bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multistep process through which adenoviral vector vaccine overcomes anergy to tumor-associated antigens
Authors: Tang Yucheng , Zhang Lixin , Yuan Jing , Akbulut Hakan , Maynard Jonathan , Linton Phyllis-Jean , Deisseroth Albert 
Published: July 2004

AbstractOur goal in the present work was to characterize the multiple steps involved in overcoming the anergy that exists in tumor hosts to tumor-associated antigen (TAA). Our studies showed that the subcutaneous injection of the Ad-sig-TAA/ecdCD40L vector resulted in secretion of the TAA/ecdCD40L protein for at least 10 days from infected cells. Binding of the TAA/ecdCD40L protein to dendritic cells (DCs) resulted in the induction of CCR-7 chemokine receptor expression and cytokine release. This was followed by migration of the DCs to regional lymph nodes. Tetramer staining, enzyme-linked immunospot (ELISPOT) assay, and cytotoxicity assay all showed that the Ad-sig-TAA/ecdCD40L vector increased the levels of splenic CD8+ T cells specific for the 2 TAAs (human MUC1 [hMUC1] and HPV E7) tested. Vaccination with the Ad-sighMUC1/ecdCD40L vector suppressed the growth of hMUC1 antigen-positive tumor cells in 100% of the test mice that were previously anergic to the hMUC1 antigen. These data suggest that Ad-sig-TAA-ecd/ecdCD40L vector injections may be of value in treating the many epithelial malignancies in which TAA-like hMUC1 is overexpressed. (Blood. 2004;104:2704-2713)
Reactive oxygen species limit neutrophil life span by activating death receptor signaling
Authors: Scheel-Toellner Dagmar , Wang Keqing , Craddock Rachel , Webb Paul R. , McGettrick Helen M. , Assi Lakhvir Kaur , Parkes Neal , Clough Louise E. , Gulbins Erich , Salmon Mike , Lord Janet M. 
Published: July 2004

AbstractNeutrophils are abundant, short-lived leukocytes, and their death by apoptosis is central to hemostasis and the resolution of inflammation, yet the trigger for their entry into apoptosis is unknown. We show here that death receptor signaling, including CD95 death-inducing signaling complex (DISC) formation and caspase 8 activation, occurred early in neutrophil apoptosis. However, death receptor ligation was not required for apoptosis, suggesting a novel mechanism for caspase 8 activation. We detected ceramide generation and clustering of CD95 in lipid rafts early in neutrophil apoptosis, and neutrophil apoptosis and ceramide generation were both significantly inhibited in acid sphingomyelinase knockout (ASM–/–) mice compared to wild-type littermates. Further studies revealed that ceramide generation, CD95 clustering, and neutrophil apoptosis were dependent on reactive oxygen species (ROSs) and were preceded by a fall in reduced glutathione levels. We propose that accumulation of ROSs, as a consequence of altered redox status, initiates ligand-independent death receptor signaling via activation of ASM and clustering of preformed DISC components in lipid rafts and is therefore a primary factor limiting neutrophil life span.
Susceptibility of human fetal mesencyhmal stem cells to Kaposi sarcoma-associated herpesvirus
Authors: Parsons Christopher H. , Szomju Barbara , Kedes Dean H. 
Published: July 2004

AbstractRecent reports link Kaposi sarcoma-associated herpesvirus (KSHV) infection of bone marrow cells to bone marrow failure and lymphoproliferative syndromes. The identity of the infected marrow cells, however, remains unclear. Other work has demonstrated that circulating mononuclear cells can harbor KSHV where its detection predicts the onset and severity of Kaposi sarcoma. In either setting, bone marrow precursors may serve as viral reservoirs. Since mesenchymal stem cells (MSCs) in human bone marrow regulate the differentiation and proliferation of adjacent hematopoietic precursors, we investigated their potential role in KSHV infection. Our results indicate that primary MSCs are susceptible to both cell-free and cell-associated KSHV in culture. Moreover, infection persisted within nearly half of the cells for up to 6 weeks. Thus, MSCs possess a clear capacity to support KSHV infection and warrant further exploration into their potential role in KSHV-related human disease. (Blood. 2004;104:2736-2738)
Strong expression of FOXP1 identifies a distinct subset of diffuse large B-cell lymphoma (DLBCL) patients with poor outcome
Authors: Barrans Sharon L. , Fenton James A. L. , Banham Alison , Owen Roger G. , Jack Andrew S. 
Published: July 2004

Abstract
FOXP1 (Forkhead box-P1) is a winged-helix transcription factor that is differentially expressed in resting and activated B cells. FOXP1 expression has been demonstrated in a subset of diffuse large B-cell lymphomas (DLBCLs) and is more common in the nongerminal center (non-GC), activated B-cell type; however, its prognostic significance is uncertain. We analyzed presentation lymph nodes from 126 patients with nodal DLBCL, previously classified according to GC and BCL2 status, for FOXP1 protein expression using standard immunocytochemistry. Uniform high FOXP1 expression was demonstrated in 23 of 126 patients with DLBCL. This high level of expression was almost exclusively confined to patients who lacked the GC phenotype, who expressed MUM-1 and BCL2 in the absence of t(14; 18), and who were identified as a subgroup of patients with particularly poor outcomes in a group with already poor prognoses. The data presented suggest that high FOXP1 expression is an independent prognostic factor in DLBCL.
Association of immune abnormalities with telomere shortening in autosomal-dominant dyskeratosis congenita
Authors: Knudson Matt , Kulkarni Shashikant , Ballas Zuhair K. , Bessler Monica , Goldman Frederick 
Published: July 2004

Abstract
Dyskeratosis congenita (DC) is an inherited bone marrow failure disorder characterized by abnormal skin pigmentation and nail dystrophy. We have recently described, in 10 members of a large 3-generation family, an autosomal-dominant form of DC (AD DC) that is due to a mutation in the gene-encoding human telomerase RNA (TERC), resulting in telomere shortening. In studying the immunologic consequences of TERC mutations, severe B lymphopenia and decreased immunoglobulin M (IgM) levels were noted. T cells were found to overexpress senescent markers, including CD57 and Fas receptor, and were moderately reduced in cell number. To determine whether these in vivo findings were related to cellular replicative defects, short-term cultures of AD DC lymphocytes were established to measure proliferation, mitoses, and apoptosis. AD DC lymphocytes displayed a markedly reduced proliferative capacity and increased basal apoptotic rate. Finally, telomere shortening was most prominent in third-generation subjects, and there appeared to be a correlation between telomere length and in vivo and in vitro immune findings. In summary, the observed lymphopenia and hypogammaglobulinemia in AD DC is likely a consequence of replicative failure and premature senescence of lymphocytes, supporting a role of telomerase activity in immune homeostasis.
Markedly Diminished Lipolysis and Partial Restoration of Glucose Metabolism, without Changes in Fat Distribution after Extended Discontinuation of Protease Inhibitors in Severe Lipodystrophic Human Immunodeficient Virus-1-Infected Patients
Authors: van der Valk Marc , Allick Gideon , Weverling Gerrit Jan , Romijn Johannes A. , Ackermans Mariette T. , Lange Joep M. A. , van Eck-Smit Berthe L. F. , van Kuijk Cornelis , Endert Erik , Sauerwein Hans P. , Reiss Peter 
Published: July 2004

Abstract
Treatment for HIV-1 infection is often complicated by a lipodystrophy syndrome associated with insulin resistance and an elevated rate of lipolysis. In eight HIV-1 infected men with lipodystrophy syndrome, we studied the effects of replacement of protease inhibitor (PI) by abacavir on insulin sensitivity and lipolysis by hyperinsulinemic euglycemic clamp and on fat distribution assessed by dual-energy x-ray absorptiometry and computed tomography scan.
Glucose metabolism and lipolysis were assessed by tracer dilution employing [6,6-2H2]glucose and [2H5]glycerol, respectively. Data are expressed as mean ± sd or 95% confidence interval (CI), as appropriate.
There were no significant changes in fat distribution assessed by dual-energy x-ray absorptiometry and computed tomography scan at wk 36 and wk 96. The fasting total glucose production decreased from 16.1 ± 2.5 at study entry by 1.1 (range, −2.1 to −0.1) to 15.0 ± 1.5 μmol/kg·min after PI withdrawal at wk 36 (n = 8). In an analysis restricted to the patients on treatment at wk 96 (n = 6), the decrease was 0.9 (range, −2.1 to 0.3) μmol/kg·min. During insulin infusion, glucose oxidation (as percent of total glucose disposal) increased from 36.8 ± 12.7% by 11.0% (range, 1.3–20.8) to 47.9 ± 13.9% in the wk 36 analysis. In the analysis restricted to the patients on treatment at wk 96 (n = 6) the increase was 7.7 (−4.0 to 19.4)%. Fasting lipolysis decreased from 2.7 ± 0.6 μmol/kg·min by 0.9 (−1.6 to −0.2) to 1.8 ± 0.3 μmol/kg·min in the wk-96 analysis (n = 6).
The replacement of the studied PIs by abacavir in severe lipodystrophic HIV-1-infected patients results in a marked reduction of lipolysis. In contrast, fasting glucose production and insulin-stimulated glucose oxidation improve moderately, whereas insulin-stimulated glucose disposal and fat distribution do not change.
Relationship between Follicle-Stimulating Hormone Levels at the Beginning of the Human Menstrual Cycle, Length of the Follicular Phase and Excreted Estrogens: The FREEDOM Study
Authors: Miro F. , Parker S. W. , Aspinall L. J. , Coley J. , Perry P. W. , Ellis J. E. 
Published: July 2004

Abstract
Although reproductive aging has been separately related to elevated FSH and shorter follicular phase (FP), the direct association between both parameters has not been investigated. Also, the exact effects of increased FSH on estrogen production are yet to be established.
A large database of daily urinary concentrations of FSH, LH, and estrone 3-glucuronide (E1G) from 37 regularly menstruating women (median 11 cycles per patient) was used. Initial FSH levels (iFSH) were estimated as the mean value of d 1–5. The day of E1G take-off (ETO) was determined by an algorithm, and accordingly, the FP was divided into early (d 1 to ETO) and late (ETO+1 to LH peak). FP maximum and integrated E1G were calculated.
Subjects were distributed according to their mean iFSH into three categories (≤5, &gt;5 to 10, and &gt;10 IU/liter). There was a gradual decrease in FP length with increasing category (15.2 ± 3.8, 14.1 ± 3.6, and 13 ± 2.6 d, respectively; P &lt; 0.0001). A similar effect occurred in early FP (7.5 ± 4, 6.4 ± 3.7, and 5.4 ± 2.7; P &lt; 0.0001); in contrast, late FP was unaffected (7.7 ± 2.1, 7.7 ± 2.1, and 7.6 ± 2.4; P = 0.86). No consistent increase in E1G was found with advancing iFSH category; however, women with mean initial LH higher than 6 IU/liter had significantly elevated maximum (P &lt; 0.0001) and integrated (P = 0.002) E1G.
FP length decreases in parallel with increasing iFSH, with a selective effect on the early FP. Increased FSH does not affect E1G; however, elevated initial LH level was related to higher E1G.
Ginsenoside-Rb1 from Panax ginseng C.A. Meyer Activates Estrogen Receptor-α and -β, Independent of Ligand Binding
Authors: Cho JungYoon , Park Wankyu , Lee SeungKi , Ahn Woongshick , Lee YoungJoo 
Published: July 2004

Abstract
We studied the estrogenic activity of a component of Panax ginseng, ginsenoside-Rb1. The activity of ginsenoside-Rb1 was characterized in a transient transfection system, using estrogen receptor isoforms and estrogen-responsive luciferase plasmids, in COS monkey kidney cells. Ginsenoside-Rb1 activated both α and β estrogen receptors in a dose-dependent manner with maximal activity observed at 100 μm, the highest concentration examined. Activation was inhibited by the estrogen receptor antagonist ICI 182,780, indicating that the effects were mediated through the estrogen receptor. Treatment with 17β-estradiol or ginsenoside-Rb1 increased expression of the progesterone receptor, pS2, and estrogen receptor in MCF-7 cells and of AP-1-driven luciferase genes in COS cells. Although these data suggest that it is functionally very similar to 17β-estradiol, ginsenoside-Rb1 failed to displace specific binding of [3H]17β-estradiol from estrogen receptors in MCF-7 whole-cell ligand binding assays. Our results indicate that the estrogen-like activity of ginsenoside-Rb1 is independent of direct estrogen receptor association.
Polymorphisms in the Cytotoxic T Lymphocyte Antigen-4 Gene Region Confer Susceptibility to Addison’s Disease
Authors: Blomhoff Anne , Lie Benedicte A. , Myhre Anne G. , Kemp E. Helen , Weetman Anthony P. , Akselsen Hanne E. , Huseby Eystein S. , Undlien Dag E. 
Published: July 2004

Abstract
The cytotoxic T lymphocyte antigen-4 (CTLA4) gene on chromosome 2q33 encodes a key regulator in the adaptive immune system. The CTLA4 surface molecule is expressed on activated T lymphocytes and involved in down-regulation of the immune response. Previous studies on a possible association between autoimmune Addison’s disease and CTLA4 polymorphisms have shown conflicting results. A recent study identified new candidate polymorphisms in the CTLA4 region, influencing gene splicing and thereby the relative abundance of soluble CTLA4. We genotyped 134 patients with Addison’s disease and 413 healthy controls from Norway and United Kingdom for these newly identified polymorphisms. Our data demonstrate that the same polymorphisms that have recently been demonstrated to confer susceptibility to autoimmune thyroid disease and type 1 diabetes also confer susceptibility to Addison’s disease. This finding suggests that polymorphisms in CTLA4 confer general risk to develop autoimmunity and identifies a potential therapeutic target in the prevention of autoimmune endocrine disorders.
Calcium Kinetics Are Altered in Clinically Stable Girls with Cystic Fibrosis
Authors: Schulze Kerry J. , O’Brien Kimberly O. , Germain-Lee Emily L. , Booth Sarah L. , Leonard Amanda , Rosenstein Beryl J. 
Published: July 2004

Abstract
Reduced bone mass in individuals with cystic fibrosis (CF) may result from alterations in calcium metabolism. Bone calcium deposition and resorption rates, calcium balance, and markers of bone turnover were assessed using stable isotopes of calcium in 22 prepubertal and pubertal girls with CF. Bone calcium deposition was associated with the availability of dietary calcium, total serum osteocalcin, and leptin concentrations.
Reduced bone mass in individuals with CF may result from inadequate bone calcium (Ca) deposition, and excessive resorption, although these parameters have not been directly assessed in children with CF.
We used stable Ca isotopes to measure rates of bone Ca deposition (Vo+), resorption, and retention in 22 clinically stable girls with CF (aged 7–18 yr). Rates of bone Ca deposition were determined by mathematically modeling the disappearance of iv Ca stable isotope (42Ca) for 6 d post dosing. Indirect markers of bone turnover and hormones associated with pubertal development were also assessed.
Rates of bone Ca deposition and retention were highest during early puberty (Tanner stages 2 and 3). Calcium deposition rates in prepubertal (Tanner 1) and postmenarchal girls (Tanner stages 4 and 5) did not support substantial bone Ca retention. Net absorption of dietary Ca and serum osteocalcin and leptin concentrations were positively associated with Vo+. Time post menarche and serum leptin concentrations explained 91% of the variability in Vo+ (P = 0.0007). Serum total osteocalcin was low (10.9 ± 5.4 ng/ml), and a substantial percentage of osteocalcin was undercarboxylated (54.3 ± 11.8%).
We concluded that increased calcium absorption and serum leptin concentrations were significantly associated with rates of bone Ca deposition, demonstrating an impact of nutritional status on this process. Rates of bone Ca deposition were lower than typically reported in healthy children, as were indirect markers of bone formation. These alterations in bone turnover contribute to reduced bone mass in girls with CF.
Sources of Dietary Iodine: Bread, Cows’ Milk, and Infant Formula in the Boston Area
Authors: Pearce Elizabeth N. , Pino Sam , He Xuemei , Bazrafshan Hamid R. , Lee Stephanie L. , Braverman Lewis E. 
Published: July 2004

AbstractDietary iodine is essential for thyroid hormone production. Although U.S. dietary iodine is generally adequate, some groups, especially women of childbearing age, are at risk for mild iodine deficiency. Children’s average urinary iodine is higher than that of adults. U.S. dietary iodine sources have not been assessed recently. A survey of iodine content in 20 brands of bread, 18 brands of cows’ milk, and eight infant formulae was performed between 2001 and 2002. Three bread varieties contained more than 300 μg iodine per slice. Iodine content in other brands was far lower (mean ± sd, 10.1 ± 13.2 μg iodine/slice). All cows’ milk samples had at least 88 μg iodine/250 ml, ranging from 88–168 μg (116.0 ± 22.1 μg/250 ml). Infant formulae values ranged from 16.2 to 56.8 μg iodine/5 oz (23.5 ± 13.78 μg/5 oz). The public should be aware of the need for adequate dietary iodine intake and should be aware that ingredient lists do not reflect the iodine content of foods.
Estrogen to Antiestrogen with a Single Methylene Group Resulting in an Unusual Steroidal Selective Estrogen Receptor Modulator
Authors: Zhang Jing-xin , Labaree David C. , Mor Gil , Hochberg Richard B. 
Published: July 2004

AbstractSelective estrogen receptor (ER) modulators (SERMs) are important therapeutic agents for breast cancer prevention and treatment. We have synthesized two analogs, E11–2,1 [methyl-(3,17β-dihydroxyestra-1,3,5(10)-triene-11β-yl)acetate] and E11–2,2 [ethyl-(3,17β-dihydroxyestra-1,3,5(10)-triene-11β-yl)acetate], the methyl and ethyl esters of an estradiol analog, substituted in the B ring at C-11β with a carboxymethyl group. The shorter methyl ester, E11–2,1, has high ER affinity and high estrogenic potency in the Ishikawa estrogen cell bioassay, whereas the longer ethyl ester, E11–2,2, has even higher ER affinity, but little or no estrogenic activity. We found that this minor change of one methylene group transforms a potent estrogenic agonist into an antagonist in vitro with either ER α or β. In the rat, E11–2,2 acts as a SERM in the uterus, where it inhibits estradiol-induced proliferation, and as an estrogen agonist in the liver and skeleton, where it decreases plasma cholesterol and increases bone growth. The characteristic feature of antiestrogens, including SERMs, is a long and polar side-chain that prevents agonist-induced conformation of helix 12 of ER. E11–2,2 with its short, nonpolar side-chain, lacks this critical structure, presenting the possibility that it might act through a unique mechanism.
Regulation of the Somatotropic Axis by Intensive Insulin Therapy during Protracted Critical Illness
Authors: Mesotten Dieter , Wouters Pieter J. , Peeters Robin P. , Hardman Kevin V. , Holly Jeff M. , Baxter Robert C. , Van den Berghe Greet 
Published: July 2004

Abstract
The catabolic state of critical illness has been linked to the suppressed somatotropic GH-IGF-binding protein (IGFBP) axis. In critically ill patients it has been demonstrated that, compared with the conventional approach, which only recommended insulin therapy when blood glucose levels exceeded 12 mmol/liter, strict maintenance of blood glucose levels below 6.1 mmol/liter with intensive insulin therapy almost halved intensive care mortality, acute renal failure, critical illness polyneuropathy, and bloodstream infections. Poor blood glucose control in diabetes mellitus has also been associated with low serum IGF-I levels, which can be increased by insulin therapy. We hypothesized that intensive insulin therapy would improve the IGF-I axis, possibly contributing to the clinical correlates of anabolism. Therefore, this study of 363 patients, requiring intensive care for more than 7 d and randomly assigned to either conventional or intensive insulin therapy, examines the effects of intensive insulin therapy on the somatotropic axis. Contrary to expectation, intensive insulin therapy suppressed serum IGF-I, IGFBP-3, and acid-labile subunit concentrations. This effect was independent of survival of the critically ill patient. Concomitantly, serum GH levels were increased by intensive insulin therapy. The suppression of IGF-I in association with the increased GH levels suggests GH resistance induced by intensive insulin therapy, which was reflected by the decreased serum GH-binding protein levels. Intensive insulin therapy did not affect IGFBP-3 proteolysis, which was markedly higher in protracted critically ill patients compared with healthy controls. Also, intensive insulin therapy did not suppress the urea/creatinine ratio, a clinical correlate of catabolism. In conclusion, our data suggest that intensive insulin therapy surprisingly suppressed the somatotropic axis despite its beneficial effects on patient outcome. GH resistance accompanied this suppression of the IGF-I axis. To what extent and through which mechanisms the changes in the GH-IGF-IGFBP axis contributed to the survival benefit under intensive insulin therapy remain elusive.
Body Mass Index Determines Evoked Growth Hormone (GH) Responsiveness in Normal Healthy Male Subjects: Diagnostic Caveat for Adult GH Deficiency
Authors: Bonert Vivien S. , Elashoff Janet D. , Barnett Philip , Melmed Shlomo 
Published: July 2004

Abstract
GH secretion is decreased in obese subjects, whereas age-adjusted IGF-I concentrations are normal. This study was undertaken to rigorously delineate the extent of obesity [elevated body mass index (BMI)] associated with decreased somatotrope secretory function resulting in apparent adult GH deficiency. The peak GH response evoked by combined arginine (0.5 g/kg infused iv over 30 min) and GHRH (1 μg/kg iv bolus) was measured in 59 healthy male subjects with BMIs ranging from normal to obese. BMI correlated with the peak evoked GH response (Pearson r = −0.59; P &lt; 0.01), and the percentage of subjects exhibiting an abnormal evoked GH response, i.e. less than 9 ng/ml, increased from 5% for those with a BMI less than 25 (normal), to 13% for those with a BMI of 25–26.9 (mildly overweight), to 33% for those with a BMI of 27–29.9 (moderately overweight), and to 64% for those with a BMI of 30 or more (obese). BMI is a major determinant of evoked adult GH response to provocative testing. The diagnosis of adult GH deficiency using the evoked GH response in patients with even mild BMI elevation does not accurately distinguish normal from deficient responses and may result in the erroneous classification of obese subjects as GH deficient and thus unnecessarily requiring GH replacement.