumulation of intracellular drug of HL60/A and HL60 cells and its possible molecular mechanism. METHODS: Lentiviral transfection technology was used to construct HL60/A and HL60 cells with knocked down or overexpressed TCP1 and their control cells. The efficiency of knockdown and overexpression was evaluated by Western blot. The cell proliferation was detected by CCK-8 assay. The intracellular drug accumulation was detected by laser confocal detection and flow cytometry. The expression levels of MRP1, P-gP and p-AKT were evaluated by flow cytometry and Western blot. RESULTS: After TCP1 was knocked down,the proliferation ability of HL60/A cells was significantly reduced, the accumulation of intracellular drug was significantly increased and the expression of MRP1 and P-gP protein were decreased. After TCP1 was overexpressed, the proliferation ability of HL60 was significantly increased, the accumulation of intracellular drug was significantly decreased and the expression of MRP1 and P-gP protein were increased. Intervention of LY294002 significantly antagonized the promotion on cell proliferation, the inhibition on intracellular drug accumulation and the expression of MRP1 and P-gP mediated by TCP1 overexpressing in HL60 cells. CONCLUSION: TCP1 can promote cell proliferation, improve the expression of MRP1 and P-gP by activating PI3K/AKT signal, and reduce intracellular drug accumulation.
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Resistencia a Antineoplásicos , Proteínas Proto-Oncogénicas c-akt , Humanos , Células HL-60 , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Proliferación Celular , Chaperonina con TCP-1RESUMEN
OBJECTIVE: To analyze the effect of granulocyte colony-stimulating factor (G-CSF) on outcomes in patients with acute myeloid leukemia (AML). METHODS: A total of 526 patients with AML in the Haematology Department were enrolled. They were divided into a G-CSF treatment group and a no G-CSF group according to whether G-CSF was administered in the induction chemotherapy period, with 355 cases in the G-CSF group and 171 cases in the no G-CSF group. Cox regression analysis and Kaplan-Meier curve analysis were used to analyze the effect of G-CSF on the first complete remission (CR1) phase and overall survival (OS). In addition, further analysis was performed based on an initial white blood cell count of 50 * 10^9/L. RESULTS: The application of G-CSF significantly shortened the CR1 phase and OS in patients with high leukocytes. CONCLUSIONS: G/GM-CSF should be used with caution in patients with AML, especially those with high leukocytes.
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Protocolos de Quimioterapia Combinada Antineoplásica , Leucemia Mieloide Aguda , Humanos , Pronóstico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Factor Estimulante de Colonias de Granulocitos y Macrófagos/efectos adversos , Leucocitos , Factor Estimulante de Colonias de Granulocitos/uso terapéuticoRESUMEN
The cure rate of acute lymphoblastic leukemia (ALL) in adolescents and adults remains poor. This study aimed to establish a prognostic model for ≥14-year-old patients with ALL to guide treatment decisions. We retrospectively analyzed the data of 321 ALL patients between January 2017 and June 2020. Patients were randomly (2:1 ratio) divided into either the training or validation set. A nomogram was used to construct a prognostic model. Multivariate Cox analysis of the training set showed that age > 50 years, white blood cell count > 28.52×109/L, and MLL rearrangement were independent risk factors for overall survival (OS), while platelet count >37×109/L was an independent protective factor. The nomogram was established according to these independent prognostic factors in the training set, where patients were grouped into two categories: low-risk (≤13.15) and high-risk (>13.15). The survival analysis, for either total patients or sub-group patients, showed that both OS and progression-free survival (PFS) of low-risk patients was significantly better than that of high-risk patients. Moreover, treatment analysis showed that both OS and progression-free survival (PFS) of ALL with stem cell transplantation (SCT) were significantly better than that of ALL without SCT. Further stratified analysis showed that in low-risk patients, the OS and PFS of patients with SCT were significantly better than those of patients without SCT. In contrast, in high-risk patients, compared with non-SCT patients, receiving SCT can only significantly prolong the PFS, but it does not benefit the OS. We established a simple and effective prognostic model for ≥ 14-year-old patients with ALL that can provide accurate risk stratification and determine the clinical strategy.
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Nomogramas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adolescente , Humanos , Adulto , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Supervivencia sin Progresión , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapiaRESUMEN
Background: Fibronectin (FN) can improve organ function and slow the progression of sepsis, but full-length FN is hard to be exacted as a therapeutic. Objective: This study aimed to investigate the beneficial effects of C-terminal heparin-binding domain polypeptide of FN (rhFNHC-36) in a cecal ligation and puncture (CLP)-mediated murine septic model and explore its regulatory effects on macrophages. Methods: Mice were randomly assigned to four groups: unoperated control (Normal), sham operation control (Sham), CLP-operation with intravenous injection of phosphate-buffered saline (CLP+PBS), and CLP-operation with rhFNHC-36 treatment (CLP+rhFNHC-36). Blood and abdominal fluid samples were subjected to bacterial colony formation assays. Organs (liver, spleen, and lung) were undergone histopathological analyses and/or weighed to obtain organ indices. Serum interleukin-6 (IL-6) levels, nitric oxide (NO) release from isolated abdominal macrophages, and chemotactic effect of macrophages were measured with commercial kits. Surface programmed death ligand 1 (PD-L1) expression on macrophages was measured by flow cytometry. Results: Mice in the CLP+PBS group showed a lower survival rate than that in the CLP+rhFNHC-36 group. Improved survival was associated with better clearance of bacterial pathogens, as evidenced by colony formation assays. The CLP-induced decrease in thymus and spleen indices was attenuated by rhFNHC-36 treatments. rhFNHC-36 alleviated sepsis-associated tissue damage in liver, spleen, and lung. CLP-mediated increases in plasma IL-6 levels were reversed by rhFNHC-36 treatment. NO levels in peritoneal macrophages after lipopolysaccharides (LPS)-stimulation in the CLP+rhFNHC-36 group were lower than that in the CLP+PBS group. Notably, macrophages from the CLP+rhFNHC-36 group retained better chemotaxis ability. After LPS challenge, these macrophages had a reduced percentage of PD-L1-positive cells compared to those in the CLP+PBS group. Conclusion: rhFNHC-36 improved survival of mice with CLP-induced sepsis by reducing tissue damage and modulating macrophage function. Our work provides critical insight for developing FN-based and macrophages-targeted therapeutics for treating sepsis.
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Objectives: To compare the outcomes of tyrosine kinase inhibitors (TKIs) in combination with reduced-dose chemotherapy with those of standard induction chemotherapy, as well as the outcomes between chemotherapy and transplantation, in adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL).Methods: We retrospectively reviewed cases of Ph+ ALL treated with TKIs and combination chemotherapy. The patients were allocated to either the TKIs with reduced-dose chemotherapy group or the TKIs with standard chemotherapy group. In additions, patients were further stratified into either the transplant group or the non-transplant group.Results: The complete remission rate (88.7% vs. 83.9%, p = 0.372), major molecular response (58.9% vs. 56.0%, p = 0.750), molecular complete response (20.5% vs. 22.0%, p = 0.891), and early mortality rate (3.2% vs. 3.5%, p = 0.922) were similar between the TKIs with reduced-dose chemotherapy group and the TKIs with standard chemotherapy group. The proportions of lung infections, bloodstream infections, patients with >21 days of hospitalization, the total costs, transfusion costs, and antimicrobial costs were higher in the standard chemotherapy group than in the TKIs with reduced-dose chemotherapy group. The 3-year overall survival rates (59.0% [95% CI, 46.6-74.7%] vs. 38.4% [95% CI, 29.9-49.4%]) and disease-free survival rates (48.6% [95% CI, 34.2-69.1%] vs. 32.0% [95% CI, 23.5-43.7%]) were significantly better in the transplant group than in the non-transplant group.Conclusion: An induction regimen combining TKIs with reduced-dose chemotherapy and transplantation during the first complete remission remains a suitable and effective option for patients with Ph+ ALL.
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Trasplante de Células Madre Hematopoyéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adulto , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Cromosoma Filadelfia , Inhibidores de Proteínas Quinasas/uso terapéutico , Estudios RetrospectivosRESUMEN
BACKGROUND: Efficient mobilization of CD34+ hematopoietic stem cells plays a vital role in successful autologous stem cell transplantation (ASCT) in patients with multiple myeloma (MM), especially in cases with high-risk cytogenetic recommended for tandem ASCT. However, the optimal mobilization strategy remains a matter of debate in the era of lenalidomide. The combination of etoposide with Cytarabine plus G-CSF as a novel mobilization regimen in MM has not been reported previously. METHODS: This research retrospectively studied mobilization efficacy and safety using etoposide combined with Cytarabine (etoposide 50-100 mg/m2, qd d1-3; AraC 0.5 g/m2, q12h d1~3) plus G-CSF (5 µg/kg/day, from d5 until the day of apheresis) in 128 patients with MM. 70(54.7%) patients received lenalidomide-based induction regimens treatment. RESULTS: A median of 27.75×106 CD34+ cells/kg was collected in the first apheresis, and 28.23×106 CD34+ cells/kg were collected overall. Of the 128 patients, all achieved adequate collection (≥2×106 CD34+ cells/kg), 121(94.5%) achieved optimal collection for single ASCT (≥5×106 CD34+ cells/kg), and 114(89.1%) harvested optimal collection for tandem ASCT (≥10×106 CD34+ cells/kg). In particular, the target yield of optimal collection for tandem ASCT was reached in 82.8% (106/128) by a single apheresis procedure. 14 patients obtained deeper response post mobilization. In multivariate analysis, cycles of prior chemotherapy independently affected the optimal achievement of CD34+ cells (p=0.004, OR 0.695, 95% CI 0.544~0.888). Previous lenalidomide exposure did not significantly impair CD34+ cells collection. Although 68% episodes of antibiotic usage were observed, no severe infection or treatment-related mortality occurred. CONCLUSION: Stem cell mobilization with Etoposide + Cytarabine plus G-CSF was highly efficient and safe in patients with MM, which could be considered in high-risk MM patients who were referred for tandem ASCT.
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The value of plasma fibronectin (pFN) in the diagnosis and prognosis of sepsis has not been fully established. Previous studies finding that pFN is significantly reduced in sepsis, however, whether reduced pFn affects the prognosis of sepsis has not been clarified. Here, we detected and analyzed pFN and other conventional inflammatory markers in advanced sepsis patients and performed correlation analysis with SOFA score. We also used Fn gene conditional knockout mice which were performed by cecum ligation and puncture (CLP) to investigate the effect of FN deficiency on sepsis prognosis. We found, compared with procalcitonin, c-reactive protein, and interleukin-6, pFN was more correlated with SOFA score in advanced sepsis patients (r -.720, p < .001). In animal experiments, Fn gene knockout mice showed significantly greater mortality after CLP compared with the control group because of inhibited phagocytosis and bacterial clearance ability of macrophages, with double cytokine storm. Furthermore, FN can regulate macrophages through the integrin α5ß1/Fak/Src signaling pathway. Overall, we found pFN can more accurately reflect the severity and prognosis of advanced sepsis. The absence of FN altered the cytokine storm and phagocytic function of macrophages, suggesting that FN could be a potential therapeutic target in sepsis.
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Citocinas/metabolismo , Fibronectinas/metabolismo , Macrófagos/metabolismo , Sepsis/metabolismo , Animales , Células Cultivadas , Fibronectinas/sangre , Fibronectinas/genética , Proteína-Tirosina Quinasas de Adhesión Focal/metabolismo , Humanos , Integrina alfa5beta1/metabolismo , Ratones , Ratones Endogámicos C57BL , Sepsis/sangre , Familia-src Quinasas/metabolismoRESUMEN
Allogeneic haploidentical HSCT (haplo-HSCT) and unrelated umbilical cord blood transplantation(UCBT)are used in patients lacking HLA-identical sibling or unrelated donors. With myeloablative condition and GVHD prophylaxis of using low-dose ATG and post-transplantation cyclophosphamide (PTCY), we conducted a prospective clinical trial. Of eligible 122 patients from February 2015 to December 2019 in the study, 113 patients were involved. Forty-eight patients were in the group of sequential haplo-cord transplantation (haplo-cord HSCT), and 65 patients were in the group of single UCBT. The primary endpoint of 2-year disease-free survival (DFS) was no statistical difference between groups (64.1 vs. 56.5%), p>0.05. The analysis of subgroup patients with relapsed/refractory showed haplo-cord HSCT was associated with better OS (HR 0.348, 95% CI, 0.175-0.691; p=0.0025), DFS (HR 0.402, 95% CI, 0.208-0.779; p=0.0069), and GRFS (HR 0.235, 95% CI, 0.120-0.457, p<0.0001) compared to the single cord group. The 2-year's probability in OS, DFS, and GRFS was 64.9 vs. 31.6%, 64.5 vs. 31.6%, and 60.8 vs. 15.0% in the haplo-cord group and single cord group, respectively. III-IV acute GVHD 8.3 vs. 6.2%, chronic GVHD 25.8 vs. 13.7%, and extensive chronic GVHD 5.3 vs. 1.8% were shown in corresponding group, p>0.05. The patients engrafted persistently with UCB showed better survival outcomes. Our sequential Haplo-cord HSCT with ATG/PTCY improved the survival of patients and might be an alternative transplantation approach for patients with relapsed/refractory hematologic malignancies.
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Suero Antilinfocítico/uso terapéutico , Trasplante de Células Madre de Sangre del Cordón Umbilical , Enfermedad Injerto contra Huésped/prevención & control , Neoplasias Hematológicas/terapia , Acondicionamiento Pretrasplante/métodos , Adolescente , Adulto , Niño , Resistencia a Medicamentos , Femenino , Neoplasias Hematológicas/mortalidad , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Recurrencia , Análisis de Supervivencia , Trasplante Haploidéntico , Adulto JovenRESUMEN
T-complex protein 1 (TCP1) is one of the subunits of chaperonin-containing T complex (CCT), which is involved in protein folding, cell proliferation, apoptosis, cell cycle regulation, and drug resistance. Investigations have demonstrated that TCP1 is a factor being responsible for drug resistance in breast and ovarian cancer. However, the TCP1 role in acute myeloid leukemia (AML) remains elusive. In the present study, we discovered that the TCP1 expression was elevated in AML patients and high TCP1 expression was associated with low complete response rate along with poor overall survival. TCP1 showed higher expression in the adriamycin-resistant leukemia cell line HL60/A and K562/A, comparing to their respective parent cells HL60 and K562 cells. TCP1 inhibition suppressed drug resistance in HL60/A and K562/A cells, whereas TCP1 overexpression in HL60 cells incremented drug resistance, both in vitro and in vivo. Mechanistic investigations revealed that TCP1 inhibited autophagy and adriamycin-induced cell apoptosis, and TCP1-mediated autophagy inhibition conferred resistance to adriamycin-induced cell apoptosis. Furthermore, TCP1 interacted with AKT and mTOR to activate AKT/mTOR signaling, which negatively regulates apoptosis and autophagy. Pharmacological inhibition of AKT/mTOR signal particularly activated autophagy and resensitized TCP1-overexpressing HL60 cells to adriamycin. These findings identify a novel role of TCP1 regarding drug resistance in AML, which advise a new strategy for overcoming drug resistance in AML through targeting TCP1/AKT/mTOR signaling pathway.
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Chaperonina con TCP-1/metabolismo , Leucemia Mieloide Aguda/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Animales , Autofagia , Estudios de Casos y Controles , Resistencia a Antineoplásicos , Humanos , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/patología , Masculino , Ratones , Pronóstico , Transducción de Señal , Análisis de Supervivencia , TransfecciónRESUMEN
Efforts to improve the prognosis of steroid-resistant gut acute graft-versus-host-disease (SR-Gut-aGVHD) have suffered from poor understanding of its pathogenesis. Here we show that the pathogenesis of SR-Gut-aGVHD is associated with reduction of IFN-γ+ Th/Tc1 cells and preferential expansion of IL-17-IL-22+ Th/Tc22 cells. The IL-22 from Th/Tc22 cells causes dysbiosis in a Reg3γ-dependent manner. Transplantation of IFN-γ-deficient donor CD8+ T cells in the absence of CD4+ T cells produces a phenocopy of SR-Gut-aGVHD. IFN-γ deficiency in donor CD8+ T cells also leads to a PD-1-dependent depletion of intestinal protective CX3CR1hi mononuclear phagocytes (MNP), which also augments expansion of Tc22 cells. Supporting the dual regulation, simultaneous dysbiosis induction and depletion of CX3CR1hi MNP results in full-blown Gut-aGVHD. Our results thus provide insights into SR-Gut-aGVHD pathogenesis and suggest the potential efficacy of IL-22 antagonists and IFN-γ agonists in SR-Gut-aGVHD therapy.
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Linfocitos T CD8-positivos/inmunología , Disbiosis/inmunología , Enfermedad Injerto contra Huésped/inmunología , Interferón gamma/inmunología , Interleucinas/inmunología , Fagocitos/inmunología , Animales , Linfocitos T CD8-positivos/patología , Linfocitos T CD8-positivos/trasplante , Receptor 1 de Quimiocinas CX3C/genética , Receptor 1 de Quimiocinas CX3C/inmunología , Modelos Animales de Enfermedad , Disbiosis/genética , Disbiosis/microbiología , Disbiosis/patología , Microbioma Gastrointestinal/inmunología , Regulación de la Expresión Génica , Enfermedad Injerto contra Huésped/genética , Enfermedad Injerto contra Huésped/microbiología , Enfermedad Injerto contra Huésped/patología , Interferón gamma/deficiencia , Interferón gamma/genética , Interleucina-17/deficiencia , Interleucina-17/genética , Interleucina-17/inmunología , Interleucinas/genética , Intestinos/inmunología , Intestinos/microbiología , Intestinos/patología , Depleción Linfocítica , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas Asociadas a Pancreatitis/genética , Proteínas Asociadas a Pancreatitis/inmunología , Fagocitos/citología , Receptor de Muerte Celular Programada 1/genética , Receptor de Muerte Celular Programada 1/inmunología , Transducción de Señal , Linfocitos T Colaboradores-Inductores , Linfocitos T Reguladores , Irradiación Corporal Total , Interleucina-22RESUMEN
Donor T cells mediate both graft-versus-leukemia (GVL) activity and graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (allo-HCT). Development of methods that preserve GVL activity while preventing GVHD remains a long-sought goal. Tolerogenic anti-interleukin-2 (IL-2) monoclonal antibody (JES6-1) forms anti-IL-2/IL-2 complexes that block IL-2 binding to IL-2Rß and IL-2Rγ on conventional T cells that have low expression of IL-2Rα. Here, we show that administration of JES6 early after allo-HCT in mice markedly attenuates acute GVHD while preserving GVL activity that is dramatically stronger than observed with tacrolimus (TAC) treatment. The anti-IL-2 treatment downregulated activation of the IL-2-Stat5 pathway and reduced production of granulocyte-macrophage colony-stimulating factor (GM-CSF). In GVHD target tissues, enhanced T-cell programmed cell death protein 1 (PD-1) interaction with tissue-programmed cell death-ligand 1 (PD-L1) led to reduced activation of protein kinase-mammalian target of rapamycin pathway and increased expression of eomesodermin and B-lymphocyte-induced maturation protein-1, increased T-cell anergy/exhaustion, expansion of Foxp3-IL-10-producing type 1 regulatory (Tr1) cells, and depletion of GM-CSF-producing T helper type 1 (Th1)/cytotoxic T cell type 1 (Tc1) cells. In recipient lymphoid tissues, lack of donor T-cell PD-1 interaction with tissue PD-L1 preserved donor PD-1+TCF-1+Ly108+CD8+ T memory progenitors and functional effectors that have strong GVL activity. Anti-IL-2 and TAC treatments have qualitatively distinct effects on donor T cells in the lymphoid tissues, and CD8+ T memory progenitor cells are enriched with anti-IL-2 treatment compared with TAC treatment. We conclude that administration of tolerogenic anti-IL-2 monoclonal antibody early after allo-HCT represents a novel approach for preventing acute GVHD while preserving GVL activity.
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Anticuerpos Monoclonales/uso terapéutico , Enfermedad Injerto contra Huésped/prevención & control , Efecto Injerto vs Leucemia/efectos de los fármacos , Trasplante de Células Madre Hematopoyéticas , Interleucina-2/inmunología , Animales , Anticuerpos Monoclonales/inmunología , Enfermedad Injerto contra Huésped/inmunología , Inmunosupresores/uso terapéutico , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Tacrolimus/uso terapéutico , Trasplante HomólogoRESUMEN
Objectives: Cigarette smoking is involved in the pathogenesis of head and neck squamous cell carcinoma (HNSCC). However, the underlying molecular mechanisms of cigarette smoking-induced HNSCC carcinogenesis are unclear and may involve cancer stem-like cell generation. We examined the effects of cigarette smoke condensate (CSC) on the formation of cancer stem-like cells, which are rich in octamer-binding transcription factor (OCT)-4, inhibitor of differentiation 1 (ID1), nuclear factor (NF)-κB, and B lymphoma Mo-MLV insertion region 1 homolog (BMI-1). Materials and Methods: We used in vitro, in vivo, and archival human HNSCC tissue analysis to evaluate the effects of CSC on cancer stem-like cell formation. Results: We found that CSC regulated OCT-4 expression, which subsequently regulated ID1 and NF-κB, at the promoter, mRNA, and protein levels in vitro. Furthermore, OCT-4 knockdown with siRNA reduced ID1 expression. ID1 and NF-κB synergistically increased the expression of BMI-1 and stimulated keratinocyte sphere generation. In vivo, ID1 and NF-κB acted together to generate malignant xenograft tumors, which were aggressive locally and systemically metastatic. Clinical data confirmed that ID1- and NF-κB-positive patients had poor clinical outcomes and 5-year disease-free survival. Conclusion: Our data suggest that smoking cigarettes promoted cancer stem-like cell generation in the head and neck area via the OCT-4/ID1/NF-κB/BMI-1 signaling pathway.
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Fibronectin (FN) is a multi-functional glycoprotein that primarily acts as a cell adhesion molecule and tethers cells to the extra cellular matrix. In order to clarify the effect of FN deficiency on hematopoiesis, biochemical and immune parameters in mice. We constructed a tamoxifen-induced conditional (cre-loxp system) fibronectin knock-out (FnKO) mouse model on a C57BL/6 background, and monitored their behavior, fertility, histological, hematopoietic, biochemical and immunological indices. We found that the Fn KO mice had reduced fertility, high platelet counts, smaller bone marrow megakaryocytes and looser attachment between the hepatocyte and vascular endothelial junctions compared to the wild type (WT) mice. In contrast, the behavior, hematological counts, serum biochemical indices and vital organ histology were similar in both Fn KO and WT mice. This model will greatly help in elucidating the role of FN in immune-related diseases in future.
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Carcinoma Hepatocelular/genética , Chaperonina con TCP-1/genética , Proteína p53 Supresora de Tumor/genética , Proteínas Wnt/genética , beta Catenina/genética , Anciano , Carcinoma Hepatocelular/patología , Movimiento Celular/genética , Proliferación Celular/genética , Supervivencia sin Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Vía de Señalización Wnt/genéticaRESUMEN
Objectives: Multiple myeloma (MM) often develops as a secondary primary malignancy (SPM). The retinoblastoma susceptibility gene (RB1) was the first tumour suppressor gene to be identified. We pooled and analyzed available data to compare the incidence of RB1 gene deletions and other cytogenetic abnormalities in patients with MM alone or as an SPM.Methods: We conducted a retrospective study of 475 patients. The experimental group comprised 18 patients with MM as an SPM, and the control group comprised 457 MM patients. We analyzed the baseline information in both groups, and used the odds ratio (OR), 95% confidence interval (CI), and forest plot to determine the incidence of SPMs with and without cytogenetic abnormalities.Results: The incidence of RB1 gene deletion was higher in the experimental group. There was no significant difference in other cytogenetic abnormalities.Conclusions: RB1 gene deletions appear to be associated with MM that develops as an SPM.
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Aberraciones Cromosómicas , Mieloma Múltiple/genética , Neoplasias Primarias Secundarias/genética , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
BACKGROUND: Human parvovirus B19 (B19V) infection exhibits a broad range of clinical outcomes. Blood transfusion is a common route of B19V transmission. However, information about the overall prevalence of B19V infection and B19V genotypes among blood donors in mainland China is lacking. METHODS: This meta-analysis was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A literature search for studies reporting the B19V prevalence among blood donors in mainland China from 2000 to 2018 was performed. The prevalence of B19V was estimated through a meta-analysis of the relevant literature. A comprehensive meta-analysis program was used for data processing and statistical analysis. RESULTS: Twenty-one eligible articles were included, involving 48,923 participants assessed for B19V-DNA, 12,948 participants assessed for anti-B19V immunoglobulin M (IgM), and 8244 participants assessed for anti-B19V immunoglobulin G (IgG). The analysis revealed the pooled estimates of the prevalence rates of B19V-DNA, anti-B19V IgM, and anti-B19V IgG among blood donors to be 0.7% (95% confidence interval [CI] 0.2-2.4%), 2.7% (95% CI 1.7-4.3%), and 33.6% (95% CI 28.2-39.4%), respectively. Moreover, phylogenetic analyses indicated that 142 of 169 (84.0%) B19V isolates belonged to Genotype 1. CONCLUSIONS: The overall prevalence of B19V among blood donors is not high in mainland China, and most isolates belong to Genotype 1.
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Donantes de Sangre , Genotipo , Infecciones por Parvoviridae/epidemiología , Infecciones por Parvoviridae/virología , Parvovirus B19 Humano/genética , Transfusión Sanguínea , China/epidemiología , ADN Viral/sangre , Humanos , Inmunoglobulina G/sangre , Inmunoglobulina M/sangre , PrevalenciaRESUMEN
Sepsis has always been a severe clinical problem in critical care medicine due to its rather high mortality and poor prognosis. The current study reported for the first time a practical immunosensor for fibronectin (FN) detection in human serum by electrochemistry. A simple but robust sandwich-type strategy was employed without any complex design or material modifications, which exhibited a linear calibration plot over the 15.625-500 ng/mL concentration range and a detection limit of 15 ng/mL. The results showed that the proposed strategy displayed an excellent selectivity against other non-target substances in human serum, a higher accuracy and a better stability when compared with the traditional enzyme-linked immunosorbent assay (ELISA) in detecting the same or mixed serum from 21 healthy subjects. Furthermore, the proposed electrochemical immunosensor successfully monitored the level of serum FN at various time points in five septic patients during the treatment. These findings demonstrate that the proposed strategy is highly sensitive and accurate in monitoring sepsis progress and has significant clinical improvements over the ELISA methodology, signifying a great potential of a commercial kit.
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Técnicas Biosensibles , Técnicas Electroquímicas , Ensayo de Inmunoadsorción Enzimática , Fibronectinas/sangre , Sepsis/sangre , Humanos , Sepsis/diagnósticoRESUMEN
Programmed death ligand-1 (PD-L1) expression and the presence of tumor-infiltrating lymphocytes (TILs) in tumor microenvironment were common in chronic inflammatory tumor types and frequently responded to the PD-L1 pathway immune checkpoint blockade in the clinic. Animal models to optimize such immunotherapeutics comprise an important strategy but often fail to predict the efficacy of clinical approaches. To address this, we aimed to establish new mouse models. In this study, we found that the expression of PD-L1was present at the beginning stage but a gradual decline over time in the in vitro cell culture and also in the mouse model. Based upon this finding, we established the IFN-γ-(human peripheral blood mononuclear cell) PBMC-CDX (cell line-derived xenograft) and IFN-γ-PBMC-PDX (patient-derived xenograft) mouse models, which recapitulate human tumor and human immune system interactions. IFN-γ was injected peritumorally to maintain the positivity of PD-L1 in the tumor microenvironment. Under this circumstance, the PD-1 molecule on the human T lymphocyte surface is in contact with the PD-L1 molecule on the human tumor cells and, thus, the formatin of the PD-L1/PD-1 pathway in the tumor microenvironment.Treatment with anti-PD-1 monoclonal antibody (mAb) significantly inhibited the growth of both CDX and PDX tumors, but not non-human NCG models (without allogeneic human PBMCs and IFN-γ) . These experimental data provide an important and promising platform for the development of drugs and the evaluation of the drug efficacy of immunotherapies with anti-PD-1 mAb as well as the basis of preclinical mAb drug research.