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1.
Glob Health Med ; 5(6): 366-371, 2023 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-38162429

RESUMO

Immunocompromised coronavirus disease 2019 patients are at a higher risk of prolonged viral shedding than immunocompetent patients. However, as of August 2023, there is no clear international standard for de-isolating vulnerable patients. A comprehensive assessment is advisable based on various information, such as the increase in immune escape of specific mutant strains as well as the patient's innate immunity and vaccination status; therefore, consultation with an infectious disease specialist is recommended. The patient population defined as moderately or severely immunocompromised by the Centers for Disease Control and Prevention and the European Centre for Disease Prevention and Control is significantly broad. A boundary between the two remains to be delineated, and the existing protocols allow the release of patients based on their symptoms alone. This may lead to an unnecessary extension or premature termination of isolation. In this study, we searched for studies, particularly those that used real-world data, discussed the results with experts in our hospital, and proposed new isolation criteria based on both testing and clinical symptoms. We classified patients into three groups namely severely, moderately, and mildly immunocompromised, defined by their background and the administration of immunosuppressive drugs. A separate flowchart for ending isolation is indicated for each group. This standard may be a useful support material, especially for non-specialists. Nevertheless, our criteria must be revised and added continuously; accumulating real-world data to support revision of and addition to the list is becoming increasingly important.

2.
Intern Med ; 57(8): 1151-1154, 2018 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-29269668

RESUMO

Rituximab is a highly effective agent that is used in the treatment of B-cell lymphoma. Rituximab-induced acute thrombocytopenia is a rare side effect that has previously been reported in a small number of patients with malignant lymphoma; its mechanism is still unknown. We herein report the case of a 74-year old man who was diagnosed with follicular lymphoma and who developed severe acute thrombocytopenia the day after the administration of rituximab. Coagulation abnormality, which mimicked disseminated intravascular coagulation, also appeared. When physicians use rituximab to treat high-risk patients, the platelet count should be closely monitored to avoid possible adverse events.


Assuntos
Antineoplásicos/efeitos adversos , Rituximab/efeitos adversos , Trombocitopenia/induzido quimicamente , Idoso , Antineoplásicos/uso terapêutico , Humanos , Linfoma Folicular/tratamento farmacológico , Masculino , Contagem de Plaquetas , Rituximab/uso terapêutico , Trombocitopenia/diagnóstico
3.
FASEB J ; 31(6): 2625-2637, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28270519

RESUMO

Adhesive small bowel obstruction remains a common problem for surgeons. After surgery, platelet aggregation contributes to coagulation cascade and fibrin clot formation. With clotting, fibrin degradation is simultaneously enhanced, driven by tissue plasminogen activator-mediated cleavage of plasminogen to form plasmin. The aim of this study was to investigate the cellular events and proteolytic responses that surround plasminogen activator inhibitor (PAI-1; Serpine1) inhibition of postoperative adhesion. Peritoneal adhesion was induced by gauze deposition in the abdominal cavity in C57BL/6 mice and those that were deficient in fibrinolytic factors, such as Plat-/- and Serpine1-/- In addition, C57BL/6 mice were treated with the novel PAI-1 inhibitor, TM5275. Some animals were treated with clodronate to deplete macrophages. Epidermal growth factor (EGF) experiments were performed to understand the role of macrophages and how EGF contributes to adhesion. In the early phase of adhesive small bowel obstruction, increased PAI-1 activity was observed in the peritoneal cavity. Genetic and pharmacologic PAI-1 inhibition prevented progression of adhesion and increased circulating plasmin. Whereas Serpine1-/- mice showed intra-abdominal bleeding, mice that were treated with TM5275 did not. Mechanistically, PAI-1, in combination with tissue plasminogen activator, served as a chemoattractant for macrophages that, in turn, secreted EGF and up-regulated the receptor, HER1, on peritoneal mesothelial cells, which led to PAI-1 secretion, further fueling the vicious cycle of impaired fibrinolysis at the adhesive site. Controlled inhibition of PAI-1 not only enhanced activation of the fibrinolytic system, but also prevented recruitment of EGF-secreting macrophages. Pharmacologic PAI-1 inhibition ameliorated adhesion formation in a macrophage-dependent manner.-Honjo, K., Munakata, S., Tashiro, Y., Salama, Y., Shimazu, H., Eiamboonsert, S., Dhahri, D., Ichimura, A., Dan, T., Miyata, T., Takeda, K., Sakamoto, K., Hattori, K., Heissig, B. Plasminogen activator inhibitor-1 regulates macrophage-dependent postoperative adhesion by enhancing EGF-HER1 signaling in mice.


Assuntos
Receptores ErbB/metabolismo , Macrófagos/fisiologia , Piperazinas/uso terapêutico , Serpina E2/antagonistas & inibidores , Aderências Teciduais/patologia , para-Aminobenzoatos/uso terapêutico , Animais , Antígeno CD11b , Ensaios de Migração Celular , Movimento Celular/efeitos dos fármacos , Cetuximab/farmacologia , Fator de Crescimento Epidérmico , Receptores ErbB/genética , Regulação da Expressão Gênica/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Complicações Pós-Operatórias/prevenção & controle , Células RAW 264.7 , Serpina E2/genética , Serpina E2/metabolismo , Transdução de Sinais , Aderências Teciduais/metabolismo , Ativador de Plasminogênio Tecidual/genética , Ativador de Plasminogênio Tecidual/metabolismo
4.
Blood ; 128(8): 1063-75, 2016 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-27283026

RESUMO

Tissue plasminogen activator (tPA), aside from its vascular fibrinolytic action, exerts various effects within the body, ranging from synaptic plasticity to control of cell fate. Here, we observed that by activating plasminogen and matrix metalloproteinase-9, tPA expands murine bone marrow-derived CD45(-)TER119(-)Sca-1(+)PDGFRα(+) mesenchymal stromal cells (PαS-MSCs) in vivo through a crosstalk between PαS-MSCs and endothelial cells. Mechanistically, tPA induces the release of Kit ligand from PαS-MSCs, which activates c-Kit(+) endothelial cells to secrete MSC growth factors: platelet-derived growth factor-BB (PDGF-BB) and fibroblast growth factor 2 (FGF2). In synergy, FGF2 and PDGF-BB upregulate PDGFRα expression in PαS-MSCs, which ultimately leads to PαS-MSC expansion. These data show a novel mechanism by which the fibrinolytic system expands PαS-MSCs through a cytokine crosstalk between niche cells.


Assuntos
Células Endoteliais/metabolismo , Fibrinólise , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Animais , Ataxina-1/metabolismo , Medula Óssea/efeitos dos fármacos , Medula Óssea/metabolismo , Proliferação de Células , Técnicas de Cocultura , Células Endoteliais/efeitos dos fármacos , Fibrinólise/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Antígenos Comuns de Leucócito/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Células-Tronco Mesenquimais/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Plasminogênio/metabolismo , Proteínas Proto-Oncogênicas c-kit/metabolismo , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Fator de Células-Tronco/metabolismo , Ativador de Plasminogênio Tecidual/administração & dosagem , Ativador de Plasminogênio Tecidual/farmacologia , Regulação para Cima/efeitos dos fármacos
5.
Adv Drug Deliv Rev ; 99(Pt B): 172-179, 2016 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-26588878

RESUMO

The tumor microenvironment is recognized as a key factor in the multiple stages of cancer progression, mediating local resistance, immune-escape and metastasis. Cancer growth and progression require remodeling of the tumor stromal microenvironment, such as the development of tumor-associated blood vessels, recruitment of bone marrow-derived cells and cytokine processing. Extracellular matrix breakdown achieved by proteases like the fibrinolytic factor plasmin and matrix metalloproteases is necessary for cell migration crucial for cancer invasion and metastasis. Key components of the fibrinolytic system are expressed in cells of the tumor microenvironment. Plasmin can control growth factor bioavailability, or the regulation of other proteases leading to angiogenesis, and inflammation. In this review, we will focus on the role of the fibrinolytic system in the tumor microenvironment summarizing our current understanding of the role of the fibrinolytic factors for the modulation of the local chemokine/cytokine milieu, resulting in myeloid cell recruitment, which can promote neoangiogenesis.


Assuntos
Fibrinólise/efeitos dos fármacos , Fibrinolíticos/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Movimento Celular/efeitos dos fármacos , Progressão da Doença , Humanos , Células Mieloides/efeitos dos fármacos , Células Mieloides/patologia , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/patologia , Microambiente Tumoral/efeitos dos fármacos
6.
Cell Mol Life Sci ; 72(24): 4759-70, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26350342

RESUMO

Tissue regeneration during wound healing or cancer growth and progression depends on the establishment of a cellular microenvironment. Mesenchymal stem cells (MSC) are part of this cellular microenvironment, where they functionally modulate cell homing, angiogenesis, and immune modulation. MSC recruitment involves detachment of these cells from their niche, and finally MSC migration into their preferred niches; the wounded area, the tumor bed, and the BM, just to name a few. During this recruitment phase, focal proteolysis disrupts the extracellular matrix (ECM) architecture, breaks cell-matrix interactions with receptors, and integrins, and causes the release of bioactive fragments from ECM molecules. MSC produce a broad array of proteases, promoting remodeling of the surrounding ECM through proteolytic mechanisms. The fibrinolytic system, with its main player plasmin, plays a crucial role in cell migration, growth factor bioavailability, and the regulation of other protease systems during inflammation, tissue regeneration, and cancer. Key components of the fibrinolytic cascade, including the urokinase plasminogen activator receptor (uPAR) and plasminogen activator inhibitor-1 (PAI-1), are expressed in MSC. This review will introduce general functional properties of the fibrinolytic system, which go beyond its known function of fibrin clot dissolution (fibrinolysis). We will focus on the role of the fibrinolytic system for MSC biology, summarizing our current understanding of the role of the fibrinolytic system for MSC recruitment and the functional consequences for tissue regeneration and cancer. Aspects of MSC origin, maintenance, and the mechanisms by which these cells contribute to altered protease activity in the microenvironment under normal and pathological conditions will also be discussed.


Assuntos
Microambiente Celular , Células-Tronco Mesenquimais/fisiologia , Modelos Biológicos , Neoplasias/patologia , Regeneração , Cicatrização , Adesão Celular , Sobrevivência Celular , Progressão da Doença , Neoplasias/metabolismo , Inibidor 1 de Ativador de Plasminogênio/fisiologia , Receptores de Ativador de Plasminogênio Tipo Uroquinase/fisiologia , Microambiente Tumoral
7.
Gastroenterology ; 148(3): 565-578.e4, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25490065

RESUMO

BACKGROUND & AIMS: Activated proteases such as plasmin and matrix metalloproteinases (MMPs) are activated in intestinal tissues of patients with active inflammatory bowel diseases. We investigated the effect of plasmin on the progression of acute colitis. METHODS: Colitis was induced in Mmp9(-/-), Plg(-/-), and C57BL/6 (control) mice by the administration of dextran sulfate sodium, trinitrobenzene sulfonic acid, or CD40 antibody. Plasmin was inhibited in control mice by intraperitoneal injection of YO-2, which blocks its active site. Mucosal and blood samples were collected and analyzed by reverse-transcription polymerase chain reaction and immunohistochemical analyses, as well as for mucosal inflammation and levels of cytokines and chemokines. RESULTS: Circulating levels of plasmin were increased in mice with colitis, compared with controls. Colitis did not develop in control mice injected with YO-2 or in Plg(-/-) mice. Colons from these mice had reduced infiltration of Gr1+ neutrophils and F4/80+ macrophages, and reduced levels of inflammatory cytokines and chemokines. Colonic inflammation and colitis induction required activation of endogenous MMP9. After colitis induction, mice given YO-2, Plg(-/-) mice, and Mmp9(-/-) mice had reduced serum levels of tumor necrosis factor and C-X-C motif chemokine ligand 5, compared with control mice. CONCLUSIONS: In mice, plasmin induces a feedback mechanism in which activation of the fibrinolytic system promotes the development of colitis via activation of MMP9 or proteolytic enzymes. The proteolytic environment stimulates the influx of myeloid cells into the colonic epithelium and the production of tumor necrosis factor and C-X-C motif chemokine ligand 5. In turn, myeloid CD11b+ cells release the urokinase plasminogen activator, which accelerates plasmin production. Disruption of the plasmin-induced chronic inflammatory circuit therefore might be a strategy for colitis treatment.


Assuntos
Colite/metabolismo , Fibrinolisina/antagonistas & inibidores , Metaloproteinase 9 da Matriz/metabolismo , Células Mieloides/metabolismo , Animais , Antígenos CD40/antagonistas & inibidores , Quimiocina CXCL5/imunologia , Colite/induzido quimicamente , Colite/imunologia , Sulfato de Dextrana/toxicidade , Dipeptídeos/farmacologia , Modelos Animais de Doenças , Fibrinolisina/imunologia , Inflamação/imunologia , Interleucina-1beta/imunologia , Interleucina-6/imunologia , Mucosa Intestinal/imunologia , Macrófagos/imunologia , Metaloproteinase 9 da Matriz/imunologia , Camundongos , Camundongos Knockout , Células Mieloides/imunologia , Neutrófilos/imunologia , Ácido Trinitrobenzenossulfônico/toxicidade , Fator de Necrose Tumoral alfa/imunologia
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