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1.
Pediatr Blood Cancer ; 67(6): e28237, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32277798

RESUMO

BACKGROUND: The SRP54 (signal recognition protein 54) is a conserved component of the ribonucleoprotein complex that mediates cotranslational targeting and translocation of proteins to the endoplasmic reticulum. In 2017, mutations in the gene have been described as a cause of congenital neutropenia with or without pancreatic insufficiency, and since then, only limited cases were added to the literature. METHODS: Two patients with neutropenia underwent hematological, immunological, and genetic work-up, including lymphocyte phenotyping, immunoglobulins, and complement levels, antineutrophil and antinuclear antibodies, bone marrow FISH panel for myelodysplastic syndrome, whole-exome sequencing, and in silico proteomic analysis. RESULTS: Clinical findings in the two families revealed a wide spectrum of immunological and clinical manifestations, ranging from mild asymptomatic neutropenia during febrile illnesses to severe neutropenia and life-threatening infection requiring leg amputation. Immunological and hematological work-up showed isolated neutropenia with normal lymphocyte subpopulations, immunoglobulin and complement levels, and negative autoimmune tests. Bone marrow aspirations showed variability ranging from normal myelopoiesis to myeloid maturation arrest at the promyelocytic stage, with normal FISH panel for myelodysplastic syndrome. Genetic analysis identified a novel, de novo, in-frame deletion in the SRP54 gene, c.342-344delAAC, p.T115del. In silico proteomic analysis suggested impaired SRP54 protein function due to reduced GTP activity and stability. CONCLUSIONS: We describe congenital neutropenia with variable clinical presentation in novel mutation of the SRP54 gene.


Assuntos
Mutação , Neutropenia/congênito , Neutropenia/patologia , Partícula de Reconhecimento de Sinal/genética , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Neutropenia/genética , Neutropenia/metabolismo , Linhagem , Prognóstico , Proteômica , Sequenciamento Completo do Exoma
2.
Ann N Y Acad Sci ; 1466(1): 83-92, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32083314

RESUMO

Cyclic neutropenia (CyN) is a hematologic disorder in which peripheral blood absolute neutrophil counts (ANCs) show cycles of approximately 21-day intervals. The majority of CyN patients harbor ELANE mutations, but the mechanism of ANC cycling is unclear. We performed analysis of bone marrow (BM) subpopulations in CyN patients at the peak and the nadir of the ANC cycle and detected high proportions of BM hematopoietic stem cells (HSCs) and hematopoietic stem and progenitor cells (HSPCs) at the nadir of the ANC cycle, as compared with the peak. BM HSPCs produced fewer granulocyte colony-forming unit colonies at the ANC peak. To investigate the mechanism of cycling, we found that mRNA expression levels of ELANE and unfolded protein response (UPR)-related genes (ATF6, BiP (HSPA5), CHOP (DDIT3), and PERK (EIF2AK3)) were elevated, but antiapoptotic genes (Bcl-2 (BCL2) and bcl-xL (BCL2L1)) were reduced in CD34+ cells tested at the ANC nadir. Moreover, HSPCs revealed increased levels of reactive oxygen species and gH2AX at the ANC nadir. We suggest that in CyN patients, some HSPCs escape the UPR-induced endoplasmic reticulum (ER) stress and proliferate in response to granulocyte colony-stimulating factor (G-CSF) to a certain threshold at which UPR again affects the majority of HSPCs. There is a cyclic balance between ER stress-induced apoptosis of HSPCs and compensatory G-CSF-stimulated HSPC proliferation followed by granulocytic differentiation.


Assuntos
Estresse do Retículo Endoplasmático/fisiologia , Elastase de Leucócito/genética , Neutropenia/etiologia , Resposta a Proteínas não Dobradas/fisiologia , Medula Óssea/efeitos dos fármacos , Medula Óssea/metabolismo , Medula Óssea/patologia , Células Cultivadas , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Estresse do Retículo Endoplasmático/genética , Seguimentos , Fator Estimulador de Colônias de Granulócitos/farmacologia , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Hematopoese/efeitos dos fármacos , Hematopoese/genética , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/patologia , Células-Tronco Hematopoéticas/fisiologia , Humanos , Elastase de Leucócito/fisiologia , Mutação , Neutropenia/tratamento farmacológico , Neutropenia/metabolismo , Neutropenia/patologia , Espécies Reativas de Oxigênio/metabolismo , Índice de Gravidade de Doença , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Resposta a Proteínas não Dobradas/efeitos dos fármacos , Resposta a Proteínas não Dobradas/genética
3.
Int J Radiat Biol ; 96(1): 155-166, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31216213

RESUMO

Purpose: Evaluation of the pharmacodynamics (PD) and pharmacokinetics (PK) of romiplostim alone and in combination with pegfilgrastim in a non-human primate (NHP) model of acute radiation syndrome (ARS).Materials and methods: Male and female rhesus macaques were subjected to Cobalt-60 γ irradiation, at a dose of 550 cGy 24 h prior to subcutaneous administration of either romiplostim alone as a single (2.5 or 5.0 mg/kg on Day 1) or repeat dose (5.0 mg/kg on Days 1 and 8), pegfilgrastim alone as a repeat dose (0.3 µg/kg on Day 1 and 8), or a combination of both agents (romiplostim 5.0 mg/kg on Day 1; pegfilgrastim 0.3 µg/kg on Days 1 and 8). Clinical outcome, hematological parameters and PK were assessed throughout the 45 d study period post-irradiation.Results: Administration of romiplostim, pegfilgrastim or the combination of both resulted in significant improvements in hematological parameters, notably prevention of severe thrombocytopenia, compared with irradiated, vehicle control-treated NHPs. The largest hematologic benefit was observed when romiplostim and pegfilgrastim were administered as a combination therapy with much greater effects on both platelet and neutrophil recovery following irradiation compared to single agents alone.Conclusions: These results indicate that romiplostim alone or in combination with pegfilgrastim is effective at improving hematological parameters in an NHP model of ARS. This study supports further study of romiplostim as a medical countermeasure to improve primary hemostasis and survival in ARS.


Assuntos
Filgrastim/farmacologia , Neutropenia/tratamento farmacológico , Polietilenoglicóis/farmacologia , Lesões Experimentais por Radiação/tratamento farmacológico , Proteínas Recombinantes de Fusão/farmacologia , Trombocitopenia/tratamento farmacológico , Trombopoetina/farmacologia , Animais , Coagulação Sanguínea/efeitos dos fármacos , Coagulação Sanguínea/efeitos da radiação , Relação Dose-Resposta a Droga , Interações Medicamentosas , Feminino , Macaca mulatta , Masculino , Neutropenia/sangue , Neutropenia/metabolismo , Lesões Experimentais por Radiação/sangue , Lesões Experimentais por Radiação/metabolismo , Receptores Fc/uso terapêutico , Proteínas Recombinantes de Fusão/farmacocinética , Proteínas Recombinantes de Fusão/uso terapêutico , Trombocitopenia/sangue , Trombocitopenia/metabolismo , Trombopoetina/farmacocinética , Trombopoetina/uso terapêutico , Fatores de Tempo
4.
J Clin Exp Hematop ; 59(4): 202-206, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31866622

RESUMO

CD3+/CD57+ T-cell large granular lymphocyte leukemia (T-LGLL) is an indolent neoplasm, exhibiting mostly CD8+, less frequently CD4+ phenotypes, and T-LGLL consisting of 2 populations with CD8+ and CD4+ phenotypes is markedly rare. An 87-year-old female was admitted under a diagnosis of immune thrombocytopenia (ITP) with a platelet count of 5.0×109/L and increased number of LGL with unknown etiology. Her neutrophil count also decreased to 0.27×109/L and she was positive for antineutrophil antibody. The WBC count was 2.7×109/L with 34.7% LGL and flow cytometry (FCM) analysis revealed 16% CD3+/CD4+/CD8dim/CD57+ and 20.9% CD3+/CD8+/CD57+ populations. These populations also expressed granzyme B and perforin. Circulating mononuclear cells were found to be clonal by PCR analysis of T-cell receptor ß-chain gene. Serum immunofixation and bone marrow FCM analyses demonstrated 2 clonal B-cells producing IgG-λ and IgA-λ. Deep amplicon sequencing of STAT3 and STAT5B genes revealed a STAT3 R302G mutation with an allele burden of 2.6%. The thrombocytopenia and neutropenia were successfully treated by prednisolone and romiplostim with negative conversion of antineutrophil antibody. This is the first reported case of T-LGLL with dual components of CD4+/CD8dim and CD4-/CD8+ populations in terms of multiple comorbidities related to the respective CD8+ and CD4+ T-LGLLs.


Assuntos
Linfócitos B , Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos , Leucemia Linfocítica Granular Grande , Linfocitose , Mutação de Sentido Incorreto , Proteínas de Neoplasias , Neutropenia , Púrpura Trombocitopênica Idiopática , Fator de Transcrição STAT3 , Idoso de 80 Anos ou mais , Substituição de Aminoácidos , Linfócitos B/metabolismo , Linfócitos B/patologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/patologia , Feminino , Humanos , Cadeias lambda de Imunoglobulina/genética , Cadeias lambda de Imunoglobulina/metabolismo , Leucemia Linfocítica Granular Grande/genética , Leucemia Linfocítica Granular Grande/metabolismo , Leucemia Linfocítica Granular Grande/patologia , Linfocitose/genética , Linfocitose/metabolismo , Linfocitose/patologia , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Neutropenia/genética , Neutropenia/metabolismo , Neutropenia/patologia , Púrpura Trombocitopênica Idiopática/genética , Púrpura Trombocitopênica Idiopática/metabolismo , Púrpura Trombocitopênica Idiopática/patologia , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo
5.
Cancer Sci ; 110(11): 3573-3583, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31505087

RESUMO

This study determined individual optimal amrubicin doses for Japanese patients with lung cancer after platinum-based treatment. We carried out population pharmacokinetic and pharmacodynamic modeling incorporating gene polymorphisms of metabolizing enzymes and transporters. Fifty patients with lung cancer, who were given 35-40 mg/m2 amrubicin on days 1-3 every 3-4 weeks, were enrolled. Mechanism-based modeling described relationships between the pharmacokinetics of amrubicin and absolute neutrophil counts. A population pharmacokinetic and pharmacodynamic model was developed for amrubicin and amrubicinol (active metabolite), connected by a delay compartment. The final model incorporated body surface area as a covariate of amrubicin and amrubicinol clearance and distribution volume. SLC28A3 single nucleotide polymorphism (rs7853758) was also incorporated as a constant covariate of the delay compartment of amrubicinol. Performance status was considered a covariate of pharmacokinetic (amrubicinol clearance) and pharmacodynamic (mean maturation time) parameters. Twenty-nine patients with grade 4 neutropenia showed higher amrubicinol area under the plasma concentration-time curve from 0 to 72 hours (AUC0-72 , P = .01) and shorter overall survival periods than other patients did (P = .01). Using the final population pharmacokinetic and pharmacodynamic model, median optimal dose to prevent grade 4 neutropenia aggravation was estimated at 22 (range, 8-40) mg/m2 for these 29 patients. We clarified correlations between area under the plasma concentration-time curve from 0 to 72 hours of amrubicinol and severity of neutropenia and survival of patients given amrubicin after platinum chemotherapy. This analysis revealed important amrubicin pharmacokinetic-pharmacodynamic covariates and provided useful information to predict patients who would require prophylactic granulocyte colony stimulating factor.


Assuntos
Antraciclinas/administração & dosagem , Antineoplásicos/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Neutropenia/prevenção & controle , Adulto , Idoso , Idoso de 80 Anos ou mais , Antraciclinas/farmacocinética , Antineoplásicos/farmacocinética , Área Sob a Curva , Grupo com Ancestrais do Continente Asiático , Superfície Corporal , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Esquema de Medicação , Feminino , Humanos , Japão , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidade , Masculino , Proteínas de Membrana Transportadoras/genética , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Neutropenia/metabolismo , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Índice de Gravidade de Doença
6.
Drug Dev Res ; 80(6): 807-813, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31294492

RESUMO

Neutropenia is a condition of an abnormally low number of neutrophils which render patients more susceptible to infections, especially to bacterial infections, as the condition may become life threatening and deadly without prompt medical attention. Various factors such as, anticancer drugs, radiotherapy, infectious diseases, congenital defects, or vitamin B12/B9 deficiency can trigger neutropenia. GX-G3, a human hybrid (hy) Fc-fused granulocyte colony stimulating factor (G-CSF), was developed as next-generation G-CSF for the treatment of cancer therapy-induced neutropenia. In this study, with the aim of investigating this promising potential next-generation G-CSF, comparative pharmacokinetic and pharmacodynamic studies were conducted in healthy and neutropenia-induced rats. It was found that t1/2 of GX-G3 is longer than same mass injection of filgrastim and pegfilgrastim and AUEClast (area under theeffect-time curve from time zero to the last measurable ANC level) of absolute neutrophil count showed a significant increase after GX-G3 injection compared with filgrastim and pegfilgrastim in healthy rats. Besides, in duration of neutropenia after the same mass injection GX-G3 showed about 3.3 days of reduction effect compared with that of filgrastim, and 1.3 days of reduction effect compared with that of pegfilgrastim in neutropenia-induced rats. These results demonstrate that the half-life of GX-G3 is longer than pegfilgrastim and GX-G3 is more effective than filgrastim and pegfilgrastim in neutropenia-induced rats.


Assuntos
Fator Estimulador de Colônias de Granulócitos/farmacologia , Fator Estimulador de Colônias de Granulócitos/farmacocinética , Neutropenia/imunologia , Neutropenia/metabolismo , Proteínas Recombinantes de Fusão/farmacologia , Proteínas Recombinantes de Fusão/farmacocinética , Animais , Meia-Vida , Injeções Subcutâneas , Contagem de Leucócitos , Masculino , Neutrófilos/efeitos dos fármacos , Ratos
7.
Sci Rep ; 9(1): 8460, 2019 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-31186479

RESUMO

Cerebral hypoperfusion in the first hours after subarachnoid haemorrhage (SAH) is a major determinant of poor neurological outcome. However, the underlying pathophysiology is only partly understood. Here we induced neutropenia in C57BL/6N mice by anti-Ly6G antibody injection, induced SAH by endovascular filament perforation, and analysed cerebral cortical perfusion with laser SPECKLE contrast imaging to investigate the role of neutrophils in mediating cerebral hypoperfusion during the first 24 h post-SAH. SAH induction significantly increased the intracranial pressure (ICP), and significantly reduced the cerebral perfusion pressure (CPP). At 3 h after SAH, ICP had returned to baseline and CPP was similar between SAH and sham mice. However, in SAH mice with normal neutrophil counts cortical hypoperfusion persisted. Conversely, despite similar CPP, cortical perfusion was significantly higher at 3 h after SAH in mice with neutropenia. The levels of 8-iso-prostaglandin-F2α in the subarachnoid haematoma increased significantly at 3 h after SAH in animals with normal neutrophil counts indicating oxidative stress, which was not the case in neutropenic SAH animals. These results suggest that neutrophils are important mediators of cortical hypoperfusion and oxidative stress early after SAH. Targeting neutrophil function and neutrophil-induced oxidative stress could be a promising new approach to mitigate cerebral hypoperfusion early after SAH.


Assuntos
Antígenos Ly/genética , Pressão Sanguínea/genética , Neutrófilos/metabolismo , Hemorragia Subaracnóidea/terapia , Animais , Anticorpos Anti-Idiotípicos/imunologia , Anticorpos Anti-Idiotípicos/farmacologia , Antígenos Ly/imunologia , Pressão Sanguínea/imunologia , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Circulação Cerebrovascular/fisiologia , Modelos Animais de Doenças , Humanos , Pressão Intracraniana/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neutropenia/metabolismo , Neutropenia/patologia , Neutrófilos/imunologia , Neutrófilos/patologia , Hemorragia Subaracnóidea/diagnóstico por imagem , Hemorragia Subaracnóidea/etiologia , Hemorragia Subaracnóidea/metabolismo
12.
Eur J Clin Pharmacol ; 75(7): 921-928, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30877327

RESUMO

AIM: There is accumulating evidence that neutropenic patients require higher dosages of vancomycin. To prevent sub-therapeutic drug exposure, it is of utmost importance to obtain adequate exposure from the first dose onwards. We aimed to quantify the effect of neutropenia on the pharmacokinetics of vancomycin. METHODS: Data were extracted from a matched patient cohort of patients known with (1) hematological disease, (2) solid malignancy, and (3) patients not known with cancer. Pharmacokinetic analysis was performed using non-linear mixed effects modeling with neutropenia investigated as a binary covariate on clearance and volume of distribution of vancomycin. RESULTS: A total of 116 patients were included (39 hematologic patients, 39 solid tumor patients, and 38 patients not known with cancer). In total, 742 paired time-concentration observations were available for the pharmacokinetic analysis. Presence of neutropenia showed to significantly (p = 0.00157) increase the clearance of vancomycin by 27.7% (95% CI 10.2-46.2%), whereas it did not impact the volume of distribution (p = 0.704). CONCLUSIONS: This study shows that vancomycin clearance is increased in patients with neutropenia by 27.7%. Therefore, the vancomycin maintenance dose should be pragmatically increased by 25% in neutropenic patients at the start of treatment. Since the volume of distribution appeared unaffected, no adjustment in loading dose is required. These dose adjustments do not rule out the necessity of further dose individualization by means of therapeutic drug monitoring.


Assuntos
Antibacterianos/farmacocinética , Neutropenia/metabolismo , Vancomicina/farmacocinética , Adulto , Idoso , Antibacterianos/administração & dosagem , Antibacterianos/sangue , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Vancomicina/administração & dosagem , Vancomicina/sangue
13.
Proc Natl Acad Sci U S A ; 116(4): 1241-1250, 2019 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-30626647

RESUMO

Neutropenia represents an important problem in patients with genetic deficiency in either the glucose-6-phosphate transporter of the endoplasmic reticulum (G6PT/SLC37A4) or G6PC3, an endoplasmic reticulum phosphatase homologous to glucose-6-phosphatase. While affected granulocytes show reduced glucose utilization, the underlying mechanism is unknown and causal therapies are lacking. Using a combination of enzymological, cell-culture, and in vivo approaches, we demonstrate that G6PT and G6PC3 collaborate to destroy 1,5-anhydroglucitol-6-phosphate (1,5AG6P), a close structural analog of glucose-6-phosphate and an inhibitor of low-K M hexokinases, which catalyze the first step in glycolysis in most tissues. We show that 1,5AG6P is made by phosphorylation of 1,5-anhydroglucitol, a compound normally present in human plasma, by side activities of ADP-glucokinase and low-K M hexokinases. Granulocytes from patients deficient in G6PC3 or G6PT accumulate 1,5AG6P to concentrations (∼3 mM) that strongly inhibit hexokinase activity. In a model of G6PC3-deficient mouse neutrophils, physiological concentrations of 1,5-anhydroglucitol caused massive accumulation of 1,5AG6P, a decrease in glucose utilization, and cell death. Treating G6PC3-deficient mice with an inhibitor of the kidney glucose transporter SGLT2 to lower their blood level of 1,5-anhydroglucitol restored a normal neutrophil count, while administration of 1,5-anhydroglucitol had the opposite effect. In conclusion, we show that the neutropenia in patients with G6PC3 or G6PT mutations is a metabolite-repair deficiency, caused by a failure to eliminate the nonclassical metabolite 1,5AG6P.


Assuntos
Antiporters/metabolismo , Glucose-6-Fosfatase/metabolismo , Glucose/metabolismo , Proteínas de Transporte de Monossacarídeos/metabolismo , Neutropenia/metabolismo , Fosforilação/fisiologia , Animais , Morte Celular/fisiologia , Linhagem Celular , Retículo Endoplasmático/metabolismo , Feminino , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/metabolismo , Ratos Wistar
14.
Exp Hematol ; 71: 51-60, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30615903

RESUMO

We describe the establishment of an embryoid-body-based protocol for hematopoietic/myeloid differentiation of human induced pluripotent stem cells that allows the generation of CD34+ cells or mature myeloid cells in vitro. Using this model, we were able to recapitulate the defective granulocytic differentiation in patients with severe congenital neutropenia (CN), an inherited preleukemia bone marrow failure syndrome. Importantly, in vitro maturation arrest of granulopoiesis was associated with an elevated unfolded protein response (UPR) and enhanced expression of the cell cycle inhibitor p21. Consistent with this, we found that CD34+ cells of CN patients were highly susceptible to DNA damage and showed diminished DNA repair. These observations suggest that targeting the UPR pathway or inhibiting DNA damage might protect hematopoietic cells of CN patients from leukemogenic transformation, at least to some extent.


Assuntos
Transformação Celular Neoplásica/metabolismo , Dano ao DNA , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Leucemia/etiologia , Modelos Biológicos , Neutropenia/congênito , Resposta a Proteínas não Dobradas , Antígenos CD34/metabolismo , Biomarcadores , Células Cultivadas , Reprogramação Celular , Síndrome Congênita de Insuficiência da Medula Óssea , Estresse do Retículo Endoplasmático , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Humanos , Imunofenotipagem , Células-Tronco Pluripotentes Induzidas/patologia , Leucemia/metabolismo , Leucemia/patologia , Neutropenia/etiologia , Neutropenia/metabolismo , Neutropenia/patologia
15.
Br J Haematol ; 184(2): 223-231, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30203425

RESUMO

Bendamustine is used in combination with rituximab (BR) to treat indolent non-Hodgkin lymphomas (iNHL) and mantle cell lymphoma (MCL). The variability in treatment efficacy and toxicity could be related to single nucleotide polymorphisms (SNPs) in immune response genes. We would like to show a correlation between SNPs and treatment outcome in iNHL and MCL patients receiving BR. We investigated some SNPs that had already been associated with NHL outcome. Samples were genotyped for the IL2 (rs2069762), IL10 (rs1800890, rs10494879), VEGFA (rs3025039), IL8 (rs4073), CFH (rs1065489) and MTHFR (rs1801131) SNPs by allelic discrimination assays. We enrolled 70 patients that received rituximab 375 mg/m2 and bendamustine 90 mg/m2 every 28 days, both as first-line treatment and ≥ second-line regimens. Overall response rate was 97·1% (complete response [CR] rate 73·9%). Treatment toxicity included grade 3-4 neutropenia (24/70 patients), infections (21/70 patients; 1/70 grade 3), skin rash (26/70 patients; 2/70 grade 3). After a median follow-up of 24 months we did find any correlation between the analysed SNPs, CR rate and PFS. However, we demonstrated an association between the SNP in IL2 (rs2069762) and the onset of skin rash (P = 0·0001). Our study suggests a role for cytokine SNPs in bendamustine-related toxicity, which could represent a promising research field.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Erupção por Droga , Interleucina-2 , Linfoma de Célula do Manto , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cloridrato de Bendamustina/administração & dosagem , Cloridrato de Bendamustina/efeitos adversos , Erupção por Droga/genética , Erupção por Droga/metabolismo , Erupção por Droga/patologia , Feminino , Seguimentos , Humanos , Interleucina-2/genética , Interleucina-2/metabolismo , Linfoma de Célula do Manto/tratamento farmacológico , Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/metabolismo , Linfoma de Célula do Manto/patologia , Masculino , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Neutropenia/genética , Neutropenia/metabolismo , Neutropenia/patologia , Rituximab/administração & dosagem , Rituximab/efeitos adversos
16.
Toxicol Lett ; 302: 60-74, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30447258

RESUMO

BACKGROUND: Fine ambient particle matter (PM2.5) induces inflammatory lung injury; however, whether intratracheal administration of PM2.5 increases pulmonary polymorphonuclear leukocyte (PMN) infiltration, the mechanism of infiltration, and if these cells exacerbate PM2.5-induced lung injury are unknown. METHODS: Using 32,704 subjects, the association between blood PMNs and ambient PM2.5 levels on the previous day was retrospectively analyzed. Neutropenia was achieved by injecting mice with PMN-specific antibodies. Inhibition of PMN infiltration was achieved by pretreating PMNs with soluble vascular cell adhesion molecule-1 (sVCAM-1). The effects of PMNs on PM2.5-induced lung injury and endothelial dysfunction were observed. RESULT: Short-term PM2.5 (> 75 µg/m3 air) exposure increased the PMN/white blood cell ratio and the PMN count in human peripheral blood observed during routine examination. A significant number of PM2.5-treated PMNs was able to bind sVCAM-1. In mice, intratracheally-instilled PM2.5 deposited in the alveolar space and endothelial cells, which caused significant lung edema, morphological disorder, increased permeability of the endothelial-alveolar epithelial barrier, and PMN infiltration with increased VCAM-1 expression. Depletion of circulatory PMNs inhibited these adverse effects. Replenishment of untreated PMNs, but not those pretreated with soluble VCAM-1, restored lung injury. In vitro, PM2.5 increased VCAM-1 expression and endothelial and epithelial monolayer permeability, and promoted PMN adhesion to, chemotaxis toward, and migration across these monolayers. PMNs, but not those pretreated with soluble VCAM-1, exacerbated these effects. CONCLUSION: VCAM-1-mediated PMN infiltration was essential for a detrimental cycle of PM2.5-induced inflammation and lung injury. Results suggest that drugs that inhibit PMN function might prevent acute deterioration of chronic pulmonary and cardiovascular diseases triggered by PM2.5.


Assuntos
Lesão Pulmonar/induzido quimicamente , Pulmão/metabolismo , Infiltração de Neutrófilos , Neutrófilos/metabolismo , Material Particulado , Edema Pulmonar/induzido quimicamente , Molécula 1 de Adesão de Célula Vascular/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Células Epiteliais Alveolares/imunologia , Células Epiteliais Alveolares/metabolismo , Células Epiteliais Alveolares/patologia , Animais , Permeabilidade Capilar , Adesão Celular , Células Cultivadas , Citocinas/imunologia , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Células Endoteliais da Veia Umbilical Humana/imunologia , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/patologia , Humanos , Pulmão/imunologia , Pulmão/patologia , Lesão Pulmonar/imunologia , Lesão Pulmonar/metabolismo , Lesão Pulmonar/patologia , Masculino , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Neutropenia/imunologia , Neutropenia/metabolismo , Neutropenia/patologia , Neutrófilos/imunologia , Neutrófilos/patologia , Tamanho da Partícula , Edema Pulmonar/imunologia , Edema Pulmonar/metabolismo , Edema Pulmonar/patologia , Estudos Retrospectivos , Molécula 1 de Adesão de Célula Vascular/imunologia , Adulto Jovem
17.
Artigo em Inglês | MEDLINE | ID: mdl-30373794

RESUMO

Tedizolid phosphate, the prodrug of the active antibiotic tedizolid, is an oxazolidinone for the treatment of acute bacterial skin and skin structure infections. Studies in a mouse thigh infection model demonstrated that tedizolid has improved potency and pharmacokinetics/pharmacodynamics (PK/PD) compared with those of linezolid. Subsequent studies showed that the efficacy of tedizolid was enhanced in immunocompetent (IC) mice compared with neutropenic (immunosuppressed [IS]) mice, with stasis at clinically relevant doses being achieved only in the presence of granulocytes. The tedizolid label therefore contains a warning about its use in neutropenic patients. This study reevaluated the PK/PD of tedizolid and linezolid in the mouse thigh infection model in IC and IS mice using a methicillin-resistant Staphylococcus aureus (MRSA) strain (ATCC 33591) and a methicillin-susceptible S. aureus (MSSA) strain (ATCC 29213). The antistaphylococcal effect of doses ranging from 1 to 150 mg/kg of body weight tedizolid (once daily) or linezolid (twice daily) was determined at 24, 48, and 72 h after initiating treatment. In IC mice, stasis was achieved in the absence of antibiotics, and both tedizolid and linezolid reduced the burden further beyond a static effect. In IS mice, tedizolid achieved stasis against MRSA ATCC 33591 and MSSA ATCC 29213 at 72 h at a human clinical dose of 200 mg, severalfold lower than that in earlier studies. Linezolid achieved a static effect against MRSA ATCC 33591 in IS mice at a dose lower than that used clinically. This study demonstrates that, with time, both tedizolid and linezolid at clinically relevant exposures achieve stasis in neutropenic mice with an MRSA or MSSA thigh infection.


Assuntos
Antibacterianos/farmacologia , Linezolida/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Neutropenia/metabolismo , Organofosfatos/farmacologia , Oxazóis/farmacologia , Infecções Cutâneas Estafilocócicas/tratamento farmacológico , Animais , Antibacterianos/farmacocinética , Modelos Animais de Doenças , Linezolida/farmacocinética , Camundongos , Testes de Sensibilidade Microbiana , Organofosfatos/farmacocinética , Oxazóis/farmacocinética , Infecções Cutâneas Estafilocócicas/microbiologia
18.
Artigo em Inglês | MEDLINE | ID: mdl-30420477

RESUMO

Herein, we evaluated sustainability of humanized exposures of cefiderocol in vivo over 72 h against pathogens with cefiderocol MICs of 0.5 to 16 µg/ml in the neutropenic murine thigh model. In Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacteriaceae displaying MICs of 0.5 to 8 µg/ml (n = 11), sustained kill was observed at 72 h among 9 isolates. Postexposure MICs revealed a single 2-dilution increase in one animal compared with controls (1/54 samples, 1.8%) at 72 h. Adaptive resistance during therapy was not observed.


Assuntos
Acinetobacter baumannii/patogenicidade , Acinetobacter baumannii/efeitos dos fármacos , Animais , Antibacterianos/uso terapêutico , Cefalosporinas/farmacologia , Farmacorresistência Bacteriana Múltipla/genética , Enterobacteriaceae/efeitos dos fármacos , Enterobacteriaceae/metabolismo , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Negativas/genética , Camundongos , Testes de Sensibilidade Microbiana , Neutropenia/tratamento farmacológico , Neutropenia/metabolismo , Infecções por Pseudomonas/tratamento farmacológico , Infecções por Pseudomonas/microbiologia , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/patogenicidade , Coxa da Perna/microbiologia
19.
Curr Opin Hematol ; 26(1): 34-40, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30431463

RESUMO

PURPOSE OF REVIEW: The development of a myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) in patients with congenital neutropenia is now the major cause of mortality. Treatment options are limited and there are no effective prevention strategies. This review focuses on mechanisms of leukemic transformation in severe congenital neutropenia (SCN) and Shwachman-Diamond syndrome (SDS), the two most common types of congenital neutropenia. RECENT FINDINGS: AML/MDS that develops in the setting of congenital neutropenia has distinct molecular features. Clonal hematopoiesis because of TP53 mutations is seen in nearly 50% of patients with SDS, but is not seen in patients with SCN. Accordingly, there is a very high frequency of TP53 mutations in AML/MDS arising in the setting of SDS but not SCN. The rate of mutation accumulation in hematopoietic stem cells (HSCs) from patients with congenital neutropenia is not increased. SUMMARY: Both HSC cell-intrinsic and noncell-intrinsic changes contribute to the development of clonal hematopoiesis in congenital neutropenia and likely accounts for the high rate of leukemic transformation. In SCN, the persistently high levels of granulocyte colony-stimulating factor drive expansion of HSCs carrying truncation mutations of CSF3R. In SDS, impaired ribosome biogenesis induces p53-mediated growth inhibition and drives expansion of HSCs carrying TP53 mutations.


Assuntos
Transformação Celular Neoplásica , Síndrome Congênita de Insuficiência da Medula Óssea , Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Neutropenia/congênito , Síndrome de Shwachman-Diamond , Animais , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Síndrome Congênita de Insuficiência da Medula Óssea/complicações , Síndrome Congênita de Insuficiência da Medula Óssea/genética , Síndrome Congênita de Insuficiência da Medula Óssea/metabolismo , Síndrome Congênita de Insuficiência da Medula Óssea/patologia , Humanos , Leucemia Mieloide Aguda/etiologia , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Mutação , Síndromes Mielodisplásicas/etiologia , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/metabolismo , Síndromes Mielodisplásicas/patologia , Neutropenia/complicações , Neutropenia/genética , Neutropenia/metabolismo , Neutropenia/patologia , Receptores de Fator Estimulador de Colônias/genética , Síndrome de Shwachman-Diamond/complicações , Síndrome de Shwachman-Diamond/genética , Síndrome de Shwachman-Diamond/metabolismo , Síndrome de Shwachman-Diamond/patologia , Proteína Supressora de Tumor p53/genética
20.
Yakugaku Zasshi ; 138(10): 1249-1253, 2018.
Artigo em Japonês | MEDLINE | ID: mdl-30270267

RESUMO

 Whereas granulopoiesis during Gram-negative bacterial infection is accelerated through activation of toll-like receptor 4 (TLR4), it has not been elucidated whether Gram-positive bacterial infection can stimulate granulopoiesis. Using the well-known TLR2 agonist peptidoglycan (PGN), it was shown that neutrophils in bone marrow and spleen and plasma granulocyte colony-stimulating factor were increased in mice that had received intraperitoneal administration of PGN. Incorporation of bromodeoxyuridine into bone marrow neutrophils increased in mice administered PGN, demonstrating that PGN promotes granulopoiesis. These results illustrate that bacterial recognition by TLR2 facilitates granulopoiesis during Gram-positive bacterial infection. Thus, granulopoiesis is accelerated to suppress bacterial infection, but some bacteria can still cause severe infections. Clostridium perfringens is a Gram-positive, anaerobic pathogenic bacterium and causes life-threatening gas gangrene in humans. Of the many toxins produced by C. perfringens, α-toxin is known to be a major virulence factor during infection. Recently, it has been revealed that C. perfringens α-toxin impairs the innate immune system by inhibiting neutrophil differentiation, which is crucial for the pathogenesis of C. perfringens. Moreover, the toxin also attenuates erythropoiesis, which would cause severe anemia in clinical settings. The findings provide new insight to understand how hosts strengthen innate immunity to fight pathogenic bacteria and how they evade the hosts' immune systems.


Assuntos
Toxinas Bacterianas/toxicidade , Infecções por Bactérias Gram-Negativas/imunologia , Infecções por Bactérias Gram-Positivas/imunologia , Interações Hospedeiro-Patógeno/imunologia , Imunidade Inata/efeitos dos fármacos , Imunidade Inata/imunologia , Neutropenia/imunologia , Peptidoglicano/farmacologia , Animais , Bromodesoxiuridina/metabolismo , Proteínas de Ligação ao Cálcio/toxicidade , Diferenciação Celular/efeitos dos fármacos , Clostridium perfringens/patogenicidade , Gangrena/microbiologia , Fator Estimulador de Colônias de Granulócitos/metabolismo , Humanos , Camundongos , Neutropenia/etiologia , Neutropenia/metabolismo , Neutrófilos/efeitos dos fármacos , Neutrófilos/fisiologia , Peptidoglicano/administração & dosagem , Receptor 2 Toll-Like/agonistas , Receptor 4 Toll-Like/imunologia , Fosfolipases Tipo C/toxicidade
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