bluuebunny/crossref_metadata_2025_split huggingface dataset:
Leukemogenic Ptpn11 causes fatal myeloproliferative disorder via cell-autonomous effects on multiple stages of hematopoiesis
Authors: Chan Gordon , Kalaitzidis Demetrios , Usenko Tatiana , Kutok Jeffery L. , Yang Wentian , Mohi M. Golam , Neel Benjamin G. 
Published: January 2009

Abstract
PTPN11, which encodes the tyrosine phosphatase SHP2, is mutated in approximately 35% of patients with juvenile myelomonocytic leukemia (JMML) and at a lower incidence in other neoplasms. To model JMML pathogenesis, we generated knockin mice that conditionally express the leukemia-associated mutant Ptpn11D61Y. Expression of Ptpn11D61Y in all hematopoietic cells evokes a fatal myeloproliferative disorder (MPD), featuring leukocytosis, anemia, hepatosplenomegaly, and factor-independent colony formation by bone marrow (BM) and spleen cells. The Lin−Sca1+cKit+ (LSK) compartment is expanded and “right-shifted,” accompanied by increased stem cell factor (SCF)–evoked colony formation and Erk and Akt activation. However, repopulating activity is decreased in diseased mice, and mice that do engraft with Ptpn11D61Y stem cells fail to develop MPD. Ptpn11D61Y common myeloid progenitors (CMPs) and granulocyte-monocyte progenitors (GMPs) produce cytokine-independent colonies in a cell-autonomous manner and demonstrate elevated Erk and Stat5 activation in response to granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulation. Ptpn11D61Y megakaryocyte-erythrocyte progenitors (MEPs) yield increased numbers of erythrocyte burst-forming units (BFU-Es), but MEPs and erythrocyte-committed progenitors (EPs) produce fewer erythrocyte colony-forming units (CFU-Es), indicating defective erythroid differentiation. Our studies provide a mouse model for Ptpn11-evoked MPD and show that this disease results from cell-autonomous and distinct lineage-specific effects of mutant Ptpn11 on multiple stages of hematopoiesis.
Complement fraction 3 binding on erythrocytes as additional mechanism of disease in paroxysmal nocturnal hemoglobinuria patients treated by eculizumab
Authors: Risitano Antonio M. , Notaro Rosario , Marando Ludovica , Serio Bianca , Ranaldi Danilo , Seneca Elisa , Ricci Patrizia , Alfinito Fiorella , Camera Andrea , Gianfaldoni Giacomo , Amendola Angela , Boschetti Carla , Di Bona Eros , Fratellanza Giorgio , Barbano Filippo , Rodeghiero Francesco , Zanella Alberto , Iori Anna Paola , Selleri Carmine , Luzzatto Lucio , Rotoli Bruno 
Published: January 2009

AbstractIn paroxysmal nocturnal hemoglobinuria (PNH) hemolytic anemia is due mainly to deficiency of the complement regulator CD59 on the surface of red blood cells (RBCs). Eculizumab, an antibody that targets complement fraction 5 (C5), has proven highly effective in abolishing complement-mediated intravascular hemolysis in PNH; however, the hematologic benefit varies considerably among patients. In the aim to understand the basis for this variable response, we have investigated by flow cytometry the binding of complement fraction 3 (C3) on RBCs from PNH patients before and during eculizumab treatment. There was no evidence of C3 on RBCs of untreated PNH patients; by contrast, in all patients on eculizumab (n = 41) a substantial fraction of RBCs had C3 bound on their surface, and this was entirely restricted to RBCs with the PNH phenotype (CD59−). The proportion of C3+ RBCs correlated significantly with the reticulocyte count and with the hematologic response to eculizumab. In 3 patients in whom 51Cr labeling of RBCs was carried out while on eculizumab, we have demonstrated reduced RBC half-life in vivo, with excess 51Cr uptake in spleen and in liver. Binding of C3 by PNH RBCs may constitute an additional disease mechanism in PNH, strongly enhanced by eculizumab treatment and producing a variable degree of extravascular hemolysis.
EGFR-TKI and lung adenocarcinoma with CNS relapse: interest of molecular follow-up
Authors: Ruppert A-M. , Beau-Faller M. , Neuville A. , Guerin E. , Voegeli A-C. , Mennecier B. , Legrain M. , Molard A. , Jeung M-Y. , Gaub M-P. , Oudet P. , Quoix E. 
Published: January 2009

The epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) erlotinib improves survival of lung cancer as second- or third-line therapy. However, after an initial response, most patients will recur, particularly within the central nervous system.The present study reports the case of a 27-yr-old nonsmoking male presenting with a metastatic lung adenocarcinoma withEGFRexon 19 deletion, associated with sensitivity to EGFR-TKI. Gefitinib, followed by chemotherapy and finally erlotinib resulted in prolonged disease control, until multiple liver metastases were detected. After stopping EGFR-TKI, brain metastases with carcinomatous meningitis were diagnosed. A secondary T790M mutation, associated with resistance to EGFR-TKI, was found on the liver biopsy but not in the cerebrospinal fluid. Erlotinib was reintroduced and allowed a quick neurological improvement, even though the extra-cranial disease remained resistant to erlotinib.The present report underscores the interest of molecular monitoring in lung cancer. Persistent cerebral tyrosine kinase inhibitor sensitivity should be considered in patients presenting with an early central nervous system relapse after stopping epidermal growth factor receptor tyrosine kinase inhibitor, even with a T790M-resistant mutation in noncerebral metastases. Questions remain concerning the selection of sub-clones during epidermal growth factor receptor tyrosine kinase inhibitor therapy, which could differ according to metastatic sites, especially in the central nervous system.
Serum adipocyte-fatty acid binding protein level is elevated in severe OSA and correlates with insulin resistance
Authors: Lam D. C-L. , Xu A. , Lam K. S-L. , Lam B. , Lam J. C-M. , Lui M. M-S. , Ip M. S-M. 
Published: January 2009

Obstructive sleep apnoea (OSA) is associated with insulin resistance and metabolic syndrome. There is evidence that adipocyte-fatty acid binding protein (A-FABP) may be involved in the development of cardiometabolic dysfunction. The present authors hypothesise that A-FABP is upregulated in OSA.A total of 124 males without hypertension, diabetes mellitus, hyperlipidaemia or cardiovascular disease were recruited and underwent polysomnography. Serum A-FABP levels showed significant positive correlations with duration of oxygen desaturation and minimal oxygen saturation, fasting insulin and insulin resistance index by homeostasis model assessment. When subjects were divided into tertiles according to apnoea/hypopnoea index (AHI), serum A-FABP levels were significantly higher in the group with AHI ≥34.4 events·h−1than the groups with AHI 13.2–34.4 events·h−1or with AHI <13.2 events·h−1. Serum A-FABP levels were significantly higher in the AHI ≥34.4 group than obesity-matched subjects with AHI <34.4 events·h−1.Serum adipocyte-fatty acid binding protein levels correlated with obstructive sleep apnoea and insulin resistance, independently of obesity, and were significantly higher in severe obstructive sleep apnoea. Adipocyte-fatty acid binding protein may play a role in obstructive sleep apnoea and metabolic dysfunction.
The psychobiology of nicotine dependence
Authors: Balfour D. J. K. 
Published: January 2009

There is abundant evidence to show that nicotine is the principal addictive component of tobacco smoke. The results of laboratory studies have shown that nicotine has many of the behavioural and neurobiological properties of a drug of dependence.This article focuses on the evidence that nicotine has the rewarding and reinforcing properties typical of an addictive drug and that these properties are mediated, in part, by its effects on mesolimbic dopamine neurones. However, in many experimental models of dependence, nicotine has relatively weak reinforcing properties that do not appear to explain adequately the powerful addiction to tobacco smoke experienced by many habitual smokers. Some of the reasons for this conundrum will be covered herein. This article focuses on the hypothesis that sensory stimuli and other pharmacologically active components in tobacco smoke play a pivotal role in the addiction to nicotine when it is inhaled in tobacco smoke.The article will discuss the evidence that dependence upon tobacco smoke reflects a complex interaction between nicotine and the components of the smoke, which are mediated by complementary effects of nicotine on the dopamine projections to the shell and core subdivisions of the accumbens.It will also discuss the extent to which the complexity of the dependence explains why nicotine replacement therapy does not provide a completely satisfying aid to smoking cessation and speculate on the properties treatments should exhibit if they are to provide a better treatment for tobacco dependence than those currently available.
Pharmacological treatments for tobacco dependence
Authors: Fagerström K. O. , Jiménez-Ruiz C. A. 
Published: January 2009

There are currently three licensed therapies for smoking cessation: nicotine replacement (NR), bupropion and varenicline.NR can be indicated for: 1) aid in abrupt cessation; 2) gradual reduction in order to quit smoking; 3) temporary abstinence; and 4) smoking reduction maintenance. A meta-analysis has found that the relative risk of abstinence for any form of NR relative to control was 1.6. It has been found that starting NR treatment 1–3 weeks before smoking cessation and combining NR products, usually patch and gum, increases efficacy. Recently some new nicotine administration forms,i.e.lozenge, mouth spray and a pouch, have been developed. They seem to have the potential to relieve cravings faster than the current high-dose gum, and also be more preferred.Varenicline is a selective partial agonist at the α4β2nicotinic acetylcholine receptors (nAChR). It decreases cravings and alleviates the symptoms of withdrawal. It can also reduce the rewarding and reinforcing effects of nicotine. Trials have shown varenicline to have increased efficacy relative to bupropion. Varenicline has also been compared with NR (21 mg transdermal patch) in one randomised study. Abstinence at the end of treatment at 12 weeks was significantly increased for varenicline (56%) compared with for nicotine patch (43%). Some post-marketing reports have expressed concern about psychiatric adverse effects, such as aggression, depression and suicides. The European Medicines Agency and the Food and Drug Administration of the USA are monitoring reported side-effects, but so far no confirmed casual relationship between these adverse effects and varenicline has been established.Bupropion inhibits neuronal re-uptake of dopamine and norepinephrine and is an antagonist on the nAChR. Its efficacy, compared with placebo, has been proved in several meta-analyses. A recent study suggests that longer pre-cessation use of bupropion,e.g.for 4 weeks, can improve efficacy results.Under development for the treatment of tobacco dependence are cannabinoid antagonists, immunotherapy against nicotine, monoaminooxidase inhibitors, dopamine receptor D3 receptor antagonists and partial agonists, glutamatergic and GABA-ergic compounds and novel selective nicotine cholinergic receptor agonists and antagonists.
Clinical and public health significance of treatments to aid smoking cessation
Authors: West R. , Stapleton J. 
Published: January 2009

There is good epidemiological evidence to show that for every continued year of smoking over the age of 40 yrs, the average smoker loses 3 months of life expectancy.Treatments to aid smoking cessation have the potential to save tens of thousands of lives annually if they: 1) lead users of those treatments to stop significantly earlier than they would otherwise have done; 2) do not undermine quitting in nonusers; and 3) are used by a significant proportion of smokers. There is strong evidence from high-quality randomised controlled trials to show that currently available treatments improve the chances of a cessation attempt succeeding permanently by between 2.5 and 10% points. For each success this brings forward quitting by an average of 25–30 yrs. Failure of a cessation attempt at 40 yrs of age costs an estimated 6–7 yrs of life expectancy.There is no evidence that introducing and publicising treatments undermines quitting in nonusers. The major factor limiting the public health benefit of treatments to aid cessation is the numbers of smokers that use them. At present, the most effective treatment combination of behavioural support plus medication is used by a very small minority of smokers.It is estimated that for every 100,000 smokers who use proven treatments to aid cessation, between 7,500 and 30,000 life-years will be saved in the future depending on the treatment. In England (UK), the use of smoking cessation treatment in 2008 is expected to save 270,000 life-years. A major priority for tobacco control should be finding ways of encouraging more smokers to use the most effective treatments.
Implications and priorities of tobacco control in Belgium and Europe: FIGURE 1.
Authors: Bartsch P. 
Published: January 2009

The present article aims to define what tobacco control is both in Europe and around the world. The situation of tobacco control in Belgium will be compared to other European countries using the tobacco control scale (TCS). If countries demonstrating a high TCS score have lower tobacco smoking prevalence than countries with a low TCS, it is not known whether the decrease in smoking prevalence over several years is well correlated with the increase in TCS score in each country during the same period.Moreover the article will raise the question of how far research will continue control into controlling the use of tobacco.The remaining 20% of smokers in the best tobacco control scale countries who are still smoking are not similar to the 20% that are now ex-smokers. Indeed we are now facing the “hard core smokers”, who show great resistance to policy measures and be considered as ill individuals requiring specialised care rather than individuals with bad habits. The future tobacco control scale should place more importance on the quality of care and the implication of European countries providing improved access to this form of care and validated forms of treatment of this chronic, difficult to treat disease.
Crystallizing short-read assemblies around seeds
Authors: Hossain Mohammad Sajjad , Azimi Navid , Skiena Steven 
Published: January 2009

Abstract

Background
New short-read sequencing technologies produce enormous volumes of 25–30 base paired-end reads. The resulting reads have vastly different characteristics than produced by Sanger sequencing, and require different approaches than the previous generation of sequence assemblers. In this paper, we present a short-read de novo assembler particularly targeted at the new ABI SOLiD sequencing technology.

Results
This paper presents what we believe to be the first de novo sequence assembly results on real data from the emerging SOLiD platform, introduced by Applied Biosystems. Our assembler SHORTY augments short-paired reads using a trivially small number (5 – 10) of seeds of length 300 – 500 bp. These seeds enable us to produce significant assemblies using short-read coverage no more than 100×, which can be obtained in a single run of these high-capacity sequencers. SHORTY exploits two ideas which we believe to be of interest to the short-read assembly community: (1) using single seed reads to crystallize assemblies, and (2) estimating intercontig distances accurately from multiple spanning paired-end reads.

Conclusion
We demonstrate effective assemblies (N50 contig sizes ~40 kb) of three different bacterial species using simulated SOLiD data. Sequencing artifacts limit our performance on real data, however our results on this data are substantially better than those achieved by competing assemblers.
REMAS: a new regression model to identify alternative splicing events from exon array data
Authors: Zheng Hao , Hang Xingyi , Zhu Ji , Qian Minping , Qu Wubin , Zhang Chenggang , Deng Minghua 
Published: January 2009

AbstractBackgroundAlternative splicing (AS) is an important regulatory mechanism for gene expression and protein diversity in eukaryotes. Previous studies have demonstrated that it can be causative for, or specific to splicing-related diseases. Understanding the regulation of AS will be helpful for diagnostic efforts and drug discoveries on those splicing-related diseases. As a novel exon-centric microarray platform, exon array enables a comprehensive analysis of AS by investigating the expression of known and predicted exons. Identifying of AS events from exon array has raised much attention, however, new and powerful algorithms for exon array data analysis are still absent till now.ResultsHere, we considered identifying of AS events in the framework of variable selection and developed a regression method for AS detection (REMAS). Firstly, features of alternatively spliced exons were scaled by reasonably defined variables. Secondly, we designed a hierarchical model which can represent gene structure and transcriptional influence to exons, and the lasso type penalties were introduced in calculation because of huge variable size. Thirdly, an iterative two-step algorithm was developed to select alternatively spliced genes and exons. To avoid negative effects introduced by small sample size, we ranked genes as parameters indicating their AS capabilities in an iterative manner. After that, both simulation and real data evaluation showed that REMAS could efficiently identify potential AS events, some of which had been validated by RT-PCR or supported by literature evidence.ConclusionAs a new lasso regression algorithm based on hierarchical model, REMAS has been demonstrated as a reliable and effective method to identify AS events from exon array data.
Network-based support vector machine for classification of microarray samples
Authors: Zhu Yanni , Shen Xiaotong , Pan Wei 
Published: January 2009

AbstractBackgroundThe importance of network-based approach to identifying biological markers for diagnostic classification and prognostic assessment in the context of microarray data has been increasingly recognized. To our knowledge, there have been few, if any, statistical tools that explicitly incorporate the prior information of gene networks into classifier building. The main idea of this paper is to take full advantage of the biological observation that neighboring genes in a network tend to function together in biological processes and to embed this information into a formal statistical framework.ResultsWe propose a network-based support vector machine for binary classification problems by constructing a penalty term from theF∞-norm being applied to pairwise gene neighbors with the hope to improve predictive performance and gene selection. Simulation studies in both low- and high-dimensional data settings as well as two real microarray applications indicate that the proposed method is able to identify more clinically relevant genes while maintaining a sparse model with either similar or higher prediction accuracy compared with the standard and theL1penalized support vector machines.ConclusionThe proposed network-based support vector machine has the potential to be a practically useful classification tool for microarrays and other high-dimensional data.
Searching for bidirectional promoters in Arabidopsis thaliana
Authors: Wang Quan , Wan Lin , Li Dayong , Zhu Lihuang , Qian Minping , Deng Minghua 
Published: January 2009

Abstract

Background
A "bidirectional gene pair" is defined as two adjacent genes which are located on opposite strands of DNA with transcription start sites (TSSs) not more than 1000 base pairs apart and the intergenic region between two TSSs is commonly designated as a putative "bidirectional promoter". Individual examples of bidirectional gene pairs have been reported for years, as well as a few genome-wide analyses have been studied in mammalian and human genomes. However, no genome-wide analysis of bidirectional genes for plants has been done. Furthermore, the exact mechanism of this gene organization is still less understood.

Results
We conducted comprehensive analysis of bidirectional gene pairs through the whole Arabidopsis thaliana genome and identified 2471 bidirectional gene pairs. The analysis shows that bidirectional genes are often coexpressed and tend to be involved in the same biological function. Furthermore, bidirectional gene pairs associated with similar functions seem to have stronger expression correlation. We pay more attention to the regulatory analysis on the intergenic regions between bidirectional genes. Using a hierarchical stochastic language model (HSL) (which is developed by ourselves), we can identify intergenic regions enriched of regulatory elements which are essential for the initiation of transcription. Finally, we picked 27 functionally associated bidirectional gene pairs with their intergenic regions enriched of regulatory elements and hypothesized them to be regulated by bidirectional promoters, some of which have the same orthologs in ancient organisms. More than half of these bidirectional gene pairs are further supported by sharing similar functional categories as these of handful experimental verified bidirectional genes.

Conclusion
Bidirectional gene pairs are concluded also prevalent in plant genome. Promoter analyses of the intergenic regions between bidirectional genes could be a new way to study the bidirectional gene structure, which may provide a important clue for further analysis. Such a method could be applied to other genomes.
A structural interpretation of the effect of GC-content on efficiency of RNA interference
Authors: Chan Chi Yu , Carmack C Steven , Long Dang D , Maliyekkel Anil , Shao Yu , Roninson Igor B , Ding Ye 
Published: January 2009

Abstract

Background
RNA interference (RNAi) mediated by small interfering RNAs (siRNAs) or short hairpin RNAs (shRNAs) has become a powerful technique for eukaryotic gene knockdown. siRNA GC-content negatively correlates with RNAi efficiency, and it is of interest to have a convincing mechanistic interpretation of this observation. We here examine this issue by considering the secondary structures for both the target messenger RNA (mRNA) and the siRNA guide strand.

Results
By analyzing a unique homogeneous data set of 101 shRNAs targeted to 100 endogenous human genes, we find that: 1) target site accessibility is more important than GC-content for efficient RNAi; 2) there is an appreciable negative correlation between GC-content and RNAi activity; 3) for the predicted structure of the siRNA guide strand, there is a lack of correlation between RNAi activity and either the stability or the number of free dangling nucleotides at an end of the structure; 4) there is a high correlation between target site accessibility and GC-content. For a set of representative structural RNAs, the GC content of 62.6% for paired bases is significantly higher than the GC content of 38.7% for unpaired bases. Thus, for a structured RNA, a region with higher GC content is likely to have more stable secondary structure. Furthermore, by partial correlation analysis, the correlation for GC-content is almost completely diminished, when the effect of target accessibility is controlled.

Conclusion
These findings provide a target-structure-based interpretation and mechanistic insight for the effect of GC-content on RNAi efficiency.