A Mismatch-Based Model for Memory Reconsolidation and Extinction in Attractor Networks

The processes of memory reconsolidation and extinction have received increasing attention in recent experimental research, as their potential clinical applications begin to be uncovered. A number of studies suggest that amnestic drugs injected after reexposure to a learning context can disrupt either of the two processes, depending on the behavioral protocol employed. Hypothesizing that reconsolidation represents updating of a memory trace in the hippocampus, while extinction represents formation of a new trace, we have built a neural network model in which either simple retrieval, reconsolidation or extinction of a stored attractor can occur upon contextual reexposure, depending on the similarity between the representations of the original learning and reexposure sessions. This is achieved by assuming that independent mechanisms mediate Hebbian-like synaptic strengthening and mismatch-driven labilization of synaptic changes, with protein synthesis inhibition preferentially affecting the former. Our framework provides a unified mechanistic explanation for experimental data showing (a) the effect of reexposure duration on the occurrence of reconsolidation or extinction and (b) the requirement of memory updating during reexposure to drive reconsolidation

Characterization of indeterminate spleen lesions in primary CT after blunt abdominal trauma: potential role of MR imaging

The purpose of this study was to determine the value of magnetic resonance imaging (MRI) for characterization of indeterminate spleen lesions in primary computed tomography (CT) of patients with blunt abdominal trauma. Twenty-five consecutive patients (8 female, 17 male, mean age 51.6 ± 22.4 years) with an indeterminate spleen lesion diagnosed at CT after blunt abdominal trauma underwent MRI with T2- and T1-weighted images pre- and post-contrast material administration. MRI studies were reviewed by two radiologists. Age, gender, injury mechanism, injury severity score (ISS), management of patients, time interval between CT and MRI, and length of hospital stay were included into the analysis. Patient history, clinical history, imaging, and 2-month clinical outcome including review of medical records and telephone interviews served as reference standard. From the 25 indeterminate spleen lesions in CT, 11 (44 %) were traumatic; nine (36 %) were non-traumatic (pseudocysts, n = 5; hemangioma, n = 4) and five proven to represent artifacts in CT. The ISS (P  0.05). The MRI features ill-defined lesion borders, variable signal intensity on T1- and T2-weighted images depending on the age of the hematoma, focal contrast enhancement indicating traumatic pseudoaneurysm, perilesional contrast enhancement, and edema were most indicative for traumatic spleen lesions. As compared with CT (2/25), MRI (5/25) better depicted thin subcapsular hematomas as indicator of traumatic spleen injury. In conclusion, MRI shows value for characterizing indeterminate spleen lesions in primary CT after blunt abdominal trauma

Estrogen- and Progesterone (P4)-Mediated Epigenetic Modifications of Endometrial Stromal Cells (EnSCs) and/or Mesenchymal Stem/Stromal Cells (MSCs) in the Etiopathogenesis of Endometriosis

Endometriosis is a common chronic inflammatory condition in which endometrial tissue appears outside the uterine cavity. Because ectopic endometriosis cells express both estrogen and progesterone (P4) receptors, they grow and undergo cyclic proliferation and breakdown similar to the endometrium. This debilitating gynecological disease affects up to 15% of reproductive aged women. Despite many years of research, the etiopathogenesis of endometrial lesions remains unclear. Retrograde transport of the viable menstrual endometrial cells with retained ability for attachment within the pelvic cavity, proliferation, differentiation and subsequent invasion into the surrounding tissue constitutes the rationale for widely accepted implantation theory. Accordingly, the most abundant cells in the endometrium are endometrial stromal cells (EnSCs). These cells constitute a particular population with clonogenic activity that resembles properties of mesenchymal stem/stromal cells (MSCs). Thus, a significant role of stem cell-based dysfunction in formation of the initial endometrial lesions is suspected. There is increasing evidence that the role of epigenetic mechanisms and processes in endometriosis have been underestimated. The importance of excess estrogen exposure and P4 resistance in epigenetic homeostasis failure in the endometrial/endometriotic tissue are crucial. Epigenetic alterations regarding transcription factors of estrogen and P4 signaling pathways in MSCs are robust in endometriotic tissue. Thus, perspectives for the future may include MSCs and EnSCs as the targets of epigenetic therapies in the prevention and treatment of endometriosis. Here, we reviewed the current known changes in the epigenetic background of EnSCs and MSCs due to estrogen/P4 imbalances in the context of etiopathogenesis of endometriosis

Tumor suppressor PTEN signaling is up-regulated in mammary epithelial cells by soy isoflavone genistein: implications for breast cancer protection.

Abstract Abstract #4069 Breast cancer is the second leading cause of death in the Western hemisphere affecting one of eight women in their lifetime. In addition to chromosomal and genetic alterations, nutrition is considered a risk determinant for breast cancer. Prevailing evidence suggests a negative correlation between intake of soy-rich foods and breast cancer incidence. Epidemiological and case control studies have shown a two-to eight fold lower occurrence of the disease in Asian women whose early intake of soy products is 20-25 times higher than their American counterparts. Previous work from our group has shown diet-induced protection against DMBA- and NMU-induced mammary tumors in vivo, with decreased tumor incidence and increased tumor latency in rats exposed to dietary soy protein isolate (SPI) or casein (CAS) supplemented with the major soy isoflavone genistein (GEN) when compared to those fed the control casein (CAS) diet. We also have shown that GEN enhanced apoptosis in mammary epithelial cells in vivo and in vitro (MCF-7 cells), attendant with increased expression of the tumor suppressor PTEN and several pro-apoptotic genes Bax, Bok, and p21. Here, we test the hypothesis that GEN induction of PTEN expression and nuclear localization in mammary epithelial cells result in decreased cellular proliferation and enhanced cellular differentiation, to confer protection from mammary tumorigenesis. Using the non-tumor human mammary epithelial cell line MCF-10A, we show that GEN at physiologically relevant concentrations (40 nM, 2 µM) increased PTEN mRNA and protein levels and enhanced nuclear accumulation of active (non-phosphorylated) PTEN. GEN induction of PTEN transcript levels was lost with the inclusion of the transcription inhibitor actinomycin D, suggesting PTEN is a direct GEN target. Further, cells treated with GEN for 6 days had lower cell viability when compared to control cells, concomitant with decreased expression of cyclin D1 and of the PTEN regulated gene pleiotrophin. Interestingly, GEN up-regulation of PTEN expression was accompanied by similar effects on another tumor suppressor p53, which co-localized with PTEN in the nuclei of GEN-treated cells. PTEN siRNA targeting, which decreased basal PTEN expression by 60%, significantly increased cyclin D1 but not p53 expression. Our findings provide support to the hypothesis that the protective effects of GEN in the mammary epithelium may be mediated by PTEN to enhance differentiation and inhibit cellular proliferation, and suggest the participation of another key tumor suppressor p53. Funding by USDA-CRIS 6251-5100002-06S. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4069.</jats:p

Regulation of adipocyte lipid homeostasis by genistein alters mammary epithelial cell differentiation: a paracrine mechanism for mammary tumor protection.

Abstract Abstract #5082 Epidemiological and animal studies have shown a negative correlation between breast cancer incidence and intake of soy-rich foods. Our laboratory has used soy protein isolate (SPI), the primary component of soy infant formula, as a paradigm to evaluate diet as a risk factor in mammary cancer. We previously demonstrated that lifetime exposure to dietary SPI reduced the incidence of NMU-induced mammary tumors in young adult rats relative to those fed the control Casein diet (CAS). This protection was associated with increased differentiation status of mammary epithelial cells prior to carcinogen insult, suggesting enhanced differentiation as a mechanism for mammary tumor protection. To identify early events contributing to diet-induced mammary differentiation, we used Affymetrix RAE230A GeneChips containing 14280 probes and GeneSpring Gx to analyze genomic profiles of mammary glands of prepubertal [postnatal day (PND) 21] rats which were lifetime exposed to dietary SPI or CAS. Of the 8 genes down-regulated by SPI, 4 are involved in lipid homeostasis: malic enzyme 1, fatty acid synthase (Fasn), stearoyl CoA desaturase-1 (Scd1), and insulin-induced gene 1. One of five SPI-induced genes is 11β-hydroxysteroid dehydrogenase 1 (Hsd1), which converts 11β-dehydrocorticosterone to corticosterone. Quantitative RT-PCR confirmed that Fasn and Scd1 transcript levels were down-regulated and Hsd1 was up-regulated, in PND21 mammary tissues of SPI vs CAS group. We evaluated potential paracrine effects of soy-mediated alterations in adipocyte lipid metabolism on mammary epithelial cell phenotype. In these studies, we used the mouse fibroblast 3T3-L1 cell line treated with the bioactive soy isoflavone genistein (GEN) and mouse mammary epithelial cell line HC11 as in vitro systems to recapitulate in vivo stromal/epithelial interactions. GEN (0.5 μM) regulated lipid homeostasis in fully differentiated 3T3-L1 adipocytes. GEN decreased Fasn and Scd1 and increased Hsd1 transcript levels in the absence of effects on leptin and PPARγ2 gene expression. To evaluate whether factors produced by GEN-treated adipocytes regulate mammary epithelial differentiation, mature adipocytes were incubated in medium with or without GEN (0.5 μM) for 48 h. Cells were refreshed with maintenance medium without GEN and 24 h later, conditioned medium (CM) was harvested, supplemented with prolactin (5 ng/ml), and added full-strength to HC11 cells. Cells incubated for 72 h in CM from GEN-exposed adipocytes had higher differentiation-associated β-casein transcript levels than those grown in non-GEN-treated CM. Our data support the hypothesis that GEN modulation of mammary fat pad metabolism and secretion constitutes one mechanism by which mammary epithelial differentiation is enhanced by diet to confer increased resistance to breast cancer. Studies are in progress to identify adipocyte-secreted factors regulated by this dietary isoflavone. USDA-CRIS-6251-5100-002-06S. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5082.</jats:p