bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bridging the gap: improving clinical development and the regulatory pathways for health products for neglected diseases
Authors: Bollyky Thomas J , Cockburn Iain M , Berndt Ernst 
Published: November 2010

Background There has been tremendous progress over the last decade in the development of health products — drugs, vaccines, and diagnostics — for neglected diseases. There are now dozens of candidate products in the pipeline. Purpose Our purpose is to assess challenges that will arise in later-stage clinical development of these candidate health products and propose a strategy that would help bring the costs, risks, and finances for their clinical trials into a better, more sustainable balance. Methods We conducted a literature review of clinical trial-related publications, interviewed individuals sponsoring and conducting interventional clinical trials for neglected diseases, and analyzed data from Clinicaltrials.gov, a clinical trials registry, on neglected disease clinical trials initiating subject recruitment between January 1, 2003 and December 31, 2009. We quantified Clinicaltrials.gov data into country-specific participation in clinical trials and aggregated them into geographic regions. We employed bioinformatics and keyword methods to classify trials by type of intervention, sponsor, study phase, and therapeutic area. Results Two substantial bottlenecks threaten our capacity to bring these candidate neglected disease therapies to those in need. First, the research and regulatory capacity in many neglected disease-endemic settings is not adequate to support the clinical trials that need to occur there in order to complete the development of these products. Second, even with expected attrition in the pipeline, current levels of financing are insufficient to support the clinical development of these products under current cost assumptions. Limitations The proportion of trials of relevant studies not registered on Clinicaltrials.gov is not known, but is thought to be smaller post-2005, after the International Committee of Medical Journal Editors initiated a policy requiring investigators to deposit information about trial design into an accepted clinical trials registry before beginning patient enrollment. Conclusions Realizing the promise of the neglected disease product pipeline will require not only increased funding for large-scale clinical trials and capacity building, but also greater attention to how these trials and their regulatory pathways can be improved to reduce unnecessary costs, delays, and risks to trial subjects. We propose a two-prong strategy: (1) adaptation and adoption of emerging research on ‘sensible guidelines’ for reducing large-scale, randomized clinical trial costs to the demands of the neglected disease product pipeline and (2) regional approaches to regulation and ethical review of clinical trials for health products for neglected diseases.
Efficacy and safety of etanercept in moderate-to-severe asthma: a randomised, controlled trial
Authors: Holgate S.T. , Noonan M. , Chanez P. , Busse W. , Dupont L. , Pavord I. , Hakulinen A. , Paolozzi L. , Wajdula J. , Zang C. , Nelson H. , Raible D. 
Published: November 2010

Increased tumour necrosis factor-α levels have been observed in bronchial biopsies and induced sputum from subjects with severe asthma. We investigated etanercept (ETN) as a therapeutic option for treating moderate-to-severe persistent asthma.In this 12-week, randomised, double-blind, placebo-controlled, phase 2 trial, subjects (n = 132) with moderate-to-severe persistent asthma received subcutaneous injections of 25 mg ETN or placebo twice weekly, and were evaluated at baseline, and at weeks 2, 4, 8 and 12. The primary end-point was the change from baseline to week 12 in pre-bronchodilator forced expiratory volume in 1 s (FEV1) % predicted. Secondary end-points included morning peak expiratory flow, FEV1% pred, Asthma Control Questionnaire (5-item version), asthma exacerbations, provocative concentration of methacholine causing a 20% decrease in FEV1, and the Asthma Quality of Life Questionnaire.No significant differences were observed between ETN and placebo for any of the efficacy end-points. ETN treatment was well tolerated, with no unexpected safety findings observed during the study.Clinical efficacy of ETN was not shown in subjects with moderate-to-severe persistent asthma over 12 weeks. However, ETN treatment was a well-tolerated therapy. Studies in specific subsets of patients with asthma with longer-term follow-up may be needed to fully evaluate the clinical efficacy of ETN in this population.
Influenza pneumonia: a comparison between seasonal influenza virus and the H1N1 pandemic
Authors: Riquelme R. , Torres A. , Rioseco M.L. , Ewig S. , Cillóniz C. , Riquelme M. , Inzunza C. , Polverino E. , Gomez Y. , Marcos M.A. , Contreras C. , Gabarrús A. , Fasce R. 
Published: November 2010

We compared clinical presentation, complications and outcome in patients with influenza A (H1N1) and seasonal influenza pneumonia.The group of patients with influenza A (H1N1) pneumonia consisted of 75 patients. 52 patients with pneumonia associated with seasonal influenza were included for comparison.Patients with pneumonia associated with novel H1N1 influenza were younger (mean age 39.7 yrsversus69.6 yrs) and had fewer chronic comorbidities and less alcoholism. Infiltrates were more extensive and frequently interstitial. Respiratory failure was more frequent (those with an arterial oxygen tension/inspiratory oxygen fraction ratio <200 28%versus12%, p = 0.042), leading to a higher rate of intensive care unit (ICU) admission and mechanical ventilation (29.3%versus7.7% (p<0.0030) and 18.7%versus2% (p<0.0045)). Mortality was twice as high in patients with novel H1N1 (12%versus5.8%; p = 0.238), although this was not significant, and was attributable to pneumonia in most instances (77.8%versus0%; p = 0.046).Younger age, fewer comorbidities, more extensive radiographic extension and more severe respiratory compromise, and ICU admissions are key features of the clinical presentation of patients with novel H1N1-associated pneumonia compared with seasonal influenza pneumonia.
GlutathioneS-transferase, incense burning and asthma in children
Authors: Wang I-J. , Tsai C-H. , Chen C-H. , Tung K-Y. , Lee Y.L. 
Published: November 2010

Incense burning is a popular practice in many family homes and temples. However, little is known about the effects of indoor incense burning and genetic polymorphisms on asthma. This study evaluated the effects of indoor incense burning and glutathioneS-transferase (GST) genetic polymorphisms on asthma and wheeze.In 2007, 3,764 seventh-grade schoolchildren (mean±sdage 12.42±0.65 yrs) were evaluated using a standard questionnaire for information about respiratory symptoms and environmental exposures. Multiple logistic regressions were performed to assess the association between GST polymorphisms and incense burning frequency on asthma and wheeze, after adjusting for potential confounders.The frequency of incense burning at home was associated with increased risk of current asthma (p = 0.05), medication use (p = 0.03) and exercise wheeze (p = 0.001). GSTθ1 (GSTT1) null genotypes were associated with current asthma (OR 1.43, 95% CI 1.00–2.04) and medication use (OR 1.46, 95% CI 1.01–2.22).GSTT1showed a significant interactive effect with incense burning on current asthma, current wheeze and nocturnal wheeze. The frequency of incense burning was associated with increased risk of current asthma, medication use, lifetime wheeze, nocturnal wheeze and exercise wheeze in an exposure–response manner among children withGSTT1null genotype (p<0.05).Incense burning is a risk factor for asthma and wheezing, especially inGSTT1genetically susceptible children.
A genome-wide study of PDZ-domain interactions in C. elegans reveals a high frequency of non-canonical binding
Authors: Lenfant Nicolas , Polanowska Jolanta , Bamps Sophie , Omi Shizue , Borg Jean-Paul , Reboul Jérôme 
Published: November 2010

AbstractBackgroundProteins may evolve through the recruitment and modification of discrete domains, and in many cases, protein action can be dissected at the domain level. PDZ domains are found in many important structural and signaling complexes, and are generally thought to interact with their protein partners through a C-terminal consensus sequence. We undertook a comprehensive search for protein partners of all individual PDZ domains inC. elegansto characterize their function and mode of interaction.ResultsCoupling high-throughput yeast two-hybrid screens with extensive validation by co-affinity purification, we defined a domain-orientated interactome map. This integrates PDZ domain proteins in numerous cell-signaling pathways and shows that PDZ domain proteins are implicated in an unexpectedly wide range of cellular processes. Importantly, we uncovered a high frequency of non-canonical interactions, not involving the C-terminus of the protein partner, which were directly confirmed in most cases. We completed our study with the generation of a yeast array representing the entire set of PDZ domains fromC. elegansand provide a proof-of-principle for its application to the discovery of PDZ domain targets for any protein or peptide of interest.ConclusionsWe provide an extensive domain-centered dataset, together with a clone resource, that will help future functional study of PDZ domains. Through this unbiased approach, we revealed frequent non-canonical interactions between PDZ domains and their protein partners that will require a re-evaluation of this domain's molecular function.[The protein interactions from this publication have been submitted to the IMEx (http://www.imexconsortium.org) consortium through IntAct (PMID: 19850723) and assigned the identifier IM-14654]
Phosphorylated Smad2 in Advanced Stage Gastric Carcinoma
Authors: Shinto Osamu , Yashiro Masakazu , Toyokawa Takahiro , Nishii Takafumi , Kaizaki Ryoji , Matsuzaki Taro , Noda Satoru , Kubo Naoshi , Tanaka Hiroaki , Doi Yosuke , Ohira Masaichi , Muguruma Kazuya , Sawada Tetsuji , Hirakawa Kosei 
Published: November 2010

Abstract

Background
Transforming growth factor β (TGFβ) receptor signaling is closely associated with the invasion ability of gastric cancer cells. Although Smad signal is a critical integrator of TGFβ receptor signaling transduction systems, not much is known about the role of Smad2 expression in gastric carcinoma. The aim of the current study is to clarify the role of phosphorylated Smad2 (p-Smad2) in gastric adenocarcinomas at advanced stages.

Methods
Immunohistochemical staining with anti-p-Smad2 was performed on paraffin-embedded specimens from 135 patients with advanced gastric adenocarcinomas. We also evaluated the relationship between the expression levels of p-Smad2 and clinicopathologic characteristics of patients with gastric adenocarcinomas.

Results
The p-Smad2 expression level was high in 63 (47%) of 135 gastric carcinomas. The p-Smad2 expression level was significantly higher in diffuse type carcinoma (p = 0.007), tumours with peritoneal metastasis (p = 0.017), and tumours with lymph node metastasis (p = 0.047). The prognosis for p-Smad2-high patients was significantly (p = 0.035, log-rank) poorer than that of p-Smad2-low patients, while a multivariate analysis revealed that p-Smad2 expression was not an independence prognostic factor.

Conclusion
The expression of p-Smad2 is associated with malignant phenotype and poor prognosis in patients with advanced gastric carcinoma.
Simultaneous detection of Human Immunodeficiency Virus 1 and Hepatitis B virus infections using a dual-label time-resolved fluorometric assay
Authors: Myyryläinen Tiina , Talha Sheikh M , Swaminathan Sathyamangalam , Vainionpää Raija , Soukka Tero , Khanna Navin , Pettersson Kim 
Published: November 2010

Abstract
A highly specific and novel dual-label time-resolved immunofluorometric assay was developed exploiting the unique emission wavelengths of the intrinsically fluorescent terbium (Tb3+) and europium (Eu3+) tracers for the simultaneous detection of human immunodeficiency virus 1 (HIV-1) and hepatitis B virus (HBV) infections, respectively. HIV-1 infection was detected using a double antigen sandwich format wherein anti-HIV-1 antibodies were captured using an in vivo biotinylated version of a chimeric HIV-1 antigen and revealed using the same antigen labeled with Tb3+ chelate. Hepatitis B surface antigen (HBsAg), which served as the marker of HBV infection, was detected in a double antibody sandwich using two monoclonal antibodies (mAbs), one chemically biotinylated to capture, and the other labeled with Eu3+ nanoparticles, to reveal. The performance of the assay was evaluated using a collection (n = 60) of in-house and commercially available human sera panels. This evaluation showed the dual-label assay to possess high degrees of specificity and sensitivity, comparable to those of commercially available, single analyte-specific kits for the detection of HBsAg antigen and anti-HIV antibodies. This work demonstrates the feasibility of developing a potentially time- and resource-saving multiplex assay for screening serum samples for multiple infections in a blood bank setting.
Detection and characterization of two chimpanzee polyomavirus genotypes from different subspecies
Authors: Deuzing Ilona , Fagrouch Zahra , Groenewoud Marlous J , Niphuis Henk , Kondova Ivanela , Bogers Willy , Verschoor Ernst J 
Published: November 2010

Abstract
The complete nucleotide sequences of three chimpanzee polyomavirus genetic variants were determined. Phylogenetic analysis indicated that the viruses form two different genotypes of ChPyV. Comparison with other primate polyomaviruses revealed a putative agnogene, and an unusually long VP1 open reading frame. The transcriptional control regions (TCR) of the viruses were extremely short (155 nucleotides), and highly conserved amongst the genotypes. Analysis of the TCR from different chimpanzee subspecies, and from a series of tissues from five individuals confirmed its genetic stability, and also indicates that double-infections with different genotypes can occur.
The Meq oncoprotein of Marek's disease virus interacts with p53 and inhibits its transcriptional and apoptotic activities
Authors: Deng Xufang , Li Xiangdong , Shen Yang , Qiu Yafeng , Shi Zixue , Shao Donghua , Jin Yamei , Chen Hongjun , Ding Chan , Li Li , Chen Puyan , Ma Zhiyong 
Published: November 2010

Abstract

Background
Marek's disease virus (MDV) is an oncogenic herpesvirus, which causes malignant lymphoma in chickens. The Meq protein of MDV, which is expressed abundantly in MDV-infected cells and in Marek's disease (MD) tumor cells, functions as a transcriptional activator and has been proposed to play an important role in oncogenic transformation. Preliminary studies demonstrated that Meq is able to bind p53 in vitro, as demonstrated using a protein-binding assay. This observation prompted us to examine whether the interaction between Meq and p53 occurs in cells, and to investigate the biological significance of this interaction.

Results
We confirmed first that Meq interacted directly with p53 using a yeast two-hybrid assay and an immunoprecipitation assay, and we investigated the biological significance of this interaction subsequently. Exogenous expression of Meq resulted in the inhibition of p53-mediated transcriptional activity and apoptosis, as analyzed using a p53 luciferase reporter assay and a TUNEL assay. The inhibitory effect of Meq on transcriptional activity mediated by p53 was dependent on the physical interaction between these two proteins, because a Meq deletion mutant that lacked the p53-binding region lost the ability to inhibit p53-mediated transcriptional activity and apoptosis. The Meq variants L-Meq and S-Meq, but not VS-Meq and ∆Meq, which were expressed in MD tumor cells and MDV-infected cells, exerted an inhibitory effect on p53 transcriptional activity. In addition, ∆Meq was found to act as a negative regulator of Meq.

Conclusions
The Meq oncoprotein interacts directly with p53 and inhibits p53-mediated transcriptional activity and apoptosis. These findings provide valuable insight into the molecular basis for the function of Meq in MDV oncogenesis.
Molecular Basis for the Dosing Time-Dependency of Anti-Allodynic Effects of Gabapentin in a Mouse Model of Neuropathic Pain
Authors: Kusunose Naoki , Koyanagi Satoru , Hamamura Kengo , Matsunaga Naoya , Yoshida Miyako , Uchida Takahiro , Tsuda Makoto , Inoue Kazuhide , Ohdo Shigehiro 
Published: November 2010

Background: Neuropathic pain is characterized by hypersensitivity to innocuous stimuli (tactile allodynia) that is nearly always resistant to NSAIDs or even opioids. Gabapentin, a GABA analogue, was originally developed to treat epilepsy. Accumulating clinical evidence supports the effectiveness of this drug for diverse neuropathic pain. In this study, we showed that the anti-allodynic effect of gabapentin was changed by the circadian oscillation in the expression of its target molecule, the calcium channel α2δ−1 subunit. Results: Mice were underwent partial sciatic nerve ligation (PSL) to create a model of neuropathic pain. The paw withdrawal threshold (PWT) in PSL mice significantly decreased and fluctuated with a period length about 24 h. The PWT in PSL mice was dose-dependently increased by intraperitoneal injection of gabapentin, but the anti-allodynic effects varied according to its dosing time. The protein levels of α2δ−1 subunit were up-regulated in the DRG of PSL mice, but the protein levels oscillated in a circadian time-dependent manner. The time-dependent oscillation of α2δ−1 subunit protein correlated with fluctuations in the maximal binding capacity of gabapentin. The anti-allodynic effect of gabapentin was attenuated at the times of the day when α2δ−1 subunit protein was abundant. Conclusions: These findings suggest that the dosing time-dependent difference in the anti-allodynic effects of gabapentin is attributable to the circadian oscillation of α2δ−1 subunit expression in the DRG and indicate that the optimizing its dosing schedule helps to achieve rational pharmacotherapy for neuropathic pain.
Comparison of cardiothoracic surgery training in usa and germany
Authors: Tchantchaleishvili Vakhtang , Mokashi Suyog A , Rajab Taufiek K , Bolman R Morton , Chen Frederick Y , Schmitto Jan D 
Published: November 2010

Abstract

Background
Training of cardiothoracic surgeons in Europe and the United States has expanded to incorporate new operative techniques and requirements. The purpose of this study was to compare the current structure of training programs in the United States and Germany.

Methods
We thoroughly reviewed the existing literature with particular focus on the curriculum, salary, board certification and quality of life for cardiothoracic trainees.

Results
The United States of America and the Federal Republic of Germany each have different cardiothoracic surgery training programs with specific strengths and weaknesses which are compared and presented in this publication.

Conclusions
The future of cardiothoracic surgery training will become affected by technological, demographic, economic and supply factors. Given current trends in training programs, creating an efficient training system would allow trainees to compete and grow in this constantly changing environment.
In Lysinuric Protein Intolerance system y+L activity is defective in monocytes and in GM-CSF-differentiated macrophages
Authors: Barilli Amelia , Rotoli Bianca Maria , Visigalli Rossana , Bussolati Ovidio , Gazzola Gian C , Kadija Zamir , Rodi Giuseppe , Mariani Francesca , Ruzza Maria Lorena , Luisetti Maurizio , Dall'Asta Valeria 
Published: November 2010

Abstract

Background
In the recessive aminoaciduria Lysinuric Protein Intolerance (LPI), mutations of SLC7A7/y+LAT1 impair system y+L transport activity for cationic amino acids. A severe complication of LPI is a form of Pulmonary Alveolar Proteinosis (PAP), in which alveolar spaces are filled with lipoproteinaceous material because of the impaired surfactant clearance by resident macrophages. The pathogenesis of LPI-associated PAP remains still obscure. The present study investigates for the first time the expression and function of y+LAT1 in monocytes and macrophages isolated from a patient affected by LPI-associated PAP. A comparison with mesenchymal cells from the same subject has been also performed.

Methods
Monocytes from peripheral blood were isolated from a 21-year-old patient with LPI. Alveolar macrophages and fibroblastic-like mesenchymal cells were obtained from a whole lung lavage (WLL) performed on the same patient. System y+L activity was determined measuring the 1-min uptake of [3H]-arginine under discriminating conditions. Gene expression was evaluated through qRT-PCR.

Results
We have found that: 1) system y+L activity is markedly lowered in monocytes and alveolar macrophages from the LPI patient, because of the prevailing expression of SLC7A7/y+LAT1 in these cells; 2) on the contrary, fibroblasts isolated from the same patient do not display the transport defect due to compensation by the SLC7A6/y+LAT2 isoform; 3) in both normal and LPI monocytes, GM-CSF induces the expression of SLC7A7, suggesting that the gene is a target of the cytokine; 4) GM-CSF-induced differentiation of LPI monocytes is comparable to that of normal cells, demonstrating that GM-CSF signalling is unaltered; 5) general and respiratory conditions of the patient, along with PAP-associated parameters, markedly improved after GM-CSF therapy through aerosolization.

Conclusions
Monocytes and macrophages, but not fibroblasts, derived from a LPI patient clearly display the defect in system y+L-mediated arginine transport. The different transport phenotypes are referable to the relative levels of expression of SLC7A7 and SLC7A6. Moreover, the expression of SLC7A7 is regulated by GM-CSF in monocytes, pointing to a role of y+LAT1 in the pathogenesis of LPI associated PAP.
Age-related synaptic loss of the medial olivocochlear efferent innervation
Authors: Fu Benjamin , Le Prell Colleen , Simmons Dwayne , Lei Debin , Schrader Angela , Chen Amelia B , Bao Jianxin 
Published: November 2010

Abstract
Age-related functional decline of the nervous system is consistently observed, though cellular and molecular events responsible for this decline remain largely unknown. One of the most prevalent age-related functional declines is age-related hearing loss (presbycusis), a major cause of which is the loss of outer hair cells (OHCs) and spiral ganglion neurons. Previous studies have also identified an age-related functional decline in the medial olivocochlear (MOC) efferent system prior to age-related loss of OHCs. The present study evaluated the hypothesis that this functional decline of the MOC efferent system is due to age-related synaptic loss of the efferent innervation of the OHCs. To this end, we used a recently-identified transgenic mouse line in which the expression of yellow fluorescent protein (YFP), under the control of neuron-specific elements from the thy1 gene, permits the visualization of the synaptic connections between MOC efferent fibers and OHCs. In this model, there was a dramatic synaptic loss between the MOC efferent fibers and the OHCs in older mice. However, age-related loss of efferent synapses was independent of OHC status. These data demonstrate for the first time that age-related loss of efferent synapses may contribute to the functional decline of the MOC efferent system and that this synaptic loss is not necessary for age-related loss of OHCs.