RESUMO
PURPOSE OF REVIEW: Recent studies indicate that the risk of thrombosis in hematologic patients may be similar or even higher than that found in patients with solid tumors. However, available information about pathogenesis and incidence of thrombosis in acute leukemia is limited. This review focuses on mechanisms underlying thrombosis in acute leukemia and discusses recent literature data. RECENT FINDINGS: In the last few years, proofs have been provided that leukemic cells release free prothrombotic products, such as micro-vesicles, tissue factors, circulating free DNA and RNA. Furthermore, leukemic blasts can activate the procoagulant population of platelets, which initiate and amplify coagulation, causing thrombosis. In addition to factors produced by acute leukemia itself, others concur to trigger thrombosis. Some drugs, infections and insertion of central venous catheter have been described to increase risk of thrombosis in patients with acute leukemia. SUMMARY: Thrombosis represents a serious complication in patients affected by myeloid and lymphoid acute leukemia. A proper knowledge of its pathophysiology and of the predisposing risk factors may allow to implement strategies of prevention. Improving prevention of thrombosis appears a major goal in patients whose frequent conditions of thrombocytopenia impede an adequate delivery of anticoagulant therapy.
Assuntos
Leucemia Mieloide Aguda/sangue , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangue , Trombose/patologia , Adulto , Humanos , Leucemia Mieloide Aguda/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologiaRESUMO
Endocannabinoids (eCBs), among which N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG) are the most biologically active members, are polyunsaturated lipids able to bind cannabinoid, vanilloid and peroxisome proliferator-activated receptors. Depending on the target engaged, these bioactive mediators can regulate different signalling pathways, at both central and peripheral levels. The biological action of eCBs is tightly controlled by a plethora of metabolic enzymes which, together with the molecular targets of these substances, form the so-called "endocannabinoid system". The ability of eCBs to control manifold peripheral functions has received a great deal of attention, especially in the light of their widespread distribution in the body. In particular, eCBs are important regulators in blood, where they modulate haematopoiesis, platelet aggregation and apoptosis, as well as chemokine release and migration of immunocompetent cells. Here, we shall review the current knowledge on the pathophysiological roles of eCBs in blood. We shall also discuss the involvement of eCBs in those disorders affecting the haematological system, including cancer and inflammation. Knowledge gained to date underlines a fundamental role of the eCB system in blood, thus suggesting that it may represent a therapeutic promise for a broad range of diseases involving impaired hematopoietic cell functions.
Assuntos
Células Sanguíneas/fisiologia , Endocanabinoides/fisiologia , Doenças Hematológicas/fisiopatologia , Hematopoese/fisiologia , Modelos Biológicos , Transdução de Sinais/fisiologia , Células Sanguíneas/metabolismo , Endocanabinoides/química , Endocanabinoides/metabolismo , Humanos , Estrutura MolecularRESUMO
It has been reported that the incidence of thrombotic events can display a gender disparity. In particular, a lower thrombotic risk has been described in female gender. The mechanisms underlying this disparity are still poorly understood. Of great interest is the hypothesis that hormones, estrogen in particular, could play a key role. In fact, the possibility that some hormonal factors could protect women from thrombotic events appears well documented in literature. For instance, several studies aimed at the analysis of the impact of estrogen and estrogen receptors in thrombogenesis claim for the implication of these hormones either in megakaryocyte differentiation or, more intriguingly, directly affecting platelet integrity and function. In consideration of the absence of the nucleus, platelet susceptibility appears quite striking and probably due to the non-nuclear estrogen receptor function. In this review we briefly summarize our knowledge as concerns the role of estrogen and estrogen receptors in determining megakaryocyte/platelet functions and thrombogenicity.
Assuntos
Estrogênios/fisiologia , Receptores de Estrogênio/fisiologia , Trombose/epidemiologia , Trombose/etiologia , Coagulação Sanguínea/fisiologia , Plaquetas/fisiologia , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Feminino , Humanos , Masculino , Fatores de Risco , Fatores SexuaisRESUMO
SIGNIFICANCE: An imbalance between the production and the detoxification of reactive oxygen species and reactive nitrogen species (ROS/RNS) can be implicated in many pathological processes. Platelets are best known as primary mediators of hemostasis and can be either targets of ROS/RNS or generate radicals during cell activation. These conditions can dramatically affect platelet physiology, leading even, as an ultimate event, to the cell number modification. In this case, pathological conditions such as thrombocytosis (promoted by increased cell number) or thrombocytopenia and myelodysplasia (promoted by cell decrease mediated by accelerated apoptosis) can occur. RECENT ADVANCES: Usually, in peripheral blood, ROS/RNS production is balanced by the rate of oxidant elimination. Under this condition, platelets are in a nonadherent "resting" state. During endothelial dysfunction or under pathological conditions, ROS/RNS production increases and the platelets respond with specific biochemical and morphologic changes. Mitochondria are at the center of these processes, being able to both generate ROS/RNS, that drive redox-sensitive events, and respond to ROS/RNS-mediated changes of the cellular redox state. Irregular function of platelets and enhanced interaction with leukocytes and endothelial cells can contribute to pathogenesis of atherosclerotic and thrombotic events. CRITICAL ISSUES: The relationship between oxidative stress, platelet death, and the activation-dependent pathways that drive platelet pro-coagulant activity is unclear and deserves to be explored. FUTURE DIRECTIONS: Expanding knowledge about how platelets can mediate hemostasis and modulate inflammation may lead to novel and effective therapeutic strategies for the long and growing list of pathological conditions that involve both thrombosis and inflammation.
Assuntos
Plaquetas/metabolismo , Animais , Humanos , Oxirredução , Espécies Reativas de Nitrogênio/metabolismo , Espécies Reativas de Oxigênio/metabolismoRESUMO
Fibrosis may represent the final step induced by autoimmune mechanism(s). This may be due to the excess in fibroblast recruitment, activation and differentiation in myofibroblasts. These events may be triggered by cytokines, chemokines and growth factors released by lymphocytes or macrophages. Autophagy is an essential conserved homeostatic process that has long been appreciated for cell adaptation to nutrient deprivation. Autophagy is also recognized as an important component of both innate and acquired immunity to pathogens. Recently, dysregulation of autophagy in haematopoietic cells has been suggested to amplify the autoimmune responses. On the other hand, it is possible that defective autophagy in non-haematopoietic cells contributes to the progression to fibrosis. In fibroblasts some alterations in the metabolic pathways and pharmacological data suggest that a defective autophagy could contribute to excess in the production of extracellular matrix by altering the turnover of protein such as collagen. Our goal in this review is to describe the current knowledge on the role of autophagy in the development of fibrotic autoimmune diseases. Further studies could confirm whether agents modulating autophagy may be used in the treatment of these autoimmune diseases.
Assuntos
Doenças Autoimunes/patologia , Autofagia , Fibroblastos/patologia , Animais , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/fisiopatologia , Autofagia/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Fibrose , Sistema Hematopoético/efeitos dos fármacos , Sistema Hematopoético/fisiopatologia , Humanos , Terapia de Alvo Molecular , Escleroderma Sistêmico/tratamento farmacológico , Escleroderma Sistêmico/patologiaRESUMO
Trans-plasma membrane electron transport (t-PMET) has been established since the 1960s, but it has only been subject to more intensive research in the last decade. The discovery and characterization at the molecular level of its novel components has increased our understanding of how t-PMET regulates distinct cellular functions. This review will give an update on t-PMET, with particular emphasis on how its malfunction relates to some diseases, such as cancer, abnormal cell death, cardiovascular diseases, aging, obesity, neurodegenerative diseases, pulmonary fibrosis, asthma, and genetically linked pathologies. Understanding these relationships may provide novel therapeutic approaches for pathologies associated with unbalanced redox state.
Assuntos
Membrana Celular/metabolismo , Transporte de Elétrons/fisiologia , Envelhecimento/metabolismo , Animais , Apoptose , Asma/metabolismo , Autofagia , Doenças Cardiovasculares/metabolismo , Redutases do Citocromo/metabolismo , Citocromos b/metabolismo , Fertilização , Homeostase , Humanos , Mamíferos , Doenças Metabólicas/metabolismo , NADH NADPH Oxirredutases/metabolismo , Neoplasias/metabolismo , Doenças Neurodegenerativas/metabolismo , Fibrose Pulmonar/metabolismo , Espermatogênese , Canais de Ânion Dependentes de Voltagem/metabolismoRESUMO
We have explored MICA/B expression and its relationship with innate inflammatory infiltrate in renal cell carcinoma (RCC). The expression of MICA/B, CD16, CD56, and CD68 in 140 RCC lesions contained in a tissue microarray (TMA) was investigated by immunohistochemistry. MICA/B gene and protein expressions in Caki-1 cells were analyzed by reverse transcription-polymerase chain reaction and flow cytometry, respectively. Natural killer (NK) cells were studied by flow cytometry. All the RCC lesions (n = 140) were MICA/B-positive. MICA/B was mainly expressed in the cytoplasm of tumor cells, whereas stromal cells were negative. Renal cell carcinoma lesions showed low NK cell infiltration, although they were rich in CD16(+)CD56(-) cells, strongly resembling macrophages. CD16(+) macrophage infiltration was more frequently detectable in metastatic lesions compared with primary tumors (P = .0223) and was associated with poor RCC differentiation (P = .007). To investigate mechanisms potentially underlying the lack of NK cells infiltration into MICA/B-positive RCC lesions, we used Caki-1 RCC cells. Caki-1 expressed MICA and MICB genes. However, MICA protein was not detectable in Caki-1 cells, whereas MICB protein was detectable in their cytoplasm and on the cell membrane. Coculture of peripheral blood mononuclear cells with Caki-1, K562, HCT116, respectively, resulted in CD56(+)CD16(+) NK cells deletion without affecting CD56(+)/CD16(-) NK subset and immature NK cells generated in vitro from CD34(+) cells. Natural killer cell apoptosis seemed to be preferentially triggered by cancer cells because HLA-A0201(+) NK cells were only marginally affected by allogeneic HLA-A0201(-) peripheral blood mononuclear cells. Caki-1 cell-mediated NK cell apoptosis was reduced by an anti-beta(2)-integrin (CD18) monoclonal antibody but was NKG2D-, granule exocytosis-, and caspase-independent.
Assuntos
Antígenos CD18/metabolismo , Carcinoma de Células Renais/imunologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Neoplasias Renais/imunologia , Células Matadoras Naturais/imunologia , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Apoptose/imunologia , Antígeno CD56/metabolismo , Carcinoma de Células Renais/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Citometria de Fluxo , Proteínas Ligadas por GPI , Humanos , Imuno-Histoquímica , Neoplasias Renais/metabolismo , Células Matadoras Naturais/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Receptores de IgG/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Análise Serial de TecidosRESUMO
BACKGROUND: Consensus guidelines for diagnosis and treatment of acute childhood idiopathic thrombocytopenic purpura (ITP) were published in 2000 by the Italian Association of Pediatric Haematology and Oncology (AIEOP). The assessment of guideline implementation was the primary objective of the present study. PATIENTS AND METHODS: Information on each newly diagnosed case of ITP referring to centres conforming with the guidelines was obtained by a questionnaire. RESULTS: Data concerning 609 new cases of acute childhood ITP were collected including 346 (56.8%) asymptomatic-paucisymptomatic forms (type A), 262 (43%) intermediate clinical forms (type B), and 1 (0.2%) severe form (type C). At diagnosis, 82% of cases were hospitalized. Age, platelet count and duration of hospitalization were significantly different in type A and type B cases. Of the total number of cases, 25% were kept under observation, 38.6% received intravenous immunoglobulins, 23.9% oral or parenteral steroids, and 12.7% other treatments. The initial treatment turned out to be appropriate for 428 cases (72.2%), of uncertain appropriateness in 71 (11.9%), and inappropriate in 95 cases (15.9%). The total level of implementation was 84.1%. CONCLUSIONS: A high rate of guideline implementation was observed during the study period. The guidelines should be reviewed taking into account more recent evidence.
Assuntos
Púrpura Trombocitopênica Idiopática/terapia , Doença Aguda , Adolescente , Corticosteroides/uso terapêutico , Criança , Pré-Escolar , Feminino , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Lactente , Tempo de Internação , Masculino , Contagem de Plaquetas , Estudos Prospectivos , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Inquéritos e QuestionáriosRESUMO
Anaplastic large cell lymphoma (ALCL) is characterized by preferential paracortical and intrasinusoidal lymph node involvement by large anaplastic tumor cells expressing the CD30 antigen. Up to 80% of pediatric patients with ALCL can be cured with multi-agent chemotherapeutic regimens. Patients resistant to chemotherapy or suffering from early relapse have a poor prognosis and a poor chance of survival. In these cases, the highly aggressive clinical course of ALCL, associated with systemic symptoms and extranodal involvement, has been treated with different approaches in various cooperative trials, including conventional chemotherapy and human stem cell transplantation (HSCT). However, the optimal treatment has not yet been defined, in particular in cases of relapse. More recently, radioimmunotherapy has been studied with encouraging results in cancer patients, including non-Hodgkin's lymphoma. Here we describe the case of a pediatric ALCL, relapsing after HSCT, treated with pretargeted antibody-guided radioimmunotherapy, obtaining a complete remission, with excellent quality of life over the past 10 months.
Assuntos
Anticorpos Antineoplásicos/uso terapêutico , Linfoma Anaplásico de Células Grandes/diagnóstico por imagem , Radioimunoterapia/métodos , Criança , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Neoplasias Pulmonares/secundário , Cintilografia , Terapia de Salvação/métodosAssuntos
Linhagem da Célula/imunologia , Células Matadoras Naturais/citologia , Linfócitos do Interstício Tumoral/citologia , Receptores de IgG/metabolismo , Humanos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Receptores de IgG/imunologiaRESUMO
The clinical course of B-cell chronic lymphocytic leukemia (B-CLL) is variable, and novel biologic parameters need to be added to the clinical staging systems to predict an indolent or aggressive outcome. We investigated the 70-kDa zeta-associated protein (ZAP-70), CD38, soluble CD23 (sCD23), and cytogenetics in 289 patients with B-CLL. Both a shorter progression-free survival (PFS) and overall survival (OS) were observed in ZAP-70(+) (P < .001), in CD38(+) (P < .001) and in sCD23(+) patients (P < .001 and P = .013, respectively). ZAP-70(+)CD38(+) or ZAP-70(+) patients with an unmutated IgV(H) status showed both a shorter PFS (P < .001) and OS (P < .001 and P < .001, respectively) as compared with ZAP-70(-)/CD38(-) or ZAP-70(-) patients with mutated IgV(H) genes. Discordant patients showed an intermediate outcome. Note, ZAP-70(+) patients even if CD38(-) or mutated showed a shorter PFS, whereas ZAP-70(-) patients even if CD38(+) or unmutated had a longer PFS. Furthermore, ZAP-70 positivity was associated with a shorter PFS both within normal karyotype (P < .001) and within the poor-risk cytogenetic subset (P = .02). The predictive value of ZAP-70 expression was confirmed in multivariate analysis. Thus, ZAP-70 protein determined by flow cytometry improves the prognostic significance of cytogenetics and appears to be a better predictor of outcomes than IgV(H) gene mutational status. On this line, we recommend and are also interested in conducting a prospective randomized trial of early intervention versus observation for ZAP-70(+) patients.
Assuntos
Regulação Leucêmica da Expressão Gênica , Leucemia Linfocítica Crônica de Células B/diagnóstico , Proteína-Tirosina Quinase ZAP-70/análise , ADP-Ribosil Ciclase 1/análise , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise Citogenética , Feminino , Citometria de Fluxo , Humanos , Região Variável de Imunoglobulina/genética , Leucemia Linfocítica Crônica de Células B/genética , Masculino , Pessoa de Meia-Idade , Mutação , Valor Preditivo dos Testes , Prognóstico , Receptores de IgE/análise , Proteína-Tirosina Quinase ZAP-70/genéticaAssuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical , Síndromes Mielodisplásicas/terapia , Adolescente , Criança , Pré-Escolar , Transplante de Células-Tronco de Sangue do Cordão Umbilical/efeitos adversos , Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Antígenos HLA/imunologia , Histocompatibilidade , Humanos , Fatores de Risco , Transplante HomólogoRESUMO
Concurrent resistance mechanisms, such as P-glycoprotein (PGP) and bcl-2, may contribute to a worse outcome in adult acute lymphoblastic leukaemia (ALL). Between 1990 and 2000, we analysed PGP and bcl-2 by flow cytometry, using two anti-PGP (C219 and JSB-1) monoclonal antibodies (mAbs) and an anti-bcl-2 mAb in 115 de novo adult ALL patients. Both a longer overall survival (OS) and longer disease-free survival (DFS) were observed in PGP-negative patients (23%vs 0% at 3 years, P = 0.011 and 29%vs 0% at 2 years, P = 0.006 for C219 respectively; 42%vs 0% at 1.5 years, P = 0.004 and 53%vs 0% at 8.5 months, P = 0.00006 for JSB-1 respectively). Bcl-2 positivity was associated with a significantly higher complete remission rate (90%vs 66%, P = 0.01). Moreover, in 69 patients not presenting with either t(9;22) or B-mature immunophenotype, PGP negativity (JSB-1) maintained its significant favourable prognostic impact with regard to OS (41%vs 0% at 1.5 years, P = 0.009) and DFS (83%vs 0% at 6 months, P = 0.0005). Importantly, within a subset of 62 patients with normal (n = 31) or unknown (n = 31) karyotype, PGP (JSB-1)-negative patients showed both a significantly longer OS and DFS (63%vs 0% at 1.4 years, P = 0.018 and 84%vs 0% at 6 months, P = 0.001 respectively). In multivariate analysis, JSB-1 (P = 0.008) and cytogenetics (P = 0.02) were found to be independent prognostic factors with regard to DFS. Therefore, in adult ALL, PGP and bcl-2 represent sensitive indicators of clinical outcome, and potential targets of novel molecules aimed at overcoming chemoresistance and recurrent relapses.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Adolescente , Adulto , Idoso , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , PrognósticoRESUMO
The endocannabinoid 2-arachidonoylglycerol (2-AG) has been shown to activate human platelets in platelet-rich plasma, by binding to a "platelet-type" cannabinoid receptor (CB(PT)). Here, washed human platelets were used to characterize the binding of [(3)H]2-AG to CB(PT), showing a dissociation constant (Kd) of 140 +/- 31 nM and a maximum binding (Bmax) of 122 +/- 10 pmol.mg protein(-1). Selective antagonists of both CB1 and CB2 cannabinoid receptors inhibited this binding, which was enhanced up to approximately 230% over the controls by 1 micro M serotonin (5-hydroxytryptamine, 5-HT). Human platelets were also able to bind [(3)H]5-HT (Kd = 79 +/- 17 nM, Bmax = 14.6 +/- 1.3 pmol.mg protein(-1)), and 1 micro M 2-AG enhanced this binding up to approximately 150%. Moreover, they were able to take up [(3)H]5-HT through a high affinity transporter (Michaelis-Menten constant = 22 +/- 2 nM, maximum velocity = 344 +/- 15 pmol.min(-1).mg protein(-1)), which was not affected by 2-AG. Interestingly, 5-HT did not affect the activity of the 2-AG transporter of human platelets. Treatment of washed platelets with 1 micro M 2-AG led to increased intracellular inositol-1,4,5-trisphosphate (up to approximately 300%) and decreased cyclic AMP (down to approximately 50%). Furthermore, treatment of pre-loaded platelets with 1 micro M 2-AG induced a approximately 300% increase in [(3)H]2-AG release, according to a CBPT-dependent mechanism. Also, 1 micro M 5-HT enhanced the effect of 2-AG on inositol-1,4,5-trisphosphate ( approximately 500% of the controls), cyclic AMP ( approximately 20%) and [(3)H]2-AG release ( approximately 570%), and the latter process was shown to be partly ( approximately 50%) involved in the 5-HT-dependent platelet activation. Taken together, reported findings represent the first demonstration that 2-AG and 5-HT can mutually reinforce their receptor binding on platelet surface, which might have therapeutic implications.
Assuntos
Ácidos Araquidônicos , Glicerídeos/farmacologia , Proteínas de Membrana Transportadoras , Proteínas do Tecido Nervoso , Ativação Plaquetária/efeitos dos fármacos , Serotonina/farmacologia , Adulto , Plaquetas/metabolismo , Moduladores de Receptores de Canabinoides , Proteínas de Transporte/metabolismo , AMP Cíclico/biossíntese , Sinergismo Farmacológico , Endocanabinoides , Ácidos Graxos Insaturados/fisiologia , Humanos , Inositol 1,4,5-Trifosfato/biossíntese , Cinética , Masculino , Glicoproteínas de Membrana/metabolismo , Receptores de Canabinoides , Receptores de Droga/efeitos dos fármacos , Receptores de Droga/fisiologia , Sistemas do Segundo Mensageiro/efeitos dos fármacos , Proteínas da Membrana Plasmática de Transporte de SerotoninaRESUMO
Autosomal-recessive osteopetrosis is a severe genetic disease caused by osteoclast failure. Approximately 50% of the patients harbor mutations of the ATP6i gene, encoding for the osteoclast-specific a3 subunit of V-ATPase. We found inactivating ATP6i mutations in four patients, and three of these were novel. Patients shared macrocephaly, growth retardation and optic nerve alteration, osteosclerotic and endobone patterns, and high alkaline phosphatase and parathyroid hormone levels. Bone biopsies revealed primary spongiosa lined with active osteoblasts and high numbers of tartrate-resistant acid phosphatase (TRAP)-positive, a3 subunit-negative, morphologically unremarkable osteoclasts, some of which located in shallow Howship lacunae. Scarce hematopoietic cells and abundant fibrous tissue containing TRAP-positive putative osteoclast precursors were noted. In vitro osteoclasts were a3-negative, morphologically normal, with prominent clear zones and actin rings, and TRAP activity more elevated than in control patients. Podosomes, alphaVbeta3 receptor, c-Src, and PYK2 were unremarkable. Consistent with the finding in the bone biopsies, these cells excavated pits faintly stained with toluidine blue, indicating inefficient bone resorption. Bone marrow transplantation was successful in all patients, and posttransplant osteoclasts showed rescue of a3 subunit immunoreactivity.