bluuebunny/crossref_metadata_2025_split huggingface dataset:
p16 overexpression in malignant and premalignant lesions of the oral and esophageal mucosa following allogeneic hematopoietic stem cell transplantation
Authors: Kakei Yasumasa , Akashi Masaya , Komatsubara Hideki , Minamikawa Tsutomu , Komori Takahide 
Published: September 2012

Abstract

Objectives
Secondary malignancy in the oral mucosa is recognized as one of the most serious complications in patients who received allogenic hematopoietic stem cell transplantation (HSCT). However, potential risk factors associated with carcinogenesis after HSCT that have been reported remain elusive. We experienced a rare case of secondary malignancies of the oral and esophageal mucosa and analyzed the expression of tumor suppressor gene product p16.

Case report
A 35-year-old male had malignant lesions of the oral and esophageal mucosa two years after HSCT. Partial maxillectomy and endoscopic submucosal dissection were performed. Immunohistochemical analyses revealed that the tumor cells of malignant and premalignant lesions of the oral cavity and esophagus but not keratosis were positive for p16.

Conclusions
Pathological examinations with p16 immunohistochemistry may contribute to an early diagnosis of secondary malignancy after HSCT.
Out-patient psychological therapies for adults with anorexia nervosa: randomised controlled trial
Authors: Schmidt Ulrike , Oldershaw Anna , Jichi Fatima , Sternheim Lot , Startup Helen , McIntosh Virginia , Jordan Jennifer , Tchanturia Kate , Wolff Geoffrey , Rooney Michael , Landau Sabine , Treasure Janet 
Published: September 2012

BackgroundVery limited evidence is available on how to treat adults with anorexia nervosa and treatment outcomes are poor. Novel treatment approaches are urgently needed.AimsTo evaluate the efficacy and acceptability of a novel psychological therapy for anorexia nervosa (Maudsley Model of Anorexia Nervosa Treatment for Adults, MANTRA) compared with specialist supportive clinical management (SSCM) in a randomised controlled trial.MethodSeventy-two adult out-patients with anorexia nervosa or eating disorder not otherwise specified were recruited from a specialist eating disorder service in the UK. Participants were randomly allocated to 20 once weekly sessions of MANTRA or SSCM and optional additional sessions depending on severity and clinical need (trial registration: ISRCTN62920529). The primary outcomes were body mass index, weight and global score on the Eating Disorders Examination at end of treatment (6 months) and follow-up (12 months). Secondary outcomes included: depression, anxiety and clinical impairment; neuropsychological outcomes; recovery rates; and additional service utilisation.ResultsAt baseline, patients randomised to MANTRA were significantly less likely to be in a partner relationship than those receiving SSCM (3/34v.10/36;P< 0.05). Patients in both treatments improved significantly in terms of eating disorder and other outcomes, with no differences between groups. Strictly defined recovery rates were low. However, MANTRA patients were significantly more likely to require additional in-patient or day-care treatment than those receiving SSCM (7/34v.0/37;P=0.004).ConclusionsAdults with anorexia nervosa are a difficult to treat group. The imbalance between groups in partner relationships may explain differences in service utilisation favouring SSCM. This study confirms SSCM as a useful treatment for out-patients with anorexia nervosa. The novel treatment, MANTRA, designed for this patient group may need adaptations to fully exploit its potential.
Interaction Between IGF Binding Protein-3 and TGFβ in the Regulation of Adipocyte Differentiation
Authors: de Silva Hasanthi C. , Firth Sue M. , Twigg Stephen M. , Baxter Robert C. 
Published: September 2012

Abstract
The development of white adipose tissue involves both the hypertrophy of existing adipocytes and the proliferation and differentiation of preadipocytes. Adipogenic differentiation is inhibited by TGFβ signaling through Smad2/3, and IGF binding protein-3 (IGFBP-3) is also known to activate Smad2/3 signaling in some cell types. We previously reported that exogenous or overexpressed IGFBP-3 inhibits adipogenesis in 3T3-L1 cells, but the role of endogenous IGFBP-3 in this process, and its possible interaction with TGFβ, is not known. During 10-d adipogenic differentiation initiated by insulin, dexamethasone, and 3-isobutyl-1-methylxanthine, 3T3-L1 cells expressed increasing levels of IGFBP-3 and TGFβ1, secreting over 1000 pg/ml of both proteins. Exogenous recombinant human IGFBP-3 paralleled TGFβ1 in stimulating Smad2 phosphorylation in 3T3-L1 preadipocytes, but no additive effect was observed for the two agents. In contrast, knockdown of endogenous IGFBP-3 by small interfering RNA (siRNA) significantly impaired Smad2 activation by 0.25 ng/ml TGFβ1. Transient expression of human IGFBP-3 significantly inhibited the induction of adipogenic markers adiponectin and resistin, and the appearance of lipid droplets, but down-regulation of endogenous IGFBP-3 by siRNA had little effect on the expression of either marker during the 10-d differentiation, compared with nonsilencing control siRNA. However, down-regulation of endogenous IGFBP-3 using two different siRNA significantly reversed the inhibitory effect of TGFβ1 on both adiponectin and resistin induction. We conclude that IGFBP-3 activates inhibitory Smad signaling in 3T3-L1 cells and that endogenous IGFBP-3 modulates their adipogenic differentiation by regulating cell sensitivity towards the inhibitory effect of TGFβ.
Absence of Herpes Virus Entry Mediator (HVEM) Increases Bone Mass by Attenuating Receptor Activator of Nuclear Factor-κB ligand (RANKL)-Induced Osteoclastogenesis
Authors: Kim Woon-Ki , Sul Ok-Joo , Choi Eun-Kyung , Lee Mi-Hyun , Jeong Choon-Soo , Kim Hyun-Ju , Kim Shin-Yoon , Suh Jae-Hee , Yu Rina , Choi Hye-Seon 
Published: September 2012

AbstractHerpes virus entry mediator (HVEM), which is constitutively expressed at a high level on myeloid lineage cells, is also expressed on bone marrow-derived macrophages, suggesting that it may play a role in bone metabolism by affecting osteoclasts (OC) derived from bone marrow-derived macrophages. To address this question, we evaluated bone mass by micro-computed tomography and the number and activity of OC by tartrate-resistant acid phosphatase (TRAP) and pit formation on dentine slices, comparing HVEM-knockout mice with wild-type mice. The absence of HVEM led to a higher bone mass and to decreased levels of serum collagen type I fragments and serum TRACP5b in vivo. In vitro HVEM deficiency resulted in a reduced number and activity of OC and an impaired receptor activator of nuclear factor-κB ligand signaling through reduced activation of nuclear factor-κB and of nuclear factor of activated T-cells cytoplasmic 1. Exogenous soluble HVEM decreased expression of TRAP, whereas soluble LIGHT (a ligand of HVEM) increased it, indicating the occurrence of a positive signaling through HVEM during osteoclastogenesis. Our findings indicate that HVEM regulates bone remodeling via action on OC. The higher bone mass in the femurs of HVEM-knockout mice could be, at least in part, due to attenuated osteoclastogenesis and bone resorption resulting from decreased receptor activator of nuclear factor-κB ligand signaling in the OC.
Single-Transmembrane Domain IGF-II/M6P Receptor: Potential Interaction with G Protein and Its Association with Cholesterol-Rich Membrane Domains
Authors: Amritraj Asha , Posse de Chaves Elena I. , Hawkes Cheryl , MacDonald Richard G. , Kar Satyabrata 
Published: September 2012

AbstractThe IGF-II/mannose 6-phosphate (M6P) receptor is a single-transmembrane domain glycoprotein that plays an important role in the intracellular trafficking of lysosomal enzymes and endocytosis-mediated degradation of IGF-II. The receptor may also mediate certain biological effects in response to IGF-II binding by interacting with G proteins. However, the nature of the IGF-II/M6P receptor's interaction with the G protein or with G protein-coupled receptor (GPCR) interacting proteins such as β-arrestin remains unclear. Here we report that [125I]IGF-II receptor binding in the rat hippocampal formation is sensitive to guanosine-5′-[γ-thio]triphosphate, mastoparan, and Mas-7, which are known to interfere with the coupling of the classical GPCR with G protein. Monovalent and divalent cations also influenced [125I]IGF-II receptor binding. The IGF-II/M6P receptor, as observed for several GPCRs, was found to be associated with β-arrestin 2, which exhibits sustained ubiquitination after stimulation with Leu27IGF-II, an IGF-II analog that binds rather selectively to the IGF-II/M6P receptor. Activation of the receptor by Leu27IGF-II induced stimulation of extracellular signal-related kinase 1/2 via a pertussis toxin-dependent pathway. Additionally, we have shown that IGF-II/M6P receptors under normal conditions are associated mostly with detergent-resistant membrane domains, but after stimulation with Leu27IGF-II, are translocated to the detergent-soluble fraction along with a portion of β-arrestin 2. Collectively these results suggest that the IGF-II/M6P receptor may interact either directly or indirectly with G protein as well as β-arrestin 2, and activation of the receptor by an agonist can lead to alteration in its subcellular distribution along with stimulation of an intracellular signaling cascade.
Müllerian Inhibiting Substance Recruits ALK3 to Regulate Leydig Cell Differentiation
Authors: Wu Xiufeng , Zhang Ningning , Lee Mary M. 
Published: September 2012

AbstractMüllerian inhibiting substance (MIS) not only induces Müllerian duct regression during male sexual differentiation but also modulates Leydig cell steroidogenic capacity and differentiation. MIS actions are mediated through a complex of homologous receptors: a type II ligand-binding receptor [MIS type II receptor (MISRII)] and a tissue-specific type I receptor that initiates downstream signaling. The putative MIS type I receptors responsible for Müllerian duct regression are activin A type II receptor, type I [Acvr1/activin receptor-like kinase 2 (ALK2)], ALK3, and ALK6, but the one recruited by MIS in Leydig cells is unknown. To identify whether ALK3 is the specific type I receptor partner for MISRII in Leydig cells, we generated Leydig cell-specific ALK3 conditional knockout mice using a Cre-lox system and compared gene expression and steroidogenic capacity in Leydig cells of ALK3fx/fxCyp17cre+ and control mice (ALK3fx/fxCyp17cre− or ALK3fx/wtCyp17cre− littermates). We found reduced mRNA expression of the genes encoding P450c17, StAR, and two enzymes (17βHSD-III and 3βHSD-VI) that are expressed in differentiated adult Leydig cells and increased expression of androgen-metabolizing enzymes (3α-HSD and SRD5A2) and proliferating cell nuclear antigen (PCNA) in Leydig cells of ALK3fx/fxCyp17cre+ mice. Despite down-regulation of steroidogenic capacity in ALK3fx/fxCyp17cre+ mice, the loss of MIS signaling also stimulates Leydig cell proliferation such that plasma testosterone and androstenedione concentrations are comparable to that of control mice. Collectively, these results indicate that the phenotype in ALK3 conditional knockout mice is similar to that of the MIS-knockout mice, confirming that ALK3 is the primary type I receptor recruited by the MIS-MISRII complex during Leydig cell differentiation.
Acylation Type Determines Ghrelin's Effects on Energy Homeostasis in Rodents
Authors: Heppner Kristy M. , Chaudhary Nilika , Müller Timo D. , Kirchner Henriette , Habegger Kirk M. , Ottaway Nickki , Smiley David L. , DiMarchi Richard , Hofmann Susanna M. , Woods Stephen C. , Sivertsen Bjørn , Holst Birgitte , Pfluger Paul T. , Perez-Tilve Diego , Tschöp Matthias H. 
Published: September 2012

Abstract
Ghrelin is a gastrointestinal polypeptide that acts through the ghrelin receptor (GHSR) to promote food intake and increase adiposity. Activation of GHSR requires the presence of a fatty-acid (FA) side chain on amino acid residue serine 3 of the ghrelin molecule. However, little is known about the role that the type of FA used for acylation plays in the biological action of ghrelin. We therefore evaluated a series of differentially acylated peptides to determine whether alterations in length or stability of the FA side chain have an impact on the ability of ghrelin to activate GHSR in vitro or to differentially alter food intake, body weight, and body composition in vivo. Fatty acids principally available in the diet (such as palmitate C16) and therefore representing potential substrates for the ghrelin-activating enzyme ghrelin O-acyltransferase (GOAT) were used for dose-, time-, and administration/route-dependent effects of ghrelin on food intake, body weight, and body composition in rats and mice. Our data demonstrate that altering the length of the FA side chain of ghrelin results in the differential activation of GHSR. Additionally, we found that acylation of ghrelin with a long-chain FA (C16) delays the acute central stimulation of food intake. Lastly, we found that, depending on acylation length, systemic and central chronic actions of ghrelin on adiposity can be enhanced or reduced. Together our data suggest that modification of the FA side-chain length can be a novel approach to modulate the efficacy of pharmacologically administered ghrelin.
Neurokinin B and the Control of the Gonadotropic Axis in the Rat: Developmental Changes, Sexual Dimorphism, and Regulation by Gonadal Steroids
Authors: Ruiz-Pino F. , Navarro V. M. , Bentsen A. H. , Garcia-Galiano D. , Sanchez-Garrido M. A. , Ciofi P. , Steiner R. A. , Mikkelsen J. D. , Pinilla L. , Tena-Sempere M. 
Published: September 2012

Abstract
Neurokinin B (NKB), encoded by Tac2 in rodents, and its receptor, NK3R, have recently emerged as important regulators of reproduction; NKB has been proposed to stimulate kisspeptin output onto GnRH neurons. Accordingly, NKB has been shown to induce gonadotropin release in several species; yet, null or even inhibitory effects of NKB have been also reported. The basis for these discrepant findings, as well as other key aspects of NKB function, remains unknown. We report here that in the rat, LH responses to the NK3R agonist, senktide, display a salient sexual dimorphism, with persistent stimulation in females, regardless of the stage of postnatal development, and lack of LH responses in males from puberty onward. Such dimorphism was independent of the predominant sex steroid after puberty, because testosterone administration to adult females failed to prevent LH responses to senktide, and LH responsiveness was not restored in adult males treated with estradiol or the nonaromatizable androgen, dihydrotestosterone. Yet, removal of sex steroids by gonadectomy switched senktide effects to inhibitory, both in adult male and female rats. Sexual dimorphism was also evident in the numbers of NKB-positive neurons in the arcuate nucleus (ARC), which were higher in adult female rats. This is likely the result of differences in sex steroid milieu during early periods of brain differentiation, because neonatal exposures to high doses of estrogen decreased ARC NKB neurons at later developmental stages. Likewise, neonatal estrogenization resulted in lower serum LH levels that were normalized by senktide administration. Finally, we document that the ability of estrogen to inhibit hypothalamic Tac2 expression seems region specific, because estrogen administration decreased Tac2 levels in the ARC but increased them in the lateral hypothalamus. Altogether, our data provide a deeper insight into relevant aspects of NKB function as major regulator of the gonadotropic axis in the rat, including maturational changes, sexual dimorphism, and differential regulation by sex steroids.
Transcriptional Response to Calcium-Sensing Receptor Stimulation
Authors: Thiel Gerald , Lesch Andrea , Keim Anja 
Published: September 2012

Abstract
Elevated extracellular Ca2+ concentrations stimulate the G-protein coupled receptor calcium-sensing receptor. Here we show that this stimulation induces the expression of biologically active early growth response protein 1 (Egr-1), a zinc finger transcription factor. Expression of a dominant-negative mutant of the ternary complex factor Ets-like protein-1 (Elk-1), a key transcriptional regulator of serum response element-driven gene transcription, prevented Egr-1 expression, indicating that Elk-1 or related ternary complex factors connect the intracellular signaling cascade elicited by activation of calcium-sensing receptors with transcription of the Egr-1 gene. These data were corroborated by the fact that stimulation of calcium-sensing receptors increased the transcriptional activation potential of Elk-1. In addition, activator protein-1 (AP-1) transcriptional activity was significantly elevated after the stimulation of calcium-sensing receptors. The expression of a dominant-negative mutant of Elk-1 reduced c-Fos expression and prevented the up-regulation of AP-1 activity as a result of calcium-sensing receptor stimulation, indicating that ternary complex factors control both Egr-1- and AP-1-regulated transcription. In addition, AP-1 activity was reduced after the expression of a dominant-negative mutant of c-Jun in cells expressing an activated calcium-sensing receptor. Stimulus-transcription coupling leading to the up-regulation of Egr-1 and AP-1 controlled transcription in cells expressing calcium-sensing receptors required the protein kinases Raf and ERK, whereas the overexpression of MAPK phosphatase-1 interrupted the signaling cascade connecting calcium-sensing receptor stimulation with transcription of Egr-1 and AP-1 controlled genes. The fact that calcium-sensing receptor stimulation activates the transcription factors Egr-1, Elk-1, and AP-1 indicates that regulation of gene transcription is an integral part of calcium-sensing receptor induced signaling.
Diverse Functions of IGF/Insulin Signaling in Malignant and Noncancerous Prostate Cells: Proliferation in Cancer Cells and Differentiation in Noncancerous Cells
Authors: Heidegger Isabel , Ofer Philipp , Doppler Wolfgang , Rotter Varda , Klocker Helmut , Massoner Petra 
Published: September 2012

AbstractThe insulin-like growth factor (IGF) pathway represents one of the most studied molecular regulatory networks in oncology. Clinical trials investigating the therapeutic value of anti-IGF1 receptor (IGF1R) therapies in cancer, including prostate cancer, are ongoing. However, the multiple functions of the IGF network in the prostate are not entirely known. To elucidate the effects of IGF and insulin (INS) on prostate cells, we stimulated prostate cancer (PC3, DU145, LNCaP, DUCaP) and noncancerous prostate cells (EP156T, RWPE-1) and observed differing responses: whereas cancer cells responded to IGF and INS exposure by way of enhanced cell proliferation and glucose consumption, basal to luminal differentiation was induced in noncancerous cells. The same diverse responses were observed when the growth factor receptors IGF1R or INSR were overexpressed. Down-regulation of IGF1R or INSR isoform A (INSRA) also inhibited only proliferation of cancer cells. The proliferative response induced by the INSR in cancer cells was mediated solely by the INSRA. Moreover we observed that the receptors of the IGF network mutually influence their expression and exert redundant functions, thus underscoring the functional molecular network formed by IGF, INS, IGF1R, and INSR. Collectively we found that both IGF1R and INSRA have oncogenic effects in prostate cancer, but the IGF network also has important physiological functions in the noncancerous prostate. These data provide new insights into the biology of the IGF network in the prostate, thereby facilitating the design and interpretation of clinical studies investigating IGF1R targeting agents.
Lipopolysaccharide-Induced Fever Depends on Prostaglandin E2 Production Specifically in Brain Endothelial Cells
Authors: Engström Linda , Ruud Johan , Eskilsson Anna , Larsson Anders , Mackerlova Ludmila , Kugelberg Unn , Qian Hong , Vasilache Ana Maria , Larsson Peter , Engblom David , Sigvardsson Mikael , Jönsson Jan-Ingvar , Blomqvist Anders 
Published: September 2012

AbstractImmune-induced prostaglandin E2 (PGE2) synthesis is critical for fever and other centrally elicited disease symptoms. The production of PGE2 depends on cyclooxygenase-2 and microsomal prostaglandin E synthase-1 (mPGES-1), but the identity of the cells involved has been a matter of controversy. We generated mice expressing mPGES-1 either in cells of hematopoietic or nonhematopoietic origin. Mice lacking mPGES-1 in hematopoietic cells displayed an intact febrile response to lipopolysaccharide, associated with elevated levels of PGE2 in the cerebrospinal fluid. In contrast, mice that expressed mPGES-1 only in hematopoietic cells, although displaying elevated PGE2 levels in plasma but not in the cerebrospinal fluid, showed no febrile response to lipopolysaccharide, thus pointing to the critical role of brain-derived PGE2 for fever. Immunohistochemical stainings showed that induced cyclooxygenase-2 expression in the brain exclusively occurred in endothelial cells, and quantitative PCR analysis on brain cells isolated by flow cytometry demonstrated that mPGES-1 is induced in endothelial cells and not in vascular wall macrophages. Similar analysis on liver cells showed induced expression in macrophages and not in endothelial cells, pointing at the distinct role for brain endothelial cells in PGE2 synthesis. These results identify the brain endothelial cells as the PGE2-producing cells critical for immune-induced fever.
Identification of an MRAP-Independent Melanocortin-2 Receptor: Functional Expression of the Cartilaginous Fish, Callorhinchus milii, Melanocortin-2 Receptor in CHO Cells
Authors: Reinick Christina L. , Liang Liang , Angleson Joseph K. , Dores Robert M. 
Published: September 2012

Abstract
Phylogenetic analyses indicate that the genome of the cartilaginous fish, Callorhynchus milii (elephant shark), encodes a melanocortin-2 receptor (MC2R) ortholog. Expression of the elephant shark mc2r cDNA in Chinese hamster ovary (CHO) cells revealed that trafficking to the plasma membrane and functional activation of the receptor do not require coexpression with an exogenous melanocortin receptor-2 accessory protein (mrap) cDNA. Ligand selectivity studies indicated that elephant shark MC2R-transfected CHO cells produced cAMP in a dose-dependent manner when stimulated with either human ACTH (1–24) or [Nle4, d-Phe7]-MSH. Furthermore, the order of ligand selectivity when elephant shark MC2R-transfected CHO cells were stimulated with cartilaginous fish melanocortins was as follows: ACTH (1–25) = γ-MSH = δ-MSH &gt; αMSH = β-MSH. Elephant shark MC2R is the first vertebrate MC2R ortholog to be analyzed that does not require melanocortin receptor-2 accessory protein 1 for functional activation. In addition, elephant MC2R is currently the only MC2R ortholog that can be activated by either ACTH- or MSH-sized ligands. Hence, it would appear that MC2R dependence on melanocortin receptor-2 accessory protein 1 for functional activation and the exclusive selectivity of this melanocortin receptor for ACTH are features that emerged after the divergence of the ancestral cartilaginous fishes and the ancestral bony fishes more than 400 million years ago.