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1.
Nature ; 532(7597): 122-6, 2016 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-27027284

RESUMO

Cerebral cavernous malformations (CCMs) are common inherited and sporadic vascular malformations that cause strokes and seizures in younger individuals. CCMs arise from endothelial cell loss of KRIT1, CCM2 or PDCD10, non-homologous proteins that form an adaptor complex. How disruption of the CCM complex results in disease remains controversial, with numerous signalling pathways (including Rho, SMAD and Wnt/ß-catenin) and processes such as endothelial-mesenchymal transition (EndMT) proposed to have causal roles. CCM2 binds to MEKK3 (refs 7, 8, 9, 10, 11), and we have recently shown that CCM complex regulation of MEKK3 is essential during vertebrate heart development. Here we investigate this mechanism in CCM disease pathogenesis. Using a neonatal mouse model of CCM disease, we show that expression of the MEKK3 target genes Klf2 and Klf4, as well as Rho and ADAMTS protease activity, are increased in the endothelial cells of early CCM lesions. By contrast, we find no evidence of EndMT or increased SMAD or Wnt signalling during early CCM formation. Endothelial-specific loss of Map3k3 (also known as Mekk3), Klf2 or Klf4 markedly prevents lesion formation, reverses the increase in Rho activity, and rescues lethality. Consistent with these findings in mice, we show that endothelial expression of KLF2 and KLF4 is increased in human familial and sporadic CCM lesions, and that a disease-causing human CCM2 mutation abrogates the MEKK3 interaction without affecting CCM complex formation. These studies identify gain of MEKK3 signalling and KLF2/4 function as causal mechanisms for CCM pathogenesis that may be targeted to develop new CCM therapeutics.


Assuntos
Células Endoteliais/metabolismo , Hemangioma Cavernoso do Sistema Nervoso Central/metabolismo , Fatores de Transcrição Kruppel-Like/metabolismo , MAP Quinase Quinase Quinase 3/metabolismo , Sistema de Sinalização das MAP Quinases , Proteínas ADAM/metabolismo , Animais , Animais Recém-Nascidos , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Modelos Animais de Doenças , Células Endoteliais/enzimologia , Feminino , Hemangioma Cavernoso do Sistema Nervoso Central/etiologia , Hemangioma Cavernoso do Sistema Nervoso Central/patologia , Humanos , Fator 4 Semelhante a Kruppel , Fatores de Transcrição Kruppel-Like/deficiência , MAP Quinase Quinase Quinase 3/deficiência , Masculino , Camundongos , Ligação Proteica , Proteínas rho de Ligação ao GTP/metabolismo
2.
Pediatr Radiol ; 51(9): 1762-1765, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33638694

RESUMO

Chyluria is characterized by chyle in the urinary tract and often presents as milky-white urine. We present a case of chyluria from a lymphatic malformation in a 13-year-old boy diagnosed using dynamic intranodal contrast-enhanced magnetic resonance (MR) lymphangiography. This report demonstrates the utility of intranodal lymphangiography and interstitial lymphatic embolization to treat a pediatric patient presenting with persistent chyluria. Glue migration into the urinary collecting system is a potential complication of this procedure that can be mitigated by adjusting the n-butyl cyanoacrylate dilution with Lipiodol.


Assuntos
Quilo , Embolização Terapêutica , Nefropatias , Vasos Linfáticos , Adolescente , Criança , Humanos , Linfografia , Masculino , Urina
4.
bioRxiv ; 2024 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-39314286

RESUMO

Background: Smooth muscle cell (SMC) plasticity and phenotypic switching play prominent roles in the pathogenesis of multiple diseases, but their role in tumorigenesis is unknown. We investigated whether and how SMC diversity and plasticity plays a role in tumor angiogenesis and the tumor microenvironment. Methods and Results: We use SMC-specific lineage-tracing mouse models and single cell RNA sequencing to observe the phenotypic diversity of SMCs participating in tumor vascularization. We find that a significant proportion of SMCs adopt a phenotype traditionally associated with macrophage-like cells. These cells are transcriptionally similar to 'resolution phase' M2b macrophages, which have been described to have a role in inflammation resolution. Computationally predicted by the ligand-receptor algorithm CellChat, signaling from BST2 on the surface of tumor cells to PIRA2 on SMCs promote this phenotypic transition; in vitro SMC assays demonstrate upregulation of macrophage transcriptional programs, and increased proliferation, migration, and phagocytic ability when exposed to BST2. Knockdown of BST2 in the tumor significantly decreases the transition towards a macrophage-like phenotype, and cells that do transition have a comparatively higher inflammatory signal typically associated with anti-tumor effect. Conclusion: As BST2 is known to be a poor prognostic marker in multiple cancers where it is associated with an M2 macrophage-skewed TME, these studies suggest that phenotypically switched SMCs may have a previously unidentified role in this immunosuppressive milieu. Further translational work is needed to understand how this phenotypic switch could influence the response to anti-cancer agents and if targeted inhibition of SMC plasticity would be therapeutically beneficial.

5.
Nat Commun ; 15(1): 8034, 2024 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-39271657

RESUMO

Atherosclerosis is an inflammatory disorder responsible for cardiovascular disease. Reactivation of efferocytosis, the phagocytic removal of cells by macrophages, has emerged as a translational target for atherosclerosis. Systemic blockade of the key 'don't-eat-me' molecule, CD47, triggers the engulfment of apoptotic vascular tissue and potently reduces plaque burden. However, it also induces red blood cell clearance, leading to anemia. To overcome this, we previously developed a macrophage-specific nanotherapy loaded with a chemical inhibitor that promotes efferocytosis. Because it was found to be safe and effective in murine studies, we aimed to advance our nanoparticle into a porcine model of atherosclerosis. Here, we demonstrate that production can be scaled without impairing nanoparticle function. At an early stage of disease, we find our nanotherapy reduces apoptotic cell accumulation and inflammation in the atherosclerotic lesion. Notably, this therapy does not induce anemia, highlighting the translational potential of targeted macrophage checkpoint inhibitors.


Assuntos
Anemia , Aterosclerose , Antígeno CD47 , Modelos Animais de Doenças , Inflamação , Macrófagos , Nanopartículas , Fagocitose , Animais , Aterosclerose/tratamento farmacológico , Aterosclerose/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Nanopartículas/química , Antígeno CD47/metabolismo , Antígeno CD47/antagonistas & inibidores , Suínos , Inflamação/patologia , Fagocitose/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Humanos , Placa Aterosclerótica/patologia , Camundongos , Masculino
6.
J Vasc Surg Cases Innov Tech ; 8(3): 542-544, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36081740

RESUMO

Mycotic extracranial carotid artery aneurysms are a rare vascular phenomenon with a number of implicated pathogens, most commonly Staphylococcus aureus and Salmonella. Presentation of a mycotic extracranial carotid artery aneurysm after dental abscess or procedure is similarly not frequently described in the literature. We present a unique case of a large, distal mycotic internal carotid artery aneurysm, which developed secondary to Haemophilus parainfluenzae infection and dental abscess.

7.
J Am Coll Surg ; 235(5): 778-786, 2022 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-36102567

RESUMO

BACKGROUND: Therapeutic anticoagulation with either a vitamin K antagonist (VKA) or direct anticoagulant (DOAC) is often newly prescribed to patients undergoing lower extremity bypass (LEB) to aid in graft patency when risk factors for thrombosis are present or to treat postoperative venous thromboembolism or atrial fibrillation. There is a gap in knowledge as to how DOAC usage impacts postoperative outcomes compared with the standard-of-care VKAs. STUDY DESIGN: To determine temporal trends in DOAC prescription after infrainguinal LEB, impact on length of stay (LOS), and associated bleeding and thrombotic complications, patients undergoing elective LEB were identified from the Vascular Quality Initiative between January 2013 and May 2019. Postoperative bleeding, LOS, and graft occlusion for patients receiving VKA compared with DOAC were evaluated. RESULTS: A total of 24,459 LEBs were performed during the study period. Among 2,656 patients newly prescribed an anticoagulant, 78.0% (n = 2,072) received VKA and 22.0% (n = 584) received a DOAC, with DOAC use increasing throughout the study period. There was no significant difference in postoperative bleeding (VKA 2.3%, DOAC 1.7%, p = 0.413) or graft occlusion (VKA 1.2%, DOAC 1.4%, p = 0.762) between the anticoagulant classes. LOS was shorter in the DOAC group than in the VKA group (5.7 vs 6.8 days; p < 0.001). CONCLUSIONS: This analysis demonstrates that DOAC use is increasing with time in Vascular Quality Initiative centers. DOACs are a safe and comparable alternative to VKAs in the postoperative setting with similar rates of bleeding complications and early graft patency and are associated with a reduced postoperative LOS.


Assuntos
Fibrilação Atrial , Trombose , Administração Oral , Anticoagulantes/efeitos adversos , Fibrilação Atrial/tratamento farmacológico , Hemorragia , Humanos , Extremidade Inferior/cirurgia , Trombose/etiologia , Trombose/prevenção & controle , Vitamina K/uso terapêutico
8.
BMJ Case Rep ; 14(8)2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34376411

RESUMO

Vestibular schwannoma is a known cause of progressive sensorineural hearing loss. Treatment options include observation, radiation therapy and surgical resection. Cerebrospinal fluid (CSF) fistula is a known postsurgical complication that can lead to CSF otorrhoea, rhinorrhoea or CSF leakage from the surgical wound. We present a case report of a patient who underwent vestibular schwannoma resection and postoperatively developed CSF rhinorrhoea, which was refractory to multiple attempts at surgical repair. This was successfully treated under endoscopic and fluoroscopic guidance using a biliary cytology brush to disrupt the surface of the eustachian tube followed by injection of n-Butyl cyanoacrylate.


Assuntos
Rinorreia de Líquido Cefalorraquidiano , Tuba Auditiva , Neurilemoma , Otorreia de Líquido Cefalorraquidiano , Endoscopia , Tuba Auditiva/cirurgia , Humanos , Estudos Retrospectivos
9.
J Clin Invest ; 129(12): 5489-5500, 2019 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-31710307

RESUMO

Deep venous thrombosis (DVT) and secondary pulmonary embolism cause approximately 100,000 deaths per year in the United States. Physical immobility is the most significant risk factor for DVT, but a molecular and cellular basis for this link has not been defined. We found that the endothelial cells surrounding the venous valve, where DVTs originate, express high levels of FOXC2 and PROX1, transcription factors known to be activated by oscillatory shear stress. The perivalvular venous endothelial cells exhibited a powerful antithrombotic phenotype characterized by low levels of the prothrombotic proteins vWF, P-selectin, and ICAM1 and high levels of the antithrombotic proteins thrombomodulin (THBD), endothelial protein C receptor (EPCR), and tissue factor pathway inhibitor (TFPI). The perivalvular antithrombotic phenotype was lost following genetic deletion of FOXC2 or femoral artery ligation to reduce venous flow in mice, and at the site of origin of human DVT associated with fatal pulmonary embolism. Oscillatory blood flow was detected at perivalvular sites in human veins following muscular activity, but not in the immobile state or after activation of an intermittent compression device designed to prevent DVT. These findings support a mechanism of DVT pathogenesis in which loss of muscular activity results in loss of oscillatory shear-dependent transcriptional and antithrombotic phenotypes in perivalvular venous endothelial cells, and suggest that prevention of DVT and pulmonary embolism may be improved by mechanical devices specifically designed to restore perivalvular oscillatory flow.


Assuntos
Células Endoteliais/metabolismo , Regulação da Expressão Gênica , Hemodinâmica/fisiologia , Trombose Venosa/prevenção & controle , Adulto , Animais , Feminino , Fatores de Transcrição Forkhead/fisiologia , Proteínas de Homeodomínio/fisiologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Pessoa de Meia-Idade , Fluxo Sanguíneo Regional , Proteínas Supressoras de Tumor/fisiologia
10.
Dev Cell ; 43(3): 274-289.e5, 2017 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-29056552

RESUMO

Hemodynamic forces play an essential epigenetic role in heart valve development, but how they do so is not known. Here, we show that the shear-responsive transcription factor KLF2 is required in endocardial cells to regulate the mesenchymal cell responses that remodel cardiac cushions to mature valves. Endocardial Klf2 deficiency results in defective valve formation associated with loss of Wnt9b expression and reduced canonical WNT signaling in neighboring mesenchymal cells, a phenotype reproduced by endocardial-specific loss of Wnt9b. Studies in zebrafish embryos reveal that wnt9b expression is similarly restricted to the endocardial cells overlying the developing heart valves and is dependent upon both hemodynamic shear forces and klf2a expression. These studies identify KLF2-WNT9B signaling as a conserved molecular mechanism by which fluid forces sensed by endothelial cells direct the complex cellular process of heart valve development and suggest that congenital valve defects may arise due to subtle defects in this mechanotransduction pathway.


Assuntos
Endocárdio/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/genética , Valvas Cardíacas/crescimento & desenvolvimento , Hemodinâmica/fisiologia , Transdução de Sinais/genética , Animais , Proliferação de Células/fisiologia , Fator 4 Semelhante a Kruppel , Fatores de Transcrição Kruppel-Like/metabolismo , Camundongos Transgênicos , Organogênese/fisiologia , Fatores de Transcrição/genética , Proteínas Wnt/metabolismo , Peixe-Zebra , Proteínas de Peixe-Zebra/metabolismo
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