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1.
Clin Infect Dis ; 72(7): 1220-1229, 2021 04 08.
Artículo en Inglés | MEDLINE | ID: mdl-32133490

RESUMEN

BACKGROUND: Sepsis disproportionately affects allogeneic hematopoietic cell transplant (HCT) recipients and is challenging to define. Clinical criteria that predict mortality and intensive care unit end-points in patients with suspected infections (SIs) are used in sepsis definitions, but their predictive value among immunocompromised populations is largely unknown. Here, we evaluate 3 criteria among allogeneic HCT recipients with SIs. METHODS: We evaluated Systemic Inflammatory Response Syndrome (SIRS), quick Sequential Organ Failure Assessment (qSOFA), and National Early Warning Score (NEWS) in relation to short-term mortality among recipients transplanted between September 2010 and July 2017. We used cut-points of ≥ 2 for qSOFA/SIRS and ≥ 7 for NEWS and restricted to first SI per hospital encounter during patients' first 100 days posttransplant. RESULTS: Of the 880 recipients who experienced ≥ 1 SI, 58 (6.6%) died within 28 days and 22 (2.5%) within 10 days of an SI. In relation to 10-day mortality, SIRS was the most sensitive (91.3% [95% confidence interval {CI}, 72.0%-98.9%]) but least specific (35.0% [95% CI, 32.6%-37.5%]), whereas qSOFA was the most specific (90.5% [95% CI, 88.9%-91.9%]) but least sensitive (47.8% [95% CI, 26.8%-69.4%]). NEWS was moderately sensitive (78.3% [95% CI, 56.3%-92.5%]) and specific (70.2% [95% CI, 67.8%-72.4%]). CONCLUSIONS: NEWS outperformed qSOFA and SIRS, but each criterion had low to moderate predictive accuracy, and the magnitude of the known limitations of qSOFA and SIRS was at least as large as in the general population. Our data suggest that population-specific criteria are needed for immunocompromised patients.


Asunto(s)
Puntuación de Alerta Temprana , Trasplante de Células Madre Hematopoyéticas , Sepsis , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Mortalidad Hospitalaria , Humanos , Puntuaciones en la Disfunción de Órganos , Pronóstico , Estudios Retrospectivos , Sepsis/diagnóstico , Síndrome de Respuesta Inflamatoria Sistémica/diagnóstico , Receptores de Trasplantes
2.
Protein Expr Purif ; 175: 105714, 2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-32738434

RESUMEN

Cancer immunotherapy has recently attracted attention as an approach for cancer treatment through the activation of the immune system. Group-specific component (Gc) protein is a precursor for macrophage activating factor (GcMAF), which has a promising immunomodulatory effect on the suppression of tumor growth and angiogenesis. In this study, we successfully purified Gc protein from human serum using anion-exchange chromatography combined with affinity chromatography using a 25-OH-D3-immobilized column. The purity of Gc protein reached 95.0% after anion-exchange chromatography. The known allelic variants of Gc protein are classified into three subtypes-Gc1F, Gc1S and Gc2. The fragment sequence of residues 412-424 determined according to their MS/MS spectra is available to evaluate the subtypes of Gc protein. The data showed that the Gc protein purified in this study consisted of the Gc1F and Gc2 subtypes. Our method improved the purity of Gc protein, which was not affected by the treatment to convert it into GcMAF using ß-galactosidase- or neuraminidase-immobilized resin, and will be useful for biological studies and/or advanced clinical uses of GcMAF, such as cancer immunotherapy.


Asunto(s)
Cromatografía de Afinidad , Factores Activadores de Macrófagos , Proteína de Unión a Vitamina D , Humanos , Factores Activadores de Macrófagos/química , Factores Activadores de Macrófagos/aislamiento & purificación , Proteína de Unión a Vitamina D/química , Proteína de Unión a Vitamina D/aislamiento & purificación
3.
J Natl Compr Canc Netw ; : 1-4, 2020 03 20.
Artículo en Inglés | MEDLINE | ID: mdl-32197238

RESUMEN

The first confirmed case of coronavirus disease 2019 (COVID-19) in the United States was reported on January 20, 2020, in Snohomish County, Washington. At the epicenter of COVID-19 in the United States, the Seattle Cancer Care Alliance, Fred Hutchinson Cancer Research Center, and University of Washington are at the forefront of delivering care to patients with cancer during this public health crisis. This Special Feature highlights the unique circumstances and challenges of cancer treatment amidst this global pandemic, and the importance of organizational structure, preparation, agility, and a shared vision for continuing to provide cancer treatment to patients in the face of uncertainty and rapid change.

4.
Biol Blood Marrow Transplant ; 25(6): 1122-1127, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-30599207

RESUMEN

Patients with early relapse of acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) after hematopoietic cell transplantation (HCT) have a poor prognosis, and no standard treatment. Twenty-nine patients with early disease recurrence post-transplantation were treated with azacitidine (AZA; median dose, 40 mg/m2/day for 5 to 7 days). At a median follow-up of 6.3 months (range, 1.3 to 41.1 months), 7 patients (27%) had a response to AZA, defined as complete remission, hematologic improvement, or improved donor chimerism. Response occurred after a median of 3 cycles, and the median duration of response was 70 days (range, 26 to 464 days). Median survival was 6.8 months (95% confidence interval, 3.8 to 11.1 months). Survival was similar in the patients receiving an AZA dose ≤40 mg/m2 and those receiving an AZA dose >40 mg/m2. Six patients receiving donor lymphocyte infusion with AZA had a response or stable disease without worsening graft-versus-host-disease. We retrospectively used a flow cytometry assay to explore DNA-methyltransferase-1 in blood mononuclear cells as a potential pharmacodynamic marker to assess intracellular drug targeting in 8 patients. No correlation with AZA dose or response was observed. Low-dose AZA appears to have comparable efficacy to higher-dose AZA post-HCT. A significant proportion of this poor-risk population responded to low-dose AZA, suggesting a dose-independent, noncytotoxic mechanism for antileukemic activity.


Asunto(s)
Antimetabolitos Antineoplásicos/uso terapéutico , Azacitidina/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Síndromes Mielodisplásicos/tratamiento farmacológico , Adulto , Anciano , Antimetabolitos Antineoplásicos/farmacología , Azacitidina/farmacología , Femenino , Humanos , Leucemia Mieloide Aguda/patología , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/patología , Recurrencia
5.
Nihon Koshu Eisei Zasshi ; 65(11): 646-654, 2018.
Artículo en Japonés | MEDLINE | ID: mdl-30518703

RESUMEN

Objectives This study aimed to separately ascertain and examine the association between sleep and mental health among primiparas and multiparas at one month postpartum.Methods The subjects were 234 primiparas and 223 multiparas (a total of 457) at one month postpartum who agreed to participate in the questionnaire survey during a health check-up at a maternity hospital. According to the delivery records, they had no history of mental diseases. The survey items of the questionnaire concerned living environment, sleep status, subjective mental health (depressive mood, anxiety, low motivation, irritability) and sleep-related lifestyle. At first, we compared these items between primiparas and multiparas. Next, multiple regression analysis by a general linear model was used to investigate the association between sleep status and mental health. The dependent variables were sleep satisfaction, total sleep time, the existence of sleep problems (difficulty initiating sleep, difficulty maintaining sleep, waking up too early), irregularity of bedtime, and five kinds of sleep-related lifestyle. The independent variables were the four mental health indices according to a visual analog scale.Results In primiparas, total sleep time was shorter, bedtime and sleeping time were later, two kinds of sleep-related lifestyle were worse, and the symptoms of tinnitus and tired feeling were higher than in multiparas. In multiparas, sleep onset latency was longer, the number of times of night awakening was higher, irritability was stronger, and the prevalence of headache was higher than in primiparas. Sleep satisfaction was related to all four indices of mental health for both primiparas and multiparas. In primiparas, the existence of sleep problems was related to depressive mood and anxiety, and the irregularity of bedtime was related to anxiety. "Getting up immediately after awakening" was related to irritability, as well as low motivation, in multiparas. "A nap shorter than 30 minutes before 3 PM" was related to anxiety and low motivation in primiparas. The irregularity of bedtime was negatively related to anxiety, low motivation, and irritability in multiparas.Conclusion It is suggested that sleep problems, which tend to be overlooked, are related to subjective mental health at one month postpartum. Thus, we conclude that sleep education during pregnancy and sleep evaluations at postpartum check-ups are necessary for postpartum women's mental health.


Asunto(s)
Salud Mental , Periodo Posparto/psicología , Sueño/fisiología , Adulto , Ansiedad , Depresión , Emociones , Femenino , Humanos , Motivación , Paridad , Medio Social , Factores de Tiempo , Adulto Joven
6.
Biol Blood Marrow Transplant ; 23(7): 1117-1121, 2017 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-28396160

RESUMEN

Allogeneic hematopoietic cell transplantation (HCT) is recommended for patients with T cell acute lymphoblastic leukemia (T-ALL) in second or later complete remission (CR) and high-risk patients in first CR. Given its relative rarity, data on outcomes of HCT for T-ALL are limited. We conducted a multicenter retrospective cohort study using data from 208 adult patients who underwent HCT between 2000 and 2014 to describe outcomes of allogeneic HCT for T-ALL in the contemporary era. The median age at HCT was 37 years, and the majority of patients underwent HCT in CR, using total body irradiation (TBI)-based myeloablative conditioning regimens. One-quarter of the patients underwent alternative donor HCT using a mismatched, umbilical cord blood, or haploidentical donor. With a median follow up of 38 months, overall survival at 5 years was 34%. The corresponding cumulative incidence of non-relapse mortality and relapse was 26% and 41%, respectively. In multivariable analysis, factors significantly associated with overall survival were the use of TBI (HR, 0.57; P = .021), age >35 years (HR, 1.55; P = .025), and disease status at HCT (HR, 1.98; P = .005 for relapsed/refractory disease compared with CR). Relapse was the most common cause of death (58% of patients). Allogeneic HCT remains a potentially curative option in selected patients with adult T-ALL, although relapse is a major cause of treatment failure.


Asunto(s)
Trasplante de Células Madre Hematopoyéticas/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Acondicionamiento Pretrasplante/métodos , Trasplante Homólogo/métodos , Adolescente , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Análisis de Supervivencia , Adulto Joven
7.
Electrophoresis ; 34(16): 2303-10, 2013 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-23580137

RESUMEN

A combination of two online sample concentration techniques, large-volume sample stacking with an electroosmotic flow pump (LVSEP) and field-amplified sample injection (FASI), was investigated in CE to achieve highly sensitive oligosaccharide analysis. In CE with LVSEP-FASI, analytes injected throughout the capillary were concentrated on the basis of LVSEP, followed by an electrokinetic introduction of concentrated analytes from the inlet vial by the FASI mechanism. After switching the inlet vial solution from the sample to running buffer, the concentrated analytes were then separated by CZE. In the present LVSEP-FASI-CZE, pressure was applied to the capillary inlet until the inlet vial solution was exchanged. The applied pressure generated a counterflow against the EOF. It kept the stacked sample zone within the capillary, minimizing loss of concentrated analytes. Fluorescein was first analyzed by LVSEP-FASI-CZE to optimize preconcentration condition. Up to 110 000-fold sensitivity increase was obtained with 200 µL of sample, compared to normal CZE with sample injection of 0.3 psi for 3 s (ca. 1.7 nL). From the results, the pressure application improved the efficiency of the FASI-mode concentration significantly at total concentration time longer than 10 min. In the analysis of maltoheptaose, a 10 000-fold sensitivity increase was achieved, which is the highest concentration efficiency ever reported in CE of oligosaccharides. The relative standard deviations of the detection time and peak height were 2.4 and 11%, respectively. In the analysis of glucose oligomer, up to 8600-fold sensitivity increases were achieved without reducing the separation performance of conventional CZE.


Asunto(s)
Electroósmosis/métodos , Electroforesis Capilar/métodos , Oligosacáridos/análisis , Electroósmosis/instrumentación , Electroforesis Capilar/instrumentación , Fluoresceína/química , Límite de Detección , Reproducibilidad de los Resultados
8.
Front Oncol ; 10: 327, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32211336

RESUMEN

Glycogen synthase kinase-3 (GSK3) inhibitors induce differentiation and growth inhibition of acute myeloid leukemia (AML) cells. Our pre-clinical studies showed GSK3 inhibition leads to sensitization of AML cells to tretinoin-mediated differentiation. We conducted a phase I trial of lithium, a GSK3 inhibitor, plus tretinoin for relapsed, refractory non-promyelocytic AML. Nine patients with median (range) age 65 (42-82) years were enrolled. All subjects had relapsed leukemia after prior therapy, with a median (range) of 3 (1-3) prior therapies. Oral lithium carbonate 300 mg was given 2-3 times daily and adjusted to meet target serum concentration (0.6 to 1.0 mmol/L); tretinoin 22.5 or 45 mg/m2/day (two equally divided doses) was administered orally on days 1-7 and 15-21 of a 28-day cycle. Four patients attained disease stability with no increase in circulating blasts for ≥4 weeks. Median (range) survival was 106 days (60-502). Target serum lithium concentration was achieved in all patients and correlated with GSK3 inhibition in leukemic cells. Immunophenotypic changes associated with myeloid differentiation were observed in five patients. The combination treatment led to a reduction in the CD34+ CD38- AML stem cell population both in vivo and in vitro. The combination of lithium and tretinoin is well-tolerated, induces differentiation of leukemic cells, and may target AML stem cells, but has limited clinical activity in the absence of other antileukemic agents. The results of this clinical trial suggest GSK3 inhibition can result in AML cell differentiation and may be a novel therapeutic strategy in this disease, particularly in combination with other antileukemic agents. Lithium is a weak GSK3 inhibitor and future strategies in AML treatment will probably require more potent agents targeting this pathway or combinations with other antileukemic agents. This trial is registered at ClinicalTrials.gov NCT01820624.

9.
Nurs Health Sci ; 11(2): 114-9, 2009 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-19519696

RESUMEN

In this longitudinal intervention study, a 6 week health education program consisting of lectures and exercises was implemented for 39 Japanese menopausal women. The effects of the program were assessed by measuring their exercise participation, climacteric symptoms, and quality of life immediately before, 6 weeks after, and 1 year after the program. The Simplified Menopausal Index was used to assess the climacteric symptoms and the Medical Outcomes Study 36-Item Short-Form Health (SF-36) Survey was used to assess the quality of life. Significant improvements were observed in the subscale score for general health perception and the summary score for the physical component summary in the SF-36 Survey. Favorable results also were found for women without a previous exercise habit before the program but who participated in regular exercise 1 year after the program. No improvements were observed in the climacteric symptoms. We concluded that our program was effective for menopausal women in spite of the intervention period being relatively short.


Asunto(s)
Educación en Salud , Menopausia , Calidad de Vida , Análisis de Varianza , Femenino , Encuestas Epidemiológicas , Humanos , Japón , Estudios Longitudinales , Actividad Motora , Evaluación de Programas y Proyectos de Salud , Psicometría
10.
J Biomater Sci Polym Ed ; 30(16): 1542-1558, 2019 11.
Artículo en Inglés | MEDLINE | ID: mdl-31354063

RESUMEN

The objective of this study is to investigate the effect of lipopolysaccharide (LPS) addition on the gene transfection of human mesenchymal stem cells (hMSC). hMSC were treated with the LPS at different concentrations and the complex of spermine-introduced pullulan and luciferase plasmid DNA for 3 h. The maximum level of gene expression was observed for hMSC treated with a certain concentration range of LPS. In addition, the cytotoxicity, cellular internalization of complexes, and cell cycle after LPS treatment were investigated. The cytotoxicity increased with an increase in the LPS concentration treated. On the other hand, the cellular internalization of complexes increased with the increased LPS concentration, although the internalization was sharply reduced at the high concentration. The LPS treatment increased the actin polymerization of cells to allow to spread more. The enhanced cells spreading would enhance the cellular internalization of complexes. In addition, the LPS treatment increased the rate of cell cycle. It is possible that the balance of cytotoxicity, cellular internalization, and cell cycle caused by the LPS addition results in the enhanced gene transfection at a certain LPS concentration. It is concluded that LPS treatment positively modified the cellular internalization and the cell cycle, resulting in the enhanced gene transfection.


Asunto(s)
Glucanos/química , Lipopolisacáridos/farmacología , Plásmidos/química , Espermina/química , Actinas/metabolismo , Ciclo Celular/efectos de los fármacos , Línea Celular , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Humanos , Células Madre Mesenquimatosas/efectos de los fármacos
11.
Bone Marrow Transplant ; 54(4): 497-507, 2019 04.
Artículo en Inglés | MEDLINE | ID: mdl-30038353

RESUMEN

Relapse is a major cause of treatment failure after stem cell transplantation. Novel agents given as maintenance or preemptive post transplant were discussed at the 3rd International Workshop on Biology, Prevention, and Treatment of Relapse after Stem Cell Transplantation in Hamburg/Germany in November 2016 under the auspices of EBMT and ASBMT. Maintenance therapy is started after SCT without detectable disease, while preemptive therapy is triggered by the detection of minimal residual disease (MRD). The maintenance approach treats all patients, and overtreats a significant amount. Maintenance therapy requires an agent without significant off-target toxicity. The preemptive approach only initiates therapy upon detection of MRD, while sparing further therapy to those who remain in remission. Preemptive strategies require sensitive and clinically reliable assays to detect MRD. Here current development of tyrosine kinase inhibitors (TKIs) immunomodulating drugs (IMiDs), deacetylase inhibitors, and hypomethylating agents were reviewed.


Asunto(s)
Trasplante de Células Madre Hematopoyéticas/métodos , Inmunomodulación/inmunología , Inhibidores de Proteínas Quinasas/uso terapéutico , Acondicionamiento Pretrasplante/métodos , Femenino , Humanos , Masculino , Estudios Prospectivos , Inhibidores de Proteínas Quinasas/farmacología , Recurrencia
12.
Clin Lymphoma Myeloma Leuk ; 19(2): 73-82, 2019 02.
Artículo en Inglés | MEDLINE | ID: mdl-30528848

RESUMEN

INTRODUCTION: Induction chemotherapy with cytarabine and an anthracycline (7+3) remains the standard of care for acute myeloid leukemia (AML). PATIENTS AND METHODS: We retrospectively analyzed 183 newly diagnosed AML patients to compare the utility of rapid peripheral blast clearance (PBC), day of peripheral blast disappearance, residual blasts, and cellularity at day 14 bone marrow biopsy (D14BM) in predicting clinical response to 7+3 induction, overall survival (OS), and relapse-free survival (RFS). RESULTS: In multivariable logistic regression analysis, day 2 PBC > 85% [P = .0016] was the only predictor of remission status, with sensitivity and specificity of 75%. Peripheral blast disappearance within 5 days after induction and < 10% cellularity in D14BM predicted superior OS and RFS in multivariate analysis. Median follow-up of patients was 28 months since diagnosis. Two-year OS and RFS for patients with ≤ 10% versus > 10% cellularity at D14BM was 60.6% [95% confidence interval (CI), 50.8%-72.2%] versus 32.5% [95% CI, 23.0%-45.8%], and 51.9% [95% CI, 41.9%-64.3%] versus 28.8% [95% CI, 19.1%-43.4%], respectively [P = .0003 for OS and .002 for RFS]. CONCLUSION: Rapid PBC after 7+3 induction showed a significant improvement in specificity compared with D14BM, with similar sensitivity. Neither of these methods were reliably specific tools for the decision of early reinduction, despite their prognostic value. Our findings indicate that morphological cellularity in D14BM is an independent prognostic factor for OS and RFS, regardless of blast percentage, and that ≤ 10% cellularity defines D14BM hypoplasia.


Asunto(s)
Crisis Blástica/tratamiento farmacológico , Quimioterapia de Inducción/métodos , Leucemia Mieloide Aguda/tratamiento farmacológico , Adulto , Anciano , Biopsia , Femenino , Humanos , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Análisis de Supervivencia
13.
Nihon Koshu Eisei Zasshi ; 55(1): 3-10, 2008 Jan.
Artículo en Japonés | MEDLINE | ID: mdl-18318265

RESUMEN

OBJECTIVE: The present study aimed to investigate a simple education program that is effective for sleep improvement among medical students who will be medical doctors in the future. The education program applied in the present study was developed for sleep improvement based on behavioral science and changes in knowledge and sleeping habits were observed. METHODS: Subjects were 6th-year medical students of 2002 and 2003. Students of 2002 attended a program including a 90-minute lecture and a 2-week practice learning session, and students of 2003 attended only the lecture. In the lecture, behavior therapy for chronic insomnia was explained using a booklet. In the practice learning session, students set a target behavior for improvement and conducted self-monitoring of their sleep and the targeted behavior. Changes in knowledge about sleep, attitude toward the therapy, sleep, and sleep-related habits were observed and compared between the 2 groups of subjects immediately and 2-weeks after the lecture. RESULTS: It was found that after both programs subjects had more knowledge about sleep than before. In the program including practice learning session, subjects' attitude for managing patients changed from before the lecture to after the lecture, and after the practice learning session. It was found that more than half of the students thought that they could provide sleep guidance based on the behavior therapy. Regarding the subjects' sleep, significant improvements were observed for "having nightmares upon falling asleep," "sleepiness during daytime," "sense of getting a sound sleep," and "mood upon waking up." Regarding sleep-related habits, significant improvements were observed for "taking a nap," "dozing off," and "eating breakfast." On the other hand, only the lecture subjects improved irregularity of bedtime and sleeping time. Although an increase in knowledge and improvement of sleep were observed among students who attended only the lecture, a further increase in knowledge and improvement of sleeping habits were observed among students who also attended the practice learning session. CONCLUSION: The results described herein suggest developing and providing a simple and convenient education program for sleep improvement was effective for increasing students' knowledge about sleep, developing improved coping methods regarding sleep, and improving sleep. It is also suggested that behavioral scientific instructive methods, including practice learning, are effective for medical education.


Asunto(s)
Ciencias de la Conducta , Sueño , Estudiantes de Medicina , Adulto , Terapia Conductista , Educación de Pregrado en Medicina , Femenino , Humanos , Masculino
14.
Keio J Med ; 67(2): 35, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29937455

RESUMEN

Graft-versus-host disease (GVHD) is a major contributor to early and late morbidity and mortality after allogeneic stem cell transplantation. Despite results from a randomized controlled trial demonstrating an increased risk of chronic GVHD with use of growth factor-mobilized peripheral blood stem cells (PBSC) compared with bone marrow, PBSCs are the most widely used graft source in allogeneic transplantation for hematologic neoplasms in the U.S. This lecture will review established, recent, and novel strategies for GVHD prevention in unrelated donor PBSC transplantation and will highlight ongoing clinical research at Fred Hutchinson Cancer Research Center. Clinical trials aimed at defining standard-of-care GVHD prophylaxis after myeloablative and nonmyelablative conditioning will be presented. In addition, novel pharmacologic agents and graft manipulation strategies under investigation will be discussed. (Presented at the 1962nd Meeting, May 12, 2018).


Asunto(s)
Trasplante de Médula Ósea/métodos , Enfermedad Injerto contra Huésped/prevención & control , Neoplasias Hematológicas/terapia , Trasplante de Células Madre de Sangre Periférica/métodos , Neoplasias Hematológicas/inmunología , Neoplasias Hematológicas/patología , Humanos , Agonistas Mieloablativos/uso terapéutico , Acondicionamiento Pretrasplante , Trasplante Homólogo , Donante no Emparentado
15.
Blood Rev ; 32(2): 106-115, 2018 03.
Artículo en Inglés | MEDLINE | ID: mdl-28958644

RESUMEN

Immunoglobulins are used to prevent or reduce infection risk in primary immune deficiencies and in settings which exploit its anti-inflammatory and immune-modulatory effects. Rigorous proof of immunoglobulin efficacy in persons with lympho-proliferative neoplasms, plasma cell myeloma, and persons receiving hematopoietic cell transplants is lacking despite many clinical trials. Further, there are few consensus guidelines or algorithms for use in these conditions. Rapid development of new therapies targeting B-cell signaling and survival pathways and increased use of chimeric antigen receptor T-cell (CAR-T) therapy will likely result in more acquired deficiencies of humoral immunity and infections in persons with cancer. We review immunoglobulin formulations and discuss efficacy and potential adverse effects in the context of preventing infections and in graft-versus-host disease. We suggest an algorithm for evaluating acquired deficiencies of humoral immunity in persons with hematologic neoplasms and recommend appropriate use of immunoglobulin therapy.


Asunto(s)
Neoplasias Hematológicas/terapia , Inmunización Pasiva , Antineoplásicos Inmunológicos/administración & dosificación , Antineoplásicos Inmunológicos/efectos adversos , Antineoplásicos Inmunológicos/uso terapéutico , Enfermedades Autoinmunes/complicaciones , Neoplasias Hematológicas/complicaciones , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/etiología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Inmunización Pasiva/efectos adversos , Inmunización Pasiva/métodos , Inmunoterapia/efectos adversos , Inmunoterapia/métodos , Resultado del Tratamiento
16.
Blood Adv ; 2(21): 2890-2903, 2018 11 13.
Artículo en Inglés | MEDLINE | ID: mdl-30385433

RESUMEN

Acute myeloid leukemia (AML) is a devastating disease with poor patient survival. As targetable mutations in AML are rare, novel oncogenic mechanisms are needed to define new therapeutic targets. We identified AML cells that exhibit an aberrant pool of nuclear glycogen synthase kinase 3ß (GSK3ß). This nuclear fraction drives AML growth and drug resistance. Nuclear, but not cytoplasmic, GSK3ß enhances AML colony formation and AML growth in mouse models. Nuclear GSK3ß drives AML partially by promoting nuclear localization of the NF-κB subunit, p65. Finally, nuclear GSK3ß localization has clinical significance as it strongly correlates to worse patient survival (n = 86; hazard ratio = 2.2; P < .01) and mediates drug resistance in cell and animal models. Nuclear localization of GSK3ß may define a novel oncogenic mechanism in AML and represent a new therapeutic target.


Asunto(s)
Núcleo Celular/metabolismo , Proliferación Celular , Resistencia a Antineoplásicos , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Leucemia Mieloide Aguda/patología , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Femenino , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/mortalidad , Ratones , Ratones Endogámicos NOD , Ratones SCID , Proteína de la Leucemia Mieloide-Linfoide/metabolismo , FN-kappa B/metabolismo , Proteínas de Fusión Oncogénica/metabolismo , Modelos de Riesgos Proporcionales , Tasa de Supervivencia , Trasplante Heterólogo , Regulación hacia Arriba
17.
Brain Res ; 1124(1): 1-4, 2006 Dec 08.
Artículo en Inglés | MEDLINE | ID: mdl-17070506

RESUMEN

Since many nuclear proteins are ectopically localized in the cytoplasm in the vulnerable neurons in Alzheimer disease (AD), we speculated that there is failure of the cytoplasmic-nuclear transport machinery in AD. In support of this notion, we found that importin alpha1, an essential component of cytoplasmic-nuclear transport, is abnormally accumulated in Hirano bodies in vulnerable hippocampal neurons in AD. These data suggest a hindrance in importin-mediated cytoplasmic-nuclear transport in AD.


Asunto(s)
Enfermedad de Alzheimer/patología , Hipocampo/patología , Neuronas/metabolismo , alfa Carioferinas/metabolismo , Actinas/metabolismo , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/metabolismo , Estudios de Casos y Controles , Humanos , Inmunohistoquímica/métodos , Ovillos Neurofibrilares/metabolismo , Enfermedad de Pick/metabolismo , Enfermedad de Pick/patología
18.
Ocul Immunol Inflamm ; 14(5): 277-83, 2006 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-17056461

RESUMEN

PURPOSE: Demonstration of experimental autoimmune uveitis (EAU) with extremely small, fragmented peptides (12-30 amino acid residues) of interphotoreceptor retinoid-binding protein (IRPB). METHOD: Very small fragmented peptides (no. 854, 888, 907, and 1057) were conjugated to heat-killed Group A Streptococcus cells and administered as a single intravenous injection to Lewis rats. A non-uveitogenic peptide 950 was also conjugated to heat-killed Streptococcus and administered. Administration of a mixture of small peptides and Streptococcus was a control for the peptides conjugated with Streptococcus. RESULTS: The uveitogenic peptide/Streptococcus conjugates produced uveitis inflammatory responses in the uvea, retina and pineal gland. Administration of mixtures of small peptides and Streptococcus cells, and a non-uveitogenic peptide 950 conjugated with Streptococcus did not produce autoimmune uveitis. CONCLUSIONS: Since mixtures of small uveitogenic peptides and Streptococcal cells did not develop autoimmune uveitis, conjugated Streptococcal cells provided a vehicle for macrophage phagocytosos of very small uveitogenic IRBP peptides. Subsequent antigen presentation from macrophages to lymphocytes developed autoimmune uveitis. Peptide 888, one of four IRBP peptides that encompass the major uveitogenic domain, proved to be the most effective in development of uveitis.


Asunto(s)
Enfermedades Autoinmunes/inducido químicamente , Proteínas del Ojo/inmunología , Inmunoconjugados/toxicidad , Fragmentos de Péptidos/inmunología , Proteínas de Unión al Retinol/inmunología , Streptococcus pyogenes/inmunología , Uveítis/inducido químicamente , Animales , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/patología , Activación de Macrófagos , Modelos Animales , Glándula Pineal/efectos de los fármacos , Glándula Pineal/inmunología , Glándula Pineal/patología , Ratas , Ratas Endogámicas Lew , Retina/efectos de los fármacos , Retina/inmunología , Retina/patología , Úvea/efectos de los fármacos , Úvea/inmunología , Úvea/patología , Uveítis/inmunología , Uveítis/patología
19.
Mol Cancer Ther ; 15(7): 1485-1494, 2016 07.
Artículo en Inglés | MEDLINE | ID: mdl-27196775

RESUMEN

Standard therapies used for the treatment of acute myeloid leukemia (AML) are cytotoxic agents that target rapidly proliferating cells. Unfortunately, this therapeutic approach has limited efficacy and significant toxicity and the majority of AML patients still die of their disease. In contrast to the poor prognosis of most AML patients, most individuals with a rare subtype of AML, acute promyelocytic leukemia, can be cured by differentiation therapy using regimens containing all-trans retinoic acid. GSK3 has been previously identified as a therapeutic target in AML where its inhibition can lead to the differentiation and growth arrest of leukemic cells. Unfortunately, existing GSK3 inhibitors lead to suboptimal differentiation activity making them less useful as clinical AML differentiation agents. Here, we describe the discovery of a novel GSK3 inhibitor, GS87. GS87 was discovered in efforts to optimize GSK3 inhibition for AML differentiation activity. Despite GS87's dramatic ability to induce AML differentiation, kinase profiling reveals its high specificity in targeting GSK3 as compared with other kinases. GS87 demonstrates high efficacy in a mouse AML model system and unlike current AML therapeutics, exhibits little effect on normal bone marrow cells. GS87 induces potent differentiation by more effectively activating GSK3-dependent signaling components including MAPK signaling as compared with other GSK3 inhibitors. GS87 is a novel GSK3 inhibitor with therapeutic potential as a differentiation agent for non-promyelocytic AML. Mol Cancer Ther; 15(7); 1485-94. ©2016 AACR.


Asunto(s)
Antineoplásicos/farmacología , Diferenciación Celular/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Glucógeno Sintasa Quinasa 3/antagonistas & inhibidores , Glucógeno Sintasa Quinasa 3/metabolismo , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patología , Animales , Biomarcadores , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Ratones , Ratones Noqueados , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
20.
Int J Pharm ; 245(1-2): 45-54, 2002 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-12270241

RESUMEN

A chitosan dispersed system (CDS), which was composed of active ingredient reservoir and the outer drug release-regulating layer dispersing chitosan powder in hydrophobic polymer, was newly developed for colon-specific drug delivery. An aminoalkyl methacrylate copolymer RS (Eudragit) RS) was selected as a hydrophobic polymer because it is hardly dissolved in acidic medium in which easily dissolves chitosan. In order to obtain the bi-functional releasing characteristics, i.e. time dependent and site specific, capsules containing the active ingredient (Drug Capsules) were coated by the chitosan dispersed hydrophobic polymer, resulting in CDS Capsules. The release rate could be controlled by changing the thickness of the layer. Furthermore, for colon-specific drug delivery, an additional outer enteric coating was necessary to prevent the drug release from CDS Capsules in the stomach, since chitosan dispersed in the layer dissolves easily under acidic conditions. Resultant enteric-coated CDS Capsules reached the large intestine within 1-3 h after oral administration and they were degraded at the colon in beagle dogs.


Asunto(s)
Quitina/análogos & derivados , Quitina/química , Portadores de Fármacos/química , Acetaminofén/administración & dosificación , Acetaminofén/sangre , Acetaminofén/química , Resinas Acrílicas/química , Administración Oral , Analgésicos no Narcóticos/administración & dosificación , Analgésicos no Narcóticos/sangre , Analgésicos no Narcóticos/química , Animales , Cápsulas , Quitosano , Colon , Perros , Tránsito Gastrointestinal , Concentración de Iones de Hidrógeno , Técnicas In Vitro , Masculino , Tamaño de la Partícula , Polvos
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