bluuebunny/crossref_metadata_2025_split huggingface dataset:
Randomized Double-Blind Trial of Combined Modality Treatment With or Without Amifostine in Unresectable Stage III Non–Small-Cell Lung Cancer
Authors: Leong Swan Swan , Tan Eng Huat , Fong Kam Weng , Wilder-Smith Einar , Ong Yew Kwang , Tai Bee Choo , Chew Lita , Lim Shih Hui , Wee Joseph , Lee Khai Mun , Foo Kian Fong , Ang Peter , Ang Peng Tiam 
Published: April 2003

Purpose: Greater toxicities have been recognized to be a consequence of combined chemotherapy and radiotherapy in the treatment of locally advanced non–small-cell lung cancer (NSCLC). This study was designed to determine if the use of amifostine could reduce treatment-related toxicities associated with the use of paclitaxel plus carboplatin and thoracic radiotherapy. Patients and Methods: Sixty patients with unresectable stage III NSCLC were treated with two cycles of paclitaxel 175 mg/m2 and carboplatin (area under the time-concentration curve = 6), followed by thoracic radiotherapy (64 Gy) with concurrent weekly paclitaxel 60 mg/m2. Patients were randomly assigned to receive 740 mg/m2 of amifostine (arm A) or placebo (arm B) before each dose of paclitaxel and carboplatin. Treatment-related toxicities were evaluated at each visit and nerve conduction tests were performed before and after treatment for the objective assessment of neurotoxicity. Results: There was no significant difference between arms A and B in grade 3 to 4 neutropenia. In all 72 neurophysiological parameters measured, there was no significant difference between the two treatment arms, although there was a trend toward fewer patients showing deterioration in arm A for six of the parameters. Grade 2 to 3 esophagitis occurred in 43% of patients in arm A and in 70% of patients in arm B. The difference of −27% (95% confidence limit = −50%, 0.4%) was not statistically significant. Response rates and survival were also not significantly different between the two arms. Conclusion: Pretreatment with amifostine showed a trend toward reducing the severity of esophagitis associated with concurrent chemoradiotherapy, but it did not reach statistical significance. There was no significant protective effect on hematologic or neurologic toxicities induced by paclitaxel and carboplatin.
Human Estrogen Receptor β 548 Is Not a Common Variant in Three Distinct Populations
Authors: Xu Li , Pan-Hammarström Qiang , Försti Asta , Hemminki Kari , Hammarström Lennart , Labuda Damian , Gustafsson Jan-Åke , Dahlman-Wright Karin 
Published: April 2003

Abstract
Several isoforms of estrogen receptor (ER) β (also known as NR3A2) have been reported, including variants with different N-terminal ends. In rodents, two in-frame initiation codons (ATGs) are used to produce proteins of 530 and 549 amino acids, respectively. In humans, the upstream ATG is out of frame in all clones reported, until recently, when human clones with an extra A-T base pair placing the upstream ATG in frame were reported. The authors suggested that this could represent a novel polymorphism in the ERβ gene. Because human ERβ548 (hERβ548) and hERβ530 display different functional characteristics in vitro, it is of interest to determine if this variant constitutes a polymorphism in human populations. We therefore determined the frequency of this novel isoform in several populations including African (n = 96), Caucasian (n = 100), and Asian (n = 128) subjects using denaturing HPLC. We did not detect any alleles that correspond to hERβ548 in these samples or in additional samples of heterogeneous origin. It is concluded that hERβ548 is not a common variant in Africans, Caucasians, or Asians.
Differential Expression of Steroidogenic Factor-1 and FTF/LRH-1 in the Rodent Ovary
Authors: Falender Allison E. , Lanz Rainer , Malenfant Daniel , Belanger Luc , Richards JoAnne S. 
Published: April 2003

AbstractSteroidogenic factor-1 (SF-1) (NR5A1) is an orphan nuclear receptor that plays a premier role in ovarian organogenesis. Recent studies document mRNA expression of the structurally related factor NR5A2 (FTF, LRH-1, SF-2) in the adult ovary and more specifically in granulosa cells and luteal cells but not theca cells. Conversely, SF-1 was shown to be expressed at higher levels in theca/interstitial cells. These latter observations raised the possibility that FTF/LRH-1 may control target gene expression in granulosa cells of developing follicles. Using quantitative PCR our results show that FTF/LRH-1 message is expressed at higher levels in the ovary than in liver or other tissues analyzed. We show by in situ hybridization and LacZ expression in ovaries of transgenic mice bearing an FTF-promoter-LacZ fusion gene that FTF/LRH-1 is selectively expressed in granulosa cells of rat and mouse ovaries and is not present in theca cells or interstitial cells. However, by a variety of approaches, we showed that SF-1 mRNA and protein are expressed in greater amounts than FTF/LRH-1 in granulosa cells of follicles at all stages of development. Expression of SF-1 mRNA and protein in granulosa cells was verified by in situ hybridization, immunohistochemistry of ovarian sections, and immunocytochemistry of cultured rat granulosa cells. The significance of SF-1 in regulating target gene activation was supported by EMSA. An abundant granulosa cell protein binding to the SF-1-binding motif (CCAAGGTCA) present in the aromatase promoter and an FTF/LRH-1 motif (TGTCCTTGAACA) in the α-fetoprotein promoter was supershifted by two SF-1-specific antibodies but not by an FTF antibody. Conversely, with the same probes, a less abundant protein/DNA complex present in liver and ovarian cell extracts was shifted by an FTF antibody but not by the SF-1 antibodies. SF-1 and FTF/LRH-1 were differentially regulated in vivo by estradiol, FSH and prolactin. Collectively these data indicate that granulosa cells of small and preovulatory follicles express both SF-1 and FTF/LRH-1 and that each orphan receptor may regulate target gene expression in these cells.
Molecular Cloning of Otoconin-22 Complementary Deoxyribonucleic Acid in the Bullfrog Endolymphatic Sac: Effect of Calcitonin on Otoconin-22 Messenger Ribonucleic Acid Levels
Authors: Yaoi Yuichi , Suzuki Masakazu , Tomura Hideaki , Sasayama Yuichi , Kikuyama Sakae , Tanaka Shigeyasu 
Published: April 2003

AbstractAnuran amphibians have a special organ called the endolymphatic sac (ELS), containing many calcium carbonate crystals, which is believed to have a calcium storage function. The major protein of aragonitic otoconia, otoconin-22, which is considered to be involved in the formation of calcium carbonate crystals, has been purified from the saccule of the Xenopus inner ear. In this study, we cloned a cDNA encoding otoconin-22 from the cDNA library constructed for the paravertebral lime sac (PVLS) of the bullfrog, Rana catesbeiana, and sequenced it. The bullfrog otoconin-22 encoded a protein consisting of 147 amino acids, including a signal peptide of 20 amino acids. The protein had cysteine residues identical in a number and position to those conserved among the secretory phospholipase A2 family. The mRNA of bullfrog otoconin-22 was expressed in the ELS, including the PVLS and inner ear. This study also revealed the presence of calcitonin receptor-like protein in the ELS, with the putative seven-transmembrane domains of the G protein-coupled receptors. The ultimobranchialectomy induced a prominent decrease in the otoconin-22 mRNA levels of the bullfrog PVLS. Supplementation of the ultimobranchialectomized bullfrogs with synthetic salmon calcitonin elicited a significant increase in the mRNA levels of the sac. These findings suggest that calcitonin secreted from the ultimobranchial gland, regulates expression of bullfrog otoconin-22 mRNA via calcitonin receptor-like protein on the ELS, thereby stimulating the formation of calcium carbonate crystals in the lumen of the ELS.
Seasonal Plasticity within the Gonadotropin-Releasing Hormone (GnRH) System of the Ewe: Changes in Identified GnRH Inputs and Glial Association
Authors: Jansen Heiko T. , Cutter Christopher , Hardy Steven , Lehman Michael N. , Goodman Robert L. 
Published: April 2003

Abstract
The annual reproductive cycle in sheep may reflect a functional remodeling within the GnRH system. Specifically, changes in total synaptic input and association with the polysialylated form of neural cell adhesion molecule have been observed. Whether seasonal changes in a specific subset(s) of GnRH inputs occur or whether glial cells specifically play a role in this remodeling is not clear. We therefore examined GnRH neurons of breeding season (BS) and nonbreeding season (anestrus) ewes and tested the hypotheses that specific (i.e. γ-aminobutyric acid, catecholamine, neuropeptide Y, or β-endorphin) inputs to GnRH neurons change seasonally, and concomitant with any changes in neural inputs is a change in glial apposition. Using triple-label immunofluorescent visualization of GnRH, glial acidic fibrillary protein and neuromodulator/neural terminal markers combined with confocal microscopy and optical sectioning techniques, we confirmed that total numbers of neural inputs to GnRH neurons vary with season and demonstrated that specific inputs contribute to these overall changes. Specifically, neuropeptide Y and γ-aminobutyric acid inputs to GnRH neurons increased during BS and β-endorphin inputs were greater during either anestrus (GnRH somas) or BS (GnRH dendrites). Associated with the changes in GnRH inputs were seasonal changes in glial apposition, glial acidic fibrillary protein density, and the thickness of glial fibrils. These findings are interpreted to suggest an increase in net stimulatory inputs to GnRH neurons during the BS contributes to the seasonal changes in GnRH neurosecretion and that this increased innervation is perhaps stabilized by glial processes.
Retinoic Acid-Induced Stimulation of Sodium Iodide Symporter Expression and Cytotoxicity of Radioiodine in Prostate Cancer Cells
Authors: Spitzweg C. , Scholz I. V. , Bergert E. R. , Tindall D. J. , Young C. Y. F. , Göke B. , Morris J. C. 
Published: April 2003

AbstractWe reported recently the induction of androgen-dependent iodide uptake activity in the human prostatic adenocarcinoma cell line LNCaP using a prostate-specific antigen (PSA) promoter-directed expression of the sodium iodide symporter (NIS) gene. This offers the potential to treat prostate cancer with radioiodine. In the current study, we examined the regulation of PSA promoter-directed NIS expression and therapeutic effectiveness of 131I in LNCaP cells by all-trans-retinoic acid (atRA). For this purpose, NIS mRNA and protein expression levels in the NIS-transfected LNCaP cell line NP-1 were examined by Northern and Western blot analysis following incubation with atRA (10 −9 to 10−6m) in the presence of 10−9m mibolerone (mib). In addition, NIS functional activity was measured by iodide uptake assay, and in vitro cytotoxicity of 131I was examined by in vitro clonogenic assay. Following incubation with atRA, NIS mRNA levels in NP-1 cells were stimulated 3-fold in a concentration-dependent manner, whereas NIS protein levels increased 2.3-fold and iodide accumulation was stimulated 1.45-fold. This stimulatory effect of atRA, which has been shown to be retinoic acid receptor mediated, was completely blocked by the pure androgen receptor antagonist casodex (10−6m), indicating that it is androgen receptor dependent. The selective killing effect of 131I in NP-1 cells was 50% in NP-1 cells incubated with 10−9m mib. This was increased to 90% in NP-1 cells treated with atRA (10−7m) plus 10−9m mib. In conclusion, treatment with atRA increases NIS expression levels and selective killing effect of 131I in prostate cancer cells stably expressing NIS under the control of the PSA promoter. Therefore atRA may be used to enhance the therapeutic response to radioiodine in prostate cancer cells following PSA promoter-directed NIS gene delivery.
Regulation of 90-Kilodalton Ribosomal S6 Kinase Phosphorylation in the Rat Pineal Gland
Authors: Ho A. K. , Mackova M. , Cho C. , Chik C. L. 
Published: April 2003

AbstractIn this study we investigated diurnal changes in the activation state of the 90-kDa ribosomal S6 kinase (p90RSK) in the rat pineal gland. In animals housed under a lighting regimen with 12 h of light, we found an increase in phosphorylated p90RSK during the dark phase, and this increase was abolished by treatment with propranolol or continuous exposure to light. To determine the intracellular mechanism involved, rat pinealocytes were treated with norepinephrine. Norepinephrine caused a parallel increase in phosphorylated p42/44 MAPK (p42/44MAPK) and p90RSK that was reduced by prazosin or propranolol, indicating involvement of both α1- and β-adrenergic receptors. Treatment with dibutyryl cGMP, 4β-phorbol 12-myristate 13-acetate, or ionomycin mimicked norepinephrine-stimulated p90RSK phosphorylation, whereas dibutyryl cAMP caused a decrease in p90RSK phosphorylation. Inhibition of p42/44MAPK activation by UO126 was effective in reducing norepinephrine-stimulated p90RSK phosphorylation. Moreover, UO126 had an inhibitory effect on norepinephrine-stimulated arylalkyl-N-acetyltransferase activity. These results indicate that the adrenergically regulated nocturnal increase in p90RSK phosphorylation is mainly mediated through a cGMP→p42/44MAPK-dependent mechanism.
Overexpression of Activin βC or Activin βE in the Mouse Liver Inhibits Regenerative Deoxyribonucleic Acid Synthesis of Hepatic Cells
Authors: Chabicovsky Monika , Herkner Kurt , Rossmanith Walter 
Published: April 2003

Abstract
Activins are dimeric growth factors composed of β-subunits, four of which have been isolated so far. Whereas activin βA and βB are expressed in many tissues, the expression of activin βC and βE is confined to the liver. To date no biological role or activity has been assigned to activins formed from βC or βE subunits (activin C and E). Because activin A (βAβA), among its various functions in other tissues, appears to be a negative regulator of liver growth, we hypothesized a similar role for activin C and E. Using a nonviral gene transfer system we specifically delivered genes encoding activin βC, βE, or βA to the mouse liver. The mRNA analysis and reporter gene coexpression both indicated a reproducible temporal and spatial transgene expression pattern. The effects of activin overexpression were studied in the context of a regenerative proliferation of hepatic cells, a result of the tissue damage associated with the hydrodynamics based gene transfer procedure. Activin βC, βE, or βA expression, all temporarily inhibited regenerative DNA synthesis of hepatocytes and nonparenchymal cells, though to a varying degree. This first report of a biological activity of activin C and E supports an involvement in liver tissue homeostasis and further emphasizes the role of the growing activin family in liver physiology.
Anti‐neuronal nuclear autoantibody type 2: Paraneoplastic accompaniments
Authors: Pittock Sean J. , Lucchinetti Claudia F. , Lennon Vanda A. 
Published: April 2003

AbstractWe identified the IgG autoantibody ANNA‐2 (“anti‐Ri”) in 34 patients in a 12‐year period by immunofluorescence screening of sera from approximately 75,000 patients with subacute neurological disorders that were suspected to be paraneoplastic. Detailed clinical information was available for 28 patients (10 men, 18 women). Cancer was diagnosed in 24 patients (86%); 21 had histologically proven carcinoma (10 lung, 9 breast, 1 cervical, 1 bladder), and 3 had an intrathoracic imaging abnormality. Cancer anteceded neurological symptoms in 4 of 28 patients. Cancer detection frequency increased with continued surveillance. Neurological disorders, in decreasing frequency, were brainstem syndrome (including opsoclonus, myoclonus, or both), cerebellar syndrome, myelopathy, peripheral neuropathy, cranial neuropathy, movement disorder, encephalopathy, Lambert–Eaton syndrome, and seizures. Four patients had laryngospasm and four had jaw opening dystonia (two with neck dystonia). Nine (32%) were wheelchair‐bound 1 month after neurological symptom onset. Most improved neurologically after immunomodulatory or tumor‐directed therapy. Accompanying autoantibodies, found in 73% of sera, included ANNA‐1, ANNA‐3, CRMP‐5‐IgG, P/Q‐type and N‐type Ca2+ channel antibodies, and muscle‐type acetylcholine receptor antibody. Some neurological accompaniments of ANNA‐2 may reflect potentially pathogenic humoral or cell‐mediated responses to coimmunogenic tumor antigens, for example, Lambert–Eaton syndrome (P/Q‐type Ca2+ channel antibody) and peripheral neuropathy (ANNA‐1 effector T cells). Ann Neurol 2003
Endogenous dopamine release after pharmacological challenges in Parkinson's disease
Authors: Piccini Paola , Pavese Nicola , Brooks David J. 
Published: April 2003

AbstractUsing 11C‐raclopride positron emission tomography after methamphetamine challenge, we have evaluated regional brain changes in synaptic dopamine (DA) levels in six volunteers and six advanced Parkinson's disease (PD) patients. The pharmacological challenge induced significant release of endogenous DA in putamen not only in the normal subjects, as reflected by a 25.2% reduction in 11C‐raclopride binding potential as compared with placebo, but also in the PD patients (6.8%). In individual PD patients, we found a correlation between putamen DA release and DA storage, as measured by 18F‐dopa uptake. Localization of significant changes in 11C‐raclopride binding after methamphetamine at a voxel level with statistical parametric mapping identified striatal and prefrontal DA release in both cohorts. Statistical comparisons between normal subjects and PD confirmed significantly reduced DA release in striatal areas in PD, but normal levels of prefrontal DA release. In conclusion, significant endogenous DA release can still be induced by pharmacological challenges in the putamen of advanced PD patients, and this release correlates with residual DA storage capacity. Our data also show that the capacity to release normal DA levels in prefrontal areas after a pharmacological challenge is preserved in severe stages of the disease. Ann Neurol 2003
Efficient central nervous system remyelination requires T cells
Authors: Bieber Allan J. , Kerr Scott , Rodriguez Moses 
Published: April 2003

AbstractWe demonstrate a role for immune functions in the spontaneous remyelination of central nervous system (CNS) axons after lysolecithin‐induced demyelination in the spinal cord. Rag‐1–deficient mice lack both B cells and T cells and show significantly reduced spontaneous remyelination compared with control mice of matching genetic background. Mice lacking or depleted of either CD4+ T cells or CD8+ T cells also exhibit reduced remyelination. These data indicate that T cells are necessary for efficient CNS remyelination. Thus, general nonspecific immunosuppression as a therapeutic approach for the treatment of CNS injury and demyelinating disease may have undesirable effects on subsequent tissue repair. Ann Neurol 2003;53:680–684
Development of a bulgur‐like product using extrusion cooking
Authors: Köksel Hamit , Ryu Gi‐Hyung , Özboy‐Özbas Özen , Basman Arzu , Ng Perry K W 
Published: April 2003

AbstractIn this study we (1) developed a new bulgur‐like foodstuff using a durum wheat cultivar and an extrusion technique, (2) investigated the physicochemical properties of the extrudates produced and (3) sensorially evaluated the end‐product after cooking. Durum wheat was processed in a laboratory‐scale co‐rotating twin‐screw extruder with different levels of moisture content of the feed (367, 417 and 455 g kg−1), screw speed (150 and 200 rpm) and feed rate (2.4 and 2.9 kg h−1) to develop the bulgur‐like product. The effects of extrusion conditions on system variables (die pressure and specific mechanical energy (SME)), physical properties (die swell and bulk density), pasting properties (peak, trough and final viscosities) and cooking and sensory properties of the bulgur‐like products were determined. The results indicated that increased feed moisture content resulted in significant decreases in the die pressure and SME values of the extruded durum wheat products. As the moisture content and screw speed increased, the changes in die swell values were not significant. The lowest die swell and highest bulk density values were obtained at the highest feed moisture content. The extrusion variables also affected the pasting properties of the extrudates. Significant increases in each of the pasting properties occurred when the moisture content of the feed was increased. Some of the sensory properties (bulkiness, firmness, stickiness and taste–aroma) improved significantly as the feed moisture content increased, indicating better quality. Increased feed moisture content significantly improved cooking quality as determined by a decrease in colorimetric test results. Extrusion seems to be promising for the production of dry, relatively inexpensive bulgur‐like products with acceptable sensory properties.© 2003 Society of Chemical Industry
Detecting early response to cyclophosphamide treatment of RIF‐1 tumors using selective multiple quantum spectroscopy (SelMQC) and dynamic contrast enhanced imaging
Authors: Poptani Harish , Bansal Navin , Graham Robert A. , Mancuso Anthony , Nelson David S. , Glickson Jerry D. 
Published: April 2003

AbstractThe purpose of this study was to develop a reliable, noninvasive method for early detection of tumor response to therapy that would facilitate optimization of treatment regimens to the needs of the individual patient. In the present study, the effects of cyclophosphamide (Cp, a widely used alkylating agent) were monitored in a murine radiation induced fibrosarcoma (RIF‐1) using in vivo 1H NMR spectroscopy and imaging to evaluate the potential of these techniques towards early detection of treatment response. Steady‐state lactate levels and Gd‐DTPA uptake kinetics were measured using selective multiple quantum coherence (Sel‐MQC) transfer spectroscopy and dynamic contrast enhanced imaging, respectively in RIF‐1 tumors before, 24 and 72 h after 300 mg/kg of Cp administration. High‐resolution 1H NMR spectra of perchloric acid extracts of the tumor were correlated with lactate and glucose concentrations determined enzymatically. In vivo NMR experiments showed a decrease in steady‐state lactate to water ratios (5.4 ± 1.6 to 0.6 ± 0.5, p < 0.05) and an increase in Gd‐DTPA uptake kinetics following treatment response. The data indicate that decreases in lactate result from decreased glycolytic metabolism and an increase in tumor perfusion/permeability. Perchloric acid extracts confirmed the lower lactate levels seen in vivo in treated tumors and also indicated a higher glycerophosphocholine/phosphocholine (GPC/PC) integrated intensity ratio (1.39 ± 0.09 vs 0.97 ± 0.04, p < 0.01), indicative of increased membrane degradation following Cp treatment. Steady‐state lactate levels provide metabolic information that correlates with changes in tumor physiology measured by Gd‐DTPA uptake kinetics with high spatial and temporal resolution. Both of these parameters may be useful for monitoring early tumor response to therapy. Copyright © 2003 John Wiley & Sons, Ltd.