RESUMEN
SeviL, a galactoside-binding lectin previously isolated from the mussel Mytilisepta virgata, was demonstrated to trigger apoptosis in HeLa ovarian cancer cells. Here, we show that this lectin can promote the polarization of macrophage cell lines toward an M1 functional phenotype at low concentrations. The administration of SeviL to monocyte and basophil cell lines reduced their growth in a dose-dependent manner. However, low lectin concentrations induced proliferation in the RAW264.7 macrophage cell line, which was supported by the significant up-regulation of TOM22, a component of the mitochondrial outer membrane. Furthermore, the morphology of lectin-treated macrophage cells markedly changed, shifting from a spherical to an elongated shape. The ability of SeviL to induce the polarization of RAW264.7 cells to M1 macrophages at low concentrations is supported by the secretion of proinflammatory cytokines and chemokines, as well as by the enhancement in the expression of IL-6- and TNF-α-encoding mRNAs, both of which encode inflammatory molecular markers. Moreover, we also observed a number of accessory molecular alterations, such as the activation of MAP kinases and the JAK/STAT pathway and the phosphorylation of platelet-derived growth factor receptor-α, which altogether support the functional reprogramming of RAW264.7 following SeviL treatment. These results indicate that this mussel ß-trefoil lectin has a concentration-dependent multifunctional role in regulating cell proliferation, phenotype, and death in macrophages, suggesting its possible involvement in regulating hemocyte activity in vivo.
Asunto(s)
Bivalvos , Lectinas , Macrófagos , Animales , Ratones , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Células RAW 264.7 , Lectinas/farmacología , Proliferación Celular/efectos de los fármacos , Humanos , Citocinas/metabolismo , Fenotipo , Transducción de Señal/efectos de los fármacosRESUMEN
Somatic mutations in the ASXL1 gene are commonly observed in myeloid neoplasms. Pathogenic ASXL1 mutations induce the expression of C-terminally truncated mutant ASXL1 protein. We have shown that wild-type ASXL1 is a phase-separating protein involved in the formation of paraspeckles, one of the best known membraneless organelles (MLOs). Mutant ASXL1 lacks the intrinsically disordered region, which is important for phase separation and fails to support paraspeckle formation. Additionally, paraspeckles are disrupted in hematopoietic cells derived from ASXL1-MT knockin mice. The disruption of paraspeckles in hematopoietic cells results in a dysfunction of the hematopoietic reconstitution capacity. Therefore, this review presents our findings and summarizes the knowledge of phase separation and MLOs as a hot topic in cell biology.
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Leucemia , Paraspeckles , Animales , Ratones , Leucemia/genética , Factores de TranscripciónRESUMEN
A 31-year-old man underwent allogeneic bone marrow transplantation (BMT) for the treatment of transfusion-dependent aplastic anemia (AA) after conditioning with a regimen including fludarabine, cyclophosphamide, and antithymocyte globulin. The patient developed a late graft rejection on day 103 and showed autologous hematologic recovery not requiring transfusions on day 76. Peripheral blood leukocytes were of 100% recipient origin on day 103, and paroxysmal nocturnal hematuria (PNH)-type granulocytes were detected 5 months after BMT. The patient suddenly experienced hemolytic symptoms triggered by cold stimulation, and was diagnosed with autoimmune hemolytic anemia (AIHA) 37 months after BMT. Although anemia was ameliorated by prednisolone (PSL), hemolytic attacks repeatedly occurred, which became refractory to corticosteroids. Moreover, the patient underwent a splenectomy for the steroid-resistant AIHA and achieved AIHA remission without the need for PSL at 53 months after BMT. The immune tolerance breakdown to erythrocyte antigens was thought to have occurred due to various factors including immune AA, medication, cold stimulation, and infection, leading to AIHA development in this case.
Asunto(s)
Anemia Aplásica , Anemia Hemolítica Autoinmune , Trasplante de Células Madre Hematopoyéticas , Adulto , Anemia Aplásica/terapia , Anemia Hemolítica Autoinmune/diagnóstico , Anemia Hemolítica Autoinmune/etiología , Anemia Hemolítica Autoinmune/terapia , Suero Antilinfocítico/uso terapéutico , Hematuria , Hemólisis , Humanos , Masculino , Prednisolona/uso terapéuticoRESUMEN
Idiopathic CD4+ lymphocytopenia (ICL) is the depletion of CD4+ lymphocytes to <300 cells/mm3 without human immunodeficiency virus infection or other causes of lymphocytopenia. ICL causes fatal infections; its etiology remains unclear and it lacks consensus regarding therapeutic options. We report the first patient with ICL who had a successful clinical course following a cord blood transplant (CBT). A 45-year-old woman was diagnosed with ICL and underwent partial hepatectomy for an abscess caused by the Mycobacterium avium complex. No specific gene alterations were detected through next generation sequencing-based evaluation. Following a reduced-intensity conditioning (RIC) regimen consisting of fludarabine, busulfan, and 4 Gy total body irradiation, a single-unit CBT was performed. Neutrophils were engrafted on day +14. CD4+ lymphocyte counts increased to over 300 cells/mm3 on day +436. After 75 months, she was alive without any sequelae. CBT with an RIC regimen could be a curable treatment option for ICL.
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Linfocitos T CD4-Positivos/inmunología , Trasplante de Células Madre de Sangre del Cordón Umbilical , Linfopenia/terapia , Linfocitos T CD4-Positivos/citología , Linfocitos T CD4-Positivos/metabolismo , Femenino , Hepatectomía , Humanos , Absceso Hepático/etiología , Absceso Hepático/cirugía , Recuento de Linfocitos , Linfopenia/diagnóstico , Linfopenia/inmunología , Persona de Mediana Edad , Complejo Mycobacterium avium/patogenicidad , Neutrófilos/trasplante , Tomografía Computarizada por Rayos X , Irradiación Corporal TotalRESUMEN
Depression is an independent risk factor of cardiovascular disease (CVD); however, the causal association remains undefined. We exposed mice to repeated social defeat (RSD) to precipitate depressive-like behaviors, and investigated the effects on atherosclerosis. Eight-week-old male apoE-/- mice were exposed to RSD by housing with a larger CD-1 mouse in a shared home cage. They were subjected to vigorous physical contact daily for 10 consecutive days and fed a high-cholesterol diet (HCD) for 6 weeks. The social interaction ratio and immobility time showed dramatic social avoidance before and after HCD feeding. Defeated mice showed higher increase in atherosclerotic lesion areas in the aortic root and entire aorta than control mice. Mean blood pressure and lipid profile were equivalent in both groups. While Ly-6G- and Mac3-positive areas in the aortic root were comparable between the groups, citrullinated histone H3 (Cit-H3)- and myeloperoxidase (MPO)-positive areas, markers of neutrophil extracellular traps (NETs), were significantly increased in the defeated mice. Treatment with DNase I completely diminished the exaggerated atherosclerosis. The proportion of peripheral blood polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC), but not of inflammatory monocytes, was markedly increased. Moreover, in vitro NETs formation from bone marrow (BM) PMN-MDSC was markedly augmented, accompanied by higher expression of Nox2 gene and reactive oxygen species. Our findings demonstrate that exposure to RSD promotes atherosclerosis by augmenting NETs formation within the plaque. This provides new insight into the underlying mechanism of depression-related CVD.
Asunto(s)
Apolipoproteínas E/deficiencia , Aterosclerosis/patología , Trampas Extracelulares/metabolismo , Neutrófilos/metabolismo , Conducta Social , Animales , Apolipoproteínas E/metabolismo , Aterosclerosis/sangre , Médula Ósea/patología , Movimiento Celular , Desoxirribonucleasa I/metabolismo , Masculino , Ratones Endogámicos C57BL , Células Supresoras de Origen Mieloide/metabolismo , Estrés Psicológico/patologíaRESUMEN
Brown adipose tissue (BAT) has been found as an endocrine organ that maintains metabolic homeostasis; however, the effects on atherosclerosis remain undefined. Here, we investigated the effect of experimental BAT transplantation on atherosclerosis. Interscapular BAT was dissected from wild-type mice and transplanted into the visceral cavity of 12-week-old apoE-/- mice. Oil-red O staining of whole aortas after 3 months of a high-cholesterol diet showed a significant decrease in atherosclerotic lesion area in BAT-transplanted mice by 32% compared with the sham control mice. Lipid profiles, except for serum triglyceride level, showed no difference between the 2 groups. BAT-transplanted mice showed higher concentrations of serum noradrenalin, fibroblast growth factor 21 (FGF-21), and adiponectin. Treatment with the ß3-adrenergic receptor (AR) blocker completely abrogated the atheroprotective effects of BAT transplantation, with serum concentrations of FGF-21 and adiponectin being equivalent between the 2 groups. Homologous transplantation of BAT from apoE-/- mice also showed a significant decrease in atherosclerotic lesion area by 28% without affecting lipid profiles, while epidydimal white adipose tissue transplantation did not affect atherosclerosis. Serum and endogenous BAT concentrations of FGF-21 were significantly higher in BAT-transplanted mice than sham control mice. Concomitantly, serum adiponectin levels were elevated in BAT-transplanted mice and showed a significant inverse correlation with atherosclerotic lesion area. Our findings show for the first time that atheroprotective effect of BAT transplantation is BAT-specific and independent of lipid-lowering effect, accompanied by AR-mediated activation of the FGF-21-adiponectin axis.
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Adiponectina/metabolismo , Tejido Adiposo Pardo/trasplante , Aterosclerosis/prevención & control , Factores de Crecimiento de Fibroblastos/metabolismo , Receptores Adrenérgicos/fisiología , Animales , Apolipoproteínas E/deficiencia , Apolipoproteínas E/genética , Aterosclerosis/terapia , Ratones , Ratones NoqueadosRESUMEN
Perivascular adipose tissue (PAT) is associated with vascular homeostasis; however, its causal effect on atherosclerosis currently remains undefined. Here, we investigated the effect of experimental PAT transplantation on atherosclerosis. The thoracic periaortic adipose tissue (tPAT) was dissected from 16-week-old wild-type mice and transplanted over the infrarenal aorta of 20-week-old apoE deficient (apoE-/-) mice fed high-cholesterol diet for 3 months. Oil-red O staining after 4 weeks showed a significant 20% decrease in the atherosclerotic lesion of suprarenal aorta compared with that of sham control mice, while that of infrarenal aorta showed no difference between the two groups. TGF-ß1 mRNA expression was significantly higher in grafted tPAT than donor tPAT, accompanied by a significant increase in serum TGF-ß1 concentration, which was inversely correlated with the suprarenal lesion area (râ¯=â¯-0.63, Pâ¯=â¯0.012). Treatment with neutralizing TGF-ß antibody abrogated the anti-atherogenic effect of tPAT transplantation. Immunofluorescent analysis of grafted tPAT showed that TGF-ß-positive cells were co-localized with Mac-2-positive cells and this number was significantly increased compared with donor tPAT. There was also marked increase in mRNA expression of alternatively activated macrophages-related genes. Furthermore, the percentage of eosinophils in stromal vascular fraction of donor tPAT was much higher than that in epididymal white adipose tissue, concomitant with the significantly higher protein level of IL-4. IL-4 mRNA expression levels in grafted tPAT were increased in a time-dependent manner after tPAT transplantation. Our findings show that tPAT transplantation inhibits atherosclerosis development by exerting TGF-ß1-mediated anti-inflammatory response, which may involve alternatively activated macrophages.
Asunto(s)
Tejido Adiposo/trasplante , Aterosclerosis/prevención & control , Factor de Crecimiento Transformador beta1/metabolismo , Tejido Adiposo/metabolismo , Tejido Adiposo/patología , Animales , Anticuerpos Neutralizantes/administración & dosificación , Aorta Torácica/metabolismo , Aorta Torácica/patología , Apolipoproteínas E/deficiencia , Apolipoproteínas E/genética , Aterosclerosis/metabolismo , Aterosclerosis/patología , Eosinófilos/patología , Inflamación/metabolismo , Inflamación/patología , Inflamación/prevención & control , Interleucina-4/metabolismo , Activación de Macrófagos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados para ApoE , ARN Mensajero/genética , ARN Mensajero/metabolismo , Factor de Crecimiento Transformador beta1/antagonistas & inhibidores , Factor de Crecimiento Transformador beta1/genéticaRESUMEN
Increasing evidence indicates that the gut microbiota is closely associated with acute graft-versus-host disease (aGVHD) in stem cell transplantation (SCT). Fecal microbiota transplantation (FMT) could represent an alternative treatment option for aGVHD. However, FMT for SCT patients carries a potential risk of infection by infused microbiota because of the severely immunosuppressed status. We therefore conducted a pilot study to evaluate the safety of FMT in SCT. A total of 4 patients with steroid-resistant (n = 3) or steroid-dependent gut aGVHD (n = 1) received FMT. No severe adverse events attributed to FMT were observed. All patients responded to FMT, with 3 complete responses and 1 partial response. Temporal dynamics of microbiota seemed to be linked to the gut condition of patients and peripheral effector regulatory T cells also increased during response to FMT. FMT was safely performed in our patients and might offer a novel therapeutic option for aGVHD. This trial was registered at the University Hospital Medical Information Network (https://upload.umin.ac.jp/cgi-open-bin/icdr_e/ctr_view.cgi?recptno=R000017575) as #UMIN000015115.
Asunto(s)
Trasplante de Microbiota Fecal , Microbioma Gastrointestinal , Enfermedad Injerto contra Huésped/terapia , Enfermedades Intestinales/terapia , Enfermedad Aguda , Adulto , Aloinjertos , Femenino , Enfermedad Injerto contra Huésped/inmunología , Enfermedad Injerto contra Huésped/microbiología , Enfermedad Injerto contra Huésped/patología , Trasplante de Células Madre Hematopoyéticas , Humanos , Huésped Inmunocomprometido , Enfermedades Intestinales/inmunología , Enfermedades Intestinales/microbiología , Enfermedades Intestinales/patología , Leucemia Mieloide Aguda/inmunología , Leucemia Mieloide Aguda/microbiología , Leucemia Mieloide Aguda/patología , Leucemia Mieloide Aguda/terapia , Masculino , Persona de Mediana Edad , Proyectos Piloto , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/patologíaRESUMEN
OBJECTIVE: Maternal obesity elicits offspring's metabolic disorders via developmental modifications of visceral adipose tissue; however, its effect on atherogenesis remains undefined. Perivascular adipose tissue has recently been implicated in vascular remodeling and vasoreactivity. We hypothesize that developmental modifications of perivascular adipose tissue by maternal high-fat diet (HFD) exposure promotes atherosclerosis in adult offspring. APPROACH AND RESULTS: Eight-week-old female apolipoprotein E-deficient mice were fed an HFD or normal diet (ND) during gestation and lactation. Offspring were fed a high-cholesterol diet from 8 weeks of age. Twenty-week-old male offspring of HFD-fed dams (O-HFD) showed a 2.1-fold increase in atherosclerotic lesion of the entire aorta compared with those of ND-fed dams (O-ND). Although mRNA expressions of interleukin-6, tumor necrosis factor, and monocyte chemotactic protein-1 and accumulation of macrophages in epididymal white adipose tissue were less in O-HFD than in O-ND, thoracic periaortic adipose tissue (tPAT) showed an exaggerated inflammatory response in O-HFD. Intra-abdominal transplantation of tPAT from 8-week-old O-HFD alongside the distal abdominal aorta exaggerated atherosclerosis development of the infrarenal aorta in recipient apolipoprotein E-deficient mice compared with tPAT from O-ND (210%, P<0.01). Although macrophage accumulation was rarely detected in tPAT of 8-week-old offspring, mRNA expression and protein levels of macrophage colony-stimulating factor were markedly elevated in O-HFD (2.3-fold, 3.3-fold, respectively, P<0.05), suggesting that increased macrophage colony-stimulating factor expression contributes to the augmented accumulation of macrophages, followed by the enhanced proinflammatory response. CONCLUSIONS: Our findings demonstrate that maternal HFD exaggerates atherosclerosis development in offspring by augmenting tPAT-specific inflammatory response proceeded by an increased expression of macrophage colony-stimulating factor.
Asunto(s)
Tejido Adiposo/metabolismo , Fenómenos Fisiológicos Nutricionales de los Animales , Enfermedades de la Aorta/metabolismo , Aterosclerosis/metabolismo , Dieta Alta en Grasa/efectos adversos , Mediadores de Inflamación/metabolismo , Inflamación/metabolismo , Fenómenos Fisiologicos Nutricionales Maternos , Efectos Tardíos de la Exposición Prenatal , Tejido Adiposo/inmunología , Tejido Adiposo/fisiopatología , Tejido Adiposo/trasplante , Factores de Edad , Animales , Aorta Torácica/inmunología , Aorta Torácica/metabolismo , Enfermedades de la Aorta/genética , Enfermedades de la Aorta/inmunología , Enfermedades de la Aorta/fisiopatología , Apolipoproteínas E/deficiencia , Apolipoproteínas E/genética , Aterosclerosis/genética , Aterosclerosis/inmunología , Aterosclerosis/fisiopatología , Modelos Animales de Enfermedad , Femenino , Genotipo , Inflamación/genética , Inflamación/inmunología , Inflamación/fisiopatología , Factor Estimulante de Colonias de Macrófagos/genética , Factor Estimulante de Colonias de Macrófagos/metabolismo , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Fenotipo , Embarazo , ARN Mensajero/metabolismo , Factores de Riesgo , Transducción de Señal , Factores de Tiempo , Regulación hacia ArribaRESUMEN
BACKGROUND: Granulocyte-colony stimulating factor (G-CSF) is widely used to mobilize peripheral blood stem cells (PBSCs) in healthy donors. A few reports have shown that some healthy donors developed acute respiratory distress syndrome or capillary leak syndrome after more than several rounds of G-CSF administration or leukapheresis. CASE REPORT: We report the case of a healthy donor for allogeneic stem cell transplantation who developed severe hypoxemia 1 h after only the first administration of G-CSF. The donor was administered 10 µg/kg G-CSF (lenograstim) subcutaneously for PBSC mobilization. 1 h after the first administration of G-CSF, the donor suddenly presented with dry cough and dyspnea. The oxygen saturation by pulse oximetry (SpO2) in the room air was 88%. An electrocardiogram and chest radiography revealed no abnormalities. We excluded other causes of severe hypoxemia and diagnosed the donor with hypoxemia due to G-CSF administration, which was subsequently terminated. The donor was administered 2 l/min oxygen via a nasal cannula and 100 mg hydrocortisone intravenously. He subsequently recovered, and SpO2 in the room air returned to 98% 10 h after hypoxemia. CONCLUSION: These respiratory symptoms might be related to anaphylactoid or hypersensitivity reaction. The donors should be observed for at least 1 h after the first administration of G-CSF.
RESUMEN
We describe herein the clinical outcomes of 16 patients with chronic myeloid leukemia in the chronic phase who stopped the administration of tyrosine kinase inhibitors (TKI) after maintaining undetectable levels of major BCR-ABL1, based on real-time quantitative polymerase chain reaction, for prolonged periods (undetectable MR for a median of 2,100 days (822-4,068). The reasons for discontinuing TKI were enrollments in a clinical trial testing discontinuation of these agents (n=9), adverse effects (n=2) or financial problems (n=5). After TKI discontinuation, patients were followed for a median of 551 days (154-2,446). A total of 8 patients (50%) experienced molecular relapse after a median of 119 days (28-171). Among them, 6 patients who lost major molecular response (MMR) were treated with imatinib (n=2) or dasatinib (n=4), while 2 patients who lost undetectable MR after discontinuing TKI (1 each had taken bostinib and imatinib) but maintained MMR were carefully monitored without re-administration of TKI. Of 6 patients who re-started TKI, 4 (67%) achieved undetectable MR but the other 2 achieved only MMR. The results of this small, retrospective study may support the current understanding of treatment discontinuation, possibly leading to a sustained deep molecular response in some patients.
Asunto(s)
Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Terminación Anticipada de los Ensayos Clínicos , Femenino , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/enzimología , Masculino , Persona de Mediana Edad , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/economía , Estudios Retrospectivos , Insuficiencia del Tratamiento , Resultado del TratamientoRESUMEN
A 53-year-old woman was admitted with right upper-extremity pain and multiple subcutaneous masses. Bone marrow aspirate showed hypercellular marrow with increased myeloid components at all stages of maturation. Cytogenetic analysis of the bone marrow revealed 100% Philadelphia chromosome positivity along with BCR/ABL gene rearrangement, as demonstrated by polymerase chain reaction (PCR). A diagnosis of chronic phase of chronic myeloid leukemia (CML) was therefore made. Biopsy of one of the subcutaneous masses showed proliferation of granulocytes in various stages of differentiation. There were also erythroid cells and megakaryocytes, without p53 and CD34-positive blasts. These results suggested that the subcutaneous masses had developed from extramedullary hematopoiesis, not blastomas. The patient was administered dasatinib (DA) 140 mg, combined with radiation therapy for pain and peripheral neuropathy from the right axial extramedullary tumor. The patient showed complete hematological remission and the subcutaneous masses had disappeared 1 month after starting administration of DA. Because the patient did not achieve a cytogenetic response, the tyrosine kinase inhibitor nilotinib was administered. She will undergo allogeneic stem cell transplantation in the near future. Extramedullary hematopoiesis in the early stages of CML is uncommon. Our case emphasizes the need to elucidate the pathogenesis of extramedullary hematopoiesis in the early stages of CML.
Asunto(s)
Hematopoyesis Extramedular , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Neoplasias Cutáneas/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Femenino , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Persona de Mediana Edad , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Inducción de Remisión , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/patologíaRESUMEN
A 58-year-old female was diagnosed with Philadelphia chromosome positive chronic myeloid leukemia (CML) in blast crisis (BC) in 2004. The patient received imatinib, which quickly induced molecular remission, and subsequently underwent bone marrow transplantation (BMT) from an unrelated human leukocyte antigen (HLA)-identical donor. The post-transplant clinical course was essentially uneventful. In 2014, ten years after the BMT, the patient was admitted to our hospital complaining of lymphadenopathy, and blasts were observed in peripheral blood. The patient was diagnosed as having a CML relapse in myeloid BC, with leukemic infiltration in lymph nodes, and was treated with dasatinib. Subsequently, pleural effusion developed and nilotinib was administered, which induced normal blood counts without blasts and partial cytogenetic remission, one month after administration. Six months after the relapse, this patient underwent a second BMT from an HLA-matched unrelated donor. Recent studies have demonstrated the cumulative incidence of CML relapse more than five years after allogeneic hematopoietic stem cell transplantation (allo-HSCT) to be higher than in acute myeloid leukemia. Although rare, the possibility of late relapse should be considered in patients diagnosed with CML after allo-HSCT.
Asunto(s)
Trasplante de Médula Ósea , Leucemia Mielógena Crónica BCR-ABL Positiva/terapia , Biopsia , Femenino , Proteínas de Fusión bcr-abl/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Persona de Mediana Edad , Recurrencia , Factores de Tiempo , Trasplante HomólogoRESUMEN
A 60-year-old man with myelodysplastic syndrome underwent allogeneic transplantation of female umbilical cord blood in 2010 and sustained a complete remission. He experienced severe pain in his left hip joint and was admitted to the orthopedic surgery division of our institution in February 2015. After admission, he was suspected to have hemophagocytic syndrome (HPS) and was thus transferred to the hematology division. Bone marrow aspiration revealed hyper-cellular marrow filled with abnormal collapsed cells, consistent with bone marrow necrosis (BMN). As there was no evidence of infection, collagen disease, or occult cancer, he was diagnosed with HPS of unknown origin and treated with dexamethasone, cyclosporine A, and etoposide according to the HLH-2004 protocol. Although his general condition and laboratory findings showed amelioration, morphologically abnormal cells appeared in peripheral blood two weeks after treatment. Bone marrow aspiration showed BMN with increased abnormal cells, positive for CD117 and MPO. Sex chromosome FISH analysis revealed donor chimerism and cytogenetic analysis showed 46XX, +1, der (1;7) (q10;q10). He was diagnosed with donor cell leukemia (DCL) and received salvage chemotherapy. However, he died because of severe pneumonia and sepsis without neutrophil recovery at day 68. We herein report this rare case of DCL with BMN.
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Enfermedades de la Médula Ósea/complicaciones , Enfermedades de la Médula Ósea/patología , Fracturas Óseas/etiología , Leucemia/terapia , Resultado Fatal , Trasplante de Células Madre Hematopoyéticas , Humanos , Linfohistiocitosis Hemofagocítica , Masculino , Persona de Mediana Edad , Necrosis/complicaciones , Donantes de TejidosRESUMEN
Previously we proposed an eccentric figure-eight coil that can cause threshold stimulation in the brain at lower driving currents. In this study, we performed numerical simulations and magnetic stimulations to healthy subjects for evaluating the advantages of the eccentric coil. The simulations were performed using a simplified spherical brain model and a realistic human brain model. We found that the eccentric coil required a driving current intensity of approximately 18% less than that required by the concentric coil to cause comparable eddy current densities within the brain. The eddy current localization of the eccentric coil was slightly higher than that of the concentric coil. A prototype eccentric coil was designed and fabricated. Instead of winding a wire around a bobbin, we cut eccentric-spiral slits on the insulator cases, and a wire was woven through the slits. The coils were used to deliver magnetic stimulation to healthy subjects; among our results, we found that the current slew rate corresponding to motor threshold values for the concentric and eccentric coils were 86 and 78 A/µs, respectively. The results indicate that the eccentric coil consistently requires a lower driving current to reach the motor threshold than the concentric coil. Future development of compact magnetic stimulators will enable the treatment of some intractable neurological diseases at home.
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Estimulación Magnética Transcraneal/instrumentación , Encéfalo/fisiología , Simulación por Computador , Electromiografía , Diseño de Equipo , Potenciales Evocados Motores , Humanos , Modelos Neurológicos , Estimulación Magnética Transcraneal/métodosRESUMEN
Acute myeloid leukemia (AML) with t(8;21)(q22;q22.1);RUNX1-ETO is one of the most common subtypes of AML. Although t(8;21) AML has been classified as favorable-risk, only about half of patients are cured with current therapies. Several genetic abnormalities, including TP53 mutations and deletions, negatively impact survival in t(8;21) AML. In this study, we established Cas9+ mouse models of t(8;21) AML with intact or deficient Tpr53 (a mouse homolog of TP53) using a retrovirus-mediated gene transfer and transplantation system. Trp53 deficiency accelerates the in vivo development of AML driven by RUNX1-ETO9a, a short isoform of RUNX1-ETO with strong leukemogenic potential. Trp53 deficiency also confers resistance to genetic depletion of RUNX1 and a TP53-activating drug in t(8;21) AML. However, Trp53-deficient t(8;21) AML cells were still sensitive to several drugs such as dexamethasone. Cas9+ RUNX1-ETO9a cells with/without Trp53 deficiency can produce AML in vivo, can be cultured in vitro for several weeks, and allow efficient gene depletion using the CRISPR/Cas9 system, providing useful tools to advance our understanding of t(8;21) AML.
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Cromosomas Humanos Par 21 , Cromosomas Humanos Par 8 , Subunidad alfa 2 del Factor de Unión al Sitio Principal , Modelos Animales de Enfermedad , Leucemia Mieloide Aguda , Translocación Genética , Proteína p53 Supresora de Tumor , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/etiología , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/deficiencia , Animales , Ratones , Cromosomas Humanos Par 8/genética , Cromosomas Humanos Par 21/genética , Humanos , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Subunidad alfa 2 del Factor de Unión al Sitio Principal/deficiencia , Proteínas de Fusión Oncogénica/genéticaRESUMEN
Preventing, diagnosing, and treating diseases requires accurate clinical biomarkers, which remains challenging. Recently, advanced computational approaches have accelerated the discovery of promising biomarkers from high-dimensional multimodal data. Although machine-learning methods have greatly contributed to the research fields, handling data sparseness, which is not unusual in research settings, is still an issue as it leads to limited interpretability and performance in the presence of missing information. Here, we propose a novel pipeline integrating joint non-negative matrix factorization (JNMF), identifying key features within sparse high-dimensional heterogeneous data, and a biological pathway analysis, interpreting the functionality of features by detecting activated signaling pathways. By applying our pipeline to large-scale public cancer datasets, we identified sets of genomic features relevant to specific cancer types as common pattern modules (CPMs) of JNMF. We further detected COPS5 as a potential upstream regulator of pathways associated with diffuse large B-cell lymphoma (DLBCL). COPS5 exhibited co-overexpression with MYC, TP53, and BCL2, known DLBCL marker genes, and its high expression was correlated with a lower survival probability of DLBCL patients. Using the CRISPR-Cas9 system, we confirmed the tumor growth effect of COPS5, which suggests it as a novel prognostic biomarker for DLBCL. Our results highlight that integrating multiple high-dimensional data and effectively decomposing them to interpretable dimensions unravels hidden biological importance, which enhances the discovery of clinical biomarkers.
RESUMEN
Monocytic acute myeloid leukemia (AML) responds poorly to current treatments, including venetoclax-based therapy. We conducted in vivo and in vitro CRISPR-Cas9 library screenings using a mouse monocytic AML model and identified SETDB1 and its binding partners (ATF7IP and TRIM33) as crucial tumor promoters in vivo. The growth-inhibitory effect of Setdb1 depletion in vivo is dependent mainly on natural killer (NK) cell-mediated cytotoxicity. Mechanistically, SETDB1 depletion upregulates interferon-stimulated genes and NKG2D ligands through the demethylation of histone H3 Lys9 at the enhancer regions, thereby enhancing their immunogenicity to NK cells and intrinsic apoptosis. Importantly, these effects are not observed in non-monocytic leukemia cells. We also identified the expression of myeloid cell nuclear differentiation antigen (MNDA) and its murine counterpart Ifi203 as biomarkers to predict the sensitivity of AML to SETDB1 depletion. Our study highlights the critical and selective role of SETDB1 in AML with granulo-monocytic differentiation and underscores its potential as a therapeutic target for current unmet needs.
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Diferenciación Celular , N-Metiltransferasa de Histona-Lisina , Células Asesinas Naturales , Leucemia Mieloide Aguda , Leucemia Mieloide Aguda/patología , Leucemia Mieloide Aguda/inmunología , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/genética , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Animales , Ratones , N-Metiltransferasa de Histona-Lisina/metabolismo , N-Metiltransferasa de Histona-Lisina/genética , Humanos , Ratones Endogámicos C57BL , Línea Celular Tumoral , Vigilancia Inmunológica , Monocitos/metabolismo , Monocitos/inmunología , ApoptosisRESUMEN
In this study, we examined the modification of polypropylene non-woven fabrics (PP NWFs) via a one-step oxidation treatment using photo-activated chlorine dioxide radicals (ClO2Ë). The oxidised PP NWFs exhibited excellent antibacterial activity against both Escherichia coli (Gram-negative) and Staphylococcus aureus (Gram-positive). The mound structure and antibacterial activity in the modified PP NWFs disappeared upon washing with a polar organic solvent. After washing, nanoparticles of around 80 nm in diameter were observed in the solution. The results of several mechanistic studies suggest that nanoparticles can contribute to the antimicrobial activity of oxidised PP NWFs.
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Polipropilenos , Textiles , Polipropilenos/farmacología , Polipropilenos/química , Textiles/microbiología , Óxidos/farmacología , Antibacterianos/farmacología , Antibacterianos/químicaRESUMEN
Decitabine (DAC) is clinically used to treat myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Our genome-wide CRISPR-dCas9 activation screen using MDS-derived AML cells indicates that mitotic regulation is critical for DAC resistance. DAC strongly induces abnormal mitosis (abscission failure or tripolar mitosis) in human myeloid tumors at clinical concentrations, especially in those with TP53 mutations or antecedent hematological disorders. This DAC-induced mitotic disruption and apoptosis are significantly attenuated in DNMT1-depleted cells. In contrast, overexpression of Dnmt1, but not the catalytically inactive mutant, enhances DAC-induced mitotic defects in myeloid tumors. We also demonstrate that DAC-induced mitotic disruption is enhanced by pharmacological inhibition of the ATR-CLSPN-CHK1 pathway. These data challenge the current assumption that DAC inhibits leukemogenesis through DNMT1 inhibition and subsequent DNA hypomethylation and highlight the potent activity of DAC to disrupt mitosis through aberrant DNMT1-DNA covalent bonds.