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1.
Gynecol Oncol ; 181: 8-11, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38096674

RESUMO

OBJECTIVE: To identify correlations between disease recurrence and adherence to NCCN posttreatment surveillance guidelines in patients who develop recurrent uterine cancer. METHODS: Retrospective analysis identified patients (n = 60) with recurrent uterine cancer and at least one surveillance visit with a gynecologic oncologist between 2011 and 2020. Adherence to NCCN guidelines and details of recurrence were recorded. RESULTS: Recurrent uterine cancer was identified in 60 patients with an average time to recurrence (TTR) of 25 months. Of those, 39 (65%) were adherent to NCCN surveillance guidelines and 36 (60%) were symptomatic at the time of recurrence diagnosis. Asymptomatic recurrence was diagnosed by imaging in 11 (46%), physical exam in 7 (29%), and blood work in 6 (25%) patients. Patients who were adherent to NCCN guidelines were diagnosed with recurrence on average 11 months earlier (p = 0.0336). Adherence was an independent predictor of TTR for all patients regardless of symptoms. There was no significant effect of age, race, primary language, or stage of disease on adherence. CONCLUSION: Adherence to NCCN posttreatment surveillance guidelines for uterine cancer is independently associated with an earlier diagnosis of recurrence.


Assuntos
Neoplasias do Endométrio , Neoplasias Uterinas , Humanos , Feminino , Estudos Retrospectivos , Neoplasias Uterinas/diagnóstico , Neoplasias Uterinas/terapia , Fidelidade a Diretrizes
2.
J Int AIDS Soc ; 22(4): e25276, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-31037845

RESUMO

INTRODUCTION: Geographic and transportation barriers are associated with poorer HIV-related health outcomes in sub-Saharan Africa, but data on the impact of these barriers on prevention interventions are limited. We estimated the association between distance to clinic and other transportation-related barriers on pre-exposure prophylaxis (PrEP) uptake and initial clinic visit attendance in a rural community in southwestern Uganda enrolled in the ongoing SEARCH study (NCT01864603). METHODS: Community-wide HIV testing was conducted and offered to adult (≥15 years) participants in Ruhoko. Participants were eligible for PrEP based on an empiric risk score, having an HIV-discordant partner, or self-referral at either the community health campaign or during home-based testing from March to April 2017. We collected data from PrEP-eligible households on GPS-measured distance to clinic, walking time to clinic and road difficulty. A sample of participants was also asked to identify their primary barriers to PrEP use with a semi-quantitative questionnaire. We used multivariable logistic regression to evaluate the association between transportation barriers and (1) PrEP uptake among PrEP-eligible individuals and (2) four-week clinic visit attendance among PrEP initiators. RESULTS: Of the 701 PrEP-eligible participants, 272 (39%) started PrEP within four weeks; of these, 45 (17%) were retained at four weeks. Participants with a distance to clinic of ≥2 km were less likely to start PrEP (aOR 0.34; 95% CI 0.15 to 0.79, p = 0.012) and less likely to be retained on PrEP once initiated (aOR 0.29; 95% CI 0.10 to 0.84; p = 0.024). Participants who were deemed eligible during home-based testing and did not have the option of same-day PrEP start were also substantially less likely to initiate PrEP (aOR 0.16, 95% CI 0.07 to 0.37, p < 0.001). Of participants asked to name barriers to PrEP use (N = 98), the most frequently cited were "needing to take PrEP every day" (N = 18) and "low/no risk of getting HIV" (N = 18). Transportation-related barriers, including "clinic is too far away" (N = 6) and "travel away from home" (N = 4) were also reported. CONCLUSIONS: Distance to clinic is a significant predictor of PrEP uptake and four-week follow-up visit attendance in a community in rural Uganda. Interventions that address geographic and transportation barriers may improve PrEP uptake and retention in sub-Saharan Africa.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Adolescente , Adulto , Assistência Ambulatorial , Instituições de Assistência Ambulatorial , Feminino , Infecções por HIV/epidemiologia , Infecções por HIV/fisiopatologia , Infecções por HIV/psicologia , Acessibilidade aos Serviços de Saúde , Humanos , Masculino , Adesão à Medicação , Profilaxia Pré-Exposição , População Rural , Uganda/epidemiologia , Caminhada , Adulto Jovem
3.
Endocrinology ; 151(2): 576-85, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19952270

RESUMO

Hypothalamic insulin signaling is essential to the maintenance of glucose and energy homeostasis. During pathological states, such as obesity and type 2 diabetes mellitus, insulin signaling is impaired. One key mechanism involved in the development of insulin resistance is lipotoxicity, through increased circulating saturated fatty acids. Although many studies have begun to determine the underlying mechanisms of lipotoxicity in peripheral tissues, little is known about the effects of excess lipids in the brain. We used a hypothalamic, neuronal cell model, mHypoE-44, to understand how the highly prevalent nonesterified fatty acid, palmitate, affects neuronal insulin signaling. Through Western blot analysis, we discerned that prolonged exposure to palmitate impairs insulin activation, as assessed by phosphorylation of Akt. We investigated the role of endoplasmic reticulum (ER) stress, which is known to promote cellular insulin resistance and apoptosis in peripheral tissues. Palmitate treatment induced ER stress through a c-Jun N-terminal kinase (JNK)-dependent pathway because a selective JNK inhibitor blocked palmitate activation of the ER stress pathways eIF2 alpha and X-box binding protein-1. Interestingly, JNK inhibition did not prevent the palmitate-mediated cleaved caspase-3 increase, an apoptotic marker, or insulin signaling attenuation. However, pretreatment with the AMP kinase activator, aminoimidazole carboxamide ribonucleotide, blocked JNK phosphorylation and importantly prevented caspase-3 cleavage and restored insulin signaling during short-term exposure to palmitate. Thus, activation of AMP kinase prevents the deleterious effects of palmitate on hypothalamic neurons by inhibiting the onset of insulin resistance and apoptosis.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Apoptose/fisiologia , Retículo Endoplasmático/fisiologia , Hipotálamo/fisiologia , Insulina/fisiologia , Ácido Palmítico/farmacologia , Proteínas Quinases Ativadas por AMP/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Retículo Endoplasmático/efeitos dos fármacos , Retículo Endoplasmático/ultraestrutura , Fator de Iniciação 2 em Eucariotos/metabolismo , Ácidos Graxos não Esterificados/farmacologia , Hipotálamo/citologia , Hipotálamo/efeitos dos fármacos , MAP Quinase Quinase 4/metabolismo , Camundongos , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Fosforilação , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/efeitos dos fármacos
4.
Endocrinology ; 151(1): 75-84, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19887566

RESUMO

Central insulin signaling is critical for the prevention of insulin resistance. Hyperinsulinemia contributes to insulin resistance, but it is not yet clear whether neurons are subject to cellular insulin resistance. We used an immortalized, hypothalamic, clonal cell line, mHypoE-46, which exemplifies neuronal function and expresses the components of the insulin signaling pathway, to determine how hyperinsulinemia modifies neuronal function. Western blot analysis indicated that prolonged insulin treatment of mHypoE-46 cells attenuated insulin signaling through phospho-Akt. To understand the mechanisms involved, time-course analysis was performed. Insulin exposure for 4 and 8 h phosphorylated Akt and p70-S6 kinase (S6K1), whereas 8 and 24 h treatment decreased insulin receptor (IR) and IR substrate 1 (IRS-1) protein levels. Insulin phosphorylation of S6K1 correlated with IRS-1 ser1101 phosphorylation and the mTOR-S6K1 pathway inhibitor rapamycin prevented IRS-1 serine phosphorylation. The proteasomal inhibitor epoxomicin and the lysosomal pathway inhibitor 3-methyladenine prevented the degradation of IRS-1 and IR by insulin, respectively, and pretreatment with rapamycin, epoxomicin, or 3-methyladenine prevented attenuation of insulin signaling by long-term insulin exposure. Thus, a sustained elevation of insulin levels diminishes neuronal insulin signaling through mTOR-S6K1-mediated IRS-1 serine phosphorylation, proteasomal degradation of IRS-1 and lysosomal degradation of the IR.


Assuntos
Sistema Nervoso Central/efeitos dos fármacos , Sistema Nervoso Central/metabolismo , Proteínas Substratos do Receptor de Insulina/metabolismo , Insulina/metabolismo , Insulina/farmacologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Receptor de Insulina/metabolismo , Animais , Células Cultivadas , Sistema Nervoso Central/fisiologia , Regulação para Baixo/efeitos dos fármacos , Insulina/administração & dosagem , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Redes e Vias Metabólicas/efeitos dos fármacos , Redes e Vias Metabólicas/fisiologia , Camundongos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Proteína Oncogênica v-akt/metabolismo , Fosforilação/efeitos dos fármacos , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Quinases S6 Ribossômicas 90-kDa/metabolismo , Serina/metabolismo , Serina-Treonina Quinases TOR , Fatores de Tempo
5.
Mol Cell Endocrinol ; 307(1-2): 99-108, 2009 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-19524132

RESUMO

Insulin plays a key role in the maintenance of nutrient homeostasis through central regulation of neuropeptides. Neuropeptide Y (NPY) and agouti-related peptide (AgRP) are vital orexigenic peptides that are regulated by insulin, although the processes utilized are unknown. Using a hypothalamic, clonal cell line, mHypoE-46, which endogenously expresses NPY, AgRP and the insulin receptor, we studied the mechanisms involved in the regulation of the NPY/AgRP neuron by insulin. We determined that insulin has direct actions on the neurons and acts to repress NPY/AgRP gene expression through a MAPK MEK/ERK-dependent pathway. Transient transfection analysis determined that human NPY and AgRP 5' flanking gene regions were not regulated by insulin in the mouse cell line, while sequence comparison analysis indicated only a 50% sequence similarity between human and mouse NPY and AgRP 5' flanking regions. These experiments indicate that insulin acts directly on specific hypothalamic neurons to regulate neuropeptide transcription.


Assuntos
Proteína Relacionada com Agouti/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Hipotálamo/citologia , Insulina/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Neurônios/enzimologia , Neuropeptídeo Y/genética , Região 5'-Flanqueadora/genética , Proteína Relacionada com Agouti/metabolismo , Animais , Butadienos/farmacologia , Linhagem Celular , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Camundongos , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Neurônios/efeitos dos fármacos , Neuropeptídeo Y/metabolismo , Nitrilas/farmacologia , Fosforilação/efeitos dos fármacos , Plasmídeos/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Sequências Reguladoras de Ácido Nucleico/genética , Homologia de Sequência do Ácido Nucleico
6.
Front Neuroendocrinol ; 30(3): 405-23, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19341762

RESUMO

The hypothalamus is the control center for most physiological processes; yet has been difficult to study due to the inherent heterogeneity of this brain region. For this reason, researchers have turned towards cell models. Primary hypothalamic cultures are difficult to maintain, are heterogeneous neuronal and glial cell populations and often contain a minimal number of viable peptide-secreting neurons. In contrast, immortalized, clonal cell lines represent an unlimited, homogeneous population of neurons that can be manipulated using a number of elegant molecular techniques. Cell line studies and in vivo experimentation are complementary and together provide a powerful tool to drive scientific discovery. This review focuses on three key neuroendocrine systems: energy homeostasis, reproduction, and circadian rhythms; and the use of hypothalamic cell lines to dissect the complex pathways utilized by individual neurons in these systems.


Assuntos
Linhagem Celular , Hipotálamo/citologia , Sistemas Neurossecretores/fisiologia , Animais , Ritmo Circadiano/fisiologia , Metabolismo Energético/fisiologia , Homeostase/fisiologia , Humanos , Hipotálamo/metabolismo , Hipotálamo/fisiologia , Modelos Biológicos , Reprodução/fisiologia
7.
J Neurosci ; 28(25): 6473-82, 2008 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-18562618

RESUMO

It is established that increases in neuropeptide Y (NPY) expression are associated with hyperphagia and obesity. These effects can be reversed by estrogen, a recognized anorexigen. We found that 17beta-estradiol (E(2)) regulates biphasic NPY gene expression in a clonal, immortalized hypothalamic cell line, N-38, through estrogen receptor (ER) action at the level of the NPY promoter. However, rapid, nongenomic actions of estrogen, linked to the phosphatidylinositol 3-kinase (PI3-K)/Akt and ERK1/2 mitogen-activated protein kinase (MAPK) pathways, may also play a role. We therefore examined the changes in the phosphorylation status of Akt, ERK1/2, and cAMP response element-binding protein (CREB) after treatment with 10 nm E(2) in the N-38 neurons and found activation of these signaling proteins within 5-30 min. We also demonstrated possible cross talk between the estrogen-activated PI3-K/Akt and MAPK/extracellular signal-regulated kinase pathways using pharmacological inhibitors. We find that only ERalpha is involved in the early signaling events using the ERalpha agonist 4,4',4''-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol and the ERbeta agonist 2,3-bis(4-hydroxyphenyl)-propionitrile. Furthermore, we can detect colocalization of ERalpha and caveolin-1, a membrane-associated signaling protein. Remarkably, we find that the membrane-mediated events are critical for the long-term estrogen-mediated repression of NPY gene expression that can be mapped to within -97 bp of the NPY promoter. To link the early signaling events to downstream effectors, we detected induction of c-fos and inactivation of MSK-1 by estrogen and binding of CREB to this minimal promoter region. These observations suggest that rapid estrogen-mediated signaling is mediated by ERalpha, and the signal transduction events potentiate the genomic actions of estrogen on NPY gene expression in the N-38 NPY neurons.


Assuntos
Estrogênios/fisiologia , Proteína Quinase 1 Ativada por Mitógeno/fisiologia , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Neurônios/enzimologia , Neuropeptídeo Y/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Linhagem Celular Transformada , Membrana Celular/enzimologia , Membrana Celular/metabolismo , Células Clonais , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/fisiologia , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/fisiologia , Neurônios/citologia , Neurônios/metabolismo , Neuropeptídeo Y/metabolismo , Fosfatidilinositol 3-Quinases/fisiologia , Proteínas Proto-Oncogênicas c-akt/fisiologia , Transdução de Sinais/fisiologia , Fatores de Tempo
8.
Biochem Biophys Res Commun ; 307(4): 847-54, 2003 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-12878188

RESUMO

The mechanisms dictating the developmental expression of individual neuropeptides within the hypothalamus have not yet been elucidated. In this paper we have studied the cis-acting elements involved in the repression of neuropeptide Y (NPY) gene expression in a gonadotropin-releasing hormone (GnRH) neuronal cell model, GT1-7 cells. Using transient transfection of the human NPY 5(') regulatory region into the GT1-7 neurons, we have found a repressor region located between -867 and -1078. DNase I footprint analysis of this region revealed three specific protein binding elements. Further analysis of the region between -942 and -922bp using electrophoretic mobility shift assays revealed that four different transcription factor-DNA complexes form with GT1-7 nuclear proteins, whereas only three complexes are detected using baby hamster kidney (BHK) cell nuclear extract. Mutation of the consensus binding sequence abolishes all complex formation on the -924/-922 oligonucleotide. Antibody supershift assays revealed that Oct-1 and Pbx-1 antibodies were able to eliminate the appearance of two specific complexes. Therefore we suggest that this region may be important for transcriptional repression of the NPY gene in a heterologous cell model, through complex, coordinate protein-protein interactions.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Neurônios/metabolismo , Neuropeptídeo Y/genética , Proteínas Proto-Oncogênicas/metabolismo , Elementos Silenciadores Transcricionais , Fatores de Transcrição/metabolismo , Região 5'-Flanqueadora , Animais , Sequência de Bases , Sítios de Ligação , Linhagem Celular , Sequência Consenso , Cricetinae , Fator C1 de Célula Hospedeira , Humanos , Fator 1 de Transcrição de Octâmero , Fator de Transcrição 1 de Leucemia de Células Pré-B
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