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1.
Hum Mol Genet ; 30(17): 1607-1617, 2021 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-34075397

RESUMO

Neurofibromatosis Type II (NF2) is an autosomal dominant cancer predisposition syndrome in which germline haploinsufficiency at the NF2 gene confers a greatly increased propensity for tumor development arising from tissues of neural crest derived origin. NF2 encodes the tumor suppressor, Merlin, and its biochemical function is incompletely understood. One well-established function of Merlin is as a negative regulator of group A serine/threonine p21-activated kinases (PAKs). In these studies we explore the role of PAK1 and its closely related paralog, PAK2, both pharmacologically and genetically, in Merlin-deficient Schwann cells and in a genetically engineered mouse model (GEMM) that develops spontaneous vestibular and spinal schwannomas. We demonstrate that PAK1 and PAK2 are both hyper activated in Merlin-deficient murine schwannomas. In preclinical trials, a pan Group A PAK inhibitor, FRAX-1036, transiently reduced PAK1 and PAK2 phosphorylation in vitro, but had insignificant efficacy in vivo. NVS-PAK1-1, a PAK1 selective inhibitor, had a greater but still minimal effect on our GEMM phenotype. However, genetic ablation of Pak1 but not Pak2 reduced tumor formation in our NF2 GEMM. Moreover, germline genetic deletion of Pak1 was well tolerated, while conditional deletion of Pak2 in Schwann cells resulted in significant morbidity and mortality. These data support the further development of PAK1-specific small molecule inhibitors and the therapeutic targeting of PAK1 in vestibular schwannomas and argue against PAK1 and PAK2 existing as functionally redundant protein isoforms in Schwann cells.


Assuntos
Neurofibromatose 2/genética , Quinases Ativadas por p21/metabolismo , Animais , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Genes Supressores de Tumor/efeitos dos fármacos , Indóis , Longevidade , Camundongos , Neurilemoma/genética , Neurofibromatose 2/metabolismo , Neurofibromina 2/genética , Fosforilação , Piperidinas , Pirimidinas , Células de Schwann/metabolismo , Quinases Ativadas por p21/genética
2.
Circ Res ; 124(5): 696-711, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30620686

RESUMO

RATIONALE: Secreted and membrane-bound proteins, which account for 1/3 of all proteins, play critical roles in heart health and disease. The endoplasmic reticulum (ER) is the site for synthesis, folding, and quality control of these proteins. Loss of ER homeostasis and function underlies the pathogenesis of many forms of heart disease. OBJECTIVE: To investigate mechanisms responsible for regulating cardiac ER function, and to explore therapeutic potentials of strengthening ER function to treat heart disease. METHODS AND RESULTS: Screening a range of signaling molecules led to the discovery that Pak (p21-activated kinase)2 is a stress-responsive kinase localized in close proximity to the ER membrane in cardiomyocytes. We found that Pak2 cardiac deleted mice (Pak2-CKO) under tunicamycin stress or pressure overload manifested a defective ER response, cardiac dysfunction, and profound cell death. Small chemical chaperone tauroursodeoxycholic acid treatment of Pak2-CKO mice substantiated that Pak2 loss-induced cardiac damage is an ER-dependent pathology. Gene array analysis prompted a detailed mechanistic study, which revealed that Pak2 regulation of protective ER function was via the IRE (inositol-requiring enzyme)-1/XBP (X-box-binding protein)-1-dependent pathway. We further discovered that this regulation was conferred by Pak2 inhibition of PP2A (protein phosphatase 2A) activity. Moreover, IRE-1 activator, Quercetin, and adeno-associated virus serotype-9-delivered XBP-1s were able to relieve ER dysfunction in Pak2-CKO hearts. This provides functional evidence, which supports the mechanism underlying Pak2 regulation of IRE-1/XBP-1s signaling. Therapeutically, inducing Pak2 activation by genetic overexpression or adeno-associated virus serotype-9-based gene delivery was capable of strengthening ER function, improving cardiac performance, and diminishing apoptosis, thus protecting the heart from failure. CONCLUSIONS: Our findings uncover a new cardioprotective mechanism, which promotes a protective ER stress response via the modulation of Pak2. This novel therapeutic strategy may present as a promising option for treating cardiac disease and heart failure.


Assuntos
Estresse do Retículo Endoplasmático , Insuficiência Cardíaca/enzimologia , Miócitos Cardíacos/enzimologia , Quinases Ativadas por p21/metabolismo , Animais , Apoptose , Linhagem Celular , Modelos Animais de Doenças , Terapia Genética , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/terapia , Células-Tronco Pluripotentes Induzidas/enzimologia , Macaca mulatta , Masculino , Proteínas de Membrana/metabolismo , Camundongos Knockout , Miócitos Cardíacos/patologia , Proteína Fosfatase 2/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Transdução de Sinais , Proteína 1 de Ligação a X-Box/metabolismo , Quinases Ativadas por p21/deficiência , Quinases Ativadas por p21/genética
3.
J Theor Biol ; 496: 110229, 2020 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-32259543

RESUMO

In this paper, we develop a mathematical model for the early stage of atherosclerosis, as a chronic inflammatory disease. It includes also processes that are relevant for the "thickening" of the vessel walls, and prepares a more complete model including also the later stages of atherosclerosis. The model consists of partial differential equations: Navier-Stokes equations modeling blood flow, Biot equations modeling the fluid flow inside the poroelastic vessel wall, and convection/chemotaxis-reaction-diffusion equations modeling transport, signaling and interaction processes initiating inflammation and atherosclerosis. The main innovations of this model are: a) quantifying the endothelial permeability to low-density-lipoproteins (LDL) and to the monocytes as a function of WSS, cytokines and LDL on the endothelial surface; b) transport of monocytes on the endothelial surface, mimicking the monocytes adhesion and rolling; c) the monocytes influx in the lumen, as a function of factor increasing monocytopoiesis; d) coupling between Navier-Stokes system, Biot system and convection/chemotaxis-reaction-diffusion equations. Numerical simulations of a simplified model were performed in an idealized two-dimensional geometry in order to investigate the dynamics of endothelial permeability, and the growth and spread of immune cells populations and their dependence in particular on low-density-lipoprotein and wall-shear stress.


Assuntos
Aterosclerose , Modelos Cardiovasculares , Humanos , Lipoproteínas LDL , Permeabilidade , Estresse Mecânico
4.
Eur Heart J ; 40(31): 2566-2584, 2019 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-31112213

RESUMO

This consensus document is the second of two reports summarizing the views of an expert panel organized by the European Association of Percutaneous Cardiovascular Interventions (EAPCI) on the clinical use of intracoronary imaging including intravascular ultrasound (IVUS), optical coherence tomography (OCT), and near infrared spectroscopy (NIRS)-IVUS. Beyond guidance of stent selection and optimization of deployment, invasive imaging facilitates angiographic interpretation and may guide treatment in acute coronary syndrome. Intravascular imaging can provide additional important diagnostic information when confronted with angiographically ambiguous lesions and allows assessment of plaque morphology enabling identification of vulnerability characteristics. This second document focuses on useful imaging features to identify culprit and vulnerable coronary plaque, which offers the interventional cardiologist guidance on when to adopt an intracoronary imaging-guided approach to the treatment of coronary artery disease and provides an appraisal of intravascular imaging-derived metrics to define the haemodynamic significance of coronary lesions.


Assuntos
Síndrome Coronariana Aguda/diagnóstico por imagem , Angiografia Coronária/tendências , Doença da Artéria Coronariana/terapia , Intervenção Coronária Percutânea/efeitos adversos , Síndrome Coronariana Aguda/terapia , Adulto , Idoso , Estudos de Casos e Controles , Ensaios Clínicos como Assunto , Consenso , Angiografia Coronária/métodos , Doença da Artéria Coronariana/patologia , Tomada de Decisões , União Europeia/organização & administração , Feminino , Hemodinâmica/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Intervenção Coronária Percutânea/métodos , Placa Aterosclerótica/patologia , Valor Preditivo dos Testes , Ruptura/diagnóstico por imagem , Espectroscopia de Luz Próxima ao Infravermelho/métodos , Stents , Tomografia de Coerência Óptica/métodos , Ultrassonografia de Intervenção/métodos
5.
Eur Heart J ; 39(35): 3281-3300, 2018 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-29790954

RESUMO

This Consensus Document is the first of two reports summarizing the views of an expert panel organized by the European Association of Percutaneous Cardiovascular Interventions (EAPCI) on the clinical use of intracoronary imaging including intravascular ultrasound (IVUS) and optical coherence tomography (OCT). The first document appraises the role of intracoronary imaging to guide percutaneous coronary interventions (PCIs) in clinical practice. Current evidence regarding the impact of intracoronary imaging guidance on cardiovascular outcomes is summarized, and patients or lesions most likely to derive clinical benefit from an imaging-guided intervention are identified. The relevance of the use of IVUS or OCT prior to PCI for optimizing stent sizing (stent length and diameter) and planning the procedural strategy is discussed. Regarding post-implantation imaging, the consensus group recommends key parameters that characterize an optimal PCI result and provides cut-offs to guide corrective measures and optimize the stenting result. Moreover, routine performance of intracoronary imaging in patients with stent failure (restenosis or stent thrombosis) is recommended. Finally, strengths and limitations of IVUS and OCT for guiding PCI and assessing stent failures and areas that warrant further research are critically discussed.


Assuntos
Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/cirurgia , Intervenção Coronária Percutânea , Tomografia de Coerência Óptica , Ultrassonografia de Intervenção , Angiografia Coronária , Oclusão de Enxerto Vascular , Humanos , Intervenção Coronária Percutânea/efeitos adversos , Complicações Pós-Operatórias , Falha de Prótese , Stents/efeitos adversos , Resultado do Tratamento
6.
Blood ; 127(16): 1967-75, 2016 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-26932803

RESUMO

Cytoskeletal remodeling of hematopoietic stem and progenitor cells (HSPCs) is essential for homing to the bone marrow (BM). The Ras-related C3 botulinum toxin substrate (Rac)/cell division control protein 42 homolog (CDC42) effector p21-activated kinase (Pak2) has been implicated in HSPC homing and engraftment. However, the molecular pathways mediating Pak2 functions in HSPCs are unknown. Here, we demonstrate that both Pak2 kinase activity and its interaction with the PAK-interacting exchange factor-ß (ß-Pix) are required to reconstitute defective ITALIC! Pak2 (ITALIC! Δ/Δ)HSPC homing to the BM. Pak2 serine/threonine kinase activity is required for stromal-derived factor-1 (SDF1α) chemokine-induced HSPC directional migration, whereas Pak2 interaction with ß-Pix is required to regulate the velocity of HSPC migration and precise F-actin assembly. Lack of SDF1α-induced filopodia and associated abnormal cell protrusions seen in ITALIC! Pak2 (ITALIC! Δ/Δ)HSPCs were rescued by wild-type (WT) Pak2 but not by a Pak2-kinase dead mutant (KD). Expression of a ß-Pix interaction-defective mutant of Pak2 rescued filopodia formation but led to abnormal F-actin bundles. Although CDC42 has previously been considered an upstream regulator of Pak2, we found a paradoxical decrease in baseline activation of CDC42 in ITALIC! Pak2 (ITALIC! Δ/Δ)HSPCs, which was rescued by expression of Pak2-WT but not by Pak2-KD; defective homing of ITALIC! Pak2-deleted HSPCs was rescued by constitutive active CDC42. These data demonstrate that both Pak2 kinase activity and its interaction with ß-Pix are essential for HSPC filopodia formation, cytoskeletal integrity, and homing via activation of CDC42. Taken together, we provide mechanistic insights into the role of Pak2 in HSPC migration and homing.


Assuntos
Células-Tronco Hematopoéticas/fisiologia , Fatores de Troca de Nucleotídeo Guanina Rho/metabolismo , Proteína cdc42 de Ligação ao GTP/metabolismo , Quinases Ativadas por p21/fisiologia , Animais , Comunicação Celular , Movimento Celular/genética , Células Cultivadas , Citoesqueleto/metabolismo , Células-Tronco Hematopoéticas/citologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Nicho de Células-Tronco/genética , Quinases Ativadas por p21/genética , Quinases Ativadas por p21/metabolismo
7.
Circulation ; 133(7): 650-60, 2016 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-26762519

RESUMO

BACKGROUND: The pathomechanisms underlying very late stent thrombosis (VLST) after implantation of drug-eluting stents (DES) are incompletely understood. Using optical coherence tomography, we investigated potential causes of this adverse event. METHODS AND RESULTS: Between August 2010 and December 2014, 64 patients were investigated at the time point of VLST as part of an international optical coherence tomography registry. Optical coherence tomography pullbacks were performed after restoration of flow and analyzed at 0.4 mm. A total of 38 early- and 20 newer-generation drug-eluting stents were suitable for analysis. VLST occurred at a median of 4.7 years (interquartile range, 3.1-7.5 years). An underlying putative cause by optical coherence tomography was identified in 98% of cases. The most frequent findings were strut malapposition (34.5%), neoatherosclerosis (27.6%), uncovered struts (12.1%), and stent underexpansion (6.9%). Uncovered and malapposed struts were more frequent in thrombosed compared with nonthrombosed regions (ratio of percentages, 8.26; 95% confidence interval, 6.82-10.04; P<0.001 and 13.03; 95% confidence interval, 10.13-16.93; P<0.001, respectively). The maximal length of malapposed or uncovered struts (3.40 mm; 95% confidence interval, 2.55-4.25; versus 1.29 mm; 95% confidence interval, 0.81-1.77; P<0.001), but not the maximal or average axial malapposition distance, was greater in thrombosed compared with nonthrombosed segments. The associations of both uncovered and malapposed struts with thrombus were consistent among early- and newer-generation drug-eluting stents. CONCLUSIONS: The leading associated findings in VLST patients in descending order were malapposition, neoatherosclerosis, uncovered struts, and stent underexpansion without differences between patients treated with early- and new-generation drug-eluting stents. The longitudinal extension of malapposed and uncovered stent was the most important correlate of thrombus formation in VLST.


Assuntos
Vasos Coronários/patologia , Stents Farmacológicos/efeitos adversos , Stents Farmacológicos/tendências , Trombose/diagnóstico , Trombose/etiologia , Tomografia de Coerência Óptica/métodos , Idoso , Vasos Coronários/cirurgia , Estudos Transversais , Stents Farmacológicos/normas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Falha de Prótese , Fatores de Tempo
8.
Blood ; 125(19): 2995-3005, 2015 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-25824689

RESUMO

Megakaryocyte maturation and polyploidization are critical for platelet production; abnormalities in these processes are associated with myeloproliferative disorders, including thrombocytopenia. Megakaryocyte maturation signals through cascades that involve p21-activated kinase (Pak) function; however, the specific role for Pak kinases in megakaryocyte biology remains elusive. Here, we identify Pak2 as an essential effector of megakaryocyte maturation, polyploidization, and proplatelet formation. Genetic deletion of Pak2 in murine bone marrow is associated with macrothrombocytopenia, altered megakaryocyte ultrastructure, increased bone marrow megakaryocyte precursors, and an elevation of mature CD41(+) megakaryocytes, as well as an increased number of polyploid cells. In Pak2(-/-) mice, platelet clearance rate was increased, as was production of newly synthesized, reticulated platelets. In vitro, Pak2(-/-) megakaryocytes demonstrate increased polyploidization associated with alterations in ß1-tubulin expression and organization, decreased proplatelet extensions, and reduced phosphorylation of the endomitosis regulators LIM domain kinase 1, cofilin, and Aurora A/B/C. Together, these data establish a novel role for Pak2 as an important regulator of megakaryopoiesis, polyploidization, and cytoskeletal dynamics in developing megakaryocytes.


Assuntos
Plaquetas/metabolismo , Citoesqueleto/patologia , Megacariócitos/metabolismo , Mitose/genética , Fator de Transcrição PAX2/fisiologia , Trombocitopenia/genética , Trombopoese/fisiologia , Animais , Plaquetas/patologia , Medula Óssea/metabolismo , Medula Óssea/patologia , Citoesqueleto/metabolismo , Megacariócitos/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos SCID , Microscopia de Fluorescência , Poliploidia , Células-Tronco/metabolismo , Células-Tronco/patologia , Trombocitopenia/patologia
9.
Catheter Cardiovasc Interv ; 89(4): 679-689, 2017 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-28109054

RESUMO

By providing valuable information about the coronary artery wall and lumen, intravascular imaging may aid in optimizing interventional procedure results and thereby could improve clinical outcomes following percutaneous coronary intervention (PCI). Intravascular optical coherence tomography (OCT) is a light-based technology with a tissue penetration of approximately 1 to 3 mm and provides near histological resolution. It has emerged as a technological breakthrough in intravascular imaging with multiple clinical and research applications. OCT provides detailed visualization of the vessel following PCI and provides accurate assessment of post-procedural stent performance including detection of edge dissection, stent struts apposition, tissue prolapse, and healing parameters. Additionally, it can provide accurate characterization of plaque morphology and provides key information to optimize post-procedural outcomes. This manuscript aims to review the current clinical and research applications of intracoronary OCT and summarize the analytic OCT imaging software packages currently available. © 2017 Wiley Periodicals, Inc.


Assuntos
Doença da Artéria Coronariana/diagnóstico , Vasos Coronários/diagnóstico por imagem , Intervenção Coronária Percutânea/métodos , Placa Aterosclerótica/diagnóstico , Cirurgia Assistida por Computador/métodos , Tomografia de Coerência Óptica/métodos , Doença da Artéria Coronariana/cirurgia , Humanos , Placa Aterosclerótica/cirurgia , Reprodutibilidade dos Testes
10.
J Math Biol ; 72(4): 973-996, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26385578

RESUMO

In this paper, a model is developed for the evolution of plaques in arteries, which is one of the main causes for the blockage of blood flow. Plaque rupture and spread of torn-off material may cause closures in the down-stream vessel system and lead to ischemic brain or myocardial infarctions. The model covers the flow of blood and its interaction with the vessel wall. It is based on the assumption that the penetration of monocytes from the blood flow into the vessel wall, and the accumulation of foam cells increasing the volume, are main factors for the growth of plaques. The dynamics of the vessel wall is governed by a deformation gradient, which is given as composition of a purely elastic tensor, and a tensor modeling the biologically caused volume growth. An equation for the evolution of the metric is derived quantifying the changing geometry of the vessel wall. To calculate numerically the solutions of the arising free boundary problem, the model system of partial differential equations is transformed to an ALE (Arbitrary Lagrangian-Eulerian) formulation, where all equations are given in fixed domains. The numerical calculations are using newly developed algorithms for ALE systems. The results of the simulations, obtained for realistic system parameters, are in good qualitative agreement with observations. They demonstrate that the basic modeling assumption can be justified. The increase of stresses in the vessel wall can be computed. Medical treatment tries to prevent critical stress values, which may cause plaque rupture and its consequences.


Assuntos
Modelos Cardiovasculares , Placa Aterosclerótica/etiologia , Algoritmos , Artérias/fisiopatologia , Fenômenos Biomecânicos , Velocidade do Fluxo Sanguíneo , Simulação por Computador , Hemorreologia , Humanos , Hidrodinâmica , Conceitos Matemáticos , Placa Aterosclerótica/fisiopatologia
11.
Blood ; 121(13): 2474-82, 2013 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-23335370

RESUMO

The p21-activated kinases (Paks) are serine/threonine kinases that are major effectors of the Rho guanosine 5'\x{2011}triphosphatase, Rac, and Cdc42. Rac and Cdc42 are known regulators of hematopoietic stem and progenitor cell (HSPC) function, however, a direct role for Paks in HSPCs has yet to be elucidated. Lin(-)Sca1(+)c-kit(+) (LSK) cells from wild-type mice were transduced with retrovirus expressing Pak inhibitory domain (PID), a well-characterized inhibitor of Pak activation. Defects in marrow homing and in vitro cell migration, assembly of the actin cytoskeleton, proliferation, and survival were associated with engraftment failure of PID-LSK. The PID-LSK demonstrated decreased phosphorylation of extracellular signal-regulated kinase (ERK), whereas constitutive activation of ERK in these cells led to rescue of hematopoietic progenitor cell proliferation in vitro and partial rescue of Pak-deficient HSPC homing and engraftment in vivo. Using conditional knock-out mice, we demonstrate that among group A Paks, Pak2(-/-) HSPC show reduced homing to the bone marrow and altered cell shape similar to PID-LSK cells in vitro and are completely defective in HSPC engraftment. These data demonstrate that Pak proteins are key components of multiple engraftment-associated HSPC functions and play a direct role in activation of ERK in HSPCs, and that Pak2 is specifically essential for HSPC engraftment.


Assuntos
Movimento Celular/genética , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/fisiologia , Quinases Ativadas por p21/fisiologia , Animais , Movimento Celular/fisiologia , Proliferação de Células , Sobrevivência Celular/genética , Células Cultivadas , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/fisiologia , Células-Tronco Hematopoéticas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Quinases Ativadas por p21/genética , Proteínas rac de Ligação ao GTP/metabolismo , Proteínas rac de Ligação ao GTP/fisiologia
12.
Platelets ; 26(6): 521-9, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25166751

RESUMO

AIM: To investigate whether an intensified antiplatelet regimen could improve prognosis in stable or non-ST elevation in acute coronary syndrome (ACS) patients exhibiting high on-treatment platelet reactivity (HTPR) on clopidogrel and treated with percutaneous coronary intervention (PCI). There is a wide variability in the platelet reactivity to clopidogrel and HTPR has been associated with a poor prognosis. METHODS: In this observational study, 923 consecutive patients without ST-elevation myocardial infarction (STEMI) and adequately pre-treated with clopidogrel were screened for HTPR with multiple electrode aggregometry after assessment of the coronary anatomy. Patients were grouped based on their response to clopidogrel and the assigned antiplatelet strategy. The primary endpoint was a composite of cardiovascular death, myocardial infarction, stroke, or stent thrombosis. RESULTS: HTPR was demonstrated in 237 patients (25.7%). Of these, 114 continued on conventional clopidogrel therapy, while the remaining 123 received intensified antiplatelet therapy with either double-dose clopidogrel (150 mg daily, n = 55) or the newer P2Y12-inhibitors, prasugrel or ticagrelor (n = 68) for at least 30 days after the index procedure. The median follow-up was 571 days (interquartile range, 373-746). Intensifying antiplatelet therapy reduced the rate of the composite endpoint (p < 0.001). After adjustment for potential confounders, HTPR in combination with conventional clopidogrel therapy remained independently associated with an increased risk of cardiovascular events (hazard ratio (HR), 2.92; 95% CI, 1.90-4.48), whereas intensified treatment reduced the risk to a level equivalent to that of patients exhibiting normal platelet reactivity (HR, 1.08; 95% CI, 0.59-1.99). CONCLUSION: Tailored antiplatelet therapy significantly reduced the event rate in patients exhibiting HTPR prior to PCI.


Assuntos
Síndrome Coronariana Aguda/tratamento farmacológico , Angina Estável/tratamento farmacológico , Inibidores da Agregação Plaquetária/uso terapêutico , Síndrome Coronariana Aguda/mortalidade , Síndrome Coronariana Aguda/cirurgia , Angina Estável/mortalidade , Angina Estável/cirurgia , Clopidogrel , Feminino , Humanos , Masculino , Intervenção Coronária Percutânea , Ativação Plaquetária/efeitos dos fármacos , Inibidores da Agregação Plaquetária/efeitos adversos , Prognóstico , Estudos Prospectivos , Antagonistas do Receptor Purinérgico P2Y/efeitos adversos , Antagonistas do Receptor Purinérgico P2Y/uso terapêutico , Ticlopidina/efeitos adversos , Ticlopidina/análogos & derivados , Ticlopidina/uso terapêutico , Fatores de Tempo , Resultado do Tratamento
13.
Eur Heart J ; 35(12): 795-807, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24132187

RESUMO

OBJECTIVES: The purpose of this study was to assess the occurrence, predictors, and mechanisms of optical coherence tomography (OCT)-detected coronary evaginations following drug-eluting stent (DES) implantation. BACKGROUND: Angiographic ectasias and aneurysms in stented segments have been associated with a risk of late stent thrombosis. Using OCT, some stented segments show coronary evaginations reminiscent of ectasias. METHODS: Evaginations were defined as outward bulges in the luminal contour between struts. They were considered major evaginations (MEs) when extending ≥3 mm along the vessel length, with a depth ≥10% of the stent diameter. A total of 228 patients who had sirolimus (SES)-, paclitaxel-, biolimus-, everolimus (EES)-, or zotarolimus (ZES)-eluting stents implanted in 254 lesions, were analysed after 1, 2, or 5 years; and serial assessment using OCT and intravascular ultrasound (IVUS) was performed post-intervention and after 1 year in 42 patients. RESULTS: Major evaginations occurred frequently at all time points in SES (∼26%) and were rarely seen in EES (3%) and ZES (2%, P = 0.003). Sirolimus-eluting stent implantation was the strongest independent predictor of ME [adjusted OR (95% CI) 9.1 (1.1-77.4), P = 0.008]. Malapposed and uncovered struts were more common in lesions with vs. without ME (77 vs. 25%, P < 0.001 and 95 vs. 20%, P < 0.001, respectively) as was thrombus [49 vs. 14%, OR 7.3 (95% CI: 1.7-31.2), P = 0.007]. Post-intervention intra-stent dissection and protrusion of the vessel wall into the lumen were associated with an increased risk of evagination at follow-up [OR (95% CI): 2.9 (1.8-4.9), P < 0.001 and 3.3 (1.6-6.9), P = 0.001, respectively]. In paired IVUS analyses, lesions with ME showed a larger increase in the external elastic membrane area (20% area change) compared with lesions without ME (5% area change, P < 0.001). CONCLUSION: Optical coherence tomography-detected MEs are a specific morphological footprint of early-generation SES and are nearly absent in newer-generation ZES and EES. Evaginations appear to be related to vessel injury at baseline; are associated with positive vessel remodelling; and correlate with uncoverage, malapposition, and thrombus at follow-up.


Assuntos
Doença das Coronárias/patologia , Vasos Coronários/patologia , Stents Farmacológicos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ensaios Clínicos Controlados não Aleatórios como Assunto , Estudos Prospectivos , Tomografia de Coerência Óptica , Moduladores de Tubulina/administração & dosagem , Ultrassonografia de Intervenção , Remodelação Vascular/efeitos dos fármacos
14.
J Biol Chem ; 288(2): 974-83, 2013 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-23204526

RESUMO

p21-activated kinase-1 (Pak1) is a serine/threonine kinase that plays a key role in mediating antigen-stimulated extracellular calcium influx and degranulation in mast cells. Another isoform in this kinase family, Pak2, is expressed at very high levels in mast cells, but its function is unknown. Here we show that Pak2 loss in murine bone marrow-derived mast cells, unlike loss of Pak1, induces increased antigen-mediated adhesion, degranulation, and cytokine secretion without changes to extracellular calcium influx. This phenotype is associated with an increase in RhoA-GTPase signaling activity to downstream effectors, including myosin light chain and p38(MAPK), and is reversed upon treatment with a Rho-specific inhibitor. Pak2, but not Pak1, negatively regulates RhoA via phosphorylation of the guanine nucleotide exchange factor GEF-H1 at an inhibitory site, leading to increased GEF-H1 microtubule binding and loss of RhoA stimulation. These data suggest that Pak2 plays a unique inhibitory role in mast cell degranulation by down-regulating RhoA via GEF-H1.


Assuntos
Fatores de Troca do Nucleotídeo Guanina/metabolismo , Mastócitos/metabolismo , Camundongos Endogâmicos C57BL/metabolismo , Receptores de IgE/metabolismo , Transdução de Sinais , Animais , Sequência de Bases , Células da Medula Óssea/metabolismo , Cálcio/metabolismo , Adesão Celular , Células Cultivadas , Primers do DNA , Camundongos , Reação em Cadeia da Polimerase , Quinases Ativadas por p21
15.
J Biol Chem ; 288(29): 21117-21125, 2013 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-23760270

RESUMO

Signaling from small GTPases is a tightly regulated process. In this work we used a protein microarray screen to identify the Rac-specific GAP, ArhGAP15, as a substrate of the Rac effectors Pak1 and Pak2. In addition to serving as a substrate of Pak1/2, we found that ArhGAP15, via its PH domain, bound to these kinases. The association of ArhGAP15 to Pak1/2 resulted in mutual inhibition of GAP and kinase catalytic activity, respectively. Knock-down of ArhGAP15 resulted in activation of Pak1/2, both indirectly, as a result of Rac activation, and directly, as a result of disruption of the ArhGAP15/Pak complex. Our data suggest that ArhGAP15 plays a dual negative role in regulating small GTPase signaling, by acting at the level of the GTPase itself, as well interacting with its effector, Pak kinase.


Assuntos
Proteínas Ativadoras de GTPase/metabolismo , Transdução de Sinais , Proteínas rac de Ligação ao GTP/antagonistas & inibidores , Proteínas rac de Ligação ao GTP/metabolismo , Sequência de Aminoácidos , Regulação para Baixo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Proteínas Ativadoras de GTPase/antagonistas & inibidores , Proteínas Ativadoras de GTPase/química , Células HEK293 , Humanos , Sistema de Sinalização das MAP Quinases , Modelos Biológicos , Dados de Sequência Molecular , Fosforilação , Ligação Proteica , Estrutura Terciária de Proteína , Especificidade por Substrato , Quinases Ativadas por p21/metabolismo
16.
Platelets ; 25(7): 506-12, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24245960

RESUMO

High on-treatment platelet reactivity (HTPR) is associated with poor prognosis in patients undergoing percutaneous coronary intervention (PCI). The antiplatelet effect and safety of prasugrel was compared to that of double-dose clopidogrel in patients with stable coronary artery disease or acute coronary syndrome (ACS) exhibiting HTPR on clopidogrel and treated with PCI, using multiple electrode aggregometry (MEA) to assess platelet reactivity. Of 923 patients screened, 237 (25.7%) exhibited HTPR. Of these, 106 were eligible for participation in a randomized trial comparing two intensified antiplatelet regimen: 52 were assigned to double maintenance-dose clopidogrel and 54 to standard-dose prasugrel. At 1 month, tailoring antiplatelet therapy improved platelet inhibition to a level considered as therapeutic in 73.1% of patients. Prasugrel entailed greater platelet inhibition (p = 0.02) and a lower rate of persisting HTPR at follow-up compared to double-dose clopidogrel (HTPR persisted in 20.4% and 42% respectively, p = 0.02). Within the 30-day follow-up, no major bleeds were observed and the incidence of major adverse cardiovascular events (MACE) was similar in the two treatment arms. Prasugrel demonstrated superiority to double-dose clopidogrel in overcoming HTPR and reducing platelet activity. Intensifying antiplatelet therapy in both ACS and stable angina pectoris (SAP) patients exhibiting HTPR prior to PCI was well tolerated.


Assuntos
Plaquetas/efeitos dos fármacos , Doença da Artéria Coronariana/terapia , Intervenção Coronária Percutânea/métodos , Piperazinas/administração & dosagem , Inibidores da Agregação Plaquetária/administração & dosagem , Tiofenos/administração & dosagem , Ticlopidina/análogos & derivados , Idoso , Clopidogrel , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/tratamento farmacológico , Doença da Artéria Coronariana/cirurgia , Feminino , Humanos , Masculino , Piperazinas/efeitos adversos , Inibidores da Agregação Plaquetária/efeitos adversos , Cloridrato de Prasugrel , Prognóstico , Tiofenos/efeitos adversos , Ticlopidina/administração & dosagem , Ticlopidina/efeitos adversos , Resultado do Tratamento
17.
Heliyon ; 10(13): e33519, 2024 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-39027521

RESUMO

Free movement of production factors in the enlarged EU has led to immigration flows from East to West and from South to North with a significant impact on EU labor markets. Fiscal federalism also determined large immigration flows into EU area and affected unemployment rate in the EU countries. The aim of this paper is to investigate the impact of factors such as number of immigrants, tax on profits, social contributions, economic growth and population growth on unemployment rates in EU area using a panel quantile regression and an PMG-ARDL approach as robustness test during 1991-2020. The results show a positive association between population growth and unemployment rate, whereas the remaining exogenous factors are negatively associated with unemployment rate. Still, social contributions are statistically significant only for upper quantiles. The overall impact of social contribution on unemployment rate is positive as per PMG-ARDL estimations. We have also demonstrated that the immigrant flows impact on unemployment rate is very weak. The factors that are exerting the most significance influence on unemployment rate, are economic and population growth, followed by tax on profits. Findings support policy recommendation in EU area in terms of fiscal policy.

18.
Heliyon ; 10(11): e31772, 2024 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-38841480

RESUMO

Electrical discharge machining with solid electrodes represents an efficient solution to generate blind cavities with complex geometry. Vegetable oils represent an alternative to conventional dielectrics, which are considered harmful for the environment and human health. This study tested the feasibility of two widely used vegetable oils, sunflower and soybean, under intense machining of three alloys with application in aeronautic industry, aiming for high process productivity and a good surface quality. The results have revealed that vegetable oils are capable to ensure an improvement of the material removal rates that can reach up to 55.15 % compared to mineral oil. Also, the vegetable dielectrics allowed an improvement of surface quality for non-ferrous alloys, up to a maximum of 19.70 %, whereas for the stainless steel, the mineral oil has provided a better surface finish.

19.
Antibiotics (Basel) ; 13(4)2024 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-38667001

RESUMO

Candida auris is a newly emerging yeast, which is raising public health concerns due to its outbreak potential, lack of protocols for decontamination and isolation of patients or contacts, increased resistance to common antifungals, and associated high mortality. This research aimed to describe the challenges related to identifying the outbreak, limiting further contamination, and treating affected individuals. We retrospectively analyzed all cases of C. auris detected between October 2022 and August 2023, but our investigation focused on a three-month-long outbreak in the department of cardio-vascular surgery and the related intensive care unit. Along with isolated cases in different wards, we identified 13 patients who became infected or colonized in the same area and time, even though the epidemiological link could only be traced in 10 patients, according to the epidemiologic investigation. In conclusion, our study emphasizes the substantial challenge encountered in clinical practice when attempting to diagnose and limit the spread of an outbreak. Therefore, it is crucial to promptly apply contact precaution measures and appropriate environmental cleaning, from the first positive case detected.

20.
Circ J ; 77(9): 2327-33, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23979567

RESUMO

BACKGROUND: The prevalence and clinical sequelae of optical frequency domain imaging (OFDI)-detected intimal flaps caused by vessel trauma or plaque rupture in the proximal native coronary arteries have not been described. METHODS AND RESULTS: OFDI investigation was performed following stent implantation in patients with ST-segment elevation myocardial infarction (STEMI). We defined a flap-like structure (FS) as a disruption or discontinuation of the endoluminal vessel surface, and classified as actual flap or artifact. FS in the left main stem, or maximally 20mm distal to the guiding catheter in the proximal right coronary artery were assessed. A total of 8,931 frames in 97 patients were analyzed in a frame-by-frame fashion (0.125-mm interval). OFDI identified 8 FS in 7 patients, none of which was evident angiographically. All FS were left untreated because the operators per protocol were blinded to the OFDI images. A total of 5 FS in 5 patients (5.1%) appeared to be actual flaps in which only the intima was involved (mean distance from guiding catheter: 4.8±2.7mm). The remaining 3 FS in 3 patients were artifacts; namely, residual blood and interface light reflectivity. There were no adverse cardiac events during 6-months follow-up. CONCLUSIONS: In 5.1% of STEMI patients, post-procedural OFDI identified flaps with minimal involvement of the intima in the proximal coronary arteries. A precise interpretation of FS may help decision making to avoid unnecessary procedures. ( CLINICAL TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov identifier: NCT01271361.)


Assuntos
Vasos Coronários/patologia , Stents , Tomografia Óptica , Túnica Íntima/lesões , Túnica Íntima/patologia , Idoso , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Angiografia Coronária , Vasos Coronários/cirurgia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/cirurgia
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