bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bone loss following hematopoietic stem cell transplantation: a long-term follow-up
Authors: Schulte Claudia M. S. , Beelen Dietrich W. 
Published: November 2003

AbstractTransplantation-associated bone loss is a well-known phenomenon, however, effects of hematopoietic stem cell transplantation are insufficiently characterized. We conducted a prospective, unicentric, long-term follow-up in 280 patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). Bone mineral density (BMD) was measured before transplantation and then yearly for at least 4 years. Patients received vitamin D plus calcium until steroid withdrawal. Mean baseline BMD was normal. We demonstrated significant bone loss with nadir BMD at month 6 for the spine and at month 24 for total body and femoral neck. Average annual bone loss was 0.6% for spine, 0.4% for total body, 2.3% for femoral neck, and 3.5% for Ward triangle. While spine and total body BMD returned to baseline, bone loss at femoral neck sites was attenuated, but BMD did not return to baseline until month 48 (P &lt; .0001 for femoral neck and Ward triangle). Univariate factor analysis of 15 potential risk factors for rapid bone loss revealed a positive correlation of bone loss with steroid and cyclosporine A use, baseline BMD, and loss of muscle mass (overwhelming power of steroid use in multifactor analysis). Such rapid BMD changes probably increase fracture risk consecutive to irreversible microarchitectural changes even if osteodensitometry shows long-term recovery.
Role of p300 and PCAF in regulating cyclooxygenase-2 promoter activation by inflammatory mediators
Authors: Deng Wu-Guo , Zhu Ying , Wu Kenneth K. 
Published: November 2003

AbstractCoactivators p300 and CREB (cyclic adenosine monophosphate [cAMP]–response element binding protein)–binding protein (CBP) serve as an integrator for gene transcription. Their relative involvement in regulating cyclooxygenase-2 (COX-2) promoter activity had not been characterized. Using fibroblast and macrophage COX-2 transcription as a model, we determined p300 and CBP levels in nuclear extracts and their binding to a COX-2 promoter probe. CBP level was barely detectable and there was little CBP binding. In contrast, p300 was detectable in nucleus and its binding to a COX-2 promoter probe was enhanced by phorbol 12-myristate 13-acetate (PMA), interleukin-1β (IL-1β), or lipopolysaccharide (LPS). Binding of p300/CBP-associated factor (PCAF) was also up-regulated. COX-2 proteins and promoter activities induced by these agonists were augmented by p300 overexpression. Early region 1A (E1A), but not its deletion mutant, abrogated COX-2 expression induced by inflammatory mediators and with or without p300 overexpression. Molecular analysis of p300 revealed the requirement of multiple domains, including histone acetyltransferase (HAT) for COX-2 transactivation. Furthermore, roscovitine, an indirect inhibitor of p300 HAT, and histone deacetylase-1 transfection completely abolished COX-2 promoter activity. We conclude that p300 is the predominant coactivator that is essential for COX-2 transcriptional activation by proinflammatory mediators.
Immunomodulatory effect of decoy receptor 3 on the differentiation and function of bone marrow-derived dendritic cells in nonobese diabetic mice: from regulatory mechanism to clinical implication
Authors: Wu Shu-Fen , Liu Tan-Mei , Lin Yu-Chun , Sytwu Huey-Kang , Juan Hsueh-Fen , Chen Shui-Tein , Shen Kuo-Liang , Hsi Sheng-Chuan , Hsieh Shie-Liang 
Published: November 2003

AbstractTo investigate the regulatory effects of decoy receptor 3 (DcR3) on the differentiation and function of dendritic cells (DCs), bone marrow-derived DCs (BM-DCs) from nonobese diabetic (NOD) mice were cultured with recombinant DcR3.Fc protein. Their differentiating phenotypes and T cell-stimulating functions were then evaluated. Expression of CD11c, CD40, CD54, and major histocompatibility complex I-Ag7 was reduced in cells cultured with additional DcR3.Fc, compared with DCs incubated with granulocyte macrophage-colony stimulating factor and interleukin (IL)-4, indicating that DcR3 interferes with the differentiation and maturation of BM-DCs. One of the most striking effects of DcR3.Fc on the differentiation of DCs was the up-regulation of CD86 and down-regulation of CD80, suggesting a modulatory potential to skew the T cell response toward the T helper cell type 2 (Th2) phenotype. Consistent with this, the proliferation of CD4+ T cells cocultured with DcR3.Fc-treated DCs was significantly reduced compared with that of T cells stimulated by normal DCs. Moreover, the secretion of interferon-γ from T cells cocultured with DcR3.Fc-treated DCs was profoundly suppressed, indicating that DcR3 exerts a Th1-suppressing effect on differentiating DCs. Furthermore, adoptive transfer experiments revealed that NOD/severe combined immunodeficiency mice received DcR3.Fc-treated DCs, and subsequently, autoreactive T cells showed delayed onset of diabetes and a decrease in diabetic severity compared with mice that received normal DCs and T cells, suggesting a future therapeutic potential in autoimmune diabetes. Data from two-dimensional gel electrophoresis and matrix-assisted laser desorption/ionization-time-of-flight analysis show an up-regulation of some proteins—such as mitogen-activated protein kinase p38 β, cyclin-dependent kinase 6, and signal-induced proliferation-associated gene 1—and a down-regulation of the IL-17 precursor; tumor necrosis factor-related apoptosis-inducing ligand family member-associated nuclear factor-κB activator-binding kinase 1; and Golgi S-nitroso-N-acetylpenicillamine in cells treated with DcR3, further demonstrating its effect on DC differentiation and function.
Age-dependent decrease in Toll-like receptor 4-mediated proinflammatory cytokine production and mitogen-activated protein kinase expression
Authors: Boehmer Eric D , Goral Joanna , Faunce Douglas E , Kovacs Elizabeth J 
Published: November 2003

AbstractAge-related changes in immunity render elderly individuals more susceptible to infections than the young. Previous work by our laboratory and others showed that macrophages from aged mice are functionally impaired. Macrophages produce proinflammatory cytokines, tumor necrosis factor α (TNF-α) and interleukin (IL)-6, when stimulated with lipopolysaccharide (LPS), which signals through Toll-like receptor-4 (TLR4) and requires activation of mitogen-activated protein kinases (MAPKs). We investigated whether aging is associated with alterations in TNF-α and IL-6 production and MAPK expression and activation in thioglycollate-elicited peritoneal macrophages from mice. Kinetics and LPS dose-responsiveness of macrophage TNF-α production did not differ by age. Unstimulated macrophages did not differ by age in their cytokine production. However, LPS-stimulated (100 ng/mL) cultures from aged mice produced 100 ± 30 pg/mL TNF-α and 6000 ± 2000 pg/mL IL-6, and those from young mice produced 280 ± 50 pg/mL and 10,650 ± 10 pg/mL, respectively (P&lt;0.05). Likewise, levels of activated MAPKs did not differ by age in unstimulated macrophages, and LPS-stimulated macrophages from aged mice had &lt;70% activated p38 and c-jun NH2-terminal kinase (JNK) than those of young controls. Of particular interest, we observed &gt;25% reduction of total p38 and JNK in macrophages from aged mice relative to young. In addition, surface TLR4 levels did not vary with age. We conclude that macrophages from aged mice exhibited suppressed proinflammatory cytokine production, which correlated with diminished total levels and LPS-stimulated activation of p38 and JNK. These observations suggest that decreased MAPK expression could be a mechanism responsible for age-related deterioration of the immune system.
Phase II Trial of Gefitinib in Recurrent Glioblastoma
Authors: Rich Jeremy N. , Reardon David A. , Peery Terry , Dowell Jeannette M. , Quinn Jennifer A. , Penne Kara L. , Wikstrand Carol J. , Van Duyn Lauren B. , Dancey Janet E. , McLendon Roger E. , Kao James C. , Stenzel Timothy T. , Ahmed Rasheed B.K. , Tourt-Uhlig Sandra E. , Herndon James E. , Vredenburgh James J. , Sampson John H. , Friedman Allan H. , Bigner Darell D. , Friedman Henry S. 
Published: November 2003

Purpose To evaluate the efficacy and tolerability of gefitinib (ZD1839, Iressa; AstraZeneca, Wilmington, DE), a novel epidermal growth factor receptor tyrosine kinase inhibitor, in patients with recurrent glioblastoma. Patients and Methods This was an open-label, single-center phase II trial. Fifty-seven patients with first recurrence of a glioblastoma who were previously treated with surgical resection, radiation, and usually chemotherapy underwent an open biopsy or resection at evaluation for confirmation of tumor recurrence. Each patient initially received 500 mg of gefitinib orally once daily; dose escalation to 750 mg then 1,000 mg, if a patient received enzyme-inducing antiepileptic drugs or dexamethasone, was allowed within each patient. Results Although no objective tumor responses were seen among the 53 assessable patients, only 21% of patients (11 of 53 patients) had measurable disease at treatment initiation. Seventeen percent of patients (nine of 53 patients) underwent at least six 4-week cycles, and the 6-month event-free survival (EFS) was 13% (seven of 53 patients). The median EFS time was 8.1 weeks, and the median overall survival (OS) time from treatment initiation was 39.4 weeks. Adverse events were generally mild (grade 1 or 2) and consisted mainly of skin reactions and diarrhea. Drug-related toxicities were more frequent at higher doses. Withdrawal caused by drug-related adverse events occurred in 6% of patients (three of 53 patients). Although the presence of diarrhea positively predicted favorable OS from treatment initiation, epidermal growth factor receptor expression did not correlate with either EFS or OS. Conclusion Gefitinib is well tolerated and has activity in patients with recurrent glioblastoma. Further study of this agent at higher doses is warranted.
Subcellular Pathways of β-Endorphin Synthesis, Processing, and Release from Immunocytes in Inflammatory Pain
Authors: Mousa Shaaban A. , Shakibaei Mehdi , Sitte Nicolle , Schäfer Michael , Stein Christoph 
Published: November 2003

AbstractThe opioid peptide β-endorphin (END) as well as mRNA for its precursor proopiomelanocortin (POMC) are found not only in the pituitary gland, but also within various types of immune cells infiltrating inflamed sc tissue. During stressful stimuli END is released and interacts with peripheral opioid receptors to inhibit pain. However, the subcellular pathways of POMC processing and END release have not yet been delineated in inflammatory cells. The aim of the present study was to examine the presence of POMC, carboxypeptidase E, the prohormone convertases 1 (PC1), and 2 (PC2), PC2-binding protein 7B2, and the release of END from inflammatory cells in rats. Using immunohistochemistry we detected END and POMC alone or colocalized with PC1, PC2, carboxypeptidase E, and 7B2 in macrophages/monocytes, granulocytes, and lymphocytes of the blood and within inflamed sc paw tissue. Immunoelectron microscopy revealed that END is localized within secretory granules packed in membranous structures in macrophages, monocytes, granulocytes, and lymphocytes. Finally, END is released by noradrenaline from immune cells in vitro. Taken together, our results indicate that immune cells express the entire machinery required for POMC processing into functionally active peptides such as END and are able to release these peptides from secretory granules.
Human Placental Growth Hormone Increases Expression of the P85 Regulatory Unit of Phosphatidylinositol 3-Kinase and Triggers Severe Insulin Resistance in Skeletal Muscle
Authors: Barbour Linda A. , Shao Jianhua , Qiao Liping , Leitner Wayne , Anderson Marianne , Friedman Jacob E. , Draznin Boris 
Published: November 2003

Abstract
The insulin resistance of normal pregnancy is necessary to divert fuels to the fetus to meet fetal growth demands and is mediated by placental hormones. We recently demonstrated that human placental GH (hPGH) can trigger severe insulin resistance in transgenic (TG) mice. In this study we sought to elucidate the cellular mechanisms by which hPGH interferes with insulin signaling in muscle in TG mice. Insulin-stimulated GLUT-4 translocation to the plasma membrane (PM) was reduced in the TG compared with wild-type (WT) mice (P = 0.05). Insulin receptor (IR) levels were modestly reduced by 19% (P &lt; 0.01) in TG mice, but there were no changes in phosphorylation of IR or IR substrate-1 (IRS-1) between WT and TG mice. A singular finding was a highly significant increase in the p85α regulatory subunit of phosphatidylinositol 3-kinase (PI 3-kinase; P &lt; 0.001), yet a reduced ability of insulin to stimulate IRS-1-associated PI 3-kinase activity (P &lt; 0.05). Although the levels of the p110 catalytic subunit protein of PI 3-kinase and IRS-1 were unchanged in the TG mice, insulin’s ability to stimulate p110 association with IRS-1 was markedly reduced (P &lt; 0.0001). We demonstrate a unique mechanism of insulin resistance and suggest that hPGH may contribute to the insulin resistance of normal pregnancy by increasing the expression of the p85α monomer, which competes in a dominant negative fashion with the p85-p110 heterodimer for binding to IRS-1 protein.
Steroids and Oocyte Maturation—A New Look at an Old Story
Authors: Hammes Stephen R. 
Published: November 2003

AbstractFemale fertility requires precise regulation of oocyte meiosis. Oocytes are arrested early in the meiotic cycle until just before ovulation, when ovarian factors trigger meiosis, or maturation, to continue. Although much has been learned about the late signaling events that accompany meiosis, until recently less was known about the early actions that initiate maturation. Studies using the well-characterized model of transcription-independent steroid-induced oocyte maturation in Xenopus laevis now show that steroid metabolism, classical steroid receptors, G protein-mediated signaling, and novel G protein-coupled receptors, all may play important roles in regulating meiosis. Furthermore, steroids appear to promote similar events in mammalian oocytes, implying a conserved mechanism of maturation in vertebrates. Interestingly, testosterone is a potent promoter of mammalian oocyte maturation, suggesting that androgen actions in the oocyte might be partially responsible for the polycystic ovarian phenotype and accompanying infertility associated with high androgen states such as polycystic ovarian syndrome or congenital adrenal hyperplasia. A detailed appreciation of the steroid-activated signaling pathways in frog and mammalian oocytes may therefore prove useful in understanding both normal and abnormal ovarian development in humans.
High-Dose Versus Standard-Dose Amoxicillin for Acute Otitis Media
Authors: Garrison Gina Daubney , Sorum Paul C , Hioe Wayne , Miller Margaret M 
Published: November 2003

BACKGROUND: Emergence of drug-resistant bacteria has led to a recommendation to use high-dose (HD) amoxicillin (80–90 mg/kg/d) rather than standard-dose (SD) amoxicillin (40–45 mg/kg/d) to treat children with acute otitis media (AOM). OBJECTIVE: To compare the efficacy and tolerability of HD versus SD amoxicillin among children with AOM who were considered at low risk for infection with antibiotic-resistant bacteria. METHODS: A double-blind, randomized, 3-year clinical trial was conducted using participants who met the following criteria: age >3 mo, weight ≤18 kg, diagnosed with AOM, and candidates for treatment with amoxicillin. The primary endpoint was treatment success at a 3- to 4-day follow-up visit based on the clinical decision to continue the prescribed antibiotic therapy for AOM. Other endpoints included duration of illness, number of office visits and telephone calls related to illness, total number of subsequent AOM episodes, and number of adverse effects. RESULTS: The absolute difference in antibiotic failure rate with SD versus HD amoxicillin at the follow-up visit was nonsignificant (95% CI–1.5% to 3.4%; p = 0.78). The mean duration of illness was similar for both doses of amoxicillin (3 ± 2 d). The number of office visits and telephone calls related to illness and the number of subsequent AOM episodes did not differ between the 2 treatment groups. HD amoxicillin did not result in a greater incidence of adverse effects than SD amoxicillin. CONCLUSIONS: HD amoxicillin had neither benefit nor detriment compared with SD for AOM in children at low risk for infection with antibiotic-resistant bacteria.
Nighttime Bracing or Exercise in Moderate-Grade Adolescent Idiopathic Scoliosis
Authors: Charalampidis Anastasios , Diarbakerli Elias , Dufvenberg Marlene , Jalalpour Kourosh , Ohlin Acke , Ahl Anna Aspberg , Möller Hans , Abbott Allan , Gerdhem Paul ,   CONTRAIS Study Group, Öberg Birgitta , Tropp Hans , Grauers Anna , Bodén Ylva , Hoffsten Mats , Näsman Per , Hedevik Henrik 
Published: January 2024

ImportanceModerate-grade adolescent idiopathic scoliosis (AIS) may be treated with full-time bracing. For patients who reject full-time bracing, the effects of alternative, conservative interventions are unknown.ObjectiveTo determine whether self-mediated physical activity combined with either nighttime bracing (NB) or scoliosis-specific exercise (SSE) is superior to a control of physical activity alone (PA) in preventing Cobb angle progression in moderate-grade AIS.Design, Setting, and ParticipantsThe Conservative Treatment for Adolescent Idiopathic Scoliosis (CONTRAIS) randomized clinical trial was conducted from January 10, 2013, through October 23, 2018, in 6 public hospitals across Sweden. Male and female children and adolescents aged 9 to 17 years with an AIS primary curve Cobb angle of 25° to 40°, apex T7 or caudal, and skeletal immaturity based on estimated remaining growth of at least 1 year were included in the study. Dates of analysis were from October 25, 2021, to January 28, 2023.InterventionsInterventions included self-mediated physical activity in combination with either NB or SSE or PA (control). Patients with treatment failure were given the option to transition to a full-time brace until skeletal maturity.Main Outcomes and MeasuresThe primary outcome was curve progression of 6° or less (treatment success) or curve progression of more than 6° (treatment failure) seen on 2 consecutive posteroanterior standing radiographs compared with the inclusion radiograph before skeletal maturity. A secondary outcome of curve progression was the number of patients undergoing surgery up until 2 years after the primary outcome.ResultsThe CONTRAIS study included 135 patients (45 in each of the 3 groups) with a mean (SD) age of 12.7 (1.4) years; 111 (82%) were female. Treatment success was seen in 34 of 45 patients (76%) in the NB group and in 24 of 45 patients (53%) in the PA group (odds ratio [OR], 2.7; 95% CI, 1.1-6.6). The number needed to treat to prevent curve progression with NB was 4.5 (95% CI, 2.4-33.5). Treatment success occurred in 26 of 45 patients (58%) in the SSE group (OR for SE vs PA, 1.2; 95% CI, 0.5-2.8). Up to 2 years after the primary outcome time point, 9 patients in each of the 3 groups underwent surgery.Conclusions and RelevanceIn this randomized clinical trial, treatment with NB prevented curve progression of more than 6° to a significantly higher extent than did PA, while SSE did not; in addition, allowing transition to full-time bracing after treatment failure resulted in similar surgical frequencies independent of initial treatment. These results suggest that NB may be an effective alternative intervention in patients rejecting full-time bracing.Trial RegistrationClinicalTrials.gov Identifier: NCT01761305
Building CRISPR Gene Therapies for the Central Nervous System
Authors: Salomonsson Sally E. , Clelland Claire D. 
Published: January 2024

ImportanceGene editing using clustered regularly interspaced short palindromic repeats (CRISPR) holds the promise to arrest or cure monogenic disease if it can be determined which genetic change to create without inducing unintended cellular dysfunction and how to deliver this technology to the target organ reliably and safely. Clinical trials for blood and liver disorders, for which delivery of CRISPR is not limiting, show promise, yet no trials have begun for central nervous system (CNS) indications.ObservationsThe CNS is arguably the most challenging target given its innate exclusion of large molecules and its defenses against bacterial invasion (from which CRISPR originates). Herein, the types of CRISPR editing (DNA cutting, base editing, and templated repair) and how these are applied to different genetic variants are summarized. The challenges of delivering genome editors to the CNS, including the viral and nonviral delivery vehicles that may ultimately circumvent these challenges, are discussed. Also, ways to minimize the potential in vivo genotoxic effects of genome editors through delivery vehicle design and preclinical off-target testing are considered. The ethical considerations of germline editing, a potential off-target outcome of any gene editing therapy, are explored. The unique regulatory challenges of a human-specific therapy that cannot be derisked solely in animal models are also discussed.Conclusions and RelevanceAn understanding of both the potential benefits and challenges of CRISPR gene therapy better informs the scientific, clinical, regulatory, and timeline considerations of developing CRISPR gene therapy for neurologic diseases.
Plasma proteomic profiles of UK Biobank participants with multiple sclerosis
Authors: Jacobs Benjamin M. , Vickaryous Nicola , Giovannoni Gavin , Proitsi Petroula , Waters Sheena , Dobson Ruth 
Published: January 2024

AbstractObjectiveWe aimed to describe plasma protein biomarkers of multiple sclerosis risk and to explore protein biomarkers of disease severity using radiological outcome measures.MethodsMultiple sclerosis cases and controls were identified in UK Biobank, a longitudinal cohort study of ~500,000 British adults. Plasma proteins were assayed in ~50,000 UK Biobank participants using the Olink proximity extension assay. We performed case–control association testing to examine the association between 2911 proteins and multiple sclerosis, using linear models adjusted for confounding covariates. Associations with radiological lesion burden and brain volume were determined in a subset of the cohort with available magnetic resonance imaging, using normalized T2‐hyperintensity volume or whole brain volume as the outcome measure.ResultsIn total, 407 prevalent multiple sclerosis cases and 39,979 healthy controls were included. We discovered 72 proteins associated with multiple sclerosis at a Bonferroni‐adjusted p value of 0.05, including established markers such as neurofilament light chain and glial fibrillary acidic protein. We observed a decrease in plasma Granzyme A, a marker of T cell and NK cell degranulation, which was specific to multiple sclerosis. Higher levels of plasma proteins involved in coagulation were associated with lower T2 lesion burden and preserved brain volume.InterpretationWe report the largest plasma proteomic screen of multiple sclerosis, replicating important known associations and suggesting novel markers, such as the reduction in granzyme A. While these findings require external validation, they demonstrate the power of biobank‐scale datasets for discovering new biomarkers for multiple sclerosis.