bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase III Trial of Paclitaxel at Two Dose Levels, the Higher Dose Accompanied by Filgrastim at Two Dose Levels in Platinum-Pretreated Epithelial Ovarian Cancer: An Intergroup Study
Authors: Omura George A. , Brady Mark F. , Look Katherine Y. , Averette Hervy E. , Delmore James E. , Long Harry J. , Wadler Scott , Spiegel Gregory , Arbuck Susan G. 
Published: June 2003

Purpose: To determine if increasing the dose of paclitaxel increases the probability of clinical response, progression-free survival, or overall survival in women who have persistent or recurrent ovarian cancer, and whether doubling the dose of prophylactic filgrastim accompanying the higher paclitaxel dose decreases the frequency of neutropenic fever. Patients and Methods: Consenting patients with persistent, recurrent, or progressing ovarian cancer, despite first-line platinum therapy (but no prior taxane), were randomly assigned to paclitaxel 135 mg/m2, 175 mg/m2, or 250 mg/m2 over 24 hours every 3 weeks. Patients receiving paclitaxel 250 mg/m2 were also randomly assigned to 5 or 10 μg/kg of filgrastim per day subcutaneously. Results: Accession to the paclitaxel 135-mg/m2 arm was closed early. Among the 271 patients on the other regimens with measurable disease, partial and complete response on paclitaxel 250 mg/m2 (36%) was significantly higher than on 175 mg/m2 (27%, P = .027). This difference was more evident among patients who never responded to prior platinum. However, progression-free and overall survival results were similar. The median durations of overall survival were 13.1 and 12.3 months for paclitaxel 175 mg/m2 and 250 mg/m2, respectively. Thrombocytopenia, neuropathy, and myalgia were greater with paclitaxel 250 mg/m2 (P < .05). The incidence of neutropenic fever after the first cycle of paclitaxel 250 mg/m2 was 19% and 18% on the 5-μg/kg and 10-μg/kg filgrastim dose, respectively (22% for paclitaxel 175 mg/m2 without filgrastim). Conclusion: Paclitaxel exhibits a dose effect with regard to response rate, but there is more toxicity and no survival benefit to justify paclitaxel 250 mg/m2 plus filgrastim. Doubling the filgrastim dose from 5 to 10 μg/kg did not reduce the probability of neutropenic fever after high-dose paclitaxel.
Effects of Chronic Ethanol on Hepatic and Renal CYP2C11 in the Male Rat: Interactions with the Janus-Kinase 2-Signal Transducer and Activators of Transcription Proteins 5b Pathway
Authors: Badger T. M. , Ronis M. J. J. , Frank S. J. , Chen Y. , He L. 
Published: June 2003

AbstractChronic alcohol intake in male rats results in: 1) demasculinization of the GH pulse pattern; 2) reduced serum testosterone concentrations; and 3) decreased expression hepatic CYP2C11. Hepatic CYP2C11 expression is regulated by the male pattern of GH through the Janus-kinase/signal transducer and activators of transcription proteins (JAK/STAT) signal transduction pathway in the male rat. Renal CYP2C11 is regulated by testosterone, not GH. The involvement of the JAK/STAT5b signal transduction pathway in renal CYP2C11 signaling has not been studied. We tested the hypothesis that ethanol reduces CYP2C11 levels by interfering with the JAK/STAT5b pathway. Using a total enteral nutrition (TEN) model to feed rats a well-balanced diet, we have studied the effects of chronic ethanol intake (21 d) on hepatic and renal JAK/STAT pathway of adult male rats (8–10/group). We found decreased hepatic and renal expression of CYP2C11 in ethanol-fed rats with concomitant decreases in STAT5b and phospho-STAT5b, decreased in vitro hepatic STAT5b binding to a CYP2C11 promoter element and no effects on hepatic GHR levels. Ethanol caused tissue specific effects in phospho-JAK2 and JAK2, with increased levels in the liver, but decreased JAK2 expression in the kidney. We conclude that ethanol suppression of CYP2C11 expression is clearly associated with reductions in STAT5b levels, but not necessarily in reductions of JAK2 levels. The mechanisms underlying ethanol-induced suppression of STAT5b is yet to be determined, as is the question of whether this is secondary to hormonal effects or a direct ethanol effect.
Obese Zucker Rats Have Reduced Mineralocorticoid Receptor and 11β-Hydroxysteroid Dehydrogenase Type 1 Expression in Hippocampus—Implications for Dysregulation of the Hypothalamic-Pituitary-Adrenal Axis in Obesity
Authors: Mattsson Cecilia , Lai Maggie , Noble June , McKinney Eoin , Yau Joyce L. , Seckl Jonathan R. , Walker Brian R. 
Published: June 2003

Abstract
Obese Zucker rats have elevated basal corticosterone levels and an increased stress response suggestive of an increased activity of the hypothalamic-pituitary-adrenal (HPA) axis. We hypothesized that altered central expression of glucocorticoid receptors (GR), mineralocorticoid receptors (MR), and/or 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) contribute to these changes.
In brains from young adult male rats, in situ hybridization and Western blotting showed that obese rats had normal hippocampal GR mRNA and protein levels. In contrast, in obese rats, 11βHSD1 mRNA levels were reduced in a subpopulation of hippocampal cells in the main neuronal layers (by 37–47%, P &lt; 0.05), whereas 11βHSD1 levels in sparse high-expressing cells did not differ. MR mRNA was decreased in all regions of the hippocampus (by 37–49%, P &lt; 0.05 for CA1–2 and P &lt; 0.01 for dentate gyrus) and in frontal cortex (by 16%, P &lt; 0.05) in obese rats. In whole hippocampal homogenates, however, neither the protein concentration of MR by Western blot nor activity of 11βHSD1 was measurably different between the phenotypes. To test the functional importance of lower central MR expression, groups of lean and obese rats were given spironolactone before restraint stress. In vehicle-treated animals, obese rats had higher plasma corticosterone levels than lean rats after stress (by ANOVA, P &lt; 0.05). Spironolactone markedly increased the corticosterone response in both groups, but the incremental rise was smaller in the obese rats, so that spironolactone abolished the differences between groups.
We conclude that lower levels of MR, but not GR, contribute to the increased HPA activity in the obese Zucker rats and that this seems more influential during stress than in the basal state. This may be exacerbated by impaired local regeneration of corticosterone by 11βHSD1. These abnormalities could contribute to the subtle changes in the HPA axis in rodent and human obesity.
Brain Region-Specific Neuroprotective Action and Signaling of Corticotropin-Releasing Hormone in Primary Neurons
Authors: Bayatti Nadhim , Zschocke Jürgen , Behl Christian 
Published: June 2003

AbstractCRH regulates the body’s response to stressful stimuli by modulating the activity of the hypothalamic pituitary axis. In primary cultures and cell lines, CRH also acts as a potent neuroprotective factor in response to a number of toxins. Using primary neuronal cultures from the cerebellum, cerebral cortex, and hippocampus, we demonstrate that CRH exerts a brain region-specific neuroprotective effect on amyloid β 25–35 toxicity. At low CRH concentrations (10−8m), neuroprotective effects can be observed only in cerebellar and hippocampal cultures, but a higher CRH concentration (10−7m) additionally led to the protection of cortical neurons. These neuroprotective effects were inhibited by H89, a specific protein kinase A inhibitor. Western blot analysis, carried out using phospho-specific antibodies directed against MAPK, cAMP response element-binding protein (CREB), and glycogen synthase kinase (GSK)3β also resulted in brain legion-specific differences regarding intracellular signaling. Correlating with cell survival, low CRH concentrations resulted in activation of the CREB pathway and inactivation of GSK3β in cerebellar and hippocampal cultures, but higher concentrations additionally resulted in activated CREB and inactivated GSK3β in cortical cultures. In contrast, MAPK activation occurred only in cortical neurons. Differences in signaling were found to be independent of receptor expression levels because RT-PCR analysis indicated no region-specific differences in CRHR1 mRNA expression.
Modulation by Steroid Receptor Coactivator-1 of Target-Tissue Responsiveness in Resistance to Thyroid Hormone
Authors: Kamiya Yuji , Zhang Xiao-Yong , Ying Hao , Kato Yusuhito , Willingham Mark C. , Xu Jianming , O’Malley Bert W. , Cheng Sheue-Yann 
Published: June 2003

AbstractMutations in the thyroid hormone receptor-β gene (TRβ) cause resistance to thyroid hormone. How the action of mutant thyroid hormone nuclear receptors (TRs) is regulated in vivo is not clear. We examined the effect of a TR coactivator, steroid receptor coactivator-1 (SRC-1), on target-tissue responsiveness by using a mouse model of resistance to thyroid hormone, TRβPV knockin mice, in the SRC-1 null background. Lack of SRC-1 intensified the dysfunction of the pituitary-thyroid axis and impaired growth in TRβPV/+ mice but not in TRβPV/PV mice. In TRβPV/PV mice, however, lack of SRC-1 intensified the pathological progression of thyroid follicular cells to papillary hyperplasia, reminiscent of papillary neoplasia. In contrast, lack of SRC-1 did not affect responsiveness in the liver in regulating serum cholesterol in either TRβPV/+ or TRβPV/PV mice. Lack of SRC-1 led to changes in the abnormal expression patterns of several T3 target genes in the pituitary and liver. Thus, the present studies show that a coactivator such as SRC-1 could modulate the in vivo action of TRβ mutants in a tissue-dependent manner.
Minireview: From Anorexia to Obesity—The Yin and Yang of Body Weight Control
Authors: Zigman Jeffrey M. , Elmquist Joel K. 
Published: June 2003

Abstract
Over the past decade, there has been a tremendous increase in the understanding of the molecular and neural mechanisms that control food intake and body weight. Yet eating disorders and cachexia are still common, and obesity cases are rising at alarming rates. Thus, despite recent progress, an increased understanding of the molecular and neural substrates that control body weight homeostasis is a major public health goal. In this review, we discuss the mechanisms by which metabolic signals interact with key behavioral, neuroendocrine, and autonomic regulatory regions of the central nervous system. Additionally, we offer a model in which hormones such as leptin and ghrelin interact with similar central nervous system circuits and engage them in such a way as to maintain an appropriate and tight regulation of body weight and food intake. Our model predicts that overstimulation or understimulation of these central pathways can result in obesity, anorexia, or cachexia.
Monosodium Glutamate-Sensitive Hypothalamic Neurons Contribute to the Control of Bone Mass
Authors: Elefteriou Florent , Takeda Shu , Liu Xiuyun , Armstrong Dawna , Karsenty Gerard 
Published: June 2003

AbstractUsing chemical lesioning we previously identified hypothalamic neurons that are required for leptin antiosteogenic function. In the course of these studies we observed that destruction of neurons sensitive to monosodium glutamate (MSG) in arcuate nuclei did not affect bone mass. However MSG treatment leads to hypogonadism, a condition inducing bone loss. Therefore the normal bone mass of MSG-treated mice suggested that MSG-sensitive neurons may be implicated in the control of bone mass. To test this hypothesis we assessed bone resorption and bone formation parameters in MSG-treated mice. We show here that MSG-treated mice display the expected increase in bone resorption and that their normal bone mass is due to a concomitant increase in bone formation. Correction of MSG-induced hypogonadism by physiological doses of estradiol corrected the abnormal bone resorptive activity in MSG-treated mice and uncovered their high bone mass phenotype. Because neuropeptide Y (NPY) is highly expressed in MSG-sensitive neurons we tested whether NPY regulates bone formation. Surprisingly, NPY-deficient mice had a normal bone mass. This study reveals that distinct populations of hypothalamic neurons are involved in the control of bone mass and demonstrates that MSG-sensitive neurons control bone formation in a leptin-independent manner. It also indicates that NPY deficiency does not affect bone mass.
Minireview: Human Obesity—Lessons from Monogenic Disorders
Authors: O’Rahilly Stephen , Farooqi I. Sadaf , Yeo Giles S. H. , Challis Benjamin G. 
Published: June 2003

Abstract
Genetic influences on the determination of human fat mass are profound and powerful, a statement that does not conflict with the obvious influence of environmental factors that drive recent changes in the prevalence of obesity. The assertion of the importance of genetic factors has, until recently, largely been based on twin and adoption studies. However, in the last 6 yr, a number of human genes have been identified in which major missense or nonsense mutations are sufficient in themselves to result in severe early-onset obesity, usually associated with disruption of normal appetite control mechanisms. Progress in the identification of more common, subtler genetic variants that influence fat mass in larger numbers of people has been slower, but discernible. Human genetics will continue to make an invaluable contribution to the study of human obesity by identifying critical molecular components of the human energy balance regulatory systems, pointing the way toward more targeted and effective therapies and assisting the prediction of individual responses to environmental manipulations.
Minireview: The Adipocyte—At the Crossroads of Energy Homeostasis, Inflammation, and Atherosclerosis
Authors: Rajala Michael W. , Scherer Philipp E. 
Published: June 2003

AbstractAdipose tissue evolved to efficiently store energy for times of caloric restriction. The large caloric excess common in many Western diets has negated the need for this thrifty function, leaving adipose tissue ill-equipped to handle this increased load. An excess of adipose tissue increases risk for a number of conditions including coronary artery disease, hypertension, dyslipidemias, type 2 diabetes, and even cancer. Indeed, the ability of the adipocyte to function properly when engorged with lipid can lead to lipid accumulation in other tissues, reducing their ability to function and respond normally. The role of adipose tissue as an endocrine organ capable of secreting a number of adipose tissue-specific or enriched hormones, known as adipokines, is gaining appreciation. The normal balance of these adipose tissue secretory proteins is perturbed in obesity. Paradoxically, the lack of normal adipose tissue, as seen in cases of lipodystrophy and lipoatrophy, is also associated with pathologic sequelae similar to what is seen with obesity. The pathologic findings associated with lack of adipose tissue, largely due to inability to properly store lipids, may also be due to a lack of adipokines. In this review, we highlight the role of adipose tissue as an endocrine organ focusing on some of the recent advances in the identification and pharmacological characterization of adipokines as well as their regulation in the context of obesity and insulin-resistant states.
Overexpression of Bcl-w in the Testis Disrupts Spermatogenesis: Revelation of a Role of BCL-W in Male Germ Cell Cycle Control
Authors: Yan Wei , Huang Jun-Xing , Lax Anna-Stina , Pelliniemi Lauri , Salminen Eeva , Poutanen Matti , Toppari Jorma 
Published: June 2003

AbstractTo explore physiological roles of BCL-W, a prosurvival member of the BCL-2 protein family, we generated transgenic (TG) mice overexpressing Bcl-w driven by a chicken β-actin promoter. Male Bcl-w TG mice developed normally but were infertile. The adult TG testes displayed disrupted spermatogenesis with various severities ranging from thin seminiferous epithelium containing less germ cells to Sertoli cell-only appearance. No overpopulation of any type of germ cells was observed during testicular development. In contrast, the developing TG testes displayed decreased number of spermatogonia, degeneration, and detachment of spermatocytes and Sertoli cell vacuolization. The proliferative activity of germ cells was significantly reduced during testicular development and spermatogenesis, as determined by in vivo and in vitro 5′-bromo-2′deoxyuridine incorporation assays. Sertoli cells were structurally and functionally normal. The degenerating germ cells were TUNEL-negative and no typical apoptotic DNA ladder was detected. Our data suggest that regulated spatial and temporal expression of BCL-W is required for normal testicular development and spermatogenesis, and overexpression of BCL-W inhibits germ cell cycle entry and/or cell cycle progression leading to disrupted spermatogenesis.
Review of the in Vivo Functions of the p160 Steroid Receptor Coactivator Family
Authors: Xu Jianming , Li Qingtian 
Published: June 2003

AbstractThe p160 steroid receptor coactivator (SRC) gene family contains three homologous members, which serve as transcriptional coactivators for nuclear receptors and certain other transcription factors. These coactivators interact with ligand-bound nuclear receptors to recruit histone acetyltransferases and methyltransferases to specific enhancer/promotor regions, which facilitates chromatin remodeling, assembly of general transcription factors, and transcription of target genes. This minireview summarizes our current knowledge about the molecular structures, molecular mechanisms, temporal and spatial expression patterns, and biological functions of the SRC family. In particular, this article highlights the roles of SRC-1 (NCoA-1), SRC-2 (GRIP1, TIF2, or NCoA-2) and SRC-3 (p/CIP, RAC3, ACTR, AIB1, or TRAM-1) in development, organ function, endocrine regulation, and nuclear receptor function, which are defined by characterization of the genetically manipulated animal models. Furthermore, this article also reviews our current understanding of the role of SRC-3 in breast cancer and discusses possible mechanisms for functional specificity and redundancy among SRC family members.
Structures and Magnetic Properties of Double Perovskites A2LnMO6 and 6H-Perovskites Ba3LnRu2O9 (A = Sr, Ba; Ln = Y, Lanthanides; M = Nb, Ta, Ru)
Authors: Hinatsu Yukio , Doi Yoshihiro 
Published: June 2003

Abstract
This account describes the synthesis, crystal structures and magnetic properties of double perovskites A2LnMO6 and 6H-perovskites Ba3LnRu2O9 (A = Sr, Ba; Ln = Y, lanthanides; M = Nb, Ta, Ru). The double perovskites A2LnMO6 have two kinds of cations, Ln and M, in the B site of the perovskite ABO3. These cations adopt the alternative ordered arrangement. Measurements of the magnetic susceptibility, specific heat, and powder neutron diffraction showed that all of the A2LnRuO6 compounds exhibited an antiferromagnetic transition at low temperatures and a complex temperature dependence of the magnetic susceptibility below their transition temperatures. In these compounds, the magnetic interaction between the Ln (4f electrons) and Ru (4d electrons) ions via the Ln–O–Ru pathway contributes greatly to their magnetic cooperative phenomena. The structural and magnetic studies for the 6H-perovskites Ba3LnRu2O9 show that the Ln cations occupy the corner-sharing octahedra (LnO6 octahedron) and the Ru cations occupy the face-sharing octahedra (Ru2O9 dimer). The Ba3LnRu2O9 compounds show a characteristic temperature-dependence of the magnetic susceptibilities, that is, a broad maximum at temperatures above 135 K and a magnetic transition at 5–15 K. These magnetic properties mainly reflect two kinds of the magnetic interactions: the interaction between Ln and Ru ions and that between Ru ions in the Ru2O9 dimer.
Asymmetric Strecker Route toward the Synthesis of Biologically Active α,α-Disubstituted α-Amino Acids
Authors: Ohfune Yasufumi , Shinada Tetsuro 
Published: June 2003

Abstract
A series of optically active α,α-disubstituted α-amino acids have been synthesized starting with an achiral or a racemic α-hydroxy or α-diazo ketone. In the present synthesis, the key transformation is an asymmetric version of the Strecker synthesis. An α-acyloxy ketone having a chiral amino acid as the acyloxy group afforded cyclic α-amino nitrile in a highly stereoselective manner; in this reaction the amino group and the chirality were diastereoselectively transplanted into the internal ketone group via an imine-enamine equilibrium of the cyclic ketimine intermediate. Oxidation of the amino group followed by removal of the resulting imino group and hydrolysis of the nitrile group afforded α-hydroxymethyl α-amino acid. The use of l-amino acid as the acyloxy group gave R enantiomer, and its S enantiomer was obtained when d-amino acid was employed. Some problematic processes that remained in the Strecker synthesis, i.e., preparation of the starting α-acyloxy ketone and oxidative conversion of α-amino nitrile into α-imino nitrile, are much improved as regards efficiency by the development of a Cu-catalyzed insertion of α-diazo ketone into N-protected α-amino acid, and as regards yields by the use of ozone as the oxidant. With these methods, various types of α,α-disubstituted α-amino acids have been synthesized including cyclic analogs, which can be viewed as a conformational variant of serine. Their incorporations into Leu-enkephalin have revealed that these amino acids play an important role not only to constrain the peptide conformation but also for high affinity bindings to the opioid receptors. Applications to the synthesis of biologically active natural products have been exemplified by the syntheses of the Corey intermediate of lactacystin and of marine natural products, manzacidin A and C.
Anisotropic Ring Current Effect of p-Nitrophenolate Ion Inclusion on the 1H NMR Signals of the Pyridinio Derivatives of α-Cyclodextrin
Authors: Ohtsuki Hideki , Ahmed Jalaluddin , Nagata Takuya , Yamamoto Tatsuyuki , Matsui Yoshihisa 
Published: June 2003

Abstract
The p-nitrophenolate ion (pNP−) was strongly bound to the mono- and dipyridinio derivatives of α-cyclodextrin (α-CD) in an aqueous 0.1 mol dm−3 Na2CO3 solution, and shifted the 1H NMR signals due to the α-CD C5-H’s to different directions, depending on the position of α-d-glucopyranose (anisotropic ring-current effect). In contrast, the iodide ion and p-hydroxybenzoate ion showed no such effect upon complexation. Furthermore, the C5-H’s of a dipyridinio derivative of β-CD was not subject to such an anisotropic ring-current effect of pNP−. These results indicate that the molecular rotation of pNP− is significantly retarded within the cavities of the pyridinio derivatives of α-CD by electrostatic and van der Waals interactions. Thus, electrostatic interactions are available for controlling the molecular motion or orientation of an ionic guest compound in a CD cavity and for the design of an enzyme-mimic modified CD.