bluuebunny/crossref_metadata_2025_split huggingface dataset:
Selective translational repression of HIV-1 RNA by Sam68DeltaC occurs by altering PABP1 binding to unspliced viral RNA
Authors: Marsh Kim , Soros Vanessa , Cochrane Alan 
Published: October 2008

Abstract
HIV-1 structural proteins are translated from incompletely spliced 9 kb and 4 kb mRNAs, which are transported to the cytoplasm by Crm1. It has been assumed that once in the cytoplasm, translation of incompletely spliced HIV-1 mRNAs occurs in the same manner as host mRNAs. Previous analyses have demonstrated that Sam68 and a mutant thereof, Sam68ΔC, have dramatic effects on HIV gene expression, strongly enhancing and inhibiting viral structural protein synthesis, respectively. While investigating the inhibition of incompletely spliced HIV-1 mRNAs by Sam68ΔC, we determined that the effect was independent of the perinuclear bundling of the viral RNA. Inhibition was dependent upon the nuclear export pathway used, as translation of viral RNA exported via the Tap/CTE export pathway was not blocked by Sam68ΔC. We demonstrate that inhibition of HIV expression by Sam68ΔC is correlated with a loss of PABP1 binding with no attendant change in polyadenosine tail length of the affected RNAs. The capacity of Sam68ΔC to selectively inhibit translation of HIV-1 RNAs exported by Crm1 suggests that it is able to recognize unique characteristics of these viral RNPs, a property that could lead to new therapeutic approaches to controlling HIV-1 replication.
Evolution of the Randomized Controlled Trial in Oncology Over Three Decades
Authors: Booth Christopher M. , Cescon David W. , Wang Lisa , Tannock Ian F. , Krzyzanowska Monika K. 
Published: October 2008

Purpose The randomized controlled trial (RCT) is the gold standard for establishing new therapies in clinical oncology. Here we document changes with time in design, sponsorship, and outcomes of oncology RCTs. Methods Reports of RCTs evaluating systemic therapy for breast, colorectal (CRC), and non–small-cell lung cancer (NSCLC) published 1975 to 2004 in six major journals were reviewed. Two authors abstracted data regarding trial design, results, and conclusions. Conclusions of authors were graded using a 7-point Likert scale. For each study the effect size for the primary end point was converted to a summary measure. Results A total of 321 eligible RCTs were included (48% breast, 24% CRC, 28% NSCLC). Over time, the number and size of RCTs increased considerably. For-profit/mixed sponsorship increased substantially during the study period (4% to 57%; P < .001). There was increasing use of time-to-event measures (39% to 78%) and decreasing use of response rate (54% to 14%) as primary end point (P < .001). Effect size remained stable over the study period. Authors have become more likely to strongly endorse the experimental arm (P = .017). A significant P value for the primary end point and industry sponsorship were each independently associated with endorsement of the experimental agent (odds ratio [OR] = 19.6, 95% CI, 8.9 to 43.1, and OR = 3.5, 95% CI, 1.6 to 7.5, respectively). Conclusion RCTs in oncology have become larger and are more likely to be sponsored by industry. Authors of modern RCTs are more likely to strongly endorse novel therapies. For-profit sponsorship and statistically significant results are independently associated with endorsement of the experimental arm.
Fertility Preservation in Girls with Turner Syndrome: Prognostic Signs of the Presence of Ovarian Follicles
Authors: Birgit Borgström , Julius Hreinsson , Carsten Rasmussen , Maryam Sheikhi , Gabriel Fried , Victoria Keros , Margareta Fridström , Outi Hovatta 
Published: October 2008

Abstract
Context: Many girls with Turner syndrome have follicles in their ovaries at adolescence.
Objective: Our objective was to study which girls might benefit from ovarian tissue freezing for fertility preservation.
Design: Clinical and laboratory parameters and ovarian follicle counts were analyzed among girls referred by 25 pediatric endocrinologists.
Subjects and Setting: Fifty-seven girls with Turner syndrome, aged 8–19.8 yr, were studied at a university hospital.
Interventions: Ovarian tissue was biopsied laparoscopically, studied for the presence of follicles, and cryopreserved. Blood samples were drawn for hormone measurements.
Main Outcome Measures: Presence of follicles in the biopsied tissue related to age, signs of spontaneous puberty, karyotype, and serum concentrations of gonadotropins and anti-Müllerian hormone were assessed.
Results: Ovarian biopsy was feasible in 47 of the 57 girls. In 15 of the 57 girls (26%), there were follicles in the tissue piece analyzed histologically. Six of seven girls (86%) with mosaicism, six of 22 (27%) with structural chromosomal abnormalities, and three of 28 with karyotype 45X (10.7%) had follicles. Eight of the 13 girls (62%) with spontaneous menarche had follicles, and 11 of the 19 girls (58%) who had signs of spontaneous puberty had follicles. The age group 12–16 yr had the highest proportion of girls with follicles. Normal FSH and anti-Müllerian hormone concentrations for age and pubertal stage were more frequent in girls with follicles.
Conclusions: Signs of spontaneous puberty, mosaicism, and normal hormone concentrations were positive and statistically significant but not exclusive prognostic factors as regards finding follicles.
Maturation of Luteinizing Hormone (Gonadotropin-Releasing Hormone) Secretion across Puberty: Evidence for Altered Regulation in Obese Peripubertal Girls
Authors: McCartney Christopher R. , Prendergast Kathleen A. , Blank Susan K. , Helm Kristin D. , Chhabra Sandhya , Marshall John C. 
Published: October 2008

Abstract
Context: Peripubertal obesity (body mass index-for-age ≥ 95%) in girls is associated with hyperandrogenemia. LH likely contributes to this relationship, but overnight LH secretion in obese girls is poorly characterized.
Objective: The aim of the study was to evaluate LH pulse characteristics in obese girls throughout pubertal maturation.
Design: We conducted a cross-sectional analysis.
Setting: The study was performed in a general clinical research center.
Participants: Eight nonobese and five obese Tanner 1–2 girls participated, as well as 32 nonobese and 12 obese Tanner 3–5 girls.
Intervention: Blood samples were collected every 10 min overnight (from 1900 to 0700 h).
Main Outcome Measures: LH pulse frequency, amplitude, and mean LH were measured in three 4-h time blocks (block 1, 1900–2300 h; block 2, 2300–0300 h; and block 3, 0300–0700 h).
Results: Tanner stage 1–2 nonobese girls demonstrated nocturnal increases of LH frequency (P &lt; 0.01, block 1 vs. 2) and mean LH (P &lt; 0.05, block 1 vs. 2 and 3). Obese Tanner 1–2 girls had lower 12-h LH frequency and LH amplitude (P &lt; 0.05 for both), with no overnight changes of LH pulse parameters. Compared to normal, LH frequency was elevated in Tanner 3–5 obese girls (P &lt; 0.01 in all blocks), whereas LH amplitude was low (P &lt; 0.05 in all blocks). Overnight increases of LH amplitude were observed in nonobese Tanner 3–5 girls (P &lt; 0.0001), but not in obese Tanner 3–5 girls.
Conclusions: Obesity in prepubertal and early pubertal girls is associated with reduced LH secretion and reduced nocturnal changes of LH. In later pubertal girls, obesity is linked with reduced LH amplitude, but elevated LH frequency; the latter may reflect effects of hyperandrogenemia.
Effect of Weight Loss on Liver Free Fatty Acid Uptake and Hepatic Insulin Resistance
Authors: Viljanen Antti P. M. , Iozzo Patricia , Borra Ronald , Kankaanpää Mikko , Karmi Anna , Lautamäki Riikka , Järvisalo Mikko , Parkkola Riitta , Rönnemaa Tapani , Guiducci Letizia , Lehtimäki Terho , Raitakari Olli T. , Mari Andrea , Nuutila Pirjo 
Published: October 2008

AbstractObjective: Weight loss has been shown to decrease liver fat content and whole-body insulin resistance. The current study was conducted to investigate the simultaneous effects of rapid weight reduction with a very-low-calorie diet on liver glucose and fatty acid metabolism and liver adiposity.Hypothesis: We hypothesized that liver insulin resistance and free fatty acid uptake would decrease after weight loss and that they are associated with reduction of liver fat content.Design: Thirty-four healthy obese subjects (body mass index, 33.7 ± 8.0 kg/m2) were studied before and after a very-low-calorie diet for 6 wk. Hepatic glucose uptake and endogenous glucose production were measured with [18F]fluorodeoxyglucose during hyperinsulinemic euglycemia and fasting hepatic fatty acid uptake with [18F]fluoro-6-thia-heptadecanoic acid and positron emission tomography. Liver volume and fat content were measured using magnetic resonance imaging and spectroscopy.Results: Subjects lost weight (11.2 ± 2.9 kg; P &lt; 0.0001). Liver volume decreased by 11% (P &lt; 0.002), which was partly explained by decreased liver fat content (P &lt; 0.0001). Liver free fatty acid uptake was 26% lower after weight loss (P &lt; 0.003) and correlated with the decrement in liver fat content (r = 0.54; P &lt; 0.03). Hepatic glucose uptake during insulin stimulation was unchanged, but the endogenous glucose production decreased by 40% (P &lt; 0.04), and hepatic insulin resistance by 40% (P &lt; 0.05).Conclusions: The liver responds to a 6-wk period of calorie restriction with a parallel reduction in lipid uptake and storage, accompanied by enhancement of hepatic insulin sensitivity and clearance.
Epithelial-to-mesenchymal transition of peritoneal mesothelial cells is regulated by an ERK/NF-κB/Snail1 pathway
Authors: Strippoli Raffaele , Benedicto Ignacio , Pérez Lozano Maria Luisa , Cerezo Ana , López-Cabrera Manuel , del Pozo Miguel A. 
Published: October 2008

SUMMARYEpithelial-to-mesenchymal transition (EMT) occurs in fibrotic diseases affecting the kidney, liver and lung, and in the peritoneum of patients undergoing peritoneal dialysis. EMT in the peritoneum is linked to peritoneal membrane dysfunction, and its establishment limits the effectiveness of peritoneal dialysis. The molecular regulation of EMT in the peritoneum is thus of interest from basic and clinical perspectives. Treatment of primary human mesothelial cells (MCs) with effluent from patients undergoing peritoneal dialysis induced a genuine EMT, characterized by downregulated E-cadherin and cytokeratin expression, cell scattering, and spindle-like morphology. This EMT was replicated by co-stimulation with transforming growth factor (TGF)-β1 and interleukin (IL)-1β. Retroviral overexpression of a mutant inhibitor of kappaB (IκB) demonstrated that NF-κB activation is required for E-cadherin and cytokeratin downregulation during EMT. Pre-treatment with the MAP kinase kinase (MEK)-1/2 inhibitor U0126 showed that cytokine-triggered NF-κB nuclear translocation and transcriptional activity are mediated by activation of extracellular regulated kinase (ERK). Cytokine-mediated induction of mRNA expression of the transcription factor Snail1, a repressor of E-cadherin expression and a potent inducer of EMT, was prevented by blockade of ERK or NF-κB. Finally, blockade of ERK/NF-κB signaling in ex vivo MCs that were cultured from peritoneal dialysis effluents reverted cells to an epithelioid morphology, upregulated E-cadherin and cytokeratin expression, and downregulated Snail1 expression. Modulation of the ERK/NF-κB/Snail1 pathway may provide a means of counteracting the progressive structural and functional deterioration of the peritoneal membrane during peritoneal dialysis.
Therapeutic Strategy for Treatment of Metastatic Non-Small Cell Lung Cancer
Authors: Berhoune Malik , Banu Eugeniu , Scotte Florian , Prognon Patrice , Oudard Stephane , Bonan Brigitte 
Published: October 2008

Objective: To review the current practices for metastatic non–small cell lung cancer (NSCLC) management and highlight the latest progress. Data Sources: A literature review using HighWire Press (1960–May 2008) was conducted using the following key words: non–small cell lung cancer, chemotherapy. supportive care, therapeutic strategy, quality of life (QOL), and targeted therapies. Study Selection and Data Extraction: Review articles, clinical trials, and case reports, as well as the references of those articles, were reviewed. Statistical significance and number of patients included in the studies were some of the aspects that were considered seriously. Response rates, overall survival, and progression-free survival were the major data considered. Data Synthesis: The therapeutic management of metastatic NSCLC has undergone a profound evolution over the past 10 years. The positive impact of chemotherapy on survival compared with supportive care atone has been demonstrated by several meta-analyses. The development of third-generation agents with better efficacy/toxicity ratios, such as vinorelbine, paclitaxel, docetaxel, gemcitabine, and pemetrexed, has led to improved therapeutic management of NSCLC, especially when tailored to patients' comorbidities and performance status. First-line platinum-based combinations remain the standard of care, with median survival 8 months and 1-year survival 35%, but no particular combination has yet shown superiority. First-line platinum regimens in combination with bevacizumab, a targeted inhibitor of vascular endothelial growth factor, have further improved NSCLC median survival. Moreover, second- and third-line treatments have evolved. The addition of small-molecule epidermal growth factor inhibitors and other targeted therapies has modified the pattern of NSCLC treatment. Specific management of the elderly and patients with poor performance status should be applied. Conclusions: Although there has been progress in the treatment of NSCLC, the gain in terms of clinical response and survival is still modest. Maintaining QOL and tailoring therapy for patients based on age, performance status, comorbidities, and toxicities, remain the first priority for clinicians.
Long-Acting Bronchodilator Therapy for the Treatment of Chronic Obstructive Pulmonary Disease
Authors: Chen Andrea M , Bollmeier Suzanne G , Finnegan Patrick M 
Published: October 2008

Objective: To review clinical data on the use of long-acting bronchodilator agents as monotherapy and in combination for the treatment of moderate-to-severe chronic obstructive pulmonary disease (COPD). Data Sources: A literature search was performed via MEDLINE (1966–April 2008). In addition, references from publications identified were reviewed. These searches were limited to human data published in the English language. Searches used the following terms: COPD, long-acting β2-agonisls, long-acting anticholinergics, combination therapy, pharmacoeconomics, safety, tiotropium, salmeterol, and formoterol. Study Selection and Data Extraction: Relevant information on the pharmacology, safety, efficacy, pharmacoeconomics, adherence, and available agents used in the treatment of COPD was selected. Randomized clinical trials and retrospective reviews were included. Data Synthesis: The Global Initiative for Chronic Obstructive Lung Disease guidelines provide general management recommendations to guide providers regarding treatment choices for COPD; however, they lack clarity regarding which long-acting bronchodilator to use and when combining agents becomes appropriate. Prospective trials evaluating short-acting anticholinergics and long-acting β2-agonists have utilized spirometric endpoints that relate most to short-term symptomatic relief. Tiotropium trials have focused more on patient-oriented outcomes, with data being reported for one year. Tiotropium significantly lowers exacerbation rates and improves health resource usage as well as health-related quality of life. Tiotropium also provides superior bronchodilation and improvement in dyspnea at all timo points, although onset of bronchodilation is slower than with long-acting β2-agonists. Combining these agents has been shown to decrease daytime rescue inhaler use, improve morning and evening peak expiratory flow rates, and improve bronchodilator efficacy compared with monotherapy. Pharmacoeconomic data lend support to the recommendation of tiotropium as a first-line long-acting agent. Conclusions: Tiotropium appears to be the best option as a first-line drug for patients with moderate-to-severe COPD because of its ability to sustain bronchodilator effect, improve quality of life, reduce COPD exacerbations, and reduce health resource usage. Patients who remain symptomatic may benefit from the addition of a long-acting β2-agonist to tiotropium monotherapy.
Tocilizumab: An lnterleukin-6 Receptor Inhibitor for the Treatment of Rheumatoid Arthritis
Authors: Plushner Susyn L 
Published: October 2008

Objective:To review the pharmacology, pharmacokinetics, clinical trial data, and safety profile of tocilizumab, a new biologic agent targeting the lnterleukin-6 cytokine receptor.Data Sources:A systematic search of MEDLINE (1998–June 2008) and International Pharmaceutical Abstracts (1970–June 2008) was performed to identify published clinical trials and review articles. Key search terms were tocilizumab, MRA, interleukin-6/receptors, interleukln-6/immunology, and rheumatoid arthritis. The search was limited to studies in humans that were published in the English language. References from articles located during this search were evaluated for other relevant citations. Abstracts from national and international rheumatology meetings (American College of Rheumatology and European League Against Rheumatism) and from unpublished Phase 3 clinical trials in progress (using www.clinicaltrials.gov ) were also reviewed.Study Selection and Data Extraction:All available human studies describing the pharmacology, pharmacokinetics, efficacy, safety, and adverse effects of tocilizumab were included.Data Synthesis:At doses greater than 4 mg/kg, tocilizumab use has resulted In significant improvement in clinical outcomes, including the American College of Rheumatology parameters indicating a patient's level of improvements and disease remission. Improvements were noted when tocilizumab was used as monotherapy or in combination with methotrexate or other disease-modifying antirheumatic drugs. The most effective dose of tocilizumab appears to be 8 mg/kg, which has shown significant improvements in radiographic measures of joint damage. The most common adverse effects have included abnormal results of liver function tests, hyperlipidemia, neutropenia, infections, nasopharyngitis, gastrointestinal complaints, musculoskeletal disorders, headache, rash, and pruritus.Conclusions:Tocilizumab represents a promising new treatment for rheumatoid arthritis. Additional research is warranted to confirm its radiographic benefits, clarify its safely profile, and identify its place in rheumatoid arthritis treatment relative to current biologic agents.
Pediatric Antiphospholipid Syndrome: Clinical and Immunologic Features of 121 Patients in an International Registry
Authors: Avčin Tadej , Cimaz Rolando , Silverman Earl D. , Cervera Ricard , Gattorno Marco , Garay Stella , Berkun Yackov , Sztajnbok Flavio R. , Silva Clovis A. , Campos Lucia M. , Saad-Magalhaes Claudia , Rigante Donato , Ravelli Angelo , Martini Alberto , Rozman Blaž , Meroni Pier Luigi 
Published: October 2008

OBJECTIVES. The purpose of this study was to obtain data on the association of antiphospholipid antibodies with clinical manifestations in childhood and to enable future studies to determine the impact of treatment and long-term outcome of pediatric antiphospholipid syndrome.
PATIENTS AND METHODS. A European registry extended internationally of pediatric patients with antiphospholipid syndrome was established as a collaborative project of the European Antiphospholipid Antibodies Forum and Lupus Working Group of the Pediatric Rheumatology European Society. To be eligible for enrollment the patient must meet the preliminary criteria for the classification of pediatric antiphospholipid syndrome and the onset of antiphospholipid syndrome must have occurred before the patient's 18th birthday.
RESULTS. As of December 1, 2007, there were 121 confirmed antiphospholipid syndrome cases registered from 14 countries. Fifty-six patients were male, and 65 were female, with a mean age at the onset of antiphospholipid syndrome of 10.7 years. Sixty (49.5%) patients had underlying autoimmune disease. Venous thrombosis occurred in 72 (60%), arterial thrombosis in 39 (32%), small-vessel thrombosis in 7 (6%), and mixed arterial and venous thrombosis in 3 (2%). Associated nonthrombotic clinical manifestations included hematologic manifestations (38%), skin disorders (18%), and nonthrombotic neurologic manifestations (16%). Laboratory investigations revealed positive anticardiolipin antibodies in 81% of the patients, anti-β2-glycoprotein I antibodies in 67%, and lupus anticoagulant in 72%. Comparisons between different subgroups revealed that patients with primary antiphospholipid syndrome were younger and had a higher frequency of arterial thrombotic events, whereas patients with antiphospholipid syndrome associated with underlying autoimmune disease were older and had a higher frequency of venous thrombotic events associated with hematologic and skin manifestations.
CONCLUSIONS. Clinical and laboratory characterization of patients with pediatric antiphospholipid syndrome implies some important differences between antiphospholipid syndrome in pediatric and adult populations. Comparisons between children with primary antiphospholipid syndrome and antiphospholipid syndrome associated with autoimmune disease have revealed certain differences that suggest 2 distinct subgroups.
Transhumant Pastoralism in Yak Production in the Lower Mustang District of Nepal
Authors: Degen A. Allan , Kam Michael , Pandey Shambhu B. , Upreti Chet R. , Pandey Sanjeev , Regmi Prajwal 
Published: October 2008

Abstract
There are thirty yak herd owners, all men and mainly Thakalis, between Jomsom and Lete in Lower Mustang. Transhumance is used in herding yaks, which migrate seasonally between winter pastures at about 3,000-4,000 metres and summer pastures at about 4,000-5,000 metres above sea level. Absentee herd ownership, in which shepherds (usually members of a non-Thakali ethnic group) herd only yaks and do not own any animals themselves, is common. Yaks are raised primarily for meat and milk, though substantial income is realized from selling blood during two blood-drinking ceremonies and from selling yaks as pack animals. Milk is used for products such as butter/ghee and a dry, hard curd cheese (chhurpi), which are mainly sold but also used for home consumption and for making 'salty butter tea'. Yak wool has little commercial value today but is used to make rope and tents. Yak owner estimations of how much of their income is derived from their herds range widely between 10 percent and 90 percent, but average about 50 percent. Additional income is made from the sale of seasonal crops, in particular apples, potatoes, maize, millet and barley that are produced on the owners' land. Owners also raise chickens, cows, buffalo, oxen, horses and goats. Two of the herd owners owned hotels that were run by their families. In this study, annual earnings from yaks totalled approximately Nepalese Rupees (N.Rs) 72,780 and total income for the herd owner was about N.Rs 145,560 (U.S. $2,079). We concluded that for these herd owners, yak raising is not a subsistence economic activity but rather part of a market economy based on speculative investments and accumulation. Moreover, yak production is a very high-risk enterprise as disasters can decimate large proportions of a herd quickly.