RESUMEN
Mesencephalic astrocyte-derived neurotrophic factor (MANF) is the only human neurotrophic factor with an evolutionarily-conserved C. elegans homolog, Y54G2A.23 or manf-1. MANF is a small, soluble, endoplasmic-reticulum (ER)-resident protein that is secreted upon ER stress and promotes survival of target cells such as neurons. However, the role of MANF in ER stress and its mechanism of cellular protection are not clear and the function of MANF in C. elegans is only beginning to emerge. In this study, we show that depletion of C. elegans manf-1 causes a slight decrease in lifespan and brood size; furthermore, combined depletion of manf-1 and the IRE-1/XBP-1 ER stress/UPR pathway resulted in sterile animals that did not produce viable progeny. We demonstrate upregulation of markers of ER stress in L1 larval nematodes, as measured by hsp-3 and hsp-4 transcription, upon depletion of manf-1 by RNAi or mutation; however, there was no difference in tunicamycin-induced expression of hsp-3 and hsp-4 between wild-type and MANF-deficient worms. Surprisingly, larval growth arrest observed in wild-type nematodes reared on tunicamycin is completely prevented in the manf-1 (tm3603) mutant. Transcriptional microarray analysis revealed that manf-1 mutant L1 larvae exhibit a novel modulation of innate immunity genes in response to tunicamycin. The hypothesis that manf-1 negatively regulates the innate immunity pathway is supported by our finding that the development of manf-1 mutant larvae compared to wild-type larvae is not inhibited by growth on P. aeruginosa. Together, our data represent the first characterization of C. elegans MANF as a key modulator of organismal ER stress and immunity.
Asunto(s)
Antibacterianos/farmacología , Proteínas de Caenorhabditis elegans/genética , Caenorhabditis elegans/efectos de los fármacos , Caenorhabditis elegans/genética , Estrés del Retículo Endoplásmico/efectos de los fármacos , Factores de Crecimiento Nervioso/deficiencia , Factores de Crecimiento Nervioso/genética , Tunicamicina/farmacología , Animales , Caenorhabditis elegans/crecimiento & desarrollo , Caenorhabditis elegans/microbiología , Proteínas de Caenorhabditis elegans/metabolismo , Inmunidad Innata/efectos de los fármacos , Larva/efectos de los fármacos , Larva/inmunología , Factores de Crecimiento Nervioso/metabolismo , Pseudomonas aeruginosa/crecimiento & desarrollo , Pseudomonas aeruginosa/metabolismoRESUMEN
BACKGROUND: Amplification of the ERBB2 (Her-2/neu) oncogene, which occurs in approximately 25% of breast carcinomas, is a known negative prognostic factor. Available data indicate that a variable number of nearby genes on chromosome 17q may be co-amplified or deleted, forming a continuous amplicon of variable size. In approximately 25% of these patients, the amplicon extends to the gene for topoisomerase II alpha (TOP2A), a target for anthracyclines. We sought to understand the significance of these associated genomic changes for breast cancer prognosis and predicting response to therapy. METHODS AND PATIENTS: Archival tissue samples from 63 breast cancer patients with ERBB2 amplification, stages 0-IV, were previously analyzed with FISH probes for genes located near ERBB2. In the present study, the clinical outcome data were determined for all patients presenting at stages I-III for whom adequate clinical follow up was available. RESULTS: Four amplicon patterns (Classes) were identified. These were significantly associated with the clinical outcome, specifically, recurrence of breast cancer. The Amplicon class IV with deleted TOP2A had 67% (6/9) cases with recurrence, whereas the other three classes combined had only 12% (3/25) cases (p-value = 0.004) at the time of last follow-up. TOP2A deletion was also significantly associated with time to recurrence (p-value = 0.0002). After adjusting for age in Cox regression analysis, the association between TOP2A deletion and time to recurrence remains strongly significant (p-value = 0.002) whereas the association with survival is marginally significant (p-value = 0.06). CONCLUSION: TOP2A deletion is associated with poor prognosis in ERBB2-amplified breast carcinomas. Clarification of the mechanism of this association will require additional study.
Asunto(s)
Antígenos de Neoplasias/genética , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/genética , ADN-Topoisomerasas de Tipo II/genética , Proteínas de Unión al ADN/genética , Genes erbB-2 , Proliferación Celular , Cromosomas Humanos Par 17/genética , Femenino , Amplificación de Genes , Eliminación de Gen , Dosificación de Gen , Humanos , Proteínas de Unión a Poli-ADP-Ribosa , Pronóstico , Estudios RetrospectivosRESUMEN
BACKGROUND: This study investigated changes in left ventricular (LV) geometry and systolic function after corrective surgery for atrial (ASD) and ventricular septal defects (VSD). METHODS: Transesophageal LV short-axis echocardiograms were recorded before and after operative repair of ASD (n = 11) and VSD (n = 7). Preload was measured using LV end-diastolic area indexed for body surface area. Measurements of septal-freewall (D1) and anterior-posterior (D2) endocardial diameters were used to assess LV symmetry from D1/D2. Systolic indices included stroke area, area ejection fraction, and fractional shortening. RESULTS: Preload, stroke area, area ejection fraction, and fractional shortening of D1 increased after ASD repair but decreased after VSD repair (p < 0.05). End-diastolic symmetry increased after ASD closure and decreased after VSD closure (p < 0.05). Increases in stroke area and ejection fraction after ASD correction primarily reflected increased shortening of D1. A positive correlation was found overall between percent change in end-diastolic area (EDA) and percent change in area ejection fraction (r(2) = 0.80, p < 0.0001, n = 18). CONCLUSIONS: Preload was the primary determinant of changes in LV function in this series of ASD and VSD repairs. Intraoperative changes in position of the interventricular septum affected systolic and diastolic LV symmetry and septal free wall shortening. Additional studies are needed to define changes in afterload and contractility as well as diastolic compliance and systolic mechanics.
Asunto(s)
Cardiopatías Congénitas/diagnóstico por imagen , Cardiopatías Congénitas/cirugía , Niño , Preescolar , Cardiopatías Congénitas/patología , Cardiopatías Congénitas/fisiopatología , Humanos , Lactante , Cuidados Intraoperatorios , UltrasonografíaRESUMEN
OBJECTIVE: Eating disorders are a serious group of conditions that affect 3% of women in industrialized nations over their lifetimes. Recent years have seen considerable progress in the treatment of these disorders. This article reviews the current body of evidence for the pharmacologic treatment of eating disorders. METHODS: We undertook a literature review. RESULTS: For patients with anorexia nervosa (AN), drug trials have been disappointing. In contrast, numerous studies have demonstrated a clear role for antidepressants in the treatment of bulimia nervosa (BN). Pharmacologic investigations of binge eating disorder (BED), a more recently defined entity, have identified several promising drugs. There is also support for the utility of combined medication and psychotherapy. CONCLUSION: Continued research efforts are necessary, particularly regarding the long-term effects of therapy and the development of new pharmacologic strategies.