bluuebunny/crossref_metadata_2025_split huggingface dataset:
Susceptibility to liver fibrosis in mice expressing a connective tissue growth factor transgene in hepatocytes # †
Authors: Tong ZhenYue , Chen Ruju , Alt Daniel S. , Kemper Sherri , Perbal Bernard , Brigstock David R. 
Published: May 2009

Abstract
Connective tissue growth factor (CCN2) is a matricellular protein that is up-regulated in many fibrotic disorders and coexpressed with transforming growth factor β. CCN2 promotes fibrogenesis and survival in activated hepatic stellate cells, and injured or fibrotic liver contains up-regulated levels of CCN2 that are produced by a variety of different cell types, including hepatocytes. To investigate CCN2 action in vivo, transgenic FVB mice were created in which the human CCN2 gene was placed under the control of the albumin enhancer promoter to elevate hepatocyte CCN2 levels. Production of human CCN2 (hCCN2) messenger RNA and elevated CCN2 protein levels was demonstrated in transgenic livers, whereas levels of endogenous mouse CCN2 were comparable between transgenic and wild-type mice. Liver histology and liver function tests were unaffected in transgenic animals. However, after chronic administration of CCl4, α-smooth muscle actin (α-SMA)–expressing cells and collagen deposition were increased as a function of the dosage of the hCCN2 transgene (hccn2
+/+ > hccn2
+/− > hccn2−/−). Moreover, CCl4-induced serum hyaluronic acid, hepatic tissue levels of α-SMA or acid-soluble collagen, and messenger RNA expression of α-SMA, collagen α1 (I), matrix metalloprotease-2, or tissue inhibitor of metalloprotease-1 were greater in transgenic mice than in wild-type mice. Transgenic mice also exhibited enhanced hepatic deposition of collagen 2 weeks after bile duct ligation. Conclusion: Production of elevated CCN2 levels in hepatocytes of transgenic mice in vivo does not cause hepatic injury or fibrosis per se but renders the livers more susceptible to the injurious actions of other fibrotic stimuli. These studies support a central role of CCN2 in hepatic fibrosis and demonstrate a role of the microenvironment in regulating the profibrotic action of CCN2. (Hepatology 2009.)
Progesterone promotes the survival of newborn neurons in the dentate gyrus of adult male mice
Authors: Zhang Zhuo , Yang Rong , Zhou Rong , Li Liang , Sokabe Masahiro , Chen Ling 
Published: May 2009

AbstractThis study investigated the effects of progesterone (P4) on the production and survival of neurons in the hippocampal dentate gyrus of adult male mice. The administration of P4 (4 mg/kg) for 3 consecutive days beginning on the 0–2nd day after the first BrdU‐injection (BrdU‐D0–2) produced an approximately twofold increase in the number of 28‐ and 56‐day‐old BrdU+ cells in comparison to the controls, whereas it did not alter the number of 24/48‐h‐old BrdU+ cells. P4 preferentially promoted the survival of newborn neurons when administered at BrdU‐D5–7, but not at BrdU‐D10–12 and BrdU‐D15–17. Androstenedione (Ad), testosterone (TE), or estradiol (E2) at the same‐dose of P4, when administered at BrdU‐D0–2, could not replicate the effect of P4, while the inhibition of 5α‐reductase by finasteride did not affect the P4‐action, indicating that the P4‐effect is exerted by P4 itself but not by its metabolites. On the other hand, the P4R antagonist RU486 partially suppressed the P4‐effect, while inhibitors for Src, MEK, or PI3K totally suppressed the P4‐effect. Finally, the P4‐enhanced survival of newborn neurons was accompanied by a potentiation of spatial learning and memory, which was P4R‐dependent. These findings suggest that P4 enhances the survival of newborn neurons through P4R and/or the Src‐ERK and PI3K pathways independent of its influence on cell proliferation, which is well correlated with the potentiated spatial cognitive function of P4‐treated animals. © 2009 Wiley‐Liss, Inc.
Two New C21 Steroidal Glycosides from the Stems of Cynanchum paniculatumKitag.
Authors: Huang Xin , Tan Ai‐Min , Yang Shi‐Bao , Zhang An‐Yuan , Zhang Hua 
Published: May 2009

Abstractmagnified imageTwo new glycosides, (3β,8β,9α,16α,17α)‐14,16β : 15,20α:18,20β‐triepoxy‐16α,17α‐dihydroxy‐14‐oxo‐13,14 : 14,15‐disecopregna‐5,13(18)‐dien‐3‐yl α‐cymaropyranosyl‐(1→4)‐α‐digitoxopyranosyl‐(1→4)‐α‐oleandropyranoside (1) and (3β,8β,9α,16α,17α)‐14,16β : 15,20α : 18,20β‐triepoxy‐16β : 17α‐dihydroxy‐14‐oxo‐13,14 : 14,15‐disecopregna‐5,13(18)‐dien‐3‐yl α‐oleandropyranosyl‐(1→4)‐α‐digitoxopyranosyl‐(1→4)‐α‐oleandropyranoside (2) were isolated from the stems of Cynanchum paniculatum (Bunge) Kitag. The structures of the new compounds were elucidated by means of spectral data, including HR‐ESI‐MS, and 1D‐, and 2D‐NMR.
Synthesis and Evaluation of N‐Acetyl‐2‐amino‐2‐deoxy‐α‐D‐galactosyl 1‐Thio‐7‐oxaceramide, a New Analogue of α‐D‐Galactosyl Ceramide
Authors: Rajan Roshini , Mathew Thresen , Buffa Radovan , Bornancin Frédéric , Cavallari Marco , Nussbaumer Peter , De Libero Gennaro , Vasella Andrea 
Published: May 2009

Abstractmagnified imageThe N‐acetyl‐2‐amino‐2‐deoxy‐α‐D‐galactopyranosyl 1‐thio‐7‐oxaceramide 1 was synthesized by substituting the 7‐oxasphingosine triflate 3 with α‐D‐N‐acetyl‐1‐thiogalactosamine (2). The triflate 3 was obtained from azide 4. Thiol 2 was prepared according to a known procedure from α‐D‐galactosamine hydrochloride. As compared to ceramide (Cer), 1 is neither a substrate of ceramide kinase (CerK), consistent with the absence of the C(1)OH group, nor an inhibitor of Cer phosphorylation by CerK. While 1 partially displaced CD1d‐bound lipids, it failed to stimulate invariant natural killer T (iNKT) cells when presented by human CD1d‐transfected cells. These results suggest that 1 binds weakly to recombinant CD1d, but does not form immunogenic complexes with CD1d.
Syntheses of 5‐Chlorouracils/Thymines with 1‐[Phosphono(Methyl/Difluoromethyl)]‐1,2‐Unsaturated‐Moiety‐Substituted Methyl Groups at N(1) and Human Thymidine Phosphorylase Inhibitory Activity
Authors: Birck Matthew R. , Clinch Keith , Gainsford Graeme J. , Schramm Vern L. , Tyler Peter C. 
Published: May 2009

Abstractmagnified imageBy attaching (methyl)‐ or (difluoromethyl)‐phosphonate groups to the 1‐positions of ethene, cyclopentene or benzene, and attaching 1‐(methyl)‐5‐chlorouracil or 1‐(methyl)thymine groups to the corresponding 2‐positions, compounds 1–5 were prepared as potential inhibitors of recombinant human thymidine phosphorylase (TP). The products were designed to mimic the interatomic distance (ca. 3.41 Å) between the incoming phosphate and leaving pyrimidine groups at the transition state for the putative SN2 mechanism of TP. Free rotation around the (unsaturated‐CH2)–pyrimidine bonds in 1–5 enabled a span of ca. 2.40–4.40 Å between the CH2 or CF2 C‐atoms in the phosphonates and N(1) of the pyrimidines to be covered. The products were found to be ineffective inhibitors, and some reasons for this are given.
Continuous infusion idarubicin and intravenous busulphan as conditioning regimen to autologous stem cell transplantation for patients with acute myeloid leukaemia
Authors: Ferrara Felicetto , Mele Giuseppina , Palmieri Salvatore , Pedata Mariangela , Copia Carolina , Riccardi Cira , Izzo Tiziana , Criscuolo Clelia , Musto Pellegrino 
Published: May 2009

AbstractThe current study aimed to evaluate the efficacy and toxicity of a combination of intravenous (iv) busulfan (Bu) and continuous infusion Idarubicin (IDA) as a conditioning regimen to autologous haematopoietic stem cell transplantation (ASCT) in patients with acute myeloid leukaemia (AML). The protocol included IDA at 20 mg/sqm daily as 3 days continuous infusion (from day −13 to −11) and intravenous BU at 3.2 mg/kg daily from day −5 to −2. Patients aged over 60 years received a reduced schedule (2 days IDA and 3 days BU at the same dose). Twenty‐five patients with a median age of 51 years (28–72) were enrolled. All patients received peripheral blood stem cells (PBSC). The median interval between diagnosis and ASCT was 4 months. The median number of CD34+ cells infused was 5.9 × 10E6/kg. The median number of days to PMN >500/cmm and platelets >20000/cmm was 10 and 13, respectively. In order to perform a comparison in terms of haematological and non haematological toxicity, a group of 30 patients, who were previously autografted after conditioning with IDA and oral Bu was considered. Selection of factors for a matched pair analysis included median age, percentage of subjects aged over 60 years, median CD34+ cell received, cytogenetic and molecular findings and per cent of secondary AML. As compared to previous series, the occurrence of severe mucositis was dramatically reduced (80% vs. 12%, p < 0.0001). In addition, need and duration of total parenteral nutrition (TPN), iv antibiotic therapy and hospitalization were also significantly reduced. We conclude that replacement of oral with intravenous BU results in a more favourable toxicity profile. A longer follow‐up is required to assess a potential advantage in terms of disease free survival (DFS). Copyright © 2009 John Wiley & Sons, Ltd.
Effects of acute ultra‐low dose mecamylamine on cognition in adult attention‐deficit/hyperactivity disorder (ADHD)
Authors: Potter Alexandra S. , Ryan Katherine K. , Newhouse Paul A. 
Published: May 2009

AbstractObjectiveNicotinic cholinergic stimulation has known beneficial effects in attention‐deficit/hyperactivity disorder (ADHD). Mecamylamine is a non‐competitive nicotinic antagonist which is reported in several animal studies to have paradoxical positive effects on cognition at ultra‐low doses. Comparable studies in humans have not been conducted. The aim of this study was to determine the effects of acute ultra‐low doses of mecamylamine on cognition in adult ADHD.MethodsFifteen (6 female) non‐smokers with ADHD completed this acute, within subjects, double blind study of 0.2, 0.5, 1.0 mg of oral mecamylamine and placebo. Behavioral inhibition, recognition memory, and delay aversion were assessed at each dose.ResultsThe 0.5 mg dose of mecamylamine significantly improved recognition memory and reduced tolerance for delay. Mecamylamine increased participant rated irritability and investigator rated restlessness. There were no effects on vital signs or physical side effects.ConclusionThis is the first study to find measurable effects of ultra‐low doses of mecamylamine in humans. Mecamylamine did not improve core ADHD cognitive symptoms, but significantly improved recognition memory. These effects may represent mixed receptor activity (activation and blockade) at the doses tested. The finding of beneficial effects on memory processes has important clinical implications and further exploration of this effect is warranted. Copyright © 2009 John Wiley & Sons, Ltd.
Endothelial progenitor cells do not contribute to tumor endothelium in primary and metastatic tumors
Authors: Wickersheim Anke , Kerber Mark , de Miguel Lourdes Sanchez , Plate Karl H. , Machein Marcia Regina 
Published: May 2009

AbstractDespite extensive research, the contribution of bone‐marrow‐derived endothelial progenitor cells (BM‐EPC) to tumor angiogenesis remains controversial. In previous publications, the extent of incorporation of BM‐EPCs into the endothelial cell (EC) layer in different tumor models has been reported as significant in some studies but undetectable in others. Here, we studied the differentiation of BM‐EPCs and its contribution to tumor vessels in experimental and spontaneous lung metastasis (B16 melanoma and prostate carcinoma), in an autochthonous transgenic model of prostate tumorigenesis, in orthotopically implanted lung tumors [Lewis lung carcinoma (LLC)], in heterotopic subcutaneous models (LLC and C1 prostate carcinoma) growing in green fluorescent protein (GFP)‐expressing bone marrow (BM) chimeras. Immunofluorescence was performed with a set of endothelial and hematopoietic markers and confocal microscopy was used to generate 3D reconstruction images. By performing rigorously conducted morphological studies, we found no evidence of BM‐EPCs differentiation into tumor endothelium independently of tumor type, grade and organ site in primary and metastatic tumors. The vast majority of GFP+ cells were trafficking leucocytes or periendothelial myeloid cells. To explore the possibility that local overexpression of vascular endothelial growth factor (VEGF) might increase the numbers of incorporated BM‐EPCs, we analyzed tumors genetically manipulated to overexpress VEGF164. Local VEGF production induces a massive infiltration of bone‐marrow‐derived cells, but did not lead to vessel wall integration of these cells. Collectively, these findings suggest that during tumor progression vascularization occurs primarily via classical tumor angiogenesis (e.g., sprouting of pre‐existing ECs), whereas BM‐EPCs do not incorporate into the vessel wall to any significant extent. © 2009 UICC
Activity of tyrosine kinase inhibitor Dasatinib in neuroblastoma cells in vitro and in orthotopic mouse model
Authors: Vitali Roberta , Mancini Camillo , Cesi Vincenzo , Tanno Barbara , Piscitelli Marta , Mancuso Mariateresa , Sesti Fabiola , Pasquali Emanuela , Calabretta Bruno , Dominici Carlo , Raschellà Giuseppe 
Published: May 2009

AbstractStage 4 neuroblastoma (NB) is a devastating childhood cancer whose poor outcome has remained essentially unchanged in the last 20 years. Receptor tyrosine kinases have important roles in the control of proliferation, differentiation and apoptosis of NB cells. Thus, we tested the activity of second‐generation tyrosine kinase inhibitor Dasatinib in human NB cell lines in vitro and in an orthotopic mouse model. Dasatinib inhibited cell viability with an IC50 in the submicromolar range in 7 of 10 tested cell lines. In sensitive cells, Dasatinib reduced anchorage‐independent growth and, in some instances, induced senescence and apoptosis. In HTLA‐230 cells, Dasatinib treatment caused down‐regulation of c‐Kit and c‐Src phosphorylation in conjunction with strong inhibition of Erk1/2 and Akt activity. To test the efficacy of Dasatinib in vivo, HTLA‐230 and SY5Y cells were orthotopically injected in the adrenal gland of nude mice and drug treatments carried out until day 40. In mice injected with HTLA‐230 cells, tumour growth was significantly inhibited at the dose of 30 mg/(kg day) when treatment was started 7 days after injection. In animals injected with SY5Y cells that were exquisitely sensitive in vitro (IC50= 92 nM), the antitumour effect of Dasatinib was observed at the dose of 60 mg/(kg day) but only when treatment was started 1 day after injection. However, the anti‐tumour effect of Dasatinib in vivo was partial in both orthotopic models, emphasizing the importance of testing candidate new drugs in animal environments closely mimicking the human tumour. © 2009 UICC
The equity premium and the business cycle: the role of demand and supply shocks
Authors: Smith Peter N. , Sorensen Steffen , Wickens Michael 
Published: May 2009

AbstractThis paper explores the effects of the US business cycle on US stock market returns through an analysis of the equity risk premium. We propose a new methodology based on the SDF approach to asset pricing that allows us to uncover the different effects of aggregate demand and supply shocks. We find that negative shocks are more important that positive shocks, and that supply shocks have a much greater impact than demand shocks. Copyright © 2009 John Wiley & Sons, Ltd.
Preoperative therapeutic plasma exchange in patients with thyrotoxicosis
Authors: Ezer Ali , Caliskan Kenan , Parlakgumus Alper , Belli Sedat , Kozanoglu Ilknur , Yildirim Sedat 
Published: May 2009

AbstractThe purpose of this report was to determine the effectiveness of therapeutic plasma exchange (TPE) in preoperative preparation of patients with thyrotoxicosis scheduled for either thyroid or nonthyroid surgery. We retrospectively reviewed 11 patients with thyrotoxicosis and those who prepared surgery with plasmapheresis between 1999 and 2008 at our institution. Ten patients underwent thyroid surgery and one patient was operated for femur fracture during antithyroid drug treatment. The indications for plasmapheresis in all patients with severe thyrotoxicosis were poor response to medical treatment (seven patients), agronulocytosis due to antithyroid drugs (three patients), iodine‐induced thyrotoxicosis (Jodd Basedow effect in one patient), and rapid preparation for urgent orthopedic operation (one patient). After TPE, we observed a marked decrease in free thyroxin (FT3) and free triiodothyronin (FT4) levels; however, the decline in the biochemical values were not statically significant (P > 0.62, P > 0.15). Although both FT3 and FT4 levels remained above the normal limits in two of 11 patients, the signs and symptoms of thyrotoxicosis improved in all patients and no thyroid storm observed during the perioperative period. TPE can be considered a safe and effective alternative to prepare patients with thyrotoxicosis for surgery when drug treatment fails or is contraindicated and when emergency surgery is required. J. Clin. Apheresis, 2009. © 2009 Wiley‐Liss, Inc.
Intestinal epithelial cancer cell anoikis resistance: EGFR‐mediated sustained activation of Src overrides Fak‐dependent signaling to MEK/Erk and/or PI3‐K/Akt‐1
Authors: Demers Marie‐Josée , Thibodeau Sonya , Noël Dominique , Fujita Naoya , Tsuruo Takashi , Gauthier Rémy , Arguin Mélina , Vachon Pierre H. 
Published: May 2009

AbstractHerein, we investigated the survival roles of Fak, Src, MEK/Erk, and PI3‐K/Akt‐1 in intestinal epithelial cancer cells (HCT116, HT29, and T84), in comparison to undifferentiated and differentiated intestinal epithelial cells (IECs). We report that: (1) cancer cells display striking anoikis resistance, as opposed to undifferentiated/differentiated IECs; (2) under anoikis conditions and consequent Fak down‐activation, cancer cells nevertheless exhibit sustained Fak–Src interactions and Src/MEK/Erk activation, unlike undifferentiated/differentiated IECs; however, HCT116 and HT29 cells exhibit a PI3‐K/Akt‐1 down‐activation, as undifferentiated/differentiated IECs, whereas T84 cells do not; (3) cancer cells require MEK/Erk for survival, as differentiated (but not undifferentiated) IECs; however, T84 cells do not require Fak and HCT116 cells do not require PI3‐K/Akt‐1, in contrast to the other cells studied; (4) Src acts as a cornerstone in Fak‐mediated signaling to MEK/Erk and PI3‐K/Akt‐1 in T84 cells, as in undifferentiated IECs, whereas PI3‐K/Akt‐1 is Src‐independent in HCT116, HT29 cells, as in differentiated IECs; and (5) EGFR activity inhibition abrogates anoikis resistance in cancer cells through a loss of Fak–Src interactions and down‐activation of Src/MEK/Erk (T84, HCT116, HT29 cells) and PI3‐K/Akt‐1 (T84 cells). Hence, despite distinctions in signaling behavior not necessarily related to undifferentiated or differentiated IECs, intestinal epithelial cancer cells commonly display an EGFR‐mediated sustained activation of Src under anoikis conditions. Furthermore, such sustained Src activation confers anoikis resistance at least in part through a consequent sustenance of Fak–Src interactions and MEK/Erk activation, thus not only overriding Fak‐mediated signaling to MEK/Erk and/or PI3‐K/Akt‐1, but also the requirement of Fak and/or PI3‐K/Akt‐1 for survival. J. Cell. Biochem. 107: 639–654, 2009. © 2009 Wiley‐Liss, Inc.
Notch‐1 signaling is lost in prostate adenocarcinoma and promotes PTEN gene expression
Authors: Whelan Jarrett T. , Kellogg Anne , Shewchuk Brian M. , Hewan‐Lowe Karlene , Bertrand Fred E. 
Published: May 2009

AbstractProstate tumorigenesis is associated with loss of PTEN gene expression. We and others have recently reported that PTEN is regulated by Notch‐1 signaling. Herein, we tested the hypothesis that alterations of the Notch‐1 signaling pathway are present in human prostate adenocarcinoma and that Notch‐1 signaling regulates PTEN gene expression in prostate cells. Prostate adenocarcinoma cases were examined by immunohistochemistry for ligand cleaved (activated) Notch‐1 protein. Tumor foci exhibited little cleaved Notch‐1 protein, but expression was observed in benign tissue. Both tumor and benign tissue expressed total (uncleaved) Notch‐1. Reduced Hey‐1 expression was seen in tumor foci but not in benign tissue, confirming loss of Notch‐1 signaling in prostate adenocarcinoma. Retroviral expression of constitutively active Notch‐1 in human prostate tumor cell lines resulted in increased PTEN gene expression. Incubation of prostate cell lines with the Notch‐1 ligand, Delta, resulted in increased PTEN expression indicating that endogenous Notch‐1 regulates PTEN gene expression. Chromatin immunoprecipitation demonstrated that CBF‐1 was bound to the PTEN promoter. These data collectively indicate that defects in Notch‐1 signaling may play a role in human prostate tumor formation in part via a mechanism that involves regulation of the PTEN tumor suppressor gene. J. Cell. Biochem. 107: 992–1001, 2009. © 2009 Wiley‐Liss, Inc.
Nit1 and Fhit tumor suppressor activities are additive
Authors: Sun Jin , Okumura Hiroshi , Yearsley Martha , Frankel Wendy , Fong Louise Y. , Druck Teresa , Huebner Kay 
Published: May 2009

AbstractThe fragile histidine triad gene (human FHIT, mouse Fhit) has been shown to act as a tumor suppressor gene. Nit1 and Fhit form a fusion protein, encoded by the NitFhit gene in flies and worms, suggesting that mammalian Nit1 and Fhit proteins, which are encoded by genes on different chromosomes in mammals, may function in the same signal pathway(s). A previous study showed that Nit1 deficiency in knockout mice confers a cancer prone phenotype, as does Fhit deficiency. We have now assessed the tumor susceptibility of Fhit−/−Nit1−/− mice and observed that double knockout mice develop more spontaneous and carcinogen‐induced tumors than Fhit−/− mice, suggesting that the extent of tumor susceptibility due to Nit1 and Fhit deficiency is additive, and that Nit1 and Fhit affect distinct signal pathways in mammals. Nit1, like Fhit, is present in cytoplasm and mitochondria but not nuclei. Because Fhit deficiency affects responses to replicative and oxidative stress, we sought evidence for Nit1 function in response to such stresses in tissues and cultured cells: when treated with hydroxyurea, the normal kidney‐derived double‐deficient cells appear not to activate the pChk2 pathway and when treated with H2O2, show little evidence of DNA damage, compared with wild type and Fhit−/− cells. The relevance of Nit1 deficiency to human cancers was examined in human esophageal cancer tissues, and loss of Nit1 expression was observed in 48% of esophageal adenocarcinomas. J. Cell. Biochem. 107: 1097–1106, 2009. © 2009 Wiley‐Liss, Inc.