RESUMEN
Librarians at a university had planned to check the collection prior to the library renovations that began in 2015. They had previous knowledge of the presence of a light greyish-white powder with an unpleasant odour (hereinafter referred to as 'powder') sprinkled between the pages of antiquarian books in the library archive. The purpose of this study was to identify this powder with the help of experts from both inside and outside the university. The powder was qualitatively analysed using gas chromatography with mass spectrometry after hexane extraction. The powder was examined under a polarised light microscope and a field-emission scanning electron microscope equipped with an energy-dispersive X-ray spectrometer. Benzene hexachloride (BHC) was detected in the powder. Talc was the most abundant particle in the powder. The powder also contained 0.52 wt% asbestos, which belonged to the tremolite-actinolite series. No other types of asbestos were detected. The powder was presumed to be a bulking agent for BHC, and its major constituent was talc. This is the first report on asbestos-containing insecticides.
Asunto(s)
Insecticidas , Polvos , Talco , Insecticidas/análisis , Talco/química , Talco/análisis , Japón , Bibliotecas , Amianto/análisis , Cromatografía de Gases y Espectrometría de Masas , Odorantes/análisis , Libros , Hidrocarburos Clorados/análisisRESUMEN
An 80-year-old Japanese man presented with systemic lymphadenopathy, including the para-aortic area and left inguinal nodes, which was diagnosed as diffuse large B-cell lymphoma (DLBCL) and human herpesvirus (HHV) 8-positive/HIV-negative Kaposi's sarcoma (KS). Immunohistochemical examination revealed that the lymphoma cells were negative for HHV-8. The patient received combined chemotherapy with rituximab, pirarubicin, cyclophosphamide, vincristine, and prednisolone for six cycles and achieved complete remission. In the literature, five cases of simultaneous appearance of malignant lymphoma and KS in the same lymph node have been reported, but DLBCL as a histological subtype has not yet been reported.
Asunto(s)
Herpesvirus Humano 8 , Linfoma de Células B Grandes Difuso , Sarcoma de Kaposi , Masculino , Humanos , Anciano de 80 o más Años , Sarcoma de Kaposi/complicaciones , Sarcoma de Kaposi/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/complicaciones , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Ganglios Linfáticos , VIHRESUMEN
Although the role of aerobic glycolysis in activated T cells has been well characterized, whether and how fatty acids (FAs) contribute to donor T cell function in allogeneic hematopoietic stem cell transplantation is unclear. Using xenogeneic graft-versus-host disease (GVHD) models, this study demonstrated that exogenous FAs serve as a crucial source of mitochondrial respiration in donor T cells in humans. By comparing human T cells isolated from wild-type NOD/Shi-scid-IL2rγnull (NOG) mice with those from MHC class I/II-deficient NOG mice, we found that donor T cells increased extracellular FA uptake, the extent of which correlates with their proliferation, and continued to increase FA uptake during effector differentiation. Gene expression analysis showed the upregulation of a wide range of lipid metabolism-related genes, including lipid hydrolysis, mitochondrial FA transport, and FA oxidation. Extracellular flux analysis demonstrated that mitochondrial FA transport was required to fully achieve the mitochondrial maximal respiration rate and spare respiratory capacity, whereas the substantial disruption of glucose supply by either glucose deprivation or mitochondrial pyruvate transport blockade did not impair oxidative phosphorylation. Taken together, FA-driven mitochondrial respiration is a hallmark that differentiates TCR-dependent T cell activation from TCR-independent immune response after hematopoietic stem cell transplant.
Asunto(s)
Enfermedad Injerto contra Huésped , Fosforilación Oxidativa , Humanos , Animales , Ratones , Ratones Endogámicos NOD , Linfocitos T , Ácidos Grasos , Glucosa , Ratones SCID , Receptores de Antígenos de Linfocitos TRESUMEN
Objective Prolonged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been reported in immunocompromised patients, as they poorly develop antibodies against SARS-CoV-2. We conducted a clinical trial to determine the efficacy of Imdevimab/Casirivimab (Imde/Casiri), an anti-viral monoclonal antibody (mAb), for prolonged infection at our institution. Methods Nine patients with hematological malignancies (six with malignant lymphoma and three with multiple myeloma) in our institution presented with coronavirus disease 2019 caused by SARS-CoV-2 omicron variants (one, five, and one with BA.2, BA.5, and BF.7, respectively; two undetermined). Although not all nine patients developed severe disease, viral mRNA was detected in all patients after treatment with remdesivir or molnupiravir. Imde/casiri was infused 11-49 days after the disease onset. Results Within seven days of infusion, viral RNA was undetectable in five of the nine cases. Because all seven viruses isolated from patients whose viral RNA became undetectable showed low or no sensitivity to this monoclonal antibody cocktail, the disappearance of viral RNA in these cases may not be attributable to the antibody cocktail. Conclusion It may be worth considering the use of monoclonal antibodies that show some activity against these virus variants to treat persistent SARS-CoV-2 infection in immunocompromised patients.
Asunto(s)
Anticuerpos Monoclonales Humanizados , Neoplasias Hematológicas , SARS-CoV-2 , Humanos , Masculino , Persona de Mediana Edad , Femenino , Anciano , Anticuerpos Monoclonales Humanizados/uso terapéutico , Neoplasias Hematológicas/complicaciones , Neoplasias Hematológicas/tratamiento farmacológico , Tratamiento Farmacológico de COVID-19 , Antivirales/uso terapéutico , Resultado del Tratamiento , COVID-19/inmunología , COVID-19/complicaciones , Adulto , ARN Viral/sangre , Huésped Inmunocomprometido , Anciano de 80 o más Años , Combinación de Medicamentos , Anticuerpos NeutralizantesRESUMEN
Glucose is the most important energy source in all organisms; however, our understanding of the pathways and mechanisms underlying glucose transportation and localization in living cells is incomplete. Here, we prepared two glucose analogs labeled with a dansylamino group at the C-1 (1-Dansyl) or C-2 (2-Dansyl) position; the dansyl group is a highly fluorescent moiety that is characterized by a large Stokes shift between its excitation and emission wavelengths. We then examined the cytotoxicity of the two glucose analogs in mammalian fibroblast cells and in the ciliated protozoan Tetrahymena thermophila. In both cell types, 2-Dansyl had no negative effects on cell growth. The specificity of cellular uptake of glucose analogs was confirmed using an inhibitor of glucose transporter in NIH3T3 cells. In NIH3T3 cells and T. thermophila, fluorescence microscopy revealed that the glucose analogs localized throughout the cytoplasm, but especially at the periphery of the nucleus. In T. thermophila, we also found that swimming speed was comparable in media containing non-labeled glucose or one of the glucose analogs, which provided more evidence not only that the analogs were not cytotoxic in these cells but also that the analogs had no negative effect on the ciliary motion. Together, the present results suggest that the glucose analogs have low toxicity and will be useful for bioimaging of glucose-related systems.
Asunto(s)
Tetrahymena thermophila , Animales , Citoplasma , Glucosa/metabolismo , Mamíferos , Microscopía Fluorescente , Células 3T3 NIHRESUMEN
The optimal bridge strategy at the decision for allogeneic hematopoietic stem cell transplantation (HSCT) in patients with myelodysplastic syndrome (MDS) is unclear. We performed a prospective observational study in which 110 patients with MDS who were decided to undergo HSCT were enrolled. Among these 110 patients, 77 patients were enrolled in this study within 1 month from the decision for HSCT. Among these 77 patients, 13 patients had a human leukocyte antigen (HLA)-matched sibling, 54 patients started an unrelated donor search, and the other 10 patients directly selected cord blood (CB) at the decision for HSCT, and 13 (100%), 38 (70.4%), and 9 (90%) patients actually underwent HSCT within 1 year, respectively. The overall survival (OS) at 1 year from their enrollment was 70.9%, and the selection of azacitidine use at the decision for HSCT was not associated with OS. Among 60 of the 77 patients who actually underwent HSCT within a year from their enrollment, a lower relapse rate after HSCT was observed in those who selected CB at the decision to undergo HSCT. However, this preferable effect of CB selection disappeared when patients who were enrolled in this study in > 1 month from the decision for HSCT were additionally included in the analyses. In conclusion, the selection of bridge strategy at the decision for HSCT did not affect outcomes in patients with MDS. The immediate performance of HSCT may be associated with better outcomes.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Síndromes Mielodisplásicos , Humanos , Azacitidina/uso terapéutico , Estudios Prospectivos , Trasplante Homólogo , Estudios RetrospectivosRESUMEN
In our facility, anti-SARS-CoV-2 mRNA vaccines were given to 21 patients, including 8 with aplastic anemia (AA), 3 with pure red cell aplasia (PRCA), and 10 with immune thrombocytopenic purpura (ITP), and IgG antibody titers were assessed one month after vaccinations. After receiving both a second vaccine and a booster shot, all patients with AA/PRCA treated with cyclosporine A aside from one, had IgG titers that were lower than the median levels of healthy controls. Even if prednisolone (PSL) doses did not go over 10 mg/day, ITP patients receiving PSL therapy were unable to achieve adequate levels of IgG after booster immunizations.
Asunto(s)
Anemia Aplásica , COVID-19 , Enfermedades Hematológicas , Púrpura Trombocitopénica Idiopática , Aplasia Pura de Células Rojas , Humanos , COVID-19/prevención & control , Anemia Aplásica/terapia , Anticuerpos Antivirales , Inmunoglobulina G , Prednisolona , Púrpura Trombocitopénica Idiopática/tratamiento farmacológico , ARN Mensajero , VacunaciónRESUMEN
When the omicron variant became the most dominant severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) variant causing coronavirus disease 2019 (COVID-19) in Japan, 11 patients with hematological diseases infected with this new variant were treated at our institution. Among them, four of the five patients who had been treated with chemotherapy progressed to moderate-II COVID-19, and two of them died. In contrast, five of the six patients who did not receive the treatment remained at mild to moderate-I stage of COVID-19, except for a single case progressing to moderate-II COVID-19. While all four patients infused with anti-coronavirus monoclonal antibodies within 8 days after the onset survived, the other two patients, being withheld from treatment or treated later, died. In these two cases, anti-SARS-Cov-2 immunoglobulin G antibodies remained at low titers. Although the omicron variant is considered a less harmful SARS-Cov-2 variant, patients with hematological disorders, particularly those who are immunosuppressed caused by chemotherapy, should be continuously cared for as they remain at a higher risk of severe COVID-19 due to insufficient or delayed anti-viral humoral immunity development. Thus, the rapid introduction of antiviral monoclonal antibodies together with anti-viral reagents may rescue these patients.
Asunto(s)
COVID-19 , Enfermedades Hematológicas , Humanos , COVID-19/complicaciones , SARS-CoV-2 , Enfermedades Hematológicas/complicaciones , Antivirales , Anticuerpos Monoclonales , Anticuerpos AntiviralesRESUMEN
Cardiotoxicity after allogeneic stem cell transplantation (SCT) is associated with a high rate of mortality and worsening quality of life. The relation between daunorubicin dose and post- allogeneic stem cell transplantation (SCT) cardiotoxicity remains unclear. We retrospectively evaluated 171 patients with acute myeloid leukemia (AML) who underwent their first allogeneic SCT at our institution between 2005 and 2021. High-dose daunorubicin (50 mg/m2/day for 5 days) and cytarabine were usually used as induction therapy for AML. The median cumulative daunorubicin dose was 310 mg/m2 (range, 0-950 mg/m2), and 43 patients received two courses of induction therapy with high-dose daunorubicin (daunorubicin doses of ≥500 mg/m2). Cardiotoxicity developed in 12 patients, and the cumulative incidence at 2 years after SCT was 7.1%. Univariable analysis revealed that female sex, left ventricular ejection fraction (LVEF) of < 60% before SCT, and daunorubicin doses of ≥ 500 mg/m2 were associated with cardiotoxicity. Multivariable analysis showed that a daunorubicin dose of ≥ 500 mg/m2 was an independent risk factor for cardiotoxicity. LVEF decline during the study was observed with an increase in the daunorubicin dose, and only a daunorubicin dose of ≥ 500 mg/m2 was associated with a pre-SCT decreased LVEF. Second induction therapy with high-dose daunorubicin is a risk factor for cardiotoxicity after SCT. This should be taken into consideration when determining reinduction therapies for SCT-eligible patients with relapsed or refractory AML.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Cardiotoxicidad/etiología , Citarabina , Daunorrubicina , Femenino , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Calidad de Vida , Inducción de Remisión , Estudios Retrospectivos , Trasplante de Células Madre/efectos adversos , Volumen Sistólico , Función Ventricular IzquierdaRESUMEN
Triplet regimens, such as lenalidomide, bortezomib, and dexamethasone (RVd) or thalidomide, bortezomib, and dexamethasone (VTd), are standard induction therapies for transplant-eligible patients with newly diagnosed multiple myeloma (NDMM). The addition of daratumumab to RVd and VTd has been investigated in the GRIFFIN and CASSIOPEIA trials, respectively, resulting in improvement in the rate of minimal residual disease (MRD) negativity. In this study, we conducted a cost-effectiveness analysis with a 10-year time horizon to compare first-line and second-line use of daratumumab for transplant-eligible patients with NDMM. Because long-term follow-up data for these clinical trials are not yet available, we developed a Markov model that uses MRD status to predict progression-free survival. Daratumumab was used either in the first-line setting in combination with RVd or VTd or in the second-line setting with carfilzomib plus dexamethasone (Kd). Quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios were calculated from a Japanese and US payer perspective. In the Japanese analysis, D-RVd showed higher QALYs (5.43 vs 5.18) and lower costs (¥64 479,793 vs ¥71 287 569) compared with RVd, and D-VTd showed higher QALYs (5.67 vs 5.42) and lower costs (¥43 600 310 vs ¥49 471,941) compared with VTd. Similarly, the US analysis demonstrated dominance of a strategy incorporating daratumumab in first-line treatment regimens. Given that overall costs are reduced and outcomes are improved when daratumumab is used as part of a first-line regimen, the economic analysis indicates that addition of daratumumab to first-line RVd and VTd regimens is a dominant strategy compared with reserving its use for the second-line setting.
Asunto(s)
Mieloma Múltiple , Anticuerpos Monoclonales , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bortezomib/farmacología , Bortezomib/uso terapéutico , Análisis Costo-Beneficio , Dexametasona/farmacología , Dexametasona/uso terapéutico , Humanos , Mieloma Múltiple/terapia , Talidomida/uso terapéuticoRESUMEN
Tumor lysis syndrome (TLS) is a metabolic disorder caused by massive tumor lysis. Hypouricemic agents are administered to prevent TLS-related hyperuricemia and renal failure. We experienced three cases of urine xanthine crystals during TLS in patients with hematologic malignancies who received prophylactic febuxostat. Yellowish and pinkish deposits were observed in urinary tract catheters and urinary bags. Urine microscopy revealed that the deposits were xanthine crystals. In rapid tumor lysis, inhibition of xanthine oxidase can cause xanthine accumulation and urine xanthine crystallization. During TLS, urine xanthine crystals may be overlooked, so careful observation and management are required to avoid xanthine nephropathy.
Asunto(s)
Neoplasias Hematológicas , Neoplasias , Nefrolitiasis , Síndrome de Lisis Tumoral , Humanos , Síndrome de Lisis Tumoral/etiología , Xantina , Alopurinol/uso terapéutico , Microscopía , Urinálisis , Neoplasias Hematológicas/complicaciones , Neoplasias/complicacionesRESUMEN
Aprepitant (Apr) is an effective antiemetic agent for chemotherapy-induced nausea and vomiting (CINV). Current CINV guidelines recommend the antiemetic combination of a 5-HT3 receptor antagonist, Apr, and dexamethasone (Dex) for highly emetogenic chemotherapies. Apr inhibits CYP3A4 dose-dependently. Since Dex is metabolized by CYP3A4, the combined use of Apr and Dex inhibits Dex metabolism. CINV guidelines therefore recommend dose-reduction of Dex when Apr and Dex are used together. However, there is some controversy over whether or not Dex should be reduced when administered as an antitumor agent for lymphoid malignancies. We retrospectively compared the antitumor effect of Dex-containing chemotherapy in which Dex is administered at the usual dose without Apr (group A) or administered at a half-dose in combination with Apr (group B). We analyzed 62 consecutive patients with refractory or relapsed CD20 + B cell lymphoma who received R-DHAP therapy in our hospital, including 29 and 33 cases in groups A and B, respectively. The response rate at the end of the first course of R-DHAP was 62.1% and 54.5%, respectively (P = 0.61). As another endpoint to evaluate the effect of Dex, group B tended to show greater suppression of the lymphocyte count (P = 0.05). Therefore, decreasing the dose of Dex by half appeared to be reasonable when combined with Apr.
Asunto(s)
Antieméticos , Antineoplásicos , Linfoma , Antieméticos/uso terapéutico , Antineoplásicos/uso terapéutico , Aprepitant/efectos adversos , Citocromo P-450 CYP3A , Dexametasona/efectos adversos , Humanos , Linfoma/tratamiento farmacológico , Náusea/inducido químicamente , Náusea/prevención & control , Estudios Retrospectivos , Vómitos/inducido químicamente , Vómitos/prevención & controlRESUMEN
Krüppel-like factor 5 (KLF5) is a potential target for anticancer drugs. However, as an intrinsically disordered protein (IDP) whose tertiary structure cannot be solved, innovative strategies are needed. We focused on its hydrophobic α-helix structure, defined as an induced helical motif (IHM), which is a possible interface for protein-protein interaction. Using mathematical analyses predicting the α-helix's structure and hydrophobicity, a 4-amino-acid site (V-A-I-F) was identified as an IHM. Low-molecular-weight compounds that mimic the main chain conformation of the α-helix with the four side chains of V-A-I-F were synthesized using bicyclic pyrazinooxadiazine-4,7-dione. These compounds selectively suppressed the proliferation and survival of cancer cells but not noncancer cells and decreased the protein but not mRNA levels of KLF5 in addition to reducing proteins of Wnt signaling. The compounds further suppressed transplanted colorectal cancer cells in vivo without side effects. Our approach appears promising for developing drugs against key IDPs.
RESUMEN
The definition of sarcopenia assessed by computed tomography (CT) varies among different reports, and few studies have examined the effect of muscle mass loss on the prognosis of post-hematopoietic cell transplantation (HCT). We retrospectively evaluated 172 patients who underwent an initial allogeneic HCT for acute leukemia at our institution. They were divided into 3 groups according to muscle mass measured at the third lumbar vertebra as assessed by CT. Patients with low muscle mass had a worse performance status, higher comorbidity index and higher disease risk. There was a significant difference in 2-year overall survival between the 3 groups, and worse overall survival (OS) was associated with lower muscle mass (p = 0.005). Muscle mass loss did not affect non-relapse mortality (p = 0.238) but was significantly associated with relapse (p = 0.067). Pre-transplant muscle mass loss may therefore reflect a poor prognosis for the primary disease.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Enfermedades Musculares , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Músculos , Estudios Retrospectivos , Tomografía Computarizada por Rayos X , Trasplante HomólogoRESUMEN
Objective Peripherally inserted central catheters (PICCs) are widely used in patients with hematologic malignancies. However, the risks of PICC-related complications during chemotherapy for acute myeloid leukemia (AML) are not fully understood. Methods We conducted a retrospective review of 128 adult patients with AML who received induction therapy by way of PICC insertion between 2012 and 2019. Results The median duration of PICC insertion was 30 days. The incidence rate of catheter-related bloodstream infection (CRBSI) was 2.4% at 30 days, and women were more likely to suffer from CRBSI than men. Local reactions at the insertion site were observed in 56 patients; however, these events did not predict CRBSI. The incidence rates of catheter-related thrombosis (CRT) were 1.6% at 30 days. Obesity put patients at an increased risk for CRT. Unexpected PICC removal occurred in 59 patients, and women were at a higher risk of catheter removal than men. Conclusion Low PICC-related complication rates, possibly associated with high rates of catheter removal, were observed during intensive chemotherapy for AML. Women and obese patients require careful monitoring of their PICC. Procedures to achieve appropriate PICC removal without increasing the complication rate need to be considered.
Asunto(s)
Infecciones Relacionadas con Catéteres , Cateterismo Venoso Central , Cateterismo Periférico , Catéteres Venosos Centrales , Leucemia Mieloide Aguda , Adulto , Infecciones Relacionadas con Catéteres/epidemiología , Infecciones Relacionadas con Catéteres/etiología , Cateterismo Venoso Central/efectos adversos , Cateterismo Periférico/efectos adversos , Catéteres/efectos adversos , Catéteres Venosos Centrales/efectos adversos , Femenino , Humanos , Quimioterapia de Inducción/efectos adversos , Leucemia Mieloide Aguda/complicaciones , Leucemia Mieloide Aguda/epidemiología , Leucemia Mieloide Aguda/terapia , Masculino , Estudios Retrospectivos , Factores de RiesgoRESUMEN
We retrospectively examined 57 patients with multiple myeloma who underwent autologous stem cell transplantation (ASCT) at our institution. A receiver-operating characteristic curve (ROC) analysis showed that the reduction rate of quantitative serum monoclonal protein (M-protein) before ASCT and the difference in involved and uninvolved free light chains (dFLC) 30 days after ASCT, respectively, had the greatest predictive value for all patients (area under the curve [AUC] 0.791 and 0.660, respectively). Based on the ROC curve-based cutoff values of tumor burden parameters, progression-free survival (PFS) in the high serum M-protein reduction (≥90 %) group was significantly better than that in the low serum M-protein reduction group (<90 %) (2-year PFS 79.5 % vs. 17.0 %, p < 0.001), but there were no significant differences in PFS between the low (<5.2 mg/L) and high (≥5.2 mg/L) dFLC groups (2-year PFS, 72.0 % vs. 46.0 %; p = 0.149). A multivariate analysis identified the reduction in serum M-protein as an independent predictive factor before ASCT for PFS (hazard ratio [HR] 0.287, p = 0.022) and high dFLC on day 30 after ASCT for PFS (HR 3.902, p = 0.040). These results demonstrate that a good prognosis can be expected with a reduction of serum M-protein before and after ASCT.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas/métodos , Mieloma Múltiple/terapia , Carga Tumoral , Adulto , Anciano , Femenino , Humanos , Cadenas Ligeras de Inmunoglobulina/metabolismo , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Mieloma Múltiple/patología , Proteínas de Mieloma/metabolismo , Evaluación de Resultado en la Atención de Salud/métodos , Evaluación de Resultado en la Atención de Salud/estadística & datos numéricos , Pronóstico , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Factores de Tiempo , Trasplante Autólogo , Adulto JovenRESUMEN
High-dose methotrexate (MTX) is widely used for the treatment of hematological malignancies. Despite the application of routine supportive care measures, such as intensive fluid hydration and urine alkalinization, nephrotoxicity is still a problem. The present study aimed to evaluate the risk factors for MTX-induced nephrotoxicity. We retrospectively reviewed 88 patients who received a regimen consisting of high-dose MTX (1000 mg/m2) and cytosine arabinoside between 2006 and 2018. Nephrotoxicity (≥ grade 2) was observed in 11 patients. Nephrotoxicity was observed only in patients with a high MTX concentration. Other than the MTX concentration, the serum uric acid level and urine pH at day 1 were associated with nephrotoxicity. A multivariate analysis revealed that urine pH was an independent risk factor for MTX-induced nephrotoxicity. Urine pH < 7.0 at day 1 was a significant risk factor for nephrotoxicity (odds ratio, 8.05; 95% confidence interval 1.95-33.3) and was also a predictor of delayed MTX elimination at 72 h after injection. Among pre-treatment factors, a low serum calcium level predicted urine pH < 7.0 at day 1. In conclusion, the present study suggests that low urine pH at day 1 is an independent risk factor for MTX-induced nephrotoxicity.
Asunto(s)
Antimetabolitos Antineoplásicos/efectos adversos , Enfermedades Renales/inducido químicamente , Metotrexato/efectos adversos , Adolescente , Adulto , Anciano , Antimetabolitos Antineoplásicos/administración & dosificación , Antimetabolitos Antineoplásicos/uso terapéutico , Femenino , Neoplasias Hematológicas/tratamiento farmacológico , Humanos , Enfermedades Renales/sangre , Enfermedades Renales/orina , Masculino , Metotrexato/administración & dosificación , Metotrexato/uso terapéutico , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Riesgo , Ácido Úrico/sangre , Adulto JovenRESUMEN
Graft-versus-host disease is a major complication after allogeneic hematopoietic stem cell transplantation for hematological malignancies. Immunosuppressive drugs, such as anti-thymocyte globulin, alemtuzumab, and post-transplant cyclophosphamide, have been used to prevent graft-versus-host disease in HLA-mismatched haploidentical hematopoietic stem cell transplantation. Here, we investigated whether these drugs could ameliorate graft-versus-host disease without diminishing the graft-versus-leukemia effect by using a xenogeneic transplanted graft-versus-host disease/graft-versus-leukemia model. Anti-thymocyte globulin treatment diminished graft-versus-host disease symptoms, completely depleted the infiltration of inflammatory cells in the liver and intestine, and led to prolonged survival. By contrast, improvement after post-transplant cyclophosphamide treatment remained minimal. Alemtuzumab treatment modestly prolonged survival despite an apparent decrease of Tregs. In the graft-versus-leukemia model, 1.5 to 2.0 mg/kg of anti-thymocyte globulin and 0.6 to 0.9 mg/kg of alemtuzumab reduced graft-versus-host disease with minimal loss of graft-versus-leukemia effect. Mice treated with 400 mg/kg of post-transplant cyclophosphamide did not develop graft-versus-host disease or leukemia, but it was difficult to evaluate the graft-versus-leukemia effect due to the sensitivity of A20 cells to cyclophosphamide. Although the current settings provide narrow optimal therapeutic windows, further studies are warranted to maximize the benefits of each immunosuppressant.
Asunto(s)
Alemtuzumab/uso terapéutico , Suero Antilinfocítico/uso terapéutico , Ciclofosfamida/uso terapéutico , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Enfermedad Injerto contra Huésped/etiología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Adulto , Animales , Modelos Animales de Enfermedad , Femenino , Enfermedad Injerto contra Huésped/prevención & control , Humanos , Ratones Endogámicos NOD , Ratones SCID , Índice de Severidad de la Enfermedad , Carga TumoralRESUMEN
Mesenchymal stromal cells (MSCs) have been shown to inhibit aerobic glycolysis in activated T cells, leading to increased autophagy. Although tryptophan depletion induced by indoleamine 2,3-dioxygenase (IDO) generated by MSCs has been suggested as a potential mechanism, we found that this inhibition was completely abolished when T cells were physically separated from MSCs using the Transwell system. Instead, in the current study, we demonstrate that programmed cell death 1 receptor (PD-1) and its ligand PD-L1, the expression of which is induced on activated T cells and MSCs, respectively, in response to IFN-γ are involved in this inhibition. Blockade of PD-1/PD-L1 interaction by blocking antibodies significantly restored glucose uptake, glycolytic activity, and cluster formation of activated T cells, whereas a specific inhibitor of IDO, 1-methyl-DL-tryptophan, had no effect. Neither surface nor cytoplasmic glucose transporter-1 expression on T cells was changed by MSCs. In addition, glycolytic gene expression in activated T cells was not inhibited despite the presence of MSCs. However, we found that hexokinase II (HK2) protein expression was markedly decreased in activated T cells that had been cocultured with MSCs. PD-1 blocking antibody restored HK2 expression. Taken together, our findings indicate that the PD-1/PD-L1 axis is involved in the MSC-mediated suppression of T cell glycolysis by negatively regulating HK2 activity at the protein level, but not at the mRNA level.