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1.
Cancers (Basel) ; 15(16)2023 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-37627061

RESUMO

Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma. Despite decades of clinical trials, the overall survival rate for patients with relapsed and metastatic disease remains below 30%, underscoring the need for novel treatments. FGFR4, a receptor tyrosine kinase that is overexpressed in RMS and mutationally activated in 10% of cases, is a promising target for treatment. Here, we show that futibatinib, an irreversible pan-FGFR inhibitor, inhibits the growth of RMS cell lines in vitro by inhibiting phosphorylation of FGFR4 and its downstream targets. Moreover, we provide evidence that the combination of futibatinib with currently used chemotherapies such as irinotecan and vincristine has a synergistic effect against RMS in vitro. However, in RMS xenograft models, futibatinib monotherapy and combination treatment have limited efficacy in delaying tumor growth and prolonging survival. Moreover, limited efficacy is only observed in a PAX3-FOXO1 fusion-negative (FN) RMS cell line with mutationally activated FGFR4, whereas little or no efficacy is observed in PAX3-FOXO1 fusion-positive (FP) RMS cell lines with FGFR4 overexpression. Alternative treatment modalities such as combining futibatinib with other kinase inhibitors or targeting FGFR4 with CAR T cells or antibody-drug conjugate may be more effective than the approaches tested in this study.

2.
Clin Exp Ophthalmol ; 40(7): 713-20, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22429807

RESUMO

BACKGROUND: To evaluate the correlation between optic nerve head parameters and retinal nerve fiber layer thickness measured by Cirrus HD spectral-domain optical coherence tomography (Cirrus HD-OCT; Carl Zeiss Meditec) in healthy myopic eyes. DESIGN: Cross-sectional study. PARTICIPANTS: One hundred and sixty-one right eyes from 161 healthy young myopic subjects. METHODS: Optic nerve head parameters and retinal nerve fiber layer thickness were measured with the Cirrus HD-OCT. The distance between optic disc margin and scan circle (disc margin-to-scan distance) was measured on the Cirrus HD-OCT en-face optic nerve head image with aid of National Institutes of Health ImageJ image-analysis software (developed by Wayne Rasbands, National Institutes of Health, Bethesda, MD). MAIN OUTCOME MEASURES: The correlations among optic nerve head parameters, retinal nerve fibre layer thickness and the disc margin-to-scan distance were evaluated with and without adjustment of the magnification effect. RESULTS: Without correction of the magnification effect, the thicker average retinal nerve fiber layer was correlated with greater rim area and lower degree of myopia (P < 0.001). When the magnification effect was corrected, thicker average retinal nerve fibre layer was associated with greater disc area and greater rim area in univariate and multivariate analyses (P ≤ 0.028); however, degrees of myopia and the disc margin-to-scan distance were not significantly associated with average RNFL thickness (P ≥ 0.104). CONCLUSIONS: Thicker average retinal nerve fibre layer thickness was associated with greater rim and disc areas. Disc margin-to-scan distance was not significantly correlated with average retinal nerve fibre layer thickness in healthy myopic eyes.


Assuntos
Glaucoma de Ângulo Aberto/diagnóstico , Glaucoma de Baixa Tensão/diagnóstico , Miopia/complicações , Fibras Nervosas/patologia , Disco Óptico/patologia , Células Ganglionares da Retina/patologia , Tomografia de Coerência Óptica , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Feminino , Humanos , Imageamento Tridimensional , Pressão Intraocular , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Reprodutibilidade dos Testes , Adulto Jovem
4.
Obes Surg ; 24(3): 377-84, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24307434

RESUMO

Hiatal hernia (HH) repairs are commonly done concomitantly with laparoscopic Roux-en-Y gastric bypass (LRYGB) and laparoscopic adjustable gastric banding (LAGB) to decrease gastroesophageal reflux disease (GERD). There is limited evidence about the additional surgical risk these combined procedures engender. We used the United States Nationwide Inpatient Sample 2004-2009 to compare mortality risk, prolonged length of stay (PLOS), and perioperative adverse events using propensity score-matched analysis. We repeated the analysis after removing patients diagnosed with GERD. There were 42,272 weighted patients undergoing LRYGB alone representing 206,559 discharges nationally and an additional 1,945 and 9,060, respectively, undergoing LRYGB + HH repair. For LAGB, there were 10,558 records representing 52,901 LAGB-only discharges and 1,959 representing 9,893 LAGB + HH repair discharges. Thirty-eight percent (95 % CI: 36, 41 %) of the patients in the LRYGB-only group had GERD compared to 55 % (51, 59 %) in the LRYGB + HH repair group. Among the LAGB groups, 31 % (28, 34 %) of LAGB-only patients had GERD compared to 44 % (38, 49 %) in the LAGB + HH repair group. We find that the average treatment effect on the treated (considering the concomitant procedure as treatment and the single procedure as control) for PLOS was -0.12353 (-0.15909, -0.08797) between the LRYGB groups and -0.04353 (-0.07488, -0.01217) for the LAGB groups. We find no evidence of increased risk of perioperative adverse events among patients undergoing concomitant HH repair with LRYGB or LAGB. Patients undergoing the combined procedure appear to be at lower risk of PLOS; this may be due to surgical training norms.


Assuntos
Derivação Gástrica , Gastroplastia , Hérnia Hiatal/cirurgia , Herniorrafia , Laparoscopia , Tempo de Internação/estatística & dados numéricos , Obesidade Mórbida/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Índice de Massa Corporal , Bases de Dados Factuais , Feminino , Derivação Gástrica/efeitos adversos , Refluxo Gastroesofágico/epidemiologia , Refluxo Gastroesofágico/etiologia , Gastroplastia/efeitos adversos , Hérnia Hiatal/mortalidade , Herniorrafia/efeitos adversos , Humanos , Laparoscopia/efeitos adversos , Masculino , Pessoa de Meia-Idade , Obesidade Mórbida/mortalidade , Medição de Risco , Resultado do Tratamento , Estados Unidos/epidemiologia
5.
Cancer Res ; 69(21): 8455-62, 2009 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-19843855

RESUMO

The usurping of translational control by sustained activation of translation initiation factors is oncogenic. Here, we show that the primary negative regulators of these oncogenic initiation factors--the 4E-BP protein family--operate as guardians of a translational control checkpoint in lung tumor defense. When challenged with the tobacco carcinogen 4-(methylnitrosamino)-I-(3-pyridyl)-1-butanone (NNK), 4ebp1(-/-)/4ebp2(-/-) mice showed increased sensitivity to tumorigenesis compared with their wild-type counterparts. The 4E-BP-deficient state per se creates pro-oncogenic, genome-wide skewing of the molecular landscape, with translational activation of genes governing angiogenesis, growth, and proliferation, and translational activation of the precise cytochrome p450 enzyme isoform (CYP2A5) that bioactivates NNK into mutagenic metabolites. Our study provides in vivo proof for a translational control checkpoint in lung tumor defense.


Assuntos
Proteínas de Transporte/fisiologia , Fatores de Iniciação em Eucariotos/fisiologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Fosfoproteínas/fisiologia , Biossíntese de Proteínas , Proteínas Adaptadoras de Transdução de Sinal , Animais , Carcinógenos/toxicidade , Proteínas de Ciclo Celular , Proliferação de Células , Sistema Enzimático do Citocromo P-450/metabolismo , Adutos de DNA/genética , Pulmão/metabolismo , Pulmão/patologia , Neoplasias Pulmonares/induzido quimicamente , Camundongos , Camundongos Endogâmicos A , Camundongos Endogâmicos BALB C , Camundongos Knockout , Análise em Microsséries , Microssomos/metabolismo , Neovascularização Patológica , Nitrosaminas/toxicidade , Ribossomos/fisiologia
6.
Ophthalmology ; 109(9): 1607-11, 2002 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-12208706

RESUMO

OBJECTIVE: To evaluate the long-term effectiveness of glaucoma management in patients undergoing primary glaucoma triple procedure (PGTP) with and without adjunctive subconjunctival mitomycin-C (MMC). DESIGN: Case-controlled study. PARTICIPANTS: Of the 203 eyes of 203 primary open-angle glaucoma (POAG) patients who had undergone PGTP and in whom reliable Humphrey visual fields had been obtained both before and after surgery at 13.5 +/- 8.9 and 27.9 +/- 8.9 months, 124 of the 144 eyes that received MMC during surgery were matched to the other 59 eyes that did not with respect to cup-to-disc ratio and risk factors for filtration failure in addition to other variables. MAIN OUTCOME MEASURES: Both preoperative and postoperative intraocular pressure (IOP), Humphrey visual fields and their global indices, number of glaucoma medications, and best-corrected visual acuity (BCVA). RESULTS: There were no significant differences in demographics between the two groups (P > 0.05 for each). Whereas both the control and the MMC groups attained significant decreases of mean IOP (18.5 +/- 5.7 mmHg-;15.6 +/- 4.6 mmHg, P = 0.0014; 19.3 +/- 7.0 mmHg-13.7 +/- 4.9 mmHg, P = 0.0001) and mean number of medications (2.1 +/- 1.3-1.3 +/- 1.3, P = 0.0001; 2.3 +/- 1.2-1.0 +/- 1.3, P = 0.0001) at 36 months after surgery, the MMC group had significantly lower mean IOP than the control group at all postoperative visits (P < 0.05 for each). The MMC group also tended to have less medical dependency after surgery than the control group. There was no significant difference in postoperative BCVA between the two groups. Patients in both groups had mean visual acuity of 20/30 or better. There was a significant worsening of corrected pattern standard deviation (CPSD) in the control group (3.97 +/- 3.18-5.17 +/- 3.36, P = 0.001) compared with no significant change in the MMC group (5.07 +/- 4.11-5.23 +/- 3.36, P = 0.93). The mean deviation did not change significantly in either group. CONCLUSIONS: The long-term glaucoma management in POAG patients with cataract undergoing PGTP indicates a successful outcome in final IOP, medical dependency, and BCVA. Furthermore, the MMC group had better IOP control and stable visual fields (CPSD), whereas the control group had a significant worsening of CPSD.


Assuntos
Glaucoma de Ângulo Aberto/terapia , Pressão Intraocular/fisiologia , Implante de Lente Intraocular , Mitomicina/uso terapêutico , Facoemulsificação , Trabeculectomia , Campos Visuais/fisiologia , Idoso , Antibióticos Antineoplásicos/uso terapêutico , Catarata/complicações , Catarata/terapia , Feminino , Seguimentos , Glaucoma de Ângulo Aberto/complicações , Glaucoma de Ângulo Aberto/fisiopatologia , Humanos , Masculino , Estudos Retrospectivos , Malha Trabecular/fisiologia , Resultado do Tratamento , Acuidade Visual
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