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1.
Facial Plast Surg ; 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38490242

RESUMO

Otoplasty is commonly used to treat prominauris. Cartilage-sparing techniques for otoplasty are well popularized. The most common cartilage-sparing otoplasty techniques include the Mustardé and Furnas techniques. This article discusses the preparation, surgical steps, postoperative care, and associated complications for Mustardé and Furnas otoplasty in detail.

2.
N Engl J Med ; 382(23): 2207-2219, 2020 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-32492302

RESUMO

BACKGROUND: Rituximab added to chemotherapy prolongs survival among adults with B-cell cancer. Data on its efficacy and safety in children with high-grade, mature B-cell non-Hodgkin's lymphoma are limited. METHODS: We conducted an open-label, international, randomized, phase 3 trial involving patients younger than 18 years of age with high-risk, mature B-cell non-Hodgkin's lymphoma (stage III with an elevated lactate dehydrogenase level or stage IV) or acute leukemia to compare the addition of six doses of rituximab to standard lymphomes malins B (LMB) chemotherapy with standard LMB chemotherapy alone. The primary end point was event-free survival. Overall survival and toxic effects were also assessed. RESULTS: Analyses were based on 328 patients who underwent randomization (164 patients per group); 85.7% of the patients had Burkitt's lymphoma. The median follow-up was 39.9 months. Events were observed in 10 patients in the rituximab-chemotherapy group and in 28 in the chemotherapy group. Event-free survival at 3 years was 93.9% (95% confidence interval [CI], 89.1 to 96.7) in the rituximab-chemotherapy group and 82.3% (95% CI, 75.7 to 87.5) in the chemotherapy group (hazard ratio for primary refractory disease or first occurrence of progression, relapse after response, death from any cause, or second cancer, 0.32; 95% CI, 0.15 to 0.66; one-sided P = 0.00096, which reached the significance level required for this analysis). Eight patients in the rituximab-chemotherapy group died (4 deaths were disease-related, 3 were treatment-related, and 1 was from a second cancer), as did 20 in the chemotherapy group (17 deaths were disease-related, and 3 were treatment-related) (hazard ratio, 0.36; 95% CI, 0.16 to 0.82). The incidence of acute adverse events of grade 4 or higher after prephase treatment was 33.3% in the rituximab-chemotherapy group and 24.2% in the chemotherapy group (P = 0.07); events were related mainly to febrile neutropenia and infection. Approximately twice as many patients in the rituximab-chemotherapy group as in the chemotherapy group had a low IgG level 1 year after trial inclusion. CONCLUSIONS: Rituximab added to standard LMB chemotherapy markedly prolonged event-free survival and overall survival among children and adolescents with high-grade, high-risk, mature B-cell non-Hodgkin's lymphoma and was associated with a higher incidence of hypogammaglobulinemia and, potentially, more episodes of infection. (Funded by the Clinical Research Hospital Program of the French Ministry of Health and others; ClinicalTrials.gov number, NCT01516580.).


Assuntos
Antineoplásicos Imunológicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma de Células B/tratamento farmacológico , Rituximab/administração & dosagem , Adolescente , Antineoplásicos Imunológicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Infecções/etiologia , Infusões Intravenosas , Estimativa de Kaplan-Meier , Linfoma de Células B/mortalidade , Masculino , Neutropenia/induzido quimicamente , Intervalo Livre de Progressão , Rituximab/efeitos adversos
3.
CA Cancer J Clin ; 65(3): 212-20, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25754421

RESUMO

The outcome for children with cancer has improved significantly over the past 60 years, with greater than 80% of patients today becoming 5-year survivors. Despite this progress, cancer remains the leading cause of death from disease in children in the United States, and significant short-term and long-term treatment toxicities continue to impact the majority of children with cancer. The development of targeted new agents offers the prospect of potentially more effective and less toxic treatment for children. More than a decade since imatinib mesylate was introduced into the treatment of children with Philadelphia chromosome-positive acute lymphoblastic leukemia, transforming its outcome, a range of targeted agents has undergone study in pediatric cancer patients. Early lessons learned from these studies include a better understanding of the adverse event profile of these drugs in children, the challenge of developing pediatric-specific formulations, and the continued reliance on successful development for adult cancer indications on pediatric drug development. The collaborative research infrastructure for children with cancer in the United States is well positioned to advance novel treatments into clinical investigations for a spectrum of rare and ultra-rare childhood cancers. A greater investment of resources in target discovery and validation can help drive much needed development of new, more effective treatments for children with cancer.


Assuntos
Antineoplásicos/uso terapêutico , Terapia de Alvo Molecular/métodos , Neoplasias/tratamento farmacológico , Antineoplásicos/efeitos adversos , Química Farmacêutica , Criança , Descoberta de Drogas , Controle de Medicamentos e Entorpecentes , Humanos , Resultado do Tratamento , Estados Unidos
4.
Mol Ther ; 29(8): 2441-2455, 2021 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-33895329

RESUMO

Mutations in USH2A are among the most common causes of syndromic and non-syndromic retinitis pigmentosa (RP). The two most recurrent mutations in USH2A, c.2299delG and c.2276G > T, both reside in exon 13. Skipping exon 13 from the USH2A transcript presents a potential treatment modality in which the resulting transcript is predicted to encode a slightly shortened usherin protein. Morpholino-induced skipping of ush2a exon 13 in zebrafish ush2armc1 mutants resulted in the production of usherinΔexon 13 protein and a completely restored retinal function. Antisense oligonucleotides were investigated for their potential to selectively induce human USH2A exon 13 skipping. Lead candidate QR-421a induced a concentration-dependent exon 13 skipping in induced pluripotent stem cell (iPSC)-derived photoreceptor precursors from an Usher syndrome patient homozygous for the c.2299delG mutation. Mouse surrogate mQR-421a reached the retinal outer nuclear layer after a single intravitreal injection and induced a detectable level of exon skipping until at least 6 months post-injection. In conclusion, QR-421a-induced exon skipping proves to be a highly promising treatment option for RP caused by mutations in USH2A exon 13.


Assuntos
Proteínas da Matriz Extracelular/metabolismo , Mutação , Oligonucleotídeos Antissenso/administração & dosagem , Retinose Pigmentar/tratamento farmacológico , Animais , Células Cultivadas , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Éxons , Proteínas da Matriz Extracelular/química , Proteínas da Matriz Extracelular/genética , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Células-Tronco Pluripotentes Induzidas/metabolismo , Camundongos , Modelos Moleculares , Oligonucleotídeos Antissenso/farmacologia , Retina/metabolismo , Retinose Pigmentar/genética , Retinose Pigmentar/metabolismo , Peixe-Zebra , Proteínas de Peixe-Zebra/química , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
5.
Am J Hum Genet ; 102(4): 528-539, 2018 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-29526280

RESUMO

Fuchs endothelial corneal dystrophy (FECD) is a common disease for which corneal transplantation is the only treatment option in advanced stages, and alternative treatment strategies are urgently required. Expansion (≥50 copies) of a non-coding trinucleotide repeat in TCF4 confers >76-fold risk for FECD in our large cohort of affected individuals. An FECD subject-derived corneal endothelial cell (CEC) model was developed to probe disease mechanism and investigate therapeutic approaches. The CEC model demonstrated that the repeat expansion leads to nuclear RNA foci, with the sequestration of splicing factor proteins (MBNL1 and MBNL2) to the foci and altered mRNA processing. Antisense oligonucleotide (ASO) treatment led to a significant reduction in the incidence of nuclear foci, MBNL1 recruitment to the foci, and downstream aberrant splicing events, suggesting functional rescue. This proof-of-concept study highlights the potential of a targeted ASO therapy to treat the accessible and tractable corneal tissue affected by this repeat expansion-mediated disease.


Assuntos
Distrofia Endotelial de Fuchs/genética , Predisposição Genética para Doença , Oligonucleotídeos Antissenso/farmacologia , Fator de Transcrição 4/genética , Expansão das Repetições de Trinucleotídeos/genética , Idoso , Animais , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Estudos de Coortes , Células Endoteliais/metabolismo , Endotélio Corneano/patologia , Feminino , Distrofia Endotelial de Fuchs/patologia , Humanos , Masculino , Camundongos Endogâmicos C57BL , Especificidade de Órgãos , Precursores de RNA/genética , Processamento Pós-Transcricional do RNA , Fatores de Processamento de RNA/metabolismo , RNA Mensageiro/metabolismo , Fatores de Risco
6.
Pediatr Blood Cancer ; 67(9): e28435, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32558190

RESUMO

A diverse panel of pediatric cancer advocates and experts, whose collective experience spans the continuum of international academic medicine, industry, government research, and cancer advocacy, recently discussed challenges for pediatric cancer research in the context of coronavirus disease 2019 (COVID-19). Specifically, this special report addresses the following focus areas: (a) the critical role that translational research has played in transforming pediatric cancer outcomes; (b) the current and potential future impact of COVID-19 on pediatric cancer research; (c) target areas of COVID-19 research that may have application in immunity, oncogenesis, and therapeutic discovery; and (d) future considerations and directions in maintaining pediatric cancer research during and after COVID-19.


Assuntos
Betacoronavirus/metabolismo , Infecções por Coronavirus , Neoplasias , Pandemias , Pneumonia Viral , Pesquisa Translacional Biomédica , Adolescente , COVID-19 , Criança , Pré-Escolar , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/patologia , Infecções por Coronavirus/terapia , Feminino , Humanos , Lactente , Masculino , Neoplasias/epidemiologia , Neoplasias/metabolismo , Neoplasias/patologia , Neoplasias/terapia , Pneumonia Viral/epidemiologia , Pneumonia Viral/metabolismo , Pneumonia Viral/patologia , Pneumonia Viral/terapia , SARS-CoV-2
7.
Hum Mol Genet ; 26(24): 4896-4905, 2017 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-29036441

RESUMO

Mutations in rhodopsin, the light-sensitive protein of rod cells, are the most common cause of dominant retinitis pigmentosa (RP), a type of inherited blindness caused by the dysfunction and death of photoreceptor cells. The P23H mutation, the most frequent single cause of RP in the USA, causes rhodopsin misfolding and induction of the unfolded protein response (UPR), an adaptive ER stress response and signalling network that aims to enhance the folding and degradation of misfolded proteins to restore proteostasis. Prolonged UPR activation, and in particular the PERK branch, can reduce protein synthesis and initiate cell death through induction of pro-apoptotic pathways. Here, we investigated the effect of pharmacological PERK inhibition on retinal disease process in the P23H-1 transgenic rat model of retinal degeneration. PERK inhibition with GSK2606414A led to an inhibition of eIF2α phosphorylation, which correlated with reduced ERG function and decreased photoreceptor survival at both high and low doses of PERK inhibitor. Additionally, PERK inhibition increased the incidence of inclusion formation in cultured cells overexpressing P23H rod opsin, and increased rhodopsin aggregation in the P23H-1 rat retina, suggesting enhanced P23H misfolding and aggregation. In contrast, treatment of P23H-1 rats with an inhibitor of eIF2α phosphatase, salubrinal, led to improved photoreceptor survival. Collectively, these data suggest the activation of PERK is part of a protective response to mutant rhodopsin that ultimately limits photoreceptor cell death.


Assuntos
Retinose Pigmentar/metabolismo , Rodopsinas Sensoriais/metabolismo , eIF-2 Quinase/metabolismo , Adenina/análogos & derivados , Adenina/farmacologia , Animais , Linhagem Celular Transformada , Linhagem Celular Tumoral , Modelos Animais de Doenças , Retículo Endoplasmático/metabolismo , Humanos , Indóis/farmacologia , Dobramento de Proteína , Ratos , Ratos Sprague-Dawley , Ratos Transgênicos , Células Fotorreceptoras Retinianas Bastonetes/metabolismo , Retinose Pigmentar/genética , Rodopsinas Sensoriais/genética , Estresse Fisiológico/fisiologia , Resposta a Proteínas não Dobradas , eIF-2 Quinase/antagonistas & inibidores , eIF-2 Quinase/genética
8.
Pediatr Blood Cancer ; 66(6): e27672, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30767382

RESUMO

BACKGROUND: Carboplatin is often adaptively dosed based on glomerular filtration rate (GFR), usually estimated by nuclear medicine tests. At least five pediatric adaptive dosing formulas have been developed. In an effort to standardize dosing in Children's Oncology Group protocols, we explored methodologic variation in GFR estimation and adaptive-dosing formula performance. PROCEDURE: Nuclear medicine GFR data from published series of ≥100 children with cancer were compared. Data from patients for whom body surface area, weight, GFR, and tracer half-life were available were used to compare formulas. RESULTS: Differences in methods used to estimate GFR in children with cancer resulted in highly variable population results, with median GFRs ranging from 96 to 150 mL/min/1.73m2 . The choice of adaptive formula had a major impact on calculated dose. When targeting an area under the curve of 7.9 mg/mL • min, the median difference between the formula yielding the lowest and highest carboplatin dose for individual subjects was 289 (range 96-1 737) mg/m2 . CONCLUSIONS: Wide variation in GFR obtained with nuclear-medicine-based tests in children with cancer primarily results from systematic methodologic errors. Formulas for calculating carboplatin dose produce additional and substantial variation that may place children with cancer at unnecessary risk for excessive toxicity or underdosing. These findings indicate a need for the development of a uniform, validated method for GFR determination in children that should be utilized in all centers. Currently, adaptive dosing of carboplatin based on GFR has serious limitations and in most clinical settings should arguably not be used in place of body-surface-area-based dosing.


Assuntos
Antineoplásicos/farmacocinética , Carboplatina/farmacocinética , Rim/fisiopatologia , Neoplasias/tratamento farmacológico , Medicina Nuclear , Cintilografia/métodos , Algoritmos , Antineoplásicos/administração & dosagem , Área Sob a Curva , Carboplatina/administração & dosagem , Criança , Seguimentos , Taxa de Filtração Glomerular , Humanos , Rim/diagnóstico por imagem , Rim/efeitos dos fármacos , Neoplasias/metabolismo , Neoplasias/patologia , Prognóstico
9.
Pediatr Blood Cancer ; 66(7): e27747, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30968531

RESUMO

BACKGROUND: Adverse events (AEs) on Children's Oncology Group (COG) trials are reported manually by clinical research assistants (CRAs). The Common Terminology Criteria for Adverse Events (CTCAE) was developed to provide standardized definitions for identifying and grading AEs. The CTCAE has expanded significantly over its five versions, but the impact of CTCAE definitional changes has not been examined. PROCEDURE: This study compared AE number and ascertainment among the first four CTCAE versions using a case vignette. Each CTCAE version was used to create a list of AEs and grades by two separate CRAs. RESULTS: The CTCAE expanded from 9 categories and 49 AEs in v1.0 to 26 categories and 790 AEs in v4.0. CRAs independently selected different approaches to AE ascertainment-comprehensive and parsimonious. The number of AEs identified in the parsimonious approach was stable with 10-14 in each CTC version. The comprehensive approach identified 9, 20, 29, and 37 AEs in CTC versions 1.0, 2.0, 3.0, and 4.0, respectively. Only approximately 65% of AEs were conclusively graded in versions 2.0 to 4.0 using the comprehensive approach. CONCLUSIONS: CTCAE has increased in complexity. Although this increased complexity allows for more granular AE reporting, these data demonstrate potential unintended negative consequences of increasing CTC AE complexity, including the risk of varying approaches to AE capture. A comprehensive evaluation of CTC AE definitions and CRA reporting practices across COG institutions and AEs are needed to improve the accuracy and efficiency of AE reporting.


Assuntos
Registros Eletrônicos de Saúde , Neoplasias , Adolescente , Ensaios Clínicos como Assunto , Humanos , Masculino
10.
Pediatr Blood Cancer ; 66(10): e27869, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31222885

RESUMO

Overall survival rates for pediatric patients with high-risk or relapsed rhabdomyosarcoma (RMS) have not improved significantly since the 1980s. Recent studies have identified a number of targetable vulnerabilities in RMS, but these discoveries have infrequently translated into clinical trials. We propose streamlining the process by which agents are selected for clinical evaluation in RMS. We believe that strong consideration should be given to the development of combination therapies that add biologically targeted agents to conventional cytotoxic drugs. One example of this type of combination is the addition of the WEE1 inhibitor AZD1775 to the conventional cytotoxic chemotherapeutics, vincristine and irinotecan.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Desenvolvimento de Medicamentos/métodos , Descoberta de Drogas/métodos , Rabdomiossarcoma , Criança , Humanos , Projetos de Pesquisa
11.
J Immunol ; 198(3): 1093-1103, 2017 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-28039300

RESUMO

Experimental autoimmune uveitis (EAU), in which CD4+ Th1 and/or Th17 cells are immunopathogenic, mimics various clinical features of noninfectious uveitis in humans. The impact of bromodomain extraterminal (BET) inhibitors on Th17 cell function was studied in a mouse model of EAU in vivo and in mouse and human Th17 cells in vitro. Two BET inhibitors (GSK151 and JQ1) were able to ameliorate the progression of inflammation in EAU and in mouse CD4+ T cells in vitro, downregulating levels of Th17 cells. Additionally, the uveitogenic capacity of Th17 cells to transfer EAU was abrogated by BET inhibitors in an adoptive transfer model. In human CD4+ T cells, a 5-d exposure to BET inhibitors was accompanied by a significant downregulation of Th17-associated genes IL-17A, IL-22, and retinoic acid-related orphan receptor γt. However, in vitro, the inhibitors had no effect on already polarized Th17 cells. The key finding is that, in response to BET inhibitors, Th17-enriched cultures developed a regulatory phenotype, upregulated FOXP3 expression and IL-10 secretion, and lost pathogenicity in vivo. We conclude that BET targeting of Th17 cells is a potential therapeutic opportunity for a wide range of inflammatory and autoimmune diseases, including uveitis.


Assuntos
Doenças Autoimunes/tratamento farmacológico , Proteínas Cromossômicas não Histona/antagonistas & inibidores , Proteínas Nucleares/antagonistas & inibidores , Retina/efeitos dos fármacos , Células Th17/efeitos dos fármacos , Fatores de Transcrição/antagonistas & inibidores , Uveíte/tratamento farmacológico , Animais , Citocinas/biossíntese , Regulação para Baixo , Feminino , Fatores de Transcrição Forkhead/análise , Camundongos , Proteínas Nucleares/fisiologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/análise , Receptores CCR6/análise , Retina/imunologia , Células Th1/imunologia , Células Th17/imunologia , Fatores de Transcrição/fisiologia , Fator de Necrose Tumoral alfa/análise
12.
J Immunol ; 198(10): 4074-4085, 2017 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-28373581

RESUMO

Lymphocyte transendothelial migration (TEM) is critically dependent on intraendothelial signaling triggered by adhesion to ICAM-1. Here we show that endothelial MAPKs ERK, p38, and JNK mediate diapedesis-related and diapedesis-unrelated functions of ICAM-1 in cerebral and dermal microvascular endothelial cells (MVECs). All three MAPKs were activated by ICAM-1 engagement, either through lymphocyte adhesion or Ab-mediated clustering. MAPKs were involved in ICAM-1-dependent expression of TNF-α in cerebral and dermal MVECs, and CXCL8, CCL3, CCL4, VCAM-1, and cyclooxygenase 2 (COX-2) in cerebral MVECs. Endothelial JNK and to a much lesser degree p38 were the principal MAPKs involved in facilitating diapedesis of CD4+ lymphocytes across both types of MVECs, whereas ERK was additionally required for TEM across dermal MVECs. JNK activity was critical for ICAM-1-induced F-actin rearrangements. Furthermore, activation of endothelial ICAM-1/JNK led to phosphorylation of paxillin, its association with VE-cadherin, and internalization of the latter. Importantly ICAM-1-induced phosphorylation of paxillin was required for lymphocyte TEM and converged functionally with VE-cadherin phosphorylation. Taken together we conclude that during lymphocyte TEM, ICAM-1 signaling diverges into pathways regulating lymphocyte diapedesis, and other pathways modulating gene expression thereby contributing to the long-term inflammatory response of the endothelium.


Assuntos
Células Endoteliais/metabolismo , Inflamação/metabolismo , Molécula 1 de Adesão Intercelular/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Transdução de Sinais , Migração Transendotelial e Transepitelial , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Actinas/metabolismo , Encéfalo/irrigação sanguínea , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/fisiologia , Movimento Celular , Células Cultivadas , Quimiocina CCL3/genética , Quimiocina CCL3/imunologia , Quimiocina CCL4/genética , Quimiocina CCL4/imunologia , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Derme/irrigação sanguínea , Células Endoteliais/imunologia , Endotélio Vascular/citologia , Endotélio Vascular/imunologia , Endotélio Vascular/metabolismo , Ativação Enzimática , Humanos , Inflamação/imunologia , Interleucina-8/genética , Interleucina-8/imunologia , Sistema de Sinalização das MAP Quinases , Microvasos , Paxilina/metabolismo , Fosforilação , Fator de Necrose Tumoral alfa/metabolismo , Molécula 1 de Adesão de Célula Vascular/genética
13.
Proc Natl Acad Sci U S A ; 113(26): 7213-8, 2016 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-27298369

RESUMO

Lipoprotein-associated phospholipase A2 (Lp-PLA2) hydrolyses oxidized low-density lipoproteins into proinflammatory products, which can have detrimental effects on vascular function. As a specific inhibitor of Lp-PLA2, darapladib has been shown to be protective against atherogenesis and vascular leakage in diabetic and hypercholesterolemic animal models. This study has investigated whether Lp-PLA2 and its major enzymatic product, lysophosphatidylcholine (LPC), are involved in blood-retinal barrier (BRB) damage during diabetic retinopathy. We assessed BRB protection in diabetic rats through use of species-specific analogs of darapladib. Systemic Lp-PLA2 inhibition using SB-435495 at 10 mg/kg (i.p.) effectively suppressed BRB breakdown in streptozotocin-diabetic Brown Norway rats. This inhibitory effect was comparable to intravitreal VEGF neutralization, and the protection against BRB dysfunction was additive when both targets were inhibited simultaneously. Mechanistic studies in primary brain and retinal microvascular endothelial cells, as well as occluded rat pial microvessels, showed that luminal but not abluminal LPC potently induced permeability, and that this required signaling by the VEGF receptor 2 (VEGFR2). Taken together, this study demonstrates that Lp-PLA2 inhibition can effectively prevent diabetes-mediated BRB dysfunction and that LPC impacts on the retinal vascular endothelium to induce vasopermeability via VEGFR2. Thus, Lp-PLA2 may be a useful therapeutic target for patients with diabetic macular edema (DME), perhaps in combination with currently administered anti-VEGF agents.


Assuntos
1-Alquil-2-acetilglicerofosfocolina Esterase/metabolismo , Barreira Hematorretiniana/metabolismo , Diabetes Mellitus Experimental/metabolismo , Retinopatia Diabética/metabolismo , 1-Alquil-2-acetilglicerofosfocolina Esterase/antagonistas & inibidores , 1-Alquil-2-acetilglicerofosfocolina Esterase/sangue , Animais , Compostos de Bifenilo/sangue , Compostos de Bifenilo/farmacocinética , Compostos de Bifenilo/farmacologia , Masculino , Permeabilidade , Pirimidinonas/sangue , Pirimidinonas/farmacocinética , Pirimidinonas/farmacologia , Coelhos , Ratos Endogâmicos BN , Fator A de Crescimento do Endotélio Vascular/metabolismo
14.
Facial Plast Surg ; 35(4): 322-339, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31470461

RESUMO

The history of rhinoplasty is absolutely fascinating. It is replete with mysterious practices, intrigue, and imaginative thoughts. If necessity is the mother of invention, then sex, crimes, and punishment lay a legitimate claim to being the mother of rhinoplasty. The history of rhinoplasty is a global saga spanning the millennia. Practitioners of the art and science have included those demonstrating the most admirable traits espoused in the Hippocratic Oath, as well as those to whom the word "charlatan" might more aptly be applied. The truth of a story is illustrated in its telling, and we have attempted to be true historians. We recognize that observers and narrators, now well past (sic), have determined many of today's truths, and therefore their stories become our truths whether they were so or not. We have attempted to reference many who have contributed to the advance of this amazing surgical procedure, recognizing that we may have included some who have demonstrated marginal merit to be so. Assuredly, we have also unintentionally omitted some whom we should have included. From them we ask forbearance. Let the story begin, "Once upon a time…".


Assuntos
Rinoplastia , Cirurgia Plástica , Face , Humanos , Punição
15.
Am J Pathol ; 187(10): 2208-2221, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28739342

RESUMO

Current treatments for choroidal neovascularization, a major cause of blindness for patients with age-related macular degeneration, treat symptoms but not the underlying causes of the disease. Inflammation has been strongly implicated in the pathogenesis of choroidal neovascularization. We examined the inflammatory role of Toll-like receptor 2 (TLR2) in age-related macular degeneration. TLR2 was robustly expressed by the retinal pigment epithelium in mouse and human eyes, both normal and with macular degeneration/choroidal neovascularization. Nuclear localization of NF-κB, a major downstream target of TLR2 signaling, was detected in the retinal pigment epithelium of human eyes, particularly in eyes with advanced stages of age-related macular degeneration. TLR2 antagonism effectively suppressed initiation and growth of spontaneous choroidal neovascularization in a mouse model, and the combination of anti-TLR2 and antivascular endothelial growth factor receptor 2 yielded an additive therapeutic effect on both area and number of spontaneous choroidal neovascularization lesions. Finally, in primary human fetal retinal pigment epithelium cells, ligand binding to TLR2 induced robust expression of proinflammatory cytokines, and end products of lipid oxidation had a synergistic effect on TLR2 activation. Our data illustrate a functional role for TLR2 in the pathogenesis of choroidal neovascularization, likely by promoting inflammation of the retinal pigment epithelium, and validate TLR2 as a novel therapeutic target for reducing choroidal neovascularization.


Assuntos
Neovascularização de Coroide/patologia , Inflamação/patologia , Degeneração Macular/patologia , Epitélio Pigmentado da Retina/metabolismo , Epitélio Pigmentado da Retina/patologia , Receptor 2 Toll-Like/metabolismo , Idoso , Idoso de 80 Anos ou mais , Animais , Anticorpos Neutralizantes/farmacologia , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Núcleo Celular/efeitos da radiação , Chlamydia/efeitos dos fármacos , Chlamydia/efeitos da radiação , Neovascularização de Coroide/complicações , Neovascularização de Coroide/metabolismo , Citocinas/metabolismo , Dipeptídeos/farmacologia , Raios gama , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos da radiação , Humanos , Inflamação/complicações , Inflamação/genética , Lipídeos/química , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/patologia , Degeneração Macular/complicações , Degeneração Macular/metabolismo , Masculino , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Oxirredução , Transporte Proteico/efeitos dos fármacos , Transporte Proteico/efeitos da radiação
16.
Pediatr Blood Cancer ; 65(3)2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29090524

RESUMO

BACKGROUND: Erwinia asparaginase is a Food and Drug Administration approved agent for the treatment of acute lymphoblastic leukemia (ALL) for patients who develop hypersensitivity to Escherichia coli derived asparaginases. Erwinia asparaginase is efficacious, but has a short half-life, requiring six doses to replace one dose of the most commonly used first-line asparaginase, pegaspargase, a polyethylene glycol (PEG) conjugated E. coli asparaginase. Pegcristantaspase, a recombinant PEGylated Erwinia asparaginase with improved pharmacokinetics, was developed for patients with hypersensitivity to pegaspargase. Here, we report a series of patients treated on a pediatric phase 2 trial of pegcrisantaspase. PROCEDURE: Pediatric patients with ALL or lymphoblastic lymphoma and hypersensitivity to pegaspargase enrolled on Children's Oncology Group trial AALL1421 (Jazz 13-011) and received intravenous pegcrisantaspase. Serum asparaginase activity (SAA) was monitored before and after dosing; immunogenicity assays were performed for antiasparaginase and anti-PEG antibodies and complement activation was evaluated. RESULTS: Three of the four treated patients experienced hypersensitivity to pegcrisantaspase manifested as clinical hypersensitivity reactions or rapid clearance of SAA. Immunogenicity assays demonstrated the presence of anti-PEG immunoglobulin G antibodies in all three hypersensitive patients, indicating a PEG-mediated immune response. CONCLUSIONS: This small series of patients, nonetheless, provides data, suggesting preexisting immunogenicity against the PEG moiety of pegaspargase and poses the question as to whether PEGylation may be an effective strategy to optimize Erwinia asparaginase administration. Further study of larger cohorts is needed to determine the incidence of preexisting antibodies against PEG-mediated hypersensitivity to pegaspargase.


Assuntos
Asparaginase , Proteínas de Bactérias , Hipersensibilidade a Drogas/epidemiologia , Erwinia/enzimologia , Polietilenoglicóis , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiologia , Adolescente , Adulto , Asparaginase/administração & dosagem , Asparaginase/efeitos adversos , Asparaginase/farmacocinética , Proteínas de Bactérias/administração & dosagem , Proteínas de Bactérias/efeitos adversos , Proteínas de Bactérias/farmacocinética , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/efeitos adversos , Polietilenoglicóis/farmacocinética
17.
Ann Intern Med ; 175(6): 905, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35793491
18.
Facial Plast Surg ; 34(1): 29-35, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29409101

RESUMO

Alar base reduction (ABR) was first described by Weir in 1892, but continues to be a controversial topic in rhinoplasty in terms of optimal techniques. The authors describe the techniques for ABR including internal, external and combined ABR, flare excisions, and alar hooding reductions. The techniques described have resulted in consistent outcomes with acceptable scarring and high patient satisfaction.


Assuntos
Cartilagens Nasais/cirurgia , Septo Nasal/anatomia & histologia , Nariz/anatomia & histologia , Rinoplastia/métodos , Cicatriz/prevenção & controle , Estética , Feminino , Seguimentos , Humanos , Masculino , Cartilagens Nasais/anatomia & histologia , Septo Nasal/cirurgia , Nariz/cirurgia , Rinoplastia/efeitos adversos , Resultado do Tratamento
19.
Pediatr Blood Cancer ; 64(11)2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28509433

RESUMO

An analysis of dose modifications for infants in 29 Children's Oncology Group protocols across 10 cancer types revealed 11 sets of criteria defining the infant population using age, weight, body surface area (BSA), or a combination of these parameters and eight dose modification methods. A new method of dosing anticancer drugs in infants was developed based on the rationale that prior modifications were implemented to reduce toxicity, which is not cancer-specific. The new method uses BSA dose banding in dosing tables for infants and children with a BSA <0.6 m2 and gradually transitions from body weight based to BSA-based dosing.


Assuntos
Antineoplásicos/normas , Neoplasias/tratamento farmacológico , Guias de Prática Clínica como Assunto/normas , Antineoplásicos/administração & dosagem , Pré-Escolar , Relação Dose-Resposta a Droga , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Neoplasias/patologia , Prognóstico
20.
Facial Plast Surg ; 33(3): 252-259, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28571061

RESUMO

This paper presents an extensive literature review of the psychology of facelift patients as it has evolved over the past 50 years. Earlier studies revealed significant levels of pre and perioperative depression. Facelift patients generally exhibit emotional and social concerns about facial appearance that are higher than the general population. Many are undergoing midlife situational stresses and may lack the positive characteristics to deal with them. The most common diagnoses seen include depression, impulsivity, unstable personality, and passive dependence, albeit not necessarily serious. Improvement in body image is the major driver for surgery. Characteristics of female patients as defined by their age are described. These include the younger emotionally dependent group, the worker group of middle age, and the older grief group. Male patients are seen to have a higher level of psychological dysfunction, but a higher improvement in postoperative quality of life. Motivations for surgery include increasing self-esteem, making new friends, improving relationships, and getting better jobs. Overall patient satisfaction is more than 95%, with improvement seen in positive changes in their life, increased self-confidence and self-esteem, decreased self-consciousness about their appearance, and overall improvement in quality of life. Postoperative psychological reactions are seen in about half the patients, these primarily being anxiety and depression of varying degrees. Predictors of patient satisfaction include the desire for self-image improvement in contradistinction to a change in life situation. Negative predictors include male sex, young age, unrealistic expectations, relationship disturbances, and preexisting psychological pathology. The importance of good patient selection in achieving a satisfied patient is outlined and emphasized.


Assuntos
Imagem Corporal/psicologia , Satisfação do Paciente , Seleção de Pacientes , Ritidoplastia/psicologia , Humanos , Motivação , Qualidade de Vida , Fatores Sexuais
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