RESUMEN
While the mouse has been a productive model for inner ear studies, a lack of highly specific genes and tools has presented challenges. The absence of definitive otic lineage markers and tools is limiting in vitro studies of otic development, where innate cellular heterogeneity and disorganization increase the reliance on lineage-specific markers. To address this challenge in mice and embryonic stem (ES) cells, we targeted the lineage-specific otic gene Fbxo2 with a multicistronic reporter cassette (Venus/Hygro/CreER = VHC). In otic organoids derived from ES cells, Fbxo2VHC specifically delineates otic progenitors and inner ear sensory epithelia. In mice, Venus expression and CreER activity reveal a cochlear developmental gradient, label the prosensory lineage, show enrichment in a subset of type I vestibular hair cells, and expose strong expression in adult cerebellar granule cells. We provide a toolbox of multiple spectrally distinct reporter combinations for studies that require use of fluorescent reporters, hygromycin selection, and conditional Cre-mediated recombination.
Asunto(s)
Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Oído Interno/embriología , Proteínas F-Box/genética , Proteínas F-Box/metabolismo , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Animales , Linaje de la Célula , Cóclea/embriología , Cóclea/metabolismo , Oído Interno/metabolismo , Células Madre Embrionarias/fisiología , Epitelio/metabolismo , Ganglios Parasimpáticos , Ingeniería Genética/métodos , Humanos , Inmunohistoquímica/métodos , Integrasas , Ratones , Ratones Transgénicos , TamoxifenoRESUMEN
Flap endonuclease 1 (FEN1) plays a crucial role in both DNA replication and damage repair. In this study, FEN1 expression and its clinical-pathologic significance in non-small-cell lung cancer (NSCLC) was investigated. Quantitative RT-PCR and immunohistochemistry analysis identified that both FEN1 mRNA and protein were highly overexpressed in about 36% of 136 cancer tissues compared to adjacent tissues, in which FEN1 was generally undetectable. Notably, patients with FEN1-overexpressed cancers were prone to have poor differentiation and poor prognosis. A strong positive correlation between the levels of FEN1 and Ki-67 staining was identified in these NSCLC tissues (r = 0.485), suggesting overexpressed FEN1 conferred a proliferative advantage to NSCLC. Furthermore, knockdown of FEN1 resulted in G1/S or G2/M phase cell cycle arrest and suppressed in vitro cellular proliferation in NSCLC cancer cells. Consistently, a selective FEN1 inhibitor was shown to effectively inhibit cellular proliferation of NSCLC cells in a dose-dependent manner. Additionally, knockdown of FEN1 significantly attenuated homologous DNA repair efficiency and enhanced cytotoxic effects of cisplatin in NSCLC cells. Taken together, these findings have indicated that overexpressed FEN1 represents a prognostic biomarker and potential therapeutic target for NSCLC treatment, which warrants further study.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Proliferación Celular/genética , Endonucleasas de ADN Solapado/metabolismo , Neoplasias Pulmonares/metabolismo , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Apoptosis/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , Puntos de Control del Ciclo Celular/efectos de los fármacos , Puntos de Control del Ciclo Celular/genética , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cisplatino/farmacología , Relación Dosis-Respuesta a Droga , Femenino , Endonucleasas de ADN Solapado/genética , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Pronóstico , Tasa de Supervivencia , Regulación hacia ArribaRESUMEN
INTRODUCTION: For many, sleep and sex are crucial for physical, emotional, and mental well-being. Poor sleep quality is linked to a myriad of ailments from coronary artery disease to major depressive disorder. Likewise, a decrease in the frequency of sexual activity is associated with a decrease in self-rated health status. Kleine-Levin syndrome (KLS) is a rare sleep disorder that provides a unique lens to examine the intricate interplay between sleep and sex as it is one of the few sleep disorders defined by concomitant sexual dysfunction. OBJECTIVES: This study reviews the literature on links between sleep disorders and sexuality with a focus on women's health followed by a case study of unusual patient with KLS with persistent genital arousal disorder. METHODS: Literature searches were conducted for English language publications, including foreign language publications with English abstracts with ninety-five articles reviewed. The literature review is followed by a case report. RESULTS: We review the known literature linking sleep and women's sexual health with a focus on insomnia, circadian rhythm sleep disorder, obstructive sleep apnea, restless leg syndrome, sexsomnia, and KLS. We then present a case of KLS-associated persistent genital arousal disorder, which was amenable to treatment with a multimodal approach aimed at symptomatic relief with intravaginal diazepam suppositories, topical clitoral lidocaine, and duloxetine. CONCLUSION: This case highlights that hypersexuality and persistent arousal cannot effectively be treated in isolation but rather must be contextualized within a patient's broader medical history and diagnoses. Specifically, sleep quality and potential sleep disorders should be assessed for those presenting with sexual health complaints (and vice versa). Zwerling B, Keymeulen S, Krychman ML. Sleep and Sex: A Review of the Interrelationship of Sleep and Sexuality Disorders in the Female Population, Through the Lens of Sleeping Beauty Syndrome. Sex Med Rev 2021;9:221-229.