RESUMEN
BACKGROUND: Little is known about the severity of dysmenorrhoea and attitudes towards its management in young females. OBJECTIVE: The aim of this study was to evaluate the prevalence and severity of dysmenorrhoea in women aged 16-25 years. METHODS: Participants were recruited via targeted Facebook advertising and asked to complete an online questionnaire covering medications, menstruation and lifestyle-related themes. A follow-up questionnaire on dysmenorrhoea was also administered. RESULTS: The prevalence of dysmenorrhoea was 88% (n = 247, mean age 21.5 years, SD 2.6). Only 34% of participants reported consulting a healthcare provider about their pain, whereas 86% consulted other sources. Pain medication was used by 58% of the participants. Dysmenorrhoea was associated with interference with daily activities (P DISCUSSION: Dysmenorrhoea is highly prevalent among these women, with most indicating moderate to severe pain and a significant adverse impact on daily activities. Most women did not obtain information about dysmenorrhoea from healthcare providers, indicating the need for general practitioners to provide accurate information about dysmenorrhoea to young females.
Asunto(s)
Manejo de la Enfermedad , Dismenorrea/complicaciones , Dismenorrea/psicología , Adolescente , Adulto , Depresión/etiología , Depresión/psicología , Dismenorrea/epidemiología , Femenino , Humanos , Manejo del Dolor/métodos , Prevalencia , Estudios Prospectivos , Medios de Comunicación Sociales/instrumentación , Encuestas y Cuestionarios , Victoria/epidemiologíaRESUMEN
Nutlin3a is a small-molecule antagonist of MDM2 that promotes non-genotoxic activation of p53 through p53 protein stabilization and transactivation of p53 target genes. Nutlin3a is the forerunner of a class of cancer therapeutics that have reached clinical trials. Using transgenic and gene-targeted mouse models lacking the critical p53 target genes, p21, Puma, and Noxa, we found that only loss of PUMA conferred profound protection against Nutlin3a-induced killing in both non-transformed lymphoid cells and Eµ-Myc lymphomas in vitro and in vivo. CRISPR/Cas9-mediated targeting of the PUMA gene rendered human hematopoietic cancer cell lines markedly resistant to Nutlin3a-induced cell death. These results demonstrate that PUMA-mediated apoptosis, but not p21-mediated cell-cycle arrest or senescence, is a critical determinant of the therapeutic response to non-genotoxic p53 activation by Nutlin3a. Importantly, in human cancer, PUMA expression may predict patient responses to treatment with MDM2 antagonists.
Asunto(s)
Antineoplásicos/farmacología , Proteínas Reguladoras de la Apoptosis/genética , Regulación Neoplásica de la Expresión Génica , Imidazoles/farmacología , Linfoma/tratamiento farmacológico , Piperazinas/farmacología , Proteína p53 Supresora de Tumor/genética , Proteínas Supresoras de Tumor/genética , Animales , Apoptosis/efectos de los fármacos , Proteínas Reguladoras de la Apoptosis/metabolismo , Sistemas CRISPR-Cas , Puntos de Control del Ciclo Celular , Línea Celular Tumoral , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Modelos Animales de Enfermedad , Resistencia a Antineoplásicos/genética , Humanos , Linfoma/genética , Linfoma/metabolismo , Linfoma/patología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteínas Proto-Oncogénicas c-mdm2/genética , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Transducción de Señal , Proteína p53 Supresora de Tumor/agonistas , Proteína p53 Supresora de Tumor/metabolismo , Proteínas Supresoras de Tumor/metabolismoRESUMEN
Caloric restriction (CR) is proposed to decrease tumorigenesis through a variety of mechanisms including effects on glycolysis. However, the understanding of how CR affects the response to cancer therapy is still rudimentary. Here, using the Eµ-Myc transgenic mouse model of B-cell lymphoma, we report that by reducing protein translation, CR can reduce expression of the prosurvival Bcl-2 family member Mcl-1 and sensitize lymphomas to ABT-737-induced death in vivo. By using Eµ-Myc lymphoma cells lacking p53, we showed that CR mimetics such as 2-deoxyglucose led to a decrease in Mcl-1 expression and sensitized lymphoma cells to ABT-737-induced death independently of p53. In keeping with this, Eµ-Myc lymphoma cells lacking the BH3-only proapoptotic members Noxa, Puma, or Bim were also sensitized by CR mimetics to ABT-737-induced death. Remarkably, neither the loss of both Puma and Noxa, the loss of both Puma and Bim, nor the loss of all three BH3-only proteins prevented sensitization to ABT-737 induced by CR mimetics. Thus, CR can influence Mcl-1 expression and sensitize cells to BH3 mimetic-induced apoptosis, independently of the main BH3-only proteins and of p53. Exploiting this may improve the efficiency of, or prevent resistance to, cancer therapy.
Asunto(s)
Restricción Calórica , Resistencia a Antineoplásicos/fisiología , Linfoma de Células B/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/biosíntesis , Animales , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Proteína Proapoptótica que Interacciona Mediante Dominios BH3/metabolismo , Compuestos de Bifenilo/farmacología , Modelos Animales de Enfermedad , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Proteína 1 de la Secuencia de Leucemia de Células Mieloides , Nitrofenoles/farmacología , Piperazinas/farmacología , Sulfonamidas/farmacologíaRESUMEN
Two major processes govern T cell proliferation and survival: interleukin-7-mediated homeostasis and antigen-induced selection. How cells transit between the two states is unknown. Here we show that T cell receptor ligation actively inhibits homeostatic survival signals while initiating a new, dominant survival programme. This switch is mediated by a change in the expression of pro- and anti-apoptosis proteins through the downregulation of Bcl-2 and the induction of Bim, A1 and Bcl-xL. Calcineurin inhibitors prevent the initiation of the new survival programme, while permitting the dominant repression of Bcl-2. Thus, in the presence of these drugs the response to antigen receptor ligation is cell death. Our results identify a molecular switch that can serve as an attractive target for inducing antigen-specific tolerance in treating autoimmune disease patients and transplant recipients.
Asunto(s)
Supervivencia Celular , Receptores de Antígenos de Linfocitos T/fisiología , Receptores de Interleucina-7/fisiología , Transducción de Señal/fisiología , Linfocitos T/citología , Animales , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BLRESUMEN
c-Myc transformed human Burkitt's lymphoma (BL) cells are highly sensitive to TGF-ß-induced apoptosis. Previously we demonstrated that TGF-ß-mediated cell death in BL cells is regulated via the mitochondrial intrinsic apoptosis pathway, which is dependent on the activation of BAX and/or BAK. TGF-ß directly induces transcription of the BH3-only protein BIK and represses expression of the pro-survival factor BCL-X(L) but has no effect on the direct BAX/BAK "activators" BIM or BID (tBID). Here we show that TGF-ß induces the BH3-only activator PUMA to aid induction of the intrinsic cell death pathway. TGF-ß also induced PUMA in normal germinal center CD77-positive centroblasts isolated from human tonsil tissue. PUMA was a direct TGF-ß target gene in B-cells, and we identify a putative Smad-binding region within the human PUMA promoter that recruits Smad3 and Smad4 in cells in response to TGF-ß signaling. Constitutive activity of the isolated Smad-binding region in luciferase reporter assays was dependent on Smad consensus sequences and was partially dependent on endogenous TGF-ß signaling and Smad4. Knockdown of PUMA in BL cells using lentiviral shRNA resulted in slower kinetics of the TGF-ß-mediated apoptotic response. Analysis of Eµ-Myc cell lines demonstrated that c-myc-driven murine lymphomas are also sensitive to TGF-ß-mediated apoptosis. Moreover, Puma(-/-) Eµ-Myc lines demonstrated significantly delayed kinetics of the apoptotic response when compared with wild type lymphomas. TGF-ß therefore induces a polygenic response in Myc-driven lymphomas involving transcription of PUMA, which is necessary for the rapid induction of cell death.
Asunto(s)
Proteínas Reguladoras de la Apoptosis/metabolismo , Apoptosis , Regulación Neoplásica de la Expresión Génica , Linfoma de Células B/metabolismo , Proteínas Proto-Oncogénicas c-myc/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Animales , Línea Celular , Supervivencia Celular , Células HEK293 , Humanos , Cinética , Linfoma/metabolismo , Ratones , Regiones Promotoras Genéticas , Transducción de Señal , Transcripción GenéticaAsunto(s)
Apoptosis , Neoplasias/patología , Proteínas Proto-Oncogénicas c-bcl-2/química , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Animales , Humanos , Neoplasias/metabolismo , Dominios y Motivos de Interacción de Proteínas , Proteínas Supresoras de Tumor/químicaRESUMEN
DNA-damaging chemotherapy is the backbone of cancer treatment, although it is not clear how such treatments kill tumor cells. In nontransformed lymphoid cells, the combined loss of 2 proapoptotic p53 target genes, Puma and Noxa, induces as much resistance to DNA damage as loss of p53 itself. In Eµ-Myc lymphomas, however, lack of both Puma and Noxa resulted in no greater drug resistance than lack of Puma alone. A third B-cell lymphoma-2 homology domain (BH)3-only gene, Bim, although not a direct p53 target, was up-regulated in Eµ-Myc lymphomas incurring DNA damage, and knockdown of Bim levels markedly increased the drug resistance of Eµ-Myc/Puma(-/-)Noxa(-/-) lymphomas both in vitro and in vivo. Remarkably, c-MYC-driven lymphoma cell lines from Noxa(-/-)Puma(-/-)Bim(-/-) mice were as resistant as those lacking p53. Thus, the combinatorial action of Puma, Noxa, and Bim is critical for optimal apoptotic responses of lymphoma cells to 2 commonly used DNA-damaging chemotherapeutic agents, identifying Bim as an additional biomarker for treatment outcome in the clinic.