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Information regarding follow-up duration after treatment for newly diagnosed diffuse large B-cell lymphoma (DLBCL) is important. However, a clear endpoint has yet to be established. We totally enrolled 2182 patients newly diagnosed with DLBCL between 2008 and 2018. The median age of the patients was 71 years. All patients were treated with rituximab- and anthracycline-based chemotherapies. Each overall survival (OS) was compared with the age- and sex-matched Japanese general population (GP) data. At a median follow-up of 3.4 years, 985 patients experienced an event and 657 patients died. Patients who achieved an event-free survival (EFS) at 36 months (EFS36) had an OS equivalent to that of the matched GP (standard mortality ratio [SMR], 1.17; P=0.1324), whereas those who achieved an EFS24 did not have an OS comparable to that of the matched GP (SMR, 1.26; P=0.0095). Subgroup analysis revealed that relatively old patients (>60 years), male patients, those with limited-stage disease, those with a good performance status, and those with low levels of soluble interleukin 2 receptor already had a comparable life expectancy to the matched GP at an EFS24. In contrast, relatively young patients had a shorter life expectancy than matched GP, even with an EFS36. In conclusion, an EFS36 was shown to be a more suitable endpoint for newly diagnosed DLBCL patients than an EFS24. Of note, younger patients require a longer EFS period than older patients in order to obtain an equivalent life expectancy to the matched GP.
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OBJECTIVES: The cryptic fusion oncogene NUP98::NSD1 is known to be associated with FLT3-ITD mutation in acute myeloid leukemia (AML), and an independent poor prognostic factor in pediatric AML. However, there are little data regarding the clinical significance of NUP98::NSD1 in adult cohort. METHODS: We conducted a multicenter retrospective study to investigate the prevalence, clinical characteristics, and prognostic impact of NUP98::NSD1 in adult FLT3-ITD-positive AML patients. RESULTS: In a total of 97 FLT3-ITD-positive AML patients, six cases (6.2%) were found to harbor the NUP98::NSD1 fusion transcript. NUP98::NSD1 positive cases had significantly higher platelet counts and a higher frequency of FAB-M4 morphology than NUP98::NSD1 negative cases. NUP98::NSD1 was found to be mutually exclusive with NPM1 mutation, and was accompanied by the WT1 mutation in three of the six cases. The presence of NUP98::NSD1 fusion at the time of diagnosis predicted poor response to cytarabine-anthracycline-based intensive induction chemotherapy (induction failure rate: 83% vs. 36%, p = .038). Five of the six cases with NUP98::NSD1 underwent allogeneic hematopoietic stem cell transplantation (HSCT). Two of the five cases have successfully maintained remission, with one of them being rescued through a second HSCT. CONCLUSIONS: Detecting NUP98::NSD1 in adult FLT3-ITD-positive AML is crucial to recognizing chemotherapy-resistant group.
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Leucemia Mieloide Aguda , Niño , Humanos , Adulto , Estudios Retrospectivos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Pronóstico , Mutación , Tirosina Quinasa 3 Similar a fms/genética , N-Metiltransferasa de Histona-Lisina/genéticaRESUMEN
An 80-year-old man diagnosed with primary macroglobulinemia 7 years earlier had been treated with cyclophosphamide, following which he developed dyspnea on exertion. Cyclophosphamide was discontinued. The patient's dyspnea, however, failed to improve. Right heart catheterization (RHC) revealed precapillary pulmonary hypertension (PH). He was transferred to our institution for further examination. Prior use of cyclophosphamide was the patient's only risk factor for PH, and cyclophosphamide use was considered as a possible cause of PH in this case. He was treated with tadalafil and dyspnea gradually improved. A follow-up RHC exhibited improvement in mean pulmonary arterial pressure and pulmonary vascular resistance.
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Recent advances in next-generation sequencing (NGS) have enabled the detection of subclinical minute FLT3-ITD. We selected 74 newly diagnosed, cytogenetically normal acute myeloid leukaemia (AML) samples in which FLT3-ITD was not detected by gel electrophoresis. We sequenced them using NGS and found minute FLT3-ITDs in 19 cases. We compared cases with clinically relevant FLT3-ITD (n = 37), cases with minute FLT3-ITD (n = 19) and cases without detectable FLT3-ITD (n = 55). Molecular characteristics (location and length) of minute FLT3-ITD were similar to those of clinically relevant FLT3-ITD. Survival of cases with minute FLT3-ITD was similar to that of cases without detectable FLT3-ITD, whereas the relapse rate within 1 year after onset was significantly higher in cases with minute FLT3-ITD. We followed 18 relapsed samples of cases with clinically FLT3-ITD-negative at diagnosis. Two of 3 cases with minute FLT3-ITD relapsed with progression to clinically relevant FLT3-ITD. Two of 15 cases in which FLT3-ITD was not detected by NGS relapsed with the emergence of minute FLT3-ITD, and one of them showed progression to clinically relevant FLT3-ITD at the second relapse. We revealed the clonal dynamics of subclinical minute FLT3-ITD in clinically FLT3-ITD-negative AML. Minute FLT3-ITD at the initial AML can expand to become a dominant clone at relapse.
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Leucemia Mieloide Aguda , Recurrencia Local de Neoplasia , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Tirosina Quinasa 3 Similar a fms/genética , Mutación , PronósticoRESUMEN
Retinal photoreceptor cells, rods and cones, convert photons of light into chemical and electrical signals as the first step of the visual transduction cascade. Although the chemical processes in the phototransduction system are very similar to each other in these photoreceptors, the light sensitivity and time resolution of the photoresponse in rods are functionally different than those in the photoresponses of cones. To systematically investigate how photoresponses are divergently regulated in rods and cones, we have developed a detailed mathematical model on the basis of the Hamer model. The current model successfully reconstructed light intensity-, ATP- and GTP-dependent changes in concentrations of phosphorylated visual pigments (VPs), activated transducins (Tr*s) and phosphodiesterases (PDEs) in rods and cones. In comparison to rods, the lower light sensitivity of cones was attributed not only to the lower affinity of activated VPs for Trs but also to the faster desensitization of the VPs. The assumption of an intermediate inactive state, MIIi, in the thermal decay of activated VPs was essential for inducing faster inactivation of VPs in rods, and possibly also in cones.
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Fotofobia , Células Fotorreceptoras Retinianas Bastones , Humanos , Células Fotorreceptoras Retinianas Bastones/metabolismo , Células Fotorreceptoras Retinianas Conos/metabolismo , Fototransducción/fisiología , Transducina/metabolismoRESUMEN
Roles of mitochondria in sinoatrial nodal cells (SANCs) have not been fully clarified. We have previously demonstrated that mitochondrial Ca2+ efflux through the Na+-Ca2+ exchanger, NCXm, modulates sarcoplasmic reticulum (SR) Ca2+ content and automaticity of HL-1 cardiomyocytes. In this study, we extended this line of investigation to clarify the spatial and functional association between mitochondria and local calcium release (LCR) from the SR in murine SANCs. High-speed two dimensional (2D) and confocal line-scan imaging of SANCs revealed that LCRs in the early phase of the Ca2+ transient cycle length (CL) appeared with a higher probability near mitochondria. Although LCR increased toward the late phase of CL, no significant difference was noted in the occurrence of late LCRs near and distant from mitochondria. LCRs, especially in the late phase of CL, induced temporal and spatial heterogeneity of the Ca2+ transient amplitude. Attenuating mitochondrial Ca2+ efflux using an NCXm inhibitor, CGP-37157 (1 µM), reduced the amplitude, duration and size of LCR. It also attenuated early LCR occurrence, and simultaneously prolonged LCR period and CL. Additionally, CGP-37157 reduced caffeine-induced Ca2+ transient. Therefore, the inhibitory effect on LCR was attributable to the reduction of the SR Ca2+ content through NCXm inhibition. No obvious off-target effects of 1 µM CGP-37157 were found on T- and L-type voltage-gated Ca2+ currents and hyperpolarization-activated inward current. Taken together, these results suggest that mitochondria are involved in LCR generation by modulating the SR Ca2+ content through NCXm-mediated Ca2+ efflux in murine SANCs.
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Calcio , Mitocondrias , Nodo Sinoatrial , Potenciales de Acción , Animales , Calcio/metabolismo , Señalización del Calcio/fisiología , Ratones , Mitocondrias/metabolismo , Miocitos Cardíacos/metabolismo , Retículo Sarcoplasmático/metabolismo , Nodo Sinoatrial/citología , Nodo Sinoatrial/metabolismo , Intercambiador de Sodio-Calcio/metabolismoRESUMEN
An 80-year-old female with fever, edema in the lower extremities, and marked eosinophilia was referred to our hospital. Based on the presence of the Philadelphia chromosome, she was diagnosed with chronic myeloid leukemia (CML). Although imatinib induced a complete cytogenetic response (CCyR), CML relapsed after 28 months of starting it. A CCyR was achieved again by nilotinib but was lost after about 14 months. Only transient response occurred to dasatinib, and the patient died. At relapse, neutrophilia was more predominant than eosinophilia. We reviewed 6 patients with CML whose eosinophil rate in the peripheral blood was >50%. Most patients were males with palpable splenomegaly and had cardiac disorders, peripheral vascular disease, or pleural effusion. Typically, CML causes neutrophil-predominant leukocytosis. However, a subgroup of CML with marked eosinophilia resembles chronic eosinophilic leukemia or idiopathic hypereosinophilic syndrome.
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Eosinofilia/diagnóstico , Leucemia Mielógena Crónica BCR-ABL Positiva/diagnóstico , Anciano de 80 o más Años , Antineoplásicos/uso terapéutico , Dasatinib/uso terapéutico , Eosinofilia/tratamiento farmacológico , Resultado Fatal , Femenino , Humanos , Mesilato de Imatinib/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Masculino , Cromosoma Filadelfia , Inhibidores de Proteínas Quinasas , RecurrenciaRESUMEN
Upon elevation of plasma glucose concentration, pancreatic ß-cells generate bursts of action potentials to induce cyclic changes in [Ca(2+)]i regulating insulin release. Glucose-dependent insulin secretion is synergistically enhanced by glucagon-like peptide-1 (GLP-1), which increases [cAMP]i and activates protein kinase A (PKA) and exchange protein activated by cAMP (Epac). The insulinotropic effect of GLP-1 is mediated, at least in part, by modulating multiple ion channels/transporters at the plasma membrane and ER through PKA- and EPAC-dependent mechanisms, which increase membrane excitability and intracellular Ca(2+) release. However, because of complex interactions between multiple cellular factors involved in the GLP-1 effects, quantitative aspects of the molecular/ionic mechanisms have not yet been determined. We thus performed simulation studies and mathematical analysis to investigate how GLP-1 signals control [cAMP]i and subsequently modify the bursting activities and Ca(2+) dynamics. First, a GLP-1 receptor signal transduction model was developed and introduced to our ß-cells model. Secondly, modulatory effects of PKA/Epac on ion channels/transporters were incorporated based on experimental studies. Increases in the frequency and duration of the bursting activity observed during GLP-1 stimulation were well reconstructed by our model, and lead potential analysis quantitatively determined the functional role of each ion channel/transporter in modifying the burst pattern. Finally, an IP3R model was developed to reproduce GLP-1-induced Ca(2+) transients/oscillations. Instantaneous equilibrium analysis and bifurcation analysis also elucidated the quantitative mechanisms involved in generating IP3R-mediated Ca(2+) mobilization. The results of this theoretical analysis of the effects of GLP-1 on membrane excitability/Ca(2+) dynamics are discussed in this review.
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Calcio/fisiología , Péptido 1 Similar al Glucagón/fisiología , Receptor del Péptido 1 Similar al Glucagón/fisiología , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/fisiología , Potenciales de Acción , Glucemia/metabolismo , Calcio/metabolismo , Membrana Celular/fisiología , AMP Cíclico/metabolismo , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Humanos , Insulina/metabolismo , Secreción de Insulina , Modelos Teóricos , Transducción de Señal/fisiologíaRESUMEN
Glucagon-like peptide-1 (GLP-1) is an intestinally derived blood glucose-lowering hormone that potentiates glucose-stimulated insulin secretion from pancreatic ß-cells. The secretagogue action of GLP-1 is explained, at least in part, by its ability to stimulate cAMP production so that cAMP may facilitate the release of Ca(2+) from inositol trisphosphate receptor (IP3R)-regulated Ca(2+) stores. However, a quantitative model has yet to be provided that explains the molecular mechanisms and dynamic processes linking GLP-1-stimulated cAMP production to Ca(2+) mobilization. Here, we performed simulation studies to investigate how GLP-1 alters the abilities of Ca(2+) and IP3 to act as coagonists at IP3R Ca(2+) release channels. A new dynamic model was constructed based on the Kaftan model, which demonstrates dual steady-state allosteric regulation of the IP3R by Ca(2+) and IP3. Data obtained from ß-cells were then analyzed to understand how GLP-1 facilitates IP3R-mediated Ca(2+) mobilization when UV flash photolysis is used to uncage Ca(2+) and IP3 intracellularly. When the dynamic model for IP3R activation was incorporated into a minimal cell model, the Ca(2+) transients and oscillations induced by GLP-1 were successfully reconstructed. Simulation studies indicated that transient and oscillatory responses to GLP-1 were produced by sequential positive and negative feedback regulation due to fast activation and slow inhibition of the IP3R by Ca(2+). The slow rate of Ca(2+)-dependent inhibition was revealed to provide a remarkable contribution to the time course of the decay of cytosolic Ca(2+) transients. It also served to drive and pace Ca(2+) oscillations that are significant when evaluating how GLP-1 stimulates insulin secretion.
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Calcio/metabolismo , Citoplasma/metabolismo , Péptido 1 Similar al Glucagón/metabolismo , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Células Secretoras de Insulina/metabolismo , Animales , AMP Cíclico/metabolismo , Citosol/metabolismo , Péptido 1 Similar al Glucagón/farmacología , Glucosa/metabolismo , Insulina/metabolismo , Células Secretoras de Insulina/efectos de los fármacos , Ratones , Fragmentos de Péptidos/farmacologíaRESUMEN
Ca(+) sparklets are subcellular Ca(2+) signals produced by the opening of sarcolemmal L-type Ca(2+) channels. Ca(2+) sparklet activity varies within the sarcolemma of arterial myocytes. In this study, we examined the relationship between Ca(2+) sparklet activity and sarcoplasmic reticulum (SR) Ca(2+) accumulation and release in cerebral arterial myocytes. Our data indicate that the SR is a vast organelle with multiple regions near the sarcolemma of these cells. Ca(2+) sparklet sites were located at or <0.2 µm from SR-sarcolemmal junctions. We found that while Ca(2+) sparklets increase the rate of SR Ca(2+) refilling in arterial myocytes, their activity did not induce regional variations in SR Ca(2+) content or Ca(2+) spark activity. In arterial myocytes, L-type Ca(2+) channel activity was independent of SR Ca(2+) load. This ruled out a potential feedback mechanism whereby SR Ca(2+) load regulates the activity of these channels. Together, our data suggest a model in which Ca(2+) sparklets contribute Ca(2+) influx into a cytosolic Ca(2+) pool from which sarco(endo)plasmic reticulum Ca(2+)-ATPase pumps Ca(2+) into the SR, indirectly regulating SR function.
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Señalización del Calcio , Calcio/metabolismo , Músculo Liso Vascular/metabolismo , Miocitos del Músculo Liso/metabolismo , Sarcolema/metabolismo , Retículo Sarcoplasmático/metabolismo , Animales , Canales de Calcio Tipo L/metabolismo , Arterias Cerebrales/metabolismo , Proteínas Luminiscentes/biosíntesis , Proteínas Luminiscentes/genética , Microscopía Confocal , Microscopía Fluorescente , Músculo Liso Vascular/citología , Señales de Clasificación de Proteína , Ratas , Ratas Sprague-Dawley , Proteínas Recombinantes de Fusión/biosíntesis , Canal Liberador de Calcio Receptor de Rianodina/metabolismo , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico/metabolismo , Factores de Tiempo , Transfección , Proteína Fluorescente RojaRESUMEN
The prognosis of patients receiving allogeneic hematopoietic stem cell transplantation (HSCT) for refractory acute lymphoblastic leukemia (ALL) is very poor. To improve survival rates, we attempted to intensify the conditioning regimen with daunorubicin, vincristine, prednisolone, medium-dose etoposide, cyclophosphamide, and total body irradiation (DNR/VCR/PSL plus medium-dose VP/CY/TBI). Four patients in relapse or induction failure of B-precursor ALL without other complications underwent allogeneic HSCT. Initially, chemotherapy comprising DNR 60 mg/m(2) for 3 days, VCR 1.4 mg/m(2) for 1 day, and PSL 60 mg/m(2) for 3 days was administered, which was followed by medium-dose VP/CY/TBI; some modifications were made for individual patients. All patients achieved engraftment and complete remission after HSCT. Regimen-related toxicities were tolerable and no patient died within 100 days. Two patients were alive without disease on days 563 and 1,055. The third patient relapsed on day 951, while the fourth died on day 179 without disease. Our results indicate that intensified myeloablative HSCT should be considered for patients with refractory ALL.
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Trasplante de Células Madre Hematopoyéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Acondicionamiento Pretrasplante , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Terapia Combinada , Femenino , Enfermedad Injerto contra Huésped/etiología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Inducción de Remisión , Trasplante Homólogo , Resultado del Tratamiento , Irradiación Corporal Total , Adulto JovenRESUMEN
Glucagon-like peptide-1 (GLP-1) elevates intracellular concentration of cAMP ([cAMP]) and facilitates glucose-dependent insulin secretion in pancreatic ß-cells. There has been much evidence to suggest that multiple key players such as the GLP-1 receptor, G(s) protein, adenylate cyclase (AC), phosphodiesterase (PDE), and intracellular Ca(2+) concentration ([Ca(2+)]) are involved in the regulation of [cAMP]. However, because of complex interactions among these signaling factors, the kinetics of the reaction cascade as well as the activities of ACs and PDEs have not been determined in pancreatic ß-cells. We have constructed a minimal mathematical model of GLP-1 receptor signal transduction based on experimental findings obtained mostly in ß-cells and insulinoma cell lines. By fitting this theoretical reaction scheme to key experimental records of the GLP-1 response, the parameters determining individual reaction steps were estimated. The model reconstructed satisfactorily the dynamic changes in [cAMP] and predicted the activities of cAMP effectors, protein kinase A (PKA), and cAMP-regulated guanine nucleotide exchange factor [cAMP-GEF or exchange protein directly activated by cAMP (Epac)] during GLP-1 stimulation. The simulations also predicted the presence of two sequential desensitization steps of the GLP1 receptor that occur with fast and very slow reaction rates. The cross talk between glucose- and GLP-1-dependent signal cascades for cAMP synthesis was well reconstructed by integrating the direct regulation of AC and PDE by [Ca(2+)]. To examine robustness of the signaling system in controlling [cAMP], magnitudes of AC and PDE activities were compared in the presence or absence of GLP-1 and/or the PDE inhibitor IBMX.(1).
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Biología Computacional/métodos , Células Secretoras de Insulina/fisiología , Receptores de Glucagón/metabolismo , Transducción de Señal/fisiología , Análisis de Sistemas , Animales , Receptor del Péptido 1 Similar al Glucagón , Modelos Biológicos , Receptores de Glucagón/genéticaRESUMEN
BACKGROUND: The donor cell culture in animal serum-free medium is important for the clinical application of cell transplantation therapy. Recently, human-derived platelet lysate (PL) gained interest as a substitute for fetal calf serum (FCS), but there are no studies that evaluate the validity of human bone marrow stromal cells (hBMSCs) expanded with PL-containing medium for central nervous system disorders. OBJECTIVE: To test the hypothesis that hBMSCs expanded with FCS-free, PL-containing medium can promote functional recovery after cerebral infarct. METHODS: hBMSCs were cultured in the FCS- or PL-containing medium. Cell-growth kinetics were analyzed. The vehicle or hBMSCs was stereotactically transplanted into the ipsilateral striatum of the rats subjected to permanent middle cerebral artery occlusion 7 days after the insult. Motor function was assessed for 8 weeks, and the fate of transplanted hBMSCs was examined using immunohistochemistry. RESULTS: There was no significant difference in hBMSC expansion between the 2 groups. Transplantation of hBMSCs expanded with the FCS- or PL-containing medium equally promoted functional recovery compared with the vehicle group. Histological analysis revealed that there were no significant differences in their migration, survival, and neural differentiation in the infarct brain between the 2 groups. CONCLUSION: hBMSCs expanded with PL-containing medium retained their capacity of migration, survival, and differentiation and significantly promoted functional recovery when stereotactically transplanted into the infarct brain. The PL may be a clinically valuable and safe substitute for FCS in expanding hBMSCs to regenerate the infarct brain.
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Trasplante de Médula Ósea/métodos , Técnicas de Cultivo de Célula/métodos , Medio de Cultivo Libre de Suero , Infarto de la Arteria Cerebral Media/cirugía , Células del Estroma/citología , Células del Estroma/trasplante , Animales , Diferenciación Celular , Movimiento Celular/fisiología , Supervivencia Celular/fisiología , Humanos , Inmunohistoquímica , Ratas , Ratas Sprague-Dawley , Recuperación de la FunciónRESUMEN
This study was aimed to test the hypothesis that human bone marrow stromal cells (hBMSC) expanded in fetal calf serum (FCS)-free, platelet lysate (PL)-containing medium would retain their capacity of migration, survival, and neural differentiation when transplanted into the infarct brain, using serial in vivo magnetic resonance imaging (MRI). Cell growth kinetic analysis revealed that hBMSC maintain their proliferative activity when cultured either in conventional FCS-containing medium or FCS-free, PL-containing medium. Subsequently, hBMSC were labeled with a superparamagnetic iron oxide agent and were stereotactically transplanted into the ipsilateral striatum of rats at 7 days after permanent middle cerebral artery occlusion. Serial MRI performed over 8 weeks revealed that they retain their migratory capacity towards the cerebral infarct. Moreover, double fluorescence immunohistochemistry also revealed that they preserve their capacity of differentiation into the neural cells in the peri-infarct area. The hBMSC expanded in the FCS-free, PL-containing medium retain their capacity of migration, survival, and differentiation when stereotactically transplanted into the infarct brain. The present findings strongly suggest the clinical utility of PL as a substitute to expand autologous hBMSC for cerebral infarct in the future.
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The donor cell culture in animal serum-free medium is quite important for the clinical application of cell transplantation therapy. This study was aimed to test the hypothesis that the human bone marrow stromal cells (hBMSC) expanded with fetal calf serum (FCS)-free, platelet lysate (PL)-containing medium retain their biological features favoring central nervous system regeneration. The hBMSC were cultured with 5% PL or 10% FCS. Their phenotypes were analyzed with flow cytometry, and their production of growth factors was quantified with enzyme-linked immunosorbent assay. Their capacity of neural differentiation was verified by immunocytochemistry. There was no significant difference in morphology and cell surface marker between the hBMSC-FCS and hBMSC-PL. Both of them were positive for CD44, CD90, CD105, and CD166 and were negative for CD34, CD45, and CD271. The production of human brain-derived neurotrophic factor, human hepatocyte growth factor, human ß-nerve growth factor, and human platelet-derived growth factor-BB did not differ between the two groups, although the hBMSC-PL produced significantly more amount of TGF-ß1 than the hBMSC-FCS. There was no significant difference in their in vitro differentiation into the neurons and astrocytes between the two groups. The hBMSC expanded with PL-containing medium retain their biological capacity of neural differentiation and neuroprotection. The PL may be a clinically valuable and safe substitute for FCS in expanding the hBMSC for cell therapy.
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Acute myelogenous leukemia (AML) with favorable cytogenetics responds well to chemotherapy. If the leukemia relapses, allogenic hematopoietic stem transplantation (allo-HSCT) is considered as a treatment option. Since the efficacy of reduced-intensity stem cell transplantation (RIST) for AML with favorable cytogenetics has not been established, we retrospectively analyzed the outcomes of allo-HSCT in AML patients according to cytogenetic risks. The outcome of allo-HSCT for AML patients with favorable cytogenetics seemed to be superior to that for AML patients with intermediate cytogenetics. In AML patients with favorable cytogenetics, the 3-year overall survival (OS) and relapse-free survival (RFS) rates were 88 and 76%, respectively, in the RIST group. Both the 3-year OS and RFS rates were 81% in the conventional stem cell transplantation (CST) group. The outcome of RIST for AML patients with favorable cytogenetics was comparable to that for patients who received CST despite the more advanced age and greater organ dysfunction in RIST group than in CST group. None of the patients died within 90 days after RIST. Moreover, there was no relapse in patients with favorable cytogenetics who were in hematological remission prior to RIST. Thus, RIST for AML patients with favorable cytogenetics in remission is safe and effective.
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Trasplante de Células Madre Hematopoyéticas/métodos , Leucemia Mieloide Aguda/terapia , Acondicionamiento Pretrasplante/métodos , Adulto , Anciano , Citogenética , Supervivencia sin Enfermedad , Femenino , Enfermedad Injerto contra Huésped/mortalidad , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Cariotipificación , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Riesgo , Análisis de Supervivencia , Adulto JovenRESUMEN
Ca(+) sparklets are subcellular Ca(2+) signals produced by the opening of L-type Ca(2+) channels (LTCCs). In cerebral arterial myocytes, Ca(2+) sparklet activity varies regionally, resulting in low and high activity, "persistent" Ca(2+) sparklet sites. Although increased Ca(2+) influx via LTCCs in arterial myocytes has been implicated in the chain of events contributing to vascular dysfunction during acute hyperglycemia and diabetes, the mechanisms underlying these pathological changes remain unclear. Here, we tested the hypothesis that increased Ca(2+) sparklet activity contributes to higher Ca(2+) influx in cerebral artery smooth muscle during acute hyperglycemia and in an animal model of non-insulin-dependent, type 2 diabetes: the dB/dB mouse. Consistent with this hypothesis, acute elevation of extracellular glucose from 10 to 20 mM increased the density of low activity and persistent Ca(2+) sparklet sites as well as the amplitude of LTCC currents in wild-type cerebral arterial myocytes. Furthermore, Ca(2+) sparklet activity and LTCC currents were higher in dB/dB than in control myocytes. We found that activation of PKA contributed to higher Ca(2+) sparklet activity during hyperglycemia and diabetes. In addition, we found that the interaction between PKA and the scaffolding protein A-kinase anchoring protein was critical for the activation of persistent Ca(2+) sparklets by PKA in cerebral arterial myocytes after hyperglycemia. Accordingly, PKA inhibition equalized Ca(2+) sparklet activity between dB/dB and wild-type cells. These findings suggest that hyperglycemia increases Ca(2+) influx by increasing Ca(2+) sparklet activity via a PKA-dependent pathway in cerebral arterial myocytes and contributes to vascular dysfunction during diabetes.
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Glucemia/metabolismo , Canales de Calcio Tipo L/metabolismo , Señalización del Calcio , Diabetes Mellitus Tipo 2/metabolismo , Angiopatías Diabéticas/metabolismo , Hiperglucemia/metabolismo , Músculo Liso Vascular/metabolismo , Miocitos del Músculo Liso/metabolismo , Proteínas de Anclaje a la Quinasa A/metabolismo , Animales , Canales de Calcio Tipo L/efectos de los fármacos , Señalización del Calcio/efectos de los fármacos , Arterias Cerebrales/metabolismo , Colforsina/farmacología , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/fisiopatología , Angiopatías Diabéticas/fisiopatología , Modelos Animales de Enfermedad , Activación Enzimática , Activadores de Enzimas/farmacología , Hiperglucemia/complicaciones , Hiperglucemia/fisiopatología , Péptidos y Proteínas de Señalización Intracelular/farmacología , Potenciales de la Membrana , Ratones , Ratones Noqueados , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/fisiopatología , Miocitos del Músculo Liso/efectos de los fármacos , Proteína Quinasa C-alfa/genética , Proteína Quinasa C-alfa/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Proteínas/farmacología , Ratas , Ratas Sprague-Dawley , Transducción de Señal , Factores de Tiempo , Regulación hacia ArribaRESUMEN
A 44-year-old female presented with asymptomatic leukocytosis and moderate splenomegaly. The diagnosis of splenic marginal zone lymphoma (SMZL) was made by a splenectomy. A virological examination revealed the patient to be a hepatitis B virus (HBV) carrier. The lymphocyte count in her peripheral blood decreased after splenectomy, but remained high for 2 years and bone marrow infiltration was obvious. Two years after the splenectomy, she was admitted for an acute flare-up of hepatitis B. The liver dysfunction improved without any medication and thereafter returned to the normal range within a few weeks. At the same time, the lymphocyte count in her peripheral blood rapidly decreased to normal levels. Atypical lymphocytes disappeared from the peripheral blood and bone marrow aspirates and biopsy specimen revealed complete remission of SMZL, including the disappearance of the clonal rearrangement of IgH-JH. There has been no recurrence of acute hepatitis and she has been in complete remission for SMZL for more than 6 years. The clinical course of this patient suggests that an immune response against HBV also affects the clearance of lymphoma cells. This is the first report that a complete remission was achieved in a patient with SMZL after a hepatitis B flare-up.
Asunto(s)
Hepatitis B/inmunología , Linfoma de Células B de la Zona Marginal/virología , Remisión Espontánea , Neoplasias del Bazo/cirugía , Adulto , Femenino , Virus de la Hepatitis B , Humanos , Linfoma de Células B de la Zona Marginal/inmunología , Linfoma de Células B de la Zona Marginal/cirugía , EsplenectomíaRESUMEN
Two multiple myeloma patients relapsed after autologous stem cell transplantation (ASCT). Conventional chemotherapy, including thalidomide, showed very little effect, but both patients responded well to a standard dose of bortezomib. One patient was treated with two additional cycles of bortezomib, but his clinical course suddenly deteriorated. Unrelated cord blood transplantation (CBT) with reduced-intensity conditioning regimen (RIC) was performed in refractory disease. After CBT, the clinical course was aggravated by tumor lysis syndrome and other conditions, thus resulting in patient death on day 34. Thereafter, we administered CBT with RIC on the second patient after just one course of bortezomib therapy since she was in partial remission. The second patient developed acute and chronic GVHD, and both responded to the steroid therapy. She has been in complete remission for more than 48 months after CBT. These results suggested that the timing of CBT with RIC may be very important, and cytoreduction with not only ASCT but also bortezomib could give a promising chance for a successful CBT.
Asunto(s)
Antineoplásicos/uso terapéutico , Ácidos Borónicos/uso terapéutico , Trasplante de Células Madre de Sangre del Cordón Umbilical , Mieloma Múltiple/tratamiento farmacológico , Pirazinas/uso terapéutico , Acondicionamiento Pretrasplante/métodos , Bortezomib , Terapia Combinada , Femenino , Humanos , Insomnio Familiar Fatal , Masculino , Persona de Mediana Edad , RecurrenciaRESUMEN
OBJECTIVES: Recent studies have indicated that patients who receive stem cell transplantation (SCT) and rituximab demonstrate an increased risk of developing hypogammaglobulinemia. Such hypogammaglobulinemia has been found to be due to delayed recovery of memory B cells with an abnormal cell marker expression and impaired immunoglobulin production in vitro. However, no predictive factors for the levels of immunoglobulin after autologous SCT and rituximab therapy have been reported. The aim of this study is to clarify the relationships between the FCGR3A-158V/F genotype and the levels of serum immunoglobulin after SCT. METHODS: A total of 24 non-Hodgkin's lymphoma (NHL) patients received autologous SCT with an adjuvant rituximab. The FCGR3A-158V/F genotype was determined in these patients. We also included ten NHL patients who received an identical conditioning regimen and autologous SCT but no rituximab as control patients. RESULTS: The levels of IgG were significantly lower in FCGR3A-158F homozygous patients (n = 9) in comparison to those in FCGR3A-158V carriers (n = 15). Moreover, the levels of IgG and IgA of FCGR3A-158F homozygous patients, but not those of FCGR3A-158V carriers, were significantly lower than those of control patients. CONCLUSIONS: The genotype of FCGR3A determines not only the response to rituximab, but also the levels of immunoglobulin after SCT and an adjuvant rituximab.