bluuebunny/crossref_metadata_2025_split huggingface dataset:
Expression of Cyclooxygenase-2 and Prostanoid Receptors by Human Myometrium*
Authors: Erkinheimo Tiina-Liisa , Saukkonen Kirsi , Narko Kirsi , Jalkanen Jyrki , Ylikorkala Olavi , Ristimäki Ari 
Published: January 2014

AbstractProstanoids play an important role in the regulation of parturition. All reproductive tissues, including fetal membranes, decidua, and myometrium, have the capacity to synthesize prostanoids, and fetal membranes have been shown to express elevated levels of cyclooxygenase-2 (Cox-2) at the onset of labor. We have now investigated the expression of Cox-2 in human myometrium. Myometrial samples collected from women in labor during lower segment cesarean section expressed 15-fold higher levels of Cox-2 messenger ribonucleic acid (mRNA) compared to myometrial specimens collected from women not in labor, as detected by Northern blot analysis. Immunohistochemical detection of Cox-2 protein showed cytoplasmic staining in the smooth muscle cells of the myometrium. Cultured myometrial cells expressed low levels of Cox-2 mRNA under baseline conditions, but interleukin-1β (IL-1β) caused a 17-fold induction of expression of the Cox-2 transcript after incubation for 6 h. IL-1β also induced expression of biologically active Cox-2 protein, as detected by immunofluorescence, Western blot analysis, and measuring the conversion of arachidonic acid to prostanoids in the presence and absence of a Cox-2-selective inhibitor, NS-398. PGE2 receptor subtype EP2 mRNA was expressed in cultured myometrial smooth muscle cells, whereas transcripts for EP1, EP3, EP4, FP, and IP were low or below the detection limit as measured by Northern blot analysis. However, IL-1β stimulated expression of EP4 receptor mRNA. Our data suggest that expression of Cox-2 transcript is elevated at the onset of labor in myometrial smooth muscle cells, which may depend on induction by cytokines. As, in addition to Cox-2, the expression of prostanoid receptors is regulated, not only the production of prostanoids, but also responsiveness to them, may be modulated.
Linear Growth and Final Height after Treatment for Cushing’s Disease in Childhood
Authors: Lebrethon Marie-Christine , Grossman Ashley B. , Afshar Farhad , Plowman P. Nicholas , Besser G. Michael , Savage Martin O. 
Published: January 2014

AbstractCushing’s disease is associated with growth failure in childhood and adolescence. Growth and final height were analyzed in 10 patients who were cured or in remission after treatment of Cushing’s disease. Seven males and 3 females, aged 6.8–17.6 yr (bone age, 3.3- 15.4 yr), had transsphenoidal surgery, which was combined with pituitary irradiation (4500 cGy in 25 fractions) in 5 patients. At presentation, 5 patients were prepubertal (males), and 5 were pubertal (2 males and 3 females). The mean height sd score was −2.15 ± 1.26 (range, −0.21 to −4.32) compared with mean target height sd score of −0.43 ± 0.58. Height velocity in 6 patients was subnormal (0.9–3.8 cm/yr). After treatment, short-term height velocity, over a mean interval of 0.57 yr, in 8 patients not receiving human GH (hGH) therapy, was variable (range, 0.8–7.6 cm/yr). GH stimulation tests (insulin tolerance test/glucagon) in 9 subjects showed peak GH levels of 0.5–20.9 mU/L. Eight were treated with hGH (14 IU/m2·wk), combined in 2 girls and 1 boy with a GnRH analog. After 1 yr of hGH, the mean height sd score had increased from −2.45 ± 1.0 at initiation of hGH to −2.07± 1.2 (P = 0.01). GH therapy was continued until final height or latest assessment. The mean final height sd score (n = 6) was −1.24 ± 1.38, and at the latest assessment the mean height sd score (n = 4) was− 1.52 ± 1.33. Combining these 2 groups, the mean height sd score was −1.36 ± 1.29. The difference between final or latest height sd score and target height sd score was 0.93 ± 1.13, i.e. less (P = 0.005) than the difference between height and target height sd score of 1.72 ± 1.26 at presentation. In conclusion, catch-up and favorable long-term growth was seen after treatment for Cushing’s disease. Posttreatment GH deficiency was frequent, and early hGH replacement may have contributed to the encouraging outcome.
Alterations in Serum Protein Levels in Patients with Cushing’s Syndrome before and after Successful Treatment
Authors: Putignano P. , Kaltsas G. A. , Korbonits M. , Jenkins P. J. , Monson J. P. , Besser G. M. , Grossman A. B. 
Published: January 2014

Abstract
Alteration in serum protein concentration is used commonly in clinical practice as a nonspecific indicator of underlying disease or to monitor disease activity. Although hypercortisolemia may affect protein metabolism directly or indirectly, data regarding alterations of levels of serum protein in a large series of patients with Cushing’s syndrome (CS) have been lacking. We have now evaluated, retrospectively, the levels of circulating serum albumin, globulins, total proteins, and the albumin to globulin ratio in 99 patients with endogenous CS before, immediately after, and 3, 6, and 12 months following successful treatment. Subjects with concomitant infections or other chronic diseases were excluded from the analysis.
Although mean serum albumin and total protein levels were within the normal reference ranges, in general, they gradually increased after treatment with maximal values being reached at 12 months after normalization of hypercortisolemia (P &lt; 0.0001 for both); there were no significant changes in serum globulin levels or in the albumin to globulin ratio. Patients with CS as a whole showed a weak but significant negative correlation between serum albumin and 0900 h cortisol level (r = −0.303; P = 0.0035).
In conclusion, our data suggest that CS is associated with a small but significant reduction in circulating serum protein levels, which are restored following treatment of hypercortisolemia, although these changes occur within the reference range. Thus, extreme alterations in serum total protein or albumin levels in patients with CS should alert physicians to the presence of concomitant pathology, and additional specific investigation should be undertaken to elucidate the cause.
Growth and Adult Height in GH-Treated Children with Nonacquired GH Deficiency and Idiopathic Short Stature: The Influence of Pituitary Magnetic Resonance Imaging Findings
Authors: Coutant Régis , Rouleau Stéphanie , Despert François , Magontier Nathalie , Loisel Didier , Limal Jean-Marie 
Published: January 2014

We analyzed the final height of 146 short children with either nonacquired GH deficiency or idiopathic short stature. Our purpose was 1) to assess growth according to the pituitary magnetic resonance imaging findings in the 63 GH-treated children with GH deficiency and 2) to compare the growth of the GH-deficient patients with normal magnetic resonance imaging (n = 48) to that of 32 treated and 51 untreated children with idiopathic short stature (GH peak to provocative tests &gt;10 μg/liter). The mean GH dose was 0.44 IU/kg·wk (0.15 mg/kg·wk), given for a mean duration of 4.6 yr.Among the GH-deficient children, 15 had hypothalamic-pituitary abnormalities (stalk agenesis), all with total GH deficiency (GH peak&lt;5 μg/liter). They were significantly shorter and younger at the time of diagnosis than those with normal magnetic resonance imaging, had better catch-up growth (+2.7 ± 0.9 vs.+ 1.3 ± 0.8 sd score; P &lt; 0.01), and reached greater final height (−1.1 ± 1.0 vs.− 1.7 ± 1.0 sd score; P &lt; 0.05). Among patients with normal magnetic resonance imaging, there was no difference in catch-up growth and final height between partial and total GH deficiencies.GH-deficient subjects with normal magnetic resonance imaging and treated and untreated patients with idiopathic short stature had comparable auxological characteristics, age at evaluation, and target height. Although they had different catch-up growth (+1.3 ± 0.8,+ 0.9 ± 0.6, and +0.7 ± 0.9 sd score, respectively; P &lt; 0.01, by ANOVA), these patients reached a similar final height (−1.7 ± 1.0, −2.1 ± 0.8, and −2.1 ± 1.0 sd score, respectively; P = 0.13).Pituitary magnetic resonance imaging findings show the heterogeneity within the group of nonacquired GH deficiency and help to predict the response to GH treatment in these patients. The similarities in growth between the GH-deficient children with normal magnetic resonance imaging and those with idiopathic short stature suggest that the short stature in the former subjects is at least partly due to factors other than GH deficiency.
Analysis of the P3 Promoter of the Human Parathyroid Hormone (PTH)/PTH-Related Peptide Receptor Gene in Pseudohypoparathyroidism Type 1b1
Authors: Minagawa Masanori , Watanabe Tomoyuki , Kohno Yoichi , Mochizuki Hiroshi , Hendy Geoffrey N. , Goltzman David , White John H. , Yasuda Toshiyuki 
Published: January 2014

Hypocalcemia and hyperphosphatemia caused by PTH resistance are the only discernible abnormalities in pseudohypoparathyroidism type 1b (PHP-1b). Because of the selective resistance toward PTH, inactivating mutations in its receptor, the PTH/PTH-related peptide receptor (PTHR1), were thought to be responsible for PHP-1b. However, gene abnormalities responsible for PHP-1b have not been identified in the coding region and well conserved promoters (P1 and P2) of the PTHR1 gene. The purpose of the present study was to analyze the structure of the P3 promoter, the main promoter of the human PTHR1 gene in kidney, in patients with PHP-1b. Southern analysis of genomic DNA from lymphoblastoid cell lines of eight nonfamilial patients with PHP-1b revealed neither gross rearrangements nor methylation abnormalities in the P3 promoter region of the PTHR1 gene. Sequencing revealed no abnormalities in the P3 promoter region, although one patient was homozygous for an (AAAG)n polymorphic variant.
In conclusion, despite the selective resistance toward PTH in the kidney, which mainly uses the PTHR1 P3 promoter, PHP-1b in eight cases is not associated with structural abnormalities in this promoter. This study also indicates that inactivation of the P3 promoter is not achieved by methylation as tested in patients’ genomic DNA from lymphoblastoid cell lines. The influence of alterations in the polymorphic A-rich repeat sequence on promoter activity warrants further study.
A Unique Exonic Splicing Mutation in the Human Androgen Receptor Gene Indicates a Physiologic Relevance of Regular Androgen Receptor Transcript Variants1
Authors: Hellwinkel Olaf José-Carlos , Holterhus Paul-Martin , Struve Dagmar , Marschke Christine , Homburg Nicole , Hiort Olaf 
Published: January 2014

In a patient with partial androgen insensitivity syndrome (AIS), we identified a single inherited presumably silent nucleotide variation (AGC -&gt; AGT) in exon 8 (codon 888) of the AR gene. However, in the patient’s genital skin fibroblasts, a considerably shortened transcript of 5.5 kb (normal: 10.5 kb) was detected, which misses a part of exon 8 and a prominent portion of the 3′-untranslated region. The translation product includes eight missense amino acids from codon 886 onward followed by a premature stop codon. As shown by in vitro expression analysis, the mutant protein lacks any residual function. However, reverse transcribed PCRs and sequence data indicate the existence of two additional splicing variants of 6.4 kb and 7.8-kb length both in patient and normal control genital skin fibroblasts. These splicing variants comprise the complete coding region but a shortened 3′-untranslated region. Thus, a distinct alternative pre-messegner RNA-processing event leading to two additional transcripts occurs generally in genital skin fibroblasts. In addition, this process partially prevents aberrant splicing in the patient and produces a small fraction of normal, functionally intact AR-protein that could explain the partial masculinization in this patient.This first report of an exonic splicing mutation in the AR-gene indicates a physiologic relevance of the regular AR-messenger RNA variants with shortened 3′-untranslated regions and their functional translation products in human genital development.
Metabolic and Steroidogenic Alterations Related to Increased Frequency of Polycystic Ovaries in Women with a History of Gestational Diabetes1
Authors: Koivunen Riitta M. , Juutinen Jaana , Vauhkonen Ilkka , Morin-Papunen Laure C. , Ruokonen Aimo , Tapanainen Juha S. 
Published: January 2014

The prevalence of polycystic ovaries (PCO) and clinical, endocrine, and metabolic features were investigated in women with previous gestational diabetes (GDM). Thirty-three women with a history of GDM and 48 controls were studied. Glucose and insulin secretion capacity was evaluated by means of the oral glucose tolerance test (OGTT), and insulin action was determined by means of a euglycemic insulin clamp. Compared with control women, women with previous GDM more often had significantly abnormal OGTT, a higher prevalence of PCO (39.4% vs. 16.7%; P = 0.03), higher serum concentrations of cortisol, dehydroepiandrosterone, and dehydroepiandrosterone sulfate and a greater area under the glucose curve.
Women with previous GDM showed a lowered early phase insulin response to glucose and impaired insulin sensitivity, which was accounted for mainly by decreased glucose nonoxidation. They also demonstrated a significantly lower fasting serum C peptide/insulin ratio than the controls, indicating that women with previous GDM have impaired hepatic insulin extraction, which tended to be more marked among women with PCO. This may explain why women with PCO and previous GDM were significantly more hyperinsulinemic than women with normal ovaries.
In conclusion, our data demonstrate that women with previous GDM often have PCO and abnormal OGTT. They are insulin resistant as a result of lowered glucose nonoxidation and show inappropriately low insulin responses to glucose, reflecting impaired β-cell function. They also have higher adrenal androgen secretion, which may be associated with abdominal obesity.
Genomic Priming of the Antisecretory Response to Estrogen in Rat Distal Colon throughout the Estrous Cycle
Authors: O'Mahony Fiona , Alzamora Rodrigo , Chung Ho-Lam , Thomas Warren , Harvey Brian J. 
Published: January 2014

Abstract
The secretion of Cl− across distal colonic crypt cells provides the driving force for the movement of fluid into the luminal space. 17β-Estradiol (E2) produces a rapid and sustained reduction in secretion in females, which is dependent on the novel protein kinase Cδ (PKCδ) isozyme and PKA isoform I targeting of KCNQ1 channels. This sexual dimorphism in the E2 response is associated with a higher expression level of PKCδ in female compared with the male tissue. The present study revealed the antisecretory response is regulated throughout the female reproductive (estrous) cycle and is primed by genomic regulation of the kinases. E2 (1–10 nm) decreased cAMP-dependent secretion in colonic epithelia during the estrous, metestrous, and diestrous stages. A weak inhibition of secretion was demonstrated in the proestrous stage. The expression levels of PKCδ and PKA fluctuated throughout the estrous cycle and correlated with the potency of the antisecretory effect of E2. The expression of PKCδ and PKA were up-regulated by estrogen at a transcriptional level via a PKCδ-MAPK-cAMP response element-binding protein-regulated pathway indicating a genomic priming of the antisecretory response. PKCδ was activated by the membrane-impermeant E2-BSA, and this response was inhibited by the estrogen receptor antagonist ICI 182,780. The 66-kDa estrogen receptor-α isoform was present at the plasma membrane of female colonic crypt cells with a lower abundance found in male colonic crypts. The study demonstrates estrogen regulation of intestinal secretion both at a rapid and transcriptional level, demonstrating an interdependent relationship between both nongenomic and genomic hormone responses.
Osteogenic Protein-1 Up-Regulation of the Collagen X Promoter Activity Is Mediated by a MEF-2-Like Sequence and Requires an Adjacent AP-1 Sequence
Authors: Harada Shun-ichi , Sampath T. Kuber , Aubin Jane E. , Rodan Gideon A. 
Published: January 2014

AbstractBone morphogenetic proteins induce chondrogenesis and osteogenesis in vivo. To investigate molecular mechanisms involved in chondrocyte induction, we examined the effect of osteogenic protein (OP)-1/bone morphogenetic protein-7 on the collagen X promoter. In rat calvaria-derived chondrogenic C5.18 cells, OP-1 up-regulates collagen X mRNA levels and its promoter activity in a cell type- specific manner. Deletion analysis localizes the OP-1 response region to 33 bp (−310/−278), which confers OP-1 responsiveness to both the minimal homologous and heterologous Rous sarcoma virus promoter. Transforming growth factor-β2 or activin, which up-regulates the expression of a transforming growth factor-β-inducible p3TP-Lux construct, has little effect on collagen X mRNA and on this 33-bp region. Mutational analysis shows that both an AP-1 like sequence (−294/−285, TGAATCATCA) and an A/T-rich myocyte enhancer factor (MEF)-2 like sequence (−310/−298, TTAAAAATAAAAA) in the 33-bp region are necessary for the OP-1 effect. Gel shift assays show interaction of distinct nuclear proteins from C5.18 cells with the AP-1-like and the MEF-2- like sequences. OP-1 rapidly induces nuclear protein interaction with the MEF-2-like sequence but not with the AP-1 like sequence. MEF-2-like binding activity induced by OP-1 is distinct from the MEF-2 family proteins present in C2C12 myoblasts, in which OP-1 does not induce collagen X mRNA or up-regulate its promoter activity. In conclusion, we identified a specific response region for OP-1 in the mouse collagen X promoter. Mutational and gel shift analyses suggest that OP-1 induces nuclear protein interaction with an A/T-rich MEF-2 like sequence, distinct from the MEF-2 present in myoblasts, and up-regulates collagen X promoter activity, which also requires an AP-1 like sequence.
Characterization of Receptor Interaction and Transcriptional Repression by the Corepressor SMRT
Authors: Li Hui , Leo Christopher , Schroen Daniel J. , Chen J. Don 
Published: January 2014

Abstract
SMRT (silencing mediator of retinoic acid and thyroid hormone receptor) and N-CoR (nuclear receptor corepressor) are two related transcriptional corepressors that contain separable domains capable of interacting with unliganded nuclear receptors and repressing basal transcription. To decipher the mechanisms of receptor interaction and transcriptional repression by SMRT/N-CoR, we have characterized protein-protein interacting surfaces between SMRT and nuclear receptors and defined transcriptional repression domains of both SMRT and N-CoR. Deletional analysis reveals two individual nuclear receptor domains necessary for stable association with SMRT and a C-terminal helix essential for corepressor dissociation. Coordinately, two SMRT domains are found to interact independently with the receptors. Functional analysis reveals that SMRT contains two distinct repression domains, and the corresponding regions in N-CoR also repress basal transcription. Both repression domains in SMRT and N-CoR interact weakly with mSin3A, which in turn associates with a histone deacetylase HDAC1 in a mammalian two-hybrid assay. Far-Western analysis demonstrates a direct protein-protein interaction between two N-CoR repression domains with mSin3A. Finally we demonstrate that overexpression of full-length SMRT further represses basal transcription from natural promoters. Together, these results support a role of SMRT/N-CoR in corepression through the utilization of multiple mechanisms for receptor interactions and transcriptional repression.
Inhibition of the T-Type Ca2+ Current by the Dopamine D1 Receptor in Rat Adrenal Glomerulosa Cells: Requirement of the Combined Action of the Gβγ Protein Subunit and Cyclic Adenosine 3′,5′-Monophosphate
Authors: Drolet Patrick , Bilodeau Lyne , Chorvatova Alzbeta , Laflamme Liette , Gallo-Payet Nicole , Payet Marcel D. 
Published: January 2014

AbstractModulation of ionic Ca2+ currents by dopamine (DA) could play a pivotal role in the control of steroid secretion by the rat adrenal glomerulosa cells. In the present study, we report that DA decreases the T-type Ca2+ current amplitude in these cells. The use of pharmacological agonists and antagonists reveals that this effect is mediated by activation of the D1-like receptors. Modulation by cAMP is complex inasmuch as preincubation of the cells with 8-Br-cAMP or the specific adenylyl cyclase inhibitor, 2′,3′-dideoxyadenosine, have no effect per se, but prevent the DA-induced inhibition. The inhibitory effect of DA was abolished by addition of GDPβS to the pipette medium but not by pertussis toxin. If a cell is dialyzed with medium containing Gαs-GDP, the inhibitory effect is reduced and cannot be recovered by the addition of GTPγS, indicating that the αs is not involved, but rather the βγ-subunit. Indeed, DA-induced inhibition was mimicked by Gβγ in the pipette and 8-Br-cAMP in the bath. Similarly, Gβγ release from the activation of the AT1 receptor of angiotensin II did affect the current amplitude only in the presence of 8-Br-cAMP in the bath. The mitogen-activated protein kinase cascade, which can be activated by receptors coupled to Gs, was not involved as shown by the lack of activation of p42mapk by DA and the absence of effect of the mitogen-activated protein kinase inhibitor, PD 098059, on the DA-induced inhibition. Because the binding of Gβγ-subunits to various effectors involves the motif QXXER, we therefore tested the effect of the QEHA peptide on the inhibition of the T-type Ca2+ current induced by DA. The peptide, added to the medium pipette (200 μm), abolished the effect of DA. We conclude that the presence of the Gβγ and an increase in cAMP concentration are both required to inhibit the T-type Ca2+ current in rat adrenal glomerulosa cells.
The Role of Interleukin-2 in Combination Adenovirus Gene Therapy for Head and Neck Cancer
Authors: O’Malley Bert W. , Sewell Duane A. , Li Daqing , Kosai Ken-ichiro , Chen Shu-Hsia , Woo Savio L.C. , Duan Ling 
Published: January 2014

AbstractInterleukin-2 (IL-2) gene therapy alone and in combination with the herpes thymidine kinase gene (tk) was used to evaluate immunological responses and antitumor effects in head and neck cancer. Established floor of mouth squamous cell carcinomas in C3H/HeJ mice were directly injected with recombinant adenoviral vectors carrying both therapeutic and control genes. One week after adenoviral gene transfer, only the animals treated with combination IL-2+tk or tk alone demonstrated significant tumor regression. Residual tumors were harvested for microscopic evaluation and immunohistochemistry staining, which revealed a predominance of CD8+ lymphocytes in the tumor beds of the animals treated with IL-2. To evaluate the systemic immune effects of IL-2, animals treated with single or combination gene therapy received a second site challenge with parental tumor cells or a heterologous but syngeneic sarcoma cell line. Mice treated with combination IL-2 and tk demonstrated a protective systemic immunity specific to the parental tumor cell line, whereas no systemic immune response was evident in mice receiving IL-2 alone. In a separate experiment, a range of concentrations of the adenovirus IL-2 vector were used to treat established tumors. Even with the maximal single-dose adenovirus concentration, IL-2 alone was ineffective as a single therapy. These results support the use of adenovirus-mediated gene transfer of IL-2 as an effective immunotherapy when used adjuvantly with the tk “suicide gene”.