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J Heart Lung Transplant ; 37(12): 1459-1466, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30292432


BACKGROUND: The majority of children supported with ventricular assist devices (VADs) are bridged to heart transplantation. Although bridge to recovery has been reported, low recovery patient numbers has precluded systematic analysis. The aim of this study was to delineate recovery rates and predictors of recovery and to report on long-term follow-up after VAD explantation in children. METHODS: Children bridged to recovery at our institution from January 1990 to May 2016 were compared with a non-recovery cohort. Clinical and echocardiographic data before and at pump stoppages and after VAD explantation were analyzed. Kaplan‒Meier estimates of event-free survival, defined as freedom from death or transplantation after VAD removal, were determined. RESULTS: One hundred forty-nine children (median age 5.8 years) were identified. Of these, 65.2% had cardiomyopathy, 9.4% had myocarditis, and 24.8% had congenital heart disease. The overall recovery rate was 14.2%, and was 7.1% in patients with dilated cardiomyopathy. Predictors of recovery were age <2 years (recovery rate 27.8%, odds ratio [OR] 5.64, 95% confidence interval [CI] 2.0 to 16.6) and diagnosis of myocarditis (rate 57.1%; OR 17.56, 95% CI 4.6 to 67.4). After a median follow-up of 10.8 years, 15 patients (83.3%) were in Functional Class I and 3 (16.7%) in were in Class II. Mean left ventricular ejection fraction was 53% (range 28% to 64%). Ten- and 15-year event-free survival rates were both 84.1 ± 8.4%. CONCLUSIONS: Children <2 years of age and those diagnosed with myocarditis have the highest probability of recovery. Long-term survival after weaning from the VAD was better than after heart transplantation, as demonstrated in the excellent long-term stability of ejection fraction and functional class.

Transplante de Coração , Coração Auxiliar , Complicações Pós-Operatórias/etiologia , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Seguimentos , Transplante de Coração/mortalidade , Humanos , Estimativa de Kaplan-Meier , Masculino , Complicações Pós-Operatórias/mortalidade , Intervalo Livre de Progressão , Fatores de Risco
Oncogene ; 35(34): 4437-46, 2016 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-26853467


Activation of the extensive cross-talk among the receptor tyrosine kinases (RTKs), particularly ErbB family-Met cross-talk, has emerged as a likely source of drug resistance. Notwithstanding brilliant successes were attained while using small-molecule inhibitors or antibody therapeutics against specific RTKs in multiple cancers over recent decades, a high recurrence rate remains unsolved in patients treated with these targeted inhibitors. It is well aligned with multifaceted properties of cancer and cross-talk and convergence of signaling pathways of RTKs. Thereby many therapeutic interventions have been actively developed to overcome inherent or acquired resistance. To date, no bispecific antibody (BsAb) showed complete depletion of dual RTKs from the plasma membrane and efficient dual degradation. In this manuscript, we report the first findings of a target-specific dual internalization and degradation of membrane RTKs induced by designed BsAbs based on the internalizing monoclonal antibodies and the therapeutic values of these BsAbs. Leveraging the anti-Met mAb able to internalize and degrade by a unique mechanism, we generated the BsAbs for Met/epidermal growth factor receptor (EGFR) and Met/HER2 to induce an efficient EGFR or HER2 internalization and degradation in the presence of Met that is frequently overexpressed in the invasive tumors and involved in the resistance against EGFR- or HER2-targeted therapies. We found that Met/EGFR BsAb ME22S induces dissociation of the Met-EGFR complex from Hsp90, followed by significant degradation of Met and EGFR. By employing patient-derived tumor models we demonstrate therapeutic potential of the BsAb-mediated dual degradation in various cancers.

Anticorpos Biespecíficos/uso terapêutico , Receptores ErbB/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Receptor ErbB-2/antagonistas & inibidores , Animais , Proliferação de Células , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB/metabolismo , Feminino , Humanos , Camundongos , Neoplasias/patologia , Proteínas Proto-Oncogênicas c-met/metabolismo , Receptor ErbB-2/metabolismo , Transdução de Sinais
Br J Radiol ; 85(1019): 1499-506, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23091290


OBJECTIVE: We compared and evaluated the differences between two models for treating bilateral breast cancer (BBC): (i) dose-volume-based intensity-modulated radiation treatment (DV plan), and (ii) dose-volume-based intensity-modulated radiotherapy with generalised equivalent uniform dose-based optimisation (DV-gEUD plan). METHODS: The quality and performance of the DV plan and DV-gEUD plan using the Pinnacle(3) system (Philips, Fitchburg, WI) were evaluated and compared in 10 patients with stage T2-T4 BBC. The plans were delivered on a Varian 21EX linear accelerator (Varian Medical Systems, Milpitas, CA) equipped with a Millennium 120 leaf multileaf collimator (Varian Medical Systems). The parameters analysed included the conformity index, homogeneity index, tumour control probability of the planning target volume (PTV), the volumes V(20 Gy) and V(30 Gy) of the organs at risk (OAR, including the heart and lungs), mean dose and the normal tissue complication probability. RESULTS: Both plans met the requirements for the coverage of PTV with similar conformity and homogeneity indices. However, the DV-gEUD plan had the advantage of dose sparing for OAR: the mean doses of the heart and lungs, lung V(20) (Gy), and heart V(30) (Gy) in the DV-gEUD plan were lower than those in the DV plan (p<0.05). CONCLUSIONS: A better result can be obtained by starting with a DV-generated plan and then improving it by adding gEUD-based improvements to reduce the number of iterations and to improve the optimum dose distribution. Advances to knowledge The DV-gEUD plan provided superior dosimetric results for treating BBC in terms of PTV coverage and OAR sparing than the DV plan, without sacrificing the homogeneity of dose distribution in the PTV.

Neoplasias da Mama/radioterapia , Dosagem Radioterapêutica/normas , Adulto , Idoso , Feminino , Humanos , Pessoa de Meia-Idade , Planejamento da Radioterapia Assistida por Computador/métodos , Radioterapia Conformacional/métodos , Radioterapia Conformacional/normas
Br J Dermatol ; 162(6): 1251-60, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20302580


BACKGROUND: The active form of vitamin D(3) , calcitriol, is widely used for the treatment of psoriasis, with or without topical corticosteroids. Topical corticosteroids are known to disrupt permeability and antimicrobial barriers, even with short-term use. Yet, the effect of topical calcitriol on epidermal permeability and antimicrobial barriers disrupted by topical corticosteroids has not been determined. OBJECTIVES: To examine the effect of calcitriol on epidermal permeability and antimicrobial barrier function that has been impaired by corticosteroids, as well as to elucidate the mechanism of improvement. MATERIAL AND METHODS: Topical calcitriol or the control vehicle was applied to each flank of hairless mice 20 min after treatment with topical clobetasol propionate and repeated every 12 h for 3·5 days. Barrier function assessment, Nile red staining, electron microscopy, immunohistochemistry, Western blotting, and real-time reverse transcriptase-polymerase chain reaction studies were performed 24 h after the last application. RESULTS: Epidermis co-treated with topical calcitriol showed an improvement of stratum corneum integrity and barrier recovery, more intense fluorescence staining with Nile red, and an increase in lamellar body (LB) maturation and density, as well as upregulation of major epidermal lipid synthesis-related enzymes (3-hydroxy-3-methylglutaryl-CoA, serine-palmitoyl transferase and fatty acid synthase), mouse beta-defensin 3, cathelin-related antimicrobial peptide and vitamin D receptor. CONCLUSIONS: We found that topical calcitriol restored both the epidermal permeability and antimicrobial barrier that had been impaired by corticosteroids. This restoration was mediated by both an activation of the cutaneous vitamin D pathway and an increase of epidermal lipids and antimicrobial peptides, promoted by the formation of the LB and the activity of epidermal lipid synthesis-related enzymes.

Calcitriol/farmacologia , Agonistas dos Canais de Cálcio/farmacologia , Epiderme/efeitos dos fármacos , Administração Tópica , Animais , Western Blotting , Calcitriol/uso terapêutico , Agonistas dos Canais de Cálcio/uso terapêutico , Clobetasol/análogos & derivados , Clobetasol/farmacologia , Modelos Animais de Doenças , Enzimas/metabolismo , Epiderme/metabolismo , Epiderme/patologia , Feminino , Glucocorticoides/farmacologia , Imuno-Histoquímica , Camundongos , Camundongos Pelados , Microscopia Eletrônica , Oxazinas/administração & dosagem , Permeabilidade/efeitos dos fármacos , Reação em Cadeia da Polimerase/métodos , Absorção Cutânea/efeitos dos fármacos , Regulação para Cima