RESUMEN

Background: Contraception screening and referral occur infrequently in cancer care for young women of reproductive age. Barriers to contraception screening and referral in this setting have not been thoroughly identified. Objectives: We sought to understand oncology clinicians' current practices and perceptions of barriers to screening and referring young women for adequate contraception during cancer treatment. Methods: We conducted individual semi-structured interviews with 19 oncology clinicians whom we recruited from an urban, northeast medical center. Participants included physicians, advanced practice clinicians, and nurses in surgical and medical oncology. The interview guide addressed core components of the Promoting Action on Research Implementation in Health Services framework, and subsequent directed content analysis identified themes indicative of barriers to contraception screening and referral. Findings: Participants varied significantly in their current contraception screening practices; many conflated early pregnancy diagnosis or pregnancy avoidance counseling with contraception, whereas others described inaccurate contraceptive recommendations for specific clinical scenarios. Participants also lacked clarity of roles and responsibilities within the oncologic care team for contraception and assumed that another team member had addressed contraception. Participants perceived themselves to lack adequate education about contraception, which precluded contraception discussions. Conclusion: We recommend cancer centers consider these possible barriers to contraception screening and referral by promoting development of institutional guidelines to standardize contraception screening and referral, clarifying roles and responsibilities for contraception discussions within the care team, and expanding oncology clinician education on contraception. National professional organizations should work to expand guidelines to inform and support this process in clinical practice.

Asunto(s)

Anticoncepción/métodos , Neoplasias/complicaciones , Adulto , Femenino , Humanos , Tamizaje Masivo , Persona de Mediana Edad , Derivación y Consulta

RESUMEN

INTRODUCTION: Endometriosis is a chronic disease manifested by pain and infertility due to ectopic implantation of endometrial glands and stroma causing inflammation. Treatment of endometriosis utilizes a significant amount of health-care resources and requires chronic therapy. Management involves a combination of surgical and medical interventions and requires long-term treatment to avoid repeated surgeries. AREAS COVERED: Whereas medical therapies exist for management of endometriosis-related pain, each class has its limitations including side effects, cost, and known duration of relief of symptoms. Development of effective, well-tolerated medical therapies that are appropriate for long-term use is crucial to provide adequate treatment for this chronic disease. This review discusses the various medical therapies available, their limitations, and emerging therapies being developed to address many of these concerns. EXPERT OPINION: The authors recommend chronic suppressive therapy for management of endometriosis symptoms, particularly in the postoperative setting. Empiric treatment is appropriate for those patients without evidence of severe disease. Currently available option may not be effective for nor tolerated by all patients. Newer compounds, including gonadotropin-releasing antagonists and aromatase inhibitors combined with hormonal contraceptives, offer possible alternatives to currently available therapies.

Asunto(s)

Endometriosis/terapia , Infertilidad Femenina/terapia , Manejo del Dolor/métodos , Animales , Terapia Combinada , Diseño de Fármacos , Endometriosis/complicaciones , Endometriosis/fisiopatología , Femenino , Humanos , Infertilidad Femenina/etiología , Dolor/etiología

RESUMEN

We recently demonstrated that mRNA levels of three members of the CCAAT/enhancer binding factor (C/EBP) family of transcription factors are increased in skeletal muscle following 12 days of spaceflight. In the present study, we further explored the expression of C/EBP-δ in atrophying fast skeletal muscle by examining its expression in muscle from food-deprived (FD) mice, and investigated its role in regulating the expression of the secreted antigrowth factor myostatin. C/EBP-δ mRNA and protein levels were significantly increased by 2 days of food deprivation in the tibialis anterior (TA) muscle, and expression of both myostatin and C/EBP-δ mRNA during food deprivation was attenuated by injection with the glucocorticoid inhibitor RU486. The increase in myostatin mRNA levels with food deprivation appears to be at least partially transcriptionally driven, since levels of myostatin pre-mRNA were significantly increased in the TA muscle. C/EBP-δ mRNA levels and promoter activity were significantly increased by transfection of C(2)C(12) myotubes with a glucocorticoid receptor construct and 24 h of treatment with the synthetic glucocorticoid dexamethasone. Furthermore, activity of the C/EBP-δ promoter was significantly increased with as little as 1 h of dexamethasone treatment, while activity of the mouse myostatin promoter was only significantly increased with longer treatment periods of 24 h or more. Activity of the myostatin promoter-reporter construct was significantly increased in C(2)C(12) myotubes by cotransfection with expression constructs for C/EBP-α, -ß, and -δ, with C/EBP-δ having the greatest effect. The myostatin promoter contains two potential C/EBP binding sequences, a CCAAT box, and a C/EBP binding element (CBE). Mutation of the CCAAT box attenuated basal myostatin promoter activity but potentiated C/EBP-δ-activated myostatin promoter activity in C(2)C(12) myotubes in vitro, while mutation of the CBE abolished glucocorticoid receptor and C/EBP-δ responsiveness. The present results support a model in which glucocorticoid-induced increases in C/EBP-δ expression may contribute to myostatin transcription during atrophic states.

Asunto(s)

Proteína delta de Unión al Potenciador CCAAT/metabolismo , Privación de Alimentos/fisiología , Fibras Musculares de Contracción Rápida/metabolismo , Miostatina/genética , Transcripción Genética , Análisis de Varianza , Animales , Western Blotting , Proteína delta de Unión al Potenciador CCAAT/genética , Diferenciación Celular , Línea Celular , Células Cultivadas , Dexametasona/farmacología , Glucocorticoides/farmacología , Ratones , Fibras Musculares de Contracción Rápida/efectos de los fármacos , Miostatina/metabolismo , Regiones Promotoras Genéticas , ARN Mensajero/efectos de los fármacos , ARN Mensajero/genética , ARN Mensajero/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transcripción Genética/efectos de los fármacos

RESUMEN

During food deprivation (FD), skeletal muscle protein is broken down to produce amino acids for hepatic gluconeogenesis to maintain blood glucose levels. However, it is unclear what role, if any, the secreted antigrowth factor myostatin (MSTN) plays in the muscle atrophy induced by FD. We therefore examined expression and function of MSTN in FD in mice. Two days of FD significantly decreased muscle mass and protein content and increased mRNA levels of ubiquitin ligases MuRF-1 and atrogin-1 in fast-twitch tibialis anterior (TA) muscle but not slow-twitch soleus (Sol) muscle, while 2 days of refeeding returned these to fed values in TA. MSTN mRNA levels were significantly increased approximately threefold by 2 days, but not 1 day, of FD and returned to fed levels with 2 days of refeeding in TA but were not significantly affected by FD or refeeding in Sol. TA mass decreased to a similar amount after 1 day of FD in wild-type mice and mice null for the MSTN gene but was decreased to a greater amount in wild-type than MSTN-null mice by 2 days of FD. In addition, blood glucose levels decreased and corticosterone levels increased to a greater extent in MSTN-null mice after 2 days of FD, but surprisingly muscle MuRF-1 and atrogin-1 mRNA levels were not affected by the lack of MSTN during FD. Similarly, changes in hepatic enzyme expression in response to FD were identical between wild-type and MSTN-null mice. Our data are consistent with the hypothesis that MSTN is dispensable for the initial atrophy occurring in response to FD but attenuates the decrease in fast-twitch muscle mass during prolonged FD.

Asunto(s)

Privación de Alimentos , Músculo Esquelético/metabolismo , Atrofia Muscular/etiología , Miostatina/metabolismo , Animales , Glucemia/metabolismo , Corticosterona/sangre , Ingestión de Alimentos , Glucoquinasa/genética , Gluconeogénesis , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Fibras Musculares de Contracción Rápida/metabolismo , Fibras Musculares de Contracción Rápida/patología , Fibras Musculares de Contracción Lenta/metabolismo , Fibras Musculares de Contracción Lenta/patología , Proteínas Musculares/genética , Músculo Esquelético/patología , Atrofia Muscular/metabolismo , Atrofia Muscular/patología , Miostatina/deficiencia , Miostatina/genética , Tamaño de los Órganos , Fosfoenolpiruvato Carboxiquinasa (GTP)/genética , ARN Mensajero/metabolismo , Proteínas Ligasas SKP Cullina F-box/genética , Factores de Tiempo , Proteínas de Motivos Tripartitos , Ubiquitina-Proteína Ligasas/genética , Regulación hacia Arriba

RESUMEN

Members of the bone morphogenetic protein-1/mammalian tolloid (BMP-1/mTLD) family of proteases cleave diverse extracellular proteins, including the growth inhibitor myostatin. The purpose of this work was to examine the expression of BMP-1/mTLD, tolloid-like-1 and -2 (TLL1 and TLL2) in hindlimb muscles of the mouse in vivo and in C(2)C(12) muscle cells in vitro. Quantitative real-time polymerase chain reaction revealed that neither BMP-1/mTLD nor TLL1 mRNA levels differed between the predominantly fast-twitch tibialis anterior (TA) and gastrocnemius (GAST) muscles and the more slow-twitch soleus (SOL) muscle; TLL2 mRNA levels were not detectable in any of the muscles examined. Interestingly, however, immunohistochemical analysis revealed that BMP-1 protein was expressed in type I and IIa but not in IIb fibers. TLL1 mRNA levels significantly increased in the TA but not the SOL with 3 days of hindlimb suspension and significantly decreased in both TA and SOL in response to 2 days of food deprivation. In contrast, BMP-1/mTLD mRNA levels were unaffected in either muscle by either condition. In addition, BMP-1/mTLD and TLL1 mRNA levels significantly decreased during C(2)C(12) myoblast differentiation in vitro, and activity of a 1,200-bp mouse TLL1 promoter construct was significantly decreased in C(2)C(12) myotubes by differentiation, by mutation of an nuclear factor kappa-beta (NF-kappaB) site, or deletion of a sma/mothers against decapentaplegic (SMAD) site. Together, these data demonstrate that TLL1 mRNA levels are altered by loading, energy status, and differentiation, and thus its expression may be regulated so as to modulate activity of myostatin or other extracellular substrates during these adaptive states.

Asunto(s)

Proteína Morfogenética Ósea 1/metabolismo , Privación de Alimentos/fisiología , Suspensión Trasera/fisiología , Desarrollo de Músculos/fisiología , Fibras Musculares Esqueléticas/metabolismo , Metaloproteinasas Similares a Tolloid/metabolismo , Animales , Secuencia de Bases , Masculino , Ratones , Ratones Endogámicos C57BL , Datos de Secuencia Molecular , FN-kappa B/genética , FN-kappa B/fisiología , Regiones Promotoras Genéticas/fisiología , Proteínas Smad/genética , Proteínas Smad/fisiología , Metaloproteinasas Similares a Tolloid/genética

RESUMEN

Expression of the cytokine interleukin-6 (IL-6) by skeletal muscle is hugely increased in response to a single bout of endurance exercise, and this appears to be mediated by increases in intracellular calcium. We examined the effects of endurance exercise on IL-6 mRNA levels and promoter activity in skeletal muscle in vivo, and the role of the calcium-activated calcineurin signaling pathway on muscle IL-6 expression in vivo and in vitro. IL-6 mRNA levels in the mouse tibialis anterior (TA) were increased 2-10-fold by a single bout of treadmill exercise or by 3 days of voluntary wheel running. Moreover, an IL-6 promoter-driven luciferase transgene was activated in TA by both treadmill and wheel-running exercise and by injection with a calcineurin plasmid. Exercise also increased muscle mRNA expression of the calcineurin regulatory gene MCIP1, as did treatment of C(2)C(12) myotubes with the calcium ionophore A23187. Cotransfection of C(2)C(12) myotubes with a constitutively active calcineurin construct significantly increased while cotransfection with the calcineurin inhibitor CAIN inhibited activity of a mouse IL-6 promoter-reporter construct. Cotransfection with a myocyte enhancer-factor-2 (MEF-2) expression construct increased basal IL-6 promoter activity and augmented the effects of calcineurin cotransfection, while cotransfection with the MEF-2 antagonist MITR repressed calcineurin-activated IL-6 promoter activity in vitro. Surprisingly, cotransfection with a dominant-negative form of another calcineurin-activated transcription factor, nuclear factor activator of T cells (NFAT), greatly potentiated both basal and calcineurin-stimulated IL-6 promoter activity in C(2)C(12) myotubes. Mutation of the MEF-2 DNA binding sites attenuated, while mutation of the NFAT DNA binding sites potentiated basal and calcineurin-activated IL-6 promoter activity. Finally, CREB and C/EBP were necessary for basal IL-6 promoter activity and sufficient to increase IL-6 promoter activity but had minimal roles in calcineurin-activated IL-6 promoter activity. Together, these results suggest that IL-6 transcription in skeletal muscle cells can be activated by a calcineurin-MEF-2 axis which is antagonized by NFAT.

Asunto(s)

Calcineurina/metabolismo , Interleucina-6/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/metabolismo , Condicionamiento Físico Animal/fisiología , Transcripción Genética/fisiología , Secuencia de Aminoácidos , Animales , Señalización del Calcio/fisiología , Proteínas de Unión al Calcio , Proteínas de Unión al ADN/metabolismo , Humanos , Interleucina-6/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Modelos Animales , Datos de Secuencia Molecular , Proteínas Musculares/metabolismo , Factores de Transcripción NFATC/metabolismo , ARN Mensajero/metabolismo , Transducción de Señal/fisiología , Factores de Transcripción/metabolismo

RESUMEN

Myostatin (MSTN) is a secreted growth inhibitor expressed in muscle and adipose. We sought to determine whether expression of MSTN, its receptor activin RIIb (ActRIIb), or its binding protein follistatin-like-3 (FSTL3) are altered in subcutaneous or visceral adipose or in skeletal muscle in response to obesity. MSTN and ActRIIb mRNA levels were low in subcutaneous (SQF) and visceral fat (VF) from wild-type mice but were 50- to 100-fold higher in both SQF and VF from ob/ob compared with wild-type mice. FSTL3 mRNA levels were increased in SQF but decreased in VF in ob/ob compared with wild-type mice. Moreover, MSTN mRNA levels were twofold greater in tibialis anterior (TA) from ob/ob mice, whereas ActRIIb and FSTL3 mRNA levels were unchanged. MSTN mRNA levels were also increased in TA and SQF from mice on a high-fat diet. Injection of ob/ob mice with recombinant leptin caused FSTL3 mRNA levels to decrease in both VF and SQF in ob/ob mice; MSTN and ActRIIb mRNA levels tended to decrease only in VF. Finally, MSTN mRNA levels and promoter activity were low in adipogenic 3T3-L1 cells, but an MSTN promoter-reporter construct was activated in 3T3-L1 cells by cotransfection with the adipogenic transcription factors SREBP-1c, C/EBPalpha, and PPARgamma. These results demonstrate that expression of MSTN and its associated binding proteins can be modulated in adipose tissue and skeletal muscle by chronic obesity and suggest that alterations in their expression may contribute to the changes in growth and metabolism of lean and fat tissues occurring during obesity.

Asunto(s)

Receptores de Activinas Tipo II/biosíntesis , Receptores de Activinas Tipo II/genética , Tejido Adiposo/metabolismo , Músculo Esquelético/metabolismo , Obesidad/genética , Obesidad/metabolismo , Proteínas/genética , Proteínas/metabolismo , Factor de Crecimiento Transformador beta/biosíntesis , Factor de Crecimiento Transformador beta/genética , Células 3T3 , Animales , Células Cultivadas , Clonación Molecular , ADN/biosíntesis , ADN/genética , Dieta , Grasas de la Dieta/farmacología , Proteínas Relacionadas con la Folistatina , Leptina/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Obesos , Miostatina , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Transducción de Señal/fisiología , Transfección