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1.
Haematologica ; 2019 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-31753925

RESUMO

Chimeric antigen receptor T-cells are a novel class of anti-cancer therapy in which autologous or allogeneic T-cells are engineered to express a chimeric antigen receptor targeting a membrane antigen. In Europe, Tisagenlecleucel (KymriahTM) is approved for the treatment of refractory/relapsed Acute Lymphoblastic Leukaemia in children and young adults as well as relapsed/refractory Diffuse Large B-cell Lymphoma; Axicabtagene ciloleucel (YescartaTM) is approved for the treatment of relapsed/refractory high-grade B-cell Lymphoma and Primary Mediastinal B-cell Lymphoma. Both agents are genetically engineered autologous T-cells targeting CD19. These practical recommendations, prepared under the auspices of the European Society of Blood and Marrow Transplantation, relate to patient care and supply chain management under the following headings: patient eligibility, screening laboratory tests and imaging and work-up prior to leukapheresis, how to perform leukapheresis, bridging therapy, lymphodepleting conditioning, product receipt and thawing, infusion of chimeric antigen receptor T-cells, short-term complications including cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, antibiotic prophylaxis, medium-term complications including cytopenias and B-cell aplasia, nursing and psychological patient support, long-term follow-up, post-authorisation safety surveillance, and regulatory issues. These recommendations are not prescriptive and are intended as guidance in the use of this novel therapeutic class.

4.
Haematologica ; 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31601686

RESUMO

Uric acid is a danger signal contributing to inflammation. Its relevance to allogeneic stem cell transplantation derives from preclinical models where the depletion of uric acid led to improved survival and reduced graft-versus-host disease. In a clinical pilot trial, peri-transplant uric acid depletion reduced acute graft-versus-host disease incidence. This prospective international multicenter study aimed to investigate the association of uric acid serum levels before start of conditioning with allogeneic stem cell transplantation outcome. We included patients with acute leukemia, lymphoma or myelodysplastic syndrome receiving a first matched sibling allogeneic stem cell transplantation from peripheral blood, regardless of conditioning. We compared outcomes between patients with high and low uric acid levels with univariate- and multivariate analysis using a cause-specific Cox model. Twenty centers from 10 countries reported data on 366 allogeneic stem cell transplantation recipients. There were no significant differences in terms of baseline co-morbidity and disease stage between the high- and low uric acid group. Patients with uric acid levels above median measured before start of conditioning did not significantly differ from remaining in term of acute graft-versus-host disease grades II-IV incidence (HR=1.5, CI=1-2.4, p=0.08). However, they had significantly shorter overall survival (HR=2.8, CI=1.7-4.7, p<0.0001) and progression free survival (HR=1.6, CI=1.1-2.4, p=0.025). Non-relapse mortality was significantly increased in allogeneic stem cell transplantation recipients with high uric acid levels (HR=2.7, CI=1.4-5.0, p=0.003). Finally, the incidence of relapse after allogeneic stem cell transplantation was increased in patients with higher uric acid levels (HR=1.6, CI=1-2.5, p=0.04). We conclude that high uric acid levels before the start of conditioning correlate with increased mortality after allogeneic stem cell transplantation.

5.
Artigo em Inglês | MEDLINE | ID: mdl-31636397

RESUMO

In many healthcare settings, benchmarking for complex procedures has become a mandatory requirement by competent authorities, regulators, payers and patients to assure clinical performance, cost-effectiveness and safe care of patients. In several countries inside and outside Europe, benchmarking systems have been established for haematopoietic stem cell transplantation (HSCT), but access is not universal. As benchmarking is now integrated into the FACT-JACIE standards, the EBMT and JACIE established a Clinical Outcomes Group (COG) to develop and introduce a universal system accessible across EBMT members. Established systems from seven European countries (United Kingdom, Italy, Belgium, France, Germany, Spain, Switzerland), USA and Australia were appraised, revealing similarities in process, but wide variations in selection criteria and statistical methods. In tandem, the COG developed the first phase of a bespoke risk-adapted international benchmarking model for one-year survival following allogeneic and autologous HSCT based on current capabilities within the EBMT registry core dataset. Data completeness, which has a critical impact on validity of centre comparisons, is also assessed. Ongoing development will include further scientific validation of the model, incorporation of further variables (when appropriate) alongside implementation of systems for clinically meaningful interpretation and governance aiming to maximise acceptance to centres, clinicians, payers and patients across EBMT.

6.
Artigo em Inglês | MEDLINE | ID: mdl-31534192

RESUMO

Plerixafor plus granulocyte-colony stimulating factor (G-CSF) enhances the mobilization of hematopoietic stem cells (HSCs) for collection and subsequent autologous hematopoietic stem cell transplantation (HSCT) in patients with multiple myeloma (MM). This international, multicenter, noninterventional registry study (NCT01362972), evaluated long-term outcomes for MM patients who received plerixafor versus other mobilization regimens. The comparisons were: G-CSF + plerixafor (G-CSF + P) versus G-CSF-; G-CSF + P versus G-CSF + chemotherapy (G-CSF + C); and G-CSF + P + C versus G-CSF + C. Propensity score matching was used to balance groups. Primary outcome measures were progression free survival (PFS), overall survival (OS), and cumulative incidence of relapse (CIR) after transplantation. After propensity matching, 77 versus 41 patients in the G-CSF + P versus G-CSF cohorts, 129 versus 129 in the G-CSF + P versus G-CSF + C cohorts, and 117 versus 117 in the G-CSF + P + C versus G-CSF + C cohorts were matched, respectively. Propensity score matching resulted in a smaller sample size and imbalances were not completely overcome. For both PFS and OS, the upper limits of the hazard ratio 95% confidence intervals exceeded prespecified boundaries; noninferiority was not demonstrated. CIR rates were higher in the plerixafor cohorts. G-CSF + P remains an option for the mobilization of HSCs in poor mobilizers with MM with no substantial differences in PFS, OS, and CIR in comparison with other regimens.

7.
Ann Hematol ; 98(9): 2197-2211, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31321454

RESUMO

Incidence and outcome of microbiologically documented bacterial/viral infections and invasive fungal disease (IFD) in children and adults after hematopoietic cell transplantation (HCT) were compared in 650 children and 3200 adults in multicenter cross-sectional nationwide study. Infections were diagnosed in 60.8% children and 35.0% adults, including respectively 69.1% and 63.5% allo-HCT, and 33.1% and 20.8% auto-HCT patients. The incidence of bacterial infections was higher in children (36.0% vs 27.6%; p < 0.0001). Infections with Gram-negative bacteria were more frequent than Gram-positives in adults (64.6% vs 44.8%; p < 0.0001). Outcome of bacterial infections was better in children (95.5% vs 91.4%; p = 0.0011). The IFD incidence (25.3% vs 6.3%; p < 0.0001) and outcome (88.0% vs 74.9%; p < 0.0001) were higher in children. The incidence of viral infections was higher in children after allo-HCT (56.3% vs 29.3%; p < 0.0001), and auto-HCT (6.6% vs 0.8%; p < 0.0001). Outcome of viral infections was better in children (98.6% vs 92.3%; p = 0.0096). Infection-related mortality was 7.8% in children and 18.4% in adults (p < 0.0001). No child after auto-HCT died of infection. Adult age, mismatched transplants, acute leukemia, chronic GVHD, CMV reactivation, infection with Gram-negatives, and duration of infection > 21 days were risk factors for death from infection. In conclusion, pediatric patients have 2.9-fold higher incidence and 2.5-fold better outcome of infections than adults after HCT.


Assuntos
Infecções Bacterianas/epidemiologia , Infecções por Citomegalovirus/epidemiologia , Doença Enxerto-Hospedeiro/epidemiologia , Transplante de Células-Tronco Hematopoéticas , Infecções Fúngicas Invasivas/epidemiologia , Doença Aguda , Adolescente , Adulto , Fatores Etários , Idoso , Infecções Bacterianas/etiologia , Criança , Pré-Escolar , Doença Crônica , Estudos Transversais , Infecções por Citomegalovirus/etiologia , Feminino , Doença Enxerto-Hospedeiro/etiologia , Humanos , Incidência , Lactente , Recém-Nascido , Infecções Fúngicas Invasivas/etiologia , Leucemia , Masculino , Pessoa de Meia-Idade , Fatores de Risco
8.
Biol Blood Marrow Transplant ; 25(9): 1786-1791, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31082473

RESUMO

Gonadal impairment is an important late effect with a significant impact on quality of life of transplanted patients. The aim of this study was to compare gonadal function after busulfan (Bu) or treosulfan (Treo) conditioning regimens in pre- and postpubertal children. This retrospective, multicenter study included children transplanted in pediatric European Society for Blood and Marrow Transplantation (EBMT) centers between 1992 and 2012 who did not receive gonadotoxic chemoradiotherapy before the transplant. We evaluated 137 patients transplanted in 25 pediatric EBMT centers. Median age at transplant was 11.04 years (range, 5 to 18); 89 patients were boys and 48 girls. Eighty-nine patients were prepubertal at transplant and 48 postpubertal. One hundred eighteen children received Bu and 19 Treo. A higher proportion of girls treated with Treo in the prepubertal stage reached spontaneous puberty compared with those treated with Bu (P = .02). Spontaneous menarche was more frequent after Treo than after Bu (P < .001). Postpubertal boys and girls treated with Treo had significantly lower luteinizing hormone levels (P = .03 and P = .04, respectively) compared with the Bu group. Frequency of gonadal damage associated with Treo was significantly lower than that observed after Bu. These results need to be confirmed in a larger population.

9.
Bone Marrow Transplant ; 54(10): 1525-1552, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30953028

RESUMO

This is the seventh special EBMT report on the indications for haematopoietic stem cell transplantation for haematological diseases, solid tumours and immune disorders. Our aim is to provide general guidance on transplant indications according to prevailing clinical practice in EBMT countries and centres. In order to inform patient decisions, these recommendations must be considered together with the risk of the disease, the risk of the transplant procedure and the results of non-transplant strategies. In over two decades since the first report, the EBMT indications manuscripts have incorporated changes in transplant practice coming from scientific and technical developments in the field. In this same period, the establishment of JACIE accreditation has promoted high quality and led to improved outcomes of patient and donor care and laboratory performance in transplantation and cellular therapy. An updated report with operating definitions, revised indications and an additional set of data with overall survival at 1 year and non-relapse mortality at day 100 after transplant in the commonest standard-of-care indications is presented. Additional efforts are currently underway to enable EBMT member centres to benchmark their risk-adapted outcomes as part of the Registry upgrade Project 2020 against national and/or international outcome data.

11.
Bone Marrow Transplant ; 54(10): 1575-1585, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30728439

RESUMO

Hematopoietic cell transplantation (HCT) is widely used for acquired and congenital disorders of the hematopoietic system. Number of transplants done in Europe and associated countries continues to rise with 45,418 HCT in 41,100 patients [(17,155 allogeneic (42%) and 23,945 autologous (58%)] reported by 683 centers in 50 countries in 2017. Main indications were myeloid malignancies 10,147 (25%; 96% allogeneic), lymphoid malignancies 26,488 (64%; 19% allogeneic), solid tumors 1,607 (3.9%; 2% allogeneic), and nonmalignant disorders 2,667 (7%; 81% allogeneic). Trends in donor choice seen before continue, with growing numbers of haploidentical HCT and decreasing use of cord blood. Of interest is that after many years of continued growth, the number of patients receiving an allogeneic HCT for marrow failure is decreasing slightly (p < 0.001). Such a change may be explained by the use of thrombopoietin analogs in aplastic anemia patients. Other nonmalignant indications, however continue to grow, most importantly HCT for hemoglobinopathies by 36%, equally for thalassemias and sickle cell disease. Non-HCT cell therapies have increased by 28% since 2015 and genetically modified T cells is type of cell therapy with the fastest growth. These annual reports reflect current activity and trends and are useful for health-care planning.

12.
Med Sci Monit ; 25: 305-311, 2019 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-30628586

RESUMO

BACKGROUND The most common etiological agents of infections in onco-hematological patients are Gram-negative rods resistant to many antimicrobials, including carbapenems. Recently, ceftolozane combined with tazobactam became a novel therapeutic option. The aim of the present study was to analyze the susceptibility to ceftolozane/tazobactam of the clinical strains of these bacteria. MATERIAL AND METHODS Material comprised rectal swabs, urine, and bronchoalveolar lavage fluid obtained from onco-hematological patients hospitalized in a clinical hospital (1050 beds) in Poland. Identification of the isolated bacteria was done by matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) using the MALDI Biotyper (Bruker). Ceftolozane/tazobactam susceptibility of the isolates was assessed using antimicrobial gradient strips (E-test, BioMérieux). Antimicrobial susceptibility testing and interpretation of the results was done according to the current recommendations of the European Committee on Antimicrobial Susceptibility Testing (EUCAST). RESULTS In total, 281 rectal swabs and 116 urine samples were tested for the presence of Gram-negative rods producing ESBL, and 531 rectal swabs and 8 bronchoalveolar lavage fluid samples were tested for the presence of Gram-negative rods resistant to carbapenems. In the analyzed period, 69 non-repetitive strains of bacteria were isolated that were in the spectrum of activity of ceftolozane/tazobactam. Among 44 clinical strains of ESBL(+) Enterobacteriaceae rods, 76% were susceptible to ceftolozane/tazobactam. All 9 strains of non-carbapenemase-producing P. aeruginosa resistant or with decreased susceptibility to carbapenems were susceptible to ceftolozane/tazobactam. CONCLUSIONS Ceftolozane/tazobactam may be an option in the therapy of infections caused by ESBL(+) strains of Enterobacteriaceae as well as non-carbapenemase-producing carbapenem-resistant strains of P. aeruginosa.


Assuntos
Cefalosporinas/uso terapêutico , Enterobacteriaceae/efeitos dos fármacos , Pseudomonas/efeitos dos fármacos , Tazobactam/uso terapêutico , Antibacterianos/farmacologia , Anti-Infecciosos/uso terapêutico , Cefalosporinas/farmacologia , Infecção Hospitalar/microbiologia , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Quimioterapia Combinada , Hospitais , Humanos , Testes de Sensibilidade Microbiana , Pacientes , Polônia , Infecções por Pseudomonas/tratamento farmacológico , Tazobactam/farmacologia
13.
Bone Marrow Transplant ; 54(5): 662-673, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30531954

RESUMO

Ocular graft-versus-host disease (GVHD) occurs in more than half of patients who develop chronic GVHD after allogeneic hematopoietic cell transplantation (HCT), causing prolonged morbidity, which affects activities of daily living and quality of life. Here we provide an expert review of ocular GVHD in a collaboration between transplant physicians and ophthalmologists through the Late Effects and Quality of Life Working Committee of the Center for International Blood and Marrow Transplant Research and the Transplant Complications Working Party of the European Society of Blood and Marrow Transplantation. Recent updates in ocular GVHD, regarding pathophysiology, preclinical models, risk factors, prevention, screening, diagnosis, response criteria, evaluation measures, and treatment are discussed in this review. Ocular GVHD has at least three biological processes: lacrimal gland dysfunction, meibomian gland dysfunction, and corneoconjunctival inflammation. Preclinical models have found several novel pathogenic mechanisms, including renin angiotensin system and endoplasmic reticulum stress signaling that can be targeted by therapeutic agents. Many studies have identified reliable tests for establishing diagnosis and response assessment of ocular GVHD. Efficacy of systemic and topical treatment for ocular GVHD is summarized. It is important for all health professionals taking care of HCT recipients to have adequate knowledge of ocular GVHD for optimal care.

14.
Bone Marrow Transplant ; 54(5): 648-661, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30531955

RESUMO

Non-graft-vs.-host disease (non-GVHD) ocular complications are generally uncommon after hematopoietic cell transplantation (HCT), but can cause prolonged morbidity affecting activities of daily living and quality of life. Here we provide an expert review of non-GVHD ocular complications in a collaboration between transplant physicians and ophthalmologists through the Late Effects and Quality of Life Working Committee of the Center for International Blood and Marrow Transplant Research and the Transplant Complications Working Party of the European Society of Blood and Marrow Transplantation. Complications discussed in this review include cataracts, glaucoma, ocular infections, ocular involvement with malignancy, ischemic microvascular retinopathy, central retinal vein occlusion, retinal hemorrhage, retinal detachment, and ocular toxicities associated with medications. We have summarized incidence, risk factors, screening, prevention and treatment of individual complicastions and generated evidence-based recommendations. Baseline ocular evaluation before HCT should be considered in all patients who undergo HCT. Follow-up evaluations should be considered according to clinical symptoms, signs and risk factors. Better preventive strategies and treatments remain to be investigated for individual ocular complications after HCT. Both transplant physicians and ophthalmologists should be knowledgeable of non-GVHD ocular complications and provide comprehensive collaborative team care.

15.
Artigo em Inglês | MEDLINE | ID: mdl-30521975

RESUMO

Non-graft-versus-host disease (non-GVHD) ocular complications are generally uncommon after hematopoietic cell transplantation (HCT), but can cause prolonged morbidity affecting activities of daily living and quality of life. Here we provide an expert review of non-GVHD ocular complications in a collaboration between transplant physicians and ophthalmologists through the Late Effects and Quality of Life Working Committee of the Center for International Blood and Marrow Transplant Research and the Transplant Complications Working Party of the European Society of Blood and Marrow Transplantation. Complications discussed in this review include cataracts, glaucoma, ocular infections, ocular involvement with malignancy, ischemic microvascular retinopathy, central retinal vein occlusion, retinal hemorrhage, retinal detachment and ocular toxicities associated with medications. We have summarized incidence, risk factors, screening, prevention and treatment of individual complications and generated evidence-based recommendations. Baseline ocular evaluation before HCT should be considered in all patients who undergo HCT. Follow-up evaluations should be considered according to clinical symptoms, signs and risk factors. Better preventive strategies and treatments remain to be investigated for individual ocular complications after HCT. Both transplant physicians and ophthalmologists should be knowledgeable of non-GVHD ocular complications and provide comprehensive collaborative team care.

16.
Artigo em Inglês | MEDLINE | ID: mdl-30481594

RESUMO

Ocular graft-versus-host disease (GVHD) occurs in more than half of patients who develop chronic GVHD after allogeneic hematopoietic cell transplantation (HCT), causing prolonged morbidity which affects activities of daily living and quality of life. Here we provide an expert review of ocular GVHD in a collaboration between transplant physicians and ophthalmologists through the Late Effects and Quality of Life Working Committee of the Center for International Blood and Marrow Transplant Research and the Transplant Complications Working Party of the European Society of Blood and Marrow Transplantation. Recent updates in ocular GVHD, regarding pathophysiology, preclinical models, risk factors, prevention, screening, diagnosis, response criteria, evaluation measures, and treatment are discussed in this review. Ocular GVHD has at least three biological processes: lacrimal gland dysfunction, meibomian gland dysfunction, and corneoconjunctival inflammation. Preclinical models have found several novel pathogenic mechanisms including renin angiotensin system and endoplasmic reticulum stress signaling that can be targeted by therapeutic agents. Many studies have identified reliable tests for establishing diagnosis and response assessment of ocular GVHD. Efficacy of systemic and topical treatment for ocular GVHD is summarized. It is important for all health professionals taking care of HCT recipients to have adequate knowledge of ocular GVHD for optimal care.

17.
Artigo em Inglês | MEDLINE | ID: mdl-30361500

RESUMO

Transplant-associated thrombotic microangiopathy (TA-TMA) is a life-threatening complication of allogeneic hematopoietic stem cell transplantation (HSCT). This study evaluated clinical and morphological practices of TA-TMA diagnosis in EBMT centers. Two questionnaires, one for transplant physician and one for morphologist, and also a set of electronic blood slides from 10 patients with TA-TMA and 10 control patients with various erythrocyte abnormalities, were implemented for evaluation. Seventeen EBMT centers participated in the study. Regarding criteria used for TA-TMA diagnosis, centers reported as follows: 41% of centers used the International Working Group (IWG) criteria, 41% used "overall TA-TMA" criteria and 18% used physician's decision. The threshold of schistocytes to establish TA-TMA diagnosis in the participating centers was significantly associated with morphological results of test cases evaluations (p = 0.002). The mean number of schistocytes reported from blood slide analyses were 4.3 ± 4.5% for TA-TMA cases (range 0-19.6%, coefficient of variation (CV) 0.7) and 1.3 ± 1.6% for control cases (range 0-8.3%, CV 0.8). Half of the centers reported schistocyte levels below 4% for 7/10 TA-TMA cases. The intracenter variability was low, indicating differences in the institutional practices of morphological evaluation. In conclusion, the survey identified the need for the standardization of TA-TMA morphological diagnosis.

18.
Hematol Oncol Stem Cell Ther ; 11(4): 195-205, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30076790

RESUMO

Kidney dysfunction is a common complication of hematopoietic cell transplantation (HCT) with proven negative impact on early and long-term mortality. Causes of this complication are diverse, usually overlapping, and poorly understood. Therefore, management implicates multidirectional investigations and simultaneous treatment of suspected causes. The etiology is frequently unconfirmed due to a lack of specific markers and prevalence of contraindications to renal biopsy among HCT recipients. Herein, we provide a summary of etiology and propose an algorithm for evaluation of kidney injury after HCT. We also map out the most urgent areas for research that aim to identify patients at risk of severe renal injury and develop nephroprotective strategies.

19.
Leukemia ; 2018 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-30050122

RESUMO

Donor cell leukaemia (DCL) is a rare complication of allogeneic haematopoietic cell transplantation (HCT). We have investigated the prevalence and outcome of donor cell haematology malignancies within centres registered with the European Society of Blood and Marrow transplantation (EBMT). We have sought to identify risk factors to shed light on the pathogenesis of DCL as a model for leukaemogenesis. DCL cases were identified by questionnaire and a follow-up questionnaire requested detailed data. Control subjects from the EBMT registry who had not developed DCL were used for a matched pair analysis to identify risk factors. We identified 38 patients with DCL; the estimated prevalence was 80.5/100,000 transplants. Patients were predominantly treated for haematological malignancy. A clone was retrospectively identified in 7/25 (28%) donors for whom data was available. Overall survival was poor with 29/38 patients dead a median of 11 (range 0-91) months after DCL diagnosis. Matched case-pair analysis identified three factors on multivariate analysis as significantly associated with an increased risk for DCL: use of growth factors within the first 100 days after transplantation, in vivo T-cell depletion and multiple allografts. The risk factors identified, support reduced immune surveillance and replicative stress as pathogenic in the development of DCL.

20.
Haematologica ; 103(11): 1843-1852, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30002127

RESUMO

A cute myeloid leukemia is a malignant disease of immature myeloid cells. Despite significant therapeutic effects of differentiation-inducing agents in some acute myeloid leukemia subtypes, the disease remains incurable in a large fraction of patients. Here we show that SK053, a thioredoxin inhibitor, induces differentiation and cell death of acute myeloid leukemia cells. Considering that thioredoxin knock-down with short hairpin RNA failed to exert antiproliferative effects in one of the acute myeloid leukemia cell lines, we used a biotin affinity probe-labeling approach to identify potential molecular targets for the effects of SK053. Mass spectrometry of proteins precipitated from acute myeloid leukemia cells incubated with biotinylated SK053 used as a bait revealed protein disulfide isomerase as a potential binding partner for the compound. Biochemical, enzymatic and functional assays using fluorescence lifetime imaging confirmed that SK053 binds to and inhibits the activity of protein disulfide isomerase. Protein disulfide isomerase knockdown with short hairpin RNA was associated with inhibition of cell growth, increased CCAAT enhancer-binding protein α levels, and induction of differentiation of HL-60 cells. Molecular dynamics simulation followed by the covalent docking indicated that SK053 binds to the fourth thioredoxin-like domain of protein disulfide isomerase. Differentiation of myeloid precursor cells requires the activity of CCAAT enhancer-binding protein α, the function of which is impaired in acute myeloid leukemia cells through various mechanisms, including translational block by protein disulfide isomerase. SK053 increased the levels of CCAAT enhancer-binding protein α and upregulated mRNA levels for differentiation-associated genes. Finally, SK053 decreased the survival of blasts and increased the percentage of cells expressing the maturation-associated CD11b marker in primary cells isolated from bone marrow or peripheral blood of patients with acute myeloid leukemia. Collectively, these results provide a proof-of-concept that protein disulfide isomerase inhibition has potential as a therapeutic strategy for the treatment of acute myeloid leukemia and for the development of small-molecule inhibitors of protein disulfide isomerase.

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