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1.
Am J Obstet Gynecol ; 231(1): 109.e1-109.e9, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38365098

RESUMO

BACKGROUND: Uterine fibroids are the most common benign tumors that affect females. A laparoscopic myomectomy is the standard surgical treatment for most women who wish to retain their uterus. The most common complication of a myomectomy is excessive bleeding. However, risk factors for hemorrhage during a laparoscopic myomectomy are not well studied and no risk stratification tool specific for identifying the need for a blood transfusion during a laparoscopic myomectomy currently exists in the literature. OBJECTIVE: This study aimed to identify risk factors for intraoperative and postoperative blood transfusion during laparoscopic myomectomies and to develop a risk stratification tool to determine the risk for requiring a blood transfusion. STUDY DESIGN: This was a retrospective cohort study of the American College of Surgeons National Surgical Quality Improvement Program database from 2012 to 2020. Women who underwent a laparoscopic (conventional or robotic) myomectomy were included. Women who received 1 or more blood transfusions within 72 hours after the start time of a laparoscopic myomectomy were compared with those who did not require a blood transfusion. A multivariable analysis was performed to identify risk factors independently associated with the risk for transfusion. Two risk stratification tools to determine the need for a blood transfusion were developed based on the multivariable results, namely (1) based on preoperative factors and (2) based on preoperative and intraoperative factors. RESULTS: During the study period, 11,498 women underwent a laparoscopic myomectomy. Of these, 331(2.9%) required a transfusion. In a multivariable regression analysis of the preoperative factors, Black or African American and Asian races, Hispanic ethnicity, bleeding disorders, American Society of Anesthesiologists class III or IV classification, and a preoperative hematocrit value ≤35.0% were independently associated with the risk for transfusion. Identified intraoperative factors included specimen weight >250 g or ≥5 intramural myomas and an operation time of ≥197 minutes. A risk stratification tool was developed in which points are assigned based on the identified risk factors. The mean probability of transfusion can be calculated based on the sum of the points. CONCLUSION: We identified preoperative and intraoperative independent risk factors for a blood transfusion among women who underwent a laparoscopic myomectomy. A risk stratification tool to determine the risk for requiring a blood transfusion was developed based on the identified risk factors. Further studies are needed to validate this tool.


Assuntos
Perda Sanguínea Cirúrgica , Transfusão de Sangue , Laparoscopia , Leiomioma , Melhoria de Qualidade , Miomectomia Uterina , Neoplasias Uterinas , Humanos , Feminino , Transfusão de Sangue/estatística & dados numéricos , Estudos Retrospectivos , Adulto , Leiomioma/cirurgia , Perda Sanguínea Cirúrgica/estatística & dados numéricos , Neoplasias Uterinas/cirurgia , Fatores de Risco , Pessoa de Meia-Idade , Medição de Risco , Estados Unidos , Estudos de Coortes
2.
Pigment Cell Melanoma Res ; 35(1): 78-87, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34347929

RESUMO

Metastatic uveal melanoma (UM) responds poorly to targeted therapies and immune checkpoint inhibitors. Loss of BRCA1-associated protein 1 (BAP1) via inactivating mutations in the BAP1 gene is associated with UM progression. Thus, molecular alterations caused by BAP1 dysfunction may be novel therapeutic targets for metastatic UM. Here, we found that phosphorylation of AMP-dependent kinase (AMPK) was elevated in BAP1-altered (or mutant) compared to BAP1-unaltered (or wild-type [WT]) UM tumors. As a readout of AMPK pathway activation, phosphorylation of an AMPK downstream effector, acetyl-CoA-carboxylase (ACC), was also elevated. BAP1 re-expression in BAP1-null UM cell lines decreased phospho-AMPK (pAMPK) and phospho-ACC (pACC) levels. AMPK phosphorylation is mediated by calcium/calmodulin dependent protein kinase kinase 2 (CaMKK2) and potentially liver kinase B1 (LKB1) in BAP1 mutant UM cells. Knockdown of AMPKα1/2 reduced the viability of BAP1 mutant UM cells, indicating a survival function of AMPK in BAP1 mutant UM. Our data suggest that the AMPK pathway is an important mechanism mediating the survival of BAP1 mutant UM. Targeting the AMPK pathway may be a novel therapeutic strategy for metastatic UM.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Melanoma/enzimologia , Mutação , Proteínas Supressoras de Tumor/genética , Ubiquitina Tiolesterase/genética , Neoplasias Uveais/enzimologia , Proteínas Quinases Ativadas por AMP/genética , Acetil-CoA Carboxilase/metabolismo , Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular , Ativação Enzimática , Humanos , Melanoma/genética , Melanoma/patologia , Fosforilação , Transdução de Sinais , Neoplasias Uveais/genética , Neoplasias Uveais/patologia
4.
Oncogene ; 40(3): 618-632, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33208912

RESUMO

Cancer cell metabolism is a targetable vulnerability; however, a precise understanding of metabolic heterogeneity is required. Inactivating mutations in BRCA1-associated protein 1 (BAP1) are associated with metastasis in uveal melanoma (UM), the deadliest adult eye cancer. BAP1 functions in UM remain unclear. UM patient sample analysis divided BAP1 mutant UM tumors into two subgroups based on oxidative phosphorylation (OXPHOS) gene expression suggesting metabolic heterogeneity. Consistent with patient data, transcriptomic analysis of BAP1 mutant UM cell lines also showed OXPHOShigh or OXPHOSlow subgroups. Integrated RNA sequencing, metabolomics, and molecular analyses showed that OXPHOShigh BAP1 mutant UM cells utilize glycolytic and nucleotide biosynthesis pathways, whereas OXPHOSlow BAP1 mutant UM cells employ fatty acid oxidation. Furthermore, the two subgroups responded to different classes of metabolic suppressors. Our findings indicate that targeting cancer metabolism is a promising therapeutic option for BAP1 mutant UM; however, tailored approaches may be required due to metabolic heterogeneities.


Assuntos
Melanoma/metabolismo , Mutação , Fosforilação Oxidativa , Proteínas Supressoras de Tumor/metabolismo , Ubiquitina Tiolesterase/metabolismo , Neoplasias Uveais/metabolismo , Linhagem Celular Tumoral , Humanos , Melanoma/tratamento farmacológico , Melanoma/genética , Melanoma/patologia , Proteínas Supressoras de Tumor/genética , Ubiquitina Tiolesterase/genética , Neoplasias Uveais/tratamento farmacológico , Neoplasias Uveais/genética , Neoplasias Uveais/patologia
5.
Mol Cancer Ther ; 19(8): 1719-1726, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32430489

RESUMO

Frequent GNAQ and GNA11 mutations in uveal melanoma hyperactivate the MEK-ERK signaling pathway, leading to aberrant regulation of cyclin-dependent kinases (CDK) and cell-cycle progression. MEK inhibitors (MEKi) alone show poor efficacy in uveal melanoma, raising the question of whether downstream targets can be vertically inhibited to provide long-term benefit. CDK4/6 selective inhibitors are FDA-approved in patients with estrogen receptor (ER)-positive breast cancer in combination with ER antagonists/aromatase inhibitors. We determined the effects of MEKi plus CDK4/6 inhibitors (CDK4/6i) in uveal melanoma. In vitro, palbociclib, a CDK4/6i, enhanced the effects of MEKi via downregulation of cell-cycle proteins. In contrast, in vivo CDK4/6 inhibition alone led to cytostasis and was as effective as MEKi plus CDK4/6i treatment at delaying tumor growth. RNA sequencing revealed upregulation of the oxidative phosphorylation (OxPhos) pathway in both MEKi-resistant tumors and CDK4/6i-tolerant tumors. Furthermore, oxygen consumption rate was increased following MEKi + CDK4/6i treatment. IACS-010759, an OxPhos inhibitor, decreased uveal melanoma cell survival in combination with MEKi + CDK4/6i. These data highlight adaptive upregulation of OxPhos in response to MEKi + CDK4/6i treatment in uveal melanoma and suggest that suppression of this metabolic state may improve the efficacy of MEKi plus CDK4/6i combinations.


Assuntos
Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , MAP Quinase Quinase 1/antagonistas & inibidores , Melanoma/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Transcriptoma/efeitos dos fármacos , Neoplasias Uveais/tratamento farmacológico , Animais , Apoptose , Benzamidas/farmacologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Proliferação de Células , Difenilamina/análogos & derivados , Difenilamina/farmacologia , Feminino , Perfilação da Expressão Gênica , Humanos , Melanoma/metabolismo , Melanoma/patologia , Camundongos , Camundongos Nus , Fosforilação Oxidativa , Consumo de Oxigênio , Piridonas/farmacologia , Pirimidinonas/farmacologia , Células Tumorais Cultivadas , Neoplasias Uveais/metabolismo , Neoplasias Uveais/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
6.
EMBO Mol Med ; 11(2)2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30610113

RESUMO

Alterations in transcriptional programs promote tumor development and progression and are targetable by bromodomain and extraterminal (BET) protein inhibitors. However, in a multi-site clinical trial testing the novel BET inhibitor, PLX51107, in solid cancer patients, liver metastases of uveal melanoma (UM) patients progressed rapidly following treatment. Mechanisms of resistance to BET inhibitors in UM are unknown. We show that fibroblast growth factor 2 (FGF2) rescued UM cells from growth inhibition by BET inhibitors, and FGF2 effects were reversible by FGF receptor (FGFR) inhibitors. BET inhibitors also increased FGFR protein expression in UM cell lines and in patient tumor samples. Hepatic stellate cells (HSCs) secrete FGF2, and HSC-conditioned medium provided resistance of UM cells to BET inhibitors. PLX51107 was ineffective in vivo, but the combination of a FGFR inhibitor, AZD4547, and PLX51107 significantly suppressed the growth of xenograft UM tumors formed from subcutaneous inoculation of UM cells with HSCs and orthotopically in the liver. These results suggest that co-targeting of FGFR signaling is required to increase the responses of metastatic UM to BET inhibitors.


Assuntos
Proliferação de Células , Fator 2 de Crescimento de Fibroblastos/metabolismo , Melanócitos/fisiologia , Melanoma/patologia , Proteínas/metabolismo , Neoplasias Uveais/patologia , Animais , Antineoplásicos/metabolismo , Células Cultivadas , Meios de Cultivo Condicionados , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos , Células Estreladas do Fígado/fisiologia , Humanos , Melanoma/tratamento farmacológico , Camundongos , Neoplasias Uveais/tratamento farmacológico
7.
Mol Cancer Ther ; 16(3): 516-528, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28138035

RESUMO

Patients with metastatic uveal melanoma usually die within 1 year of diagnosis, emphasizing an urgent need to develop new treatment strategies. The liver is the most common site of metastasis. Mitogen-activated protein kinase kinase (MEK) inhibitors improve survival in V600 BRAF-mutated cutaneous melanoma patients but have limited efficacy in patients with uveal melanoma. Our previous work showed that hepatocyte growth factor (HGF) signaling elicits resistance to MEK inhibitors in metastatic uveal melanoma. In this study, we demonstrate that expression of two BH3-only family proteins, Bim-EL and Bmf, contributes to HGF-mediated resistance to MEK inhibitors. Targeting HGF/cMET signaling with LY2875358, a neutralizing and internalizing anti-cMET bivalent antibody, and LY2801653, a dual cMET/RON inhibitor, overcomes resistance to trametinib provided by exogenous HGF and by conditioned medium from primary hepatic stellate cells. We further determined that activation of PI3Kα/γ/δ isoforms mediates the resistance to MEK inhibitors by HGF. Combination of LY2801653 with trametinib decreases AKT phosphorylation and promotes proapoptotic PARP cleavage in metastatic uveal melanoma explants. Together, our data support the notion that selectively blocking cMET signaling or PI3K isoforms in metastatic uveal melanoma may break the intrinsic resistance to MEK inhibitors provided by factors from stromal cells in the liver. Mol Cancer Ther; 16(3); 516-28. ©2017 AACR.


Assuntos
Antineoplásicos/farmacologia , Fator de Crescimento de Hepatócito/metabolismo , Melanoma/metabolismo , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-met/metabolismo , Transdução de Sinais/efeitos dos fármacos , Neoplasias Uveais/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Apoptose/efeitos dos fármacos , Apoptose/genética , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/genética , Células Estreladas do Fígado/metabolismo , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Melanoma/tratamento farmacológico , Melanoma/genética , Melanoma/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase , Piridonas/farmacologia , Pirimidinonas/farmacologia , Neoplasias Uveais/tratamento farmacológico , Neoplasias Uveais/genética , Neoplasias Uveais/patologia
8.
Mar Pollut Bull ; 54(12): 1857-67, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17928009

RESUMO

A novel toxicity method to determine sublethal and lethal effects of manmade contaminants on the bioluminescence output from marine dinoflagellates has been developed and tested over the course of 16 years. The toxicity system, QwikLite, was developed for the sole purpose of evaluating the potential toxicity of various materials used in bay sediments, storm water discharges, industrial discharges from Naval facilities, and antifoulant paints. Bioluminescence inhibition was observed in the following dinoflagellates: Lingulodinium polyedrum (formerly known as Gonyaulax polyedra), Ceratocorys horrida, Pyrocystis noctiluca, Pyrocystis lunula, Pyrocystis fusiformis, and Pyrophacus steinii. Cultured cells were exposed to various concentrations of contaminants from hours through 10 days. Further application with bioluminescent dinoflagellates in a variety of toxicity testing schemes have shown that these species can be used as a screening assay organism in lieu of the more costly, labor intensive bioassays presently in use.


Assuntos
Dinoflagellida/efeitos dos fármacos , Monitoramento Ambiental/métodos , Medições Luminescentes , Poluentes Químicos da Água/toxicidade , Anfípodes/efeitos dos fármacos , Animais , Bioensaio/instrumentação , Bioensaio/métodos , Dinoflagellida/metabolismo , Monitoramento Ambiental/instrumentação , Sedimentos Geológicos/análise , Metais Pesados/toxicidade , Medição de Risco/métodos , Ouriços-do-Mar/efeitos dos fármacos , Dodecilsulfato de Sódio/toxicidade , Testes de Toxicidade/instrumentação , Testes de Toxicidade/métodos
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