Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Doenças Autoimunes/tratamento farmacológico , Metotrexato/uso terapêutico , Neutropenia/diagnóstico , Trombocitopenia/diagnóstico , Adulto , Autoanticorpos/sangue , Doenças Autoimunes/complicações , Doenças Autoimunes/diagnóstico , Humanos , Masculino , Neutropenia/complicações , Neutrófilos/citologia , Contagem de Plaquetas , Trombocitopenia/complicações , Trombocitopenia/imunologiaRESUMO
BACKGROUND: In 2019, a new coronavirus disease emerged in Wuhan, China, known as SARS-CoV-2, severe acute respiratory syndrome coronavirus 2, and caused an ongoing pandemic. Symptomatology of the syndrome is variable, with complications extending to hematopoiesis and hemostasis. Approximately a year after onset of the virus, four vaccination formulas became available to the public, based on a viral vector or mRNA technology. These vaccine formulas have been hampered with hematological complications, like vaccine-induced immune thrombotic thrombocytopenia (VITT) and vaccine-related ITP (immune thrombocytopenic purpura). ITP is a disease with autoimmune pathogenesis characterized by antibody production against platelets and an increased hemorrhagic risk. A decent number of cases have been referred to as possible adverse effects of COVID-19 vaccinations. CASE PRESENTATION: in this case report, we present two cases of newly diagnosed ITP after vaccination with ChAdOx1-S (AstraZeneca), with a good response to treatment with thrombopoietin-receptor agonists (TPO-RAs). DISCUSSION: we observed an absence of response after corticosteroids and IVIG therapy and a positive therapeutic outcome on TPO-RA. CONCLUSIONS: in the ongoing pandemic, there is an urgent need to create therapeutic guidelines for vaccination-related clinical entities and to clarify indications for the vaccination of patients with pre-existing hematological diseases.
RESUMO
Many microorganisms excrete typical cytoplasmic proteins into the culture supernatant. As none of the classical secretion systems appears to be involved, this type of secretion was referred to as "nonclassical protein secretion." Here, we demonstrate that in Staphylococcus aureus the major autolysin plays a crucial role in release of cytoplasmic proteins. Comparative secretome analysis revealed that in the wild type S. aureus strain, 22 typical cytoplasmic proteins were excreted into the culture supernatant, although in the atl mutant they were significantly decreased. The presence or absence of prophages had little influence on the secretome pattern. In the atl mutant, secondary peptidoglycan hydrolases were increased in the secretome; the corresponding genes were transcriptionally up-regulated suggesting a compensatory mechanism for the atl mutation. Using glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as a cytoplasmic indicator enzyme, we showed that all clinical isolates tested excreted this protein. In the wall teichoic acid-deficient tagO mutant with its increased autolysis activity, GAPDH was excreted in even higher amounts than in the WT, confirming the importance of autolysis in excretion of cytoplasmic proteins. To answer the question of how discriminatory the excretion of cytoplasmic proteins is, we performed a two-dimensional PAGE of cytoplasmic proteins isolated from WT. Surprisingly, the most abundant proteins in the cytoplasm were not found in the secretome of the WT, suggesting that there exists a selection mechanism in the excretion of cytoplasmic proteins. As the major autolysin binds at the septum site, we assume that the proteins are preferentially released at and during septum formation.
Assuntos
Proteínas de Bactérias/metabolismo , Citoplasma/metabolismo , N-Acetil-Muramil-L-Alanina Amidase/metabolismo , Infecções Estafilocócicas/metabolismo , Northern Blotting , Western Blotting , Eletroforese em Gel Bidimensional , Humanos , Processamento de Imagem Assistida por Computador , N-Acetil-Muramil-L-Alanina Amidase/genética , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Staphylococcus aureus/patogenicidadeRESUMO
The recognition of cytologic dysplasia in blood and bone marrow remains the cornerstone of myelodysplastic syndromes (MDS) diagnosis because it distinguishes MDS from clonal hematopoiesis of indeterminate potential or clonal cytopenia of undetermined significance. Expert morphologists achieve high concordance in the diagnosis of MDS if appropriate clinical information is provided. Because of the low prevalence of MDS, diagnostic approaches based solely on molecular diagnosis will likely be erroneous.
Assuntos
Medula Óssea/patologia , Citodiagnóstico , Técnicas de Diagnóstico Molecular , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/etiologia , Biomarcadores , Citodiagnóstico/métodos , Citodiagnóstico/normas , Diagnóstico Diferencial , Suscetibilidade a Doenças , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Leucócitos/metabolismo , Leucócitos/patologia , Mutação , Taxa de Mutação , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
The BRAF-V600E mutation has been established as a signature alteration occurring almost universally in hairy cell leukemia. Moreover, it can be detected in a small percentage of patients with non-small cell lung cancer. We report the case of a patient with a metastatic BRAF-V600E-mutated lung adenocarcinoma suffering from concomitant hairy cell leukemia. The identification of an identical BRAF mutation in both malignancies raises physiopathological considerations and might offer unique therapeutic strategies for this group of patients.
Assuntos
Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/patologia , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Tiazóis/uso terapêutico , Idoso , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Dasatinibe , Humanos , Imageamento por Ressonância Magnética , Masculino , Indução de RemissãoRESUMO
Lenalidomide has particular activity in patients with transfusion-dependent del(5q) myelodysplastic syndromes (MDS), but mechanistic information is limited regarding the relationship between erythroid and cytogenetic responses. We reviewed medical records from three distinct subgroups of del(5q) MDS patients who had unexpected effects with lenalidomide treatment: 1. two patients with complex karyotypes who achieved both cytogenetic remissions and transfusion independence; 2. two patients with 5q- syndrome who took lenalidomide for less than 12 weeks but remained transfusion independent for 15+ months still displaying del(5q) metaphases after 6 and 12 months; and 3. one patient who was a non-responder on lenalidomide during treatment but became transfusion independent for 13+ months after discontinuation. All but the latter patient in this series had reduction of affected metaphases, suggesting that erythroid responses might be mediated by result from partial or complete suppression of the malignant clone, either directly or indirectly through modulation of the bone marrow microenvironment. These clinical observations illustrate the heterogeneity of del(5q)MDS pathogenesis and the diversity of lenalidomide responses within this patient subset.
Assuntos
Deleção Cromossômica , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/genética , Talidomida/análogos & derivados , Adulto , Idoso , Feminino , Humanos , Cariotipagem , Lenalidomida , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/patologia , Talidomida/efeitos adversos , Talidomida/uso terapêutico , Resultado do TratamentoRESUMO
Apoptosis of dentate granule cells is a typical feature of several animal models of disease. In 20 autopsy cases of subarachnoid hemorrhage (SAH) and global cerebral hypoxia caused by protracted shock or respiratory failure, we evaluated by light microscopy and in situ tailing whether this pattern of neuronal damage also occurs in humans. In subarachnoid hemorrhage, 4.0/mm2 (0-13.0/mm2) apoptotic neurons were observed in the dentate gyrus, in cerebral hypoxia 3.6/mm2 (0-19.9/mm2) (p>0.05), and in 10 aged-matched control cases dying rapidly from non-neurological diseases 0/mm2 (0-0/mm2) (median [range]) (p<0.001 versus SAH and hypoxia). Neuronal apoptosis in the dentate gyrus was most frequent, when death occurred later than 24 hours and less than 11 days after disease onset. Neuronal damage in the hippocampus was always necrotic. It was more severe in hypoxia than in SAH (median neuronal damage score 3 [range: 0-3] versus 0 [0-3], p<0.001). Apoptosis appears to be the predominant mechanism of death in dentate granule cells irrespective of the underlying disease, whereas neuronal death in the hippocampus generally is of necrotic morphology.
Assuntos
Apoptose , Giro Denteado/patologia , Hipocampo/patologia , Hipóxia Encefálica/patologia , Neurônios/patologia , Hemorragia Subaracnóidea/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Autopsia , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Necrose , Insuficiência Respiratória/complicações , Fatores de TempoRESUMO
Lenalidomide is a novel thalidomide analogue with enhanced immunomodulatory and antiangiogenic action lacking most of the typical thalidomide-associated adverse events. In myelodysplastic syndromes (MDS), it has been used primarily in the IPSS low- and intermediate-1 risk setting. Several trials have demonstrated its potential to lead to both erythroid and cytogenetic responses in these disease groups. In a clinical trial of patients with a del(5q) chromosomal abnormality, lenalidomide treatment resulted in red blood cell (RBC) transfusion independence in 67% of patients. Moreover, 45% of patients achieved a complete cytogenetic remission, and 28% achieved a minor cytogenetic remission. This result was independent of karyotype complexity. Lenalidomide might also induce long-term remissions in del(5q) patients with an elevated medullary blast count. In non-del(5q) patients, 43% of patients with confirmed low- and intermediate-1 risk achieved transfusion independence or a reduction of at least 50% of pre-treatment RBC transfusion levels. Adverse events are common but manageable and include neutropenia and thrombocytopenia, pruritus, rash, diarrhea, and others. Lenalidomide will prove an essential part in the armamentarium of MDS therapeutics. Combination therapies with cytokines, demethylating agents, tyrosine kinase inhibitors, or chemotherapy are being investigated and may show additional benefit in both low- and high risk MDS.
Assuntos
Plaquetas/efeitos dos fármacos , Catarata/terapia , Perda Auditiva Neurossensorial/terapia , Nefrite Hereditária/terapia , Receptores Fc/administração & dosagem , Proteínas Recombinantes de Fusão/administração & dosagem , Insuficiência Renal/terapia , Trombocitopenia/terapia , Trombopoetina/administração & dosagem , Adulto , Plaquetas/patologia , Catarata/etiologia , Catarata/genética , Catarata/fisiopatologia , Criança , Pré-Escolar , Análise Mutacional de DNA , Perda Auditiva Neurossensorial/complicações , Perda Auditiva Neurossensorial/genética , Perda Auditiva Neurossensorial/fisiopatologia , Humanos , Masculino , Proteínas Motores Moleculares/genética , Mutação/genética , Cadeias Pesadas de Miosina/genética , Nefrite Hereditária/complicações , Nefrite Hereditária/genética , Nefrite Hereditária/fisiopatologia , Contagem de Plaquetas , Transfusão de Plaquetas , Receptores de Trombopoetina/agonistas , Proteínas Recombinantes de Fusão/efeitos adversos , Diálise Renal , Insuficiência Renal/etiologia , Insuficiência Renal/genética , Insuficiência Renal/fisiopatologia , Trombocitopenia/complicações , Trombocitopenia/genética , Trombocitopenia/fisiopatologia , Trombopoetina/efeitos adversos , Falha de TratamentoRESUMO
All-trans-retinoic acid (ATRA) alone or in combination with cytokines and vitamins has been shown to stimulate erythropoiesis in low-risk myelodysplastic syndromes (MDS). We performed a phase II study on 29 patients with MDS and isolated del(5q) including bands q31-q33 to determine the efficacy and safety of ATRA in combination with tocopherol-alpha. All patients had low/intermediate-1 risk MDS according to the international prognostic scoring system. They received 45 mg/m(2) ATRA on days 1 to 90, and 90 mg/m(2) on days 91 to 180. Tocopherol dosage was 600 IU three times daily. Twenty-four patients completed dose level I, and 12 patients dose level II. Eighty-six percent of patients experienced side effects. Thirty discontinued the drug treatment due to such events as skin reactions, cheilitis, conjunctivitis, joint pain, creatinine increase, or CNS symptoms. One patient (3%) achieved a major erythroid response resulting in transfusion independence throughout the study. Four patients (14%) achieved a minor erythroid response with >50% reduction of transfusion needs. None of the participants had a cytogenetic response. There was no significant improvement in quality of life among responding patients as measured by the European Organization for the Research and Treatment of Cancer (EORTC) quality of life questionnaire. Based on these results, the combination of ATRA and tocopherol-alpha is not recommended for the treatment of del(5q) MDS.