RESUMEN
Mast cells and eosinophils are considered pivotal contributors to the pathogenesis of chronic spontaneous urticaria (CSU). However, emerging evidence suggests that neutrophils also play a central role. Cutaneous mast cells and macrophages orchestrate the recruitment of neutrophils through the regulation and activation of diverse processes, including heightened local vascular permeability and chemokine release. Studies have demonstrated increased activation and elevated levels of neutrophil-related cytokines in CSU patients. Moreover, neutrophils have been proposed as antigen-presenting cells during the late-phase reaction of immunoglobulin E-mediated allergy and have been associated with the expression of calcitonin gene-related protein and vascular endothelial growth factor in CSU. Histopathological analysis of lesional skin in CSU patients revealed significantly higher eosinophil and neutrophil counts than unaffected skin. However, the extent of neutrophil infiltration in the skin does not appear to correlate with the number of neutrophils in peripheral blood. The utility of the neutrophil-lymphocyte ratio as a marker for disease activity or remission in CSU remains inconclusive. Neutrophil-targeted therapy may confer benefits for CSU patients who exhibit resistance to antihistamines. Omalizumab has demonstrated its ability to reduce neutrophil counts, the neutrophil-lymphocyte ratio, and the neutrophil-monocyte ratio in peripheral blood. While dapsone and colchicine are recommended as alternative treatment options for CSU, their evidential support from published studies remains limited. Inhibitors targeting interleukin-1 and neutrophil-related cytokines have been proposed as potential therapeutic interventions for patients exhibiting neutrophil predominance. Further research is warranted to gain deeper insights into the involvement of neutrophils in CSU and to explore potential therapeutic interventions.
Asunto(s)
Urticaria Crónica , Urticaria , Humanos , Neutrófilos/metabolismo , Mastocitos/metabolismo , Factor A de Crecimiento Endotelial Vascular/uso terapéutico , Urticaria Crónica/tratamiento farmacológico , Citocinas , Enfermedad CrónicaRESUMEN
This study aimed to identify factors that significantly influence the pharmacokinetics of voriconazole in Thai adults with hematologic diseases, and to determine optimal voriconazole dosing regimens. Blood samples were collected at steady state in 65 patients (237 concentrations) who were taking voriconazole to prevent or treat invasive aspergillosis. The data were analyzed using a nonlinear mixed-effects modeling approach. Monte Carlo simulation was applied to optimize dosage regimens. Data were fitted with the one-compartment model with first-order absorption and elimination. The apparent oral clearance (CL/F) was 3.43 L/h, the apparent volume of distribution (V/F) was 47.6 L, and the absorption rate constant (Ka) was fixed at 1.1 h-1. Albumin and omeprazole ≥ 40 mg/day were found to significantly influence CL/F. The simulation produced the following recommended maintenance doses of voriconazole: 50, 100, and 200 mg every 12 h for albumin levels of 1.5-3, 3.01-4, and 4.01-4.5 g/dL, respectively, in patients who receive omeprazole ≤ 20 mg/day. Patients who receive omeprazole ≥ 40 mg/day and who have serum albumin level 1.5-3 and 3.01-4.5 g/dL should receive voriconazole 50 and 100 mg, every 12 h, respectively. Albumin level and omeprazole dosage should be carefully considered when determining the appropriate dosage of voriconazole in Thai patients.
RESUMEN
Iron overload is common in patients undergoing hematopoietic cell transplantation (HCT). Peritransplant events, such as total body irradiation (TBI), and the effects of donor cell infusion may contribute to iron overload, in addition to disease-associated anemia and RBC transfusions. Using murine models we show complex time- and dose-dependent interactions of TBI and transplanted donor cells with expression patterns of iron regulatory genes in the liver. Infusion of allogeneic or syngeneic donor T lymphocytes increased serum iron, transiently up-regulated interleukin-6 (IL-6) and hepcidin (Hamp), and down-regulated ferroportin1 (Fpn1). After 7 to 14 days, however, changes were significant only with allogeneic cells. TBI (200 to 400 Gy) also induced IL-6 and Hamp expression but had little effect on Fpn1. TBI combined with allogeneic donor cell infusion resulted in modest early up-regulation of IL-6, followed by a decline in IL-6 levels and Hamp as well as Fpn1, and was accompanied by increased liver iron content. Injection of Fas ligand-deficient T lymphocytes from gld mice resulted in substantially lower alterations of gene expression than infusion of wild-type T cells. The agonistic anti-Fas antibody, JO2, triggered early up-regulation of Stat3 and IL-6, followed by an increase in Hamp and decreased expression of Fpn1 by 7 to 14 days, implicating Fas as a key modulator of gene expression in HCT. Minimal histologic changes were observed in mouse liver and duodenum. These data show profound and interacting effects of TBI and cell transplantation on the expression of iron regulatory genes in murine recipients. Alterations are largely related to induction of cytokines and Fas-dependent signals.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas/efectos adversos , Sobrecarga de Hierro/etiología , Hierro/metabolismo , Irradiación Corporal Total/efectos adversos , Animales , Citocinas/metabolismo , Regulación de la Expresión Génica , Proteínas Reguladoras del Hierro/genética , Hígado/metabolismo , Ratones , Linfocitos T/metabolismo , Trasplante Homólogo , Receptor fas/fisiologíaRESUMEN
Hematopoietic cell transplantation is curative in many patients. However, graft-versus-host disease (GVHD), triggered by alloreactive donor cells, has remained a major complication. Here, we show an inverse correlation between plasma α-1-antitrypsin (AAT) levels in human donors and the development of acute GVHD in the recipients (n = 111; P = .0006). In murine models, treatment of transplant donors with human AAT resulted in an increase in interleukin-10 messenger RNA and CD8(+)CD11c(+)CD205(+) major histocompatibility complex class II(+) dendritic cells (DCs), and the prevention or attenuation of acute GVHD in the recipients. Ablation of DCs (in AAT-treated CD11c-DTR donors) decreased CD4(+)CD25(+)FoxP3(+) regulatory T cells to one-third and abrogated the anti-GVHD effect. The graft-versus-leukemia (GVL) effect of donor cells (against A20 tumor cells) was maintained or even enhanced with AAT treatment of the donor, mediated by an expanded population of NK1.1(+), CD49B(+), CD122(+), CD335(+) NKG2D-expressing natural killer (NK) cells. Blockade of NKG2D significantly suppressed the GVL effect. Metabolic analysis showed a high glycolysis-high oxidative phosphorylation profile for NK1.1(+) cells, CD4(+)CD25(+)FoxP3(+) T cells, and CD11c(+) DCs but not for effector T cells, suggesting a cell type-specific effect of AAT. Thus, via altered metabolism, AAT exerts effective GVHD protection while enhancing GVL effects.
Asunto(s)
Metabolismo Energético , Enfermedad Injerto contra Huésped/prevención & control , Efecto Injerto vs Leucemia/inmunología , Células Madre Hematopoyéticas/metabolismo , Mitocondrias/metabolismo , Donantes de Tejidos , alfa 1-Antitripsina/farmacología , Animales , Antígeno CD11c/metabolismo , Proliferación Celular/efectos de los fármacos , Citotoxicidad Inmunológica/efectos de los fármacos , Demografía , Metabolismo Energético/efectos de los fármacos , Femenino , Enfermedad Injerto contra Huésped/sangre , Enfermedad Injerto contra Huésped/inmunología , Células Madre Hematopoyéticas/efectos de los fármacos , Prueba de Histocompatibilidad , Humanos , Células Asesinas Naturales/efectos de los fármacos , Células Asesinas Naturales/inmunología , Lactatos/metabolismo , Masculino , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones Endogámicos C57BL , Persona de Mediana Edad , Mitocondrias/efectos de los fármacos , Subfamilia K de Receptores Similares a Lectina de Células NK/metabolismo , Consumo de Oxígeno/efectos de los fármacos , Hermanos , Superóxidos/metabolismo , Regulación hacia Arriba/efectos de los fármacos , alfa 1-Antitripsina/sangreRESUMEN
Both DNA and histone methylation are dysregulated in the myelodysplastic syndromes (MDS). Based on preliminary data we hypothesized that dysregulated interactions of KDM2B, let-7b and EZH2 signals lead to an aberrant epigenetic landscape. Gene expression in CD34+ cells from MDS marrows was analyzed by NanoString miR array and validated by real-time polymerase chain reaction (PCR). The functions of KDM2B, let-7b and EZH2 were characterized in myeloid cell lines and in primary MDS cells. Let-7b levels were significantly higher, and KDM2B and EZH2 expression was lower in primary CD34+ MDS marrow cells (n = 44) than in healthy controls (n = 21; p<0.013, and p<0.0001, respectively). Overexpression of let-7b reduced EZH2 and KDM2B protein levels, and decreased cells in S-phase while increasing G0/G1 cells (p = 0.0005), accompanied by decreased H3K27me3 and cyclin D1. Silencing of KDM2B increased let-7b expression. Treatment with the cyclopentanyl analog of 3-deazaadenosine, DZNep, combined with the DNA hypomethylating agent 5-azacitidine, decreased levels of EZH2, suppressed methylation of di- and tri-methylated H3K27, and increased p16 expression, associated with cell proliferation. Thus, KDM2B, via let-7b/EZH2, promotes transcriptional repression. DZNep bypassed the inhibitory KDM2B/let-7b/EZH2 axis by preventing H3K27 methylation and reducing cell proliferation. DZNep might be able to enhance the therapeutic effects of DNA hypomethylating agents such as 5-azacitidine, currently considered standard therapy for patients with MDS.
Asunto(s)
Epigénesis Genética , Proteínas F-Box/genética , Histona Demetilasas con Dominio de Jumonji/genética , MicroARNs/genética , Síndromes Mielodisplásicos/genética , Complejo Represivo Polycomb 2/genética , Azacitidina/farmacología , Células de la Médula Ósea/efectos de los fármacos , Células de la Médula Ósea/metabolismo , Células de la Médula Ósea/patología , Línea Celular Tumoral , Análisis por Conglomerados , Proteína Potenciadora del Homólogo Zeste 2 , Expresión Génica , Perfilación de la Expresión Génica , Técnicas de Silenciamiento del Gen , Histonas/metabolismo , Humanos , Metilación , Terapia Molecular Dirigida , Síndromes Mielodisplásicos/patología , Síndromes Mielodisplásicos/terapiaRESUMEN
Hepatic iron overload is common in patients undergoing hematopoietic cell transplantation. We showed previously in a murine model that transplantation of allogeneic T cells induced iron deposition and down-regulation of hepcidin (Hamp) in hepatocytes. We hypothesized that hepatic injury was related to disrupted iron homeostasis triggered by the interaction of Fas-ligand, expressed on activated T cells, with Fas on hepatocytes. In the current study, we determined the effects of modified expression of the Flice inhibitory protein (FLIP long [FLIPL]), which interferes with Fas signaling, on the impact of Fas-initiated signals on the expression of IL-6 and Stat3 and their downstream target, Hamp. To exclude a possible contribution by other pathways, we used agonistic anti-Fas antibodies (rather than allogeneic T cells) to trigger Fas signaling. Inhibition of FLIPL by RNA interference resulted, as expected, not only in enhanced hepatocyte apoptosis in response to Fas signals, but also in decreased levels of IL-6, Stat3, and Hamp. In contrast, overexpression of FLIPL protected hepatocytes against agonistic anti-Fas antibody-mediated apoptosis and increased the levels of IL-6 and Stat3, thereby maintaining the expression of Hamp in an NF-κB-dependent fashion. In vivo overexpression of FLIPL in the liver via hydrodynamic transfection, similarly, interfered with Fas-initiated apoptosis and prevented down-regulation of IL-6, Stat3, and Hamp. These data indicate that Fas-dependent signals alter the regulation of iron homeostasis and suggest that signals initiated by Fas may contribute to peritransplantation iron accumulation.
Asunto(s)
Hepcidinas/metabolismo , Sobrecarga de Hierro/etiología , Linfocitos T/trasplante , Receptor fas/metabolismo , Animales , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/farmacología , Apoptosis/fisiología , Proteína Reguladora de Apoptosis Similar a CASP8 y FADD/antagonistas & inhibidores , Proteína Reguladora de Apoptosis Similar a CASP8 y FADD/biosíntesis , Proteína Reguladora de Apoptosis Similar a CASP8 y FADD/metabolismo , Línea Celular Tumoral , Proteína Ligando Fas/metabolismo , Femenino , Hepatocitos/inmunología , Hepatocitos/metabolismo , Hepcidinas/biosíntesis , Hepcidinas/genética , Humanos , Interleucina-6/biosíntesis , Interleucina-6/genética , Sobrecarga de Hierro/genética , Sobrecarga de Hierro/metabolismo , Ratones , Ratones Endogámicos C57BL , Factor de Transcripción STAT3/biosíntesis , Factor de Transcripción STAT3/genética , Transducción de Señal , Linfocitos T/inmunología , Linfocitos T/metabolismo , Transfección , Trasplante Homólogo , Resultado del Tratamiento , Receptor fas/inmunologíaRESUMEN
Hematopoietic cell transplantation (HCT) is the only therapy with curative potential for patients with myelodysplastic syndrome. Many conditioning regimens have been developed that, along with the use of cord blood or HLA-haploidentical donors, allow doctors to offer HCT to a growing proportion of patients. New classification schemes identify more narrowly characterized risk groups, which may facilitate decisions with regard to HCT. Disease stage and cytogenetics remain the major determinants of HCT outcome. The use of peripheral blood progenitor cells may offer an advantage over marrow for engraftment and relapse prevention, but graft-versus-host disease remains a problem. The age of patients undergoing HCT has increased significantly over the past 25 years, and comorbid conditions are the major patient characteristic impacting transplant success. Recent studies show that drugs used in the non-HCT setting may be beneficial in the context of HCT.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas/métodos , Trasplante de Células Madre Hematopoyéticas/tendencias , Síndromes Mielodisplásicos/terapia , Adulto , Humanos , Persona de Mediana Edad , Acondicionamiento Pretrasplante , Trasplante HomólogoRESUMEN
BACKGROUND: Granulomatous mycosis fungoides is an unusual histopathological variant of cutaneous T-cell lymphoma without clinical distinction from classic mycosis fungoides. Symptoms associated with peripheral nerve involvement have rarely been reported in the literature. CASE REPORT: The authors described a case of granulomatous MF stage IIB with large cell transformation who initially presented with leprosy-like condition and chronic left peroneal neuropathy The patient received six courses ofgemcitabine with greater than 90% improvement of skin lesions. The rest of the lesions were successfully treated with local electron beam radiation. CONCLUSION: Granulomatous MF with neuropathy can be clinically misdiagnosed if there is no histopathological and immunohistochemical finding to support the diagnosis of lymphoma.
Asunto(s)
Granuloma/diagnóstico , Micosis Fungoide/diagnóstico , Neoplasias Cutáneas/diagnóstico , Antimetabolitos Antineoplásicos/uso terapéutico , Transformación Celular Neoplásica/patología , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapéutico , Errores Diagnósticos , Progresión de la Enfermedad , Granuloma/complicaciones , Granuloma/patología , Humanos , Lepra/diagnóstico , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Debilidad Muscular/etiología , Debilidad Muscular/patología , Micosis Fungoide/complicaciones , Micosis Fungoide/tratamiento farmacológico , Neoplasias Cutáneas/complicaciones , Neoplasias Cutáneas/patología , Resultado del Tratamiento , GemcitabinaRESUMEN
Hairy cell leukemia (HCL) has been mainly reported from the Western countries. Herein we describe a case of HCL diagnosed in a Thai patient. A 36-year-old man presented with abdominal discomfort, frequent gum bleeding and significant weight loss for 2 months. Physical examination revealed moderate anemia, petechial hemorrhage on the extremities and an enlarged spleen down to the umbilicus. No hepatomegaly or lymphadenopathy was detected. Complete blood counts revealed a hemoglobin (Hb) of 6.6 g/dL, a white blood cell (WBC) count of 1.6 x 10(9)/L (neutrophil 16%, lymphocyte 71%, monocyte 11%, atypical lymphocyte 1%), and a platelet (PLT) count of 17 x 10(9)/L. Abnormal large mononuclear cells with villous projections were seen in the blood smear. Although bone marrow (BM) aspiration resulted in a dry tap, abnormal lymphocytes with villous projections could again be identified in the touch preparation. Flow cytometric analysis showed a distinct population above the normal lymphocyte region on CD45/SSC gates with a strong expression of CD19, CD20, CD22, CD25, CD11c, and kappa. CD5, CD23, CD10, CD4, and CD8 were all negative. BM biopsy was consistent with HCL. The patient was treated with splenectomy followed by 8 cycles of fludarabine and cyclophosphamide chemotherapy. At 21 months after diagnosis, the patient was doing well with a Hb of 16.9 g/dl, a WBC count of 6.8 x 10(9)/L, neutrophil 49.9%, lymphocyte 39.6%, monocyte 8.6%, and a PLT count of 329 x 10(9)/L). No abnormal lymphoid cells were detected in the blood smear. This present report represents the first Thai HCL case that was immunophenotypically confirmed by flow cytometry and successfully treated at Siriraj Hospital.