bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differential Activation of the IGF Binding Protein-3 Promoter by Butyrate in Prostate Cancer Cells
Authors: Tsubaki Junko , Hwa Vivian , Twigg Stephen M. , Rosenfeld Ron G. 
Published: January 2014

AbstractSodium butyrate (NaB), a dietary micronutrient, is a potent growth inhibitor that initiates cell differentiation in many cell types, including prostate cancer cells. The molecular mechanisms by which these effects occur remain largely unknown. In this study, we investigated the effects of NaB on the expression of IGF binding protein (IGFBP)-3, a known growth regulator, in two human prostate cancer cell lines (PC-3 and LNCaP).Treatment with NaB (0–10 mm) caused a dose-dependent stimulation of IGFBP-3 mRNA expression and parallel increases in protein levels. A specific histone deacetylase inhibitor, trichostatin A (TSA) similarly induced IGFBP-3 expression, indicating that histone hyperacetylation may be critical in the regulation of IGFBP-3 expression.To investigate the molecular mechanism of NaB-regulated IGFBP-3 expression, 1.87 kb of the human IGFBP-3 gene promoter was cloned into the pGL2-basic luciferase reporter vector. In both PC-3 and LNCaP cells, NaB (10 mm) significantly increased luciferase activity 20- to 30-fold, compared with the untreated control. However, using 5′ sequential deletion constructs of the IGFBP-3 promoter, the NaB response sequences in the IGFBP-3 promoter were different in PC-3 and LNCaP cells. Our studies identified a region, −75 to +69 from the start of transcription (+1), that is fully inducible by NaB treatment in LNCaP cells, but not in PC-3 cells. Unlike other well characterized NaB-regulated genes, Sp1 DNA sequences are not involved in NaB up-regulation of IGFBP-3 gene in LNCaP cells. Further deletion studies identified two independent regions critical for NaB-induced transactivation in LNCaP cells. These regions contain consensus binding sites for p53 and GATA, respectively, but mutational analyses and gel shift assays suggested that, while the p53 response element is required for NaB responsiveness, neither p53 nor GATA are involved.In summary, we have demonstrated that 1) NaB significantly up-regulates IGFBP-3 mRNA and protein levels in PC-3 and LNCaP prostate cancer cells; and 2) novel butyrate- responsive elements lacking consensus Sp1 sites are used in LNCaP cells.
Estrogen Receptor α Inhibits IL-1β Induction of Gene Expression in the Mouse Liver
Authors: Evans Mark J. , Lai Kehdih , Shaw Lucinda J. , Harnish Douglas C. , Chadwick Christopher C. 
Published: January 2014

AbstractEstrogens have been suggested to modulate several inflammatory processes. Here, we show that IL-1β treatment induced the expression of approximately 75 genes in the liver of ovariectomized mice. 17α-Ethinyl estradiol (EE) pretreatment reduced the IL-1β induction of approximately one third of these genes. Estrogen receptor α (ERα) was required for this inhibitory activity, because EE inhibition of IL-1β-stimulated gene expression occurred in ERβ knockout mice, but not in ERα knockout mice. EE treatment induced expression of 40 genes, including the transcriptional repressor short heterodimer partner and prostaglandin D synthase, known modulators of nuclear factor-κB signaling. However, the ER agonists genistein and raloxifene both inhibited IL-1β gene induction without stimulating the expression of prostaglandin D synthase, short heterodimer partner, or other ER-inducible genes, indicating that induction of gene expression was not required for ER inhibition of IL-1β signaling. Finally, the ability of EE to repress IL-1β gene induction varied among tissues. For example, EE inhibited IL-1β induction of lipopolysaccharide-induced c-x-c chemokine (LIX) in the liver, but not in the spleen or lung. The degree of EE repression did not correlate with ER expression. cAMP response element binding protein-binding protein (CBP)/p300 levels also varied between tissues. Together, these results are consistent with a model of in vivo ER interference with IL-1β signaling through a coactivator-based mechanism.
Depression in Women with Spontaneous 46, XX Primary Ovarian Insufficiency
Authors: Schmidt Peter J. , Luff Jamie A. , Haq Nazli A. , Vanderhoof Vien H. , Koziol Deloris E. , Calis Karim A. , Rubinow David R. , Nelson Lawrence M. 
Published: January 2014

Context: A high prevalence of depressive symptoms is observed in women with primary ovarian insufficiency (POI) compared with women in whom the menopause is normally timed. Indeed, studies suggest that depression and/or its pharmacological treatment contribute to the onset of POI.
Objectives: We characterize the prevalence of psychiatric disorders and the timing of onset of clinically significant depression relative to both the diagnosis of POI and the onset of menstrual irregularity in women with POI.
Design and Setting: We conducted a cross-sectional clinic-based study at the National Institutes of Health Clinical Research Center.
Patients: A total of 174 women with spontaneous 46, XX POI and 100 women with Turner syndrome participated in the study.
Main Outcome Measures: The structured clinical interview for DSM-IV was performed.
Results: Lifetime histories of depression in POI exceeded rates of depression reported in women with Turner syndrome and community-based samples of women (P &lt; 0.001). The onset of depression frequently preceded the diagnosis of POI but occurred after the onset of menstrual irregularity. Analyses standardizing the periods of risk for depression showed that similar numbers of depressions occurred before and after these events.
Conclusions: POI is associated with an increased lifetime risk for major depression. Attention to the presence of depression in POI should become an important part of the care for these women. The onset of depression frequently occurs after signs of altered ovarian function but before the diagnosis of POI. Thus, in some women the association between POI and depression suggests an overlapping pathophysiology rather than a causal relationship.
25-Hydroxyvitamin D, Insulin-Like Growth Factor-I, and Bone Mineral Accrual during Growth
Authors: Breen M. E. , Laing E. M. , Hall D. B. , Hausman D. B. , Taylor R. G. , Isales C. M. , Ding K. H. , Pollock N. K. , Hamrick M. W. , Baile C. A. , Lewis R. D. 
Published: January 2014

Context: The extent to which 25-hydroxyvitamin D [25(OH)D] and IGF-I influence bone mineral content (BMC) accrual from early to mid-puberty is unclear.
Objective, Setting, and Participants: This study sought to determine relationships among 25(OH)D, IGF-I, and BMC in community-dwelling prepubertal females (n = 76; aged 4–8 yr at baseline) over a period of up to 9 yr.
Design: The hypothesis that changes in IGF-I vs. 25(OH)D are more strongly associated with BMC accrual was formulated after data collection. 25(OH)D and IGF-I were log-transformed and further adjusted using two-way ANOVA for differences in season and race. Linear mixed modeling (including a random subject-specific intercept and a random subject-specific slope on age) was employed to analyze the proportion of variance the transformed 25(OH)D and IGF-I variables explained for the bone outcomes.
Results: IGF-I was more strongly associated with BMC accrual than 25(OH)D at the total body (R2 = 0.874 vs. 0.809), proximal femur (R2 = 0.847 vs. 0.771), radius (R2 = 0.812 vs. 0.759), and lumbar spine (R2 = 0.759 vs. 0.698). The rate of BMC accrual was positively associated with changes in IGF-I but negatively associated with 25(OH)D. When IGF-I and 25(OH)D were included in the same regression equation, 25(OH)D did not have a significant predictive effect on BMC accrual above and beyond that of IGF-I.
Conclusions: These prospective data in early adolescent females indicate that both 25(OH)D and IGF-I have a significant impact on bone mineral accrual; however, the positive association of IGF-I and BMC accrual is greater than the negative association of 25(OH)D and BMC accrual.
Effect of Endocrine Therapies on Bone in Breast Cancer Patients
Authors: Santen R. J. 
Published: January 2014

Recent data suggest that AIs are more effective than tamoxifen in the adjuvant and advanced disease settings and are now being more commonly used. Tamoxifen, as a selective estrogen receptor modulator, exerts estrogenic effects to preserve bone, whereas the AIs profoundly lower estrogen levels and cause bone loss. Recent comparative studies of these agents provide extensive data on fracture rates, bone mineral density, and markers of bone formation and resorption.
Objective: The aim of the study was to review the mechanistic effects of estrogen on bone and clinical data regarding bone density, bone turnover markers, and fracture rates in women with breast cancer taking tamoxifen or AIs.
Evidence Acquisition and Synthesis: Data presented reflect a review of the literature and data integration from the perspective of the author’s knowledge of the field.
Results: Tamoxifen increases bone density and reduces fractures in postmenopausal women with breast cancer, whereas AIs increase rate of fracture, accelerate loss of bone mineral density, and enhance levels of markers of bone formation and resorption. Bisphosphonates and denosumab counteract the effects of the AIs on bone. Guidelines for management of AI-induced bone loss are available from several sources, but a simple algorithm guides decision making most effectively.
Conclusions: Endocrine therapy for postmenopausal women with breast cancer exerts substantial effects on bone, and guidelines are available to assist in the management of bone-related problems.
Novel Pyrazolopyrimidine Derivatives as Tyrosine Kinase Inhibitors with Antitumoral Activity in Vitro and in Vivo in Papillary Dedifferentiated Thyroid Cancer
Authors: Antonelli Alessandro , Bocci Guido , La Motta Concettina , Ferrari Silvia Martina , Fallahi Poupak , Fioravanti Anna , Sartini Stefania , Minuto Michele , Piaggi Simona , Corti Alessandro , Alì Greta , Berti Piero , Fontanini Gabriella , Danesi Romano , Da Settimo Federico , Miccoli Paolo 
Published: January 2014

Aim: We have studied the antitumoral activity of two new pyrazolo[3,4-d]pyrimidine compounds (CLM3 and CLM29) in primary papillary dedifferentiated thyroid cancer cells (DePTC cells).
Methods: The antiproliferative effect was tested in DePTC cells obtained at reoperation from patients with recurrence of the tumor. The concentrations of CLM3 and CLM29 used in the in vitro experiments were 1, 10, 30, and 50 μm.
Results: Proliferation assays in DePTC cells showed a significant reduction of proliferation by CLM3 and CLM29, which was by 12% with CLM3 (the most potent compound) 10 μm, 43% with CLM3 30 μm, and 60% with CLM3 50 μm. CLM3 and CLM29 increased the percentage of apoptotic cells in DePTC cells dose dependently (P &lt; 0.001) and inhibited migration (P &lt; 0.001). A DePTC cell line (AL) was injected sc in CD nu/nu mice, and tumor masses became detectable 10 d after xenotransplantation. CLM3 (40 mg/kg·die) significantly inhibited tumor growth and weight, and the therapeutic effect was significant starting on the 19th day after cell implantation (4 d after the beginning of treatment). The CLM3-treated group of animals did not show any appreciable toxicity. CLM3 and CLM29 increased thrombospondin-1 expression in the AL cell line. A significant reduction of microvessels and in the percentage of antivascular endothelial growth factor antibody immunoreactivity was observed in the CLM3 treated tumors, with a simultaneous increase of the percentage of necrosis.
Conclusion: The antitumoral activity of two new pyrazolo[3,4-d]pyrimidine compounds (CLM3, CLM29) in vitro and CLM3 in vivo in DePTC has been shown, opening the way to a future clinical evaluation.
Surfactant Protein-A (SP-A) Selectively Inhibits Prostaglandin F2α (PGF2α) Production in Term Decidua: Implications for the Onset of Labor
Authors: Snegovskikh Victoria V. , Bhandari Vineet , Wright Jo Rae , Tadesse Serkalem , Morgan Thomas , MacNeill Colin , Foyouzi Nastaran , Park Joong Shin , Wang Yuguang , Norwitz Errol R. 
Published: January 2014

Abstract

Context:
Labor is characterized by “decidual activation” with production of inflammatory mediators. Recent data suggest that surfactant protein-A (SP-A) may be critical to the onset of labor in mice. Whether this is also true in humans is unclear.

Objectives:
The aim was to investigate: 1) the expression of SP-A at the maternal-fetal interface; 2) the effect of SP-A on the production of inflammatory mediators by human decidua; and 3) the association between single nucleotide polymorphisms in maternal SP-A genes and spontaneous preterm birth.

Research Design and Methods:
In situ expression of SP-A was investigated by immunohistochemistry and quantitative RT-PCR. Term decidual stromal cells were isolated, purified, and treated with/without SP-A (1-100 μg/ml), IL-1β, and/or thrombin. Levels of inflammatory mediators [IL-6, IL-8, TNFα, MMP-3, MCP-1, IL-1β, PGE2, prostaglandin F2α (PGF2α)] and angiogenic factors (sFlt-1, VEGF) were measured in conditioned supernatant by ELISA and corrected for protein content. The effect of SP-A on eicosanoid gene expression was measured by quantitative RT-PCR.

Results:
SP-A localized to endometrium/decidua. High-dose SP-A (100 μg/ml) inhibited PGF2α by term decidual stromal cells without affecting the production of other inflammatory mediators, and this effect occurred at a posttranscriptional level. Decidual SP-A expression decreased significantly with labor. Single nucleotide polymorphisms in the SP-A genes do not appear to be associated with preterm birth.

Conclusions:
SP-A is produced by human endometrium/decidua, where it significantly and selectively inhibits PGF2α production. Its expression decreases with labor. These novel observations suggest that decidual SP-A likely plays a critical role in regulating prostaglandin production within the uterus, culminating at term in decidual activation and the onset of labor.
Functioning Thoracic Paraganglioma: Association with Von Hippel-Lindau Syndrome*
Authors: Bender Bernhard U. , Altehöfer Carsten , Januszewicz Andrzej , Gärtner Roland , Schmidt Heinrich , Hoffmann Michael M. , Heidemann Peter H. , Neumann Hartmut P. H. 
Published: January 2014

AbstractFunctioning thoracic paraganglioma (pheochromocytoma) is unusual and therefore suggestive of a pathogenesis distinct from that of sporadic adrenal pheochromocytoma. To determine whether the pheochromocytoma-associated syndromes Von Hippel-Lindau disease (VHL) and multiple endocrine neoplasia type 2 (MEN 2) play a role in the development of thoracic functioning paragangliomas, germline DNA from five unselected patients with this rare tumor was analyzed for mutations in the genes that predispose to VHL and MEN 2. Genetic investigations and further clinical data revealed that three had VHL, with two different germline mutations of the vhl gene, but no individual was affected by MEN 2. Two of the three patients with VHL did not show any additional VHL-associated lesions. This result suggests that VHL should be considered in the differential diagnosis of thoracic pheochromocytoma, as such a diagnosis carries further important implications for the patient and family. Conversely, in patients suspected of a catecholamine-secreting tumor and known VHL, thoracic localization should be considered if an adrenal pheochromocytoma cannot be detected.
Endothelin-1 Stimulates Steroid Secretion of Human Adrenocortical Cells ex Vivo Via Both ETA and ETB Receptor Subtypes
Authors: Rossi G. P. , Albertin G. , Neri G. , Andreis P. G. , Hofmann S. , Pessina A. C. , Nussdorfer G. G. 
Published: January 2014

Abstract
The role played by endothelins (ETs) and their receptor subtypes (ETA and ETB) in the regulation of steroid hormone secretion in human adrenal gland remains unclear. Therefore, we investigated the gene expression of ET-1 and its receptors in highly pure preparations of human adrenocortical cells and the effect of ET-1 on their secretory activity. Reverse transcription-PCR with primers specific for prepro-ET-1, ET-converting enzyme-1, ETA, and ETB complementary DNAs demonstrated the expression of all of these genes in human adrenocortical cells. ET-1 increased the secretion of aldosterone and cortisol by enhancing both earlier and late steps of their synthesis. The secretory response to ET-1 was partially (60%) inhibited by BQ-123 and BQ-788, which are selective antagonists of the ETA and ETB receptors, respectively. When added together, the two antagonists suppressed the secretagogue effect of ET-1. Collectively, these findings suggest that ET-1, acting via both ETA and ETB receptors, may exert an autocrine/paracrine regulation of the function of the human adrenal cortex.
Cortisol Reduces Hippocampal Glucose Metabolism in Normal Elderly, but Not in Alzheimer’s Disease*
Authors: de Leon M. J. , McRae T. , Rusinek H. , Convit A. , De Santi S. , Tarshish C. , Golomb J. , Volkow N. , Daisley K. , Orentreich N. , McEwen B. 
Published: January 2014

AbstractGlucocorticoids are known to play a role in the regulation of peripheral glucose mobilization and metabolism. Although several animal studies have shown that hippocampal glucose metabolism is reduced acutely and chronically by the action of corticosterone and that excess glucocorticoids are harmful to hippocampal neurons, little is known about the central effects of glucocorticoids in the human. In this study we examined the brain glucose utilization (CMRglu) response to hydrocortisone (cortisol) in seven normal elderly and eight Alzheimer’s disease (AD) patients. On 2 separate days, immediately after the administration of a bolus of either 35 mg hydrocortisone or placebo, we administered 2-deoxy-2-[18F]fluoro-d-glucose. After a 35-min radiotracer uptake period, positron emission tomography (PET) images were collected. PET CMRglu images were analyzed using two methods: an image transformation that allowed analyses across cases on a voxel by voxel basis, and an anatomically based region of interest method that used coregistered magnetic resonance imaging scans. Both image analysis methods yielded similar results, identifying relative to placebo, a specific hippocampal CMRglu reduction in response to the hydrocortisone challenge that was restricted to the normal group. The region of interest technique showed CMRglu reductions of 16% and 12% in the right and left hippocampi, respectively. Blood collected during the PET scans showed, for the normal group, a rise in plasma glucose levels, starting approximately 25 min after hydrocortisone administration. The AD group did not show this effect. Baseline cortisol was elevated in the AD group, but the clearance of hydrocortisone was not different between the groups. In conclusion, these data show that among normal individuals in the presence of a pharmacological dose of cortisol, the glucose utilization of the hippocampus is specifically reduced, and serum glucose levels increase. Based in part on other studies, we offer the interpretation that glucocorticoid-mediated regulation of glucose transport is altered in AD, and this may underlie both the hippocampal insensitivity to cortisol and the failure in these patients to mount a peripheral glucose response. As our findings could reflect an altered state of the AD patients, we interpret our results as preliminary with respect to evidence for metabolic abnormalities in AD. The results suggest the continued study of the hydrocortisone challenge as a test of hippocampal responsivity.
Thyrotropin-Receptor and Thyroid Peroxidase-Specific T Cell Clones and Their Cytokine Profile in Autoimmune Thyroid Disease1
Authors: Fisfalen Maria Elena , Palmer Ellen M. , van Seventer Gijs A. , Soltani Keyoumars , Sawai Yoshikuni , Kaplan Edwin , Hidaka Yoh , Ober Carole , DeGroot Leslie J. 
Published: January 2014

We studied the cytokine profile and the immune responses to thyroid antigens of specific T cell clones (TCC) isolated from patients with Hashimoto’s thyroiditis (HT) and Graves’ disease (GD). Antigen-specific TCC were reactive to thyroid peroxidase (TPO), thyroglobulin (Tg) or human recombinant TSH-receptor extracellular domain (TSH-R), and/or their respective peptides. Of the 43 clones derived from HT patients, 65% were reactive to TPO, and 59% of the 32 clones derived from GD patients were reactive to TSH-R. TPO epitopes 100–119 and 625–644 were recognized by 75% of HT-derived clones, whereas TSH-R epitopes 158–176, 207–222, and 343–362/357–376 were recognized by 85% of GD-derived TCC.The TCC were classified according to their cytokine profile into T helper cell (Th)0 [secreting interleukin (IL)-4, IL-5, interferon (IFN)-γ], Th1 (secreting IFN-γ) and Th2 (secreting IL-4 and/or IL-5). Tumor necrosis factor-β and IL-10 were produced by all subsets. The specific TCC were predominantly Th1-like cells in HT, and were Th0- and Th1-like cells in GD. Fifty three percent of Th0 clones were derived from GD patients and were reactive to TSH-R, whereas 50% of Th1 clones were derived from HT patients and were reactive to TPO or Tg. Most Th2 clones (82%) were reactive to TPO and were established from peripheral blood. All these clones produced IL-5, and 64% produced IL-4 and IL-10. Interestingly, IFN-γ was highly produced by TPO- or Tg-specific clones established from HT thyroid tissue.These results confirm at the clonal level our previous studies regarding T cell epitopes on TPO and TSH-R molecules and support the concept that immunodominant T cell epitopes are located on amino acid residues 100–119 and 625–644 of TPO in HT and amino acid residues 158–176, 207–222 and 343–362/357–376 of TSH-R in GD. Our studies also demonstrate that thyroid-specific T cells can be classified into Th0, Th1, and Th2 subsets. TPO- or Tg-specific clones with Th1 phenotype appear to be involved in the pathogenesis of HT, mediating thyroid tissue destruction, whereas TSH-R clones with Th0 phenotype may induce thyroid-stimulating autoantibodies in GD.