RESUMO
Lysophosphatidic acid (LPA) is a natural bioactive lipid that acts through six different G protein-coupled receptors (LPA1-6) with pleiotropic activities on multiple cell types. We have previously demonstrated that LPA is necessary for successful in vitro osteoclastogenesis of bone marrow cells. Bone cells controlling bone remodeling (i.e. osteoblasts, osteoclasts, and osteocytes) express LPA1, but delineating the role of this receptor in bone remodeling is still pending. Despite Lpar1(-/-) mice displaying a low bone mass phenotype, we demonstrated that bone marrow cell-induced osteoclastogenesis was reduced in Lpar1(-/-) mice but not in Lpar2(-/-) and Lpar3(-/-) animals. Expression of LPA1 was up-regulated during osteoclastogenesis, and LPA1 antagonists (Ki16425, Debio0719, and VPC12249) inhibited osteoclast differentiation. Blocking LPA1 activity with Ki16425 inhibited expression of nuclear factor of activated T-cell cytoplasmic 1 (NFATc1) and dendritic cell-specific transmembrane protein and interfered with the fusion but not the proliferation of osteoclast precursors. Similar to wild type osteoclasts treated with Ki16425, mature Lpar1(-/-) osteoclasts had reduced podosome belt and sealing zone resulting in reduced mineralized matrix resorption. Additionally, LPA1 expression markedly increased in the bone of ovariectomized mice, which was blocked by bisphosphonate treatment. Conversely, systemic treatment with Debio0719 prevented ovariectomy-induced cancellous bone loss. Moreover, intravital multiphoton microscopy revealed that Debio0719 reduced the retention of CX3CR1-EGFP(+) osteoclast precursors in bone by increasing their mobility in the bone marrow cavity. Overall, our results demonstrate that LPA1 is essential for in vitro and in vivo osteoclast activities. Therefore, LPA1 emerges as a new target for the treatment of diseases associated with excess bone loss.
Assuntos
Reabsorção Óssea/patologia , Proteínas de Membrana/metabolismo , Fatores de Transcrição NFATC/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Osteoclastos/patologia , Receptores de Ácidos Lisofosfatídicos/fisiologia , Animais , Células da Medula Óssea/patologia , Reabsorção Óssea/tratamento farmacológico , Reabsorção Óssea/genética , Diferenciação Celular/efeitos dos fármacos , Movimento Celular , Feminino , Isoxazóis/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Ácidos Oleicos/farmacologia , Organofosfatos/farmacologia , Osteoclastos/efeitos dos fármacos , Osteoclastos/metabolismo , Propionatos/farmacologia , Receptores de Ácidos Lisofosfatídicos/antagonistas & inibidores , Receptores de Ácidos Lisofosfatídicos/genéticaRESUMO
Patients with relapsed or refractory acute myeloid leukemia (RR-AML) with mutations of FMS-like tyrosine kinase 3 (FLT3) have a poor prognosis even after allogeneic hematopoietic cell transplantation (allo-HCT). Multiple FLT3 inhibitors, including gilteritinib, have been developed and serve as treatment options for RR-AML. Here, we describe three cases of FLT3 mutated RR-AML that were successfully treated with gilteritinib administration before and after allo-HCT. Gilteritinib treatment before HCT was helpful in achieving remission. However, HCT often resulted in mild liver damage, and careful introduction of gilteritinib after HCT at a lower dose may be helpful for its safe usage. The three cases discussed had a successful clinical outcome in terms of disease control as well as the management of side effects associated with gilteritinib treatment.
RESUMO
We herein report a patient with a high bleeding tendency as a result of acquired factor V inhibitor and immune thrombocytopenia (ITP). The administration of prednisolone increased the platelet count, but a fatal bleeding event occurred before platelet levels had sufficiently increased. Factor V is stored in not only plasma but also platelets, and platelet-derived factor V might play a local hemostatic role. Bleeding tendency may be high in rare cases where factor V inhibitor is complicated with severe thrombocytopenia. In such patients, physicians should consider aggressive hemostatic therapy, including plasma exchange, in addition to immunosuppressive therapy.
Assuntos
Púrpura Trombocitopênica Idiopática , Trombocitopenia , Plaquetas , Fator V , Humanos , Contagem de Plaquetas , Púrpura Trombocitopênica Idiopática/complicações , Púrpura Trombocitopênica Idiopática/diagnóstico , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Trombocitopenia/induzido quimicamenteRESUMO
A previously healthy 49-year-old Japanese woman presented with cervical lymph node swelling and tenderness. Lymph node biopsy revealed reactive lymphadenitis without granulomas. No malignant cells were found, and no acid-fast positive bacilli were identified by Ziehl-Neelsen staining. She was treated unsuccessfully with various antibiotics, and it was very challenging to reach a diagnosis. 18F-Fluorodeoxyglucose (18F-FDG) uptake in bones was evaluated using positron emission tomography-computed tomography (PET-CT), and disseminated mycobacterial infection was suspected. The interferon-gamma (IFN-γ) release assays QuantiFERON (QFT) and T-SPOT were used to diagnose tuberculosis infection. On testing, a difference in mitogen response was found between these assays. The response was low for QFT but adequate for T-SPOT, suggesting the presence of anti-IFN-γ antibodies. This difference depended on whether the patient's plasma (including anti-IFN-γ antibodies) was used within the assay system. Mycobacterium abscessus was isolated from lymph node cultures, and plasma anti-IFN-γ antibodies were confirmed. The patient was diagnosed with disseminated M. abscessus infection with underlying adult-onset immunodeficiency caused by anti-IFN-γ antibodies. Granulomas are a pathological hallmark of mycobacterial infection, but may not fully form in immunodeficient patients. Clinicians should be aware of the possibility of mycobacterial infection without granuloma formation due to anti-IFN-γ antibodies.
Assuntos
Anticorpos/imunologia , Granuloma/diagnóstico , Granuloma/etiologia , Interferon gama/imunologia , Linfadenite/diagnóstico , Linfadenite/etiologia , Infecções por Mycobacterium não Tuberculosas/diagnóstico , Infecções por Mycobacterium não Tuberculosas/microbiologia , Anticorpos/sangue , Gerenciamento Clínico , Suscetibilidade a Doenças , Feminino , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons , Avaliação de SintomasRESUMO
Acquired coagulation factor inhibitor is a rare coagulation disorder. We herein report a patient with acquired factor V inhibitor showing a decrease in multiple coagulation factor activities. A high titer of factor V inhibitor presumably led to a marked inhibition of factor V activity in the specific factor-deficient plasma used in coagulation factor activity assays based on either an activated partial thromboplastin time (APTT) or prothrombin time (PT) clotting assay, resulting in false low values of the coagulation activity. We re-examined the coagulation factor activity using several dilutions of the patient's plasma and confirmed that the high factor V inhibitor titer had caused an apparent decrease in multiple coagulation factor activities.
Assuntos
Anti-Inflamatórios/uso terapêutico , Transtornos da Coagulação Sanguínea/tratamento farmacológico , Transtornos da Coagulação Sanguínea/imunologia , Inibidores dos Fatores de Coagulação Sanguínea/sangue , Fator V/antagonistas & inibidores , Prednisolona/uso terapêutico , Idoso , Povo Asiático , Transtornos da Coagulação Sanguínea/fisiopatologia , Testes de Coagulação Sanguínea , Feminino , Humanos , Tempo de Tromboplastina Parcial , Tempo de Protrombina , Resultado do TratamentoRESUMO
BACKGROUND: Acute compartment syndrome is an orthopedic emergency requiring urgent fasciotomy to prevent irreversible damage. In hematological malignancies, acute compartment syndrome caused by severe soft tissue bleeding is extremely rare. We present a patient with chronic-phase chronic myeloid leukemia who had acute compartment syndrome caused by severe soft tissue bleeding in her right forearm. CASE PRESENTATION: A 72-year-old Japanese woman was referred to our hospital with swelling and pain of her right forearm without a previous history of trauma. She was diagnosed with chronic-phase chronic myeloid leukemia. Extreme thrombocytosis was present, although no evidence of acquired von Willebrand disorder was found. Compartment syndrome caused by soft tissue bleeding was confirmed. An emergency fasciotomy for decompression was conducted. However, sustained postoperative bleeding occurred and required massive red cell concentrate transfusion. As her platelet count decreased by cytoreductive therapy, complete hemostasis was achieved. CONCLUSIONS: Patients with an extremely high platelet count might be at high risk for severe bleeding complications even without acquired von Willebrand disease. For the control of severe bleeding complications in patients with myeloproliferative disorder, the importance of thrombocyte reduction should be recognized.